title,abstract,doi,has_route
Synthesis of HIV Protease Inhibitor ABT-378 (Lopinavir),"A large scale process for the synthesis of HIV protease inhibitor candidate ABT-378 has been developed which utilizes an intermediate common to the synthesis of ritonavir, Abbott's first generation compound. The synthesis relies on the sequential acylation of this intermediate which is carried through as a mixture of diastereomers until the penultimate step. A synthesis of acid 5, derived from l -valine, is also reported.",10.1021/op990202j,1
Efficient Molar-Scale Synthesis of 1-Methyl-5-acylimidazole Triflic Acid Salts,"A new process for the molar-scale preparation of 1-methyl-5-acylimidazole triflic acid salts was developed. The new process consists of: (i) regioselective 3 N -tritylation of 5-acylimidazole to give 3-trityl-5-acylimidazoles, (ii) 1 N -methylation of 3-trityl-5-acylimidazoles, and (iii) hydrolysis of the resulting quaternary ammonium salts to afford 1-methyl-5-acylimidazole triflic acid salts. This process is highly efficient, affording 1-methyl-5-acylimidazole triflic acid salts in 86−88% overall yield in three steps without chromatographic separation of products.",10.1021/op990201r,0
The Preparation and Isolation of Chloramphenicol Palmitate in Toluene,The development of a process for the preparation of the antibiotic chloramphenicol palmitate that did not use methylene chloride and that fit into the production plant with improved yields and product quality is described. Addition of DMF as a co-solvent allowed the use of toluene for the reaction and the isolation. The product distribution observed by competitive esterification at the primary and secondary hydroxyl groups of chloramphenicol was well modeled by simple expressions for parallel consecutive reactions and estimated a 1000-fold difference in the rate constants for the two sites. A small increase in the impurity levels found during production plant trials was traced to trans-esterification during the extended processing time required at the 1000-kg scale.,10.1021/op990200z,0
Discovery and Development of a Commercial Synthesis of Azafenidin,"A commercial synthesis of the DuPont herbicide azafenidin is described. Discovery of a novel synthesis of the triazolinone ring system and a practical, environmentally benign process to 5-cyanovaleramide were critical breakthroughs in enabling azafenidin to be manufactured at an acceptable cost. The process began with the selective hydrolysis of DuPont's nylon intermediate, adiponitrile, to 5-cyanovaleramide. This was converted via Hofmann rearrangement and Pinner-type cyclization to afford the key amidine carboxylate intermediate containing both carbon atoms of the triazolinone ring. The preservation of all six carbon atoms of adiponitrile set up a 2 + 3 cyclocondensation with arylhydrazines, which replaced a costly 4 + 1 cyclocondensation of an amidrazone with phosgene or a phosgene surrogate used in the original route. This new triazolinone process was optimized to afford the commercial product in a highly efficient and economical fashion.",10.1021/op9901994,1
"A Facile, One-Pot Procedure for the Preparation of 2-Phenyl-1,3-propanediol Monocarbamate, a Metabolite of Felbamate","A simple, one-pot procedure for the preparation of 2-phenyl-1,3-propanediol monocarbamate (MCF) has been developed. This procedure represents the most efficient method for preparing MCF published to date, and it is amenable to the large-scale laboratory production of this biologically relevant metabolite of felbamate.",10.1021/op990198b,0
The Development of a Manufacturable Synthesis of LY213829,"The development of a manufacturable synthesis of LY213829 (4-thiazolidinone-5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] methyl) is described. Rather than reduction to eliminate the thiocarbonyl from the rhodanine moiety, the new route utilizes a novel concurrent ring opening with ammonia and re-cyclization with formaldehyde. This change obviates a potentially problematic zinc solid waste stream.",10.1021/op990197j,1
A Concise Asymmetric Synthesis of A β-Lactam-Based Cholesterol Absorption Inhibitor,"A concise, four-step, asymmetric synthesis of a β-lactam-based cholesterol absorption inhibitor, Sch 57939, was developed. The discovery of a one-step enantio- and diastereoselective synthesis of a trans -β-lactam provided easy access to the desired three chiral centers. A novel zinc phenoxide-promoted ether synthesis was reported for the completion of the side chain.",10.1021/op990196r,1
Use of Sodium Bromate for Aromatic Bromination:  Research and Development,"Sodium bromate is a powerful brominating agent for aromatic compounds that contain deactivating substituents. A bromination process, in which sodium bromate was utilized, was optimized on laboratory scale. Addition of a strong acid into a stirred aqueous solution, or slurry, of the substrate and bromate salt at 40−100°C, leads to the decomposition of the bromate ions and production of the active brominating species. Substrates such as nitrobenzene, benzoic acid, and benzaldehyde were brominated in high yields (85−98%) and specificity. The reaction is especially useful for the bromination of disubstituted benzenes, such as 4-nitrofluorobenzene or 4-fluorobenzoic acid. Several substrates, such as dinitrobenzenes or nitrobenzoic acids, did not undergo bromination at all. The main parameters of the reaction and some of its synthetic potential are discussed.",10.1021/op9901947,1
Efficient Synthesis of the Anticancer Drug Etoposide 4‘-Phosphate:  Use of Benzylic Ether-Protecting Groups on the Carbohydrate Segment<sup>1</sup>,"The prodrug etoposide phosphate 2 is synthesized efficiently in three steps in 54.6% overall yield from 4‘-demethylepipodophyllotoxin 3 . The strategy pursued in the synthesis of 2 places the phosphate on 3 prior to coupling with the sugar and employs benzyl ether-protecting groups on both the phosphate and the sugar, allowing easy removal in one step. The importance of solvent, steric effects, and electronic effects in the coupling reaction is demonstrated. Two features of the synthesis are an unusual thermal anomerization of the carbohydrate component 5a and completely diastereoselective, one-pot crystallization of the coupled product 6a -β. The process has been demonstrated on multi-kilogram scale.",10.1021/op990193e,1
"Synthesis of a Spiro[cyclohex-1,1‘-isobenzofuranyl] Dopamine Receptor Antagonist","Two syntheses of the novel CNS agent, 2-fluoro-4-( trans )-(4-(3‘H-spiro[cyclohex-1,1‘-isobenzofuran]-4-yl)-piperazin-1-yl)-benzonitrile, 1, are presented. The first relied on a reductive alkylation with low regioselectivity (1:1) but was sufficient for the preparation of kilogram quantities. The second used a selective ketone reduction of 3‘H-spiro[cyclohexane-1,1‘-isobenzofuran]-4-one, 8, with sodium borohydride to provide the cis -alcohol, 3‘H-spiro[cyclohexane-1,1‘-isobenzofuran]-( cis )-4-ol, 11 . A simple process for the conversion of 11 to 1 is described. Regioselective reactions with 2,4-difluorobenzonitrile under mild conditions are described.",10.1021/op990191u,1
Process Development of (2-Nitrophenylcarbamoyl)-(<i>S</i>)-prolyl-(<i>S</i>)-3- (2-naphthyl)alanyl-<i>N</i>-benzyl-<i>N</i>-methylamide (SDZ NKT343),"(2-Nitrophenylcarbamoyl)-( S )-prolyl-( S )-3-(2-naphthyl)alanyl- N -benzyl- N -methylamide ( 1; SDZ NKT343) is a human NK-1 tachykinin receptor antagonist. The development of a robust process for a multikilogram scale, chromatography-free preparation of this compound is described. The new four-step synthesis was based on a convergent approach, which utilized a peptide coupling of 1-[(2-nitrophenylamino)carbonyl]- l -proline ( 11 ) with free base of ( S )-3-(2-naphthyl)alanyl- N -benzyl- N -methylamide hydrochloride ( 4 ) as the key step in the presence of 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as coupling agents. A scale-up of the well-known mixed anhydride coupling method, using isobutyl chloroformate, to produce 4 was found to be problematic due to coupling of the amine at the undesired carbonyl group of the mixed anhydride. This problem was overcome. The drug substance, initially an amorphous powder, was obtained with the desired purity without any chromatography. A process for crystallization of 1 was also developed.",10.1021/op990188a,1
A Cost-Efficient Synthesis of Simvastatin via High-Conversion Methylation of an Alkoxide Ester Enolate,"A cost-efficient synthesis of simvastatin ( 2 ), starting from mevinolin (lovastatin) ( 1a ) or its precursor mevinolinic acid ( 1b ), is reported. This synthesis involves the use of a new intermediate, lovastatin cyclopropylamide ( 3 ), eliminating two chemical steps of protection and deprotection of the open dihydroxy form of ( 1a ). Synthesis is based on the high-conversion methylation of an alkoxide ester enolate and involves only four chemical steps. Methylation reaction conditions have been optimized to get >99.5% conversion. Process is economical on large-scale and product ( 2 ) is obtained in 85% overall yield.",10.1021/op990187i,1
Dilevalol via Resin-Mediated Epimerization:  A Case Study. Reaction Mechanism to Reactor Design to a Viable Process,"A case study on a novel commercial process for the preparation of dilevalol, 5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]ethyl]salicylamide, ( R, R )- 1, from crude ( S, R )- 1, is described. This covers all of the work from the initial laboratory observation of an acid-induced racemization of the benzylic carbinol (epimerization) of pure ( R, R )- 1, to the identification and optimization of an acidic resin that facilitated the epimerization of the core-process-generated crude ( S, R )- 1 on a solid support, and the subsequent reactor modification culminating in a cost-efficient, industrial-scale, semi-continuous batch process for the preparation of dilevalol.",10.1021/op990185y,1
Large-Scale Synthesis of Antisense Oligonucleotides without Chlorinated Solvents,"It is demonstrated that mixed-sequence phosphorothioate oligodeoxyribonucleotides can be synthesized on scales from 1 μmol up to 80 mmol without using chlorinated solvents such as dichloromethane or dichloroethane, while preserving both high yield and purity of the product. A solution of dichloroacetic acid in organic solvents (e.g., toluene, xylenes, benzotrifluoride) cleanly and efficiently removes the 4,4‘-dimethoxytrityl (DMTr) group from the 5‘-terminus of the growing oligonucleotide chain during synthesis on solid support. We have therefore replaced hazardous dichloromethane, formerly used in oligonucleotide synthesis, as the solvent for DMTr-removal, with toluene.",10.1021/op990183d,0
"Process Research for the Synthesis of RWJ-51204, A Novel Anxiolytic Agent","RWJ-51204, the lead compound in our pyrido [1,2- a ] benzimidazole (PBI) series, was shown to exhibit anxiolytic efficacy in animal models at doses which did not cause central nervous system side effects commonly observed with other anxiolytic agents. To prepare supplies of drug substance for early toxicological and clinical studies, we needed to develop a safe and scaleable synthesis. Our main focus was to improve the last two steps of the process which involved formation of the penultimate carboxamide intermediate followed by alkylation using potentially toxic chloromethyl ethyl ether. Due to safety issues concerning storage and handling of this reagent during the large scale synthesis, we investigated alternate routes to minimize potential exposure risks. The process research carried out for the final steps that led to the safe and cost-effective multi-kilogram synthesis of RWJ-51204 is described herein.",10.1021/op990182l,1
Preparation of Grignard Reagents:  FTIR and Calorimetric Investigation for Safe Scale-Up,"Preparation of Grignard reagents from organic halides and magnesium pose potential safety hazards on scale-up due to their high exothermic potential which can lead to overpressurization, discharge of contents, or explosion. One of the main challenges arises in ensuring the reaction has initiated before excessive accumulation of organic halide occurs or that the reaction does not stall and then reinitiate. Specifically, in production-scale equipment, it is sometimes difficult to ascertain whether initiation has occurred at all and whether it is safe to proceed. By using in situ infrared technology (FTIR), we have developed a method for safer scale-up of Grignard chemistry that can definitively identify that initiation has occurred. The process would involve adding approximately 5% of the organic halide charge and waiting for the initiation to occur using an in situ FTIR probe. FTIR spectroscopy can be used to monitor the accumulation of the halide and reveal when initiation occurs by the resulting decrease in the infrared absorbance. Once it has been determined that the organic halide has reacted as a result of the initiation, it is safe to proceed with the remaining halide charge. The organic halide concentration can then be continuously monitored after initiation to ensure the reaction does not stall or to halt the feed if it does stall. Further, it was shown that IR can be used to quantify the amount of water that is present in THF which is needed to confirm that the THF is dry. The IR results along with reaction calorimetry and vent-sizing data are discussed.",10.1021/op9901801,0
"A Large, Laboratory-Scale Synthesis of [4-(2-(2<i>H</i>)-Tetrahydropyranyloxy)phenyl]boronic Acid","A large, laboratory-scale synthesis of a useful intermediate for coupling reactions, [4-(2-(2 H )-tetrahydropyranyloxy)phenyl]boronic acid, is described.",10.1021/op990107a,0
Shedding Some Light on Crystallization Issues:  Lecture Transcript from the First International Symposium on Aspects of Polymorphism and Crystallization − Chemical Development Issues<sup>1</sup>,"ADVERTISEMENT RETURN TO ISSUEPREVSummary of Lecture T...Summary of Lecture TranscriptNEXTShedding Some Light on Crystallization Issues: Lecture Transcript from the First International Symposium on Aspects of Polymorphism and Crystallization − Chemical Development Issues1Norman LewisView Author Information Synthetic Chemistry Department, SmithKline Beecham Pharmaceuticals, Old Powder Mills, Leigh, Nr. Tonbridge, Kent TN11 9AN, UK Cite this: Org. Proc. Res. Dev. 2000, 4, 5, 407–412Publication Date (Web):March 24, 2000Publication History Received2 December 1999Published online24 March 2000Published inissue 1 September 2000https://pubs.acs.org/doi/10.1021/op990104yhttps://doi.org/10.1021/op990104yorationACS PublicationsCopyright © 2000 American Chemical SocietyRequest reuse permissionsArticle Views539Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Crystallization,Differential scanning calorimetry,Ethyl groups,Medicinal chemistry,Organic compounds Get e-Alerts",10.1021/op990104y,1
"A Practical and Efficient Synthesis of <i>p</i>-Menthane-3,8-diols","The diastereomeric repellents of p -menthane-3,8-diol were produced from citronellal by treatment with 0.25% sulfuric acid at 50 °C for 11 h to give 97.9% conversion and 92.3% selectivity and citronellal acetal by-products with only 2.7%. The crude products were crystallized from n -heptane at −50 °C for 20 h to give p -menthane-3,8-diols in 80% yield and high purity. The stereochemistry of the citronellal acetal by-products was determined by 2D NMR and NOE.",10.1021/op9901036,0
Efficient Large Scale Synthesis of 2‘-<i>O</i>-Alkyl Pyrimidine Ribonucleosides,An efficient process to synthesize 2‘- O -alkyl pyrimidine ribonucleosides in high yield has been described. The inexpensive method was used on a multikilogram-scale synthesis and optimized reaction conditions have been investigated.,10.1021/op990100t,0
"Synthesis and Scale-Up of 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane from 2,6,8,12-Tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW, CL-20)","A two-stage conversion of 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane to 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane, involving nitrosation followed by nitration, is described. It is shown that the purity of the final product obtained by this method is superior to that obtained by the reported one-pot method. Nitrosation of 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane in acetic acid is considered to be safer than nitrosation in pure dinitrogen tetroxide.",10.1021/op990097d,0
A Liquid-Phase Process Suitable for Large-Scale Synthesis of Phosphorothioate Oligonucleotides,"A new process for the preparation of large amounts of thioate oligonucleotides in a quasi-classical solution condition is described. This method takes advantage of the use of poly(ethylene glycol) as a soluble, inert support during the synthesis. The quality and amount of the desired oligonucleotides are improved by the use of pre-formed dimeric phosphoramidite as synthons. The easy intermediate purification from moderate excess of reagents allows obtaining very high coupling yields, and, consequently, the efficient production of quite long sequences as those required for their pharmacological applications.",10.1021/op990096l,0
The Dimethoxytrityl Resin Product Anchored Sequential Synthesis Method (DMT PASS):  A Conceptually Novel Approach to Oligonucleotide Synthesis,"Presented is a conceptually novel approach to oligonucleotide synthesis referred to herein as dimethoxytrityl resin product anchored sequential synthesis (DMT PASS). The DMT PASS process is characterized by the reaction of a 3‘-protected nucleoside or oligonucleotide with an excess of a nucleotide 3‘-phosphoramite or H -phosphonate which is bound to a dimethoxytrityl functionalized polystyrene resin. As a result, successfully coupled oligonucleotide product is then attached to the solid support, allowing for removal and potential recovery of starting materials. The protected oligonucleotide product is then released and subjected to an aqueous/organic extractive purification, which serves to remove monomeric impurities. The PASS process is anticipated to provide for the cost-effective manufacture of oligonucleotides on a scale which would allow for clinical development and pharmaceutical product commercialization. Herein we describe some aspects of our process development progress and discuss preliminary applications of the process to the synthesis of short oligodeoxyribonucleotide sequences, as well as a number of challenges confronting the PASS development effort.",10.1021/op990095t,0
Development of a Catalytic Tributyltin Hydride Cyclisation Process,The development of a pilot plant process to prepare the spirocyclic piperidine ( 2 ) from the tetrahydropyridine ( 4 ) via a radical cyclisation reaction is described. The pilot plant process involves the use of a catalytic amount of tributyltin hydride (0.14 equiv) generated in situ by the reaction of tributyltin chloride with sodium borohydride (1.1 equiv) in 2-propanol/ethanol containing azo-bis(isobutyronitrile) (AIBN). Initial laboratory conditions are described as well as the changes made on transfer to the pilot plant. Measurement of the levels of residual amounts of tin in the batches of ( 2 ) produced are reported.,10.1021/op9900941,0
New Synthesis of a Protected Ketonucleoside by a Non-Cryogenic Oxidation with TFAA/DMSO<sup>1</sup>,"An improved synthesis of the ketonucleoside 2‘-Oxo-3‘,5‘- O -[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]-cytidine ( 6 ), an intermediate in the synthesis of the potent anti-tumor agent 1 (MDL 101,731 or FMdC), is reported which incorporates a trifluoroacetic acid/dimethylsulfoxide oxidation process. This oxidation procedure eliminates the cryogenic reaction conditions and the necessity of protection at the N-4 amine used in the previously published route. Simplified isolation procedures for 3 and 4 eliminate two chromatographic purification steps. Overall yields are comparable to those reported previously.",10.1021/op9900939,1
"Large-Scale Synthesis of Oligonucleotide Phosphorothioates Using 3-Amino-1,2,4-dithiazole-5-thione as an Efficient Sulfur-Transfer Reagent","A commercially available and inexpensive compound, 3-amino-1,2,4-dithiazole-5-thione (ADTT), is discovered to be a new sulfur-transfer reagent for solid-phase synthesis of oligonucleotide phosphorothioates via the phosphoramidite method. The efficiency of ADTT was investigated by solid-phase syntheses of dinucleotide and oligonucleotide phosphorothioates. The results show that ADTT is a highly efficient sulfur-transfer reagent and fully compatible with automated solid-phase synthesis. ADTT has been applied in manufacture of oligonucleotide phosphorothioates to reduce the cost significantly.",10.1021/op990092g,0
Process Development for Purification of Therapeutic Antisense Oligonucleotides by Anion-Exchange Chromatography,This article describes the development of an anion-exchange chromatography method for purification of phosphorothioate antisense oligonucleotides. A variety of operating conditions were studied and optimized at small scale. These optimized parameters were used to generate data at multigram scale. The selected method can give a high purity product at a very good yield of the full-length desired product. This method can be suitably scaled up for antisense oligonucleotide purification at large scales.,10.1021/op990091o,0
Clay-Supported Liquid−Liquid−Solid Phase Transfer Catalysis:  Synthesis of Benzoic Anhydride,Solid-supported phase transfer catalysed reactions typically involve polystyrene supports cross-linked with divinyl benzene. The use of commercially available clay as a support for the PTC reaction is attractive. This paper reports the preparation of benzoic anhydride from benzoyl chloride and sodium benzoate using clay-supported quaternary ammonium salts at 30 °C. The selectivity to the product is 100%. The mechanistic and kinetic aspects are also reported. The clay-supported catalyst was found to be more active than polymer-supported catalysts.,10.1021/op990087c,0
Improved Process for the Preparation of Nucleosidic Phosphoramidites Using a Safer and Cheaper Activator,"A new, simplified commercial process for the preparation of nucleosidic phosphoramidites, key raw materials for the automated solid-supported synthesis of oligonucleotide-based drugs, was developed. Phosphitylation of a variety of protected nucleosidic derivatives ( 1 − 4 ) with a small excess of 2-cyanoethyl- N, N, N ‘, N ‘-tetraisopropyl phosphoramidite ( 5, bis-reagent) and pyridinium trifluoroacetate (Py·TFA) as the activator in an appropriate solvent at room temperature formed 75−96% of desired nucleosidic phosphoramidite products in less than 2 h. An efficient nonaqueous work-up has been developed to further streamline the isolation of moisture-sensitive P(III) nucleosidic compounds. The key finding is the use of Py·TFA, which is effective, inexpensive, stable, less acidic (p K a 5.2) than 1 H -tetrazole, nontoxic, safe, and highly soluble in organic solvents. The reaction mechanism for phosphitylation with Py·TFA as an activator has also been studied. An improved, robust, and versatile process for the preparation of nucleotide phosphoramidites under very concentrated reaction conditions was developed to support commercial manufacture of oligonucleotide-based drugs.",10.1021/op990086k,0
"Development Summary towards a Manufacturable Process for R 83842 [(<i>S</i>)-6-[(4-chlorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole]","A scalable process to produce enantiomeric R 83842, ( S )-6-[(4-chlorophenyl) (1 H -1,2,4-triazol-1-yl)methyl]-1-methyl-1 H -benzotriazole, is developed and described as a lecture* transcript. Cheap and safe reagents have been used. A typical procedure for oxidative destruction of aqueous cyanide waste, and stability data on N -acetyl hydrazine are provided. Special focus is on cost analysis as an important tool in developing performant synthetic methods. The method consists of preparing a chiral monosubstituted hydrazine which is ring closed to the chiral 1-alkylated 1,2,4-triazole title compound.",10.1021/op990081n,1
On-Line Monitoring of Process HPLC by Sensors,"On-line process control with a SAW (surface acoustic wave) sensor-based gas-sensor microsystem (SAGAS PC = surface acoustic wave based aroma and gas analyzing system) for industrial applications is presented. The monitoring of the gradient former of a preparative HPLC system is a useful tool for the on-line process control of pilot plant production. All applications deal with the detection and subsequent qualification as well as quantitation of volatile organic compounds (VOCs), for example, organic solvents or even water, by investigating their vapor with the SAGAS PC-system. To demonstrate the suitability of the system for the above-mentioned purpose different examples of typical binary solvent mixtures for normal phase (NP) HPLC have been chosen. The accuracy, precision, and robustness of the applied method are determined, and the results meet the specification requirements. Furthermore, on-line measurements in a pilot plant environment are presented.",10.1021/op990080v,0
"Process Research and Development of <scp>l</scp>-Alanyl-<scp>l</scp>-glutamine, a Component of Parenteral Nutrition","A large-scale manufacturing method of l -alanyl- l -glutamine used for a component of parenteral nutrition has been studied. The method consisted of a reaction of d -2-chloro- or d -2-bromopropionic acid with thionyl chloride and Schotten−Baumann reaction with l -glutamine followed by ammonolysis reaction. The intermediate d -2-chloropropionyl- l -glutamine was found to be more stable than its bromo analogue. In the ammonolysis reaction, the former intermediate needed a higher reaction temperature, but the by-products produced had little effect on the quality of the final product. The structures of the by-products were conjectured mainly by mass spectrometry and they were removed by anion resin treatment and recrystallization.",10.1021/op990079w,1
"Synthesis of Antisense Oligonucleotides:  Replacement of 3H-1,2-Benzodithiol-3-one 1,1-Dioxide (Beaucage Reagent) with Phenylacetyl Disulfide (PADS) As Efficient Sulfurization Reagent:  From Bench to Bulk Manufacture of Active Pharmaceutical Ingredient",It is demonstrated that phosphorothioate oligodeoxyribonucleotides can be synthesized on scales from 1 μmol to 150 mmol using phenylacetyl disulfide (PADS) as an efficient and economical replacement for Beaucage reagent. A 0.2 M solution of PADS in a mixture of 3-picoline and acetonitrile (1:1 v/v) as solvent with 60−120 s contact time efficiently (>99.6%) sulfurizes phosphite triesters to phosphorothioate triester linkages. Phenylacetyl disulfide reagent is inexpensive and scaleable and is currently being used by us for the manufacture of antisense phosphorothioate oligodeoxyribonucleotide active pharmaceutical ingredients (API).,10.1021/op990077b,0
"Process Chemistry in the Pharmaceutical Industry Edited by Kumar G. Gadamasetti. Marcel Dekker:  New York, Basel. 1999. 473 pp. $195.00. ISBN 0-8247-1981-6","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Chemistry in the Pharmaceutical Industry Edited by Kumar G. Gadamasetti. Marcel Dekker: New York, Basel. 1999. 473 pp. $195.00. ISBN 0-8247-1981-6Derek RobinsonView Author Information Little Mill, Pontypool, Gwent, U.K. Cite this: Org. Proc. Res. Dev. 1999, 3, 6, 493–494Publication Date (Web):November 4, 1999Publication History Published online4 November 1999Published inissue 1 November 1999https://doi.org/10.1021/op990075rCopyright © 1999 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views156Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (19 KB) Get e-AlertsSUBJECTS:Industrial manufacturing,Materials,Pharmaceuticals,Pharmaceutics Get e-Alerts",10.1021/op990075r,0
The Chemical Development of the Commercial Route to Sildenafil:  A Case History,"This paper is a case history of the chemical development of sildenafil which covers various aspects of work in chemical development namely: route selection, scale-up issues, the development of an efficient synthesis with high throughput, process safety, and environmental issues. Interesting chemical points include improved methods of preparing pyrazolo[4,3-d]pyrimidines and the unusual isolation of an intermediate as its double salt ( 10 ). The potential dangers of nitrating pyrazole-5-carboxylic acids which are activated to a decarboxylation reaction are discussed.",10.1021/op9900683,1
New Practical Synthesis of Tenidap,"The development of a new, practical synthesis to tenidap is described. N, O -Dialkoxy(aryloxy)carbonylation of 5-chloro-2-oxo-2,3-dihydroindole, followed by removal of the O- alkoxy(aryloxy)carbonyl group gave 1-[alkoxy(aryloxy)carbonyl]-5-chloro-2-oxo-2,3-dihydroindoles in good yields. The latter compounds were thenoylated in the 3-position. The role of DMAP in the acylation reaction is discussed. The structures of the thenoylated products and their enolate salts were investigated both in solution and solid phases. Ammonolysis of 5-chloro-3-[1-hydroxy-1-(2-thienyl)methylene]-2-oxo-1-phenoxycarbonyl-2,3-dihydroindole afforded the corresponding 1-carbamoyl derivative (tenidap) in high yield. The corresponding 1-ethoxy- and 1-methoxycarbonyl derivatives could not be similarly transformed to tenidap; loss of the alkoxycarbonyl moiety occurred instead of carbamoylation.",10.1021/op990067a,1
Process Improvements in the Production of a Novel Non-Xanthine Adenosine A<sub>1</sub> Receptor Antagonist. A “One-Pot” Horner-Emmons Isomerization Reaction,"Pilot plant scale synthesis of 2-[3-(2-phenylpyrazolo[1,5- a ]pyridin-3-yl-1(6 H )-pyridazin-6-one)-1-cyclohexen-1-yl] acetic acid (FR166124) is described. The process involved efficient isomerization of regioisomers produced in a Horner-Emmons reaction and employed ester exchange and hydrolysis with NaOH in MeOH. Challenges encountered in the final purification stage to afford high quality drug substance in pure crystalline form are also described. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a straightforward, practical, and cost-effective synthesis of FR166124. These methods were successfully scaled up in a pilot plant to give bulk drug suitable for pharmacological and toxicological evaluation.",10.1021/op990066i,1
"Analysis, Synthesis and Design of Chemical Processes by R. Turton, R. C. Bailie, W. B. Whiting, and J. A. Shaeiwitz. Prentice Hall:  New Jersey, 1999. 814 pp. ISBN 0-13-570565-70. £66.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewAnalysis, Synthesis and Design of Chemical Processes by R. Turton, R. C. Bailie, W. B. Whiting, and J. A. Shaeiwitz. Prentice Hall: New Jersey, 1999. 814 pp. ISBN 0-13-570565-70. £66.Cite this: Org. Proc. Res. Dev. 1999, 3, 6, 494Publication Date (Web):August 3, 1999Publication History Published online3 August 1999Published inissue 1 November 1999https://doi.org/10.1021/op990061lCopyright © 1999 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views2923Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (19 KB) Get e-AlertsSUBJECTS:Allyl group,Anions,Chemical engineering and industrial chemistry,Chemical synthesis,Ketones Get e-Alerts",10.1021/op990061l,0
A Practical Synthesis of Phenylpropargyl Aldehyde from Phenylacetylene and <i>N</i>-Formylmorpholine,A synthesis of phenylpropargyl aldehyde is described employing formylation of a phenylacetylenic Grignard reagent with N -formylmorpholine. This method afforded the product in excellent yield.,10.1021/op9900582,1
"Phosphorus Ylides; Chemistry and Application in Organic Synthesis by Oleg I Kolodiazhnyi. Wiley-VCH:  Weinheim, 1999. 555 pp. ISBN 3-527-29531-3. DM 248.",,10.1021/op990057+,0
Chlorobenzyl Alcohols from Chlorobenzyl Chlorides via Corresponding Benzoate Esters:  Process Development Aspects,"Kinetic studies in conversion of benzyl chlorides to corresponding alcohols via the benzoates are presented in this paper. The esterification reaction of 2-chlorobenzyl chloride, 4-chlorobenzyl chloride, 2,4-dichlorobenzyl chloride and benzyl chloride with aqueous sodium benzoate in the presence of phase transfer catalysts was investigated. The parameters studied are stirring speed, catalysts, the catalyst loading, temperature and the concentration of aqueous phase. The esterification reaction follows pseudo-first-order kinetics. The esters, were hydrolysed with and without a phase transfer catalyst to give corresponding benzyl alcohols without involving respective dibenzyl ethers. Material balance for the laboratory batch process of each chlorobenzyl alcohol has also been presented. A recycle strategy presented is shown to be effective in terms of alkali and benzoic acid consumption as the reactants are consumed to near stoichiometric levels.",10.1021/op9900535,0
"Practical Chemo-Enzymatic Process for the Preparation of (1<i>R</i>,<i>cis</i>)-2-(2,2-Dihaloethenyl)-3,3-dimethylcyclopropane Carboxylic Acids","A practical chemo-enzymatic process for the preparation of optically active (1 R, cis )-2-(2,2-dichloro (or dibromo)ethenyl)-3,3-dimethylcyclopropane carboxylic acids (permethrinic or deltamethrinic acids) from racemic 1,1,1-trichloro-2-acetoxy-4-methyl-3-pentene is described. The key intermediate, enantiopure ( R )-1,1,1-trichloro-2-hydroxy-4-methyl-3-pentene, is prepared by a lipase catalysed kinetic resolution of the racemic acetate. The reaction mixture, containing ( R )-alcohol and the unreacted ( S )-acetate, is directly acetylated by a haloacetyl halide, and the products are separated by distillation. The ( S )-acetate is racemized, and the ( R )-haloacetate is transformed to the corresponding glycinate hydrochloride, followed by diazotization to ( R )-1,1,1-trichloro-4-methyl-3-penten-2-yl diazoacetate. The stereoselective carbenic dediazotization of the ( R )-diazoacetate furnishes the optically active (1 R,4 R,5 S )-6,6-dimethyl-4-trichloromethyl-3-oxobicyclo[3.2.0]hexan-2-one, which is transformed to the desired enantiopure (1 R, cis )-permethrinic or deltamethrinic acid in high optical yield (>99% ee) and overall chemical yield of 10−15%.",10.1021/op990052c,1
"Continuous and Batch Organomagnesium Synthesis of Ethyl-Substituted Silanes from Ethylchloride, Tetraethoxysilane, and Organotrichlorosilane for Production of Polyethylsiloxane Liquids. 1. Batch One-Step Synthesis of Ethylethoxysilanes and Ethylchlorosilanes","Development of batch one-step manufacturing process for ethylethoxy- and ethylchlorosilanes is desribed. The methodology of synthesis of ethyl-substituted silanes has been improved. The important factors for the successful synthesis have been determined. Among them are the replacement of the part tetraethoxysilane 3 by ethyltrichlorosilane 10, the optimum concentration of 3 and 10 resulting in high yield of triethylsilanes, low duration of synthesis, and high selectivity of Grignard reagent. Batch one-step synthesis has been assimilated into industry (up to a scale 240 kg of magnesium) for production of oligoethylsiloxanes with the high content (>40%) of a terminal triethylsiloxy group. The rules for R/D process of the Grignard synthesis are described.",10.1021/op990049t,0
"Hydrolases in Organic Synthesis. by U. T. Bornscheuer and R. J. Kaslauskas. Wiley-VCH:  Weinheim, 1999. 336 pp. ISBN 3-527-30104-6.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTHydrolases in Organic Synthesis. by U. T. Bornscheuer and R. J. Kaslauskas. Wiley-VCH: Weinheim, 1999. 336 pp. ISBN 3-527-30104-6.Nicholas J. TurnerView Author Information University of EdinburghCite this: Org. Proc. Res. Dev. 1999, 3, 6, 494Publication Date (Web):September 23, 1999Publication History Published online23 September 1999Published inissue 1 November 1999https://pubs.acs.org/doi/10.1021/op9900481https://doi.org/10.1021/op9900481book-reviewACS PublicationsCopyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views165Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical specificity,Chemical structure,Nitrogen compounds,Organic synthesis,Peptides and proteins Get e-Alerts",10.1021/op9900481,0
Process Development of a Novel Non-Xanthine Adenosine A<sub>1</sub> Receptor Antagonist,"(+)−( R )-1-[( E )-3-(2-phenylpyrazolo[1,5- a ]pyridin-3-yl)acryloyl]-2-piperidine ethanol (FK453) is a novel, potent adenosine A 1 receptor antagonist for the regulation of renal function. The development of a reliable process suitable for large scale manufacture is described. A Horner−Emmons reaction and a 1,3-dipolar cycloaddition were successfully scaled up to afford ethyl ( E )-3-(2-phenylpyrazolo[1,5- a ]pyridin-3-yl)acryloylate, with excellent regioselectivity and stereoselectivity. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a straightforward, practical synthesis of FK453.",10.1021/op990044w,1
Synthesis of <i>p</i>-Aminophenol by Catalytic Hydrogenation of Nitrobenzene,"The present work describes the preparation of p- aminophenol via single-step catalytic hydrogenation of nitrobenzene in acid medium. A conventional method of synthesis of p- aminophenol is a two-step reaction involving iron−acid reduction of p -nitrophenol. This method causes serious effluent disposal problems due to the stoichiometric use of iron−acid, which leads to the formation of Fe−FeO sludge (≅1.2 kg/kg of product) in the process, which cannot be recycled. The single-step hydrogenation of nitrobenzene was carried out using platinum catalyst, and the process conditions were optimized. Complete conversion of nitrobenzene was achieved with selectivity to p- aminophenol as high as 75% under the best set of conditions. Furthermore, the catalyst can be easily recovered and efficiently recycled giving the TON as high as 1.38 × 10. 5 This paper presents studies on the effect of various process parameters such as temperature, hydrogen pressure, and substrate and acid concentration on the rate of reaction and selectivity to p -aminophenol.",10.1021/op990040r,0
Pyridinium Trifluoroacetate/<i>N</i>-Methylimidazole as an Efficient Activator for Oligonucleotide Synthesis via the Phosphoramidite Method,"A new activator is reported for coupling phosphoramidites to a free 5‘-hydroxyl group during oligonucleotide synthesis. Pyridinium trifluoroacetate/ N -methyl imidazole is a remarkably efficient replacement for 1 H -tetrazole in the solid-supported synthesis of oligonucleotides. This reagent is safe and inexpensive, is not moisture-sensitive, and is soluble in acetonitrile.",10.1021/op9900378,0
Practical Large-Scale Synthesis of Endothelin Receptor Antagonist S-0139,Semisynthetic endothelin receptor antagonist S-0139 was synthesized in 14 steps from oleanolic acid 2 in a 20% overall yield on a multi-kilogram scale. Our previous synthesis of the oleanane skeleton was modified and improved to give phosphonate 9 as a key intermediate. The side chain on the 27-position was introduced by Horner−Wadsworth−Emmons olefination of phosphonate 9 with aldehyde 5 . Aldehyde 5 was prepared in a one-pot reduction−acylation process starting from 5-hydroxy-2-nitrobenzaldehyde. The entire sequence of the synthesis can be done without chromatography and yields S-0139 of high purity.,10.1021/op990036f,0
"Tartaric and Malic Acids in Synthesis:  A Source Book of Building Blocks, Ligands, Auxiliaries, and Resolving Agents By Jacek Gawronski and Krystyna Gawronska. Wiley Interscience:  New York, 1999. 591 pp. ISBN 0471244511. £96.50.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTTartaric and Malic Acids in Synthesis: A Source Book of Building Blocks, Ligands, Auxiliaries, and Resolving Agents By Jacek Gawronski and Krystyna Gawronska. Wiley Interscience: New York, 1999. 591 pp. ISBN 0471244511. £96.50.Martin FoxView Author Information Chirotech Technology Limited Cite this: Org. Proc. Res. Dev. 1999, 3, 5, 380Publication Date (Web):June 22, 1999Publication History Published online22 June 1999Published inissue 1 September 1999https://pubs.acs.org/doi/10.1021/op990034vhttps://doi.org/10.1021/op990034vbook-reviewACS PublicationsCopyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views235Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Circuits,Enantioselective synthesis,Ligands,Materials,Reaction products Get e-Alerts",10.1021/op990034v,0
Development of the Process of <i>p</i>-Nitroacetophenone and Benzoic Acid Manufacture by the Liquid-Phase Oxidation of Aromatic Compounds,The kinetic model of the ethyl benzene oxidation was applied to the design of the large-scale reactors of p -nitroacetophenone (chloramphenicol key intermediate) synthesis by p -nitroethyl benzene oxidation and benzoic acid synthesis by acetophenone oxidation. The factors allowing simplification of the above model are discussed. The height of the frothy (aerated) liquid layer in the oxidation tower securing the explosion-proof reaction conditions of acetophenone and p -nitroethyl benzene oxidation both in the kinetic and diffusion fields was calculated.,10.1021/op990030q,0
Synthesis of <i>m</i>-Phenoxybenzaldehyde Starting from Chlorobenzene and <i>m</i>-Cresol: Some Aspects of Process Development,"m -Phenoxybenzaldehyde (MPB) is an important intermediate for synthetic pyrethroids. In the present paper, an economic process scheme was developed to synthesize MPB starting from cheaper reactants. The process scheme was started with the synthesis of m -phenoxytoluene (MPT). Oxidation of MPT by air gave MPB, but the selectivity was found to be high at low conversions of about 10%, and if the conversion level was increased, then large amounts of the undesired m -phenoxybenzoic acid (MPBA) was formed. To obtain the desired aldehyde, Rosenmund reduction of MPBA was carried out to give high yields of the MPB. The effects of different parameters such as catalyst, substrate concentration, temperature, etc., were studied for all three of the reactions, viz., Ullmann ether synthesis, oxidation, and Rosenmund reduction. MPT was prepared from chlorobenzene, a relatively cheaper starting material, in the presence of poly(ethylene glycol) as cosolvent and cuprous chloride as the catalyst. A selectivity of 97% was obtained with 86% conversion to the product. Oxidation of MPT was carried out by air in the presence of cobalt acetate as catalyst and sodium bromide as catalyst promoter. The selectivity with respect to the aldehyde and the ester was 37.4 and 30.6%, respectively, at a restricted overall conversion of 24%. The process parameters were controlled to achieve high selectivity towards the aldehyde. The acid, formed as the side product, was reduced to the aldehyde by Rosenmund reduction via the acyl chloride. At a conversion level of 85%, a selectivity of 87% to MPB was obtained using Pd/C.",10.1021/op990028z,1
Studies in Selectivity Aspects in the Synthesis of Aliphatic α-Bromoaldehydes,"A highly selective process scheme was developed to synthesize α-bromoaldehydes by regulating the important process parameters from a reaction-engineering point of view. Thus, α-bromobutyraldehyde and α-bromoheptaldehyde were synthesized in very high selectivity starting with butyraldehyde and heptaldehyde. In the bromination reaction at 40% conversion ratio, the selectivity was as high as 98% by using liquid bromine as the brominating agent.",10.1021/op990025m,0
Breaking the New Bottleneck: Automated Synthesis in Chemical Process Research and Development,"An overview of the current methods, available systems, and applications of laboratory automation in chemical process research and development is given. Examples of the successful implementation of automated synthesis into reaction optimisation and process development are discussed.",10.1021/op990020p,0
Development of a Pilot Scale Process for the Anti-Alzheimer Drug (−)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion,"(−)-Galanthamine has been synthesised using an efficient nine-step procedure, which in large scale affords 12.4 (6.7−19.1)% overall yield. The process improvements and optimization of each step are described. Notable steps include (i) an oxidative phenol coupling and (ii) crystallisation-induced chiral conversion of (±)-narwedine to (−)-narwedine. This is a practical and cost-effective synthesis of (−)-galanthamine which is amenable to pilot plant scale-up to afford sufficient material for use in clinical trials.",10.1021/op990019q,1
Kinetics and Process Parameter Studies in Catalytic Air Oxidation of Veratraldehyde to Veratric Acid,"Kinetics and different process parameters for the air oxidation of veratraldehyde to veratric acid were studied. At a temperature of 130 °C, air pressure of 1 MPa, cobalt acetate loading of 0.03 mol/L, and an initial concentration of 30% w/v of veratraldehyde, the reaction was found to be first order with respect to veratraldehyde. In 3 h at an aldehyde conversion level of 100%, as high as 99% selectivity was achieved.",10.1021/op990018y,0
"Industrial Synthesis of the Key Precursor in the Synthesis of the Anti-Influenza Drug Oseltamivir Phosphate (Ro 64-0796/002, GS-4104-02):  Ethyl (3<i>R</i>,4<i>S</i>,5<i>S</i>)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate","Starting from (−)-quinic acid, the title compound was synthesized in seven chemical steps and an overall yield of 35−38%. The route of the improved Gilead synthesis was not changed. However, significant improvements in each step led to a doubled overall yield, a 30% reduction in the number of unit operations, and an excellent quality (≥99%) of the resulting epoxide. A highly regioselective method for the dehydration of a quinic acid to a shikimic acid derivative and for the reduction of a cyclic ketal was found. Alternatively, the title compound was synthesized in six chemical steps and 63−65% yield from commercially available (−)-shikimic acid. Compared to the optimized quinic acid route, the production time was reduced by about 50%. The quality of epoxide produced from either natural product was equivalent. Therefore (−)-shikimic acid is the preferred raw material. The absolute configuration of the epoxide was determined by X-ray single crystal structure analysis and it was demonstrated that the epoxide was stereoisomerically pure.",10.1021/op9900176,1
A Practical Approach to Accelerated Process Screening and Optimisation,"The development and operation of an automated workstation for performing solution-phase organic synthesis and on-line HPLC analysis is described. A wide scope of applications and chemistries, typically encountered in process development laboratories, are reported. The application of this workstation to process screening and optimisation studies coupled with statistical design of experiments (DOE) is illustrated using three simple case studies. The utility of this approach in accelerating core aspects of process research and development by performing multiple experiments in parallel and generating quality data more efficiently has been explored.",10.1021/op990016d,0
"Modern Catalytic Methods for Organic Synthesis with Diazo Compounds (From Cyclopropanes to Ylides) By M. P. Doyle, M. A. McKervey, and T. Ye. Wiley-Interscience:  New York. 1998. 652 pp. ISBN 0-47113556-9. £100.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewModern Catalytic Methods for Organic Synthesis with Diazo Compounds (From Cyclopropanes to Ylides) By M. P. Doyle, M. A. McKervey, and T. Ye. Wiley-Interscience: New York. 1998. 652 pp. ISBN 0-47113556-9. £100.Cite this: Org. Proc. Res. Dev. 1999, 3, 3, 235–236Publication Date (Web):March 27, 1999Publication History Published online27 March 1999Published inissue 1 May 1999https://doi.org/10.1021/op990015lCopyright © 1999 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views805Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (23 KB) Get e-AlertsSUBJECTS:Azides,Hydrocarbons,Organic reactions,Rearrangement,Versatile synthesis Get e-Alerts",10.1021/op990015l,0
"Azolides in Organic Synthesis and Biochemistry By H. A. Staab, H. Bauer, and K. M. Schneider. Wiley-VCH:  Weinheim, 1998. 502 pp. ISBN3-527-29314-0. £95.00.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTAzolides in Organic Synthesis and Biochemistry By H. A. Staab, H. Bauer, and K. M. Schneider. Wiley-VCH: Weinheim, 1998. 502 pp. ISBN3-527-29314-0. £95.00.Cite this: Org. Proc. Res. Dev. 1999, 3, 3, 235Publication Date (Web):March 27, 1999Publication History Published online27 March 1999Published inissue 1 May 1999https://doi.org/10.1021/op9900131Copyright © 1999 American Chemical SocietyRequest reuse permissions Article Views155Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (23 KB) Get e-AlertscloseSUBJECTS:Amides,Anions,Reactivity,Substitution reactions,Transfer reactions Get e-Alerts",10.1021/op9900131,0
Continuous Single-Stage Organomagnesium Synthesis of a Mixture of Ethylethoxysilanes and Dimethylethylethoxysilane,"Simultaneous synthesis of ethylethoxysilanes and dimethylethylethoxysilane from a mixture of ethyl chloride, tetraethoxysilane, and dimethyldichlorosilane with magnesium (supply rate 75−100 g h - 1 ) was studied. Schemes of intermediate processes are proposed. Reactivity of dimethyldichlorosilane and diethyldichlorosilane relative to each other is evaluated. Various grades of magnesium are tested. To reduce the amount of regenerated solvent (toluene) its mixtures with oligodiethylsiloxanes are used. The mixture of ethyl-substituted silanes can be used in subsequent preparation of oligo-ethylsiloxane liquids modified with the terminal dimethylethylsiloxy groups, which are characterised by improved lubricating properties.",10.1021/op990011g,0
Production of (<i>R</i>)-Aminoglutethimide:  A New Route from 1-Chloro-4-nitrobenzene,"The development of a short, safe and enantioselective route for the preparation of ( R )-aminoglutethimide is described. The process was designed for economic large-scale manufacture of the bulk drug substance to acceptable quality standards, to allow clinical evaluation of the single enantiomer over the existing racemate. ( R )-Aminoglutethimide was prepared from 1-chloro-4-nitrobenzene using a six-stage synthetic sequence, via chemoresolution of key intermediate racemic 4-cyano-4-(4-nitrophenyl)hexanoic acid using (−)-cinchonidine. The process allowed for preparation of several kilograms of the precursor ( R )-nitroglutethimide, to cGMP at pilot-plant scale, along with demonstration of the final hydrogenation step to ( R )-aminoglutethimide in the laboratory. This route avoids the problems of hazardous nitration technology, and therefore regio-isomer contamination of the product, associated with other procedures. The resolution chemistry described represents an improvement on literature procedures. Optimisation of the asymmetric Michael addition offers an attractive alternative approach.",10.1021/op9900075,1
"A Convenient Practical Method for the Preparation of (−)-(1<i>S</i>,2<i>S</i>)-5-Norbornene-2-carboxylic Acid, Incorporating Efficient Recovery of the Chiral Auxiliary <scp>d</scp>-Pantolactone","A convenient practical method was developed for the preparation of enantiomerically pure (−)-(1 S,2 S )-5-norbornene-2-carboxylic acid, wherein the chiral auxiliary d -pantolactone was recovered efficiently.",10.1021/op990006c,0
A Versatile and Cost-Effective Approach to Automated Laboratory Organic Synthesis,"The application of a commercial laboratory automated synthesis system, the Anachem SK233 Workstation, is described for use in organic synthesis. A novel reactor design feature has been developed to enable the sampling of reactions under ambient to reflux temperatures while maintaining an effective inert atmosphere. Up to 10 reactions can be run simultaneously on the reactor block supplied. Examples are reported of multiple parallel reactions covering a range of chemistries encountered in synthesis encompassing heterogeneous and homogeneous reactions, air-sensitive and aggressive reagents, ambient to full reflux temperature, and full inert atmospheres with concomitant automated HPLC product analysis. The equipment and modifications described are of moderate cost, are robust in use, are of acceptable size for modern chemistry laboratories, and are readily acceptable to practising chemists.",10.1021/op990005k,0
"A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194.","ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionA Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194.Janak Singh, Gregory S. Bisacchi, Saleem Ahmad, Jollie D. Godfrey, Thomas P. Kissick, Toomas Mitt, Octavian Kocy, Truc Vu, Chris G. Papaioannou, Michael K. Wong, James E. Heikes, Robert Zahler, and Richard H. MuellerCite this: Org. Proc. Res. Dev. 1999, 3, 3, 235Publication Date (Web):January 21, 1999Publication History Published online21 January 1999Published inissue 1 May 1999https://pubs.acs.org/doi/10.1021/op990004shttps://doi.org/10.1021/op990004scorrectionACS PublicationsCopyright © 1999 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views591Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (20 KB) Get e-Alertsclose Get e-Alerts",10.1021/op990004s,0
Fine Chemicals from Lignosulfonates. 2. Synthesis of Veratric Acid from Acetovanillon,"An optimisation study based upon experimental data obtained from multivariate statistical experimental design and modelling for the haloform reaction used for synthesis of 3,4-dimethoxybenzoic acid from 3,4-dimethoxy acetophenone is reported. It is shown how the different controllable process variables influence both the yield of 3,4-dimethoxybenzoic acid and the formation of the side product 2-chloro-4,5-dimethoxybenzoic acid. Two predictive multivariate models are derived and used to predict optimal conditions for the oxidation process. Using these models, a yield of 90% (from approximately 60%) of desired product is achieved. Moreover, the model describing the formation of the side-product can in fact also be applied to optimise a procedure for obtaining 2-chloro-4,5-dimethoxybenzoic acid in substantial quantities. One experiment showed that the side-product could be formed in a quantity of >20%.",10.1021/op9900030,1
Fine Chemicals from Lignosulfonates. 1. Synthesis of Vanillin by Oxidation of Lignosulfonates,"The oxidation of lignosulfonates (LS) to vanillin by persulphate, oxygen, and a variety of catalytic systems has been investigated. Cobalt and copper catalysts appeared to be the most effective in the oxidation by oxygen. An investigation where multivariate mathematical and statistical design and modelling have been used for the process optimisation has led to the development of a multivariate mathematical model which describes the oxidation process with high predictive capacity. By using this model, an increase of the vanillin yield from 4.1% of the current procedure to 7.2% is obtained, this corresponding to 75% relative improvement of the yield.",10.1021/op9900028,0
A Practical Synthesis of Multitargeted Antifolate LY231514,"A concise and scalable synthesis of LY231514 ( 1 ), a new pyrrolo[2,3- d ]pyrimidine-based antitumor agent, is presented. Reaction of 2-bromo-4-arylbutanal 9 with 2,4-diamino-6-hydroxypyrimidine ( 10 ) regioselectively provided pyrrolo[2,3- d ]pyrimidine 11, representing the core structure of the drug, in good yield. Assimilation of the glutamic acid residue by conventional means completed the synthesis. Development of the optimized synthetic route emphasized avoiding isolation of the relatively unstable aldehyde and bromoaldehyde intermediates.",10.1021/op9802172,1
Application of Modified Flavone Closure for the Preparation of Racemic L86-8275,The laboratory preparation of racemic L86-8275 ( 1a ) and the salt ( 1b ) is described in 7% overall yield. Our method eliminated a number of chromatography steps from the patent procedure and improved the flavone-forming reaction by employing a stepwise mechanism. Solvent-free conditions for the demethylation step are also described.,10.1021/op980215h,1
"Synthesis of ABT-378, an HIV Protease Inhibitor Candidate:  Avoiding the Use of Carbodiimides in a Difficult Peptide Coupling","An alternative to carbodiimide-mediated peptide coupling protocols has been developed for a carboxylic acid prone to decomposition by polymerization. This method, involving the in situ generation of an acyl imidazolide, has been applied to the preparation of a lead clinical HIV protease inhibitor candidate, ABT-378. The nature of the polymerization and optimization of the new reaction conditions are presented.",10.1021/op980214p,0
"Enantioselective Synthesis of Brinzolamide (AL-4862), a New Topical Carbonic Anhydrase Inhibitor. The “DCAT Route” to Thiophenesulfonamides","A large scale synthesis of the topical carbonic anhydrase inhibitors AL-4623A ( 13a ·HCl) and AL-4862 ( 13b ) from 3-acetyl-2,5-dichlorothiophene (“DCAT”, 1 ) is described. Reaction of 1 with NaSBn gave thioether 2, which was converted via sulfenyl chloride 3 and sulfenamide 5 to sulfonamide 6 . Bromination of 6 gave bromo ketone 7, which upon reduction with (+)-B-chlorodiisopinocampheylborane and cyclization of the resulting bromohydrin produced S thieno[3,2- e ]-1,2-thiazine 8a (96% ee) after chromatography. Treatment of 8a in THF with n -BuLi at −70 °C resulted in Li−Cl exchange. Reaction of the thienyllithium with SO 2 and hydroxylamine O-sulfonic acid afforded bis-sulfonamide 11a . Protection of 11a as the acetimidate 12a, followed by tosylation and amination, gave R amine 13a . The synthesis of 13b proceeded via primary sulfonamide 16, which was brominated, reduced, and cyclized to give S thieno[3,2- e ]-1,2-thiazine 18 (>98% ee). By virtue of the ionizable NH, 18 was separable from reduction byproducts by base extraction. Alkylation of 18 with 3-bromopropyl methyl ether afforded 8b, which was converted as above, via 11b, to AL-4862 ( 13b ). These procedures provided multihundred gram lots of 13a and 13b .",10.1021/op9802125,1
Scale Up of a Ritter Reaction,The Ritter reaction of secondary or tertiary alcohols with acrylonitrile provides easy access to acrylamides which would otherwise be difficult to prepare. A safe procedure for conducting this reaction is described.,10.1021/op980211c,0
"New Disulfide Route to 3-(1-Piperazinyl)-1,2-benzisothiazole. Nucleus for Atypical Antipsychotic Drugs","A new, one-step commercial process for the preparation of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, a key intermediate for the syntheses of some new, “atypical antipsychotic” drugs, was developed. Reaction of bis(2-cyanophenyl) disulfide with excess piperazine at 120−140 °C for 3−24 h in the presence of small amounts of DMSO and 2-propanol formed 3-(1-piperazinyl)-1,2-benzisothiazole in 75−80% yields. The DMSO oxidized the liberated 2-mercaptobenzonitrile to regenerate bis(2-cyanophenyl) disulfide, thereby enabling the utilization of both halves of the symmetrical disulfide to generate product. The reaction mechanism for the conversion of the bis(2-cyanophenyl) disulfide to 3-amino-1,2-benzisothiazole involves the formation of ring-opened sulfenamide and benzamidine intermediates and then their subsequent ring closure to regenerate the 1,2-benzisothiazole nucleus. A safe, efficient, and robust process to prepare 3-(1-piperazinyl)-1,2-benzisothiazole under very concentrated reaction conditions was developed and successfully scaled up in the pilot plant to support the development of ziprasidone.",10.1021/op980210k,1
"Synthesis of CMI-977, a Potent 5-Lipoxygenase Inhibitor","CMI-977 is a potent 5-lipoxygenase inhibitor that intervenes in the production of leukotrienes and is presently being developed for the treatment of chronic asthma. It is a single enantiomer with an all - trans (2 S,5 S ) configuration. Of the four isomers of CMI-977, the S, S isomer was found to have the best biological activity and was selected for further development. The enantiomerically pure product was synthesized on a 2-kg scale from ( S )-(+)-hydroxymethyl-γ-butyrolactone.",10.1021/op980209l,1
"Synthesis of (<i>R</i>)-(−)-1-Piperidino-3,3-dimethylbutan-2-ol:  Application in the Molar Scale Asymmetric Ethylation of <i>trans</i>-Crotonaldehyde","A simple three-step preparation of ( R )-(−)-1-piperidino-3,3-dimethylbutan-2-ol (amino alcohol catalyst for the Noyori asymmetric alkylation of aldehydes) based on a classical resolution of the racemate is described. Use of this catalyst in a detailed study of the asymmetric ethylation of trans -crotonaldehyde producing trans -( S )-4-hexen-3-ol is also described. The impact of catalyst enantiopurity and loading on the product enantiopurity and yield is studied, which led to optimized conditions for reaction scale-up.",10.1021/op980208t,0
Reduction of an Enaminone:  Synthesis of the Diamino Alcohol Core of Ritonavir,"The reduction of (5 S )-2-amino-5-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene was optimized for diastereoselectivity and overall conversion to (2 S,3 S,5 S )-5-amino-2-dibenzylamino-3-hydroxy-1,6-diphenylhexane ( 2a ). A two-step reduction sequence is described wherein the enamine is reduced with a borane-sulfonate derivative followed by reduction of the resulting ketone with sodium borohydride. The desired 2a was obtained with 84% diastereoselectivity and an acyclic 1,4 stereoinduction ratio of 14:1. This methodology has been used to produce multikilogram quantities of the diamino alcohol core of Ritonavir and should be general to the synthesis of related diamino hydroxyethylene isosteres.",10.1021/op9802071,1
"A Practical Synthesis of Cycloheptane-1,3-dione","A three-step synthesis of cycloheptane-1,3-dione has been developed which avoids the use of heavy metal or explosive reagents and provides access to multigram quantities of this material.",10.1021/op9802069,1
Preparation of Carboxamides via Carboxylic−Phosphoric Anhydrides,A number of reagents used to prepare carboxamides via a carboxylic−phosphoric anhydride intermediate have been reexamined. It was found that a simple carboxylic−phosphoric anhydride prepared from a carboxylic acid and commercially available diethyl chlorophosphate provided several significant advantages over more complex intermediates in many cases.,10.1021/op980205g,0
"Improved Stereoselective Synthesis of the β-Anomer of 1-[3,5-Bis-<i>O</i>-(<i>p</i>-chlorobenzoyl)-2-deoxy-<scp>d</scp>-ribofuranosyl]-5-iodo-2-pyrimidinone",The lack of stereochemical control has been a major hurdle in synthesizing β-nucleosides in large scale. This paper reports a study of the effects of different catalysts used in the synthesis of β-nucleosides. The effects of time and temperature on α- and β-anomers are illustrated in this paper. The yield and selectivity of the β-nucleoside have been improved vastly at temperatures between −30 and −40 °C and by using SnCl 4 as the catalyst.,10.1021/op980204o,0
A Concise Two-Step Synthesis of Thalidomide,A two-step synthesis of thalidomide is presented. The sequence requires no purifications. Treatment of l -glutamine with N -carbethoxyphthalimide produces N -phthaloyl- l -glutamine. Cyclization of N -phthaloyl- l -glutamine to afford thalidomide is accomplished by treatment with CDI in the presence of a catalytic amount of DMAP.,10.1021/op980201b,1
"Preparation of 2-[(Aryl)methyl]sulfinyl-1<i>H</i>-imidazo[4,5-<i>c</i>]pyridine, Useful as an Antiosteoporotic Agent","A new process for the oxidation of 2-[(aryl)methyl]thio-1 H -imidazo[4,5- c ]pyridine to 2-[(aryl)methyl]sulfinyl-1 H -imidazo[4,5- c ]pyridine was achieved using NCS under mild condition. The reaction selectively affords the desired sulfoxide as the only product in high yield without further oxidation to the sulfone side product.",10.1021/op980184q,0
Development of a Process for Triazine-Promoted Amidation of Carboxylic Acids,"A process has been developed for the triazine-promoted amidation of carboxylic acids. We have identified 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) as a cost-effective reagent for this transformation. The procedure is a suitable alternative to traditional amidation processes when an acid chloride cannot be prepared from the corresponding carboxylic acid due to safety, stability, or handling concerns.",10.1021/op980097y,0
Fast Scale-Up Using Solid-Phase Chemistry,"A novel approach using solid-phase chemistry for scale-up was developed. The method makes use of commercially available high-load Merrifield resin. Three representative solid-phase chemistries leading to a diketopiperazine, a tetramic acid, and a β-lactam were scaled-up effectively and resulted in products with good yields and high crude purities. Affording close to 1 g of product per 1 g of Merrifield resin, the high-load resins showed high-volume productivity. The advantages of the work-ups, consisting simply of resin washes, are discussed. The need for low reactant and reagent equivalents results from higher reactant concentration, and it is shown that these stoichiometries can be reduced to affordable amounts.",10.1021/op9800966,1
"Synthetic Process Development of Antitumor Agent KT6587, an Indolocarbazole Alkaloid K252a Derivative","A facile and large-scale preparation process of an antitumor agent KT6587 ( 2 ), derived from an indolocarbazole alkaloid K252a ( 1 ), has been developed. The new synthetic process requires four steps: (i) selective N -silylation of the amide group of 1 with tert -butyldimethylsilyl chloride, (ii) methylation of the hydroxy group, (iii) deprotection under aqueous acidic conditions to afford 3, and (iv) reduction of the methoxycarbonyl group to obtain 2 . The key strategic improvement is to obtain fine quality of the intermediate 3 in a reasonable yield with reproducibility. This new process improves the overall yield from 33% to 70% without tedious chromatographic separations and hazardous conditions. Multikilogram quantities of KT6587 ( 2 ) for early clinical evaluation have been obtained by this method.",10.1021/op980087x,0
Application of Oxathiazolidine-S-oxide Chemistry to the Large-Scale Single-Step Synthesis of an O-Arylethanolamine,"Alternative routes to the arylethanolamine subunit of a development drug have been investigated. The selected route, involving O-alkylation of a phenol using N-benzyloxathiazolidine-S-oxide, was developed to give a process used successfully for pilot plant manufacture.",10.1021/op9800865,1
Process Research and Development of Melatonin,"A short, simple, and industrially feasible process for the preparation of melatonin ( N -acetyl-5-methoxy tryptamine), starting from phthalimide and 1-bromo-3-chloropropane, in essentially four steps is discussed. The present article elucidates the preparative process along with the impurity profile of each intermediate.",10.1021/op9800820,1
A Kinetic Model of the Choline Chloride Synthesis,"The process of ethylene oxide interaction with trimethylamine hydrochloride, giving choline chloride, has been studied. The reactions that proceed in the system were established. A kinetic model adequately describing the experimental data was developed.",10.1021/op980080f,0
Multikilogram-Scale Synthesis of a Biphenyl Carboxylic Acid Derivative Using a Pd/C-Mediated Suzuki Coupling Approach,"Reaction of 4-bromo-3-methylaniline with 4-chlorobutyryl chloride/TEA and subsequent treatment of the resulting secondary amide intermediate with KO t -Bu gives 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one in 65% yield. This procedure has been optimised (74−76% overall yield) and has been carried out on 41 molar scale. In a variation of this process, we have employed NaOH as the ring-closing base under phase-transfer conditions. NaOH is added to a mixture of 4-bromo-3-methylaniline, 4-chlorobutyryl chloride, and catalytic TBAC in THF/H 2 O. A further 2 equiv of aqueous NaOH is added, and the mixture is heated at 40−45 °C, providing access to cyclised product in an improved 86% yield. 1-(4-Bromo-3-methylphenyl)pyrrolidin-2-one is subsequently coupled with 4-carboxyphenylboronic acid under standard Suzuki coupling conditions [Pd(PPh 3 ) 4, Na 2 CO 3, DME/H 2 O] to give 2‘-methyl-4‘-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic acid in 64% yield, contaminated with 40−80 ppm of residual Pd. In a modification of this process, we have used Pd/C as the catalyst. Reaction in MeOH/H 2 O gives an improved yield of the biphenylcarboxylic acid with residual Pd levels of <6 ppm. This process has been carried out on 24 molar scale. The synthesis of the arylpyrrolidinone and subsequent Suzuki coupling have been combined into a one-pot procedure, providing access to 2‘-methyl-4‘-(2-oxo-1-pyrrolidinyl)biphenyl-4-carboxylic acid in 82% overall yield from 4-bromo-3-methylaniline.",10.1021/op980079g,1
Response to Comment on “An Ecofriendly Catalytic Route for the Preparation of Perfumery Grade Methyl Anthranilate from Anthranilic Acid and Methanol”,"ADVERTISEMENT RETURN TO ISSUEPREVCommunication to Edi...Communication to EditorNEXTResponse to Comment on ""An Ecofriendly Catalytic Route for the Preparation of Perfumery Grade Methyl Anthranilate from Anthranilic Acid and Methanol""G. D. Yadav and M. S. KrishnanView Author Information Chemical Engineering Division, University Department of Chemical Technology (UDCT), University of Mumbai, Matunga, Mumbai-400 019, India Cite this: Org. Proc. Res. Dev. 1998, 2, 6, 432Publication Date (Web):November 4, 1998Publication History Published online4 November 1998Published inissue 1 November 1998https://pubs.acs.org/doi/10.1021/op980074jhttps://doi.org/10.1021/op980074jrapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views215Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Catalysts,Ethers,Liquids,Mixtures Get e-Alerts",10.1021/op980074j,0
Comment on “An Ecofriendly Catalytic Route for the Preparation of Perfumery Grade Methyl Anthranilate from Anthranilic Acid and Methanol”,"ADVERTISEMENT RETURN TO ISSUEPREVCommunication to Edi...Communication to EditorNEXTComment on “An Ecofriendly Catalytic Route for the Preparation of Perfumery Grade Methyl Anthranilate from Anthranilic Acid and Methanol”Keith TurnerView Author Information Kappa Tau Consulting, 12 The Avenue, Fairfield, Stockton-on-Tees, TS19 7EY, U.K.Cite this: Org. Proc. Res. Dev. 1998, 2, 6, 431Publication Date (Web):November 4, 1998Publication History Received2 July 1998Published online4 November 1998Published inissue 1 November 1998https://doi.org/10.1021/op980073rCopyright © 1998 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views198Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (13 KB) Get e-AlertsSUBJECTS:Alcohols,Alkyls,Catalysts,Liquids,Separation science Get e-Alerts",10.1021/op980073r,0
"Studies toward an Improved Process for <i>N</i><sup>4</sup>,<i>N</i><sup>4</sup>-Disubstituted-2-cyano-<i>N</i><sup>1</sup>,<i>N</i><sup>1</sup>-dimethyl-1<i>H</i>-imidazole-1,4-disulfonamides","The development of a practical and cost-effective process for the manufacture of the title fungicidal compounds is described. In particular, substantial improvements in the chlorosulfonation of imidazole, studies on the stability of various cyanating agents, and a novel formylation/oximation/dehydration sequence to introduce the 2-cyano group are described.",10.1021/op9800717,0
"A New and Convergent Synthesis of (2<i>S</i>)-7-(4,4‘-Bipiperidinylcarbonyl)-2,3,4,5- tetrahydro-4-methyl-3-oxo-1<i>H</i>-1,4-benzodiazepine-2-acetic Acid Using a Palladium-Catalysed Aminocarbonylation Reaction","Palladium-catalysed aminocarbonylation of a 7-bromo- or 7-iodo-1,4-benzodiazepine with N -Cbz-4,4‘-bipiperidine hydrochloride efficiently introduced the 7-(4,4‘-bipiperidinylcarbonyl) moiety of (2 S )-7-(4,4‘-bipiperidinylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid.",10.1021/op980068n,1
Process Optimization in the Synthesis of 9-[2-(Diethylphosphonomethoxy)ethyl]adenine:  Replacement of Sodium Hydride with Sodium <i>tert</i>-Butoxide as the Base for Oxygen Alkylation,"9-[2-(Diethylphosphonomethoxy)ethyl]adenine (diethyl-PMEA), a key intermediate in the production of the antiviral drug adefovir dipivoxil, was originally produced via a process utilizing sodium hydride (NaH) to couple hydroxyethyl adenine with diethyl p -toluenesulfonyloxymethanephosphonate. The use of NaH presented safety and consistency problems. It was found that sodium tert -butoxide (NaO t Bu) was a suitable replacement for NaH as the base to effect the coupling reaction. Optimization of reagent stoichiometry and introduction of a simplified filtration workup procedure led to a robust process affording diethyl-PMEA in consistent yields and purities. The modifications and process improvements were scaled-up successfully to batch sizes of >100 kg.",10.1021/op980067v,1
The Bicyclo[3.2.0]heptan-<i>endo</i>-2-ol and Bicyclo[3.2.0]hept-3-en-6-one Approaches in the Synthesis of Grandisol:  The Evolution of an Idea and Efforts to Improve Versatility and Practicality,"In this paper we will disclose a chemistry story that started with a single molecule, the monoterpene grandisol, used in protecting cotton crops from an important pest, Anthonomus grandis Boheman. Initially, efforts were aimed at giving ever more practicality, versatility, and efficiency to a synthetic scheme that was centered on the key role of the 2,5-dimethylbicyclo[3.2.0]heptan- endo -2-ol, available from intermolecular photocyclization and methylation or, better and more conveniently, by an intramolecular copper(I)-catalyzed photobicyclization of the 3,6-dimethylhepta-1,6-dien-3-ol. We have developed an enantiospecific synthesis of both enantiomers of grandisol although some drawbacks would preclude scale up and commercialisation. The major limits of this original single-target synthetic scheme are pointed out along with the changed landscape resulting from recent developments in the fields of bioorganic chemistry and entomology. These changes prompted the elaboration of a new strategy focused on the conception and the development of a practical and efficient preparation bicyclo[3.2.0]hept-2-en-6-ones. The “bicyclo[3.2.0]hept-2-en-6-one approach” stems from a very convenient and general preparation, without photochemical steps, of bicyclo[3.2.0]hept-2-en-6-ones. These compounds proved to be amenable to selective manipulations to prepare not only grandisol but also other important molecules such as lineatin, filifolone, and raikovenal in multitarget and versatile synthetic schemes. Moreover, through resolution of the bicyclo[3.2.0]hept-2-en-6-ones, the procedures can be used to produce enantiomerically pure products. The bismethylation of the carbon atom adiacent to the carbonyl group as well as the conversion into the corresponding unsaturated bicyclic lactones are two important reactions that amplify the potential utility of bicyclo[3.2.0]hept-2-en-6-ones. Their peculiar reactivity, ascribed to the fact that the carbonyl group and the carbon−carbon double bond are attached to the same bridge-head carbon atom, has been demonstrated by the high chemio-, regio-, and stereoselectivity of the NBS-induced lactonization.",10.1021/op9800663,1
"Azolides in Organic Synthesis and Biochemistry By H. A. Staab, H. Bauer, and K. M. Schneider. Wiley-VCH:  Weinheim, Germany. 1998. 502 pp. ISBN 3-527-29314-0. £95.00.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewAzolides in Organic Synthesis and Biochemistry By H. A. Staab, H. Bauer, and K. M. Schneider. Wiley-VCH: Weinheim, Germany. 1998. 502 pp. ISBN 3-527-29314-0. £95.00.J. Ian GraysonCite this: Org. Proc. Res. Dev. 1998, 2, 6, 433–434Publication Date (Web):September 30, 1998Publication History Published online30 September 1998Published inissue 1 November 1998https://pubs.acs.org/doi/10.1021/op980062yhttps://doi.org/10.1021/op980062ybook-reviewACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views280Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Carbonyls,Chemical reactions,Elimination reactions,Reagents Get e-Alerts",10.1021/op980062y,0
Process Research and Structural Studies on Nabumetone,"A short, simple and economical process for large-scale preparation of nabumetone has been developed. The single-crystal structures of nabumetone and one of its key intermediates have been determined by X-ray diffraction studies. Two impurities have been isolated and characterised.",10.1021/op980060d,1
Application of Heterogeneous Acid Catalysts to the Large-Scale Synthesis of 2- and 3-(<i>p</i>-Methoxyphenyl)-6-methoxybenzo[<i>b</i>]thiophenes,"2-( p -Methoxyphenyl)-6-methoxybenzothiophene ( 3 ) was synthesized by acid-catalyzed cyclization and rearrangement of the β-ketosulfide precursor 1 . The use of Amberlyst 15 resin as a catalyst for the cyclization increased the isomer ratio from 75:25 to 88:12, compared to a conventional approach using polyphosphoric acid (PPA). Although solid acid catalysts were also evaluated for the rearrangement, a two-phase mixture of methanesulfonic acid in toluene was found to be the best alternative to the use of PPA for this reaction. The rearrangement, which was shown to be equilibrium controlled, was driven towards completion by crystallization of the product as it formed. An Amberlyst 15 catalyzed cyclization, combined with an MsOH-catalyzed rearrangement, raised the overall isolated yield from 70 to 80%, and difficulties associated with the use of PPA on a large scale were eliminated. This process has been successfully scaled to a pilot plant and manufacturing scale.",10.1021/op980059e,0
"Optimisation of the Preparation and Isolation of 5-Amino-2,4,6-triiodoisophthalic Acid Dichloride","A scaleable process for the chlorination of 5-amino-2,4,6-triiodoisophthalic acid to the corresponding acid chloride, a building block for the synthesis of iodinated X-ray contrast agents, has been developed. Two dimeric byproducts have been isolated and assigned structures consistent with an amide and an anhydride. Hydrolysis of the N-sulfinyl intermediate and simultaneous crystallisation of the phthalic acid chloride have been optimised by applying fractional factorial design.",10.1021/op980055+,0
Process Development of a Platelet Aggregation Inhibitor,"A practical and efficient method for N -amination of piperazine via a nitrosoamine, suitable for a large scale synthesis, is described. This method involved the temporary transformation of an in situ prepared aminopiperazine to a hydrazone, allowing efficient separation of zinc salt byproducts from the system. Acylation and deprotection with hydroxylamine directly afforded FR062732 in satisfactory quality for pharmacological evaluation. These methods solved the operational problems usually inherent in zinc reduction of nitrosoamines.",10.1021/op980050c,1
"Process for the Capture and Reuse of the 4,4‘-Dimethoxytriphenylmethyl Group during Manufacturing of Oligonucleotides","In a standard amidite coupling-based automated oligonucleotide synthesis campaign, the 4,4‘-dimethoxytriphenylmethyl (DMT) protecting group is discarded as waste along with large amounts of dichloromethane. Herein, we report a straightforward and simple process for complete capture and recovery of the DMT group and dichloromethane, rendering the oligonucleotide manufacturing process safer and more economical.",10.1021/op980048l,0
"Kinetics and Process Parameter Studies in Highly Selective Air Oxidation of Side-Chain Alkyl Groups in Picolines, 2-Methylnaphthalene, and Pseudocumene","Picolines, 2- methylnaphthalene, and pseudocumene were oxidized by air in acetic acid medium. Process parameters and kinetics of the reaction were studied from the viewpoint of proces research and development. Use of lithium chloride as the promoter was worth considering for this oxidation to obtain a higher rate of reaction. At 170 °C and at a reactant concentration of 15% w/v, 52% conversion of β - picoline with a selectivity of 97% was achieved in 8 h.",10.1021/op980047t,0
Investigation of Cocatalysis Conditions Using an Automated Microscale Multireactor Workstation:  Synthesis of <i>m</i><i>eso</i>-Tetramesitylporphyrin,"Prior manual work has shown that the condensation of mesitaldehyde and pyrrole leading to tetramesitylporphyrin depends sensitively on concentration and requires cocatalysis involving BF 3 ·O(Et) 2 and ethanol or other protic species. We have applied an automated microscale chemistry workstation capable of parallel or adaptive experimentation to systematically investigate these cocatalysis conditions. Examination of experimental grids spanning a 1000-fold range of the concentrations of BF 3 ·O(Et) 2 and ethanol identified the best cocatalysis conditions for various mesitaldehyde and pyrrole concentrations. As the reaction concentration increased from 10 to 200 mM, the optimal yields were achieved with a parallel increase in BF 3 ·O(Et) 2 concentration (from 3.3 to 56 mM), but the amount of ethanol remained relatively constant. Catalysis conditions were identified that afforded ∼30% yields for reactants in the range of 10−73 mM, thereby enabling the reaction to be performed at increased concentration without loss in yield. Application of a catalyst searching protocol identified ethylene glycol, 2-methoxyethanol, and methanol as effective cocatalysts from a set of 12 candidates. Collectively, these results show the utility of an automated chemistry workstation in acquiring a comprehensive set of data concerning the scope of cocatalysis in the reaction of mesitaldehyde and pyrrole.",10.1021/op9800459,0
Facile Synthesis of β-Keto Esters from Methyl Acetoacetate and Acid Chloride:  The Barium Oxide/Methanol System<sup>1</sup>,"The synthesis of β-keto esters has been performed in good yield by reacting excess methyl acetoacetate with barium oxide, acylating the resulting barium complex with acid chloride, and then cleaving the α-acyl β-keto ester with methanol at a mild temperature. Using this new procedure, various β-keto esters were prepared. Thus, methyl 4-phenyl-3-oxobutanoate, methyl 3-phenyl-3-oxopropionate, methyl 4-cyclohexyl-3-oxobutanoate, and methyl 3-oxooctadecanoate were prepared from methyl acetoacetate and the corresponding acid chloride in 69%, 84%, 67%, and 74% yields, respectively.",10.1021/op980044g,0
"Ecofriendly Fast Batch Synthesis of Dioxolanes, Dithiolanes, and Oxathiolanes without Solvent under Microwave Irradiation","2,2-Dimethoxypropane and 3,3-dimethoxypentane react with 1,2-ethanediol, thio, and oxathio analogues to give the corresponding protected carbonyls in high yield under mild solvent-free conditions. These environmentally benign conditions under microwave irradiation are applied to a large-scale synthesis.",10.1021/op980043o,0
Process Development Aspects of Production of Dibenzyl Ether,"To develop an economically viable process for the synthesis of dibenzyl ether, the reaction of benzyl chloride with aqueous sodium hydroxide in the presence of phase-transfer catalysts has been investigated. The effects of agitation speed, catalyst type and concentration, reaction temperature, mole ratio of reactants, concentration of aqueous sodium hydroxide on the conversion of benzyl chloride, and yield of dibenzyl ether have been evaluated. Tributylamine is found to be a suitable catalyst. The reaction is favored by high molar ratio of sodium hydroxide to benzyl chloride. Conversion of benzyl chloride to benzyl alcohol is found to be the rate-controlling step at high sodium hydroxide concentration. Deprotonation of benzyl alcohol at the interphase by aqueous sodium hydroxide is a key step in the formation of dibenzyl ether. The yield of dibenzyl ether is dependent on the concentration of sodium hydroxide in the aqueous phase, the yield being almost 100% at high concentrations of sodium hydroxide. The successful recycle of excess NaOH in the aqueous phase in subsequent batches, without affecting the progress of the reaction, has been demonstrated.",10.1021/op980042w,0
A Scalable Process for the Novel Antidepressant ABT-200,"A scalable process for the novel antidepressant ABT-200, starting with 5,6-methylenedioxy-1-tetralone, is described. The new process improves the scale-up and safety concerns associated with the previously employed route to ABT-200. The scalable process eliminates the potential for HCN exposure to employees and produces ABT-200 in a stereospecific fashion. (TMS)CN was replaced by nitromethane as a reagent to introduce the nitrogen in the ABT-200 molecule. This stereospecific process employs an epimerization procedure which takes advantage of a key difference in the solubility of the two diastereomers of the succinimide intermediate, 9a/b and 10a/b. Balancing the rate of epimerization with the solubility of the diastereomers in the reaction medium was an essential factor in optimizing the yield and efficiency of this simple, one-pot reaction. The solubility-directed epimerization was demonstrated in both a predominantly aqueous and an organic solvent mixture. The succinimide derivative 10a/b was then converted to ABT-200. This improved procedure was used to prepare kilogram quantities of ABT-200.",10.1021/op9800414,1
"Pilot-Scale Synthesis of a Novel Non-Xanthine Adenosine A<sub>1</sub> Receptor Antagonist. 1,3-Dipolar Cycloaddition of Pyridine <i>N</i>-Imine to an Acetylene","Adenosine A 1 receptor antagonist, FK838, has been synthesized in 44% overall yield by a five-step sequence which is operationally straightforward and readily carried out on a large scale. Investigations into the 1,3-dipolar cycloaddition process that afforded a pyrazolo[1,5- a ]pyridine derivative are also described. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a practical and cost-effective synthesis of FK838. These methods were successfully scaled up in a pharmaceutical pilot plant to give bulk drug used in clinical trials.",10.1021/op980039c,1
Practical Synthesis of the High-Quality Antitumor Agent KW-2189 from Duocarmycin B2 Using a Facile One-Pot Synthesis of an Intermediate,"A facile and large-scale preparation process of a potent antitumor agent KW-2189 ( 2 ), derived from the antitumor antibiotic duocarmycin B2 ( 1 ), has been developed. This new synthetic route required three steps: (i) one-pot carbamoylation and subsequent reduction, (ii) Wagner−Meerwein rearrangement of the methoxycarbonyl group for the production of the pyrrole compound 6, and (iii) formation of the hydrobromide salt 2 . The key strategic improvement was to obtain good quality hydroxy compound 4 in a reasonable yield without isolation of the unstable keto intermediate 3a . During commercial-scale production at a scale of about 50 g, this strategy provided high-quality KW-2189 ( 2 ) in a 55% overall yield from 1 . Potential degradation compounds 7 − 9 were also synthesized and shown to be absent in the KW-2189 ( 2 ) prepared.",10.1021/op980038k,1
"Handbook of Batch Process Design Edited by P. N. Sharratt. Blackie/Chapman and Hall:  London, UK. 1997. 320 pp. ISBN 0 7514 0369 5. £75.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTHandbook of Batch Process Design Edited by P. N. Sharratt. Blackie/Chapman and Hall: London, UK. 1997. 320 pp. ISBN 0 7514 0369 5. £75.T. LairdCite this: Org. Proc. Res. Dev. 1998, 2, 4, 280Publication Date (Web):May 20, 1998Publication History Published online20 May 1998Published inissue 1 July 1998https://pubs.acs.org/doi/10.1021/op980037shttps://doi.org/10.1021/op980037sbook-reviewACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views469Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Extraction,Filtration,Separation science,Solvents,Wastes Get e-Alerts",10.1021/op980037s,0
A Process Scheme Involving Transalkylation Reactions To Prepare <i>o</i>-Bromophenol from Phenol,"The bromination of phenol to o -bromophenol was carried out by protecting the para position with a tert -butyl group. The latter group was subsequently transferred to toluene using aluminum chloride as a catalyst. The resulting mixture of p - and m - tert -butyltoluene could be converted back to p - tert -butylphenol by transalkylation of the former with phenol in the presence of Engelhard, F-24. Thus, a process scheme based on transalkylation reactions as the intermediate steps has been proposed to synthesize o -bromophenol from phenol via p - tert -butylphenol. The effect of reaction parameters on overall conversion to and selectivity with respect to the desired product was studied for the transalkylation reactions involved in the process.",10.1021/op9800360,0
"Organic Synthesis in Water. Edited by Paul A Grieco. Blackie/Thomson Science:  London, UK, 1998. 320 pp. £75. ISBN 0 7514 0410 1.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewOrganic Synthesis in Water. Edited by Paul A Grieco. Blackie/Thomson Science: London, UK, 1998. 320 pp. £75. ISBN 0 7514 0410 1.T. LairdCite this: Org. Proc. Res. Dev. 1998, 2, 5, 338Publication Date (Web):June 9, 1998Publication History Published online9 June 1998Published inissue 1 September 1998https://pubs.acs.org/doi/10.1021/op9800358https://doi.org/10.1021/op9800358book-reviewACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views239Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aldol reactions,Catalysis,Organic synthesis,Redox reactions,Water Get e-Alerts",10.1021/op9800358,0
Scale-Up of a Chiral Resolution Using Cross-Linked Enzyme Crystals,"The scale-up of a biocatalytic process using a cross-linked enzyme crystal (ChiroCLEC-PC, Altus Biologics Inc., Cambridge, MA) for the resolution of a racemic mixture ( R / S - sec -phenethyl acetate to R - sec -phenethyl alcohol) is reported. Reaction parameters were initially investigated at the 20-mL and 1-L scale to determine optimum reactor conditions for operation at the 100-L scale. At this scale, reproducibility trials were conducted with a single charge of 50 g of ChiroCLEC-PC for the entire nine trials. Results demonstrated that, although there was a steady decrease in reaction rate over the trials (primarily as a result of sub-optimal CLEC catalyst recovery between each trial) all nine reactions proceeded to >48% conversion, with ee p 's of 99.9% and ee s 's of 91−95% recorded. In total, 270 kg of racemate was converted into R -phenethyl alcohol and S -phenethyl acetate during the reproducibility trials using a standard stirred tank design with pH control. With further work to improve CLEC catalyst recovery between runs, the technology is suitable for industrial exploitation to compete favourably alongside alternative chiral technologies.",10.1021/op980032v,0
A Synthesis of Atenolol Using a Nitrile Hydration Catalyst,"The synthesis of atenolol is described using a platinum containing homogeneous catalyst for the conversion of a nitrile to an amide. The catalytic reaction may be employed as the final step in the synthesis or in the preparation of the intermediate 4-hydroxyphenylacetamide. The structure of the nitrile intermediate, 1-(4‘-cyanomethylphenoxy)-2-hydroxy-3-isopropylaminopropane, has been determined by X-ray crystallography.",10.1021/op9800313,1
Development of a Seeding Technique for the Crystallization of the Metastable A Modification of Abecarnil,"Abecarnil, a partial agonist of the benzodiazepine receptor, crystallizes in three modifications, A, B, and C. Depending on the solvent, the form crystallized in an unseeded process is one of the two metastable forms A or B. Isopropyl acetate was chosen as solvent for the crystallization of the drug substance Abecarnil, yielding the B form for an unseeded crystallization. However, the crystals undergo a slow solution-mediated phase transformation into the stable C form. More readily observed is a partial phase transformation into the A modification. The rate of transformation depends sensitively on the purity of the material. To access this second metastable form quantitatively, reproducibly and irrespective of the purity of the material, a seeding strategy for a batch cooling crystallization from isopropyl acetate is developed. The technique is optimized under laboratory conditions and transferred to pilot plant scale. The physicochemical data necessary for the effective development are given and their relevance is discussed.",10.1021/op980029b,0
Catalytic Processes of Oxidation by Hydrogen Peroxide in the Presence of Br<sub>2</sub> or HBr. Mechanism and Synthetic Applications,"The mechanism and the synthetic applications for the oxidation of alcohols, ethers, and aldehydes by H 2 O 2 catalyzed by Br 2 or Br - in a liquid two-phase system (aqueous and organic) are reported. Aliphatic and benzylic primary alcohols and ethers show an opposite behavior, which has been rationalized on the ground of the different electronic configurations of the intermediate alkyl (π-type) and acyl (σ-type) radicals and their influence on enthalpic and polar effects. A two-phase system is particularly useful also for an efficient benzylic bromination by Br 2 or Br -; the substitution of the benzyl bromide by OH, OR, and OCOR regenerates Br -, which can be recycled. The evaluation of the relative reactivities of the involved substrates and intermediates has allowed to develop a variety of simple, facile, convenient, and selective syntheses of alcohols, aldehydes, ketones, esters, and benzyl bromides, which fulfill the conditions for practical applications.",10.1021/op980028j,0
Synthesis of Phenethyl Alcohol by Catalytic Hydrogenation of Styrene Oxide,"In the current work, phenethyl alcohol was synthesized by the hydrogenation of styrene oxide, which may be obtained by the oxidation of styrene. Conventional method of synthesis of phenethyl alcohol is by the Friedel−Crafts alkylation of benzene by using ethylene oxide and molar quantities of aluminum chloride. This method causes effluent disposal problems due to the stoichiometric use of aluminum chloride as the aluminum oxychloride formed in the process is normally not recycled. The hydrogenation of styrene oxide was conducted by using Raney nickel catalyst and process conditions were established. The yield of phenethyl alcohol obtained was 90.2% with 92% overall conversion of styrene oxide under suitable conditions. Styrene oxide was also synthesized in the laboratory.",10.1021/op980027r,0
Production of (<i>R</i>)-2-Bromo-5-phthalimidopentanoic Acid via a Diazotisation Process from (<i>R</i>)-Ornithine,A scaleable “one-pot” preparation of ( R )-2-bromo-5-phthalimidopentanoic acid from ( R )-ornithine is described. The use of this chirality pool method allowed for rapid development of the process. Acetic acid was found to be an efficient antifoaming agent during the diazotisation reaction. The use of an extractive workup procedure has the benefit of reducing operator exposure to the corrosive reaction mixture and minimised manual handling operations.,10.1021/op980026z,0
Large-Scale Preparation of Iodobenzene Dichloride and Efficient Monochlorination of 4-Aminoacetophenone,Large-scale monochlorination of 4-aminoacetophenone using iodobenzene dichloride is described. Special emphasis was given to the characterization of the iodobenzene dichloride and to the development of a practical procedure for handling this agent from the viewpoint of hazards. This process was successfully scaled up in a pilot plant.,10.1021/op980024e,0
"A Liquid−Liquid Process for Production of 2,4-Diphenyl-4-methyl-1-pentene by Dimerization of α-Methylstyrene","A liquid−liquid process for the dimerization of α-methylstyrene (AMS) in order to produce selectively the commercially useful 2,4-diphenyl-4-methyl-1-pentene has been developed. The aqueous phase contained sulfuric acid as a catalyst and methanol as an additive, and the organic phase was 97% α-methylstyrene (AMS). An AMS conversion of 55% was achieved in 7 h when the dimerization was conducted at 80 °C. The product dimer contained 93% 2,4-diphenyl-4-methyl-1-pentene and only 0.06% 1,1,3-trimethyl-3-phenylindan, the saturated dimer. The liquid−liquid process can be used commercially to produce selectively 2,4-diphenyl-4-methyl-1-pentene at locations where cation-exchange resins are not readily available.",10.1021/op980023m,0
Synthesis of Alkyl Glyoxylates,Glyoxylic acid esters are prepared using commercially available 50% w/w aqueous solution of glyoxylic acid. The method involves neutralization of aqueous solution of glyoxylic acid with sodium hydroxide followed by isolation of glyoxylic acid as a calcium salt by double decomposition technique. Suspending this calcium salt of glyoxylic acid in an alcohol and liberating free glyoxylic acid by concentrated sulfuric acid gives an alcoholic solution of glyoxylic acid containing insoluble anhydrous calcium sulfate. Glyoxylic acid being a strong acid readily forms an ester. The effect of various reaction parameters on overall conversion of glyoxylic acid and selectivity with respect to alkyl glyoxylate were studied.,10.1021/op9800212,0
Technical-Scale Homologation of a Cholanic Acid Derivative through the Barton Ester. A Practical Approach to 25-Hydroxy Vitamin D<sub>3</sub> and Congeners,"A novel method was developed of the homologation of a cholanic acid derivative using the Barton ester, as a practical approach to 25-hydroxy vitamin D and congeners. The method involves transformation of a cholanic acid derivative into a nor-bromide by using 2-mercaptopyridine N -oxide sodium salt and bromotrichloromethane and then alkylation of the bromide with dimethylmalonate followed by demethoxycarbonylation by Krapcho procedure. The major byproducts of the synthesis were isolated, and their structures were identified by spectroscopic and chemical methods. Our method is designed especially for the large-scale manufacturing of vitamin D compounds because it involves an intermediate that can be easily purified and it avoids the use of toxic and explosive diazomethane that is employed in the classical synthesis of vitamins D from natural steroids.",10.1021/op980018i,1
Enhanced Selectivity in the Preparation of Linear Alkylbenzenes Using Hexagonal Mesoporous Silica Supported Aluminium Chloride<sup>1</sup>,"For decades sulphonated linear alkylbenzenes have been one of the worlds most important detergents. Industrially, their preparation involves the use of either aluminium chloride or hydrogen fluoride as catalysts in the alkylation stage of the reaction. The use of these catalysts presents severe problems in terms of both their environmental impact and their lack of selectivity towards the desired product. Solid acids, such as zeolites, can overcome these problems but at the expense of activity. It has now been discovered that by chemically supporting aluminium chloride on a MCM-41 type silica a reuseable catalyst is produced. It can be easily separated from the products and is environmentally benign. In addition, the new catalyst exhibits significant improvements in selectivity towards both the monoalkylated product and the preferred 2-phenyl isomer. Selectivity can be further increased by maximizing the relative activity of the catalytic sites situated within the pores of the catalyst.",10.1021/op980017q,0
"Process Safety AnalysisAn Introduction By R. Skelton. Institute of Chemical Engineers:  Rugby, UK. 1997. 213 pp. ISBN 0-85295-378X. £26.00.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Safety AnalysisAn Introduction By R. Skelton. Institute of Chemical Engineers: Rugby, UK. 1997. 213 pp. ISBN 0-85295-378X. £26.00.Cite this: Org. Proc. Res. Dev. 1998, 2, 5, 337Publication Date (Web):February 19, 1998Publication History Published online19 February 1998Published inissue 1 September 1998https://doi.org/10.1021/op980013lCopyright © 1998 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views176Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (16 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Materials,Mathematical methods,Physical and chemical processes,Safety Get e-Alerts",10.1021/op980013l,0
Research &amp; Development Management By P. Bamfield. VCH:  Weinheim. 1997. 178 pp. ISBN 3-527-28778-7. £50.00.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTResearch & Development Management By P. Bamfield. VCH: Weinheim. 1997. 178 pp. ISBN 3-527-28778-7. £50.00.Cite this: Org. Proc. Res. Dev. 1998, 2, 5, 338Publication Date (Web):February 19, 1998Publication History Published online19 February 1998Published inissue 1 September 1998https://doi.org/10.1021/op980012tCopyright © 1998 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views88Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (15 KB) Get e-AlertsSUBJECTS:Interfaces,Stability Get e-Alerts",10.1021/op980012t,0
Is Your Process R &amp; D Department Under-Resourced?,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTIs Your Process R & D Department Under-Resourced?Cite this: Org. Proc. Res. Dev. 1998, 2, 2, 63Publication Date (Web):February 19, 1998Publication History Published online19 February 1998Published inissue 1 March 1998https://doi.org/10.1021/op980009+Copyright © 1998 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views434Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (20 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Physical and chemical processes Get e-Alerts",10.1021/op980009+,0
"Development of a Continuous Homogeneous Metal Complex Catalyzed, Asymmetric Hydrogenation under High Pressure (270 bar)","A kinetic model and simulation as well as a continuous stirred tank reactor (CSTR) system for the synthesis of ( S )-2-(4-fluorophenyl)-3-methylbutanoic acid, an important optically active intermediate in the synthesis of mibefradil (POSICOR, a new type of calcium antagonist), by asymmetric hydrogenation of 2-(4-fluorophenyl)-3-methylbut-2-enoic acid under high pressure (270 bar) are described. It was demonstrated that a continuous, homogeneous metal complex catalyzed, enantioselective hydrogenation under high pressure is not only feasible but also a very attractive possibility. Using such a CSTR system one may achieve a space-time yield of 5.0 kg/L/day. Compared to a batch mode under high pressure, the CSTR reactor system has a more favourable space-time yield, is safer, would need less investment, and allows easier temperature control.",10.1021/op980007p,0
Process Development of 5-Methoxy-1<i>H</i>-indole-2-carboxylic Acid from Ethyl 2-Methylmalonate,"Development is described of a new process for the preparation from malonates of 5-methoxy-1 H -indole-2-carboxylic acid esters, useful intermediates in the synthesis of pharmaceutical compounds. The process uses readily available starting materials, produces little waste, can be operated safely on at least 1 molar scale, and gives high yields. The main areas of optimization included the azo coupling of a diazonium salt with malonate derivatives, the Japp−Klingemann rearrangement, and the Fischer indole synthesis.",10.1021/op980006x,1
Pilot Scale Synthesis of a Novel Nonpeptide Angiotensin II Receptor Antagonist,"FR143187 is a novel nonpeptide angiotensin II receptor antagonist under development at Fujisawa Pharmaceutical Co. for the treatment of hypertension. Development of a process for preparation on a large scale is described. The optimized process is 10 steps in length and uses only commercially available materials for each step. Efficient methylation of the 2-position of a pyrrole derivative was achieved by reduction of a Mannich base via the quaternary ammonium salt. Selective cyanation directed by a solvent effect was also investigated. Process improvement efforts focused on optimized reaction conditions for each step, leading to a high-quality product according to a new and concise synthetic route.",10.1021/op9800055,1
Scale-Up of an Intermolecular Barbier Reaction,"Addition of n -BuLi to a mixture of ketone (2) and 1,4-diiodobenzene provides access to alcohol (1) in high yield. This procedure has successfully been used on molar scale.",10.1021/op980003k,0
"Process Improvements in the Synthesis of 2,4,5-Trifluorobenzoic Acid. Selective Hydrodefluorination of Tetrafluorophthalimides","An improved preparation of the fluoroquinolone antibacterial intermediate 2,4,5-trifluorobenzoic acid is described. A combination of a selective hydrodefluorination and hydrolysis reaction of 3,4,5,6-tetrafluoro- N -methylphthalimide leading to 3,5,6-trifluorophthalic acid was key to the success of the process. In addition the development of a two-step, one-pot imidization/halogen exchange from tetrachlorophthalic anhydride to 3,4,5,6-tetrafluoro- N -methylphthalimide in sulfolane solvent is detailed.",10.1021/op970244c,1
"Reaction Kinetics of a Condensation Polymer between 1,10-Dibromodecane and Hexamethylenediamine:  Scale-Up Considerations","The end point, rates of reaction, and heat of reaction have been determined for the reaction of 1,10-dibromodecane and 1,6-hexamethylenediamine, which forms a moderately cross-linked polymer useful as a bile acid sequestrant in the treatment of elevated cholesterol. The parameters have been used to predict scale-up of the polymerization from the laboratory to pilot plant and full-scale production. A novel application of a bromide-specific electrode analytical method was developed to determine the extent of polymerization.",10.1021/op970243k,0
Efficient Large Scale Preparation of Neutral Endopeptidase/Angiotensin-Converting Enzyme Dual Inhibitor CGS30440,"The development and piloting of a potential manufacturing process for ACE/NEP dual inhibitor CGS30440 is described. The synthesis proceeds sequentially from 1-aminocyclopentanecarboxylic acid via N-protection, peptide coupling with l -tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]- l -tyrosine ethyl ester, N-deprotection, peptide coupling of [(1-amino-1-cyclopentyl)carbonyl]- O -methyl- l -tyrosine ethyl ester with d -2-bromo-3-methylbutyric acid, and final displacement of bromide with thioacetate. This approach is superior to shorter Discovery routes based upon final peptide coupling of l -2-(acetylthio)-3-methylbutanoic acid to [(1-amino-1-cyclopentyl)carbonyl]- O -methyl- l -tyrosine ethyl ester.",10.1021/op970242s,1
"Process Research and Large-Scale Synthesis of 4‘‘,6‘‘-Bis((2-fluorophenyl)carbamoyl)hecogenyl β-<i>O</i>-Cellobioside:  A Potent Cholesterol Absorption Inhibitor","This paper describes process research leading to the successful scale-up of a potent cholesterol absorption inhibitor 4‘‘,6‘‘-bis((2-fluorophenyl)carbamoyl)hecogenyl β- O -cellobioside 3 . The synthesis of 3 from hecogenyl β- O -cellobioside 4 required five synthetic steps: (1) the selective protection of the 4‘‘,6‘‘-diol group, (2) acylation of the remaining five hydroxyl groups, (3) unmasking of the diol moiety, (4) carbamoylation with 2-fluorophenyl isocyanate, and finally, (5) deacylation. The synthesis by our discovery group utilized chloroacetate protecting groups for five of the sugar alcohols at step two, which led to problems on scale-up due to the instability of this group in solution and the poor crystallinity of the intermediates. Methoxyacetates were identified as the optimal acyl-protecting group. The identification of mild reaction conditions led to an efficient synthesis of bis(carbamate) 3 in very high purity and 42% yield from 4 over five synthetic steps and one recrystallization/polymorph conversion. The process was simple to operate and was carried out to provide 80 kg of 4‘‘,6‘‘-bis(2-fluorophenylcarbamoyl)hecogenyl β- O -cellobioside 3 .",10.1021/op9702206,0
"Isoquinoline Alkaloids. 3. Synthesis of the 6-Ethyl and 6-Butyl Analogs of <i>d,l</i>-6-Methyl-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-4<i>H</i>-dibenzo[<i>de,g</i>]- quinoline 1.5 Phosphate (<i>d,l</i>-Glaucine 1.5 Phosphate)","The syntheses of the 6-ethyl ( 12b ) and 6-butyl ( 12c ) analogs of d,l -glaucine 1.5 phosphate ( 12a ) in 10 steps from papaverine hydrochloride ( 1 ) are described. Mechanistic rationale for the formation of Hofmann degradation products observed during the methylation of the 6-ethyl ( 7b ) and 6-butyl ( 7c ) analogs of d,l -1,2,9,10-tetrahydroxyaporphine ( 7a ) with phenyltrimethylammonium hydroxide are discussed. Detailed analyses and assignments of the 1 H and 13 C NMR spectra of 12a − c and the corresponding free base forms 8a − c are presented.",10.1021/op970217m,1
"Isoquinoline Alkaloids. 2. Preparation of <i>d,l</i>-Glaucine 1.5 Phosphate from <i>d,l</i>-Laudanosoline Hydrobromide","A high-yield, commercially viable synthesis of d,l -glaucine 1.5 phosphate ( 1 ) from d,l -laudanosoline hydrobromide ( 2 ) is described. Oxidation of 2 with ferric chloride in ethanol/ water buffered with sodium acetate gave d,l -1,2,9,10-tetrahydroxyaporphine hydrochloride ( 3 ) in 76−83% yield. This was converted to the free base, 4, which was methylated with phenyltrimethylammonium hydroxide ( 5 ) in 1,2-dichlorobenzene to give, after precipitation with 48% hydrobromic acid, crude d,l -glaucine hydrobromide ( 6 ) in 74% yield. The crude 6 was purified by recrystallization from 50/50 (v/v) ethanol/water to remove by-product 1-(2-(dimethylamino)ethyl)-3,4,6,7-tetramethoxyphenanthrene hydrobromide ( 7 ). The purified 6 was converted to 1 in 86−88% yield by formation of the free base followed by treatment with 85% phosphoric acid in 80% ethanol and subsequent crystal digestion for 6 h.",10.1021/op970216u,0
Development of a Commercially Viable Clonazepam Process,"A commercial process to clonazepam ( 1 ) is described. An advanced chloro intermediate, 2-(2-chloroacetamido)-5-nitro-2‘-chlorobenzophenone ( 6 ), is activated to the corresponding iodide 2-(2-iodoacetamido)-5-nitro-2‘-chlorobenzophenone ( 7 ) via substitution with potassium iodide. Subsequent alkylation of ammonia with 7 yields the open form of clonazepam ( 8 ). The intermediate 8 is isolated as the hydrochloride salt 8b, cyclized to 1, and purified to yield United States Pharmacopoeia specification material. Formation of the known impurity 3-amino-4-(2-chlorophenyl)-6-nitro-2(1 H )-quinolinone ( 9 ), as well as of the newly identified dimeric impurity N -[2-(2-chlorobenzoyl)-4-nitrophenyl]-2-{[[[2-(2-chlorobenzoyl)-4-nitrophenyl]carbamoyl]methyl]amino}acetamide ( 10 ), is minimized. The robust purification scheme readily removes both organic and inorganic impurities. This synergistic combination of pieces of several patented routes results in a process that is more viable than any previously described process.",10.1021/op9702152,1
"A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194","A practical synthesis of the antiviral agent lobucavir, [1 R -(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6 H -purin-6-one (BMS-180194), is described. The key chiral intermediate, [1 S -(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate with ketene dimethyl acetal followed by sequential diester reduction, benzoylation, deketalization, and stereoselective ketone reduction. Regioselective N9-alkylation of the tetra- n -butylammonium salt of 2-amino-6-iodopurine with the derived cyclobutyltriflate furnished the purinecyclobutyl dibenzoate. Methanolysis followed by acid hydrolysis produced lobucavir in a 35% overall yield with an ee > 99%.",10.1021/op970214+,0
Process Development of 5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1- piperazinyl]propyl]-1<i>H</i>-indole Dihydrochloride,"5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1 H -indole dihydrochloride ( 1 ) facilitates 5-HT neurotransmission and was an antidepressant drug candidate. The development of a safe, rugged process for the large-scale, chromatography-free preparation of this compound is described. The main areas of optimization included a Fischer indole synthesis, preparation and chlorination of a monohydroxypyrimidine, and coupling of the resultant fragments to prepare the drug substance.",10.1021/op970213h,0
"Preparation of 9,9-Disubstituted 4,5-Diazafluorenes Useful as Cognitive Enhancers","A novel synthesis of symmetric and nonsymmetric 9,9-disubstituted 4,5-diazafluorenes has been developed. These compounds have activity in both an in vitro acetylcholine release assay and in vivo rodent models of learning and memory. Preparation of these compounds involves a unique aldol condensation between 4,5-diazafluoren-9-one ( 4 ) and 4-picoline. Reduction of aldol product 5 (5-(4-pyridinylmethylene)-5 H -cyclopenta[2,1- b:3,4- b ‘]dipyridine) provides monoalkylated diazafluorene 6 (5-(4-pyridinylmethyl)-5 H -cyclopenta[2,1- b:3,4- b ‘]dipyridine) which proved to be a key intermediate for synthesis of nonsymmetric analogs.",10.1021/op970212p,1
"Scale-Up of the Nitration of 1-Acetyl-3,4-dichloro-1,2-(ethylenedioxy)benzene Using Nitric Acid/Trifluoroacetic Acid","The process development of the nitration of 3-acetyl-4,5-dichloro-1,2-(ethylenedioxy)benzene ( 1 ) to 3-acetyl-4,5-dichloro-1,2-(ethylenedioxy)-6-nitrobenzene ( 2 ) led to two potential scale-up processes. The two nitration processes were a solids addition to nitric acid and nitric acid addition to a trifluoroacetic acid solution. The detailed hazards safety evaluation of the two processes was carried out using abuse studies, CHETAH calculations, the reactive system screening tool, accelerating rate calorimetry, and differential scanning calorimetry. The nitric acid addition to a trifluoroacetic acid solution process was chosen because of the better safety profile. This process was successfully scaled up in a pharmaceutical pilot plant.",10.1021/op970211x,0
Generation and Fate of Regioisomeric Side-Chain Impurities in the Preparation of Fosinopril Sodium,"A regioisomeric impurity is routinely formed during preparation of the first intermediate of the fosinopril sodium side chain. This first step, the radical-initiated condensation of 4-phenyl-1-butene ( 1 ) and aqueous hypophosphorous acid, provides low levels of the phosphinic acid ( 8 ) resulting from carbon−phosphorus bond formation to the internal olefin carbon. This impurity was isolated by preparative chromatography, and its structure was proven by independent synthesis. Subsequent reactions of 8 in the two following steps produce the corresponding regioisomeric impurities. Pure samples of these impurities were prepared for HPLC analysis to determine potential impact on the quality of intermediates downstream. The initial regioisomer averages 2 area % in manufacturing batches, and the levels of regioisomeric impurities diminish sharply with sequential conversion to further side-chain intermediates. After two steps, the levels of the regioisomeric impurities have been less than 0.08 area % in production batches; therefore, no significant amount of side-chain regioisomeric impurities (i.e., <0.1%) is expected to be found in production batches of fosinopril sodium side chain.",10.1021/op9702105,1
Preparation of 3‘-Bromodiphenyl Ethers from 3‘-Carboxydiphenyl Ethers Using Free Radical Methodology,"The ability to convert commercial 3‘-carboxydiphenyl ether herbicides to 3‘-alkoxydiphenyl ether herbicides could allow more cost efficient preparation of the 3‘-alkoxydiphenyl ethers. The free radical brominative decarboxylation of 3‘-carboxydiphenyl ethers was explored and optimized. Yields of 50% were obtained, which are not high enough for commercialization. The intermediate 3‘-bromodiphenyl ethers can, however, be used in the synthesis of other diphenyl ether analogues.",10.1021/op9702051,0
"Efficient Synthesis of <i>N-tert</i>-Butyl-2-{3(<i>R</i>)-[3-(3-chlorophenyl)ureido]- 8-methyl-2-oxo-5(<i>R</i>)-phenyl-1,3,4,5-tetrahydrobenz[<i>b</i>]azepin-1-yl}acetamide and Related CCK<sub>B</sub> Antagonists","An efficient synthesis of the CCK B antagonist N - tert -butyl-2-{3( R )-[3-(3-chlorophenyl)ureido]-8-methyl-2-oxo-5( R )-phenyl-1,3,4,5-tetrahydrobenz[ b ]azepin-1-yl}acetamide [( R )- 1a ] in optically active form is presented. The synthesis of the core 3-amino-5-phenylbenzazepin-2-one moiety started with the coupling of 2-amino-4-methylbenzophenone ( 6a ) and diethyl 3-phosphono-2-(methoxyimino)propionic acid ( 8 ). The resulting amide diethyl 2-[3-phosphono-2-(methoxyimino)propionamido]-4-methylbenzophenone ( 9a ) underwent intramolecular benzazepinone ring formation in tetrahydrofuran with 2 equiv of potassium tert -butoxide to provide 8-methyl-5-phenyl-1 H -benz[ b ]azepine-2,3-dione 3-( O -methyloxime) ( 10a ) in high yield. Hydrogenation over Raney nickel in methanol reduced both the O -methyloxime and the 4,5-double bond, giving cis -3-amino-8-methyl-5-phenyl-1,3,4,5-tetrahydrobenz[ b ]azepin-2-one ( 7a ) with high selectivity. A classical resolution of amino lactam 7a and attachment of the N-1 and C-3 side chains afforded the title compound. The sequence was repeated with other 2-aminophenyl ketones and was shown to work well for C-5 substituents such as methyl and cyclohexyl or as part of a fluorenyl group, thus providing an easy access to these molecules from readily available starting materials.",10.1021/op9702049,1
Process Development for the Preparation of a Monopril Intermediate by a Trimethylsilyl-Modified Arbuzov Reaction,"A safe, rugged process for the manufacture of a Monopril intermediate using a trimethylsilyl-mediated Arbuzov reaction was developed. The problems encountered and overcome in iterations from pilot plant to manufacturing are described. The final process gives high-quality product (99.9% purity) in 82% yield. One key was developing an addition sequence to allow for the safe control of the reaction exotherm, complicated by the reflux temperature which decreased with conversion of reagents. Quantitative assessment of the reaction boiling point and exotherm led to the selection of the best addition and heating protocol. The output quality was assured by development of a thermally controlled process that crystallized the product without passing through an intermediate oil dispersion. Alternative conditions for safe control of the exotherm are suggested. Routine safety testing is demonstrated to be critical for rapid development of a safe, optimized process.",10.1021/op970202o,1
Biphasic Synthesis of 2-Phenylpropionic Acid and Ester by Interfacial Carbonylation of α-Methylbenzyl Bromide,"An interfacial synthesis technique has been successfully extended to the carbonylation of α-methylbenzyl bromide in an organic−aqueous sodium hydroxide mixture at 35−60 °C and 1 atm using surface-active palladium−(4-dimethylaminophenyl)diphenylphosphine complex as the catalyst and dodecyl sodium sulfate as the emulsifier. Depending on the reaction conditions, 2-phenylpropionate in the form of sodium salt and an ester was obtained in 0−83% yield, along with varying amounts of side products that included α-methylbenzyl alcohol, 2,3-diphenylbutane, di(α-methylbenzyl)ether, and an asymmetric ether derived from the substrate and an alcoholic medium. When 2-methyl-1-butanol or 2-ethyl-1-hexanol was used as the organic phase, 2-phenylpropionate ester and sodium salt were obtained in 40−83% yield, with a maximum yield obtained at an optimal aqueous base concentration of about 5 M. At a lower aqueous base concentration, more of α-methylbenzyl alcohol was formed, whereas at a higher aqueous base concentration, more of 2,3-diphenylbutane and asymmetric ether were formed. When toluene was used as the organic phase, 2-phenylpropionate salt was obtained in less than 13% yield, and the major side product was α-methylbenzyl alcohol at a low aqueous base concentration and 2,3-diphenylbutane at a high aqueous base concentration. In all cases, the formation of 2,3-diphenylbutane was accompanied by a stoichiometric formation of carbonate. The latter implicates the involvement of an oxidative intermediate tentatively identified as hypobromous acid that could deactivate the catalyst complex through ligand degradation. Along with the carbonylation reaction, carbon monoxide also underwent a slow, base-induced hydrolysis reaction to form formic acid. With 2-ethyl-1-hexanol as the organic phase, the carbonylation of α-methylbenzyl bromide showed an apparent temperature-dependent activation energy, a first-order dependence each on the substrate, catalyst, and ligand concentrations up to the catalyst concentration of 0.0020 M and a ligand:catalyst ratio of 3:1, and a variable-order dependence on the carbon monoxide pressure that switched from first to zeroth order as the carbon monoxide pressure was increased above 450 mmHg. A reaction mechanism is proposed which yields model rate and yield expressions in accord with the experimental findings. Results of control experiments with α,α-dibromotoluene in a toluene−aqueous sodium hydroxide mixture indicate that replacement of the α-methyl group in α-methylbenzyl bromide by a second bromo group suppressed the formation of substituted benzyl alcohol and coupled product. They suggest that the broad product distribution in the carbonylation of α-methylbenzyl bromide relative to the carbonylation of benzyl chloride and α,α-dibromotoluene is attributable to the electron-releasing α-methyl group making the substrate susceptible to hydrolysis and coupling reactions.",10.1021/op9701292,0
A Practical Synthesis of (<i>R</i>)-(−)-Phenylephrine Hydrochloride,"( R )-(−)-Phenylephrine hydrochloride is a clinically potent adrenergic agent and β-receptor sympathomimetic drug, exclusively marketed in the optically active form. An asymmetric synthesis has been developed with high enantiomeric excess based on hydrolytic kinetic resolution of a styrene oxide derivative using ( R,R )-SalenCo III OAc complex.",10.1021/op970128+,0
Independent Synthesis and Fate Studies of Impurities in Process Intermediates of the Anti-AIDS Drug d4T,"Impurities in isolated intermediates in a process to prepare d4T were identified, independently synthesized, and then taken through the process to determine their ultimate fate. Some of the products from these fate studies were also independently synthesized and used in the validation of impurity assay methods.",10.1021/op970126p,1
"Process Development in the Synthesis of the ACE Intermediate MDL 28,726","MDL 28,726 is a key intermediate in the synthesis of the ACE inhibitors MDL 27,210A and MDL 100,240. An efficient nine-step synthesis of this tricyclic acid, which has three chiral centers, was developed beginning with 3,4-dihydro-2 H -pyran. A key step in the synthesis features an enzyme-catalyzed resolution of the lithium salt of the N -trifluoroacetamide of ( R,S )-6-hydroxynorleucine. All of the steps were optimized and completed in reactor equipment using environmentally acceptable processes. Process development of this route is described.",10.1021/op970125x,0
Development of the Carbocyclic Nucleoside MDL 201449A:  A Tumor Necrosis Factor-α Inhibitor,"An efficient synthesis of (1 S,4 R )-(−)-4- tert -butyldimethylsilyloxy-2-cyclopentenyl acetate and (1 R,4 S )-(−)-4- tert -butyldimethylsilyloxy-2-cyclopentenol is described utilizing a furfuryl alcohol rearrangement, followed by a lithium aluminum hydride reduction with high facial selectivity and an efficient enzymatic resolution with pancreatin. Both of these intermediates were successfully utilized in the preparation of the carbocyclic nucleoside 9 N -[(1‘ R,3‘ R )- trans -3‘-hydroxycyclopentanyl]adenine hydrochloride, an agent which inhibits the formation of tumor necrosis factor-α.",10.1021/op9701245,1
An Efficient and Scalable Synthesis of Perfluorinated Phosphatidylcholines,"Perfluorinated glycerophosphocholine ( 1 ), which is useful as an emulsifier in fluorocarbon suspensions, was prepared in multikilogram scale in 38% overall yield. The desired phosphocholine was prepared from diacylglycerol ( 6 ) by sequential phosporylation by POCl 3, reaction with choline p -toluenesulfonate, and aqueous hydrolysis. Purification was accomplished by treatment of crude 1 with ion-exchange resin. Diacylglycerol ( 6 ) was prepared by esterification of rac -1-benzyloxy-2,3-propanediol with perfluorinated acid followed by hydrogenolysis of the protective group.",10.1021/op970123c,0
"Development and Pilot-Scale Demonstration of a Process for Inhibitors of the HIV Nucleocapsid Protein, NCp7","A manufacturing process to prepare two antiretroviral agents that denature the HIV-1 nucleocapsid protein (NCp7) has been developed and demonstrated on a pilot scale. 2,2‘-Dithiobis(benzoyl chloride) (4), prepared from commercially available 2,2‘-dithiobis(benzoic acid) (3), was coupled directly with l -isoleucine to give the potential anti-HIV compound [ S -( R *, R *)]-2-{[2-[[2-[(1-carboxy-2-methylbutyl)carbamoyl]phenyl]dithio]benzoyl]amino}-3-methylpentanoic acid (2) thereby eliminating the α-amino acid protection and deprotection steps used in the original synthesis. Compound 2 was oxidized by bromine to a second potential anti-HIV compound [ S -( R *, R *)]-3-methyl-2-(3-oxo-3 H -benzo[ d ]isothiazol-2-yl)pentanoic acid (1). The intermediacy of the hydrobromide salt of 1 provided an effective purity control in the production of the pharmaceutical agent. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.",10.1021/op9701191,1
"Large-Scale Synthesis of Enantio- and Diastereomerically Pure (<i>R</i>,<i>R</i>)-Formoterol","( R, R )-Formoterol ( 1 ) is a long-acting, very potent β 2 -agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure ( R, R )-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1 R, 2 S )-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give ( R, R )-formoterol ( 1) as the pure stereoisomer (ee, de >99.5%).",10.1021/op970116o,1
A Calorimetric Investigation To Safely Scale-Up a Curtius Rearrangement of Acryloyl Azide,"N -Vinyl- O -benzyl urethane was prepared for use as a starting material in a multistep synthesis of a drug candidate. After unsuccessful attempts to employ non-Curtius options to prepare this intermediate, we decided to assess the thermodynamic and kinetic parameters of the acyl azide Curtius rearrangement and trapping of the intermediate isocyanate. (Prepared in analogy to the literature method of Hegedus et al.: Wieber, G. M.; Hegedus, L. S.; Akermark, B.; Michalson, E. T. J. Org. Chem. 1989, 54, 4649−4653.) Reaction calorimetry was utilized to show that the rate of the Curtius rearrangement was completely dose-rate controlled, and that under carefully defined conditions this reaction could be safely performed on limited scale. In addition to addressing the thermal hazard issues, profiling the reaction with reaction calorimetry and interfaced technologies resulted in significant process improvements.",10.1021/op970115w,0
Utilization of a Benzoyl Migration To Effect an Expeditious Synthesis of the Paclitaxel C-13 Side Chain,"A benzoyl migration has been used to remove two steps during the asymmetric dihydroxylation literature route to (2 R,3 S )- N -benzoyl-3-phenylisoserine, the C-13 position side chain of paclitaxel. The modification provides the product as its more desirable methyl ester in similar overall yields with no loss of enantiomeric purity when scaled up to multigram quantities.",10.1021/op970113b,1
"Facile Synthesis of 5,6-Dimethoxy-1-tetralone","A facile synthesis of 5,6-dimethoxy-1-tetralone, a key intermediate in the synthesis of an antidepressant compound, ABT-200, was developed from the inexpensive starting material guaiacol.",10.1021/op970111r,1
"Practical Synthesis of 4-Chloro-2-(2-naphthyl)quinoline, a Precursor to Triple-Helix DNA Intercalators","Several synthetic approaches to the title compound and analogs have been evaluated. This compound is a practical precursor to N -substituted 2-(2-naphthyl)quinolin-4-amines, the triple-helix DNA specific intercalators.",10.1021/op970110z,1
Optimization and Scale-Up of an Asymmetric Route to the LTB<sub>4</sub> Inhibitor Ontazolast,"An efficient asymmetric synthesis of the LTB 4 inhibitor Ontazolast is described. Commercially available ( S )-α-pinene, which contains a 93.5% enantiomeric excess (ee) of the desired isomer, can be oxidized using phase-transfer conditions to the corresponding ( R )-hydroxy ketone. Condensation of this keto alcohol with 2-(aminomethyl)pyridine provides an intermediate imine that can be alkylated with cyclohexylmethyl bromide or iodide. The alkylation proceeds with nearly complete transfer of chirality under mild conditions. Cleavage of the chiral auxiliary and isolation of the resulting ( S )-pyridylamine by crystallization with l -tartaric acid furnishes the key amine building block in >99% ee and in excellent overall yield. The tartrate salt is then directly converted to the final product. The reaction sequence is described on a multigram scale.",10.1021/op9701090,1
In Pursuit of Higher Purity:  Use of <sup>13</sup>C NMR and <sup>13</sup>C-Enriched Substrates To Trace Impurity Generation and Removal in the Synthesis of Atorvastatin,The use of 13 C-labeled starting materials and intermediates in the synthesis of the lipid regulator atorvastatin is described. 13 C NMR of the 13 C-enriched intermediates allowed monitoring of problematic nonchromophoric low-level impurities which were unobservable using standard analytical techniques.,10.1021/op9701088,0
Fenleuton:  Development of a Manufacturing Process,"The evolution and development of a commercially viable synthesis of fenleuton, a second-generation 5-lipoxygenase inhibitor, is discussed. Special emphasis is given to the challenges and operational issues encountered on scale-up in the pilot plant. Three separate processes were developed and scaled up, providing valuable information about operational parameters and physical characteristics of the drug substance. A novel displacement reaction was discovered and developed and was incorporated as the key transformation in the final manufacturing process.",10.1021/op970106n,1
"An Efficient Large-Scale Synthesis of Methyl 5-[2-(2,5-Dimethoxyphenyl)ethyl]-2-hydroxybenzoate","Methyl 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate ( 1 ) is a new chemical entity designed by Novartis Pharmaceuticals Corporation for the treatment of hyperproliferative and inflammatory disorders and cancer. Development of a prototype adequate process for its preparation is described. The finalized process was six steps in length and started with the commercially available compounds 2,5-dimethoxybenzaldehhyde and 5-formylsalicylic acid. The methyl ester of 5-formylsalicylic acid was condensed with dimethyl [(2,5-dimethoxyphenyl)methyl]phosphonate, prepared from 2,5-dimethoxybenzaldehyde in three steps, to afford methyl 5-[2-(2,5-dimethoxyphenyl)ethenyl]-2-hydroxy-( E )-benzoate. Without purification, this intermediate was hydrogenated using 10% Pd/C at 40 °C to afford 1, in >99.5% purity after recrystallization from absolute ethanol. The process research into the Horner−Wadsworth−Emmons-type olefination and a bromination reaction are also discussed; improvements in these transformations permitted elimination of column chromatography.",10.1021/op9701043,1
One-Pot Process for the Preparation of a β-Alkynyl β-Amino Acid Ester,"The large-scale preparation of the β-alkynyl β-amino acid ester (±)-1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate ( A ) is discussed. It was discovered that addition of a catalytic amount of lithium bis(trimethylsilyl)amide (LHMDS) to a mixture of tert -butyl acetate and N,3-bis(trimethylsilyl)-2-propyn-1-imine ( B ) initiated a self-perpetuating reaction and gave high yields of the β-amino ester A upon quench. This one-pot procedure eliminated the need to prepare the unstable lithium tert -butyl acetate in a separate reactor and enabled the reaction to be scaled up and run at a more acceptable process temperature (−20 °C) compared to the analogous two-pot reaction (−45 °C). Addition of 3-(trimethylsilyl)-2-propynal to LHMDS in THF at −20 °C followed by chlorotrimethylsilane formed the imine B in situ . tert -Butyl acetate (6 equiv) was added followed by a substoichiometric quantity (0.15−0.20 equiv) of LHMDS. After quenching with aqueous ammonium chloride the product A was obtained in a yield averaging 70%.",10.1021/op970102i,0
Development of a Manufacturing Process for Zatosetron Maleate,"Zatosetron maleate is a potent, selective 5-hydroxytryptamine receptor antagonist. In anticipation of commercialization, a manufacturing synthesis of zatosetron from tropinone and 5-chlorosalicylic acid was developed. Development efforts focused on addressing several key issues including the supply and quality of the critical raw material tropinone, improvements in the stereoselective formation of 3- endo -tropanamine, and the compatibility with existing manufacturing capabilities of process requirements for the Claisen rearrangement used to produce a crucial benzofuran intermediate. The results of these studies and an improved route to zatosetron maleate are described.",10.1021/op970101q,1
Risk Analysis and Reduction in the Chemical Process Industries By J. M. Santamaría Ramiro and P. A. Braña Aísa. Translated by J. Hutchinson. Blackie Academic &amp; Professional:  London. English language edition 1998. 370 pp. Hardcover. ISBN 7514-0374-1.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTRisk Analysis and Reduction in the Chemical Process Industries By J. M. Santamaría Ramiro and P. A. Braña Aísa. Translated by J. Hutchinson. Blackie Academic & Professional: London. English language edition 1998. 370 pp. Hardcover. ISBN 7514-0374-1.Paul LambertCite this: Org. Proc. Res. Dev. 1998, 2, 3, 208Publication Date (Web):March 31, 1998Publication History Published online31 March 1998Published inissue 1 May 1998https://doi.org/10.1021/op970061qCopyright © 1998 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views272Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (13 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Redox reactions,Safety,Students,Transfer reactions Get e-Alerts",10.1021/op970061q,0
A Scalable Synthesis of the Thromboxane Receptor Antagonist 3-{3-[2-(4-Chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic Acid via a Regioselective Heck Cross-Coupling Strategy,"A regioselective Heck cross-coupling strategy is presented for the large-scale preparation of the thromboxane receptor antagonist 3-{3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl}propionic acid ( 1 ). Commercially available 3-bromo-5-iodobenzoic acid was first converted to the corresponding acid chloride, and this was then condensed with 4-fluorobenzene via a Friedel−Crafts acylation reaction to give 3-bromo-5-iodophenyl 4-fluorophenyl ketone. Regioselective cross-coupling with ethyl acrylate and then N -vinylphthalimide, each under phosphine-free Heck conditions, led to formation of ethyl 3-[3-(4-fluorobenzoyl)-5-(2-phthalimidovinyl)phenyl]propenoate. Reduction of the benzophenone moiety and saturation of the olefin double bonds, followed by phthalimide ring cleavage, then gave ethyl 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propionate monocitrate salt. This was converted to the sulfonamido-substituted arylpropionic acid 1 via a two-step one-pot procedure in which sulfonamide formation was achieved via condensation with 4-chlorobenzenesulfonyl chloride, followed by ethyl ester saponification. The route described avoids hazards identified with the original medicinal chemistry based synthesis and allows bulk quantities of drug substance to be produced for toxicological and clinical trials.",10.1021/op970060y,1
Selective Catalytic Hydrogenation of Organic Compounds in Supercritical Fluids as a Continuous Process,"We report a new method for continuous hydrogenation in supercritical fluids (CO 2 or propane) using heterogeneous noble metal catalysts on Deloxan aminopolysiloxane supports. The method has considerable promise both for laboratory-scale hydrogenation and for the industrial production of fine chemicals. It can be applied to a wide range of organic compounds including alkenes, alkynes, aliphatic and aromatic ketones and aldehydes, epoxides, phenols, oximes, nitrobenzenes, Schiff bases, and nitriles. Conversion of starting materials, product selectivity, and space−time yields of the catalyst are all high, and the reactors themselves are very small (5- and 10-mL volume). Supercritical hydrogenation enables the reaction parameters to be controlled very precisely. Results are presented for a series of different reactions showing product distributions, which are dependent on temperature, pressure, H 2 concentration, and the loading and nature of the catalyst. The hydrogenation of cyclohexene has been studied in some detail, and our results are related to the phase diagrams of the ternary system cyclohexane + CO 2 + H 2, which we present in a novel way, more suited to continuous reactors. Finally, we report that the supercritical hydrogenation of isophorone has advantages over conventional methods.",10.1021/op970056m,0
Process Improvement in the Production of a Pharmaceutical Intermediate Using a Reaction Calorimeter for Studies on the Reaction Kinetics of Amination of a Bromopropyl Compound,"A synthetic process to produce a pharmaceutical intermediate, [3-(dimethylamino)propyl]triphenylphosphonium bromide ( 1 ), was established in the laboratory. Process safety evaluations did not show any severe problems. In order to scale up to plant scale, we simulated the reaction for both heat production and byproduct production profiles with kinetic parameters. The kinetic parameters were obtained by laboratory experiments and reaction calorimeter measurements. Under the established conditions, the production operated in a safe manner with high quality.",10.1021/op970055u,0
"Efficient Large-Scale Synthesis of 4-Phenyl-3-butyn-2-one, a Key Intermediate for a Novel Potent Adenosine Antagonist","Phenylacetylenic Grignard reagent reacts with acetic anhydride under mild conditions to give 4-phenyl-3-butyn-2-one in high yield. This method was applicable to a large-scale synthesis, and optimized reaction conditions have been investigated.",10.1021/op9700486,0
An Ecofriendly Catalytic Route for the Preparation of Perfumery Grade Methyl Anthranilate from Anthranilic Acid and Methanol,"Methyl anthranilate is a very important perfumery ester and also a precursor to a number of Schiff bases which are used in several fragrance formulations. The current practice is to use homogeneous acids as catalysts in the manufacture of methyl anthranilate either starting with isatoic anhydride and methanol or by the esterification of anthranilic acid with methanol. These routes pose problems of disposal of liquid acids after the reaction, and substantial quantities of acids are required in order that the amine group be initially blocked as an amine hydrochloride. This paper deals with the application of ecofriendly heterogeneous catalysts including ZSM-5; acid-treated clays such as Filtrol-24 and K10; ion-exchange resins such as Nafion-H, Indion-130, Amberlyst-15, Amberlyst-18, Dowex M-32 and Bayer K-24; and dodecatungstophosphoric acid, a heteropolyacid. Among these catalysts, Amberlyst-15 and Indion-130 resins were found to be the most effective. Other heterogeneous catalysts such as ZSM-5, Filtrol-24, and dodecatungstophosphoric acid were found to be totally ineffective. A theoretical model was employed for the analysis of this solid-catalysed slurry reaction, and effects of various parameters on the rate of reaction were evaluated. There was no effect of external as well as internal mass-transfer resistance on the rate of reaction. The reaction was found to be intrinsically kinetically controlled, and the kinetic parameters were established. The product was isolated and confirmed by spectroscopic methods. The odour value matched with that of the commercially available perfumery grade sample.",10.1021/op970047d,0
"Synthesis of 4-Sulfur-Substituted (2<i>S</i>,3<i>R</i>)-3-Phenylserines by Enzymatic Resolution. Enantiopure Precursors for Thiamphenicol and Florfenicol","Enantiomerically pure 4-methylthio- and 4-methylsulfonyl-substituted (2 S, 3 R )-3-phenylserines are prepared by enzymatic resolution of the corresponding racemic threo amides using the amidase from Ochrobactrum anthropi NCIMB 40321. The unwanted (2 R, 3 S ) enantiomers of the amides are separated from the enantiopure amino acids and easily racemized after Schiff base formation with the corresponding 4-(methylthio)- and 4-(methylsulfonyl)benzaldehyde. The racemization can be combined with the preparation of the racemic amides by aldol reaction under crystallization conditions to yield only the threo isomers. Enantiopure (2 S, 3 R )-3-[4-(methylthio)phenyl]serine and (2 S, 3 R )-3-[4-(methylsulfonyl)phenyl]serine are thus obtained in 78% and 62% overall yields starting from the corresponding substituted benzaldehydes. (2 S, 3 R )-3-[4-(Methylthio)phenyl]serine is reduced to (1 R, 2 R )-2-amino-1-[4-(methylthio)phenyl]propane-1,3-diol with NaBH 4 /H 2 SO 4 and can be used for the synthesis of thiamphenicol and florfenicol.",10.1021/op970045t,0
Process Development of a Novel Anti-Inflammatory Agent. The Regiospecific Bromination of 4‘-Acetylmethanesulfonanilide,"An efficient, practical synthesis of a novel antiinflammatory agent (FK3311, 1 ) which is acceptable environmentally and could be used for pilot plant manufacture is described. Regiospecific bromination of 4‘-acetylmethanesulfonanilide, allowing selective side chain or nuclear halogenation, also has been investigated. Development efforts focused on the optimized Ullmann coupling reaction conditions and the isolation and purification of 1 to give satisfactory quality product (99.8% purity) according to the new and concise synthetic route.",10.1021/op970039x,1
"Process Development of the PDE IV Inhibitor 3-(Cyclopentyloxy)-<i>N</i>-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide","Development of an industrial process for 3-(cyclopentyloxy)- N -(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, a potent PDE IV type inhibitor, is described. The rapid identification of scalable reaction conditions allowed pilot-scale synthesis of kilogramme quantities for early clinical evaluation. However, as more compound was demanded, better reaction conditions were required in the interests of safety, economics, and environmental impact. This led to the derivation of a high-yielding and very robust procedure which included various safeguards to ensure that high-quality product was obtained and that new trace impurities were effectively removed. The large-scale oxidation of a benzaldehyde derivative to the corresponding benzoic acid using hydrogen peroxide under aqueous alkaline conditions is described.",10.1021/op9700385,1
Development of Large-Scale Syntheses of Ropinirole in the Pursuit of a Manufacturing Process<sup>1</sup>,"Two plant syntheses of ropinirole {4-[2-(di- n -propylamino)ethyl]-1,3-dihydro-2 H -indolin-2-one hydrochloride, SK&F-101468-A} using the ferric chloride mediated cyclisation of β-nitrostyrenes to form 3-chlorooxindoles as the key step are described. The first synthesis suffered the severe limitation of the final-step chemistry being nonselective in the reaction between di- n -propylamine and the bromide precursor to ropinirole as both substitution and elimination pathways were promoted and by-product formation at a level of 40% resulted. This problem was rectified in the latter synthesis by the more selective reaction between di- n -propylamine and the sulfonate ester precursor promoting ropinirole formation to a level of 88%. This second synthesis is now used as the commercial route, and problems (and their solutions) identified during the development of this route are now described. The identification of novel by-products which enabled the Sommelet oxidation step to be optimised is also reported. A unimolecular decomposition mechanism during hydrolysis of the hexaminium salt to form the key benzaldehyde intermediate is proposed and substantiated with experimental data.",10.1021/op970037c,1
Synthesis and Use of<i>N</i>-(Trimethylsilyl)imines,"The introduction of aminic nitrogen in organic molecules has been achieved in many different ways, one of the most popular being the use of imines. The main disadvantage of these starting materials lies in the difficulty of synthesising and using imines of ammonia, due to their instability, which results in their tendency to trimerize, giving the corresponding triazine. Recently a new class of imines, the N -metalloimines, a stable form of the corresponding elusive imines of ammonia, has found very useful applications in the synthesis of nitrogen-containing organic compounds. This review will cover the syntheses and applications of N -(trialkylsilyl)imines. It is not intended to be a comprehensive review of the literature; rather it is intended to highlight novel and potentially useful applications. In this context, particular emphasis will be devoted to methodologies which could be easily scaled up to kilogram scale. The synthesis of important small-ring heterocycles such as aziridines, β-lactams, pyrrolines, and piperidines and hetero-Diels−Alder derived compounds will be reviewed. Some aspects of the synthesis of commercially interesting acyclic compounds, such as amines, aminols, nitriles, and amino acids, obtained using N -(trialkylsilyl)imines, will be reported.",10.1021/op970036k,0
Runaway Reaction Hazards in Processing Organic Nitro Compounds,"Pure organic nitro compounds, i.e., aromatic or aliphatic nitro compounds, decompose at high temperatures, exhibiting large decomposition exotherms. In most cases, the decomposition is violent or explosive. In practical process situations, nitro compounds are mixed with other chemicals or contaminated by impurities which lower their thermal stability. Contaminated nitro compounds or solutions of nitro compounds may decompose at much lower temperatures than the pure products. Their decomposition is less rapid but remains highly exothermic. Therefore, for practical reasons, the most relevant information in the field of process safety is to describe how reactants, solvents, and impurities may affect the organic nitro compounds' thermal stability and in which process situations this may be a hazard.",10.1021/op970035s,0
The Use of Ultrasound in Industrial Chemical Synthesis and Crystallization. 1. Applications to Synthetic Chemistry,"Sonochemistry, or the application of power ultrasound to chemical processes, is a technology that has undergone very intensive research and development in the last 15−20 years, with respect to both its range of application and the methods employed for its implementation at industrial manufacturing scales. In a series of two papers, the authors review progress of the application of ultrasound to chemistry and chemical processing, and the development of equipment and scale-up methods. This first paper focuses on chemistry and also covers mechanisms of action of ultrasound and its in situ detection and measurement. Part 2 will deal with the application of ultrasound to crystallization processes (sonocrystallization) and with scale-up and equipment development.",10.1021/op9700340,0
Improved Synthetic Route to Dexamethasone Acetate from Tigogenin,"In the synthesis of dexamethasone acetate from tigogenin, the introduction of the 17α-hydroxy-16α-methyl and the 1,4-diene moieties was improved. For the introduction of the 17α-hydroxy-16α-methyl moiety, the key step, epoxidation, was accomplished in high yield with peracetic acid in a buffer solution of sodium acetate and acetic acid (overall yield from 17-ene substrate to 17α-hydroxy-16α-methyl intermediate: 95.3%). Then the introduction of the 1,4-diene in the A-ring was greatly improved by bromination−dehydrobromination, in which dehydrobromination proceeded smoothly in a solvent system that was a mixture of DMF and 6% of water (82.6% isolated yield of 1,4-diene based on 3-oxo compound).",10.1021/op9700338,1
Sharpless Asymmetric Dihydroxylation on an Industrial Scale,It is shown in this study that the inexpensive N -methylmorpholine N -oxide can be successfully employed as a reoxidant in the Sharpless asymmetric dihydroxylation reaction on a large scale. The reaction of o -isopropoxy- m -methoxystyrene on a 2 kg scale gave the corresponding diol in high yield and high enantiomeric excess. The extension of this synthetic method to other olefins is also presented.,10.1021/op970030v,0
"Practical Synthesis of 8α-Amino-2,6-dimethylergoline:  An Industrial Perspective","8 α-Amino-2,6-dimethylergoline is the key intermediate for the synthesis of a number of ergot derivatives under clinical development. They are structurally related to the better known lysergic acid and its derivative, the diethylamide (LSD). The use of lysergic acid or its isomer, paspalic acid, both of which are readily available by fermentation on an industrial scale, as a starting material for the synthesis of 8α-amino-2,6-dimethylergoline appears to be the obvious choice as the basic structural elements already exist. Whereas the transformation of the acid function to the amino moiety proceeded under well-established conditions, the introduction of the single methyl group posed a major challenge to the industrial chemist. Various methodologies are available to solve this problem, and the approach that involves direct metalation and methylation is found to be most suitable for up-scaling to multiton quantities. The importance of using on-line monitoring techniques (FT-IR) in process research and development will be exemplified by this report.",10.1021/op9700284,0
Process Research and Development for the Production of Intermediates for the Synthesis of Carbocyclic Nucleosides,"The synthesis of [3a R,4 S,6 R,6a S ]-6-amino- N -ethyltetrahydro-2,2-dimethyl-4 H -cyclopenta-1,3-dioxole-4-carboxamide, a key single enantiomer intermediate to carbocyclic nucleosides such as adenosine agonists, is reported involving a scalable catalytic osmium tetraoxide dihydroxylation of (−)-2-azabicyclo[2.2.1]hept-5-en-3-one. The acetonide-protected diol [3a S,4 R,7 S,7a R ]-tetrahydro-2,2-dimethyl-4,7-methano-1,3-dioxolo[4,5- c ]pyridin-6(3a H )-one is subject to lactam ring opening with anhydrous ethylamine to give the carbocyclic key intermediate. The rate of this known reaction, carried out in a pressure vessel, is considerably enhanced by acid catalysis using ethylammonium ion. In addition, the need for a pressure vessel is circumvented by using anhydrous ethylamine with acid catalysis. Alternatively stoichiometric ethylammonium ion in an appropriate cosolvent can be used to form the key intermediate in high yield.",10.1021/op970026j,1
6-(Trifluoromethyl)pyrid-2-one:  Development and Scale-Up of a Ring Synthesis Route Based on Trifluoroacetic Anhydride,"Three routes to 6-(trifluoromethyl)pyrid-2-one involving de novo synthesis of the pyridine ring have been investigated which would potentially allow rapid semi-technical scale manufacture. A route starting from ethyl 4,4,4-trifluoroacetoacetate (β-keto ester route) has been demonstrated. Development of the route was attempted; however, poor yields at a number of stages and scale-up difficulties made this route unattractive for commercial use. A four-stage route starting from trifluoroacetic anhydride and an alkyl vinyl ether (TFAA route) has been developed which gives good yields and productivity for all stages. The final stage of this route is a difficult decarboxylation of a nicotinic acid derivative, but an 80% yield of the required pyridone with a purity of >99.5% could be achieved without a separate purification stage. The route was scaled up to 2000 L, and several hundred kilograms of product was prepared.",10.1021/op970024z,1
"Pilot Plants and Scale-up of Chemical Processes Edited by W. Hoyle. Royal Society of Chemistry:  London, UK. 1997. 98 pp. ISBN 0-85404-796-4. £42.50.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTPilot Plants and Scale-up of Chemical Processes Edited by W. Hoyle. Royal Society of Chemistry: London, UK. 1997. 98 pp. ISBN 0-85404-796-4. £42.50.Trevor LairdCite this: Org. Process Res. Dev. 1997, 1, 5, 391Publication Date (Web):September 15, 1997Publication History Published online15 September 1997Published inissue 1 September 1997https://pubs.acs.org/doi/10.1021/op970019vhttps://doi.org/10.1021/op970019vbook-reviewACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views519Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Manufacturing,Organic reactions,Post-translational modification,Thiophenes Get e-Alerts",10.1021/op970019v,1
Catalytic Oxidation of Ethylbenzene to Acetophenone Using Alumina-Supported Dichromate:  Process Optimisation and Development of a Continuous Process,"Potassium dichromate supported on neutral alumina is a heterogeneous catalyst for the liquid phase oxidation of hydrocarbons. The material has been used to catalyse the oxidation of ethylbenzene to acetophenone using air as the consumable oxidant with high selectivity and is truly catalytic in the metal, unlike homogeneous Cr(VI) systems. Optimisation of reaction conditions has been achieved in terms of air flow rate, agitator speed, and catalyst quantity. An induction period prior to achievement of maximum catalytic turnover, which is proportional to both temperature and the concentration of catalyst, may be reduced by doping the substrate with 5−15% acetophenone (w/w) and eliminated by doping with 30% (w/w) acetophenone. A rate of conversion of ca. 3.8% h - 1 (0.39 turnover s - 1 ) may be achieved at a reaction temperature of 130 °C for a period of ca. 10 h before catalyst deactivation occurs. However, this rate may be maintained for periods in excess of 24 h by continuous addition of substrate to the reaction vessel in order to maintain a constant molar ratio of substrate to product. It may thus be concluded that, at high agitator speeds, the rate-limiting factor is adsorption/desorption at the catalyst surface (and is therefore affected by the overall polarity of the medium) rather than mass transfer between solid−liquid−gas interfaces. The catalyst has been successfully recovered and reused with no induction period, and initial activity is comparable with that for fresh catalyst, although deactivation occurs readily thereafter.",10.1021/op9700183,0
Recent Developments in the Assessment of Thermal Risks of Chemical Processes,"In the past two decades, the assessment of thermal risks linked to the practice of chemical reactions on an industrial scale has made great progress. Nowadays chemists understand these risks and are able to assess them. Nevertheless, incidents still occur which indicate that some weaknesses still exist, especially in risk management systems. Recent developments aim at providing production staff with improved tools for the assessment of these risks and also for training purposes. Furthermore, for some special situations, more specific and more accurate experimental techniques and estimation methods are required. In the present paper, some recent developments realized in our safety research laboratories are reviewed.",10.1021/op970016i,0
Kinetic and Calorimetric Considerations in the Scale-Up of the Catalytic Reduction of a Substituted Nitrobenzene,"A reaction calorimetric investigation was conducted to assess proposed scale-up conditions (30 psig, 10 °C, initial reactant concentration = 0.69 M, catalyst concentration of 6.66 × 10 -3 g/g of reactant) for the batchwise reduction of a substituted nitrobenzene to give the corresponding aniline in the presence of H 2, Pd/C catalyst, and ethyl acetate solvent. Heat evolution rates under these conditions were judged to be too large for safe plant operation. Alternative processing conditions were investigated, accounting for heat removal, pressure limitations, and gas−liquid mass transfer rates in the plant equipment as well as differences in reactivity between plant- and laboratory-prepared reactants. The recommended conditions (30 psig, 20 °C, and catalyst concentration of 7.53 × 10 -3 g/g of reactant) were employed in the pilot plant, which resulted in conversion rates almost identical to those in the laboratory reactor, demonstrating the value of reaction calorimetry for scaling up a highly exothermic reaction without byproduct formation. Major improvements over the originally proposed process included operation at 20 °C to take advantage of the greater cooling capacity and decreasing the batch holding time by more than 35% with the additional constraints imposed by mass transfer. Additional experiments using nitrobenzene reactant demonstrated that water produced by the reaction promotes catalyst activity; in reactions where no water was initially present, a maximum was observed in the reaction rate, whereas a monotonically decreasing rate was observed for a 0.44 M initial water concentration.",10.1021/op970015q,0
A New Era Begins for Process Chemistry,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTA New Era Begins for Process ChemistryView Author InformationEditor%Cite this: Org. Process Res. Dev. 1997, 1, 1, 1Publication Date (Web):January 15, 1997Publication History Published online15 January 1997Published inissue 1 January 1997https://doi.org/10.1021/op970006hCopyright © 1997 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1319Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (33 KB) Get e-AlertsSUBJECTS:Physical and chemical processes,Chemical engineering and industrial chemistry,Process chemistry Get e-Alerts",10.1021/op970006h,0
Synthetic Routes to Quinoline Derivatives:  Novel Syntheses of 3-Butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline and 3-Butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quinoline,"The 3,4,8-trisubstituted quinoline derivatives 2-butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quinoline were prepared using five novel synthetic strategies, each involving a different disconnection as a basis for the key step. One such strategy led to the development of highly efficient processes for the large-scale preparations of both compounds and featured a facile cyclisation of an [(arylamino)methylene]malonate and an unusual Reformatsky reaction of a quinoline-3-carboxylate with tert -butyl 2-bromobutyrate in the presence of zinc.",10.1021/op9700035,1
Industrial Scale Synthesis of Thiophosgene and Its Derivatives,"Thiophosgene is manufactured on a mulittonne scale, using the continuous chlorination of carbon disulfide under aqueous conditions to prepare the key intermediate perchloromethyl mercaptan. The development of this process is described, and the uses of thiophosgene in the manufacture of chlorothioformates and isothiocyanates are reviewed.",10.1021/op970002c,0
Synthesis of a Serinamide by Aminolysis of an N-Unsubstituted α-Amino Ester,l -2-Amino-3-hydroxy- N -pentylpropanamide ( 1 ) was readily prepared and isolated as its oxalate salt in 81% yield and >99% ee through a “one-pot” process from l -serine methyl ester ( 4 ).,10.1021/op960044l,0
Asymmetric Synthesis of the Antiarrhythmia Agent <i>d</i>-Sotalol,A chiral synthesis of d -Sotalol was developed starting from commercially available 4‘-(chloroacetyl)methanesulfonanilide ( 2 ).,10.1021/op960043t,1
"Chemical Development of a Pilot Scale Process for the ACAT Inhibitor 2,6-Diisopropylphenyl [(2,4,6-Triisopropylphenyl)acetyl]sulfamate","A manufacturing process to prepare the ACAT inhibitor 2,6-diisopropylphenyl [(2,4,6-triisopropylphenyl)acetyl]sulfamate ( 1; CI-1011) has been developed and successfully demonstrated on a pilot scale. Commercially available 1,3,5-triisopropylbenzene ( 9 ) was chloromethylated to give 2,4,6-triisopropylbenzyl chloride ( 8 ). Cyanation of 8 under phase-transfer-catalyzed conditions followed by basic hydrolysis of the intermediate and nonisolated 2,4,6-triisopropylbenzyl cyanide ( 7 ) gave 2,4,6-triisopropylphenylacetic acid ( 2 ), a key intermediate in the convergent synthesis of 1 . Commercially available 2,6-diisopropylphenol ( 12 ) was converted to [(2,6-diisopropylphenyl)oxy]sulfonyl isocyanate ( 13 ) when reacted with chlorosulfonyl isocyanate under thermodynamically controlled conditions. Hydrolysis and decarboxylation of 13 in situ gave 2,6-diisopropylphenyl sulfamate ( 3 ), the other key intermediate. A robust process to couple 2 and 3 was developed via the intermediacy of (2,4,6-triisopropylphenyl)acetyl chloride ( 15 ) to give the final pharmaceutical product that met specifications for clinical and toxicological use. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.",10.1021/op9600419,1
Development of a Large-Scale Process for an HIV Protease Inhibitor,"An efficient large-scale process to prepare the HIV protease inhibitor urea intermediate, N -[3( S )-[bis(phenylmethyl)amino-2( R )-hydroxy-4-phenylbutyl]- N ‘-(1,1-dimethylethyl)- N -(2methylpropyl)urea was developed. The protected alcohol, β( S )-[bis(phenylmethyl)amino]benzenepropanol, was obtained in 95% yield in one step by the benzylation of l -phenylalaninol with benzyl bromide under aqueous conditions. Oxidation of protected alcohol with sulfur trioxide pyridine complex in DMSO at 15 °C gave the corresponding aldehyde in quantitative yield. The dimethyl sulfide byproduct was easily removed by nitrogen sparging and treatment of the effluent gas stream with bleach solution. Diastereoselective reaction of the chiral amino aldehyde with (chloromethyl)lithium at −35 °C followed by warming to room temperature gave the desired epoxide stereoselectively in good yield. A DOE (statistical design of experiment) study indicated that the reaction concentration and halogen reagent were important factors for this reaction. To simplify the operations and to increase the productivity of epoxide, a continuous process was developed. Regioselective ring opening of epoxides with isobutylamine followed by reaction of the resulting amine with tert -butyl isocyanate in isopropyl alcohol gave the urea N -[3( S )-[bis(phenylmethyl)amino]-2( R )-hydroxy-4-phenylbutyl]- N ‘-(1,1-dimethylethyl)- N -(2-methylpropyl)urea, in good yield. The process improvements for the crystallization of urea are also discussed.",10.1021/op960040g,1
Evaluation and Rapid Scale-Up of the Synthesis of the Pyrrolopyrimidines U-101033E and U-104067F,"Large quantities of pure bulk drug were required to initiate development for possible indications as antiasthma and neuroprotective agents. Safety concerns and reproducibility problems encountered with the laboratory procedures (Bundy, G. L.; et al. J . Med . Chem . 1995, 38, 4161) forced the development of a reliable large-scale process which within six months produced >100 kg of U-104067 free base in a single campaign. During the course of this work, procedures were also developed which allowed for the bulk preparation of analytically pure, pharmaceutically acceptable salt forms of both of the title compounds.",10.1021/op960038p,1
A Commercially Viable Synthesis of Cyanotrimethylsilane,"The important synthetic reagent cyanotrimethylsilane is readily formed by the direct trimethylsilylation of 3 equiv of hydrogen cyanide with 1 equiv each of trimethylchlorosilane and hexamethyldisilazane in a solvent-free reaction. This results in the formation of cyanotrimethylsilane in 98% yield. The product, which comes out of the reactor in 97.5% purity, does not require distillation. The process has been scaled to a level of 1780 lb in a single batch.",10.1021/op9600365,0
One-Step Synthesis of Biphenylacetic Acids via Pd/C-Catalyzed Arylation,"An efficient, convenient, one-step synthesis of biphenylacetic acids using Pd/C as a catalyst is described. This has been successfully used for the preparation of mole amounts of acids.",10.1021/op960035c,0
Diastereoselective Reaction of a Grignard Reagent with Chiral Imides:  A Practical Preparation of a Key Intermediate in the Synthesis of Ifetroban Sodium,"A novel and highly efficient synthesis of [1 S -(1α,2α,3α,4α)]-2-[[2-(3-methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]heptane-3-carboxylic acid ( A ), a key intermediate in the synthesis of ifetroban sodium, BMS-180291, is described. Reaction of chiral imides such as [2( S ),3aα,4β,7β,7aα]-hexahydro-2-(1-phenylethyl)-4,7-epoxy-1 H -isoindole-1,3(2 H )-dione ( B ) with the Grignard reagent derived from 2-(2-bromophenyl)-1,3-dioxolane and subsequent in situ transformations give [2 S -(2α,3aα,4β,7β,7aα)]-2-(octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde, converted in two steps to A . Efficient syntheses of B from furan and maleic anhydride are described.",10.1021/op960034k,1
"Chemical Development of CI-1008, an Enantiomerically Pure Anticonvulsant","Development of a manufacturing process for ( S )-3-(aminomethyl)-5-methylhexanoic acid, an anticonvulsant, is described. Initial preparation employed an Evans chiral alkylation on (4 R,5 S )-4-methyl-3-(1-oxo-4-methylpentyl)-5-phenyl-2-oxazolidinone, using benzyl bromoacetate. Use of tert -butyl bromoacetate proved advantageous for large-scale preparation. Route selection for a low-cost manufacturing process was based on “ideal process” cost projections. Four routes were evaluated in the laboratory. Of the four, two were scaled up in the pilot plant, resulting in selection of a route based on synthesis of racemic 3-(aminomethyl)-5-methylhexanoic acid, followed by resolution with ( S )-(+)-mandelic acid.",10.1021/op9600320,1
"Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E)","A practical synthesis of atevirdine mesylate, Pharmacia & Upjohn's first-generation non-nucleoside reverse transcriptase (RT) inhibitor for treatment of AIDS, is described. The route consists of three steps. In the first step, the starting material, 3-amino-2-chloropyridine, is N -ethylated by conversion into the acetimidate (1.25 equiv of trimethyl orthoacetate, 0.003 equiv of HOTs·H 2 O, neat; then distill off the MeOH to drive the amine/imidate equilibrium to imidate) followed by reduction with DIBAL (2.27 equiv, toluene, <−10 °C). In the second step, the N -ethyl derivative is heated in 5.13 equiv of piperazine at ∼170 °C in a closed system under moderate pressure (∼10 psig) to give 3-( N -ethylamino)-2-(1-piperazinyl)pyridine, which is purified by crystallization from water. An X-ray crystallographic study revealed that the crystal contains five molecules of water per molecule of 3-( N -ethylamino)-2-(1-piperazinyl)pyridine. The molecules pack in an interesting way, with two layers of piperazinylpyridine molecules sandwiched between layers of water molecules, as in the lipid bilayer structure of the biological cell membrane. The yield for the first two steps is 79.2% (overall, average of six plant runs). In the third step, the pentahydrate is coupled with 5-methoxyindole-2-carboxylic acid (MICA; 1.07 equiv of CDI, CH 2 Cl 2, 30 °C, 2−3 h; then add 1.06 equiv of 3-( N -ethylamino)-2-(1-piperazinyl)pyridine, CH 2 Cl 2, 30 °C) to give atevirdine free base, which is converted into the mesylate salt (1.01 equiv of MeSO 3 H, methanol, 25 °C) and crystallized. The yield of the third step is 83.3% (overall from MICA; average of eight plant runs). The bulk drug typically contains <0.1% total impurities (by HPLC). This process was used to produce multiton quantities of bulk drug used in phase II clinical trials.",10.1021/op9600318,1
A Cationic Surfactant as a Phase-Transfer Catalyst for Reactions in Liquid/Liquid and Solid/Liquid Systems. Its Use in the Manufacturing of Trichlorobenzene from Lindane Wastes and Vitamin A Production,The results of pilot plant experiments on phase-transfer-catalysed dehydrochlorination of hexachlorocyclohexane and vitamin A manufacturing using phase-transfer catalysis are discussed. A long-chain cationic surfactant (Katamine AB) was a suitable catalyst in these cases. Phase-transfer catalysis is shown to provide advantageous process results and characteristics for these two commercially important reactions under scaled up conditions.,10.1021/op960030f,0
Use of a Titanium Thienyl Anion and a Simple Procedure for Introducing a Thiol Group into Thiophene in the Development of a Manufacturing Route to the 5-Lipoxygenase Inhibitor ZD4407,"Process development has been conducted to identify a synthetic route to the 5-lipoxygenase inhibitor ZD4407 that could be used for pilot plant manufacture. Efficient and environmentally acceptable carbon-functionalisation of the 3-position of thiophene using readily available 3-bromothiophene has been achieved using a titanium carbanionic intermediate. An efficient functionalisation of the 5-position with a thiol group has also been realised using dimethyl disulphide, where the side product of the functionalisation reaction is used in situ as the reagent for the subsequent deprotections, thereby considerably reducing the impact on the environment.",10.1021/op960029g,1
Unnatural Amino Acids. 1. A Facile Synthesis of the Methyl Ester of Aziridine-2-carboxylic Acid,"The methodology of aziridine-2-carboxylic acid methyl ester ( 4 ) synthesis by aziridine ring formation from methyl 3-(2,2,2-trimethylhydrazinio)propionate bromide ( 1a ) has been developed by N−N bond cleavage. The process gives the title compound in 75% theoretical yield (>99% purity). We found important factors for a successful key reaction, including the optimal temperature range between 140 and 160 °C, a 4−6-fold excess of K 2 CO 3 as the base of choice, drying and smoothing of starting materials, an increase in the surface of reactants by rotation, and a lack of water and other solvents in the reaction mixture. The influence of other basic cyclization materials and other reaction conditions in the formation of side products 8 − 16 is discussed.",10.1021/op960027w,0
Efficient Preparation of (<i>R</i>)- and (<i>S</i>)-2-Amino-1-phenylethanol,"The preparation of optically pure 2-amino-1-phenylethanol was investigated using three methods. The opening of styrene oxide with ammonia, the reduction of mandelamide, and the resolution of (±)-2-amino-1-phenylethanol were compared from a process R&D viewpoint. The resolution using di- O - p -toluoyltartaric acid was found to be the method of choice and was optimised to yield 62% of optically pure substance.",10.1021/op9600264,1
Concise Large-Scale Synthesis of the Highly Active Cephalosporin Cefdaloxime,"Cefdaloxime ( 1a ) is the bioactive principle of the 1-( S )-(pivaloyloxy)ethyl ester prodrug HR916K ( 1b ). To provide material for biological investigations a short and efficient large-scale synthesis of 1a was developed, which avoids chromatographic purification steps. Commercially available (6 R,7 R )-7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (AMCA) ( 2 ) is acylated with trityl-protected mercaptobenzothiazole thioester in the presence of bis(trimethylsilyl)acetamide to yield tritylated cefdaloxime. The trityl group is then removed by treatment with formic acid, followed by pH-adjusted precipitation of 1a . For a final purification, which has to consider cefdaloxime specific side reactions, crude 1a is dissolved in dimethyl sulfoxide and precipitated with methanol to obtain 1a in 66% overall yield on a kilogram scale.",10.1021/op960025b,1
Synthesis of Aldehydes by Rosenmund Reduction,"Important perfumery aldehydes such as 10-undecenal could be synthesized by Rosenmund reduction. This reduction by hydrogen is usually effected in the presence of a supported Pd catalyst. The main by-product is the alcohol, and it is formed by the subsequent reduction of the aldehyde. This can be prevented by the use of a catalyst poison or regulator. The regulator deactivates the catalyst for the desired reaction and renders the repeated use of the catalyst difficult. However, reuse of the catalyst is of great industrial relevance, because the incidence of cost due to catalyst may be prohibitive if it is used for only a single run. Therefore, attempts to dispense with the use of a regulator acquire considerable significance. It may be possible to obtain very high selectivities to the aldehyde even in the absence of a regulator, provided that the temperature employed is about 30−40 °C and the reduction is carried out at atmospheric pressure, at which the rate of hydrogenolysis is acceptable. The present work is an attempt in this direction. Under this condition it was possible to obtain 10-undecenal conforming to perfumery industry specifications.",10.1021/op960024j,1
Scale-Up Studies on Styrene−Butyl Methacrylate Copolymerization Reaction,"The scale-up of the radical-initiated copolymerization of styrene with butyl methacrylate is studied here. The reaction is scaled up from 3 to 100 L scale. The problems encountered during the scale-up are agglomeration, foaming, and material loss. The techniques employed to overcome these problems are discussed in detail. Kinetic studies indicate that the reaction exhibits autoacceleration behaviour, with induction time varying with reactor size. The effects of initiator concentration and reactor size on the molecular weight and melt flow index of the final sample are also studied.",10.1021/op960023r,0
Preparation of Pure Anhydrous Solutions of Hydrogen Iodide in Acetic Acid,"The presence of molecular iodine in anhydrous solutions of hydrogen iodide in acetic acid gives rise to unstable impurities during the hydriodination of isolated double bonds. This can be overcome by using aqueous hydriodic acid, as the source of hydrogen iodide, from which the iodine has been removed by washing with a solution of an organic soluble ion exchange resin.",10.1021/op9600116,0
A Practical Synthesis of “Metabolite A<sub>1</sub>” (AAMU) of Caffeine,"A three-pot, preparative scale synthesis of 5-acetamido-6-amino-3-methyluracil, “metabolite A 1 ” (AAMU) ( 2 ) of caffeine, from readily available 6-aminouracil ( 3 ) in 72% overall yield is described.",10.1021/op960010d,1
Heterogeneous Catalysis in Liquid Phase Transformations of Importance in the Industrial Preparation of Fine Chemicals,"This review focuses on the use of heterogeneous catalysts in the production of fine and speciality chemicals. The major emphasis is on those systems which have been commercialised already and those which are close to commercialisation. These include the use of TS-1 for oxidation reactions including the production of hydroquinone, caprolactam, and alkene oxides, and clay-supported catalysts such as clayzic, which are commercially available for acid-catalysed reactions, in particular Friedel−Crafts reactions. Base catalysis and acid-catalysed halogenation and nitration are also covered.",10.1021/op960008m,0
A Model for Mother Liquor Recycle in Batch Processing,"A simple model for the continuous recycle of mother liquors from a crystallization or precipitation is discussed. It is shown that the impurity profile of the mother liquors, at moderate recycle levels, quickly reaches a steady state according to (1 − x n +1 )/(1 − x ), where n is the number of times the process is operated and x is the fraction of mother liquors recycled. Practical applications of the procedure are discussed, and it is shown that a relatively small amount of laboratory work would be required to test a real system under the continuous recycle conditions. An example of the successful application of the procedure to a multitonne per annum manufacturing operation is described.",10.1021/op960007u,0
Baeyer−Villiger Oxidation of 5-endo-(Biphenyl-4-ylmethoxy)-7-anti-piperidinobicyclo[2.2.1]heptan-2-one:  Process Development and Scale-Up,"The Baeyer−Villiger oxidation of 7- anti -piperidino, 5- endo -biphenyl-4-ylmethoxy substituted norbornan-2-one was developed to provide a robust, reproducible process for manufacture of the regioisomeric lactone which results from migration of the bridgehead carbon atom. Yields of 60−63% theory were obtained in a 2250 L plant.",10.1021/op9600062,0
An Improved Large-Scale Synthesis of Benz[<i>cd</i>]indol-2(1<i>H</i>)-one and 5-Methylbenz[<i>cd</i>]indol-2(1<i>H</i>)-one,"An improved synthesis of benz[ cd ]indol-2(1 H )-one ( 3 ) and a novel synthesis of 5-methylbenz[ cd ]indol-2(1 H )-one ( 4 ) utilizing analogous methodology is reported. Starting from 1,8-naphthoic anhydride and 4-nitro-1,8-naphthoic anhydride, an appropriately substituted N -(2,4-dinitrophenoxy)naphthalimide is prepared. Subjecting these intermediates to improved Lossen rearrangement conditions yields 3 and 5-nitrobenz[ cd ]indol-2(1 H )-one ( 11 ). 11 is converted to 5-iodobenz[ cd ]indol-2(1 H )-one ( 13 ) by standard reduction and diazonium chemistry. 13 is converted to 4 by palladium(II)-catalyzed coupling of the aryl iodide with methyl-Grignard.",10.1021/op960005+,0
Synthesis of Trimegestone:  The First Industrial Application of Bakers' Yeast Mediated Reduction of a Ketone,"Trimegestone (17α-methyl-17β-(2( S )-hydroxy-1-oxopropyl)estra-4,9-dien-3-one) is a new progestomimetic molecule developed by Roussel Uclaf for the treatment of postmenopausal diseases. It is produced on an industrial scale from a related 3-ketal, 17-keto norsteroid intermediate in a nine-step sequence involving hydrocyanation of the 17-keto group, alkylation of the protected cyanohydrin with ethyl magnesium bromide to give a 17α-hydroxy 20-ketone, stereospecific 17α-methylation of the corresponding 17,20-enolate, and oxidation of the 20,21-enolate with air and ketal deprotection to give 3,20,21-triketone. The key step of the synthesis is the chemo-, regio-, and almost stereospecific bioreduction of this triketone to the desired 21( S ) alcohol, Trimegestone (de = 99%). This bioreduction is performed with bakers' yeast in water, thus showing the efficiency of this method at an industrial level.",10.1021/op960004h,1
Integration of a Highly Selective Demethylation of a Quaternized Ergoline into a One-Pot Synthesis of Pergolide,"We have developed a high-yielding one-pot synthesis of pergolide ( 10 ) from dihydrolysergol ( 1 ), which was isolated as pergolide mesylate ( 6, Permax), a semisynthetic ergot alkaloid marketed for the adjunctive treatment of Parkinson's disease. The process involved the formation of quaternized amine intermediates, followed by a highly selective demethylation and thioether formation via thiomethoxide ion. A novel tandem chromatography procedure was used to remove closely related byproducts, which included an unexpected and unusual thiomethyl ether homologue of pergolide.",10.1021/op9600015,1
Cu-Based Nanoalloys in the Base-Free Ullmann Heterocyle-Aryl Ether Synthesis,We report the first liquid−liquid Ullmann etherification process mediated not only by oxidatively stable Cu but also by CuZn and CuSn nanoparticle catalysts in conjunction with microwave heating that also avoids the use of solid and expensive bases. Conditions have led to improved turnovers and excellent yields in heteroaromatic Ullmann-type coupling reactions. Further enhancement is achieved upon the addition of 18-crown-6 as a kinetic promoter.,10.1021/op9003423,0
"Development of a Scalable and Safe Process for the Production of 4-Chloro-2,3-dimethylpyridine-<i>N</i>-oxide as a Key Intermediate in the Syntheses of Proton Pump Inhibitors<sup>†</sup>","2-(Pyridin-2-ylmethanesulfinyl)-1 H -benzimidazole-based drugs belong to the most prominent and successfully applied proton pump inhibitors. To fulfill the demand for a flexible and safe procedure for the synthesis of early-stage intermediates which are known to possess a strong exothermal decomposition potential, we have developed a high-yielding telescoped procedure for the synthesis of a key intermediate in the synthesis of these drugs. This strategy turned out to be highly reproducible in laboratory as well as on pilot-plant scale. As the starting material, as well as some of the intermediates, shows a highly exothermal decomposition potential, extensive safety investigations were undertaken. The whole process was adapted in a safe and reliable manner based on the outcome of this systematic approach. Considering these precautions, no safety issues were observed, neither in the laboratory nor in the pilot plant.",10.1021/op9003357,1
Monitoring and Control of Genotoxic Impurity Acetamide in the Synthesis of Zaurategrast Sulfate,"In this article we describe the strategy adopted to minimize the risk of acetamide presence in zaurategrast sulfate drug candidate. A risk of acetamide formation (a potential genotoxic impurity) was identified in the API formation step of the process during the early development phase. In order to keep the project development timelines unchanged and without having the appropriate analytical method ready developed, we chose to minimize the risk of acetamide impurity presence by applying an adequate chemical process design. The implementation of a workup sequence involving initially three aqueous washes was later proven to be successful when an appropriate analytical method to detect acetamide below ppm levels was available. Additionally the analytical tool gave us the opportunity to assess and fine-tune the designed process for acetamide elimination by spiking experiments. Data acquired during this evaluation showed that a single aqueous wash associated with two efficient crystallization steps were finally enough to deliver API with a content of acetamide below the level defined as the acceptance criterion.",10.1021/op900330e,1
An Improved Synthesis of Etravirine,"Etravirine ( 1 ) is a novel diarylpyrimidine non-nucleoside reverse transcriptase inhibitor and has recently been approved by the U.S. Federal Drug Administsration for the treatment of AIDS. Its reported synthesis is fraught with many difficulties, the foremost being the poor yield and long reaction time required at the aminolysis stage. We attributed this problem to the presence of a bromide group adjacent to the reaction site of the advance intermediate ( 6 ). In order to circumvent this issue, we proposed to defer the installation of the bromide group at a later stage, preferably after aminolysis. Indeed, this protocol has worked well. However, in the process of installation of diarylether and diarylamine functionalities at appropriate positions, we had to reverse the sequence of displacement reactions of the dichloride intermediate ( 9 ) with 3,5-dimethyl-4-hydroxybenzonitrile ( 5 ) and 4-aminobenzonitrile ( 3 ). The classical bromination led to the completion of etravirine synthesis.",10.1021/op9003289,1
Large-Scale Polycondensation of Lactic Acid Using Microwave Batch Reactors,"Chemical processes assisted by microwave heating are attractive energy-saving processes. We applied microwave heating to the polycondensation of lactic acid, which conventionally is known as a high-energy-consuming process. We herein studied the microwave-assisted reaction at scales ranging from several tens of milliliters to several tens of liters. Poly(lactic acid) polymers with average molecular weights exceeding 10,000 were obtained after 5 h of microwave heating. Analysis of the consumed microwave power also showed that the energy used by the polycondensation per mole of substrate was saved by scaling up the reaction.",10.1021/op900325e,0
"A Synthesis of 3,5-Disubstituted Phenols","Robust and scalable syntheses of some synthetically useful 3,5-disubstituted phenols are presented. The process involves the selective displacement of a halogen by nucleophilic aromatic substitution using a preformed mixture of potassium tert -butoxide and p -methoxybenzyl alcohol (PMB−OH), followed by deprotection of the PMB ether with acid in the presence of 1,3-dimethoxybenzene. These processes have been demonstrated on kilogram scale, providing crystalline phenols in good yield and high purity.",10.1021/op900322u,1
"Nonchromatographic Isolation of 2-Alkyl-2<i>H</i>-1,2,3-Triazoles in the Synthesis of NK3 Receptor Antagonists","A nonchromatographic isolation of a 2-alkyl-2 H -triazole from a 1:1 mixture with the corresponding 1-alkyl-1 H isomer was developed in a scalable synthesis of a synthetic intermediate for NK3 receptor antagonists. Based on the fundamental nucleophilicity difference in the isomeric triazoles, this method could be used as a general tactic in the isolation of 2 H -triazoles.",10.1021/op900320j,0
"Improved Synthesis of RO4858542, a 5-HT<sub>6</sub> Receptor Antagonist","An improved synthesis of a 5-HT 6 antagonist is described. A problematic amide reduction step was avoided by a reductive amination. Overall, 2.9 kg was produced over 6 steps with an overall yield of 56%.",10.1021/op900319p,1
Kilogram Synthesis of a LFA-1/ICAM Inhibitor,The process development and the kilogram-scale synthesis of BMS-587101 ( 1 ) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.,10.1021/op9003168,1
Fulvestrant: From the Laboratory to Commercial-Scale Manufacture,"The development of a commercial manufacturing process for fulvestrant (the active ingredient in ‘Faslodex’) is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.",10.1021/op900315j,1
"Improved Process for the Preparation of Montelukast: Development of an Efficient Synthesis, Identification of Critical Impurities and Degradants","An improved and scalable process for the production of montelukast (Singulair, drug for asthma) based on a new and advantageous method of carrying out the key substitution reaction has been developed. The present procedure is distinguished from the previous solutions in the use of linear or cyclic polyethers, which ensures higher selectivity of the key step. The improved process for the preparation of montelukast is able to minimize a content of impurities and allows the effective production of montelukast and its scale-up.",10.1021/op900311z,1
Process Development of a Diacyl Glycerolacyltransferase-1 Inhibitor,"A synthesis of a selective diacyl glycerolacyltransferase-1 (DGAT-1) inhibitor, 1, is described. The synthesis illustrates a diketone Favorskii reaction on 9 in place of the more common ketoester variant for generation of the dicarboxycyclopentane core, the development of an efficient classical resolution of a key cyclopentyl ketoacid intermediate 4, and an ambient temperature Suzuki−Miyaura coupling which avoids epimerization of the labile aryl ketone of 1 .",10.1021/op900310v,1
ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing,"A newly developed ReactIR flow cell is reported as a convenient and versatile inline analytical tool for continuous flow chemical processing. The flow cell, operated with ATR technology, is attached directly into a reaction flow stream using standard OmniFit (HPLC) connections and can be used in combination with both meso- and microscale flow chemistry equipment. The iC IR analysis software (version 4.0) enables the monitoring of reagent consumption and product formation, aiding the rapid optimisation of procedures. Short-lived reactive intermediates can also be observed in situ, giving further mechanistic insight into complex transformations.",10.1021/op900305v,0
A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharmaceutical Manufacturing Processes,"Sulfonate esters of lower alcohols possess the capacity to react with DNA and cause mutagenic events, which in turn may be cancer inducing. Consequently, the control of residues of such substances in products that may be ingested by man (in food or pharmaceuticals) is of importance to both pharmaceutical producers and to regulatory agencies. Given that a detailed study of sulfonate ester reaction dynamics (mechanism, rates, and equilibria) has not been published to date, a detailed kinetic and mechanistic study was undertaken and is reported herein as a follow-up to our earlier communication in this journal. The study definitively demonstrates that sulfonate esters cannot form even at trace level if any acid present is neutralized with even the slightest excess of base. A key conclusion from this work is that the high level of regulatory concern over the potential presence of sulfonate esters in API sulfonate salts is largely unwarranted and that sulfonate salts should not be shunned by innovator pharmaceutical firms as a potential API form. Other key findings are that (1) an extreme set of conditions are needed to promote sulfonate ester formation, requiring both sulfonic acid and alcohol to be present in high concentrations with little or no water present; (2) sulfonate ester formation rates are exclusively dependent upon concentrations of sulfonate anion and protonated alcohol present in solution; and (3) acids that are weaker than sulfonic acids (including phosphoric acid) are ineffective in protonating alcohol to catalyze measurable sulfonate ester even when a high concentration of sulfonate anion is present and water is absent. Implications of the mechanistic and kinetic findings are discussed under various situations where sulfonic acids and their salts are typically used in active pharmaceutical ingredient (API) processing, and kinetic models are presented that should be of value to process development scientists in designing appropriate controls in situations where risk for sulfonate ester formation does exist.",10.1021/op900301n,0
<i>In Situ</i> FTIR Study and Scale-Up of An Enolization−Azidation Sequence,"A key step in the synthesis of an optically active aminoalcohol-containing active pharmaceutical ingredient (API) involved the diastereoselective introduction of an azido functional group on a functionalized chiral oxazolidinone. This was accomplished via a low-temperature enolization, followed by a quench with triisopropylbenzenesulfonyl azide. To enable scale-up of this process, the enolization temperature had to be increased from the original <−65 °C to approximately −40 °C. In situ FTIR was used to study the enolization and quench stages of the reaction. The half-life of the enolate at −45 °C was estimated to be 12 h on the basis of in situ FTIR profiling. Examination of the in situ FTIR data also provided evidence that the reaction between the enolate and triisopropylbenzenesulfonyl azide was instantaneous and demonstrated that accumulation of triisopropylbenzenesulfonyl azide did not occur. A combination of in situ FTIR experiments and traditional parameter ranging experiments resulted in a process that was successfully run at −40 °C without an appreciable erosion of facial selectivity or yield.",10.1021/op900299c,1
Translating High-Temperature Microwave Chemistry to Scalable Continuous Flow Processes,"A comparison between batch microwave and conventionally heated continuous flow scale-up protocols for three selected model reactions is presented. Using high-temperature/-pressure conditions as process intensification principles, reaction times for all three transformations were reduced to a few seconds or minutes at temperatures ranging from 180−270 °C utilizing sealed vessel microwave conditions on small scale (2 mL). Successful scale-up of two out of three reactions in a multimode batch microwave reactor on a ∼1 L scale produced product quantities of ∼0.5 kg within less than one hour of overall processing time. Moving to a continuous flow format in a high-temperature/high-pressure stainless steel microcapillary microreactor (4−16 mL reactor volume) all three transformations were scalable with significantly increased space-time yields compared to the microwave batch protocols. A critical evaluation of both scale-up principles is made.",10.1021/op900297e,0
"Practical and Scalable Process for the Preparation of 4-Amino-1,3-dimethylpyrazole Hydrochloride","A practical and scalable process for the preparation of 4-amino-1,3-dimethylpyrazole hydrochloride 1 is described. Compound 1 is a useful starting material; its preparation is achieved via a three-step sequence from methyl hydrazine and technical grade acetaldehyde dimethylacetal. The target molecule is isolated in high chemical and isomeric purity (>99.0% with respect to 4-amino-1,5-dimethylpyrazole).",10.1021/op900296p,0
Ambient Pressure Desorption Ionization Mass Spectrometry in Support of Preclinical Pharmaceutical Development,"The use of ambient pressure desorption ionization mass spectrometry for the rapid analytical support of process and pharmaceutical development is demonstrated. The ability of direct analysis in real time (DART) technology to analyze both active pharmaceutical ingredients (APIs) and intermediates without sample preparation or the development of LC-based separations provided critical experimental results with minimal time required for method development. The utility and versatility of DART is shown for applications such as degradation studies, analysis of high-throughput catalyst screens, preparative-scale chromatography fractions, and impurity determination.",10.1021/op9002938,0
A Practical Synthesis of Regioisomeric 6- and 7-Methoxytetrahydro-3-benzazepines,A concise and versatile synthetic route for 6- and 7-methoxy tetrahydro-3-benzazepines is described. The key feature of the synthesis is a one-pot acylation/cyclization/elimination sequence to construct either of the isomeric dihydrobenzazepine ring systems from the same starting material. The route is high yielding and chromatography-free.,10.1021/op900292j,1
Towards a Process for the Reduction of Monomer Content in MDI-Based Prepolymers,The selective removal of methylene diphenylene diisocyanate (MDI) monomers from commercially important MDI-based prepolymers by means of fractionation through a semipermeable polymeric solvent-resistant nanofiltration (SRNF) membrane is demonstrated at laboratory scale.,10.1021/op9002906,0
Scaleable Preparation of Functionalized Organometallics <i>via</i> Directed Ortho Metalation Using Mg- and Zn-Amide Bases,"A range of aryl and heteroaryl organometallics are efficiently prepared in THF via directed ortho metalation by using the previously reported amide bases tmpMgCl·LiCl (tmp = 2,2,6,6-tetramethylpiperidyl), tmp 2 Mg·2LiCl and tmp 2 Zn·2MgCl 2 ·2LiCl. These metalation reactions are carried out at 80−100 mmol scale. The unsaturated organometallic compounds undergo smooth reactions with various electrophiles, e.g. additions to carbonyl groups, Pd-catalyzed cross-coupling reactions or Cu-catalyzed acylations. In all cases, the metalation rates have been compared with corresponding small-scale reactions (1−2 mmol). Moreover, a procedure for the recovery of the valuable tmp-H from the aqueous layer is reported.",10.1021/op9002888,0
Exploring the Scope for Scale-Up of Organic Chemistry Using a Large Batch Microwave Reactor,"A new batch microwave reactor has been evaluated in the context of palladium-mediated transformations, condensation reactions, nucleophilic aromatic substitution reactions, and alkylations. Importantly, a linear scaling approach was taken, no changes being made to the protocol when moving from the small, developmental scale to larger scales. In some cases reactions were scaled over 18,000-fold when moving from small (0.1−1 mmol) to large (1−18 mol) runs.",10.1021/op900287j,0
Fit for Purpose Experimental Designs and Analyses in Chemical Development,"Classical experimental designs have been used as configurations of choice at GlaxoSmithKline within Chemical Development in establishing robust products and processes while achieving other goals such as reduction of cost, waste, process investigation times and most importantly improved quality. Occasionally, as in this paper, these first intent designs have been proved to be unworkable through irregularly shaped experimental regions induced through chemistry constraints. To achieve optimum efficiency, a fit for purpose computer-aided D-Optimal Design in considering the reduction of cyclic imides to amines has been investigated here, proving to be an invaluable additional tool in applying the appropriate design at the relevant time. In addition, partial least squares (PLS) analyses has been explored with a view of simultaneously modelling the responses whilst primarily identifying those factors having the largest impact across the responses of interest (quantity of reducing agent and solvent, temperature, and time). This combined with process analytical technology (PAT) through online IR monitoring has facilitated part of this cyclic process of investigations using scientific and business judgment.",10.1021/op900286r,0
Synthesis and Process Optimization of Amtolmetin: An Antiinflammatory Agent,Efforts toward the synthesis and process optimization of amtolmetin guacil 1 are described. High-yielding electrophilic substitution followed by Wolf−Kishner reduction are the key features in the novel synthesis of tolmetin 2 which is an advanced intermediate of 1 .,10.1021/op900284w,1
Selection of a Purification Process for the Removal and Recycling of Cesium Catalyst after Polyol Production,"The aim of this study was the development of a crystallization process for the removal of the alkaline catalyst (cesium hydroxide) from crude polyether polyols and its recycling process. Hydrochloric, phosphoric, carbonic, and sulphuric acids were tested to choose the best neutralization agent. Sulphuric acid was chosen because its recycling process seems to be easier than with the other acids assayed. The process involves a first step of neutralization with an aqueous solution of sulphuric acid. After that, the removal of water must be done following an adequate profile of pressure and temperature with time to reach a large particle size that makes possible the filtration of the polyol. The influence of the water/polyol ratio and the P − T profiles were studied in order to decrease the process time and enlarge the size of the crystals. Once polyol is filtrated, the cake of Cs 2 SO 4 was dissolved again to precipitate the sulphate ion with barium hydroxide, thus obtaining a solution of CsOH that can be recycled in the process. It has been confirmed that the recycled cesium hydroxide can be used in a new cycle.",10.1021/op900282v,0
Book Review of Flash Chemistry: Fast Organic Synthesis in Microsystems,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Flash Chemistry: Fast Organic Synthesis in MicrosystemsTrevor LairdCite this: Org. Process Res. Dev. 2009, 13, 6, 1432Publication Date (Web):October 30, 2009Publication History Received22 October 2009Published online30 October 2009Published inissue 20 November 2009https://doi.org/10.1021/op900275qCopyright © 2009 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views383Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (34 KB) Get e-Alerts Get e-Alerts",10.1021/op900275q,0
Development of a Biocatalytic Process as an Alternative to the (−)-DIP-Cl-Mediated Asymmetric Reduction of a Key Intermediate of Montelukast,"A KetoREDuctase (KRED) engineered via directed evolution technologies catalyzed the asymmetric reduction of ( E )-methyl 2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoate to the corresponding ( S )-alcohol, a key intermediate in the synthesis of montelukast sodium (Singulair). Through synergistic efforts in process chemistry, molecular biology, bioinformatics and high throughput screening, a KRED with very high enantioselectivity (>99.9% ee) was developed for an economical and simple process that takes advantage of the physical properties of the substrate and product. The evolved KRED is an efficient and robust enzyme for catalyzing the reaction of an essentially water insoluble substrate ( c log P ≈ 7) at a 100 g/L loading in the presence of ∼70% organic solvents at 45 °C. The biocatalytic process currently runs at >200 kg scale.",10.1021/op900272d,0
Scale-Up of Organic Reactions in a Pharmaceutical Kilo-Lab Using a Commercial Microwave Reactor,"A range of pharmaceutically relevant reactions were investigated for scale-up in a kilo-lab environment using a commercial batch microwave reactor. Typical scale-up issues are discussed, taking into account the specific limitations of microwave heating in large-scale experiments. Examples of scale-up from 15 mL to 1 L are presented and demonstrate that the synthesis of compounds on greater than 100 g scale is feasible in one batch. Aided by this new technology reaction times have been significantly reduced and the productivity of our scale-up laboratory has been enhanced. Production rates of several hundred grams per day were achieved using microwave technology. The article concludes with a brief discussion of advantages and disadvantages of this type of batch microwave reactor.",10.1021/op900269y,0
"Practical Application of Oxidation Using a Novel Na<sub>2</sub>WO<sub>4</sub>−H<sub>2</sub>O<sub>2</sub>System under Neutral Conditions for Scale-Up Manufacturing of 12α-Hydroxy-3-oxooleanano-28,13-lactone: Key Intermediate of Endothelin A Receptor Antagonist S-0139","Novel alcohol oxidation using a Na 2 WO 4 −H 2 O 2 system was applied to manufacture 12α-hydroxy-3-oxooleanano-28,13-lactone which is a key intermediate of S-0139. Oxidation of the hydroxyl group of oleanolic acid was optimized based on the design of experiment (DoE) approach. Statistical analysis was used to maximize the yield of the corresponding ketone and minimize the generation of byproducts. The safety evaluation of this oxidation was also conducted in detail, and pilot manufacturing was achieved.",10.1021/op900265h,1
Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride,"A four-step process to generate 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride starting with 5-hydroxymethyl-2-furfuraldehyde is described. Raney nickel-mediated reduction of 5-hydroxymethyl-2-furfuraldehyde afforded 2,5-bis(hydroxymethyl)tetrahydrofuran with a predominantly cis configuration. Conversion of the diol to a ditosylate, followed by cyclization with benzylamine generated the 8-oxa-3-aza-bicyclo[3.2.1]octane core. The title compound was prepared via hydrogenolysis of the N -benzyl group with Pearlman’s catalyst and isolated as the hydrochloride salt from a mixture of 2-propanol and heptane. The overall yield for the process was 43−64%. An impurity generated during scale up highlighted the need for a strict in-process specification for acetonitrile content prior to performing the final hydrogenolysis. Ethanol conditioning of all processing equipment that had acetonitrile contact prior to the introduction of the substrate stock solution is highly recommended.",10.1021/op9002642,1
Sonogashira Reactions with Propyne: Facile Synthesis of 4-Hydroxy-2-methylbenzofurans from Iodoresorcinols,"The Sonogashira reaction of terminal alkynes and ortho-halophenols with subsequent cyclization is a well-precedented method for the synthesis of substituted benzofurans. Here we describe the extension of this method to the coupling of 2-iodoresorcinols and terminal alkynes, including propyne, to give 4-hydroxy-2-substituted benzofurans. In particular, we describe the screening, method development, and scaleup of the reaction with propyne using standard hydrogenation equipment.",10.1021/op900263b,1
"Instantaneous, Facile and Selective Synthesis of Tetrabromobisphenol A using Potassium Tribromide: An Efficient and Renewable Brominating Agent","An instantaneous method for the bromination of bisphenol A has been reported using potassium tribromide for the first time as an efficient brominating agent affording the corresponding tetrabromobisphenol A in a reaction time of only 5−10 min at ambient temperature in high yields (99%) and purity (>99%), free from reaction byproduct and having very low ionic impurities. Mild reaction conditions and simple workup provide a practical and commercially viable route for the synthesis of the largest selling flame retardant. The generated HBr during the bromination reaction is used either in the preparation of value-added brominated products or is disposed of as waste, causing serious environmental problems. An environmentally acceptable method for an inbuilt recycling of HBr by its neutralisation, thereby generating additional amounts of metal bromide and recovering the solvent from the liquid mixture has been designed and developed. The KBr used for the preparation of potassium tribromide can be recovered, regenerated in additional amounts, and reused without any significant loss.",10.1021/op900262f,0
"Improved Synthesis of the Selective Rho-Kinase Inhibitor 6-Chloro-<i>N</i>4-{3,5-difluoro-4-[(3-methyl-1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridin-4-yl)oxy]phenyl}pyrimidin-2,4-diamine",A highly potent and selective Rho-kinase inhibitor containing a 7-azaindole moiety has been developed at Bayer Schering Pharma. Herein we disclose details of a significantly improved synthesis of the compound in 8.2% overall yield. Key aspects include cost and safety considerations and the uncommon use of a trifluoromethyl group with controllable reactivity as a masked methyl group.,10.1021/op900260k,1
An Improved Process for the Production of Lansoprazole: Investigation of Key Parameters That Influence the Water Content in Final API,"An improved large-scale synthesis of lansoprazole 1 an anti-ulcer drug is described. The synthesis commences with condensation of 2-mercaptobenzimadazole 3 with 2-chloromethyl-3methyl-4-(2, 2, 2-trifluoro ethoxy) pyridine hydrochloride 2 using water as a solvent to yield thioether 4 . Subsequently, 4 was selectively oxidized to 1 by using sodium hypochlorite, a mild, economic, and eco-friendly oxidizing agent. A systematic investigation of crystallization parameters in the final stage, which enabled us to control the water content in the final API to <0.10%, were also discussed. (As recommended by USP 28 monograph ( The United States Pharmacopeia: USP 28: NF 23, 28th rev. of The Pharmacopeia of the U.S., 23rd ed. of The National Formulary; United States Pharmacopeial Convention; Rockville, MD, 2005; p 1110.)",10.1021/op900258b,1
Flow Processing of Microwave-Assisted (Heterogeneous) Organic Reactions,"A commercially available continuous-flow reactor was adapted to run three organic reactions, e.g. two heterogeneous and one homogeneous mixture under microwave heating. The setup was operated either as a batch-loop reactor for running a biocatalyzed esterification of ( R,S )-1-phenylethanol with vinyl acetate and the esterification of ( S )-pyroglutamic acid with n -decanol (i.e., Laurydone process) or in a single pass for the aspirin synthesis as a homogeneous mixture. The tubular reactor has been characterized to perform a series of three equally sized, continuously operated stirred tank reactors on average. Although the (operational) costs of the microwave-heated tubular reactor are higher than conventionally heated processes in fine chemical operations, it was demonstrated that the experimental data can be used for process design. Plugging remains an important obstacle to be dealt with. However, benefits with respect to safety and scalability are expected to enable a fair compensation for the costs when implementing this novel technique.",10.1021/op900257f,0
Quaternary Chiral Center <i>via</i> Diastereoselective Enolate Amination Enables the Synthesis of an Anti-inflammatory Agent,"The d -leucine amino acid residue necessary for the synthesis of BMS-561392, 1, was employed as a chiral directing group for a diastereoselective enolate amination to establish the quaternary chiral center. Enhanced diastereomeric ratios were observed while conducting the enolate amination with 1-chloro-1-nitrosocyclopentane 6 in the presence of LiCl. Analogies are drawn between known tertiary amide amino alcohol chiral auxiliaries which have been used to effect diastereoselective enolate alkylations and aminations. Once the stereochemical features of 1 were established, an efficient reaction sequence was devised to complete its synthesis. During the course of this research, accelerated reaction calorimetry (ARC) data substantiated that the aminating agent 1-chloro-1-nitrosocyclopentane 6 was not safe to use as a neat compound. Consequently, a preparation and use of 6 as a stock solution in methyl tert -butyl ether (MTBE) was developed that rendered it safe for use.",10.1021/op900255k,1
Process Development and Pilot-Scale Synthesis of New Cyclization Conditions of Substituted Phenylacetamides to Tetrahydroisoquinoline-2-ones Using Eaton’s Reagent,"Tetrahydroisoquinoline is a ubiquitous structural framework presented in numerous pharmacologically relevant molecules. Although accessible by the Pictet−Spengler cyclization, conditions commonly used for such cyclizations are often difficult to implement on scale. Herein, we report the development of a scaleable approach utilizing Eaton’s reagent for the cyclization of substituted phenylacetamide analogues to tetrahydroisoquinoline-2-one. The development, optimization, and safety hazard evaluations, which outline the benefits and ease of workup of this new process, are discussed.",10.1021/op9002533,1
"Synthesis of an Antibacterial Compound Containing a 1,4-Substituted 1<i>H</i>-1,2,3-Triazole: A Scaleable Alternative to the “Click” Reaction","The copper-catalyzed “click” reaction of an azide with an alkyne has become a popular method to build up 1,4-substituted 1 H -1,2,3-triazoles in medicinal chemistry and this approach was used on a laboratory scale during the preparation of novel macrolide 1 . However, the manufacture of the key azide component, as well as its subsequent use in the presence of a copper catalyst on a large scale, was associated with potential safety concerns. Therefore, a sequence was developed in which construction of the 1,4-substituted 1 H -1,2,3-triazole in 1 was accomplished via cyclocondensation of an α,α-dichloro tosyl hydrazone with an amine.",10.1021/op900252a,0
A New Method for Synthesis of Nolatrexed Dihydrochloride,"A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate/sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide/methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.",10.1021/op9002517,1
Development of an Efficient Process Towards the Benzimidazole BYK308944: A Key Intermediate in the Synthesis of a Potassium-Competitive Acid Blocker,"An entirely new synthesis of the important benzimidazole building block BYK308944 was elaborated using the Stobbe reaction as central element. BYK308944 constitutes an important intermediate for the preparation of 3,6,7,8-tetrahydrochromeno[7,8- d ]imidazoles as potassium-competitive acid blockers. The new route relies on the hydroxymethylation of 1,2-dimethylimidazole as cheap starting material followed by oxidation of the corresponding alcohol and Stobbe condensation of the resulting aldehyde with diethyl succinate. All synthetic steps of this new approach were optimized particularly with the goal to establish a process amenable for large-scale preparation.",10.1021/op9002505,1
An Efficient Synthesis of a Cyclic Ether Key Intermediate for 9-Membered Masked Enediyne Using an Automated Synthesizer,"Naturally occurring antibiotics containing 9-membered enediynes have received considerable attention for many years due to their potent DNA-cleaving activity. We previously reported the design and synthesis of a synthetic, masked 9-membered enediyne that possesses DNA-cleaving activity. Despite the importance of the 9-membered enediynes, application of these molecules is limited by their difficult synthesis. Herein, we report an improved process for the generation of a synthetic, masked 9-membered enediyne that uses an automated synthesizer for the production of a key synthetic intermediate.",10.1021/op9002455,0
Attrition-Enhanced Deracemization in the Synthesis of Clopidogrel - A Practical Application of a New Discovery,"The recently discovered technique of deracemization by means of attrition-induced grinding of a solid conglomerate in contact with a solution wherein racemization occurs has been used with a derivative of 2-chlorophenyl glycine, the key chiral component in the synthesis of Clopidogrel (Plavix). Deracemization of the racemate proceeds to a single enantiomer and in essentially absolute enantiomeric excess. Further conversion of enantiomerically pure material to Clopidogrel was achieved in 88% yield.",10.1021/op900243c,1
Application of Quality by Design Principles to Support Development of a Control Strategy for the Control of Genotoxic Impurities in the Manufacturing Process of a Drug Substance,"As part of the search for drugs with activity on the central nervous system (CNS) a fluoroaryl-amine was identified and developed by GlaxoSmithKline. The manufacturing process was developed and optimised by following a quality by design approach whereby a control strategy was developed, underpinned by process understanding and risk analysis, for enhanced level of quality assurance. A summary of the overall control strategy for this process includes different elements of control (Quality Process Parameters, control of the Quality Attributes of starting materials, intermediates, solvents, in-process controls). The drug substance Critical Quality Attributes (drug substance-CQAs) related to the genotoxin content, methyl methanesulfonate (methyl mesylate, MMS), ethyl methanesulfonate (ethyl mesylate, EMS) and isopropyl methanesulfonate (isopropyl mesylate, IMS) are identified and discussed in detail to show the process development studies carried out to ensure quality control for the final drug substance. The process understanding developed could allow for the elimination of testing of the genotoxic impurities in the final drug substance.",10.1021/op900242x,0
Development of an Extremely Efficient Oxidative Chlorination Reaction: The Value of Routine Data Collection,"This contribution describes the development of an extremely efficient process for the oxidative chlorination of a benzyl, alkyl thioether to yield an alkylsulfonyl chloride. This process was subsequently run on >100 kg scale. The product alkylsulfonyl chloride was required as an intermediate, being used by several drug projects, to prepare sulfonamides. Routine data collection and reaction profiling has led to understanding, which has allowed an alternative reaction pathway to be exploited for the development of a two-step, oxidation−chlorination process. The scope of this new two-step process was briefly examined. The results of this study have allowed us to propose an empirical method for predicting the course of these oxidative chlorination reactions. During these studies we have developed a simple laboratory rig, constructed from inexpensive, readily available equipment, which allows the controlled accurate delivery of known volumes (100s of milliliters) of chlorine gas at a given rate. In our laboratories, this has made the use of gaseous chlorine a considerably less onerous task. This work is testimony to the fruit which may be borne from attempts to gain process understanding, even of an already high-yielding reaction.",10.1021/op900241e,0
An Improved Synthetic Route for Preparative Process of Vardenafil,"A new, convergent synthetic route for the process optimization of vardenafil (Levitra), a potent and effective PDE5 inhibitor, is described. Key improved steps in the preparative process are that the chlorosulfonation reaction is at the beginning and the dehydration-cyclisation reaction is at a later stage so that the synthetic route has a better overall yield and simpler workup operations. The yield of vardenafil produced from this synthetic route is around 45% over seven steps with purity at 99.2% (HPLC).",10.1021/op900235p,1
Comparison of Large-Scale Routes to Manufacture Chiral <i>exo</i>-2-Norbornyl Thiourea,"Two routes aimed at the manufacture of chiral exo -2-norbornyl thiourea ( 1 ) on large scale are described. The first approach involves five chemical steps and hinges on a classical resolution via diastereomeric salt formation. The synthesis utilizes amine 2 as the resolution handle. The second approach includes two chemical steps and a chiral chromatography of (±)- 1 . Despite the larger initial investment necessary to acquire the chiral stationary phase used in the chromatographic approach, the shorter reaction sequence and efficiency of the chromatographic separation make the second route a more attractive option for long-term applications.",10.1021/op9002328,1
"Development of a Scalable Synthetic Process for DG-051B, A First-in-Class Inhibitior of LTA4H","DG-051B is a first-in-class small molecule inhibitor of leukotriene A4 hydrolase (LTA4H), currently in Phase II clinical development for the prevention of heart attack. Process optimization led from a linear seven-step synthetic procedure to a convergent four-step manufacturing sequence that has been used to manufacture at 100-kg scale. The entire process can be telescoped due to high conversion reactions, low impurity levels, efficient separations, and a very effective final purification. Two key aspects of the process are: (a) bypassing the isolation of a reactive electrophile by using its aqueous-washed reaction mixture directly into a coupling reaction with a phenoxide nucleophile and (b) modulating the properties of the final product solutions for optimal extraction, purification, and crystallization.",10.1021/op900231j,1
"A Practical and Efficient Synthesis of (3<i>R</i>,4<i>S</i>)-1-Benzyl-4-phenylpyrrolidine-3-carboxylic acid via an Aziridinium Ion Intermediate","A practical and efficient synthesis of (3 R,4 S )-1-benzyl-4-phenylpyrrolidine-3-carboxylic acid ( 1 ), a key chiral building block for synthesis of biologically active compounds was established by utilizing a stereospecific and regioselective chlorination of in situ generated aziridinium ion, followed by a nitrile anion cyclization. Starting from commercially available ( R )-styrene oxide and 3-(benzylamino)propionitrile, the four-step synthesis features a through process without purification of intermediates until isolation of crystalline 1 . The robust, chromatography-free and reproducible synthesis of 1 achieved an 84% overall yield from ( R )-styrene oxide. This highly efficient process was successfully demonstrated at pilot scale with 17 kg output of 1 .",10.1021/op900230r,1
"An Efficient Large-Scale Synthesis of EDP-420, a First-in-Class Bridged Bicyclic Macrolide (BBM) Antibiotic Drug Candidate","A multistep, practical, and cost-effective synthesis of novel bridged bicyclic macrolide drug candidate EDP-420 ( 1 ) is described. Starting from inexpensive and commercially available erythromycin A 9-oxime, the current chemical process involves a series of transformations: triacetylation, Pd-catalyzed O,O -bis-allylation (bridge formation), acid-catalyzed sugar cleavage, oxime reduction, acetylation, Os-catalyzed bridge olefin oxidative cleavage, Corey−Kim oxidation, bridge oxime formation, deprotection, and final purification. Multikilogram quantities have been synthesized.",10.1021/op900228u,1
"Preparation of Saxagliptin, a Novel DPP-IV Inhibitor","The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin ( 1 ), is described from the two unnatural amino acid derivatives 2 and 3 . After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4 . Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1 . While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9 . Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.",10.1021/op900226j,1
Development of a Practical Biocatalytic Process for (<i>R</i>)-2-Methylpentanol,"( R )-2-Methylpentanol is an important chiral intermediate for the synthesis of certain medicinally important compounds, natural products, and liquid crystals. Here we describe the development of a practical kinetic resolution utilizing an enantiospecific biocatalytic reduction of racemic 2-methylvaleraldehyde. The process utilizes an evolved ketoreductase enzyme to selectively reduce the ( R )-enantiomer of racemic 2-methylvaleraldehyde to the desired product with high volumetric productivity. A scaleable method for separating the desired product from the off-enantiomer of the starting material is also described. The process is cost-effective, green, and amenable to manufacturing scale.",10.1021/op9002246,1
Book Review of Thermal Safety of Chemical Processes: Risk Assessment and Process Design,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Thermal Safety of Chemical Processes: Risk Assessment and Process DesignW. J. WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW,United Kingdom E-mail: [email protected].Cite this: Org. Process Res. Dev. 2009, 13, 5, 1035Publication Date (Web):August 21, 2009Publication History Received17 August 2009Published online21 August 2009Published inissue 18 September 2009https://pubs.acs.org/doi/10.1021/op900217zhttps://doi.org/10.1021/op900217zbook-reviewACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views697Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts",10.1021/op900217z,0
Practical Enantioselective Synthesis of a 3-Aryl-3-trifluoromethyl-2-aminopropanol Derivative,"Development of a large-scale enantioselective synthesis of a lead compound containing a 3-aryl-3-trifluoromethyl-2-aminopropanol core is described. A single isomer of 3,3-disubstituted acrylic acid derivative was prepared via Perkin condensation or Horner−Wadsworth−Emmons olefination, followed by hydrolysis. The acid was converted to a chiral acryloxazolidinone derivative. Hydrogenation of the latter on Pd/C in the presence of MgBr 2 proceeded via a chelation-controlled conformation to yield the desired isomer with high selectivity. Subsequent Evans azidation, hydrogenation, reductive cleavage of the chiral auxiliary, and sulfonylation afforded the target compound as a single isomer in high overall yield.",10.1021/op900216v,1
IMRET 10: Process Intensification via New Reactor Technologies and New Ways of Processing,editorial,10.1021/op900211d,0
"Understanding and Controlling the Formation of an Impurity during the Development of Muraglitazar, a PPAR Dual Agonist","Impurity A, observed during the process research and development of muraglitazar, was isolated via preparative HPLC for structural identification using one-dimensional and two-dimensional NMR techniques. The origin of impurity A was identified as arising three steps earlier as a minor contaminant present in one of the starting materials: 4-hydroxybenzaldehyde. As a result, a series of corresponding impurities were formed in each synthetic step leading up to impurity A. These findings permitted the addition of a new specification for this starting material to eliminate the problem.",10.1021/op9002104,1
"The Discovery and Development of a Safe, Practical Synthesis of ABT-869","The discovery, development and implementation of two chemical routes to ABT-869 is reported. Optimization of the first-generation heterocycle formation and Suzuki coupling is briefly described. Key features of the second-generation synthesis include the development of a safe hydrazine condensation by utilizing an inorganic base to increase the onset temperature of exothermic decomposition. The second-generation Suzuki reaction is discussed in detail, culminating in the use of an oxygen monitor as a PAT to maximize reproducibility on scale.",10.1021/op900208y,1
Straightforward Enzymatic Process Based on HNL CLEA-Catalysis towards Cyanohydrin Derivatives,"An efficient enzymatic process based on HNL-CLEA catalysis in buffer-saturated organic media was developed to limit the amount of overall waste generated and the number of safety issues incurred by handling HCN-containing waste. Starting from benzaldehyde as a model substrate, ( R )- and ( S )-mandelonitrile can be obtained under these reaction conditions without an extraction step being required. The crude cyanohydrin intermediate was sufficiently pure to be used as starting material in a second step towards a range of derivatives.",10.1021/op900207n,0
"The Development of a New Manufacturing Route to the Novel Anticonvulsant, SB-406725A","The development of an efficient manufacturing route to 3-acetyl- N -(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methylethoxy)-benzamide hydrochloride SB-406725A ( 1 ) is described. The synthesis begins with dichlorination of isoquinoline, followed by nitration using nitronium tetrafluoroborate in sulpholane. Nitroisoquinoline ( 12 ) was hydrogenated under pressure using Pt/C. The resultant tetrahydroisoquinoline ( 13 ) was selectively coupled with benzoate side chain ( 15 ) under base-promoted conditions using sodium hexamethyldisilazane to yield the parent molecule SB-406725 ( 16 ). SB-406725 was then converted to the HCl salt SB-406725A ( 1 ). This process has been successfully demonstrated on a pilot-plant scale to prepare ∼30 kg of SB-406725A ( 1 ).",10.1021/op9002054,1
"Synthesis of the NK1 Receptor Antagonist GW597599. Part 3: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine Urea, A Happy End","GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of central nervous system disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1 . In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.",10.1021/op9002032,1
"An Efficient Kilogram-Scale Synthesis of <i>N</i>,<i>N</i>′-Bis(4,6-disubstituted 1,3,5-triazin-2-yl)-4-aminophenetylamine","A practical large-scale synthesis was developed for the preparation of N, N ′-bis(4,6-disubstituted 1,3,5-triazin-2-yl)-4-aminophenethylamine derivatives exemplified by compound 2 . This route is a six-step procedure starting from commercially available cyanuric chloride and 3-( tert- butoxycarbonylamino) aniline based on the reactivity differences of the three chlorine atoms on the triazine ring. The optimized procedure was scaled up to give the final product 2 in an overall yield of 61% and 99.9% purity. These low-molecular weight compounds mimic the ability of protein A to bind to IgG antibody.",10.1021/op900202b,1
Development of a Scalable Synthesis of Dipeptidyl Peptidase-4 Inhibitor ABT-279,"A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis -2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermediate. The amine coupling partner was prepared by a novel Hofmann rearrangement promoted by 1,3-dibromo-5,5-dimethylhydantoin. The final product was isolated as the l -malic acid salt. The scale-up campaign consisted of 15 steps and delivered 42 kg of ABT-279 in 14% overall yield. A second-generation synthesis that addresses some of the issues encountered during scale-up was developed and demonstrated on kilogram scale.",10.1021/op900197r,1
Short and Efficient Process for the Synthesis of <i>trans-</i>4-Aminocyclohexanecarboxylic Acid Derivatives,"This contribution relates to an industrially feasible process for the preparation of isomerically pure trans -4-amino-1-cyclohexanecarboxylic acid derivatives that are useful building blocks in the synthesis of several pharmacologically active compounds such as glimepiride, L-370518.",10.1021/op900195w,1
On Scale Up of Organic Reactions in Closed Vessel Microwave Systems,"Scale up of reactions with existing laboratory-scale microwave technologies and factors affecting extension of the scope, including the influences of putative nonthermal microwave “effects,” mechanisms of energy transfer, interactions of microwaves with materials, temperature measurement, and reproducibility between systems, are discussed.",10.1021/op900194z,0
"A Multidisciplinary Approach Toward the Rapid and Preparative-Scale Biocatalytic Synthesis of Chiral Amino Alcohols: A Concise Transketolase-/ω-Transaminase-Mediated Synthesis of (2<i>S</i>,3<i>S</i>)-2-Aminopentane-1,3-diol","Chiral amino alcohols represent an important class of value-added biochemicals and pharmaceutical intermediates. Chemical routes to such compounds are generally step intensive, requiring environmentally unfriendly catalysts and solvents. This work describes a multidisciplinary approach to the rapid establishment of biocatalytic routes to chiral aminodiols taking the original synthesis of (2 S,3 S )-2-aminopentane-1,3-diol as a specific example. An engineered variant of Escherichi coli transketolase (D469T) was used for the initial asymmetric ynthesis of (3 S )-1,3-dihydroxypentan-2-one from the achiral substrates propanal and hydroxypyruvate. A bioinformatics led strategy was then used to identify and clone an ω-transaminase from Chromobacterium violaceum (DSM30191) capable of converting the product of the transketolase-catalysed step to the required (2 S,3 S )-2-aminopentane-1,3-diol using isopropylamine as an inexpensive amine donor. Experiments to characterize, optimize and model the kinetics of each reaction step were performed at the 1 mL scale using previously established automated microwell processing techniques. The microwell results provided excellent predictions of the reaction kinetics when the bioconversions were subsequently scaled up to preparative scales in batch stirred-tank reactors. The microwell methods thus provide process chemists and engineers with a valuable tool for the rapid and early evaluation of potential synthetic strategies. Overall, this work describes a concise and efficient biocatalytic route to chiral amino alcohols and illustrates an integrated multidisciplinary approach to bioconversion process design and scale-up.",10.1021/op900190y,0
Investigation of Synthetic Routes to a Key Benzopyran Intermediate of a 5HT<sub>4</sub> Agonist,The supply route to GlaxoSmithKline’s 5HT 4 receptor agonist 1 centred on the construction of key benzopyran fragment 2 . Our attempts to define the final manufacturing route for this component are described through a series of disconnections. The systematic approach undertaken towards the construction of the benzopyran skeleton focused on cyclisation strategies from appropriate precursors and evaluation of the performance of the key steps.,10.1021/op900188v,1
Process Development and Scale Up of a Glycine Antagonist,"A synthetic route amenable to large-scale synthesis of the glycine antagonist (2 R,4 E )-7-chloro-4-(2-oxo-1-phenyl-pyyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (2 R,3 R,4 R,5 S )-6-(methylamino)hexane-1,2,3,4,5-penta-ol 12 is presented. The route consists of four stages of chemistry. Stage 1 starts from 5-chloro-2-iodoaniline hydrochloride and is a three-step telescoped stage consisting of an imine formation with ethyl glyoxalate, Mannich reaction using vinyloxytrimethylsilane, and subsequent Wittig reaction with (2-oxo-1-phenyl-3-pyrrolidinyl)triphenylphosphonium bromide. The stage 1 product (4 E )-2[(5-chloro-2-iodophenyl)amino]-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)butanoic acid ethyl ester 17 is subjected to an enzyme-catalysed kinetic resolution to prepare the single (2 R )-enantiomer 19 as the ethyl ester. Stage 3 is the intramolecular Heck reaction to yield (2 R,4 E )-7-chloro-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester 31 . The final stage is ester saponification and meglumine salt formation to afford the drug candidate molecule 12 . In total, more than 300 kg of target 12 was produced with a purity >99.9%. Aspects of route selection as well as elements of process understanding and control are discussed.",10.1021/op9001824,1
"Book Review of Validation of Pharmaceutical Processes, edited by J. Agalloco and F. J. Carleton","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Validation of Pharmaceutical Processes, edited by J. Agalloco and F. J. CarletonTrevor LairdCite this: Org. Process Res. Dev. 2009, 13, 5, 1034Publication Date (Web):July 23, 2009Publication History Received15 July 2009Published online23 July 2009Published inissue 18 September 2009https://doi.org/10.1021/op900181hCopyright © 2009 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views577Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (52 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Manufacturing,Pharmaceuticals,Separation science Get e-Alerts",10.1021/op900181h,0
"Response to the Comments by Bercu and Callis on our communication “Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol” [<i>Org. Process Res. Dev</i>. <b>2009</b>, <i>13</i>, 786−791; DOI: 10.1021/op9000737]","ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTResponse to the Comments by Bercu and Callis on our communication ""Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol"" [Org. Process Res. Dev. 2009, 13, 786−791; DOI: 10.1021/op9000737]Brian P. Haney*, Paul Mason*, and Neal G. Anderson¶View Author Information Chemical Development and Analytical and Quality Services, AMRI, P.O. Box 15098, Albany, New York 12212-5098, U.S.A., and Anderson's Process Solutions, 7400 Griffin Lane, Jacksonville, Oregon 97530, U.S.A.* To whom correspondence should be addressed. (B.P.H.) Telephone: (518) 512-2400; e-mail: [email protected]. (P.M.) Telephone: (518) 433-7742; e-mail: [email protected]†Chemical Development, AMRI.§Analytical and Quality Services, AMRI.¶Anderson's Process Solutions.Cite this: Org. Process Res. Dev. 2009, 13, 5, 939Publication Date (Web):August 10, 2009Publication History Published online10 August 2009Published inissue 18 September 2009https://pubs.acs.org/doi/10.1021/op900179nhttps://doi.org/10.1021/op900179nletterACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views935Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Anions,Impurities,Salts,Toxicology Get e-Alerts",10.1021/op900179n,0
Development of a Practical Large-Scale Synthesis of Denagliptin Tosylate,"A large-scale synthesis of denagliptin tosylate has been developed. The efficiency of the synthesis has been improved from the initially scaled route by changing the order of steps (performing a dehydration at a late stage). The key step of the synthesis is a single-step peptide coupling/dehydration, mediated by n -propanephosphonic acid cyclic anhydride. The challenges of developing this synthesis into a robust and practical manufacturing route are described.",10.1021/op900178d,0
Microreactor-Based Synthesis of Molecularly Imprinted Polymer Beads Used for Explosive Detection,"Molecularly imprinted polymer (MIP) beads based on acrylate formulations have been successfully synthesized in two different types of microreactors capable of generating spherical prepolymer droplets of controlled size in continuous segmented flow processes. After polymerizing and curing the droplets monodisperse acrylate particles have been obtained. Particle sizes have been adjusted in a wide range from 10 to 140 μm by choosing appropriate flow rates of the continuous and the disperse phase. By adding trinitrotoluene (TNT) as a template and PEG as a coporogen to the disperse phase MIP beads with TNT-selective sites and a sufficiently high porosity have been synthesized, as required, for explosive detection techniques.",10.1021/op9001774,0
Pilot-Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist. Part 3. Process Research and Development of a Diisopropylcarbodiimide and Catalytic 1-Hydroxybenzotriazole Peptide Coupling,"Studies directed toward the process research, development, and scale-up preparation of the potential α v β 3 integrin antagonist 1 are described. A convergent approach is detailed wherein tetrahydropyrimidine hydroxybenzoic acid 2 is linked to the β-amino acid ester 3 via a diisoproylcarbodiimide, catalytic HOBt coupling reaction. Saponification of the resulting ethyl ester, isolation of the corresponding zwitterion, H 3 PO 4 salt formation, crystallization, and acetonitrile-to-acetone exchange give rise to 1 as a crystalline monohydrate in 67% overall yield from 4 .",10.1021/op900173f,0
Development of a Multikilogram Synthesis of a Chiral Epoxide Precursor to a CCR1 Antagonist. Use of in Situ Monitoring for Informed Optimisation via Fragile Intermediates,"The optimisation and scale up of a manufacturing route to a key intermediate, acetic acid 4-acetylamino-3-(2-methyl-oxiranylmethoxy)phenyl ester ( 2 ), utilising a S N Ar coupling, the hydrogenation of a nitro moiety and the conversion of a chiral acetonide into a chiral epoxide is described along with other routes to access intermediate 2 including the chemoselective reduction of a nitro moiety in the presence of an epoxide.",10.1021/op900172t,1
Polymorphism in Processes of Crystallization in Solution: A Practical Review,"Here we review the polymorphism of organic molecules, obtained through batch crystallization in solution carried out in a stirred vessel. Preferential formation of a polymorph, crystal habit, and size depend strongly on the kinetics of the mechanisms involved. First, we recall the concepts of crystallization from solution. Second, phase transitions are introduced, discussed, and illustrated. Third, we focus on the development of batch-crystallization processes to obtain a given polymorph. Prerequisites are recalled, and experimental techniques used for the screening of polymorphs are presented. Recent developments in the determination of the kinetics of solution-mediated phase transition are reviewed, and the advantages and drawbacks of using process analytical technologies to monitor such transitions are discussed. Lastly, we present control strategies.",10.1021/op900168f,0
"A Continuously Operated Bimembrane Reactor Process for the Biocatalytic Production of (2<i>R</i>,5<i>R</i>)-Hexanediol","Alcohol dehydrogenase-catalyzed reductions of prochiral ketones to chiral alcohols require the regeneration of consumed cofactors such as NADH or NADPH. In the substrate-coupled cofactor regeneration approach, where 2-propanol is oxidized to acetone, complete conversion is inhibited by a thermodynamic limitation. This can be overcome by applying methods of in situ product removal techniques such as pervaporation. Here we present a new reactor concept which enables a continuous biocatalytic ketone reduction process with concurrent in situ removal of the byproduct acetone. In such a bimembrane reactor system recombinant Escherichia coli cells expressing alcohol dehydrogenase from Lactobacillus brevis were applied for the continuous reduction of 2,5-hexanedione. The product (2 R,5 R )-hexanediol could be synthesized with exceedingly high space-time yield of >170 g/(L·d) and catalyst usage (17.9 g P /g wetcellweight ).",10.1021/op9001643,0
Routes for the Synthesis of (2<i>S</i>)-2-Methyltetrahydropyran-4-one from Simple Optically Pure Building Blocks,"Routes to (2 S )-2-methyltetrahydropyran-4-one of high optical purity starting from readily available chiral pool precursors and suitable for large-scale manufacture are described. In one approach, the key step is cyclisation of ( S )-5-hydroxyhex-1-en-3-one, derived either from an alkyl ( S )-3-hydroxybutyrate or ( S )-propylene oxide. Formation of the tetrahydropyran ring directly via an intramolecular oxy-Michael reaction under acid-catalysed conditions resulted in loss of optical purity, whereas proceeding through the intermediate (2 S )-2-methyl-2,3-dihydropyran-4-one, via an oxidative Pd-catalysed ring closure, followed by hydrogenation of the alkenyl bond, preserved the optical purity. An alternative approach to (2 S )-2-methyl-2,3-dihydropyran-4-one is also reported, again starting from an alkyl ( S )-3-hydroxybutyrate by elaboration to a carbonyl-protected (6 S )-6-methyl-5,6-dihydropyran-2,4-dione derivative, followed by partial reduction and dehydration. Alternatively, the carbonyl group can be reduced out completely in one step to furnish (2 S )-2-methyltetrahydropyran-4-one directly after deprotection.",10.1021/op900163a,1
Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins,"A stereospecific synthesis of the drug-candidate &lt;b&gt;1&lt;/b&gt; is described. The synthetic sequence, aimed at accomplishing modularity and cost savings, features a series of organometallic steps to afford stereospecifically the desired trisubstituded olefin active pharmaceutical ingredient. Key developments consist of a mild Sonogashira reaction of aryl bromide &lt;b&gt;7a&lt;/b&gt; with the polymerization prone propargyl alcohol and a stereospecific hydroalumination, Zn/Al exchange, and Pd-catalyzed cross-coupling sequence facilitated by the commercially available PEPPSI catalyst.",10.1021/op9001609,0
"Development of Manufacturing Processes for a New Family of 2,6-Dihaloaryl 1,2,4-Triazole Insecticides","Details are presented on the process development work for the new 2,6-dihaloaryl-1,2,4-triazole insecticide 1, and the development of a one-pot process toward a potential commercial manufacturing process.",10.1021/op9001577,1
The Challenges of Developing an API Crystallization Process for a Complex Polymorphic and Highly Solvating System. Part I,"Developing a robust crystallization process for an active pharmaceutical ingredient (API) molecule with a complex polymorphic profile can present a significant challenge. The presented case illustrates an unusual crystallization development problem where a polymorphically complex API has the additional obstacles of poor solubility in standard crystallization solvents as well as a propensity for forming solvates. After early polymorph screening of this candidate highlighted the potential for a complex solid form profile, a variety of experimental approaches was utilized to determine the low-energy polymorph and characterize the various solvates formed. Characterization of the API crystallization process identified a critical solvent composition range for the transformation from a metastable solvate form to the desired polymorph. During subsequent crystallization process development studies, a new lower-energy polymorph was discovered. Examination of the crystal structures led to a rationale for the formation of solvates and the existence of a new lower-energy form.",10.1021/op9001559,0
An Efficient Laboratory Automation Concept for Process Chemistry,This concept article presents and outlines a successful strategy to roll out an automation concept on a broad basis to AstraZeneca Process R&D laboratories. Examples of hardware and software are presented as well as a couple of examples related to process safety.,10.1021/op900154c,0
An Improved Process for the Production of Rabeprazole Sodium Substantially Free from the Impurities,The present work details the journey towards development of a simple and cost-viable process for large-scale synthesis of rabeprazole sodium substantially free from the impurities. The detailed study of different parameters affecting the quality and yield percentage of the compound has been presented. Yield is increased from 40% (reported process) to 75% with the improved process at sulfoxidation stage.,10.1021/op900148x,1
Large-Scale Synthesis of a Selective Inhibitor of the Norepinephrine Transporter: Mechanistic Aspects of Conversion of Indolinone Diol to Indolinone Aminoalcohol and Process Implications,"Development of a scalable synthesis of WAY-315193 is described. Use of LiHMDS as a base and Ti(O- i -Pr) 4 as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylation−methylamination. The possibility of selective formation of the amidine side product, as well as its utilization for alternative selective preparation of the target aminoalcohol, was demonstrated.",10.1021/op900141r,1
Scalable Process for the Premix of Esomeprazole,"An efficient, scalable process for the premix of unstable esomeprazole base is described that allows accessibility to the stable amorphous form of esomeprazole 1 .",10.1021/op9001406,0
A Practical Solid Form Screen Approach To Identify a Pharmaceutical Glutaric Acid Cocrystal for Development,"Pharmaceutical cocrystals could be used to improve the physicochemical properties of active pharmaceutical ingredients. Here, a practical solid form screen approach to identify pharmaceutical cocrystals in the early development stage is proposed. This approach first used a cogrinding screen to identify potential cocrystal former leads that could form cocrystals with the compound of interest, followed by a solvent-based screen to identify, evaluate, and generate the cocrystal candidates. This approach not only allows fast identification of the cocrystal candidates but also provides insights on their scalability. Using this approach for the development drug candidate, a glutaric acid cocrystal was identified that provided an improved intrinsic dissolution rate in comparison to that of the free form, and therefore this cocrystal is potentially a better solid form for development. The effects of solvents and structures of cocrystal formers on the cocrystal formation and the rationales for this approach are also discussed.",10.1021/op900137j,0
From Batch to Flow Processing: Racemization of <i>N</i>-Acetylamino Acids under Microwave Heating,"The racemization of N -acetylindoline-2-carboxylic acid in p -xylene revealed beneficial rate enhancements due to microwave effects, by comparing conventional and microwave heating. The magnitude of this effect was governed by the degree of heterogeneity of the reaction system. The amount of catalyst, the temperature and the amount of cosolvent played a decisive role. The microwave effect completely vanished when a homogeneous solution was heated. During the microwave-assisted heterogeneous racemization of N -acetylphenylalanine in p -xylene a comparable microwave effect was observed. The microwave effects could be rationalized by adapting selective heating in the phase boundary region of solid and liquid. Additionally, a straightforward translation was achieved from batchwise operation in a stirred reactor to a batch-loop reactor. The (heterogeneous) racemization of N -acetylindoline-2-carboxylic acid retained its microwave effect in the loop reactor. Our results demonstrated that avoiding plugging of the tubular reactor is a severe challenge in scaling up.",10.1021/op9001356,0
An Improved Process for Pioglitazone and Its Pharmaceutically Acceptable Salt,An improved process for pioglitazone ( 1 ) is described. The process features high-yielding transformations employing inexpensive reagents and recoverable solvents.,10.1021/op900131m,1
An Improved Procedure for Preparation and Isolation of Cephalosporin Antibiotic: Cefozopran as Free Base,"An efficient synthesis of cephalosporin antibiotic, cefozopran is described. The present process does not involve chromatographic purification for isolation and is cost-effective and amenable to large-scale synthesis.",10.1021/op900128z,0
A New Industrial Process for 10-Methoxyiminostilbene: Key Intermediate for the Synthesis of Oxcarbazepine,"A new industrial process, involving only two isolation and drying steps, for 10-methoxyiminostilbene (MISB), an advance intermediate of widely prescribed antiepileptic drug, oxcarbazepine, has been developed. A salient feature of this process is the novel use of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) to afford bromohydrin methyl ether from N -acetyliminostilbene. The byproducts of this process namely acetic acid, 5,5-dimethylhydantoin and Et 3 N·HBr are recyclable as well as nontoxic. This process is amenable for the large-scale production of MISB.",10.1021/op900127v,1
Crystallisation from Water-in-Oil Emulsions As a Route to Spherical Particulates: Glycine and the Hydrochloride Salts of Glutamic Acid and Ephedrine,"Emulsion crystallization has been reported as an approach to controlling particle properties, and is part of a wider set of techniques that can be used to form spherical particles. In the pharmaceutical industry, spherical particles are known to present distinctive advantages in terms of flow and compression properties, for example over needles or laths. This study sought to define a possible working space for the development of emulsion crystallisation of materials that could mimic pharmaceutically active compounds. Crystallisation of three water-soluble materials, glycine, l -glutamic acid hydrochloride, and ephedrine hydrochloride from water-in-oil emulsions is explored. In particular, work on these compounds shows that the combined importance of stirring and surfactant and templating additive choice is evident in developing a practical route to utilising this technology. It is also evident that the relative solubility of the solute in the two liquid phases may totally preclude the use of the drops as crystallisation environments and lead to the unwanted growth of large crystals in the continuous phase.",10.1021/op900123n,0
Development of a Practical Synthesis of a Purine Nucleoside Phosphorylase Inhibitor: BCX-4208,"A practical synthesis of the purine nucleoside phosphorylase (PNP) inhibitor BCX-4208 ( 1) was accomplished in three telescoped steps. Mannich condensation of the 4-benzyloxy-9-deazahypoxanthine with (3 R,4 R )-3-hydroxy-4-(hydroxymethyl)pyrrolidine and formaldehyde followed by removal of the protecting group and crystallization furnished the desired product as a hydrochloride salt in 85% overall yield and 99.8% purity. A scalable synthesis of 9-deazahypoxanthine is also reported.",10.1021/op9001142,1
"First Multigram Preparation of SCP-123, A Novel Water-Soluble Analgesic",A short multi-gram process for the preparation of the analgesic compound SCP-123 (4) and its sodium salt has been developed.,10.1021/op900113b,1
A Low-Waste Process To Sertraline By Diastereomeric Crystal Resolution and Waste Isomer Racemisation,"A semi-continuous method for recovering waste sertraline isomers from a diastereomeric crystallisation process is described in which the mother liquors from a highly selective mandelic acid resolution for the (1 S,4 S ) isomer are treated sequentially with SCRAM, an iridium-based chiral amine racemisation catalyst, and then catalytic potassium tertiary butoxide to epimerise the methine chiral centre. The green, low-waste process also deals with recovery and recycle of the precious-metal catalyst, providing both good economics and high-quality product.",10.1021/op900112f,0
"Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile","The development and implementation of a scaleable process for the manufacture of the nonsteroidal progesterone receptor antagonist 8 is described. Key aspects of the synthesis include (i) a telescoped chlorination−etherification sequence to prepare diketone 4 and (ii) separation of pyrazole regioisomers 6 and 7 through formation of their hydrogen sulfate salts and selective crystallization, followed by oxidation to 8 .",10.1021/op900110k,1
"Practical Diastereoselective Synthesis and Scale-up Study of (+)-2-((1<i>R</i>,2<i>R</i>,3<i>R</i>,5<i>S</i>)-2-Amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol: A Key Intermediate of the Novel Prostaglandin D<sub>2</sub>Receptor Antagonist S-5751","A new synthetic process was developed for (+)-2-((1 R,2 R,3 R,5 S )-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)ethanol, a key intermediate of S-5751. Diastereoselective alkylation of (+)-nopinone with ethyl bromoacetate, formation of O -methyl oxime, and diastereoselective reduction with NaBH 4 −AlCl 3 could be safely carried out. Stereochemistry of the (1 R,2 R,3 R,5 S )-6,6-dimethylbicyclo[3.1.1]heptane ring was discussed to achieve high diastereoselectivity on these reactions. For the scale-up, detailed consideration was given to the safety of the NaBH 4 −AlCl 3 reduction.",10.1021/op9001092,1
Development of a Supply Route for the Synthesis of an iNOS Inhibitor: Complications of the Key S<sub>N</sub>2 Reaction,"The original medicinal chemistry synthesis of an iNOS inhibitor presented several challenges that had to be overcome in order to constitute a supply route suitable for operation on a multikilo scale. The key step in the synthesis is an S N 2 reaction that assembles the chiral carbon framework, but this reaction proved far more complex than we anticipated. Significant improvements were made to all stages. The modified route performed well over two pilot-plant campaigns and delivered over 250 kg of the active pharmaceutical ingredient (API).",10.1021/op900108b,0
Process Development for A Novel Pleuromutilin-Derived Antibiotic,"A scalable synthesis of a novel pleuromutilin-based antibiotic is reported. The synthesis features the scale-up of an interesting skeletal rearrangement of the pleuromutilin core and isolation of a highly purified product despite starting with relatively impure pleuromutilin. The use of Design of Experiment (DoE) and Principal Component Analysis (PCA) tools to achieve these goals is also discussed. Furthermore, the novel coupling of a carbamate and N -acyl-imidazole to produce the imidodicarbonate portion of the target molecule is described.",10.1021/op900104g,0
Removal of Heavy Metals from Organic Reaction Mixtures: Preparation and Application of Functionalized Resins,"Using a toolbox, sulfur and amine ligands are attached to a variety of hydrophobic and hydrophilic resins, and the combinations were tested for the removal of heavy metals from a number of products, prepared by metal-catalyzed reactions. As a result, cheap combinations of silica resins and simple polyamines proved to be among the most effective metal scavengers particularly in apolar solvents such as cyclohexane. Expensive cyclic polyamines are not suitable, owing to kinetic retardation of complexation. Functionalized PEG-based polymers, originally designed for solid phase synthesis, show promising performance as metal scavengers. The results are discussed and compared to alternative approaches for purification such as salt-formation and chemical downstream transformation.",10.1021/op900102a,0
An Improved and Single Pot Process for the Production of Quetiapine Hemifumarate Substantially Free from Potential Impurities,"An improved and single pot process for the preparation of Quetiapine hemifumarate ( 1 ), an antipsychotic drug, free from potential impurities is reported with an overall yield of 80%. The reported process for its preparation suffers from the drawback of producing potential impurities identified as 11-piperazin-1-yldibenzo[ b, f ][1,4]thiazepine ( 6 ), 2-(4-dibenzo[ b, f ][1,4]thiazepin-11-ylpiperazin-1-yl)ethanol ( 10 ), dimer ( 9 ), and N -methyl- N -phenyldibenzo[ b,f ][1,4]thiazapine-11-amine ( 14 ). Elimination of these impurities in the process is achieved by chlorination of 3 followed by in situ condensation of obtained 4 with highly pure 8 and subsequently establishing the pH based workup to obtain free base 2, which is further converted to quetiapine hemifumarate salt free from all these impurities. In this report, different aspects of process development such as scheme selection, optimization of different process parameters, identification, synthesis, origin and control of impurities, and development of an accurate analytical method during the development of a scalable process for quetiapine hemifumarate are discussed.",10.1021/op900097q,1
"A Simple, Efficient, Green, Cost Effective and Chemoselective Process for the Esterification of Carboxylic Acids","Carboxylic acids have been esterified under mild and solvent-free conditions in high yield and purity using the green reagents, dimethyl carbonate and diethyl carbonate, under acid catalysis. The present methodology is free of the disadvantages of base catalysis described earlier, such as high temperatures, use of autoclaves, use of the expensive DBU as base in stoichiometric amounts and the carbonate as solvent. High chemoselectivity is observed in the case of hydroxybenzoic acids.",10.1021/op900096y,0
Optimisation of Permanganate Oxidation and Suzuki−Miyaura Coupling Steps in the Synthesis of a Na<sub>v</sub>1.8 Sodium Channel Modulator,"The development is described of a viable kilo-scale synthesis of the Na v 1.8 sodium channel modulator, N -methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide (PF-1247324) in five steps, starting from 6-amino-5-bromo-2-picoline, in 33% overall yield. Two key steps required significant optimisation to improve yield and reproducibility. Oxidation of 6-acetamido-5-bromo-2-methylpyridine by permanganate to give the corresponding carboxylic acid derivative was improved by adding potassium dihydrogen phosphate, which moderated the reaction mixture pH and doubled the yield. The potassium fluoride-promoted Suzuki−Miyaura coupling between 2,4,5-trichlorophenylboronic acid and methyl 6-amino-5-bromopyridine-2-carboxylate, catalysed by tri( tert -butyl)phosphinepalladium (0), proceeded reliably to completion at room temperature in high yield when water was added. Anhydrous reaction mixtures reacted much more slowly, and ‘wet’ mixtures led to significant proto-deboronation in the absence of sufficient active catalyst. In the final step, amidation of the ester with methylamine gave PF-1247324.",10.1021/op900092h,1
New and Improved Manufacturing Process for Valsartan,"A new and improved industrially viable manufacturing process for valsartan, an antihypertension drug, is described.",10.1021/op9000912,1
Aqueous Process Chemistry: The Preparation of Aryl Sulfonyl Chlorides,"The use of aqueous acidic conditions for the preparation of arylsulfonyl chlorides from diazonium salts in the presence of copper salts, preferably CuCl, together with thionyl chloride as the sulfur dioxide source, has considerable advantages over recommended literature procedures, whereby reactions are carried out in acetic acid with minimisation of water content of the solvent. The method has been shown to be successful for a wide range of electron-deficient and electron-neutral aryl substrates. The sulfonyl chlorides are protected from hydrolysis by their low solubility in water, which results in their direct precipitation from the reaction mixture in good yields (>70%) and high strength (>98% w/w). The aqueous process, which is additionally safer and more robust, can be readily scaled up and has significant environmental benefits.",10.1021/op9000862,0
Renaissance of Traditional Organic Reactions under Microfluidic Conditions: A New Paradigm for Natural Products Synthesis,"Continuous flow synthesis for bioactive natural products is described. Efficient procedures using the microfluidic system were developed for the large-scale synthesis of important synthetic units of asparagine-linked oligosaccharide in glycoprotein. Advantageous aspects of microfluidic conditions, i.e., efficient mixing, fast heat transfer, and residence time control led to cation-mediated reactions, such as α-sialylation, β-mannosylation, and reductive opening of the benzylidene acetal groups in high yields. Microfluidic dehydration was developed for the industrial-scale synthesis of the immunostimulating natural terpenoid, pristane. The base-mediated aldol condensation in an aqueous biphasic system enabled the multigram synthesis of β-hydroxyketones in high yields.",10.1021/op900084f,0
"Intensification of the Capillary-Based Kolbe−Schmitt Synthesis from Resorcinol by Reactive Ionic Liquids, Microwave Heating, or a Combination Thereof","The continuous Kolbe−Schmitt synthesis of 2,4-dihydroxybenzoic acid from resorcinol was carried out using a setup with a capillary reactor of mm-internals and a micro heat exchanger. The process intensification potential of microwave irradiation for heating up the reactant solution and/or of using ionic liquids as carbonating reactants was evaluated. For the M icrowave assisted A queous K olbe− S chmitt synthesis ( MAKS ), power-to-temperature graphs were calibrated with water and real-case (ion-containing) solutions, revealing several features relevant for process control. Due to higher mean reaction temperatures inside the reactor thanks to faster heating, the yields of all MAKS experiments were higher as compared to the C onventionally H eated (oil bath) aqueous K olbe− S chmitt synthesis ( CHKS ) without use of microwave irradiation. The highest yield (before isolation and purification) obtained by MAKS was 52% (at 160 °C, 8 bar, 1 L/h, 90 s), exceeding the yield of CHKS by 5% (at 140 °C, 40 bar, 84 mL/h, 390 s) at a concurrent reduction of reaction time. The MAKS productivity, although lower than possible due to setup limitations (large internal volumes), was up to 67 g/h being in the same range as the CHKS productivity from 25 g/h (39%, 43 s) to 86 g/h (34%, 11 s). Two solutions of ionic liquids were used as CO 2 donating agents, a diluted (1.57 mol/L) and concentrated one (3.2 mol/L) with ethyl based methyl imidizoalium hydrogen carbonate (EMIMHC) and a concentrated one (2.7 mol/L) with butyl based methyl imidizoalium hydrogen carbonate (BMIMHC). The yield obtained for the ethyl based ionic liquid (e- CHILKS ) operation was 44% (at 180 °C, 35 bar, 0.17 L/h, 130 s) at a productivity of 5.9 g/h. The yield of b- CHILKS was 59% under the same conditions, yet with a higher productivity of 14.2 g/h. For the M icrowave assisted butyl I onic L iquid K olbe− S chmitt synthesis (e- MILKS ) a yield of 58% at a productivity of 25.3 g/h was derived.",10.1021/op9000803,0
Safety Advantages of On-Site Microprocesses,"Usually large-scale capacities are preferred in process industry because of the economics of scale. However, small capacities bring along several other advantages, which are emphasized especially in on-site production. By producing on-site, the transportation of dangerous chemicals can be avoided. Moreover, smaller on-site production processes also mean a step towards inherently safer technology. Microreactors represent a technology that efficiently utilizes safety advantages resulting from small scale. These safety advantages of microreactors in on-site production are studied in this contribution. Production of peracetic acid is used as a test case. This unstable and explosive chemical is used, e.g. in treatment of municipal wastewater and pulp bleaching. This study is based on comparison of a conventional batch process with the capacity of 170 kg/h and an on-site continuous microprocess producing 10 kg/h peracetic acid. Preliminary design of these processes was carried out. Four different methods were used to analyze the safety of the processes. It was found that the conventional methods for analysis of process safety might not be reliable and adequate for radically novel technology, such as microprocesses. This is understandable because the methods are partly based on experience, which is very limited in the connection of totally novel technology.",10.1021/op900079f,0
Controlling the Genotoxins Ethyl Chloride and Methyl Chloride Formed During the Preparation of Amine Hydrochloride Salts from Solutions of Ethanol and Methanol,"The genotoxins ethyl chloride (EtCl) and methyl chloride (MeCl) were generated during the preparation of the hydrochloride salts of two tertiary amines in the presence of ethanol and methanol, respectively. In EtOH five batches of a tertiary amine hydrochloride were prepared on 0.3−18 kg scale using 37% aqueous HCl; residual EtCl was detected at less than 10 ppm in each batch. The preparation of the hydrochloride salt of another tertiary amine in MeOH on a 3 kg scale produced salt with 11−12 ppm of MeCl, and these higher levels precipitated investigations into controlling the levels of residual MeCl in batches of the HCl salt of the second amine. Four rework procedures were developed to reduce the level of MeCl in one batch of HCl salt. Generating the salts at a lower temperature (10 °C) was the key parameter to minimize the concentration of these impurities in this drug candidate when HCl was charged as 37% aqueous HCl. Control of the process was demonstrated by preparing a 30 kg batch containing 1 ppm of MeCl without rework processing; this level of MeCl is well within the guideline of ≤1.5 μg for the daily dosage of this drug candidate. The analytical methods to detect EtCl and MeCl, which were critical for the development of these processes, are also described.",10.1021/op9000737,0
Development of an Open-Air and Robust Method for Large-Scale Palladium-Catalyzed Cyanation of Aryl Halides: The Use of <i>i</i>-PrOH to Prevent Catalyst Poisoning by Oxygen,"Palladium-catalyzed cyanation of aryl halides is an often capricious reaction and lacks robustness due to catalyst poisoning by oxygen. In this report, an open-air and robust method for large-scale cyanation was developed and the use of commercially available i -propanol as an additive was critical for achieving the open-air, robust and scaleable process. Under the protection by i -propanol, the catalyst life was significantly prolonged.",10.1021/op9000725,0
"A Novel Chiral Resolving Reagent, Bis((<i>S</i>)-Mandelic acid)-3-nitrophthalate, for Amlodipine Racemate Resolution: Scalable Synthesis and Resolution Process","A novel bis(( S )-mandelic acid)-3-nitrophthalate ( 1 ), a chiral resolving reagent for the separation of ( S )-(−)-isomers of amlodipine from the racemate thereof, is designed and synthesized. A simple three-step pilot-scale preparation of 1, along with the optimization of a resolution process on the racemate amlodipine, is reported.",10.1021/op900070c,1
A Convergent Synthesis of AR-C123196 Utilising Reaction Between a Cyclic Carbonate and a Phenol for Aryl Alkyl Ether Formation,The development of a convergent synthesis of AR-C123196 is reported in which the alkyl aryl ether linkage was formed by nucleophilic attack of a phenolic hydroxyl group onto a cyclic carbonate. This approach was successfully operated on a multikilogram scale.,10.1021/op9000687,1
Kilogram-Scale Synthesis of the CXCR4 Antagonist GSK812397,"An improved, scalable synthesis of the CXCR4 antagonist GSK812397 is described. This new route was recently scaled up in 50 L fixed equipment to afford 1.2 kg of drug substance in five steps with an overall yield of 20% and >99% chemical and enantiomeric purity.",10.1021/op9000675,1
An Ozonolysis−Reduction Sequence for the Synthesis of Pharmaceutical Intermediates in Microstructured Devices,"The advantages of microstructured reactors were utilized in a two-step process for the preparation of intermediates of vitamin D analogues, which are known to be important compounds in bone and mineral metabolism. The reaction sequence consisting of an ozonolysis step of a double bond and a subsequent reduction was successfully performed in a microplant. Concerning the feasibility and optimization of the two reaction steps in different microreactors, ozonolysis and reduction have initially been investigated separately. A miniaturized ATR sensor was employed for online monitoring of the ozonolysis step. The overall process was then performed in a continuous manner. The utilization of microstructured devices allows for the realization of a safe and highly controlled multistep process with online analysis via FTIR.",10.1021/op9000669,0
The Process Development of Ravuconazole: An Efficient Multikilogram Scale Preparation of an Antifungal Agent,"The development of a safe, robust process for the preparation of ravuconazole ( 1 ), an antifungal agent, is described. The discovery and development of procedures enabling the efficient synthesis of multikilogram quantities of 1 and the process demonstration through plant scale preparations are presented. A controlled means to prepare a Grignard reagent and utilization of Fourier Transform Infrared spectroscopy (FTIR) monitoring to safely conduct the reaction is featured.",10.1021/op900065c,1
An Efficient Process of Racemization of 3-(Carbamoylmethyl)-5-methylhexanoic acid: A Pregabalin Intermediate,"A simple and cost-effective process for racemization of undesired ( S )-3-(carbamoylmethyl)-5-methylhexanoic acid ( 9 ), produced during the resolution step, is described. The literature procedure is fraught with many difficulties including number of steps and hazardous reagents. We have developed a one pot process for the above-mentioned racemization of S -enantiomer. The basic objective is to convert S -enantiomer into the symmetrical glutarimide derivative followed by hydrolysis with an alkali. The transformation of 9 into glutarimide derivative ( 10 ) has been achieved with piperidine in refluxing toluene.",10.1021/op900064x,1
An Improved Process for the Preparation of Diphenylmethyl 7β-Phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate,"An efficient and improved process for the preparation of diphenylmethyl 7β-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate was developed. With the commercially available 7-aminocephalosporanic acid (7-ACA) as starting material, up to 73.5% overall isolated yield of the titled compound was synthesized in two steps via direct phenylacetylation with phenylacetyl chloride, followed by basic hydrolysis and esterification with diphenyldiazomethane. The newly developed process obviated the use of protecting groups, reduced the environmental footprint, and could be easily controlled and conveniently scaled up for this pivotal intermediate in cephalosporin chemistry.",10.1021/op900063e,1
"Efficient Synthesis of 1,4-Diaryl-5-methyl-1,2,3-triazole, A Potential mGluR1 Antagonist, and the Risk Assessment Study of Arylazides","A concise and practical synthesis of a 1,4-diaryl-5-methyl-1,2,3-triazole is described. A mGluR1 antagonist 1 was prepared with one-pot operation by the Negishi coupling reaction between two building blocks, 5-bromophthalimidine ( 2 ) and 1-aryl-5-methyl-4-triazolylzinc ( 3- Zn ). Bromide 2 was synthesized via N -selective cyclization of o -hydroxymethylbenzamide 8 easily prepared from phthalide 4 . Zinc species 3- Zn was generated in situ by transmetalation of 1-aryl-4-magnesio-5-methyltriazole ( 3- Mg ), which in turn was generated by the regioselective click chemistry between 2,4-difluorophenylazide ( 5 ) and propynylmagnesium bromide. The risk assessment of potentially explosive arylazides is also mentioned.",10.1021/op900062p,1
"Practical Synthesis of 5-Fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a Key Intermediate in the Preparation of Potent Deoxycytidine Kinase Inhibitors","A practical synthesis of 5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine, a key intermediate in the preparation of a new class of potent deoxycytidine kinase (dCK) inhibitors, is described. The commercially available 2,4-dichloro-5-fluoropyrimidine ( 12 ) is converted in four telescoped steps to tert -butyl 4-(4-amino-5-fluoropyrimidin-2-yloxy)piperidine-1-carboxylate ( 6a ) which upon deprotection gives 5-fluoro-2-(piperidin-4-yloxy)pyrimidin-4-amine dihydrochloride ( 1a ) in about 68% overall yield. This process proved to be an economical alternative to a Mitsunobu-based synthesis.",10.1021/op900060u,1
Model-Based Solvent Selection during Conceptual Process Design of a New Drug Manufacturing Process,"Using models, we have demonstrated an efficient approach to identify optimal solvent compositions during conceptual design of an active pharmaceutical ingredient (API) process. A ternary solvent system was considered for a reaction, extraction, distillation, and crystallization sequence. Two thermodynamic models, NRTL-SAC and NRTL, as well as Aspen modeling tools, were employed to predict the liquid−liquid, vapor−liquid, and solid−liquid phase behaviors. We used these modeling tools to identify a solvent composition space for the reaction that allows for reasonable reaction volume while continuously removing a byproduct into a second aqueous phase. This composition also reduces API loss during subsequent aqueous extractions. Furthermore, the composition of the organic phase allows for an efficient azeotropic distillation during solvent exchange, resulting in a shorter cycle time needed to achieve the desired composition for final crystallization. Overall solvent usage for the process is also significantly reduced. This approach was applied retrospectively to a late-stage API process under experimental development and was validated with the production of API of excellent quality at the pilot scale with solvent compositions of the process in agreement with those predicted by the models.",10.1021/op900058e,0
"A Facile, One-Pot Synthesis of Lacidipine Using in Situ Generation of Wittig Intermediates","An improved, one-pot process for the preparation of lacidipine ( 1 ) via an efficient in situ generation of Wittig intermediates is reported. Generation of ylide ( 4 ) by dehydrobromination of phosphonium salt ( 3 ) followed by in situ condensation of 4 with o- phthalaldehyde ( 5 ) to yield corresponding olefin ( 6 ) and its subsequent reaction with crotonate derivative ( 7 ) in the same pot furnished the drug substance 1 with an overall yield of about 51% over the reported yield of about 24% starting from the corresponding ylide. The present work overcomes the challenges associated with prior art processes such as chromatographic purifications, handling of unstable intermediates, and formation of byproducts as potential impurities. The interesting insights on the safety aspects of the process, drawn through calorimetric studies, rendered the successful implementation of the process at manufacturing facility.",10.1021/op900055u,1
An Improved and Scaleable Preparation of 7-Amino-3-vinylcephem-4-carboxylic acid,"A practical and efficient multikilogram-scale preparation of 7-amino-3-vinylcephem-4-carboxylic acid (7-AVCA), a key intermediate used in the synthesis of cefixime and cefdinir, is described utilizing p -methoxybenzyl 7-phenylacetamido-3-chloromethylcephem-4-carboxylate (GCLE) as a starting material. Reaction conditions were optimized to simplify the process, to improve the quality and to increase the yield. The process has been demonstrated on a multikilogram scale in 77% overall yield with a purity of >99%.",10.1021/op900053j,1
Adaptation of an Exothermic and Acylazide-Involving Synthesis Sequence to Microreactor Technology,"The original three-step batchwise synthesis of the pharmaceutical intermediate (1 R,2 S,4 S )-(7-oxa-bicyclo[2.2.1]hept-2-yl)-carbamic acid ethyl ester ( 4 ) from (1 R,2 S,4 S )-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester ( 1 ) encompassed a highly exothermic hydrazine quenching step as well as an acylazide intermediate. After appropriately modifying the reaction conditions, all three steps could be adapted to a microreactor system and a continuous process which permitted the desired carbamate 4 to be prepared under safe operating conditions in yields of 96%, 94%, and 84% for the three individual steps.",10.1021/op9000516,0
"An Efficient Synthetic Process for Scale-Up Production of 4,5-Diamino-2-(trifluoromethyl)benzonitrile and 5-Bromo-3-(trifluoromethyl)benzene-1,2-diamine","Starting from 4-amino-2-(trifluoromethyl)benzonitrile ( 6 ), an efficient and nonchromatographic process was developed for multihundred gram production of 4,5-diamino-2-(trifluoromethyl)benzonitrile ( 1 ) in 73% yield and 98 HPLC area% purity over four synthetic steps. The same synthetic strategy was applied to 4-bromo-2-(trifluoromethyl)aniline ( 7 ) that afforded 5-bromo-3-(trifluoromethyl)benzene-1,2-diamine ( 5 ) in 81% overall yield and 99% HPLC area% purity.",10.1021/op9000498,1
Preparation and Characterization of Theophylline−Nicotinamide Cocrystal,"Cocrystals have been increasingly recognized as an attractive alternative for solid forms of drug products. In this work, nicotinamide (NCT) was employed as a cocrystal former with the active pharmaceutical ingredient theophylline (TP). The theophylline−nicotinamide cocrystal (hereafter TP-NCT cocrystal) was prepared by solid-state grinding and slow evaporation from ethanol, and was characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage optical microscopy (HSM), Raman spectroscopy, and powder X-ray diffraction (PXRD) techniques. Pharmaceutically relevant properties such as powder dissolution rate, solubility and dynamic vapour sorption (DVS) of the TP-NCT cocrystal were evaluated. The results show that, the TP-NCT cocrystal, obtained in a 1:1 molar ratio of theophylline and nicotinamide, possesses unique thermal, spectroscopic, and X-ray diffraction properties. In addition, the solubility and hygroscopicity of the TP-NCT cocrystal were considerably higher than those of anhydrous theophylline.",10.1021/op900047r,0
"Special Issue Dedicated to Chris Schmid, Former Associate Editor of <i>Organic Process Research and Development</i>, Who Died in 2007","ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Issue Dedicated to Chris Schmid, Former Associate Editor of Organic Process Research and Development, Who Died in 2007Trevor LairdCite this: Org. Process Res. Dev. 2009, 13, 2, 127Publication Date (Web):March 3, 2009Publication History Received27 February 2009Published online3 March 2009Published inissue 20 March 2009https://pubs.acs.org/doi/10.1021/op900042mhttps://doi.org/10.1021/op900042meditorialACS PublicationsCopyright © 2009 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1527Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (46 KB) Get e-AlertscloseSUBJECTS:Paper,Process chemistry Get e-Alerts",10.1021/op900042m,0
"Response to the Comments by Snodin on Our Article “Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances” [<i>Org. Process Res. Dev</i>. Web publication November 13, 2008; DOI: 10.1021/op8002129; <b>2009</b>, <i>13</i>, 285−291.]","ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTResponse to the Comments by Snodin on Our Article ""Approaches to Assessment, Testing Decisions, and Analytical Determination of Genotoxic Impurities in Drug Substances"" [Org. Process Res. Dev. Web publication November 13, 2008; DOI: 10.1021/op8002129; 2009, 13, 285−291.]Duane PiersonView Author Information Eli Lilly and Company, Indianapolis, Indiana 46285, U.S.A.Cite this: Org. Process Res. Dev. 2009, 13, 3, 410Publication Date (Web):April 14, 2009Publication History Published online14 April 2009Published inissue 15 May 2009https://pubs.acs.org/doi/10.1021/op900041qhttps://doi.org/10.1021/op900041qletterACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views1601Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Impurities,Testing and assessment Get e-Alerts",10.1021/op900041q,0
Formation of 2-Trifluoromethylphenyl Grignard Reagent via Magnesium−Halogen Exchange: Process Safety Evaluation and Concentration Effect,"The thermal stability profile for a solution of 2-trifluoromethylphenyl magnesium chloride at 1.5 M concentration in THF was determined using an Advanced Reactive System Screening Tool (ARSST). The solution generated by employing Knochel’s magnesium−halogen exchange protocol showed highly exothermic decomposition. The decomposition begins at a low-onset temperature accompanied by a rapid temperature and pressure rise. Analysis of the decomposition mixture revealed the destruction of trifluoromethyl group and formation of fluoride ion. This decomposition profile was substantially attenuated by reducing the concentration of the solution to 0.5−0.6 M. Thus, it is strongly recommended that selecting an appropriate concentration for the reagent based on calorimetric evaluation should be included with procedural and engineering controls when considering any strategy for safe scale-up of trifluoromethyl-substituted phenyl Grignard solutions.",10.1021/op900040y,0
An Improved and Scalable Process for the Synthesis of Ezetimibe: An Antihypercholesterolemia Drug,"An efficient, cost-effective and large-scale synthesis of ezetimibe 1, an antihypercholesterolemia drug, is described. Chiral oxazolidinone chemistry was used to fix the required stereochemistry of the β-lactam ring, and the chiral oxazaborolidine chemistry was used to fix the hydroxyl group stereochemistry. The synthesis significantly lowers the cost and provides easy access to ezetimibe on large scale.",10.1021/op900039z,1
A Simple and Efficient Large-Scale Synthesis of Metal Salts of Medium-Chain Fatty Acids,"A simple, inexpensive, one-step general procedure was developed for the preparation of medium-chain fatty acid (MCFA) metal salts. This approach offers the advantage of a practical route and is superior to literature methods. Also, it overcomes many of the limitations previously reported for the preparation of fatty acid salts. The potential utility of this method is illustrated by the production of pilot-scale quantities of high-purity (>99.9%) sodium decanoate.",10.1021/op900038v,0
Preparative Chromatography with Extreme Productivity: HPLC Preparation of an Isomerically Pure Drug Intermediate on Multikilogram Scale,"A highly productive method for HPLC preparation of 7.5 kg of an isomerically pure drug intermediate is described. The method employs an IPA/heptane eluent with a Chromegabond Nitro stationary phase, and affords an unusually large productivity of 5.5 kkd (kilograms of desired product per kilogram of stationary phase per day). Details relating to the development and execution of the separation are provided, and possibilities for further improvements are discussed.",10.1021/op900035y,0
Development of an Acid-Washable Tag for the Separation of Enantiomers from Bioresolutions,"A separation tool involving the use of a vinyl ester amino acid as acyl donor in a bioresolution has been developed. The acid-washable acyl group acts as a removable tag, facilitating separation of the secondary alcohol from the bioresolution product mixture. The use of these acyl donors from cheap, commercially available amino acids has been demonstrated in conjunction with the hydrolase enzyme Candida antarctica lipase B in the selective acylation of a variety of secondary alcohols.",10.1021/op900028d,0
"A Practical, Kilogram-Scale Implementation of the Wolff−Kishner Reduction",A safe and practical strategy has been developed for the large-scale preparation of imidazole 7 . The key transformation involved the Wolff−Kishner reduction of the sterically demanding neopentyl-trifluoromethylcyclopropyl imidazole ketone 8 . The described process provided the desired product in 74% overall yield without recourse to chromatographic purification. Safety considerations which allowed for the reaction to be conducted safely on kilogram scale are discussed.,10.1021/op9000274,0
Book Review of Inherently Safer Chemical Process: A Life Cycle Approach,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Inherently Safer Chemical Process: A Life Cycle ApproachCite this: Org. Process Res. Dev. 2009, 13, 3, 656Publication Date (Web):March 18, 2009Publication History Received5 February 2009Published online18 March 2009Published inissue 15 May 2009https://doi.org/10.1021/op900026hCopyright © 2009 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views314Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (35 KB) Get e-Alerts Get e-Alerts",10.1021/op900026h,0
Endoscopy-Based in Situ Bulk Video Imaging of Batch Crystallization Processes,"External bulk video imaging (eBVI) of crystallization processes has proven to be a promising technique for metastable zone determination. In this contribution the endoscopy-based in situ bulk video imaging (iBVI) method is introduced. The video data are processed using the mean gray intensity method and by a digital image processing technique which aims to detect the first crystals during nucleation. The experiments have been carried out in a small-scale calorimeter CRCv4, during which the compensation heater and infrared spectroscopy signals were monitored. It is concluded that monitoring the onset of the apparent nucleation, formation of particles with detectable size, using the mean gray intensity (MGI) trend delivers similar performance to the calorimetric and IR spectroscopy signal, whereas the crystal recognition method is the fastest, allowing detection of nucleation earlier. The endoscopy-based nucleation monitoring technique is proposed as a complementary tool to existing process analytical technologies (PAT) since it provides an in situ, low-cost, robust, probe-based method for metastable zone identification which can be easily integrated and automated with existing laboratory hardware and software.",10.1021/op900019b,0
Utilization of Sequential Palladium-Catalyzed Cross-Coupling Reactions in the Stereospecific Synthesis of Trisubstituted Olefins,"A stereospecific synthesis of the drug-candidate 1 is described. The synthetic sequence, aimed at accomplishing modularity and cost savings, features a series of organometallic steps to afford stereospecifically the desired trisubstituded olefin active pharmaceutical ingredient. Key developments consist of a mild Sonogashira reaction of aryl bromide 7a with the polymerization prone propargyl alcohol and a stereospecific hydroalumination, Zn/Al exchange, and Pd-catalyzed cross-coupling sequence facilitated by the commercially available PEPPSI catalyst.",10.1021/op900015g,1
"Scale-Up of Trisodium [(3β,5β,12α)-3-[[4(<i>S</i>)-4-[Bis[2-[bis[(carboxy-<i>kO</i>)methyl]amino-<i>kN</i>]ethyl]amino-<i>kN</i>]-4-(carboxy-<i>kO</i>)-1-oxobutyl]amino]-12-hydroxycholan-24-oato(6-)]gadolinate(3-)], a Gd(III) Complex under Development As a Contrast Agent for MRI Coronary Angiography","Process chemistry involved in the discovery and development routes to trisodium [(3β,5β,12α)-3-[[4( S )-4-[bis[2-[bis[(carboxy- kO )methyl]amino- kN ]ethyl]amino- kN ]-4-(carboxy- kO )-1-oxobutyl]amino]-12-hydroxycholan-24-oato(6-)]gadolinate(3-)] ( B22956/1 ) starting from l -glutamic acid and (3α,5β,12α)-3,12-dihydroxycholan-24-oic acid is described. The best process is based on seven chemical steps and overcomes difficult purification protocols. Such process has been successfully implemented to prepare multikilogram batches of the target compound in 20% overall yield from (3α,5β,12α)-3,12-dihydroxycholan-24-oic acid.",10.1021/op900008a,1
"Research and Development of the Catalytic Oxidation of Methylacrylate to 3,3-Dimethoxy Methyl Propionate","A selective synthesis of 3,3-dimethoxy methyl propionate has been developed using a green approach, in which the key step is a palladium-catalyzed oxidation of methylacrylate in methanol using oxygen as oxidant. The relationship between several reaction parameters including catalyst composition, oxygen pressure, substrate/solvent ratio, reaction temperature and reaction performance have been discussed. The data obtained in combination with data on explosion limits enabled successful scale-up to a 2 L scale, giving the desired product in 82% yield and 99% purity. Special attention is paid to catalyst activity, catalyst cost contribution, solvent recovery and safety. The product is a valuable industrial fine chemical for the synthesis of pharmaceuticals, functionalized polymers and adhesives, as it contains a protected aldehyde functional group, an ester functional group and an activated methylene function.",10.1021/op900001p,0
Orthogonal Experiments in the Development of Organic Synthetic Processes,"A new strategy is presented for the design of explorative experiments in synthetic chemistry when the objective is to identify the important experimental variables. The methodology is based on Taylor expansion (response surface) models, and the principles are: A grid of possible settings of the experimental variables is laid out in the experimental domain. These experiments define a candidate design matrix, D C . From D C, a candidate model matrix, X C is defined by appending columns for each variable in the Taylor model X C is then factored by singular value decomposition (SVD), and X C = USV T . The rows in X C that are most parallel to the singular column vectors in V are selected, and the corresponding experiments in D C are identified. This gives the experimental design. The selected experiments are nearly orthogonal, and they span the dimensions of the model space. The experiments can be run in sequence, and thus, they allow for a systematic search, one experiment at a time. The design principles are illustrated by an example of the dibromination of an acetal. Four variables were studied, and from 12 experiments, all the main effects and all two-factor interaction effects were estimated. From the response surface model, conditions for quantitative yield were predicted, and a mol-scale synthesis carried out under these conditions afforded 98% yield of the isolated pure, >97% product.",10.1021/op800322h,0
Process Development of a Potent Bradykinin 1 Antagonist,"As part of Merck’s continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin 1 antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal−halogen exchange reaction on 1,2-dibromo-5-chloro-3-fluorobenzene using isopropyl magnesium chloride to install the 1,2,4-oxadiazole ring structure. Suzuki cross-coupling reaction between a highly functionalized and sterically hindered electrophile and boronic ester generated the biaryl ring system, which was converted to the target molecule ( 1 ) using standard chemistry. The safe installation of a 1,2,4-oxadiazole ring proved to be challenging since the original synthetic route relied on the preparation of a highly functionalized benzonitrile using potassium cyanide and resulted in low yields and large amounts of potentially hazardous waste. Overall, a safe and robust synthesis was developed, which occurred in eight linear steps with an overall yield of 28%.",10.1021/op8003184,1
Continuous Biocatalytic Processes,"In this review article, recently developed continuous biotransformation processes are discussed. The processes are used to carry out resolution, redox reactions, hydrolysis/esterification, C−C bond formation, and other reactions. Examples of continuous downstream processing are also included.",10.1021/op800314f,0
A Convenient One-Step Synthesis of Methyl 2-Benzamidomethyl-3-oxobutanoate,"A convenient one-step process for the preparation of methyl 2-benzamidomethyl-3-oxobutanoate ( 1 ), a raw material used in the synthesis of (2 R,3 R )-3-(( R )-1-( tert -butyldimethylsilyloxy)ethyl)-2,3-dimethyl-4-oxoazetidin-2-yl acetate ( 2 ), a key intermediate for carbapenem synthesis is reported. The process is carried out under mild reaction conditions and is amenable to large-scale synthesis.",10.1021/op800313t,1
Development and Large-Scale Preparation of an Oral TACE Inhibitor,"An efficient, expedient synthesis of BMS-561392, 1, which enabled rapid delivery of drug substance for clinical development is described. The key features of the synthesis include an efficient synthesis of a phenolic α,α-disubstituted amino ester via carbon alkylation without protection of the phenol, an effective enzymatic resolution of this racemic amino ester, and a process for the preparation of a hydroxamic acid drug substance with undetectable levels of hydroxylamine.",10.1021/op800308t,1
The Synthesis of a Dopamine D<sub>2</sub> Partial Agonist for the Treatment of Schizophrenia,"The synthesis of the phosphoric acid salt of dopamine D 2 partial agonist 2-{4-[4-(7-fluoro-naphthalen-1-yl)-piperazin-1-yl]-butoxy}-5,6,7,9-tetrahydro-1,7,9-triaza-benzocyclohepten-8-one ( 1 ) is reported. The most prominent feature of the molecule is a seven-membered ring urea functionality that has been prepared via an efficient one-pot, three-step transformation. The original synthesis from the Medicinal Chemistry group provided precursor 13 in 10 steps and 2% overall yield, required four chromatographies and employed unsafe reagents such as 2-iodoxybenzoic acid (IBX) and HClO 4 . The optimized synthetic route for the preparation of phosphate salt 1 consists of 12 linear steps with a 10% overall yield. Safer and more robust reaction conditions have been developed with only one required chromatography. Another key step in the synthesis is the coupling of iodide 25 with naphthalenopiperazine 12 to provide 13 . Due to the difficulty to purify this intermediate, a protocol had to be developed to obtain crude material with the required purity, suitable for use in the subsequent salt formation step. Finally, considerable work was carried out to determine the most stable polymorph of the API. As a result, a robust set of conditions has been developed for the formation of phosphoric acid salt 1, providing the desired polymorph in excellent yield and purity.",10.1021/op800307k,1
Book Review of Good Manufacturing Practices for Pharmaceuticals,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Good Manufacturing Practices for PharmaceuticalsDerek RobinsonView Author Information Little Mill, Monmouthshire, [email protected]Cite this: Org. Process Res. Dev. 2009, 13, 2, 362Publication Date (Web):January 6, 2009Publication History Received9 December 2008Published online6 January 2009Published inissue 20 March 2009https://doi.org/10.1021/op8003053Copyright © 2009 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1230Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (36 KB) Get e-AlertsSUBJECTS:Industrial manufacturing,Manufacturing,Pharmaceuticals Get e-Alerts",10.1021/op8003053,0
Practical One-Pot and Large-Scale Synthesis of <i>N</i>-(<i>tert</i>-Butyloxycarbonyl)-3-pyrroline,"N -( tert -Butyloxycarbonyl)-3-pyrroline was prepared with high purity in large scale starting from cis -1,4-dichloro-2-butene via delepine reaction and subsequent cyclization in the presence of potassium carbonate followed by N- Boc protection in methanol. Judicious selection of base and solvent led to the use of a single solvent, i.e., methanol, for cyclization as well as for N- Boc protection to render the one-pot process from compound 2 more practical and greener than the stepwise version.",10.1021/op8003037,1
Application of a Batch Microwave Unit for Scale-Up of Alkoxycarbonylation Reactions Using a Near-Stoichiometric Loading of Carbon Monoxide,"The ethoxycarbonylation of iodobenzene was performed on the 1 mol scale in batch mode using microwave heating. The reaction was performed using both an excess and a near stoichiometric loading of carbon monoxide, comparable yields being obtained. Six different alkoxycarbonylation reactions were then performed simultaneously on the 50 mmol scale using a near-stoichiometric loading of carbon monoxide with excellent conversions in each case.",10.1021/op800296d,0
"Development of a Multigram Asymmetric Synthesis of 2-(<i>R</i>)-2-(4,7,10-Tris <i>tert</i>-Butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic Acid, 1-<i>tert</i>-Butyl Ester, (<i>R</i>)-<i>tert</i>-Bu<sub>4</sub>-DOTAGA","A process for the multigram asymmetric synthesis of the chiral tetraazamacrocycle 2-( R )-2-(4,7,10-tris tert -butylcarboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)-pentanedioic acid, 1- tert -butyl ester (( R )- tert -Bu 4 -DOTAGA, 4 ) has been devised and demonstrated. The nine-step synthesis features an improved synthesis of 2-( S )-5-oxotetrahydrofuran-2-carboxylic acid, tert -butyl ester 8, the precursor to the novel alkylating agent ( S )-5-benzyl 1- tert -butyl 2-(methylsulfonyloxy)pentanedioate 12, which was used to introduce an orthogonally protected chiral glutarate arm to the 1,4,7,10-tetraazacyclododecane (cyclen) nucleus in high optical purity. Cyclen derivative ( R )- t -Bu 4 -DOTAGA, 4, a key intermediate for the manufacture of a magnetic resonance imaging (MRI) candidate, was produced with high chemical (≥95%) and optical (ee ≥ 97%) purity. The process developed was successfully applied to the kilogram-scale cGMP synthesis of ( R )- t -Bu 4 -DOTAGA.",10.1021/op8002932,1
A New Approach to the Synthesis of 4-Hydroxyethylsulfonylstyrene,"A new, more environmentally benign route to hydroxyethylsulfonylstyrene has been developed, starting from 4-bromobenzenethiol, involving a solventless thioether formation, water-based perborate oxidation, and Suzuki−Miyaura cross coupling with a vinylborate reagent.",10.1021/op800292b,1
Development of a Scaleable Synthesis of a Partial Nicotinic Acid Receptor Agonist,"A practical and efficient synthesis of 1,4,5,6-tetrahydro-3-(1 H -tetrazol-5-yl)cyclopenta[ c ]pyrazole, 1, is described. A new one-pot process has been developed, starting from the commercially available 1 H -tetrazole-5-carboxylic acid-ethyl ester sodium salt which is reacted in a pseudo -Claisen condensation reaction with cyclopentanone, followed by the addition of hydrazine.",10.1021/op800290t,1
"An Investigation on Key Parameters that Influence the Synthesis of (<i>S</i>)-(+)-<i>N</i>,<i>N</i>-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine: A Key Intermediate for Duloxetine","This document highlights the systematic study of influencing factors such as temperature, base, catalyst, and solvent volume in the synthesis of ( S )-(+)- N, N -dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine oxalate 11a, without affecting the chiral purity.",10.1021/op800289h,1
"Practical, Highly Convergent, Asymmetric Synthesis of a Selective PPARγ Modulator","A practical, highly convergent, asymmetric synthesis of a selective PPARγ modulator 1 is described. The inhibitor contains two key components, a 6-trifluoromethoxy-3-acylindole ( 6 ) and ( R )-α-aryloxybutanoic acid derivative ( 10 ). Two methods were developed to overcome the regioselectivity issues encountered in the preparation of the 6-substituted indole. The first involved an intramolecular Heck reaction of an iodoaryl enamine. The second involved application of a catalytic Meerwein arylation reaction between 2-nitro-4-trifluoromethoxyaniline and isopropenyl acetate and subsequent reductive cyclization. The α-aryloxybutanoic acid was prepared via an asymmetric hydrogenation of the corresponding α-aryloxy-α,β-unsaturated acid. Tetrabutylammonium iodide-catalyzed coupling of the two fragments and ester hydrolysis completed the convergent synthesis. The described convergent synthesis was used to prepare >3 kg of drug substance 1 in 50% overall yield and with >99.5% ee.",10.1021/op8002882,1
Book Review of Clean-In-Place for Biopharmaceutical Processes,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Clean-In-Place for Biopharmaceutical ProcessesDerek RobinsonView Author Information 38 Millbrook Court, Little Mill, Pontypool NP4 0HT, United KingdomCite this: Org. Process Res. Dev. 2009, 13, 1, 125Publication Date (Web):December 18, 2008Publication History Received12 November 2008Published online18 December 2008Published inissue 16 January 2009https://pubs.acs.org/doi/10.1021/op800287bhttps://doi.org/10.1021/op800287bbook-reviewACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views788Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Beverages,Chemical engineering and industrial chemistry,Elements,Manufacturing,Materials Get e-Alerts",10.1021/op800287b,0
"A Simple and Efficient Process for the Preparation of 1,6-Dimethoxynaphthalene","1,6-Dimethoxynaphthalene (1,6-DMN) was prepared by the O -dimethylation of 1,6-dihydroxynaphthalene (1,6-DHN) with dimethyl sulfate (DMS) in the presence of sodium hydroxide and additives in different solvents. The main reaction determining factors were divided into three categories with respect to yield and purity of 1,6-DMN: (1) Type of solvents and adding methods of NaOH had the highest effect on the results. (2) Amount of DMS and concentration of NaOH were less important. (3) Reaction time and temperature were the least important factors. The best reductant was Na 2 S 2 O 4, and it was only under N 2 atmosphere that yield and purity were also good. The improved process provides more than 99% yield, which considerably reduces the cost of 1,6-DMN, and more than 98% purity eliminates the purification process in the follow-up industrial production.",10.1021/op800285t,1
Practical Synthesis of Roscovitine and CR8,"Roscovitine and CR8 are potent inhibitors of cyclin-dependent kinases. A scalable synthesis of both inhibitors is described. In the case of CR8, the biarylmethylamine moiety was obtained as a stable and high-purity salt.",10.1021/op800284k,1
Synthesis of the NK1 Receptor Antagonist GW597599. Part 2: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine,"GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields, and produced high levels of wastes. Through a targeted process of research and development, application of novel techniques, and extensive route scouting, a synthetic route for GW597599 has been developed. This paper reports the optimisation work of the second stage in the chemical synthesis of GW597599: the development of a pilot-plant-suitable process for the manufacturing of an optically pure arylpiperazine derivative. In particular, the new process eliminates the need to purchase and store dangerous and expensive borane by generating it in situ and also the need for a chlorinated solvent, thereby improving the safety of the process and substantially reducing the overall waste. The final yield and throughput will be significantly enhanced.",10.1021/op8002823,1
Lipase-Catalyzed Polycondensation in Water: A New Approach for Polyester Synthesis,"The lipase-catalyzed polycondensation of sebacic aid and 1,4-butanediol can be performed in a biphasic reaction system composed of an aqueous reaction phase and an organic extraction phase. The shift of the equilibrium to higher product yields can be realized by the integrated product removal (IPR). In this biphasic reaction system the product yield, molecular weight and polydispersity is depending on the partitioning of the substrates and the product between the phases. By the biphasic approach substrate inhibition as well as molecular weight and polydispersity can be controlled by medium engineering. The polyester concentration can be increased up to 98% by optimising the reaction conditions. The molecular weight is limited in the biphasic system due to its removal while the polydispersity is independent of the reaction conditions but connected to the biphasic approach. Additional to the conversion the partition coefficients have been investigated either experimentally and via calculation by the quantum chemical program COSMO-RS.",10.1021/op8002807,0
A Practical Palladium-Catalyzed Telomerization for the Synthesis of Functionalized Alcohols,"The synthesis of octadienyl-substituted alcohols via palladium-catalyzed telomerization is described. 2- N -Methylaminoethanol, ethylene glycol, and 1,2-propylenediol react smoothly with 1,3-butadiene to give valuable intermediates for speciality polymers in high selectivity and quantitative yield on multi-100 g-scale.",10.1021/op800278g,0
A Scalable Synthesis of the INOS Inhibitor PHA-399733,This contribution describes a scalable synthesis of the INOS inhibitor PHA-399733 using the Bucherer−Bergs hydantoin synthesis to introduce the amino acid function.,10.1021/op8002745,1
"Development of a Sequential Tetrahydropyran and Tertiary Butyl Deprotection: High-Throughput Experimentation, Mechanistic Analysis, and DOE Optimization","The synthesis of compound 1 by deprotection of the THP, tert -butyl protected amino-pyrazolopyridine ( 2 ), is described. The original conditions for this transformation were conducted in a one-pot procedure and necessitated the use of large quantities of either TsOH or benzenesulfonic acid (5 equiv) and trifluoroacetic acid (10−25 equiv) and produced 1 in moderate yield (50−65%). A series of high-throughput screens of Brønstead acids, Lewis acids, and solvents was rapidly performed with the goal of identifying improved efficiency and reaction yield. Through these screens, sulfuric acid was discovered to be a suitable replacement; however, yields of 1 were still unacceptable. A decoupling of the two deprotection steps revealed that the THP byproduct resulting from removal of the THP protecting group was problematic in the subsequent removal of the tert -butyl group. Consequently, a two-step deprotection protocol was developed which, in combination with design of experiment (DOE) optimization, improved the overall yield to ∼86%.",10.1021/op8002739,0
"New Efficient Asymmetric Synthesis of Taranabant, a CB1R Inverse Agonist for the Treatment of Obesity","Taranabant ( 1 ) is a cannabinoid-1 receptor (CB1R) inverse agonist that was recently in late-stage clinical development for the treatment of obesity. The previously employed synthesis exhibited a number of shortcomings for continuing development, and in this paper we report an improved synthesis of the target molecule that is suitable for large-scale implementation. Palladium-catalyzed amidation of an enol tosylate afforded a stereodefined tetrasubstituted enamide, and asymmetric hydrogenation thereof provided the target molecule.",10.1021/op800270e,1
"Facile, Fast and Safe Process Development of Nitration and Bromination Reactions Using Continuous Flow Reactors","Chemists working in a pilot plant often face safety issues during scale-up operations. With the help of emerging microfluidic applications and microdevices, running hazardous, highly exothermic or potentially unstable reactions can be easily transposed into a safe continuous flow mode. This paper describes how a potentially hazardous pyrazole nitration and the bromination of a variety of electron-rich heteroaromatic substrates were efficiently performed using a cheap and easily available system for bench chemists. Advantages of the continuous flow mode in organic synthetic chemistry will be exemplified by the large-scale production of raw materials under safe, green and reproducible conditions.",10.1021/op8002695,0
"A Scalable, Enantioselective Synthesis of the α<sub>2</sub>-Adrenergic Agonist, Lofexidine","A scalable and high-yielding synthetic route toward pure enantiomers of the α 2 -adrenergic agonist, lofexidine hydrochloride, is presented. Salient features include a rapid one-pot amide alkylation-imidazoline formation sequence on the carboxamide function of α-(2,6-dichlorophenoxy)propionamide, while preserving the sensitive configuration about the α-carbon of the resulting product. A means to accelerate the sluggish O -alkylation of the carboxamide function of α-(2,6-dichlorophenoxy)propionamide by Me 3 O + BF 4 − is also described, which may be of general applicability.",10.1021/op8002689,1
Preparation of a Corticotropin-Releasing Factor Antagonist by Nucleophilic Aromatic Substitution and Copper-Mediated Ether Formation,"Several synthetic approaches to a corticotropin-releasing factor (CRF) antagonist containing a tetrasubstituted pyridine were evaluated. In particular, nucleophilic aromatic substitutions on 2,4-dichloropyridine derivatives were attempted using 2,6-dimethyl-4-chlorophenol ( 4 ), ( S )-2-aminobutanol ( 7 ), and several sulfur nucleophiles. It was found that a copper-mediated coupling of a phenoxymesylate ( 26 ) was preferred for preparation of the diarylether followed by nucleophilic aromatic substitution to introduce the amine side chain, affording the desired drug candidate ( 1 ) in two steps from the commercially available methyl 2,4-dichloro-6-methylnicotinate ( 2 ).",10.1021/op800266x,1
"Improved Synthesis of 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes","A batch process was developed to produce 1-(azidomethyl)-3,5-bis-(trifluoromethyl)benzene, 1, in 94% yield by an efficient nucleophilic substitution reaction between 3,5-bis-(trifluoromethyl)benzyl chloride, 4, and sodium azide. Hydrazoic acid (HN 3 ), a toxic volatile compound with explosive properties, can be formed in the reactor headspace during conventional batch processing that requires significant engineering controls. In order to improve the overall safety profile, the process to produce azide 1 was optimized for operation in a microcapillary tube reactor. In addition, azide 1 was prepared in a simple biphasic solvent system using phase-transfer catalysis which results in an overall low e -factor. The product was purified via wiped film evaporation (WFE) technology.",10.1021/op800265e,1
"Preparation, Use, and Safety of <i>O</i>-Mesitylenesulfonylhydroxylamine",The aminating reagent O -mesitylsulfonylhydroxylamine (MSH) has a known potential hazard since it contains high-energy functional groups in its structure. There are references in the literature that report several incidents involving the use of pure and crystalline MSH. The preparation and safe use of this reagent at kilo scale are described herein.,10.1021/op800264p,0
Loss Prevention and Waste Minimization with Cascade-Engineered Green Synthesis of Bisphenol-A from Cumene Hydroperoxide and Phenol using Heteropoly Acid-Supported Clay Catalysts,"Bisphenol-A (BPA), an important raw material for the synthesis of epoxy resins and other polymers, is conventionally synthesised by acid-catalysed condensation of phenol and acetone, which produces 28 known byproducts. This leads to heavy costs for purification of the final product and loss of raw material. Phenol itself is almost exclusively manufactured via the three-step Hock process which includes vapour-phase isopropylation of benzene to cumene, autoxidation of cumene to cumene hydroperoxide (CHP), and finally the highly exothermic liquid acid-catalysed cleavage of CHP to acetone and phenol. The second step in the Hock process produces around 35% w/w CHP, which is then concentrated to 80% w/w. There are inherent process hazards involved in the manufacture and/or concentration of CHP, leading to run-away situations and explosions. Cascading these two series reactions in a single pot using the same catalyst fits elegantly into the concept of waste minimization and results in a greener and cleaner environment with added economic incentives. Traditionally, single-pot synthesis overlooks the concepts of atom economy, reaction mass efficiency and the environmental impact factor which are of prime importance to any methodology desiring to be called “green synthesis”. In this work, a novel technique of BPA synthesis from CHP and phenol was engineered in a single pot by using 20% w/w dodecatungstophosphoric acid (DTP) supported on acidic clay (K-10) at 100 °C, wherein CHP produced in cumene itself and was used along with phenol to make BPA. The process is atom economical, producing water as a coproduct. In comparison with the traditional process of making BPA from phenol and acetone, there is 58% enhancement in yield and 33% enhancement in BPA selectivity. There is also a 28% improvement in reaction mass efficiency and 25% reduction in the environmental impact factor. Along with preserving the atom economy, the hazard involved in the concentration and handling of CHP, which has resulted in numerous accidents in process industries, has been eliminated. In the current process CHP produced from cumene by the Hock process is used as such without separation, and this strategy avoids the hazards of concentration and costs of separation. Finally, a comprehensive parametric sensitivity was also done, and a Langmuir−Hinshelwood−Hougen−Watson (LHHW) model was developed to describe the reaction mechanism. The theoretical predictions were found to match the experimental data.",10.1021/op800262u,0
"Synthesis of 2-Methyl-2,5-diazabicyclo[2.2.1]heptane, Side Chain to Danofloxacin","Various syntheses of the side chain of the quinolone antibiotic danofloxacin are described. The realization that the N -methyl substitution on the side chain 2-methyl-2,5-diazabicyclo[2.2.1]heptane can reside on either nitrogen, due to the symmetry of the molecule, played a major role in the design of the commercial synthetic route.",10.1021/op8002618,1
"Efficient Synthesis of (2<i>S</i>,3<i>S</i>)-2-Ethyl-3-methylvaleramide Using (1<i>S</i>,2<i>S</i>)-Pseudoephedrine as a Chiral Auxiliary","An efficient and scaleable synthesis of (2 S,3 S )-2-ethyl-3-methylvaleramide ( 1 ) has been developed starting from inexpensive and readily available l -isoleucine. The key step in this process is an asymmetric alkylation using (1 S,2 S )-pseudoephedrine as a chiral auxiliary. A practical procedure was developed to remove the sterically hindered pseudoephedrine auxiliary from the amide. The process consists of eight chemical steps and five isolations without any chromatographic purification. It has been successfully implemented to prepare several multikilogram batches of the target compound 1 in 41% overall yield.",10.1021/op800260j,1
The Impact of Process Chemists and Engineers on Green Chemistry,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTThe Impact of Process Chemists and Engineers on Green ChemistryNealG. AndersonView Author Information Anderson's Process Solutions LLC, 7400 Griffin Lane, Jacksonville, Oregon 97530, U.S.A. E-mail: [email protected]Cite this: Org. Process Res. Dev. 2008, 12, 6, 1019–1020Publication Date (Web):November 6, 2008Publication History Received9 October 2008Published online7 November 2008Published inissue 21 November 2008https://pubs.acs.org/doi/10.1021/op800259phttps://doi.org/10.1021/op800259peditorialACS PublicationsCopyright © 2008 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3361Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (58 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Green chemistry,Materials,Separation science,Wastes Get e-Alerts",10.1021/op800259p,0
An Efficient Synthesis of a Multipotent Eicosanoid Pathway Modulator,"An efficient, scalable synthesis of the multipotent eicosanoid pathway modulator 2-[3-[3[[5-ethyl-4′-fluoro-2-hydroxyl[1,1′-biphenyl]-4-yl]oxy]-propoxy]2-propoxylphenoxy]benzoic acid ( 1 ) is described. The process consists of nine chemical steps with the longest linear sequence having six isolations. Palladium metal-mediated cross-coupling assembles the biaryl fragment, and selective S N Ar chemistry is used to construct the resorcinol fragment. The synthesis converges at a phenolic coupling with an alkyl chloride to give the core structure of the active pharmaceutical ingredient (API). Further elaborations of the core and salt formation provides the final API. This process produced the drug candidate in 41% overall yield at multikilogram scale.",10.1021/op800257u,1
"Development of a Practical and Efficient Synthesis of CP-945,598-01, a CB<sub>1</sub> Antagonist for the Treatment of Obesity","Development of an efficient bond-forming sequence and optimization of reaction conditions are described for the synthesis of CP-945,598-01 ( 1 ·HCl), a CB 1 antagonist in clinical studies for the treatment of obesity. Reordering of the bond-forming sequence provided a more efficient synthesis and avoided the use of phosphorous oxychloride. A telescoped reaction sequence ( 4 → 9 ) was developed to avoid a problematic isolation. Product isolations were developed so as to provide efficient throughput by minimizing solvent volumes and avoiding slow filtrations.",10.1021/op800255j,1
Development of Scaffold Synthesis for the Preparation of New Insulin-Like Growth Factor 1 Receptor Inhibitors,"The synthesis of new insulin-like growth factor 1 receptor (IGF-1R) inhibitors is reported. The described molecules have a new sulfonyl-indazole structure. We describe the process research and development for the scaffold synthetic procedure in order to provide the large amount of product required for lead optimization, candidate selection, and preclinical studies.",10.1021/op8002536,1
Development of a Practical Synthesis of a p38 MAP Kinase Inhibitor,"A practical synthesis of the phthalazine-based p38 MAP kinase inhibitor [( S )- 2 ] was needed for an ongoing program. Vibrational circular dichroism provided the assignment of the absolute stereochemistry of the target compound. The selected synthetic route for ( S )- 2 required identification of efficient reaction conditions for the construction of carbon−oxygen, carbon−carbon, and carbon−nitrogen bonds to connect the key building blocks. An efficient two-step method (chlorodehydroxylation, aromatic nucleophilic substitution) for the synthesis of arylether [( S )- 10 ] was developed. PAT ( in situ Raman spectroscopy) was utilized to monitor and control the formation of a lithium alkoxide in this reaction. The synthesis of ( S )- 2 was completed using high-yielding Suzuki- and amide-coupling reactions. The isolation conditions for these steps were optimized to obtain material of very high purity without the need for any complicated workup procedures.",10.1021/op800250v,1
Crystallisation Design Space: Avoiding a Hydrate in a Water-Based Process,"Many compounds can exist in either hydrated or anhydrous crystalline forms. The demands of robust processing and consistent product performance usually mean that only one of these two forms is desired, and that mixtures are unacceptable. Where the crystallisation is preceded by a phase separation and a distillation, liquid−liquid, vapor−liquid and solid−liquid equilibria all affect the outcome. The theory behind these equilibria is presented to show how they intersect. This approach is applied to a practical example in which a nominally “nonaqueous” liquid layer is separated from an “aqueous” layer and then distilled with simultaneous crystallisation. In-line technology is used in the laboratory to assist in the definition of a “Design Space”— an area in which this complicated isolation process operates robustly at scale using simple, conventional measurements.",10.1021/op800249r,0
The Role of New Technologies in Defining a Manufacturing Process for PPARα Agonist LY518674,"The impact of several new technologies on the development of a manufacturing process for LY518674 is described. Extensive use of process analytical technology (PAT) throughout development, both at laboratory and pilot-plant scale, enabled data-rich experiments, shortened development cycle times, and obviated the requirement of PAT for process control at larger scale. In situ ReactIR was used to develop a kinetic model for a one-pot preparation of a semicarbazide intermediate. Parallel crystallizers fitted with online focused-beam reflectance measurement (FBRM) and particle vision and measurement (PVM ) probes were used in the development of several challenging crystallization processes. Application of the process knowledge afforded by these technologies, combined with the principles of Quality by Design, resulted in excellent purity control throughout the four-step process. A single, 5-min, MS-friendly method capable of separating over 30 components was developed using a combination of chromatography modeling software, sub-2 μm column technology, and higher-pressure LC equipment. The method was used across all four processing steps, greatly facilitating impurity tracking, and reducing assay time and solvent use by 85% and 93%, respectively.",10.1021/op8002486,1
"Practical Synthesis of Chiral 2-Morpholine: (4-Benzylmorpholin-2-(<i>S</i>)-yl)-(tetrahydropyran-4-yl)methanone Mesylate, a Useful Pharmaceutical Intermediate","A commercial synthesis was developed for the production of (4-benzylmorpholin-2-( S )-yl)-(tetrahydropyran-4-yl)methanone mesylate, 1a, a key starting material for a phase 2, new investigational drug candidate at Eli Lilly and Company. The target compound was produced in the clinical pilot plant by the combination of two key steps: resolution of a morpholine amide intermediate to install the S -morpholino stereocenter in 35% yield and a high-yielding (89%) Grignard reaction to generate the title compound 1a, isolated as a mesylate salt. The Grignard reaction was found to proceed optimally when using a combination of I 2 and DIBAL-H for the initiation. In addition, the Grignard reagent formation was monitored by ReactMax calorimetry, and proof-of-concept studies were completed, demonstrating that the Grignard step could potentially be run as a continuous process with magnesium recycling.",10.1021/op800247w,1
"Scalable Non-Aqueous Process to Prepare Water Soluble 3-Amino-pentan-1,5-diol","The development of a nonaqueous process for the synthesis of 3-amino-pentan-1,5-diol is described. Beginning with dimethyl acetone-1,3-dicarboxylate, a telescoped sequence of reductive amination, Boc protection, sodium borohydride reduction, and acidic resin-mediated deprotection generates the title compound. The key to this efficient process is the telescoped deprotection, purification and nonaqueous isolation of the 3-amino-pentan-1,5-diol. The process involves four optimized chemical reactions using two solvents in 89% overall yield and 97−98 area % purity.",10.1021/op800245v,1
The Newman−Kwart Rearrangement Revisited: Continuous Process under Supercritical Conditions,"A continuous process that is suitable for large-scale manufacture of the biphenylthiol 1 using dimethoxyethane as solvent at 320 °C and 1000 psi under supercritical conditions has been developed. Due to the use of the low-boiling solvent, the workup through a solvent switch to heptane makes the process suitable for continuous production.",10.1021/op800244m,0
Development of a Practical Synthesis of an Aminoindanol-Derived M1 Agonist,An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration protocol in the presence of the unprotected alcohol to afford the requisite nitro-aminoindanol in one step. Challenges addressed in the remainder of the synthesis include a nitro group reduction to afford ppm levels of unreacted Ar-NO 2 (a mutagen) and a novel amidine formation under mild conditions via DMAP/K 2 CO 3 -promoted reaction with a thioimidate-activated amide. A convenient protocol for freebasing the API was provided by stirring with solid K 2 CO 3 and monitoring disappearance of HI by reverse-phase HPLC.,10.1021/op800243q,1
Crystallization Process Development for a Stable Polymorph of Treprostinil Diethanolamine (UT-15C) by Seeding,"Process development of treprostinil diethanolamine salt ( UT-15C ) involved the development of crystallization and slurry protocols to address the polymorph and morphology control issues. Two forms of UT-15C were evaluated by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA). Two crystallization solvent systems were developed to produce the thermodynamically stable form in high quality and yield. One solvent system gave dense particles while the other gave lighter and fly-away particles. Slurrying the lighter particles in heptane converted them to denser particles. The protocol was executed successfully on large-scale cGMP batches.",10.1021/op800239m,0
Identification and Suppression of a Dimer Impurity in the Development of Delafloxacin,"Delafloxacin is a 6-fluoroquinolone antibiotic which is under development at Rib-X Pharmaceuticals. During initial scale-up runs to prepare delafloxacin, up to 0.43% of a new impurity arose in the penultimate chlorination step. This was identified as a dimeric adduct of delafloxacin. Subsequent application of design of experiments (DoE) led to the identification of the factors responsible for this impurity. Implementation of the knowledge gained from the DoE reproducibly enabled the suppression of this impurity to acceptable levels.",10.1021/op800238q,1
"Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 3. Development of an Acid-Catalyzed Racemization Process for (<i>S</i>)-2,8-(Dimethoxy)-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}−11,12-dihydro-<i>5H</i>-6,13-dioxabenzo[3,4]cyclohepta[1,2-<i>a</i>]naphthalene","A novel and economical process was developed for recycling the undesired enantiomer, ( S )-2,8-dimethoxy-5-{4-[2-(1-piperidinyl)ethoxy]phenyl}-11,12-dihydro- 5H -6,13-dioxabenzo[3,4]cyclohepta[1,2- a ]naphthalene ( 1b ) obtained from chiral chromatographic separation, by refluxing 1b with HCl (4.0 equiv) in EtOH for 76 h, or with H 2 SO 4 (2.0 equiv) in water for 68 h to afford a near racemic mixture (( R )- 1a /( S )- 1b = 41−42%/49−53%, chiral HPLC area%) in >96% isolated yield and good chemical purity (87−95%).",10.1021/op800237y,0
Identifying Scale Sensitivity for API Crystallizations from Desupersaturation Measurements,"The present report details a methodology for discriminating between mass transfer- and surface integration-controlled crystallizations. Initial desupersaturation rates were measured, and a simple kinetic model was developed as a diagnostic tool for identifying scale sensitivity. The model was further extended to evaluate the impact of trace impurities on crystallization kinetics. Together, these results highlight the importance of understanding the factors that affect crystallization kinetics upon scale-up.",10.1021/op8002344,0
Development of an Efficient Palladium-Catalyzed Intramolecular Carbometalation Reaction for the Synthesis of a Dibenzoxapine Containing Tetra-substituted Exocyclic Alkene,"A practical and scaleable synthesis of ( Z )-3-(1-(8-bromodibenzo[ b, e ]oxepin-11(6 H )-ylidene)ethyl)aniline hydrochloride ( 1 · HCl ), a key intermediate in the synthesis of a selective nuclear hormone receptor modulator, is described. The target compound is prepared in five steps from commercially available (5-bromo-2-iodophenyl)methanol ( 5 ) with a 47% overall yield. The key step involves a palladium-catalyzed intramolecular carbometalation of an alkyne, which affords the dibenzoxapine containing tetrasubstituted exocyclic alkene framework stereoselectively in a single step from readily available building blocks 4-bromo-2-(2-iodo-phenoxymethyl)-1-prop-1-ynyl-benzene ( 3 ) and 3-nitrophenylboronic acid ( 4 ). The development of each step is described. The main focus of the paper is the description and optimization of the intramolecular carbometalation of an alkyne. Eventually, the target compound 1 · HCl was prepared in multikilogram quantities with >97% purity.",10.1021/op800231b,1
An Improved Process for the Synthesis and Isolation of (<i>S</i>)-<i>N</i>-(1-Phenylethyl)hydroxylamine,"A three-step, single-solvent telescoped process amenable to the large-scale manufacture of ( S )- N -(1-phenylethyl)hydroxylamine p -toluenesulfonic acid salt is reported. This synthetic protocol has been applied to the preparation of other chiral hydroxylamines.",10.1021/op800230f,0
Process Development for Sodelglitazar: A PPAR Panagonist,"Three efficient syntheses of sodelglitazar ( 1 ) have been developed. In particular, the third synthesis avoids the use of zinc and eliminates the resulting heavy metal waste stream as well as the potential genotoxic methanesulfonate in the two earlier syntheses. This process produces sodelglitazar in 74% overall yield from readily available thiophenol ( 8 ) and thiazole alcohol ( 3 ).",10.1021/op8002294,1
"A Novel Method for Large-Scale Synthesis of Lamivudine through Cocrystal Formation of Racemic Lamivudine with (<i>S</i>)-(−)-1,1′-Bi(2-naphthol) [(<i>S</i>)-(BINOL)]","A large-scale synthesis of (−)-[2 R,5 S ]-4-amino-1- [2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1 H )-pyrimidin-2-one (lamivudine) through resolution of racemic lamivudine by cocrystal formation with ( S )- BINOL has been demonstrated. Lamivudine of very high purity with an enantiomeric excess of more than 99.9% was obtained. All four isomers of lamivudine have also been separated and characterized. Interestingly, cis -(−)- and trans -(−)-enantiomers form cocrystals with ( S )-BINOL.",10.1021/op800228h,1
"Large-Scale Preparation of (+)-<i>p</i>-Menth-2-ene-1,8-diol, a Key Intermediate in the Synthesis of Δ-9-Tetrahydrocannabinol","A manufacturing-scale process for the preparation of p -menth-2-ene-1,8-diol, a key intermediate for the preparation of Δ-9-tetrahydrocannabinol (Δ-9-THC), was developed. The process entails a large-scale olefin migration/epoxidation and hydrolytic epoxide opening in organic solvent. The water-soluble product is isolated without the need for exhaustive extraction.",10.1021/op8002272,0
Second-Generation Process for the HCV Protease Inhibitor BILN 2061: A Greener Approach to Ru-Catalyzed Ring-Closing Metathesis,"The ring-closing metathesis (RCM) step, a key reaction in our process to BILN 2061, was dramatically improved from the first-generation process by the selection of a more appropriate substrate as well as the use of a more effective catalyst. The two RCM reactions are compared in detail using criteria that are of high significance to the process chemist.",10.1021/op800225f,0
Book Review of Process Systems Engineering: Volumes 3 and 4: Supply Chain Optimization - parts I and II,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Process Systems Engineering: Volumes 3 and 4: Supply Chain Optimization - parts I and IICite this: Org. Process Res. Dev. 2008, 12, 6, 1315Publication Date (Web):October 10, 2008Publication History Received11 September 2008Published online10 October 2008Published inissue 21 November 2008https://doi.org/10.1021/op800223kCopyright © 2008 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views153Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (55 KB) Get e-AlertsSUBJECTS:Optimization,Pharmaceuticals,Process systems Get e-Alerts",10.1021/op800223k,0
Pilot-Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist: Process Development of a Carbonyldiimidazole Peptide Coupling,"The process development of a peptide coupling with CDI is discussed. Various solvents, addition orders, stoichiometries, and reaction temperatures were investigated. A reliable crystallization procedure was also developed. The new process was piloted to provide 342 kg of product in two batches with an average 85% yield and 99% assay.",10.1021/op8002213,0
Book Review of The Management of Chemical Process Development in the Pharmaceutical Industry,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of The Management of Chemical Process Development in the Pharmaceutical IndustryJohn KnightView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom, E-mail: [email protected]Cite this: Org. Process Res. Dev. 2008, 12, 6, 1314–1315Publication Date (Web):October 20, 2008Publication History Received8 September 2008Published online21 October 2008Published inissue 21 November 2008https://doi.org/10.1021/op800219tCopyright © 2008 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views263Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (55 KB) Get e-AlertsSUBJECTS:Chemical structure,Pharmaceuticals,Pharmaceutics,Safety Get e-Alerts",10.1021/op800219t,0
Heavy-Metal-Free Reduction Methodology for Large-Scale Synthesis Applicable to Heterocyclic and Arylhydrazines,A green chemistry methodology that uses a heavy-metal-free reduction in aqueous medium is described to produce 5-hydrazinoquinoline [1-(quinolin-5-yl)hydrazine] ( 6a ) as the anhydrous dihydrochloride salt at large scale. The process is entirely aqueous and utilizes l -ascorbic acid to reduce the diazonium salt ( 2a ) derived from 5-aminoquinoline [quinolin-5-amine] ( 1a ).,10.1021/op8002163,0
Syntheses of a Selective Peroxisome Proliferator Activated Receptor Modulator and Practical New Preparations of 2-(4-Alkoxyphenyl)ethylamines,"This article describes chemistry that was developed to give access to multigram quantities of the selective peroxisome proliferator activated receptor modulator (SPPARM), compound 1 . 1 Fischer esterifications, phase transfer-catalyzed alkylations, amide couplings, crystallizations, and a new synthesis were developed to accomplish this task. In addition, an efficient method for preparing 2-(4-alkoxyphenyl)ethylamines 7a−d from tyramine 9 was developed that involves O-alkylation of intermediate Schiff base 11 and subsequent acid-catalyzed hydrolysis to afford the target molecules as crystalline hydrochloride salts.",10.1021/op800215a,1
Process Development and Scale-Up of a PPARγ Agonist: Selection of the Manufacture Route,"Two short, high-yielding routes to the selective PPARγ agonist GSK376501A were developed and carried out on scale. The key bond -forming reaction in each synthesis was the substitution of a 3,5-difluoro or 3,5-dibromo aryl intermediate with 2-methoxyethanol. A nucleophilic aromatic (S N Ar) substitution reaction under basic conditions was developed for the aryl fluoride substrate. The 3,5-dibromo aryl halide intermediate required copper-catalyzed conditions to achieve substitution of the second bromide. In addition, a 2-methoxyethanol decomposition pathway to generate methanol and ethylene oxide under basic reaction conditions as well as its effect on impurity formation, was elucidated. Both the difluoro and dibromo intermediates were considered as the basis for the final route of manufacture. The difluoro substrates were chosen due to straightforward chemistry, controllable impurity profile, and ease of fluoride removal.",10.1021/op800211c,1
"Development of an Acyl Sulfonamide Anti-Proliferative Agent, LY573636·Na","The synthesis of 5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt on multikilogram scale is described. The initial clinical supplies were made using carbonyl diimidazole to converge the two fragments. A more efficient acid chloride process has been developed, which also provides better control of impurities and color throughout the synthesis.",10.1021/op800210x,1
"First Scale-Up Synthesis of WAY-262398, a Novel, Dual-Acting SSRI/5HT1a Antagonist","An alternative synthesis of WAY-262398, 1, a novel, dual-acting SSRI/5-HT 1A antagonist, has been developed. The target compound was initially synthesized as a part of diastereomeric mixture which was separated by chiral preparative HPLC. The new route was designed around intermediates suitable for chiral resolution and/or chiral reduction of a suitable intermediate. Both processes had to be employed to achieve the target optical purity.",10.1021/op8002085,1
"Response to Dancer’s Comments on Our Article “Substrate Modification Approach to Achieve Efficient Resolution: Didesmethylcitalopram: A Key Intermediate for Escitalopram” [<i>Org. Process Res. Dev.</i> <b>2007</b>, <i>11</i>, 289−292]","Recently, we published a synthesis of escitalopram ( S - 1 ) consisting of the resolution of didesmethylcitalopram ( 3 ) and subsequent methylation of S -didesmethylcitalopram ( S-3 ) ( Org. Process Res. Dev. 2007, 11, 289−292). Some of our observations regarding citalopram resolution and C-alkylation of a benzofuran analogue ( 2 ) to produce didesmethylcitalopram ( 3 ) were disputed by Dr. Dancer of H. Lundbeck (preceding article). A detailed response to his comments regarding stabilization of the 3-chloroproylamine free base by dilution with certain solvents, its storage and handling, optimized experimental conditions for C-alkylation to prepare didesmethylcitalopram, and a corrected process for citalopram resolution are included.",10.1021/op8002079,1
Microwave-Irradiated Synthesis of Nitrophen Using PEG 400 as Phase Transfer Catalyst and Solvent,"Nitrophen is a widely used herbicide which is commonly produced by an energy intensive process using high temperature and pressure. In the current work, nitrophen is synthesized by using PEG-400 as a phase transfer catalyst in a solid−liquid (S-L) system from potassium 2,4-nitrophenolate and p -nitrochlorobenzene using xylene as a solvent under microwave irradiation. It gives 100% selectivity to nitrophen. The use of PEG-400 as a solvent was also examined both under microwaves and conventional heating at 120 °C. The synergism of microwave activation and S-L PTC using PEG 400 as a catalyst and solvent results in enhancements in the rate of reaction and selectivity of nitrophen. The proposed method for the synthesis of nitrofen reduces the total reaction time and also allows easy separation of the product. The kinetics and mechanism of S-L PTC and the homogeneous reaction were also established with PEG 400.",10.1021/op800206c,0
"Practical Syntheses of Oxindole Derivatives: Chemical Development towards 2-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)acetamide and (<i>S</i>)-2-(5-Chloro-2-oxo-2,3-dihydroindol-1-yl)propionamide",We describe development of scalable syntheses of novel oxindole-type SV2A ligands with improved potency towards seizure suppression.,10.1021/op800203p,1
"Book Review of Process Chemistry in the Pharmaceutical Industry, Vol. 2","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Process Chemistry in the Pharmaceutical Industry, Vol. 2W. J. WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom.E-mail: [email protected]Cite this: Org. Process Res. Dev. 2008, 12, 6, 1315Publication Date (Web):October 9, 2008Publication History Received18 August 2008Published online9 October 2008Published inissue 21 November 2008https://pubs.acs.org/doi/10.1021/op8001992https://doi.org/10.1021/op8001992book-reviewACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views394Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical synthesis,Peptides and proteins,Pharmaceuticals,Pharmaceutics,Process chemistry Get e-Alerts",10.1021/op8001992,0
A Facile Two-Step Synthesis of 3-Fluoro-6-methoxyquinoline,"A facile two-step synthesis of 3-fluoro-6-methoxyquinoline is described. p -Anisidine was heated at reflux with 2-fluoromalonic acid in the presence of phosphorus oxychloride to produce 2,4-dichloro-3-fluoro-6-methoxyquinoline. This was followed by hydrogenolysis to produce 3-fluoro-6-methoxyquinoline.",10.1021/op800198b,1
Book Review of Asymmetric Organic Synthesis with Enzymes,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Asymmetric Organic Synthesis with EnzymesCite this: Org. Process Res. Dev. 2008, 12, 6, 1313–1314Publication Date (Web):September 13, 2008Publication History Received15 August 2008Published online13 September 2008Published inissue 21 November 2008https://pubs.acs.org/doi/10.1021/op800197fhttps://doi.org/10.1021/op800197fbook-reviewACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views341Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Peptides and proteins,Redox reactions,Transfer reactions Get e-Alerts",10.1021/op800197f,0
Measurement of Gas Flow Rates from Small-Scale Reactions,"The rate and total volume of noncondensable gas generation are important parameters in the safe, successful scale-up of chemical processes. Information regarding the evolution of noncondensable gas is used to (1) ensure the gas can be vented from the reactor without overpressurization, (2) calculate the concentration of flammable gases (or oxygen) to avoid creating an explosive mixture in the equipment, and (3) size the scrubber to ensure the capacity and heat removal rate are sufficient. The data are used in parallel with information regarding the heat of reaction from the desired chemistry, thermal stability of reaction mixtures/components, and an intimate knowledge of the process to analyze the risk associated with scaling up. If the level of risk is judged to be unacceptable, the analysis can be used to make rational process changes in order to reduce the risk to an acceptable level. Several techniques have been developed to study the gas hazards associated with a particular reaction. In general, these techniques suffer from at least one of two primary limitations: (1) the volume is not measured directly, causing the condition and/or composition of the gas to influence the accuracy of the measurement, or (2) the sensitivity is too low to take reliable measurements from small-scale reactions. The Pfizer Global Process Safety Network set out to develop a new device that could solve both of these problems and be used in conjunction with a microcalorimeter to provide heat of reaction data in parallel. This paper describes a new device that is used in series with a thermal mass flow meter to accomplish this goal. Detailed discussion of the error bounds on the flow rate from this device is also included.",10.1021/op800194g,0
Mechanism and Processing Parameters Affecting the Formation of Methyl Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example for Sulfonate Ester Impurity Formation,"Sulfonate salts offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups, but there are regulatory concerns over the presence of sulfonate esters as potential genotoxic impurities (PGIs). Whilst sulfonate esters could theoretically result from interaction between sulfonic acids and alcohols, literature on their formation is sparse. GC−MS analysis of reactions of methanesulfonic acid (MSA) and isotopically labeled methanol ( 18 O-label) confirm methanol C−O bond cleavage in the formation of the methyl methanesulfonate (MMS), consistent with reversal of well-established mechanisms for solvolysis of sulfonate esters. Studies of reaction profiles quantify methyl methanesulfonate formation under a range of conditions relevant to API processing. Maximum conversion to MMS in reaction mixtures was 0.35%, determined by analytical methods developed specifically for reaction mixture analysis. Sulfonate ester formation is dramatically reduced at lower temperatures, in the presence of small amounts of water, or when acid is partially neutralized by substoichiometric amounts of the weak base, 2,6-lutidine, used to mimic conversion of a basic API to a salt in pharmaceutical manufacture. In the presence of a slight excess of base, ester formation was not detected. These findings, particularly those involving an excess of base, are compelling and provide a scientific understanding to allow for the design of processing conditions to minimize and control sulfonate ester formation.",10.1021/op800192a,0
"High Conversion, Solvent Free, Continuous Synthesis of Imidazolium Ionic Liquids In Spinning Tube-in-Tube Reactors",A spinning tube-in-tube (STT) reactor has been used for the accelerated solvent-free synthesis of a number of 1-methylimidazole-based ionic liquids with excellent conversions (>99%) and high throughputs (tens of kg/day).,10.1021/op8001917,0
Calcium Pantothenate. Part 3. Process for the Biologically Active Enantiomer of the Same via Selective Crystallization and Racemization,"Optically pure calcium ( R )-pantothenate has been obtained from the racemic compound via direct fractional crystallization of the single enantiomer. Efficient racemization of the biologically inactive calcium ( S )-pantothenate without its decomposition to pantolactone has been developed, resulting in a simple, complete, and efficient technology. The results elaborated in the laboratory have been then successfully applied in the industrial scale process.",10.1021/op800189g,0
Continuous Processes,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTContinuous ProcessesTrevor LairdCite this: Org. Process Res. Dev. 2008, 12, 5, 904Publication Date (Web):August 12, 2008Publication History Received1 August 2008Published online12 August 2008Published inissue 19 September 2008https://doi.org/10.1021/op800183cCopyright © 2008 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views876Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (27 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Materials,Microreactors,Pharmaceutics,Quality management Get e-Alerts",10.1021/op800183c,0
"Isolation, Synthesis, and Characterization of Impurities and Degradants from the Clofarabine Process","The identification of clofarabine process impurities and their subsequent isolation, synthesis, and characterization is described. Two isomeric process impurities resulting from N 6 -attachment of a fluoroarabinose to clofarabine were found. Clofarabine’s base degradation products, which were different from the process impurities, were also synthesized and characterized. These compounds resulted from modifications to the sugar moiety, the purine ring, or both. A mechanistic rationale for the formation of the various process impurities and degradation products is provided.",10.1021/op800182x,1
A Large Scale Process for the Preparation of Thymitaq,"The large scale manufacturing of the anticancer agent 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3 H -quinazolin-4-one dihydrochloride (thymitaq) from 6-bromo-5-methylanthranilic acid is described. The chemical route consists of two chemical steps: formation of a bromoquinazolinone and a copper-mediated Ullman-like coupling between 4-mercaptopyridine and the bromoquinazolinone. During process development, sodium hydride was replaced with sodium hydroxide and a method for removal of copper, based on 2,4,6-trimercapto- s -triazine, was developed. A number of purification operations were performed to ensure a product of pharmaceutical quality.",10.1021/op800181e,1
A Catalyzed and Highly Selective Ester Reduction in the Synthesis of an<i>N</i>-Acylpyrrolidine: Safe Design through Reaction Calorimetry and Modeling,"The asymmetric synthesis of an N -acylpyrrolidine for HCV inhibition features a unique and highly selective reduction of an ester to an alcohol with NaBH 4 −MeOH catalyzed by NaB(OAc) 3 H. This reagent combination provides excellent chemoselectivity while avoiding formation of the thermodynamically favored but undesired epimer. Significant process safety issues including delayed onset of reaction initiation and latent, abrupt release of heat and hydrogen gas are encountered. The pyridine impurity responsible for the reaction inhibition is identified in the reaction calorimetry investigation. A series of reaction calorimetry and modeling studies have led to the safe design of a process which has been scaled up to 300 gallons for production of multikilogram quantities of the N -acylpyrrolidine target.",10.1021/op8001799,1
"Large-Scale Asymmetric Synthesis of the 3,6,7,8-Tetrahydrochromeno[7,8-<i>d</i>]imidazole BYK 405879: A Promising Candidate for the Treatment of Acid-Related Diseases","A process for the synthesis of the potassium-competitive acid blocker BYK 405879 ( 8 ) was established based on the approach used in medicinal chemistry (asymmetric hydrogenation of prochiral ketone 15 and Mitsunobu cyclization of the resulting alcohol 34 ). Several critical reaction steps were optimized. The synthesis of prochiral ketones was accomplished using ethyl 3-(2-methylphenyl)-3-oxopropanoate instead of 1-[1-(2-methylphenyl)vinyl]pyrrolidine, a reagent that was difficult to prepare and possesses limited shelf life. The catalyst loading of the asymmetric hydrogenation step was reduced significantly from a S/C ratio of 100:1 to a S/C ratio of 2500:1 by benzyl protection of ketone 15 . After the Mitsunobu cyclization, the removal of byproduct was easily accomplished through acid−base extraction, and pure BYK 405879 ( 8 ) was then obtained by means of crystallization in the presence of succinic acid.",10.1021/op800177x,1
"A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor Agonist","The development of a scalable synthesis of a potent cholecystokinin (CCK) 1R receptor agonist is described. The focus on a rapid short-term delivery rather than longer-term development allowed for the preparation of multihundred gram quantities to support aggressive timelines and evaluate safety and pharmacological studies. Key improvements involved streamlining the preparation of imidazole acid 7 and discovery of a more efficient preparation of naphthyl piperazine fragment 23, including an improved preparation of 3-bromonaphthallic anhydride 16 .",10.1021/op800176e,1
An Improved Synthesis of Antiulcerative Drug: Tenatoprazole,"An efficient, cost-effective and multikilogram-scale process for the synthesis of tenatoprazole 1, an antiulcerative drug, is described. The key steps in this synthesis involve the coupling of 2-mercapto-5-methoxyimidazo[4,5- b ]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 and its subsequent oxidation with m -CPBA to produce sulfoxide 1 . The process has been scaled up for the multikilogram-scale of compound 1 with an overall yield of 72%. The new process requires no purification process and affords the target compound 1 with 99.8% purity by HPLC.",10.1021/op800173u,1
Mild and Selective Synthesis of an Aryl Boronic Ester by Equilibration of Mixtures of Boronic and Borinic Acid Derivatives,"Quenching of aryl Grignard reagents with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropyl pinacol borate) under noncryogenic conditions can lead to mixtures of the corresponding boronic ester along with, generally undesired, borinic acid derivatives. We have found that in certain cases gentle heating of the crude reaction mixtures leads to complete equilibration to give the borinic esters as the sole product which can then be isolated in high yield. This novel equilibration can reduce the need for use of cryogenic conditions or large excesses of reagents to obtain selectivity during boronic ester syntheses.",10.1021/op800169s,1
Pharmaceutical Manufacturing Handbook . Edited by Shayne Cox Gad . Wiley-Interscience . 2008 . 1370  + xiii pp £103. ISBN 978-0-470-25958-0 .,"ADVERTISEMENT RETURN TO ISSUEPREVArticleCite this: Org. Process Res. Dev. 2008, 12, 5, 1016–1017Publication Date (Web):August 22, 2008Publication History Received21 July 2008Published online22 August 2008Published inissue 19 September 2008https://doi.org/10.1021/op800168uCopyright © 2008 American Chemical SocietyRequest reuse permissions Article Views269Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (40 KB) Get e-AlertscloseSUBJECTS:Crystallinity,Manufacturing,Pharmaceuticals,Salts,Solvates Get e-Alerts",10.1021/op800168u,0
An Improved and Scalable Process for Celecoxib: A Selective Cyclooxygenase-2 Inhibitor,"An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.",10.1021/op800158w,1
Global Green Chemistry Metrics Analysis Algorithm and Spreadsheets: Evaluation of the Material Efficiency Performances of Synthesis Plans for Oseltamivir Phosphate (Tamiflu) as a Test Case,"This work discloses an easy-to-use algorithm to evaluate the global material efficiency performance of any kind of synthesis plan regardless of complexity to a given target molecule according to green metrics criteria. The algorithm is robust and has been adapted to Excel spreadsheets for rapid calculation and graphing of the numerical results. In order to demonstrate the facile utility of this exceptional tool for process and synthetic chemists in the evaluation and ranking of synthetic performance, various synthesis plans for oseltamivir phosphate, a neuraminidase inhibitor used to treat the H5N1 influenza virus, have been investigated. In particular, six industrial syntheses and nine plans from academic groups have been thoroughly and rigorously evaluated according to kernel and global reaction mass efficiencies and E -factors, atom economy, and overall yield performances. In addition, all reported plans were evaluated according to new synthesis elegance parameters including fraction of sacrificial reagents by molecular weight, hypsicity (oxidation level) index, and number of target bonds made per reaction step. Target structure bond maps and profiles are introduced as convenient ways to visually describe synthetic strategy compactly. These powerful algorithms and visual aids can be used to immediately spot bottlenecks in a synthesis plan. Moreover, they allow deeper understanding and critiquing of synthesis plans, thereby assisting chemists in suggesting new directions for further optimization.",10.1021/op800157z,1
Practical Synthesis of a HIV Integrase Inhibitor,"A practical and efficient synthesis of the potent HIV integrase inhibitor 1 is described. Starting from readily available 3,4-dihydro-2 H -pyran, the six-step synthesis features a through process without purification of any of the intermediates until the isolation of crystalline intermediate 7 . After deprotection and classical resolution, amine 8 was isolated with excellent enantiopurity. A final amide coupling completed the synthesis of 1 in 7.6% overall yield from DHP. This chromatography-free route is more cost effective and increases the overall yield by nearly 3 times when compared with the original Med Chem synthethic route. This improved chemistry was used successfully to prepare multikilogram quantities of integrase inhibitor 1 .",10.1021/op800153y,1
Optimization of Solvent Chasing in API Manufacturing Process: Constant Volume Distillation,"Solvent exchange by distillation is a common unit operation in active pharmaceutical ingredient (API) manufacturing processes. Either a stepwise solvent displacement mode or a constant volume solvent displacement mode can be used to carry out the solvent exchange. The constant volume mode can be more efficient as the chasing solvent acts as an effective displacer by keeping concentrations of the solvent being displaced at higher levels. As demonstrated during a production application at Abbott Laboratories, the constant volume solvent displacement mode resulted in a 30% reduction in the quantity of displacing solvent, 2-propanol (IPA), when compared with the equivalent process using a stepwise solvent displacement mode. As a consequence, 30% reduction in the waste solvent generation was realized. This mode of operation dose not adversely impact product quality nor process yield.",10.1021/op800152n,0
Use of a Fiber-Optic Turbidity Probe to Monitor and Control Commercial-Scale Unseeded Batch Crystallizations,"This article describes how a fiber-optic turbidity probe may be used as an inferential sensor to aid in the control of commercial-scale batch crystallizations. The discussion focuses on several unseeded crystallization examples involving cooling or cooling plus addition of antisolvent. In a typical control scheme, the fiber-optic probe is used to detect an initial nucleation event, to control a subsequent digestion step for fines dissolution with the potential for modification of nuclei size, number, and purity, and then to monitor a growth period. During the digestion step, temperature is increased and adjusted to achieve a desired reduction in the fiber-optic signal in order to control the extent of digestion. Within Dow, this approach has proven to be robust and cost-effective for numerous commercial-scale batch crystallizations including those with highly fouling or corrosive environments.",10.1021/op8001504,0
Enzymatic Preparation of a<scp>d</scp>-Amino Acid from a Racemic Amino Acid or Keto Acid,"The d -amino acid ( R )-2-amino-3-(7-methyl-1 H -indazol-5-yl)propanoic acid ( 3 ) is a key intermediate needed for synthesis of a drug candidate compound. Enzymatic routes to 3 were explored. d -Amino acid 3 was prepared in 68% isolated yield with >99% ee from racemic amino acid 1 using l -amino acid deaminase from Proteus mirabilis expressed in Escherichia coli in combination with a commercially available d -transaminase using d -alanine as amino donor. The d -enantiomer was also prepared in 79% isolated yield with >99% ee from the corresponding keto acid 2 using the d -transaminase with racemic alanine as the amino donor. The rate and yield of this reaction could be accelerated by addition of lactate dehydrogenase (with NAD, formate and formate dehydrogenase to regenerate NADH) to remove the inhibitory pyruvate produced during the reaction. A d -transaminase was purified from a soil organism identified as Bacillus thuringiensis and cloned and expressed in E. coli . The d -transaminase was very effective for the preparation of 3 and gave a nearly complete conversion of 2 to 3 without the need for additional enzymes for pyruvate removal.",10.1021/op800149q,0
Synthesis of the NK1 Receptor Antagonist GW597599. Part 1: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine,"GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The initial synthetic route devised from the medicinal chemistry one, used several hazardous reagents, gave low yields, and produced high levels of wastes. By targeted process of research and development, application of novel techniques, and extensive route scouting, a novel synthetic route for GW597599 has been developed. This paper reports the optimisation work of the first stage in the chemical synthesis of GW597599: the development of a pilot-plant suitable process for the synthesis of the arylpiperazine derivative 7 in an optically pure fashion. In particular, the process definition allowed eliminating the initial need for cryogenic conditions and copper catalysis in Grignard chemistry. It also allowed replacing a classical resolution step with a more efficient dynamic kinetic resolution, substantially enhancing the overall yield and throughput.",10.1021/op800146d,1
A Practical Synthesis of a Chiral Analogue of FTY720,A practical synthesis of 1 involving a catalytic enantioselective construction of the quaternary carbon from imine 10 (derived from 13 and 14 ) and alkyl iodide 5 using Maruoka’s chiral catalyst 11 is described. This asymmetric alkylation followed by hydrolysis to amino acid 9 was accomplished in good yield with high chemical purity (>98%) and chiral purity (>96% ee). The improved synthesis enabled production of 1 in seven chemical steps (six isolations) in an overall yield of 22%.,10.1021/op800144h,1
"A Practical Synthesis of a Diazepinylbenzoic Acid, a Retinoid X Receptor Antagonist","An optimized convergent synthetic route for the preparation of retinoid X receptor (RXR) antagonist ( 1 ) in an overall yield of 35% is described. The formation of the benzodiazepine was achieved in 85% yield using POCl 3 in toluene. The drug substance 14 was obtained by treatment of aryl bromide with vinyl butyl ether in the presence of palladium acetate, DPPP, and cesium carbonate This one-pot operation incorporating three chemical transformations (i.e., Heck reaction, hydrolysis of vinyl ether, and hydrolysis of ester) was achieved in 85% yield.",10.1021/op800142b,1
An Improved and Scalable Process for Zafirlukast: An Asthma Drug,"An improved and scalable process for the large-scale production of zafirlukast (Accolate), an important drug for asthma, is discussed along with impurity and scale-up-related issues.",10.1021/op800137b,1
Green Chemistry with a Novel 5.8-GHz Microwave Apparatus. Prompt One-Pot Solvent-Free Synthesis of a Major Ionic Liquid: The 1-Butyl-3-methylimidazolium Tetrafluoroborate System,"This article reports for the first time the rapid one-pot solvent-free synthesis of 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF 4 ), a major ionic liquid, in good yields (87%) after 30 min of microwave irradiation with microwaves at a frequency of 5.8 GHz in a batch-mode reactor. By contrast, the yields of [bmim]BF 4 are about 3-to-4-fold smaller when using 2.45-GHz microwave radiation and oil bath heating: 28% and 21%, respectively, under otherwise identical conditions. This further shows the advantage(s) of the 5.8-GHz microwave radiation and the accompanying apparatus as a novel synthetic tool reported in some detail elsewhere { Org. Process Res. Dev. . 2008, 12, 257−263}. The three synthetic methods (viz., 5.8-GHz and 2.45-GHz microwave heating, and oil bath heating) were examined in reactors used in both the batch and reflux modes. In the latter mode, the yields of [bmim]BF 4 were less than 10% even after a 60-min reaction period. The dependence of the synthesis on the frequency of the microwave radiation is discussed in terms of the chemical yields of the product and the dielectric factors of each substrate in the synthesis mixtures composed of 1-methylimidazole, 1-chlorobutane, and sodium tetrafluoroborate.",10.1021/op800135t,0
Continuous Reaction/Crystallization Process for Production of a Hazardous Intermediate,"Perchloric acid appears unique in its ability to catalyze stereoselective trans-acetalizations of steroids. However, the requisite recipes result in an intermediate phase enriched in perchlorate and organic material with the potential for catastrophic decomposition. We present here a discussion of the relevant chemistry and the engineering of a continuous reactor/crystallizer/quench for the safe production of a candidate for asthma and irritable bowel syndrome.",10.1021/op800128g,0
Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway?,"Microreactors have shown their ability to improve chemical processes and routes; however, their integration into chemical production processes depends not only on technical advances. Cost issues and productions logistics play a crucial role, too, and are highlighted with two different case studies. Economical drivers for the pharmaceutical industry are described with emphasis on future development of microprocess engineering.",10.1021/op8001273,0
Scale-Up of Microwave-Promoted Reactions to the Multigram Level Using a Sealed-Vessel Microwave Apparatus,"A range of synthetic transformations have been scaled up successfully using a sealed-vessel multimode microwave unit. These include metal-catalyzed couplings, synthesis of heterocycles, reactions under an atmosphere of reactive gas and two-step one-pot procedures. Also, observations have been made along the way that are of use to chemists addressing scale-up of microwave-promoted reactions.",10.1021/op8001239,0
Development of a Synthesis For a Long-Term Oxazolidinone Antibacterial,"Linezolid, compound 1, is a member of the oxazolidinone class of antibacterials and has had recent clinical interest due to its potential use as a long-term treatment for bacterial infection. Detailed herein are improvements to the original synthesis to enable phase I clinical trials. Of particular interest is the preparation of a key oxindole subunit utilizing a Pd-mediated cyclization. Optimization of the synthesis of the oxindole included the use of trifluorotoluene as the solvent.",10.1021/op8001195,1
"The Synthesis of (<i>S</i>)-5-Fluoro-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1<i>H</i>-indazole, a Norepinephrine/Serotonin Reuptake Inhibitor for the Treatment of Fibromyalgia","Compound 1, a norepinephrine/serotonin reuptake inhibitor (NSRI) for the treatment of fibromyalgia, has been synthesized in optically pure form in six linear steps and 48% overall yield with no chromatography. This route features a novel and efficient intramolecular cyclization to generate the indazolone core via a diazotization reaction and the preparation of a stable polymorph of the tartaric acid salt as the desired final form. The original synthetic route has been modified to avoid the use of toxic and expensive reagents, thus enabling the preparation of multigram quantities of API for toxicology studies.",10.1021/op800113s,1
"A Practical, Efficient Synthesis of 1,1-Dioxo-hexahydro-1λ<sup>6</sup>-thiopyran-4-carbaldehyde","A practical, efficient, and scalable procedure for the preparation of 1,1-dioxo-hexahydro-1λ 6 -thiopyran-4-carbaldehyde is reported. Synthesis of this aldehyde was complicated by high aqueous solubility of the product and the intermediates. The isolation and purification of the aldehyde was accomplished by conversion to the crystalline bisulfite adduct.",10.1021/op800108s,1
Microscale HPLC Predicts Preparative Performance at Millionfold Scale,"The use of microscale HPLC for piloting the large-scale preparative chromatographic resolution of the enantiomers of a chiral pharmaceutical intermediate is reported with an example of a millionfold scale-up from a 300 μm i.d. column to a 30 cm i.d column. Performance and productivity at scale are accurately predicted by the microscale approach, which consumes only a small fraction of the material typically used for conventional loading studies. These results suggest a great potential for use of microscale HPLC loading studies during early synthetic route investigations, when only a small amount of sample is typically available.",10.1021/op800107u,0
Improved Process for the Preparation of 6-Chloro-5-(2-chloroethyl)oxindole,The current process for ziprasidone involves preparation and isolation of the key intermediate 6-chloro-5-(2-chloroethyl)oxindole. An improved process for the synthesis of this intermediate is reported here. The new process involves use of a novel Lewis acid-mediated selective deoxygenation of the precursor ketone with tetramethyldisiloxane. The new method affords the desired compound in a one-pot process obviating the need for isolation of the potentially hazardous precursor ketone. This process was successfully scaled up to multikilo scale.,10.1021/op800105j,1
An Improved Preparation Process for Gemcitabine,"An improved, cost-effective, and convenient process, using cinnamoyl as hydroxyl protective group and tosyl as the leaving group for gemcitabine ( 1 ) is described. The overall yield obtained from this newly developed process is around 10%, including two stereospecific crystallizations, and the quality of the product complies with the requirements of USP30.",10.1021/op800104r,1
"AMD070, a CXCR4 Chemokine Receptor Antagonist: Practical Large-Scale Laboratory Synthesis",An efficient and convergent four-step synthetic route to the CXCR4 chemokine receptor antagonist AMD070 ( 1 ) has been developed which employs only a single chromatographic step in the entire sequence. Novel reductive amination methods have been developed for the coupling of 2 and 3 in which a dehydrative imine formation is followed by reduction with an attenuated borohydride reagent (zinc chloride and sodium borohydride). Selective extraction methods were employed to purify synthetic intermediates and remove reagents and impurities. A procedure has also been developed to isolate 1 in a pure crystalline form.,10.1021/op8000993,1
Development of a New Variant of the Migita Reaction for Carbon−Sulfur Bond Formation Used in the Manufacture of Tetrahydro-4-[3-[4-(2-methyl-1<i>H</i>-imidazol-1-yl)phenyl]thio]phenyl-2<i>H</i>-pyran-4-carboxamide,"Palladium-catalyzed carbon−sulfur bond formation using modified Migita reaction conditions was explored and applied to the synthesis of a former antiasthma drug candidate, tetrahydro-4-[3-[4-(2-methyl-1 H -imidazol-1-yl)phenyl]thio]phenyl-2 H -pyran-4-carboxamide ( 5 ). The reaction was developed into a general method for thioaryl halide cross-coupling, and a specific example of its use to synthesize a key intermediate, tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-2 H -pyran-4-carboxamide ( 6 ) was demonstrated at large scale to provide phase II clinical supplies of 5 . Comparison of the multistep phase I process and the two-step phase II process showed an overall yield advantage over the bond-forming steps from common starting material (1) to API 5 of 40%. The ligand effect in the modified Migita reaction is described in detail. The second step of the scale-up process illustrated formation of carbon−nitrogen bonds without use of palladium catalysis, providing a contrast to the first reaction; both reactions were developed into efficient single-vessel direct isolation processes.",10.1021/op800098a,1
Preparation of a HMG-CoA Reductase Inhibitor via an Optimized Imidazole-Forming Condensation Reaction,"Development work toward an enabling synthesis of preparative scale batches of an imidazole-based HMG-CoA reductase inhibitor is described. The desired target was synthesized in 16% yield over 7 steps, highlighted by an imidazole-forming condensation reaction in which the yield was improved from 20% to >70% via modification of the solvent, acid, and amine equivalents. The step 2 acylation was improved, and a problematic benzyl ester in step 4 was converted into the corresponding benzyl amide to decrease trans-amidation during the step 5 imidazole formation. A highly effective salt formation and crystallization protocol was also developed.",10.1021/op800092e,1
"Development of a Suitable Process for the Preparation of a TNF-α Converting Enzyme Inhibitor, WAY-281418","A suitable process for the preparation of kilogram quantities of a TNF-α converting enzyme (TACE) inhibitor (WAY-281418) was developed using isatin 13 as starting material and an efficient coupling step for the formation of sulfonamide 8 in a 15% overall yield. Process preparation of (+)-(1 S,2 R )-2-aminocyclopentane-1-carboxylic acid ( 7, (+)-cispentacin), a chiral component for WAY-281418, was successfully scaled up via an asymmetric hydrogenation reaction. Crystallization allowed the isolation of all intermediates and the final product 9 .",10.1021/op800090s,1
Development and Scale-Up of Three Consecutive Continuous Reactions for Production of 6-Hydroxybuspirone,"This paper describes the development of a continuous, high yielding, and scalable enolization, oxidation, and quench process for the hydroxylation of the azapirone psychtropic agent buspirone to afford 6-hydroxybuspirone (6-hydroxy-8-[4-(4-pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione). Two feed streams were reacted continuously using an in-line static mixer followed by oxidation in a continuous flow trickle-bed reactor. The laboratory reactor operation was demonstrated at steady state for over 40 h. The process was scaled up using both volumetric (enolization) and numbering-up (oxidation) scale-up strategies. A pilot-plant reactor was developed and successfully implemented in a three-batch campaign (47 kg input per batch).",10.1021/op800079u,0
"Development of a Kilogram-Scale Synthesis of <i>cis</i>-LC15-0133 Tartrate, a Potent Dipeptidyl Peptidase IV Inhibitor","(4 S )- N -Boc-4-fluoro- l -proline methyl ester ( 4 ) was prepared from the following sequence of reactions: esterification of trans -4-hydroxy- l -proline ( 2 ), Boc protection, and fluorination by DAST. Reaction of 4 with lithiated oxadiazole provided oxadiazolyl ketone 7 . Deprotection of the Boc group of 7 and subsequent coupling with bromoacetyl bromide gave bromide 9 . Coupling reaction of 9 with excess oxazolidine 16 provided coupled product 17 . Unexpectedly, the stereogenic center of 17 was completely epimerized to a virtually 1:1 mixture of cis - and trans - 17 at this stage. After the deprotection of the N,O -methylene acetal group of 17 using aqueous ammonium chloride, crystallization induced dynamic resolution (CIDR) of cis - and trans -mixture of LC15-0133 ( 1 ) in the course of tartrate salt formation provided cis -LC15-0133 ( 1a ) tartrate salt in 83% yield (>98% de).",10.1021/op800076r,1
Development of a Pilot-Plant Process for a Nevirapine Analogue HIV NNRT Inhibitor,"The pilot-plant synthesis of nevirapine analogue 1 is described. The compound was prepared in eight steps from substituted pyridine raw materials and 4-hydroxyquinoline. The key transformation involves a novel one-pot conversion of an arylhalide to arylacetic acid under palladium catalysis, followed by regioselective reduction via in situ generated BH 3 /THF to the arylethanol intermediate 2 . All stages were carried out on 10−150-kg scale.",10.1021/op8000756,1
"A Scalable Synthesis of MN-447, an Antagonist for Integrins α<sub>v</sub>β<sub>3</sub> and α<sub>IIb</sub>β<sub>3</sub>","(2 S )-Benzenesulfonylamino-3-[3-methoxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid, MN-447, is a potent antagonist of the integrins α v β 3 and α IIb β 3 . Herein, we report a novel synthetic protocol that produces MN-447 in an overall yield of 45%. This protocol, when compared with the original synthetic route for MN-447, is more cost-effective, requires fewer steps, does not require chromatographic purification of intermediates and MN-447, and increases the overall yield by 35%. This report focuses on the synthetic strategies that were developed for this protocol. Now, the large quantities of MN-447 that are needed for preclinical and toxicological studies can be readily obtained.",10.1021/op800073z,1
Chemical Development of NBI-75043. Use of a Flow Reactor to Circumvent a Batch-Limited Metal−Halogen Exchange Reaction,"The discovery route and subsequent scale-up routes for NBI-75043 are presented. When traditional batch chemistry was found to limit the scale of a key reaction, a flow reactor was designed and optimized to provide an alternate method of production.",10.1021/op800071m,1
Identification of Critical Process Impurities and Their Impact on Process Research and Development,"The identification of low-level critical process impurities and degradants encountered during pharmaceutical development is crucial to the process development, but can often be challenging and can negatively impact the timeline of the developmental program. This is demonstrated during the early stage of process research and development of a Factor Xa inhibitor, the caprolactam 1 . Details focusing on rapid identification of impurities in the active pharmaceutical ingredient (API), recognition of their root causes of formation, and the impact on process development are described.",10.1021/op800067v,1
An Improved and Efficient Process for the Production of Donepezil Hydrochloride: Substitution of Sodium Hydroxide for <i>n</i>-Butyl Lithium via Phase Transfer Catalysis,"A simple, efficient and highly economic process for the production of donepezil hydrochloride ( 1 ), an anti-Alzheimer drug is reported. The process relies upon improved and large-scale synthesis of a key intermediate: 1-benzylpiperidine-4-carboxaldehyde ( 2 ), and the introduction of operationally simple chemistry at the penultimate stage wherein 2 is reacted with 5,6-dimethoxy indanone ( 3 ) in the presence of sodium hydroxide and a phase transfer catalyst (PTC) in a biphasic solvent to furnish the intermediate 4, which is reduced and directly treated with hydrochloric acid to furnish highly pure donepezil hydrochloride with desired polymorphic form. The improved process provides donepezil hydrochloride at considerably lower cost and allows the omission of hazardous chemicals.",10.1021/op800066m,1
A Convergent Process for the Preparation of Adamantane 11-β-HSD-1 Inhibitors,"A convergent, scalable process was developed for the synthesis of adamantane 11-β-hydroxysteroid dehydrogenase-1 inhibitors E -4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionylamino)adamantane-1-carboxylic acid ( 1 ) and E -4-(2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)propionylamino)adamantane-1-carboxamide ( 2 ) to rapidly deliver material for development. The process was high yielding and provided 1 in 52% overall yield over six total steps with a five-step longest linear sequence and 2 in 45% overall yield over seven total steps with a six-step longest linear sequence. A process to prepare active pharmaceutical ingredient (API) of >99% purity at the kilogram scale has been developed under tight delivery timelines.",10.1021/op800065q,1
Optimization and Scale-Up of a Suzuki−Miyaura Coupling Reaction: Development of an Efficient Palladium Removal Technique,"A ligand−solvent−base screen was performed on a Suzuki−Miyaura coupling reaction, and the screening data, followed by a set of focused experiments, helped to optimize reaction conditions. Further work was carried out that centered on reducing the level of residual palladium in the isolated product. Treatment of the reaction mixture with toluene and 20% aqueous NaHSO 3 at elevated temperature lowered the palladium content from ∼8000 ppm to 100 ppm or less. The Suzuki−Miyaura coupling and palladium removal process were demonstrated on 20-L scale, are highly efficient and cost-effective, and require short cycle times.",10.1021/op800064y,0
"Process Research and Scale-up of a Commercialisable Route to Maraviroc (UK-427,857), a CCR-5 Receptor Antagonist","A six-step synthetic route to the CCR-5 receptor antagonist, Maraviroc (UK-427,857) ( 1 ) has been developed and demonstrated at scale in a pilot plant. The route has supported four Pilot-Plant campaigns and has produced multikilogram quantities of 1 . Continued development of the synthetic route has resulted in a robust process with improved throughput compared to that of the original synthesis (Haycock-Lewandowski, S. J.; Mawby, N. J.; Wilder, A.; Ahman, J. Org. Process Res. Dev. 2008, 12, 1094−1103).",10.1021/op800062d,1
"Development of a Bulk Enabling Route to Maraviroc (UK-427,857), a CCR-5 Receptor Antagonist","A bulk enabling synthesis of the CCR-5 receptor antagonist, Maraviroc (UK-427,857) ( 1 ), is presented. Synthesis of the three key fragments, β-amino ester 3, 4,4-difluorohexanecarboxylic acid ( 2 ), and 1,3,4-triazole-substituted tropane fragment 4 are described. Coupling strategies for these fragments are discussed and described, including synthetic challenges, protection strategies, impurity generation, and final scale-up of the developed route to 1 .",10.1021/op8000614,1
"Development and Manufacture of the Inosine Monophosphate Dehydrogenase Inhibitor Merimepodib, VX-497","A process for the manufacture of merimepodib (VX-497), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, has been developed and efficiently scaled to produce clinical supply. The process comprises five steps, incorporating simple and robust chemistry that ultimately yielded 96.5 kg with a purity of 100% (by HPLC analysis) and 99.7% w/w assay. Highlights of the process are the effective use of production-scale phosgene, manipulation of Schotten−Baumann reaction conditions to give a low pH procedure that avoids a critical impurity, and the use of online tools to better identify parameters of the API purification.",10.1021/op800060h,1
Scale-Up Synthesis of Swainsonine: A Potent α-Mannosidase II Inhibitor,"The large-scale synthesis of Swainsonine 1, a potent α-mannosidase II inhibitor, has been achieved with several improvements. The key modifications were (a) performing the Wittig olefination under mild conditions and isolation of the product 4 with modified workup conditions, (b) introduction of the azido group on a large scale under Mitsunobu conditions to produce 12, (c) performing the 1, 3-dipolar cycloaddition of an unactivated azide 12 to afford the imino carboxylic ester 7, (d) formation of amide 10 from 7 under mild acidic conditions, and (e) isolation of the final compound 1 as a stable hydrochloride salt. In addition, synthesis of 11 was accomplished from 12 by telescoping the four steps.",10.1021/op800059y,1
Solving a Scale-Up Problem in the <i>O</i>-Alkylation of Isovanillin Under Phase-Transfer Catalysis Conditions,The alkylation of isovanillin with cyclopentyl bromide in the presence of potassium carbonate and a phase-transfer catalyst in THF is investigated. Successful completion of the reaction depends on the particle size of potassium carbonate.,10.1021/op800058n,0
The Swern Oxidation: Development of a High-Temperature Semicontinuous Process,"The Swern oxidation has been widely exploited for the oxidation of alcohols to their respective carbonyl compounds. The cryogenic operating conditions (<−60 °C) employed for the Swern oxidation, however, limit its utility for scale-up operations. Process development efforts on the Swern oxidation have demonstrated that an in-line reactor system can be used for the successful formation of the alkoxysulfonium salt precursor of the carbonyl compound. Two reagent streams, consisting of the alcohol/dimethylsulfoxide/methylene chloride and the oxalyl chloride, are loaded at ambient temperature to an in-line reactor, allowing the temperature to rise to 40 °C. The alkoxysulfonium chloride intermediate is discharged directly into triethylamine to complete the reaction. Residence times of 0.1−1.4 s in the in-line reactor were demonstrated to produce successful results in 750-gal pilot-plant equipment.",10.1021/op800057d,0
"Microwaves in Organic Synthesis, Volumes 1 and 2. Edited by André  Loupy. Wiley-VCH, Verlag GmbH and Co. KGaA: Weinheim. 2006. $375. Vol 1, 517 pp, Vol 2, 466 pp. Hard back. ISBN 978-3-527-31452-2 .","ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTJohn KnightView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield TN20 6EW, U.K.Cite this: Org. Process Res. Dev. 2008, 12, 3, 545–546Publication Date (Web):April 5, 2008Publication History Received11 March 2008Accepted11 March 2008Published online5 April 2008Published inissue 1 May 2008https://pubs.acs.org/doi/10.1021/op8000564https://doi.org/10.1021/op8000564book-reviewACS PublicationsCopyright © 2008 American Chemical SocietyRequest reuse permissionsArticle Views176Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysis,Electromagnetic radiation,Organic reactions,Organic synthesis,Solvents Get e-Alerts",10.1021/op8000564,0
Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/<scp>d</scp>-Fructose (Eraxis),"Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and d -fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN·HCl) and the active ester 1-({[4′′-(pentyloxy)-1,1′:4′,1′′-terphenyl-4-yl]carbonyl}oxy)-1 H -1,2,3-benzotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.",10.1021/op800055h,0
Continuous Organic Synthesis in a Spinning Tube-in-Tube Reactor: TEMPO-Catalyzed Oxidation of Alcohols by Hypochlorite,"Continuous production of aldehydes in high yields (≥90%) can be accomplished by feeding aqueous (sodium hypochlorite/sodium bicarbonate, pH 8.5) and organic (TEMPO/tetrabutylammonium bromide/primary alcohol/toluene or CH 2 Cl 2 ) solutions through the inlets of a spinning tube-in-tube reactor (STT reactor manufactured by Kreido Biofuels [STT is a registered trademark of Kreido Biofuels]) at rotor speeds of 4000−6000 RPM with residence times as short as 1−2 min. This approach eliminates the need for slow addition of the bleach reagent to control this exothermic reaction.",10.1021/op800051t,0
"A Concise Synthesis of Racemic 1-(6,7-Dimethoxy-2-naphthyl)-1-(1<i>H</i>-imidazol-4-yl)-2-methylpropan-1-ol for a Potent C<sub>17</sub>,<sub>20</sub>-Lyase Inhibitor","ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionA Concise Synthesis of Racemic 1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-imidazol-4-yl)-2-methylpropan-1-ol for a Potent C17,20-Lyase InhibitorJun-ichi Kawakami, Kazuhiro Kimura, and Masayoshi YamaokaCite this: Org. Process Res. Dev. 2008, 12, 3, 544Publication Date (Web):March 22, 2008Publication History Received4 March 2008Accepted10 March 2008Published online22 March 2008Published inissue 1 May 2008https://doi.org/10.1021/op800050kCopyright © 2008 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views408Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (27 KB) Get e-AlertscloseSUBJECTS:Inhibitors Get e-Alerts",10.1021/op800050k,0
The First 200-L Scale Asymmetric Baeyer−Villiger Oxidation Using a Whole-Cell Biocatalyst,"Biocatalytic Baeyer−Villiger oxidations using oxygen as an environmentally friendly oxidant in aqueous media have been shown to proceed with excellent stereo- and enantioselectivity for a large number of substrates at laboratory scale. These are good starting boundary conditions for process research and development compared to systems with reactive oxidants and flammable organic solvents. In this paper we discuss some of the considerations required to scale up a whole-cell biocatalytic oxidation from the laboratory to pilot-plant (200 L) scale. Issues for fermentation, bioconversion, and product recovery are discussed, supported by data from pilot-plant and scale-down experimentation. A simple fed-batch approach has been used.",10.1021/op800046t,0
A High-Throughput Impurity-Free Process for Gatifloxacin,"An improved process to obtain gatifloxacin ( 1 ) through use of boron chelate intermediates has been developed. The methodology involves an initial activation step which accelerates the formation of the first chelate under low-temperature conditions and prevents demethylation of the starting material. To increase the overall yield and to avoid the isolation and manipulation of the resulting intermediates, the process has been designed to be carried out in one pot. As a result, we present here an easy, scaleable and substantially impurity-free process to obtain gatifloxacin ( 1 ) in high yield.",10.1021/op800042a,1
Ligandless Heck Coupling between a Halogenated Aniline and Acrylonitrile Catalyzed by Pd/C: Development and Optimization of an Industrial-Scale Heck Process for the Production of a Pharmaceutical Intermediate,"The aniline derivative 3 is a key building block of rilpivirine (TMC278) 2, a new potent NNRTI compound under clinical evaluation. In this paper we describe the development of a new synthesis of 3 based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as catalyst. This resulted in a process which has been successfully transferred into production on 2400 mol-scale (6000 L reactor)",10.1021/op8000383,0
Kepner-Tregoe Decision Analysis as a Tool To Aid Route Selection. Part 3. Application to a Back-Up Series of Compounds in the PDK Project,"Kepner-Tregoe Decision Analysis was used to rank 22 potential routes to a back-up series of compounds in the PDK project. The ten highest scoring routes were evaluated practically, affording four new synthetic sequences for preparing the target compounds.",10.1021/op8000355,1
Kepner-Tregoe Decision Analysis as a Tool to Aid Route Selection. Part 1,"Kepner-Tregoe Decision Analysis is a logic-based tool that has been used by AstraZeneca to prioritise the investigation of alternative routes to drug candidates. This paper describes how the tool can be used in route selection work, with subsequent papers discussing application to AstraZeneca projects.",10.1021/op8000349,0
"Kepner-Tregoe Decision Analysis as a Tool To Aid Route Selection. Part 2. Application to AZD7545, a PDK Inhibitor","Kepner-Tregoe decision analysis was formally used as an aid to route selection, as outlined in the preceding paper. Over 40 paper routes were assessed for suitability for both immediate and longer term manufacture of AZD7545, a compound in the early stages of development. Eight routes were then investigated in full in the laboratory, and a further four in part, over a period of 3−4 months. From this exercise, the preferred long-term manufacturing route was identified before the first pilot scale manufacture had been completed. This route selection exercise worked well in this case where a large number of potential routes had to be considered using limited resources. It was also an effective means of bringing some long-term manufacturing issues to the fore at an early stage in development.",10.1021/op800033c,1
An Integrated Microreactor for the Multicomponent Synthesis of α-Aminonitriles<sup>1</sup>,"Initial steps have been taken to develop an integrated microreactor, capable of performing multicomponent reactions consisting of both solution phase and heterogeneously catalyzed steps. Using the multicomponent Strecker reaction as a model, five α-aminonitriles were synthesized in excellent yields (>99.5%) and analytical purity, under continuous flow conditions.",10.1021/op800025p,1
"Using Potassium Carbonate to Scavenge Hydrogen Fluoride: A Scale-Up Process for Quantitative Production of (1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinolinecarboxylato-κO3)difluoro−Boron","Hydrogen fluoride is a byproduct from the reaction of treating 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ( 4, 1.0 equiv) with borontrifluoride etherate (1.15−1.35 equiv) in refluxing THF solution. Scavenging the hydrogen fluoride evolved with potassium carbonate (1.15 equiv, 325 mesh) affords the desired (1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-(oxo-κO)-3-quinolinecarb-oxylato-κO3)difluoro−boron ( 5 ) in almost quantitative yield (>97%) with excellent chemical purity ( ≥ 99%). Hence, this reproducible and nonchromatographic process offers a benign method for large-scale (multikilogram) production of difluoro−boron complex 5 .",10.1021/op8000228,0
Development of a Mild and Robust Method for Large-Scale Palladium-Catalysed Cyanation of Aryl Bromides: Importance of the Order of Addition,"A mild and robust method for the large-scale palladium-catalysed cyanation of aryl bromides has been developed. The reaction is sensitive to cyanide poisoning of the catalyst, and it was found that the order of adding the reagents had a strong impact on the performance of the reaction. Addition of the cyanide source to a preheated mixture of the other reagents was critical for achieving a robust and scaleable process. This improved protocol allowed the reaction to be run to full conversion within 3 h at 50 °C on a 6.7 kg scale. Furthermore, it led to the identification of several new efficient catalysts for the reaction.",10.1021/op800020r,0
UnyLinker: An Efficient and Scaleable Synthesis of Oligonucleotides Utilizing a Universal Linker Molecule: A Novel Approach To Enhance the Purity of Drugs,"A novel universal linker (UnyLinker) molecule which has a conformationally rigid and chemically stable bridge head ring oxygen atom carrying a conventional 4,4′-dimethoxytrityl (DMT) and succinyl groups locked in a syn orientation has been developed to carry out oligonucleotide synthesis efficiently and smoothly. The geometry of the vicinal syn oxygen functionalized group allows fast and clean cleavage under standard aqueous ammonia deprotection conditions to afford high-quality oligonucleotides. No base modification is observed, based on the ion-pair HPLC−UV−MS (IP-HPLC−UV−MS) method with detection limit of <0.1%. A class of impurities formed by branching from the exocyclic amino group of nucleosides loaded onto a solid support has been eliminated by the use of this method. Examples demonstrating the versatile nature of this molecule are shown by syntheses of different chemistries such as 2′-deoxy, 2′- O -methyl, 2′- O -methoxyethyl, Lock nucleic acids (LNA), 2′-α-fluoro nucleic acids (FANA), conjugates such as 5′-phosphate monoester and biotin, and phosphate diester and phosphorothioate backbone modifications. This molecule was loaded onto several commercial solid supports and used in both gas-sparged and packed-bed automated DNA/RNA synthesizers. Large-scale syntheses (up to 700 mmol) of multiple phosphorothioate first- and second-generation antisense drugs on GE-Amersham’s OligoProcess synthesizer are demonstrated further, showing that this chemistry could be used for efficient synthesis of multiple oligonucleotide drugs using a single raw material, thereby eliminating a difficult to characterize nucleoside-loaded polymer matrix used as a starting material. A mechanism for deprotection and cleavage of the linker molecule to liberate the free oligonucleotide is proposed. Characterization of the cyclic byproduct formed during release of the oligonucleotide is presented. The exo-syn configuration of the dihydroxy structure of the UnyLinker molecule is conclusively established by X-ray crystallography studies. A novel method to remove the last traces of osmium used during the synthesis of the UnyLinker molecule to reach undetectable levels (<1 ppm) is also described.",10.1021/op8000178,1
Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT<sub>1B</sub> Receptor Antagonist,"Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core ( R )-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C−N bond between an aromatic ring and a heterocyclic moiety. The methodology employed a Buchwald−Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc) 2 as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with ( R )-BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110−115 °C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N -debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.",10.1021/op8000146,1
Particle Shape Characterisation via Image Analysis: from Laboratory Studies to In-process Measurements Using an in Situ Particle Viewer System,"A recent evaluation of a new in situ particle viewer (ISPV) system for the examination of particle shape and its subsequent development during crystal growth is presented. Precharacterization studies using conventional and hot-stage microscopy reveal that the ISPV probe system together with a commercial image analysis software is capable of generating representative high-quality images which can be processed and analysed. ISPV studies of the batch crystallization of l -glutamic acid in a 20-L reactor are shown to be able to characterise effectively crystallization and polymorphic phase transformation processes, revealing potential applications in both small- and large-scale reactor systems. Some improvements to the probe, such as increasing the resolution and reducing the encrustation using thermal coating, are suggested.",10.1021/op800011v,0
Development of One-Pot Synthesis of New Antiarthritic Drug Candidate S-2474 with High <i>E</i>-Selectivity,"A one-pot synthesis of S-2474 was developed to overcome the problems of a large number of steps, low stereoselectivity, low yield, a large amount of waste, and severe reaction conditions. Aldol-type condensation of 3,5-di- tert -butyl-4-hydroxybenzaldehyde and N -ethyl-γ-sultam was carried out with LDA and then quenched with water. Dehydration proceeded under basic conditions, providing S-2474 directly as a single isomer on the benzylidene double bond. The reaction mechanism appears to involve a quinone methide intermediate. Environmental assessment of the development of this compound is also discussed in this paper.",10.1021/op800008w,1
Concise Synthesis of Vinylheterocycles through β-Elimination under Solventless Phase Transfer Catalysis Conditions,Various vinylheterocycles compounds have been prepared in excellent yields through β-elimination of the corresponding sulfonate esters with 50% aq NaOH under phase transfer catalysis conditions without organic solvent. The new approach provides an economic and environmentally friendly solution to removal of hazardous bases as well as toxic and expensive dipolar aprotic solvents.,10.1021/op800001d,0
Large-Scale Synthesis of the Glucosylceramide Synthase Inhibitor <i>N</i>-[5-(Adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin,"A synthetic route for the preparation of glucosylceramide synthase inhibitor N -[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research laboratory at milligram-scale to the final optimized route that was implemented in a cGMP miniplant on kilogram-scale. The definitive route starts with the separate synthesis of building blocks 2,3,4,6-tetra- O -benzyl-1-deoxynojirimycin and 5-(adamantan-1-yl-methoxy)-pentanal. The aldehyde was synthesized from 1,5-pentanediol in five steps and 45% overall yield. Protected 1-deoxynojirimycin was prepared by a successive hemiacetal reduction/Swern oxidation/double reductive amination sequence of 2,3,4,5-tetra- O -benzyl- d -glucopyranose in 52% overall yield. Reductive amination of the two building blocks produced the benzyl-protected penultimate that was isolated as its crystalline (+)DTTA salt in 68% yield. Hydrogenolysis of the penultimate and crystallization of the end product as its methanesulfonic acid salt produced AMP-DNM in 76% yield with a purity of >99.5%. The described route enables the production of multikilogram amounts of inhibitor AMP-DNM as a stable crystalline solid with high purity under cGMP control.",10.1021/op700295x,1
Industrial Applications of Online Monitoring of Drying Processes of Drug Substances Using NIR,"Drying is an important part of manufacturing processes in the chemical and pharmaceutical industry. The product quality often depends on the drying conditions and efficiency. Moreover, this unit operation frequently represents the bottleneck of the whole process. Therefore, online monitoring of the drying operation can lead to a significant improvement of the cycle time as well as to a reduction of the analytical work and costs. This paper demonstrates the effectiveness of NIR spectroscopy to control drying processes on an industrial scale. The examples shown in this study are realized using different kinds of dryers (filter dryer, paddle dryer, and spherical dryer) and various solvents (water and organic solvents). The spectral data are evaluated using multivariate calibration methods (partial least squares regression). These studies show that the solvent concentrations determined using NIR are in good agreement with the reference analyses. Moreover, the direct measurement in the powder allows stopping the drying process at a given residual solvent concentration (which is crucial in certain processes, e.g. to obtain specific hydrate forms). All together, the implementation of NIR for online monitoring of drying processes leads to a significant optimization of plant equipment utilization and to a higher throughput while reducing the risk of out-of-specifications batches.",10.1021/op700293p,0
Chemical Reactions with a Novel 5.8-GHz Microwave Apparatus. 1. Characterization of Properties of Common Solvents and Application in a Diels–Alder Organic Synthesis,"Microwave radiation emitted at a frequency of 5.8 GHz in a novel fabricated apparatus is herein proposed for carrying out organic syntheses. Temperature profiles (rates of increase of temperature and superheating) and dielectric parameters are reported for water and 22 common organic solvents. For comparison, solvent properties were also examined using the more common 2.45-GHz microwave radiation under conditions otherwise identical to those used for the 5.8-GHz microwaves. The usefulness of 5.8-GHz microwaves to carry out organic syntheses is demonstrated by the synthesis of 3,6-diphenyl-4- n -butylpyridazine through a Diels–Alder process in three representative solvents of various polarities: dichloromethane, ethyl acetate, and xylene. For comparison, the synthesis of 3,6-diphenyl-4- n -butylpyridazine was similarly undertaken by conventional heating of the reacting mixture in an oil bath and by 2.45-GHz microwave heating. Results indicate the usage of 5.8-GHz microwaves in organic syntheses might be more beneficial than the 2.45-GHz microwaves.",10.1021/op700292s,0
"Microreactor Technology: Continuous Synthesis of 1<i>H</i>-Isochromeno[3,4-<i>d</i>]imidazol-5-ones","A synthetic method was evaluated to form 1 H -isochromeno[3,4- d ]imidazol-5-ones via ring closure starting from 3-amino-4-(arylamino)-1 H -isochromen-1-ones. The method was implemented and optimized in a microreactor environment. It was possible to synthesize these compounds in a continuous mode with an output up to 2.2 g/h.",10.1021/op700289e,0
"Development of a Robust Ring-Closing Metathesis Reaction in the Synthesis of SB-462795, a Cathepsin K Inhibitor","The development of a robust and high-yielding ring-closing metathesis (RCM) reaction and its demonstration on multikilogram scale are described. A detailed understanding of the impact of impurities on the RCM reaction was achieved using a variety of chemical and statistical methods. Specifically, individual impurities were evaluated in spiking studies to identify those that negatively affected the RCM reaction. Projection methods (PCA and PLS) were applied to historical data to identify the main sources of variation in starting material quality and determine the main detrimental impurities that impeded the RCM reaction. The synthesis of the starting material was then modified to adequately control these key impurities, which in turn ensured a robust RCM process. Finally, the robustness of the RCM reaction was assessed using a probability-based approach.",10.1021/op700288p,1
A Practical and Improved Copper-Catalyzed Synthesis of the Central Intermediate of Diafenthiuron and Related Products,"A bioinspired Cu(I)/ N -methylimidazole catalyst system is used for the synthesis of the diaryl ether part of diafenthiuron, a widely used insecticide. The convenient protocol proceeds smoothly with high selectivity and quantitative yield. Applying the optimized procedure various diaryl ether analogs are synthesized in good to excellent yield.",10.1021/op700287s,0
Synthesis of Enantiopure Fmoc-α-Methylvaline,"An efficient synthesis of enantiopure Fmoc-α-methylvaline has been developed. The racemate was prepared in two steps from 3-methyl-2-butanone and was resolved using a chiral amine, ( S )-1,2,3,4-tetrahydro-1-naphthylamine to give the desired, enantiopure S -isomer in 23% overall yield.",10.1021/op700286u,1
Streamlined Synthesis of the Bippyphos Family of Ligands and Cross-Coupling Applications,"We describe the efficient preparation of Bippyphos, 1 . The key precursor to Bippyphos, 5, was prepared via a one-pot bromination of diketone 2 followed by alkylation with pyrazole and condensation with phenylhydrazine. Lithiation of 5 and trapping with di- tert -butylchlorophosphine afforded Bippyphos, 1 . Using this approach we have prepared several derivatives of Bippyphos to probe the structure and activity relationships of this family of phosphine ligands. We also demonstrate the utility of these ligands in Pd-catalyzed amination reactions and other cross-coupling reactions.",10.1021/op7002858,1
Process Development for the Sulfonamide Herbicide Pyroxsulam,"The development of a manufacturing process for the initial commercial production of pyroxsulam sulfonamide herbicide is described. The process encompasses seven reaction steps, and includes a new route to 4-(trifluoromethyl)pyridines, a scaleable method of lithiating a pyridine intermediate, and a sulfilimine-catalyzed formation of a sulfonamide.",10.1021/op700281w,1
"Development of a Scalable Synthetic Route to GSK369796 (<i>N-tert</i>-Butyl Isoquine), a Novel 4-Aminoquinoline Antimalarial Drug","An improved process to the novel 4-aminoquinoline antimalarial GSK369796 is described. Although the initial synthetic route consisted of only two steps from readily available starting materials, the product isolated via the key Mannich reaction was hampered by both low yields and low purity. In addition to instability under the reaction conditions used for the Mannich reaction, the drug substance was found to decompose during attempts to purify by recrystallisation. Reaction conditions were developed that resolved these issues, culminating in the successful production of multi-kg quantities of GSK369796 in >98% a/a purity and in 57% overall yield.",10.1021/op7002776,1
A Facile Total Synthesis of Imatinib Base and Its Analogues,Imatinib and its analogues were successfully synthesized by an improved method in 19.5– 46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N -(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by copper-catalyzed N -arylation of heteroarylamine in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C−N bond-forming reaction. The intermediate nitro compound was reduced by a N 2 H 4 ·H 2 O/FeCl 3 /C system using water as a solvent in good yield.,10.1021/op700270n,1
Practical Synthesis of a Peptide Deformylase (PDF) Inhibitor,"A practical chromatography-free synthesis of an N -formylated hydroxylamine peptide deformylase inhibitor LCD320 is described. A diastereoselective Michael reaction of (4 S )-3-[2-(cyclobutylmethyl)-1-oxo-2-propenyl]-4-(phenylmethyl)-2-oxazolidinone with O -benzyl hydroxylamine was used to establish the key stereogenic center. We found that traces of residual Li + from a previous step had a great impact on the diastereoselectivity of this reaction. A very efficient amidation coupling reaction of proline derivative (2 S,4 R )-4-fluoro-1,2-pyrrolidinedicarboxylic acid 1,1-dimethylethyl ester with weakly nucleophilic 3-pyridazinamine using methanesulfonyl chloride in the presence of 1-methylimidazole in DMF was also developed that proceeded without racemization.",10.1021/op700265n,1
Practical Asymmetric Synthesis of Trifluoromethyl-Containing Aminoester Using a Modified Davis Protocol,"Practical synthesis of aminoester 1 starting from 1,1,1-trifluoro-3-iodopropane is presented. Use of Ti(O i -Pr) 4 as a Lewis acid for condensation of intermediate aldehyde 8 with ( S )-(+)- p -toluenesulfinamide was found to be critical. Conditions for a reproducible and high-yielding Wittig reaction of aldehyde hydrate with phosphorus ylide 4, that appear to have general applicability, are described.",10.1021/op700259d,1
Route Scouting and Process Development of Lu AA26778,"Route scouting and process development for the synthesis of ( S )-2-({3-[( S )-5-chloro-1-(4-chloro-phenyl)indan-1-yl]propyl}methylamino)propionic acid, Lu AA26778, are described. The strategy is based on a short synthesis and SMB resolution of a key chiral intermediate for the introduction of one of the two stereocenters. The second stereocenter is introduced via a commercially available alanine ester, optionally bearing a N -methyl group. The main concern during scale-up of the synthesis was the safety of a step incorporating sodium dimsylate (the sodium salt of DMSO): this problem was solved using THF as a safety blanket in the large-scale process.",10.1021/op7002584,1
Reduction of Ethyl Benzoylacetate and Selective Protection of 2-(3-Hydroxy-1-phenylpropyl)-4-methylphenol: A New and Facile Synthesis of Tolterodine,"A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel–Crafts alkylation utilizing FeCl&lt;sub&gt;3&lt;/sub&gt;·6H&lt;sub&gt;2&lt;/sub&gt;O as catalyst lead to the known 2-(3-hydroxy-1-phenylpropyl)-4-methylphenol intermediate. Consecutive protection of phenolic OH with &lt;i&gt;p&lt;/i&gt;-toluenesulfonyl chloride via two-phase reaction and conversion of aliphatic OH using &lt;i&gt;p&lt;/i&gt;-nitrobenzenesulfonyl chloride facilitates direct substitution of diisopropylamine. After simultaneous deprotection of the tosyl group, optically pure (&lt;i&gt;R&lt;/i&gt;)-tolterodine·l-tartrate was obtained by resolution using l-tartaric acid with 99.99% purity.",10.1021/op7002562,0
"Preparative Asymmetric Synthesis of 4,4-Dimethoxytetrahydro-2H-pyran-3-ol with a Ketone Reductase and in Situ Cofactor Recycling using Glucose Dehydrogenase","The asymmetric enzymatic ketone reduction of 4,4-dimethoxytetrahydro-2H-pyran-3-one provided the ( R )-α-hydroxyketal, an important chiral precursor for a pharmaceutical intermediate, with high enantioselectivity (>99% ee). An economical process including in situ NADPH-cofactor regeneration using glucose dehydrogenase has been developed to produce the desired material in high yield (96–98%). The two-enzyme process was employed at pilot-plant scale to produce 80 kg of ( R )-4,4-dimethoxytetrahydro-2H-pyran-3-ol. Critical factors for scale-up were found to be pH control and agitation speed.",10.1021/op700255b,0
"Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 2. Process Improvement for Scale-Up of 2,5,8-Substituted 11,12-Dihydro-5<i>H</i>-6,13-dioxabenzo[3,4]cyclohepta-[1,2-<i>a</i>]naphthalene Derivatives","ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionSynthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 2. Process Improvement for Scale-Up of 2,5,8-Substituted 11,12-Dihydro-5H-6,13-dioxabenzo[3,4]cyclohepta-[1,2-a]naphthalene DerivativesXun Li, Michael Reuman, Ronald K. Russell, Scott Youells, Sandra Beish, Zhiyong Hu, Shawn Branum, Nareshkumar Jain, and Zhihua SuiCite this: Org. Process Res. Dev. 2008, 12, 1, 125Publication Date (Web):December 27, 2007Publication History Published online27 December 2007Published inissue 1 January 2008https://pubs.acs.org/doi/10.1021/op700254fhttps://doi.org/10.1021/op700254fcorrectionACS PublicationsCopyright © 2007 . This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views542Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (34 KB) Get e-AlertscloseSUBJECTS:Aromatic compounds,Materials,Modulators,Receptors Get e-Alerts",10.1021/op700254f,0
Chemoenzymatic Deracemization of Chiral Secondary Alcohols: Process Optimization for Production of (<i>R</i>)-1-Indanol and (<i>R</i>)-1-Phenylethanol,"A process for preparing chiral secondary alcohols by chemoenzymatic deracemization was optimized. First, the transesterification process of 1-indanol and 1-phenylethanol with vinyl acetate as the acyl donor was optimized using lipase Novozym 435 as biocatalyst. The effects of acyl donors, substrate concentration, solvent type, and enzyme amount on activity and enantioselectivity of the said transesterification were investigated. Second,on the basis of the optimized conditions, an efficient biocatalytic resolution system was established with high selectivity, where volumetric productivity of the reaction against ( R )-1-indanol and ( R )-1-phenylethanol reached 529 and 198 g L −1 d −1, respectively, during reuse of the enzyme in repeated-batch transesterification reactions. After 10 batches of the reaction, the enzyme still remained stable. Finally, ( R )-1-indanol and ( R )-1-phenylethanol were obtained in 95% and 97% ee and in 67% and 71% isolated yields from the corresponding resolution mixture, through an in situ Mitsunobu inversion of the unreacted alcohols followed by chemical hydrolysis of ( R )-acetates.",10.1021/op700253t,0
A Highly Practical and General Route for α-Arylations of Ketones Using Bis-phosphinoferrocene-Based Palladium Catalysts,"Well-defined, air-stable Pd complexes of bis-phosphinoferrocene family of catalysts have been studied in the arylation of various ketones with aryl chlorides and aryl bromides. Bis(di- tert -butyl)phosphinoferrocene (DtBPF)-based catalysts such as (DtBPF)PdCl 2 and (DtBPF)PdBr 2 have been identified as two of the most active catalysts for the α-arylation of a model reaction involving propiophenone and 4-chlorotoluene. The scope of the (DtBPF)PdCl 2 catalyst has been efficiently expanded to the arylation of various ketones with aryl chlorides and bromides with up to 97% isolated yields, under relatively mild reaction conditions at low catalyst loadings. The efficacy of the (DtBPF)PdCl 2 catalyst was demonstrated at very low catalyst loadings with S/C 10,000 for the difficult aryl bromide, 4-bromoanisole, and 2000 for the electron-neutral aryl chloride, 4-chlorotoluene, on ∼10-g scale with excellent isolated yields and lower Pd in the product (6 and 48 ppm, respectively). Comparative studies on the Pd:DtBPF molar ratios between in situ catalysts and preisolated catalysts revealed that preisolated (DtBPF)PdX 2 (X = Cl, Br) are the catalysts of choice due to various practical reasons.",10.1021/op7002503,0
Cu-Catalyzed Formation of Triazole-Linked Glycoamino Acids and Application in Chemoenzymatic Peptide Synthesis,"Novel stable triazole-linked glycoamino acids have been prepared, with the heterocyclic moiety being established by efficient Cu-mediated cycloaddition between the corresponding azido and acetylene moieties. Selected reactions were scaled up and successfully subjected to chemoenzymatic peptide-coupling reactions involving the proteolytic enzyme alcalase, resulting in several glycosylated di- and tripeptide structures. Since chemoenzymatic approaches have several advantages over chemical peptide coupling, especially concerning large-scale peptide synthesis, these results may be regarded as initial steps in the direction of production via fully chemoenzymatic peptide synthesis.",10.1021/op700249f,0
"Development of a Scaleable Process for the Synthesis of the A2a Agonist, UK-371,104","The development and utilization of a scaleable process for the manufacture of the A2a agonist UK-371,104 ( 1 ) is described. Key steps in the synthesis include (i) a palladium-catalyzed cyanation reaction to prepare the nitrile 10, (ii) a telescoped conversion of the acid 11 to the glycosidation substrate 9, and (iii) the stereoselective coupling of 8 with 9 in a glycosidation reaction mediated by TMS triflate in 1,2-dimethoxyethane followed by conversion through to 1 .",10.1021/op700248t,1
"Development of an Enantioselective, Kilogram-Scale, Rhodium-Catalysed 1,4-Addition","A rhodium-catalysed 1,4-addition of an arylboron species to an α,β-unsaturated ester was the key chirality-inducing step in the synthesis of an API. We describe herein the development of this chemistry, including optimization of reagent charges, reaction conditions, and metal recovery, in order to allow manufacture at multikilogram scale. A key result was the unexpected discovery that the use of a minimal quantity of an alcohol, rather than water, reduces the extent of rhodium-mediated protodeboronation of the boron species. This allowed the charge of this expensive reagent to be significantly reduced. Furthermore, the use of an alcohol instead of water avoided the agglomeration of the inorganic base present in the reaction, making the process more robust and operationally simpler. To our knowledge this is the first time that this type of C−C bond-forming chemistry has been used in a multikilo manufacture.",10.1021/op700246g,1
Debottlenecking the Synthesis Route of Asenapine,"The discovery synthesis of asenapine that was used for the manufacture of drug substance batches up to 10 kg contained two chemical steps that were major bottlenecks for scale-up. One of these steps involved a magnesium/methanol reduction of an enamide moiety that was severely hampered by safety and efficiency problems. The other step was a laborious chromatography and isomerization cycle that was marked by a poor yield and extremely low throughput. The safety issues of the magnesium/methanol reduction could be solved by adding portions of magnesium to a solution of the enamide. In addition, an alternative process for the conversion of the mixture of cis - and trans -lactam into the desired trans -isomer was developed, circumventing the chromatographic separation.",10.1021/op700240c,1
Engineering Selectivity in Novel Synthesis of 3-(Phenylmethoxy)phenol from Resorcinol and Benzyl Chloride under Liquid–Liquid−Liquid Phase Transfer Catalysis,"Monobenzyl ether of resorcinol, namely, 3-(phenylmethoxy)phenol is used as an intermediate for the synthesis of various chemically and biologically active molecules. The synthesis of 3-(phenylmethoxy)phenol can be accomplished by using phase transfer catalysis (PTC), either as liquid–liquid (L−L) or solid–liquid (S−L) PTC. Creation of a third phase in a biphasic reaction leads to several advantages in this type of reaction. A catalyst rich middle phase is formed between the other two phases wherein the main reaction takes place in the liquid–liquid−liquid (L−L−L) PTC and this offers a number of advantages over L−L PTC in terms of intensification of rate, higher selectivity and the possibility to reuse the catalyst. It is an excellent way for waste reduction and improving profitability. The catalyst rich phase is recovered and reused to up to six times with little impact to reactivity. This also helps in waste minimization which is a major theme of Green Chemistry. In the current work, synthesis of 3-(phenylmethoxy)phenol was accomplished by the reaction of resorcinol with benzyl chloride using tetrabutylammonium bromide (TBAB) under liquid–liquid−liquid phase transfer catalysis (L−L−L PTC) at 90 °C. The studies cover the effects of various kinetic and process parameters which lead to enhancement in rates and selectivities. A theoretical model was developed and validated against experimental data. It follows zero-order kinetics in the mono- O -benzylation of resorcinol. There is 100% selectivity for 3-(phenylmethoxy)phenol with no discernible amount of bis-alkylated product detectable. O -Alkylation of hydroquinone and catechol were also studied using the same technique to realise the same high selectivity. The order of reactivity and apparent activation energy is as follows: hydroquinone > resorcinol> catechol.",10.1021/op7002369,0
Development of a Practical Synthesis of DPP IV Inhibitor LY2497282,"A new synthetic route to LY2497282 ( 1 ), a potent and selective DPP IV inhibitor for the potential treatment of diabetes, suitable for the preparation of multikilogram quantities is described. The key step involved a stereoselective addition of the dianion of nicotinamide 8 to N -dibenzyl-protected α-amino aldehyde 12, which was derived from N -acetyl-protected amino ester 14 without epimerization. The desired Felkin-Anh nonchelation controlled anti -amino alcohol 11 was isolated with >99% HPLC area and >99% ee by crystallization. After removing the dibenzyl protecting group under transfer hydrogenation conditions, LY2497282 ( 1 ) was finally obtained in 39% overall yield with a six-step longest linear sequence starting from N -acetyl-protected amino ester 14 .",10.1021/op700235c,1
Continuous Processes in Small-Scale Manufacture,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTContinuous Processes in Small-Scale ManufactureTrevor LairdCite this: Org. Process Res. Dev. 2007, 11, 6, 927Publication Date (Web):October 31, 2007Publication History Published online31 October 2007Published inissue 1 November 2007https://pubs.acs.org/doi/10.1021/op700233ehttps://doi.org/10.1021/op700233eeditorialACS PublicationsCopyright © 2007 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1151Altmetric-Citations14LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (46 KB) Get e-AlertscloseSUBJECTS:Crystallization,Industrial manufacturing,Separation science,Solvents Get e-Alerts",10.1021/op700233e,0
Sulfur Contamination Due to Quenching of Halogenation Reactions with Sodium Thiosulfate: Resolution of Process Problems via Improved Quench Protocols,"Many metal-mediated cross-couplings involve the use of organic halides, which are usually accessed by halogenation reactions. Cross-couplings are sensitive to the presence of impurities in the halides. This paper describes the origin of one such problematic impurity (sulfur) during the synthesis of organic halides and proposes alternatives to minimize or eliminate its formation.",10.1021/op700227p,1
Continuous Flow Microwave-Assisted Reaction Optimization and Scale-Up Using Fluorous Spacer Technology,"Microwave-assisted organic synthesis in a laboratory-scale monomodal microwave reactor is investigated for continuous flow applications using fluorous spacer technology. The benchtop continuous flow microwave described allows sequential processing of multiple plugs using small amounts of reagents for reaction optimization, scale-up and array synthesis. The system features online monitoring of temperature, pressure and microwave power. Several different reactions have been scaled up, including a Suzuki−Miyaura cross-coupling reaction and nucleophilic substitutions. In all cases it was possible to optimize the reaction conditions on a small scale (∼300 μL processing volume), and achieve similar conversions on an intermediate scale (∼30 mL), offering the potential for further scale-up without modifying the optimized conditions (direct scalability) producing similar isolated yields in the C−C bond formation reaction.",10.1021/op700225u,0
Development of a Chemoenzymatic Manufacturing Process for Pregabalin,"A new manufacturing process for ( S )-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac -2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester ( 1 ) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexanoic acid ( 2 ). A heat-promoted decarboxylation of 2 efficiently generates ( S )-3-cyano-5-methylhexanoic acid ethyl ester ( 3 ), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of ( R )- 1 . The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40–45% after one recycle of ( R )- 1 ), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.",10.1021/op7002248,1
Development of a Practical Route for the Manufacture of <i>N</i>-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]acetamide,"An efficient synthesis of a potent candidate in our respiratory program is described. The synthesis based on a key Darzens condensation−α,β-epoxide rearrangement circumvented the toxicity and safety issues encountered in the original synthesis route. Subsequent functionalization and formation of an heterocyclic moiety is presented with a particular emphasis on the practicality, robustness, and streamlining of the process.",10.1021/op700222r,1
"Process Development of TRI-999, a Fatty-Acid-Modified HIV Fusion Inhibitory Peptide","TRI-999 is a HIV fusion inhibitory peptide designed to improve upon the efficacy and convenience of Enfuvirtide (ENF, Fuzeon), the first approved HIV entry inhibitor. Derived from a gp41 HR2 region partially overlapping the ENF sequence, TRI-999 is modified using a fatty acid conjugation strategy through a poly(ethylene glycol) (PEG) linker to maintain potency while achieving the desired PK. Synthetic route comparison, process development, and GMP manufacturing at the kilo scale of TRI-999 are reported.",10.1021/op7002198,0
Application of an Enantiomerically Pure Bicyclic Thiolactone in the Synthesis of a Farnesyl Transferase Inhibitor,"An efficient manufacturing route to a novel farnesyl transferase inhibitor is described. The target molecule is a pro-drug, and its synthesis is complicated by the presence of labile functionality. The Medicinal Chemistry synthesis required trityl mercaptan to introduce a thiol group stereospecifically. An important objective of a new route was avoidance of such an atom-inefficient protecting group, and this was achieved by use of a bicyclic thiolactone. Reduction of the thiolactone with DIBAL afforded a masked aldehyde which participated cleanly in the key reductive amination step without loss of stereochemical integrity. The reported procedure for making the thiolactone was found to give inconsistent results. Development work resulted in a telescoped process that was operated successfully and reproducibly on the large scale. Removal of an N-Boc protecting group in the final step of the drug synthesis required careful choice of conditions to avoid cleaving other ester groups in the molecule. An impurity formed in the deprotection step was identified as the S- tert- butyl analogue arising from attack of the tert -butyl cation on the methionine residue; its identity was confirmed by independent synthesis.",10.1021/op700218j,1
Modeling-Based Approach towards On-Scale Implementation of a Methanethiol-Emitting Reaction,"Utilizing kinetic process modeling, the conditions for a pharmaceutical guanylation reaction were optimized to promote controlled generation of methanethiol and efficient removal from the off-gas stream via wet scrubbing. Optimization of the kinetic model identified two guanylation reaction temperature profiles that reduced the maximum off-gas flow rate by approximately 75% while increasing the reaction cycle time by only 15−23%. The identified reaction conditions were quickly verified in laboratory-scale experiments and implemented in the scale-up of this process from kilo laboratory to pilot plant scale. Additionally, computational fluid dynamics calculations of the sodium hypochlorite and sodium hydroxide wet scrubber were used to demonstrate that methanethiol oxidation within the wet scrubber was rapid. Within this system, methanethiol bubbles were only expected to travel approximately 40 mm before being completely oxidized. Upon scale-up, the process-modeling-based approach described here provided methanethiol removal efficiencies of greater than 99.9999% for methanethiol inlet concentrations between 10 and 60 wt % using standard pilot plant equipment.",10.1021/op7002166,0
"Catalysts for Fine Chemical Synthesis, Volume 5: Regio- and Stereo-Controlled Oxidations and Reductions. Stanley M. Roberts and John Whittall , Eds. Wiley : West Sussex, U.K. 2007 . 312 + xxii pages. £100. ISBN 978-0-470-09022-0 .","ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 6, 1151Publication Date (Web):November 16, 2007Publication History Published online16 November 2007Published inissue 1 November 2007https://doi.org/10.1021/op700213vCopyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views145Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (62 KB) Get e-AlertsSUBJECTS:Materials,Organic reactions,Oxidation,Redox reactions,Separation science Get e-Alerts",10.1021/op700213v,0
Implementation on Pilot-Plant Scale of the Titanocene-Catalyzed Reduction of a Lactone with Poly(methylhydrosiloxane),"The titanocene-catalyzed reduction of the lactone 1 into the lactol 2 was studied. This process uses poly(methylhydrosiloxane) as stoichiometric reductant. Thermodynamic and safety data was collected in order to develop a reliable, safe and scalable process that was successfully implemented in the pilot plant. Using this new process, the target lactol was obtained on 30-kg scale with better yield and purity than with a former process using DIBALH, while decreasing the amount of waste.",10.1021/op700207m,0
"Encyclopedic Dictionary of Named Processes in Chemical Technology, 3rd ed . By Alan E. Comyns . CRC Press/Taylor and Francis : Boca Raton . 2007 . £85. ISBN 978-0-8493-9163-7 .","ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 6, 1149–1150Publication Date (Web):October 19, 2007Publication History Received6 September 2007Published online19 October 2007Published inissue 1 November 2007https://pubs.acs.org/doi/10.1021/op700205yhttps://doi.org/10.1021/op700205ybook-reviewACS PublicationsCopyright © 2007 American Chemical SocietyRequest reuse permissionsArticle Views99Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Beverages,Catalysts,Physical and chemical processes,Sandwich compounds Get e-Alerts",10.1021/op700205y,0
"Process Research on the Preparation of 1-(3-Trimethylsilylphenyl)-2,2,2-trifluoroethanone by a Friedel–Crafts acylation Reaction","Zifrosilone (1-(3-trimethylsilylphenyl)-2,2,2-trifluoroethanone) ( 3 ) is a cholinesterase inhibitor that has been studied for the treatment of Alzheimer’s disease. Process research has been carried out on a route to convert phenyltrimethylsilane to 3 by Friedel–Crafts acylation using trifluoroacetic anhydride. Kinetics and products analyses suggest that the optimal conditions for this reaction are noncatalytic amounts of aluminum chloride, dichloromethane solvent and as low a temperature as can be practically used in a scaled-up process. Significant separation challenges to isolate 3 from the isomer byproduct 1-(4-trimethylsilylphenyl)-2,2,2-trifluoroethanone) ( 4 ) remain. These challenges were investigated using vapor–liquid equilibrium studies.",10.1021/op700199p,0
Large-Scale Preparation of 2-Methyloxazole-4-carboxaldehyde,"The large-scale preparation of 2-methyloxazole-4-carboxaldehyde presents a significant challenge due to the physical characteristics of the molecule. A method for the preparation of 10-kg batches of 2-methyloxazole-4-carboxaldehyde is described. The key reaction is the reduction of the corresponding N -methoxy- N -methyl amide using lithium aluminium hydride, followed by workup and isolation by crystallization.",10.1021/op700198s,1
Efficient Multikilogram Synthesis of 5-Bromo-2-cyclopropyl-1-methyl-1<i>H</i>-imidazole,"Herein we describe the optimization and application of a copper(I) chloride-mediated protocol for the multikilogram synthesis of 5-bromo-2-cyclopropyl-1-methyl-1 H -imidazole hydrochloride ( 1 ), a key building block used in the preparation of several biologically active small molecules.",10.1021/op700195j,1
Process Research and Development of an NK-1 Receptor Antagonist. Enantioselective Trifluoromethyl Addition to a Ketone in the Preparation of a Chiral Isochroman,"CJ-17,493 ( 4 ) is a chiral NK-1 receptor antagonist. It was first prepared through a diastereoselective crystallization, then through chiral chromatography of a key intermediate, and ultimately via asymmetric synthesis. Multiple routes for the preparation of a key isochroman were demonstrated, and conditions for improved regioselectivity of a Friedel–Crafts acylation were identified. Cesium fluoride was found to be an acceptable initiator for the generation of a nucleophilic trifluoromethyl anion from CF 3 TMS. A cinchonine-derived catalyst was identified for the enantioselective addition of the trifluoromethyl group to the ketone, and it was found that the product of the addition would be converted directly to the isochroman by treatment with t -BuOK. A Duff reaction was used for the formylation, and the resulting aldehyde was coupled to amine 5 to afford CJ-17,493 ( 4 ).",10.1021/op7001886,1
Approaches for Scale-Up of Microwave-Promoted Reactions,"In this report, we look at a range of classes of reaction involving microwave heating and show how different processing techniques can be used to address scale-up needs. We look at both batch and continuous-flow processing. We have shown that when using batch methodologies working using an open reaction vessel offers operational advantages while still giving good yields of desired products. In cases where open-vessel conditions are not amenable or where particularly volatile or toxic reagents are used, parallel sealed vessels can offer an alternative approach. For continuous-flow processing, homogeneity of the reaction mixture is key. When the mixture is homogeneous, it is possible to move from small-scale sealed-vessel conditions to the continuous-flow apparatus without any modification of reaction conditions or loss in product yield. When either the starting materials or the product mixture contains particulate matter, continuous processing can prove a challenge, but reoptimization of reaction conditions as well as reduction of the concentration may allow these difficulties to be overcome.",10.1021/op700187w,0
A Comparison of Commercial Microwave Reactors for Scale-Up within Process Chemistry,"Seven commercially available microwave reactors designed for limited scale-up have been investigated using a highly reliable and robust reaction (the Newman−Kwart rearrangement). The use of a single reaction has enabled the comparison to be made across the range of different reactor types and scales. Overall, all reactors gave reliable scale-up from small scale, and performance equivalent to one another on large scale. A more detailed comparison between them is given in the concluding section.",10.1021/op700186z,1
A Synthesis Is Not the Same as a Process,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTA Synthesis Is Not the Same as a ProcessTrevor LairdCite this: Org. Process Res. Dev. 2007, 11, 5, 783Publication Date (Web):September 6, 2007Publication History Received14 August 2007Accepted14 August 2007Published online6 September 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op700185vhttps://doi.org/10.1021/op700185veditorialACS PublicationsCopyright © 2007 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views864Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (42 KB) Get e-AlertscloseSUBJECTS:Elements,Organic chemistry,Organic synthesis,Process chemistry,Separation science Get e-Alerts",10.1021/op700185v,0
"A Practical Synthesis of Enantiopure 7-Alkoxy-4-aryl-tetrahydroisoquinoline, a Dual Serotonin Reuptake Inhibitor/Histamine H<sub>3</sub> Antagonist","An efficient synthesis of compound 1 featuring a novel sequential Friedel–Crafts alkylation strategy to construct the 4-aryl-tetrahydroisoquinoline core structure has been developed. Resolution with ( d / l )-di- p -toluoyl-tartaric acid is utilized to provide the enantiomerically pure material. Overall, the route is concise and amenable for large-scale synthesis.",10.1021/op700183q,1
"First Scale-Up: Problems and Resolutions on the Synthesis of WAY-253752, a Novel, Dual-Acting SSRI/5HT<sub>1A</sub> Antagonist","An alternative synthesis of WAY-253752, 1, a novel, dual-acting SSRI/5HT 1A antagonist, was developed and used for the first scale-up. Initially, the target compound was synthesized as part of a diasteromeric mixture separated by chiral preparative HPLC. The new route was designed around intermediates suitable for chiral resolution, and its conditions were successfully determined.",10.1021/op700181n,1
Development of a Phase Transfer Catalyzed Asymmetric Synthesis for an Estrogen Receptor Beta Selective Agonist,"A practical asymmetric synthesis of the estrogen receptor beta selective agonist (7β-9aβ)-1,4-dichloro-2-hydroxygibba-1(10a),2,4,4b-tetraen-6-one ( 1 ), proceeding by way of six isolated intermediates and without recourse to chromatography, is described. Highlights of the process route developed are two chemoselective chlorinations, a lithiated hydrazone alkylation and an asymmetric Michael addition of indanone 11 to methyl vinyl ketone (using 15 mol % of cinchonine-derived catalyst 20g ) to set the all-carbon quaternary asymmetric stereocenter. The challenges addressed in scaling the latter heterogeneous biphasic phase transfer reaction to 44 mol (14 kg) scale are discussed in detail. Overall, the chemistry developed has been used to prepare >6 kg of drug candidate 1 in 18% overall yield and with >99% ee.",10.1021/op700178q,1
pH Control in Aqueous Processes: <i>N</i>-4-Methylsulfonylphenylguanidine,"The kinetics and mechanism of the synthesis of the sulfonylguanidine 2 by reaction of the corresponding aniline, 1, with cyanamide have been investigated in aqueous acid solution. The reaction is acid-catalysed, but at low pH, where substantial protonation of 1 occurs, the dominant reaction occurring is a competing hydrolysis of cyanamide to urea. It is shown that reactions run under pH control in the region of pH 2 achieve close to maximum selectivity with respect to the desired guanidine formation, whilst still occurring at a practical rate.",10.1021/op700175d,0
"The Art of Drug Synthesis. By Douglas S. Johnson and Jie Jack Li . Wiley-Interscience: New York . 2007 . 276 pp. £50.50, $89.95. ISBN 978-0-471-75215-8 .","ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 5, 925Publication Date (Web):August 22, 2007Publication History Received2 August 2007Accepted2 August 2007Published online22 August 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op7001744https://doi.org/10.1021/op7001744book-reviewACS PublicationsCopyright © 2007 American Chemical SocietyRequest reuse permissionsArticle Views837Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Inhibitors,Medicinal chemistry,Organic synthesis,Pharmaceuticals Get e-Alerts",10.1021/op7001744,0
Arylethenylbenzofuroxan Derivatives as Drugs for Chagas Disease: Multigram Batch Synthesis using a Wittig−Boden Process,"In the present work, we developed robust processes for the preparation of new antitrypanosomal benzofuroxans, E and Z isomers of 5-arylethenylbenzo[1,2- c ]1,2,5-oxadiazole N 1 -oxide 1 – 6, in multigram batch through Wittig−Boden conditions as the key synthetic step. In these conditions, the generation of the benzofurazans, as secondary byproduct, was minimized.",10.1021/op7001722,1
"Comparison of the Crystal Chemistry, the Process Conditions for Crystallization and the Relative Structural Stability of Two Polymorphic Forms of<i>N</i><sup>G</sup>-monomethyl-<scp>l</scp>-arginine Hydrochloride","Crystal structures of two conformational polymorphs (Form A and Form D) of N G -monomethyl- l -arginine hydrochloride, a drug developed to treat septic shock, are presented. Form A is orthorhombic in a tetra-molecular unit cell and Form D is monoclinic in a bimolecular unit cell (space groups P 2 1 2 1 2 1 and P2 1, respectively). The two forms display differences in the conformation of the terminal N -methyl group, which is cis in Form D and trans in Form A. Structural energy calculations demonstrate that Form D has a lower lattice energy compared to Form A (−134.7 and −128.8 kcal/mol, respectively). This is supported by solution stability studies where the potential for solution-mediated phase transformation was investigated and Form D is found to be the more stable polymorphic structure at room temperature. The melting behavior of forms A and D indicates a monotropic phase transformation relationship between the two polymorphic forms albeit their melting points (215.7 and 203.7 °C for forms A and D, respectively) would be more consistent with enantiotropic behavior. Solution-mediated phase transformation is thought to be the likely mechanism for monotropic phase interconversion between the two polymorphs. Graph set analysis of the hydrogen bond patterns for both forms reveals the respective first-order graph sets to consist solely of chain motifs involving only the cation moieties. The overall hydrogen bond patterns for both forms were also found to exhibit characteristic packing motifs around the chloride counterion associated with it acting as a hydrogen bond acceptor, bonding to donor groups from three different molecular cations. In this respect, Form A hydrogen bonds with two donor groups towards the carboxylic end and one towards the N -methyl end of the molecular cation and Form D hydrogen bonds with two donor groups towards the N -methyl end and one towards the carboxylic end. With the presence of a high number of hydrogen bond donors and acceptors, the potential for the formation of other packing motifs and associated polymorphic forms is reviewed.",10.1021/op700171b,0
"Discovery of the Decarboxylative Blaise Reaction and Its Application to the Efficient Synthesis of Ethyl 2,6-Dichloro-5-fluoronicotinoylacetate","An efficient synthesis of 2,6-dichloro-5-fluoronicotinoylacetate ( 1 ) has been accomplished in a single step using the unprecedented decarboxylative Blaise reaction of 3-cyano-2,6-dichloro-5-fluoropyridine ( 4 ) with potassium ethyl malonate in the presence of zinc chloride.",10.1021/op7001694,0
"Development of a Scalable Synthesis of GSK183390A, a PPAR α/γ Agonist","A scalable synthesis of GSK183390A, a PPAR α/γ agonist, is described. This synthesis is highlighted by (1) a regioselective formal 1,3-dipolar cycloaddition reaction between an enamine and a nitrile imine dipole to form a 1,3,5-trisubstituted pyrazole and (2) a regioselective amidomethylation of an ο -cresol derivative using 2-chloro- N -hydroxymethylacetamide.",10.1021/op700164t,1
A Scalable Process for the Synthesis of the Bcl Inhibitor Obatoclax,"Recently we created the novel indolylprodigiosin derivative 2 (obatoclax) and demonstrated its ability to antagonize multiple members of the B-cell lymphoma (Bcl) family of antiapoptotic proteins. The compound has shown potent anticancer activity in several animal tumor models. Obatoclax is now in Phase 1b and 2 clinical trials directed against multiple hematologic and solid tumor malignancies. To support its clinical development, a new scalable synthesis was required. Obatoclax has been prepared using a three-step synthesis, starting from commercially available 4-methoxy-3-pyrrolin-2-one. The reaction sequence involves a haloformylation reaction followed by a Suzuki cross-coupling reaction with an indole-2-boronic acid. The synthesis is completed by an acid-mediated condensation with 2,4-dimethyl-1 H -pyrrole.",10.1021/op7001613,1
"Research and Development of an Efficient Synthesis of Hexahydrofuro[2,3-<i>b</i>]furan-3-ol Moiety—A Key Component of the HIV Protease Inhibitor Candidates","A highly efficient method for synthesizing racemic hexahydrofuro[2,3- b ]furan-3-ol has been developed utilizing a lanthanide catalyst, such as Yb(fod) 3, to promote condensation of 2,3-dihydrofuran and glycolaldehyde dimer. Access to either optically enriched enantiomer of bisfuran alcohol can be obtained by using this method employing chiral ligands with the lanthanide catalyst. In support of Gilead Sciences’ protease inhibitor project, this method has been demonstrated to be a robust and scalable process with potential application for the construction of a variety of furo[2,3- b ]furan derivatives.",10.1021/op700160a,1
An Efficient and Practical Synthesis of the HIV Protease Inhibitor Atazanavir via a Highly Diastereoselective Reduction Approach,"An efficient and practical synthesis of the HIV-1 protease inhibitor Atazanavir was developed by employing the diastereoselective reduction of ketomethylene aza-dipeptide isostere 10 as the key and final step. The high diastereoselectivity of the amino ketone reduction by lithium tri- tert -butoxyaluminum hydride in diethyl ether to afford the desired syn -1,2-amino alcohol structure was achieved by Felkin−Anh control as a result of the bulky and chiral N -(methoxycarbonyl)- l - tert -leucinyl moiety as the nitrogen protecting group. The coupling of the two key intermediates, N -(methoxycarbonyl)- l - tert -leucine acylated benzyl hydrazine 7 and chloromethyl ketone 9, via an S N 2 reaction furnished the amino ketone 10 in high yield under our optimized conditions. Our new methodology features the late introduction of the S -hydroxyl group and the early acylation of benzyl hydrazine and chloromethyl ketone with N -(methoxycarbonyl)- l - tert -leucine, respectively, which confers high efficiency and easy purification.",10.1021/op7001563,1
Practical Alternative Synthesis of 1-(8-Fluoro-naphthalen-1-yl)piperazine,"Convergent synthesis of 8-fluoronaphthalen-1-ylamine ( 6 ) was achieved through the reaction of 1 H -naphtho[1,8- de ][1,2,3]triazine ( 15 ) with HF-pyridine under mild conditions. This new synthesis for the preparation of 6 overcame many scale-up challenges that exist in the methods reported in the literature and provided a practical alternative synthesis of 1-(8-fluoronaphthalen-1-yl)piperazine ( 1 ).",10.1021/op7001535,1
Organic Synthesis – State of the Art 2003–2005. By Douglass F. Taber . Wiley-Interscience : New York . 2006 . 216 pp. $99.95. ISBN 0-470-05331-3.,"ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 5, 924–925Publication Date (Web):July 31, 2007Publication History Received28 June 2007Accepted28 June 2007Published online31 July 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op700150xhttps://doi.org/10.1021/op700150xbook-reviewACS PublicationsCopyright © 2007 American Chemical SocietyRequest reuse permissionsArticle Views91Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical synthesis,Metathesis,Organic synthesis Get e-Alerts",10.1021/op700150x,0
Kinetics and Process Development for Deoxofluorination of a Steroid,In this paper investigations for developing a continuous process for the fluorination of a steroid derivative with bis(methoxyethyl)-aminosulfurtrifluoride are presented. A kinetic model is suggested for this reaction. A simulation-based experimental design approach was implemented to find the optimum conditions for the flow reaction in a microreactor system.,10.1021/op7001485,0
Efficient Large-Scale Synthesis of 9-Alkylfluorenyl Phosphines for Pd-Catalyzed Cross-Coupling Reactions,"The reactions of aliphatic alcohols with fluorene coupled with a transfer hydrogenation result in the facile formation of 9-alkylfluorenes, whose deprotonation with n BuLi and quenching of the fluorenyl anion with Cy 2 PCl in MTBE gave 9-alkylfluorenyl-dicyclohexyl phosphines, which are conveniently isolated as the respective phosphonium tetrafluoroborates after treatment with aqueous HBF 4 . This route enables the facile large-scale (kilogram) synthesis of new ligands highly effective in Pd-catalyzed cross-coupling reactions.",10.1021/op7001479,1
A Chemoenzymatic Synthesis of an Androgen Receptor Antagonist,"A new scalable enzymatic resolution approach to both enantiomers of trans -2-hydroxycyclohexanecarbonitrile ( 9 and 11 ) was developed. Treatment of the racemic mixture ( 4 ) with succinic anhydride in the presence of Novozym 435 led to selective acylation of one enantiomer to the corresponding hemisuccinate, which was separated from the unreacted enantiomer by a simple basic extraction. This procedure produced the desired enantiomer in high ee, while obviating the need for chromatography or expensive catalysts and ligands. The application of this protocol to the large-scale synthesis of an androgen receptor antagonist ( 1 ) is described.",10.1021/op700146c,1
"Synthesis of a 5-((Aryloxy)methyl)-3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazole Derivative: A Promising PPARα,δ Agonist","The preparation of the PPARα,δ agonist 2-methyl-2-(2-methyl-4-(3-(4-(trifluoromethyl)phenyl)[1,2,4]thiadiazol-5-ylmethoxy)phenoxy)propionic acid sodium salt ( 17 ) is described and compared with earlier in-house preparations of this important target compound. Key concerns around a large-scale synthesis of this thiadiazole derivative were a large number of purification steps, the use of dichlorobenzene as a solvent, and a possible large-scale Baeyer–Villiger oxidation. This paper describes a straightforward preparation of the target agonist using methylhydroquinone (MHQ) as an inexpensive precursor that eliminates the need of an oxidation step.",10.1021/op700141u,1
"Common Fragrance and Flavor Materials: Preparation, Properties and Uses,<b>5th ed.</b>By Horst Surburg and Johannes Panten . Wiley-VCH Verlag GmbH: Weinheim . 2006. 318 + xii pp. Euro 139.00. ISBN 3-527-31315-X.","ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCite this: Org. Process Res. Dev. 2007, 11, 5, 924Publication Date (Web):July 21, 2007Publication History Published online21 July 2007Published inissue 1 September 2007https://pubs.acs.org/doi/10.1021/op700137shttps://doi.org/10.1021/op700137sbook-reviewACS PublicationsCopyright © 2007 American Chemical SocietyRequest reuse permissionsArticle Views240Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aromatic compounds,Heterocyclic compounds,Hydrocarbons,Materials,Quality control Get e-Alerts",10.1021/op700137s,0
"Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments","Methods for introducing fluorine into organic molecules are reviewed, with an emphasis on preparation of compounds designed for biomedicinal applications. Electrophilic fluorination, nucleophilic fluorination, and enantioselective monofluorination procedures are discussed. This is followed by a review of the development of nucleophilic and electrophilic trifluoromethylation procedures. The final sections highlight recent applications of fluorine chemistry in drug development with selected examples.",10.1021/op700134j,0
A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate,"A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate ( 1b ), starting from 5-bromo-2-methoxypyridine ( 8 ) and 4-fluorobenzaldehyde ( 9 ), is described. Key steps in the process include lithium–bromine exchange of 8, addition of the resulting lithiate to aldehyde 9, regioselective nitration of pyridone 12, and Pd-catalyzed alkoxycarbonylation of bromopyridine 15b . Overall yield of the five-stage synthesis was 23%; intermediates 10, 12, 13, 15b, and final product 1b ·HCl were isolated as filterable solids. Compounds 1a,b are important intermediates in the synthesis of 7-benzylnaphthyridinones (e.g., 2 ) and related HIV-1 integrase inhibitors.",10.1021/op7001326,1
An Improved Synthesis of a Selective Serotonin Reuptake Inhibitor,"A practical synthesis of 3-((1 S, 2 S )-2-dimethylaminomethylcyclopropyl)-1 H -indole-5-carbonitrile hydrochloride ( 1 ), a selective serotonin reuptake inhibitor (SSRI), is described. The process to prepare 1 was demonstrated on laboratory scale and highlights an enantioselective Simmons−Smith cyclopropanation of allylic alcohol 3 using Charette’s chiral dioxaborolane ligand. The improved synthesis enabled production of 1 in 8 chemical steps (5 isolations) in an overall yield of 38%.",10.1021/op700126w,1
Kilogram Synthesis of a Selective Serotonin Reuptake Inhibitor,Process development of a selective serotonin reuptake inhibitor ( 1 ) is described. The synthesis features Nishiyama catalyst-mediated asymmetric cyclopropanation of vinyl indole 2 with ethyldiazoacetate to install the trans- disubstituted cyclopropane. The active pharmaceutical ingredient ( 1 ) was prepared in 13 chemical steps with 9 isolations and proceeded in an overall yield of 34%.,10.1021/op700125z,0
"Development of a Scaleable Synthesis for 1,2-Bis(2-aminophenylthio)ethane (APO-Link) Used in the Production of Bismaleimide Resin","The diamine reagent 1,2-bis(2-aminophenylthio)ethane is no longer commercially available but is still required for the synthesis of the bismaleimide resin, APO-BMI, used in syntactic foams. In this work, we examined the hydrolysis of benzothiazole followed by reaction with dichloroethane or dibromoethane. The deprotonation of 2-aminothiophenol followed by reaction with dibromoethane was also investigated and later optimized for scale-up by scrutinizing all aspects of the reaction conditions, work-up, and recrystallization. On bench-scale, the optimized procedure consistently produced a 75–80% overall yield of finely divided, high purity product (>95%). The material was also produced on both a 100 lb scale and a 200 lb scale using the optimized process, giving high quality material in excellent yield.",10.1021/op700122q,1
The Synthesis of a 5HT<sub>2C</sub> Receptor Agonist,"This report describes the large-scale synthesis of 1 that features a Fischer indole strategy to form an advanced intermediate followed by reduction to the indoline to construct the tetracyclic core of the molecule. Resolution using dibenzoyl- d -tartaric acid affords access to a single enantiomer, from which a Suzuki coupling builds in the biaryl functionality. Deprotection followed by salt formation furnishes the desired target molecule.",10.1021/op700121y,1
A High-Throughput Process for Valsartan,"With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4′-methyl-biphenyl-2-carbonitrile (6) to 4′-bromomethyl-biphenyl-2-carbonitrile (5), halogenated solvents are no longer used in the whole valsartan production process. The alkylation of ( S )-2-amino-3-methyl-butyric acid benzyl ester (8) with 4′-bromomethyl-biphenyl-2-carbonitrile (5), and the acylation of ( S )-2-[(2′-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid benzyl ester (4) to ( S )-2-[(2′-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid benzyl ester (3) were thoroughly modified. In the acylation of 4 to 3, N- ethyldiisopropylamine was replaced by aqueous sodium hydroxide by using the conditions of the Schotten–Baumann reaction, leading to a better quality of intermediate 3. In the alkylation of 8 with 5, N -ethyldiisopropylamine was indirectly replaced by aqueous sodium hydroxide. The reaction runs under homogenous conditions with ( S )-2-amino-3-methyl-butyric acid benzyl ester (8) acting as acceptor for hydrobromic acid; recycling of 8 is performed by extraction with aqueous sodium hydroxide.",10.1021/op700120n,1
Purification of Difluoromethylornithine by Global Process Optimization: Coupling of Chemistry and Chromatography with Enantioselective Crystallization,"An industrial process for the purification of metric tons of enantiomerically pure difluoromethylornithine (DFMO HCl) is described. The amino acid DFMO HCl is cyclized to form the lactam, which is acylated with pivaloyl chloride to form rac - N -pivaloyl-DFMO lactam ( 4 ). The lactam 4 provides enhanced separation compared to a direct resolution of racemic DFMO HCl ( 1 ). A hybrid chiral resolution process is proposed to separate the enantiomers of 4 . This process involves a multicolumn continuous enantioselective chromatographic process (V ari C ol ) coupled with enantioselective crystallization of ( d )- N -pivaloyl-DFMO lactam 5 . The interest of this hybrid process is based on a favorable eutectic point providing a higher productivity of the V ari C ol process and lower purification costs than the chromatographic process alone. A final chemical modification (hydrolysis) is used to form the single enantiomers of both ( d )-DFMO ( 6 ) and ( l )-DFMO in high chemical purity and enantiomeric excess. A global optimization approach is applied to design an economical industrial process, which is based on a parametric study of the V ari C ol process and enantioselective crystallization to obtain maximum recovery and purity while significantly lowering the cost of manufacturing the single enantiomers. A detailed description of the global process optimization is presented.",10.1021/op700118m,0
One-Step Synthesis of 5-(4-Fluorobenzyl)-2-furyl Methyl Ketone: A Key Intermediate of HIV-Integrase Inhibitor S-1360,"Practical one-step synthesis of 5-(4-fluorobenzyl)-2-furyl methyl ketone was accomplished by Friedel–Crafts benzylation of 2-furyl methyl ketone with 4-fluorobenzyl chloride in the presence of ZnCl 2 . Two reaction conditions and their work-up procedures are reported. The first utilizes an anhydrous condition in dichloromethane, providing a convenient procedure for the isolation of the product. The second involves an aqueous condition, which offers a large-scale ecological and safe manufacturing process.",10.1021/op700117q,1
"Development of HIV-Integrase Inhibitor S-1360: Selection of the Protecting Group on the 1,2,4-Triazole Ring","HIV-integrase inhibitor S-1360 was synthesized by Claisen-type reaction of 5-(4-fluorobenzyl)-2-furyl methyl ketone with N-protected 1 H -1,2,4-triazole-3-carboxylate. The protecting group on the triazole ring is essential for the reaction to proceed. Tetrahydropyranyl and 1-methoxy-1-methylethyl groups were examined for manufacturing S-1360 on a large scale. High throughput and a convenient procedure were realized by using the 1-methoxy-1-methylethyl group.",10.1021/op700116y,1
An Alternate Route to 2-Amino-3-nitro-5-bromo-4-picoline: Regioselective Pyridine Synthesis via 2-Nitramino-picoline Intermediate,"The 2-nitramino functionality in 2-nitramino-4-picoline was successfully exploited not only as a protecting group but also as a directional handle to afford an efficient, atom-economic, and regioselective synthesis of 2-amino-5-bromo-3-nitro-4-picoline (4), a precursor for a drug candidate in development.",10.1021/op700114d,1
Reduction of Ethyl Benzoylacetate and Selective Protection of 2-(3-Hydroxy-1-phenylpropyl)-4-methylphenol: A New and Facile Synthesis of Tolterodine,"A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel–Crafts alkylation utilizing FeCl 3 ·6H 2 O as catalyst lead to the known 2-(3-hydroxy-1-phenylpropyl)-4-methylphenol intermediate. Consecutive protection of phenolic OH with p -toluenesulfonyl chloride via two-phase reaction and conversion of aliphatic OH using p -nitrobenzenesulfonyl chloride facilitates direct substitution of diisopropylamine. After simultaneous deprotection of the tosyl group, optically pure ( R )-tolterodine· l -tartrate was obtained by resolution using l -tartaric acid with 99.99% purity.",10.1021/op7001134,1
"Process Research and Development and Scale-up of a 4,4-Difluoro-3,3-dimethylproline Derivative","The multikilogram production of the proline derivative 1, a key intermediate of a HIV protease inhibitor, required the design of a synthetic route able to be safely, effectively, and easily scaled up. Synthesis of the proline skeleton began with construction of racemic glycine derivative 4, via an ester enolate Claisen rearrangement of Boc-glycine 3-methyl-but-2-enyl ester ( 3 ) in the absence of a Lewis acid. After a classical resolution of 4 with ( S )-phenylglycinol, ( S )- 4 was transformed into bromo-lactone 6b with NBS. The bromo-lactone was transformed to proline alcohol 8 via a base-promoted rearrangement involving lactone solvolysis. An NMR study suggested that a bicyclic lactone was initially formed, which subsequently opened by the methanol solvent to form 8 . The requisite ketone for fluorination was prepared via oxidation of the enantiomerically pure 8, using NaClO and catalytic TEMPO. gem -Difluoro proline 1 was then prepared from the ketone via fluorination with Deoxo-Fluor. During this study it was discovered that SiO 2 promoted fluorination by Deoxo-Fluor. This study allowed the production of 7.5 kg of 1 after 10 steps, in 4.5% molar yield and high purity (94–99% HPLC assay).",10.1021/op7001112,1
An Improved Synthesis of Rimonabant: Anti-Obesity Drug,"A novel, cost-effective, and efficient process was developed for the large-scale synthesis of Rimonabant 1, an anti-obesity drug. The process involves the conversion of 4-chloro propiophenone 2 to cyclized acid 6 as a key intermediate that afforded Rimonabant 1 in good yield.",10.1021/op700110b,1
"Development of a Scalable Process for DG-041, a Potent EP<sub>3</sub> Receptor Antagonist, via Tandem Heck Reactions","DG-041 is a small molecule antagonist of the EP 3 receptor for prostaglandin E 2 that is in clinical development for treatment of peripheral artery disease (PAD). Originally produced using a six-step synthetic procedure, process optimization led to development of a four-step sequence that is readily scalable. The key step in the optimized sequence contains two sequential Heck reactions, involving an intramolecular Heck cyclization followed by an intermolecular Heck coupling, performed in one pot to produce a highly substituted indole core.",10.1021/op700107h,1
An Expedient and Multikilogram Synthesis of a Naphthalenoid H<sub>3</sub> Antagonist,"A facile and scaleable synthesis of potent and selective histamine H 3 receptor antagonist 1 is described, starting from commercially available 6-bromo-naphthalene-2-carboxylic acid methyl ester 3a . The key intermediate, 2-(6-bromonaphthalen-2-yl)ethanol 5 was prepared in good yield (78%) and purity (99%) via a one-carbon homologation of 3a . The coupling of 5 with pyridazinone 12 was accomplished effectively by a copper-catalyzed cross-coupling reaction. Activation of the hydroxyl group of 4, followed by displacement reaction with 2( R )-methylpyrrolidine 13, afforded the free base of 1, which was subsequently converted to its corresponding salt. The new process consisted of eight chemical steps and one salt formation step and required no chromatographic purification throughout the synthesis. It has been successfully implemented on pilot plant scale to prepare over 10 kg quantities of the target compound 1 in 43% overall yield in high purity (99%) and with the desired physical properties.",10.1021/op700102k,1
"Kinetics for Scale-Up of a One-Pot Pathway to 5-(3-Fluorophenyl)-2,4-dihydro-2,4-dimethyl-3<i>H</i>-1,2,4-triazole-3-thione Using a Hybrid Model of Parallel and Consecutive Reactions","Kinetic results are reported for the one-pot reaction of 2,4-dimethylthiosemicarbazide (1) and 3-fluorobenzoyl chloride (2) to the unisolated benzamide intermediate (3), and on to the ring-closed product, 5-(3-fluorophenyl)-2,4-dihydro-2,4-dimethyl-3 H -1,2,4-triazole-3-thione (4). The sensitivity of the synthetic route to competing side reactions was examined by studying the kinetics of each reaction step. A first-order kinetic Model of the hybrid consecutive and parallel reaction scheme was developed and fit to experimental data. The Model was extended to address potential mixing concerns resulting from the formation of the insoluble intermediate 3 upon scale-up where a more concentrated reaction would be used. Scale-up of the product drug substance from laboratory to 50-gal scale was successfully completed using this recently developed one-pot pathway.",10.1021/op700101g,0
Boric Acid Catalyzed Amidation in the Synthesis of Active Pharmaceutical Ingredients,"Application of a boric acid catalyzed process for the synthesis of the carboxamides, key reaction intermediates in the preparation of various active pharmaceutical ingredients (APIs), has been explored.",10.1021/op700098w,0
Optimized Synthesis of <scp>l</scp>-<i>m</i>-Tyrosine Suitable for Chemical Scale-Up,This paper demonstrates how l - m -tyrosine 1 can be synthesized on larger-scale via enzyme-catalyzed kinetic resolution of N -acyl m -tyrosine methyl ester 4 . N -Acyl m -tyrosine methyl ester 4 was prepared by a modification of Erlenmeyer’s azalactone synthesis followed by hydrogenation of the resultant dehydroamino acid 12 . The optimized four-step synthesis utilizes cheap and readily available starting materials and circumvents difficult purification protocols.,10.1021/op700093y,1
"Scale-Up of the Preparation of (1<i>R</i>,2<i>R</i>,4<i>S</i>)-1-Methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanol","Chiral β-amino alcohols are widely recognized as effective chiral auxiliaries for a variety of asymmetric organic transformations. Recently, (1 R,2 R,4 S )-1-methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanol has been reported to be an effective chiral auxiliary for the asymmetric addition of diethylzinc to benzaldehyde and the asymmetric addition of lithium cyclopropylacetylide to 4-(trifluoromethyl)-2(1H)-quinazolinones. This paper describes the scale-up of the reaction of morpholine with cis / trans -( S )-(-)-limonene oxide (99% ee) in the presence of water to produce 125 g of (1 R,2 R,4 S )-1-methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanol of 99.6% diastereomeric purity.",10.1021/op700092n,0
Development of an Alternative Process for the Manufacture of a Key Starting Material for Cefovecin Sodium,"A process has been developed for the use of trimethylphosphite for the formation of the six-membered 3,6-dihydro-2 H -[1,3]thiazine ring in the cephem architecture by an intramolecular Horner−Emmons−Wadsworth condensation. The process is a suitable alternative to the traditional Wittig process, which uses trimethylphosphine. The process developed is a highly telescoped reaction pathway consisting of at least six known reaction intermediates that was scaled for production use to produce 2 .",10.1021/op700091d,1
Scalable Reactor Design for Pharmaceuticals and Fine Chemicals Production. 2: Evaluation of Potential Scale-up Obstacles for Asymmetric Transfer Hydrogenation,"This paper is a continuation of our previous work, which reviewed the main factors that inhibit fine chemical and pharmaceutical reactor scalability. For scalable reactor design, it is suggested to first identify potential scale-up obstacles and then use shortcut calculations for their evaluation. This approach is demonstrated in this paper for the asymmetric transfer hydrogenation of acetophenone to its chiral alcohols, in the presence of the homogeneous catalyst, (1 R, 2 S -amino-indanol/pentamethylcyclopentadienylrhodium) with isopropanol as hydrogen donor. The investigation reveals that removal of the by-product acetone from the reaction system shortens the required reaction time to achieve high conversion and reduces enantioselectivity erosion. A simple search algorithm is presented which can be used in principle for liquid reactions systems, where stripping of a reaction product or by-product is beneficial. The algorithm identified that the most influential factors that accelerate acetone removal are the acetone vapor–liquid equilibrium and the ratio of stripping gas flow rate per liquid volume. Because acetone removal efficiency is different in different batch reactor scales, this issue poses a scalability problem if optimal reaction performance is desired. Regardless of scale, the stirred vessel operated as a gas–liquid batch reactor has limitations with regards to allowable gas flow rate through the vessel due to impeller flooding. Therefore, reactor systems not constrained by limits in gas flow rate are advantageous.",10.1021/op700089q,0
An Improved Procedure for Preparation of Carbapenem Antibiotic:  Meropenem,"An efficient synthesis of a 1β-methyl carbapenem antibiotic, meropenem, is described. The present process does not involve cryogenic temperatures, chromatographic purification, or reverse osmosis and is amenable to large scale synthesis.",10.1021/op700088y,1
Process Development of the Synthetic Route to R116301,"We describe in this paper the synthesis of compound 1 (R116301), which was developed to prepare pilot scale quantities (20–50 kg) of drug substance. The synthesis involves the s BuLi deprotonation of Boc-protected piperidone acetal 2, followed by benzaldehyde addition and ring closure to cyclic carbamate 4 . Piperidine acetal 5 is resolved with Brown’s acid and acylated. The ketone obtained after piperidine acetal deprotection undergoes reductive amination with N -benzyl piperazine, the most critical step in the synthesis. After debenzylation, final coupling and salt formation, compound 1 is obtained over 10 steps with 4% overall yield.",10.1021/op700086d,1
"Development of a Scaleable Synthesis of NDT 9533750, a Key Intermediate to a Series of Novel Subtype Preferring GABA<sub>A</sub> Partial Agonists","A scaleable route to 6-chloro-4-[2-(3-fluoropyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (NDT 9533750), a key intermediate to a series of novel subtype preferring GABA A partial agonists, is described in which various scaleup issues were addressed to provide an efficient and robust route for the preparation of kilogram quantities of the compound.",10.1021/op700084h,1
<i>SPECIAL FEATURE SECTION:  <u>ASYMMETRIC SYNTHESIS ON LARGE SCALE</u></i>,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: ASYMMETRIC SYNTHESIS ON LARGE SCALEHans Jürgen Federsel and Karel M. J. BrandsView Author Information Global Process R&D, AstraZeneca E-mail: [email protected] Department of Process Research, Merck Research Laboratories E-mail: [email protected]Cite this: Org. Process Res. Dev. 2007, 11, 3, 494Publication Date (Web):May 18, 2007Publication History Published online18 May 2007Published inissue 1 May 2007https://pubs.acs.org/doi/10.1021/op700081fhttps://doi.org/10.1021/op700081feditorialACS PublicationsCopyright © 2007 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views862Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (13 KB) Get e-AlertscloseSUBJECTS:Enantioselective synthesis,Hydrogenation,Molecules,Pharmaceuticals,Stereoselectivity Get e-Alerts",10.1021/op700081f,0
"A Novel, Safe, and Robust Nitration Process for the Synthesis of 4-(4-Methoxy-3-nitrophenyl)morpholine","A novel nitration process was developed for the production of 4-(4-methoxy-3-nitrophenyl)morpholine. Crude 4-(4-methoxyphenyl)morpholine produced in step 1 was converted to its nitric acid salt. The nitration reaction was carried out by adding a dichloromethane solution of the isolated salt to concentrated sulfuric acid. This protocol provided an easy and reliable way to obtain a 1:1 molar ratio of the substrate and nitric acid in the reaction mixture and was proven to be the most effective method to prevent under-/over-nitration. The incorporation of the protocol into the process resulted in substantial improvement of the robustness and safety profile of the whole process. In addition, 59% overall yield improvement, 30% capacity increase, 40% waste reduction, and simplified operations were achieved. A detailed thermal hazard analysis of the process was also performed.",10.1021/op700074k,1
"A Facile Preparation of an Octahydropyrrolo[2,3-<i>c</i>]pyridine Enantiomer","A facile synthesis of octahydro-pyrrolo[2,3- c ]pyridine 1 using an intramolecular [3+2]-cycloaddition of an azomethine ylide as the key step and employing DW-therm heat-transfer fluid as a solvent is disclosed. Enantiomerically pure 1 was obtained either via a chromatographic separation of the diastereoisomers 12 and 13 resulting from the cycloaddition with a chiral appendage or by a classical resolution of racemate 19 .",10.1021/op700073g,1
Mesoscale Flow Chemistry:  A Plug-Flow Approach to Reaction Optimisation,"In recent years, chemistry in flowing systems has become more prominent as a method of carrying out chemical transformations, ranging in scale from analytical-scale (microchemistry) through to kilogram-scale synthesis (macrochemistry). The advantages are readily apparent increased control of conditions leading to greater reproducibility, scaleability, and increased safety/reduced loss although its acceptance as a viable synthesis technique has been limited due to its drawbacks, primarily precipitation, liquid handling, and diffusion of the reaction within the reactor. Here, we present details of a system which bridges the gap between micro- and macroreactors and has enabled fast reaction optimisation (using small amounts of reagents) and subsequent multigram scale-up using a commercial reactor.",10.1021/op7000707,0
A Scaleable Synthesis of Dutasteride: A Selective 5α-Reductase Inhibitor,"An improved and scaleable process for Dutasteride ( 1 ), a synthetic 4-azasteroid derivative essentially used for the treatment of prostate diseases, is described.",10.1021/op700068g,1
"The Preparation of Two, Preclinical Amino-quinazolinediones as Antibacterial Agents","This paper describes the synthesis of two amino-quinazolinediones which are potent gyrase/topoisomerase inhibitors and useful as antibacterial agents. The early scale-up work to prepare a chiral side chain on multigram scale and two different amino-quinazolinedione cores is detailed. The enabling synthesis for the side chain employed a previously reported Michael addition of MeNO 2 to an enantiomerically enriched δ-amino-enoate and a two-step de-oxygenation of a lactam. Key synthetic steps for core preparation and completion of the amino-quinazolinediones include dianion-promoted cyclization via intramolecular, nucleophilic aromatic substitution, electrophilic amination, nucleophilic aromatic substitution of the side chain to the core, deprotection and isolation of the hydrochloride salt in acceptable yield.",10.1021/op7000639,1
One-Pot Process for the Amination of Oxazolidinyl-methyl Mesylate by Sodium Diformylamide,"An efficient one-pot process for the preparation of pure ( R )- N -[3-(4-iodophenyl)-2-oxo-5-oxazolidinyl]methylacetamide 1 from the mesylate 2b in 91% yield has been developed. The one-pot process makes use of commercially available sodium diformylamide 3 and avoids the use of highly hazardous reagents, simplifies workup procedures, and precludes detrimental impurity issues.",10.1021/op700062c,1
"Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 2. Process Improvement for Scale-Up Of 2,5,8-Substituted 11,12-Dihydro-5<i>H</i>-6,13-dioxabenzo[3,4]cyclohepta-[1,2-<i>a</i>]naphthalene Derivatives","An improved, reproducible nonchromatographic process for scale-up synthesis of 2,5,8-substituted 11,12-dihydro-5 H -6,13-dioxabenzo[3,4]cyclohepta[1,2- a ]naphthalene derivatives as selective estrogen receptor modulators (SERMs) is described. The titled compounds were prepared in 9−21% overall yield with high chemical purity (>97%) after nine consecutive synthetic steps.",10.1021/op700061x,1
Green Chemical Synthesis of 2-Benzenesulfonyl-pyridine and Related Derivatives,"A practical synthesis of 2-benzenesulfonylpyridine, 1, is described which is a key starting material for the manufacture of an investigational new drug candidate at Eli Lilly and Company. An optimized green chemical process was developed which features a novel tandem S N Ar/oxidation under mild conditions to produce the target sulfone, 1, in 86% yield and>99% purity. In addition, this novel, environmentally friendly methodology was found to be general for the synthesis of substituted aromatic pyridyl sulfides and sulfones.",10.1021/op700060e,0
"Development of a Large-Scale Stereoselective Process for (1<i>R</i>,4<i>S</i>)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine Hydrochloride","A convenient, multikilogram-scale, stereoselective process for the synthesis of (1 R,4 S )-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride 1 is described. The key steps involve synthesis of sulfinyl imine ( R s, 4 S )-5 from ( S )-tetralone (4 S )-3 and ( R )- tert -butylsulfinamide ( R s )-4, and its stereoselective reduction with 9-BBN to produce the (1 R )-amine center of 1 . The process has been scaled up to multikilogram scale and gives 1 in an overall yield of >50% with a chemical purity of 99.7 A% by HPLC and stereochemical purity of >99.9% by chiral HPLC.",10.1021/op7000589,1
Process Intensification for Substrate-Coupled Whole Cell Ketone Reduction by In Situ Acetone Removal,"Three different reactor configurations for in situ acetone removal in whole cell biotransformation processes with substrate-coupled cofactor regeneration were applied. The reduction of 2,5-hexanedione to the corresponding (2 R,5 R )-hexanediol was catalyzed by recombinant Escherichia coli cells expressing an alcohol dehydrogenase from Lactobacillus brevis . The reaction was carried out in a substrate-coupled cofactor regeneration approach using 2-propanol as redox equivalent for intracellular cofactor regeneration. In contrast to a process without acetone removal, where 54% yield could be reached, the yield was increased to >90% when a pervaporation system was applied or when acetone was removed by sparging air through the reaction mixture. In a third system, conversion was driven using a biphasic system to extract acetone continuously from the biocatalyst containing aqueous phase and to allow high concentrations of the hydrophobic substrate 1-phenyl-2-propanone. When methyl tert -butyl ether was applied as the non-aqueous phase, only 24% yield was achieved. When the ionic liquid 1-butyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)amide was applied as the non-aqueous phase, >95% yield was reached as a result of the preferential partitioning behaviour of acetone over 2-propanol into the ionic liquid.",10.1021/op700055e,0
Convergent Approach for Commercial Synthesis of Gefitinib and Erlotinib,"An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable formamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3 H )-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.",10.1021/op700054p,1
A Concise Synthesis of a Novel Insulin-Like Growth Factor I Receptor (IGF-IR) Inhibitor,"An efficient synthesis of a potent insulin-like growth factor I receptor (IGF-IR) inhibitor AEW541 (1) is described. The key step in the synthesis is the cis -selective reductive amination of cyclobutanone, which sets up the desired 1,3-stereochemistry of the cyclobutane ring. The amino group thus generated is used as a handle to build the pyrrolopyrimidine ring. The final step resulting in 1 is accomplished by alkylation of in situ generated mesylate with azetidine.",10.1021/op700052u,1
Optimization and Scale-Up of the Grandberg Synthesis of 2-Methyltryptamine,"An efficient, safe, and cost-effective synthesis of 2-methyltryptamine ( 2 ), a key starting material in the synthesis of the histone deacetylase inhibitor LBH589 ( 1 ) is described. The reaction of phenylhydrazine ( 7 ) with a stoichiometric amount of 5-chloro-2-pentanone ( 8 ) in aqueous ethanol at reflux furnished crude 2-methyltryptamine ( 2 ). The product 2 was obtained in 47% yield and >99% purity after crystallization from toluene.",10.1021/op7000518,1
"Improved and Practical Synthesis of 6-Methoxy-1,2,3,4- tetrahydroisoquinoline Hydrochloride","6-Methoxy-1,2,3,4-tetrahydroisoquinoline ( 1 ) or its hydrochloride salt ( 4 ) is an expensive chemical with limited commercial availability. We report an improved and practical synthesis of 4 from inexpensive 2-(3-methoxyphenyl)ethylamine ( 2 ) using a Pictet−Spengler condensation via a novel aminal intermediate. The synthesis significantly lowers the cost and provides easy access to 6-methoxy-1,2,3,4-tetrahydroisoquinoline or its HCl salt on a large scale.",10.1021/op7000468,1
Generation of Fine Pharmaceutical Particles via Controlled Secondary Nucleation under High Shear Environment during Crystallization − Process Development and Scale-up,"A unique semibatch crystallization process, coupling with a high-speed rotor-stator device, was developed for generation and control of fine particles. The key underlying mechanism of this process is controlled secondary nucleation under a high shear environment during crystallization, in contrast to the conventional particle breakage mechanism, i.e., milling, after the crystallization. A recycle mode operation is employed to control the residence time of the batch in the high shear domain so as to ensure the scalability of this process. In this work, the operational sensitivity to the supersaturation and particle size were first explored in the laboratory. Based on the results of the laboratory investigation, this process was successfully demonstrated in multiple 1000-L pilot scale production batches. The practical issues for the large scale operation are also illustrated.",10.1021/op700045j,0
"A Practical and Scaleable Synthesis of 1<i>R</i>,5<i>S</i>-Bicyclo[3.1.0]hexan-2-one:  The Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP) Mediated Intramolecular Cyclopropanation of (<i>R</i>)-1,2-Epoxyhex-5-ene","An efficient synthesis of 1 R,5 S -bicyclo[3.1.0]hexan-2-one from ( R )-1,2-epoxyhex-5-ene is described. Development of a catalytic intramolecular cyclopropanation of ( R )-1,2-epoxyhex-5-ene gives the key homochiral bicycle[3.1.0]hexan-1-ol, which is then oxidized to the desired ketone. This process has been successfully demonstrated on a multi-kilogram scale.",10.1021/op700042w,1
New Practical Synthesis of the Key Intermediate of Candesartan,"The development of a new, practical synthesis of methyl 3-amino- N -[(2‘-cyanobiphenyl-4-yl)methyl]anthranilate, key intermediate of candesartan, is described, starting from methyl anthranilate. The features of our approach are as follows: ( i ) introduction of the 3-nitro group by acid catalysed rearrangement of the corresponding methyl N -nitroanthranilate; ( ii ) introduction of a (2‘-cyanobiphenyl-4-yl)methyl side chain by N -alkylation of the appropriate N -nitroanthranilic acid derivative. In the most efficient procedure methyl N,3-dinitroanthranilate was N -alkylated with 4‘-bromomethyl-biphenyl-2-nitrile. Catalytic reduction of the aromatic nitro group was accompanied with the removal of the N -nitro function to afford the required key intermediate in good yield.",10.1021/op700041z,1
A Convergent Kilogram-Scale Synthesis of the PPARα Agonist LY518674:  Discovery of a Novel Acid-Mediated Triazolone Synthesis,"The first kilogram-scale synthesis of the PPARα agonist LY518674 ( 1 ) is described. The de novo convergent synthetic approach involved coupling of two rapidly assembled components, triazolone formation via a novel acid-promoted cyclization reaction, and final step saponification, delivering the compound in 32.5% overall yield via eight total steps with a six-step longest linear sequence. A regioselective alkylation on the dianion of 4-hydroxyphenylbutyric acid allowed the direct preparation of one of the convergent coupling partners, carboxylic acid 12, and an unusual solvent effect enabled the installation of a urea group on a protected hydrazine, permitting the regiospecific preparation of the other coupling partner, semicarbazide mesylate 17 . Sulfonic acids were found to effect the desired triazolone ring formation, affording 25 from the coupled precursor acyl semicarbazide 23 . Following saponification of 25 to 1, a wide solubility differential between ethyl acetate extracts of 1 and solutions of 1 in anhydrous ethyl acetate was harnessed in the final crystallization step to deliver the final compound in high yield and purity. The novel acid-mediated triazolone formation was further evaluated on a range of additional substrates, showing the new methodology to be largely complementary to existing base-mediated triazolone syntheses.",10.1021/op700040v,1
Execution of a Performic Acid Oxidation on Multikilogram Scale,"In order to run a peracid oxidation on multikilogram scale in a pilot plant facility with an acceptable level of risk, an extensive study of the thermal characteristics of the reaction, reactants, and quench was undertaken. A number of features were engineered into the process in order to confidently run the process without the potential for a thermal or pressure excursion on scale.",10.1021/op700039r,0
"Route Development and Bulk Synthesis of CP-865,569","The synthesis of zwitterionic CP-865,569 by three different synthetic routes is described. The first two routes differ in the method of introducing the sulfonic acid at the penultimate step: by sulfite displacement of a benzylic chloride and by oxidation of a benzylic thioacetate. The third route is a convergent route to the drug candidate. The synthesis strategy was primarily driven by the need to introduce the sulfonic acid functionality at the final stage of the synthesis due to the high water solubility and low organic solubility of the desired product.",10.1021/op7000386,1
"Scale-Up Syntheses of Two Naturally Occurring Procyanidins:  (−)-Epicatechin-(4β,8)-(+)-catechin and (−)-Epicatechin-3-<i>O-</i>galloyl-(4β,8)-(−)-epicatechin-3-<i>O</i>-gallate","A scaleable process for the synthesis of two naturally occurring procyanidins, namely (−)-epicatechin-(4β,8)-(+)-catechin ( 1 ) and (−)-epicatechin-3- O -galloyl-(4β,8)-(−)-epicatechin-3- O -gallate ( 2 ), is described. The key steps were highlighted by improvements for the benzylation of (+)-catechin ( 3 ), stereoselective reduction of the C-3 keto group of (2 R )-5,7,3‘,4‘-tetrakis(benzyloxy)flavan-3-one ( 10 ), and coupling between 4-hydroxyethoxy-5,7,3‘,4‘-tetra- O -benzyl-(−)-epicatechin ( 11 ) and 5,7,3‘,4‘-tetra- O -benzyl-(+)-catechin ( 4 ) or 5,7,3‘,4‘-tetra- O -benzyl-(-)-epicatechin ( 6 ), respectively. The debenzylation performed in a biphasic system resulted in an improved yield and purity of the target compounds. The chemistry was scaled-up to produce multigram quantities of the title compounds ( 1 and 2 ) for various in vitro, ex vivo, and in vivo studies. Moreover, the scale-up process provided a detailed description for the preparation of multihundred to kilogram scale quantities of intermediates used in the synthesis of these two titled procyanidins.",10.1021/op700031n,0
"Catalytic, Enantioselective Synthesis of Taranabant, a Novel, Acyclic Cannabinoid-1 Receptor Inverse Agonist for the Treatment of Obesity","Chiral amide 1 (MK-0364, taranabant) is a potent, selective, and orally bioavailable cannabinoid-1 receptor (CB-1R) inverse agonist indicated for the treatment of obesity. An asymmetric synthesis featuring a dynamic kinetic resolution via hydrogenation for the preparation of the bromo alcohol 5 is disclosed. Conversion of the alcohol intermediate to the chiral amide 1 is accomplished in good overall yield.",10.1021/op700026n,1
Synthetic Improvements in the Preparation of Clopidogrel,"Synthetic improvements in the preparation of clopidogrel are described. The synthesis was accomplished in four steps or one-pot in above 70% overall yield. The process featured PTC catalyzed alkaline hydrolysis of the key intermediate 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2- c ]pyridin-5(4 H )-yl)acetonitrile and highly effective kinetic resolution of racemic clopidogrel using l -camphorsulphonic acid in toluene and has been successfully used in a 50-kg pilot test.",10.1021/op700025d,1
"Synthesis of Tetracyclic Heterocompounds as Selective Estrogen Receptor Modulators. Part 1. Process Development for Scale-up of 2,5,8-Substituted 5,11-Dihydrochromeno[4,3-<i>c</i>]chromene Derivatives","Unsymmetrical benzopyranobenzopyran compounds are novel selective estrogen receptor modulators (SERMs). A reproducible and nonchromatographic process was developed to prepare multihundred gram quantities of 5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,11-dihydrochromeno[4,3- c ]chromene-2,8-diyl-bis(2,2-dimethylpropanoate) ( 14 ). The overall yield of this 11-step synthesis was improved from 0.17% to 7.1% after three scale-up campaigns.",10.1021/op700020f,1
"Process Development for ABT-472, a Benzimidazole PARP Inhibitor","A nine-step convergent process was developed for the synthesis of ABT-472, a benzimidazole PARP inhibitor. The identity and origin of several impurities were determined, and the process was modified to reduce or eliminate these impurities. A number of safety and control issues were investigated. The original synthesis was shortened to 9 steps and streamlined while maintaining a convergent strategy. A stable salt was selected, and control of the API solid form was established. The process was successfully scaled up to provide 8.5 kg of final product of >99% purity in 33% yield over 9 steps.",10.1021/op7000194,1
A Microcapillary Flow Disc Reactor for Organic Synthesis,"This paper reports proof of concept, development, and trials for a novel plastic microcapillary flow disc (MFD) reactor. The MFD was constructed from a flexible, plastic microcapillary film (MCF), comprising parallel capillary channels with diameters in the range of 80−250 μm. MCFs were wound into spirals and heat treated to form solid discs, which were then capable of carrying out continuous flow reactions at elevated temperatures and pressures and with a controlled residence time. Three reaction schemes were conducted in the system, namely the synthesis of oxazoles, the formation of an allyl-ether, and a Diels−Alder reaction. Reaction scales of up to four kilograms per day could be achieved. The potential benefits of the MFD technology are compared against those of other reactor geometries including both conventional lab-scale and other microscale devices.",10.1021/op700015f,0
Practical Synthesis and Molecular Structure of a Potent Broad-Spectrum Antibacterial Isothiazoloquinolone,"We report the synthesis of the new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate ( 5 ). Sulfone 5 is a key intermediate used in the optimized synthesis of the isothiazoloquinolone 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9 H -isothiazolo[5,4- b ]quinoline-3,4-dione ( 1 ), a potent broad-spectrum antibacterial agent that is effective against clinically important resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA). Our synthetic method is free of chromatographic purification and amenable to large-scale synthesis. The molecular structures of 1, 9-cyclopropyl-6,7-difluoro-8-methoxy-9 H -isothiazolo[5,4- b ]quinoline-3,4-dione ( 4 ), 5, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-4-oxo-4 H -thiochromene-3-carboxylate ( 10 ) were established unambiguously using multinuclear NMR spectroscopy and X-ray crystallography.",10.1021/op700014t,1
Improvement of Process Safety and Efficiency of Grignard Reactions by Real-Time Monitoring,"Grignard reactions possess considerable hazard potentials due to the spontaneous heat release during the initiation of these strongly exothermic reactions and the high reactivity of the Grignard compounds. To establish an industrially applicable method for an objective real-time detection of the reaction start-up and for the accumulation of the organic halide during the process, a heat/mass balance-based real-time monitoring approach was developed and tested by miniplant experiments. In addition to the concentration profiles provided by the approach, the real-time estimation of the safety-relevant parameters, such as adiabatic temperature rises and corresponding pressures, enables application of advanced control strategies up to the point of a safety-oriented, fully automated control of Grignard reactions. At the same time, such systems can contribute to improved process efficiency by increasing the space-time yield as well as enhancing the inherent safety of the process.",10.1021/op700012g,0
Development of a Preparative-Scale Asymmetric Synthesis of (<i>R</i>)-<i>p</i>-Tolyl Methyl Sulfoxide for Use in a One-Pot Synthesis of a Drug Intermediate Containing a Trifluoromethyl-Substituted Alcohol Functionality,"A one-pot process for the synthesis of ( S )-1,1,1-trifluoro-4-(5-fluoro-2-methoxy-phenyl)-4-methyl-2-(( R )-toluene-4-sulfinylmethyl)pentan-2-ol ( 3 ) is described, which was a key intermediate for the preparation of a class of novel glucocorticoid receptor ligands. The chemistry features the preparative-scale synthesis of ( R )- p -tolyl methyl sulfoxide [( R )- p TMSO] from (2 R,4 S,5 R )-4-methyl-5-phenyl-3-(tolene-4-sulfonyl)oxathiazolidine-2-oxide ( 5) and the synthesis of 3 from 5 without isolation of ( R )- p TMSO during the process.",10.1021/op700010a,1
"An Efficient Synthesis of Dibenzo[<i>c</i>,<i>f</i>]-2,7-naphthyridine Ring System through Design of Experiments","The dibenzo[ c, f ]-2,7-naphthyridine ring system was found to be of biological interest, but had limited synthetic accessibility. The initial compound of interest, 10,11-dimethoxy-4-methyldibenzo[ c, f ]-2,7-naphthyridine-3,6-diamine, was obtained in <25% yield by reacting 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile with 2-methyl-benzene-1,3-diamine. A reliable high-yielding procedure was identified through the use of design of experiments (DOE). The effects of stoichiometry of reagents, catalyst, and temperature were explored in this study. The DOE optimization suggested temperatures higher than the boiling point of our solvent. Hence, microwave heating was used, resulting in 80% yield of the desired product.",10.1021/op700009t,1
"Process Development for (<i>S,S</i>)-Reboxetine Succinate via a Sharpless Asymmetric Epoxidation","Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The ( S,S )-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. ( S,S )-Reboxetine has usually been prepared by resolution of the racemate as the (−)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield ( R,R )-phenylglycidol was developed. ( R,R )-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated. Conversion of ( R,S )- 4 to reboxetine parallels the racemic synthesis with streamlined and optimized processing conditions. ( S,S )-Reboxetine free base was converted directly to the succinate salt without isolation as the mesylate salt.",10.1021/op700007g,1
Process Development and Scale-up for (±)-Reboxetine Mesylate,"Redevelopment of the commercial process for the synthesis of (±)-reboxetine methanesulfonate is described. An optimized and efficient process for the synthesis of (±)-reboxetine starting from cinnamyl alcohol was developed. The redeveloped process minimizes impurity formation and utilizes simplified processing to substantially improve process yield and throughput, and is suitable for the efficient synthesis of multiton quantities of reboxetine.",10.1021/op7000063,1
Fundamentals of Early Clinical Drug Development:  From Synthesis Design to Formulation Edited by A. F. Abdel-Magid and S. Caron. Wiley:  New Jersey. 2006. 323 pp. £58.95. ISBN 0-471-69278-6.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTFundamentals of Early Clinical Drug Development: From Synthesis Design to Formulation Edited by A. F. Abdel-Magid and S. Caron. Wiley: New Jersey. 2006. 323 pp. £58.95. ISBN 0-471-69278-6.Cite this: Org. Process Res. Dev. 2007, 11, 3, 649–650Publication Date (Web):February 17, 2007Publication History Published online17 February 2007Published inissue 1 May 2007https://doi.org/10.1021/op7000035Copyright © 2007 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views160Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (15 KB) Get e-AlertsSUBJECTS:Impurities,Particle size,Physical and chemical processes Get e-Alerts",10.1021/op7000035,0
Development of a Practical and Reliable Synthesis of Laquinimod,"Laquinimod (5-chloro-1,2-dihydro- N -ethyl-4-hydroxy-1-methyl-2-oxo- N -phenyl-3-quinoline carboxamide) is a drug candidate for treatment of Multiple Sclerosis. A short and industrially feasible process for the preparation of laquinimod starting from 2-amino-6-chlorobenzoic acid, in essentially four steps, is dis-cussed. The key step is a novel reaction in which a methyl ester is converted to an amide in very high yield and with excellent purity. The present article elucidates the scale-up process along with safety aspects and the impurity profiles of the intermediates and product. Initial laboratory conditions are described as well as the changes made on transfer to pilot-plant scale.",10.1021/op700001c,1
"Development of a Practical Synthesis of STA-5312, a Novel Indolizine Oxalylamide Microtubule Inhibitor","An efficient synthesis of the novel microtubule inhibitor STA-5312 (3-[(4-cyanophenyl)methyl]- N -(3-methyl-5-isothiazolyl)-α-oxo-1-indolizineacetamide) was developed. A novel DMF/Me 2 SO 4 directed regioselective synthesis of the 3-(4-cyanobenzoyl)-indolizine ( 4 ) was a critical transformation within the four-step process. Alternatively, a CuCl mediated synthesis of 3-(4-cyanobenzyl)indolizine ( 5 ) was also developed. All intermediates were obtained in high quality and were used directly for the next step without extensive purification. The drug substance itself was purified by recrystallization from a mixture of THF and water, resulting in a high purity product (HPLC >98%). The process was applied successfully in the manufacturing of kilograms of GMP API.",10.1021/op6002852,1
"Development of an Effective Palladium Removal Process for VEGF Oncology Candidate AG13736 and a Simple, Efficient Screening Technique for Scavenger Reagent Identification","AG13736 (Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under investigation as an oncology drug, is currently manufactured via a three-step process that utilizes two palladium-mediated cross-couplings. Historically, removal of residual heavy metals from the active pharmaceutical ingredient has been a persistent issue. The development of a much improved process for palladium removal and a useful screening technique developed to rapidly identify the most efficient reagents for this purpose are outlined. The performance of the new endgame process in pilot-plant scale-up is also discussed.",10.1021/op600280g,1
"Synthesis of Acetylenes, Allenes and Cumulenes:  Methods and Techniques, 1st ed by Lambert Brandsma. Elsevier Academic Press:  Boston, Amsterdam. 2004. xxxii + 469 pp. $249. ISBN 0-1212-5751-7.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTSynthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 1st ed by Lambert Brandsma. Elsevier Academic Press: Boston, Amsterdam. 2004. xxxii + 469 pp. $249. ISBN 0-1212-5751-7.Roderick BatesView Author Information Chemistry and Biological Chemistry, Nanyang Technological University, Singapore 637616, SingaporeCite this: Org. Process Res. Dev. 2007, 11, 2, 295–296Publication Date (Web):February 6, 2007Publication History Published online6 February 2007Published inissue 1 March 2007https://pubs.acs.org/doi/10.1021/op600279bhttps://doi.org/10.1021/op600279bbook-reviewACS PublicationsCopyright © 2007 American Chemical SocietyRequest reuse permissionsArticle Views444Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Allenes,Hydrocarbons,Isomerization,Post-translational modification Get e-Alerts",10.1021/op600279b,0
Enantioselective Synthesis of Hydrobenzofuranones Using an Asymmetric Desymmetrizing Intramolecular Stetter Reaction of Cyclohexadienones,A series of cyclohexadienones were synthesized by dearomatization of phenols followed by Dess-Martin oxidation. Asymmetric intramolecular Stetter reactions of these substrates provide hydrobenzofuranones in good to excellent yields and excellent stereoselectivities. Up to three stereocenters as well as quaternary stereocenter are formed from polysubstituted substrates. A scale up experiment demonstrates the utility of this transformation.,10.1021/op600278f,0
Development of a Scalable Process for the Synthesis of <i>trans</i>-2-Methylcyclopropanecarboxylic Acid,"A scalable process has been developed for the synthesis of trans -2-methylcyclopropanecarboxylic acid via the stereoselective cyclopropanation of ethyl crotonate with dimethylsulfoxonium methylide (Corey’s ylide). This well-known reaction is generally low yielding and very challenging to scale up as it involves highly reactive reagents. A design of experiment (DoE) allowed us to quickly define the optimal ranges for the reaction parameters. A very significant increase of the yield was obtained by adding the ylide to ethyl crotonate in DMSO at 80 °C in anhydrous conditions. In view of a scale-up at a multikilogram scale, several experiments were then performed combining Process Analytical Technologies (PAT) and Calorimetry (Dynamic DSC, Adiabatic Reaction Calorimetry and Vent Sizing Package). For safety reasons at high temperatures on large scale the reaction was also evaluated in a continuous flow reactor. Thanks to these studies, we were able to develop an efficient process avoiding the hazardous accumulation of the thermally unstable dimethylsulfoxonium methylide.",10.1021/op600275g,0
"An Improved Process for the Preparation of 4,4-Dimethyloxazolidine-2-thione","An improved process for the preparation of 4,4-dimethyloxazolidine-2-thione ( 1 ), an auxiliary used in the synthesis of (3 S,4 S )-[( R )-1‘-(( tert -butyldimethylsilyl)oxy)ethyl]-4-[( R )-1-carboxyethyl]-2-azetidinone ( 2 ), a key intermediate for carbapenem synthesis is reported.",10.1021/op6002677,0
A Systematic Approach for the Development of Liquid Chromatographic Methods,"Developing chromatographic methods can be laborious, time-consuming, and expensive. The definition of a strategy to find rapid separation conditions has therefore become of prime importance since the analytical development has to follow the rhythm of the generation of new compounds. To meet this demand, chemists clearly need the utilization of automation and standardized strategies of work. This paper reports a standardized and fully automated approach dedicated to the development of liquid chromatographic (LC) methods, which are widely used to provide information about chemical reactions, such as impurity profiles and structure or potency determinations. The present approach consists of automatically screening samples with predefined chromatographic conditions. Chromatography is performed under the gradient mode, and the whole dataset is generated in less than 1 day. Even if the screening does not directly provide the final conditions for the separation of the compounds of interest, it generally gives sufficient information to allow a rapid optimization of the chromatographic separation (typically less than 24 h). Different examples of development of LC methods using this strategy are presented.",10.1021/op6002665,0
Development of the Commercial Route for the Manufacture of a 5-Lipoxygenase Inhibitor PF-04191834,"A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless, and readily available commodity chemical iso-octyl-3-mercaptopropionate as a sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that, at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on a 20 kg scale.",10.1021/op500412a,1
Synthesis of Formic Acid from Monosaccharides Using Calcined Mg-Al Hydrotalcite as Reusable Catalyst in the Presence of Aqueous Hydrogen Peroxide,"Formic acid (FA) can be synthesized from monosaccharides such as glucose, galactose, xylose, arabinose and lyxose by using both calcined Mg-Al hydrotalcite as a solid catalyst and aqueous H 2 O 2 as an oxidant in ethanol solvent at 343 K for 5 h. For the glucose oxidation, the FA yield and H 2 O 2 utilization efficiency reach 78% and 100%, respectively. The used hydrotalcite catalyst can be easily separated from the reaction mixture and is reusable at least twice.",10.1021/op5004083,0
An Improved and Practical Synthesis of Tranexamic Acid,"Tranexamic acid 1, a synthetic antifibrinolytic drug with the treatment being considered highly cost-effective in many countries, has been included in the WHO list of essential medicines. In this paper, we designed the synthesis of 1 via a novel seven-step route from the readily available starting material dimethyl terephthalate, performing with 99.6% purity in 59.2% overall yield. During the process, we successfully developed a direct and efficient method for the preparation of key intermediate methyl 4-(acetamidomethyl)benzoate by one-pot hydrogenation and acylation in acetic anhydride using Ni/Al 2 O 3 as a catalyst. More importantly, it should be a straightforward and practical way to circumvent the usage of toxic reagents (CrO 3, Cl 2 ), solvent (CCl 4 ), and expensive catalyst (PtO 2 ), etc., that plagued the previous methodologies.",10.1021/op500395b,1
"A DMAP-Catalyzed Approach to the Industrial-Scale Preparation of <i>N</i>-6-Demethylated 9,10-Dihydrolysergic Acid Methyl Ester: A Key Cabergoline and Pergolide Precursor","A scalable new approach for the preparation of N -6-demethylated 9,10-dihydrolysergic acid methyl ester using 2,2,2-trichloroethyl chloroformate was developed. A key discovery that enabled the efficient and industrial-scalable process is linked to the rigorous extrusion of water in the reaction system and application of an organic catalyst such as 4-( N, N -dimethylamino)pyridine (DMAP) instead of the alkali metal bicarbonate additives. Namely, in the previously known process, the concomitant presence of bicarbonates and traces of water triggers side reaction cycles that produce and accumulate hydrochloric acid and water. The former slows down the reaction. Moreover, these cycles cause the formation of multiple carbonate and alcohol-type side products to a significant extent that provide a low-quality N -6-demethylated product. All of these shortcomings are circumvented by the application of DMAP as a catalyst and the use of a reaction medium free of water. This approach allows operation on an industrial scale (51 kg batch) with higher yields, shorter reaction times, and improved product quality.",10.1021/op500394f,1
Process Development of an N-Benzylated Chloropurine at the Kilogram Scale,"A two-step pharmaceutical manufacturing process was developed for the large-scale preparation of 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9 H -purin-2-amine methanesulfonic acid salt ( 4 ) from commercially available starting materials. In the first step, the benzylpurine free base ( 3 ) was prepared by benzylation of 6-chloro-9 H -purin-2-amine ( 1 ) with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride ( 2 ). The benzylpurine free base was then directly converted into the methanesulfonic acid salt. It was necessary to charge the pyridine hydrochloride 2 in portions into the mixture of K 2 CO 3 (−325 mesh) and the chloropurine compound 1 in dimethylacetamide (DMA). The major regioisomeric impurity ( 6 ), formed by N 7 benzylation, and inorganic salts were removed by filtration. Treatment of the DMA filtrate with MsOH afforded the target salt with negligible degradation. In the second step, recrystallization of the crude salt from DMSO–EtOAc with seeding gave crystalline API in high yield and purity despite the hydrolytic instability of the product in solution.",10.1021/op5003903,1
A Novel and Practical Synthesis of Ramelteon,"An efficient and practical process for the synthesis of ramelteon 1, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8 H -indeno[5,4- b ]furan-8-one 2 and the subsequent hydrogenation which successfully implement four processes (debromination, dehydration, olefin reduction, and cyano reduction) into one step to produce the ethylamine compound 13 where dibenzoyl- l -tartaric acid is selected both as an acid to form the salt in the end of hydrogenation and as the resolution agent. Then, target compound 1 is easily obtained from 13 via propionylation. The overall yield in this novel and concise process is almost twice as much as those in the known routes, calculated on compound 2 .",10.1021/op500386g,1
Scalable Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B RdRp: Challenges in the Production of a Diastereomeric Mixture,"A scalable process is described for the synthesis of 2′- C -methylguanosine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl- N -benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase. The route features the use of phenylboronic acid to transiently protect the 2′,3′-hydroxyls of 2′- C -methylguanosine under mild conditions. The requirement to produce a 1:1 phosphorus diastereomeric mixture precluded the use of traditional crystallization techniques. High sensitivity of the drug substance to acidic and basic conditions and its preferred solubility in mixed aqueous–organic solvents presented additional processing challenges. The use of reverse phase chromatography for the final purification was eliminated by the development of a dual liquid–liquid extraction protocol, which removed both non-polar and polar impurities whilst maintaining the 1:1 diastereomeric ratio. Ethylene sulfide, a potential genotoxic impurity that was observed at significant levels in the original procedure, was controlled to <10 ppm in the final product. This process produced 20 kg of drug substance in 59% overall yield, with >99% purity in the requisite 1:1 diastereomeric ratio.",10.1021/op5003837,1
Leveraging an Industrial–Academic Partnership To Optimize Small Molecule Process Development within the Pharmaceutical Industry,"There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.",10.1021/op5003825,0
The History of the Development of the <i>Organic Process Research</i> &amp; <i>Development</i> (OPR&amp;D) Journal—A Personal Perspective,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTThe History of the Development of the Organic Process Research & Development (OPR&D) Journal—A Personal PerspectiveTrevor LairdCite this: Org. Process Res. Dev. 2015, 19, 1, 249Publication Date (Web):January 2, 2015Publication History Published online2 January 2015Published inissue 16 January 2015https://pubs.acs.org/doi/10.1021/op5003819https://doi.org/10.1021/op5003819editorialACS PublicationsCopyright © 2015 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1242Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (118 KB) Get e-AlertscloseSUBJECTS:Crystallization,Process chemistry Get e-Alerts",10.1021/op5003819,0
Process Development of a GCS Inhibitor Including Demonstration of Lossen Rearrangement on Kilogram Scale,"A small molecule was under investigation as an inhibitor of glucosylceramide synthase (GCS) for potential use in Fabry disease. To support preclinical activities, a four-step synthesis was developed and used to prepared kilogram quantities of the drug substance. The new route features a scalable CDI-mediated Lossen rearrangement as a substitution for hazardous azide chemistry that was employed in the original route.",10.1021/op500379a,1
Effect of Reaction Parameters on the Synthesis of 5-Arylidene Barbituric Acid Derivatives in Ball Mills,"The influence of crucial reaction parameters on Knoevenagel condensation in planetary ball mills was investigated. Rotation frequency ( ν rot ), milling ball diameter ( d MB ), milling ball filling degree ( Φ MB ), and beaker size had obvious influences on yield. It was found that higher ν rot, lower d MB, milling beakers with larger diameter, and a Φ MB of ∼0.3 are advantageous for the reaction. Furthermore, the influence of the type of mill was investigated, including reactions performed in different planetary and mixer ball mills, in a stirred media mill, and with a mortar mill. Comparisons with the other solvent-free synthetic routes showed that ball milling is an effective way of performing the reaction with low energy intensity.",10.1021/op5003787,0
"Development of a Synthesis of a 2,3-Disubstituted 4,7-Diazaindole Including Large-Scale Application of CH<sub>3</sub>Li/TiCl<sub>4</sub>-Mediated Methylation of an Enolizable Ketone","The chemical development of a 2,3-disubstituted 4,7-diazaindole is described. The requisite tertiary carbinol substrate was prepared employing in situ -generated CH 3 TiCl 3 as a chemoselective and preferred reagent compared to CH 3 MgX for methyl addition to an enolizable ketone. The 4,7-diazaindole ring system was efficiently assembled via an intramolecular Chichibabin transformation. The optimized processes were performed on pilot-plant scale to provide kilogram quantities of the target molecule.",10.1021/op5003769,1
Multi-Kilo Delivery of AMG 925 Featuring a Buchwald–Hartwig Amination and Processing with Insoluble Synthetic Intermediates,"The development of a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale is reported herein. The hydrochloride salt of AMG 925 was prepared in 23% overall yield over eight steps from commercially available raw materials, and more than 8 kg of the target molecule were delivered. The synthetic route features a Buchwald–Hartwig amination using BrettPhos as ligand and conducted to afford 12 kg of product in a single batch. In addition, this work highlights the challenges associated with the use of poorly soluble process intermediates in the manufacture of active pharmaceutical ingredients. Creative solutions had to be devised to conduct seemingly routine activities such as salt removal, pH adjustment, and heavy metal scavenging due to the low solubility of the process intermediates. Finally, a slurry-to-slurry amidation protocol was optimized to allow for successful scale-up.",10.1021/op500367p,1
"A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor",We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor GDC-0980 . The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki–Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermediates allowing formylation under noncryogenic conditions. 2-Picoline·BH 3 was employed to replace Na(OAc) 3 BH in the reductive amination and to eliminate the use of molecular sieves. A concise one-step synthesis was developed for the selective monoamidation of piperazine with ( S )-lactate to produce the piperazine lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine in a one-step and protecting-group-free approach. The final crystallization in 1-propanol and water afforded the API in 59% overall yield in four steps and >99% purity by HPLC.,10.1021/op500366s,1
Commercial Synthesis of Azilsartan Kamedoxomil: An Angiotensin II Receptor Blocker,"A commercially viable process for the preparation of azilsartan kamedoxomil, an angiotensin II receptor blocker, has been developed. The present work describes the novel synthesis of azilsartan medoxomil from amidoxime methyl ester. The present work also describes the improved synthesis of amidoxime methyl ester and azilsartan kamedoxomil. This process features a high overall yield (36%) with 99.52% HPLC purity.",10.1021/op500357r,1
Synthesis of Condensed Heterocycles by the Gould–Jacobs Reaction in a Novel Three-Mode Pyrolysis Reactor,"In the present paper we report the synthesis of condensed pyrimidone heterocycles (including novel ones) prepared by the Gould–Jacobs reaction using an in-house-built vacuum-to-high pressure multipurpose “three-mode” pyrolysis reactor. Four of the ring systems have not been described in the literature to date. The pyrolysis reactor has (i) a flash vacuum pyrolysis (FVP) module that applies high vacuum (10 –3 mbar), letting the starting material through the reactor chamber heated up to 1000 °C; (ii) a pneumatic spray pyrolysis (PSP) module that can inject nonvolatile reactants to the heated reactor zone; and (iii) a high-pressure pyrolysis (HPP) continuous-flow module that operates from atmospheric to 400 bar pressure and between room temperature and 600 °C. The capabilities of the pyrolysis reactor were demonstrated by comparison experiments on two different condensed pyrimidone bicyclic ring systems, and the established reaction conditions were then successfully applied to the synthesis of another six condensed pyrimidone bicyclic systems.",10.1021/op500354z,0
Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy,"A scalable, asymmetric synthesis of (3 aS,6 aS )-6 a -(5-bromo-2-fluorophenyl)-1-(( R )-1-phenylpropyl)tetrahydro-1 H,3 H -furo[3,4- c ]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of ( R )- N -(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p -anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.",10.1021/op500351q,1
Large-Scale Continuous Flow Transformation of Oximes into Fused-Bicyclic Isoxazolidines: An Example of Process Intensification,"Here, we report a continuous flow protocol for the [3 + 2] cycloaddition of nitrones, in situ generated from oximes, into bicyclic isoxazolidines. This thermal process required very high temperatures to be efficient that were not easily reached in conventional reactors. A couple of examples are presented and in both the flow process showed a greater performance than the batch mode. The process intensification study allowed the generation of 120 g/h of a key pharmaceutical intermediate.",10.1021/op500350y,0
"Investigation of a Kumada Cross Coupling Reaction for Large-Scale Production of (2<i>S</i>, 7<i>R</i>, <i>E</i>)-2-Isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-<i>N</i>,<i>N</i>,8-trimethylnon-4-enamide","An investigation into the Kumada cross coupling reaction was conducted by developing a reliable, efficient procedure for the Grignard reagent and its subsequent cross coupling reaction. Safe Mg metal activation as well as a moisture-free system was created by using MeMgCl reagent and improved the efficiency of the Grignard reaction. The established coupling reaction was successfully demonstrated at the multikilogram (50 kg) scale, and the coupling product was purified by using an agitated thin film evaporator (ATFE) technique.",10.1021/op500343d,0
Development of a Scalable Synthesis of a Serotonin Receptor Antagonist,"An efficient process was developed for the manufacture of MSA100, a serotonin receptor antagonist, via a five-step synthetic route furnishing a high quality of active pharmaceutical ingredient. Highlights of this synthesis include: (1) replacing carcinogenic methyl iodide with methyl p -toluenesulfonate as the methylating reagent; (2) a hydrogenation protocol with optimized temperature, pressure, and mass-transfer conditions that avoided one side product and reduced the other one effectively; (3) chemical resolution employing D -camphoric acid in a mixed-solvent system; (4) amidation under anhydrous conditions for controlling a Michael adduct impurity; and (5) plausible mechanisms for the formation of side products.",10.1021/op5003402,1
Scalable Ruthenium-Catalyzed Asymmetric Synthesis of a Key Intermediate for the β2-Adrenergic Receptor Agonist,"An enantioselective and robust synthetic process to obtain a useful intermediate for the β2-adrenergic receptor agonist is described. Asymmetric transfer hydrogenation of ketone 1c by ( S, S )- 3b (Ms-DENEB) afforded chiral alcohol 2c in 71% isolated yield and 99% ee. The deprotection completed the synthesis of ( R )- 5 in 41% overall yield from 1b, which is readily commercially available.",10.1021/op500338d,0
Scalable Synthesis of 8-Amino-3-hydroxy-6<i>H</i>-benzo[<i>c</i>]chromen-6-one: Key Intermediate for SEGRA via the Hurtley Reaction,"A practical and scalable process for the preparation of 8-amino-3-hydroxy-6 H -benzo[ c ]chromen-6-one in multihundred kilogram amounts has been developed. The key features of this synthesis are the application of the Hurtley reaction with a copper and base combination and the development of a purification process. The new synthesis improved the total yield from 49.0% to 59.5% and reduced the number of steps from three to two. Compared with the conventional medicinal route, manufacturing costs were reduced significantly by the use of inexpensive, easy to procure materials.",10.1021/op500334b,1
Robust Ruthenium(II)-Catalyzed C–H Arylations: Carboxylate Assistance for the Efficient Synthesis of Angiotensin-II-Receptor Blockers,"Ruthenium(II) complexes have emerged as effective catalysts for C–H arylations of tetrazolyl-substituted arenes by chelation assistance. Particularly, bifunctional additives, such as carboxylates or phosphates, set the stage for versatile C–H functionalizations with organic halides, which allowed for the step-economical synthesis of angiotensin-II-receptor blockers (ARBs) with unprecedented levels of efficacy and substrate scope. The outstanding robustness of the ruthenium(II) complexes was among others illustrated by remarkably low catalyst loadings and applications of this technology on a preparative scale.",10.1021/op500330g,0
"Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization","An efficient synthesis of LY2886721 ( 1 ) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by “pH cycles” to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided desirable API bulk density and powder flow properties.",10.1021/op500327t,1
Special Feature Issue: Continuous Processing,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSpecial Feature Issue: Continuous ProcessingJaan A. PestiCite this: Org. Process Res. Dev. 2014, 18, 11, 1284–1285Publication Date (Web):November 21, 2014Publication History Published online21 November 2014Published inissue 21 November 2014https://pubs.acs.org/doi/10.1021/op500323ahttps://doi.org/10.1021/op500323aeditorialACS PublicationsCopyright © 2014 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views703Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (121 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Chemical reactions,Computational chemistry,Safety Get e-Alerts",10.1021/op500323a,0
"Development of an Immobilized Ketoreductase for Enzymatic (<i>R</i>)-1-(3,5-Bis(trifluoromethyl)phenyl)ethanol Production","The development of an immobilized ketoreductase via covalent binding on resin EC-HFA has demonstrated that it is highly active and stable in organic solvents and can be recycled and reused many times in both batch mode and flow reactor mode. ( R )-1-(3,5-Bis(trifluoromethyl)phenyl)ethanol, a key chiral intermediate in the synthesis of EMEND, was synthesized in 98% yield with >99% ee using the immobilized ketoreductase in a 50% hexanes/40% IPA/10% water solvent system. The immobilized ketoreductase has also been applied to the synthesis of various chiral alcohols.",10.1021/op5003215,0
Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis,"The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a critical defluorination impurity under the reaction conditions has been achieved by reducing residence time inside the catalyst bed to 15–30 min. A reactor volume throughput of 206 kg/h·m 3 was attained in a 3 L reactor (1.5 kg of 5% Pd/C catalyst) over a 9 h demonstration period, superior to the 1.3 kg/h·m 3 volume throughput obtained in batch. The reaction was successfully scaled up from 9 g/h to 550 g/h in packed beds ranging from 20 to 1500 g catalyst, demonstrating heat/mass transfer sufficiency at all examined scales. The process was monitored by online HPLC, providing real-time reaction information, using an internally developed automation cart coupled to a standard HPLC. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development, demonstrating superior control of critical impurities and catalyst utilization with minimized risk to product and increased safety due to reduced handling of hydrogen and of palladium catalyst relative to equivalent substrate throughputs in a typical batch process.",10.1021/op5003177,0
Utilization of ReactIR in Fit for Purpose Process Enablement,"An efficient four-step synthesis of 1 is described in which utilization of ReactIR was key to efficient processing and reaction monitoring. Key chemical steps included (i) nucleophilic aromatic substitution, iron reduction of aromatic nitro group to aniline, (ii) decarboxylation, and (iii) ester formation.",10.1021/op5003165,1
Route Optimization and Synthesis of Taxadienone,"Early process development toward the scalable production of taxadienone on a decagram scale is described. A continuous flow reactor was employed to safely run a potentially hazardous cyclopropane ring opening. The route featured two copper-mediated additions, a Diels–Alder reaction and a palladium-catalyzed Negishi coupling, to construct the final structure.",10.1021/op500314c,1
Rapid Synthesis of Pharmaceutical Oxidation Products Using Electrochemistry: A Systematic Study of N-Dealkylation Reactions of Fesoterodine Using a Commercially Available Synthesis Cell,"A new method for the fast and convenient synthesis of pharmaceutical oxidation products is described. Two oxidation products of fesoterodine were electrochemically synthesized, isolated, and characterized. The influence of synthetic operating parameters such as pH, percentage of organic solvent in diluent, initial electrolyte concentration, and substrate concentration on the oxidation product profile was investigated. This synthetic procedure proved to be rapid, clean, and efficient compared to traditional synthetic methods and may be particularly useful for generating milligram quantities of reference samples of degradation products used as markers in chromatographic methods.",10.1021/op500312e,0
Process Development for Biocatalytic Oxidations Applying Alcohol Dehydrogenases,"Alcohol dehydrogenases are able to catalyze the conversion of alcohols to aldehydes or ketones, simultaneously reducing the cofactor NAD + or NADP + to NAD(P)H. Because of the high costs of these pyridine cofactors, in situ cofactor regeneration is required for preparative applications in order to reach turnover numbers that are sufficient for economically viable processes. Here we present the development of a process for the enantioselective oxidation of rac-1-phenylethanol to acetophenone, applying an alcohol dehydrogenase coupled with an NAD(P)H oxidase for the enzymatic cofactor regeneration, which is active towards NADH as well as NADPH. The reaction system was investigated in view of various influential parameters with main focus on the external oxygen supply. We could show that a gassed stirred tank reactor is a promising reactor concept to run NAD(P)H oxidase-coupled alcohol dehydrogenase oxidations, including the possibility to scale-up the system.",10.1021/op500307e,0
Synthesis of an α-Amylase Inhibitor: Highly Stereoselective Glycosidation and Regioselective Manipulations of Hydroxyl Groups in Carbohydrate Derivatives,"Here, we describe the efficient synthesis of α-amylase inhibitor 1 . To introduce the most expensive C ring unit at a late stage in the synthesis, we developed 1,2- cis - O -glycosidation of AB and C ring intermediates. Taking advantage of the effect of non-neighboring protecting groups, reaction solvents, and temperature for the glycosidation led to high stereoselectivity and high yield of the 1,2- cis -glycoside product bearing the API skeleton. We also explored protection and deprotection methods for regioselective manipulation of hydroxyl groups in A and B ring intermediates. One-pot benzylation of the 2,3-hydroxyl groups of d -glucose under phase-transfer conditions and regioselective anomeric deacetylation with N -methylpiperazine were developed for the syntheses of A, B, and AB ring intermediates. Thus, the efficiency of the process was dramatically improved. The raw material cost of API was reduced to approximately one-third that of the original route, and the total process was decreased by six steps.",10.1021/op500306p,0
Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals,"This review showcases various coupling reagents which have been implemented specifically for large-scale amide synthesis via the condensation of an acid and amine, while highlighting the benefits and drawbacks of each reagent on an industrial scale.",10.1021/op500305s,0
Development of a Practical Process for the Opening of Macrocyclic Cyclosporin A and Amino Acid Deletion,"A practical and robust process for the derivatization of Cyclosporin A was demonstrated. The processes rely on the opening of Cyclosporin A and removal of amino acid fragments via Edman degradation, with the isolation of crystalline tetrafluoroboric salts of the corresponding acyclic polypeptides.",10.1021/op5003038,0
Development of a Scalable Synthesis of Oligomeric Piperidine-<i>N</i>-<i>O</i>-alkyl Ethers,"An efficient two-step manufacturing process for a novel polypiperidine- N - O -alkyl ether was developed. Starting from an oligomeric 2,2,6,6-tetramethylpiperidine derivative, oxidation by hydrogen peroxide yielded a polynitroxide radical. Subsequently, the intermediate was reacted with alkyl radicals to provide the corresponding hydroxylamine O -alkyl ether. The optimized process was amenable to scale-up, and 1 metric ton of the target compound was prepared in high yield as a product-by-process.",10.1021/op500301r,0
Quality by Design in Action 2: Controlling Critical Material Attributes during the Synthesis of an Active Pharmaceutical Ingredient,"Quality by Design (QbD) is of paramount importance not only for patient safety but also for the timely and uninterrupted supply of products at affordable prices into the market. Both of these objectives can be achieved only through a robust process, and one of the major obstacles for developing a robust process is the quality of input materials and reagents used for the manufacture of active pharmaceutical ingredients (APIs). This article demonstrates the use of QbD methodology to optimize the quality of input materials and make the process more consistent, thereby reducing the variation in the quality of API produced. This article highlights the use of failure mode and effect analysis (FMEA) for the unbiased identification of critical process parameters and critical material attributes associated with the manufacturing of key starting materials, which are later used as input for the design of experiments (DoE) study that is used for the optimization.",10.1021/op500297g,0
Applications of Gage Reproducibility &amp; Repeatability (GRR): Understanding and Quantifying the Effect of Variations from Different Sources on a Robust Process Development,"During process development, it is always a debatable issue whether the variation in analytical results is due to the measurement system (MS) or due to the process. The best approach is to quantify total variation coming from the MS prior to any process improvement activity. This quantification is done by “Gage Reproducibility & Repeatability” (GRR). This article describes the usage of GRR for quantifying variation from various sources and selecting a suitable MS for the analysis. In this study, two instruments, a potentiometer and ultra high pressure liquid chromatography (UPLC), were evaluated for the assay measurement of a key starting material (KSM) supplied by a vendor. As a result of the GRR study, it was found that the potentiometer was not a suitable instrument, because of the high variation contributed by it, whereas UPLC was found to be suitable, because of the insignificant variation contributed by it towards the assay. In addition to this, it was also observed that the variation contributed by the KSM samples was insignificant, indicating that those samples were coming from a robust process, and the vendor was found to be suitable for supplying the KSM.",10.1021/op5002935,0
Development of a Grignard-Type Reaction for Manufacturing in a Continuous-Flow Reactor,This paper describes the scale-up of a highly exothermic and fast reaction from a microreactor with an internal volume of less than 1 mL to a mesoreactor with an internal volume of 13.5 mL. The development of a continuous process for manufacturing a ketone from an ester using a Grignard reagent is described. The different steps undertaken and the considerations made to be able to operate in continuous mode and achieve a product output of ca. 0.5 kg are presented.,10.1021/op500290x,0
"Development of a Practical and Scalable Synthetic Route to YM758 Monophosphate, A Novel I<sub>f</sub> Channel Inhibitor","A novel, practical, and efficient synthesis of (−)- N -{2-[( R )-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate, ( R )-1·H 3 PO 4 (Figure 1 ) is described. The target molecule ( R )-1 has a potent I f current channel inhibitor. Medicinal chemistry synthetic routes were very long and suffered from extensive use of chlorinated solvents and silica-gel column chromatography. A number of steps in the medicinal chemistry route were also unattractive for large-scale synthesis due to some reasons for example the use of unstable intermediates. An important objective of a new synthetic route was avoidance of such a use of unstable intermediate, and it was achieved by the discovery of an important 4,5-dihydrooxazole intermediate 19 and ring-opening N -alkylation of chiral amine with 19 under acidic condition. The new procedure does not require any purification by column chromatography for all steps. The overall yield was significantly improved from 14% or 34% to 49% compared to that of the medicinal synthetic routes. This highly efficient process was successfully demonstrated at a pilot-scale operation, yielding 36.5 kg of ( R )-1·H 3 PO 4 .",10.1021/op5002885,1
Specifications of Drug Substances and Products: Development and Validation of Analytical Methods,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewSpecifications of Drug Substances and Products: Development and Validation of Analytical MethodsJohn KnightView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield TN20 6EW, U.K.Cite this: Org. Process Res. Dev. 2014, 18, 9, 1154Publication Date (Web):September 11, 2014Publication History Published online11 September 2014Published inissue 19 September 2014https://pubs.acs.org/doi/10.1021/op5002879https://doi.org/10.1021/op5002879book-reviewACS PublicationsCopyright © 2014 American Chemical SocietyRequest reuse permissionsArticle Views842Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Order,Pharmaceuticals,Quality by design,Testing and assessment Get e-Alerts",10.1021/op5002879,0
"Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate","The development of a hydrogenation process and subsequent isolation for an intermediate in the manufacture of an active pharmaceutical ingredient is described. In-line process analytical technology (PAT) approaches were applied to gain process understanding and control. First, a calibration-free, qualitative, scale-independent approach using in situ mid-infrared (MIR) spectrometry to determine the end point of a hydrogenation reaction in real time is described. A curve-fitting algorithm was developed using MATLAB software to allow the reaction rate to be calculated at any given time during the reaction on the basis of the consumption of an intermediate species. The algorithm, coupled with understanding of the process, allowed the end point to be correctly identified in triplicate during scale-up of the process from 0.2 to 20 L scale. Second, a quantitative partial least-squares (PLS) regression model was developed using near-infrared (NIR) spectrometry to determine the solvent composition during the subsequent constant-volume distillation process prior to the crystallization of the hydrogenated product. Here the application of in-line NIR spectroscopy allowed the correct crystallization seed point to be determined, enhancing the control of quality and manufacturability.",10.1021/op500285x,0
Process Safety Evaluation and Scale-up of a Lactam Reduction with NaBH<sub>4</sub> and TFA,"The development of a practical and scalable method for the synthesis of morpholine derivative 2 via reduction of lactam 1 using NaBH 4 and trifluoroacetic acid (TFA) is described. Through the mechanistic studies using 11 B NMR spectroscopy, we observed that active species were generated during TFA addition, which avoids the deactivation of the active species involved in the reduction process. Process safety assessments were performed on the basis of the reaction mechanism using reaction calorimetry and gas evolution analyses. Furthermore, safety equipment was prepared to prevent the leakage of diborane gas during the reaction, and the process was successfully scaled up to the pilot plant at a 35 kg scale.",10.1021/op500284e,0
"Organometallic Carbanions in Practical Organic Synthesis: Grignards, Organolithiums, and More","ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTOrganometallic Carbanions in Practical Organic Synthesis: Grignards, Organolithiums, and MoreAman A. Desai and Victor SnieckusView Author Information Aether Industries Limited, Surat 394230, Gujarat, India. E-mail: [email protected] Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada. E-mail: [email protected]Cite this: Org. Process Res. Dev. 2014, 18, 10, 1191Publication Date (Web):October 17, 2014Publication History Published online17 October 2014Published inissue 17 October 2014https://doi.org/10.1021/op500283pCopyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1138Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (113 KB) Get e-AlertscloseSUBJECTS:Industrial manufacturing,Ketones,Organic synthesis,Organometallic reactions Get e-Alerts",10.1021/op500283p,0
Short Synthesis of a Proline Amide Orexin Receptor Antagonist on the Pilot Plant Scale,"A three-step fully telescoped synthesis of an N -sulfonyl proline amide, a nonpeptide antagonist of human orexin receptors, is described. The process development from the medicinal chemistry route up to the 240 kg production of 1 is discussed with a focus on an economical and efficient amide bond formation and identification of a new polymorph. The routes are compared using green metrics.",10.1021/op500277s,1
Survey of Solvent Usage in Papers Published in<i>Organic Process Research</i>&amp;<i>Development</i>1997–2012,"A survey of solvent usage for papers published in Organic Process Research & Development has been carried out for the years 1997–2012. Three solvent categories were studied: (i) solvents of concern, (ii) dipolar aprotic solvents, and (iii) neoteric solvents. In the analysis of dipolar aprotic solvent use it was found that nearly 50% of DMF/DMAc/NMP/DMSO usage is attributed to nucleophilic substitution reactions (mostly S N Ar and S N 2 reactions). Ideas on how to minimise the use of these four solvents in nucleophilic substitution reactions are presented, and it is hoped that these ideas will be adopted by chemists looking at S N type reactions at all stages of development. The only neoteric solvent showing any significant use is 2-methyltetrahydrofuran; usage of this solvent grew rapidly during the survey period.",10.1021/op500276u,0
Kinetic and Scale-up Investigations of a Michael Addition in Microreactors,"Microreactors are an efficient tool for process development and intensification. However, the scale-up from lab studies to small-scale commercial production is challenging, since a change in the channel dimensions requires good knowledge of heat and mass transfer phenomena. In this work, complete process development for an exothermic Michael addition is presented. In a systematic scale-up approach, kinetic studies and experimental characterization of the employed reactors provide key parameters for detailed reactor modelling. The residence time distribution, reactant mixing, and removal of reaction heat are taken into account. It is exemplarily shown how preliminary experiments can be the basis for the prediction of scale-up effects and the development of a continuous production process. Plug flow behavior and short mixing times could be confirmed for all investigated flow reactors. Furthermore, interactions of reaction kinetics and the formation of hot spots in the reactor channel were investigated. For the examined reaction, the simulations predicted the product yield under production conditions in good accuracy.",10.1021/op5002758,0
An Improved and Efficient Process for the Preparation of Tofacitinib Citrate,"The present invention is related to a simple and efficient process for the preparation of tofacitinib citrate 1, a Pfizer molecule approved for the treatment of rheumatoid arthritis. The process relies upon an improved process for the preparation of a key intermediate (3 R,4 R )-(1-benzyl-4-methylpiperidin-3-yl)methylamine as tartarate salt 3 and its simple and impurity-free conversion to tofacitinib citrate 1 . The current invention is aimed at addressing process development issues related to quality and yields. The disclosed process is capable of delivering much higher yield compared to the prior state-of-the-art process and is able to yield very highly pure compound.",10.1021/op500274j,1
Synthesis of Akt Inhibitor Ipatasertib. Part 1. Route Scouting and Early Process Development of a Challenging Cyclopentylpyrimidine Intermediate,"Herein, the route scouting and early process development of a key cyclopentylpyrimidine ketone intermediate toward the synthesis of Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate were prepared through a method that commenced with the natural product ( R )-(+)-pulegone and relied on the early construction of a methyl-substituted cyclopentyl ring system. The first process chemistry route, detailed herein, enabled the synthesis of the ketone on a hundred-gram scale, but it was not feasible for the requisite production of multikilogram quantities of this compound and necessitated the exploration of alternative strategies. Several new synthetic approaches were investigated towards the preparation of the cyclopentylpyrimidine ketone, in either racemic or chiral form, which resulted in the discovery of a more practical route that hinged on the initial preparation of a highly substituted dihydroxypyrimidine compound. The cyclopentane ring in the target was then constructed through a key carbonylative esterification and subsequent tandem Dieckmann cyclization–decarboxylation sequence that was demonstrated in a racemic synthesis. This proof-of-concept was later developed into an asymmetric synthesis of the cyclopentylpyrimidine ketone, which will be described in a subsequent paper, along with the synthesis of Ipatasertib.",10.1021/op500271w,1
Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up,"Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a trans -substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a β 2 -amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt.",10.1021/op500270z,1
Lab-Scale Preparation of a Novel Cyclopenta[b]furan Chemokine Receptor Antagonist,"The preparation of a chemokine receptor type 2 (CCR-2) antagonist bearing a cyclopenta[b]furan core is described on a 600 g scale. Compared to our previously reported synthesis of the all-carbon core CCR-2 antagonist with a similar peripheral 3-methoxypyran appendage, our work required a redesign of the original Discovery Chemistry route and took advantage of a side product seen in the diastereoselective alkylation reaction. Elaboration by reduction and oxy-cyclization eventually led to the required N -Boc acid method. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents such as selenium and chromium that would not be used in a large-scale process setting, the overall route went through intermediates that could certainly be used for future scale-up campaigns. The synthesis provided a method to make lab-scale quantities of the final succinate salt to support tox/toleration studies. Relative to the Discovery Chemistry route, this lab-scale route featured novel intermediates that could open new avenues for future research in this area.",10.1021/op500266w,1
Lab-Scale Preparation of a Novel Carbocyclic Chemokine Receptor Antagonist,"The preparation of a novel chemokine receptor type 2 (CCR-2) antagonist is described on a 135 g scale. The synthesis of an all-carbon bicyclic core was accomplished using a radical cyclization strategy using chiral precursors, wherein elaboration led to N -Boc carboxylic acid in good yield. After amidation using a traditional coupling reaction, a reductive amination using enantiomerically enriched 3-methoxy-4-pyranone led to the final compound. Although several steps of the syntheses involved reagents that would not be preferred in process and chromatography was used to provide the free-base diastereomer of the final succinate salt, the overall route went through stable intermediates that could be used for future scale-up. This lab-scale synthesis struck a balance between a quick scale-up and a more thorough process review of all possible methods and routes.",10.1021/op500265z,1
Concise Preparation of a Stable Cyclic Sulfamidate Intermediate in the Synthesis of a Enantiopure Chiral Active Diamine Derivative,"A classical resolution was studied and developed from 2-benzoyl-pyridine in order to prepare SSR504734, a novel antipsychotic derivative. The key step of this route is the substitution of a sulfamidate derivative by a benzamide anion with complete inversion of configuration. The sulfamidate is prepared in a two-step procedure by reacting erythro phenyl-piperidine-2-yl-methanol derivative with thionyl chloride followed by oxidation with ruthenium oxide. This sulfamidate is an easily scalable intermediate that produce a diamine intermediate with the expected configuration.",10.1021/op500264v,1
Development of Multikilogram Continuous Flow Cyclopropanation of <i>N</i>-Benzylmaleimide through Kinetic Analysis,"A convenient and high-yielding method for the synthesis of trans -(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and initial mixing temperature are the critical parameters to minimize formation of byproducts and to get high reaction yield. Using a modular tubular flow reactor, the trans/cis -(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate was obtained in 92% yield and isomerized under basic conditions to produce the trans -isomer in greater than 99% diastereomeric excess. Using this approach, the reaction yield was significantly increased compared to the batch process, and the robustness and reproducibility of this flow process was demonstrated for the synthesis of this key intermediate on a multikilogram scale.",10.1021/op500263m,1
A Process for the Formation of Nanocrystals of Active Pharmaceutical Ingredients with Poor Aqueous Solubility in a Nanoporous Substrate,"A potential process for the formation of nanocrystals of the poorly soluble drug, ibuprofen, within a nanoporous material is demonstrated. Nanocrystalline ibuprofen (IBP) is prepared at ≤106 nm by adding a solution containing IBP to particles of controlled pore glass (CPG) within a column so that the pores contain IBP solution. The imbibed particles of CPG are then rinsed with a minimal amount of solvent to remove excess solution at the surface of CPG, and a flow of air within the column is used to evaporate the solvent, resulting in crystallization of IBP within the pores of CPG. Crystallinity is determined using X-ray powder diffraction. IBP is confirmed as being in the nanosize range by observation of a negative shift in the melting point measured by differential scanning calorimetry, and loading of IBP nanocrystals within the pores (% w/w) is determined by thermogravimetric analysis. Parameters were investigated for the process and demonstrate that an increase in percentage loading is achieved with increasing solution concentration and with increasing solvent viscosity. Loading of IBP within CPG was also found to be very sensitive to the volume of rinse solvent used. It is shown that rinsing with a minimal amount of solvent is necessary to avoid the significant presence of bulk micron-sized surface crystals. In vitro dissolution profiles, performed in water, demonstrate the significant dissolution rate increase offered by nanocrystalline IBP relative to bulk micron-sized crystals or even formulated tablets of IBP.",10.1021/op500262q,0
Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review,"This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.",10.1021/op500261y,0
Safe Scale-Up of Pharmaceutical Manufacturing Processes with Dimethyl Sulfoxide as the Solvent and a Reactant or a Byproduct,"Thermal hazard analyses of two reactions, one with DMSO as the solvent and a reactant and one with DMSO as the solvent and a byproduct, identified low-probability but severe consequence process risks associated with violent decomposition of DMSO during heating control failure or external heating. Although DMSO cannot be totally eliminated from these reactions, using an alternative solvent to replace DMSO proved to be an effective measure in reducing the thermal hazards to allow safe scale-up.",10.1021/op500260n,0
"Chemical Process Technology, Second Edition","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTChemical Process Technology, Second EditionTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 9, 1153Publication Date (Web):August 15, 2014Publication History Published online15 August 2014Published inissue 19 September 2014https://pubs.acs.org/doi/10.1021/op500256yhttps://doi.org/10.1021/op500256ybook-reviewACS PublicationsCopyright © 2014 American Chemical SocietyRequest reuse permissionsArticle Views1253Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Biotechnology,Chemical engineering and industrial chemistry,Petrochemicals,Students Get e-Alerts",10.1021/op500256y,0
Practical Asymmetric Hydrogenation-Based Synthesis of a Class-Selective Histone Deacetylase Inhibitor,"Two syntheses of the class-selective histone deacetylase inhibitor 1 are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording trans - rac - 5 and its resolution. In the second, asymmetric approach, the key steps were a highly selective asymmetric hydrogenation to produce the cis -( S,S )-3,4-disubstituted pyrrolidine 18 followed by an amide formation with simultaneous chiral inversion of the carboxy stereocenter to generate the key intermediate trans -( R,S )-3,4-disubstituted pyrrolidine 19 . The overall yield increased from ∼6% for the resolution approach to ∼26% for the enantioselective approach.",10.1021/op500250b,1
Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction,"A practical, scalable synthetic process for a sulfonamide was developed featuring a Semmler–Wolff aromatization as the key step. The optimized reaction conditions using HCl in HOAc give directly the desired naphthylamine in high yield as opposed to a naphthylacetamide commonly formed in the Semmler–Wolff reactions. One little known byproduct of anomalous rearrangement, ketoamine, was observed and a mechanism proposed to explain its formation. Employing the optimized process, 360 kg was prepared to support drug development.",10.1021/op500247h,1
Batch-to-Batch Variation: A Key Component for Modeling Chemical Manufacturing Processes,"For chemical manufacturing processes, the chemical kinetics literature contains virtually no mention of quantitative models that involve batch-to-batch variation. Models for chemical process manufacturing quality improvement are being more carefully considered, particularly by the pharmaceutical industry and its regulators. This is evidenced in part by the recent ICH Q11 regulatory guidance on drug substance manufacture and quality. Quality improvement has been defined as a reduction in variation about a target. Hence the modeling of process variation plays an important role in quantifying quality improvement. Given that batch-to-batch variation is often a dominant source of process variation (usually exceeding measurement error variation), it is important for process models to incorporate such variance components. In this paper, we show how chemical kinetic models can incorporate batch-to-batch variation as well as measurement error. In addition, we show that these models can be used to quantify the reliability of meeting process specifications using Bayesian statistical methods. We also compare some different Bayesian computational approaches and recommend some software packages to aid with the computations.",10.1021/op500244f,0
"How to Convert a Walk-in Hood into a Manufacturing Facility: Demonstration of a Continuous, High-Temperature Cyclization to Process Solids in Flow","An intramolecular thermal cyclization protocol was developed in a flow reactor to take advantage of the high pressures and temperatures that are easily obtained in small scale autoclave reactors that have been modified to handle slurries. This reactor was equipped with a fill/empty pumping system to enable easy and nearly complete transfer of slurries. The reaction conditions were designed to take advantage of the insolubility of the product in order to separate it from residual starting material by filtration after short reaction times. Recycling of the filtrate maximized the yield and throughput while minimizing decomposition. Recycles were accomplished using a strip to dryness protocol that was easily performed in a rotary evaporator. This new equipment set was designed with lab-hood manufacturing in mind, a minimized footprint, and the system was completely automated for charging, emptying, rinsing, and reacting. Additional efforts for quick screening and alternate modes of addition were also investigated.",10.1021/op500239f,0
Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors,"A fast and convenient synthetic route towards spiro-oxindole dihydroquinazolinones as novel and drug-like insulin-regulated aminopeptidase (IRAP) inhibitors is reported. The synthesis is performed using a MW heated continuous flow system employing 200 mm × 3 mm Ø i MW absorbing silicon carbide (SiC) or MW transparent borosilicate tubular reactors. A three-component MW-flow reaction to build up the spiro compounds (9 examples, 40–87% yield), using the SiC reactor, as well as a Suzuki–Miyaura cross-coupling reaction (71%), employing the borosilicate reactor, are presented with residence times down to 168 s. The continuous MW-flow routes provide a smooth and scalable synthetic methodology towards this class of IRAP inhibitors.",10.1021/op500237k,0
Aryldiazonium Tetrafluoroborate Salts as Green and Efficient Coupling Partners for the Suzuki–Miyaura Reaction: From Optimisation to Mole Scale,"The use of aryldiazonium tetrafluoroborate salts as coupling partners in the Suzuki–Miyaura reaction was investigated from a process chemistry perspective including safety evaluation, solvent and catalyst screening and multivariate factor optimisation. Optimised conditions were applied to a range of substrates to evaluate the scope and limitations of the reaction, and one example was carried out on mole scale to demonstrate the practicality and scalability of the process.",10.1021/op5002353,1
Investigation on Main Reaction and Side Reaction Mechanism in the Synthetic Process of 1-(5-Bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one Using Raman Spectroscopy,"High Resolution Image Download MS PowerPoint Slide 1-(5-Bromothiophen-2-yl)-3-(4-nitrophenyl) prop-2-en-1-one (BTNP) has unique and highly attractive properties, which make them a new kind of nonlinear optical (NLO) organic material for wide applications in the fields of optical communication and flat panel display. In this work, BTNP was successfully synthesized by Claisen–Schmidt condensation reaction. To optimize the synthesis process and improve the purity of the product, the synthetic process of BTNP was monitored in situ by Raman spectroscopy to find out the mechanism of main reaction and possible side reactions. The possible side reactions were proposed based on Raman spectroscopy data. The effect of reaction conditions, including dosage of sodium hydroxide and reaction temperature, was investigated and analyzed by using the proposed side reaction scheme. It was found that the sodium hydroxide dosage is the key factor for the main reaction (Claisen–Schmidt condensation reaction) and side reactions. The effect of reaction conditions on the purity of the obtained BTNP products was investigated and analyzed. The results are consistent with those of proposed side reactions. The purity of the obtained product can reach 96.88% under optimized experimental conditions.",10.1021/op500234a,0
Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6-Bromoisoquinoline-1-carbonitrile with (<i>S</i>)-3-Amino-2-methylpropan-1-ol,"This work describes the optimization and scale-up of a Buchwald–Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C–N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd(dba) 2 with BINAP and Cs 2 CO 3 in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound ( S )-3 .",10.1021/op5002319,0
Preparative Synthesis of Highly Substituted Tetrahydropyridines via a Rh(I)-Catalyzed C–H Functionalization Sequence,"High Resolution Image Download MS PowerPoint Slide We report a Rh(I)-catalyzed C–H activation/alkenylation/electrocyclization cascade and subsequent reduction for the synthesis of highly substituted tetrahydropyridines. These products can be accessed on a gram scale with low catalyst loadings and at high reaction concentrations. Additionally, a modified Rh-catalyst, prepared from [RhCl(cod)] 2 as a robust bench-stable precatalyst was developed to enable straightforward reaction set up without the use of a glovebox. To demonstrate the practicality of this reaction, a >100 mmol scale Rh-catalyzed cascade reaction sequence utilizing the air-stable precatalyst [RhCl(cod)] 2 was performed on the bench to furnish the pure tetrahydropyridine product in 93% yield.",10.1021/op500225c,0
Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C–H Functionalization Sequences,"High Resolution Image Download MS PowerPoint Slide A Rh-catalyzed C–H bond activation/alkenylation/electrocyclization cascade reaction provides diverse 1,2-dihydropyridines from simple and readily available precursors. The reaction can be carried out at low (<1%) Rh-catalyst loadings, and the use of the robust, air-stable Rh precatalyst, [RhCl(cod)] 2, enables the cascade reaction to be easily performed on the benchtop. The 1,2-dihydropyridine products serve as extremely versatile synthetic intermediates for further elaboration often without isolation. The addition of electrophiles under kinetic or thermodynamic conditions provides a wide range of iminiums. Subsequent addition of a nucleophile then generates a diverse array of differently substituted piperidine products. Additionally, [3 + 2] and [4 + 2] cycloadditions of the 1,2-dihydropyridine intermediate provides access to bridged bicyclic structures such as tropanes and isoquinuclidines. These concise reaction sequences enable the formation of highly substituted piperidines in synthetically useful yields with excellent diastereoselectivity.",10.1021/op500224x,0
"Process Development and Scale-up of T3-Sulfate, A New Prodrug Alternative to the Conventional Hormone Therapy of Hypothyroidism","An efficient and scalable preparation of the thyroid hormone analogue O -[3-iodo-4-(sulfooxy)phenyl]-3,5-diiodo- l -tyrosine sodium salt (T3-sulfate, 1 ) is reported. The synthesis involved monoiodination of O -(4-hydroxyphenyl)-3,5-diiodo- l -tyrosine to give liothyronine ( 2 ) which was sulfated with chlorosulfonic acid in N,N -dimethylacetamide. Crude T3-sulfate was initially purified by chromatography on polystyrene resin Amberlite XAD 1600 and then crystallized with ethanol. This strategy was scaled-up to give a process suitable for the production of kilogram quantities of API, needed to support preclinical and clinical studies.",10.1021/op500222p,1
Synthesis of a Carprofen Analogue Using a Continuous Flow UV-Reactor,"A continuous flow UV light reactor has been constructed using commercially available equipment, and its efficiency was demonstrated by performing a photocyclodehydrogenation reaction to prepare carbazole derivatives of the drug carprofen.",10.1021/op5002148,0
Development of a Manufacturing Process for an HCV Protease Inhibitor Candidate Molecule,"The scale-up of a prototype HCV protease inhibitor ( 1 ) from gram scale in the laboratory to kilogram scale in the pilot plant is described. Key features of the optimization included the synthesis of bulk quantities of exomethylene proline intermediate 6, separation of the diastereomers of spirocycle 2 without chromatography, isolation of the precursor to 1 to purge byproducts that might raise genotoxic structural alerts, and purification of an amorphous drug substance via a crystalline acetic acid solvate.",10.1021/op500210w,1
Enzymatic Reduction of Adamantanones to Chiral Adamantanol Intermediates for the Synthesis of 11-β-Hydroxysteroid Dehydrogenase Inhibitors,"An enzymatic reduction process was developed to convert the ketone 2-(6-oxo-2-phenyladamantan-2-yl)acetic acid to the chiral alcohol 2-((2 S, 6 S )-6-hydroxy-2-phenyladamantan-2-yl)acetic acid and to convert the fluoro ketone 2-(2-(4-fluorophenyl)-6-oxoadamantan-2-yl)acetic acid to the chiral alcohol 2-((2 S,6 S )-2-(4-fluorophenyl)-6-hydroxyadamantan-2-yl)acetic acid. These chiral adamantanols are intermediates for the 11-β-hydroxysteroid dehydrogenase inhibitors 2-((2 S,6 S )-6-hydroxy-2-phenyladamantan-2-yl)-1-(3-hydroxyazetidin-1-yl)ethanone and 2-((2 S,6 S )-2-(4-fluorophenyl)-6-hydroxyadamantan-2-yl)-1-(3-hydroxyazetidin-1-yl)ethanone, respectively. Initial batches of both intermediates were prepared with a commercial ketoreductase giving yields near 100% with 96% ee. A more selective ketoreductase was purified 1800-fold from Candida utilis ATCC 42181 and then cloned and expressed in Escherichia coli . The reaction requires the cofactor NADPH which was regenerated during initial batches using a commercial glucose dehydrogenase. In later work a glucose dehydrogenase from Gluconobacter oxydans was cloned and expressed in the same E. coli strain together with the ketoreductase. To allow easy storage and shipment of the two enzymes, the E. coli cell paste was lyophilized to produce a stable form of the enzymes.",10.1021/op5002098,0
Process Intensification for the Continuous Flow Hydrogenation of Ethyl Nicotinate,"Here we report a process intensification study for the selective, partial, and full hydrogenation of ethyl nicotinate using a trickle bed reactor for meso-flow transformations (HEL FlowCAT). The process achieved a throughput of 1219 g d –1 (78 g h –1 of product per g of active catalyst) for the partial hydrogenation to ethyl 1,4,5,6-tetrahydropyridine-3-carboxylate, whereas the productivity for the full hydrogenation process reached a 1959 g d –1 of throughput (408 g h –1 of product per g of active catalyst) on this laboratory-scale flow chemistry platform.",10.1021/op500208j,0
Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions,"A modeling-based strategy is disclosed for identifying reaction conditions for the safe and effective scale-up of highly energetic hydrogenation reactions. The model was developed within Scale-up Systems’s DynoChem 2011 and takes under consideration the kinetics of the reaction, the reactor heat transfer capabilities, and the degree of mass transfer. Fourier transform infrared spectroscopy (FT-IR), heat flow, and H 2 uptake data were used to determine the reaction kinetics that were found to be most accurately described by a Langmuir–Hinshelwood type model. The scale-up model was validated within our kilo-laboratory using a 5 L reactor.",10.1021/op500207r,0
Fully Automated Continuous Meso-flow Synthesis of 5′-Nucleotides and Deoxynucleotides,"The first continuous meso-flow synthesis of natural and non-natural 5′-nucleotides and deoxynucleotides is described, representing a significant advance over the corresponding in-flask method. By means of this meso-flow technique, a synthesis with time consumption and high-energy consumption becomes facile to generate products with great efficiency. An abbreviated duration, satisfactory output, and mild reaction conditions are expected to be realized under the present procedure.",10.1021/op5002066,0
Pilot-Scale Continuous Production of LY2886721: Amide Formation and Reactive Crystallization,"The design, development, and implementation of a pilot-scale continuous Schotten–Baumann amide bond formation and reactive crystallization to afford LY2886721 is described. The material met all API quality attributes and was comparable to material produced by a defined batch process. The scalability of the reaction and crystallization processes was confirmed during the development process. The pilot-scale equipment set was contained in a walk-in fume hood and operated at a production rate of 3 kg/day in a 72 h continuous run. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development. The continuous process provided for lab hood commercialization and provided for minimal material at risk in the process. The demonstration also confirmed the risk inherent to operation of a tubular reactor under supersaturated conditions, and fouling occurred in the plug flow reactor. Fouling also occurred in the crystallizer. Recognizing these deficiencies, the process operated within the footprint of a standard walk-in fume hood, providing a successful demonstration of the opportunities afforded by continuous processing for low volume pharmaceuticals.",10.1021/op500204z,1
Tailoring the Product Distribution with Batch and Continuous Process Options in Catalytic Hydrogenation of Furfural,"Various noble metal catalysts were screened in a batch operation for a furfural (FFR) single-step decarbonylation and hydrogenation reaction to obtain THF in high selectivity. Among these, the 3% Pd/C showed complete FFR conversion with a total of 80% selectivity to ring hydrogenated products including tetrahydrofuran (THF). The order of activity exhibited by other noble metals was Pt/C > Re/C > Ru/C. Although Pt/C exhibited the highest activity, its decarbonylation and ring hydrogenation ability were the least (24%) with a major product selectivity of 66% to furfuryl alcohol (FAL). Similarly, the Cu catalyst gave almost complete selectivity to FAL. In a continuous operation (23 g catalyst bed), the 3% Pd/C catalyst showed higher selectivity of >40% compared to THF alone with complete FFR conversion and on-stream activity of ∼100 h. The reaction pathway elucidated from some control experiments revealed that the decarbonylation of FFR to furan over the Pd/C catalyst is a prerequisite for THF formation.",10.1021/op500196x,0
A Scalable Route to 5-Substituted 3-Isoxazolol Fibrinolysis Inhibitor AZD6564,"A practical and chromatography-free multikilogram synthesis of a 3-isoxazolol containing antifibrinolytic agent, AZD6564, has been developed in eight steps and 7% overall yield starting from methyl 2-chloroisonicotinate. Highlights in the synthesis are a Negishi coupling and an enzymatic resolution of a racemic ester.",10.1021/op500193s,1
From Batch to Continuous Chemical Synthesis—A Toolbox Approach,"A toolbox approach for the transfer of batch to continuous chemical synthesis is presented. The approach considers reaction kinetics (Type A, B, C), reacting phases (single phase, liquid–liquid, gas–liquid and liquid–solid), and the reaction network (parallel and consecutive reactions) in order to select the most appropriate reactor module (Plate, Coil, or CSTR) for continuous operation. Then, three case studies using these three fundamental reactors are presented but require special considerations. For the reaction of dimethyl-oxalate with ethylmagnesium chloride, a plug-flow multi-injection technology must be used to decrease the local heat generation and improve yield. For the nitration of salicylic acid, a Plate reactor with mixing elements favoring some back-mixing followed by a plug-flow system at elevated temperatures is used instead of a tandem mixed-flow CSTR and plug-flow Coil reactor in order to minimize the risk of thermal decomposition of intermediates with a reduced volume penalty. Finally, a ring-closing metathesis reaction is discussed for which the utilization of a CSTR allows the removal of catalyst-poisoning ethylene formed during the reaction and keeps the substrate concentration low to increase the yield above that of a batch or plug-flow system.",10.1021/op5001918,0
Case Studies in the Applicability of Drug Substance Design Spaces Developed on the Laboratory Scale to Commercial Manufacturing,"A number of strategies have been employed within the pharmaceutical industry in order to mitigate the risk of applying design space boundaries developed on the laboratory scale to commercial drug substance manufacturing. The following communication presents a number of case histories from members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the aim of exemplifying strategies used to confirm applicability of design spaces developed on the laboratory scale. The strategies presented have a common aim of ensuring that appropriate quality standards are developed, maintained, and enhanced during the product lifecycle whilst delivering rapid and cost-effective mechanisms for drug substance commercialization.",10.1021/op500187u,0
Examples of Catalytic and Selective Routes for Fluorinated Building Blocks,"Examples are presented for the catalytic fluorination of chlorinated starting materials in order to produce building blocks or HFCs. The fluorination of CF 3 CH 2 Cl, of CCl 2 ═CCl 2, of trichloromethoxylbenzenes and trichloromethoxybenzene involving nucleophilic substitution are reported. In all cases, HF was the fluorinating agent. Depending on the chlorinated substrate and the degree of fluorination required, liquid- or gas-phase processes were involved. Usually, catalysts were SbCl 5 in liquid phase and chromium oxide in gas phase. In the presence of SbCl 5, at 90 °C under an initial pressure of 10 bar, the fluorination of CCl 2 ═CCl 2 leads mainly to the formation of CClF 2 CHCl 2, and the active catalyst is an antimony mixed halide (SbCl 3 F 2 ). In the same way, the presence of SbCl 5 favored the formation of 1-trifluoromethyl-3-trichloromethylbenzene from bis-1,3-trichloromethylbenzene at low temperature (50 °C) and in the presence of a low amount of HF. Moreover, trichloromethoxybenzene was totally transformed into trifluoromethoxybenzene. At 380 °C and at atmospheric pressure, the transformation of CF 3 CH 2 Cl into CF 3 CH 2 F was favored over chromium oxide-based catalyst modified by zinc (corresponding to a (Zn/Zn + Cr) molar ratio of 0.22).",10.1021/op500182w,0
Development of a Continuous Plug Flow Process for Preparation of a Key Intermediate for Brivanib Alaninate,"A thermal runaway potential was identified for the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate in the synthesis of brivanib alaninate. A continuous process was developed to mitigate the potential thermal runaway and allow for safer scale-up. This paper describes the hazard analysis, process development, reactor development, reaction engineering model development, and scale-up of the continuous process. The process includes three separate and stable feed streams that are mixed in distinct order using in-line static mixers. Heat exchangers are arranged and connected to facilitate a “plug flow” reactor scheme allowing sufficient residence time for reaction completion. The process has been scaled-up to the pilot plant and to manufacturing.",10.1021/op500176z,0
Simple Process for the Preparation of Cetyltrimethylammonium Naproxenate (Naprocet),"Specifications for cetyltrimethylammonium (CTA) naproxenate (naprocet), the active ingredient of pharmaceutical liquid preparations used as antiseptic–antinflammatory detergents, fix severe limits to the presence of residual inorganic counteranion deriving from the starting CTA salt. A new simple procedure, which avoids ionic exchange chromatography and utilizes CTAHSO 4 in place of CTABr and CTACl, exploits the quantitative precipitation of K 2 SO 4 from methanol to yield naprocet in line with such specification requirements.",10.1021/op500175v,0
Synthesis of 1-Arylcycloalkenamines by Intramolecular Arylation of Lithiated Ureas,The deprotonation of N ′-arylurea derivatives of cyclohexenamines by alkyllithiums leads to migration of the N ′-aryl substituent from N′ to the allylic position α to N via rearrangement of a urea-stabilised allyllithium intermediate. The product ureas may be solvolysed to reveal 1-arylcyclohexenamines.,10.1021/op500173q,1
"3,5-Disubstituted Piperidine Derivatives—A Scalable Route to All Four Stereoisomers","3,5-Disubstituted piperidines are versatile building blocks that find broad application in medicinal chemistry programs. Here we describe how all four diastereoisomers of a 5-aryl-substituted nipecotic acid derivative were prepared on preparative scale in high enantiomeric purity. The piperidine core structure was formed by catalytic hydrogenation of the corresponding pyridine derivatives. After Boc-protection, the resulting cis / trans mixture was separated by preparative normal phase chromatography into the pure cis and pure trans racemates. Subsequent preparative separation of those racemates by Simulated Moving Bed chromatography (SMB) allowed us to obtain all four enantiopure isomers in amounts between 80 and 140 g. The absolute configuration of all compounds was determined by crystallization and X-ray spectroscopy of suitable derivatives.",10.1021/op500170d,0
Continuous Flow Total Synthesis of Rufinamide,"Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddition reaction. Each of the three chemical steps enjoys significant benefits and has several advantages by being conducted in flow. The total average residence time of the synthesis is approximately 11 min, and rufinamide is obtained in 92% overall yield.",10.1021/op500166n,1
"Lipase Catalyzed Regioselective Lactamization as a Key Step in the Synthesis of <i>N</i>-Boc (2<i>R</i>)-1,4-Oxazepane-2-Carboxylic Acid","A synthesis of N -Boc (2 R )-1,4-oxazepane-2-carboxylic acid 1 has been developed in 39% yield over seven steps starting from methyl (2 R )-glycidate 2 . The key step was a lipase-catalyzed regioselective lactamization of amino diester 5 into seven-membered lactam 6 . The transformation was performed using SpinChem rotating flow cell technology which simplified the work up and the recycling of the enzyme. Subsequent N -Boc protection followed by chemoselective borane reduction of the lactam moiety afforded 4- tert -butyl 2-methyl (2 R )-1,4-oxazepane-2,4-dicarboxylate 8 . Finally, hydrolysis mediated by LiBr/Et 3 N in wet acetonitrile yielded the title compound (2 R )-4-( tert -butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid 1 .",10.1021/op5001644,1
"Preparation, Properties, and Safe Handling of Commercial Organolithiums: Alkyllithiums, Lithium <i>sec</i>-Organoamides, and Lithium Alkoxides","This review includes the preparation and properties of various organolithiums, which are commercially available, up to manufacturing scale. The interdependent properties, such as pyrophoricity, solubility, stability, and aggregation, are tabulated and discussed. These properties have a direct bearing on their chemical reactivity and requirements for safe handling and storage. Extensive guidance for storage, use, analysis, and disposal of these organolithium solutions is also provided.",10.1021/op500161b,0
Scale-Up Investigation of the Continuous Phase-Transfer-Catalyzed Hypochlorite Oxidation of Alcohols and Aldehydes,"The use of bleach to oxidize alcohols with the aid of a phase-transfer catalyst (PTC) offers several benefits over traditional oxidants: low material cost, mild reaction conditions, and no metallic waste. Mass transport limitations often dictate overall reaction rates of such PTC reactions, and continuous-flow reactors with superior mass and heat transport performance are consequently used to enhance their rates. Three PTC hypochlorite oxidation reactions are chosen to illustrate scaling of PTC reactions from microfluidic to mesoscale systems [Corning Low Flow Reactor (LFR) and Advanced Flow Reactor (AFR)]. The successful scaling from microliters per hour in microreactors to intermediate milliliters per minute without sacrificing mass transport performance leads to significant increases in production rate and constitutes an efficient flow reactor scaling approach. The production rate increases up to 700 times in the scaling process from a spiral microreactor to the LFR and then to the AFR.",10.1021/op500158h,0
A Novel Synthesis of Rasagiline via a Chemoenzymatic Dynamic Kinetic Resolution,"A novel synthetic route for preparing rasagiline mesylate is presented using a dynamic kinetic resolution (DKR) as the key step, catalyzed by Candida antarctica lipase B (CALB) and a Pd nanocatalyst. The chiral intermediate ( R )-2,3-dihydro-1-indanamine was obtained through the DKR of the racemic aminoindan rac -1 in high yield (>90%) and excellent enantioselectivity (>99% ee). The process could be conducted on a 73 g scale at 200 g/L. Rasagiline mesylate was synthesized in 25% overall yield and excellent enantioselectivity (99.9% ee) over 7 steps.",10.1021/op500152g,1
Development of an Enantioselective Hydrogenation Route to (<i>S</i>)-1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine,"A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig’s procedure.",10.1021/op5001513,1
Living Anionic Polymerization in Continuous Flow: Facilitated Synthesis of High-Molecular Weight Poly(2-vinylpyridine) and Polystyrene,"We describe the living anionic polymerization of 2-vinylpyridine (2VP) and styrene (S) in continuous flow, comparing two micromixing devices with different mixing principles. The use of a continuous flow setup reduces the experimental effort for living anionic polymerizations significantly, compared to a conventional batch system. By adjusting the ratio of the flow rates of the monomer and initiator solutions a variety of different molecular weights can be rapidly synthesized within several minutes, using one setup. Additionally, a comparison of the influence of the two different mixing devices—an interdigital micromixer (SIMM-V2) leading to laminar mixing and a tangential four-way jet mixing device leading to a turbulent mixing pattern—has been achieved. Both setups allow living anionic polymerization in polar solvents at room temperature with full monomer conversion within seconds and yield polymers with narrowly distributed molecular weights. A maximum M n of approximately 149,000 g mol –1 (PS-9, PDI = 1.04) for PS and 96,000 g mol –1 for P2VP (P2VP-15, PDI = 1.05) was obtained. Clearly, the turbulent four-way jet mixing device led to lower polydispersity than the laminar mixing device. All polymers were characterized by 1 H NMR spectroscopy and size exclusion chromatography (SEC).",10.1021/op500149t,0
"Asymmetric Hydrogenation of 3,5-Bistrifluoromethyl Acetophenone in Pilot Scale with Industrially Viable Ru/Diphosphine–Benzimidazole Complexes","A novel efficient asymmetric hydrogenation (AH) process was developed for the preparation of ( R )-1-(3,5-bis(trifluoromethyl)phenyl)ethanol ( 3 ), using a catalyst Ru/(4 R,5 R )-(+)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxoane-( R, R -Diop)-2 R -(α-methylmethanamine)-4,7-dimethyl-1 H -benzo[ d ]imidazole ( R -D-Me-BIMAH) in toluene in the presence of potassium t -butoxide. Various hydrogenation parameters, such as ligand, solvent, and substrate-to-catalyst (S/C) ratio, were investigated. The hydrogenation was carried out for four times on a 5 kg scale at 30 atm and 25 °C with S/C of 20 000 with an enantiomeric excess of >89%.",10.1021/op500148k,1
"A Greener Approach for the Large-Scale Synthesis of 1,4,5-Trisubstituted Pyrazole, AZD8329","The development of a convenient, safe and scalable process for AZD8329 manufacturing is reported here. Synthesis was achieved in a two-step telescopic process with an excellent overall yield of 75%. In the first step enamine ( 6 ) was synthesized with 90% yield through three chemical transformations. In the next step AZD8329 was synthesized from the reactions of 6 and 4-hydrazinobenzoic acid hydrochloride 7 through two chemical transformations. The process is very efficient and economical, and AZD8329 was manufactured in multikilogram scale. A greener approach is demonstrated through usage of a minimum number of solvents and energy and with process mass intensity (PMI) <60 in the manufacturing process.",10.1021/op5001463,1
Isothermal Suspension Conversion as a Route to Cocrystal Production: One-Pot Scalable Synthesis,"Isothermal suspension conversion is presented as a suitable method for the manufacture of pure cocrystal products once the ternary phase diagram (TPD) for the cocrystal system in the desired solvent is available. One:one and 3:2 cocrystals of p -toluenesulphonamide/triphenylphosphine oxide were produced in acetonitrile and dichloromethane using this method. Eight individual batches of product were prepared with complete conversion to pure product achieved in seven batches. Product recovery (77–99%), reaction conversion (17–89%), and volumetric productivity (0.03–0.63 g/cm 3 ) were calculated for each product batch. These parameters are essentially determined by the batch operating mass fraction composition selected from the TPD, allowing for tailoring of processing conditions to suit process requirements and capabilities by careful selection of the optimum operating mass fraction composition.",10.1021/op500145a,0
Sequential Nitration/Hydrogenation Protocol for the Synthesis of Triaminophloroglucinol: Safe Generation and Use of an Explosive Intermediate under Continuous-Flow Conditions,"A continuous-flow process for the synthesis of triaminophloroglucinol has been developed. The synthetic procedure is based on a sequential nitration/reduction protocol which uses phloroglucinol as an inexpensive substrate. During the initial exothermic nitration step employing a combination of ammonium nitrate and sulfuric acid, the temperature was controlled through the enhanced heat transfer derived from the high surface-to-volume ratio of the utilized capillary tubing. Clogging of the tubing due to precipitation of trinitrophloroglucinol (TNPG) was avoided by immersing the tubular reactor in an ultrasound bath during the process. The nitration mixture was diluted with water and immediately subjected to catalytic hydrogenation of the nitro groups using a commercially available continuous-flow reactor and PtO 2 as heterogeneous catalyst, thus avoiding the isolation of the highly unstable and explosive TNPG intermediate.",10.1021/op5001435,1
"A Scalable Synthesis of (<i>R</i>,<i>R</i>)-2,6-Dimethyldihydro-2<i>H</i>-pyran-4(3<i>H</i>)-one","A scalable synthesis of ( R, R )-2,6-dimethyldihydro-2 H -pyran-4(3 H )-one is reported. Key to this strategy is the Ti(O i Pr) 4 -catalyzed Kulinkovich cyclopropanation of silyl protected ( R )-ethyl 3-hydroxybutanoate, and subsequent oxidative fragmentation of the cyclopropanol. The resulting vinyl ketone intermediate was then subjected to oxidative Heck cyclization to form the enone substrate required for conjugate addition. A diastereoselective copper-catalyzed Grignard addition procedure was implemented to install the requisite methyl group, with the inclusion of 1,3-bis(diphenylphosphino)propane and trimethylsilyl chloride greatly increasing the robustness of this process.",10.1021/op500135x,1
"A One-Pot Asymmetric Synthesis of a <i>N</i>-Acylated 4,5-Dihydropyrazole, A Key Intermediate of Thrombin Inhibitor AZD8165","A short, chromatography-free, and scalable synthetic route to thrombin inhibitor 1, the active metabolite of the propionic ester prodrug AZD8165, has been developed. The key synthetic step involved cycloaddition of TMS–diazomethane and ethyl acrylate to give an intermediate racemic dihydropyrazole which was reacted with enantiomerically pure 4-fluoro mandelic acid chloride in a one-pot dynamic kinetic resolution (DKR) process.",10.1021/op500134e,1
Multikilogram Scale Organolithiation Chemistry for the Manufacture of Liquid Crystal Intermediates,"This paper describes the kilogram-scale regioselective synthesis of various fluorinated arylboronic acids, aryl iodides, aryl acids, aryl aldehydes, and cyclohexenyl-substituted aryls in good to high yields via in situ fluorine-directed ortho-lithiation of fluorinated aryls and their subsequent reactions in a one-pot manner with nucleophiles such as triisobutyl borate, iodine, carbon dioxide, N, N -dimethylformamide, and cyclohexyl ketones.",10.1021/op500133p,0
Application of In Situ Raman Spectroscopy To Facilitate Use of Hydrogen Peroxide on Kilogram Scale,"The safe implementation of a hydrogen-peroxide-mediated oxidation of a poorly reactive sulfide to the corresponding sulfone is described. A three-tiered approach incorporating process understanding, safety studies, and real time PAT (in situ Raman spectroscopy) was leveraged to ensure safe operation. Further investigation of an in situ Raman spectroscopy model for the reaction and its use for in-process control and end-point determination is discussed.",10.1021/op500132s,0
Synthesis of Ionic Liquids Equipped with 2-Methoxyethoxymethyl/Methoxymethyl Groups Using a Simple Microreactor System,A simple microreactor system has been utilized for the continuous flow synthesis of novel ionic liquids having a (2-methoxyethoxy)methyl or methoxymethyl substituent. Conversion rates of N -bases and tributylphosphine in the microreactor system are faster than those in the batch system because of less diffusion distance in the tube reactor. This method allows us to prepare ionic liquids in efficient yields with high purity.,10.1021/op500131u,0
"Scale-Up of a Recombinant Pig Liver Esterase-Catalyzed Desymmetrization of Dimethyl Cyclohex-4-ene-<i>cis</i>-1,2-dicarboxylate","A recombinant isoenzyme of pig liver esterase was used for the highly enantioselective desymmetrization of dimethyl cyclohex-4-ene- cis -1,2-dicarboxylate. The selected recombinant esterase showed a significant advantage in enantioselectivity over the commonly used esterase from the mammalian source. The process was scaled up to yield 265 g of product with a simplified pH control, and the target molecule was obtained with an enantiopurity of >99.5% ee.",10.1021/op500129e,0
An Atom-Efficient Route to Ethyl 3-(difluoromethyl)-1-methyl-1<i>H</i>-pyrazole-4-carboxylate (DFMMP)—A Key Building Block for a Novel Fungicide Family,"A growing number of fluorine-containing active ingredients in the pharmaceutical and agrochemical industries inevitably raises the demand for new fluorinated building blocks. Their availability is mainly constricted by suitable chemistry and available bulk fluorine containing starting materials. Because of the high cost impact especially in the agrochemical industry, the choice of a synthetic route is heavily driven by economic aspects; thus, the environmental profile often is handled as a “secondary factor” or finally falls aside. DFMMP is a key building block for a fast growing new fungicide family, like Syngenta’s Sedaxane, and BASF’s Fluxapyroxad and Bayer’s Bixafen currently made by environmetally less friendly routes. Herein we present a cost-competitive and green route, developed at Solvay laboratories, displaying significantly lower environmental impact.",10.1021/op500128p,1
The Institute of Process Research and Development at the University of Leeds,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTThe Institute of Process Research and Development at the University of LeedsTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 5, 561Publication Date (Web):May 16, 2014Publication History Published online16 May 2014Published inissue 16 May 2014https://pubs.acs.org/doi/10.1021/op500124jhttps://doi.org/10.1021/op500124jeditorialACS PublicationsCopyright © 2014 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views810Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (106 KB) Get e-AlertscloseSUBJECTS:Crystallization,Industrial manufacturing,Organic synthesis,Reaction engineering,Students Get e-Alerts",10.1021/op500124j,0
Improved Synthesis of Fluticasone Propionate,"A novel process for the preparation of fluticasone propionate ( 1 ), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H 5 IO 6 as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH 2 F was replaced by AgNO 3 and Selectfluor in decarboxylative fluorination.",10.1021/op5001226,1
"PhenoFluor: Practical Synthesis, New Formulation, and Deoxyfluorination of Heteroaromatics","We report a practical synthesis method of the reagent PhenoFluor on decagram scale, provide a new formulation of PhenoFluor as a toluene solution, which should decrease challenges associated with the moisture sensitivity of the reagent, and expand the substrate scope of deoxyfluorination with PhenoFluor to heteroaromatics.",10.1021/op500121w,1
Multigram Laboratory Scale Synthesis of α-Trifluoromethoxy Carbonyl Compounds,"α-trifluoromethoxy carbonyl compounds are valuable building blocks for the synthesis of various trifluoromethoxylated compounds. The best way to easily obtain them is the direct trifluoromethoxylation with the CF 3 O – anion, generated in situ from trifluoromethyl triflate. However, the necessary autogenous pressure generated during this reaction constitutes a main drawback for a multigram scale extrapolation. A specific procedure using adapted glassware has allowed a laboratory large-scale production (up to 50 g) of such building blocks with good yields.",10.1021/op500118r,0
"Development of a Total Telescoped Synthesis of a Renin Inhibitor Containing 3,4,5-Substituted Piperidine with Sterically Hindered Amide Bonds","A telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the byproduct-controlled amidation protocol using Ghosez’s reagent in the presence of a mild acid scavenger for the formation of the first sterically hindered amide bond; (2) the chemoselective hydrolysis of a sterically hindered ester; (3) an efficient amidation reaction employing a soluble carbodiimide leading to the second sterically hindered amide bond; (4) filtration of the fumarate salt of the final drug substance, being the only necessary isolation step throughout the total synthesis. Without the necessity of isolating any intermediates, this telescoped process conserved equipment usage, consumed less solvents, and minimized process waste generation, energy consumption, personnel exposure, and environmental impact. It furnished kilogram quantities of high-quality active pharmaceutical ingredients.",10.1021/op500116w,1
Synthesis of Fluorinated and Nonfluorinated Tebufenpyrad Analogues for the Study of Anti-angiogenesis MOA,High Resolution Image Download MS PowerPoint Slide In this contribution we report the synthesis of fluorinated and nonfluorinated tebufenpyrad analogues to explore potential druglike properties through the phenotypic screening as part of the Lilly Open Innovation Drug Discovery (OIDD) program.,10.1021/op500114v,1
Continuous Process for Production of CuCF<sub>3</sub> via Direct Cupration of Fluoroform,"The first continuous flow process has been developed for the synthesis of a superior trifluoromethylating reagent, “ligandless” CuCF 3, from fluoroform, by far the best CF 3 source in terms of availability, cost, and atom economy. Optimization of the residence time and feed rates for CHF 3 (gas), the cuprating reagent (premade from CuCl and t -BuOK in a 1:2 ratio) in DMF, and the stabilizer (Et 3 N·3HF) at 23 °C and atmospheric pressure has allowed for the continuous production of CuCF 3 in consistently high yields of up to 94%. The thus produced CuCF 3 has been shown to be as highly efficient a trifluoromethylating agent as the one from the previously developed batch process.",10.1021/op500109v,0
Exploiting the Differential Reactivities of Halogen Atoms: Development of a Scalable Route to IKK2 Inhibitor AZD3264,An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments.,10.1021/op500105n,1
Industrial Process Scale-Up,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewIndustrial Process Scale-UpTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 4, 560Publication Date (Web):April 2, 2014Publication History Published online2 April 2014Published inissue 18 April 2014https://doi.org/10.1021/op5001034Copyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1223Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (109 KB) Get e-AlertsSUBJECTS:Absorption,Amines,Materials processing,Petrochemicals,Polymers Get e-Alerts",10.1021/op5001034,1
A New Synthesis and Process Development of Bis(fluoroalkyl)pyrazoles As Novel Agrophores,"The synthesis of 3,5-bis(fluoroalkyl)-pyrazoles as novel agrophores is described. Commercially available fluoroacetoacetates are treated with BF 3 -activated TFEDMA affording in a straightforward one-pot sequence pyrazole carboxylates in good yields and with excellent regioselectivity. The carboxylate intermediates have been converted into the corresponding pyrazolic acids and submitted to decarboxylation, affording valuable building blocks for the design of novel bioactive ingredients. The found process is suitable for scale up and preparation of compounds in kilogram quantity.",10.1021/op500102h,1
"Multivariate Optimization of a Cyclopropanation, the Key Step in the Synthesis of 3,3,4,4-Tetraethoxybut-1-yne","3,3,4,4-Tetraethoxybut-1-yne (TEB) is a versatile synthon that can be produced in a four-step synthesis. The third step of the synthesis is a cycloproanation, which has been thoroughly investigated and optimized by means of statistical experimental design and multivariate modeling. At the outset, an exhaustively pre-experimental design was performed resulting in a copious Ishikawa cause–effect diagram. In total six of the experimental variables were assessed to be of large importance and thus selected for further investigation by fractional factorial design. The results of that screening and first step optimization formed the basis for a response surface modeling (RSM) study. The RSM investigation was completed by using a central composite design from which a response surface was graphically produced as an iso-contour projection. The derived multivariate predictive model in terms the iso-contour projection plots were ultimately utilized to establish experimental conditions that concomitantly provided excellent yield (>99%) and minimized amounts of inputs and thus obtain the desired product at the lowest production cost and minimized side-streams.",10.1021/op5001012,1
"Process Development and Control with Recent New FBRM, PVM, and IR","Process analytical technologies (PATs) have played an important role in process development and optimization throughout the pharmaceutical industry. Recent new PATs, including in-process video microscopy (PVM), a new generation of focused-beam reflectance measurement (FBRM), miniature process IR spectroscopy, and a flow IR sensor, have been evaluated, demonstrated, and utilized in the process development of many drug substances. First, PVM has filled a technical gap by providing the capability to study morphology for particle engineering by visualizing particles in real time without compromising the integrity of sample. Second, the new FBRM G series has closed gaps associated with the old S series with respect to probe fouling, bearing reliability, data analysis, and software integration. Third, a miniaturized process IR analyzer has brought forth the benefits of increased robustness, enhanced performance, improved usability, and ease of use, especially at scale-up. Finally, a miniaturized flow IR sensor has provided process flow chemistry development with a smaller, faster-performing, less expensive analytical tool.",10.1021/op5000978,0
Facile Production Scale Synthesis of (<i>S</i>)-Taniguchi Lactone: A Precious Building-Block,"A cost-efficient and facile synthesis of ( S )-4-vinyldihydrofuran-2( 3H )-one ( ( S ) -1 ), better known as ( S )-Taniguchi lactone, is described. Racemic Taniguchi lactone rac -1 was ring-opened with ( S )-1-benzylmethylamine providing a diastereomeric mixture of hydroxyl-amides. The desired diastereomer ( S,S ) -2 was isolated by crystallization and subjected to acidic hydrolysis to release enantiopure title compound in good overall yield with an er in excess of 99%. The process was successfully scaled up to kilogram quantities.",10.1021/op500096j,1
Optimization and Scale-up of a Bioreduction Process for Preparation of Ethyl (<i>S</i>)-4-Chloro-3-hydroxybutanoate,"Ethyl 4-chloro-3-oxobutanoate (COBE) was asymmetrically reduced with Escherichia coli cells expressing a reductase (ScCR) from Streptomyces coelicolor to afford enantiopure ethyl ( S )-4-chloro-3-hydroxybutanoate [( S )-CHBE], which is an important precursor for preparing the drug atorvastatin. The substrate load was fixed at 100 g/L, and the concentration of coenzyme NAD + was limited to 0.1 mM based on cost considerations. Under these conditions, the other reaction parameters were optimized as 25 °C and pH 6.5, with a biocatalyst dose of 10 kU/L in the presence of isopropanol (1.5 equiv of COBE), which acted as a cosubstrate for regenerating NADH. The reaction was performed in a toluene–aqueous biphasic system (1:1, v/v), with agitation at the maximal linear rate of 0.88 m/s. Finally, the bioreaction was performed on a pilot scale using a 50 L thermostated stirred-tank-reactor, affording ( S )-CHBE in 85.4% yield and 99.9% ee, and a total turnover number (TTN) of 6060 for the cofactor NAD + . The specific production was calculated to be 36.8 g product /g dcw, which is the highest value reported to date among the whole-cell-mediated processes for producing ( S )-CHBE.",10.1021/op500088w,0
An Integrated Process Analytical Technology (PAT) Approach for Process Dynamics-Related Measurement Error Evaluation and Process Design Space Development of a Pharmaceutical Powder Blending Bed,"In this work, a model pharmaceutical powder blending system consisting of ibuprofen (drug), MCC, and lactose anhydrous was monitored in real-time via inline near-infrared (NIR) spectroscopy for dual purposes: (1) to examine the effects of formulation variables (drug and MCC contents) and a process variable (impeller rotation speed) on powder blending process kinetics via a 3 3 full factorial design, and (2) to examine the measurement errors associated with the real-time NIR monitoring environment. The NIR probe was in direct contact with the powder bed for process monitoring. Selected powder blend samples were collected at certain prespecified time points for UV analysis. Three consecutive spectra were used to calculate the standard deviation (stdev) of NIR absorbance at each wavelength. A moving window average was applied to establish the evolution of stdev over the course of powder blending. Two distinct process segments were found: an initial period during which the stdev rapidly decreases and a following fluctuation period during which both the mean and the stdev vary with the formulation and process parameters. Analysis of the process thermodynamics indicated that the initial period of rapid decrease was due to rapid decrease of the thermodynamic driving force, i.e., the powder component concentration gradient. Analysis of the moving powder bed dynamics suggested that the subsequent period of relative stability punctuated by minor fluctuation corresponds to the powder bed’s microstructure fluctuation, i.e., dynamics in compactness, density, and porosity, due to mechanic rotation of the impeller. The analysis was confirmed by ANOVA results. ANOVA shows that the formulation compositions are primary factors dictating how fast the powder system could achieve the macro-homogeneity (often within 1–2 min); both the impeller rotation speed and the formulation composition are the primary factors dictating both the powder blending homogeneity at microlevel and the measurement error associated with real-time dynamic PAT monitoring environment. General Linear Models (GLM) were used to link the critical formulation and process parameters (CPPs) with the derived response variables and to construct a powder blending process design space. For the model powder blending system, it was shown that selection of appropriate impeller rotation speed range is critical to ensure optimal powder blending performance with practically acceptable dynamic noise. Therefore, this work provided an integrated PAT approach and methodology to address practical powder blending challenges from both process engineering and regulatory science perspectives.",10.1021/op500085m,0
"Identification, Synthesis, and Strategy for the Reduction of Potential Impurities Observed in Dabigatran Etexilate Mesylate Processes","Synthetic impurities that are present in dabigatran etexilate mesylate were studied, and possible pathways by which these impurities are formed during the manufacturing process were examined. The impurities were monitored by high-performance liquid chromatography, and their structures were determined by mass spectrometry and 1 H and 13 C NMR. Potential causes for the formation of these impurities are discussed, and strategies to minimize their formation are also described.",10.1021/op500084q,1
An Improved Process for the Preparation of Highly Pure Solifenacin Succinate via Resolution through Diastereomeric Crystallisation,"An improved process for the preparation of solifenacin succinate ( 1 ) involving resolution through diastereomeric crystallization is described. (1 S )-IQL derivative ( 5 ) is esterified to form (1 S )-ethoxycarbonyl IQL derivative ( 6 ) which is condensed with ( RS )-3-quinuclidinol ( 7 ) to form a solifenacin diastereomeric mixture ( 8 ); this is subjected to resolution through diastereomeric crystallization to produce solifenacin succinate ( 1 ), which is used for the treatment of an overactive bladder.",10.1021/op500083y,1
A Challenging Synthesis of the Highly Functionalized Echinocandin ASP9726: A Successor of Micafungin,"Here, we describe a practical, scalable, and challenging synthesis of the highly functionalized novel echinocandin ASP9726 ( 1 ) starting from the natural product FR901379 ( 3 ), which is a starting material of micafungin ( 2 ). The synthesis includes transformations that address significant synthetic challenges due to the need to control the chemoselectivity of the reactions during modification of the highly functionalized peptide core. In the present study, we discovered an efficient, high-yielding route to ASP9726 ( 1 ) that is suitable for large-scale production. Namely, dehydration of carboxamide ( 14 ) to nitrile ( 15 ) was accomplished by use of EDC·HCl with pyridine. Further, the transformation of nitrile ( 15 ) to primary amine ( 17 ) was conducted via hydrogenation with Sponge Nickel catalyst without decomposition, followed by one-pot debenzylation with Pd/C. Reductive amination between primary amine ( 17 ) with dihydroxyacetone (DHA) was accomplished using 2-picoline/borane complex as a reducing agent in MeOH, yielding 66.6 kg of peptide core unit ( 18 ). After the C 15 H 31 chain cleavage by bioconversion, reductive amination between the core peptide unit ( 4 ) and side chain ( 10 ) was achieved in high yield by making use of tert -butyl amine/borane complex as a reducing agent. Consequently, highly pure ASP9726 ( 1 ) was obtained in a practical manner without using silica gel or ODS column chromatography purification in any step. Overall yield was drastically increased from 0.71% to 13.8% compared to that of the prior synthetic method.",10.1021/op500078y,0
A Green and Facile Approach for Synthesis of Nitro Heteroaromatics in Water,"A convenient and green method for the oxidation of nitrogen-rich heterocyclic amines to nitro-substituted heteroaromatics using potassium peroxymonosulfate (2KHSO 5 ·KHSO 4 ·K 2 SO 4, Oxone) in water was developed. This method has several advantages over previous methods: operational simplicity, safety, inexpensive reagents, the use of H 2 O as the sole solvent, and mild conditions. The utility of the present oxidative system was demonstrated by the synthesis of the important energetic compounds 3,4,5-trinitro-1 H -pyrazole (TNP) and 5-amino-3-nitro-1 H -1,2,4-triazole (ANTA).",10.1021/op5000754,0
"Continuous Flow Synthesis of Thieno[2,3-<i>c</i>]isoquinolin-5(4<i>H</i>)-one Scaffold: A Valuable Source of PARP-1 Inhibitors","An efficient multistep method for the continuous flow synthesis of thieno[2,3- c ]isoquinolin-5(4 H )-one-A (TIQ-A), an important pharmacological tool and building block for PARP-1 inhibitors, has been developed. The synthesis involves a Suzuki coupling reaction to generate 3-phenylthiophene-2-carboxylic acid which is transformed into the corresponding acyl azide and readily cyclized by a thermal Curtius rearrangement. A statistical design of experiments (DoE) was employed as a valuable support for decision-making of further experiments enabling the development of a robust and reliable protocol for large-scale preparation. As a result, the reactions are facile, safe, and easy to scale-up. The large-scale applicability of this improved flow method was tested by conducting the reactions on multigram scale to produce the desired product in high yield and quality for biopharmacological appraisals.",10.1021/op500074h,1
Multikilogram-Scale Production of Cycloartenol Triterpenoid Glycosides as Synthetic Intermediates for a γ-Secretase Modulator,The process development and production of two cycloartenol triterpenoid glycosides on a multikilogram scale are described. The two compounds were used as key intermediates for the synthesis of a γ-secretase modulator and a novel potential therapeutic agent for Alzheimer’s disease (SPI-1865). This practical and efficient process includes extraction of precursor triterpenoid glycosides from Actaea racemosa (black cohosh) and a ZrCl 4 -catalyzed rearrangement reaction.,10.1021/op5000732,0
Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator,This work describes the demonstration of a kilogram-scale synthesis of a γ-secretase modulator from a plant-sterol-derived starting material. Key to developing a synthetic route capable of delivering a kilogram of the target compound was the development of a four-reaction telescope process and a selective O-alkylation of a triol intermediate. These improvements enabled the successful delivery of kilogram-scale batches of API for preclinical development studies.,10.1021/op500072b,1
"Amidation and N-Boc Deprotection Process Improvement for the Preparation of 5-(1-Piperazinyl)benzofuran-2-carboxamide, a Key Intermediate of Vilazodone","An improved process for the preparation of 5-(1-piperazinyl)benzofuran-2-carboxamide, a key intermediate used in the synthesis of antidepressant drug vilazodone is reported.",10.1021/op500070t,1
Development of Efficient Processes for the Preparation of Di-<i>tert</i>-butyl Potassium Phosphate and Di-<i>tert</i>-butyl (Chloromethyl) Phosphate,"A new and efficient process to prepare di- tert -butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di- tert -butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficiency, an improved synthesis of DTBPP was required. The two-step process to DTBPP starts from PCl 3 and leverages a H 2 O 2 /catalytic KI mediated oxidation of di- tert- butyl phosphite to provide DTBPP in 81% yield and high purity. In the development of the new process to di- tert -butyl (chloromethyl) phosphate, a comparison to the corresponding tosylate derivative was made. A rational selection of base, phase-transfer catalyst (PTC), and stabilizing additive minimized CMCS decomposition and led to an optimized yield (90% solution yield), improved product purity, and identification of a technique to enable the long-term storage of di- tert -butyl (chloromethyl) phosphate.",10.1021/op500066f,1
Synthesis and Process Optimization of Boceprevir: A Protease Inhibitor Drug,"Efforts toward the synthesis and process optimization of boceprevir 1 are described. Boceprevir synthesis was optimized by telescoping the first three steps and last two steps of the five-step process. Optimization of oxidation, which is one of the critical steps in the total synthesis, is discussed. A control strategy for the three impurities is described. A novel process for the synthesis of fragment A ( 2 ) has been developed, which is the key starting material for the synthesis of boceprevir.",10.1021/op500065t,1
Scale-up of Microwave Assisted Flow Synthesis by Transient Processing through Monomode Cavities in Series,"A new scale-up concept for microwave assisted flow processing is presented where modular scale-up is achieved by implementing microwave cavities in series. The scale-up concept is demonstrated for case studies of a packed-bed reactor and a wall-coated tubular reactor. With known kinetics and reaction temperature, a packed-bed reactor gave a conversion of 99% with the highest production rate of 170 kg prod /kg cat ·h for esterification of acetic acid and ethanol catalyzed by ion-exchange resin in 18 cavities. A similar approach for a multicomponent reaction of benzaldehyde, piperidine, and phenylacetylene catalyzed by a thin Cu film in a wall-coated tubular reactor gave 99% conversion with the highest production rate of 7740 kg prod /kg cat ·h in 28 cavities. In both cases, the pseudo first order reaction rate with respect to the limiting reactant yielded a typical rise in conversion and production rate. In a packed-bed reactor-heat exchanger operated at a temperature between 343 and 348 K, the conversion in the esterification reaction increased from 22% to 88% when the number of cavities was increased from one to eight. The experimental conversions matched the predictions of a packed bed reactor model within 5%. The production capacity in flow reactors, restricted to smaller sizes due to a limited microwave penetration depth and dominated mainly by the reaction kinetics, was increased by modular scale-up with implementation of the microwave multicavity assembly.",10.1021/op500064k,0
"Development of a Safe, Scalable Process for the Preparation of an Oxaisoxazolidinone","This report describes the development and scale up of the synthesis of oxaisoxazolidinone 1, a significant synthon in the synthesis of the MRSA development compound AZD5847. Studies were carried out to ensure a short-term, risk based preparation of 9 on a 5 L scale with a solid isolation procedure and a safe, long-term manufacturing process for both 1 and 9 through extensive hazards evaluation.",10.1021/op500063g,1
Process Chemistry Awards,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTProcess Chemistry AwardsWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross Mayfield, East Sussex TN20 6EW, United KingdomE-mail: [email protected]Cite this: Org. Process Res. Dev. 2014, 18, 3, 359Publication Date (Web):February 26, 2014Publication History Published online26 February 2014Published inissue 21 March 2014https://pubs.acs.org/doi/10.1021/op500058ghttps://doi.org/10.1021/op500058geditorialACS PublicationsCopyright © 2014 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1487Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (109 KB) Get e-AlertscloseSUBJECTS:Amides,Biocatalysis,Hydrogen,Process chemistry Get e-Alerts",10.1021/op500058g,0
An Integrated Process Analytical Technology (PAT) Approach for Pharmaceutical Crystallization Process Understanding to Ensure Product Quality and Safety: FDA Scientist’s Perspective,"In this review, a brief overview of the current regulatory science framework pertinent to pharmaceutical crystallization and process characterization is made first. The FDA’s scientific research on pharmaceutical crystallization process understanding and product characterization is then illustrated via several aspects: (1) Combined real-time PAT monitoring and process chemometrics for mapping the state of a pharmaceutical crystallization process; (2) Combined real-time PAT process monitoring and first-principle modeling for elucidating the nucleation mechanisms of a dynamic pharmaceutical crystallization process; (3) Combined real-time PAT process monitoring, Design of Experiments (DOE), and General Linear Modeling (GLM) to establish a hybrid approach for process characterization and process design space development; and (4) Integrated PAT approach for nucleation induction time measurement. Finally, some of the current challenges and future outlook on pharmaceutical crystallization process and product characterization across the pipeline, from drug substance to drug product development, manufacturing, and process scale-up to ensure product quality and safety, and ultimately to protect and promote public health is discussed from both a regulatory science and process engineering point of view.",10.1021/op500056a,0
Commercial Synthesis of Cefprozil: Development and Control of Process Impurity,"A process impurity, ethoxycarbonylcefprozil ( 9 ), formed in the synthesis of cefprozil ( 1 ) was controlled with addition of a catalytic amount of methanesulfonic acid.",10.1021/op5000545,1
Enantioselective Synthesis of a Highly Substituted Tetrahydrofluorene Derivative as a Potent and Selective Estrogen Receptor Beta Agonist,"The development and execution of a practical asymmetric synthesis of the estrogen receptor beta selective agonist (8 R,10a S )-6-(trifluoromethyl)-8,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5- d ][1,2,3]triazol-7(3 H )-one is described. The optimized route features a key chiral auxiliary-mediated dialkylation approach to set the all-carbon quaternary center with exceptional stereocontrol. Overall, the chemistry has been used to prepare >30 kg of drug candidate in 21% overall yield through 13 longest linear steps and with >99% ee.",10.1021/op5000489,1
Improved Procedure for Preparation of Abiraterone Acetate,"An improved procedure for the preparation of abiraterone acetate is described. The present process highlights reduced reaction time, isolation with acid–base treatment without involving column chromatography, multiple crystallization and is amenable to large-scale synthesis.",10.1021/op500044p,1
Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B Polymerase: Phenylboronate as a Transient Protecting Group,"A synthetic process for 2′- C -methylcytidine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl- N -benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase, is described. The route developed was demonstrated on 100 g scale and featured the key application of phenylboronic acid as an effective transient means to protect the 2′,3′-hydroxyls of 2′- C -methylcytidine. This synthetic methodology resulted in a reduction in the number of isolations from five to two and an increase in the overall yield by 50% relative to the original unscalable discovery route. The synthesis and characterization of 2′- C -methylcytidine-2′,3′- O -phenylboronate is also provided.",10.1021/op500042u,1
Stereoselective Lithiation and Carboxylation of Boc-Protected Bicyclopyrrolidine: Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir,"A stereoselective process for the manufacture of bicyclopyrrolidine 7 to 2 has been developed. The process utilizes a stereoselective lithiation/carboxylation sequence. The achiral diamine ligand DPBP induces excellent diastereocontrol, and resolution with ( S )-THNA provides the corresponding salt of 8 in high er and dr. Subsequent processing of 8 gives 2 as the oxalate salt in an overall yield of 27% from 7 (based on total molar charge of 7 ). Compound 2 was obtained with high chemical and chiral purities. The process was successfully demonstrated on >100 kg scale.",10.1021/op500040j,0
A Scalable One-Pot Process for the Synthesis of Florfenicol Phosphodiester,"A practical and scalable one-pot process for the preparation of florfenicol phosphodiester ( 3 ), a new water-soluble prodrug of florfenicol ( 1 ), has been developed by adopting the phosphorylating system of POCl 3 /pyridine/CH 3 CN. The yield of 3 was 80.72%, and its HPLC purity reached as high as 99.20%, while the content of the maximum impurity was reduced to 0.28% under the optimum conditions. The present process has proven to be reliable on 500-g and 4-kg scale in the pilot plant.",10.1021/op500038s,1
Unnecessary Development of Highly Sensitive Assays for Potentially Mutagenic Impurities (PMIs),"ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTUnnecessary Development of Highly Sensitive Assays for Potentially Mutagenic Impurities (PMIs)David J. SnodinView Author Information Xiphora Biopharma Consulting, United Kingdom[email protected]Cite this: Org. Process Res. Dev. 2014, 18, 3, 360–361Publication Date (Web):February 13, 2014Publication History Published online13 February 2014Published inissue 21 March 2014https://pubs.acs.org/doi/10.1021/op5000368https://doi.org/10.1021/op5000368letterACS PublicationsCopyright © 2014 American Chemical SocietyRequest reuse permissionsArticle Views1457Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Aldehydes,Anions,Assays,Impurities,Solvents Get e-Alerts",10.1021/op5000368,0
Real-Time Process Analytical Technology Assurance for Flow Synthesis of Oligonucleotides,"A feasibility study has been conducted using Process Analytical Technology (PAT) monitoring and chemometric modeling techniques to mitigate risks identified for the solid-phase synthesis of a model oligonucleotide compound in a flow reactor manifold. This paper will discuss three of the key risks identified for this automated process that are generally applicable to oligonucleotide manufacturing: (1) connection of an incorrect chemical solution to a designated input port of the synthesizer; (2) incorrect quantitative preparation of a chemical solution; and (3) errors that may come from mechanical or other unknown sources associated with the synthesizer. Mid-infrared and Raman spectroscopy were the key PAT techniques used to monitor the automated synthetic process in real time. Classification, quantitative (partial least-squares), and multivariate statistical process control (MSPC) modeling were then used to analyze the acquired data and detect the occurrence of the aforementioned failure modes. MSPC models were constructed and tested with intentionally induced key process deviations to explore their sensitivity and detection capability. Suggestions are proposed for more stringent validated processes that would be required to implement these techniques in a manufacturing environment.",10.1021/op500035j,0
A Single-Pot Synthesis of Atovaquone: An Antiparasitic Drug of Choice,"The present article relates to a practical, economically viable, and validated at industrial scale, single-pot synthetic route for preparation of atovaquone, one of the most versatile antiparasitic drugs of choice used for the prophylaxis and treatment of diseases such as pneumocystis, toxoplasmosis, babesiosis, coccidiosis, and malaria. However, owing to the extremely poor yields of synthesis and very high doses of treatment (due to poor bioavailability) the cost of treatment with this drug is not affordable by the patients in need, particularly in the third world countries where these diseases are most prevalent. Unlike most of the reported processes which use 2-chloronaphthoquinone and pure trans -4-chlorophenyl cyclohexane carboxylic acid, our process is based on the decarboxylative alkylation of isomeric mixture of 4-chlorophenyl cyclohexane carboxylic acid with 1,4-naphthoquinone to give 42% overall yield of atovaquone, 10 times higher than from the reported process (4%) from the innovators of this drug.",10.1021/op500032w,1
Development of a Robust Process for the Preparation of High-Quality Dicyclopropylamine Hydrochloride,"A short and efficient process for the preparation of high-quality dicyclopropylamine HCl salt is described. An oxygen-mediated Chan–Lam coupling of N -cyclopropyl 4-nitrobenzenesulfonamide with cyclopropylboronic acid was followed by an optimized p -nosyl deprotection with 1-decanethiol, providing the title compound in high chemical yield. This process addresses many of the challenges and liabilities inherent in previous synthetic approaches to this challenging molecule. The collection of key safety data enabled implementation of an oxygen-mediated process on-scale and ensured safe operation throughout development, optimization, and processing.",10.1021/op500031z,1
Exploratory Process Development and Kilogram-Scale Synthesis of a Novel Oxazolidinone Antibacterial Candidate,"A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1 H -pyrazol-4-yl)pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21 . The mixture was prepared from a nucleophilic SNAr reaction by selective C–N coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1 H -pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid–liquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.",10.1021/op500030v,1
Development of a Hydrogenative Reductive Amination for the Synthesis of Evacetrapib: Unexpected Benefits of Water,"For the synthesis of cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, a hydrogenative reductive amination was chosen to join the substituted cyclohexyl subunit to the benzazepine core. The addition of water, which suppressed undesired epimerization without affecting the rate of product formation, was key to the reaction’s success. The process was scaled to produce more than 1100 kg of material.",10.1021/op500025v,1
Development of a Biocatalytic Process to Prepare (<i>S</i>)-<i>N</i>-Boc-3-hydroxypiperidine,"( S )- N -Boc-3-hydroxypiperidine ( S -NBHP) is a useful synthon for the synthesis of pharmaceutical intermediates including ibrutinib, the API of the newly approved drug Imbruvica, for the treatment of lymphoma. To our knowledge, there are no published biotransformation methods scalable to prepare S -NBHP. We report here the development of an efficient process catalyzed by recombinant ketoreductase (KRED) to reduce N -Boc-piperidin-3-one to obtain optically pure S -NBHP. The process has been optimized and demonstrated to have commercial potential with 100 g/L of substrate concentration, product of >99% ee with under 5% of enzyme loading (w/w).",10.1021/op500022y,0
"Synthesis of 2,6,8,12-Tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane (TAIW) from 2,6,8,12-Tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADBIW) by Catalytic Hydrogenolysis Using a Continuous Flow Process","Synthesis of 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane (TAIW) by catalytic hydrogenolysis of 2,6,8,12-tetraacetyl-4,10-dibenzyl-2,4,6,8,10,12-hexaazaisowurtzitane (TADBIW), a key step for the synthesis of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW), has been first implemented under continuous flow conditions using the commercially available H-Cube Pro reactor. Several variables (i.e., reaction temperature, flow rate, and pressure) and the stability of the system have been investigated to optimize the operating conditions. The results show that a continuous flow system provides a better yield than a batch system. For instance, the yield is 99% at the optimized conditions, while the best yield from batch reactions is 92%. Continuous flow synthesis of TAIW has potential applications in improving the production technologies of HNIW for its many advantages over batch reactions.",10.1021/op500020d,0
Model Driven Process Design and Development for a Continuous Process,"This paper presents a case study where kinetic models were used to drive process development of an amination reaction in a continuous process. The kinetic model was first used to optimize the process by minimizing impurity formation. Then, the kinetic parameters were put into a two-in-series CSTR (continuous stirred tank reactor) model and a separate PFR (plug flow reactor) model to guide reactor selection and optimize the reactor design. Once the model predictions were validated with experimental data, the simulated impurity profile from each reactor type was compared. While the results showed that both reactors delivered similar impurity profiles at steady state, the model was used to conduct perturbation analysis on the two reactors to assess the impurity and operational control strategy. The simulations showed that the CSTR can tolerate a process upset time up to 10% of its residence time with materials meeting product specification as compared to the PFR. Since the CSTR offers additional buffering capacity during process upsets due to the dilution effect inside the reactors, the project team selected the CSTR as the final reactor choice. This case study shows that a kinetic model can positively impact development of a continuous process even at an early development phase, which is consistent with quality by design (QbD) principles.1 Most importantly, the model can simulate various perturbation scenarios to provide understanding of the process dynamics and provide guidance in determining the process operational boundaries with computer simulations. This resulted in substantial savings in cost of material, development time, and resources. To our knowledge, this is the first example of utilizing a model for continuous reactor selection in the pharmaceutical industry where the reactor choice was based on its ability to tolerate process upsets rather than the impurity profile obtained.",10.1021/op500016n,0
Improved Operation of Concentration Control for Antisolvent Crystallization Processes,"Concentration control (C-control) strategy for semibatch antisolvent crystallization processes has been recently developed with the aid of new sensors that measure in situ process variables. This control strategy gives better robustness over the traditional flow control in the presence of process variations. However, the existing C-control is implemented through trial-and-error procedure and hence gives suboptimal product quality in most cases. This motivates the current study to develop an integrated modeling framework to enhance control performance of C-control strategy using semibatch antisolvent crystallization process as a case study. Simulation results show that the performance of C-control strategy by incorporating the proposed modeling framework is superior to that obtained by the existing C-control strategy.",10.1021/op5000144,0
Synthesis of an ORL-1 Receptor Antagonist via a Radical Bromination and Deoxyfluorination to Afford a <i>gem</i>-Difluorospirocycle,The development of a synthesis of an ORL-1 receptor antagonist is described. The key process improvements in the synthetic sequence include a multikilogram bromination process and the development of a convergent coupling strategy. The process improvements resulted in the production of the active pharmaceutical ingredient (API) on a multikilogram scale.,10.1021/op5000094,1
Large-Scale Crystallization of a Pure Metastable Polymorph by Reaction Coupling,A maximum of more than 40 g of acetaminophen Form II crystals with a yield of 65 mol % is made reproducibly in a 500 mL reactor by coupling the acetylation of p -aminophenol with the neutralization of acetic acid before the crystallization of acetaminophen Form II crystals. This novel working principle involves a sudden drop of the solubility of acetaminophen from the acetic acid–water environment to the acetate–water system in addition to temperature cooling but without agitation. This particular processing pathway is capable of maintaining a large supersaturation for quite some time for the system to enter the metastable zone of Form II with respect to the acetate–water system. The large amount of Form II crystals so produced are then isolated by filtration and oven drying to prevent Form II crystals in the mother liquor from transforming to the thermodynamically stable Form I crystals by the Ostwald’s rule of stages.,10.1021/op500003k,0
The Use of PAT and Off-line Methods for Monitoring of Roller Compacted Ribbon and Granule Properties with a View to Continuous Processing,"Real-time process monitoring using process analytical technology (PAT) tools can augment process understanding, enable improved process control, and hence facilitate the production of high-quality pharmaceutical products. While beneficial for batch processes, the availability of PAT tools to monitor continuous processes in real time is required to ensure product quality. This paper presents the application of novel process analytical technology (PAT) tools in combination with off-line analytical techniques for the study of a laboratory-scale roller compaction dry granulation process. An experiment whereby roll pressure was linearly increased and the effects thereof on roller compacted ribbon and granule properties of a placebo formulation is described. Analysis of the ribbons and granules was performed using both in-line and off-line techniques. Ribbon envelope density was measured using the GeoPyc, and the results were compared to off-line near-infrared (NIR) measurements and a novel in-line NIR tool, the Multieye. Particle size analysis of roller compacted granules was assessed with traditional sieve analysis, Camsizer and a novel technique, the Eyecon. Both Camsizer and Eyecon have the potential of being used as PAT tools in-line. Additionally the compressibility of the granules was determined using in-die Heckle analysis and the hardness of the resultant compacts was assessed. The compacts were subsequently analysed using off-line Raman spectroscopy to investigate the surface smoothness which was shown to indicate crushing strength for compacts prepared. The results of this initial study demonstrate a good relationship between in-line and off-line measurement of key in-process material attributes. The findings thus support the further exploitation of these new in-line PAT methods in monitoring of continuous unit operations at a commercial scale.",10.1021/op5000013,0
Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewTransition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical IndustryWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomE-mail: [email protected]Cite this: Org. Process Res. Dev. 2014, 18, 1, 277Publication Date (Web):January 6, 2014Publication History Published online6 January 2014Published inissue 17 January 2014https://pubs.acs.org/doi/10.1021/op400369yhttps://doi.org/10.1021/op400369ybook-reviewACS PublicationsCopyright © 2014 American Chemical SocietyRequest reuse permissionsArticle Views1774Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Coupling reactions,Cross coupling reaction,Pharmaceuticals,Pharmaceutics,Process chemistry Get e-Alerts",10.1021/op400369y,0
"A Practical and Economical High-Yielding, Six-Step Sequence Synthesis of a Flavone: Application to the Multigram-Scale Synthesis of Ladanein","Herein we report a short and economic synthesis of the antiviral flavonoid lead ladanein ( 1 ). Ladanein is obtained from 2,6-dimethoxyquinone ( 11 ) in six steps with 51% overall yield. After a high-yielding reductive acetylation and Fries rearrangement, the flavone skeleton is built by means of a Baker–Venkataraman rearrangement. Throughout the synthetic pathway no chromatographic columns were used, and the reaction products were isolated and purified by optimized work-up and crystallization processes. This new process has been tested on a multigram-scale with an improved overall yield from 16 to 51% through six steps, and three chromatographic purifications used in the earlier synthesis were eliminated.",10.1021/op4003642,1
Single-Frequency Ultrasonic Crystallization Monitoring (UCM): Innovative Technique for In-Line Analyzing of Industrial Crystallization Processes,"The development, principles, and application of the single-frequency, ultrasonic crystallization monitoring (UCM) technique is discussed. It is shown that the three most important process parameters to control industrial crystallization processes (mean crystal size, suspension density, and liquid concentration) can be monitored simultaneously in-line by means of only one measuring technique holding two sensors. A proof of concept is presented that clearly shows the feasibility and applicability of the UCM method. In demarcation to alternative PAT in the field of industrial crystallization, advantages, potentials, and limits are outlined and discussed with particular reference to the applicability of the technology and the material systems together with the transferability to other substances as well as the scale-up ability of the underlying mathematical model. Additionally, the reliability of the UCM technique is validated by comparing the results with established and commercially available PAT for the solid phase.",10.1021/op400362f,0
Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development,"High Resolution Image Download MS PowerPoint Slide The IQ Consortium reports on the current state of process analytical technology (PAT) for active pharmaceutical ingredient (API) development in branded pharmaceutical companies. The article uses an API process workflow (process steps from raw material identification through to finished API) to provide representative examples, including why and how the pharmaceutical industry uses PAT tools in API development. The use of PAT can improve R&D efficiency and minimize personnel hazards associated with sampling hazardous materials for in-process testing. Although not all steps or chemical processes are readily amenable to the use of the PAT toolbox, when appropriate, PAT enables reliable and rapid (real or near time) analyses of processes that may contain materials that are highly hazardous, transient, or heterogeneous. These measurements can provide significant data for developing process chemistry understanding, and they may include the detection of previously unknown reaction intermediates, mechanisms, or relationships between process variables. As the process becomes defined and understanding is gained through these measurements, the number of parameters suspected to be critical is reduced. As the process approaches the commercial manufacturing stage and the process design space is established, a simplification of the monitoring and control technology, as much as is practical, is desired. In many cases, this results in controls being either off-line, or if in situ control is required, the results from PAT are correlated with simple manufacturing measurements such as temperature and pressure.",10.1021/op400358b,0
A Novel Process for Antimalarial Drug Pyronaridine Tetraphosphate,"A novel process for preparation of pyronaridine tetraphosphate, an antimalarial drug substance, is reported. The overall yields are 54% and >99.8% (including five chemical steps). Formation and control of possible impurities are also described.",10.1021/op400357f,1
Scalable Synthesis of a Nonracemic α-Arylpropionic Acid via Ketene Desymmetrization for a Glucokinase Activator,"Process research and development for a synthesis of the chiral carboxylic acid ( R )-2 as a key intermediate of the glucokinase activator ( R )-1 is described. The construction of the stereocenter at the α-carbon is a key point for the synthesis of ( R )-2 . The proposed process utilizes desymmetrization of a ketene in situ generated from the corresponding racemic carboxylic acid Rac -2 with ( R )-pantolactone as a chiral auxiliary followed by hydrolysis of the resulting ester. This key step has been successfully scaled up to 20 kg, which demonstrates that this synthetic approach is comparable with a previously reported approach via enantioselective hydrogenation.",10.1021/op400354g,1
An Improved Synthesis of Nomegestrol Acetate,"Oral contraceptives (OCs) are synthetic steroids, or progestins, which are structurally related to testosterone or to progesterone. Many progestins have been synthesized and approved for OCs, hormonal replacement therapy (HRT), or the treatment of some gynecological disorders. Nomegestrol acetate (NOMAc) is a newly approved OC and has gained rapid acceptance in many countries for OC or HRT. The synthesis of NOMAc remains challenging and costly. We have developed a novel and improved procedure for the synthesis of NOMAc with a total of 11 steps and an overall good yield without the use of hazardous reagents.",10.1021/op4003533,1
Combining Metabolic Pathway Design and Retrosynthetic Planning for the Design of a Novel Semisynthetic Manufacturing Scheme for Paclitaxel,"Using the example of paclitaxel, this paper expounds how retrosynthetic analysis can be combined with metabolic pathway design to devise novel semisynthetic schemes for manufacturing natural products. The analytical framework presented herein leverages the latest developments in chem- and bioinformatics, metabolic engineering, and retrosynthetic planning, and the proposed schemes commence with the microbially aided synthesis of an advanced intermediate that is then recruited for target-oriented synthesis (TOS). A technoeconomic analysis of the scheme devised using bioretrosynthetic analysis for manufacturing paclitaxel suggests that the new process competes favorably with the current route for producing paclitaxel. Additionally, since TOS can access precise regions of chemical space, either a single molecule or a small assortment of molecules exhibiting minor variations on a chemical theme, bioretrosynthesis also doubles as a tool for drug discovery.",10.1021/op4003505,1
"Development of a Practical, Biocatalytic Reduction for the Manufacture of (<i>S</i>)-Licarbazepine Using an Evolved Ketoreductase","This contribution describes the development of a ketoreductase enzyme over four rounds of directed evolution and the associated process development that enabled a practical, scalable process to ( S )-licarbazepine (eslicarbazepine).",10.1021/op4003483,0
"A Scalable Route to an Unusual 3,3-Dimethyl-2,3-dihydrobenzofuran Ring System Present in an HCV Drug Candidate","A scalable synthesis of a key intermediate used for the preparation of an HCV inhibitor containing an unusual dimethyldihydrobenzofuran ring is described. A key element for the successful completion of the synthesis was the correct ordering of a sequence of bromination, chlorination, and methylation to provide optimized selectivity and improved yield. A tin hydride-mediated ring closure was replaced with a more environmentally benign sulfuric acid-catalyzed Friedel–Crafts reaction. The overall yield for the preparation of the key intermediate was increased from less than 5 to 40%.",10.1021/op4003467,1
Process Intensification of the Suzuki–Miyaura Reaction over Sol–Gel Entrapped Catalyst Silia<i>Cat</i> DPP-Pd Under Conditions of Continuous Flow,"We report the newly developed conditions for the process intensification of the Suzuki–Miyaura reaction under flow over sol–gel entrapped Silia Cat DPP-Pd catalyst with the aim of practical applications. Considerably more concentrated solutions (0.5–1.0 M) are applied, and flow rate is increased up to the practically relevant 1.0 mL/min threshold. Results indicate complete coupling conversion of several different aryl halides and provide important information of general validity of vital importance for successful process intensification.",10.1021/op4003449,0
Processing of <i>o</i>-Halobenzoates by Toluene Dioxygenase. The Role of the Alkoxy Functionality in the Regioselectivity of the Enzymatic Dihydroxylation Reaction,"In order to investigate the relationship between the size of a substituent on the aromatic substrate and its directing effect on the dihydroxylation, a series of 2-halobenzoates was synthesized and subjected to metabolism by toluene dioxygenase in preparative-scale fermentation cultures of Escherichia coli JM109 (pDTG601A). Larger ester substituents were shown to have a greater directing effect on the dihydroxylation reaction. Furthermore, significant increases in regioselectivity were observed using propargyl substituents, relative to the use of any other ester substituent. The selectivity and the product ratios are reported for o -fluoro-, o -chloro-, o -bromo-, and o -iodobenzoate esters (methyl, ethyl, n -propyl, allyl, and propargyl). Experimental and spectral data, as well as absolute stereochemistry, are provided for all new compounds.",10.1021/op400343c,0
"Process Intensification: Engineering for Efficiency, Sustainability and Flexibility","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Intensification: Engineering for Efficiency, Sustainability and FlexibilityTrevor LairdCite this: Org. Process Res. Dev. 2014, 18, 1, 276Publication Date (Web):December 13, 2013Publication History Published online13 December 2013Published inissue 17 January 2014https://doi.org/10.1021/op400341eCopyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views929Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (115 KB) Get e-AlertsSUBJECTS:Chemical reactions,Industrial manufacturing,Organic compounds,Petrochemicals,Pharmaceutics Get e-Alerts",10.1021/op400341e,0
Development and Scale-Up of Cocrystals Using Resonant Acoustic Mixing,"In the present work resonance acoustic mixing was applied to afford a practical and environmentally friendly approach to produce and scale up cocrystals. Scale-up options for producing cocrystals are limited. Solution-phase cocrystallizations, although amenable to scale-up in stirred tanks, may be limited due to multiple solubility constraints on both coformers and the product cocrystals, resulting in challenges to find feasible processing conditions. While mechanochemical methods such as liquid-assisted grinding (LAG), solid drop grinding (SDG), and ball-milling have been shown to be more general than solution-phase methods, they are also more difficult and impractical to scale up. In the present work a resonant acoustic mixer was used to intimately mix active pharmaceutical ingredient (API) compound and coformer at high frequency, in the presence of a small amount of solvent, to induce conversion to cocrystals with no grinding media required. Carbamazepine (CBZ) and nicotinamide (NCT) were used as a model system for successfully producing CBZ:NCT cocrystals. Thus, it was shown that resonant acoustic mixing provides the mixing intensity required of lab-scale mechanochemical methods, such as liquid -assisted grinding, but now on a platform more amenable to larger-scale manufacture. Resonant acoustic mixing in general has been demonstrated to be scalable to volumes greater than 200 L and thus affords a potential new platform for cocrystallization processes.",10.1021/op4003399,0
Multiscale Multiblock Batch Monitoring: Sensor and Process Drift and Degradation,"A multiblock multiscale multiway principal component analysis (MSPCA) modeling approach is presented for multivariate statistical process performance monitoring of batch processes. Process measurements, representing the cumulative effect of many underlying process phenomena, are decomposed into scales using wavelet transformations. The decomposed process measurements are then arranged into blocks of scales and approximations. MSPCA is then used to build a model that can be used for fault detection and identification of incipient sensor and process malfunctions. The proposed method was evaluated on a benchmark fed-batch penicillin fermentation process for the detection and diagnosis of subtle sensor and process faults, and the results were compared with those obtained using conventional multiway PCA (MPCA). This study contributes to the discussions of the advantages and benefits from using multiscale-based multivariate statistical process monitoring schemes over conventional multivariate statistical process control approaches.",10.1021/op400337x,0
Improved and Efficient Process for the Production of Highly Pure Iloperidone: A Psychotropic Agent,"The present work describes an improved and highly efficient process for the synthesis of iloperidone ( 1 ), an antipsychotic agent, which is free from potential impurities. The synthesis comprises N -alkylation of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone ( 4 ) with 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride ( 5 ) in a mixture of water and heptane as solvent and sodium hydroxide as a base in the presence of tetrabutylammonium bromide as a phase transfer catalyst to yield iloperidone ( 1 ) with a yield of around 95% and a purity of 99.80% by HPLC. The present work also describes the optimization details performed to achieve the process attributes responsible for high yield and purity.",10.1021/op400335p,1
Practical Synthesis of A Macrocyclic HCV Protease Inhibitor: A High-Yielding Macrolactam Formation,"A practical synthesis of a macrocyclic HCV protease inhibitor, MK-1220, is described. The key features are a new synthesis of the trisubstituted isoquinoline, Sonogashira fragment coupling, and a high-yielding, 18-membered macrolactam formation.",10.1021/op400331j,1
"Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-dione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1","The development of a reproducible process for multihundred gram production of ( Z )-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1 H -indazol-5-yl)methylene)-3-((3 R,4 R )-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione ( 26 ), a potent and selective inhibitor of estrogen-related receptor 1 (ERR1), is described. This multihundred gram synthesis was achieved via magnesium perchlorate-catalyzed regioselective epoxide ring-opening of tert -butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate ( 9 ) with thiazolidine-2,4-dione ( 6, TZD) to form a diastereomeric mixture tert -butyl 4-(2,4-dioxothiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate ( 17 ), of which the 3-hydroxyl group was functionally transformed to 3-fluoro derivative 19 after treatment with Deoxo-Fluor. Chiral separation of 19 provided the desired diastereomer (3 R,4 R )- 21 that was converted to the secondary amine 23 TFA salt. Reductive amination of 23 produced the key intermediate N -methyl 24 . Knoevenagel condensation of 24 with 1-(4-chloro-2-(trifluoromethyl)benzyl)-1 H -indazole-5-carbaldehyde ( 5 ) produced the final product 26 in 10% overall yield (99.7% HPLC area% with ≥99.5% de) after a convergent eight synthetic steps with the only column purification being the chiral HPLC separation of 3 R,4 R - 21 from 3 S,4 S - 22 .",10.1021/op400325r,1
Route Design and Development of a MET Kinase Inhibitor: A Copper-Catalyzed Preparation of an <i>N</i>1<i>-</i>Methylindazole,"The synthesis of a MET kinase inhibitor in an overall yield of 22% was achieved over eight steps starting with 3-hydroxybenzaldehyde, an improvement from the initial 12-step process with a 5.4% yield. Highlights of the process chemistry design and development are a Cu-catalyzed cyclization to form an important N 1-methylindazole ring, a selective nitro reduction in the presence of an aryl bromide, a late-stage Suzuki cross-coupling, and a base-promoted Boc deprotection to form the desired drug candidate.",10.1021/op400317z,1
Special Feature Section on Safety of Chemical Processes,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSpecial Feature Section on Safety of Chemical ProcessesTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 12, 1572Publication Date (Web):November 19, 2013Publication History Published online19 November 2013Published inissue 20 December 2013https://pubs.acs.org/doi/10.1021/op400316vhttps://doi.org/10.1021/op400316veditorialACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views984Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (112 KB) Get e-AlertscloseSUBJECTS:Physical and chemical processes,Safety Get e-Alerts",10.1021/op400316v,0
"An Efficient, Scalable Process for Benzphetamine Hydrochloride","Commercial manufacturing of benzphetamine hydrochloride along with its impurity profiling is disclosed. Deoxygenation of pseudoephedrine is reported with ∼100% retention by shielding the amine group as its tert -butyl carbamate, which is very straightforward to eliminate at the end. Four unknown process-related impurities are isolated from the samples of final API and characterized on the basis of their NMR and mass spectral analysis. Structures of the isolated impurities are confirmed by independent syntheses and coinjecting with the isolated one.",10.1021/op400313y,1
"Influence of Cofactor Regeneration Strategies on Preparative-Scale, Asymmetric Carbonyl Reductions by Engineered <i>Escherichia coli</i>","High Resolution Image Download MS PowerPoint Slide This study was designed to determine whether whole cells or crude enzyme extracts are more effective for preparative-scale ketone reductions by dehydrogenases as well as learning which cofactor regeneration scheme is most effective. Based on results from three representative ketone substrates (an α-fluoro-β-keto ester, a bis -trifluoromethylated acetophenone, and a symmetrical β-diketone), our results demonstrate that several nicotinamide cofactor regeneration strategies can be applied to preparative-scale dehydrogenase-catalyzed reactions successfully.",10.1021/op400312n,0
Sad Times for Process Chemistry,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSad Times for Process ChemistryTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 12, 1463Publication Date (Web):November 15, 2013Publication History Published online15 November 2013Published inissue 20 December 2013https://pubs.acs.org/doi/10.1021/op400311dhttps://doi.org/10.1021/op400311deditorialACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2974Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (114 KB) Get e-AlertscloseSUBJECTS:Process chemistry Get e-Alerts",10.1021/op400311d,0
Transaminases Applied to the Synthesis of High Added-Value Enantiopure Amines,"Critical parameters affecting the stereoselective amination of (hetero)aromatic ketones using transaminases have been studied, such as temperature, pH, substrate concentration, cosolvent, and source and percentage of amino donor, to further optimize the production of enantiopure amines using both ( S )- and ( R )-selective biocatalysts from commercial suppliers. Interesting enantiopure amino building blocks have been obtained, overcoming some limitations of traditional chemical synthetic methods. Representative processes were scaled up, affording halogenated and heteroaromatic amines in enantiomerically pure form and good isolated yields.",10.1021/op4003104,0
An Improved Process for the Preparation of (+)-3-Methoxy-<i>N</i>-formylmorphinan,"Two major steps, N -formylation of (−)-octabase and cyclization of the N -formylated product, involved in synthesis of (+)-3-methoxy- N -formylmorphinan, a key intermediate for production of dextromethorphan (DXM), have been improved to achieve higher yields in shorter time with fewer effluents. Methods of analysis of chemical and enantiomeric purities of the intermediates by HPLC and strategies for easy recovery and recycle of the reagents have been devised.",10.1021/op400309q,1
Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a Highly Selective Hydrolysis of a Nitrile to an Amide,"A combination of mechanism-guided experimentation and kinetic modeling was used to develop a mild, selective, and robust hydroxide-promoted process for conversion of a nitrile to an amide using a substoichiometric amount of aqueous sodium hydroxide in a mixed water and N -methyl-2-pyrrolidone solvent system. The new process eliminated a major reaction impurity, minimized overhydrolysis of the product amide by selection of a solvent that would be sacrificially hydrolyzed, eliminated genotoxic impurities, and improved the intrinsic safety of the process by eliminating the use of hydrogen peroxide. The process was demonstrated in duplicate on a 90 kg scale, with 89% isolated yield and greater than 99.8% purity.",10.1021/op4003054,0
Process Development and Multikilogram-Scale Synthesis of a TRPV1 Antagonist,"The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3- b ]pyrazine 1 was prepared in a convergent manner by the coupling of two key fragments, glyoxal 2 and diamine 3 . Glyoxal 2 was synthesized in six chemical steps in 20% overall yield, the key step being a challenging Grignard reaction to install the glyoxalate moiety. Diamine 3 was also prepared in six chemical steps in 46% overall yield, exploiting a regioselective nucleophilic aromatic substitution to obtain the key nitrodiamine intermediate 19 .",10.1021/op400304h,1
Biphasic Catalysis with Disaccharide Phosphorylases: Chemoenzymatic Synthesis of α-<scp>d</scp>-Glucosides Using Sucrose Phosphorylase,"Thanks to its broad acceptor specificity, sucrose phosphorylase (SP) has been exploited for the transfer of glucose to a wide variety of acceptor molecules. Unfortunately, the low affinity ( K m > 1 M) of SP towards these acceptors typically urges the addition of cosolvents, which often either fail to dissolve sufficient substrate or progressively give rise to enzyme inhibition and denaturation. In this work, a buffer/ethyl acetate ratio of 5:3 was identified to be the optimal solvent system, allowing the use of SP in biphasic systems. Careful optimization of the reaction conditions enabled the synthesis of a range of α- d -glucosides, such as cinnamyl α- d -glucopyranoside, geranyl α- d -glucopyranoside, 2- O -α- d -glucopyranosyl pyrogallol, and series of alkyl gallyl 4- O -α- d -glucopyranosides. The usefulness of biphasic catalysis was further illustrated by comparing the glucosylation of pyrogallol in a cosolvent and biphasic reaction system. The acceptor yield for the former reached only 17.4%, whereas roughly 60% of the initial pyrogallol was converted when using biphasic catalysis.",10.1021/op400302b,0
Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances,"A commercially viable manufacturing process for propofol ( 1 ) is described. The process avoids acid–base neutralization events during isolation of intermediate, 2,6-di-isopropylbenzoic acid ( 3 ) and crude propofol, and thus simplifies the synthesis on industrial scale to a considerable extent. Syntheses of five impurities/related substances (USP and EP) are also described.",10.1021/op400300t,1
Chromatography- and Lyophilization-Free Synthesis of a Peptide-Linker Conjugate,"An optimized and scalable process to manufacture peptide–linker conjugate 1 is reported that avoids the chromatographic purification and lyophilization that are typically required for the isolation of this type of compound. An operationally simple protocol has been developed that couples the peptide to the linker in DMF followed by precipitation with MeCN. A scalable synthesis of the linker is also described which features the N -acylation of 2-azetidinone promoted by 1-propanephosphonic acid anhydride (T3P). The number of operations during the second step of the synthesis (nitrobenzene reduction to aniline) has been simplified by telescoping the aniline into the next step (reaction with diglycolic anhydride to form an acid), thus avoiding an additional isolation. Finally, two efficient activation methods for the acid have been developed by means of the corresponding pentafluorophenyl (PFP) and p -nitrophenyl (PNP) esters.",10.1021/op4002998,0
An Efficient Catalytic Asymmetric Synthesis of a β<sup>2</sup>-Amino Acid on Multikilogram Scale,"We describe herein a scalable catalytic asymmetric hydrogenation process for the multikilogram-scale production of a β 2 -amino acid. A short and efficient synthesis of the starting unsaturated N -Boc-protected β 2 -enamide was developed followed by extensive catalysis screening and optimization studies that identified a simple Ru-BINAP catalyst system to directly afford the ( S ) product in high enantiomeric excess and yield. The final process enabled the multikilogram production in >99% ee, to be used as a key component for one of our clinical candidates.",10.1021/op4002966,1
"Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical","The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h –1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid–liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90–95%) under closed-loop control despite process disturbances.",10.1021/op400294z,1
Evaluation and Development of Practical Routes to an Enantiomerically Pure <i>C</i><sub>2</sub>-Symmetric Diamine Building Block,"Several routes to an enantiomerically pure C 2 -symmetric diamine were evaluated and modified to scalable methods. A Zn/Me 3 SiCl-mediated reductive coupling of an imine was found to be superior to the other methods investigated, allowing us to safely prepare the enantiomerically pure diamine also on a large scale. One key step in this method was a highly efficient resolution of a stereoisomeric mixture of the diamine through salt formation with (−)-dibenzoyl- l -tartaric acid. The enantiomerically pure C 2 -symmetric diamine obtained was further used as a key building block for the synthesis of potent Kv1.5 channel blockers.",10.1021/op400292m,1
Development of an Early-Phase Bulk Enabling Route to Sodium-Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin,"The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation–selective monodesilylation, primary alcohol oxidation, aldol-crossed-Cannizzaro reaction, and solid-phase acid-catalyzed bicyclic ketal formation. The final API was isolated as the l -pyroglutamic acid cocrystal.",10.1021/op400289z,1
Development of a Multi-Kilogram-Scale Synthesis of AZD1283: A Selective and Reversible Antagonist of the P2Y<sub>12</sub> Receptor,"Ethyl 6-chloro-5-cyano-2-methylnicotinate ( 4 ) was coupled with 4-piperidinecarboxylic acid (isonipecotic acid) in 81% yield to pyridine acid 10 . An amide coupling between 10 and benzylsulfonamide ( 6 ) afforded AZD1283 ( 1 ) in 79% yield using CDI as coupling reagent. The synthesis has been developed and scaled up to 20 kg batches of 1, supporting preclinical and clinical studies. Development work towards 2-chloropyridine 4 and benzylsulfonamide ( 6 ) is included.",10.1021/op400288v,1
"PAT Application in the Expedited Development of a Three-Step, One-Stage Synthesis of the Dipeptide Intermediate of HCV Protease Inhibitor Faldaprevir","A concise scalable synthesis of a chiral dipeptide acid, key substructure of the HCV protease inhibitor faldaprevir, has been developed. A green process with an E-factor of 9.2 was achieved utilizing process analytical technology (PAT) to allow effective processing of multiple-steps in a one-stage operation. Mixed anhydride/oxazolone formation, peptide coupling, saponification, and then crystallization of the desired dipeptide acid were completed within 10 h. MultiMaxIR was used to detect the formation and consumption rates of key intermediates and to provide initial safety data which was subsequently confirmed by more comprehensive process safety testing. Further kinetic analysis was performed to determine the range of operability space to ensure conditions for a robust process.",10.1021/op400285y,1
"Development of a Scalable Synthesis of a Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor: Efficient Construction of a 6-Etherified [1,2,4]Triazolo[1,5-<i>a</i>]pyridine-2-amine Core","A practical and scalable synthesis of the vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitor 1 has been developed. The key features of the process development include facile preparation of the key raw material 3-amino-4-fluorophenol, chemoselective nucleophilic aromatic substitution of 5-chloro-2-nitropyridine with phenol, a safe one-pot synthesis of a substituted urea using an isothiocyanate generated in situ from inexpensive materials, and improvement of the yield of acylation in the end game. The optimized six-step synthesis afforded 1 ·H 2 O in 54% overall yield, twice as much as the yield of the original synthesis, without chromatographic purification. In addition, a robust recrystallization procedure to afford the desired crystal form of 1 was also developed.",10.1021/op4002824,1
Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin,"A practical synthesis of SGLT2 inhibitor candidate ertugliflozin ( 1 ) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra- O -benzyl- d -glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39 . A cocrystalline complex of the amorphous solid 1 with l -pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.",10.1021/op4002802,1
Controlling the Exothermicity of <i>O</i>-Arylation by Evaporative Cooling during the Process Development of Fluoxetine Hydrochloride,"This study illustrates the optimization of the O -arylation step of fluoxetine hydrochloride ( 1 ) synthesis. In the entire process, this is the most critical step that dictates the yield and quality of the product. The highlight of the process is the concept of evaporative cooling that was employed in manipulating the above highly exothermic reaction by introducing toluene as the cosolvent. The evaporative cooling not only aided in getting an efficient procedure but also increased the yield of 1 and simplified the work-up procedure. This was a protective approach adopted for process safety, considering the worst-case scenario in the plant.",10.1021/op400279n,1
Evaluation of Several Routes to Advanced Pregabalin Intermediates: Synthesis and Enantioselective Enzymatic Reduction Using Ene-Reductases,"This publication describes the evaluation of four synthetic routes to the advanced pregabalin (Lyrica) intermediate 7 . Asymmetric reduction of ( E )- 7 with an ene-reductase (OPR1 from Lycopersicon esculentum ) gave a saturated cyanoester intermediate 5 with the desired S stereocenter in >99% ee. OPR1 also catalyzed the reduction of ( Z )- 7 to ( S )- 5, but with lower conversion and selectivity.",10.1021/op4002774,1
Chiral Supercritical Fluid Chromatography in the Preparation of Enantiomerically Pure (<i>S</i>)-(+)-<i>tert</i>-Butyl-3-hydroxyazepane-1-carboxylate,"We report herein the isolation and characterization of ( S )-(+)- tert -butyl-3-hydroxyazepane-1-carboxylate via resolution of the commercially available racemate, using chiral supercritical fluid chromatography (SFC). After optimization of the experimental chromatographic conditions, preparative scale separation using a stacked injections protocol led to 10.5 g of the dextrogyre enantiomer. Assignment of the absolute stereochemistry of the latter was accomplished by transforming (−)- tert -butyl-3-hydroxyazepane-1-carboxylate into known ( R )-(−)-benzyl-3-hydroxyazepane-1-carboxylate.",10.1021/op400274b,0
"Development of an Efficient Process for the Decomposition of the Borate Complexes Formed during the Large-Scale Synthesis of (<i>S</i>)-1,2,4-Butanetriol","An improved multikilogram-scale process for the production of ( S )-1,2,4-butanetriol has been developed. This process involves the efficient removal of residual boric acid and the decomposition of the borate complexes formed during the reduction of (−)-dimethyl malate with sodium borohydride by methanolysis using a circular distillation-coupled hydrolysis apparatus.",10.1021/op400271k,0
Diastereospecific Enolate Addition and Atom-Efficient Benzimidazole Synthesis for the Production of L/T Calcium Channel Blocker ACT-280778,"A scalable access to 1 ( ACT-280778 ), a potent L/T calcium channel blocker, has been developed. The synthesis, amenable to kilogram manufacturing, comprises 10 chemical steps from enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one ( 3 ) and 1,4-dimethoxybenzene with a longest linear sequence of 7 steps. Key to the success of this fit-for-purpose approach are a robust and atom-efficient access to benzimidazole 4, the substrate-controlled diastereoselective enolate addition toward carboxylic acid 2 that was isolated by simple crystallization with high dr (>99:1), the convenient selective N -deacylation of intermediate 10, and the identification of a suitable solid form of 1 as the bis-maleate salt ( 1 · 2 C 4 H 4 O 4 ). As an illustration of the robustness of this process, 14 kg of drug substance, suitable for human use, was produced with an overall yield of 38% over the longest linear sequence (7 steps).",10.1021/op400269b,1
"Catalytic Asymmetric Reduction of a 3,4-Dihydroisoquinoline for the Large-Scale Production of Almorexant: Hydrogenation or Transfer Hydrogenation?","Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity eroded upon scale-up. A broad screening exercise identified TaniaPhos as ligand for the iridium-catalyzed asymmetric hydrogenation with a dedicated catalyst pretreatment protocol, culminating in the manufacture of more than 6 t of the acetate salt of the tetrahydroisoquinoline. The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH was later successfully reduced to practice, delivering several hundreds of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst cost contribution significantly. The two methods are compared with regard to green and efficiency metrics.",10.1021/op400268f,1
Synthesis of Enantiomerically Pure 4-Hydroxy-2-cyclopentenones,"Conversion of furfuryl alcohol to 4-hydroxy-2-cyclopentenone was studied in a microreactor channel of 0.5 mm diameter and 1.5 m length. Addition of 1 M N -methylpyrrolidinone as a cosolvent significantly reduces the polymeric material normally formed during the reaction in purely aqueous solution. The reaction follows pseudo-first-order kinetics at constant pressure (200 bar) with the values of Δ H ⧧ = 18 ± 2 kcal/mol and Δ S ⧧ = −38 ± 3 cal/mol/K. At 240 °C, 200 bar pressure, and residence time of 1.5 min, the product is obtained with 98% conversion and is isolated as a stable O -phenylacetyl derivative in 80% yield. This racemic mixture was resolved into enantiomerically pure forms by kinetic resolution with penicillin G acylase (E.C.3.5.1.11) immobilized on epoxy-activated polymer in 90–92% theoretical yield and >99% ee.",10.1021/op400266k,1
Process for Producing Optically Active (<i>R</i>)-Tetrahydrothiophene-3-ol with High Optical Purity and High Purity: Bioconversion and Crystallization,"( R )-Tetrahydrothiophene-3-ol ( 1 ) is a key intermediate in the synthesis of penem-based antibiotics. However, it is a viscous liquid at room temperature, which makes it impossible to purify the ( R )-isomer especially in the presence of the ( S )-isomer. In this study, we successfully developed a process for producing ( R )-alcohol 1 with high optical purity by combining bioconversion and crystallization. ( R )-Alcohol 1 was prepared by enantioselective bioreduction which used tetrahydrothiophene-3-one ( 2 ) as the substrate, and the optical purity was 70–92% ee. The ( R )-alcohol 1 liquid was collected from incubation solution and purified to furnish ( R )-alcohol 1 with 98.7% ee by cooling crystallization from organic solvents. The scale-up using common crystallization process was difficult, but we developed a crystallization process that employed a jacketed pressure filtration vessel equipped with an agitator which can be operated under low temperature from crystallization to filtration. This led to the establishment of a process for producing ( R )-alcohol 1 with high optical purity, and the validity of this process was proved by the scale-up test.",10.1021/op4002627,0
Improved Process for Pilot-Scale Synthesis of Danshensu ((±)-DSS) and Its Enantiomer Derivatives,"A pilot-scale process has been developed for green and scalable synthesis of (±)-β-(3,4-dihydroxyphenyl) lactic acid ((±)-DSS) and their two important derivatives, namely, (±)-IDHP [(±)-isopropyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate] and (±)-DBZ [(±)-bornyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate]. Subsequent hydrogenation has been carried out by employing Raney Ni as catalyst. The improved process results in higher yields of 47.5% for (±)-DBZ and 49.2% for (±)-IDHP compared to the initial process with a yield of 12% for (±)-DBZ and 18% for (±)-IDHP in our original medicinal chemistry route. Furthermore, kilograms of optical DBZ [(−)- S -DBZ and (+)- R -DBZ, >99% ee] and IDHP [(−)- S -IDHP and (+)- R -IDHP, >99% ee] have been produced by chiral high-performance liquid chromatography in good yield (>84%).",10.1021/op4002593,1
Safe Scale-Up of a Hydrazine Condensation by the Addition of a Base,"Herein we describe an observation where an exothermic event encountered during the safety evaluation of the scale-up of the synthesis of 4-chloro-1 H -indazol-3-amine was mitigated upon the addition of a base. The 100 °C adiabatic temperature rise was attributed to the hydrazine condensation reaction, which could cause the batch to self-heat beyond the onset temperature of the exothermic decomposition of the reaction mass. Switching from 1-methyl-2-pyrrolidinone to a lower-boiling-point solvent was explored, but that alone did not guarantee the safe operation in the event cooling is lost. The reaction byproduct, HCl, was identified as a possible cause for the decreasing onset temperature of hydrazine monohydrate. The addition of a base to the reaction mixture increased the onset temperature and decreased the severity of the observed decomposition of the reaction mass. By the introduction of sodium acetate as a base in combination with a lower-boiling-point solvent, safe operating conditions for the process were identified. This base-stabilizing effect has been observed with other hydrazine condensation reactions in our laboratory.",10.1021/op4002577,0
Sanofi’s Solvent Selection Guide: A Step Toward More Sustainable Processes,"Sanofi’s solvent selection guide helps chemists in early development select sustainable solvents that will be accepted in all production sites. Solvents are divided into four classes, from “recommended” to “banned”. This ranking is derived from Safety, Health, Environmental, Quality, and Industrial constraints. Each solvent has its own ID card that indicates the overall ranking, H, S & E hazard bands, as well as its ICH limit, physical properties, cost, and substitution advice.",10.1021/op4002565,0
Use of a Miniature Mass Spectrometer To Support Pharmaceutical Process Chemistry,"In this study we describe the evaluation of a recently developed miniaturized single-quadrupole mass spectrometer to support pharmaceutical process research investigations. Mass spectrometry is becoming an indispensable tool for analytical support of synthetic chemistry; however, current mass spectrometers are too expensive and too large for widespread deployment. In addition, current instruments often have features and capabilities that, while useful for trace component or bioanalysis applications, are beyond the comparatively simple requirements of synthetic chemists, where samples are often abundant and unit mass resolution is generally sufficient. An evaluation of the Microsaic 3500 MiD shows this small and inexpensive mass spectrometer to be well-suited for providing reliable support for certain pharmaceutical process research investigations.",10.1021/op400253x,0
Women in Process R&amp;D,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTWomen in Process R&DTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 10, 1220Publication Date (Web):September 17, 2013Publication History Published online17 September 2013Published inissue 18 October 2013https://doi.org/10.1021/op400251pCopyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1443Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (110 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Quality management Get e-Alerts",10.1021/op400251p,0
A Scalable Synthesis of an Atropisomeric Drug Substance via Buchwald–Hartwig Amination and Bruylants Reactions,"A practical, chromatography-free synthesis for a chemokine receptor antagonist NIBR-1282 ( 1 ) is described. Highlights of this scalable synthesis include (1) Buchwald–Hartwig amination reaction using ( t -Bu) 3 P as the ligand and 5–12 mol % of water as an additive affording 6 with yield increase of more than 2-fold; (2) a variant of the Bruylants reaction for the synthesis of α-methyl amine 10 via aminotriazole 15a, instead of classical amino nitrile 8; and (3) development of a crystallization-induced, atropisomer transformation leading to predominantly one atropisomer 1 . The new approach was employed for the manufacturing of kilogram quantities of the target active pharmaceutical ingredient.",10.1021/op400250s,1
Special Feature Section: Engineering Contributions to Chemical Process Development,"U pon initial consideration, the idea of a special Organic Process Research & Development (OPRD) feature devoted to ""Engineering Contributions to Chemical Process Development"" may seem unnecessary.After all, chemical engineering principles are deeply embedded in the strategy of process development, especially as it relates to the consistent, safe, and robust scale-up of processes for the manufacturing scale.However, there are specific examples where the application of chemical engineering principles leads to new or improved capabilities for the development of organic processes.This special feature section highlights such aspects of chemical process development.Reaction kinetics analysis can provide insight into the controlling mechanisms of reactions and thus enable successful reaction scale-up even for complex heterogeneous systems.Crump et al. illustrate this through their first-principles analysis of the kinetics of a metal-catalyzed nitro reduction where they determined the relative importance of hydrogen gas-liquid mass transfer, liquid-phase diffusion, and surface reaction as a function of hydrogen pressure.The recent development of metal-free hydrogenation catalysts, particularly for imine reduction, is a significant advance, but the commercial implementation of these catalysts has been hampered by their sensitivity to catalyst poisoning.Thompson and his associates demonstrate how the use of inexpensive scavengers can lead to robust reactions and significantly improve the industrial feasibility of these catalysts.Scale-up and design-space mapping of batch reactive distillation are approached by Figueroa et al. through firstprinciples modeling and experimentation by considering both scale-dependent and scale-independent factors for reaction kinetics and chemical equilibrium, VLE, LLE, and heat transfer.This technique enabled on-scale prediction and design-space mapping, providing acceptable ranges of the parameters for onscale operation.Active pharmaceutical ingredients (APIs) are often isolated as crystalline or amorphous solids.Processing steps include solids formation steps (crystallization and precipitations), slurry filtrations, agitated drying, wet and dry milling operations, delumping, and blending.Engineering approaches are frequently needed to ensure not only that the desired physical and chemical properties are obtained but also that the purification and isolation steps are completed safely.Several articles in this special feature section describe advances in these processing areas.Computational fluid dynamics (CFD) is shown to be useful in the development and scale-up of a crystallization of a thermally unstable API in a helical coil heat exchanger (Vashistha et al.).CFD analysis afforded greater process understanding and a rapidly optimizable process evaluation resulting in a more robust, finalized process successfully meeting the targeted yield and quality on scale.The article by Ivan Lee describes the use of antistatic additives during the crystallization of pharmaceutical com-",10.1021/op400248x,0
Pharmaceutical Roundtable Study Demonstrates the Value of Continuous Manufacturing in the Design of Greener Processes,"The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable conducted a study to elucidate the value of continuous processing, which had been defined as a key research area for green engineering. In the course of defining the business case for continuous processing, individual cases were collected and evaluated to determine specific drivers to implement continuous processing and to find key success factors. The magnitude and timing of effects and the relation to the principles of green chemistry were investigated.",10.1021/op400245s,0
Commercial Synthesis of a Pyrrolotriazine–Fluoroindole Intermediate to Brivanib Alaninate: Process Development Directed toward Impurity Control,"The development of a practical, commercial process for the preparation of 4-fluoro-2-methyl-indol-5-ol and its subsequent coupling with a pyrrolotriazine to form an advanced intermediate of the oncology therapy brivanib alaninate is described. A key aspect is the multikilogram-scale preparation of the fluoroindole intermediate from trifluoronitrobenzene and the subsequent coupling while achieving impurity minimalization. As brivanib alaninate is a high-dose drug, the synthesis of high-quality API with low levels of impurities is critical.",10.1021/op400242j,1
Synthesis of Filibuvir. Part III. Development of a Process for the Reductive Coupling of an Aldehyde and a β-Keto-lactone,"Development of a reductive coupling of a β-keto-lactone and an aldehyde is described, in which the Hantzsch ester serves as an inexpensive and convenient reducing agent. Structural features in the β-keto-lactone rendered standard reductive coupling conditions ineffective, requiring development of a specific addition and temperature protocol. Identification of one of the reactants as Ames positive required a single-digit parts per million control strategy for this impurity in the final active pharmaceutical ingredient (API).",10.1021/op400237j,1
"Synthesis of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted 2<i>H</i>-Pyranone via Dieckmann Cyclization of a β-Acetoxy Ester","This paper describes an improved sequence for the conversion of an oxazolidinone ( 3 ) to a β-keto lactone ( 5 ). The primary drivers behind this change were the modest and variable yields observed in the intramolecular cyclization to generate the β-keto lactone. Changing the cyclization substrate from oxazolidinone to alkyl ester offered a significantly improved cyclization, as well as improvements in the alkyne hydrogenation. Selection of the optimal substrates for methanolysis and intermediate salt formation are also described.",10.1021/op400236r,1
"Synthesis of Filibuvir. Part I. Diastereoselective Preparation of a β-Hydroxy Alkynyl Oxazolidinone and Conversion to a 6,6-Disubstituted 2<i>H</i>-Pyranone","This is the first in a series of three papers describing the identification and development of a commercial synthesis of filibuvir ( 1 ). This contribution describes development of an Evans aldol reaction to control the tertiary alcohol stereocenter, a challenging variant of that strategy in that both reacting partners were nonstandard (acetate enolate and ketone electrophile). A sequence consisting of Sonogashira coupling, acylation and hydrogenation delivered acetate 24, and Dieckmann cyclization provided β-keto lactone 2 .",10.1021/op4002356,1
Process Safety Evaluation To Identify the Inherent Hazards of a Highly Exothermic Ritter Reaction Using Adiabatic and Isothermal Calorimeters,"This paper describes the process safety studies that were carried out prior to the scale-up for the initial process containing the reaction of 1,3-dimethyladamantane with sulfuric acid and acetonitrile. The reaction temperature is set at 13 °C followed by heating to 23 °C for progress of the reaction. Thermal screening studies showed the exotherm onset to occur at 30 °C, which is very close to the desired final process temperature, with high rate of temperature rise and pressure rise. Also understood was the better option for selecting the sequence of reagent addition, i.e., either acetonitrile or sulfuric acid. These thermal hazard evaluation results helped to redesign the process temperature at 38 ± 2 °C, which was evaluated for safety aspects to prevent the untoward situation using an adiabatic calorimeter and an isothermal reaction calorimeter.",10.1021/op400234w,0
Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib,"Process development of the synthesis of the orally active poly(ADP-ribose)polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed N -arylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C–N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form.",10.1021/op400233z,1
Introduction to Biological and Small Molecule Drug Research and Development: Theory and Case Studies,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewIntroduction to Biological and Small Molecule Drug Research and Development: Theory and Case StudiesTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 9, 1218Publication Date (Web):September 4, 2013Publication History Published online4 September 2013Published inissue 20 September 2013https://pubs.acs.org/doi/10.1021/op400230qhttps://doi.org/10.1021/op400230qbook-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views737Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Peptides and proteins,Pharmaceuticals,Protein structure,Receptors,Therapeutics Get e-Alerts",10.1021/op400230q,1
Copper-Catalyzed C–N Coupling in the Synthesis of Integrase Inhibitors of Immunodeficiency Viruses,"This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the selective C–N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate functionalities. The transformation was accomplished with CuI catalysis using bypiridine as the ligand in the presence of base and enabled a convergent approach to the target molecule.",10.1021/op400228z,1
Use of Modeling and Process Analytical Technologies in the Design of a Catalytic Amination Reaction: Understanding Oxygen Sensitivity at the Lab and Manufacturing Scales,"A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process analytical technology alongside kinetic and unit operation models to better characterize the oxidative deactivation pathways of the catalyst. Interplay between ligand excess, oxygen inertion, and additional degassing due to reflux were all found to contribute to reaction rate variability. This mechanistic approach allowed for appreciation and clear communication of the risks, development of protocols to mitigate those risks, and successful scale-up under rapid development timelines.",10.1021/op400226m,0
Preparation of Phosphonooxymethyl Prodrugs of HIV-1 Attachment Inhibitors,"A practical and scalable synthesis of phosphonooxymethyl prodrugs of HIV-1 attachment inhibitors is described. Starting from azaindoles 1 and 2, this two-step sequence features an efficient alkylation using chloromethyl phosphate 5 and an exceptionally mild deprotection for tert -butyl phosphates. After a salt formation, the API is formed in 82% and 70% overall yield for 3a and 4a, respectively. This chemistry was used to prepare multikilogram quantities of API.",10.1021/op400225q,0
Virtual Issue on Crystallisation and Polymorphism in Organic Process Development: 25 Papers Specially Selected by the Editor,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTVirtual Issue on Crystallisation and Polymorphism in Organic Process Development: 25 Papers Specially Selected by the EditorTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 10, 1219Publication Date (Web):September 20, 2013Publication History Published online20 September 2013Published inissue 18 October 2013https://pubs.acs.org/doi/10.1021/op400220hhttps://doi.org/10.1021/op400220heditorialACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1223Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (111 KB) Get e-AlertscloseSUBJECTS:Crystallization,Pharmaceuticals Get e-Alerts",10.1021/op400220h,0
Convergent Asymmetric Synthesis of a Renin Inhibitor: A Highly Efficient Construction Method of Three Stereogenic Centers,"An improved asymmetric synthesis of renin inhibitor DS-8108b (1) is described. This compound consists of three intermediates: 4-aminoadamantan-1-ol, ketopiperazine, and chiral lactone which contains three stereogenic centers. Especially, the chiral lactone is a key intermediate, and development of a scalable synthetic method was required, considering the quality, speed, and manufacturing cost. We established a scalable synthetic method of 1 from 4,6- O -benzylidene- d -glucose for early clinical studies. Furthermore, a highly efficient synthetic route of the chiral lactone for manufacturing was also successfully developed from n- butyryl chloride via Evans stereoselective alkylation, followed by stereoselective bromolactonization. In addition, a unique and highly efficient conversion protocol was developed from α-bromo- N -(2-nitrobenzenesulfonyl)amide to apparent rearranged diamine derivatives with a sequential aziridination–substitution reaction in one-pot.",10.1021/op400219y,1
Process Understanding: For Scale-Up and Manufacture of Active Ingredients,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Understanding: For Scale-Up and Manufacture of Active IngredientsJörgen BlixtView Author Information Chemovix AB Lostigen 25, SE-151 50 Enhörna, SwedenE-mail: [email protected]Cite this: Org. Process Res. Dev. 2013, 17, 9, 1216Publication Date (Web):September 4, 2013Publication History Published online4 September 2013Published inissue 20 September 2013https://pubs.acs.org/doi/10.1021/op400218nhttps://doi.org/10.1021/op400218nbook-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views891Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Impurities,Manufacturing,Separation science Get e-Alerts",10.1021/op400218n,0
Glucokinase Activator: Practical Asymmetric Hydrogenation and Scalable Synthesis of an API Fragment,"The enantioselective synthesis of ( R )-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl propionic acid ( R )- 2 is described. The key intermediate ( E )- 7, a trisubstituted α-aryl β-alkyl acrylic acid, was conveniently accessed as its dicyclohexylamine salt by Perkin reaction in good yield and purity. Subsequent asymmetric hydrogenation with ruthenium catalysts was achieved with complete conversion and catalyst loadings up to S / C 75000 and enantiomeric excess up to 99% after crystallization.",10.1021/op4002164,1
Exploratory Process Development of a Novel Diacylglycerol Acyltransferase-1 (DGAT-1) Inhibitor,"A practical large-scale synthesis was developed for 1, a DGAT-1 inhibitor, involving an aza-Michael reaction, amidation, Dieckman cyclization, and conjugate addition of cyanamide followed by cyclization, to form the fused 4-amino-7,8-dihydropyrido[4,3- d ]pyrimidin-5-one scaffold. The enabled process presented here substantially improved safety (in particular, due to eliminating a nitration step and optimizing a high-energy intermediate step), reproducibility, and scalability, resulting in delivery of a multikilogram quantity of the API with high purity. The controls of API quality and particle size were also discussed.",10.1021/op400215h,1
"Development of a Practical and Scalable Synthesis of the Side Chain for ASP9726, a Successor of Micafungin","Here, we describe a practical and scalable synthesis of 1, which is a useful side chain of ASP9726 ( 2 ), a successor of Micafungin. For large-scale synthesis of 1, reaction conditions were optimized to control impurities and increase yield. In particular, we utilized a high-yield thiadiazole ring formation to prepare thiadiazole 12, a step which was improved by optimization of reaction conditions and isolation method. Further, the number of steps was reduced from 10 to 9, and hazardous reactions were also avoided. Consequently, this process was scaled to produce 21.7 kg of 1 with overall yield improvement from 36.7% to 56.6%.",10.1021/op400211t,1
A Scalable Route to the SMO Receptor Antagonist SEN826: Benzimidazole Synthesis via Enhanced in Situ Formation of the Bisulfite–Aldehyde Complex,"A practical and scalable route to the SMO antagonist SEN826 1 is described herein, including the discussion of an alternative approach to the synthesis of the target molecule. The optimized route consists of five chemical steps. A new and efficient access to the key intermediate 6 via the bisulfite–aldehyde complex was developed, significantly enhancing the yields and reducing costs. As a result, a synthetic procedure for preparation of multihundred gram quantities of the final product has been developed.",10.1021/op4002092,1
Safer Preparation of <i>m-</i>CPBA/DMF Solution in Pilot Plant,"The usage of m -CPBA ( meta -chloroperbenzoic acid) is limited on large scale due to its thermal instability, although it is a good oxidant and well-accepted in laboratory scale. In our recent project, m -CPBA was used for an oxidation reaction, and an explosion hazard was identified. To ensure the safe use of m -CPBA on large scale, the stability of m -CPBA in different solvents was investigated, and it was found that besides the incompatibility between m -CPBA and DMF reported earlier, the intrinsic instability of m -CPBA/DCM solution at high concentration (low onset temperature and large exotherm) can also cause a major problem on large scale. Therefore, process parameters such as concentration of m -CPBA, addition sequence, and handling temperature have been investigated and successfully applied in pilot plant for a large scale reaction using 8 kg of m -CPBA.",10.1021/op400208b,0
"An Improved and Economical Process for the Manufacture of the Key Intermediate of Aliskiren, a New Potent Renin Inhibitor","An improved, practical, economical and efficient process for the production of (2 S,4 S )-2-amino-4-(4-methoxy-3-(3-methoxypropoxy)benzyl)-5-methylhexanoic acid, a key intermediate of the new potent renin inhibitor of aliskiren, in a total yield over 30% is described. This process avoids expensive reagents and chromatographic purifications, and is easily scaled up in industry.",10.1021/op400205k,1
Practical and Scalable Synthesis of a Benzonitrile Derivative via Palladium-Catalyzed Cyanation with Potassium Ferrocyanide,"A practical and reproducible synthetic method for the preparation of a benzonitrile derivative ( 1 ) from an aryl bromide ( 2 ) via Pd-catalyzed cyanation was established with dimethylacetamide (DMAc)–toluene as a mixed solvent. Optimization was examined by a design of experiments (DoE) technique to enhance reaction conversion and reduce the dimeric impurity 3, and desired benzonitrile derivative 1 was successfully obtained in high yields with excellent quality control on a 117 kg scale.",10.1021/op400204g,1
Merck’s Reaction Review Policy: An Exercise in Process Safety,"Process safety is an important consideration not only when conducting reactions on manufacturing scale, but also on lab and kilo lab scale. This contribution presents a discussion of Merck’s Reaction Review policy, originally specific to Process Chemistry and now applied broadly across the whole chemistry organization. Details of the policy and case studies are included.",10.1021/op4002033,0
A Stereoselective Process for the Manufacture of a 2′-Deoxy-β-<scp>d</scp>-Ribonucleoside Using the Vorbrüggen Glycosylation,"A practical and scalable process for the manufacture of cladribine ( 1 ) is described. Vorbrüggen glycosylation of doubly silylated 2-chloroadenine 2 with protected 1- O -acetyl-2-deoxy-α,β- d -ribofuranose 3 under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired β-anomer β- 4a whilst leaving the unwanted α-anomer α- 4a in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of α- 4a to β- 4a, thereby improving the isolable yield of the β-anomer. Direct filtration of the product mixture without a catalyst quench or aqueous workup furnished the crude β-anomer β- 4a in good yield (up to 68%) and purity (>95% by HPLC) with no regioisomers detected and only ∼1–3% (by HPLC) of the undesired α-anomer. Deprotection of the crude, unpurified intermediate β- 4a followed by recrystallisation provided drug-grade cladribine ( 1 ). The process includes three isolation steps and was demonstrated on kilogram scales using cGMP providing 99.8–99.9% pure cladribine in up to an overall 43% yield based on 2-chloroadenine ( 5 ). In contrast to previous methods, column chromatography and/or bulky directing groups were not required in the glycosylation step, a high pressure vessel was not needed in the deprotection step, and only one dedicated recrystallisation step was necessary.",10.1021/op4002005,0
Development of an Improved and Scalable Process for 2-(5-Ethylpyridin-2-yl)ethan-1-ol: Solvent-Free Reaction and Recycling of the Starting Material 5-Ethyl-2-picoline,"The main objective of this exercise was to develop a more efficient process for 2-(5-ethylpyridin-2-yl)ethan-1-ol ( 1 ), which is the key intermediate in the synthesis of pioglitazone hydrochloride. This process not only features the yield improvement of ( 1 ) by optimizing reaction variables in solvent-free conditions but also highlights improving the mass efficiency of 5-ethyl-2-picoline ( 2 ), thereby reducing the effluent load per kilogram of the intermediate.",10.1021/op400196y,0
Evolution and Application of an Automated Platform for the Development of Crystallization Processes,"An automated crystallization platform enabled by FTIR and FBRM in combination with automation and chemometrics has provided a versatile tool for efficient crystallization process development. This system allows users to perform a “walkup” operation for routine process evaluation and also execute automated feedback control of crystallization based on a preset supersaturation profile via cooling and/or antisolvent addition. The concept, procedure, and benefits of the PAT-enabled crystallization platform are presented in general terms and then illustrated through several case studies where feedback control is applied to cooling, antisolvent addition, and “fed batch” (hot batch solution charged to lower-temperature seed bed) crystallization.",10.1021/op400187h,0
Asymmetric Synthesis of a TRPV1 Antagonist via <i>tert</i>-Butanesulfinamide-Directed Reductive Amination with a Chromanone,"An expedient asymmetric synthesis of TRPV1 antagonist 1 has been developed and demonstrated on multikilogram scale. The enabling route to 1 is detailed herein and characterized by the following key transformations: an aldol-cyclodehydration sequence to install the chromanone, and an auxiliary-mediated diastereoselective reductive amination.",10.1021/op400184f,1
"Pilot-Scale Production of Dimethyl 1,4-Cubanedicarboxylate","A scalable process for the preparation of high purity dimethyl 1,4-cubanedicarboxylate ( 3 ) is reported. The work described herein builds on previous synthetic work from this and other laboratories, to provide a reliable process that can be used to prepare multigram quantities of 3 in a partially telescoped, 8 step process, with minimal purification of intermediates.",10.1021/op400181g,1
Application of Ultrasound Measurements as PAT Tools for Industrial Crystallization Process Development of Pharmaceutical Compounds,"Within this work, 12 different pharmaceutical compounds were analyzed by the single-frequency ultrasound measurement technique for its applicability to determine concentrations, as an important process parameter during crystallization processes, or to determine the metastable zone widths, as an important precondition for the development of crystallization processes. The results were compared to the applicability of inorganic and nonpharmaceutical compounds that have been discussed in the literature. It was found that according to the change of ultrasound velocity and adiabatic compressibility, a grouping of compounds can be derived. From this grouping it can be concluded that some organic compounds and especially inorganic compounds show an excellent applicability for concentration determination, while the application for pharmaceutical compounds is most often limited. Furthermore, a cost- and time-efficient possibility is shown for the integration of this technique in a pilot-plant-scale setup. A direct transferability of calibration models developed at the laboratory scale was found as long as the influence of undissolved air/gas was low in the pilot-plant setup.",10.1021/op4001803,0
Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound,"In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.",10.1021/op400179f,1
Right First Time in Fine-Chemical Process Scale-Up: Avoiding Scale-Up Problems: The Key to Rapid Success,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTRight First Time in Fine-Chemical Process Scale-Up: Avoiding Scale-Up Problems: The Key to Rapid SuccessJohn BlackerView Author Information Institute of Process R&D, University of Leeds, U.K.Cite this: Org. Process Res. Dev. 2013, 17, 9, 1214–1215Publication Date (Web):August 12, 2013Publication History Published online12 August 2013Published inissue 20 September 2013https://pubs.acs.org/doi/10.1021/op400176ghttps://doi.org/10.1021/op400176gbook-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views1921Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical engineering and industrial chemistry,Crystallization,Physical and chemical processes,Safety,Separation science Get e-Alerts",10.1021/op400176g,0
"Evaluation of Novel Synthetic Methods for the Preparation of the Sodium Channel Inhibitor, GW273225X","The evaluation of efficient synthetic methods for the preparation of ( R )-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine, GW273225X ( 1 ), is described. The initial synthesis using ethylfluoroacetate was evaluated against three alternative routes using either nucleophilic fluorination, electrophilic fluorination, or sodium fluoroacetate.",10.1021/op4001753,1
Practical Nonazide Synthesis of a <scp>d</scp>-Amino Acid Oxidase Inhibitor via a Sequential Erlenmeyer–Plöchl Reaction and Ligand-Free Copper(I) Amination Protocol,"A synthetic route to fused heterocycle 5 (R 1 = Et) was developed that avoids the use of troublesome azido functionality. In this approach, 3-bromofuran aldehyde 7 was synthesized from 3-bromofuran 6 using highly regioselective formylation conditions. The crude solution of 7 was treated with hippuric acid under Erlenmeyer–Plöchl conditions to give enamide product 16, which was isolated by crystallization. Intramolecular amination/cyclization to the fused pyrrole was achieved under ligand-free Cu(I) catalysis in toluene, followed by diamine workup to remove the benzoyl protecting group and residual copper. The final product 5 (R 1 = Et) was crystallized directly from the reaction mixture, providing up to 60% overall yield over five chemical steps and two isolations.",10.1021/op4001737,1
Improved “Oxazole” Method for the Practical and Efficient Preparation of Pyridoxine Hydrochloride (Vitamin B<sub>6</sub>),"Vitamin B 6, a well-studied vitamin B, has been synthesized using an oxazole method for the past 20 years. The oxazole method provided 56.2% overall yield but also generated safety, environmental, and health problems, such as using toxic benzene as solvent and unstable, corrosive, and pollutive HCl and POCl 3 as reagents. To use the same equipment but the least amount of toxic agents, we developed new reaction conditions for the early steps. For example, we successfully replaced toxic HCl/benzene conditions with NaHSO 4 /PhCH 3 conditions and also developed a novel and efficient dehydrating agent trichloroisocyanuric acid/Ph 3 P/Et 3 N to synthesize the key intermediate 5-butoxy-4-methyl oxazole, instead of using phosphorus oxychloride. These improvements resolved safety, waste avoidance, and workup issues that plagued the previous methodologies. Our process comprised six easy synthetic steps and generated vitamin B 6 with 99.4% purity in 56.4% overall yield.",10.1021/op4001687,1
Advances in the Process Development of Biocatalytic Processes,"Biocatalysis is already established in chemical synthesis on an industrial scale, in particular in the pharmaceutical sector. However, the wider implementation of biocatalysis is currently hindered by the extensive effort required to develop a competitive process. In order that resources spent on development are used in the most efficient manner for these challenging systems, a holistic view on process development and a more in-depth understanding of the underlying constraints (process related as well as biocatalyst related) are required. In this concept article a systematic approach to solve this problem is proposed, involving the use of process tools and methods to assist in development.",10.1021/op4001675,0
The Fit For Purpose Development of S1P<sub>1</sub> Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate,"A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P 1 receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.",10.1021/op400162p,1
Use of Computational Fluid Dynamics for Development and Scale-Up of a Helical Coil Heat Exchanger for Dissolution of a Thermally Labile API,"Computational fluid dynamics (CFD) is well established as a tool of choice for solving complex problems that involve interplay of the various transport phenomena (fluid flow, heat transfer, mass transfer) and/or chemical reaction. CFD modelling in such applications can be an effective tool for understanding the process and thereby identifying optimal operating conditions. In this paper, we discuss the use of CFD as a tool for modelling the fluid flow and heat transfer in a helical flow reactor. The reactor is part of a crystallization process for a thermally labile Active Pharmaceutical Ingredient (API) and is being used to heat the incoming feed material to dissolution and then later to cool the solution with a minimum possible total residence time. The time scale to carry out dissolution process by heating followed by cooling of the product solution has been shown to have a significant impact on product yield and quality. Further, CFD results were used to guide scale-up of the reactor from lab scale (15–100 g) to the pilot scale (5–10 kg) so as to achieve desired yield and quality of the product. CFD simulations were able to provide insight that was used to guide a more efficient and effective development and scale-up approach.",10.1021/op400161s,0
"A Scalable Process to the Key Intermediate of Cilazapril, (<i>S</i>)-1-Benzyloxycarbonylhexahydropyridazine-3-carboxylic Acid, Through a Novel Cascade Course","A novel and efficient manufacturing technology is disclosed in the present work for the preparation of ( S )-1-benzyloxycarbonylhexahydropyridazine-3-carboxylic acid, which is a key intermediate of cilazapril. The whole process includes only three steps; the first two steps were conducted in one pot, followed by a novel selective removal of a Cbz group in a cascade course.",10.1021/op400155u,1
Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (<i>E/Z</i>)-Tamoxifen,"A new enabling technology for the pumping of organometallic reagents such as n -butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of ( E/Z )-tamoxifen using continuous-flow organometallic reagent-mediated transformations.",10.1021/op4001548,0
Scaling Up of Continuous Flow Processes with Gases Using a Tube-in-Tube Reactor: Inline Titrations and Fanetizole Synthesis with Ammonia,"The development of a tube-in-tube reactor based on a semipermeable polymer membrane has enabled the efficient transfer of gases into liquid flow streams. In this work we describe the scalability and throughput of this reactor when applied to ammonia gas. This is made possible by a convenient titration method to rapidly assess a wide range of parameters including the liquid and gas configuration, reactor temperatures, flow rates, and solvent polarity. These data are then employed in a scaling-up process affording alkyl thioureas and are ultimately applied to a telescoped procedure leading to the anti-inflammatory agent fanetizole on a multigram scale.",10.1021/op400152r,0
Practical Asymmetric Synthesis of a Chiral Piperazinone Derivative,"A practical asymmetric route to a chiral piperazinone derivative, a fragment of MK-3207, is reported. The amine-bearing benzylic stereocenter is introduced via an asymmetric Pd-catalyzed hydrogenation of a cyclic sulfimidate in the presence of a chiral phosphine ligand. An efficient synthesis of the hydrogenation substrate is described, together with process development of the hydrogenation step and elaboration of the resulting cyclic sulfamate product to the desired piperazinone.",10.1021/op400150w,1
"Process Development and Scale-Up for the Preparation of the 1-Methyl-quinazoline-2,4-dione Wnt Inhibitor SEN461","A practical and scalable route to the Wnt inhibitor SEN461 1 is described herein. The optimized route consists of nine chemical steps. The intermediates are solids and were isolated by filtrations. Critical reactions steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, we developed a synthetic procedure for the preparation of multihundred gram quantities of the final product. A further process development for the phase 1 clinical batch campaign is reported.",10.1021/op400145w,1
"Improved Process for Preparation of (3<i>R</i>,4<i>R</i>)-3-(3,4-Dimethyl-4-piperidinyl)phenol, A Key Intermediate for the Synthesis of Alvimopan","This report discloses an industrially feasible and cost efficient process for the preparation of the compound [(3 R, 4 R )-3-(3,4-dimethyl-4-piperidinyl)phenol] ( 1 ), which is used as the key intermediate for preparation of the opioid drug Alvimopan. The overall yield in this process is increased from 15 to 30%, mainly due to the improvement in yield from 26 to 53% for intermediate 7 .",10.1021/op400144z,1
Process Development and Multikilogram Syntheses of XL228 Utilizing a Regioselective Isoxazole Formation and a Selective S<sub>N</sub>Ar Reaction to a Pyrimidine Core,"Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported. Key aspects of the developed route are a regioselective [3 + 2] isoxazole formation on a pyrimidine core and a selective S N Ar addition of an aryl amine to a symmetrical dichloro substituted pyrimidine. The route contains six synthetic steps and was demonstrated twice on scale, delivering 4.6 and 11.2 kg (25% and 16% overall yield), for Phase I clinical studies.",10.1021/op400137m,1
Lipase-Catalyzed One-Step and Regioselective Synthesis of Clindamycin Palmitate,"Chemical synthesis of clindamycin palmitate, a prodrug with taste greatly improved more than that of clindamycin, involves laborious steps of protection and deprotection to achieve the monoacylation only at 2-hydroxyl group of clindamycin and gives an overall yield below 50%. Here we report the first example of one-step synthesis of clindamycin palmitate with high regioselectivity using immobilized Candida antarctica lipase B (Novozym 435) as the catalyst. The lipase-catalyzed synthesis reached a conversion above 90% in 12 h using toluene as solvent and, moreover, a highly regioselective acylation at the 2-hydroxyl of clindamycin. The significantly improved conversion achieved at an excellent regioselectivity makes this enzymatic process attractive for the synthesis of clindamycin ester derivatives.",10.1021/op400135y,0
Use of ω-Transaminase Enzyme Chemistry in the Synthesis of a JAK2 Kinase Inhibitor,"ω-Transaminase enzyme chemistry provides an excellent methodology to build synthetically useful chiral amines from their corresponding ketones. An application of this methodology, providing a long-term commercial manufacturing route to a JAK2 kinase inhibitor, is reported herein.",10.1021/op400133d,1
Efficient Synthesis of (<i>S</i>)-1-(5-Fluoropyrimidin-2-yl)ethylamine Using an ω-Transaminase Biocatalyst in a Two-Phase System,"Screening of 60 transaminases using three different amine donors found that the ω-transaminase from Vibrio fluvialis together with ( S )-α-methylbenzylamine to be the most promising combination to deliver the desired ( S )-1-(5-fluoropyrimidin-2-yl)-ethylamine ( 2 ) in almost quantitative conversion. The process was further improved by the addition of immiscible organic solvents with toluene identified as most suitable concerning the distribution of the reactants without negatively impacting the performance of the biocatalyst. Further process optimization using commercial enzyme preparations of V. fluvialis led to product/catalyst ratios of 15 g/g cell dry weight. This approach led to a process that provided ( S )-1-(5-fluoropyrimidin-2-yl)ethylamine ( 2 ) in 77% yield with 99.8% ee. In addition, a recombinant E. coli -based whole-cell biocatalyst was also designed and applied to this process. The use of this low cost enzyme formulation gave product of similar quality to that obtained using the commercial formulation of V. fluvialis . This process was further optimized and scaled-up to deliver ( S )-1-(5-fluoropyrimidin-2-yl)ethylamine ( 2 )with a yield of 66% and an optical purity of 97.3% ee. These results confirm the efficiency and competitiveness of the transaminase technology for the production of chiral amines.",10.1021/op400131h,0
"Engineering Reaction and Crystallization and the Impact on Filtration, Drying, and Dissolution Behaviors: The Study of Acetaminophen (Paracetamol) by In-Process Controls","Acetaminophen was synthesized by reacting p -aminophenol with acetic anhydride. Overall materials balance was compiled. Three different crystallization paths (i.e., cases I, II, and III) involving various modes in agitation and addition of sodium hydroxide were taken to produce acetaminophen particles with different particle size distributions (PSDs) and polymorphism. The concentration profile of acetaminophen, temperature, and pH values throughout reaction and crystallization were monitored mainly by in-process control (IPC). The rates of nucleation, crystal growth, and agglomeration during crystallization were quantified by the mixed-suspension mixed-product removal (MSMPR) formalism. The average specific cake resistance for filtration, Krischer rate-moisture plot for drying, Carr’s index for powder flowability, and dissolution rate for drug delivery of acetaminophen crystals generated in cases I, II, and III were thoroughly studied and compared.",10.1021/op400129n,0
The Literature of Organic Process Research &amp; Development,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTThe Literature of Organic Process Research & DevelopmentTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 6, 885Publication Date (Web):May 24, 2013Publication History Published online24 May 2013Published inissue 21 June 2013https://pubs.acs.org/doi/10.1021/op400124bhttps://doi.org/10.1021/op400124beditorialACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2797Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (114 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Crystallization,Industrial manufacturing,Process chemistry Get e-Alerts",10.1021/op400124b,0
"An Efficient, Selective Process for the Conversion of Glycerol to Propylene Glycol Using Fixed Bed Raney Copper Catalysts","Propylene glycol is formed in yields of up to 95% at 100% conversion using a Raney Cu catalyst in a fixed bed reactor. The reaction uses an 80% aqueous glycerol solution and a hydrogen pressure of 600 psi. The primary byproduct is ethylene glycol formed in 1–3% yield. In a reaction run continuously for 24 d using a sample of a commercial preparation of Raney Cu, the selectivity to propylene glycol at 100% glycerol conversion was 94.6% with a space–time yield (STY) of 0.49 g of 1,2-propylene glycol/mL Raney Cu/h. Ethylene glycol was formed in 2.5% yield, while methanol, ethanol, n -propanol 1,3-propylene glycol, and acetol were present in less than 1% yield.",10.1021/op400123f,0
Hydrazine and Aqueous Hydrazine Solutions: Evaluating Safety in Chemical Processes,"This contribution provides a summary of the hazards of hydrazine and its aqueous solutions and an understanding of the important role dilution plays in increasing the inherent safety of aqueous hydrazine solutions. Rather than provide an extensive description of the hazardous properties of hydrazine, the intent is to provide enough information to allow the reader to decide if hydrazine may be acceptable for a given application, and if so, what concentration range may provide an acceptable safety and environmental risk. Calculations are used to explore the favorable effect of dilution on the risk of fire, explosions, runaway reactions, and toxic exposure. Examples are provided to illustrate the strong effect catalysts can have on decomposition reactions. An analysis indicates the previously published lower flammability limit (LFL) is nonconservative.",10.1021/op400120g,0
"Identification, Synthesis, and Strategy for Minimization of Potential Impurities in the Preclinical Anti-HBV Drug <b>Y101</b>","The identification of actual, potential, and theoretical impurities of N -[ N -benzoyl- O -(2-dimethylaminoethyl)- l -tyrosyl]- l -phenylalaninol ( Y101 ), a preclinical anti-HBV drug, is described in this article. The impurities were monitored by HPLC, and their structures were established on the basis of NMR, IR, and MS. Most of the impurities were synthesized, and their assigned constitutions were confirmed by HPLC co-injection with an ordinary column (Phenomenex Gemini, 250 mm × 4.6 mm, 5 μm) or a chiral column (DAICEL Chiralcel OD-H). According to the synthetic route, the origins of all of these related impurities were analyzed, and some practical strategies were applied for minimizing these impurities to the level accepted by the International Conference on Harmonization (ICH), and therefore, these strategies can be well applied to the quality control in Y101 clinical sample manufacture.",10.1021/op400119b,1
Greening the Valsartan Synthesis: Scale-up of Key Suzuki–Miyaura Coupling over Silia<i>Cat</i> DPP-Pd,"The study of the scale-up of the heterogeneous Suzuki-Miyaura coupling reaction in batch conditions between 2-chlorobenzonitrile and 4-tolylboronic acid, a key step in valsartan synthesis, to produce 4′-methyl-2-biphenylcarbonitrile over the Silia Cat DPP-Pd catalyst in ethanol under reflux allows to identify the optimal reaction conditions. The catalyst, regardless of limited Pd leaching, is not reusable, and the method can be effectively applied to the high yield synthesis of several coupling products, opening the route to efficient continuous coupling syntheses.",10.1021/op400118f,0
Process Development and Scale-up of a β-Secretase Inhibitor via a Stereospecific Jocic Reaction,A scalable process for the synthesis of a spiropiperidine β-secretase inhibitor is described. Key stereochemical transformations utilized are a diastereoselective trichloromethyl addition followed by an unprecedented stereospecific Jocic reaction with an aniline nucleophile. Simplified processing was developed for a Dieckmann cyclization/decarboxylation sequence to give a process suitable for the production of kilogram quantities of API.,10.1021/op400115g,1
An Improved Process for Trimethobenzamide Hydrochloride,"An improved process for the preparation of trimethobenzamide hydrochloride conforming to regulatory specification is reported. Specifically, a process for the preparation of trimethobenzamide hydrochloride, which is free from the associated impurities that are normally encountered during coupling of 4-(2-dimethylaminoethoxy)benzyl amine with 3,4,5-trimethoxy benzoic acid is described.",10.1021/op400113a,1
Model-Based Scale-up and Design Space Determination for a Batch Reactive Distillation with a Dean–Stark Trap,"Batch reactive distillations are commonly used unit operations in the pharmaceutical industry to drive chemical equilibrium reactions to completion. Their scale-up and transfer to manufacturing is not straightforward due to the interplay of scale dependent and scale independent phenomena. The increased process knowledge as required by the Quality by Design (QbD) approach calls for a first-principles-based design, scale-up and transfer of such processes. This paper presents a systematic approach consisting of a combination of first principles modeling and experimentation for the scale-up from bench to pilot-plant scale. The model is then used to estimate the process performance at different scales and study the sensitivity of the process to operational parameters such as heat transfer driving force, solvent recycle, removed fraction of volatiles. This approach is capable of robustly predicting process outcomes at lab and pilot-plant scale and delivers a better understanding of the underlying physics governing the process. The model is used further to map the design space (a region in the space of operating parameters where given quality and/or performance constraints are met) taking into account both model parameter uncertainty and routine operational variability.",10.1021/op4001127,0
I-MR Control Chart: A Tool for Judging the Health of the Current Manufacturing Process of an API and for Setting the Trial Control Limits in Phase I of the Process Improvement,"It has been observed that the main focus during the process development and manufacturing of an API is to meet the customer’s specifications (LSL and USL) rather than estimating and improving the natural control limits (LCL and UCL) of the process. It results in the overlap of the natural control limit and customer’s specification, which in turn increases the chance of failure with respect to the customer’s specifications. A better approach is to work on decreasing the variability of the process so that natural control limits become much tighter than customer’s specification. The statistical control charts not only help in estimating these internal/natural control limits but also raises an alert when the process goes out of control. These alerts trigger the investigation through root cause analysis leading to the process improvements which in turn lead to the decrease in variability of the process. This process continues till inherent variability of the process is due to common causes only and cannot be attributed to assignable causes. At this point, the natural control limits of the process can be taken as internal specification for an output quality parameter.",10.1021/op4001093,0
Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy,"A scalable and convergent synthesis of a BTK (Bruton’s tyrosine kinase) inhibitor has been developed. Synthetic routes to key intermediates were explored for the scale-up campaign, especially the process for 6-dimethylaminodihydroisoquinolinone, which was prepared via a regioselective cyclization of an isocyanate, mediated by AlCl 3 . Improved routes to key building blocks were demonstrated by expedient multikilogram productions. The target compound was assembled through a Pd-catalyzed amidation reaction followed by a Suzuki–Miyaura cross-coupling reaction.",10.1021/op4001077,1
"Synthesis of a <i>cis</i> 2,5-Disubstituted Morpholine by De-epimerization: Application to the Multigram Scale Synthesis of a Mineralocorticoid Antagonist","A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from ( R )-phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an S N Ar reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.",10.1021/op400101p,1
"A New Efficient Synthetic Process for an Endothelin Receptor Antagonist, Bosentan Monohydrate","A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p - tert -butyl- N -(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide ( 7 ) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol ( 14 ) as a key step. This new process provides desired bosentan monohydrate ( 1 ) with better quality and yields. Our new methodology consists of technical innovations/improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13 in the final drug substance.",10.1021/op400100s,1
Formulation and Process Development Strategies for Manufacturing Biopharmaceuticals,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTFormulation and Process Development Strategies for Manufacturing BiopharmaceuticalsTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 5, 883Publication Date (Web):May 6, 2013Publication History Published online6 May 2013Published inissue 17 May 2013https://pubs.acs.org/doi/10.1021/op400098hhttps://doi.org/10.1021/op400098hbook-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views887Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Computational chemistry,Manufacturing,Quality management,Spray drying,Stability Get e-Alerts",10.1021/op400098h,0
Understanding and Avoidance of Agglomeration During Drying Processes: A Case Study,"A systematic investigation into possible causes of agglomeration during drying was carried out, with a view to reduce the amount of agglomerates present in an active pharmaceutical ingredient. Several tools used in this study are described, including rheology to elucidate how the interplay of agitation (during drying and critical solvent levels) can aggravate agglomeration, and sieving to quantify the extent of agglomeration and the hardness of the resulting agglomerates. Finally, the implementation of a modified wash and the use of a blow-through protocol were demonstrated at pilot-plant scale to be effective in dramatically reducing the extent of agglomeration.",10.1021/op4000972,0
An Improved Kilogram-Scale Synthesis of 2-Bromo-4-nitro-1<i>H</i>-imidazole: A Key Building Block of Nitroimidazole Drugs,"An efficient two-step method for the synthesis of 2-bromo-4-nitroimidazole, 6, a key building block for nitroimidazole drugs, has been developed. The synthesis involves dibromination of 4-nitroimidazole 10 followed by selective debromination using in situ reductive deiodination strategy. The reactions are facile, safe, and easy to scale up. The large-scale applicability of this improved method was tested by conducting the reactions on kilogram scale to produce the desired product in high yield and quality.",10.1021/op400095f,1
Book Review of Modern Gold Catalyzed Synthesis,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Modern Gold Catalyzed SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 5, 882Publication Date (Web):April 19, 2013Publication History Published online19 April 2013Published inissue 17 May 2013https://pubs.acs.org/doi/10.1021/op400093khttps://doi.org/10.1021/op400093kbook-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views518Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysts,Gold,Hydrocarbons,Molecules Get e-Alerts",10.1021/op400093k,0
The Synthesis of Bromomethyltrifluoroborates through Continuous Flow Chemistry,"A continuous flow process was developed for the synthesis of potassium bromomethyltrifluoroborate, a key precursor for Suzuki–Miyaura coupling reagents. The continuous flow process was used to produce potassium bromomethyltrifluoroborate on scales from grams to kilograms, and the successful process utilized a fraction of the resources required for the batch synthesis. In the plant, a team of three people produced approximately 100 kg of potassium bromomethyltrifluoroborate in less than 4 weeks. This process makes it both practical and economical to use potassium bromomethyltrifluoroborate and its derivatives for multikilogram-scale Suzuki–Miyaura couplings.",10.1021/op400090a,0
Development of an Efficient Pd-Catalyzed Coupling Process for Axitinib,"The manufacturing process of axitinib ( 1 ) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.",10.1021/op400088k,1
Development and Application of Laboratory Tools To Predict Particle Properties upon Scale-Up in Agitated Filter-Dryers,"Agitated filter-dryers (AFDs) are commonly used for performing both filtration and drying operations in the manufacture of active pharmaceutical ingredients (APIs) and intermediates. Successful scale-up from the laboratory to manufacturing AFD equipment requires that physical properties specifications such as particle size be consistently met in addition to chemical purity specifications. Depending on the API–solvent system and equipment operational parameters, undesired attrition or agglomeration may occur, so an improved understanding of these phenomena upon scale-up is of key importance. In this paper, we describe recent advances in laboratory methods, based on material characterization methods common to drug product formulation development, to better assess the risk of agglomeration and attrition potential upon scale-up. These methods provide data to evaluate solid behavior, in both wet and dry states, associated with processing in an AFD. For agglomeration prediction, the application of mixer torque rheometry for measuring the propensity to form granules or agglomerates of API wet cake is described as well as how to categorize agglomeration risk based on the output of this testing. For measuring attrition propensity, the application of powder rheometry is described, and risk categories are proposed. For both testing methods, good agreement was seen between laboratory predictions and actual behavior upon scale-up. For compounds evaluated as high risk for attrition or agglomeration, alternate drying protocols are recommended to mitigate risk. In addition, progress on enhancing cycle times for difficult to dry materials is discussed.",10.1021/op400080x,0
Book Review of Strategies for Green Organic Synthesis,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Strategies for Green Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 4, 721Publication Date (Web):April 11, 2013Publication History Published online11 April 2013Published inissue 19 April 2013https://pubs.acs.org/doi/10.1021/op4000785https://doi.org/10.1021/op4000785book-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views509Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Green chemistry,Organic chemistry,Peptides and proteins,Reagents Get e-Alerts",10.1021/op4000785,0
"Book Review of Organic Synthesis Using Transition Metals, 2nd edition","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Organic Synthesis Using Transition Metals, 2nd editionTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 4, 720Publication Date (Web):April 11, 2013Publication History Published online11 April 2013Published inissue 19 April 2013https://pubs.acs.org/doi/10.1021/op4000779https://doi.org/10.1021/op4000779book-reviewACS PublicationsCopyright © 2013 American Chemical SocietyRequest reuse permissionsArticle Views435Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Hydrocarbons,Organic synthesis,Physical and chemical processes,Reactivity,Transition metals Get e-Alerts",10.1021/op4000779,0
Full-Scale Continuous Mini-Reactor Setup for Heterogeneous Grignard Alkylation of a Pharmaceutical Intermediate,"A reactor setup consisting of two reactors in series has been implemented for a full-scale, heterogeneous Grignard alkylation. Solutions pass from a small filter reactor into a static mixer reactor with multiple side entries, thus combining continuous stirred tank reactor (CSTR) and plug flow reactor (PFR) technologies. Through the use of the reactor train in combination with in-line NIR analysis, on scale a 35% reduction in solvent volume was realized, and the formation of a key impurity was suppressed. The mini-reactor solution achieved many of the economic advantages attributed to microreactor technology, while avoiding the difficulties associated with handling of solids in microreactors.",10.1021/op400069e,0
Book Review of Enzyme Catalysis in Organic Synthesis,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Enzyme Catalysis in Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 4, 718Publication Date (Web):April 11, 2013Publication History Published online11 April 2013Published inissue 19 April 2013https://doi.org/10.1021/op400067sCopyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views748Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (115 KB) Get e-AlertsSUBJECTS:Biocatalysis,Hydrolysis,Organic synthesis,Peptides and proteins,Redox reactions Get e-Alerts",10.1021/op400067s,0
Development of a Safe and Economical Synthesis of Methyl 6-Chloro-5-(trifluoromethyl)nicotinate: Trifluoromethylation on Kilogram Scale,"Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emphasis on the development work which led to this effective process.",10.1021/op400061w,1
"Development of a Practical and Efficient Synthesis of SIPI-4884, a HMG CoA Reductase Inhibitor for the Treatment of Hypercholesterolemia","An improved process of the novel HMG CoA reductase inhibitor SIPI-4884 has been developed for early preclinical pharmacology and safety studies, and it was made up with an efficient nine-step and scalable process. Significant improvements in the nucleophilic substitution, reduction, Wittig–Horner reaction, and preparation of calcium salt were demonstrated. The overall yield was improved to 17.2%.",10.1021/op400060z,1
Acidity Removal and Cesium Catalyst Recovery from Polyol Synthesis Process,"In this work, a suitable method for removing the final acidity of the polyol and for recovering cesium hydroxide from polyols synthesis has been developed. Different treatments were performed in order to remove the final acidity of the polyol: adsorption with two different adsorbents (Ambrosol and basic alumina) and ion-exchange with resin Amberlite IRA. Only when the anionic ion-exchange resin was used, was the acidity value decreased until a final value of 0.93 mg KOH/g. In order to recover the cesium, a chemical treatment of the cesium sulfate salt (obtained after the acid neutralization) with barium hydroxide was chosen. Barium hydroxide was added to precipitate the sulfate ion in barium sulfate, and a solution of cesium hydroxide remained. The dissolution of cesium sulfate salt and the amount of precipitating agent were optimized. The technical and economic feasibility of the catalyst recovery process was established.",10.1021/op400056w,0
The P-Chiral Phosphane Ligand (MeO-BIBOP) for Efficient and Practical Large-Scale Rh-Catalyzed Asymmetric Hydrogenation of <i>N</i>-Acetyl Enamides with High TONs,"A highly electron-rich P-chiral bis(trialkylphosphane) ligand MeO-BIBOP ( 1 ) was efficiently synthesized on large scale. The MeO-BIBOP–rhodium complex exhibited remarkably high reactivities (up to 200,000 TON) for the hydrogenation of N -acetyl enamides to provide chiral acetamides on kilogram scale. In the meantime, a high-yielding, cost-effective, and practical preparation of N -acetyl enamide by reductive acylation of oxime was developed employing an in situ formation of Fe(II) acetate from Fe/AcOH/Ac 2 O.",10.1021/op400055z,0
A Practical Synthesis of an Aminopyridine as a Component of a BTK Inhibitor,"Development of a new route to the BTK intermediate, 5-(1-(azetidin-1-yl)-2-methylpropan-2-yloxy)pyridin-2-amine ( 7 ), has resulted in significant improvements in terms of yield, purity, and operability over the previously known synthesis. The new route was demonstrated on a multihundred-gram scale, and the overall yield of 7 from 2-chloro-5-hydroxypyridine ( 1 ) was improved to 72%. Lithium aluminum hydride, a Swern oxidation, cesium carbonate, azetidine free base, and four chromatographic purifications used in the earlier synthesis were eliminated.",10.1021/op400046y,1
Optimization of a Crude Deoxyribose-5-phosphate Aldolase Lyzate-Catalyzed Process in Synthesis of Statin Intermediates,"A process for providing intermediate compounds as building blocks for effectively producing statins is described. The presented process is based on acetoxyacetaldehyde and acetaldehyde as substrates, which are presented in an aldol reaction catalyzed by a crude deoxyribose-5-phosphate aldolase (DERA) expressing culture lysate. Different addition regimes of both reactants into a reaction mixture were applied. For the highest concentration of product ((2 S,4 R )-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate, in the presented crude DERA expressing culture lysate-catalyzed reaction used further in the production of statins, the best addition time of reactants is described. Improved process conditions and reactants’ feeding regime were achieved by converting a batch reaction to a fed-batch process, reaching the highest concentration of product ((2 S,4 R )-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate near 77 g/L. The complete process was designed in a practical and economical manner and could be used further on an industrial scale.",10.1021/op400040b,0
Development and Scale-Up of an Optimized Route to the Pyridazin-3-one Histamine H3 Receptor Antagonist CEP-32215,"The evolution of the process to prepare CEP-32215, 3-(1′-cyclobutylspiro[4H-1,3-benzodioxine-2,4′-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazine-6-one, is presented. Two routes detailing preparation of supplies for biological screening are discussed along with the optimized fit-for-purpose process used to prepare several hundred grams for preclinical testing. Details on the development of the formation of the key spiroketal moiety are presented along with the discovery of a novel Suzuki coupling approach for synthesis of the backbone of the molecule.",10.1021/op400039d,1
Improved Synthesis of the C16–C20 Segment of Resolvin E1 Using Enantioselective Ketone Reduction and Lipase-Catalyzed Resolution,A practical synthesis targeting the C16–C20 segment of the endogenous metabolite Resolvin E1 (RvE1) is described. The original route was revised to avoid the use of source-constrained raw materials and chemistries that were problematic on larger scale. The revised route utilizes commercially available ( E )-1-chloropent-1-en-3-one as the key raw material to replace ( S )-glycidol. The ( E )-vinyl iodide functionality was installed by an addition/elimination sequence to prepare the segment required for a subsequent Sonogashira coupling. The chiral secondary hydroxyl group at C18 was established by Corey–Bakshi–Shibata (CBS) reduction followed by lipase-catalyzed acetylation to achieve chiral purity in excess of 98% ee. The revised route offered a viable multikilogram process to support early clinical production of this pro-resolution therapeutic agent.,10.1021/op4000384,1
"Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic","An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.",10.1021/op400034f,1
In Praise of the Peer Review Process and Reviewers/Referees,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTIn Praise of the Peer Review Process and Reviewers/RefereesTrevor LairdCite this: Org. Process Res. Dev. 2013, 17, 3, 317Publication Date (Web):February 18, 2013Publication History Published online18 February 2013Published inissue 15 March 2013https://pubs.acs.org/doi/10.1021/op400029fhttps://doi.org/10.1021/op400029feditorialACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1090Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (115 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Quality management Get e-Alerts",10.1021/op400029f,0
"A New Scalable Route to 4-(2-Hydroxyethyl)-1,3-dihydro-2<i>H</i>-indol-2-one: A Key Intermediate for Ropinirole Hydrochloride","A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2 H -indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nitro reduction/ring-closing/debenzylation takes place in one pot. All the intermediates can be used directly for the next step without purification in this process.",10.1021/op400024a,1
"Asymmetric Preparation of <i>prim</i>-, <i>sec</i>-, and <i>tert</i>-Amines Employing Selected Biocatalysts","High Resolution Image Download MS PowerPoint Slide This account focuses on the application of ω-transaminases, lyases, and oxidases for the preparation of amines considering mainly work from our own lab. Examples are given to access α-chiral primary amines from the corresponding ketones as well as terminal amines from primary alcohols via a two-step biocascade. 2,6-Disubstituted piperidines, as examples for secondary amines, are prepared by biocatalytical regioselective asymmetric monoamination of designated diketones followed by spontaneous ring closure and a subsequent diastereoselective reduction step. Optically pure tert -amines such as berbines and N -methyl benzylisoquinolines are obtained by kinetic resolution via an enantioselective aerobic oxidative C–C bond formation.",10.1021/op4000237,1
Process R&amp;D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development,Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.,10.1021/op4000219,1
"The Large-Scale Synthesis of (<i>S</i>)-2,4-Dichloro-1-(1,2-dichloroethyl)benzene","ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTThe Large-Scale Synthesis of (S)-2,4-Dichloro-1-(1,2-dichloroethyl)benzeneWeiguo Liu*, Canhui Wang, Qianying Liu, Yucheng Jiang, and Peng GuoCite this: Org. Process Res. Dev. 2013, 17, 5, 881Publication Date (Web):March 14, 2013Publication History Received24 January 2013Published online28 March 2013Published inissue 17 May 2013https://doi.org/10.1021/op4000187Copyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1441Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (106 KB) Get e-Alertsclose Get e-Alerts",10.1021/op4000187,1
Latest Highlights in Liquid-Phase Reactions for Organic Synthesis in Microreactors,"The attention for microreactors for organic synthesis reactions, in both academia and industry, has considerably increased over the past few years, as indicated by the progressively growing number of publications. A review of articles on liquid-phase organic syntheses in microreactors in 2011–2012 is presented in this contribution. The main topics discussed in this review are noncatalytic and homogeneously catalyzed reactions, multistep syntheses, heterogeneously catalyzed reactions, microwave-assisted reactions, and photocatalytic reactions. A number of important publications from the period 2008–2010 are also mentioned to complete the overview. The goal of the present review is to illustrate the important topics of the publications during the past few years on organic synthesis in microreactors.",10.1021/op4000169,1
Enzymatic Preparation of an<i>R</i>-Amino Acid Intermediate for a γ-Secretase Inhibitor,"( R )-5,5,5-Trifluoronorvaline, an intermediate for a γ-secretase inhibitor (BMS-708163) under development, was initially prepared from the corresponding keto acid using a commercially available d -amino acid dehydrogenase for reductive amination and glucose dehydrogenase for cofactor recycling. This amino acid could also be prepared using a d -amino acid transaminase with alanine as the amino donor, but the transamination also requires lactate dehydrogenase, NAD, formate, and formate dehydrogenase to remove pyruvate in order to bring the reaction to completion. An effective proprietary d -amino acid dehydrogenase was constructed by modification of the d -diaminopimelic acid dehydrogenase gene from Bacillus sphaericus, and a glucose dehydrogenase gene was cloned from Gluconobacter oxidans . Both genes were expressed in the same strain of Escherichia coli, and the glutamate dehydrogenase gene was inactivated in the expression strain to eliminate background production of the S -amino acid and improve the ee of the product to 100%. The amino acid could be isolated or converted without isolation to a p -chlorophenylsulfonamide carboxamide intermediate needed for the synthetic route to the γ-secretase inhibitor development candidate.",10.1021/op400013e,1
Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale,"A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting azaindole 7 under the Friedel–Crafts conditions is studied using monoesters of chlorooxalic acid in the presence of aluminum chloride. Polymorphism of 1 is also investigated to develop conditions suitable for preparation of the desired Form 1 of the target compound. The new route is further optimized and scaled up to establish a new process that is applied to the synthesis of kilogram quantites of the target active pharmaceutical ingredient.",10.1021/op400012p,1
"Development and Scale-Up of an Optimized Route to the Peptide Boronic Acid, CEP-18770","CEP-18770 is an unstable peptide boronic acid and an amorphous solid, making it a challenging synthetic target. Process R&D led to a new process that avoided chromatography through crystalline intermediates, increased atom and volume efficiency, provided a chromophore, and gave higher yields and purity. A stable, crystalline diethanolamine adduct was discovered that has the potential to be used as a prodrug.",10.1021/op400010u,1
Special Feature Sections of <i>Organic Process Research &amp; Development</i> in 2013 and 2014,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Feature Sections of Organic Process Research & Development in 2013 and 2014Trevor LairdCite this: Org. Process Res. Dev. 2013, 17, 2, 159Publication Date (Web):January 30, 2013Publication History Published online30 January 2013Published inissue 15 February 2013https://pubs.acs.org/doi/10.1021/op400009xhttps://doi.org/10.1021/op400009xeditorialACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1499Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (118 KB) Get e-AlertscloseSUBJECTS:Biocatalysis,Coupling reactions,Crystallization,Impurities,Safety Get e-Alerts",10.1021/op400009x,0
"An Improved and Efficient Process for the Production of Dronedarone Hydrochloride, an Antiarrhythmia Drug","An improved, high-yielding, and efficient process for the production of dronedarone hydrochloride (1), a class III antiarrhythmia drug for the prevention of cardiac arrhythmias such as atrial fibrillation (AF) is described. The developed process avoids isolation of unstable intermediates at several stages by telescoping the steps upon individual optimization, thereby minimizing the turnaround time of the batch cycle and increasing the throughput. Potential impurities (byproducts) arise during the reaction at various stages, and carry-over impurities from starting materials were controlled selectively by designing reaction conditions and suitable workup procedures, resulting in an increased overall yield from 33% (as per processes reported in the literature) to 66%.",10.1021/op400008e,1
Synthesis of Donepezil Hydrochloride via Chemoselective Hydrogenation,"ADVERTISEMENT RETURN TO ISSUEPREVRetractionNEXTSynthesis of Donepezil Hydrochloride via Chemoselective HydrogenationAjay Singh Rawat*, Sachin Pande, Nilay Bhatt, Raju Kharatkar, Chandrakant Belwal, and Anand VardhanCite this: Org. Process Res. Dev. 2013, 17, 12, 1617Publication Date (Web):April 9, 2013Publication History Received10 January 2013Published online6 May 2013Published inissue 20 December 2013https://pubs.acs.org/doi/10.1021/op400007phttps://doi.org/10.1021/op400007pretractionACS PublicationsCopyright © 2013 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3609Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (111 KB) Get e-AlertscloseSupporting Info (7)»Supporting Information Supporting Information Get e-Alerts",10.1021/op400007p,1
"Development of a Scalable Synthesis of a Pyridinyl-3-azabicyclononene, a Novel Nicotinic Partial Agonist","The process research and development of two syntheses of a novel nicotinic partial agonist, TC-8817 ( (+)-5 ), are described. The original Medicinal Chemistry route had multiple flaws, making it unsuitable for further development. A second approach was explored which was more amenable to optimization. The key steps were an intramolecular Lewis acid-promoted cyclization, a dibromination/elimination sequence to provide a vinyl bromide, and subsequent Suzuki coupling with 3-pyridineboronic acid. The overall yield of ∼3–16% over nine steps was offset by the low cost of goods and ease of synthesis. A major drawback was the need for simulated moving bed chiral separation on the penultimate intermediate to afford the subsequently desired single enantiomer version. A third-generation, asymmetric variation afforded a key intermediate in good yield and enantiomeric purity, providing proof of concept for a more efficient production of the desired ( + )-enantiomer.",10.1021/op400002r,1
A Fast and Effective Hydrogenation Process of Protected Pentasaccharide: A Key Step in the Synthesis of Fondaparinux Sodium,"An improved method for the simultaneous removal of O -benzyl and N -carboxybenzyl groups as well as reducing azide groups to amines in protected heparin-like pentasaccharides, a key process in fondaparinux sodium synthesis, is reported. Under catalytic transfer hydrogenation conditions, using readily available and inexpensive ammonium formate, the hydrogenolysis is done in less than an hour in good yield and purity. This procedure represents a major advantage over the previously published procedures, the latter of which involve several hours/days of hydrogenation reaction under catalytic reduction using gaseous hydrogen.",10.1021/op300367c,1
A Novel Scalable Process to the GSK3β Inhibitor AZD8926 Based on a Heterocyclic Ziegler Coupling,"Development of a new, safe, and scalable route to the GSK3β inhibitor, AZD8926, is presented. In brief, the process constitutes of (i) a synthesis of 1-(pyran-4-yl)-2-trifluoromethyl-imidazole, 14; (ii) a Ziegler-type coupling of lithiated 14 with commercially available 2-chloro-5-fluoropyrimidine via 1,2-addition over the 3,4-C–N bond; (iii) a copper-catalyzed dehydrogenative aromatization using oxygen as the stoichiometric oxidant; and (iv) an aromatic C–N bond formation using either a Buchwald–Hartwig coupling or an acid-catalyzed amination. This process circumvents the main issue in the early-phase route, in which serious process safety constraints were associated with the hazardous properties of the structure, formation, and reduction of 5-methyl-4-nitroisoxazole, 2 (4200 J/g). The new process has been demonstrated on a multigram, 2-L scale. The overall yield was improved from 4 to 14%, and the number of steps decreased from 12 to 10.",10.1021/op300365e,1
On the Fischer Indole Synthesis of 7-Ethyltryptophol—Mechanistic and Process Intensification Studies under Continuous Flow Conditions,"7-Ethyltryptophol, a key intermediate in the synthesis of the anti-inflammatory agent etodolac, was produced by Fischer indole synthesis of 2-ethylphenylhydrazine and 2,3-dihydrofuran under continuous flow conditions. The reaction generates several undesired byproducts and therefore product yields could not be improved above 40–50%. The mechanism of this transformation was studied in detail and the structure of the byproducts carefully elucidated. Despite the only moderate product yield, the synthesis of 7-ethyltryptophol by this protocol remains interesting compared to alternative methods and starts from inexpensive reagents. The developed process is executed in an environmentally benign solvent (methanol) and, importantly, the majority of byproducts can be removed from the 7-ethyltryptophol product by a straightforward extraction process.",10.1021/op300363s,0
Integration of Process Analytical Technology Tools in Pilot-Plant Setups for the Real-Time Monitoring of Crystallizations and Phase Transitions,"In this study it was demonstrated that the usage of an access unit connected to a pump-around loop cycle is a good solution for the integration of various online analytical measurement techniques in pilot-plant or industrial-scale reactors without time and cost intensive modifications of the existing setup. As a model system the crystallization as well as the polymorphic transition of α- and β- l -glutamic acid (LGA) was investigated in real-time by Raman-, NIR-, and UV–vis spectroscopy. All three techniques have been shown to be powerful tools for the process optimization of crystallizations. While all three techniques can be used for the detection of the dissolution point and the crystallization end point, Raman-spectroscopy has the advantage of being able to provide quantitative information on the actual polymorph solid fraction in the solid product. In this work special interest was put into the possibility to transfer quantitative spectroscopic models, which were established on laboratory scale, to pilot-plant scale. Furthermore, it was successfully shown that it is possible to use spectroscopic models, which originated from the calibration of solid mixtures of the polymorphs by off-line Raman spectroscopy, for the evaluation of Raman spectra recorded in suspensions during the crystallization processes. In case of the quantification of α- and β polymorph content in LGA samples peak integration (PI) as well as partial-least-squares (PLS) models were established for solid binary mixtures using the software PEAXACT (S-PACT GmbH). It was possible to transfer the PI model (valid for solid mixtures) also for evaluation of the spectra of suspensions. Consequently, the model can be applied not only in a lab scale but also for pilot plant or industrial scales.",10.1021/op300359p,0
Safety/Hazard Indices: Completion of a Unified Suite of Metrics for the Assessment of “Greenness” for Chemical Reactions and Synthesis Plans,"An overall Safety/Hazard Index (SHI) is introduced and defined in the same way as the previously described benign index (BI) covering various environmental impacts. Following the same themes and symbolism usage found in the Workplace Hazardous Materials Information System (WHMIS) and National Fire Protection Association (NFPA) 704 code, SHI covers the following safety-hazard potentials: corrosive gas (CGP), corrosive liquid/solid (CLP), flammability (FP), oxygen balance (OBP) applied to combustion reactions and oxidation reactions, hydrogen gas generation (HGP), explosive vapour (XVP), explosive strength (XSP), impact sensitivity (ISP), risk phrase (RPP), occupational exposure limit (OELP), maximum allowable concentration (MACP), dermal absorption (DAP), and skin dose (SDP). In addition, reaction temperature hazard (RTHI) and reaction pressure hazard (RPHI) indices are defined with respect to reference ambient reaction conditions of 25 °C and 1 atm. All three indices vary in value between 0 and 1 to conform to the formalism of BI and other well-known material efficiency green metrics. The methodology is illustrated using single-step and multistep synthesis plans for aniline, phenol, and phenyl isocyanate. Using the best available data, the overall “greenest” routes for these industrially important commodity chemicals are determined with respect to material efficiency, environmental impact, and safety/hazard impact. Results are conveniently presented using radial polygon diagrams and are compared with a modified Edwards–Lawrence inherent safety index formalism.",10.1021/op300352w,1
Development of a Scalable Synthesis of Oxadiazole Based S1P<sub>1</sub> Receptor Agonists,A robust and scalable synthesis was developed for the preparation of oxadiazole based S1P 1 inhibitors. A new method for the separation of triphenylphosphine oxide from reaction products and an improved method for the synthesis of oxadiazoles in the presence of DBU were incorporated into the process to achieve its scalability.,10.1021/op300345v,1
Development of an Alternate Synthesis for a Key JAK2 Inhibitor Intermediate via Sequential C–H Bond Functionalization,The development of an alternative synthetic route to a functionalized imidazopyridazine which strategically streamlines the synthesis and avoids a number of problematic reagents is described. Key to the success of this alternative route is the use of two C–H functionalization reactions: a Pd-catalyzed direct benzylation reaction to functionalize a C–H bond with a substituted benzyl group and a V-catalyzed NMO addition reaction to install a benzylic morpholine moiety.,10.1021/op300344m,1
"One-Pot Racemization Process of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline: A Key Intermediate for the Antimuscarinic Agent Solifenacin","( S )-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the N -chloroamine into the imine hydrochloride, and reduction of the imine double bond. The racemized amine was successfully resolved by d -(−)-tartaric acid obtaining ( S )-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield and with 96.7% ee and, from the crystallization mother liquors, the R enriched form. This was racemized by the same one-pot process and resolved by d -(−)-tartaric acid with the same efficiency. Such an approach to the racemization of 1-phenyl-1,2,3,4-tetrahydroisoquinoline can be industrially useful to recycle the waste R enantiomer resulting from the classical resolution used to obtain the S enantiomer on a large scale.",10.1021/op300343q,1
Optimization of the Manufacturing Route to PF-610355 (2): Synthesis of the API,"PF-610355 is a novel inhaled β-2 adrenoreceptor agonist. Process development of the final intermediate and the API are discussed with emphasis on the control of physical properties and subsequent isolations. This includes development of a constant volume distillation and evaluation of Nutsche filtration, agitated filter drying, and centrifugation to prevent particle attrition. The optimized process employed to manufacture 100 kg of the API is described.",10.1021/op300342y,1
Optimization of the Manufacturing Route to PF-610355 (1): Synthesis of Intermediate <b>5</b>,"Tertiary carbinamine 5 is an isolated intermediate in the synthesis of a novel, inhaled β-2 adrenoreceptor agonist PF-610355 . Process development for the key amide-formation and Ritter reactions, together with reaction understanding studies are discussed in context of the synthesis of 5 . The optimized process employed to manufacture 140 kg of 5 is described, and was shown to have superior metrics to the preliminary commercial route.",10.1021/op300341n,0
Practical and Efficient Large-Scale Preparation of Dimethyldioxirane,"An improved procedure for large-scale and also commercially viable preparation of dimethyldioxirane (DMDO), a common and widely used oxidation agent in organic synthesis, was developed using a conventional laboratory plant. All reaction parameters were optimized, and the stability of a freshly prepared solution of DMDO in acetone was monitored over an extended period of time to ensure long-term use after preparation, transport, and storage. This discontinuous approach, suitable for batch processing, is of interest basically to research laboratories but also to suppliers in the research and fine chemicals market.",10.1021/op300338q,0
"Commercial Scale Process of Galanthamine Hydrobromide Involving Luche Reduction: Galanthamine Process Involving Regioselective 1,2-Reduction of α,β-Unsaturated Ketone","Effect of lanthanide chloride in the Luche regioselective 1,2-reduction of 1-bromo-11-formyl-nornarwedine ( 5 ) was studied. Thus, 1-bromo-11-formyl-nornarwedine ( 5 ) is reduced with sodium borohydride in the presence of lanthanide chloride to yield 1-bromo-11-formyl-galanthamine isomers ( 6 ), which is a key intermediate for the commercial production of highly pure galanthamine hydrobromide ( 1 ), a modern drug against Alzheimer’s disease.",10.1021/op300337y,1
Development of a Robust and Sustainable Process for Nucleoside Formation,A practical and robust process for the synthesis of an Isatoribine pro-drug was demonstrated. The process relies on a streamlined glycosylation carried out in xylene and an effective regioselective enzymatic hydrolysis that can be run in a semicontinuous way. Analysis of the process mass intensity established the high impact from an environmental standpoint of our process improvement.,10.1021/op300335d,1
Chemical and Process Safety,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTChemical and Process SafetyTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 12, 1979Publication Date (Web):November 30, 2012Publication History Published online30 November 2012Published inissue 21 December 2012https://pubs.acs.org/doi/10.1021/op3003322https://doi.org/10.1021/op3003322editorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1879Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (103 KB) Get e-AlertscloseSUBJECTS:Azides,Manufacturing,Safety,Transfer reactions Get e-Alerts",10.1021/op3003322,0
Synthesis of a Sodium–Hydrogen Exchange Type 1 Inhibitor: An Efficient Cu-Catalyzed Conjugated Addition of a Grignard Reagent to an Acetyl Pyridinium Salt,"A facile and economical five-step process for the synthesis of a sodium–hydrogen exchange type I inhibitor (NHE-1) was developed from readily available starting materials in 43% overall yield. Key transformations included a highly efficient copper-catalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts, a facile hydrogenation of 4-aryl dihydropyridines, a regioselective aromatic bromination, an efficient palladium-catalyzed carbonylation of aryl bromides, and a high-yielding acyl guanidine formation. A safe and scalable protocol for preparation of 2-trifluoromethyl phenyl Grignard reagent was developed, and a facile method for controlling the palladium content with N -acetyl- L -cysteine as the scavenger was demonstrated. Process issues in controlling the formation of a key diacylation side product during acyl guanidine formation are also addressed.",10.1021/op300331b,1
Development of a Practical Synthesis of a TORC1/2 Inhibitor: A Scalable Application of Memory of Chirality,"Progression toward a scalable synthesis of TORC1/2 inhibitor bulk drug, culminating in the first GMP manufacturing campaign, is described. Process research and development was needed to obtain the prerequisite stereocenter in high enantiomeric excess for kilogram-scale production. Through route selection, a six-linear step synthesis was developed which afforded the API in 20% overall yield. Development included an application of memory of chirality (MOC) to install a quaternary chiral center with near complete retention, a reductive cyclization to form a piperazinone core, and a palladium-catalyzed C–C bond-forming step.",10.1021/op300330f,1
"A Practical and Scalable Manufacturing Process for an Antifungal Agent, Nikkomycin Z","A scalable and reliable manufacturing process for Nikkomycin Z HCl on a 170 g scale has been developed and optimized. The process is characterized by a 2.3 g/L fermentation yield, 79% purification yield, and >98% relative purity of the final product. This method is suitable for further scale up and cGMP production. The Streptomyces tendae ΔNikQ strain developed during the course of this study is superior to any previously reported strain in terms of higher yield and purity of Nikkomycin Z.",10.1021/op3003294,0
How To Use the Lasentec FBRM Probe on Manufacturing Scale,"A Lasentec FBRM probe was installed in a 450-L production unit and deployed to monitor the final three stages of the manufacturing process. Each step features a different type of crystallization: reactive, pH switch and cooling. In total over 100 batches were monitored. The probe detected ‘oiling out’ and seeding with agitation but did not detect ‘bearding’ or seeding without agitation. There was remarkable consistency from batch to batch, except for the first batches in some campaigns, which more closely resembled laboratory experiments. The challenge of interpreting Lasentec FBRM data in a production environment is addressed and compared with the alternative, in process control (IPC).",10.1021/op300326b,1
Application of Continuous Flow Micromixing Reactor Technology for Synthesis of Benzimidazole Drugs,"Synthesis of pharmaceutically active compounds by employing continuous flow micromixing reactor technology is an interesting research area. In this article we describe the synthesis of benzimidazole core drugs, such as lansoprazole ( 1a ), pantaprazole ( 1b ), and rabeprazole ( 1c ) by using a continuous flow micromixing reactor technology. A key feature of the sulfoxidation includes the decreasing the reaction time from 3 h to ∼1 s to minimize the formation of sulfone impurities and improve the yields.",10.1021/op300325f,1
Development of a Scalable Route to a Dual NK-1/Serotonin Receptor Antagonist,"The evolution of a process for the preparation of a new heterocyclic dual NK1/serotonin receptor antagonist is described. The final synthesis features a telescoped sequence in which an iron(III)-catalyzed Grignard coupling is followed by a benzylic chlorination utilizing trichlorocyanuric acid to construct an unsymmetrical 2,4,6-trisubstituted pyridine. Etherification of a 4,4′-arylhydroxymethane substituted piperidine fragment completes the synthesis of the active pharmaceutical ingredient in 44% overall yield.",10.1021/op300323k,1
Synthesis of a Spiroindolinone Pyrrolidinecarboxamide MDM2 Antagonist,"A practical synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist 2 is reported. Cycloaddition of dipolarophile 3 with imine 30 afforded a complex mixture of diastereomers that were isomerized to the desired stereoisomer 31 by heating the mixture in the presence of DBU. After hydrolysis, the resulting product was resolved with a chiral amine to give an enantiopure acid which was converted to the target product 2 . The process has been scaled up to a multihundred-gram scale. In addition, an asymmetric synthesis of 31 catalyzed by AgOAc and a chiral phosphine ligand was developed to give enantiomerically enriched 31, which was also converted to enantiopure 2 .",10.1021/op3003213,1
Biodiesel Synthesis Evaluated by Using Real-Time ATR-FTIR,Real-time attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was used as an analytical method capable of providing quantitative data regarding the yield of biodiesel synthesis. 1 H NMR was used as a reference technique to check the consistency of the data obtained by ATR-FTIR. The evaluation of the conversion of soybean oil into biodiesel was performed by measuring the consumption of methanol during the reaction.,10.1021/op300318k,0
Industrial Scale-Up of Enantioselective Hydrogenation for the Asymmetric Synthesis of Rivastigmine,"Two efficient processes for the synthesis of rivastigmine, one of the most potent drugs for the treatment of mild-to-moderate dementia of the type presenting in Alzheimer’s disease, has been developed. Of particular note is the processes used for the asymmetric hydrogenation by applying the highly efficient chiral spiro catalyst, Ir-SpiroPAP. The first route was easy to scale up in industry and provided the commercial intermediate ( S )-3-(1-dimethylaminoethyl)phenol, 6, which is suitable for the manufacture of rivastigmine in active pharmaceutical ingredient (API) demand. The second route was convenient for operation and purification and completed the synthesis of rivastigmine ( 1 ) in four steps and 84% overall yield.",10.1021/op3003147,1
Process Development of a Potent Neuroprotector Agent: Collismycin A,"An efficient synthetic process for the natural product of marine origin, collismycin type A, a potent neuroprotector agent, has been developed. This new synthetic route avoids chromatographic steps, implies an improvement cost, and provides easy access to large scale.",10.1021/op3003129,1
Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor,"( R )- N- (3-(7-Methyl-1 H -indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazine-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide ( 1 ) is a potent calcitonin gene-related peptide (CGRP) receptor antagonist. We have developed a convergent, stereoselective, and economical synthesis of the hydrochloride salt of 1 and demonstrated the synthesis on a multikilogram scale. Two different routes to the chiral indazolyl amino ester subunit were developed utilizing either a Rh-catalyzed asymmetric hydrogenation or a biocatalytic process to install the single chiral center. The advantages and disadvantages of each of these process routes are discussed, as are challenges addressed in the assembly of the final drug substance.",10.1021/op3003097,1
Practical Synthesis of PGI<sub>2</sub> Agonist: Resolution–Inversion–Recycle Approach of Its Chiral Intermediate,"Practical synthesis of ((2 R )-5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol ( ( R )-7b ), a key chiral intermediate for the synthesis of the novel PGI 2 agonist, ( R )-[6-[(diphenylcarbamoyloxy)methyl]-6-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yloxy]acetic acid ( 1 ), was achieved via optical resolution by diastereoselective crystallization of ester derivative 18 of racemic (5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol ( 7b ) with (1 S,4 R )-(−)-camphanic acid ( (−)-CpOH ) followed by saponification. Starting from commercially available 5-hydroxy-1-tetralone ( 2 ), this process features recycling of the undesired enantiomer ( S )-7b via inversion of the C2 hydroxyl group by acid-catalyzed hydrolysis of its epoxide derivative ( S )-11 . Performing this resolution–inversion–recycle approach provided a 44% overall yield of ( R )-7b (>99% ee) from racemic 7b . The enantiopure ( R )-7b synthesized by this approach was then used to prepare 1 . This robust, reproducible, and scalable synthesis of 1 was successfully demonstrated on a pilot scale.",10.1021/op3003085,1
An Efficient Large-Scale Synthesis of a Naphthylacetic Acid CRTH2 Receptor Antagonist,"An efficient and practical synthesis of a naphthylacetic acid CRTH2 receptor antagonist is reported. Michael addition of ethyl t -butyl malonate to an allenoate afforded a triester, which was selectively hydrolyzed and decarboxylated to give a benzylidenepentanedioic acid monoester. Treatment of this compound with potassium acetate and acetic anhydride produced the naphthylacetate core. The triflate of the key building block was coupled with a zinc reagent of the side chain under improved Negishi coupling conditions to afford the target product. The process was successfully scaled up to produce over 2 kg of the API.",10.1021/op300306c,1
"An Efficient Process for the Large-Scale Synthesis of a 2,3,6-Trisubstituted Indole","The efficient synthesis of a key trisubstituted indole intermediate 1 is described. The synthetic route required the use of an aryl Grignard reagent which was not commercially available, and the large-scale formation of this fragment and the thermal evaluation for this step is presented. The key step in the sequence was a Truce–Smiles rearrangement to provide an advanced ketone intermediate which, upon reduction, cyclized to the desired indole 1 . Design of experiment (DoE) optimization of this reduction is also presented. In total >50 kg of target indole 1 were synthesized in 55% overall yield over five steps using this new route.",10.1021/op300303p,1
"Process Research on a Phenoxybutyric Acid LTB4 Receptor Antagonist. Efficient Kilogram-Scale Synthesis of a 3,5-Bisarylphenol Core","An improved, kilogram-scale synthesis of a LTB4 receptor antagonist is reported. The title compound was prepared in four linear steps (seven steps total) and 54% overall yield. The 3,5-bisarylphenol core was obtained in nearly quantitative yield by the condensation of 1-benzotriazol-1-ylpropan-2-one with a chalcone. Although all the intermediates were oils, no chromatography purification was required.",10.1021/op300302s,1
"Development of a Multigram Synthesis of URB937, a Peripherally Restricted FAAH Inhibitor","A new synthetic approach to URB937 was developed starting from the inexpensive and widely available 4-benzyloxyphenol. A reproducible four-step procedure, requiring no chromatographic purifications, was optimized that allowed the preparation of 100 g of URB937 in 45% overall yield.",10.1021/op300301u,1
Rapid Analysis of Residual Palladium in Pharmaceutical Development Using a Catalysis-Based Fluorometric Method,"Measurement of residual metals in pharmaceutical intermediates is routinely performed using inductively coupled plasma-optical emission spectroscopy (ICP-OES) or inductively coupled plasma-mass spectrometry (ICP-MS). However, these techniques suffer from drawbacks that limit their utility in pharmaceutical process development, including the requirement for expensive instrumentation, complex sample preparation, slow turnaround time, limited sample throughput, and the difficulty of performing the required measurements on the ‘spot’ within pilot plants or manufacturing environments. We investigate the use of a fast and inexpensive high-throughput approach for detection of residual palladium (Pd), based on the Pd-catalyzed Tsuji–Trost deallylation of an allylic ether substrate to produce a highly fluorescent product. We demonstrate the effectiveness of this fluorescence assay for accurate quantitation of Pd levels in a variety of ‘real world’ samples, including mixed oxidation-state samples containing strong Pd ligands.",10.1021/op3003008,0
A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate,We report a practical synthesis of PI3K inhibitor GDC-0941 . The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.,10.1021/op3002992,1
Development of Related HCV Protease Inhibitors: Macrocyclization of Two Highly Functionalized Dienyl-ureas via Ring-Closing Metathesis,"A novel assembly of two structurally related 14-membered ring macrocyclic hepatitis C virus protease inhibitors is presented. Key to their successful construction was an ultimate ring-closing metathesis step on the respective highly functionalized dienyl-ureas. In the case of IDX316, this procedure significantly outperformed the original macrocyclizations in terms of reaction conditions, impurity profile, product isolation, and basic efficiency metrics. Simple nonchromatographic purification methods achieved sub-10-ppm ruthenium content in the isolated product. Overall yields to IDX316 from all five starting materials ranged from 11 to 40%, and the estimated process mass intensity was improved by a factor of 50 relative to the original unscalable discovery-based routes. Application of similar methodology in the case of IDX320 and first scale-up to half-kilogram batch sizes was demonstrated.",10.1021/op300296t,1
"Efficient Large-Scale Synthesis of a 2,4,5-Triarylimidazoline MDM2 Antagonist","An improved, kilogram-scale synthesis of a triarylimidazoline MDM2 antagonist is reported. The nicotinic acid component was prepared in three steps from ethyl 2-dimethylaminomethylene-3-oxo-butyrate. The coupling of the nicotinic acid with the meso -diamine selectively produced the monoamide which was cyclized in the presence of p -TSA/pyridine to give the imidazoline core. Phosgenation using bis(trichloromethyl) carbonate provided the key carbamoyl chloride intermediate, which was coupled with the side-chain amine, followed by chiral resolution with ( R )-camphorsulfonic acid to give the final API.",10.1021/op300294g,1
"Development of Synthetic Routes, via a Tropinone Intermediate, to a Long-Acting Muscarinic Antagonist for the Treatment of Respiratory Disease","This contribution describes the development of two synthetic routes to an investigational muscarinic antagonist for the treatment of chronic obstructive pulmonary disease. The first route used a starting material which was in plentiful supply within the GSK network and was used to make material for early clinical trials and safety assessment studies. Further investigations identified a second, potential long-term manufacturing route from commercially available building blocks, using substrate control to install the two stereocentres with excellent selectivity. A key step was a substrate-directed epoxide reduction which also gave rise to a minor byproduct through a skeletal rearrangement of the tropane ring. A deuterium-labeling experiment was carried out, which shed light on the origin of the byproduct, and also guided the improvement of reaction conditions.",10.1021/op3002933,0
Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry,"Process mass intensity (PMI) is a key metric for evaluating the sustainability of a manufacturing process. Within Eli Lilly and Co. (Lilly), a process based on the molecular complexity and the projected market demand has been adopted to set PMI targets for prospective drugs. This strategy is described. PMIs for relevant molecules from publications in this journal were also calculated and compared to the model. These data illustrate the strengths and weaknesses of the model.",10.1021/op3002917,0
Optimization of Reaction Parameters for the Synthesis of Chromium Methionine Complex Using Response Surface Methodology,"This study deals with a new and better protocol to prepare chromium methionine using aqueous ethanol solution as the reaction medium. Response surface methodology (RSM) coupled with Box-Behnken design was employed to model and optimize the operational parameters of this protocol. The ethanol content of aqueous ethanol, the molar ratio of methionine and Cr(III), reaction temperature, and reaction time were chosen as independent variables, and their combined effects on the conversion of Cr(III) (response 1) and the yield of chromium methionine (response 2) were investigated. The optimal values of the parameters were found to be the following: ethanol content of aqueous ethanol is 48.5%; n (Met)/ n (NaOH)/ n (CrCl 3 ·6H 2 O) = 4.31:4.31:1; reaction time is 127 min; reaction temperature is 81.1 °C; initial Cr(III) concentration is 0.25 mol/L. The conversion of Cr(III) and the yield of chromium methionine are up to 99.79% and 99.23%, respectively, under the optimal conditions. The analysis of variance (ANOVA) and regression with R 2 values of 0.9984 for the conversion of Cr(III) and 0.9974 for the yield of chromium methionine illustrate that the experimental results are in good agreement with the predicted values, and the models can be used to predict the synthesis of chromium methionine successfully.",10.1021/op3002905,0
Scalable Synthesis of a Cis-Substituted Cyclobutyl-Benzothiazole Pyridazinone: Process Development of an Efficient Copper Catalyzed C–N Cross-Coupling Reaction,"A scalable process for the preparation of 2-(2-( cis -3-(piperidin-1-yl)cyclobutyl)benzothiazol-6-yl)pyridazin-3(2H)-one in multi-kilogram amounts and in high purity has been developed. The key features of this synthesis are the copper-catalyzed C–N cross-coupling reaction and the development of a highly diastereoselective reductive amination using NaBH(OPiv) 3 as a reducing agent. Controls were implemented to minimize both base- and acid-catalyzed isomerization of the 1,3- cis -substituted cyclobutane ring.",10.1021/op3002883,1
Improved Process for Azilsartan Medoxomil: A New Angiotensin Receptor Blocker,"An improved process for the active pharmaceutical ingredient of a new angiotensin II AT 1 receptor antagonist, azilsartan medoxomil, has been developed. The results include reinvestigation of the described process as well as its novel modifications. This new process includes transformation of the CN group into amidoxime moiety by aqueous hydroxylamine, its cyclization into the corresponding oxadiazole by treatment with dialkyl carbonates, and the following hydrolysis of the ester and transformation into the medoxomil ester. Several thus far undocumented side products were identified, and some of them were synthesized and duly characterized as potential impurities. Formation and control of possible critical impurities are described.",10.1021/op3002867,1
The Large-Scale Synthesis of (<i>S</i>)-<i>N</i>-Boc-bis(4-fluorophenyl)alanine,"The synthesis of ( S )- N -Boc-bis(4-fluorophenyl)alanine, an intermediate in the synthesis of denagliptin, is described from the synthesis of a 12 g proof of principle sample to a >900 kg cGMP manufacturing campaign. The chiral centre was established by the asymmetric hydrogenation of the sterically crowded precursor, ethyl 2-acetamido-3,3-bis(4-fluorophenyl)acrylate. The ability to isolate the various intermediates in a physical form that would readily allow filtration, washing, and ultimately purification underpinned the successful manufacturing campaign.",10.1021/op3002855,0
The Development of Practical Synthetic Routes to a CB<sub>2</sub> Agonist: Efficient Construction of a Densely Substituted Purine Core,"An efficient and scalable process for the preparation of a purine-based CB 2 agonist was developed. The production route to the requisite purine core relies on N -acylation and sequential substitution of a 5-amino-4,6-dichloropyrimidine with two amine building blocks followed by a cyclocondensation reaction. The chemistry was successfully employed to rapidly prepare over 5 kg of the active pharmaceutical ingredient. To further improve efficiencies, postproduction development resulted in a rearranged synthesis which reduced the need for pressure reactors and introduced the most costly reagent in the final step.",10.1021/op300278c,1
Applications of Transition Metal Catalysis in Drug Discovery and Development,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTApplications of Transition Metal Catalysis in Drug Discovery and DevelopmentTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 11, 1874Publication Date (Web):October 18, 2012Publication History Published online18 October 2012Published inissue 16 November 2012https://doi.org/10.1021/op300277xCopyright © 2012 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1163Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (108 KB) Get e-AlertsSUBJECTS:Catalysis,Cross coupling reaction,Hydrogenation,Process chemistry,Transition metals Get e-Alerts",10.1021/op300277x,0
Evaluation of Different Process Concepts for the Indirect Hydration of Cyclohexene to Cyclohexanol,"An indirect hydration process route for the production of cyclohexanol was proposed by Steyer et al., which uses formic acid as a reactive entrainer ( Steyer, F.; Freund, H.; Sundmacher, K. Ind. Eng. Chem. Res. 2008, 47, 9581−9587; Steyer, F.; Sundmacher, K. Ind. Eng. Chem. Res. 2007, 46, 1099–1104). This route overcomes several limitations of the conventional Asahi process for cyclohexene hydration to cyclohexanol ( Steyer, F.; Sundmacher, K. Ind. Eng. Chem. Res. 2007, 46, 1099−1104; Mitsui, O.; Fukuoka, Y. Process for producing cyclic alcohol. U.S. Patent 4,588,846, 1986; Ishida, H. Catal. Surv. Jpn. 1997, 1, 241–246; Ishida, H.; Fukuoka, Y.; Mitsui, O.; Köono, M. Liquid-Phase Hydration of Cyclohexane with Highly Silicious Zeolities. In Zeolites and Microporous Crystals: Proceedings of the International Symposium on Zeolites and Microporous Crystals, Nagoya, August 22–25, 1993; Hattori, T., Yashima, T., Eds.; Studies in Surface Science and Catalysis, Vol. 83; Elsevier: Tokyo, NY, 1994; pp 473–480). A coupled-column reactive distillation process concept, developed earlier in our group ( Kumar, R.; Katariya, A.; Freund, H.; Sundmacher, K. Org. Process Res. Dev. 2011, 15, 527−529; Katariya, A.; Freund, H.; Sundmacher, K. Ind. Eng. Chem. Res. 2009, 48, 9534–9545; Freund, H.; Katariya, A.; Kumar, R.; Steyer, F.; Sundmacher, K. DGMK Tagungsber. 2007, 2, 237–239), is feasible, but the energy consumption is very high, and the process concept is limited by multiple steady states with a narrow operating window. There is a need to develop other promising process options. In this direction the present work analyses different process concepts and discusses in detail the challenges involved. Various process options were developed and analyzed. Dedicated experiments were carried out in order to ensure the validity of the kinetic model at a wide range of process conditions. Long-time batch experiments provided an accurate estimation of the heat of formation of cyclohexylformate. The developed process concepts are compared and evaluated with respect to the benchmark Asahi process. As an important indicator of the economic viability, the energy consumption is analyzed.",10.1021/op300276e,0
Continuous Flow Synthesis of <i>n</i>-Alkyl Chlorides in a High-Temperature Microreactor Environment,"Applying continuous flow processing in a high-temperature/high-pressure regime, n -alkyl chlorides can be prepared in high yields and selectivity by direct uncatalyzed chlorodehydroxylation of the corresponding n -alcohols with 30% aqueous hydrochloric acid. Optimum conditions for the preparation of n -butyl and n -hexyl chloride involve the use of a glass microreactor chip, a reaction temperature of 160–180 °C (20 bar backpressure) and a residence time of 15 min.",10.1021/op300273u,0
A Robust Process for an mGluR5 Negative Allosteric Modulator: Difluoromethylation and Sonogashira Coupling on Large Scale,"The development of the potent and selective mGluR5 negative allosteric modulator (NAM) 1 is described. Key features in the process, which has been implemented on a multikilogram scale, include a high-temperature difluoromethylation reaction, a Sonogashira coupling, and careful control of residual Pd and Cu in the final API. Due to the relative nonpolar nature of the intermediates, water-miscible solvents were employed in all four steps to allow for direct crystallizations upon reaction completion. In addition, several crystalline morphologies of the API were discovered, and the isolation of the desired form II will be discussed.",10.1021/op3002728,1
A Concise Synthesis of a Tetrahydropyrazolopyrazine Building Block,"A concise synthesis of a tetrahydropyrazolopyrazine building block is described. 5-Methyl-4,5,6,7-tetrahydropyrazolo[1,5- a ]pyrazin-2-ylamine was prepared in three steps and 80% yield from 5-nitro-2 H -pyrazole-3-carboxylic acid. This compound was then coupled with 4-bromo-6-chloro-2-methyl-2 H -pyridazin-3-one in the presence of sodium tert -pentoxide to give the target product in 87% yield. The process was successfully scaled up to a multihundred gram scale.",10.1021/op300270r,1
Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist,"MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselective O -alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.",10.1021/op3002678,1
Heart-Cutting Two-Dimensional Ultrahigh-Pressure Liquid Chromatography for Process Development: Asymmetric Reaction Monitoring,"This contribution presents the first application of two-dimensional, ultrahigh-pressure liquid chromatography (2D-UHPLC) for monitoring asymmetric reactions in process development. Several asymmetric transformations were studied to illustrate the operation of the instrument and evaluate the performance of 2D-UHPLC. Two-dimensional UHPLC is particularly advantageous because it allows a simultaneous analysis of the reaction conversion and its enantiomeric excess. By employing UHPLC the analysis time can be reduced significantly, and the achiral–chiral 2D coupling approach allows for direct injection of the reaction mixture. This study demonstrates the utility of 2D-UHPLC in asymmetric transformations for drug development.",10.1021/op300266j,0
Scale-up of Azide Chemistry: A Case Study,"We report research and development conducted to enable the safe implementation of a highly enantioselective palladium-catalyzed desymmetrization of a meso – bis -ester using trimethylsilylazide (TMSN 3 ) as the nucleophile. This work is used as a case example to discuss safe practices when considering the use of azide reagents or intermediates, with a focus on the thermodynamic and quantitative analysis of the hazards associated with hydrazoic acid (HN 3 ).",10.1021/op3002646,0
Synthesis of the Pleuromutilin Antibiotic SB-268091: A New Practical and Efficient Synthesis of Quinuclidine-4-thiol,A synthesis of the pleuromutilin antibiotic SB-268091 is described which includes a new and improved route to the quinuclidine-4-thiol ligand. This chemistry has been run on multikilo scale and involved a reductive double debenzylation using sodium in liquid ammonia. Alternative conditions have been developed to prepare quinuclidine-4-thiol which avoid the use of sodium in liquid ammonia. The generality of this process to prepare differentially S -protected quinuclidine-4-thiols is also discussed and exemplified by the preparation of a range of analogues.,10.1021/op300263w,1
Process Development and Scale-Up of an Hsp90 Inhibitor,A scalable process for the manufacture of a Hsp90 inhibitor was developed and optimized. Key features in the seven-step process include a selective S N Ar reaction followed by an Ullmann-type coupling of indazolone to an aryl halide. This improved process afforded 65% yield over two critical steps compared to 25% following the Medicinal Chemistry route.,10.1021/op300262z,1
A New and Improved Process for <i>N</i>-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide,"A new and improved synthetic route to N -(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide ( 1 ) is described on a kilogram scale. The key step is the basic cyclization of o -[(2-cyanovinyl)amino]benzoate ( 14 ) in t BuONa/ t BuOH system to give the 3-cyano-4-hydroxyquinoline ( 7 ). The final product 1 is obtained with 49% overall yield (seven steps) and 98.9% purity (HPLC), which makes it a cost-effective and commercially friendly process for scale-up operations.",10.1021/op300260m,1
Improved One-Pot Synthesis of Citalopram Diol and Its Conversion to Citalopram,"An improved process is developed for the preparation of citalopram diol, 2 which involves two consecutive Grignard reactions in situ followed by an efficient and simple workup process with improved overall yield. Process development efforts for conversion of 2 into citalopram, 1, and a control strategy for impurities are discussed. The present work addresses the challenges associated with the process development and scale-up of citalopram such as handling of unstable intermediates, control of various potential impurities, and process safety to achieve an economic and scalable process.",10.1021/op3002596,1
"Development and Practical Synthesis of a Triple Reuptake Inhibitor, (1<i>R</i>,2<i>S</i>)-SIPI 5357","A new chromatography-free synthetic route to triple reuptake inhibitor (1 R,2 S )-SIPI 5357 was developed and demonstrated on a 300-g scale. The key feature of this route is an asymmetric induction reaction, where the (2 S,3 S )-aminoketone 6 was highly stereoselectively reduced to (1 R,2 S,3 S )-amino alcohol 7 . After hydrogenation, chlorination, and cyclization, (1 R,2 S )-SIPI 5357 was prepared in 33% overall yield via seven steps from α-bromo ketone 3 .",10.1021/op300258w,1
Development of a Selective Friedel–Crafts Alkylation Surrogate: Safe Operating Conditions through Mechanistic Understanding,"This article describes a selective one-pot, Friedel–Crafts acylation/ketone reduction protocol, effectively a surrogate for the Friedel–Crafts alkylation reaction with a primary alkyl halide. A potentially dangerous failure mode was identified, resulting in the uncontrolled evolution of hydrogen. A series of mechanistic experiments, including analysis by 27 Al NMR, was undertaken, and the reaction mechanism elucidated. Finally, the use of React IR to ensure real-time reaction safety was demonstrated.",10.1021/op300257z,1
"A Practical Synthesis of a <i>cis</i>-4,5-Bis(4-chlorophenyl)imidazoline Intermediate for Nutlin Analogues","A practical synthesis of cis -4,5-bis(4-chlorophenyl)imidazoline, a key intermediate for Nutlin analogues, is reported. The title compound was prepared in 81–88% yield by boric acid catalyzed direct condensation of meso -bis(4-chlorophenyl)ethane-1,2-diamine with a benzoic acid. The process was successfully scaled up in a pilot plant, resulting in >15 kg of the product.",10.1021/op300254q,0
"Development of a Practical Synthesis of a Functionalized Pyrrolo[2,1-f][1,2,4]triazine Nucleus","Functionalized pyrrolotriazine 1b is a key heterocyclic building block in the synthesis of BMS-690514, a potent anticancer agent. Described herein are our development activities that led to the efficient preparation of 1b on a large scale. The key transformations include a selective C-alkylation of an oxalacetate salt with a hydrazonyl bromide to form a 2-hydrazonoethyl-3-oxosuccinate, followed by cyclodehydration to an aminopyrrole. Subsequent deprotection and condensation with formamidine afforded the pyrrolotriazine scaffold. Further elaboration of this core provided the desired pyrrolotriazinyl amine.",10.1021/op300252n,1
Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α-Phenyl Benzyl Cation,"Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti -selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.",10.1021/op300249q,1
Application of Flow Photochemical Bromination in the Synthesis of a 5-Bromomethylpyrimidine Precursor of Rosuvastatin: Improvement of Productivity and Product Purity,"In this report we present a flow photochemical bromination of a 5-methyl-substituted pyrimidine precursor of rosuvastatin. The study demonstrated that the reaction productivity can be increased markedly with a flow-mode approach compared to a batch-mode synthesis. Indeed, reaction times can be significantly shortened from a range of hours to a range of minutes. Moreover, in addition to process intensification, the study demonstrated that significantly lower overall levels of side products are obtained when photochemical bromination is conducted in a flow mode.",10.1021/op300248y,0
Development of a Process for the Preparation of Chloromethyl Chlorosulfate,"A new and efficient synthesis of chloromethyl chlorosulfate (CMCS) from chloroiodomethane and chlorosulfonic acid is described. This process leverages a chlorosulfonic acid-mediated iodide oxidation to drive the equilibrating displacement process to full conversion. The resulting iodine byproduct is further oxidized and removed as iodate, to prevent iodide-induced decomposition of CMCS. This new process provides an efficient and scalable protocol for the preparation of CMCS in 92% solution yield and high purity (>99 GC area %).",10.1021/op300246d,0
Development and Characterization of a Cocrystal as a Viable Solid Form for an Active Pharmaceutical Ingredient,"A phosphoric acid cocrystal of a drug substance candidate at Boehringer Ingelheim was identified from the standard salt form screen and was characterized and shown to have desirable physicochemical properties, stability characteristics, and improved solubility and bioavailability compared to those of the free form. The cocrystal structure was determined by single-crystal X-ray structure analysis and resolved hydrogen-bonding interactions between chains of phosphoric acid molecules and chains of molecules of the free base. Comparison of the key physicochemical properties and biopharmaceutical properties of the cocrystal against a salt form demonstrated the advantage of the cocrystal over the sulfate salt with its superior stability characteristics. The cocrystal was developed as a robust drug substance form for further development and scale-up. The crystallization of the cocrystal form from organic solutions exhibited a strong relationship between water content in the crystallization system and the crystallization kinetics. The effect on the kinetics was used for effective particle size control for the cocrystals, important for optimizing the surface area, dissolution rate, and thus, bioavailability of the drug substance.",10.1021/op300239h,0
Development of a Practical and Scalable Synthesis of a Potent p38 Mitogen-Activated Protein Kinase Inhibitor,"Process research and development of a practical and scalable synthetic method toward a potent inhibitor of p38 mitogen-activated protein kinase 1 is described. The medicinal chemistry synthetic method had several issues in scale-up synthesis. In contrast, the synthetic method described here does not require purification by column chromatography for all steps, and the formation of impurities is suppressed well. Aminopyrazole ring formation was achieved by reaction between a new chiral amine building block 7 and bromoketone unit 4 as a key reaction. This highly efficient and scalable process was successfully demonstrated in the large-scale synthesis of 1·HBr .",10.1021/op300237b,1
Development of a Scalable Strategy for the Synthesis of PI3Kδ Inhibitors: Selective and Efficient Functionalization of Purine Derivatives,"The first-generation development route used to prepare the PI3Kδ inhibitor GNE-293 ( 3 ) for early toxicology studies is described. Through the use of a metal-free S N Ar reaction in place of a Pd-catalyzed C–N coupling, the synthesis was both simplified and made more reproducible in preparation for scale-up by reducing the number of operations required for purification and eliminating the need for column chromatography. The utility of the recently developed reagent TMPZnCl·LiCl is highlighted by a novel method of iodination to access the key aryl halide intermediate.",10.1021/op300235t,1
Demonstration of a Scalable One-Pot Synthesis of Fmoc-<i>O</i>-Benzylphospho-<scp>l</scp>-serine,"A cost-effective one-pot synthesis of Fmoc- O -benzylphospho- l -serine, an amino acid commonly used in the synthesis of phosphorylated peptides, has been developed. Two methods for executing this synthesis are described, and both have been scaled to provide kilogram quantities of the title compound in ∼50% isolated yield. Development of both processes has led to the identification of crystallization conditions which provide the product as a solvate with high purity. An efficient process for generating the solvent-free product from the solvate has also been developed.",10.1021/op300233g,0
Science of Synthesis Workbench Edition: Water in Organic Synthesis,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTScience of Synthesis Workbench Edition: Water in Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 9, 1571Publication Date (Web):September 4, 2012Publication History Published online4 September 2012Published inissue 21 September 2012https://pubs.acs.org/doi/10.1021/op300231ahttps://doi.org/10.1021/op300231abook-reviewACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views570Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Cyclization,Organic reactions,Organic synthesis,Redox reactions,Solvents Get e-Alerts",10.1021/op300231a,0
"Process Development, Impurity Control, and Production of a Novel Tubulin Inhibitor","Process development and production of a novel tubulin inhibitor are described. The desired API was obtained through selective iodination of the 12′ position of vinblastine and subsequent thiomethylation. Most of the impurities were identified, and process parameters were adjusted to control such impurities. The optimized process was scaled up under cGMP conditions to afford 230 g of the desired API.",10.1021/op3002307,0
"A Scalable Synthesis of CE-157119 HCl Salt, an SRI/5-HT<sub>2A</sub> Antagonist","A scalable synthesis of CE-157119 HCl salt ( 1 ), an SRI/5-HT 2A antagonist, was developed via the regioselective S N Ar etherification between a phenol and an N -methylamide. This early development route shortened the original 5-step synthesis to three steps, eliminated all chromatography and increased the overall yield from 15% to 34%. The process was implemented for API manufacture from 100-g scale to multikilogram scale.",10.1021/op3002273,1
"The Development of a Scalable, Chemoselective Nitro Reduction","We have demonstrated a scalable chemoselective reduction of a nitro functional group in the presence of an aryl imine using (NH 4 ) 2 S/EtOH or hydrogenation (Sponge Nickel) to afford the corresponding amino-imines in moderate to excellent yields. Other reducible groups such as aryl halides, styryl olefins, and ether linkages survived as well.",10.1021/op3002239,0
An Approach to Control Strategies for Sulfonate Ester Formation in Pharmaceutical Manufacturing Based on Recent Scientific Understanding,"The issue of sulfonate ester formation is one that has been of significant concern to regulatory authorities since the start of the millennia. These concerns, focused primarily on the risk of ester formation where sulfonic acid salts are formed in alcoholic solvents, has led to the need for specific analysis for such species in the final API in any product containing a sulfonic acid counterion. This concept article examines the growing experimental data that exist showing how this risk can be negated through the application of simple process controls that effectively eliminate this risk. These data are also compared to specific product data, illustrating the practical experience of organizations. The article also reflects on the Viracept incident and how the mechanistic understanding of the reaction between sulfonic acids and alcohols readily predicts the observed outcome. It is the conclusion of the authors that the continued need for exhaustive analytical testing should be replaced instead by a scientific risk-based approach, taking into full consideration the specific process conditions.",10.1021/op300216x,0
Efficient Purification of an Active Pharmaceutical Ingredient via Cocrystallization: From Thermodynamics to Scale-Up,"Cocrystallization as a purification step was the only way to isolate an active pharmaceutical ingredient with acceptable chemical and physical specifications. The process design controlling chemical quality and polymorphism issues is described, from the thermodynamics of cocrystal formation and cleavage, to microscale data acquisition, to laboratory scale-up and transfer to the pilot plant.",10.1021/op300214p,0
A Facile Total Synthesis for Large-Scale Production of Imatinib Base,"An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N -(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.",10.1021/op300212u,1
"Demonstration on Pilot-Plant Scale of the Utility of 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Catalyst in the Efficient Amidation of an Unactivated Methyl Ester","The utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene as a reagent to facilitate efficient amide formation by reaction of an amine with an unactivated ester was demonstrated on pilot-plant scale as a key step in the synthesis of an H-PGDS inhibitor.",10.1021/op300210j,0
Telescoped Flow Process for the Syntheses of <i>N</i>-Aryl Pyrazoles,"N -Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N -aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl 2 to give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N -aryl pyrazoles. The heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the purification of the final N -aryl pyrazole.",10.1021/op300209p,1
Practical Process Research and Development - A Guide For Organic Chemists,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTPractical Process Research and Development - A Guide For Organic ChemistsWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom[email protected]Cite this: Org. Process Res. Dev. 2012, 16, 9, 1569Publication Date (Web):August 17, 2012Publication History Published online17 August 2012Published inissue 21 September 2012https://pubs.acs.org/doi/10.1021/op300207uhttps://doi.org/10.1021/op300207ubook-reviewACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views2338Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Crystallization,Impurities,Pharmaceutics,Reagents,Safety Get e-Alerts",10.1021/op300207u,0
A Novel Integrated Bioprocess for Efficient Production of (<i>R</i>)-(−)<i>-</i>Mandelic Acid with Immobilized <i>Alcaligenes faecalis</i> ZJUTB10,"An integrated bioprocess for the enantioselective hydrolysis of mandelonitrile to ( R )-(−)-mandelic acid (R-MA) with immobilized Alcaligenes faecalis ZJUTB10 cells was constructed. Production of A. faecalis ZJUTB10 nitrilase in a pilot-scale fermenter (700 L) with high activity was achieved after optimizing cultivation conditions. A. faecalis ZJUTB10 cells were then immobilized in Ca-alginate. Efficient reusability of the biocatalyst up to 9 batches was obtained by immobilization, and treatment with polyethyleneimine (PEI) and glutaraldehyde (GA) further extended the longevity to 19 batches. The immobilized cells showed maximum activity at 40 °C and pH 8.0. A method for in situ product recovery (ISPR) based on an external extraction loop was established to overcome product inhibition. Anion-exchange column containing resin HZ202 was coupled to the packed bed bioreactor and enabled product recovery by continuously recirculating reaction mixture through the ISPR unit. This integrated bioprocess led to a high productivity of 8.87 mM/h after 16 h of reaction. The productivity of R-MA did not drop significantly even after 80 h of reaction, and the accumulative R-MA amount reached a final value of 550 mmol with excellent enantiomeric excess (>99%). The present studies demonstrated the potential of using the integrated bioprocess for continuous production of R-MA on an industrial scale.",10.1021/op3001993,0
"Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor","TAK-733 ( 1 ) is an investigational, novel MEK kinase inhibitor that bears a 6-fluoropyridopyrimidone core. Process research of 1 was conducted, and an efficient, scalable route was developed. The key intermediate, a multisubstituted fluoropyridone, was formed in one pot via a three-step cascade reaction: condensation between α-fluoromalonate and malononitrile, methyl amide formation, and intramolecular cyclization. Chlorination of the hydroxyl functionality and cyclization with formic acid provided the desired pyridopyrimidone core in high yield. Subsequent N -alkylation with the nosylate of ( R )-glycerol acetonide and displacement of the chlorine with 2-fluoro-4-iodoaniline proceeded successfully with good yields. Final acid-catalyzed deprotection of the acetonide functionality followed by a controlled crystallization protocol afforded the active pharmaceutical ingredient (API) with the desired polymorph. Compared to the initial synthesis, this route was more concise (six steps compared to the original nine steps), and the overall yield was improved significantly (from 3% to 25%). These improvements allowed for production of multikilograms of 1 .",10.1021/op300198a,1
Multikilogram Synthesis of a Hepatoselective Glucokinase Activator,"This work describes the process development and manufacture of early-stage clinical supplies of a hepatoselective glucokinase activator, a potential therapy for type 2 diabetes mellitus. Critical issues centered on challenges associated with the synthesis of intermediates and API bearing a particularly racemization-prone α-aryl carboxylate functionality. In particular, a T3P-mediated amidation process was optimized for the coupling of a racemization-prone acid substrate and a relatively non-nucleophilic amine. Furthermore, an unusually hydrolytically-labile amide in the API also complicated the synthesis and isolation of drug substance. The evolution of the process over multiple campaigns is presented, resulting in the preparation of over 110 kg of glucokinase activator.",10.1021/op300194c,1
An Improved and Scalable Process for the Synthesis of 5-Azacytidine: An Antineoplastic Drug,"An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine ( 1 ), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approach used to streamline the process into a very robust and practical manufacturing process are described.",10.1021/op300192e,1
Lewis Acid-Catalyzed Synthesis of 4-Aminopyrimidines: A Scalable Industrial Process,Pyrimidine synthesis starting from acrylonitrile has been known since the 1960s. The new Lewis acid-catalyzed condensation reaction allows the synthesis of 4-aminopyrimidines starting from the easily accessible chemical acrylonitrile without the need for carcinogenic chemicals and costly derivatization in up to 90% yield. The method is versatile and applicable for industrial-scale synthesis of biologically relevant substances such as vitamin B1 and trimethoprim.,10.1021/op300190s,1
The Manufacture of a Homochiral 4-Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues,"A process is described for the synthesis of kilogram quantities of homochiral 4-silyloxycyclopentenone ( R )- 1, a key intermediate useful for the synthesis of a plurality of prostaglandin analogue drugs. Cyclopentenone ( R )- 1 was synthesized in 14 isolated steps from furfural. Key steps in the synthesis include a Wittig reaction, Piancatelli rearrangement, and an enzymatic resolution featuring in situ recycling of the undesired enantiomer furnishing the desired homochiral alcohol in ≥99.5% ee. As a retort to the unsatisfactory coformation of about 8% at best of the trans -olefin in the Wittig reaction, a change to the order of several steps and the identification of a recrystallisable, amine salt derivative, 2, allowed the unwanted isomer to be controlled to as low as 0.2%.",10.1021/op300188x,1
Process Optimization of Aldol-Type Reaction by Process Understanding Using in Situ IR,"A high-yield robust LHMDS-mediated aldol-type reaction of benzyl maltol ( 2 ) and benzaldehyde ( 3 ) was developed using in situ IR to overcome the problems of low yield and yield fluctuation of the pilot synthesis. In situ IR studies indicated that unexpected side reactions of LHMDS and 3 reduced the yield of the aldol-type reaction. On the basis of the results, the reaction conditions were optimized.",10.1021/op300186p,1
Identification and Development of an Efficient Route to SB-649915,"The discovery and development of an efficient manufacturing route to the SSRI-5-HT1A receptor antagonist 6-[(1-{2-[(2-methyl-5-quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2 H -1,4-benzoxazin-3(4 H )-one (SB-649915) 1 is described. The existing route to 1 involved coupling quinoline 6 with piperidine 5 and was considered lengthy as a consequence of the nine synthetic steps required to prepare 5 . Two new routes to the key piperidine intermediate 5 are identified which deliver this compound in five and two steps respectively, from readily available materials using novel lithiation and Friedel–Crafts methodology respectively. The latter of these two routes was successfully demonstrated at 5 L scale to deliver 700 g of 5 . Development to the methanesulfonate 34, an alternative to quinoline 6, is also described as is the final alkylation of piperidine 5 with this methanesulfonate 34 to deliver SB-649915 1 .",10.1021/op300185s,1
Development of a Practical Synthesis of a p38 Kinase Inhibitor via a Safe and Robust Amination,"The development of a practical synthesis for a p38 kinase inhibitor is described. The key advances include an improved route to the key intermediate, a substituted pyrrole, and a subsequent animation utilizing O -(4-nitrobenzoyl)hydroxylamine, which provides a safe, scalable, and robust amination method. The new protocol was successfully demonstrated to generate 1.6 kg of API in seven steps and 26% overall yield.",10.1021/op300181r,1
"An Efficient, Commercially Viable, and Safe Process for Preparation of Losartan Potassium, an Angiotensin II Receptor Antagonist","An efficient, commercially viable and safe process for the preparation of losartan potassium, an antihypertensive drug substance, with an overall yield of 55.5% and ∼99.9% purity (including five chemical reactions and two recrystallizations) and meeting all other regulatory requirements is described. Formation and control of all the possible impurities are also described.",10.1021/op300179u,1
Use of Footnotes and References in <i>Org. Process Res. Dev.</i> Papers,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTUse of Footnotes and References in Org. Process Res. Dev. PapersTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 8, 1319Publication Date (Web):July 25, 2012Publication History Published online25 July 2012Published inissue 17 August 2012https://pubs.acs.org/doi/10.1021/op3001756https://doi.org/10.1021/op3001756editorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1361Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (111 KB) Get e-AlertscloseSUBJECTS:Medicinal chemistry,Pharmaceuticals Get e-Alerts",10.1021/op3001756,0
"Selection and Scale-Up Evaluation of an Alternative Route to (−)-(3<i>R</i>,4<i>R</i>)-1-Benzyl-4-(benzylamino)piperidin-3-ol","An efficient, scalable synthesis of (−)-(3 R,4 R )-1-benzyl-4-(benzylamino)piperidin-3-ol ( 4 ) is described. Reduction of the pyridinium salt prepared from pyridine and benzyl chloride generated the corresponding tetrahydropyridine derivative. A two-stage epoxidation, followed by ring-opening of the epoxide with BnNH 2, established the regiochemistry of the amino alcohol and served to set the trans -relationship between the amine and the hydroxyl group. The resulting racemic intermediate was then resolved by salt formation with ( R )- O -acetyl mandelic acid. The process produced the O -acetyl mandelic acid salt of (−)- 4 in 27% overall yield from benzyl chloride.",10.1021/op300174w,1
Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler–Wolff Aromatisation for Synthesis of the Indole-4-amide Core,"A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler–Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal–Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.",10.1021/op300173z,1
Scale-Up Synthesis of Antidepressant Drug Vilazodone,"A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel–Crafts acylation of 1-tosyl-1 H -indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH 4 /CF 3 COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2-carboxylate hydrochloride, one-step deprotection and esterolysis, and the final ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity. This convenient and economical procedure is remarkably applicable for scale-up production.",10.1021/op300171m,1
Development of a Scalable Route to the SMO Receptor Antagonist SEN794,"A practical and scalable route to the SMO receptor antagonist SEN794 1 is described herein. A new and efficient access to the key intermediate 7 via the Kröhnke reaction was developed, significantly simplifying the synthesis and reducing costs. The optimized route consists of six chemical steps plus a palladium scavenging step. The intermediates are solids and were isolated by filtrations, except for ester 9, which was telescoped as the crude oil into the subsequent step. In the final amide formation step, target compound 1 was conveniently crystallized from the reaction mixture in high purity.",10.1021/op300170q,1
Continuous-Flow Preparation and Use of β-Chloro Enals Using the Vilsmeier Reagent,"The Vilsmeier reagent is used in the preparation of a wide variety of heterocycles, such as pyrazoles, via formation of β-chloroacrolein intermediates. However, use of this extremely reactive reagent on large scale requires special precautions to avoid potentially dangerous exotherms. This article describes the safe preparation at room temperature of the Vilsmeier reagent under flow conditions for the formation of β-chloroacroleins and 3-formylchromones, as well as the use of these in multistep, continuous flow processes for the syntheses of β-acrylonitriles and polysubstituted pyrazoles.",10.1021/op300168z,0
Noncryogenic Preparation of Functionalized Arylboronic Esters through a Magnesium–Iodine Exchange with in Situ Quench,International audience,10.1021/op300166m,0
Discovery and Development of an Efficient Process to Atovaquone,"The discovery and development of an efficient and more sustainable manufacturing route to the anti-pneumocystic agent atovaquone (2-((1 R,4 R )-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. The existing commercial route to atovaquone delivers a poor yield of product and uses expensive reagents. The new synthesis commences with readily available phthalic anhydride, which is converted to 1,4-isochromandione 5 and then to atovaquone 1 by reaction with 4-(4-chlorophenyl)cyclohexanecarboxylic acid 3 using key bromination, Rosenmund reduction, and rearrangement chemistries. Downstream processing to atovaquone is both high yielding and robust, and the resulting process has been demonstrated on 200-kg scale. The process is simple, uses cheap raw materials, and is more sustainable in that it avoids low-yielding silver-promoted chemistry and isomerisation procedures. It includes a robust, facile, and highly efficient procedure to 1,4-isochromandione 5, and routes to 4-(4-chlorophenyl)cyclohexanecarboxaldehyde 9 have also been developed, including a Rosenmund method that was demonstrated on pilot-plant scale. Also discussed are the route-derived impurities and processing amendments to control their formation.",10.1021/op300165q,1
A Novel Method for the Large Scale Synthesis of Cinacalcet Hydrochloride Using Iron Catalyzed C–C Coupling,"A novel synthetic route for commercial preparation of cinacalcet hydrochloride ( 1 ), a calcimimetic agent and calcium-sensing receptor antagonist, is described. Our synthetic approach involves the preparation of cinacalcet using C–C bond formation catalyzed by iron acetylacetonate/NMP complex with aryl Grignard reagent benzotrifluoride magnesium bromide ( 8 ) and alkenyl halide N -chloropropene naphthylethylamine ( 6 ).",10.1021/op300164y,1
A Scalable Synthesis of a Hydroxamic Acid LpxC Inhibitor,"A short and scalable synthesis of chiral hydroxamic acid 1, a LpxC inhibitor, is described. This work discloses a novel diastereoselective addition of 2-nitropropane-generated lithium salt to tert -butanesulfinimine. Moreover, the impurity profiles of reactions giving oily products and practical means of purifying these products are discussed in detail.",10.1021/op300163n,1
Optimization of Reductive Debenzylation of Hexabenzylhexaazaisowurtzitane (the Key Step for Synthesis of HNIW) Using Response Surface Methodology,"Reductive debenzylation of hexabenzylhexaazaisowurtzitane (HBIW) was carried out using palladium hydroxide deposited on activated carbon catalyst. The catalyst has been characterized using a nitrogen adsorption/desorption isotherm, a hydrogen isotherm, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The synthesized catalyst showed pore sizes larger than 20 Å, which are attributed to mesopore structures. A multivariate optimization approach was developed by means of central composite design (CCD) for optimizing reaction conditions. The influence of four variables, including the catalyst to HBIW ( 1 ) relative percent, reaction temperature, hydrogen pressure, and acetic anhydride (Ac 2 O), on the reaction yield was investigated. The results showed that the optimum parameters for reductive debenzylation were 20% (w/w) for catalyst to HBIW ( 1 ) percent, 48.5 °C for reaction temperature, 4.25 bar for hydrogen pressure, and 10.9 for Ac 2 O/HBIW mole ratio. Under these conditions, the reaction yield increased to 73%.",10.1021/op300162d,0
Continuous Processing in the Manufacture of Active Pharmaceutical Ingredients and Finished Dosage Forms: An Industry Perspective,"Continuous manufacturing as a way of producing fine chemicals, active pharmaceutical ingredients, and finished dosage forms is gaining widespread attention. Although potential benefits over traditional batch-wise production have been discussed at many occasions and appear evident, continuous processes are only slowly being implemented. The American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable has defined “continuous processing” as one of its research priorities (1) and performed a survey of its members’ opinions, the status of implementation, and perceived hurdles blocking implementation of continuous manufacturing processes. Here we discuss the most important results of this survey and their relation to present trends in this industry to “go green”.",10.1021/op300159y,0
"A Practical Kilogram-Scale Process to a Milnacipran Analogue, <i>N</i>,<i>N</i>-Diallyl (1<i>R</i>, 2<i>R</i>)-2-(Aminomethyl)-1-(2-thienyl)cyclopropanecarboxamide","A robust chemical process to produce N, N -diallyl (1 R,2 R )-2-(aminomethyl)-1-(2-thienyl)cyclopropanecarboxamide ( 2 ) has been developed and optimized. This unique process, employing the MsCl/NaN 3 and Zn/NH 4 Cl system, overcomes many pitfalls of the literature reported processes, which mostly use chromatographic purification and catalytic hydrogenation with Pd/C. In addition, this novel process overcomes the safety concern with handling amide azide ( 8 ), as demonstrated by the results of the drop weight test and differential scanning calorimetry (DSC). This process has been successfully scaled-up to prepare several multikilogram batches of the target compound with overall yields of 80%, which is 15 times higher than those of reported procedures.",10.1021/op3001542,1
Development of a Practical and Scalable Synthesis of a Potent CRTH2 Antagonist,"This contribution describes the process research and development of a practical and scalable synthetic method towards compound 1, which has a potent CRTH2 antagonistic activity. The medicinal chemistry synthetic route and second generation synthetic route had several issues in scale-up synthesis. In contrast, the synthetic method described here does not require purification by column chromatography for all steps, and the formation of impurities is suppressed well. This highly efficient and scalable process was successfully demonstrated in the large-scale synthesis of 1 .",10.1021/op3001492,1
"Benign and High-Yielding, Large-Scale Synthesis of Diphenylphosphinodithioic Acid and Related Compounds","Diphenylphosphinodithioic acid ( 6b ) and its triethyl ammonium salt ( 6a ) were prepared by two new synthetic pathways, each employing cheap and readily available starting materials. These facile one-pot reactions were conducted on a kilogram scale and produced the desired products in high yield and quality, thereby surpassing all previously known routes. The synthesis of triethyl ammonium salts of 6 H -dibenzo[ c, e ][1,2]oxaphosphinine-6-thiolate 6-sulfide ( 3a ) was also further improved.",10.1021/op300147f,1
The Eight Criteria Defining a Good Chemical Manufacturing Process,"As pharmaceutical API projects advance from Development to Chemical Production, the primary objective of the Process Research and Development (R&D) chemists is a smooth transfer of a well-developed, safe, scalable, robust, and economical chemical process to their customers in Chemical Production. Since the definition of a Good Chemical Manufacturing Process differs widely amongst different departments and companies, we herein summarize eight useful process evaluation criteria, and then demonstrate our deployment according to the guiding principle “if it can be measured, then it can also be managed”, with the aim to offer chemists a helpful toolbox to effectively compare competing API synthesis routes.",10.1021/op300144g,0
Crystallization Engineering in Aza-Steroid: Application in the Development of Finasteride,High Resolution Image Download MS PowerPoint Slide Novel and robust crystallization approach based on solid solution formation was developed for the purification of finasteride. This is an unprecedented approach that describes the use of pure finasteride 1 to purify different lots of finasteride 1 (impure) contaminated with dihydrofinasteride 2 .,10.1021/op300142a,0
Inclusion of Environmental Impact Parameters in Radial Pentagon Material Efficiency Metrics Analysis: Using Benign Indices as a Step Towards a Complete Assessment of “Greenness” for Chemical Reactions and Synthesis Plans,"A new benign index (BI) parameter is developed and applied to assess the overall “greenness” of chemical reactions and synthesis plans. Previously described radial pentagon green metrics based solely on material efficiency are extended to include BI which takes into account the following potentials for environmental harm: acidification–basification (ABP), ozone depletion (ODP), global warming (GWP), smog formation (SFP), inhalation toxicity (INHTP), ingestion toxicity (INGTP), inhalation carcinogenicity (INHCP), ingestion carcinogenicity (INGCP), bioconcentration (BCP), abiotic resource depletion (ARDP), cancer potency (CPP), persistence (PER), and endocrine disruption (EDP). As with other material efficiency metrics, the benign index is defined as a fraction between 0 and 1 so that it may be added as another radial axis to produce an overall radial hexagon diagram that can be used to evaluate the “green” merits of any given chemical reaction. The utility of the method is demonstrated for industrial chemical reactions producing diphenyl carbonate (DPC) and phenyl isocyanate (PI) using both phosgene-based and nonphosgene-based chemistries, and for synthesis plans for the industrial production of aniline, phenol, and aspirin. A critical discussion is presented on the limitations of the method with respect to proper decision making in route selection, particularly the availability and reliability of key parameters, and the importance of obtaining experimental data for key parameters rather than relying solely on computational methods.",10.1021/op3001405,0
An Asymmetric Synthesis of a Chiral Sulfone Acid with Concomitant Hydrolysis and Oxidation to Enable the Preparation of a Glucokinase Activator,"This contribution describes the demonstration of an asymmetric synthesis of a glucokinase activator via protonation of the enolate generated from an alkylaryl ketene and ( R )-pantolactone. Additionally, a one-pot hydrolysis/oxidation protocol with lithium hydroperoxide was developed to afford a chiral sulfone acid without degradation of the labile stereocenter.",10.1021/op300139g,1
Development of a Practical and Scalable Synthesis of (<i>R</i>)- and (<i>S</i>)-3-Amino-2-[(benzyloxy)methyl]propan-1-ol Monohydrochloride: A Useful C-4 Chiral Building Block,"The development of a practical and scalable synthesis of a C-4 chiral amine building block ( R ) - 1·HCl and ( S ) - 1·HCl is described. This important chiral intermediate ( R ) - 1·HCl is efficiently synthesized from the commercially available, inexpensive, and simple 2-(hydroxymethyl)-1,3-propanediol ( 31 ) using lipase-catalyzed enantioselective hydrolysis as a key reaction. Development resulted in a telescoped process that was operated successfully and reproducibly in a pilot-plant-scale synthesis, and 22 kg of chiral amine ( R ) - 1·HCl was prepared in the first scale-up synthesis. This synthetic method is also useful for preparation of the important chiral building block ( S ) - 1·HCl, which is the enantiomer of ( R ) - 1·HCl .",10.1021/op3001383,1
An Efficient Synthesis of 3-Substituted <i>N</i>-Glycoside Indoles Useful as Sodium-Dependent Glucose Transporter Inhibitors,"A practical synthesis of two N -glycoside indoles 1 and 2, identified as highly potent sodium-dependent glucose transporter (SGLT) inhibitors is described. Highlights of the synthetic process include a selective and quantitative Vilsmeier acylation and a high-yielding Grignard coupling reaction. The chemistry developed has been applied to prepare two separate SGLT inhibitors 1 and 2 for clinical evaluation without recourse to chromatography.",10.1021/op3001355,1
Development of a Practical and Convergent Process for the Preparation of Sulopenem,"Previous synthetic processes for the preparation of sulopenem involved multistep linear sequences in which the chiral sulfoxide side chain was introduced early in the process. This contribution summarizes the development of a practical and convergent process for the large-scale preparation of 1 . The key step in the synthesis involves cyclization of an oxalimide intermediate to provide the thiopenem core. This convergent strategy allows for late introduction of the expensive and labile chiral sulfoxide subunit. Additionally, a regioselective sulfur oxidation and an improved deprotection sequence were developed. The latter provides API of high purity without the need for recrystallization.",10.1021/op300131e,1
Development of a Second-Generation Process to Antibacterial Candidate Sulopenem,"The research, development, and scale-up of the broad-spectrum antibacterial candidate sulopenem are presented. An enabled medicinal chemistry synthesis of this active pharmaceutical ingredient was utilized for Phase 1 and early Phase 2 manufacture but was not conducive to larger scale. The limitations associated with the first-generation synthesis were partially addressed in an improved second-generation synthesis of the target molecule where the penem ring is constructed via a modified Eschenmoser sulfide contraction sequence. Other highlights of the second-generation process include an improved synthesis of an important trithiocarbonate intermediate and a superior process for Pd-catalyzed deallylation of the penultimate ester to obtain low levels of residual palladium.",10.1021/op300130p,1
Route Development and Multikilogram GMP Delivery of a Somatostatin Receptor Antagonist,"Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to afford 6 kg of API. A recycle procedure augmented the yield of desired diastereomer in the Pictet–Spengler reaction from a mixture of diastereomers heavily enriched in the undesired diastereomer.",10.1021/op300128c,1
A Continuous Kilogram-Scale Process for the Manufacture of <i>o</i>-Difluorobenzene,"An expeditious and multikilogram-scale process for the Balz–Schiemann synthesis of o -difluorobenzene from o -fluoroaniline via two separate continuous flow reactors in 90.0% yield has been set up. The main steps involved the generation of stable diazonium fluoborate intermediate in situ via continuous diazotization reactor at 20 °C, and the choice of o -difluorobenzene as cosolvent to achieve the continuous flow fluorodediazoniation system. Reaction time of both steps could be brought down to within 10 s and 2 min, respectively, by increasing the reaction temperature and thereby taking advantage of improved mass and heat transfer of a continuous flow system.",10.1021/op300127x,0
Application of the Quality by Design Principles for the Development of the Crystallization Process for a Piperazinyl-Quinoline and Definition of the Control Strategy for Form 1,"The studies carried out to develop a robust crystallization method for the substituted piperazinyl-quinoline ( 1 ) a compound potentially active in the treatment of depression, are described in this contribution. These studies include the control of a solvate that could have potentially formed in the crystallization process. The principles of quality by design (QbD) were applied to generate the process understanding and to define the control strategy for the control of the formation of the solvate during the crystallization. The application of process analytical technology (PAT) tools was key in achieving the desired process control.",10.1021/op300126e,1
"Response to the Comments by Rautenstrauch et al. on our Article, “Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension”","ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTResponse to the Comments by Rautenstrauch et al. on our Article, ""Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension"" Louis-Charles Campeau* and Erin N. GuidryView Author Information Global Process Chemistry Merck, P.O. Box 2000 Rahway, New Jersey 07065, United States*[email protected]Cite this: Org. Process Res. Dev. 2012, 16, 6, 1187Publication Date (Web):May 29, 2012Publication History Published online29 May 2012Published inissue 15 June 2012https://pubs.acs.org/doi/10.1021/op3001228https://doi.org/10.1021/op3001228letterACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views1518Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysts,Hydrogenation,Ligands Get e-Alerts",10.1021/op3001228,0
"Development of an Efficient, Scalable Route for the Preparation of a Novel Insulin-Like Growth Factor-1 Receptor Modulator","A chromatography-free and efficient synthesis of insulin-like growth factor-1 receptor (IGF-1R) modulator is reported. Herein we describe an improved synthesis for the target compound, which features facile introduction of a novel pyrrolidinyl-pyrimidyl isoxazole 8, via in situ sulfone displacement by fluorine. The overall process consists of six chemical steps and five isolations, with introduction of the expensive triheterocyclic unit 8 towards the end of the synthesis.",10.1021/op300120r,1
A New Solvent System (Cyclopentyl Methyl Ether–Water) in Process Development of Darifenacin HBr,"Darifenacin is a potent and competitive M 3 selective receptor antagonist (M 3 SRA), and its hydrobromide salt ( 1 ) is the active ingredient of pharmaceutical formulations for oral treatment of urinary incontinence. The present work demonstrates an efficient, commercial manufacturing process for darifenacin hydrobromide ( 1 ).",10.1021/op300119s,1
"Nitration Under Continuous Flow Conditions: Convenient Synthesis of 2-Isopropoxy-5-nitrobenzaldehyde, an Important Building Block in the Preparation of Nitro-Substituted Hoveyda–Grubbs Metathesis Catalyst","Herein, we describe the use of continuous flow chemistry for selective, efficient and reproducible nitration of 2-isopropoxybenzaldehyde to produce the desired 2-isopropoxy-5-nitrobenzaldehyde, an important building block in the preparation of a ligand of nitro-substituted Hoveyda–Grubbs metathesis catalyst. Nitration was done with red fuming HNO 3, and this challenging and hazardous process was performed using a flow-through silicon-glass microreactor equipped with a set of temperature sensors, and with a productivity of 13 g/h, providing us with a reproducible chemical process amenable for production of sufficient quantities of 2-isopropoxy-5-nitrobenzaldehyde for ongoing large-scale synthesis of nitro-substituted Hoveyda–Grubbs metathesis catalyst.",10.1021/op300116j,1
Science of Synthesis Workbench Edition: Stereoselective Synthesis,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewScience of Synthesis Workbench Edition: Stereoselective SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 6, 1242Publication Date (Web):May 17, 2012Publication History Published online17 May 2012Published inissue 15 June 2012https://pubs.acs.org/doi/10.1021/op300112zhttps://doi.org/10.1021/op300112zbook-reviewACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views943Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Aldol reactions,Halogenation,Organic reactions,Transfer reactions Get e-Alerts",10.1021/op300112z,0
Pharmaceutical Process Development: Current Chemical and Engineering Challenges,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewPharmaceutical Process Development: Current Chemical and Engineering ChallengesWill WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United Kingdom, E-mail: [email protected]Cite this: Org. Process Res. Dev. 2012, 16, 5, 1154Publication Date (Web):May 4, 2012Publication History Published online4 May 2012Published inissue 18 May 2012https://pubs.acs.org/doi/10.1021/op300105mhttps://doi.org/10.1021/op300105mbook-reviewACS PublicationsCopyright © 2012 American Chemical SocietyRequest reuse permissionsArticle Views1585Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Crystallization,Drug discovery,Pharmaceuticals,Pharmaceutics,Separation science Get e-Alerts",10.1021/op300105m,0
Safety Assessment for the Scale-up of an Oxime Reduction with Melted Sodium in Standard Pilot-Plant Equipment,"A pilot-plant process is described for the reduction of 2-allyl cyclohexanone oxime with melted sodium in xylenes, toluene, and 4-methyl-2-pentanol. The trans / cis ratio was 3–4:1. Safety data are presented from a range of thermokinetic experiments (heat flow calorimetry, differential scanning calorimetry, and accelerating rate calorimetry). The process has been designed and developed to enable an expedient and safe scale-up in a standard enameled 100-L steel reactor and has been reproduced six times on 209 mol scale (each 4.8 kg sodium). Crystallization of the product 2-allyl cyclohexylamine with oxalic acid from the reaction mixture in tert -butyl methyl ether successfully avoided the yield losses associated with the isolation of the volatile free 2-allyl cyclohexylamine.",10.1021/op300101d,0
Sulphuric Acid as Neutralization Agent for the Removal of Caesium in the Production Process of a Commodity Polyether-Polyol,"The aim of this work was the optimization of the neutralization process to remove the catalyst from a polyether polyol. Some parameters were studied: water content, dehydration curve conditions, the acid concentration of the neutralization solution, and temperature. The final cesium content was kept under the specified value. However, the final value of polyol acidity was higher than that of the commercial specification for these kinds of polyol.",10.1021/op3000948,0
"Synthesis of an H<sub>3</sub> Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition","We describe the development of an efficient and scalable process for the preparation of fluorocyclobutane-containing H 3 antagonist, 1 . The synthesis was accomplished by the chemoselective addition of a magnesium ate complex and an amine to a 1,4-ketoester in a one-pot sequence, followed by a diastereoselective carbonyl-directed fluorination. The chemoselective addition of the magnesium ate complex to the ketoester benefited from tight stoichiometric control, short addition times, and lower reaction temperatures, and thus was amenable to rapid mixing and excellent heat transfer in a flow reactor.",10.1021/op300093j,0
"Process Development and Optimization for Production of a Potassium Ion Channel Blocker, ICA-17043","A scalable process for the manufacture of a potassium ion channel blocker was developed and optimized. Key features of the process include an optimized Grignard reaction, a direct cyanation of the intermediate trityl alcohol derivative, and an improved nitrile hydrolysis protocol, relative to the original acidic hydrolysis conditions, to generate the crude active pharmaceutical ingredient (API) with >95% HPLC purity. The Grignard and the cyanation reactions could be telescoped, resulting in an improved throughput compared to the original four-step process. An effective recrystallization of the API was also developed and the process scaled up to manufacture multiple batches at the pilot scale.",10.1021/op3000916,1
OPRD’s First Large Scale Review,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTOPRD's First Large Scale ReviewJaan PestiCite this: Org. Process Res. Dev. 2012, 16, 6, 1155Publication Date (Web):April 9, 2012Publication History Published online9 April 2012Published inissue 15 June 2012https://pubs.acs.org/doi/10.1021/op3000866https://doi.org/10.1021/op3000866editorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3304Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (112 KB) Get e-AlertscloseSUBJECTS:Chemical reactions,Evolution reactions,Oxidation,Transfer reactions Get e-Alerts",10.1021/op3000866,0
A Flow-Based Synthesis of 2-Aminoadamantane-2-carboxylic Acid,"The development of a new, high-yielding, scalable and safe process for the preparation of 2-aminoadamantane-2-carboxylic acid ( 1 ) is described. This geminal, functionalized achiral amino acid has been reported to possess interesting biological activity as a transport mediator due to its unique physiochemical properties. We report herein on the use of various mesoreactor flow devices to expedite the lab-scale synthesis of this molecule by simplifying the processing requirements for use of several potentially hazardous reagent combinations and reaction conditions.",10.1021/op300084z,1
Continuous Processes: Go with the Flow!,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTContinuous Processes: Go with the Flow!Jaan PestiCite this: Org. Process Res. Dev. 2012, 16, 5, 843Publication Date (Web):April 4, 2012Publication History Published online4 April 2012Published inissue 18 May 2012https://pubs.acs.org/doi/10.1021/op300081qhttps://doi.org/10.1021/op300081qeditorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1807Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (114 KB) Get e-AlertscloseSUBJECTS:Amorphous materials,Chemical engineering and industrial chemistry,High school chemistry,Photochemical reactions,Stability Get e-Alerts",10.1021/op300081q,0
"Identification, Synthesis, and Strategy For Minimization of Potential Impurities Observed In Raltegravir Potassium Drug Substance","Multiple sources of anticipated degradation and process impurities of raltegravir potassium drug substance observed during the laboratory optimization and later during its bulk synthesis are described in this article. The impurities were monitored by UPLC, and their structures are tentatively assigned on the basis of fragmentation patterns in LC–MS and NMR spectroscopy. Most of the impurities are synthesized, and their assigned constitutions were confirmed by co-injection in UPLC. In addition to the formation, synthesis, and characterization, strategy for minimizing these impurities to the level accepted by ICH is also described. We feel that our study will be helpful to the generic industry for obtaining chemically pure raltegravir potassium.",10.1021/op300077m,1
"Enantioselective, Chromatography-Free Synthesis of β<sup>3</sup>-Amino Acids with Natural and Unnatural Side Chains","β 3 -Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile α-amino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β 3 -amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt–Eistert homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β 3 -amino acids possessing unnatural side chains.",10.1021/op300069n,1
Process Development of a Novel Azetidinyl Ketolide Antibiotic,"Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4-carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.",10.1021/op300064b,0
Process Development and Pilot-Plant Synthesis of (<i>S</i>)-<i>tert</i>-Butyl 1-Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the Scale-Up of Kulinkovich–Szymoniak Cyclopropanation,"A practical and scalable synthesis of ( S )- tert -butyl 1-oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starting from readily available materials. A modified Kulinkovich–Szymoniak cyclopropanation of a nitrile followed by in situ amide formation with an activated carboxylic acid derivative afforded the target product in about 50% overall isolated yield and >97% purity.",10.1021/op300059b,1
"An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers","An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.",10.1021/op300056k,1
Rapid Crystallization Process Development Strategy from Lab to Industrial Scale with PAT Tools in Skid Configuration,"Batch cooling crystallization is a commonly used separation and purification step in the pharmaceutical industry. Various properties of the crystalline product from a batch crystallizer can have a strong impact on the efficiency of downstream processes such as filtration and drying, on the formulation process and on the dissolution behaviour of the drug. Development of the crystallization processes presents a major challenge in the process development of an active pharmaceutical ingredient (API). Therefore, it is beneficial to develop a rapid crystallization process development strategy to industrial scale. In this paper we present a strategy for rapid process development and apply this strategy for androsta-1,4-diene-3,17-dione, cyclic 17-(2,2-dimethyltrimethylene acetal), a pharmaceutical intermediate produced by Merck Sharp and Dohme. The major advantages of the strategy are that there is no requirement of the crystallizer design modification, the calibration of the process analytical technology (PAT) tools can be performed at industrial scale, and the determination of the operating window can be done directly at the industrial scale. This strategy allows for process optimization directly at the industrial scale, thus eliminating the need for time-intensive scale-dependent study. The implementation of this strategy at industrial scale was performed with the help of PAT tools arranged in a unique skid-based configuration. The skid which contains both the concentration sensors and the crystal size distribution (CSD) sensors can be connected to the existing crystallizers, thereby avoiding the time and cost-intensive modifications in the crystallizer design. The modular nature of the skid offers opportunities to choose the PAT tools which complement the solute–solvent model system. The skid makes it possible to gather the relevant information concerning the thermodynamics and kinetics of the model system in situ during the crystallization runs at the industrial scale. A strategy for process development based on a sensor skid is beneficial for the industry as it is intrinsically rapid and can be combined with the development of control strategies which lead to consistent product quality.",10.1021/op300055g,0
The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin,"The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline to 1-( S )-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1 S )-(3 R )-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1 H )-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl] 2 -( S )-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1–2 equiv of H 3 PO 4, 60 °C, 20 bar H 2, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).",10.1021/op3000543,1
Development of an Enantioselective Hydrogenation Based Synthesis of a Glucokinase Activator,"This article describes the development and optimization of chemical reactions and subsequent multikilogram preparation of the glucokinase activator ( R )- 1 to fund clinical evaluation as a potential therapeutic for type II diabetes. The major process developments presented here are a Wittig olefination isomerization based synthesis of an E -acrylic acid, an optimized enantioselective hydrogenation of the E -acrylic acid, and a challenging final amide coupling.",10.1021/op300053a,1
Synthesis of Phenylboronic Acids in Continuous Flow by Means of a Multijet Oscillating Disc Reactor System Operating at Cryogenic Temperatures,"A multijet oscillating disk (MJOD) millireactor system suitable for operating at cryogenic temperatures has been developed, assembled, and investigated. This new reactor system (cryoMJOD) was realized with the purpose to prepare various phenylboronic acids in a continuous two (three)-step telescoped synthetic process at temperatures in the interval −50 to −75 °C. In this process, n -butyllithium was reacted with a phenylbromide to provide the corresponding phenyllithium derivative, whereupon a borate was added under the formation of target product phenylboronic acid in good selectivity and medium-to-good yield (50–75%). These results were competitive with results previously revealed in the literature. The residence times of the telescoped two-step process were considerably shorter compared to those of batch mode operations for the identical syntheses. The flow process was optimized by means of statistical experimental design and multivariate regression, upon which the process was utilized for the production of a series of phenylboronic acid derivatives, all in medium-to-good yield. One of the substrates, 4-methoxyphenylboronic acid, was submitted for throughput improvements, resulting in a process with capability to produce the product phenylboronic acid in a quantity of 2.0 kg × day –1 .",10.1021/op3000493,0
Kinetic and Safety Characterization of the Nitration Process of Methyl Benzoate in Mixed Acid,The nitration of methyl benzoate is studied from a chemical and a kinetic point of view. The reaction network through which the system could evolve following the loss of thermal control or the uncorrect feed of the reagents is completely characterized. The data collected during the present investigation indicate that runaway phenomena can occur during the nitration of the substrate due to the development of side reactions. Isothermal experiments are thus carried out to estimate the unknown kinetic parameters through the adoption of a mathematical model able to predict the system behaviour upon variation of process parameters. The dependence of the acidity function H on the operating conditions is assessed. The proposed model and the estimated parameters are validated through the use of the results collected in a set of experimental runs performed at significantly different operating conditions from those adopted to identify them.,10.1021/op300043x,0
Process Development of Citalopram/Escitalopram Oxalate: Isolation and Synthesis of Novel Impurities,"During process optimization of Escitalopram oxalate novel impurities, 6 and 7 were observed, which were isolated and characterized, and the proposed structure was confirmed by chemical synthesis. Investigation of the cause of impurities formation improved the yield and purity of the drug product during the bulk API synthesis.",10.1021/op300039c,1
Innovation in Generic API Synthesis and Manufacture,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTInnovation in Generic API Synthesis and ManufactureTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 3, 365Publication Date (Web):March 7, 2012Publication History Published online7 March 2012Published inissue 16 March 2012https://pubs.acs.org/doi/10.1021/op300038xhttps://doi.org/10.1021/op300038xeditorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3869Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (108 KB) Get e-AlertscloseSUBJECTS:Manufacturing,Materials,Pharmaceuticals,Physical and chemical processes Get e-Alerts",10.1021/op300038x,0
Streamlined Process for the Conversion of Artemisinin to Artemether,"We report an improvement to the previously published manufacturing process for artemether, a key antimalarial drug, utilizing readily available reagents, easily controlled manufacturing conditions, and a greatly simplified workup and isolation. New analytical methods and in-process controls allow for optimization of yield through control of side product formation. A 70% overall yield from the two-step conversion of naturally or synthetically derived artemisinin to pure β-artemether is obtained. This corresponds to a usage factor of 1.35 kg of artemisinin needed to produce 1 kg of β-artemether, compared to the current industry average of 1.59 kg.",10.1021/op300037e,0
Heat Transfer Based Scale-Down of Chemical Reactions,"Mathematical models of dose controlled reactions based on heat flow data (1, 2) are quite common and well developed; however, such predictions for nondose controlled reactions from heat flow data are difficult, requiring extensive study of the kinetics of multiple chemical transformations as well as physical phenomena such as dissolution and diffusion. Presented here is a new scale-down methodology to directly observe, in the laboratory, a variety of dose controlled and nondose controlled large scale thermal effects. This experiment-based scale-down approach has been derived mathematically from first principles, as well as demonstrated experimentally. This approach limits the heat transfer of the laboratory reactor to the scale equivalent of the intended large scale vessel by dynamic jacket set points based on the ratio of the heat transfer coefficients of lab and plant scale reactors. This allows large scale reaction temperature and other temperature-related effects to be mimicked on small scale while maintaining the time/reaction temperature response profile of the large scale vessel in the laboratory. The result is a method for the direct observation, in the laboratory, of the scale-up effects of changing a wide range of process variables for both dose controlled and non-dose controlled systems. Applications for this methodology could include evaluating the effects of proposed large scale process changes on process safety, product purity, or product physical properties as well as evaluating the effects of failure scenarios.",10.1021/op300036p,0
Corey–Itsuno Reduction of Ketones: A Development of Safe and Inexpensive Process for Synthesis of Some API Intermediates,"A safe and inexpensive procedure for asymmetric reduction of ketones using in situ prepared N, N -diethylaniline borane (DEANB) and oxazaborolidine catalyst from sodium borohydride, N, N -diethylaniline hydrochloride and ( S )-α,α-diphenylprolinol is described. This protocol is demonstrated successfully to manufacture enantiopure dapoxetine at the plant scale.",10.1021/op300034u,1
"Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor","The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions.",10.1021/op300031r,1
"An Efficient and Telescopic Process for Valsartan, an Angiotensin II Receptor Blocker","An efficient, telescopic, and scalable process for an antihypertensive drug substance, valsartan with an overall yield of 58%, and ∼99.9% purity is described. A simple, and safe process is developed for the recovery of tributyltin chloride from the tributyltin hydroxide, byproduct formed in the tetrazole ring construction, and reused in the synthesis of valsartan.",10.1021/op3000306,1
Improved Process for Ranolazine: An Antianginal Agent,"An improved process has been developed for the active pharmaceutical ingredient, ranolazine with 99.9% purity and 47% overall yield (including three chemical reactions and one recrystallization). Formation and control of all the possible impurities is described. All the solvents used in the process were recovered and reused. The unreacted piperazine is recovered as piperazine monophosphate monohydrate salt.",10.1021/op300026r,1
Flexible and Scalable Route to HDAc Inhibitors Containing an Unusual Trisubstituted Pyridine Core,"A scalable route to histone deacetylase inhibitors containing an unusual 2-aryl-3-cyano-5-aminomethylpyridine core has been developed which has the flexibility to deliver a range of compounds on at least a multigram scale. The key step involves a novel Mannich reaction using 3-dimethylaminoacrolein, formaldehyde, and a secondary amine to yield a 2-(alkylaminomethyl)-3-dimethylaminoacrolein. Tuning of this reaction in process development was fundamental to the success of the approach in terms of flexibility and operability on scale-up. This new methodology will also enable access an underutilised family of 3,5-disubstituted pyrid-2-ones and 2,3,5-trisubstituted pyridines.",10.1021/op300021m,1
An Improved Scalable Route to Pure Dronedarone Hydrochloride,"An efficient scalable synthesis for dronedarone hydrochloride ( 2 ) via Friedel–Craft acylation of 2-(-2-butyl-1-benzofuran-5-yl)-1 H -isoindole-1,3(2 H )dione ( 12 ) with 4-(3-chloropropoxy) benzoic acid ( 13 ) in good yield and high purity has been developed by using Eaton’s reagent instead of hazardous and toxic metal halide catalyst like AlCl 3 or SnCl 4 .",10.1021/op300017v,1
Safety Concerns in a Pharmaceutical Manufacturing Process Using Dimethyl Sulfoxide (DMSO) as a Solvent,"During the process safety analysis of a fluoride displacement reaction, a highly exothermic event was observed when the reaction mixture was heated, which appears to be due to the decomposition of DMSO catalyzed by the HF byproduct from the displacement reaction. Although the T D24 for the decomposition is 42 °C above the reaction temperature and the synthesis reaction is mild, the consequences of the decomposition reaction are severe and could exceed the emergency venting capability of the reactor in the case of uncontrolled heating or an external fire, even at pilot plant scale. The use of several bases, cosolvents, and alternative solvents was investigated. Administrative safeguards, including temperature control system limits and removal of flammable solvents from the area, were identified to establish a basis of safety for a scale up to pilot scale. However, these safeguards would be impractical in a manufacturing facility. Eventually, an N -methyl-2-pyrrolidone (NMP)/ tert -butyl methyl ether (MTBE) solvent system was identified, which provided an acceptable process while eliminating the use of DMSO and the associated decomposition reaction. This work shows some of the potential hazards that need to be investigated when using DMSO in a process. While DMSO alone can decompose near its boiling point, the effect of impurities, including byproducts of reactions, can lower the onset and increase the rate of this decomposition. Also, although this process falls into a Stoessel criticality index of 2, which is on the lower risk side of the scale, this case provides a good example where a low probability event needs to be investigated due to the severity of the consequences.",10.1021/op300016m,0
Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor,"In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.",10.1021/op300012d,1
New Manufacturing Procedure of Cetirizine,"A new procedure for the manufacture of cetirizine dihydrochloride via the new intermediate 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)- N, N -dimethylacetamide dihydrochloride, synthesized by O-alkylation of 2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethanol with 2-chloro- N, N -dimethylacetamide, is elaborated. Hydrolysis of the resulting amide and subsequent salification provided cetirizine dihydrochloride.",10.1021/op300009y,1
Initial Process Development and Scale-Up of the Synthesis of a Triple Reuptake Inhibitor ALB 109780,"Early process development toward a triple reuptake inhibitor is described. Three different routes were evaluated; one of them was optimized and scaled up to generate 470 g of API as this route minimized the formation of undesired side products. The selected route featured Eaton’s reagent-mediated cyclization of a phenyl acetamide, copper-mediated Buchwald–Hartwig coupling to install a morpholine moiety, and palladium-catalyzed α-arylation of a dihydroisoquinolinone to construct the core structure.",10.1021/op3000064,1
Kilogram-Scale Production of Corannulene,"An efficient entry process for the synthesis of corannulene has been demonstrated on kilogram scale. Compared to the discovery and gram-scale syntheses, the amounts of solvents and reagents per gram of product were greatly reduced. Priority was given to implement the least toxic agents possible. Improvements in the purification of products obviated the need for column chromatography, alleviating four chromatographic operations. A new reduction method for the final step of the synthesis decreased reaction time from 6 to 0.5 days, and avoided the use of 100 equiv of zinc metal. The process now comprises nine steps, each of which runs smoothly at 100-L scale with a charging of 3–12 kg of educt. A total of 1.3 kg corannulene was isolated. This kilogram-scale process reduces material costs by over 2 orders of magnitude compared to that for the published gram-scale syntheses. Key opportunities in the process are identified for further improvements that should make synthesis on 100-kg scale feasible with a target price for 1 that is suitable for commercial production and engineering application.",10.1021/op200387s,1
"Preparation of Spherical Particles of 1,1-Diamino-2,2-dinitroethene (FOX-7) Using a Micellar Nanoreactor","The need and preparation of spherical 1,1-diamino-2,2-dinitroethene (FOX-7) particles to meet certain special applications in high explosives and propellant formulation have been illustrated. Preparation of spherical FOX-7 particles by using a microemulsion technique has not been reported in the literature. In the present study, the preparation of spherical FOX-7 particles has been described using the novel concept of a micelle-based nanoreactor. Micelle-based nanoreactors have been prepared using a microemulsion of Triton X-100, cyclohexane, and water. Formation of spherical FOX-7 particles in the reverse micelle reactors have been described in the subsequent sections of this article. It is observed that spherical particles of FOX-7 are formed within 2 h in the microemulsion media. Analysis of the experimental results revealed that the particle size and shape of FOX-7 can be varied by changing the water/surfactant molar ratio in the microemulsion. Spherical particles synthesized by this method have diameters that are generally in the submicrometer to nanometer range. Impact sensitivity ( h 50 ) of the spherical particles obtained by the fall-hammer method is around 45 cm compared to regular synthesized FOX-7 (i.e., 50 ± 5 cm) without any change in friction sensitivity, i.e. 36 kg. Loadability of the explosive charges can be enhanced by using these spherical particles of FOX-7.",10.1021/op200386u,0
A Safe and Scalable Procedure for Preparation of α-Picoline–Borane from Sodium Mono-acyloxyborohydrides and α-Picoline,"Sodium monobenzoxyborohydride, which is easily prepared from sodium borohydride and benzoic acid in THF in situ, is treated with α-picoline in THF under mild conditions to give α-picoline–borane in an excellent yield. This method can be a practical preparation for α-picoline–borane.",10.1021/op2003858,0
Continuous Dehydration and Hydrogenolysis of Glycerol over Non-Chromium Copper Catalyst: Laboratory-Scale Process Studies,"A non-chromium Cu:Al catalyst was developed for glycerol dehydration under N 2 atmosphere to acetol and hydrogenolysis to 1,2-propanediol (1,2-PDO). Among the various copper-based catalysts screened in this work, Cu:Al-1 catalyst showed the highest activity and acetol selectivity in water medium, whereas transfer hydrogenation in 2-propanol as the reaction medium led to the formation of 1,2-PDO (10–38%). The same catalyst was also found to catalyze the direct hydrogenolysis of glycerol to 1,2-PDO. Time on stream activity (TOS) of our Cu:Al-1 catalyst for both continuous dehydration and hydrogenolysis of glycerol was found to be 400 h with an average glycerol conversion of 90% and 65%, respectively. Maximum acetol selectivity was 55% while 1,2-PDO selectivity was 91% in dehydration and hydrogenolysis reactions separately. Effects of various reaction conditions on conversion, selectivity, and global rates of the two processes were also investigated.",10.1021/op200383r,0
Large-Scale Carbonyl Reductions in the Pharmaceutical Industry,"Herein we present a review on methods for carbonyl reductions on large scale (≥100 mmol) applied to the synthesis of drug candidates in the pharmaceutical industry. We discuss the most common and reliable methods for the reduction of aldehydes, ketones, carboxylic acids, esters, amides, imides, and acid chlorides. Representative examples illustrate detailed reaction and workup conditions and highlight the advantages and limitations of each reducing agent with special emphasis on safety, cost, and amenability to scale-up.",10.1021/op2003826,0
Asymmetric and Diastereoselective Conjugate Addition Reactions: C–C Bond Formation at Large Scale,"Asymmetric and diastereoselective conjugate addition reactions are discussed from an industrial perspective including examples of (1) Lewis acid/Brønsted base catalysis, (2) phase transfer catalysis, (3) organocatalysis, and (4) transition metal/ligand catalysis with organometallic reagents.",10.1021/op200381w,1
Development of a Practical and Scalable Synthesis of a Potent Selective Dual Antagonist for 5-HT2B and 5-HT7 Receptors,"Process research and development of a practical and scalable synthetic route toward compound ( S ) - 1 and compound ( R ) - 1, which are potent selective dual antagonists for 5-HT2B and 5-HT7 receptors, respectively, is described. The medicinal chemistry route and second generation route were also unattractive for large-scale use for a variety of reasons. The new synthetic method does not require any purification by column chromatography for all steps and highly exothermic reactions. Additionally, we developed an efficient method of optical resolution in which each carboxylic acid isomer was separated with chiral amine in high yield and high enantiopurity. This highly efficient and scalable process was successfully demonstrated in the large scale synthesis of compound ( S ) - 1 and compound ( R ) - 1 in high enantiopurity.",10.1021/op200380z,1
Scale-Up of an Enantioselective Overman Rearrangement for an Asymmetric Synthesis of a Glycine Transporter 1 Inhibitor,"An enantioselective Overman 3,3-sigmatropic rearrangement on a quinuclidine skeleton was developed for the pilot-plant synthesis of a glycine transporter 1 inhibitor. The first stereocenter was produced by a Ru-catalyzed asymmetric transfer hydrogenation process followed by chirality transfer using the Overman rearrangement. The second stereocenter was generated by a diastereoselective hydrogenation reaction.",10.1021/op200378r,1
Why Publish in <i>Organic Process Research &amp; Development</i>???,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTWhy Publish in Organic Process Research & Development???Jaan PestiCite this: Org. Process Res. Dev. 2012, 16, 2, 173Publication Date (Web):January 30, 2012Publication History Published online30 January 2012Published inissue 17 February 2012https://pubs.acs.org/doi/10.1021/op200374vhttps://doi.org/10.1021/op200374veditorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1508Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (109 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Crops,Solvents Get e-Alerts",10.1021/op200374v,0
"A Brief Review on Industrial Alternatives for the Manufacturing of Glycerol Carbonate, a Green Chemical","Glycerol carbonate is one the glycerol derivatives which attracts attention for industrial applications. This review compares strategies for its synthesis, and their analyses lead to the conclusion that (indirect) procedures starting from glycerol- and/or CO 2 -derivatives are the most attractive. These are described and compared, taking criteria of industrial feasibility into account. As a result, the transesterification of dimethyl carbonate or ethylene carbonate with glycerol using uncalcined CaO as catalyst appears to be currently the most suitable industrial process. Finally, potential applications of glycerol carbonate as a multifunctional compound are exemplified.",10.1021/op200369v,1
"Development of an Efficient and Practical Route for the Multikilogram Manufacture of Ethyl 5-Cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and Ethyl 6-Chloro-5-cyano-2-methylnicotinate, Key Intermediates in the Preparation of P2Y12 Antagonists","Elucidation of the mechanism of formation of two major impurities in the synthetic route towards key intermediate ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 1, led directly to the development of a route with significant process improvements in terms of yield, purity, and operability. The overall process yield increased from 15% to 73% without the need for extra purification steps, giving the key intermediate ethyl 6-chloro-5-cyano-2-methylnicotinate, 2, in excess of 80 kg to support clinical development.",10.1021/op200368m,1
Green Chemistry is Good Process Chemistry,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTGreen Chemistry is Good Process ChemistryTrevor LairdCite this: Org. Process Res. Dev. 2012, 16, 1, 1–2Publication Date (Web):January 5, 2012Publication History Published online5 January 2012Published inissue 20 January 2012https://pubs.acs.org/doi/10.1021/op200366yhttps://doi.org/10.1021/op200366yeditorialACS PublicationsCopyright © 2012 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views10774Altmetric-Citations104LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (87 KB) Get e-AlertscloseSUBJECTS:Aromatic compounds,Green chemistry,Hydrocarbons,Solvents,Wastes Get e-Alerts",10.1021/op200366y,0
"Route Selection and Process Development of a Multikilogram Route to the Inhaled A<sub>2a</sub> Agonist UK-432,097","This article describes the selection, process development, and scale-up of a synthetic route to a complex nucleoside analogue, the A 2a agonist UK-432,097 ( 1 ), that culminated in the manufacture of over 25 kg of the API. The key steps in the process were (1) a stereoselective glycosidation reaction; (2) a scalable bleach–TEMPO oxidation; and (3) an unusual elevated temperature crystallization process for the final API. The problems that were encountered with the scale-up of the route together with how they were overcome are also presented.",10.1021/op200365n,1
Development of Two Complementary Syntheses for a Privileged CGRP Receptor Antagonist Substructure,"1-(Piperidin-4-yl)-1 H -imidazo[4,5- b ]pyridin-2(3 H )-one ( 1 ) is a privileged substructure found in >1000 unique CGRP receptor antagonists. Two practical and efficient syntheses of 1 are described from complementary starting materials. One route features a chemoselective reductive amination, while the second route utilizes a Pd-catalyzed amination using an ammonia surrogate to overcome an issue of poor selectivity.",10.1021/op2003634,1
"Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation","A fully continuous process including an asymmetric hydrogenation reaction operating at 70 bar hydrogen, aqueous extraction, and crystallization was designed, developed, and demonstrated at pilot scale. This paper highlights safety, quality, and throughput advantages of the continuous reaction and separations unit operations. Production of 144 kg of product was accomplished in laboratory fume hoods and a laboratory hydrogenation bunker over two continuous campaigns. Maximum continuous flow vessel size in the lab hoods was 22 L glassware, and maximum plug flow tube reactor (PFR) size in the bunker was 73 L. The main safety advantages of running the hydrogenation reaction continuous rather than batch were that the flow reactor was smaller for the same throughput and, more importantly, the tubular hydrogenation reactor ran 95% liquid filled at steady state. Therefore, the amount of hydrogen in the reactor at any one time was less than that of batch. A two-stage mixed suspension–mixed product removal (MSMPR) cascade was used for continuous crystallization. Impurity rejection by continuous crystallization was superior to that by batch because scalable residence time and steady-state supersaturation enabled robust and repeatable control of enantiomer rejection in a kinetic regime, although this is a nonstandard approach, debatable as an impurity control strategy. The fully continuous wet-end process running in a laboratory infrastructure achieved the same weekly throughput that would be expected from traditional batch processing in a plant module with 400 L vessels.",10.1021/op200362h,1
Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A,"A safe, practical and scalable process for manufacture of (−)-huperzine A has been developed and scaled up to manufacture several hundred grams of (−)-huperzine A with chemical and optical purity of >99%. The process consists of 11 chemical stages starting from commercially available materials with only nine isolation steps and no chromatography purification. This process provides a reliable and cost-effective source of synthetic (−)-huperzine A and its derivatives for pharmaceutical and nutraceutical markets.",10.1021/op200360b,1
First- and Second-Generation Practical Syntheses of Chroman-4-one Derivative: A Key Intermediate for the Preparation of SERT/5-HT<sub>1A</sub> Dual Inhibitors,"Two approaches to large-scale synthesis of the key intermediate 9, a precursor of novel dual inhibitors of SERT/5-HT 1A receptor, are described. These two approaches each feature a mild and efficient method for construction of the chroman-4-one scaffold, which can be used with substrates containing base-sensitive functionalities and enable synthesis on kilogram scale without chromatographic purification. The first-generation synthesis enables quick delivery of a kilogram quantity of the key intermediate 9 with only one slurry purification step. On the other hand, the highly practical second-generation synthesis is suitable for the multikilogram campaign.",10.1021/op200357h,1
Preparation of (<i>S</i>)-1-Cyclopropyl-2-methoxyethanamine by a Chemoenzymatic Route Using Leucine Dehydrogenase,"( S )-1-Cyclopropyl-2-methoxyethanamine is a key chiral intermediate for the synthesis of a corticotropin-releasing factor-1(CRF-1) receptor antagonist. Resolution of the racemic amine by transaminase from Vibrio fluvalis gave a 38% yield of the S -amine with 53% ee. Resolution by lipase-catalyzed acylation provided the S -amine in 35% yield with 91% ee. With limited success of these resolution approaches, an efficient chemo-enzymatic route to ( S )-1-cyclopropyl-2-methoxyethanamine was devised starting from methylcyclopropyl ketone. Permanganate oxidation of the ketone gave cyclopropylglyoxylic acid, which was converted to ( S )-cyclopropylglycine by reductive amination using leucine dehydrogenase from Thermoactinomyces intermedius with NADH cofactor recycling by formate dehydrogenase from Pichia pastoris . Both enzymes were cloned and expressed in recombinant E. coli . ( S )-Cyclopropylglycine obtained from enzymatic reductive amination was isolated as the N -Boc derivative and converted to the desired amine by reduction, methylation, and deprotection to give ( S )-1-cyclopropyl-2-methoxyethanamine in 62% overall yield from cyclopropylglyoxylic acid, with no detectable R -enantiomer.",10.1021/op2003562,1
Practical Asymmetric Synthesis of (+)-erythro Mefloquine Hydrochloride,A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as the hydrogen source. The ratio of formic acid to NEt 3 was found to be very important to achieving a highly efficient process.,10.1021/op200354f,1
Multikilogram Synthesis of 4-<scp>d</scp>-Erythronolactone via Batch and Continuous Processing,"The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4, d -erythronolactone at kilogram scale was used as an example. Fully continuous processing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.",10.1021/op200352k,0
Rapid Development and Scale-Up of a 1<i>H</i>-4-Substituted Imidazole Intermediate Enabled by Chemistry in Continuous Plug Flow Reactors,"The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches to a key 1 H -4-substituted imidazole intermediate ( 5 ). In a first generation approach, rapid optimization and scale-up of a challenging cyclization reaction was demonstrated in a PFR under GMP conditions to afford 29 kg of protected product 2 . This material was further processed in batch equipment to deliver di-HCl salt 4 . This first generation approach highlights the rapid development of chemistry in research-scale PFRs and speed to material delivery through linear scale up to a pilot-scale PFR under GMP conditions. In a second generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for rapid and data-rich reaction optimization of both a key cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1 kg demonstration runs in a 0.22 L PFR for both continuous steps and shows the potential of commercialization from a lab hood footprint (1–2 MT/year).",10.1021/op200351g,1
Mixing and Dispersion in Small-Scale Flow Systems,"Continuous flow chemistry is being used increasingly; however, without detailed knowledge of reaction engineering, it can be difficult to judge whether dispersion and mixing are important factors on reaction outcome. Understanding these effects can result in improved choices of reactor dimensions and give insight for reactor scale-up. We provide an overview of both dispersive and mixing effects in flow systems and present simple relationships for determining whether mixing or dispersion is important for a given flow system. These results are summarized in convenient charts to enable the experimentalist to identify conditions with potential mixing or dispersion problems. The information also expedites design changes, such as inclusion or changes of mixers and changes in reaction tube diameters. As a case study, application of the principles to a glycosylation reaction results in increased throughput and cleaner product profiles compared to previously reported results.",10.1021/op200349f,0
Managing Solids in Microreactors for the Upstream Continuous Processing of Fine Chemicals,"The management of solid compounds is a major challenge facing the upstream, continuous processing of pharmaceuticals and fine chemicals. Many reactions relevant to fine chemical production either react with or form insoluble materials, which become problematic in continuous flow microreactors. The deposition, growth, or bridging of compounds can limit fluid flow from the micro- to the mesoscale, and thereby render continuous reactors inoperable. A comprehensive approach for managing solids consists of solids identification, the development of the root failure mechanism(s), and the application of active and passive techniques for the prevention and remediation. This review examines the basic principles of microreactor design for reactions that involve solids, toward the goal of performing the continuous flow processing of fine chemicals.",10.1021/op200348t,0
Using Continuous Processes to Increase Production,"Continuous operations have become popular in both academia and the pharmaceutical industry. Continuous operations may be developed to make high-quality material safely, or because continuous operations are the only effective and economical way to make larger quantities of material. This review surveys the area of continuous processes used to make larger quantities of material and discusses the feasibility of developing economical continuous operations.",10.1021/op200347k,0
Development of an Improved Process for Doxercalciferol via a Continuous Photochemical Reaction,"Doxercalciferol (1α-hydroxyvitamin D2) is a commercially approved vitamin D derivative used to treat chronic kidney disease (CKD) patients whose kidneys cannot metabolically introduce a hydroxyl group at C1. A new process for the production of doxercalciferol from ergocalciferol was developed using a continuous photoisomerization of a known vitamin D intermediate as the key step, thus circumventing the limitations of batch photoisomerization processes. Doxercalciferol is produced in an overall yield of about 10% from ergocalciferol.",10.1021/op200346g,1
Manufacture of a β-Hydroxyester via a Continuous Reformatsky Process,"The use of continuous processing in a Reformatsky reaction has been investigated as a means to control the large heat of reaction and reduce the inventory of hazardous materials. A laboratory-scale continuous miniplant for manufacture of an aromatic β-hydroxyester has been designed and built for a production rate of about 100 mL/h. The plant operated at steady state for several hours and provided strong evidence that a larger-scale continuous plant could readily be designed. For this chemistry, the use of continuous processing is not only a safer and more efficient technology (as compared to the typical batch process) but also cleaner, giving fewer byproduct and at much lower concentration.",10.1021/op2003453,0
Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide,"The development and scale-up of a synthetic route to tasisulam sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt, hereafter referred to as tasisulam) utilizing continuous Schotten–Baumann reaction conditions is disclosed. A new synthetic route for the cytotoxic API amenable to continuous processing was envisioned that would minimize potential worker exposure by reducing the number of unit operations and would allow commercial-scale API production in laboratory fume hoods with inexpensive glassware. The developed Schotten–Baumann conditions contained fewer unit operations than the existing batch process by utilizing the direct formation of the final sodium salt from a sulfonamide and acid chloride without isolation of the free acyl sulfonamide. Batch development, continuous proof of concept studies, 5.2 g/h lab-scale demonstration and 5 kg/day commercial-scale runs will be discussed. Very stringent release specifications were in place for the tasisulam API batch process, and the challenges of meeting these requirements for the continuous process are detailed. Finally, the quality of material generated during startup and shutdown transitions will be addressed.",10.1021/op200344a,1
"Process Development and Scale-Up of AZD7545, a PDK Inhibitor","A brief comparison of the early manufacturing routes to AZD7545 is given. Process development of the preferred long-term manufacturing route is reported in detail, and changes from the initial kilogram-scale route are discussed. Scale-up experience from the pilot-plant manufacture is included in the discussion of each stage. Noteworthy aspects throughout the development of AZD7545 concerned chemical hazards, mechanisms, analysis, and impurities, upon which this case study will focus.",10.1021/op2003419,1
Development of a Continuous Flow Scale-Up Approach of Reflux Inhibitor AZD6906,"Early scale-up work of a promising reflux inhibitor AZD6906 is described. Two steps of an earlier route were adapted to be performed in continuous flow to avoid issues related to batch procedures, resulting in a robust method with reduced cost of goods and improved product quality. Toxic and reactive reagents and starting materials could be handled in a flow regime, thereby allowing safer and more convenient reaction optimization and production.",10.1021/op200340c,1
"Process Development and Large-Scale Synthesis of MK-6186, a Non-Nucleoside Reverse Transcriptase Inhibitor for the Treatment of HIV","A new synthetic route has been developed to drug candidate 1, a second-generation NNRTI being developed as a potential treatment of HIV. Regiocontrol in a key alkylation step was achieved by selective N -alkylation of hydrazone 13 . After a deprotection and cyclisation sequence, 1 was isolated in six steps in 35% overall yield from readily available starting materials.",10.1021/op200334x,1
Kilogram-Lab-Scale Oxindole Synthesis via Palladium-Catalyzed C–H Functionalization,"A scalable method for the preparation of oxindole 8, a key intermediate en route to a serine palmitoyl transferase inhibitor, compound 1, is presented. A three-step, chromatography-free route has been designed that takes advantage of Buchwald’s palladium-catalyzed C–H functionalization to cyclize an α-chloroacetanilide to form the five-membered ring. This process has been successfully carried out in our kilogram laboratory facility on 10-kg scale in 76% yield.",10.1021/op200332p,1
Selective Continuous Flow Processes Using Fluorine Gas,"The use of continuous gas–liquid flow reactors for processes involving fluorine gas is reviewed. Falling film, microbubble, and laminar flow reactors that have been adapted to carry out direct fluorination reactions are described, and a range of selective fluorination reactions involving direct fluorination of a variety of aromatic, dicarbonyl, diester and benzaldehyde derivatives are presented as well as related continuous flow oxidation processes (such as epoxidation reactions and the transformation of amines to nitro derivatives) involving fluorine gas.",10.1021/op200331s,1
Development of a Robust Procedure for the Copper-catalyzed Ring-Opening of Epoxides with Grignard Reagents,A general procedure for the copper-catalyzed regioselective ring-opening of epoxides with Grignard reagents is described. The procedure developed provides robust reaction conditions which limit the formation of impurities and has been applied successfully using a series of epoxides and Grignard reagents to provide the desired products in >90% yield with excellent regioselectivity and purity.,10.1021/op200329x,0
Practical and Scalable Synthesis of S1P<sub>1</sub> Receptor Agonist ACT-209905,"A practical and scalable route for the fast delivery of 12 kg of S1P 1 agonist (ACT-209905) has been developed. ACT-209905 is composed of an amino pyridine group, an oxadiazole spacer, a 2-ethyl-5-methylphenol moiety and a chiral 1-amino-2-propanol side chain. The convergent synthesis consists of 16 steps with 9 isolated intermediates and is chromatography-free. Key building blocks are accessed from low-cost starting materials, such as acetone, diethyl oxalate, cyanoacetamide, and 2-ethyl-5-methyl aniline. A Negishi coupling that was troubled by the use of metal reagents and concomitant metal waste streams has been replaced by a less expensive Guareschi–Thorpe reaction to build up an amino isonicotinic acid. The chiral 1-amino-2-propanol moiety was secured by selective ring-opening of an epoxide with lithium hexamethyldisilazide as an ammonia surrogate, thus omitting the notorious double alkylated byproduct.",10.1021/op200326s,1
Process Improvements of Prasugrel Hydrochloride: An Adenosine Diphosphate Receptor Antagonist,"An improved process for the synthesis of prasugrel hydrochloride with an overall yield of 58%, 99.9% purity, and meeting all other quality requirements is described.",10.1021/op200325u,1
Understanding and Control of Dimethyl Sulfate in a Manufacturing Process: Kinetic Modeling of a Fischer Esterification Catalyzed by H<sub>2</sub>SO<sub>4</sub>,"The formation and fate of monomethyl sulfate (MMS) and dimethyl sulfate (DMS) were studied by proton NMR for a sulfuric acid catalyzed esterification reaction in methanol. The kinetic rate constants for DMS and MMS were determined at 65 °C by fitting time-dependent experimental data to a model using DynoChem . In refluxing methanol, sulfuric acid was converted to monomethyl sulfate (MMS) in nearly quantitative yield within 45 min. Once formed, the MMS underwent a reversible esterification reaction to form DMS. Dimethylsulfate reacted with methanol to regenerate MMS and form dimethyl ether. A byproduct of the esterification reaction was water, which further consumed DMS through hydrolysis. On the basis of derived rate constants, in refluxing methanol, DMS would not be expected to exceed 4 ppm in the reaction mixture at equilibrium. In the presence of the carboxylic acid substrate, DMS was not detected in the reaction mixture. The reaction pathways of this system have been systematically investigated, and the results of this study will be presented.",10.1021/op200323j,0
"Development of a Safe and Efficient Two-Step Synthesis for Preparing 1-Bromoacetyl-3,3-dinitroazetidine, a Novel Clinical Anticancer Candidate","An efficient process for synthesizing and isolating a new investigative anticancer agent, 1-bromoacetyl-3,3-dinitroazetidine, is described. The reaction entails a sequence of oxidative nitration followed by acylative dealkylation. The methods reported give 50–60-g batches of high-purity product without a designated purification step. The reaction conditions have been designed to mitigate the safety concerns associated with gem -dinitroazetidines. Some observations on the acylative dealkylation mechanism are discussed.",10.1021/op2003216,0
"An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist","An efficient scale-up synthesis of ( S )-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(difluoromethoxy)phenylamino)-pyrazin-2(1 H )-one, 1 ( BMS-665053 ), is described. This new process features a one-step direct bis-ortho-chlorination of 4-(difluoromethoxy)aniline with HCl and H 2 O 2, and a palladium-catalyzed coupling of 2,6-dichloro-4-(difluoromethoxy)aniline 2 and ( S )-3,5-dichloro-1-(1-cyclopropylethyl)pyrazin-2(1 H )-one 3 . The process was applied to the preparation of batches of 1 for preclinical toxicology studies.",10.1021/op2003198,1
Selection and Development of a Route for Cholesterol Absorption Inhibitor AZD4121,"The development of a synthetic route to the cholesterol absorption inhibitor AZD4121 is presented. Key steps are a highly enantioselective CBS reduction, a stereospecific Staudinger reaction, an amine/lithium chloride mediated ester hydrolysis, and a resolution of a 50:50 diastereomeric mixture by recrystallization. The synthesis was accomplished in 10 linear steps, and the overall yield, when compared with the lead optimization (LO) route, was improved from 1% to 20%. All purifications of intermediates through preparative HPLC or silica gel chromatography were avoided. This was possible since many of the intermediates along the route could be used as such in the next step until an intermediate with suitable crystalline properties could be identified and purified through crystallization.",10.1021/op200314z,1
Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122,"Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.",10.1021/op200313v,1
"A New Efficient Synthetic Route for the Synthesis of the Antiallergic Drug, Olopatadine Hydrochloride, via Stereospecific Palladium-Catalyzed Reaction","A new practical and efficient synthetic route for the synthesis of olopatadine hydrochloride via the intramolecular stereospecific seven-membered ring cyclization from an alkyne intermediate using palladium catalyst and hydride source was established. Furthermore, the optimization of that key stereospecific reaction was examined by design of experiment (DoE), and the desired Z -isomer could be obtained with high yield.",10.1021/op200312m,1
The Use of Glycidyl Ethers Involving Aziridinium Intermediates and Other Methodology for the Preparation of Enantiomerically Pure Drug Candidates,"An enantiospecific 1,2-amine migration process through an aziridinium intermediate involving ring-opening with potassium phthalimide derivatives to produce precursors to drug candidates was developed. The precursor amine derivatives were readily available by epoxide opening of simple glycidyl ether derivatives. The regioselectivity of the process was shown to provide approximately 85% of the desired rearranged product with subsequent conversion to the desired drug candidate occurring with excellent purity. An alternative approach using the same glycidyl ether derivatives as starting materials that overcame this regiochemical limitation was subsequently demonstrated.",10.1021/op200310y,1
New Synthetic Route to a Dipeptidyl Peptidase-4 Inhibitor,"A new synthetic route to a dipeptidyl peptidase-4 (DPP4) inhibitor was developed and demonstrated on a multigram scale. This approach takes advantage of the cheap and readily available Boc- trans -4-hydroxy- l -proline methyl ester as starting material which was derivatized through an S N 2 reaction. Several leaving groups were studied, and the nosylate group showed superiority over other derivatives. Formation of an amide using the most costly starting material, 3,3-difluoropyrrolidine, was performed late in the synthesis to minimize its economical impact on the overall cost of the API.",10.1021/op200309z,1
A Practical Stereoselective Synthesis and Novel Cocrystallizations of an Amphiphatic SGLT-2 Inhibitor,"A practical synthesis of the SGLT-2 inhibitor β- C -aryl- d -glucoside ( 1 ) has been developed. The route employed 2,3,4,6-tetra- O -trimethlysilyl- d -glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d -gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C -aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with l -phenylalanine and l -proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The l -phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale.",10.1021/op200306q,1
Design and Scale-Up of a Practical Enantioselective Route to 5-Phenylbicyclo[2.2.2]oct-5-en-2-one,"A practical enantioselective route to chiral 5-phenylbicyclo[2.2.2]oct-5-en-2-one 1 has been designed and developed. The target compound has been obtained as colorless crystals in 22% yield from 2-cyclohexenone, with an enantiomeric ratio higher than 99.5:0.5 and notably high chemical purity (> 99%). Three intermediates out of nine chemical steps are isolated. It is noteworthy that this process is devoid of any chromatography or distillation although all but one intermediate are oils. Key to success was the optimization of an intramolecular aldol reaction of an in situ prepared ketone aldehyde leading to the solid intermediate (1 R,4 R,4 S,6 S )-6-hydroxybicyclo[2.2.2]octan-2-one 9a that is isolated in very high chemical and chiral purity. This is an example of an intramolecular crystallization-induced diastereomer transformation (CIDT). The dehydration of this secondary alcohol to 1 required an extensive screen of reaction conditions to secure an excellent purity, essential for crystallization of this low-melting compound. The final process is simple and concentrated as demonstrated by an expeditious synthesis of 1 kg of 1 in a 30-L reactor in 10 working days.",10.1021/op200305y,1
Practical Synthesis of A Benzophenone-Based NNRT Inhibitor of HIV-1,"A convergent synthesis of NNRTI 1 is described. The key step involves a direct coupling of acid chloride 4 with Grignard reagent 11 in the presence of bis[2-( N, N -dimethylamino)ethyl] ether that moderates the reactivity of the Grignard reagent to give benzophenone 7 . An efficient 2-step process for the preparation of 2-fluoro-3-methyl-4-aminobenzoic acid ( 3 ) is also described.",10.1021/op200301h,1
"Convergent, Fit-For-Purpose, Kilogram-Scale Synthesis of a 5-Lipoxygenase Inhibitor",Process research and development of a synthetic route towards a novel 5-lipoxygenase inhibitor is described. The synthetic route provided 1 in 27% yield in nine steps (seven steps in the longest linear sequence) and was performed on kilogram scale. The synthesis began with the preparation of the coumarin core via an efficient von Pechmann condensation. The triazole fragment was obtained via a regioselective copper-catalyzed [3 + 2] cycloaddition between a chiral alkyne and the coumarin azide.,10.1021/op200299p,1
Development and Application of a User-Friendly Automated HPLC Dilution Macro for API Route Optimization,"Concentration determination by HPLC analysis is often utilized in pharmaceutical development activities. Traditionally, manual dilutions employing volumetric glassware have to be performed to obtain accurate concentration results. To circumvent this, an automated dilution method for the Agilent 1100 HPLC system has been developed to dilute and inject the samples online. After appropriate calibration, quantitative analysis can be achieved by placing the solution samples directly into HPLC vials without additional manipulation. This method is successfully applied to active pharmaceutical ingredient (API) solubility measurements and concentration determinations of routine mother liquor samples in the range of 0.1–100 mg/mL. It is particularly useful in crystallization development where obtaining accurate concentration information quickly drives down development time and material requirements.",10.1021/op200289r,0
"Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers","This paper describes a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystallization developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersaturation. The results indicate that the stage in which anti-solvent is added has a significant influence on the final crystal properties, while purity and yield were nearly identical. The population balance model was employed to determine growth and nucleation kinetics through parameter estimation. With the incorporation of measured equilibrium distribution coefficients, the model was used to optimize crystal purity and yield of the product with respect to operating temperature and residence time.",10.1021/op2002886,0
Evaluation of Competing Process Concepts for the Production of Pure Enantiomers,"Various promising concepts exist for improving the performance of productions of pure enantiomers. An efficient approach is developed for the systematic conceptual design of such processes. The proposed three-step procedure aids a fast selection of the optimal process configuration out of many possible candidates and leads to an optimally designed process. The approach is applied in a case study for an industrially relevant compound, considering different process concepts based on simulated moving bed chromatography, enantioselective crystallization, and racemization. It is demonstrated that mixed-integer nonlinear programming is capable of predicting simultaneously the optimal process configuration and optimal design parameters.",10.1021/op200285v,0
Efficient Synthesis of Impurity-C of Antimigraine Agent Rizatriptan Benzoate,"During the commercial manufacturing of antimigraine drug Rizatriptan benzoate, several impurities are reported to be formed. This present work demonstrates a convergent and short synthesis of the most critical impurity (C) of Rizatriptan, [2-(5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indole-2-yl)- N, N -dimethylethanamine ( 1 )], recently reported in U.S. Pharmacopeia.",10.1021/op200284m,1
Large-Scale Synthesis of Singh’s Catalyst in a One-Pot Procedure Starting from Proline,"A practical one-pot procedure for the preparation of Singh’s catalyst from either l -/ d -proline or Boc-proline is described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the corresponding amino acid ester. Moreover, a procedure for tert -butoxycarbonyl (Boc) group removal using concentrated HCl in MeOH–DCM was developed and utilized for the multigram-scale synthesis of Singh’s catalyst.",10.1021/op200283q,0
Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring,"A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.",10.1021/op200275d,0
Development of the Large-Scale Preparation of 2-(Methanesulfonyl)benzenesulfonyl Chloride,"A practical and scalable process is described for the preparation of 2-(methansulfonyl)benzenesulfonyl chloride, a key building block used in the synthesis of several drug candidates. The material is prepared by an efficient four-step sequence from inexpensive 1,2-dichlorobenzene and methanethiol, and the process has been demonstrated on a multikilogram scale in 32% overall yield with a chemical purity of >98%.",10.1021/op2002744,1
Safety of Chemical Processes 11,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSafety of Chemical Processes 11Trevor LairdCite this: Org. Process Res. Dev. 2011, 15, 6, 1406Publication Date (Web):October 17, 2011Publication History Published online17 October 2011Published inissue 18 November 2011https://pubs.acs.org/doi/10.1021/op200273hhttps://doi.org/10.1021/op200273heditorialACS PublicationsCopyright © 2011 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1508Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (610 KB) Get e-AlertscloseSUBJECTS:Mathematical methods,Reagents,Safety Get e-Alerts",10.1021/op200273h,0
Safe Scale-Up of Processes Containing Hazardous Species in the Headspace with Inline IR,"Inline IR has been applied to evaluate the scale-up of processes that potentially generate hazardous diborane, hydrazoic acid, methyl chloride, or acetylene in the headspace of reactors. In addition, a new, simplified approach to calibrate the online IR analyzer for the measurement of hydrazoic acid in the gas phase has been described.",10.1021/op200271b,0
Process Intensification via Reaction Telescoping and a Preliminary Cost Model to Rapidly Establish Value,"Process intensification via reaction telescoping has recently been demonstrated in our research laboratories. The improved process is significantly streamlined; 1 intermediate isolation vs 2, 24 workup and purification unit operations vs 49, and a batch cycle time of 116 h vs 177 h are the key improvements realized. A preliminary cost model was developed to establish the value generated, which predicts a >50% reduction in the total cost to manufacture 1 kg of the product. This cost model can serve as a preliminary method for rapidly establishing the value of process intensification in the manufacture of fine and specialty chemicals.",10.1021/op200270f,0
"Design of an Integrated Process of Chromatography, Crystallization and Racemization for the Resolution of 2′,6′-Pipecoloxylidide (PPX)","An integrated process for the chiral separation of the industrially relevant substance 2′,6′-pipecoloxylidide (PPX), an intermediate in the manufacture of a number of anesthetics, was developed. By combining three different techniques, chromatography, crystallization, and racemization, high productivity was achieved. All unit operations were executed using a common solvent system, full recycling, and a minimum of solvent exchanges or removals. The target molecule was obtained with an enantiopurity of >99.5 wt %.",10.1021/op200268h,0
Holistic Route Selection,"New agrochemical, fine chemical, and pharmaceutical products often require the development and selection of economical and effective chemical routes to enable commercial success. Atom economy and reaction step minimization are key drivers for low-cost routes. In addition, capital requirements, process operability and robustness, environmental health and safety, supply chain, quality, and intellectual property factors should be considered in the selection process. A holistic evaluation of process route options by a multidiscipline team of chemists and engineers early in the route-selection phase can result in the selection of a better route with a more focused process development research plan. Examples from three Dow AgroSciences projects illustrate route selection criteria.",10.1021/op200264t,1
Allylic Amines as Key Building Blocks in the Synthesis of (<i>E</i>)-Alkene Peptide Isosteres,"Nucleophilic imine additions with vinyl organometallics have developed into efficient, high yielding, and robust methodologies to generate structurally diverse allylic amines. We have used the hydrozirconation-transmetalation-imine addition protocol in the synthesis of allylic amine intermediates for peptide bond isosteres, phosphatase inhibitors, and mitochondria-targeted peptide mimetics. The gramicidin S-derived XJB-5-131 and JP4-039 and their analogs have been prepared on up to 160 g scale for preclinical studies. These (E)-alkene peptide isosteres adopt type II' β-turn secondary structures and display impressive biological properties, including selective reactions with reactive oxygen species (ROS) and prevention of apoptosis.",10.1021/op2002613,1
Practical Convergent Laboratory-Scale Synthesis of a CCR5 Receptor Antagonist,"An efficient laboratory-scale synthesis has been developed for the selective CCR5 antagonist 1 . The convergent route has a longest linear sequence of nine steps (15 steps overall), and has overall yields of 18–25%. The route has enabled the preparation of 550 g of 1 .",10.1021/op200259t,1
Kilogram-Scale Synthesis of an Inhaled Corticosteroid,"The development and implementation of a safe and scalable process for the manufacture of corticosteroid PF-4714224 ( 1 ) is described. Initial routes used to synthesise analogues from this series directly from fluocinolone acetonide ( 2 ) were unsuitable for large-scale use. Key aspects of the route are the efficient and simple method for the preparation of the steroid tetraol ( 6 ), acetal formation by reaction of the tetraol with a bisulphite adduct ( 12 ), and isolation of the product by sequential recrystallisations.",10.1021/op200257g,1
Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy,"Inline near-infrared (NIR) spectroscopy has been used to monitor a continuous synthesis of an active pharmaceutical ingredient (API) intermediate by a Grignard alkylation reaction. The reaction between a ketone substrate and allylmagnesium chloride may form significant impurities with excess feeding of the Grignard reagent beyond the stoichiometric ratio. On the other hand, limiting this reagent would imply a loss in yield. Therefore, accurate dosing of the two reactants is essential. A feedforward–feedback control loop was conceived in order to maintain the reaction as closely as possible to the stoichiometric ratio, leading the path to full process automation. The feedback control loop relies on NIR transmission measurements performed in a flow cell where, in contrast to labor-intensive offline HPLC analytical methods, the whole reaction product can be scanned in real time without sample dilution. A robust PLS (projection to latent structures) model was developed with a satisfactory standard error of prediction, providing quantification of the ketone substrate in solutions with a high variability of the major solution component—the alkoxide product. In addition, model performance supervision tools such as the spectral residuals or simple plots of pretreated spectra can assist in the identification of spectral outliers, which in this case could be related to Grignard reagent excess. If the sampling time of the NIR instrument is short enough, manipulating the inputs to the reactor may be used to obtain information about its dynamic behavior. This information is very useful for process control design, assessment of analytical tools and definition of sampling times. In this work, a systematic procedure for chemometric model building is followed, after which a discussion is made on some of the potential applications that can be found when exploiting the fast and rich information provided by NIR spectroscopy.",10.1021/op2002563,0
Development of Safe One-Pot Synthesis of <i>N</i>-1- and <i>C</i>-2-Substituted Benzimidazole via Reductive Cyclization of <i>o</i>-Nitroarylamine Using Na<sub>2</sub>S<sub>2</sub>O<sub>4</sub>,"We report that the reductive cyclization of o -nitroarylamine with aldehyde using sodium dithionite (Na 2 S 2 O 4 ) could be accelerated by addition of H 2 O, which made it possible to control the heat release of the reaction by semibatch-type operation. Safety evaluation was performed using DSC, ARSST, in situ IR analysis, and Multimax.",10.1021/op200251c,1
Multikilogram-Scale Synthesis of a Chiral Cyclopropanol and an Investigation of the Safe Use of Lithium Acetylide–Ethylene Diamine Complex,"A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic resolution of a racemic cyclopropanol acetate. Process safety considerations surrounding the use of 5 were examined, and an improved procedure is described which was safely demonstrated at multikilogram scale.",10.1021/op2002497,1
Diarylketone Ketoreductase Screen and Synthesis Demonstration to Access mGlu2 Receptor Potentiators,"This communication describes proof of concept for an enantioselective enzyme-based synthesis of diarylmethanol ( S )- 1 to access mGlu2 receptor potentiators. A ketoreductase (KRED) screen was applied to benzophenone 8 to afford chiral diarylmethanol ( S )- 9, which is a useful intermediate for the preparation of chiral diarylmethanol ( S )- 1 . In addition, a more practical synthesis of benzophenone 8 was demonstrated utilizing Friedel–Crafts acylation and radical bromination chemistry.",10.1021/op2002479,1
Continuous Hydrolysis and Liquid–Liquid Phase Separation of an Active Pharmaceutical Ingredient Intermediate Using a Miniscale Hydrophobic Membrane Separator,"Continuous hydrolysis of an active pharmaceutical ingredient intermediate, and subsequent liquid–liquid (L-L) separation of the resulting organic and aqueous phases, have been achieved using a simple PTFE tube reactor connected to a miniscale hydrophobic membrane separator. An alkoxide product, obtained in continuous mode by a Grignard reaction in THF, reacted with acidic water to produce partially miscible organic and aqueous phases containing Mg salts. Despite the partial THF–water miscibility, the two phases could be separated at total flow rates up to 40 mL/min at different flow ratios, using a PTFE membrane with 28 cm 2 of active area. A less challenging separation of water and toluene was achieved at total flow rates as high as 80 mL/min, with potential to achieve even higher flow rates. The operability and flexibility of the membrane separator and a plate coalescer were compared experimentally as well as from a physical viewpoint. Surface tension-driven L-L separation was analyzed in general terms, critically evaluating different designs. It was shown that microporous membrane L-L separation can offer very large operating windows compared to other separation devices thanks to a high capillary pressure (Laplace pressure) combined with a large number of pores per unit area offering low pressure drop. The separation device can easily be operated by means of a back-pressure regulator ensuring flow-independent separation efficiency. Simple monitoring and control strategies as well as scaling-up/out approaches are proposed, concluding that membrane-based L-L separation may become a standard unit operation for continuous pharmaceutical manufacturing.",10.1021/op200242s,0
Development of a Potential Manufacturing Route to PF-00610355: A Novel Inhaled β<sub>2</sub>-Adrenoreceptor Agonist,"The development of a practical, scalable route to PF-00610355 ( 8 ) is described. In this convergent approach, amine 9 is coupled to protected bromohydrin 1 to give the doubly protected intermediate 26 . TBS-Deprotection of 26 affords the benzyl protected penultimate intermediate 25 which is crystallized as the corresponding hemifumarate salt 25a . On the basis of solubility data, the final debenzylation was conducted in aqueous THF, and the API ( 8 ) is isolated from acetonitrile by an unusual distillative crystallization process. The development of an efficient process to prepare amine 9 is also described.",10.1021/op2002408,1
Intermittent Simulated Moving Bed Processes for Chromatographic Three-Fraction Separation,"Simulated moving bed (SMB) chromatography is a well-established technique to resolve racemic mixtures into pure enantiomers. However, the conventional SMB process is restricted to binary separations, and its applicability is therefore limited when impurities are present. In this contribution we address this issue by considering impurities as a third fraction which is separated from the two product streams, i.e. the pure enantiomers, by two novel intermittent SMB (I-SMB) concepts. The process schemes studied consist of four sections, each section comprising only one column, and are straightforward extensions of the original I-SMB process; therefore, the switch time is also divided into two substeps. Substep I is characterized by feed and withdrawal of two product streams, whereas in substep II only pure solvent is introduced to the unit in order to recover the third product stream and to adjust the relative positions of the concentration fronts along the column train. The two concepts presented in this contribution differ in the column configuration and in the withdrawal of the product streams. One process is characterized by withdrawal of the most retained component during substep II, whereas in the other process the least retained species is recovered in the second substep. Consequently, these processes are termed 3S-ISMB and 3W-ISMB, respectively. These process schemes are analyzed in the frame of equilibrium theory under the assumption of linear chromatographic conditions, thus yielding a graphical representation of the region of complete ternary separation similar to classical triangle theory. Furthermore, an experimental study of the 3W-ISMB concept is presented in which a ternary system consisting of a mixture of the enantiomers of γ-phenyl-γ-butyrolactone and of the (−)-Tröger’s Base enantiomer (the impurity in this context) is separated in pure ethanol on the chiral stationary phase Chiralpak AD. These experiments are carried out under linear chromatographic conditions, namely the concentration of each solute is kept constant at 0.5 g/L. A purity of at least 94% for all product streams is achieved, which demonstrates successfully the potential of this novel, three-fraction SMB-like process.",10.1021/op200239e,0
Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor,"Novel PARP inhibitor 1 is a promising new candidate for treatment of breast and ovarian cancer. A modified synthetic route to 1 has been developed and demonstrated on 7 kg scale. In order to scale up the synthesis to multikilogram scale, several synthetic challenges needed to be overcome. The key issues included significant thermal hazards present in a Leimgruber–Batcho indole synthesis, a low-yielding side-chain installation, a nonrobust Suzuki coupling and hydrogen cyanide generation during a reductive amination. In addition to these issues, changing from intravenous to oral delivery required a new salt form and therefore a new crystallization procedure. This contribution describes development work to solve these issues and scaling up of the new process in the pilot plant.",10.1021/op200238p,1
"Catalytic Hydrogenation of Esters. Development of an Efficient Catalyst and Processes for Synthesising (<i>R</i>)-1,2-Propanediol and 2-(<i>l</i>-Menthoxy)ethanol","A ruthenium catalyst for the reduction of esters by hydrogenation has been developed. Processes for the hydrogenation of esters have also been developed for ( R )-1,2-propanediol and 2-( l -menthoxy)ethanol. The catalyst shows good catalytic activity for the hydrogenation of esters in methanol. Methyl lactate was reduced at 30 °C and gave turnover numbers (TON) up to 4000. The optical purity of the ( R )-1,2-propanediol made by the hydrogenation of methyl ( R )-lactate was higher than that via the asymmetric hydrogenation of hydroxyacetone. A hydrogenation process to replace the lithium aluminum hydride (LAH) reduction used in the production of 2-( l -menthoxy)ethanol was developed.",10.1021/op200234j,0
Development of a Scaleable Synthesis of a Geminal Dimethyl Tertiary Amine as an Inhaled Muscarinic Antagonist for the Treatment of COPD,"An efficient and scalable process for the synthesis of muscarinic antagonist, PF-3635659 1, is described, illustrating redesign of an analogue-targeted synthesis which contained a scale-limiting rhodium-activated C–H amination step. The final route includes a reproducible modified Bouveault reaction which has not previously been reported on a substrate of this complexity, or on such a scale with over 5 kg of the requisite gem -dimethylamine prepared via this methodology.",10.1021/op200233r,1
"A Simplified Process for the Manufacture of Imagabalin Hydrochloride (PD-0332334), an α2δ-Ligand for the Treatment of Generalised Anxiety Disorder","The development of a highly efficient two-step process for the manufacture of the α2δ-ligand imagabalin hydrochloride 1 is described in 50% overall yield from ( R )-3-methylhexanoic acid 2 . Key aspects of this route include the development of a one-pot process for the synthesis of β-enamine ester 7 and its subsequent diastereoselective hydrogenation with a Ru-( S )-BINAP catalyst. The use of a combination of TFA, ammonium trifluoroacetate, and relatively low pressures in the asymmetric hydrogenation are novel conditions reported for this type of transformation. The simplified process described realised a 4-fold reduction in cost of goods compared with the previously described enabling route.",10.1021/op2002326,1
Development and a Practical Synthesis of the JAK2 Inhibitor LY2784544,"The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon–carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert -butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C–C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.",10.1021/op200229j,1
An Improved and Impurity-Free Large-Scale Synthesis of Venlafaxine Hydrochloride,An improved and impurity-free synthetic method for large-scale synthesis of venlafaxine hydrochloride was developed using inexpensive reagents. The overall yield obtained from this newly developed process is 55% in a highly pure state with >99.9% purity by HPLC.,10.1021/op200221y,1
Scalable Synthesis of the Desoxy-biphenomycin B Core,"We describe the evolution of a kilogram-scale synthesis of the protected cyclic tripeptide desoxy-biphenomycin B, based on an early discovery route. The retrosynthetic concept included a macrolactamization strategy to build the core ring system of biphenomycin B in combination with a double catalytic asymmetric hydrogenation protocol for the construction of the ansa -tripeptide precursor. Eventually, the kilogram process comprised a 16-step sequence with an overall yield for the longest linear sequence of 19.5%.",10.1021/op200207h,1
Genotoxic Impurities: A Regulatory Toxicology Commentary on Recent Articles in <i>Organic Process Research &amp; Development</i>,"Although it has now been over four years since the introduction of the EU guideline on limits of genotoxic impurities, even after various amendments the regulatory guidance is still associated with ambiguity and differing interpretations. In spite of this, it is believed that a critical toxicological analysis can shed light on a number of key issues ranging from the definition of a genotoxic impurity to the determination of appropriate limits and performing compound-specific risk assessments on the basis of public-domain data.",10.1021/op200205b,0
Development of Two Scalable Syntheses of 4-Amino-5-aminomethyl-2-methylpyrimidine: Key Intermediate for Vitamin B<sub>1</sub>,"Two scalable processes for the synthesis of 4-amino-5-aminomethyl-2-methylpyrimidine ( 2 ) are described. In the first approach, the less expensive 2-cyanoacetamide was reacted with Vilsmeier reagent to afford enamine 18, followed by the condensation with acetamidine to produce the 4-amino-2-methylpyrimidine-5-carbonitrile ( 6 ); subsequent hydrogenation gave 2 in 65% overall yield. In the second approach, malononitrile was treated with the ionic salt 21, prepared in situ from DMF and dimethyl sulfate, to give 18, which, without isolation was reacted with acetamidine hydrochloride to afford the common intermediate 6 . Overall yield of this approach was 70%. Both methods are performed in a convenient manner suitable for industrial use.",10.1021/op2002003,1
Process Research Towards a Scalable Synthesis of the Muscarinic M<sub>1</sub> Receptor Subtype Selective Agonist MCD-386,"An efficient process for the M 1 -selective muscarinic agonist MCD-386 has been developed that offers significant advantages over the original synthetic approach. The new process utilizes an improved preparation of a known symmetrical diamine ester, followed by elaboration to a symmetrical 5-substituted tetrahydropyrimidine. The new route avoids cryogenics and chromatography steps, circumvents an expensive protecting group strategy, and offers significant improvements in cost and throughput.",10.1021/op2001996,1
"Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist","Described is an efficient, economic, and one-pot process for the production of highly pure bosentan ( 1 ), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine ( 2 ) with 4- tert -butylbenzenesulfonamide ( 3 ) and ethylene glycol ( 4 ) in acetonitrile in the presence of potassium carbonate to yield bosentan ( 1 ) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity ( 7 ) and 6-hydroxy impurity ( 8 ) in 1 by preparation of bosentan ammonium salt ( 6 ) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate ( 1 ) with an overall yield of 68% and HPLC purity of 99.90% was achieved.",10.1021/op200197z,1
Development of a Suitable Physical Form for a Sphingosine-1-phosphate Receptor Agonist,"AMG 369 ( 1 ), a novel S1P 1 agonist, was selected for clinical development for the treatment of multiple sclerosis. Form B of the zwitterionic molecule was initially identified as a potential development form. However, because of the instability of the phase as a function of ambient relative humidity, investigations of other polymorphs of the zwitterion and basic and acidic salt screening were conducted to identify an acceptable physical form for long-term development. An HCl dihydrate, an unsolvated sulfate salt, a hexahydrate calcium salt, and a monohydrate of the zwitterion were identified as potentially viable phases. The quality attributes of these phases were then compared along with their propensity to undergo acid-promoted degradation.",10.1021/op200192n,0
Design of Crystallization Processes for the Resolution of Conglomerate-Forming Chiral Compounds Exhibiting Oiling Out,"A methodology for the design of cooling crystallization processes for chiral resolution from nonracemic initial solutions is presented. Such processes are encountered when chiral resolution is attained by hybrid processes, where the crystallization step is preceded by a pre-enrichment step accomplished by either asymmetric synthesis or another separation technique. The work focuses on substances that crystallize as conglomerates and accounts for the occurrence of oiling out, i.e., an undesired liquid–liquid phase separation during crystallization. The generic ternary phase diagrams for conglomerate-forming systems with and without oiling out are derived. This knowledge is then applied to identify suitable operating conditions for chiral resolution. As crystallization is started from saturated solutions, the crystallization process is characterized by three parameters: the initial enantiomeric excess and the initial temperature, which together implicitly define the position of the operating point in the phase diagram, and the final operating temperature, which defines the composition and the amount of the phases present at the end of crystallization. For any initial enantiomeric excess, the methodology yields distinct areas in the initial versus final temperature plane containing pairs of operating temperatures that are suitable for chiral resolution. Such operating map bears great potential in improving the design and optimization of chiral resolution processes by crystallization.",10.1021/op200191d,0
Development of an Enabling Route to PF-00610355: A Novel Inhaled β<sub>2</sub>-Adrenoreceptor Agonist,"The initial route used to prepare PF-00610355 ( 8 ) for early clinical development is described. Through careful choice of solvent, an efficient, telescoped route to carboxylic acid 23 was developed, affording this late-stage intermediate in 80% yield over 4 steps. Deprotection of 23 to give sodium salt 24a and coupling with amine 6 ·HCl afforded the desired API. Effective synthetic routes to two of the starting materials, chiral bromide 1 and amine 6, are also described.",10.1021/op2001904,1
Development of a Practical Synthesis of Stearoyl-CoA Desaturase (SCD1) Inhibitor MK-8245,A practical kilogram scale chromatography-free synthesis of stearoyl-CoA desaturase 1 (SCD1) inhibitor MK-8245 is described. The key features of this sequence include an efficient addition–elimination reaction of a piperidine fragment with a 3-bromoisoxaline followed by an iodine-mediated oxidation to the corresponding isoxazole. The development of a safe and scalable tetrazole formation protocol is also presented.,10.1021/op200186d,1
Synthesis of a Bicyclic Piperazine from<scp>l</scp>-Aspartic Acid and Application of a Fluoride-Promoted S<sub>N</sub>Ar Coupling,"The process development is reported of a pivotal C–N bond formation involving ((7 R,9a S )-octahydro-1 H -pyrido[1,2- a ]pyrazin-7-yl)methanol ( 2 ) undergoing nucleophilic aromatic substitution with 3-chlorobenzo[ d ]isoxazole ( 3 ) to furnish ((7 R,9a S )-2-(benzo[ d ]isoxazol-3-yl)octahydro-1 H -pyrido[1,2- a ]pyrazin-7-yl)methanol ( 4 ) as a key intermediate for a family of compounds ( 1 ). Essential to the success of the coupling is the use of fluoride in combination with a phase transfer catalyst. The development of an alternative route to bicyclic piperazine 2 that uses l -aspartic acid ( 20 ) as a starting material to avoid the need for a classical salt resolution is described.",10.1021/op2001854,1
"Chemical Development of an α2δ Ligand, (3<i>S</i>,5<i>R</i>)-3-(Aminomethyl)-5-methyloctanoic Acid","Three synthetic approaches, suitable for the large scale manufacture of the α2δ-ligand, (3 S,5 R )-3-(aminomethyl)-5-methyloctanoic acid 3, have been evaluated. The selected seven step manufacturing process has then been optimized and used to deliver over 20 kg of API; salient features of the synthesis include the use of 4,4,4-trimethoxybutyronitrile as an efficient four carbon amino acid equivalent. Highly selective kinetic resolution of the C3 stereocentre was accomplished via diastereoselective hydrolysis of a cyanoester intermediate using Amano Lipase PS-SD. Extensive process optimisation of the route starting from ( R) -2-methylpentanol, led to significant improvements through telescoping, with less than 62 kg of solvent being needed to produce 1 kg of API.",10.1021/op2001832,1
"Commercial Synthesis of (<i>S</i>,<i>S</i>)-Reboxetine Succinate: A Journey To Find the Cheapest Commercial Chemistry for Manufacture","The development of a synthetic process for ( S, S )-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.",10.1021/op200181f,1
"Preparative Synthesis via Continuous Flow of 4,4,5,5-Tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane: A General Propargylation Reagent","A scalable process for the preparation of 4,4,5,5-tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane from trimethylsilylpropyne, isopropyl pinacol borate, and n -butyllithium is described. Problems associated with implementing a typical aqueous workup and batch process into production due to borolane “ate” equilibration and protonolysis are presented. To address these issues, a continuous-flow and distillation process was developed which efficiently produced 297 kg of the key propargylation reagent.",10.1021/op200180t,1
Convergent Asymmetric Synthesis of Two Complex TRPV1 Antagonists,"The convergent scale-up synthesis of two complex TRPV1 antagonists to support exploratory toxicology studies is described. Both compounds contain three chiral centers introduced by asymmetric synthesis with chiral control being critical for the success of the project. Preparation of the key cyclopropyl intermediate utilised an asymmetric cyclopropanation using thermally unstable ethyl diazoacetate. Ellman’s auxiliary was used to synthesize the chiral α-methyl benzylamine fragments. This paper highlights some of the key synthetic challenges, processing issues, and safety aspects from the scale-up of this chemistry.",10.1021/op200177b,1
"Discovery of a Novel, Efficient, and Scalable Route to Bendamustine Hydrochloride: The API in Treanda","Process Research and Development activities leading to a new and efficient route to bendamustine hydrochloride, 1, the active ingredient in Treanda, a treatment for blood cancers, are disclosed. Two key features of this new process include a one-pot hydrogenation/dehydration sequence to construct the benzimidazole moiety and a novel reductive alkylation using chloroacetic acid and borane to install the bischloroethyl side chain. The number of synthetic steps has been significantly reduced to five from the eight in the current commercial process. The overall yield has been improved from 12% to 45%. Additionally, this new route eliminates chloroform, ethylene oxide, and sodium sulfide. Scale-up of the new route has been successfully demonstrated to prepare kilogram quantities of bendamustine hydrochloride.",10.1021/op200176f,1
Asymmetric Synthesis of LFA-1 Inhibitor BIRT2584 on Metric Ton Scale,"The synthesis of LFA-1 inhibitor BIRT2584 on metric-ton scale was accomplished by means of a safe and robust process. Highlights of the process include the asymmetric synthesis of the key advanced intermediate by implementation of Seebach’s self-regeneration of stereocenters principle, and a Ph 3 PCl 2 -induced dehydration of a critical urea followed by a regioselective bromination to give the elaborated 1 H -imidazo[1,2- a ]imidazol-2-one. A sulfonyl chloride intermediate was produced through Br/Mg exchange of iodoimidazole followed by addition to SO 2 in THF and subsequent oxidation. In a one-pot operation, the sulfonyl chloride was directly reacted with l -alaninamide using NaOH as base in aqueous DMF/THF to give BIRT2584.",10.1021/op200175t,1
Use of an Iridium-Catalyzed Redox-Neutral Alcohol-Amine Coupling on Kilogram Scale for the Synthesis of a GlyT1 Inhibitor,"A recent development for the efficient and environmentally friendly synthesis of aliphatic amines is the transition-metal-catalyzed redox-neutral coupling of an alcohol and an amine, generally referred to as a “borrowing hydrogen” reaction. In this work, we describe the first kilogram-scale application of this technology in the synthesis of PF-03463275, a GlyT1 inhibitor developed for the treatment of schizophrenia. Using (Cp*IrCl 2 ) 2 the reaction has been optimized to achieve catalyst loadings lower than 0.05 mol % iridium (S/C ≥ 2000) while retaining reasonable reaction times (<24 h). Water and a tertiary amine are essential for high catalytic activity, resulting in dramatically increased reaction rates compared to existing literature protocols. Methods for iridium removal are also described.",10.1021/op200174k,1
Development an Efficient Route to the 5-Lipoxygenase Inhibitor PF-04191834,"A convergent six-step process for the synthesis of PF-04191834 ( 1 ), a potent and selective 5-lipoxygenase inhibitor, has been developed and used to deliver over 20 kg of API. The process uses the same bond-forming steps as the initial medicinal chemistry route, including the use of two consecutive Pd-catalyzed Ar–S couplings to form the key diaryl thioether linkage. The reaction conditions and downstream processing have been optimized to eliminate column chromatography and aqueous work-ups and to minimize disproportionation of 1, to ensure successful scale-up.",10.1021/op200173g,1
"Pilot Plant Preparation of <i>tert-</i>Butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate, An Intermediate of Novel Antiarteriosclerotics, Via a Safe, Scalable Reformatsky-Type Reaction","Reported here is a safe, scalable process via a Reformatsky-type reaction of iminium salt ( 4 ) followed by Red-Al reduction giving tert -butyl-4-(2-hydroxyethyl)-4-(pyrrolidin-1-yl)-piperidine-1-carboxylate ( 6 ), an intermediate of novel antiarteriosclerotics ( 1 ). The key points of this safe process are the use of trifluoroacetic acid (TFA) for the iminium salt formation, vigorous stirring for the Reformatsky reaction, and slow addition of methyl bromoacetate. Pilot manufacturing on the 500 L scale was achieved.",10.1021/op2001723,1
"Chemical Development of the Casein Kinase I - Epsilon Inhibitor: 3-(3-Fluorophenyl)sulfanyl-1<i>H</i>-pyrrolo[3,2-<i>b</i>]pyridine-2-carboxylic Acid Amide","The development of a scalable process for 3-arylsulfanyl-1 H -pyrrolo[3,2- b ]pyridine-2-carboxylic acid amides ( 1 ), potent casein kinase I inhibitors, is described. The rapid identification of suitable reaction conditions expedited the lab scale synthesis of drug substances for early toxicological evaluations. Further improvements were made to achieve a safe and cost-effective process to meet increasing demands for drug substances to support clinical studies. This paper describes the synthesis at multikilogram scale.",10.1021/op200171a,1
Process Research on the Asymmetric Hydrogenation of a Benzophenone for Developing the Manufacturing Process of the Squalene Synthase Inhibitor TAK-475,"A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene synthase inhibitor TAK-475 ( 1 ), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7, employed Noyori’s ruthenium precatalyst of the type [RuCl 2 (diphosphine)(diamine)]. We focused on tuning of the chiral diphosphine, and have discovered a novel ligand, DADMP-BINAP ( 18c ), for the catalyst that has allowed reduction of the operating pressure in the asymmetric hydrogenation. The precatalyst containing 18c performed effectively at low hydrogen pressure (<1 MPa) with sufficient enantioselectivity, and the result enabled us to successfully obtain enantiomerically pure 8 on a multikilogram scale.",10.1021/op2001673,1
A Facile Stereoselective Biocatalytic Route to the Precursor of Woody Acetate,"Carbonyl reductase (CRED) technology has been shown to be an important tool for the rapid and efficient preparation of cis- and trans -4- tert -butylcyclohexanol, the precursors to the high volume fragrance ingredients known as Woody Acetate.",10.1021/op200166a,0
Screening Binary Systems of Chelating Agents Combined with Carbon or Silica Gel Adsorbents: The Development of a Cost-Effective Method to Remove Palladium from Pharmaceutical Intermediates and APIs,"The increasing use of palladium catalysts in the synthesis of pharmaceutical intermediates and active pharmaceutical ingredients (APIs) has created the rising need for cost-effective ways to remove the resulting metal contaminants. A simple binary palladium scavenging system was developed using a chelating agent in combination with either activated carbon or silica gel adsorbents. Successful palladium removal was demonstrated on several reaction streams after treating contaminated solutions with the binary system followed by filtration. The binary system is proposed to effectively provide an in situ generated metal scavenger, but typically costs much less than corresponding commercial solid-supported scavengers.",10.1021/op2001657,0
The Development of a Practical Multikilogram Synthesis of the Chiral β-Amino Acid Imagabalin Hydrochloride (PD-0332334) via Asymmetric Hydrogenation,"The development and implementation of a robust process for the manufacture of metric ton quantities of the α2δ ligand imagabalin hydrochloride 4 is described. Key aspects of the synthesis include a chromatography-free, two-step telescoped process to prepare a mixture of Z: E -enamides 7 followed by a robust asymmetric hydrogenation with the rhodium-trichickenfootphos catalyst 8 to install the (3 S )-stereocentre. Hydrolysis of the acetamide and ester protecting groups in the final step followed by isolation and recrystallisation of the hydrochloride salt gave high purity 4 in 40–50% overall yields.",10.1021/op2001639,1
Practical Aspects of Integrated Operation of Biotransformation and SMB Separation for Fine Chemical Synthesis,"Integrated operation of biotransformation and simulated moving bed (SMB) separation is an attractive option for high-yield manufacturing of commercially relevant compounds such as rare sugars and sialic acids from equilibrium-limited isomerase- or aldolase-catalyzed reactions. Here, we present the first lab-scale implementation of such a process using the production of d -psicose, which is currently under consideration as low calorie sweetener, by d -tagatose epimerase-catalyzed epimerization from d -fructose as a model system. While a typical batchwise eprimerization of d -fructose would stop at 25%, a yield of 97% was obtained when operating the fully integrated process consisting of SMB, enzyme membrane reactor (EMR) and nanofiltration (NF) for a number of days with absolute product purities. Next to the proof of principle, important process characteristics such as startup time, stability and robustness were investigated. By pre-equilibrating the NF unit to the projected conditions, startup times could be reduced to the contributions from EMR and SMB (in this case below 5 h) which was perfectly in line with the projected range of operation time of a few days. Robustness was probed by introduction of a perturbation, specifically a 2-fold increase in process feed concentration, which did not compromise any of the set specifications. Next, long-term operation of the respective units indicated a potential process time of at least 5 days, which could be easily extended in the future by engineering a more stable enzyme variant and implementing a cleaning-in-place approach for SMB column regeneration. In summary, the principle feasibility of such process integration for fine chemical synthesis could be successfully demonstrated.",10.1021/op200160e,0
Development of an Improved Immobilized CAL-B for the Enzymatic Resolution of a Key Intermediate to Odanacatib,"An immobilized form of Candida antarctica lipase B (CAL-B) has been developed with enhanced stability and activity compared to commercially available preparations. The immobilized CAL-B is more active, and 15 times more stable than the previously used preparation. This permits a continuous dynamic kinetic resolution process that is significantly less expensive than the original batch process, and with a 3-fold reduction in the process E -factor.",10.1021/op200157c,0
Synthesis of the Hepatitis B Nucleoside Analogue Lagociclovir Valactate,"2′,3′-Dideoxy-3′-fluoro-5- O -[(S)-(+)-2-( l -valyloxy)-propionyl] guanosine (lagociclovir valactate) is a prodrug of 3′-fluoro-2′,3′-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). A five-step synthesis of lagocyclovir valactate starting from 2-amino-6-chloropurine is described. The synthesis was performed at kilogram scale, and the target nucleoside prodrug was isolated as the hemisulphate salt with an overall yield of 23%. The major challenges were N-glycosylation of a 2-deoxyfluorosugar, which required separation of α- and β-anomers, and deprotection of the penultimate intermediate by hydrogenation.",10.1021/op200153s,1
Prediction of Agglomerate Type during Scale-Up of a Batch Crystallization Using Computational Fluid Dynamics Models,"The impact of hydrodynamics on agglomeration during the crystallization of an active pharmaceutical ingredient (API) was investigated. The type of agglomerate formed was experimentally observed to correlate with agitation level at the laboratory and kilo-lab scales. It was hypothesized that differences in agglomerate type were related to differences in the collision rate of primary crystals, caused by differences in the local degree of agitation (e.g., the local values of fluid turbulence dissipation rate, ε). Spatial distributions of ε were determined from computational fluid dynamics (CFD) models at process scales ranging from laboratory (200 mL) to commercial scale (875 L). Higher values of ε were calculated for conditions shown to result in the formation of rounded, compact agglomerates, while at the lower values of ε, looser agglomerates of flakelike particles were observed. Predictions for pilot-plant- and commercial-scale crystallization operating conditions were made using local ε values as the scaling parameter.",10.1021/op200152u,0
"Concise Synthesis of Two β-Adrenergic Blocking Agents in High Stereoselectivity Using the Readily Available Chiral Building Block (2<i>S</i>,2′<i>S</i>,2″<i>S</i>)-Tris-(2,3-epoxypropyl)-isocyanurate","A concise synthesis of ( S )-propranolol and ( S )-metoprolol in high stereoselectivity using the readily available chiral building block (2 S,2′ S,2″ S )-tris-(2,3-epoxypropyl)-isocyanurate (S-TGT) as the key intermediate is described.",10.1021/op2001518,1
Work-Up Optimization en Route to an Improved Process To Prepare a Progesterone Receptor Antagonist,"When the process to prepare nonsteroidal progesterone receptor antagonist 5 was scaled up, significant problems were encountered, and as a result lower than expected yields were obtained. In particular, the alkylation of pyrazole 2 with chloromethyl methyl sulfide failed to reach completion, and partial degradation of the product occurred during the work-up, resulting in a modest yield of alkylated pyrazole 3a . Further investigation has revealed the root cause of this problem, and an improved, robust process to 5 has been developed.",10.1021/op200145j,1
Route Selection and Process Development for a 5-Piperazinylquinaldine Derivative for the Treatment of Depression and Anxiety,"1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone, 1, was identified as a potential drug for the treatment of depression and anxiety. Herein is described the work carried out to select the manufacturing route and the process research studies to optimize the key stages of route B. A particular focus is given to the genotoxic impurities, related to this route, as one of the intermediates of the manufacturing route was genotoxic and many genotoxic impurities can be formed in the process. Quality by Design principles were applied for the definition of the control strategy of these impurities.",10.1021/op200140v,1
Design and Scale-Up of Diels–Alder Reactions for the Practical Synthesis of 5-Phenylbicyclo[2.2.2]oct-5-en-2-one,"Several synthetic pathways towards racemic 5-phenylbicyclo[2.2.2]oct-5-en-2-one 1 have been devised starting with a Diels–Alder reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane and α-acetoxyacrylonitrile, acrylonitrile, or α-chloroacrylonitrile. The first ‘fit-for-purpose’ route relied on α-acetoxyacrylonitrile as a dienophile and rapidly delivered kilogram amounts of 1 . Process safety data then triggered the development of a scalable Diels–Alder reaction using α-chloroacrylonitrile as the dienophile. This practical and volume-efficient route delivered 1 in a 44% yield in six chemical steps with two isolated intermediates. Notably, neither chromatography nor distillation was required for the multikilogram synthesis of 1 .",10.1021/op200139r,1
Micro Reaction Technology in Organic Synthesis,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewMicro Reaction Technology in Organic SynthesisTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 4, 947Publication Date (Web):June 6, 2011Publication History Published online6 June 2011Published inissue 15 July 2011https://pubs.acs.org/doi/10.1021/op200137whttps://doi.org/10.1021/op200137wbook-reviewACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views1112Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Microfluidic devices,Microreactors,Organic synthesis,Photochemical reactions,Purification Get e-Alerts",10.1021/op200137w,0
Sustainable Process Chemistry,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSustainable Process ChemistryRobert Appell, Dinesh Gala, and Yogesh S. Sanghvi*View Author Information Guest Editors and Members of the Editorial Advisory Board[email protected]Cite this: Org. Process Res. Dev. 2011, 15, 4, 898–899Publication Date (Web):June 6, 2011Publication History Published online6 June 2011Published inissue 15 July 2011https://pubs.acs.org/doi/10.1021/op200135vhttps://doi.org/10.1021/op200135veditorialACS PublicationsCopyright © 2011 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1988Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (638 KB) Get e-AlertscloseSUBJECTS:Alcohols,Green chemistry,Process chemistry,Solvents,Wastes Get e-Alerts",10.1021/op200135v,0
Process Safety Evaluation of a Tungsten-Catalyzed Hydrogen Peroxide Epoxidation Resulting In a Runaway Laboratory Reaction,"An investigation of a runaway chemical reaction in the laboratory highlighted the potential hazards of oxidation chemistry involving hydrogen peroxide in the presence of tungsten catalysts. Under the process conditions, a combination of a high adiabatic temperature rise, an unstable target molecule, and a potentially incompatible mixture of hydrogen peroxide and tungsten catalyst produced a reaction mixture capable of high rates of self-heating and self-pressurization. Under conditions of poor heat removal, a runaway chemical reaction and loss of containment resulted. Tungsten species can catalyze the decomposition of hydrogen peroxide at low onset temperatures. The safety aspects of this synthetic methodology must be thoroughly assessed prior to scale-up.",10.1021/op200133q,0
Lipase-Catalyzed Monostearin Synthesis under Continuous Flow Conditions,"Biodegradable, biocompatible and nontoxic nonionic surfactants are widely used in food, pharmaceutical and industrial applications being commonly produced based on alkaline-catalyzed chemical glycerolysis of natural oil and fats at high temperatures and elevated pressure under nitrogen atmosphere. In this work we have optimized a biocatalytic continuous flow process with packed bed reactor for the esterification reaction between ( R, S )-1,2-isopropylidene glycerol and stearic acid using response surface methodology (RSM) leading to the desired product in excellent conversion (95%) and short reaction time (40 s of residence time).",10.1021/op200132y,0
Fit-for-Purpose Development of the Enabling Route to Crizotinib (PF-02341066),"A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6 . A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1 .",10.1021/op200131n,1
Large-Scale Synthesis of a Substituted <scp>d</scp>-Phenylalanine Using Asymmetric Hydrogenation,"A synthetic route to an N -BOC d -phenylalanine pharmaceutical intermediate suitable for rapid scale-up to 150-kg scale was required. A seven-step route based on asymmetric hydrogenation of an N -acetyl dehydroamino-acid was developed. Starting with terephthalic dialdehyde, monoreduction of one aldehyde group, Erlenmeyer condensation, and ring-opening/ O -deacetylation with methanol provided the 4-(hydroxymethyl)-substituted dehydrophenylalanine hydrogenation substrate. Asymmetric hydrogenation of this enamide using [(( R, R )-Ethyl-DuPhos)Rh(COD)]BF 4 proceeded in high enantiomeric excess. Subsequently, the cis -2,6-piperidyl group was introduced by mesylation/displacement, the BOC group was introduced, and acetyl and methyl ester groups were removed by basic hydrolysis. This route was used to manufacture 150 kg of the BOC amino acid 1 .",10.1021/op200129m,1
Process Development of a Potent Glucosylceramide Synthase Inhibitor,"An economic, scalable process for the production of glucosylceramide synthase (GCS) inhibitor 7 has been developed. Herein we report a three-step synthesis to aldehyde 4 with high yield and purity that employs the selective cleavage of an endocyclic C–O bond of a THP ether using borane/THF as the key step. This particular methodology has not been used previously from a development standpoint and offers an attractive way towards introducing pentanol side chains. Aldehyde 4 is then coupled with deoxynojirimycin via flow hydrogenation using an H-Cube to safely produce the free base of 7, which is isolated as an MSA salt in 50% overall yield. Herein we discuss the evolution of this process from its original form and the thermodynamics of its associated chemistry.",10.1021/op2001222,1
Convergent Synthesis of a 5HT<sub>7</sub>/5HT<sub>2</sub> Dual Antagonist,"The development of an efficient and convergent route to 3-(4-fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydropyrazolo[3,4- d ]azepine ( 1 ), a potent 5HT 7 /5HT 2 dual antagonist, is described. Significant features of this route are: (a) a regioselective construction of a tetra-substituted pyrazole 6a by reacting an N -monosubstituted hydrazone 4a with an elaborated nitroolefin 5b and (b) a unique Pd-catalyzed hydrogenation method that carries out the four-step, ring-closing reductive amination sequence in a notable one-pot operation to provide 1 in excellent overall yields.",10.1021/op2001194,1
The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement,"Sodium hydride was found to be the best base for a displacement reaction on a chloropyrimidine. Due to the insolubility of sodium hydride in all solvents and high reactivity with atmospheric moisture, solutions dealing with the associated safety concerns on kilogram scale are described. The use of sodium hydride in premeasured dissolvable bag packaging (SecuBags), online process analytical technology (PAT) to monitor the hydrogen off-gas, and the development of analytical methods to monitor residual polymer and potential degradation products allowed for a successful scale-up and on-time delivery of a quality product.",10.1021/op200114t,0
Multigram Synthesis of Glyceollin I,Scaled-up procedures and preparation of glyceollin I in multigram quantities are described. The synthesis features construction of a cis-fused ring system in high enantiomeric excess after Sharpless asymmetric dihydroxylation of a key intermediate that is initially produced by an intramolecular Wittig reaction to afford the requisite alkene while simultaneously forming the first ring. The overall yield is 12% after 11 steps.,10.1021/op200112g,1
Adaptive Process Optimization for Continuous Methylation of Alcohols in Supercritical Carbon Dioxide,"A self-optimizing continuous flow reactor has been developed using the Super-Modified Simplex algorithm. This system, coupled with online gas chromatographic analysis enables automated optimization via a feedback control loop without user intervention. This has been applied to the methylation of 1-pentanol in supercritical carbon dioxide using dimethyl carbonate and methanol with γ-alumina catalyst to give 98% and ∼68% yield of pentyl methyl ether respectively. This was accomplished by variation of four reaction parameters; Temperature, Pressure, CO 2 Flow rate, and the Ratio of methylating agent.",10.1021/op200109t,0
Enzymatic Desymmetrization Route to Ethyl [3-(2-Amino-2-methylpropyl)phenyl]acetate,"An efficient process to ethyl [3-(2-amino-2-methylpropyl)phenyl]acetate 6 has been developed. Key steps include a novel enzymatic desymmetrization of diester 2 and a Ritter reaction between alcohol 4 and chloroacetonitrile, followed by chemoselective deprotection with thiourea.",10.1021/op200108k,1
The Lactol Route to Fesoterodine: An Amine-Promoted Friedel–Crafts Alkylation on Commercial Scale,"We report the discovery and optimization of an amine-promoted Friedel–Crafts alkylation of cinnamaldehyde with 4-hydroxymethyl phenol. This reaction has been used successfully on commercial scale (200 kg) in the context of the manufacture of fesoterodine, a muscarinic antagonist used for the treatment of overactive bladder. Reductive aminations of diisopropylamine and lactol 4 are also discussed, as well as the resolution of the racemic amine rac -2 into its enantiomerically pure form.",10.1021/op200107g,1
Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension,"Process research and development of a synthetic route towards a novel renin inhibitor ( 1 ) is described. The highly convergent synthetic route provided 1 in 15% yield on multikilogram scale with a longest linear sequence of 11 steps. The use of catalytic hydrogenation features prominently in our design. The proper choice of N -methylpyridone surrogate was also important, and we describe a method for the easy conversion of 2-methoxypyridines to N -methylpyridones using cheap and readily available reagents.",10.1021/op2001063,1
A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones,"Three different continuous flow strategies for the generation of important 4-aryl-2-butanone derivatives including the anti-inflammatory drug nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone] and the aroma compounds raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] and its methyl ether [4-(4-methoxyphenyl)-2-butanone] were evaluated. All three protocols involve the initial preparation of the corresponding 4-aryl-3-buten-2-ones via Mizoroki–Heck, Wittig, or aldol strategies, which is then followed by selective hydrogenation of the C═C double bond to the desired 4-aryl-2-butanones. The synthetic routes to 4-aryl-3-buten-2-ones were first optimized/intensified on small scale to reaction times of 1–10 min using batch microwave heating technology and then translated to a scalable continuous flow process employing commercially available stainless steel capillary tube reactors. For the synthesis of 4-(4-methoxyphenyl)-3-buten-2-one a further scale-up using a custom-built mesofluidic mini-plant flow system capable of processing several liters per hour was designed to further expand the scale of the process. The final hydrogenation step was performed using a fixed-bed continuous flow hydrogenator employing Ra/Ni as a catalyst.",10.1021/op2001047,1
Using the Right Green Yardstick: Why Process Mass Intensity Is Used in the Pharmaceutical Industry To Drive More Sustainable Processes,"There have been a many publications and much discussion about green metrics. While many have been proposed, The American Chemical Society Green Chemistry Institute’s Pharmaceutical Roundtable has chosen process mass intensity (PMI) as the key, high-level metric for evaluating and benchmarking progress towards more sustainable manufacturing. This paper provides the philosophical and technical arguments on why PMI was chosen above other related metrics such as E factor or atom economy.",10.1021/op200097d,0
"An Efficient, Economical Synthesis of the Novel Anti-tumor Agent CPI-613","An efficient and practical synthesis of the novel anti-tumor compound 6,8-dithiobenzyl octanoic acid, CPI-613 ( 2 ), was developed and executed on a practical scale. CPI-613 can be made in a single vessel from (±)-lipoic acid ( 1 ) via reductive opening of the disulfide ring followed by benzylation of the sulfhydryls with benzyl bromide. CPI-613 was isolated by simple crystallization in high yield and purity. The process is scaleable and has been demonstrated at up to 100 kg.",10.1021/op200091t,0
Scale-Up of Microwave-Assisted Reactions in a Multimode Bench-Top Reactor,"An evaluation of a new bench-top microwave batch reactor that uses a single 1 L reaction vessel is presented. Several microwave-assisted organic reactions have been scaled-up, including Newman Kwart and Diels–Alder reactions, Pd-catalyzed cross-couplings, heterocycle synthesis, aromatic substitution, and a Knoevenagel condensation. A range of different solvents (high and low microwave absorbing), varying reaction times (4 s up to 2 h), and temperatures (120–250 °C) have been explored in these investigations. For all studied transformations, it was possible to perform a direct scale-up (up to 720 mL reaction volume) without changing the previously optimized reaction conditions achieved in a laboratory-scale single-mode microwave instrument (2–20 mL processing volume), obtaining similar isolated product yields. A scalability up to 360-fold, when moving from 3 mmol up to 1.08 mol, was demonstrated, and isolated product yields up to 300 g (2.5 mol scale) in a single run could be accomplished, providing the potential for a kilogram output per day for specific transformations by performing multiple sequential runs.",10.1021/op200090k,0
Practical Gram Scale Asymmetric Catalysis with Boroxinate Brønsted Acids Derived from the VAPOL and VANOL Ligands,"Our laboratories have been engaged in utilizing catalysts derived from the VAPOL and VANOL ligands towards the development of efficient asymmetric processes over the last several years. Subsequent to their development, practical scale-up of these methodologies to gram scale has always been deemed necessary to demonstrate. This article will report on such successful gram scale asymmetric catalysis that has been realized in our laboratories using the boroxinate Brønsted acid catalysts derived from the VAPOL and VANOL ligands. The processes reviewed will be the catalytic asymmetric aziridination of imines and the direct catalytic asymmetric aminoallylation of aldehydes.",10.1021/op200087f,1
"Enoate Reductase-Mediated Preparation of Methyl (<i>S</i>)-2-Bromobutanoate, a Useful Key Intermediate for the Synthesis of Chiral Active Pharmaceutical Ingredients","Enoate reductases belonging to the Old Yellow Enzyme (OYE) family were employed to develop a biocatalysed approach to methyl ( S )-2-bromobutanoate, a key intermediate for the introduction of a particular stereogenic unit into the molecular skeleton of a certain class of chiral drugs. Methyl ( Z )-2-bromocrotonate afforded, respectively, ( S )-2-bromobutanoic acid (ee = 97%) and methyl ( S )-2-bromobutanoate (ee = 97%) by baker’s yeast fermentation and by OYE1–3 biotransformations. The bioreductions of other methyl 2-haloalkenoates were also considered. It was observed that the ( Z )- and ( E )-diastereoisomers of α-bromo unsaturated esters afforded the same enantiomer of the corresponding reduced product.",10.1021/op200086t,0
Biotechnological Development of a Practical Synthesis of Ethyl (<i>S</i>)-2-Ethoxy-3-(<i>p</i>-methoxyphenyl)propanoate (EEHP): Over 100-Fold Productivity Increase from Yeast Whole Cells to Recombinant Isolated Enzymes,"The coupling of the enantioselective reduction catalyzed by Old Yellow Enzymes (OYEs), together with the in situ substrate feeding product removal (SFPR) concept, significantly improved the productivity of the g-scale preparation of ethyl ( S )-2-ethoxy-3-( p -methoxyphenyl)propanoate (EEHP), an important precursor of several PPAR-α/γ agonists, such as Tesaglitazar. The OYEs and the glucose dehydrogenase for cofactor regeneration were cloned, overexpressed in Escherichia coli, and purified. The synthetic sequence was completed by a NaClO 2 oxidation employing cheap and environmentally friendly conditions. The product was obtained in 94% yield and with an ee of 98% over the two steps.",10.1021/op200085k,1
Development of a Commercial Process for (<i>S</i>)-β-Phenylalanine,"The development of a commercial manufacturing route for ( S )-β-phenylalanine 8, a key pharmaceutical building block, is described. The different approaches which were investigated, based on catalytic asymmetric hydrogenation of enamide intermediates and on biocatalysis using acylase and lipase hydrolyses, are compared. The lipase resolution route was chosen for scale-up, and the final two-step process, based on readily available raw materials, is shown to be robust at full manufacturing scale",10.1021/op200084g,1
Design and Scalable Synthesis of New Chiral Selectors. Part 2: Chiral Ionic Liquids Derived from Diaminocyclohexane and Histidine,"We disclose the conception and synthesis of new chiral selectors useful for enantioselective liquid–liquid extraction processes (ELLE). We report synthetic methods giving access to substantial amounts of the compounds, at least at the multigram scale. Two series are examined, i.e. ionic liquids based on diaminocyclohexane (DACH) and histidine, respectively.",10.1021/op200082a,1
Serendipitous Discovery of a Zidovudine Guanidine Complex: A Superior Process for the Production of Zidovudine,A superior process for the commercial production of zidovudine (AZT) has been developed. It was discovered that an AZT–guanidine complex formed when a crude zidovudine solution was treated with guanidine. This readily precipitated from protic solvents resulting in the exclusion of impurities and permitted the development of a superior isolation and purification of AZT.,10.1021/op2000805,1
"A Simplified Process for the Manufacture of AZD0530, a Potent SRC Kinase Inhibitor","An efficient process for the manufacture of AZD0530 1, a potent SRC kinase inhibitor, has been developed. The key transformation, reaction of monofluoroanilide 7 with alcohol 8, was much simplified between manufacturing campaigns. The development of a robust, efficient, and scalable process for this transformation drew on both a practical and theoretical understanding of the process and is described herein",10.1021/op200079g,1
Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor,"Compound ( 1 ) a poly(ADP-ribose)polymerase (PARP) inhibitor has been made by a fit-for-purpose large-scale synthesis using either a classical resolution or chiral chromatographic separation. The development and relative merits of each route are discussed, along with operational improvements and extensive safety evaluations of potentially hazardous reactions.",10.1021/op2000783,1
The Development of Scalable and Efficient Methods for the Preparation of Dicyclopropylamine HCl Salt,"The unique chemical properties of dicyclopropylamine (DCPA) 1 render its synthesis a challenge for process chemists despite its structural simplicity. Chemical instability and high aqueous solubility further complicate the process for DCPA’s preparation, isolation, and purification. In this note we describe the development of three strategies for the synthesis of DCPA 1, all of which provide material with excellent purity profiles (>99 GC area %). Our final route provides significant improvements in terms of cost-efficiency, safety, scalability, and impurity content. Highlights of this strategy include two chemo-selective, Pd-catalyzed, deallylation reactions and an efficient reductive amination protocol. To circumvent the chemical instability of DCPA 1, an innovative isolation procedure was developed which reliably reduced the amount of Pd residue to less than 20 ppm. Following this protocol, impurities such as N -propylcyclopropyl-, mono- cyclopropyl-, and N -ethyl-cyclopropylamines ( 3, 4, and 17 ) were minimized to 0.06, not detectable, and 0.02%, respectively.",10.1021/op2000755,1
"A Reactive Distillation Process To Produce 5-Hydroxy-2-methyl-1,3-dioxane from Mixed Glycerol Acetal Isomers","The four cyclic glycerol acetal isomers can be readily produced via the acid-catalyzed reaction of glycerol with acetaldehyde or a related acetal species. In the presence of the acid catalyst used in acetal formation, the isomers interconvert to form an equilibrated mixture that contains similar quantities of the four products. Vacuum distillation can separate the four acetals into their purified forms, with the cis -5-hydroxy-2-methyl-1,3-dioxane ( 1 ) as the most volatile. When the distillation is carried out in the presence of an acid catalyst to promote interconversion, 1 is obtained as a nearly pure distillate stream. This is further adapted to a continuous reactive distillation which produced 90–96% 1 . Thus a novel process is presented to convert glycerol to the desired acetal ( 1 ), which can be further converted to products such as 1,3-propanediol and dihydroxyacetone.",10.1021/op200072x,0
Multijet Oscillating Disc Millireactor: A Novel Approach for Continuous Flow Organic Synthesis,"This report discloses proof of concept and experimental results from a project involving design, development, and investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This device is named multijet oscillating disk (MJOD) reactor and is dedicated to continuous flow organic synthesis in milliscale. Characteristics such as the importance of the multijet disk unit, with or without oscillating, and possible limitations, such as back-mixing, have been explored, and the flow system is benchmarked with other technologies. Several well-known reactions and syntheses usefully both in the chemical industry as well as in the research laboratory have been conducted using the new system, which have been benchmarked with batch- and microreactor protocols. In particular the Haloform reaction, the Nef reaction, nucleophilic aromatic substitution, the Paal–Knorr pyrrole synthesis, sodium borohydride reduction, O -allylation, the Suzuki cross-coupling reaction, the Hofmann rearrangement and N -acylation were performed during the study of the MJOD reactor performance. Our investigations revealed that the MJOD millireactor system can produce various organic compounds at a high rate concomitant with an excellent selectivity. A Hofmann rearrangement was conducted, a reaction that involves handling of a slurry of the substrate. This reaction was successfully conducted, achieving a quantitative conversion into the target molecule.",10.1021/op2000699,0
A Large-Scale Synthesis of Potent Glucokinase Activator MK-0941 via Selective <i>O</i>-Arylation and <i>O</i>-Alkylation,"An efficient, practical preparation of MK-0941, a potent glucokinase activator, is described. Keys to the success of the synthesis are a highly selective mono- O -arylation of methyl 3,5-dihydroxybenzoate with 2-ethanesulfonyl-5-chloropyridine and the choice of a proper protective group for the subsequent S N 2 O -alkylation. With the thorough understanding of the origins and fate of in-process impurities, the second-generation robust synthesis with a minimum number of operations reproducibly prepares MK-0941 in 56% overall yield with >99% purity.",10.1021/op200068c,1
A Safe Two-Step Process for Manufacturing Glycidyl Nitrate from Glycidol Involving Solid–Liquid Phase-Transfer Catalysis,"A new and safer two-step process for manufacturing glycidyl nitrate from glycidol is reported. In the first step glycidyl tosylate is obtained by reacting glycidol with p -tosyl chloride in the presence of triethylamine according to any one of the well-known procedures for obtaining tosyl esters described in the literature. In the second step, glycidyl tosylate is reacted with NaNO 3 in refluxing acetonitrile under solid–liquid phase-transfer catalysis conditions using tetrabutylammonium nitrate as catalyst. Acetonitrile and the phase-transfer catalyst were recycled 12 times without deactivation, yielding 99% pure glycidyl nitrate in a cumulative isolated yield of 81.5% with a catalyst turnover number of 85.7 mol substrate per mol phase-transfer catalyst. This procedure avoids the use of the dangerous reactants used in the current manufacturing processes of glycidyl nitrate and could be useful as a safe and general method for obtaining nitrate esters.",10.1021/op200066e,0
"Development of an Asymmetric Hydrogenation Route to (<i>S</i>)-<i>N</i>-Boc-2,6-dimethyltyrosine","An improved, simpler and potentially more economical route to ( S )- N -Boc-2,6-dimethyltyrosine 1, based on a previously published route, is presented. Key modifications were to prepare the dehydroaminoacid hydrogenation substrate 6 in a one-pot process directly from serine methyl ester and 4-iodo-3,5-dimethylphenyl acetate 4 and to identify a significantly more active asymmetric hydrogenation catalyst that allowed a 5-fold reduction in catalyst loading.",10.1021/op200065p,1
"Book Review of Pharmaceutical Process Chemistry for Synthesis, Rethinking the Routes to Scale-Up","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Pharmaceutical Process Chemistry for Synthesis, Rethinking the Routes to Scale-UpWill WatsonView Author Information Scientific UpdateCite this: Org. Process Res. Dev. 2011, 15, 3, 727Publication Date (Web):April 1, 2011Publication History Published online1 April 2011Published inissue 20 May 2011https://pubs.acs.org/doi/10.1021/op200063uhttps://doi.org/10.1021/op200063ubook-reviewACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views1676Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Oxidation reactions,Pharmaceuticals,Process chemistry,Separation science Get e-Alerts",10.1021/op200063u,0
"Statistical Optimization of Reaction Parameters for the Synthesis of 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane","An orthogonal array design (OA 32 ) was employed as a statistical optimization method to enhance the performance of the synthesis of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (HNIW). The current application of the Taguchi method was successful in optimizing the experimental parameters of HNIW synthesis. High-purity HNIW was synthesized on a relativity large scale by the one-pot method using addition of N 2 O 4, HNO 3, and H 2 SO 4 to tetraacetyldibenzylhexaazaisowurtzitane (TADB). The effects of reaction conditions such as the TADB:N 2 O 4, N 2 O 4:HNO 3, and HNO 3:H 2 SO 4 ratio, the temperature of nitrosation, the temperature of addition of HNO 3 and addition of H 2 SO 4, the time of nitrosation, and the time of addition of HNO 3 and H 2 SO 4 on the yield of synthesized HNIW were investigated. The effects of these factors on the yield of HNIW were quantitavely evaluated by the analysis of variance (ANOVA). The results showed that the yield of HNIW synthesis can be enhanced significantly by controlling the temperature of addition of H 2 SO 4 and the time of nitrosation. Finally, optimal conditions for synthesis of HNIW by the one-pot method were proposed. The results of ANOVA showed that the optimal TADB:N 2 O 4, N 2 O 4:HNO 3, and HNO 3:H 2 SO 4 ratios are 6, 1:2, and 1:1, respectively; also, the optimal temperatures for nitrosation, addition of HNO 3, and addition of H 2 SO 4 are 60, 20, and 60 °C, respectively, and the optimal times for nitrosation, addition of HNO 3, and addition of H 2 SO 4 are 10, 0.5, and 2.5 h, respectively, for producing HNIW. Finally, under optimal conditions, the yield of the reaction is ∼96%.",10.1021/op200056j,0
A Versatile Lab to Pilot Scale Continuous Reaction System for Supercritical Fluid Processing,"A compact and versatile continuous reaction system for supercritical fluids as mobile phase was realised using commercially available components where possible. All process parameters of particular importance to the specific properties of near- or supercritical fluids such as pressure, temperature, and composition ( p, T, x ) can be accurately controlled over a wide flow range. The setup is completely automated by the help of computerised control and features a view cell for inline phase behavior observation. Coupling to supercritical fluid chromatography permits sampling under process conditions for reaction monitoring. Potential applications include continuous flow synthesis and catalysis, extractions, and other operations demanding controlled application of compressible gases. Highly efficient continuous flow asymmetric hydrogenation catalysis with integrated product separation is demonstrated.",10.1021/op200053w,0
Synthetic Route Discovery and Introductory Optimization of a Novel Process to Idebenone,"An environmentally benign, convenient, high yielding, and cost-effective synthesis leading to idebenone is disclosed. The synthesis includes a bromination process for the preparation of 2-bromo-3,4,5-trimethoxy-1-methylbenzene, a protocol for the Heck cross-coupling reaction using either thermal or microwave heating, olefin reduction by palladium catalyzed hydrogenation, and a green oxidation protocol with hydrogen peroxide as oxidant to achieve the benzoquinone framework. The total synthesis is composed of six steps that provide an overall yield of 20% that corresponds to a step yield of 76%.",10.1021/op200051v,1
Rhodium-Catalyzed C–H Amination. An Enabling Method for Chemical Synthesis,Reaction methods for selective C-H amination are finding ever-increasing utility for the preparation of nitrogen-derived fine chemicals. This brief account highlights the remarkable versatility of dirhodium-based catalysts for promoting oxidation of aliphatic C-H centers in both intra- and intermolecular reaction processes.,10.1021/op200046v,0
"A Practical Asymmetric Synthesis of Isopropyl (1<i>R</i>,2<i>S</i>)-Dehydrocoronamate","A novel asymmetric synthesis of isopropyl (1 R,2 S )-dehydrocoronamate is described from ( S )-1,2,4-butanetriol as the starting material in 28% overall yield. Highlights of this synthetic route include selective cyclopropanation between chiral cyclic sulfate 5 and diisopropyl malonate ( 8c ), formation of vinylcyclopropane 3c via elimination of halide 4c, selective monohydrolysis of diisopropyl ester 3c, and Curtius rearrangement of acid 10 to form isopropyl (1 R,2 S )-dehydrocoronamate TsOH salt 13 in >99% ee. With the involvement of only three isolations, this chromatography-free process provides a rapid and practical access to (1 R,2 S )-1-amino-2-vinylcyclopropane-1-carboxylic acid derivatives.",10.1021/op200038y,1
"A New Process for Synthesis of Apricitabine, 2-(<i>R</i>)-Hydroxymethyl-4-(<i>R</i>)-(cytosin-1′-yl)-1,3-oxathiolane, an Anti-HIV NRTI","Apricitabine is a novel inhibitor of the HIV virus reverse transcriptase polymerase which is currently in clinical development for the treatment of AIDS. A new process for the preparation of apricitabine is presented which requires only three steps from 2-( R )-benzoyloxymethyl-1,3-oxathiolane. The new process produces the cis -(2 R,4 R ) isomer in greater than 99% diastereomeric excess by preferential crystallisation of the conglomerate form of the novel 2-( R )-benzoyloxymethyl-4-( R )-( N -benzoylcytosin-1-yl)-1,3-oxathiolane intermediate without requiring chromatography. Deprotection of the intermediate in 88% yield then gives chiral apricitabine, in 30% overall yield. The new method avoids a lengthy salt formation/-break stage, does not require toluene sulphonic acid, and introduces no new byproduct to the manufacturing process.",10.1021/op2000332,1
An Improved Synthesis of Valsartan,"Biphenyltetrazole group, an important component of sartans, is usually formed in excellent yield by the reaction of 4′-alkylbiphenyl-2-carbonitrile with excessive organotin azide. However, it is restricted in industrial scale because of the difficult post-treatment. In this article, an improved synthetic method for valsartan and the quantitative recovery of tri- n -butyltin chloride are reported. During this process, the tetrazole–Sn complex and excessive organotin azide were decomposed by HCl to furnish tri-- n -butyltin chloride, and then reacted with NaF to lead to filterable polymer tributyltin fluoride which was converted again to tributyltin chloride by HCl in ethyl acetate. This approach is facile for the efficient manufacture of sartans using organotin azide to form the tetrazole group and is valuable for industry readers.",10.1021/op200032b,1
A Practical Synthesis of Biaryls via a Thermal Decarboxylative Pd-Catalyzed Cross-Coupling Reaction Operating at Moderate Temperature,"The palladium-catalyzed decarboxylative cross-coupling of aminothiophene carboxylate and 1-bromo-4-chlorobenzene to produce 3-amino-2-(4-chlorophenyl)thiophene ( 2 ) is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and TBAB. Through use of a mixed-solvent system of DMF and NMP, it was possible to operate the cross-coupling system at 80 °C. An assessment of carbon dioxide liberation, which provides insight into the reaction operating parameters, is also discussed.",10.1021/op200030t,1
Coupling Polymorphism/Solvatomorphism and Physical Stability Evaluation with Early Salt Synthesis Optimization of an Investigational Drug,"The need for effective solid-form screening approaches, especially designed for the early discovery phases, is well recognized within the pharmaceutical industry. Here we report on the early polymorphism and solvatomorphism evaluation of a new drug candidate for selective α 2C -adrenoceptor antagonists ORM10921·HCl. The approach we use is based on the systematic batch-to-batch characterization of the solids generated during the salt synthesis optimization. Within this study three crystalline forms, two anhydrous and one hemihydrate, were discovered and identified by X-ray powder diffraction (XRPD), differential scanning calorimery (DSC), and thermal gravimetry (TGA). Moreover, coupling the gravimetric vapor sorption analysis with a conventional XRPD enabled the relative stability of these solid-state forms at ambient conditions to be established and the most stable form, the hemihydrate, to be selected for further development. Hence, the utilized approach has proven to be an effective and fast tool for initial polymorphism and solvatomorphism tendency evaluation of drug candidates. While it is not obvious that this approach is sufficient for a comprehensive assessment of polymorphism, it demonstrates the importance of mindful solid-state characterization during crystallization process development.",10.1021/op200026f,0
"Synthesis, Chromatographic Purification, and Isolation of Epothilone–Folic Acid Conjugate BMS-753493","We describe the synthesis, chromatographic purification, and isolation of the epothilone–folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10–30 g) of cGMP quality BMS-753493.",10.1021/op200023g,0
Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor,A general method for the continuous processing of suspensions and particulates is reported. A commercially available agitating cell reactor which uses a transverse mixing motion to maintain solids in suspension has been successfully applied to a salt-forming reaction. The flow device delivered 208 g of N -iodomorpholinium hydroiodide salt over a 9-h period (equating to 3.88 kg/week) under optimized conditions. The reactor is suitable for the medium-scale (5 kg) processing of solid-forming reactions and appears to offer the potential for a variety of more complex applications.,10.1021/op2000223,0
"Development of a Practical Synthesis of Toll-like Receptor Agonist PF-4171455: 4-Amino-1-benzyl-6-trifluoromethyl-1,3-dihydroimidazo [4,5-<i>c</i>] pyridin-2-one","The development and implementation of a scalable process for the manufacture of the Toll-like receptor (TLR7) agonist PF-4171455 ( 1 ) is described. Initial routes used to synthesise 1 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the transfer between Medicinal Chemistry and Research-API, collaboration provided a fit for purpose route for the kilo-scale synthesis of 1 . Key aspects of the synthesis included (i) a safe and practical synthesis of a key nitropyridone intermediate 7 over four steps, (ii) a sequential regioselective chlorination to selectively functionalise 7 and (iii) use of a carbamate as a tethered carbonyl group, allowing an efficient regiospecific synthesis of 1 .",10.1021/op200021a,1
An Efficient Process for the Manufacture of Carmegliptin,"A short and high-yielding synthesis of carmegliptin ( 1 ) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using ( S, S )-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10 was coupled with ( S )-fluoromethyl lactone 31 . Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.",10.1021/op2000207,1
"Development of a Scalable Synthesis of (<i>S</i>)-3-Fluoromethyl-γ-butyrolactone, Building Block for Carmegliptin’s Lactam Moiety",Several new routes are reported for the synthesis of ( S )-3-fluoromethyl-γ-butyrolactone. An asymmetric hydrogenation-based synthesis was chosen as the enabling route to produce the lactone on a 10-kg scale. A superior stereoselective route starting from ( S )- tert -butyl glycidyl ether which afforded the desired lactone in three steps with ∼50% overall yield was finally selected for further development and production.,10.1021/op200019k,1
"Industrial Application of the Forster Reaction: Novel One-Pot Synthesis of Cinacalcet Hydrochloride, a Calcimimetic Agent","Described is a new, practical, and one-pot process, based on the Forster reaction, for the synthesis of cinacalcet hydrochloride ( 1 ), a calcimimetic agent and calcium-sensing receptor antagonist. The synthesis comprises the condensation of (1 R )-(+)-1-naphthylethyl amine ( 2 ) with benzaldehyde ( 3 ) followed by reaction of obtained Schiff’s base 4 with 1-(3-halopropyl)-3-(trifluoromethyl)benzene ( 5 ) to provide highly unstable iminium salt 6 . Subsequent hydrolysis of 6 with water in the same pot yielded cinacalcet. The treatment of cinacalcet with hydrochloric acid during the workup process furnished 1 with an overall yield of around 60%. Our synthetic approach for 1, discussed in this report demonstrates industrial application of the century-old, unexplored name reaction, “Forster’s Reaction” or Forster−Decker synthesis.",10.1021/op200016a,1
Book Review: Process Analytical Technology: Spectroscopic Tools and Implementation Strategies for the Chemical and Pharmaceutical Industries,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review: Process Analytical Technology: Spectroscopic Tools and Implementation Strategies for the Chemical and Pharmaceutical IndustriesTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 2, 480Publication Date (Web):February 11, 2011Publication History Published online11 February 2011Published inissue 18 March 2011https://pubs.acs.org/doi/10.1021/op2000139https://doi.org/10.1021/op2000139book-reviewACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views765Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Biomanufacturing,Chemometrics,Infrared light,Nuclear magnetic resonance spectroscopy,Raman spectroscopy Get e-Alerts",10.1021/op2000139,0
Book Review of Manufacturing of Pharmaceutical Proteins: From Technology to Economy,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Manufacturing of Pharmaceutical Proteins: From Technology to EconomyTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 2, 479Publication Date (Web):February 8, 2011Publication History Published online8 February 2011Published inissue 18 March 2011https://pubs.acs.org/doi/10.1021/op200012chttps://doi.org/10.1021/op200012cbook-reviewACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views327Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Biomaterials,Industrial manufacturing,Pharmaceuticals,Physical and chemical processes Get e-Alerts",10.1021/op200012c,0
"Fast, Economic, and Green Synthesis of <i>N</i>-Formylated Benzotriazoles","Formylation is an integral part of organic, medicinal, and biological chemistry both in industrial and academic set-ups. A reflection of this importance is the number of approaches and reagents that have been developed to achieve it. We have developed a fast, efficient, and environmentally friendly procedure for the synthesis of N -formylated benzotriazoles.",10.1021/op200011x,0
Optimization of the Neutralization Process for Cesium Catalyst Removal after Polyol Production,"The aim of this study was the optimization of the neutralization process to remove the catalyst cesium hydroxide from crude polyether polyols. Sulfuric acid was chosen as the neutralization agent. First of all, the water content in the neutralization agent solution was optimized. An optimum particle size was obtained for water content between 2 and 3 wt %, and even the cesium content fell within the specifications. Higher water contents cause the solubilization of the cesium sulfate crystals. An increase in the temperature decreased the cesium sulfate particle size, not being retained by the filter and increasing the final polyol cesium content. Acidity was not within specifications whatever the temperature, varying between 0.18 and 0.22 mg of KOH/g. To obtain both parameters (cesium content and acidity) within specification, temperature and time of the dehydration step were modified. An excess of H 2 SO 4 allowed us to obtain a suitable particle size for filtration; however, the acidity value was out of specification, suggesting the necessity to find a new process to remove the catalyst in the polyether polyol production.",10.1021/op200010e,0
Development of a Fully Telescoped Synthesis of the S1P1 Agonist GSK1842799,"The development of a fully telescoped synthesis of the potent and selective S1P1 agonist GSK1842799 is described. Key features in the synthesis, which has been implemented on a multikilogram scale, include a nucleophilic aromatic substitution to install a lipophilic 1-octyloxy chain, introduction of a chiral quaternary centre, and the use of Lawesson’s reagent to form a thiadiazole ring. Due to the lack of crystalline intermediates, workup protocols that took advantage of the lipophilic nature of the compounds were developed. This allowed full combination of the five chemistry stages and a salt formation, with the only isolation being that of the final hemifumarate salt of the drug substance. The synthesis of the O -phosphorylated active metabolite is also described.",10.1021/op2000095,1
Noncryogenic Preparation of Functionalized Arylboronic Esters through a Magnesium−Iodine Exchange with in Situ Quench,"Various functionalized aryl boronic esters derived from hexylene glycol and pinacol were prepared in excellent yields according to a simple, safe procedure. The metal−halogen exchange reaction between i PrMgCl·LiCl and aryl iodides is performed at 0 °C in the presence of a cyclic borate ester (MPBO i Pr or PinBO i Pr); the organomagnesium intermediate is immediately trapped in situ so that no accumulation of hazardous reactive species can occur. The reaction is very selective, and particularly clean crude products are obtained. The scope of the procedure and the tuning of reaction parameters are investigated.",10.1021/op2000089,0
Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor,"The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol. The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at >8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.",10.1021/op200002u,1
"Application of Chemoselective Pancreatin Powder-Catalyzed Deacetylation Reaction in the Synthesis of Key Statin Side Chain Intermediate (4<i>R</i>,6<i>S</i>)-4-(<i>tert</i>-Butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydropyran-2-one","A chemoselective biocatalytic procedure for the synthesis of (4 R,6 S )-4-( tert -butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydro-2 H -pyran-2-one, a key lactonized statin side chain intermediate, from its acetate precursor is described. The presented method is based on the pancreatin powder-catalyzed cleavage of the acetyl group in ((2 S,4 R )-4-( tert -butyldimethylsilyloxy)-6-oxotetrahydro-2 H -pyran-2-yl)methyl acetate. The reaction was conducted in aqueous medium. The overall process is performed in a convenient way and economical manner suitable for industrial use.",10.1021/op100341m,0
Fast Scale-Up Using Microreactors: Pyrrole Synthesis from Micro to Production Scale,"A flow chemistry method for the synthesis of pyrroles was developed. The method was optimized in 0.13 to 7 μL microreactors in continuous flow, reaching yields of nearly 100%. Subsequently, the method was scaled up in continuous flow using a 9.6-mL internal volume, glass, microstructured flow reactor, leading to production of a pyrrole derivative at a rate of 55.8 g per hour .",10.1021/op100338z,0
"Reactor Kinetics Studies via Process Raman Spectroscopy, Multivariate Chemometrics, and Kinetics Modeling","The deployment of in situ analytics for monitoring chemical reactions in process chemistry development and scale-up is facilitated by advanced instrumentation such as Raman spectrometry. Furthermore, greater process understanding can be engendered by coupling in situ Raman data with multivariate chemometrics analyses and kinetics modeling. Such information is important for devising science-based process control strategies along the concept of quality by design (QbD) initiated through the U.S. FDA process analytical technology (PAT) framework. A series of experiments using varied glass reactors, stirring speeds, and isothermal reaction temperatures were designed with acetic anhydride hydrolysis as the model reaction to successfully demonstrate the efficacy of combining in situ Raman spectroscopy, multivariate analyses, and kinetics modeling. Two different Raman measurement methods, using immersion and noncontact probe optics, were tested through a process Raman spectrometer with multiplexing capability. Information-theoretic multivariate chemometrics were applied to elicit pure component spectra and transient concentrations of chemical species, and two differential-algebraic equations modeling approaches were adopted for elucidating chemical and dissolution kinetics information. The variations in reactor vessel type and sizes, stirring speeds, Raman measurements, and kinetics models were compared in this study.",10.1021/op100337v,0
"A Safe and Efficient Synthetic Route to a 2,5-Dimethyl-1-aryl-1<i>H</i>-imidazole Intermediate","An optimized route to an iodo-imidazole intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-aryl-1 H -imidazoles ( 6 ) was devised. Important data for the optimization work was obtained by carrying out a DOE study to gain understanding of the parameters that affect the key intramolecular cyclization to build the imidazole ring. Additional information on the reaction mechanism of this step was obtained by carrying out a flow NMR experiment. In order to complete the proof of concept, the iodo-imidazole intermediate was converted to two ethynyl imidazoles ( 6a, b ) using metal-catalyzed reactions.",10.1021/op100335q,1
The Art of Process Chemistry,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTThe Art of Process ChemistryTrevor LairdCite this: Org. Process Res. Dev. 2011, 15, 2, 476Publication Date (Web):December 30, 2010Publication History Published online30 December 2010Published inissue 18 March 2011https://pubs.acs.org/doi/10.1021/op100332dhttps://doi.org/10.1021/op100332dbook-reviewACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views2583Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Crystallization,Medicinal chemistry,Process chemistry,Separation science,Teaching and learning methods Get e-Alerts",10.1021/op100332d,0
<i>N</i>-Amination of Indoles on Pilot-Plant Scale via Simultaneous and Proportional Metering of Reagents,"The N -amination of indoles on large scale, utilizing a portable Coriolis mass flow metering and pumping system that provides precise dispensing of two reagent streams simultaneously and proportionally, is described.",10.1021/op100330h,0
Key Green Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers,"In 2005, the American Chemical Society (ACS) Green Chemistry Institute (GCI) and global pharmaceutical companies established the ACS GCI Pharmaceutical Roundtable to encourage the integration of green chemistry and engineering into the pharmaceutical industry. The Roundtable developed a list of key research areas in green chemistry in 2007, which has served as a guide for focusing green chemistry research. Following that publication, the Roundtable companies have identified a list of the key green engineering research areas that is intended to be the required companion of the first list. This publication summarizes the process used to identify and agree on the top key green engineering research areas and describes these areas, highlighting their research challenges and opportunities for improvements from the perspective of the pharmaceutical industry.",10.1021/op100327d,0
"Process Development for a Key Synthetic Intermediate of LY2140023, a Clinical Candidate for the Treatment of Schizophrenia","To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer–Bergs reaction to give a hydantoin with the targeted l -glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.",10.1021/op100325h,1
"New Procedure for the Preparation of (<i>Z</i>)-2-(5-Amino-1,2,4-thiadiazole-3-yl)-2-trityloxyiminoacetic Acid","A novel and efficient procedure has been developed for the preparation of the C-7 side chain of ceftobiprole, ( Z )-2-(5-amino-1,2,4-thiadiazole-3-yl)-2-trityloxyiminoacetic acid ( 2 ) from malononitrile ( 9 ) in a total yield of 19%. The key intermediate N -(3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazol-5-yl)benzamide ( 15b ) was synthesized for the first time in 76% yield by treatment of N -(3-aminoisoxazol-5-yl)acetamide ( 13 ) with benzoyl isothiocyanate. More importantly, ( Z )- N -(3-(2-acetamido-2-oxo-1-(trityloxyimino)ethyl)-1,2,4-thiadiazol-5-yl)benzamide ( 16b ) was prepared from 15b with high stereoselectivity and good yield via successive oximation and protection of oxime hydroxy group. The process has a good prospect for industrial synthesis.",10.1021/op100323b,1
The Preparation of Desflurane by the Vapor-Phase Fluorination of Isoflurane,"There are several known processes for manufacturing the commercially important anaesthetic desflurane (CF 3 CHFOCHF 2 ) by the catalyzed reaction of commercially available isoflurane (CF 3 CHClOCHF 2 ) with hydrogen fluoride. The present available methods have the disadvantage of high catalyst usage, with consequent environmental problems, or of having to trade off low conversion against low selectivity. An alternative catalyst system was therefore sought that would avoid these problems, but would still give the benefits of a vapor-phase process and, in particular, a long catalyst life. A catalyst consisting of antimony pentafluoride supported on activated carbon has now been found to provide the basis for a novel vapor-phase process for the fluorination of isoflurane to desflurane using hydrogen fluoride. The process operates with a long catalyst life, high conversion, and high selectivity.",10.1021/op100318b,1
"Development of Safe, Scalable Nitric Acid Oxidation Using a Catalytic Amount of NaNO<sub>2</sub> for 3-Bromo-2,2-bis(bromomethyl)propanoic Acid: An Intermediate of S-013420","A safe, scalable process was developed for nitric acid oxidation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol ( 2 ) to give 3-bromo-2,2-bis(bromomethyl)propanoic acid ( 3 ), an intermediate in the synthesis of S-013420 ( 1 ). The key points are the use of a catalytic amount of NaNO 2 and addition of the starting material in portions. We achieved 3,000 L scale pilot production.",10.1021/op1003133,0
Stereoselective Synthesis of Monoamine Reuptake Inhibitor NS9544 Acetate,"(−)-3-(2-Benzothienyl)-8- H -8-azabicyclo[3,2,1]oct-2-ene acetate, NS9544 acetate, is a candidate drug intended to treat pain and other CNS disorders. In the synthetic route tropinone was enantioselective deprotonated with a chiral lithium amide derived from [ R -( R *, R *)]-bis(α-methylbenzyl)amine hydrochloride. The formed enolate was trapped as triflate and coupled with benzo[ b ]thiophene-2-boronic acid under Suzuki conditions. To further enhance the enantiomeric purity crystallisation with l -(+)-tartaric acid was performed. Finally N -demethylation with trichloroethylchloroformate followed by treatment with acetic acid afforded NS9544 as the acetate salt with high enantiomeric purity.",10.1021/op1003117,1
Enzyme and Process Development for Production of Nicotinamide,"Through screening a library of nitrile hydratases developed in-house, NHT-120 was selected to catalyze the hydration of 3-cyanopyridine for production of nicotinamide. After reaction optimization, a fed-batch method was used to alleviate the substrate inhibition. Under this approach, 200 g/L of 3-cyanopyridine could be converted to nicotinamide in 5.5 h, and no nicotinic acid was produced. Under a substrate to enzyme ratio of 100:1 (w/w), nicotinamide in the reaction solution could reach 230 g/L.",10.1021/op100309g,0
A Continuous Kilogram-Scale Process for the Manufacture of 7-Ethyltryptophol,An expeditious and multikilogram-scale process for the synthesis of 7-ethyltryptophol via a continuous flow reactor from 2-ethylphenylhydrazine and 4-hydroxybutyraldehyde in higher and high yield was described. The main steps in this synthesis involved not only the generation of the hydrazone intermediate in situ but also the catalysis of the subsequent [3 + 3] sigmatropic rearrangement in the tandem loop reactor. Decomposition of the intermediate hydrazone was found to be a key factor resulting in low yield.,10.1021/op1003083,1
Development of a Scalable Synthesis of a GPR40 Receptor Agonist,"Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, ( S )-3-(4-hydroxyphenyl)hex-4-ynoic acid ( 1 ) and 3-(bromomethyl)-4′-(trifluoromethyl)biphenyl ( 2 ). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (±)-1 . An efficient and scalable synthesis of (±)-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum’s acid derived acceptor prepared from 3 . The biaryl bromide 2 was prepared in 86% yield via a 2-step Suzuki−Miyaura coupling−bromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.",10.1021/op1003055,1
Toxicological Assessment of 2-Methyltetrahydrofuran and Cyclopentyl Methyl Ether in Support of Their Use in Pharmaceutical Chemical Process Development,"Herein we document our evaluation of the oral toxicity of MeTHF and CPME as determined in three month repeat-dose toxicity studies in rats as well as a battery of tests conducted under Good Laboratory Practice (GLP) to assess induction of micronuclei, microbial mutagenicity, and chromosomal aberrations. Based on the studies performed, human permitted daily exposure limits of 6.2 and 7.4 mg/day for MeTHF and CPME respectively have been established, with both of these solvents also considered negative for genotoxicity and mutagenicity. In addition, for future standard repeat-dose GLP animal studies a general limit of 20 mg/kg/day and a maximum concentration of 2% of MeTHF or CPME would not be expected to contribute to any toxicity potentially exhibited by an active pharmaceutical ingredient containing these solvents. By sharing these data, we hope to facilitate the use of these ethereal solvents within the pharmaceutical chemical process development community and contribute to the path to their potential ICH classification.",10.1021/op100303c,0
"Complementary Syntheses of <i>N</i>,<i>O</i>-Protected-(<i>S</i>)-2-methylserine on a Multikilogram Scale","Two complementary and scalable approaches have been used to manufacture multikilogram quantities of N, O -protected-( S )-2-methylserine. The first approach uses a diastereomeric salt resolution of 2-methylserine methyl ester as the (1 S )-(+)-camphorsulfonate salt, and was used to rapidly access 15 kg of ( S )-3- tert -butoxycarbonyl-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid with >99% ee. The second approach involves a stereoselective enolate methylation of a chiral cyclic l -serine derivative under cryogenic conditions. The four-step telescoped process, starting from l -serine methyl ester, was used to manufacture 20 kg of (2 R,4 S )-2- tert -butyl-3- tert -butoxycarbonyl-4-methyl-1,3-oxazolidine-4-carboxylic acid in 52% overall yield and 98% ee. The advantages and disadvantages for scale-up of both approaches are discussed.",10.1021/op100299d,1
"Scale-Up Synthesis of a TRPV1 Antagonist Featuring a Facile Thiazolo[5,4-<i>d</i>]pyrimidine Formation","An efficient and practical synthesis of a TRPV1 inhibitor bearing a thiazolo[5,4- d ]pyrimidine core was developed. The initial synthesis was modified to facilitate acylation of 5-aminopyrimidine and subsequent thiazole formation. The synthesis features an efficient two-pot, five-step process for the construction of the thiazolo[5,4- d ]pyrimidine ring. The new route is concise, chromatography-free, and amenable to large-scale preparation.",10.1021/op1002984,1
Process Development of the PDE4 Inhibitor K-34,"A short and practical synthesis of the PDE4 inhibitor K-34 ( 1 ) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production.",10.1021/op100291g,1
"A General, One-Step Synthesis of Substituted Indazoles using a Flow Reactor","Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues.",10.1021/op100288t,1
Development of Scalable Syntheses of Selective PI3K inhibitors,"On the basis of a more practical and scalable route to an iodothiophene, an efficient and reliable synthesis has been developed for three selective PI3K inhibitors. From this advanced intermediate, the three title compounds were each prepared in five additional steps. Key learnings also include: high throughput experimentation (HTE) screening toward a more robust Suzuki coupling, a more efficient triazole synthesis, and an acid/base cleanup developed to purify the final compounds. The final enabled synthesis required no column chromatography.",10.1021/op100286g,1
The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder,"A new synthetic route to drug candidate 1, a potent and selective dual orexin antagonist for the treatment of sleep disorders, has been developed. The key acyclic precursor 10 was prepared in a one-step process in 75% isolated yield from commercially available starting materials using novel chemistry to synthesize 2-substituted benzoxazoles. A reductive amination was followed by a classical resolution to afford chiral diazepane ( R )- 11 . Finally, coupling of ( R )- 11 with acid 5 furnished the desired drug candidate 1 .",10.1021/op1002853,1
Practical Large-Scale Preparation of (±)-2-<i>exo</i>-Norbornyl Carboxylic Acid and Its Improved Isolation As the Sodium Salt,"A practical, robust, and high-yielding three-step−one-pot procedure for the diastereoselective synthesis of (±)-2- exo -norbornyl carboxylic acid starting from norbornylene has been found and demonstrated on multikilogram scale, setting a new benchmark for low-pressure hydroformylation of cyclic, bridged olefins. The newly found, nonhygroscopic crystalline sodium salt of this acid provides a practical isolation point.",10.1021/op100284a,0
Preparation of 4-Allylisoindoline via a Kumada Coupling with Allylmagnesium Chloride,"A practical, cost-effective Kumada coupling for the preparation of 4-allylisoindoline has been developed. The first catalyst screen for this reaction with allylmagnesium reagents is described. The challenges associated with product isomerization have been minimized by a thorough understanding of the reaction parameters. Additionally, a novel workup protocol has been developed to render Mg salts soluble in aqueous media at pH 10.",10.1021/op1002837,0
Current Practices of Process Validation for Drug Substances and Intermediates,"Process validation includes laboratory optimization, pilot-plant introduction, and process implementation on manufacturing scale, as well as monitoring batches after implementation and continuously improving the manufacturing processes. There are many opportunities to change and optimize operations. The background information in this contribution describes current guidance and terminology for validation, including the integration of validation over the development lifecycle of drug substances. Various examples illustrate challenges and success stories of implementation as part of the overall approach to process validation.",10.1021/op1002825,0
Development of a Safe and Practical <i>N-</i>Oxidation Procedure Using <i>m</i>-CPBA in Acetic Acid,A safe and practical procedure for the N -oxidation of pyrazolopyridine 4 using meta -chloroperbenzoic acid ( m -CPBA) in acetic acid is described. Key safety experiments are outlined which have led to the development and implementation of this reaction on 28-kg scale in 98% isolated yield.,10.1021/op100280c,0
Asymmetric Synthesis of (<i>S</i>)-3-Amino-4-methoxy-butan-1-ol by Way of Reductive Amination,"A new synthesis of ( S )-3-amino-4-methoxy-butan-1-ol is reported. The synthesis is based on the preparation of the primary, nonprotected enamine of the commercially available β-keto ester methyl 4-methoxy-3-oxo-butanoate and asymmetric catalytic enamine hydrogenation using a Ru-MeOBIPHEP catalyst. Alternatively, the process is performed by asymmetric catalytic reductive amination of the β-keto ester with ammonium acetate and hydrogen using a similar Ru catalyst. Both process versions provided initial ee values of 97−98% which were upgraded to ≥99% by product crystallization. Ester to alcohol conversion was best accomplished by LiBH 4 reduction after transitory Boc protection of the amino group.",10.1021/op1002775,1
The Development of a Robust Process for a CRF<sub>1</sub> Receptor Antagonist,"A scalable and robust process was developed for the preparation of pexacerfont ( 2 ), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF 1 ). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in >99.5% purity with a 68% overall yield for the six synthetic steps.",10.1021/op100270u,1
Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor,"Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 ( 1 ) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.",10.1021/op100268e,1
A Robust Three-Step Telescoped Synthesis of Electron- Deficient Amide Substituted Arylboronic Acids,"A robust three-step telescoped process for the preparation of electron-deficient amide-substituted arylboronic acids from readily available bromobenzoic acids has been developed. An EDC-HOBT-promoted amide formation of a bromobenzoic acid was followed by subjection of the product stream to a palladium-mediated cross-coupling with B 2 (pin) 2 . The resultant mixture of the arylboronate ester and arylboronic acid was directly treated with NaIO 4, followed by a heptane−MeTHF crystallization, to cleanly afford the corresponding arylboronic acid in good yield. This general procedure was used to synthesize electron-deficient amide-substituted arylboronic acids with a diverse array of electron-withdrawing substituents.",10.1021/op100267p,1
A Scalable Oxidation for the Final Stage of Synthesis of Cathepsin K Inhibitor SB-462795,"In developing the manufacturing route for the cathepsin K inhibitor SB-462795, the oxidation of a secondary alcohol for the final chemical stage is described. Prospective conditions were limited by several factors, particularly general safety concerns of oxidation reactions, the requirement to control impurities and transition metals isolated in the final product, and the desire to reduce the environmental impact. Two N -oxy free radical approaches (TEMPO and PIPO) and Moffatt conditions were evaluated in depth for their potential to achieve the targets. For reasons of robustness, scalability, and cost-effectiveness, the Moffatt conditions were the best manufacturing option.",10.1021/op100266s,0
"Dialkyl Sulfide Stabilisation in a Catalytic Dicuprate 1,6-Dienone Addition Process","The catalytic dicuprate addition of 1,9-dibromononane to a sterol 1,6-dienone is strongly enhanced by the presence of dimethylsulfide. Dimethylsulfide appears to have an important stabilising effect on the active organo-dicuprate species formed by reaction of Cu(I)Cl with di(bromomagnesio)nonane. In the absence of dimethlysulfide, 1,2-addition of the Grignard and loss of acetate from the sterol are the dominant processes. The overall reaction yield is also very sensitive to the order of addition of various reagents, with controlled addition of the preformed Grignard reagent to a dienone/Cu(I)Cl/dimethyl sulfide mixture leading to high yields of the desired alkylated bis-enone.",10.1021/op1002648,0
Scalable Synthesis of Cyclotriphenolene,"Hyperpolarized xenon magnetic resonance imaging ( 129 Xe MRI) is becoming a powerful imaging method that requires cage molecules to encapsulate xenon. Cyclotriphenolene 1 is a key compound for the synthesis of cryptophane cages. A scalable procedure for the synthesis of cyclotriphenolene 1 was developed by which 40 g of 1 can now be synthesized within 3 days, starting from inexpensive benzyl alcohol.",10.1021/op100260w,0
Development of the Route of Manufacture of an Oral H<sub>1</sub>−H<sub>3</sub> Antagonist,A new route to an H 1 −H 3 antagonist was developed to address scalability and environmental and cost of goods issues associated with the initial route.,10.1021/op1002598,1
The Combination of Hydroformylation and Biocatalysis for the Large-Scale Synthesis of (<i>S</i>)-Allysine Ethylene Acetal,"The compound, ( S )-2-amino-5-[1,3]dioxolan-2-yl-pentanoic acid [( S )-allysine ethylene acetal], is a key intermediate in a number of angiotension-I converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors currently in clinical trials. Through a combination of our hydroformylation and biocatalysis technologies we have developed an efficient five-step synthetic route to this material starting from crotonaldehyde. The development of this process, leading to a large-scale commercial manufacturing campaign, is described in this paper.",10.1021/op100258j,1
"Development of a Second-Generation, Highly Efficient Manufacturing Route for the HIV Integrase Inhibitor Raltegravir Potassium","A manufacturing route for the synthesis of raltegravir potassium 1 was developed via a thermal rearrangement of amidoxime DMAD adducts 6 to construct the key, highly functionalized hydroxypyrimidinone core 7 . Utilizing this route 1 was prepared in nine linear chemical steps with 22% overall yield. A second-generation synthesis was subsequently developed that solved the key chemical, productivity, and environmental impact issues of the initial synthesis. Highlights of the new synthesis include a highly selective methylation, 3−4-fold higher productivity, and a 65% reduction of combined organic and aqueous waste produced. The efficient second-generation manufacturing route provides raltegravir potassium 1 in 35% overall yield.",10.1021/op100257r,1
Kinetic and Scale-Up Investigations of Epoxide Aminolysis in Microreactors at High Temperatures and Pressures,"A continuous-flow microreactor is applied for a kinetic study of a model β-amino alcohol formation by epoxide aminolysis. A large number of experiments are performed in a short time with minimal reagent consumption. The kinetics of formation of secondary aminolysis between starting epoxide and product are decoupled from the primary synthesis, constructing a complete model for desired product formation. The activation energy for the formation of desired product is observed to be higher than those for regioisomer formation and for secondary aminolysis, indicating that increasing temperature improves selectivity in addition to accelerating the reaction. A set of optimized conditions is then selected for best reaction performance, and the process is scaled up to a 100-fold larger reactor volume with model predictions in good agreement with measured process performance.",10.1021/op100252m,0
Second-Generation Process Research Towards Eletriptan: A Fischer Indole Approach,"The development of a second-generation process for the synthesis of eletriptan via a Fischer indole cyclisation is described. The finalised process offers several potential advantages over the current route of manufacture including cost, throughput, and safety.",10.1021/op100251q,1
"The Development of Continuous Process for Alkene Ozonolysis Based on Combined in Situ FTIR, Calorimetry, and Computational Chemistry","Two continuous apparatuses were designed that are capable of safely scaling the highly energetic ozonolysis reaction to multikilogram scale where flow chemistry allowed excellent temperature control and minimized the inventory of the highly unstable ozonide intermediate. First, a continuous stirred tank reactor was developed and proven capable of generating product at a rate of 77 mmol of product per hour while maintaing <46 mmol of ozonide. Then, a larger-scale continuous bubble reactor was designed to deliver 770 mmol of product per hour while maintaing 950 mmol of ozonide present at any given time, and the latter was utilized to deliver 2.5 kg of product. The development of these reactors relied on careful evaluation of the thermal stability and heat of reaction of ozonolysis using computational chemistry and calorimetric measurement. In addition, the reactor design benefited from in situ ATR/FTIR monitoring of the rate of ozonolysis under nonflow conditions which allowed for the flow of substrate to be matched with ozone generation, enabling complete reaction of the alkene with minimal excess of ozone.",10.1021/op100249z,1
Development of an Optimized Process for the Preparation of 1-Benzylazetidin-3-ol: An Industrially Important Intermediate for Substituted Azetidine,A thoroughly optimized and robust process for the synthesis of 1-benzylazetidin-3-ol has been emphasized. 1-Benzylazetidin-3-ol has been utilized as a starting material in the commercial synthesis of azetidin-3-ol hydrochloride. Synthesis of azetidin-3-ol hydrochloride involves the usage of very low cost and commercially available starting material (benzylamine) and with reduced formation of di(3-chloro-2-hydroxypropyl) benzylamine significantly resulting in an economical process that allows the effective production of 1-benzyl azetidin-3-ol as well as azetidin-3-ol hydrochloride.,10.1021/op100247m,1
Solvent-Free and Safe Process for the Quantitative Production of Phosgene from Triphosgene by Deactivated Imino-Based Catalysts,"Phosgene is quantitatively formed from solid triphosgene in a solvent-free and safe process without any reaction heat, catalyzed by planar N-heterocycles with deactivated imino functions. The rate of phosgene generation is adjustable to the rate of phosgene consumption in the subsequent phosgenation reaction by thermal control, catalyst concentration, and in some cases, specific properties of selected metal phthalocyanines. A thermal runaway reaction of this process is impossible.",10.1021/op100239n,0
Convenient and Practical One-Pot Synthesis of 4-Chloropyrimidines via a Novel Chloroimidate Annulation,"Reaction of aromatic or heteroaromatic 2-acyl(amino)nitriles with phosphorus pentachloride triggers a novel chloroimidate cyclization, leading directly to the corresponding annullated 4-chloropyrimidines in good to excellent yields. The reaction lends itself to the telescoped one-pot construction of 4-functionalized pyrimidines from the corresponding (hetero)aromatic 2-aminonitriles. For a pyrazolopyrimidine development intermediate, this reaction was scaled up to multikilogram scale with excellent results. A total of 10 examples with different substrates are provided. This one-pot reaction provides an attractive and sustainable alternative to the commonly used multistep methodology for this transformation.",10.1021/op1002352,0
Development of a New Practical Synthesis of a 5-HT<sub>2C</sub> Receptor Agonist,"A new practical synthesis of a 5-HT 2C receptor agonist has been developed and implemented on multikilogram scale. The key step, the selective epoxide opening in the glycidyl tosylate with the aryl Grignard reagent, allowed the incorporation of this commercially available chiral C 3 synthon into the molecule and elaboration of the resulting intermediate into the target aminomethyldihydrobenzofuran without loss of enantiomeric purity.",10.1021/op100233f,1
"Book Review of Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Review of Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and SolutionsTrevor LairdCite this: Org. Process Res. Dev. 2010, 14, 6, 1521Publication Date (Web):October 1, 2010Publication History Received24 August 2010Published online1 October 2010Published inissue 19 November 2010https://doi.org/10.1021/op100232tCopyright © 2010 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views722Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (31 KB) Get e-AlertsSUBJECTS:Asymmetric catalysis,Oxidation,Quality management,Safety Get e-Alerts",10.1021/op100232t,0
"Practical Access to Metallo Thiophenes: Regioselective Synthesis of 2,4-Disubstituted Thiophenes","This report describes a protocol for functionalization of thiophenes, utilizing a regioselective magnesiation mediated by commercial Grignard reagents and catalytic 2,2,6,6-tetramethylpiperidine. This metalation provides practical access to metallo thiophenes, avoiding cryogenic conditions, prolonged reaction times, and prohibitively expensive reagents. Application to a target thiophene-phthalazinone 6 was accomplished by addition of 2-magnesio-4-methylthiophene to phthalic anhydride, providing the product with >40:1 regioselectivity. This also solved a chemoselectivity issue encountered with analogous lithio-thiophene reagents and cyclic anhydrides, or with magnesio-thiophene generated by simultaneous lithium-to-magnesium transmetalation/anhydride acylation. These alternative in situ transmetalation sequences were plagued by an age effect dictated by the kinetic solubility of MgCl 2 /THF complexes.",10.1021/op100226k,1
Kilogram Synthesis of a Second-Generation LFA-1/ICAM Inhibitor,"The process development and the kilogram-scale synthesis of BMS-688521 ( 1 ) are described. The synthesis features a highly efficient telescoped sequence which utilizes previously described spirocyclic hydantoin ( 4b ) to produce the final intermediate via an SN AR reaction. A final deprotection step affords BMS-688521 ( 1 ) in high quality with an overall yield of 65% from the key intermediate, spirocyclic hydantoin ( 4b ).",10.1021/op100225g,1
In-Process Monitoring and Control of Supersaturation in Seeded Batch Cooling Crystallisation of <scp>l</scp>-Glutamic Acid: From Laboratory to Industrial Pilot Plant,"A measurement-based closed-loop control system using in-process ATR-FTIR spectroscopy coupled with a multivariate chemometric PLS calibration model is developed, validated, and applied to the monitoring and control of supersaturation in a 250- L industrial pilot-plant crystalliser. Supersaturation control experiments are carried out on seeded batch cooling crystallisation of β- l -glutamic acid from aqueous solutions using two methods of seeding involving addition of seeds to the solution and generation of seeds within the solution. The generic applicability of the approach is demonstrated through this challenging system reflecting this molecule’s weak chromophore for infrared and relatively low solubility compared with previous solute−solvent systems. Based on the laboratory experiments, the system was fully tested and optimised prior to a series of trials carried out in an industrial pilot plant at Syngenta, Münchwillen, Switzerland. Good control of the supersaturation is achieved at three levels, 1.1, 1.2, and 1.3, within a prescribed range of ±0.025. The average product crystal size is found to decrease with increasing supersaturation. Comparison between product crystals produced at the 20- and 250-L scales indicates that secondary nucleation is more prevalent at the smaller-scale size. For the same level of supersaturation, the rate of depletion of solute is faster at the 20-L scale size than at 250-L scale, and hence a higher cooling rate is required to maintain the desired supersaturation. However, for a given crystalliser scale size, as expected, the mean cooling rate required to maintain a constant supersaturation is found to increase with increasing supersaturation level.",10.1021/op100223a,0
A Kilolaboratory Preparation of the CNRS Chiral Auxiliary,An improved preparation at kilolaboratory scale of the CNRS chiral auxiliary is presented.,10.1021/op1002227,0
Green Progression for Synthesis of Regioselective β-Amino Alcohols and Chemoselective Alkylated Indoles,Solid acid catalysts based on zirconia materials were investigated for the first time as catalysts for regioselective organic synthesis under environmentally benign and mild conditions. The novel TiO 2 −ZrO 2 mixed oxide catalyst led to two distinct products by the formation of an N−C bond (β-amino alcohols) and a C−C bond (Friedel−Crafts alkylation).,10.1021/op1002177,0
Guidelines and Cost Analysis for Catalyst Production in Biocatalytic Processes,"Biocatalysis is an emerging area of technology, and to date few reports have documented the economics of such processes. As it is a relatively new technology, many processes do not immediately fulfill the economic requirements for commercial operation. Hence, early-stage economic assessment could be a powerful tool to guide research and development activities in order to achieve commercial potential. This study discusses the cost contribution of the biocatalyst in processes that use isolated enzymes, immobilized enzymes, or whole cells to catalyze reactions leading to the production of chemicals. A methodology for rapidly estimating the production cost of the biocatalyst is presented, and examples of how the cost of the biocatalyst is affected by different parameters are given. In particular, it is seen that the fermentation yield in terms of final achievable cell concentration and expression level as well as the production scale are crucial for decreasing the total cost contribution of the biocatalyst. Moreover, it is clear that, based on initial process performance, the potential to reduce production costs by several orders of magnitude is possible. Guideline minimum productivities for a feasible process are suggested for different types of processes and products, based on typical values of biocatalyst and product costs. Such guidelines are dependent on the format of the biocatalyst (whole-cell, soluble enzyme, immobilized enzyme), as well as product market size and value. For example commodity chemicals require productivities in the range 2000−10000 kg product/kg immobilized enzyme, while pharmaceutical products only require productivities around 50−100 kg product/kg immobilized enzyme.",10.1021/op1002165,0
Multienzyme-Catalyzed Processes: Next-Generation Biocatalysis,"Biocatalysis has been attracting increasing interest in recent years. Nevertheless, most studies concerning biocatalysis have been carried out using single enzymes (soluble or immobilized). Currently, multiple enzyme mixtures are attractive for the production of many compounds at an industrial level. In this review, a classification of multienzyme-catalyzed processes is proposed. Special emphasis is placed on the description of multienzyme ex-vivo systems where several reactions are carried out by a combination of enzymes acting outside the cell. Furthermore, reaction and process considerations for mathematical modeling are discussed for the specific case where the synthetic reactions are carried out in a single reactor, the so-called multienzyme ‘ in-pot ’ process. In addition, options for multienzyme ‘ in-pot ’ process improvements via process engineering and enzyme immobilization technology are described. Finally, enzyme modification via protein engineering is also discussed, such that a better compatibility of the enzymes in the reactor is achieved as a means of assisting the implementation of multienzyme ‘ in-pot ’ processes.",10.1021/op1002159,0
"Book Report of Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewBook Report of Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and OrganocatalysisCite this: Org. Process Res. Dev. 2010, 14, 5, 1274Publication Date (Web):August 16, 2010Publication History Received2 August 2010Published online16 August 2010Published inissue 17 September 2010https://doi.org/10.1021/op100213xCopyright © 2010 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views503Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (26 KB) Get e-AlertsSUBJECTS:Addition reactions,Organic compounds,Organic reactions,Physical and chemical processes,Redox reactions Get e-Alerts",10.1021/op100213x,0
An Efficient and Scalable Synthesis of the Spirocyclic Glycine Transporter Inhibitor GSK2137305,An efficient and scalable synthesis of a glycine transporter inhibitor is presented. The key steps in the synthetic sequence are the formation of a spirocyclic imidazolidinone from an α-amino nitrile and a cyclic ketone and an arylation of 4-methyl imidazole under ‘ligandless’ Ullmann coupling conditions.,10.1021/op100210s,1
Application of Quality by Design Principles for the Definition of a Robust Crystallization Process for Casopitant Mesylate,"GlaxoSmithKline (GSK) has identified casopitant as a potent NK 1 antagonist. It was selected for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders and others. The mesylate salt of casopitant was selected for full development using a quality by design (QbD) approach in which a control strategy was developed from a design space, underpinned by process understanding and risk analysis for an enhanced level of quality assurance. As the concepts of design space and control strategy in the QbD framework move on from their inception to implementation, the ambiguity of definition has led to considerable discussion, diversity of opinions and uncertainty around how best to define these ideas. This contribution provides an outline of the sequential experimentation and analyses that led to the construction of a Bayesian approach to the ICH Q8 definition of Design Space. This uses a predictive approach for multiple response surface optimisation to identify a region of process operating conditions where all quality attributes of the active pharmaceutical ingredient (API) are likely to meet specifications with a high degree of confidence. Boundaries of assurance for design space and control strategy are introduced that provide a basis for defining dynamic operating ranges that should enhance the scope of operation and manufacturing flexibility that the regulatory agencies are encouraging. This new paradigm provides an opportunity to move away from the traditional concept of documenting static normal operating ranges (NOR) and proven acceptable ranges (PAR) univariately in a table or providing them as a list to regulators as part of regulatory submissions. While the latter approach is practical for documentation and serves as a simple instruction to manufacturing as to where a process should be allowed to run, it is not ideally suitable for describing a multidimensional design space. Model/parameter-based control is discussed through a worked example on the casopitant crystallisation step of a particle-forming routine.",10.1021/op100209c,0
"An Integrated Chemo-enzymatic Route for Preparation of β-Thymidine, a Key Intermediate in the Preparation of Antiretrovirals","A chemo-enzymatic method for production of β-thymidine, an intermediate in the synthesis of antiretrovirals, is described. Guanosine and thymine were converted by means of enzymatic transglycosylation to yield 5-methyluridine (5-MU), which was reproducibly synthesised at a 10−20-L scale in 85% yield at a final product concentration of ∼80 g·L −1 . A downstream processing (DSP) protocol was designed to remove reaction components interfering with the subsequent synthetic step. The crystallised 5-MU produced in the biocatalytic reaction was found to behave similarly to commercially available 5-MU, and the integration of the initial biocatalytic and subsequent three-step chemical process to β-thymidine was successfully demonstrated at bench scale.",10.1021/op100208x,0
Development of a Practical Synthesis of a Pyrazolopyridinone-Based p38 MAP Kinase Inhibitor,"A practical synthesis of the pyrazolopyridinone-based p38 MAP kinase inhibitor ( 4 ) was required for an ongoing program. The synthesis of a key pyrazolopyridinone building block was refined and optimized to provide kilogram quantities of 10 without chromatography or extractive workups. An efficient building-block strategy was employed to give optimal control of the key quality attributes, and in situ Raman spectroscopy was used to monitor and understand the complex solid-state properties of 4 .",10.1021/op100205s,1
Development of a Suitable Salt Form for a GPR40 Receptor Agonist,"AMG 837 ( 1 ) is a novel GPR40 agonist selected for clinical development for the treatment of type 2 diabetes. A lysine salt was initially identified as a development form. However, due to the poor crystallinity and severe hygroscopicity of this form, investigations on the free acid form of the drug substance and salt screening were conducted to identify an acceptable physical form for long-term development. A sodium and calcium salt were identified as potentially viable phases, and polymorph screening was conducted on both. The quality attributes of the salts were then compared to determine which phase would be preferred for development.",10.1021/op100204u,0
Development of a Practical and Efficient Synthesis of Chloromethyl 2-Ethoxy-2-methylpropanoate,"An efficient synthesis of chloromethyl 2-ethoxy-2-methylpropanoate from 2-bromoisobutyric acid is reported. Four developments were key to this route: (i) a mild, base-mediated ethanolysis of a tertiary alkyl bromide, (ii) a sodium bisulfite purge of 2-methylacrylic acid, (iii) preparation of a thiomethyl ester via a formal Pummerer process with DMSO, and (iv) improved conversion of a thiomethyl ester to a chloromethyl ester through suppression of a competing chlorination pathway.",10.1021/op1002038,1
Variable Microwave Effects in the Synthesis of Ureidopyrimidinones: the Role of Heterogeneity,"Microwave-irradiated and conventionally heated nucleophilic additions of various C-6 substituted isocytosines (methyl, ethyl, isopropyl, and phenyl) to (di)isocyanates have been compared. As compared to conventional heating, the heterogeneous reaction mixtures showed higher reaction rates on using microwave heating. Variation of C-6 substituent, temperature, and amount of cosolvent influenced significantly the magnitude of these microwave effects. The magnitude of the microwave effect was governed by the solubility and the intrinsic reactivity of the variation in C-6 substitution on isocytosine. Presumably, the liquid layer near the solid surface is the area where selective heating by microwaves is occurring. As a consequence of locally higher temperatures, the solubility of the reactant as well as the rate coefficient of the reaction increase. Thus, higher reaction rates are observed than those corresponding with the measured bulk temperature. The observed microwave effects have a thermal rationale based on direct, fast, and selective heating, and the local heating effect is not found during conventional heating. This finding is crucial for a justified process scale-up scenario.",10.1021/op100202j,0
Initial Scale-Up and Process Improvements for the Preparation of a Lead Antibacterial Macrolone Compound,"Macrolones are a novel class of potent antimicrobial agents that consist of a macrolide scaffold to which a quinolone unit is tethered by various linkers to the 4′′- O -position of the cladinose sugar. In this paper is described a modified 13-step route to a lead compound in the series. Critical reaction steps in the medicinal chemistry route were modified for an initial scale-up process, and as a result, a synthetic procedure suitable for preparation of multihundred gram quantities of the final product, with 98% purity, has been developed. The new procedure does not require any purification by column chromatography for any of the reaction steps. The overall yield was increased from 5−8% in the medicinal chemistry route to 27% in the improved procedure.",10.1021/op100199t,1
"Dexmethylphenidate: An Efficient Process for the Racemization of Unwanted (2<i>S</i>,2′<i>S</i>or<i>l</i>-<i>threo</i>)-α-Phenyl-α-(2-piperidyl)acetamide","(2 R,2′ R )- d - threo -α-Phenyl-α-(2-piperidyl)acetamide ( 3 ), an advanced intermediate for dexmethylphenidate hydrochloride synthesis, is prepared by the resolution of dl - threo -α-phenyl-α-(2-piperidyl)acetamide ( 2 ) with dibenzoyl- d -tartaric acid in isopropanol with % yield and 99% ee. Although this process is efficient, there is a need to recycle the unwanted l - threo- amide and uncrystallized d - threo- amide from the mother liquor. The purpose of this study is 2-fold, first being the pollution issue to discard large amounts of unwanted isomer and the second to reduce the cost of ( 1 ). This aspect of recovery of unwanted isomer 4 formed the basic objective of this study. We have developed a new, simple, and cost-effective process for the racemization in which 4 was treated with potassium carbonate and N -chlorosuccinimide in DMF followed by treatment with DBU to afford the olefinic intermediate ( 5 ). Subsequent hydrogenation of the double bond provided dl - erythro -α-phenyl-α-(2-piperidyl)acetamide ( 6 ); the latter intermediate has already been converted into 1 .",10.1021/op100197g,0
"Scale-Up of a Chemo-Biocatalytic Route to (2<i>R</i>,4<i>R</i>)- and (2<i>S</i>,4<i>S</i>)-Monatin","Monatin, a natural sweetener, refers to a collection of four isomers of 2-((1 H -indol-3-yl)methyl)-4-amino-2-hydroxypentanedioic acid. A chemo-biocatalytic approach to kilogram quantities of enantiopure 2 S,4 S -monatin and 2 R,4 R -monatin from indole is described. Key steps in the process include a (2 + 3) cycloaddition reaction followed by nickel-catalysed reduction to construct the monatin backbone, and a highly selective enzyme resolution of the 2 S,4 S - and 2 R,4 R -monatin diastereomeric pair to afford each enantiomer in 99% ee.",10.1021/op1001947,1
Scaleable Preparation of Sensitive Functionalized Aromatics and Heteroaromatics via Directed Metalation Using tmpZnCl·LiCl,"A range of functional aryl and heteroaryl zinc reagents were prepared in THF via directed zincation using the previously reported amide base tmpZnCl·LiCl. These metalation reactions were carried out on 50 mmol scale. Diverse sensitive functional groups such as a nitro group, an aldehyde, an ester, and a nitrile are tolerated. Furthermore, the resulting zinc intermediates show excellent reactivity towards various classes of electrophiles, e.g. Pd-catalyzed cross-coupling reactions or Cu-catalyzed acylations and allylations. In all cases, the metalation rates have been compared with those of the corresponding small-scale reactions (1−2 mmol). Moreover, the recovery of the valuable tmp-H from the aqueous phase has been demonstrated.",10.1021/op1001935,0
"Selective Hydrogenolysis of Glycerol to 1,2-Propanediol: Comparison of Batch and Continuous Process Operations","The screening of copper chromite catalysts with various promoters such as Al, Zn, and Ba for glycerol hydrogenolysis to 1,2-propanediol (1,2-PDO) in a batch reaction showed that Cu−Cr (Ba) catalyst gave the highest conversion of 34% and selectivity of 84% to 1,2-PDO. In a continuous operation (23 g catalyst bed) the same catalyst showed higher conversion of glycerol and selectivity for 1,2-PDO of 65% and >90%, respectively, with an on-stream activity of ∼800 h. Better performance in a continuous operation could be due to the in situ activation of the catalyst, suppression of glycerol cracking to ethylene glycol, as well as excessive hydrogenation of 1,2-PDO to 2-propanol due to lower contact time of 1.3 h as compared to that in a batch operation (5 h). Effects of various process parameters on conversion and selectivity also have been compared for batch and continuous operations.",10.1021/op1001897,0
Development of a Novel Catalytic Distillation Process for Cyclohexanol Production: Mini Plant Experiments and Complementary Process Simulations,"A new, two-step process concept for the production of cyclohexanol by indirect hydration of cyclohexene using formic acid as a reactive entrainer is suggested, and its principle technical feasibility is demonstrated. The first step of this process is based on an ester formation reaction of cyclohexene with formic acid. This reaction was carried out in a mini plant stainless steel catalytic distillation column of 2.35 m height. The column was packed with noncatalytic structured packings (SULZER-DX) and catalytic structured packings (KATAPAK-S). The experiments were conducted under low-pressure conditions (<0.6 bar) to avoid formic acid decomposition. Concentration and temperature profiles were obtained under steady-state conditions. Up to 98.3% conversion of cyclohexene and 75.5 mol % ester concentration in the bottom product of the column was obtained. In a similar manner, the second step of the process, i.e. the hydrolysis of the cyclohexyl formate formed in the first step, was investigated experimentally in a continuous catalytic distillation column under low-pressure conditions (<0.4 bar). Important process design parameters such as the feed mole ratio of the reactants, the reboiler duty, the feed flow rate, and the column pressure were investigated with regard to their effect on the cyclohexene conversion and the purity of the bottom product. Furthermore, the experimental data were compared with results obtained from steady-state simulations of the catalytic distillation process.",10.1021/op1001879,0
"Discovery and Development of an Efficient, Scalable, and Robust Route to the Novel CENP-E Inhibitor GSK923295A","The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro- N -{(1 S )-2-[( N, N -dimethylglycyl)amino]-1-[(4-{8-[(1 S )-1-hydroxyethyl]imidazo[1,2- a ]pyridin-2-yl}phenyl)methyl]ethyl}−4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available l -phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel−Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.",10.1021/op100186c,1
A Switchable Oxidation Process Leading to Two Various Versatile Pharmaceutical Intermediates,"An efficient high-yielding and environmentally benign switchable oxidation process that can selectively produce two different versatile synthetic intermediates is disclosed. One of the two intermediates, 2,3-dimethoxy-5-methylcyclohexa-2,5-diene-1,4-dione (coenzyme Q 0 ), is obtained by means of a telescoped two-step synthetic protocol that in the first step involves treatment of the substrate (1,2,3-trimethoxy-5-methylbenzene) with hydrogen peroxide in acetic acid with p- toluene sulphonic acid present as a Brønsted acid catalyst, succeeded by a telescoped second step that entails treatment with fuming nitric acid to achieve the target molecule in an excellent isolated yield (88%). If the substrate is treated directly with nitric acid (65%) in glacial acetic acid two different products can be obtained, namely acetic acid 3,4,5-trimethoxybenzyl ester in a superb isolated yield (93%) or, under slightly altered reaction conditions, 1,2,3-trimethoxy-5-(nitromethyl)benzene in a moderate to low yield (35%) and low selectivity. The two pathways leading to the two different products in the nitric acid oxidation protocol were investigated by means of DFT calculations as an aid to elaborate a proposal for the reaction mechanism.",10.1021/op100185x,0
Robust Synthesis of Methyl 5-Chloro-4-fluoro-1<i>H</i>-indole-2-carboxylate: A Key Intermediate in the Preparation of an HIV NNRTI Candidate,"A synthetic preparation of methyl 5-chloro-4-fluoro-1 H -indole-2-carboxylate, a key intermediate towards phosphoindole inhibitors of HIV non-nucleoside reverse transcriptase, is described. The five-step synthesis involved Boc protection of the commercially available 4-chloro-3-fluoroaniline and regioselective iodination at C-2. After facile Boc deprotection, cyclization of the resultant o -iodoaniline gave the corresponding 5-chloro-4-fluoro-indole-2-carboxylic acid which was subsequently esterified to provide the target indole ester in 56% overall yield. Identification of 6-chloro-7-iodo-2(3 H )-benzoxazolone as a significant side product in the iodination step led to the development of conditions which eliminated its formation in subsequent batches. Advantages of this alternative approach relative to existing methodologies include (1) potentially hazardous diazonium and azido species were not required, (2) regioisomeric products were not generated, and (3) chromatographic isolations were avoided, as all intermediates were easily crystallized. As a result, the key indole ester was produced rapidly at 100-fold increased scale compared to previous reports with a 10-fold improvement in overall yield.",10.1021/op1001808,1
Convenient Method for Synthesis of <i>N</i>-Protected α-Amino Epoxides: Key Intermediates for HIV Protease Inhibitors,"A convenient method for synthesis of 2 R,3 S and 2 S,3 S N -Boc phenylalanine epoxides using readily available allylamine is described. Previous methods employed multistep synthetic routes from l -phenyl alanine that include use of m -chloroperbenzoic acid ( m- CPBA) and a chromatographic method for purification of the desired diastereomers. Column purification could be eliminated by bringing in much improvement in the existing process. The process was further enhanced by replacing m -CPBA with oxone, an ecofriendly reagent advantageous for commercial application. The overall green process discussed involves the recovery and recycling of enantiomers of chiral allyl amines and judicial separation of diastereomers of the epoxides using simple economical methods.",10.1021/op100174j,1
"Optimization of a Hydrogenation Process using Real-Time Mid-IR, Heat Flow and Gas Uptake Measurements","This paper describes using real-time mid-IR, heat flow, and gas uptake data to optimize the hydrogenation of a nitroaromatic to an aniline that had been difficult to control during a previous campaign in the pilot plant. A bimetallic Pt/V catalyst was identified that eliminated the buildup of reaction intermediates and consequently resulted in an inherently more controllable process. The real-time analytics were then used to rapidly optimize the reaction conditions and develop strategies for controlling the reaction rate in the plant should an unexpected deviation occur.",10.1021/op100169j,0
"An Efficient Scalable Route for the Synthesis of Enantiomerically Pure <i>tert</i>-Butyl-(1<i>R</i>,4<i>S</i>,6<i>R</i>)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate","An efficient scalable route to synthesize the enantiomerically pure tert -butyl-(1 R,4 S,6 R )-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate is described. Compared to the original routes, significant improvements were made by using an innovative approach starting from commercially available chiral lactone. In this approach, one of the key steps described is an elegant epimerization/hydrolysis of the undesired diastereoisomer avoiding tedious purification. The chemistry has been scaled up to produce kilogram amounts of tert -butyl-(1 R,4 S,6 R )-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate in 43% yield over nine chemical transformations.",10.1021/op100164v,1
Development of an Efficient and Practical Route for the Multikilogram Manufacture of the SRC Kinase Inhibitor AZD0530,"In a previous publication ( Org. Process Res. Dev. 2010, 14, DOI: 10.1021/op100161y ) we described the process research and development of a manufacturing route for the potent SRC kinase inhibitor AZD0530. While the route was successfully used to manufacture 4.5 kg of AZD0530 difumarate, it was still relatively long, used two Mitsunobu couplings, and was, in our opinion, undesirable for manufacture on a larger scale. Herein we describe the research and development of a shorter, more practical synthesis of AZD0530 difumarate. The new route, which required fewer steps, scaled well to produce >80 kg of AZD0530 difumarate in an overall yield of 38%.",10.1021/op100163m,1
Process Research and Development for the Kilogram Manufacture of the SRC Kinase Inhibitor AZD0530,"Process research and development of a synthetic route towards a novel SRC kinase inhibitor is described. The Medicinal Chemistry route was very long and suffered from extensive use of chlorinated solvents and chromatography. A number of steps in the Medicinal Chemistry route were also unattractive for large-scale use for a variety of reasons. The route was modified to produce a shorter synthetic scheme that started from more readily available materials. By using the modified route, the title compound was manufactured on kilogram scale without recourse to chromatography and in significantly fewer steps. The scaled synthesis required two Mitsunobu couplings, which were developed and scaled successfully. An interesting hydrazine impurity was identified in the second Mitsunobu coupling; a mechanism for its formation is proposed, and a method for its control is described. The formation and control of some other interesting impurities are also described.",10.1021/op100161y,1
Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone,"Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in >75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/oxidation process was developed and successfully scaled to the clinical pilot plant to produce 25 kg of 1 . For the pilot-plant campaign, the lithiation step was developed to operate at −50 °C using commercial lithium diisopropylamide (LDA), and the oxidation step employed catalytic TEMPO as the primary and NaOCl as the terminal oxidant. After completion of the pilot-plant campaign second-generation approaches to 1 were developed to improve process greenness where the lithiation and condensation step were operated as warm as −10 °C, the highly efficient AZADO catalyst was used as a substitute for TEMPO in the Anelli−Montanari oxidation, and process mass intensity was reduced 25%.",10.1021/op100157q,0
Enzymatic Preparation of an (<i>S</i>)-Amino Acid from a Racemic Amino Acid,"The ( S )-amino acid, ( S )-2-amino-3-(6- o -tolylpyridin-3-yl)propanoic acid ( 3 ), is a key intermediate needed for synthesis of an antidiabetic drug candidate. Three enzymatic routes to 3 were explored. ( S )-Amino acid 3 could be prepared in 73% isolated yield with 99.9% ee from racemic amino acid 1 using ( R )-amino acid oxidase from Trigonopsis variabilis expressed in Escherichia coli in combination with an ( S )-aminotransferase using ( S )-aspartate as amino donor. The ( S )-aminotransferase was purified from a soil organism identified as Burkholderia sp. and cloned and expressed in E. coli . ( S )-Amino acid 3 with 100% ee was also prepared in 68% solution yield and 54% isolated yield from 1 using recombinant ( R )-amino acid oxidase from T. variabilis and an ( S )-amino acid dehydrogenase from Sporosarcina ureae . The cofactor NADH required for the reductive amination reaction was regenerated using formate and formate dehydrogenase. The chemoenzymatic dynamic resolution of 1 by ( R )-selective oxidation with Celite-immobilized ( R )-amino acid oxidase in combination with chemical imine reduction using borane−ammonia complex gave an 81% solution yield and 68% isolated yield of 3 with 100% ee.",10.1021/op1001534,0
Development of an Efficient Synthesis of Two CRF Antagonists for the Treatment of Neurological Disorders,"BMS-764459 ( 1 ) and BMS-763534 ( 2 ) are CRF1 antagonists for the treatment of neurological disorders such as depression and anxiety. An efficient synthesis of 1 and 2 is described, which features an efficient palladium-catalyzed cyanation of a 5-chloropyrazinone where zinc acetate suppresses dehalogenation. This synthesis was applied to the preparation of >5 kg of 1 and 2 for clinical studies.",10.1021/op1001512,1
Development of Drug Substances as Mixture of Polymorphs: Studies to Control Form 3 in Casopitant Mesylate,"Polymorphism is characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice and this can impact the physical properties of a drug substance. In this paper the studies carried out on casopitant mesylate, a NK 1 antagonist developed in GlaxoSmithKline (GSK), are reported. During process development studies it was discovered that what was initially considered a single crystalline phase, Form 1, was actually a mixture of two different forms, Form 1 and Form 3. A retrospective analysis of all the key drug substance batches clearly indicated that Form 3 was always present as minor component in mixture with Form 1. Furthermore any attempt to generate either pure Form 1 or pure Form 3 failed. As a result of this, the project team explored the opportunity to develop the drug substance as a mixture of polymorphs. The studies performed to assess the ability of the manufacturing process to control the amount of Form 3 in the drug substance, according to the Quality by Design principle and the assessment of the impact of this finding on the drug product performance are reported in this paper. Collectively, the data demonstrated that the level of Form 3 in the drug substance (up to a level of 27% w/w) is not a drug substance critical quality attribute (drug substance-CQA) for casopitant mesylate.",10.1021/op100150b,0
"Identification of a Manufacturing Route of Novel CRF-1 Antagonists Containing a 2,3-Dihydro-1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridine Moiety","A case study on the synthesis of novel CRF-1 antagonists containing the 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridine moiety is presented. The development of ever more efficient synthetic routes allowed the progression of three candidates at the same time. A manufacturing route was identified and successfully demonstrated on a pilot-plant scale to prepare 100 kg of the CRF-1 antagonist GW876008.",10.1021/op100147h,1
The Synthesis of Two Potent β-3 Adrenergic Receptor Agonists,This contribution describes the initial preparation of two potent β-3 receptor agonists 1 and 2 . Subsequent scale up of these two compounds was required for further evaluation and proceeded via a common key amine intermediate 24 . Synthesis of this key intermediate by way of a Ritter reaction was a vital step in the sequence. Enantioselective Noyori hydrogenation reactions gave access to the chiral epoxides necessary to make the target compounds. Chemistry was developed for the selective dehalogenation of the 2-chloropyridyl group in the presence of a sensitive isoxazole unit to provide access to 1 .,10.1021/op1001462,1
An Optimized Process to 10-Bromo-1-decanol,"A multivariate design and optimization study for the synthesis of the bromoalkanol 10-bromo-1-decanol using decane-1,10-diol as substrate is reported. The bromination process was supported by the phase transfer catalyst tetrabutylammonium bromide with aqueous HBr (48%) as the brominating reagent. The optimized batch protocol provided a yield of 64% of 10-bromo-1-decanol 2 TM with a conversion of 80%, and 10% of the dibrominated alkane 1,10-dibromodecane 3, a characteristic byproduct, was formed.",10.1021/op100143t,0
"Investigation into the Formation of the Genotoxic Impurity Ethyl Besylate in the Final Step Manufacturing Process of UK-369,003-26, a Novel PDE5 Inhibitor","Sulfonate esters have a demonstrated potential for genotoxicity, and therefore their potential presence at trace levels in active pharmaceutical ingredients (APIs) has recently raised concerns [ Mesylate Ester Type Impurities Contained in Medicinal Products; Swissmedic Department for Control of the Medicinal Products Market, 23rd October 2007 and Hoog, T. J.-d. Request to Assess the Risk of Occurrence of Contamination With Mesilate Esters and Other Related Compounds in Pharmaceuticals; Coordination Group for Mutual Recognition-Human Committee (CMDh), EMEA/CMDh/98694/2008: London, 27 February, 2008, ]. Sulfonate salts however, offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups such that their use can at times offer significant advantages over other counterions [ Elder, D. P.; Delaney, E.; Teasdale, A.; Eyley, S.; Reif, V. D.; Jacq, K.; Facchine, K. L.; Oestrich, R. S.; Sandra, P.; David, F. The Utility of Sulfonate Salts in Drug Development. J. Pharm. Sci. 2010, 99, 2948−2961; DOI: 10.1002/jps.22058 ]. Indeed, the choice of benzenesulfonic acid as the counterion for the UK-369,003 API afforded many advantages over other salts such as citrate, hydrochloride, tartrate, and phosphate as well as other sulfonate salts such as tosylate, camsylate, and mesylate. The manufacturing route to the API consists of two C−C bond-forming steps (steps 1 and 2/Scheme 1) and a final salt-formation step (step 3/Scheme 1). The step 2 cyclisation process involves the use of ethanol as the reaction solvent. Residual levels of ethanol in the isolated product of the step 2 process was initially thought to be responsible for the formation of low levels of the genotoxic impurity ethyl besylate (ppm levels) during the final step salt-formation process [ Glowienke, S.; Frieauff, W.; Allmendinger, T.; Martus, H. J.; Suter, W.; Mueller, L. Mutat Res. 2005, 581, 23−34]. This was thought to result from subsequent reaction of residual ethanol with benzenesulfonic acid used in the final step (step 3). On the basis of this mechanistic hypothesis, the levels of residual ethanol in the isolated product from step 2 were controlled so that formation of ethyl besylate would be minimised or avoided in the final step. Spiking experiments coupled with deuterium labelling studies have shed doubt on this mechanism of formation. Our experimental results indicate that levels of ethyl besylate in the API are independent of the level of residual ethanol in the step 2 product (UK-369,003 free base) and are detected when higher than stoichiometric amounts of benzenesulfonic acid are used in the salt-formation process (step 3). This is thought to be due to a reaction between the excess benzenesulfonic acid and the ethoxy side chain of the API. Sensitive and selective analytical methods were also developed to detect and quantify subppm and higher levels of ethyl besylate and deuterated analogues.",10.1021/op100141g,1
Organic Solvent Nanofiltration: A New Paradigm in Peptide Synthesis,"Solid-phase synthesis is the dominant paradigm for peptide synthesis, used ubiquitously from discovery to production scale. However, the solid-phase approach produces coupling steps that may not be quantitative, introducing errors in amino acid sequences. It also entails an excess of reagents to overcome mass transfer limitations and restrictions on solvent, coupling chemistry, and protecting groups. Organic solvent nanofiltration (OSN) is a newly emerging technology capable of molecular separations in organic solvents. This contribution reports a new technology platform which advantageously combines OSN with solution-phase peptide synthesis, Membrane Enhanced Peptide Synthesis (MEPS). A first amino acid is linked to a soluble polyethylene glycol anchor. Through subsequent repeated coupling and deprotection steps, the peptide is extended to the desired length. The residual byproducts and excess reagents after each reaction are removed by diafiltration through a solvent-stable membrane which retains the peptide. Two pentapeptides are produced using this new technology. The purity of the peptides produced by MEPS is higher than that of peptides produced by solid-phase synthesis, under the same conditions. This illustrates clearly that MEPS benefits from the advantages of solution-phase synthesis, while avoiding the purification steps that have until now made solution-phase synthesis practically difficult.",10.1021/op1001403,0
Development of a New Synthesis for the Large-Scale Preparation of Triple Reuptake Inhibitor (−)-GSK1360707,"The triple reuptake inhibitor, GSK1360707, was synthesized via an efficient, scalable route, which features a vinyl triflate Suzuki coupling followed by a single-step, double alkylative cyclopropanation with a dihalomethane. Also, a mechanistic understanding of the Suzuki reaction (as it relates to the control of a polychlorinated biphenyl impurity) is discussed.",10.1021/op100139f,1
"Practical Synthesis of (1<i>s</i>,4<i>s</i>)-4-(Methylamino)-1′<i>H</i>-spiro[cyclohexane-1,3′-furo[3,4-<i>c</i>]pyridin]-1′-one","A practical and scalable process for the preparation of (1 s,4 s )-4-(methylamino)-1′ H -spiro[cyclohexane-1,3′-furo[3,4- c ]pyridin]-1′-one 2a, a highly functionalized and potentially useful building block for pharmaceutical research is described. The material is prepared via an efficient two-step sequence from readily available materials and is isolated as a single diastereomer in high chemical purity.",10.1021/op100138t,0
Review of U.S. Patents in the Field of Organic Process Development Published During February and March 2010,"ADVERTISEMENT RETURN TO ISSUEPREVHighlights From Pate...Highlights From PatentsNEXTReview of U.S. Patents in the Field of Organic Process Development Published During February and March 2010Keith TurnerView Author Information Kappa Tau Consulting, 12 The Avenue, Fairfield, Stockton-on-Tees, TS19 7EY, U.K. E-mail: [email protected]Cite this: Org. Process Res. Dev. 2010, 14, 4, 759–769Publication Date (Web):June 2, 2010Publication History Published online2 June 2010Published inissue 16 July 2010https://pubs.acs.org/doi/10.1021/op100134ahttps://doi.org/10.1021/op100134aproduct-reviewACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views1809Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical reactions,Mixtures,Salts,Separation science Get e-Alerts",10.1021/op100134a,0
Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale,"The three-step manufacturing process used in the synthesis of tenofovir disoproxil fumarate ( 1 ) was studied and optimized, leading to a more productive and robust process. The yield was improved from about 13% overall to 24%. Key process improvements identified included implementation of a telescoped process for the second stage that obviated the need for an extraction and solvent exchange, and significant optimization of the final reaction, including the beneficial effect of adding a quaternary ammonium salt to the alkylation reaction and development of a nonaqueous process for removal of NMP and triethylamine from the product mixture to decrease the level of decomposition of product during the isolation.",10.1021/op1001337,1
"Development of a Catalytic Cuprate 1,6-Conjugate Dienone Addition Process for the Manufacture of Fulvestrant EAS, a Key Intermediate in the Synthesis of Fulvestrant","The paper describes the development of a process to a key steroidal intermediate in fulvestrant, the active pharmaceutical ingredient of the anticancer agent Faslodex. Synthesis of the intermediate, known within AstraZeneca as fulvestrant EAS, involves the copper-catalysed 1,6-conjugate addition of a Grignard reagent to a steroidal dienone. The reaction temperature and the order and rate of addition of the reagents have a dramatic effect on the overall yield of the desired compound. A novel aspect of the development was the monitoring of transient colour changes associated with the catalytic cycle as an important aid to process optimisation.",10.1021/op1001319,1
"A Practical Synthesis of the PDE4 Inhibitor, KW-4490",A practical and scalable synthesis of a PDE4 inhibitor KW-4490 ( 1 ) was developed. This improved synthesis features the construction of the 1-arylcyclohexene ( 9 ) by the Diels−Alder reaction followed by a newly established Brønsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution enabled the high-yield production of the desired cis -isomer ( cis-8 ). The synthesis was achieved in seven steps in 37% overall yield.,10.1021/op1001287,1
"A Scalable Synthesis of a 1,7-Naphthyridine Derivative, a PDE-4 Inhibitor","A six-step synthesis of a 4-[8-(3-fluorophenyl)[1,7]naphthyridin-6-yl]- trans -cyclohexanecarboxylic acid with an overall yield of 27% starting from 2-cyano-3-methylpyridine, cyclohexane-1,4-dicarboxylic acid dimethyl ester, and 3-fluorophenylboronic acid is described. The trans stereochemistry in the cyclohexane moiety was achieved through a series of equilibration steps at different stages of the synthesis.",10.1021/op100124x,1
An Automated Microfluidic System for Online Optimization in Chemical Synthesis,"An automated, continuous flow system for the online, multivariable optimization of a chemical reaction is presented. Time and material required for an optimization trial are minimized by performing reactions in an integrated silicon microreactor and incorporating an HPLC for inline monitoring of the reaction performance. We use the system to optimize two different reactions to describe the potential impact of this system for reaction development. First, we demonstrate the broad operation capabilities by incorporating several feedback algorithms to optimize a weighted objective function involving the yield and the throughput of a Knoevenagel condensation reaction. After illustrating how system operations can be adapted for individual reactions, we perform a multiparameter optimization to maximize the yield of benzaldehyde in the oxidation pathway of benzyl alcohol to benzaldehyde to benzoic acid. A significant feature of the automated system is the ability to perform “black-box” optimization where no a priori information of the reaction parameters is required.",10.1021/op100123e,0
"Development of a Dynamic Kinetic Resolution for the Isolation of an Intermediate in the Synthesis of Casopitant Mesylate: Application of QbD Principles in the Definition of the Parameter Ranges, Issues in the Scale-Up and Mitigation Strategies","Process development towards the improvement of the manufacturing process of casopitant mesylate (a drug developed by GlaxoSmithKline with activity on the central nervous system) identified a dynamic kinetic resolution opportunity for the improvement of the yield. In this paper, the application of quality by design principles to the DKR is presented together with the issues that were faced during different scale-ups and the at-scale solutions that were implemented.",10.1021/op100121s,1
Process Research and Development of a MTP Inhibitor: Another Case of Disappearing Polymorphs upon Scale-up,"LAB687 is an inhibitor of microsomal triglyceride transfer protein (MTP) designed to lower triglycerides and LDL cholesterol. The discovery of its polymorphic forms closely intertwines with the synthesis development of the molecule. At the early development stage, LAB687 was known to crystallize in two modifications, Forms A and B. Knowledge of the molecule’s polymorphic nature prompted extensive polymorphic screening using drug substance produced by the earlier synthesis routes. These studies revealed the existence of a third polymorph, Form C. Subsequently, Form C was selected for further development based on data from the additional formulation and polymorphic studies. Surprisingly, a new modification, Form D, appeared when the crystallization process known to routinely produce Form C was scaled up in the pilot plant. Once Form D was introduced to the laboratory, Forms A and C could no longer be made. We hypothesize that a change in drug substance impurity profile due to the changes in synthesis, led to the emergence of the most stable Form D.",10.1021/op100115u,0
Overall Synthesis of GSK356278: Quick Delivery of a PDE4 Inhibitor Using a Fit-for-Purpose Approach,"The family of phosphodiesterase (PDE) enzymes hydrolyse cyclic nucleotides, cAMP and cGMP, leading to their inactivation as intracellular second messengers. Inhibition of these enzymes leads to an elevation of levels of cyclic nucleotides in the cell and prolongs their action on downstream signaling pathways. PDE4, of which there are four subtypes, is widely expressed throughout the brain but is also abundant in the periphery in inflammatory and immune cells, in the gastrointestinal tract, and in cardiac myocytes. GSK356278 1 is a potent, selective, and competitive inhibitor of PDE4 enzymes currently under investigation for the treatment of CNS disorders. The initial synthetic route developed by Medicinal Chemistry Department, used several hazardous and/or expensive reagents and harsh conditions and gave relatively low yields. By targeted process of research and development plus application of analytical techniques to identify byproduct and extensive route scouting, a novel synthetic route for 1 has been developed. This contribution reports the optimisation of the chemical synthesis of 1 to develop a large-scale process suitable for its synthesis.",10.1021/op1001148,1
"Development of a Pilot-Plant-Scale Synthesis of an Alkylated Dihydrobenzothiadiazole <i>S</i>,<i>S</i>-Dioxide: Incorporation of a Late-Stage Mitsunobu Reaction","The process used to prepare a functionalized dihydrobenzothiadiazole S, S -dioxide on a pilot plant scale is described. Key changes to the original synthesis included: modifying S N Ar reaction conditions between a substituted aniline and 2-fluoronitrobenzene from n -BuLi/−78 °C to KO t Am/0 to 15 °C; replacement of a NaIO 4 −RuCl 3 oxidizing system with bleach under phase transfer conditions; and a late-stage Mitsunobu reaction. The Mitsunobu reaction was used to prepare the penultimate intermediate and the process was telescoped forward through an N -Boc deprotection step that generated the active pharmaceutical ingredient. The product was efficiently extracted into the aqueous phase under acidic conditions so that the Mitsunobu byproducts could be washed away from the product with toluene. Although Mitsunobu reactions appear to be rarely used on scale, our results indicate that extraction of the API into an aqueous layer is an efficient way to separate the API from triphenylphosphineoxide and hydrazinedicarboxylate byproducts.",10.1021/op100113j,1
"Process Development for a Large Scale Stereoselective Synthesis of (<i>Z</i>)-(1-Bromobut-1-ene-1,2-diyl)dibenzene, a Key Intermediate of a Selective Estrogen Receptor Modulator","Two efficient large scale syntheses of ( Z )-(1-bromobut-1-ene-1,2-diyl)dibenzene are described. The first is a three-step synthetic sequence from trimethyl(phenylethynyl)silane in 63% overall yield. The key transformations involved the stereospecific carbometalation reaction of trimethyl(phenylethynyl)silane followed by a bromination. Subsequent Miyaura−Suzuki coupling with phenylboronic acid and transformation of the vinyltrimethylsilane to a vinyl bromide afforded the target. In an improved synthesis, a stereoselective nickel acetylacetonate catalyzed PhZnEt addition to but-1-ynylbenzene, generated an organozincate intermediate, which was brominated in 58−62% overall yield. A key feature of this work was the production of highly regiopure olefin. The optimization effort that resulted in the utilization of substoichiometric amounts of Ph 2 Zn and the safety precautions taken to facilitate process scale-up are discussed.",10.1021/op100112r,1
Scaling Up Attrition-Enhanced Deracemization by Use of an Industrial Bead Mill in a Route to Clopidogrel (Plavix),The recently discovered technique of deracemization by means of grinding a racemic conglomerate in contact with a solution wherein racemization occurs has been scaled up using an industrial bead mill to demonstrate the practical applicability. The time needed to reach the enantiopure end state is drastically reduced as a result of the efficient grinding that can be achieved using bead mills.,10.1021/op1001116,0
"A New and Efficient Synthesis of 6-[(5<i>S</i>,9<i>R</i>)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic Acid, a Potent LFA-1/ICAM Inhibitor","An efficient synthesis of 6-[(5 S,9 R )-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic acid 1 is described. This new process involves an in situ protection of 6-chloronicotinic acid as trimethylsilyl ester followed by coupling with spirocyclic hydantoin core 2 to give the target product in 89% overall yield after one-pot deprotection and final API recrystallization.",10.1021/op100104z,1
"Development of an Efficient Large-Scale Synthesis for a 4<i>H</i>-imidazo[5,1-<i>c</i>][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety","The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4 H -imidazo[5,1- c ][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis was demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.",10.1021/op100103v,1
A Facile Microwave-Mediated Drying Process of Thermally Unstable / Labile Products,"The drying behavior of ( S )- N -acetylindoline-2-carboxylic acid, precipitated ( 1a, 17 wt %) and nonprecipitated ( 1b, 5 wt %), and N -acetyl-( S )-phenylalanine (( S )-2-acetamido-3-phenylpropanoic acid, 2 ), both pharmaceutical intermediates, and of cocarboxylase hydrochloride (thiamine pyrophosphate, 3 ), a coenzyme, a bioactive form of vitamin B 1, being a thermolabile substance, has been determined in straightforward drying setups. The method of supplying energy to the system had a profound influence on the drying rate and on the internal temperature of the samples during drying. The drying time of ( S )- N -acetylindoline-2-carboxylic acid ( 1b ) with the low moisture content (5 wt %) could be reduced by a factor 4 using microwave irradiation instead of conventional heating, while keeping the sample temperature under 35 °C. N -Acetyl-( S )-phenylalanine ( 2 ) with a higher moisture content (22 wt %) demonstrated a decrease in drying time by a factor 2.5 to 4 depending on the applied microwave powers. A reduction in drying time of the precipitated ( S )- N -acetylindoline-2-carboxylic acid ( 1a, 17 wt % moisture) by a factor 2 was demonstrated for drying at 150 W of microwave irradiation instead of using a water bath at 70 °C. A dramatically shorter drying time by a factor 10 was found for cocarboxylase hydrochloride ( 3, 15 wt % water) on lab-scale which could be reproduced on pilot-plant scale. To achieve with conventional heating similar drying times as under microwave irradiation for the four examples, extremely high energy inputs should be applied, necessitating extremely high temperature differences between the heating source and the sample. The results reveal that microwave irradiation is less energy-consuming and is particularly useful for effective drying of thermally unstable materials in short periods of time.",10.1021/op100102m,0
Process Development and Large-Scale Synthesis of a c-Met Kinase Inhibitor,"A highly convergent synthesis of c-Met kinase inhibitor 1 has been demonstrated on a multikilogram scale using three key fragments: dihalotricyclic core 2, chiral sulfamide side chain 3, and pyrazole boronic ester 4 . The chirality in sulfamide side chain 3 was installed using the cheap and readily available starting material ( S )-epichlorohydrin. A total of 2.71 kg of 1 were isolated in seven steps (the longest linear sequence).",10.1021/op100101q,1
Improved Process for the Preparation of 1-Benzhydrylazetidin-3-ol: Development of an Efficient Synthesis and Identification of Process-related Impurities and/or Intermediates,"An improved, one-pot, and multikilogram-scale synthesis of 1-benzhydrylazetidin-3-ol, the pharmaceutically important moiety, has been developed. The improved process for the preparation of 1-benzhydrylazetidin-3-ol was able to minimize a content of impurities and allows the effective production of 1-benzhydrylazetidin-3-ol and its scale-up. The process was high yielding (80%) and chromatography-free with purity 99.3 area %.",10.1021/op100100y,0
A Novel Scalable Synthesis of Pramipexole,"Pramipexole is a dopamine D 2 subfamily receptor agonist that is used for the treatment of Parkinson’s disease. We report here on the successful application of the Fukuyama alkylation protocol to the development of a novel and scalable process for synthesis of pramipexole and its pharmaceutically acceptable salts. The synthesis consists of converting the crucial intermediate ( S )-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to (6 S )- N -(2-amino-4,5,6,7-tetrahydrobenzothiazole-6-yl)-2-nitrobenzenesulfonamide, which is in turn monoalkylated to (6 S )- N -(2-amino-4,5,6,7-tetrahydrobenzothiazole-6-yl)-2-nitro- N -propylbenzenesulfonamide. Deprotection of the latter yields pramipexole base, which is finally converted to a crude pramipexole dihydrochloride monohydrate with a yield of over 50% over four steps. The process allows for the telescoping of the final three steps, has high conversion rates of intermediates, offers ease of purification, and preserves high optical purity throughout all of the stages.",10.1021/op1000989,1
The Synthesis of GV143253A: A Case Study for the Use of Analytical and Statistical Tools to Elucidate the Reaction Mechanism and to Optimize the Process,"GV143253A 1 is a broad-spectrum injectable β-lactam belonging to the class of trinem antibiotics. This article describes the work which enabled a detailed process understanding via several analytical techniques and the subsequent optimization of a key intermediate. By means of a combined application of 31 P NMR spectroscopy and MS spectrometry, the main impurities have been identified and the reaction mechanisms clarified. Moreover, a design of experiments (DoE) approach was applied which substantially improved the overall yield.",10.1021/op100097c,1
Novel Preparation of H<sub>1</sub> Receptor Antagonist Fexofenadine,"A novel synthetic route for the preparation of H 1 receptor antagonist fexofenadine is described. The synthetic route started from the para-substituted aromatic derivative of methyl 4-(cyanomethyl)benzoate, 2, and gave fexofenadine in 26.0% overall yield via six steps. The whole process featured a method wherein fexofenadine could be obtained in excellent quality without ortho- or meta-unpurified regioisomers.",10.1021/op100090j,1
Scaleup of Lipase-Catalyzed Polyester Synthesis,"One of the critical steps for the commercialization of new enzyme-based products is the successful scaleup of the catalyzed reaction. In the study presented here, we achieved a scaleup for the enzymatic production of glycerol adipate on a 500 g scale in a heated, solvent-free system. The influence of various reaction conditions (i.e., temperature, pressure, enzyme concentration, reactants ratio, stirrer type, stirring rate, and reaction time) on the substrate conversion and molecular weight of the product was investigated. Conversions were higher than 0.9, and molecular weights were in the desired range of 2000−3000 Da. Space time yields of 370 g d −1 L −1 could be achieved. Maximal polymer yield was achieved at 60 °C, < 20 mbar, 3 wt % Novozym 435, glycerol:adipic acid ratio 1.1:1, <48 h while stirring at 100 rpm.",10.1021/op1000868,0
"Process for the Preparation of an Amorphous, Peptide-like Diabetes Drug: Approach to a Chromatography-Free Process","A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N -((2 R )-1-{(3 R )-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2 H )-yl}-3-(1 H -indol-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1 H -indol-2-yl)carbonyl]piperidine-4-carboxamide (1) as a drug for treating diabetes has been developed. The first kilogram quantities of 1 were prepared via a single-chromatography process that employed recyclable cation-exchange resin chromatography for an amorphous intermediate (2 R )-2-amino-1-[(3 R )-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2 H )-yl]-3-(1 H -indol-3-yl)-propan-1-one ( syn - 3a ). We have also developed a chromatography-free process that involves a combination purification of extraction of syn - 3a with crystallization of syn - 3a ·0.25H 3 PO 4 ·0.5H 2 O. The latter process afforded amorphous compound 1 with >98% purity by HPLC area analysis, the same quality as that provided by the former process.",10.1021/op100084r,1
Development of a Control Strategy for a Defluorinated Analogue in the Manufacturing Process of Casopitant Mesylate,"Casopitant mesylate was identified as part of the search for drugs with activity on the Central Nervous System (CNS) by GlaxoSmithKline. During late-phase development studies to develop the manufacturing process, a new impurity was found. This synthetic impurity, a defluorinated analogue of the drug substance, is discussed in detail to show the process development studies carried out to ensure quality control for the final drug substance following the principles of quality by design. The process understanding gained, in combination with risk analysis, allowed the development of a control strategy for enhanced level of quality assurance. This Control Strategy allows moving the control of this impurity to the point of origin instead of testing in the drug substance.",10.1021/op1000836,0
A Commercial Continuous Flow Microwave Reactor Evaluated for Scale-Up,"Six pharmaceutically relevant reactions covering a range of physical parameters have been investigated in a commercially available microwave flow reactor. The reaction conditions were scaled-up from tube or large batch scale microwave conditions, largely without change. Energy consumption measurements were also taken. In summary, this microwave flow reactor provided potentially successful manufacture for five out of six reactions investigated where homogeneous reactions solutions could be obtained. Production rates of between 0.5 and 3.0 mol/h (1−6 L/h) have been achieved with minimal redevelopment of the chemistry.",10.1021/op100082w,1
Davis Oxaziridine-Mediated Asymmetric Synthesis of Proton Pump Inhibitors Using DBU Salt of Prochiral Sulfide,"A simple and clean asymmetric synthesis of proton pump inhibitors using inexpensive 10-camphorsulfonyl oxaziridine is described. Here, we report the activation of prochiral sulfide by making the DBU salt that is capable of enhancing the reactivity and enantioselectivity.",10.1021/op100075v,0
Selection and Development of the Manufacturing Route for EP<sub>1</sub> Antagonist GSK269984B,"A potential manufacturing route for the EP 1 antagonist GSK269984B was developed. Four synthetic approaches were examined, and a successful realisation of each is presented. The rationale supporting selection of the preferred route is discussed. This route utilised a phenolic aldol reaction as the key step and relied on selective hydrogenolysis to reduce an intermediate diarylmethanol. Further optimisation of the selected route is presented, delivering GSK269984B in three stages and 46% overall yield from readily available starting materials.",10.1021/op100072y,1
A Tool for the Semiquantitative Assessment of Potentially Genotoxic Impurity (PGI) Carryover into API Using Physicochemical Parameters and Process Conditions,"ADVERTISEMENT RETURN TO ISSUEPREVLetter to the EditorNEXTA Tool for the Semiquantitative Assessment of Potentially Genotoxic Impurity (PGI) Carryover into API Using Physicochemical Parameters and Process ConditionsAndrew Teasdale*, Simon Fenner, Andrew Ray, Agnes Ford, and Andrew PhillipsView Author Information AstraZeneca, Bakewell Road, Loughborough, Leicestershire, England LE11 5RH* Author for correspondence. E-mail: [email protected]Cite this: Org. Process Res. Dev. 2010, 14, 4, 943–945Publication Date (Web):March 24, 2010Publication History Received15 March 2010Published online24 March 2010Published inissue 16 July 2010https://pubs.acs.org/doi/10.1021/op100071nhttps://doi.org/10.1021/op100071nletterACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views4553Altmetric-Citations47LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Anions,Crystallization,Impurities,Separation science,Solubility Get e-Alerts",10.1021/op100071n,0
"Enantioselective Synthesis of (1<i>R</i>,2<i>S</i>)-1-Amino-2-vinylcyclopropanecarboxylic Acid Ethyl Ester (Vinyl-ACCA-OEt) by Asymmetric Phase-Transfer Catalyzed Cyclopropanation of (<i>E</i>)-<i>N</i>-Phenylmethyleneglycine Ethyl Ester","A concise asymmetric synthesis of (1 R,2 S )-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester, a key intermediate in the preparation of many hepatitis C virus inhibitors, is described. Stereoselective cyclopropanation of ( E )- N -phenylmethyleneglycine ethyl ester was effected by treatment with trans -1,4-dibromo-2-butene in the presence of a catalytic amount of a chiral phase-transfer catalyst. Microscale high-throughput experimentation techniques were successfully used to identify a cinchonidine-derived catalyst that provided (1 R,2 S )-1-( E )- N -phenylmethyleneamino-2-vinylcyclopropanecarboxylic acid ethyl ester in up to 84% ee. This was translated to a lab scale process to attain 78% yield and 77.4% ee. Chiral purity upgrade and isolation of the ester was accomplished via preparatory supercritical fluid chromatography followed by crystallization of the ester as its tosylate salt. The improved synthesis described herein represents a potentially more economical preparation of this valuable intermediate.",10.1021/op100070d,1
Synthesis of Hexanitrostilbene (HNS) using a Kenics Static Mixer,"Previous work on a Shipp−Kaplan type synthesis of hexanitrostilbene (HNS) using a Kenics static mixer (ref 1, from Chemineer Ltd., Cranmer Road, West Meadows, Derby DE21 6XT, UK; www.chemineer.com) has been extended by using a larger mixer (9.5 mm vs 4.75 mm OD), enabling the scale to be increased from 2.5 g to 25 g of trinitrotoluene (TNT) for the same mixing time (<4 min). Various conditions for the after-reaction period (2 h) have been explored on the basis of previous work with a batch reactor, including (i) no pH control, (ii) pH control using aqueous H 2 SO 4 and NaOH solutions, and (iii) pH control using aqueous RNH 3 Cl and RNH 2 solutions. Other parameters that have been varied are the ratio of NaOCl to TNT (0.5−1.2) and the concentration of both reactants. The yields of crude HNS that have been achieved, whilst not outstanding, are an improvement over the conventional batch process. It has been demonstrated that the yield and selectivity of the HNS synthesis can be considerably increased if, during the after-reaction period, the reaction conditions are pH controlled. The yield and selectivity are also significantly enhanced by using more dilute reaction solutions.",10.1021/op1000644,0
"Application of the QbD Principles in the Development of the Casopitant Mesylate Manufacturing Process. Process Research Studies for the Definition of the Control Strategy of some Drug Substance-CQAs for Stages 2a, 2b, and 2c","Casopitant was identified as a potent NK 1 antagonist by GlaxoSmithKline (GSK). It was selected as part of a wide drug discovery programme within GSK for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders, and others. The mesylate salt of casopitant was selected for full development. The manufacturing process to casopitant mesylate was developed and optimised by following a Quality by Design approach, whereby a control strategy was developed, underpinned by process understanding and risk analysis, for an enhanced level of quality assurance. Quality process parameters and specifications levels for the Stages 2a, 2b, and 2c are the elements of the control strategy of the manufacturing process discussed in detail in this paper. The Design of Experiment approach has been extensively used to support the definition of the proven acceptable ranges for the process. The aim is to show the process development studies carried out to ensure quality control for the final drug substance.",10.1021/op1000622,1
A Practical Preparation of Ethyl<i>N</i>-Acyl-2-(dimethoxyphosphoryl)glycinate,"A practical, cost-effective preparation of ethyl N -acyl-2-(dimethoxyphosphoryl)glycinate has been developed. The two-step process achieved an 80% overall isolated yield.",10.1021/op1000594,1
"Efficient Synthesis of Imidazoles from Aldehydes and 1,2-Diketones under Superheating Conditions by Using a Continuous Flow Microreactor System under Pressure","A simple and efficient method for the synthesis of 2,4,5-trisubstituted imidazoles has been developed by using a continuous flow microreactor system under pressure; aryl-, alkyl-, and heteroaryl-substituted imidazoles were obtained in high yields within 2 min under superheating conditions.",10.1021/op100058h,0
"Efficient Synthesis of 1,3-Dialkylimidazolium-Based Ionic Liquids: The Modified Continuous Radziszewski Reaction in a Microreactor Setup","By making use of a modified Radziszewski reaction, it is demonstrated that water-soluble 1,3-dialkylimidazolium-based ionic liquids can be produced in good yields (70−90%) and purities (>95%) starting from readily available, cost-effective monoalkylamines, glyoxal, formaldehyde, and mineral or organic acids. The homosubstituted 1,3-dialkylimidazolium salts feature high thermal stabilities similar to those of their heterosubstituted counterparts, and relatively low viscosities, thus fulfilling the requirements for solvent application. The effect of various parameters has been studied with the goal of improving yields for both the batchwise and continuous synthesis (making use of a microreactor setup), allowing for the production of a wide variety of ionic liquids and the introduction of functionalities. The applicability of these ionic liquids is demonstrated on the example of cellulose dissolution and the dehydration of fructose to 5-hydroxymethylfurfural.",10.1021/op100055f,1
Process Development of Selectively Benzoylated and Fluorinated Glycosyl Donors,"Route selection, process development and large-scale preparation of selectively benzoylated and fluorinated d -glucopyranoses, required as glycosyl donors for the synthesis of the SGLT inhibitor SAR7226, are discussed.",10.1021/op100053k,1
Manufacturing Synthesis of 5-Substituted Phthalides,"A manufacturing synthesis of 5-chlorophthalide has been elaborated. The key step of the procedure is ortho-lithiation of 4-chloro -N,N -diisopropylbenzamide, followed by formylation with dimethyl formamide. Reduction of the formyl moiety and subsequent ring closure, which can be carried out also in one pot, led to 5-chlorophthalide in high overall yield. The procedure has also been successfully adapted for the synthesis of the 5-fluoro and 5-trifluoromethyl analogues. The compounds thus obtained are useful building blocks in the synthesis of various heterocyclic ring systems.",10.1021/op100049t,1
"Pilot-Plant Preparation of 3,4-Dihydropyridin-2-one Derivatives, the Core Structures of P2X<sub>7</sub>Receptor Antagonists","The pilot-plant syntheses of 3 and 4, the core structures of a series of P2X 7 antagonists are described. The sole stereogenic center in the dihydropyridinone ring was generated by catalytic desymmetrization. Selective formylation, followed by a tandem imination/lactamization sequence, produced the 3,4-dihydropyridin-2-one ring. The compounds 3 and 4 were produced at multikilogram scale in good overall yield (∼22% over six steps) and excellent stereochemical purity (97% ee for 3, 100% ee for 4) .",10.1021/op1000447,1
"Concise Synthesis of<i>C</i><sub>2</sub>-Symmetrical 2,6-Disubstituted Morpholines by<i>N → O</i>Boc Migration under SL-PTC Conditions","A novel, straightforward synthesis of enantiomerically pure 2,6-disubstituted morpholines has been developed. The ring-opening of epoxides with TsNHBoc under solid−liquid phase transfer catalysis conditions occurred with N → O migration of the Boc group, affording an intermediate carbonate that has been easily transformed to morpholines.",10.1021/op1000435,0
Preparation of Polymers under Phase-Transfer Catalytic Conditions,"The application of phase-transfer catalytic (PTC) conditions leading to substantial improvements in numerous polymerization reactions is described. Generally, better yields as well as faster and cleaner reactions are achieved compared to reactions under conventional conditions. Owing to their ionic mechanisms, polycondensation reactions are the most often applied among polymerization methods under PTC conditions; thus, a number of examples on gram scale are presented in this review.",10.1021/op100040x,0
Total Synthesis of Hematoporphyrin and Protoporphyrin: A Conceptually New Approach,"The total synthesis of protoporphyrin IX and its disodium salt using a new alternative method to the classical MacDonald condensation is reported. The key step is the reaction of the new unsymmetrical diiodo dipyrrylmethane 1 with the known dipyrrylmethane 2 . Coupling of the two fragments leads directly to porphyrin 3 without the need of an oxidizing agent. The new methodology is well suited for the synthesis of protoporphyrin IX derivatives on a multi 100 g scale in good quality without the need for chromatography. Furthermore, these preparations are completely free of any contaminant of animal origin, which represents a real improvement in the manufacturing of protoporphyrin IX derivatives.",10.1021/op100036c,1
Substituents Effect on the Erlenmeyer−Plochl Reaction: Understanding an Observed Process Reaction Time,"A systematic study on hippuric acid substituents was performed in order to better understand the influence of stereoelectronic factors on the Erlenmeyer reaction rate. In addition, two reaction systems were evaluated: Hünig’s base solvent free conditions and catalytic sodium acetate in 2-methyl-THF. The effect on reaction rate of electron withdrawing and electron donating groups are reported. Specifically, the study led to the conclusion that stereoelectronic factors have significant influence in one of our key Erlenmeyer reaction by affecting its reaction rate.",10.1021/op100032s,0
One-Pot Synthesis of Optically Active β-Amino-α-methylene Carbonyl Derivatives From α-Amidosulfones Using Quinine-Based Phase-Transfer Catalysts,"Optically active β-amino-α-methylene carbonyl derivatives (aza-Morita−Baylis−Hillman adducts) were prepared using a one-pot protocol involving an enantioselective Mannich reaction catalyzed by various quinine-based catalysts, followed by a Horner olefination.",10.1021/op1000308,0
Expedited Development through Parallel Reaction Screening: Application to PTC-Mediated Knoevenagel Condensation,"Parallel microreactor screening enabled rapid identification of effective conditions for PTC-mediated Knoevenagel condensation between aldehyde ( 1 ) and thiazalone ( 2 ), affording a dramatic reduction in cycle time when compared to traditional conditions. Interesting facets of the reaction mechanism were revealed from kinetic profiling, specifically the operation of an extractive PTC mechanism with a pH optimum for the Knoevenagel condensation, a p K a optimum for the elimination reaction and the requirement for crystallization of aldol tautomer ( 4 ) to drive the reaction to completion.",10.1021/op100026u,0
"Formation of (<i>S</i>)-5-Cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione: A Key Intermediate in the Synthesis of (<i>S</i>)-Oxybutynin Hydrochloride","The synthesis of the drug candidate ( S )-oxybutynin hydrochloride 1 is described. The procedure involves initial activation of ( S )-cyclohexylmandelic acid 2, using isobutylchloroformate, followed by reaction of the resulting intermediate with 4-(diethylamino)but-2-yn-1-ol, 3 . In this reaction, ( S )-5-cyclohexyl-5-phenyl-1,3-dioxolane-2,4-dione 7 was identified as a key transient intermediate leading to 1 . On the basis of the in situ IR spectroscopy data collected, the sequence of chemical events involved in the formation of intermediate 7, and its conversion to product and byproducts are described.",10.1021/op100021w,0
"Practical Asymmetric Synthesis of RO5114436, a CCR5 Receptor Antagonist","A practical asymmetric synthesis of a 3,7-diazabicyclo[3.3.0]octane derivative ( 1 ), a representative of a new class of potent CCR5 receptor antagonists, is described. The benzylamine stereogenic center of 1 was introduced by a ruthenium-catalyzed asymmetric reductive amination using ( R )-MeOBIPHEP as ligand. Aldehyde 4, prepared by Parikh−Doering oxidation, was used without workup in the reductive amination reaction, which not only simplified the process but also overcame the instability of 4 . The 3,7-diazabicyclo[3.3.0]octane core was obtained by a [3 + 2] cycloaddition.",10.1021/op100020z,1
An Improved Process for the Synthesis of 5-Bromo-3-(1-methylpiperidin-4-yl)-1<i>H</i>-indole: A Key Intermediate in the Synthesis of Naratriptan Hydrochloride,"An improved process has been developed for the synthesis of 5-bromo-3-(1-methylpiperidin-4-yl)-1 H -indole, a key intermediate of naratriptan hydrochloride, which is used as a drug for migraine. A novel one-pot synthetic procedure using triethyl silane was developed for scale-up.",10.1021/op100018r,1
A Novel Hybrid Chromatography−Crystallization Process for the Isolation and Purification of a Natural Pharmaceutical Ingredient from a Medicinal Herb,"In this work, a hybrid chromatography−crystallization separation process is suggested and is used to isolate and purify the antimalarial drug artemisinin from the Chinese medicinal herb Artemisia annua . Extraction of the aerial parts of A. annua by an organic solvent yielded a complex mixture of natural products. A hybrid separation process was therefore proposed to pursue higher recovery and purity of artemisinin. The crude extract was first separated by flash column chromatography, and the fractions containing artemisinin were then separated with a two-step antisolvent crystallization process to isolate artemisinin of high purity. The antisolvent crystallization process was designed on the basis of the solubility of artemisinin in different solvents and the crystallization behaviour of the two polymorphs of artemisinin. The first step in the crystallization process was used to remove impurities from the solution, and the second step was used to isolate the stable orthorhombic form of artemisinin. The results of the present work demonstrate the great potential of combining the advantages of column chromatography and crystallization to isolate and purify a target compound from plant extracts. The separation efficiency of the process can be improved by the synergistic effect of chromatography and crystallization processes.",10.1021/op1000176,0
Safe and Scaleable Oxidation of Benzaldoximes to Benzohydroximinoyl Chlorides<sup>†</sup>,"Benzohydroximinoyl chlorides are useful precursors to nitrile oxides used in the preparation of various heterocycles via 1,3-dipolar cycloadditions. These intermediates are typically accessed by oxidation of aldoximes using N -chlorosuccinimide. This simple and efficient reaction is highly exothermic and a significant induction period can be observed. The potential for a sudden and significant heat release makes large-scale reactions difficult to control and potentially hazardous. Herein we describe a thermal analysis of this reaction to determine the heat flow in the presence of common additives to determine the most effective means of safe scale-up. Of the additives screened, aqueous HCl consistently avoided an induction period and enabled a dose-controlled process to be developed.",10.1021/op100013m,0
Development of a Scaleable Process for the Synthesis of a Next-Generation Statin,"This manuscript details the process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia−Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E: Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted as a method of controlling the final API quality.",10.1021/op100010n,1
Development of a Kilogram-Scale Asymmetric Synthesis of a Potent DP Receptor Antagonist,"An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor antagonist candidate is described. The synthesis is characterized by a novel intramolecular Friedel−Crafts cyclization of an imino-pyrrole to prepare the azaindole core. Other key steps include a highly selective Horner−Wadsworth−Emmons olefination of a tricyclic ketone intermediate and subsequent catalytic asymmetric hydrogenation of a trisubstituted α,β-unsaturated ester to install the chirogenic center. Finally, a new indole sulfenylation protocol was developed to install the aromatic thioether functionality in good yield.",10.1021/op100008m,1
"Selective Crystallization of an Allylic 7α-Bromide:  A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol Diacetate","ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionSelective Crystallization of an Allylic 7α-Bromide: A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol DiacetateSusan D. Van Arnum, Barry K. Carpenter, Harold Moffet, David R. Parrish, Archibald MacIntyre, Thomas P. Cleary, and Paul FritchCite this: Org. Process Res. Dev. 2006, 10, 6, 1313Publication Date (Web):November 2, 2006Publication History Published online2 November 2006Published inissue 1 November 2006https://doi.org/10.1021/op068015qCopyright © 2006 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views301Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (20 KB) Get e-Alertsclose Get e-Alerts",10.1021/op068015q,0
Cyclopentyl Methyl Ether as a New and Alternative Process Solvent,"Cyclopentyl methyl ether (CPME) has become available in commercial quantities since November 2005 from Zeon Corporation with approval by the Toxic Substances Control Act (TSCA) and the European List of Notified Chemical Substances (ELINCS). A high boiling point (106 °C) and preferable characteristics such as low formation of peroxides, relative stability under acidic and basic conditions, formation of azeotropes with water coupled with a narrow explosion range render CPME an alternative to other ethereal solvents such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), dioxane (carcinogenic), and 1,2-dimethoxyethane (DME). Conventional drying is unnecessary for general organometallic reactions including Grignard reactions, enolate formation, Claisen condensation, general reductions, and Pd-based transformations.",10.1021/op0680136,0
A Practical Synthesis of <i>d</i>-α-Terpineol via Markovnikov Addition of <i>d</i>-Limonene Using Trifluoroacetic Acid,"d -α-Terpineol ( 1 ), which is a useful flavor and fragrance compound, has been synthesized from d -limonene by Markovnikov addition using trifluoroacetic acid, followed by hydrolysis in 76% yield with 98% purity.",10.1021/op068012d,0
Safe Handling of Boranes at Scale,"The safe handling of borane complexes and alkylboranes (trialkylboranes, dialkylboranes, and trialkylborohydride reagents) and related workup issues are addressed. Oxidation of alkylboranes and quenching of reaction mixtures to safely decompose the reagent or products are discussed. Several case studies demonstrate large-scale applications of borane reagents for carboxylic acid reduction, reductive amination, and hydroboration followed by oxidation.",10.1021/op068011l,0
"On the Synthesis of 1,1-Diamino-2,2-dinitroethene (FOX-7) by Nitration of 4,6-Dihydroxy-2-methylpyrimidine","The synthesis of 1,1-diamino-2,2-dinitroethene (FOX-7) by nitration of 4,6-dihydroxy-2-methylpyrimidine and hydrolysis of the resulting intermediate 2-dinitromethylene-5,5-dinitropyrimidine-4,6-dione has been studied. By varying the reaction parameters the optimal conditions for the synthesis of FOX-7 have been identified and gave a >90% yield of the pure product. The optimised process allowed the spent acid to be recycled without loss of yield, with almost stoichiometric consumption of nitric acid. The purity of the FOX-7 has been determined using a newly developed HPLC method",10.1021/op068010t,1
"Efficient Synthesis of 3-Hydroxy-1,4-benzodiazepines Oxazepam and Lorazepam by New Acetoxylation Reaction of 3-Position of 1,4-Benzodiazepine Ring","Simple, efficient, and scalable syntheses of 3-hydroxy-1,4-benzodiazepines, oxazepam ( 1 ), and lorazepam ( 2 ) were developed. The syntheses are based on the new acetoxylation reaction of the 3-position of the 1,4-benzodiazepine ring. The reaction involves iodine (20−50 mol %)-catalyzed acetoxylation in the presence of potassium acetate (2 equiv) and potassium peroxydisulfate (1−2 equiv) as a stoichiometric oxidant affording the corresponding 3-acetoxy-1,4-benzodiazepines in good-to-high yields. The latter were converted by selective saponification to 3-hydroxy-1,4-benzodiazepines of very high purity (>99.8%) in an overall yield of 83% (oxazepam) and 64% (lorazepam).",10.1021/op068009u,1
Developing Processes for Crystallization-Induced Asymmetric Transformation,"ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionDeveloping Processes for Crystallization-Induced Asymmetric TransformationN. G. AndersonCite this: Org. Process Res. Dev. 2006, 10, 3, 683Publication Date (Web):May 19, 2006Publication History Published online19 May 2006Published inissue 1 May 2006https://pubs.acs.org/doi/10.1021/op068005phttps://doi.org/10.1021/op068005pcorrectionACS PublicationsCopyright © 2006 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views560Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (16 KB) Get e-Alertsclose Get e-Alerts",10.1021/op068005p,0
"Recent Developments In Meerwein−Ponndorf−Verley and Related Reactions for the Reduction of Organic Functional Groups Using Aluminum, Boron, and Other Metal Reagents:  A Review","ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTRecent Developments In Meerwein−Ponndorf−Verley and Related Reactions for the Reduction of Organic Functional Groups Using Aluminum, Boron, and Other Metal Reagents: A ReviewJin Soon ChaView Author Information Department of Chemistry, Yeungnam University, Gyongsan 712-749, Korea Cite this: Org. Process Res. Dev. 2006, 10, 5, 1032–1053Publication Date (Web):September 6, 2006Publication History Received17 March 2006Published online6 September 2006Published inissue 1 September 2006https://pubs.acs.org/doi/10.1021/op068002chttps://doi.org/10.1021/op068002creview-articleACS PublicationsCopyright © 2006 American Chemical SocietyRequest reuse permissionsArticle Views3526Altmetric-Citations120LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Alcohols,Ketones,Reagents,Redox reactions,Transfer reactions Get e-Alerts",10.1021/op068002c,0
"A Short and Efficient Synthesis of (<i>R</i>,<i>R</i>)-2-Methylcyclopropanecarboxylic Acid","We report herein a short and efficient synthesis of ( R, R )-2-methylcyclopropanecarboxylic acid via a Horner−Wadsworth−Emmons reaction involving commercially available ( S )-propylene oxide and triethylphosphonoacetate (TEPA). The TEPA/base/propylene oxide stoichiometry was found critical to achieve high yields. We therefore studied the TEPA anion formation and stability using in situ IR spectroscopy. The reaction yield is strongly influenced by the counterion and solvent, whereas high diastereoselectivities are always obtained. Under the best experimental conditions (HexLi/MeTHF/150 °C), crude ( R, R )-2-methylcyclopropanecarboxylic acid is obtained in 85−90% yield with >98% trans selectivity.",10.1021/op060249m,0
Preparation of 4-Vinylphenol Using pHCA Decarboxylase in a Two-Solvent Medium,"An efficient synthesis of 4-vinylphenol (4-VP) from para -hydroxycinnamic acid (pHCA) that uses the enzyme para -hydroxycinnamic acid decarboxylase (PDC) in a two-phase aqueous−organic solvent has been developed. The 4-VP titer and catalyst productivity (17 g L - 1; 1010 g 4-VP isolated g - 1 catalyst) greatly exceed those for intact cells expressing PDC or calcium alginate bead-immobilized PDC-expressing cells in an aqueous buffer (5 g L - 1; 4.4 to 64 g of isolated 4-VP per gram of catalyst). In this two-phase reaction design, the organic solvent (e.g., toluene) enabled continuous extraction of 4-VP into the organic phase and either its recovery as a crystalline solid with low color or its direct conversion to 4-acetoxystyrene.",10.1021/op0602472,0
An Improved Synthesis of Memantine Hydrochloride:  Anti-Alzheimer's Drug,"An economical new process route has been developed for the large-scale synthesis of memantine hydrochloride ( 1 ) an anti-Alzheimer's drug. The procedure involves the conversion of 1,3-dimethyl adamantane ( 2 ) to formamide intermediate 8 as a key step, followed by hydrolysis to (1-amino-3,5-dimethyl adamantane) hydrochloride ( 1) in good yield.",10.1021/op060246+,0
"Expedient Synthesis of MLN1251, A CCR5 Antagonist for Treatment of HIV",An expedient synthesis of MLN1251 has been developed that allows for the production of multikilogram quantities of the target compound. The key transformation is synthesis of a 5-hydroxyindole by a Nenitzescu reaction. The longest linear sequence is five steps with an overall yield of approximately 31%.,10.1021/op060245h,1
An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part II,"The manufacturing process for lumefantrine, 2, one of the two active principles in the fixed-dose combination of the antimalarial drug Coartem, was reworked. For the conversion of 2-chloro-1-(2,7-dichloro-9H-fluoren-4-yl)ethanone, 5, to 2-dibutylamino-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol, 8, a one-pot process was developed that eliminated isolation of the epoxide 2-(2,7-dichloro-9H-fluoren-4-yl)oxirane, 7 . Significant increase in throughput was achieved by applying new reaction and crystallization conditions for the Knoevenagel condensation of 2-dibutylamino-1-(2,7-dichloro-9H-fluoren-4-yl)ethanol, 8, to 2-dibutylamino-1-{2,7-dichloro-9-[1-(4-chlorophenyl)meth-( Z )-ylidene]-9H-fluoren-4-yl}ethanol, 2 .",10.1021/op060244p,1
An Improved Manufacturing Process for the Antimalaria Drug Coartem. Part I,"Artemisinin and its derivatives, such as artemether, are highly sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues, the manufacturing procedure of the reduction of artemisinin with potassium borohydride to dihydroartemisinin was reinvestigated. The most important factor for obtaining optimal yields is to ensure low levels of contamination of potassium hydroxide in potassium borohydride. Application of a lower reaction temperature, fast addition rate of potassium borohydride, and careful control of the pH during the quench with acid are further important parameters in guaranteeing a robust process. In the redesign of the conversion of dihydroartemisinin to artemether, the yield was increased, and dichloromethane was replaced by the ecologically friendlier methyl acetate. A robust manufacturing process for artemether is now at hand, allowing the production of this important medicine reliably and in good quality and yield.",10.1021/op0602425,0
Development of a Concise Scaleable Synthesis of 2-Chloro-5-(pyridin-2-yl) Pyrimidine via a Negishi Cross-Coupling,"A practical and scaleable synthesis of 2-chloro-5-(pyridin-2-yl) pyrimidine, an intermediate in the synthesis of a selective PDE-V inhibitor, was developed. A Negishi cross-coupling between the in situ prepared 2-pyridylzinc chloride and 5-iodo-2-chloropyrimidine catalyzed by Pd(PPh 3 ) 4 afforded the product in one step. Development of a convenient purification did away with the necessity of chromatography, allowing the preparation of the product on kilogram scale.",10.1021/op060241c,1
"Practical Synthesis of 3-Amino-4,5-dimethylisoxazole from 2-Methyl-2-butenenitrile and Acetohydroxamic Acid","3-Amino-4,5-dimethylisoxazole was prepared from technical-grade 2-methyl-2-butenenitrile and acetohydroxamic acid in a 62% overall yield on a multimole scale. The key features of this synthesis are (1) DBU treatment of the technical-grade nitrile mixture to provide a starting material of acceptable purity and (2) use of acetohydroxamic acid as an N-protected hydroxylamine equivalent. This operationally simple method provides the title compound in reasonable overall yield and free of contamination from the isomeric 5-amino-3,4-dimethylisoxazole.",10.1021/op060239l,1
Practical Copper-Catalyzed Asymmetric Synthesis of Chiral Chrysanthemic Acid Esters,"Practical copper salicylaldimine complex catalysts have been developed for the asymmetric synthesis of chiral chrysanthemic acid esters by the cyclopropanation reaction of 2,5-dimethyl-2,4-hexadiene with tert -butyl diazoacetate. First, the effects of the substituents on the salicylaldehyde moiety in the copper salicylaldimine complex (copper Schiff base complex) on the catalytic activity and the stereoselectivities were investigated. As a result, a substitution of hydrogen at the 5-position with the nitro group on the salicylaldehyde moiety was found to enhance the catalytic efficiency. In addtition, a combination catalyst of the copper Schiff base complex with Lewis acid was found to also enhance the catalytic efficiency and achieved 90% chemical yield and 91% ee at 20 °C with 0.1 mol % catalyst loading. Furthermore, the asymmetric induction mechanism of the cyclopropanation reaction catalyzed by the copper Schiff base complex was studied using density functional calculations.",10.1021/op060238t,0
Dynamic Biphasic Counterion Exchange in a Configurationally Stable Aziridinium Ion:  Efficient Synthesis and Isolation of a Koga C<sub>2</sub>-Symmetric Tetraamine Base,"An efficient synthetic process for chiral tetraamine base ( R, R )- 5 is reported that leverages mechanistic understanding to enable control over key transformations. Specifically, a configurationally stable and observable aziridinium ion intermediate was found to undergo counterion exchange impacting the feasibility of the process. Mechanistic investigations revealed that both counterion exchange and trapping of the aziridinium ion were biphasic events and that the former could be suppressed at lower temperatures, facilitating the reaction on both small and large scales. The mechanistic insights gained have led to the development of an efficient one-pot process that enables preparation of multiple kilograms of ( R, R )- 5 as a crystalline solid without chromatography in excellent chemical and chiral purity.",10.1021/op0602371,1
A Mixed-Ligand Approach Enables the Asymmetric Hydrogenation of an α-Isopropylcinnamic Acid en Route to the Renin Inhibitor Aliskiren,"An asymmetric hydrogenation process for the α-isopropyl dihydrocinnamic acid derivative 2, an intermediate for the renin inhibitor aliskiren ( 4 ), has been developed using a rhodium catalyst ligated with a chiral monodentate phosphoramidite and a nonchiral phosphine. Whereas catalysts based on two equivalents of monodentate phosphoramidites gave promising results, the rate of hydrogenation and ee of the product could be improved spectacularly by the addition of monodentate nonchiral triarylphosphines to these catalysts. This remarkable mixed-ligand catalyst has been identified using high-throughput experimentation. With the best catalysts turnover numbers >5000 mol mol -1, turnover frequencies >1000 mol mol -1 h -1, and ee's up to 95% have been achieved.",10.1021/op0602369,0
Development of a Commercial Process to Produce Oxandrolone,"A manufacturing scale process for the preparation of the anabolic steroid Oxandrolone was developed. Key elements included the following: the bromination of methylandrostanolone with perbromide to give the 2-bromoketone in ca. 80% yield with minimal dehydration, subsequent elimination of the bromide with Li 2 CO 3 /LiBr to give the 2-enone in ca. 70% yield with minimal formation of methyltestosterone, and an ozonolysis procedure to give the penultimate intermediate in ca. 90% yield. The overall yield from methylandrostanolone to Oxandrolone using the described process was 45% as compared to the original Searle yield of 8%.",10.1021/op060231b,1
A Facile Process for the Preparation of 2-Bromoethyl Methyl Ether,A convenient and large-scale synthesis of 2-bromoethyl methyl ether is described.,10.1021/op060229k,0
Development of a Large Scale Asymmetric Synthesis of Vanilloid Receptor (TRPV1) Antagonist ABT-102,"A highly efficient asymmetric synthesis of TRPV1 antagonist ABT-102 was developed and successfully demonstrated on a multi-kilogram scale. This process incorporates a new asymmetric synthesis of ( R )- tert -butylaminoindan, which is based on a chiral auxiliary induced diastereoselective reduction of its iminoindan precursor.",10.1021/op060228s,1
Development of Practical Rhodium Phosphine Catalysts for the Hydrogenation of β-Dehydroamino Acid Derivatives,"The rhodium-catalyzed asymmetric hydrogenation of various β-dehydroamino acid derivatives to give optically active β-amino acids has been examined. Chiral monodentate 4,5-dihydro-3 H -dinaphthophosphepines, which are easily tuned and accessible in a multi-10-g scale, have been used as ligands. The enantioselectivity is largely dependent on the nature of the substituent at the phosphorous atom and on the structure of the substrate. Applying optimized conditions up to 94% ee was achieved.",10.1021/op0602270,0
Optimized Catalytic Enantioselective Aryl Transfer Process Gives Access to mGlu2 Receptor Potentiators,"An asymmetric enantioselective aryl transfer reaction was developed to give access to the diarylmethanol 7 and ultimately acetate 2 which is useful for the preparation of mGlu2 receptor potentiators (Scheme 3). The aryl transfer chemistry involved the preparation of a proposed arylalkylzinc species 14 from boroxine 16 and diethylzinc (DEZ), and reacting this mixture with aldehyde 5 in the presence of chiral ligand 15 . During the course of optimizing the preparations of proposed intermediate 14 and diarylmethanol 7, an understanding of optimal stoichiometry and reaction times was gained through empirical observation, the use of solution IR, and analyzing off-gases via real time gas analysis/mass spectroscopy. The preparation of diarylmethanol 7 and subsequent conversion into acetate 2 required carefully selected workups, selective extractions, and azeotropic distillations to generate a series of stock solutions to accommodate oil intermediates that finally gave acetate 2 as a crystalline solid with >99% ee.",10.1021/op0602268,1
"Design, Development, and Scale-Up of a Selective <i>meso</i>-Epoxide Desymmetrization Process","A pilot-plant scale desymmetrization of the cyclic meso -epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, ( R )-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.",10.1021/op060225f,1
"Efficient Asymmetric Synthesis of <i>N</i>-[(1<i>R</i>)-6-Chloro-2,3,4,9-tetrahydro-1<i>H</i>-carbazol-1-yl]-2-pyridinecarboxamide for Treatment of Human Papillomavirus Infections","An efficient asymmetric synthesis of N -[(1 R )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazol-1-yl]-2-pyridinecarboxamide 1, a potential treatment for human papillomavirus infections, is described. The key step in the synthesis of this molecule is an asymmetric reductive amination directed by chiral (phenyl)ethylamines resulting in up to 96% disastereo facial selectivity. The synthesis is also highlighted by isolation of a unique 2-picolinic acid salt of (1 R )-6-chloro-2,3,4,9-tetrahydro-1 H -carbazol-1-amine ( 13 ). Subsequent application of 1-propylphosphonic acid cyclic anhydride (T3P) for convenient amide formation from the two components of the salt provides the product 1 in high yield. The process research work leading to the final synthesis includes a racemic synthesis followed by resolution with chiral supercritical fluid chromatography, and an enantioselective reductive amination via chiral transfer hydrogenation catalyzed by Ru(II) complexes of N -[(1 S,2 S )-2-amino-1,2-diphenylethyl]-1-naphthalenesulfonamide or ( R )-BINAP. Highlighting the practicality of the synthesis, the process has been scaled up in 200-gallon reactors for delivery of multikilograms of the target compound 1 in over 99.5% enantiomeric purity.",10.1021/op060223v,1
Improved Process for Chloroxidation of Aryl Sulfides to Aryl Sulfonyl Chlorides in Commercial Grade Formic Acid,"This paper discusses the process advantages of using commercial grade formic acid as the solvent for chlorine gas oxidation of aryl sulfides to sulfonyl chlorides. Compared to chloroxidation in methylene chloride, the chloroxidation in formic acid gave a consistently higher yield and easy product isolation for a sulfonyl chloride intermediate which was used in the production of the sulfonamide herbicide, penoxsulam.",10.1021/op0602223,1
Development of an Asymmetric Acetate Aldol Reaction with a Trifluoromethyl Ketone,"We describe the discovery and development of a chiral auxiliary-controlled asymmetric acetate aldol reaction with a trifluoromethyl ketone. Chiral acetate 3d was prepared efficiently from (1 S,2 R )-1-amino-2-indanol. Reaction of the lithium enolate of 3d with trifluoromethyl ketone 2 afforded aldol adducts in 95% HPLC assay yield (by weight) with a 78:22 dr. The major isomer 5 was obtained via a robust crystallization method in 45% one-crop isolated yield with a >98.7:1.3 dr. Compound 5 was subjected to transesterification to give β-hydroxy ester 1 . The cleaved auxiliary 7 was readily recovered by a direct crystallization/filtration method. Process optimization led to better volume efficiencies, improved isolation protocols, and less consumption of organic solvents, all contributing to enhanced throughput, reduced processing labor and time, as well as reduction in chemical wastes.",10.1021/op060211+,0
"<i>N</i>,<i>N</i>-Diethyl-(<i>R</i>)-[3-(2-aminopropyl)-1<i>H</i>-indol-7-yloxy]acetamide:  Its Process Chemistry Ranging from Enantiocontrolled Construction of the Chiral Amine Side Chain to Regioselective Functionalization of the Aromatic Starting Materials","To access N, N -diethyl-( R )-[3-(2-aminopropyl)-1 H -indol-7-yloxy]acetamide ( 3 ), a key intermediate for AJ-9677 ( 2 ) acting as a potent and selective agonist for β 3 -adrenergic receptors, the ( R )-configured 2-aminopropyl side chain of 3 is elaborated in three distinct ways: (1) chiral pool synthesis featuring the C-3 acylation of 7-benzyloxy-1 H -indole ( 4a ) with N -(9-fluorenylmethoxycarbonyl)- d -alanyl chloride ( 6 ); (2) resolution of (±)-3-(2-aminopropyl)-7-benzyloxy-1 H -indole ( 8 ) via diastereomeric salt formation with O, O -di- p -toluoyl l -(2 R,3 R )-tartaric acid ( 21 ) to obtain ( R )- 8; and (3) crystallization-induced dynamic resolution (CIDR) by entrainment which transforms N, N -diethyl-(±)-[3-( N -phthaloyl-2-aminopropanoyl)-1 H -indol-7-yloxy]acetamide ( 26 ) entirely into ( R )- 26 . As regards 4a and 7-hydroxy-1 H -indole ( 4b ), the molecular scaffolds on which the above-mentioned chiral maneuvers are being executed, their synthetic approaches are explored threefold: (1) indole-ring construction on 3-benzyloxy-2-nitrotoluene [ 28; prepared from m -cresol ( 31 )] by the modified Leimgruber−Batcho method; (2) direct microbial hydroxylation of indole ( 34 ) at its C-7 position; and (3) indirect hydroxylation of indoline ( 35 ) at its C-7 position via a K 2 S 2 O 8 -mediated Baeyer−Villiger oxidation of the tricyclic product arising from the intramolecular Friedel−Crafts acylation of N -succinyl indoline ( 36 ).",10.1021/op060210h,1
Enantioselective Synthesis of a Key Intermediate in a New Process for Orlistat Using Asymmetric Hydrogenation and a Grignard Reagent Promoted Lactone Cyclization,"A new enantioselective synthesis of Orlistat suitable for large-scale preparation is described. Therein, the first isolated key intermediate ( R )-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2 H -pyran-2-one ( 12 ) is prepared via (a) the asymmetric hydrogenation of methyl 3-oxotetradecanoate to ( S )-3-hydroxytetradecanoate ( 9 ); (b) the acylation of 9 with 2-bromooctanoyl halide (bromide/chloride) to ( R )-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoic acid methyl ester ( 11 ) and finally (c) the tert -butyl magnesium chloride promoted cyclization of 11 to the single enantiomer 12 . The single enantiomer intermediate 12, previously published as a mixture of enantiomers 2, has been carried on through several steps to Orlistat ( 1 ) without any process changes.",10.1021/op060208q,1
"One-Pot Synthesis of 5-Methyl-3H-pyrrolo[2,3-<i>d</i>]pyrimidin-4(7H)-one","An efficient and environmentally benign synthesis of 5-methyl-3H-pyrrolo[2,3- d ]pyrimidin-4(7H)-one is described. An acyl-protected aminoacetone is reacted with cyanoacetamide to give 2-amino-4-methyl-1H-pyrrole-3-carboxamide, which is converted in one-pot to 5-methyl-3H-pyrrolo[2,3- d ]pyrimidin-4(7H)-one in 60% overall yield. This process avoids the use of large excess Raney nickel which is required when known methods are practiced.",10.1021/op060207y,1
Application of Band-Target Entropy Minimization to On-Line Raman Monitoring of an Organic Synthesis. An Example of New Technology for Process Analytical Technology,"The hydrolysis of acetic anhydride to acetic acid in water as solvent was monitored by Raman microscopy. Both static and flow-through configurations were used in the experiments, and various experimental designs, i.e., multiple-experimental runs and multiple-perturbation semibatch mode, were considered. Various spectral data preprocessing was performed and band-target entropy minimization (BTEM) was used in the spectral analysis to recover the pure-component spectra from the multicomponent data. Good and consistent spectral estimates of the solutes acetic anhydride and acetic acid were recovered. In addition, the pure-component spectrum of white-light interference was recovered. Together, these estimates permitted very good estimates of the individual time-dependent signal contributions. Taken together, the present results suggest that the combination of Raman spectroscopy and BTEM has considerable potential for organic syntheses and process analysis. The combination of Raman spectroscopy and BTEM represents another approach for reaction monitoring in process analytical technologies (PAT).",10.1021/op0602066,0
Development of a Scalable Synthesis of a Common Eastern Tricyclic Lactone for Construction of the Nodulisporic Acids,"A scalable, second-generation synthesis of the densely functionalized eastern tricyclic lactone (+)- 6, a common intermediate, for construction of the nodulisporic acids has been achieved. Modifications to the first-generation route now permit access to (+)- 6 in 17 steps with an overall 16.5% yield. Key carbon−carbon bond constructions include a Kirk−Petrow (phenylthio)methylation, a Sc(OTf) 3 -catalyzed hydroxymethylation, a Stille carbonylation, and a Koga three-component, conjugate addition−alkylation sequence.",10.1021/op060204l,1
An Efficient and Impurity-Free Process for Telmisartan:  An Antihypertensive Drug,"Telmisartan ( 1 ), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan ( 1 ) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).",10.1021/op060200g,1
An Efficient Synthesis of (<i>R</i>)-2-Butyl-3-hydroxypropionic Acid,An efficient synthesis of ( R )-2-butyl-3-hydroxypropionic acid ( 1 ) via a classical resolution of (±)-2-butyl-3-hydroxypropionic acid ( 7 ) with ( R )-α-methylbenzylamine is described. (±)-2-Butyl-3-hydroxypropionic acid ( 7 ) was readily available from diethyl butylmalonate ( 2 ) in two steps. Results on the enantioselective enzymatic hydrolysis of 2 with pig liver esterase and α-chymotrypsin towards 1 are also described.,10.1021/op060199l,1
<i>SPECIAL FEATURE SECTION:</i>  <u><i>SAFETY OF CHEMICAL PROCESSES</i></u> Safety HighlightsSafety Notables:  Information from the Literature,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSES Safety HighlightsSafety Notables: Information from the LiteratureGerald A. Weisenburger and Paul F. VogtView Author Information Process Safety Laboratory, Pfizer, Inc., Groton, Connecticut 06340, U.S.A. E-mail: [email protected] Chemical Development, Albany Molecular Research, Inc., Albany, New York 12212, U.S.A. E-mail: [email protected]Cite this: Org. Process Res. Dev. 2006, 10, 6, 1246–1250Publication Date (Web):October 28, 2006Publication History Published online28 October 2006Published inissue 1 November 2006https://pubs.acs.org/doi/10.1021/op060198thttps://doi.org/10.1021/op060198teditorialACS PublicationsCopyright © 2006 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2113Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (37 KB) Get e-AlertscloseSUBJECTS:Hydrogen,Materials,Mixtures,Organic reactions,Safety Get e-Alerts",10.1021/op060198t,0
Reductive Carbonylation − an Efficient and Practical Catalytic Route for the Conversion of Aryl Halides to Aldehydes,"Alternative routes for the introduction of aldehyde functionality are particularly desirable for fine chemical and pharmaceutical intermediates because of the wide range of further transformations that are possible. Catalytic processes are of particular interest for minimising waste, and therefore the reductive carbonylation of aryl halides has been explored. We have shown that high yields of aldehydes may be obtained for a wide selection of aryl iodides and bromides using mild conditions (3 bar of CO, temperatures 60−120 °C) and silanes as hydride source. A choice of conditions (catalyst, base, solvent) is required to cover the range of aryl substituents varying in electron donation and steric influence. This is related to the competing needs of the several steps of this reaction, including oxidative addition, CO substitution, CO insertion, hydride transfer, and reductive elimination.",10.1021/op060193w,0
"Efficient Synthesis of (<i>S</i>)-2-(Cyclopentyloxycarbonyl)-amino-8-nonenoic Acid:  Key Building Block for BILN 2061, an HCV NS3 Protease Inhibitor","A new procedure for the practical synthesis of ( S )-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid, a key building block for BILN 2061, an HCV NS3 protease inhibitor, has been developed. The key step features a kinetic resolution of racemic 2-acetylamino-8-nonenoic acid with acylase I. In addition, the undesired ( R )-2-acetylamino-8-nonenoic acid was recycled after racemization. The procedure was implemented for the production of ( S )-2-(cyclopentyloxycarbonyl)amino-8-nonenoic acid on pilot-plant scale.",10.1021/op0601924,1
An Improved Manufacturing Process for Fluvastatin,"An improved manufacturing process for fluvastatin 1 has been developed by performing the condensation reaction of E -[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-propenal, 4, with the dianion of tert -butyl acetoacetate and the subsequent low-temperature reduction to 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid-1,1-dimethylethylester, 2, without isolation of the intermediate 7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid-1,1-dimethylethylester, 3 . To be successful, a crucial selectivity problem in the conversion of aldehyde 4 to aldol 3 had to be understood and solved. The improved process allows the omission of two solvents, and the manufacture of fluvastatin at considerably lower cost and in higher throughput.",10.1021/op060191b,1
Synthesis of 4-Fluoro-β-(4-fluorophenyl)-<scp>l</scp>-phenylalanine by an Asymmetric Phase-Transfer Catalyzed Alkylation:  Synthesis on Scale and Catalyst Stability,"4-Fluoro-β-(4-fluorophenyl)- l -phenylalanine 1 was synthesized by the asymmetric phase-transfer catalyzed alkylation of tert -butyl glycinate-benzophenone Schiff base using the cinchona alkaloid derived catalyst 6 . Upon scaling, it was observed that to achieve high levels of enantioselectivity, it was necessary to add the catalyst or base last. From these studies, insight into the stability of the catalyst 6 under the reaction conditions was gained.",10.1021/op060190j,0
Suppression of a Palladium-Mediated Homocoupling in a Suzuki Cross-Coupling Reaction. Development of an Impurity Control Strategy Supporting Synthesis of LY451395,"Described herein is the development of a control strategy resulting in exclusion of a persistent impurity ( 6 ) formed by a palladium (II)-mediated homocoupling of boronic acid ( 3 ) during a Suzuki cross-coupling reaction. Nearly complete suppression of the undesired homocoupling reaction was achieved through two process modifications. Thus, addition of a mild reducing agent, potassium formate, and use of a facile nitrogen subsurface sparge prior to introduction of the catalyst resulted in nearly complete exclusion of homocoupling dimer 6 . These modifications apparently minimized the concentration of free Pd(II) in the reaction mixture without causing significant reduction of the oxidative addition product. In addition, use of palladium black as a heterogeneous coupling catalyst rendered the palladium control strategy trivial. Thus, the catalyst was separated from the product solution through use a clarifying filtration, resulting in near quantitative separation of palladium from LY 451395 ( 5 ). These conditions were successfully executed in three campaigns using 3-, 5-, 12-, and 22-L glassware.",10.1021/op060180i,1
Synthesis of Naturally Occurring Nitrogen Heterocycles from Carbohydrates By El Sayed H. El Ashry and Ahmed El Nemr. Blackwell Publishing:  Oxford. 2005. 443 pp. £119. ISBN 1-4051-2934-4.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewSynthesis of Naturally Occurring Nitrogen Heterocycles from Carbohydrates By El Sayed H. El Ashry and Ahmed El Nemr. Blackwell Publishing: Oxford. 2005. 443 pp. £119. ISBN 1-4051-2934-4.W. J. WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2006, 10, 6, 1314Publication Date (Web):September 20, 2006Publication History Published online20 September 2006Published inissue 1 November 2006https://pubs.acs.org/doi/10.1021/op060174mhttps://doi.org/10.1021/op060174mbook-reviewACS PublicationsCopyright © 2006 American Chemical SocietyRequest reuse permissionsArticle Views187Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Heterocyclic compounds,Nitrogen Get e-Alerts",10.1021/op060174m,0
Scale-Up of the Green Synthesis of Azacycloalkanes and Isoindolines under Microwave Irradiation,"A green approach to N- heterocyclization reactions ranging in scale from 20 mmol to 1 mol performed under microwave irradiation in open vessels has been investigated. By using water as the solvent and no transition metal catalysts, N -heterocycles are formed in a fraction of the time needed for conventional synthesis of these compounds. The obtained yields indicate that reactions can be performed at atmospheric pressure using the same reaction conditions as the corresponding sealed-vessel reactions. Single-mode and multimode microwave cavities have been used for open-vessel synthesis without changing reaction times producing similar yields.",10.1021/op0601722,0
"A Concise Synthesis of Racemic 1-(6,7-Dimethoxy-2-naphthyl)-1-(1 <i>H</i> -imidazol-4-yl)-2-methylpropan-1-ol for a Potent C <sub>17</sub> , <sub>20</sub> -Lyase Inhibitor","The development of a practical and scaleable synthesis of 1-(6,7-dimethoxy-2-naphthyl)-1-(1 H -imidazol-4-yl)-2-methylpropan-1-ol ( 2 ) is described. Racemate 2 was synthesized from commercially available 4(5)-imidazolecarboxyaldehyde ( 7 ) in three steps excluding chromatography. 4(5)-Cyanoimidazole ( 10 ) was prepared from 7 in good yield in a one-pot reaction. A Grignard reaction of cyanoimidazole 10 with isopropylmagnesium bromide followed by the addition of aqueous sulfuric acid formed acylimidazole 9 . The final racemate 2 was obtained by the direct Grignard reaction of acylimidazole 9 without N-protection. This process was accomplished efficiently to produce 2 in 70% overall yield from 7 in a large-scale synthesis.",10.1021/op060171+,1
What Type of Reactions Do Process Chemists Use on Scale?,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTWhat Type of Reactions Do Process Chemists Use on Scale?Trevor LairdView Author Information EditorCite this: Org. Process Res. Dev. 2006, 10, 5, 851–852Publication Date (Web):August 17, 2006Publication History Published online17 August 2006Published inissue 1 September 2006https://pubs.acs.org/doi/10.1021/op060164lhttps://doi.org/10.1021/op060164leditorialACS PublicationsCopyright © 2006 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2342Altmetric-Citations49LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (20 KB) Get e-AlertscloseSUBJECTS:Alcohols,Materials,Molecules,Process chemistry,Separation science Get e-Alerts",10.1021/op060164l,0
Process Development and Scale-up of <b>AG035029</b>,"A practical process for the synthesis of PPARγ agonist AG035029 was developed which involved six steps along the longest linear path. The process development utilized automated technology and computational chemistry extensively to accelerate the speed of the project in the areas of catalyst screening, reaction optimization, mechanistic studies, and polymorph control.",10.1021/op0601621,1
Enantioselective Ketone Hydrogenation:  From R&amp;D to Pilot Scale with Industrially Viable Ru/Phosphine−Oxazoline Complexes,"The development of a pilot process for the enantioselective hydrogenation of 3,5-bistrifluoromethyl acetophenone (BTMA) using a Ru/phosphine−oxazoline complex in toluene in the presence of aqueous NaOH is described. Various reaction parameters and quality risk factors such as ligand structure, substrate quality, reaction conditions, thermal safety, etc. were investigated. The reaction was carried out twice on a 140-kg scale at 20 bar and 25 °C with substrate-to-catalyst ratios of 20,000 with an enantiomeric excess of >95%. After crystallization, ( R )-3,5-bistrifluoromethyl phenyl ethanol (BTMP) was obtained with an ee between 97.7 and 98.6% in 70% chemical yield.",10.1021/op0601619,0
DMSO Can Be More than a Solvent:  Thermal Analysis of Its Chemical Interactions with Certain Chemicals at Different Process Stages,"During the process development of the product 6 via the route presented in Scheme 1, we encountered several safety issues that had to be resolved before moving these stages to production. In each case, the safety issues are related to the interaction of the solvent used, DMSO (dimethylsulphoxide, 3 ), with one of the other chemicals. Also in this case (Bollyn, M. Org. Process Res. Dev. 2005, 9, 982−996) we applied the runaway index as a guide to decide whether a process could be run at production scale. The combination of reaction calorimetry in the RC1 (Mettler Toledo's R eaction C alorimeter 1; http://www.RXEForum.com ) and thermal analysis in the ARC ( A ccelerating R ate C alorimeter; http://www.thermalhazardtechnology.com ) was used in combination with the process parameters study to design process stages that were considered safe (enough) for production scale.",10.1021/op060158p,1
Expeditious Process Improvement for the Synthesis of RWJ-333966,We improved chemical processes for synthesizing RWJ-333966 1 and obtained this compound over five steps in 40% overall yield.,10.1021/op0601565,1
Application of the Tisler Triazolopyrimidine Cyclization to the Synthesis of a Crop Protection Agent and an Intermediate,"A new synthetic route to the Dow AgroSciences early stage sulfonamide herbicide 3-(2-methoxy-4-trifluoromethyl)- N -(5,7-dimethoxy[1,2,4]triazolo[1,5- a ]pyrimidin-2-yl)pyridinesulfonamide (pyroxsulam) has been developed. The synthesis is based on formation of the triazole ring as the final step, utilizing the Tisler triazolopyrimidine cyclization. A Tisler cyclization route to 2-amino-5,7-dimethoxy-1,2,4-trazolo[1,5- a ]pyrimidine starting with 2-chloro-4,6-dimethoxypyrimidine has also been demonstrated.",10.1021/op0601518,1
Development of Large-Scale Preparations of Indole Derivatives:  Evaluation of Potential Thermal Hazards and Studies of Reaction Kinetics and Mechanisms,"Hydrogenation of ( E )-2-nitropyrrolidinostyrene in the presence of the doped rhodium catalyst is safe, scalable, and highly effective for the preparation of 6-benzyloxyindole. Reaction kinetics with/without additives also were examined using in situ IR for the first time. Results showed that the additives decelerate the hydrogenolysis of benzyl ethers, while simultaneously accelerating the de-oxygenation of N -oxy-intermediates.",10.1021/op060150f,0
"Beating the Hydrogen Bond:  First Selective and High-Yielding<i>N</i>-Acylation Process for an α,β-Diaminoalcohol","The first selective and high-yielding N -acylation of an α,β-diaminoalcohol is reported, as well as the first use as N -acylation agent of a S -mercaptobenzothiazolyl thioester of an α,β-unsaturated carboxylic acid. Other conventional coupling methods (acid chloride, uronium salt, carbonyl diimidazole, phosphonium salt) gave low yields respectively difficult to purify mixtures of N - and O, N -diacylated product ( 4b ), due to the unusually high reactivity of the primary hydroxyl group caused by an intramolecular hydrogen bond to the dialkylamino moiety in the β-position. Both the cinnamic thioester preparation and the coupling step were safely and reproducibly scaled up to a chromatography-free process in the pilot plant.",10.1021/op0601464,1
Process Safety Evaluation of a Magnesium−Iodine Exchange Reaction,"An unexpected highly exothermic decomposition was observed during routine safety analysis of the magnesium−iodine exchange reaction of 2-iodo-4-fluorotoluene ( 3 ) with commercially available i -PrMgCl (2.0 M solution in THF). When the reaction mixture was scanned in an adiabatic calorimeter with the use of a 2 °C/min temperature ramp, a rapid exothermic decomposition with an onset temperature of approximately 80 °C was observed. The system temperature rapidly rose to 210 °C at a peak rate of 200 °C/min. Subsequent testing of three simplified substrates showed the same type of exothermic decomposition for all cases. Control experiments indicated that the decomposition requires both aryl iodide and i -PrMgCl (or arylMgCl and i -PrI). While the onset temperatures for all cases studied were generally well above the typical operating temperature for these reactions (0−10 °C), it is nonetheless important to cautiously evaluate these types of processes and install proper engineering controls for analogous decomposition events.",10.1021/op060145b,0
Simple and Efficient Solution-Phase Synthesis of Oligonucleotides Using Extractive Work-Up,A solution-phase synthesis protocol amenable to scale-up was developed for the preparation of oligonucleotides employing phosphoramidite chemistry and DMTr/iBu/Bz-protected monomers. Isolation of intermediates was accomplished by means of extractions as the only purification tool. The potential of the method is demonstrated with the synthesis of a hexameric DNA fragment in high yield and purity.,10.1021/op060133q,0
Practical Synthesis of a Heterocyclic Immunosuppressive Vitamin D Analogue,"1α,25-Dihydroxyvitamin D 3 (calcitriol) 1 and synthetic analogues thereof are highly potent compounds with a wide range of pharmacological activity making them of great interest for the pharmaceutical industry. Herein we report an improved synthesis of the calcitriol analogue 2, which features a novel oxazole-containing side chain. The crucial part of the synthesis was the development of a practical route to the β-keto phosphonate 28, allowing an easy introduction of the unnatural side chain by a Wittig Horner reaction.",10.1021/op060130d,1
"Research and Development of an Efficient Process for the Construction of the 2,4,5-Substituted Pyridines of NK-1 Receptor Antagonists","Roche has identified a 2,4,5-trisubstituted pyridine template for a new class of potent NK 1 receptor antagonists. Previous strategies for construction of the pyridine core of these NK-1 receptor antagonists involved functionalization of a 2,5-disubstituted pyridine. We now report on construction of the pyridine core from commodity components. Shestopalov reported the synthesis of trans -4‘-aryl-5‘-cyano-1‘,2‘,3‘,4‘-tetrahydro-6‘-hydroxy-2‘-oxo-1,3‘-bipyridinium inner salts from 1-(2-amino-2-oxoethyl)pyridinium chloride, aromatic aldehydes, and ethyl cyanoacetate in the presence of a base. Reaction of these salts with phosphorus oxychloride affords 4-aryl-3-cyano-2,6-dichloropyridines. These are efficiently converted to nicotinamide precursors of the Roche NK-1 receptor antagonists by regioselective displacement of one chlorine by an amine, hydrogenolysis of the remaining chlorine, and nitrile hydrolysis.",10.1021/op060128m,1
Synthesis of (<i>S</i>)-3-(<i>N</i>-Methylamino)-1-(2-thienyl)propan-1-ol:  Revisiting Eli Lilly's Resolution−Racemization−Recycle Synthesis of Duloxetine for Its Robust Processes,"(±)-3-( N, N -Dimethylamino)-1-(2-thienyl)propan-1-ol ( 6 ), prepared from 2-acetylthiophene ( 4 ) in a two-step overall yield of 79%, is resolved into ( S )- 6 of 93% ee as its diastereomeric salt ( 8 ) with ( S )-mandelic acid ( 7 ) according to Eli Lilly's procedures developed for the resolution−racemization−recycle (RRR) synthesis of duloxetine ( 2 ) with some modifications in terms of practicality. On its liberation from 8, ( S )- 6 undergoes N -demethylative ethyl carbamate formation in two discrete but successive steps in an overall yield of 87% from 8: (1) O -ethyl carbonate formation and (2) ethyl carbamate formation with concomitant loss of the N -methyl group. Alkaline hydrolysis then affords ( S )-3-( N -methylamino)-1-(2-thienyl)propan-1-ol ( 1 ) of 100% ee, an alleged penultimate precursor to duloxetine ( 2 ), in 75% yield after a single recrystallization from ethylcyclohexane. In the overall process thus developed, PhMe is substituted successfully for t -BuOMe, a solvent that has been used favorably in Eli Lilly's original RRR synthesis of 2 .",10.1021/op060118l,1
"Process Development toward the Pilot Scale Synthesis of the Piperidine-Based Cocaine Analogue and Potent Dopamine and Norepinephrine Reuptake Inhibitor CTDP 31,446","(+)-Methyl 4β-(4-chlorophenyl)-1-methylpiperidine-3α-carboxylate hydrochloride (CTDP 31,446) is known as a dopamine reuptake inhibitor. This cocaine analogue lacking the tropane skeleton is being considered for potential treatment of cocaine addiction. Herein we report the development of a scalable process for the preparation of this compound. This study was mainly aimed at improving the process throughput, eliminating chromatographic purifications for the separation of (±)- 6 -cis isomer from (±)- 6 -trans isomer, and developing a robust crystallization for isolation of pure (±)- 6 -cis in a single crop with a good mass recovery. The process development work also highlights an efficient recycle of (±)- 6 -trans via a kinetic epimerization followed by crystallization of the resulting (±)- 6 -cis isomer. The resolution of (±)- 6 -cis and the crystallization of the final HCl salt were optimized and implemented to afford CTDP-31,446 with high purity and good mass recovery.",10.1021/op060114g,1
Lab Automation in Support of Safer Process Design for HWE Reaction,A scaleable process technology has been developed for a Horner−Wadsworth−Emmons reaction. The basic calorimetry capability of the MultiMax automated reactor system afforded some interesting insights regarding scale-up safety of the original process and helped guide us to improve alternative chemistry more suitable for safe scale-up.,10.1021/op060110b,0
"A Practical and Scaleable Preparation of 1,4-Anhydroerythritol","A practical and efficient kilogram-scale preparation of 1,4-anhydroerythritol from meso -erythritol is described. A novel silica gel and sodium bicarbonate slurry/filtration protocol is utilized to purify the product, giving commercial-grade material in 60−65% yield.",10.1021/op0601058,0
Synthesis of 4-Cyano Pyrroles via Mild Knorr Reactions with β-Ketonitriles,"Mild methods for conducting Knorr chemistry with β-ketonitriles were developed. This enabled the preparation of 4-cyano-penta-substituted pyrroles and gave access to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators for biological evaluation. In addition, a series of alkyl and aryl β-ketonitriles were employed in Knorr cyclizations to probe steric tolerance and the possibility of direct introduction of aromatic moieties via Knorr chemistry.",10.1021/op060104f,1
Oxidation of 4-Halo-2-nitrotoluene with Tetrabutylammonium Permanganate in Pyridine:  Development and Safety Evaluation,"4-Halo-2-nitrobenzoic acids are synthesized by oxidation of 4-halo-2-nitrotoluene with tetrabutylammonium permanganate (TBAP) in pyridine in multigram quantities. A significant induction period is observed at room temperature, and the vigorous exothermic reaction presents the risk of a run-away reaction. By control-feeding cold TBAP into the reaction mixture at 60 °C, the initiation process is managed, and the reaction is safely performed on multigram scale. However, larger-scale reaction is NOT recommended, and use of appropriate equipments is strongly encouraged.",10.1021/op060102v,0
"A Concise, Economical, and Diastereoselective Synthesis of Methyl DGJ Isopropylidene:  An Iminocyclitol Molecule Core for Analogue Synthesis","A six-step synthesis of the title compound starting from l -lyxonolactone 2,3-isopropylidene ( 6 ) is described. The synthesis is achieved by conversion of 6 to the C 5 -triflate or C 5 -mesylate 7a or 7b and their displacement by sodium azide to yield the C 5 azido compound 8 . Addition of methylmagnesium bromide and catalytic hydrogenation during which the azide group is reduced to the amine followed by an intramolecular cyclization yields the imine 15 . Concomitant reduction of the imine occurs stereoselectively to yield methyl DGJ isopropylidene ( 5 ) which is isolated via the succinic acid salt and its further neutralization with ammonia. It was found that changing the synthetic sequence, namely, instead of 7a → 8 → 9, the methylmagnesium bromide could be added first to the mesylate 7b, 7b → 11 followed by azide ion displacement 11 → 9 . This modification proved advantageous from the viewpoint of cost, use of methanesulfonyl chloride rather than trifluoromethylsulfonyl chloride, ease of operation, and yield. Methyl DGJ isopropylidene ( 5 ) is an important azasugar precursor because it can undergo N-alkyl substitution via reductive amination and be derivatized at C 2 via the secondary hydroxyl group. The synthesis reported herein allows for the production of mutikilogram amounts of this important key iminocyclitol core.",10.1021/op060100a,0
"Development of a Scalable and Safe Procedure for the Production of (3<i>R</i>)-3-(2,3-Dihydro-1-benzofuran-5-yl)-1,2,3,4-tetrahydro-9<i>H</i>-pyrrolo[3,4-<i>b</i>]- quinolin-9-one, an Intermediate in the Synthesis of PDE-V Inhibitors RWJ387273 (R301249) and RWJ444772 (R290629)","A scalable and safe process for the oxidative rearrangement of β-carboline to quinolone derivatives, intermediates in the synthesis of PDE-V inhibitors RWJ387273 (R301249) and RWJ444772 (R290629), has been developed.",10.1021/op060099f,1
Efficient Synthesis of a Highly Selective NPY-5 Receptor Antagonist:  A Drug Candidate for the Treatment of Obesity,"A concise and practical synthesis of highly selective NPY-5 receptor antagonist 1 is described. The animopyrazine intermediate 3 was synthesized via either monobromination of aminopyrazine or palladium-catalyzed regioselective debromination of dibromopyrazine followed by an efficient Suzuki−Miyaura coupling. For the preparation of the spirolactone piperidine 2, significantly improved yield was achieved by using a combination of n -BuMgCl and n -BuLi. This protocol also dramatically increased the thermal stability of the aryllithium intermediate and eliminated the requirement for costly cryogenic conditions. The union of the spirolactone piperidine 2 and aminopyrazine 3 via a carbonyl group was accomplished using phenyl chloroformate delivering the target molecule in high yield.",10.1021/op0600963,1
A Simple Preparation of a (Pyridonyl-1)propargylacetic Acid Derivative,"(Pyridonyl-1)propargyl malonate 7 was prepared through two consecutive alkylations of pyridone 2 with ethyl bromomalonate and propargyl bromide in one pot in nearly quantitative yields. Malonate 7 was hydrolyzed to give racemic acid (±)- 1, which was then resolved with (−)-norephedrine to give ( S )- 1 . The recovered acid, which was enriched with undesired ( R )- 1, was activated with CDI, and a complete racemization was achieved in the presence of triethylamine at room temperature. Malonate 7 was also treated with LiBr and underwent selective monodecarboxylation to give (pyridonyl-1)propargylacetic ester 6, an enzymatic resolution substrate, directly in 87% yield.",10.1021/op0600916,1
Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501),"A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone ( 1 ), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol ( 6 ), from the commercially available 4,6-dichloropyrimidine ( 3 ) without the isolation of pyrimidinyl phenoxy ether ( 4 ). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione ( 10 ), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate ( CKD-501, 2 ) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.",10.1021/op060087u,1
"Development of a Scalable Synthetic Route towards a Thrombin Inhibitor, LB30057","Described is a scalable synthetic route towards LB30057 ( 1 ) which is based upon a chiron approach using methyl tyrosinate hydrochloride as a starting material. In situ protection of methyl tyrosinate to its N,O -bis-trimethylsilyl derivative and subsequent N -selective introduction of naphthalenesulfonyl group provided methyl N -2-naphthalenesulfonyltyrosinate ( 9 ). After the phenol group of 9 was triflated to 10, nickel-catalyzed cyanation provided 11 in good yield. The acid chloride 11a was generated via hydrolysis of the ester group followed by the treatment with SOCl 2, and then coupled with cyclopentylmethylamine to give the amide 15 . Imidate formation followed by amidrazone generation and final salt formation with maleic acid afforded 1 .",10.1021/op060083p,1
"Organic Light-Emitting Devices:  Synthesis, Properties and Applications Edited by K. Mullen and U. Scherf. Wiley-VCH:  Weinheim. 2006. xvii + 410 pp. £139. ISBN 3-527-31218-8.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTOrganic Light-Emitting Devices: Synthesis, Properties and Applications Edited by K. Mullen and U. Scherf. Wiley-VCH: Weinheim. 2006. xvii + 410 pp. £139. ISBN 3-527-31218-8.Cite this: Org. Process Res. Dev. 2006, 10, 5, 1081Publication Date (Web):May 24, 2006Publication History Published online24 May 2006Published inissue 1 September 2006https://doi.org/10.1021/op060080cCopyright © 2006 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views375Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (24 KB) Get e-AlertsSUBJECTS:Diodes,Materials,Organic compounds,Organic semiconductors,Organic synthesis Get e-Alerts",10.1021/op060080c,0
Development of a Synthetic Process towards a Hepatitis C Polymerase Inhibitor,"The synthesis of 2-(4-{2-[(2 R )-2-Cyclopentyl-5-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-2-fluoro-phenyl)-2-methyl-propionitrile ( 1 ) on multikilogram scale is described. Initial synthesis of this clinical candidate for inhibition of the hepatitis C viral polymerase (HCVP) protein was executed via a racemic synthetic route coupled with chiral HPLC separation. Due to the achiral route and instability of key intermediates, the initial route was determined to be unsuitable for large-scale manufacture. An alternate route was developed utilizing a convergent Heck coupling, resolution of a carboxylic acid via diastereomeric salt formation, and an efficient chemical recycling of the undesired enantiomer.",10.1021/op0600761,1
Novel Synthetic Route of a Pivotal Intermediate for the Synthesis of 1β-Methyl Carbapenem Antibiotics,"A novel synthetic method using an original and practical procedure for the preparation of the N -PNZ protected 2-aminomethylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate ( S-4661 ), a new parenteral 1β-methylcarbapenem antibiotic, is described. trans -4-Hydroxy- l -proline was converted through an efficient process to (2 S,4 S )-4-acetylthio-2-( N -sulfamoyl-4-nitro-benzyloxycarbonyl - aminomethyl)-1-(4-nitrobenzyloxycarbonyl) pyrrolidine with 60−70% overall yield via a two-step sequence. This procedure requires no chromatographic purifications, no cryogenic temperatures, no haloalkane solvent, and shorter operating times and avoids the side reaction brought by acid hydrolysis. Furthermore, the product was obtained as a crystal rather than an oil, which made it to be an advantage for quantization in the pilot-scale manufacture. Several kilograms of the side chain were prepared by using this method.",10.1021/op0600714,1
Development of a Manufacturing Process for 1-(1-Pyridin-2-yl methyl-piperidin-4-yl)-1<i>H</i>-indole:  A Key Intermediate for Protein Kinase C Inhibitor LY317615,"This contribution describes process development leading to the production of 1-(1-pyridin-2-yl methyl-piperidin-4-yl)-1 H -indole ( 11 ). The title compound 11 was produced via a Leimgruber−Batcho indole synthesis using key intermediates 2-(2,2-dimethoxyethyl)benzenamine ( 6 ) and, 1-(2-pyridinylmethyl)-4-piperidinone camphor sulfonate ( 9 ). Direct crystallization of 11 from IPA or ethanol−water was developed to provide ( 11 ) with <1% impurities and high yield (78%). The combined process leads to a five-step synthesis of 11 that was efficient and reflected Eli Lilly and Company's commitment to implementation of environmental friendly processes whenever feasible.",10.1021/op060068k,1
Green Separation Processes:  Fundamentals and Applications Edited by Carlos A. M. Afonso and Joao G. Crespo. Wiley-VCH:  Weinheim. 2005. 363 pp. £100.00. ISBN 3-527-30985-3,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTGreen Separation Processes: Fundamentals and Applications Edited by Carlos A. M. Afonso and Joao G. Crespo. Wiley-VCH: Weinheim. 2005. 363 pp. £100.00. ISBN 3-527-30985-3Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, UKCite this: Org. Process Res. Dev. 2006, 10, 5, 1080–1081Publication Date (Web):April 20, 2006Publication History Published online20 April 2006Published inissue 1 September 2006https://pubs.acs.org/doi/10.1021/op060067shttps://doi.org/10.1021/op060067sbook-reviewACS PublicationsCopyright © 2006 American Chemical SocietyRequest reuse permissionsArticle Views217Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Complexation,Electromagnetic radiation,Nanoparticles,Separation science,Solvents Get e-Alerts",10.1021/op060067s,0
Open-Vessel Microwave-Promoted Suzuki Reactions Using Low Levels of Palladium Catalyst:  Optimization and Scale-Up,Representative Suzuki couplings in water using low catalyst concentrations in conjunction with microwave heating have been transferred from sealed-vessel to open-vessel reaction conditions. They have then been scaled-up to the mole scale using a dedicated multimode microwave apparatus. The reactions are complete within 20 min of heating at reflux.,10.1021/op0600613,0
Development and Optimisation of an Unsymmetrical Hantzsch Reaction for Plant-Scale Manufacture,"( S )-3-(5-Oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinolin-4-yl)benzonitrile is a potassium-channel opener developed for the treatment of urinary urge incontinence. The key step in the synthesis is an unsymmetrical Hantzsch reaction to give a 2-hydroxy-1,2,3,4-tetrahydropyridine. In our study the order of addition of reagents was found to be critical in the optimisation of the yield and the control of impurity levels in this reaction. The yield and the relative charges of the reagents were further optimised by the use of factorial experimental design. The chemistry has been scaled up to plant scale to produce multikilogram amounts of the Hantzsch product in close to 60% yield.",10.1021/op060057r,1
A Green Process for Oxidation of <i>p</i>-Nitrotoluene Catalyzed by Metalloporphyrins under Mild Conditions,"A novel synthetic technology of p -nitrobenzoic acid has been investigated with dioxygen by using metalloporphyrins RTPPM III Cl (M = Fe, Co, Mn) as biomimetic catalysts. Oxidation of p -nitrotoluene to p -nitrobenzoic acid under 2.0 MPa of O 2 in the presence of a microamount of metalloporphyrins (RTPPM III Cl) at 55 °C was achieved with the highest (up to 90.4%) yield. Further research results show that the catalytic activities were relative to the nature of the substituted groups and the central metal ions of metalloporphyrins. For the metalloporphyrins with the same center metal ions, the greater the electron-withdrawing degree of groups in the porphyrin ring, the higher the catalytic activities of the metalloporphyrins. The catalytic activities for metalloporphyrins with different center metal ions followed the order RTPPMn III Cl >RTPP Fe III Cl > RTPP Co III Cl.",10.1021/op060056z,0
Chlorination at the 8-Position of a Functionalized Quinolone and the Synthesis of Quinolone Antibiotic ABT-492,"The total synthesis of quinolone antibiotic ABT-492 has been achieved in 67% yield over nine steps from 2,4,5-trifluorobenzoic acid. The highlights of this synthesis include a novel chemoselective chlorination at the 8-position of a highly elaborated quinolone core. In addition, a Lewis acid promoted cyclization reaction to form the quinolone heterocycle was developed which was incorporated into a one-pot, three-step cyclization/coupling/protection sequence that proceeds in 93% yield.",10.1021/op0600557,1
Synthesis of the Quinolone ABT-492:  Crystallizations for Optimal Processing,"ABT-492 has been under development at Abbott Laboratories as a quinolone antibiotic. A convergent syntheses was utilized to prepare the compound on a multi-kilogram scale. Difficulties in isolation of intermediates were overcome by developing control of the physical forms. Examples of controlling the agglomeration, crystal habit, and polymorphism of intermediates and the API are described.",10.1021/op060054e,1
"A Practical Synthesis of 2-Arylamino-6-alkylaminopurines from 2,6-Dichloropurine","A practical synthesis of N -[4-(6-cyclobutylamino- 9H -purin-2-ylamino)-phenyl]- N -methyl acetamide (QAB205, 5a ), an antiasthmatic agent, is described from 2,6-dichloropurine ( 1 ) by base-assisted substitution of the 6-chloro substituent with cyclobutylamine ( 2a ) followed by a new trimethylsilyl chloride-catalyzed displacement of the 2-chloro group in intermediate 6-cycbutylamino-2-chloropurine ( 3a ) with an aromatic amine. Both steps can also be carried out in one pot without isolating the intermediate 6-cyclobutylamino-2-chloropurine ( 3a ). The general synthetic utility of this route is demonstrated by synthesizing several 2-arylamino-6-alkylaminopurines ( 5 ).",10.1021/op060053m,0
"Catalyst Separation, Recovery and Recycling:  Chemistry and Process Design Edited by D. Cole-Hamilton and R. Tooze. Springer:  Dordrect. 2006. 250 pp. £96. ISBN 1-4020-4086-5.",,10.1021/op060050+,0
Chemical Development of ZD9331:  Synthesis of a Bromomethylquinazolinone Avoiding a Nonselective Radical Bromination,"An efficient regiospecific synthesis of ZD9331 Pivaloyloxymethyl (POM) Bromide ( 4 ) has been accomplished via ZD9331 Quinacetate HCl ( 15 ) avoiding a nonselective bromination. The original route used a radical bromination on a substrate with three methyl groups, which generated a range of bromomethyl derived compounds that carried through to the final active pharmaceutical ingredient (API). A strategy, based on the Zinin reaction, was developed to synthesize the required bromomethyl compound in a regioselective manner. This approach was successfully scaled to manufacture a tonne of material.",10.1021/op060049a,1
Development of a Liquid-Phase Process for Recycling Resolving Agents within Diastereomeric Resolutions,"This paper describes a liquid-phase process for recycling of resolving agents used in the diastereomeric resolution of chiral bases. The process is applicable to the resolution of any chiral base by an organic acid resolving agent which takes place in a polar solvent. The resolving agent is first of all separated from the diastereomeric complex by addition of aqueous HCl. The initial stage of process development is selection of a water-immiscible extracting organic solvent to recover the resolving agent from the resulting acidic aqueous solution. Either distillation or organic solvent nanofiltration is subsequently used to exchange the resolving agent from the extracting organic solvent back into the polar resolution solvent. This choice between these two technologies for solvent exchange depends on the relative boiling points of the two solvents. The resolution of PPI2, a racemic amine by di- p -toluoyl- l -tartaric acid (DTTA), was selected as an example of a typical resolution used in an organic process. Using the conventional process, this resolution requires 1.75 mol equiv of DTTA for each mole of racemic base fed to resolution, and thus the bulk of the DTTA ends up in the mother liquor. Using the recycling process, DTTA from both mother liquor and crystals was recovered and recycled over seven consecutive resolutions, while the final product enantiomeric excess and resolution yield were maintained at 100% and 40%, respectively. In this way the DTTA requirement was decreased from 1.75 to 0.26 DTTA mol equiv, reducing the amount of fresh resolving agent needed for each resolution by 85%.",10.1021/op0600456,0
Safe and Practical Large-Scale Synthesis of 2-Aminoquinoline-6-Carboxylic Acid Benzyl Ester,"An efficient three-step sequence has been developed for the synthesis of 2-aminoquinoline-6-carboxylic acid benzyl ester starting from commercially available 6-quinolinecarboxylic acid. The process features a novel and exceptionally mild conversion of a quinoline N -oxide to a 2-aminoquinoline using a triethylamine/ammonium chloride buffered system. The development of this procedure is especially important since gaseous ammonia, ammonium hydroxide, and solutions of ammonia in alcohols all failed to deliver a safe and reliable process.",10.1021/op060044d,1
Synthesis of Imidazole Based p38 MAP (Mitogen-Activated Protein) Kinase Inhibitors under Buffered Conditions,"This article describes chemistry that was developed to give access to multigram quantities of imidazole 479754 and several related analogues for Eli Lilly's p38 MAPK program targeting therapies to address inflammation. The molecules of interest have an isopropyl sulfonyl group present on the 2-aminobenzimidazole heterocycyle that was found to be labile when heated in polar solvents and/or exposed to high or low pH. Due to this instability issue, the syntheses of the target molecules required optimizing Sonogashira reaction conditions, employing a buffered oxidative method to produce α-diones, developing buffered reaction conditions to generate imidazoles, and developing final recrystallization conditions.",10.1021/op060042t,1
"Enzymatic Process for the Synthesis of <i>cis/</i><i>trans</i>-(1<i>R</i>,5<i>R</i>)-Bicyclo[3.2.0]hept- 6-ylidene-acetate:  Solvent Effect and NMR Study","An efficient enzymatic process has been developed to resolve a diastereomeric mixture of racemic ethyl bicyclo[3.2.0]hept-6-ylidene-acetate ( 1 ). Using 40% acetone, not only was the enantioselectivity of Candida antarctica lipase B (CAL-B) significantly improved to E > 200 from E = 2.7, remarkably the enzyme is able to maintain low diastereoselectivity for the Z ( cis )- and E ( trans )-isomers leading to an overall high isolated yield (40−45%, vs maximum theoretical yield 50%) and excellent enantiomeric excess (>98.5% ee). Preliminary studies using 2D TROSY shows that there is probably a global conformational change in the N 15 -labeled enzyme CAL-B when the content of organic cosolvents increases from 0% to 30%. The route was successfully scaled to 63 kg for the synthesis of GABA analogues.",10.1021/op0600409,0
Process Modelling Tools for Continuous and Batch Organic Crystallization Processes Including Application to Scale-Up,"Computational fluid dynamics (CFD) is a powerful simulation tool that was successfully used to investigate mixing, turbulence, and shear in a laboratory-scale MSMPR and batch cooling crystallizer for an organic fine chemical. CFD gives a qualitative engineering insight into the effects of the impeller configuration on the crystallization rates and particle size distribution. A process-modelling tool, gPROMS (Process Systems Enterprise), was used to model particle size and size distribution in both batch and continuous laboratory-scale crystallization processes with predictive simulations in good agreement with experimental results. CFD simulations of large-scale crystallizations using constant specific power input per unit mass, predict an increase in macromixing and decrease in micromixing and turbulence. This effect should improve process performance of batch cooling crystallizers on scale-up including the product quality of the final solid form in terms of the particle size and crystal habit. This is due to improved suspension mixing and secondary nucleation effects and attrition decreasing with scale-up. CFD heat transfer simulations, however, predict varying temperature profiles together with less efficient heat transfer with the presence of distinct cooling zones, which can degrade product performance in terms of encrustation and agglomeration resulting in wider particle size distributions.",10.1021/op060039+,0
A Scalable Synthesis of 1-Cytosinyl-<i>N</i>-malayamycin A:  A Potent Fungicide,"A stereocontrolled synthesis of 1-cytosinyl- N -malayamycin A, an N -analogue of the naturally occurring malayamycin A with fungicidal activity, is reported. The approach was designed to rely solely on substrate control for introduction of the required stereochemistry, avoiding the use of chiral reagents or auxiliaries. Formation of the N -nucleoside was achieved through the activation of a thioglycoside, proceeding via sulfonium and thionium intermediates. Ring closure metathesis was used to build the bicyclic perhydrofuropyran heterocycle.",10.1021/op0600299,1
Analysis of Two-Liquid-Phase Multistep Biooxidation Based on a Process Model:  Indications for Biological Energy Shortage,"A process model for whole-cell biocatalysis in a two-liquid-phase system including cell growth and bioconversion kinetics was developed. The reaction considered is the kinetically controlled multistep oxidation of pseudocumene to 3,4-dimethylbenzaldehyde catalyzed by recombinant Escherichia coli expressing the Pseudomonas putida genes encoding xylene monooxygenase (XMO). XMO catalyzes the successive oxygenation of one methyl group of xylenes to corresponding alcohols, aldehydes, and acids. The biocatalytic process includes cells growing in fed-batch mode and a two-liquid-phase system consisting of bis(2-ethylhexyl)phthalate as organic carrier solvent and an aqueous minimal medium in a phase ratio of 1:1. The process model comprises a description of the bioconversion kinetics, mass transfer kinetics, cell growth, and mass balances for both the aqueous and the organic phase. Bioconversion kinetics and consistent process simulation indicated the occurrence of direct substrate uptake from the organic phase and provided evidence for a pH-influenced competition for NADH between XMO and the respiratory chain with its consequential impact on bioconversion and cell growth. For the simulation of such differential NADH limitation, a pH-dependent feedback inhibition of the NADH consuming bioconversions was introduced as a modeling tool, which allowed good simulations of biotransformation experiments performed at varying pH, scale, and initial substrate concentration. Moreover, modeling indicated a product inhibition in the second oxidation step, which could be confirmed experimentally. A sensitivity analysis for the aqueous−organic mass transfer coefficient showed that this transfer is not critical for the process performance and emphasized the efficient substrate-cell transfer in the investigated two-liquid-phase process. Based on a process model, this study provides an in-depth analysis of a biooxidation process based on growing cells with indications for biological energy shortage as a limiting factor.",10.1021/op060028g,0
An Efficient Multikilogram Synthesis of ABT-963:  A Selective COX-2 Inhibitor,"An efficient chemical process for the multikilogram synthesis of ABT-963 ( 3 ) is described. The potent and selective COX-2 inhibitor was prepared in four steps in 36% overall isolated yield from commercially available 3,4-difluoroaniline ( 4 ). The chemistry, which required no chromatography, involved a facile one-pot synthesis of the pyridazinone core, a selective alkoxylation, a high yielding Suzuki coupling, and a very efficient oxidation.",10.1021/op060016v,1
Synthesis of the CETP Inhibitor Torcetrapib:  The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization,"A practical, efficient synthesis of (−)-(2 R,4 S )-4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester ( 1 ), a cholesteryl ester transfer protein (CETP) inhibitor, is described. The key reaction in the synthesis, addition of an N -vinylcarbamate to an iminium ion rapidly followed by an iminium ion cyclization onto the aryl ring, sets up the cis relationship of the two subsituents of the tetrahydoquinoline ring of 6 . The origin of the high cis stereoselectivity in the cyclization was explored using high-level quantum chemistry calculations.",10.1021/op060014a,1
Asymmetric Synthesis of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib,"Previously our group reported synthetic efforts used to synthesize kilogram quantities of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, 1, via a mid-stage resolution. This account describes research conducted to develop an asymmetric route to this clinical candidate suitable for long-term manufacturing. The first asymmetric center is established via coupling of ( R )-3-aminopentanenitrile to a trifluoromethylarene. After elaboration of the nitrile to a suitable precursor, a key step in the synthesis is diastereoselective cyclization of immonium ion 7 to provide the tetrahydroquinoline core. This approach also permitted a streamlined sequence to complete the synthesis of 1 . Development of the process and synthetic rationale are described.",10.1021/op060013i,1
"Efficient Enzymatic Process for the Production of (2 <i>S</i> )-4,4-Difluoro-3,3-dimethyl- <i>N</i> -Boc-proline, a Key Intermediate in the Synthesis of HIV Protease Inhibitors","(2 S )-4,4-Difluoro-3,3-dimethyl- N -Boc-proline ( 3 ) is a key intermediate for the synthesis of HIV protease inhibitors. Here, several approaches for the preparation of enantiopure 3 and its analogues are disclosed. Among these methods, one strategy relies on resolving the racemic methyl ester of 3 through a protease-catalyzed enantioselective hydrolysis. Despite the fact that this resolution was applied to prepare kilogram quantities of optically pure acid 3 for clinical trials, this process suffered from low efficiency, high cost and difficulties in improvement by medium engineering. An alternative much more efficient and cost-effective enzymatic process was therefore developed by switching the protective group of the proline esters from a Boc to a benzyl moiety. This new process has a much higher throughput (6.3 mmol/h/L vs 0.11 mmol/h/L), and the cost of the process was also dramatically reduced to only 5% of the protease resolution process.",10.1021/op060004+,0
"Selective Lipase-Catalysed Hydrolysis of a 1,2-Diester in the Development of a New Route to AZD2563 DSP","During the development of a new route to AZD2563 DSP (DSP = disodium phosphate), a selective enzyme-catalysed hydrolysis of a 1,2-diester moiety to produce the secondary monoester was developed. Apart from two esters, the target molecule also contained three further functional groups prone to hydrolysis. A major challenge to the chosen approach was the very facile rearrangement of the desired secondary monoester product to the undesired primary monoester. This rearrangement was found to be catalysed by a wide range of chemicals and inorganic materials usually considered as inert. The unique selectivity and mild operating conditions of biocatalysis allowed the desired reaction to be developed and successfully scaled up.",10.1021/op060003h,1
"An Effective Process for Conversion of Diphenylurea to CC-2, a Potential Decontaminant of Sulfur Mustard","N, N ‘-Dichlorobis(2,4,6-trichlorodiphenyl) urea, also known as 2-chlorocarbinol (CC-2) is a potential decontaminant of Sulfur Mustard (SM), which is also known as bis(2-chloroethyl) sulfide (HD), a well-known warfare agent. A new process has been developed for the synthesis of CC-2 from diphenylurea (DPU) through an intermediate, known as hexachlorocarbanilide (HCC). The conversion of DPU to HCC was studied in the temperature range 35−100 °C in the presence of several homogeneous scavengers of HCl, like pyridine, triethylamine, ethylenediamine, hexamethylenetetramine, 4,4‘-bipyridine, diethylamine, dicyclohexylamine, etc. Experiments were carried out to study the activity of these homogeneous scavengers to get maximum conversion, yield, and purity of the product. Reaction temperature, reaction time, substrate-to-scavenger ratio, and solvent requirements were studied to optimize the reaction conditions. Both pyridine (product purity ∼80% and yield ∼89%) and ethylenediamine (product purity ∼85% and yield ∼70%) were found to be effective in improving the performance of the reaction.",10.1021/op060002p,0
"A Facile and Scaleable Synthesis of 3-<i>O</i>-Decladinose-6-methyl-10,11-dehydrate-erythromycin-3-one-2‘-acetate, an Important Intermediate for Ketolide Synthesis","A facile and scaleable synthetic process of compound 2, an important intermediate for synthesis of ketolide semisynthetic antibiotics, was developed starting from commercially available clathromycin with an overall yield of ∼74%. This synthetic pathway was composed of four steps from compound 3 which could be prepared from clathromycin without using expensive reagents such as EDC·HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) or more active reagents such as methanesulfonic anhydride. This new process was efficient and practical as demonstrated by scale-up to prepare more than 1 kg of pure compound 2 .",10.1021/op060001x,0
Modeling the Scale-Up of Contact Drying Processes,"The conventional way of scaling up a contact drying process includes a pilot-scale step. Scaling up from lab scale to production scale without the use of a pilot plant saves time and money. A method has been developed to perform a scale-up from a 200-g bench-scale Rotavap drying process to production scale (approximately 1000 kg). A mathematical model, an improvement on the so-called Schlünder model, has been developed to simulate bench-scale drying processes. This simulation is used to determine the unknown mixing parameters by regression analysis. Besides the heat transfer resistances predicted by Schlünder an additional resistance term was found which is product dependent and can also be determined by regression. Ultimately the model can be used to predict the drying curve on production scale. In five out of eight cases the developed method accurately predicted drying behaviour. In three remaining cases the model did not apply due to extreme stickiness or aggregation during drying.",10.1021/op058014i,0
A Scalable Synthesis of <scp>l</scp>-Leucine-<i>N</i>-carboxyanhydride,"Due to its relevance in the synthesis of well-defined oligopeptides, the l -leucine- N -carboxyanhydride (leucine-NCA) synthesis was selected for fine chemical scale-up with a scope on application on larger scales. The heterogeneous gas−solid−liquid nature of the leucine-NCA synthesis implied a mass transfer limited reaction rate towards phosgenation and was investigated on bench scale. Upon scale increase, the liquid−gas mass transport of HCl is drastically reduced, retarding the reaction and consequently rendering the process unsuitable for scale-up. Addition of an HCl scavenger such as (+)-limonene prevented side reactions thus allowing a cost reduction, a considerably faster reaction, and minimization of the amount of phosgene source used. The modified leucine-NCA synthesis has successfully been made scalable, maintaining high product purity on a 1.0 dm 3 scale.",10.1021/op058009e,0
"Chemical Engineering, Trends and Developments Edited by Miguel A. Galan and Eva Martin del Valle. Wiley:  Hoboken, NJ. 2005. 400 pp. $125.00/£65/99.90 Euro/160 SFR. ISBN:  0-470-02498-4.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewChemical Engineering, Trends and Developments Edited by Miguel A. Galan and Eva Martin del Valle. Wiley: Hoboken, NJ. 2005. 400 pp. $125.00/£65/99.90 Euro/160 SFR. ISBN: 0-470-02498-4.Francis McConvilleView Author Information FXM Engineering and Design, 6 Intervale Road, Worcester, Massachusetts 01602, U.S.A.Cite this: Org. Process Res. Dev. 2005, 9, 5, 699Publication Date (Web):August 13, 2005Publication History Published online13 August 2005Published inissue 1 September 2005https://doi.org/10.1021/op058008mCopyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views104Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (23 KB) Get e-AlertsSUBJECTS:Biotechnology,Chemical engineering and industrial chemistry,Chromatography,Polymer films,Thin films Get e-Alerts",10.1021/op058008m,0
Efficient Combination of Recyclable Task Specific Ionic Liquid and Microwave Dielectric Heating for the Synthesis of Lipophilic Esters,Mild and efficient esterification reactions of carboxylic acids with neo -pentanol were carried out using task-specific ionic liquids with hydrogen sulphate counteranion under microwave irradiation. The latent acidity of the ionic liquid was introduced by anion metathesis from hydrogen sulphate with the corresponding imidazolium or pyridinium halides. The catalyst [C 4 mim][HSO 4 ] modified with 5% of concentrated sulfuric acid was reused three times without considerable loss of activity in esterification using classical heating in oil bath.,10.1021/op058002x,0
First Scale-Up to Production Scale of a Ring Closing Metathesis Reaction Forming a 15-Membered Macrocycle as a Precursor of an Active Pharmaceutical Ingredient,"BILN 2061 ZW ( 4 ) is a new chemical entity which shows promising results against the Hepatitis C virus. The major issue in the synthetic route represents the scale-up of a ring closing metathesis reaction to form a 15-membered macrocycle. The parameters chosen for the macrocyclization are discussed, and the experience during large scale synthesis, trouble shooting, and possible improvements for future campaigns are described.",10.1021/op0580015,0
"Development of a Large-Scale Synthesis of Sulphostin, a Dipeptidyl Peptidase IV Inhibitor","For the progress of the in vivo study on sulphostin, a dipeptidyl peptidase IV inhibitor, its large-scale synthetic method was investigated. The optical resolution of (3 S, RS P )-1-amino(sulfoamino)phosphinyl-3-benzyloxycarbonylamino-2-piperidin-one, which was the most difficult step in the previous method, was simplified by using fractional crystallization. The use of 2 mol equiv of (1 S,2 R )-(+)-2-amino-1,2-diphenylethanol for optical resolution gave desired diastereomer 15 in good yield as a less soluble salt. In the present synthetic method, there were no requirements for purification using column chromatography, reaction at cryogenic temperature, and treatment using the haloalkane solvents. The total yield of the new method was 4.6%, which was an improvement of approximately 2-fold compared to the method reported previously.",10.1021/op058000c,1
Large-Scale Synthesis of (<i>R</i>)-2-Amino-1-(2-furyl)ethanol via a Chemoenzymatic Approach,A two-step chemoenzymatic synthesis of ( R )-2-amino-1-(2-furyl)ethanol for laboratory production was developed followed by successful up-scaling to kilogram scale. The generation of the asymmetric centre was accomplished by a highly enantioselective cyanohydrin reaction of furan-2-carbaldehyde with hydrocyanic acid catalyzed by the hydroxynitrile lyase from Hevea brasiliensis . Subsequent sodium borohydride reduction furnished the desired product with an enantiomeric excess of higher than 99.5%. This procedure can be considered a convenient general route for the stereoselective synthesis of ethanol amine derivatives underlining the role of biocatalysis for the generation of stereogenic centres in the synthesis of chiral intermediates.,10.1021/op050264b,1
"Improved Practical Asymmetric Synthesis of α-Alkylmandelic Acids Utilizing Highly Diastereoselective Alkylation of 5-Aryl-2-(1-naphthyl)-1,3-dioxolan-4-ones","A practical method for the synthesis of optically pure α-alkylmandelic acids 1 is described. The present improved robust method involved two reactions: a mild, convenient, stereoselective preparation of chiral cis -5-aryl-2-(1-naphthyl)-1,3-dioxolan-4-ones, 9a − c, and highly diastereoselective alkylation of 9a − c, followed by the hydrolysis.",10.1021/op050263j,1
Optimization and Scale-Up of a Lipase-Catalyzed Enzymatic Resolution of an Indole Ester Intermediate for a Prostaglandin D<sub>2</sub>(DP) Receptor Antagonist Targeting Allergic Rhinitis,"Pseudomonas fluorescens lipase was found to catalyze the asymmetric hydrolysis of racemic indole-ethyl ester 1. 1 The lipase converted the undesired (S) enantiomer to its corresponding acid, while leaving the desired (R) enantiomer untouched, yielding optically enhanced (R)- ester with an ee of 95% 1 at 48% conversion. The original process conditions for this resolution contained a second-phase immiscible organic solvent to solubilize the substrate, and required 128 g/L enzyme for a 100 g/L substrate charge (Shafiee, A.; Upadhyay, V.; Corley, E.; Biba, M.; Zhao, D.; Marcoux, J.-F.; Campos, K.; Journet, M.; King, A.; Larsen, R.; Grabowski, E.; Volante, R.; Tillyer, R. Tetrahedron Asymmetry 2005, 16, 3094). A study of substrate solubility and phase-partitioning behavior in a wide range of miscible and immiscible solvent concentrations demonstrated that the presence of the immiscible organic solvent caused the reaction to reach a mass transfer limited regime at conversions >40%. Process optimization led to the elimination of the second-phase immiscible organic solvent, a greater than 4-fold reduction in enzyme charge, and an increased product ee of >99%. The optimized process has been demonstrated at scale on two 40-kg batches and has resulted in product ester ee of 99.75% at 50% conversion.",10.1021/op050261z,0
Upscaling the Solid-Phase Synthesis of a Tetrahydrocarbazole in Chemical Development,"A multigram solid-phase synthesis of tetrahydrocarbazole 1 was developed based a milligram-scale synthesis from Automated Medicinal Chemistry (Koppitz, M.; Reinhardt, G.; van Lingen, A. Tetrahedron Lett. 2005, 46, 911−914). It was shown that a fast scale-up by a factor of 2000 of the solid-phase synthesis is possible in this case. Highly loaded Rink Amide resin was used, and the eight-step-synthesis was performed within 5 days, yielding 35 g (34%) of desired product 1 .",10.1021/op0502607,1
"Good Pharmaceutical Manufacturing Practice:  Rationale and Compliance By John Sharp. CRC Press:  London, UK. 2005. 503 pp. List price $229.95 (Web price $207). ISBN 0-8493-1944-3.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewGood Pharmaceutical Manufacturing Practice: Rationale and Compliance By John Sharp. CRC Press: London, UK. 2005. 503 pp. List price $229.95 (Web price $207). ISBN 0-8493-1944-3.Derek RobinsonView Author Information 38 Millbrook Court, Little Mill, Pontypool, Monmouthshire NP4 0HT, United KingdomCite this: Org. Process Res. Dev. 2006, 10, 2, 361–362Publication Date (Web):January 7, 2006Publication History Published online7 January 2006Published inissue 1 March 2006https://pubs.acs.org/doi/10.1021/op0502598https://doi.org/10.1021/op0502598book-reviewACS PublicationsCopyright © 2006 American Chemical SocietyRequest reuse permissionsArticle Views177Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical structure,Industrial manufacturing,Manufacturing,Materials,Quality management Get e-Alerts",10.1021/op0502598,0
Nitrilase-Catalysed Desymmetrisation of 3-Hydroxyglutaronitrile:  Preparation of a Statin Side-Chain Intermediate,"An efficient, scaleable synthesis of ethyl ( R )-4-cyano-3-hydroxybutyrate, a potential intermediate in the synthesis of Atorvastatin (Lipitor), has been developed. The three-stage process starts with reaction of low-cost epichlorohydrin with cyanide to give 3-hydroxyglutaronitrile (3-HGN). The second stage utilises a nitrilase-catalysed desymmetrisation of 3-HGN. The nitrilase reaction has been optimized to work at 3 M (330 g/L) substrate concentration, pH 7.5, 27 °C. Under these conditions, with an enzyme loading of 6 wt %, 100% conversion and 99% ee product is obtained in 16 h. This material is then esterified to give the target compound, ethyl ( R )-4-cyano-3-hydroxybutyrate. The cost-effectiveness of the process is determined by three factors: use of a low-cost starting material, the introduction of the chiral centre by desymmetrisation as opposed to kinetic resolution, and the use of Pf ēnex Expression Technology to allow a lower-cost supply of biocatalyst.",10.1021/op050257n,1
"Nearly Chromatography-Free Synthesis of the A<sub>3</sub>B-Porphyrin 5-(4-Hydroxymethylphenyl)-10,15,20-tri-<i>p</i>-tolylporphinatozinc(II)","Rational routes to synthetic porphyrins bearing distinct meso-substituents have typically been implemented at modest scale (<1 g quantities). The A 3 B-porphyrin 5-(4-hydroxymethylphenyl)-10,15,20-tri- p -tolylporphinatozinc(II) ( Zn-1 ) is required in multigram quantities for possible commercial use in information storage applications. The synthesis of Zn-1 has been carried out by reaction of 5-(4-hydroxymethylphenyl)dipyrromethane and the dicarbinol derived from 1,9-di- p -toluoyl-5- p -tolyldipyrromethane. Four improvements have been made to the steps leading to the dipyrromethane and dipyrromethane−dicarbinol: (i) use of 50 equiv of pyrrole in the condensation of an aldehyde to give the dipyrromethane (versus 100 equiv previously), (ii) 1,9-diacylation of a dipyrromethane using the hindered Grignard reagent 2,6-dimethylphenylmagnesium bromide and p -toluoyl chloride to give the 1,9-diacyl versus 1-acyl products in >10:1 ratio (versus 4:1 using EtMgBr), (iii) isolation of the dibutyltin complex of the 1,9-diacyldipyrromethane from the crude reaction mixture by direct crystallization using methanol/methyl tert -butyl ether (MTBE) (versus silica chromatography), and (iv) reduction of the dibutyltin complex of the 1,9-diacyldipyrromethane (250 mM) with ∼10−15 mol equiv of NaBH 4 (versus 25 mM and 40 mol equiv). The procedures have been carried out with no chromatography at large scale, affording the dipyrromethane (31, 59, or 79 g), the dibutyltin complex of a 1,9-diacyldipyrromethane (361 g), and reduction of the latter (45 g). The porphyrin-forming reaction has been performed (25 mM reactants at 50-mmol scale, or 10 mM at 64-mmol scale) in a two-step process of condensation and oxidation to give the free base porphyrin 1 in 3.7- or 5.8-g quantities. Metalation with zinc acetate afforded Zn-1, which was isolated by direct crystallization. Taken together, the various improvements facilitate synthesis of the target porphyrin Zn-1 and may have broad applicability.",10.1021/op0502553,1
Semiquantitative Process Screening for the Biocatalytic Synthesis of <scp>d</scp>-Xylulose-5-phosphate,"In this paper we report a method of semiquantitative process screening or route scouting developed to reduce the number of potential process flowsheets for a multistep biocatalytic conversion. Using the dual-enzyme-based synthesis of d -xylulose- 5-phosphate as a model, a variety of possible processes was identified. Using data from a limited number of key experiments describing important process attributes, a screening procedure was proposed. Unattractive processes were eliminated early, and the best candidates were put forward as potential options for subsequent development. The method should prove applicable to a range of process synthesis problems.",10.1021/op050254a,0
Novel Chemoenzymatic Protocol for the Synthesis of 3‘-<i>O</i>-Dimethoxytrityl-2‘-deoxynucleoside Derivatives as Building Blocks for Oligonucleotide Synthesis,"An easy, efficient, and scalable chemoenzymatic strategy for the synthesis of 3‘- O -dimethoxytrityl-2‘-deoxynucleosides has been developed. A key feature of this approach is the regioselective synthesis of 5‘- O -levulinyl-2‘-deoxynucleosides through enzymatic acylation in the presence of Candida antarctica lipase B. In addition, it was observed that the deblocking of levulinyl group from the 5‘-position is perfectly compatible with conventional base protecting groups. To demonstrate the scalability of this method, 3‘- O -dimethoxytritylthymidine ( 4a ) was synthesized on 25-g scale. These monomers ( 4 a − d ) are useful building blocks for the synthesis of oligonucleotides.",10.1021/op050253i,0
Development of an Efficient Synthesis of the Pyrrolquinolone PHA-529311,"An efficient synthesis of N -(4-chlorobenzyl)-2-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)-6-oxo-6H-pyrrol[3.2.1- ij ]quinoline-5-carboxamide ( 5 ) was developed. The route was chosen due to its reasonable length (seven steps), solubility of intermediates, and capabilities of the pilot and production facilities. The critical transformations in this route were the selective iodination of an aniline, formation of the quinolone, and Sonogashira coupling/pyrrole formation. In addition, removal of residual palladium and copper from the penultimate and final products, which was of lower concern during the discovery phase of development, became a difficult process chemistry issue on scale-up.",10.1021/op050251y,1
A Practical Synthesis of the Pseudotripeptide RC-1291,"The rapid process development of a scaleable synthesis of the pseudotripeptide RC-1291 for preclinical and clinical evaluation is described. By employing a nontraditional N -to- C coupling strategy, the peptide chain of RC-1291 was assembled in high yield, with minimal racemization and in an economical manner by introducing the most expensive component last. A one-pot deprotection/crystallization procedure was developed for the isolation of RC-1291 free base, which afforded the target compound in excellent yield and with a purity of >99.5% without chromatographic purification.",10.1021/op0502506,1
Handbook of Functionalized Organometallics:  Applications in Synthesis (Volumes 1 and 2) Edited by P. Knochel. Wiley-VCH:  Weinheim. 2005. £175. 652 + xix + 17 (index) pp. ISBN 3-527-31131-9.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTHandbook of Functionalized Organometallics: Applications in Synthesis (Volumes 1 and 2) Edited by P. Knochel. Wiley-VCH: Weinheim. 2005. £175. 652 + xix + 17 (index) pp. ISBN 3-527-31131-9.Cite this: Org. Process Res. Dev. 2006, 10, 4, 847Publication Date (Web):January 11, 2006Publication History Published online11 January 2006Published inissue 1 July 2006https://doi.org/10.1021/op0502452Copyright © 2006 American Chemical SocietyRequest reuse permissions Article Views264Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Magnesium,Metals,Organic synthesis,Reagents Get e-Alerts",10.1021/op0502452,0
"Development of a Scalable Synthetic Process for Selective Bromination of 4-Methyl-3,7-Substituted Coumarins","The hydroxyl-protected coumarin derivatives 6a − e of 4-methyl-3-(2,4-dihydroxyphenyl)-7-hydroxycoumarin ( 4 ) are key intermediates in the synthesis of unsymmetrical benzopyranobenzopyran compounds, a novel series of selective estrogen receptor modulators (SERMs). Free radical bromination of the 4-methyl group on 7-acetoxy-3-[(2,4-diacetoxy)phenyl]-4-methylcoumarin ( 6a ) with NBS resulted in incomplete reactions and low to moderate yields (25−44%) of 4-bromomethyl product 7a . Lithiation of the 4-methyl group of coumarins 6b (R = SEM), 6c (R = MOM) and 6d (R = Bz) with LDA (1.1−1.7 equiv) or LHMDS (1.2−1.7 equiv) generated carbanion in THF at −76 °C, which was quenched with bromine (1.5−2.0 equiv) to afford 4-bromomethyl derivatives 7b − d in good yields (80∼90%) in small scale reactions (2−20 g). The reaction yields declined to ∼70% when the scale was increased to ≥ 80 g. Furthermore, treatment of 3-[(2,4-dimethoxy)phenyl]-7-methoxy-4-methylcoumarin ( 6e ) with LHMDS (1.08 equiv) in THF followed by rapid inverse quenched with NBS (1.10 equiv) in THF at −76 °C, selectively produced the desired 4-bromomethyl compound 7e in excellent yield (> 90%) in both small (2−8 g) and large (80−150 g) scale reactions. A non-chromatographic process was developed to prepare 6e . This selective and efficient procedure was successfully transferred to the pilot plant to produce multi-kilograms of 4-bromomethyl coumarin 7e .",10.1021/op050242p,1
Development of a Scalable Synthesis to VEGFR Inhibitor AG-28262,"The synthesis of N,2-dimethyl-6-(2-(1-methyl-1 H -imidazol-2-yl)thieno[3,2- b ]pyridin-7-yloxy)benzo[ b ]thiophene-3-carboxamide ( 1, AG-28262) on kilogram scale is described. Initial syntheses of key components 2 and 3 worked well on laboratory scale but had significant drawbacks for larger-scale manufacture. Therefore, new routes to these two key fragments were developed and demonstrated to synthesize kilogram quantities. Key steps involve a two-step thiophenol alkylation/cyclization protocol to synthesize 2 in a convergent manner. A difficult Pd-mediated coupling to produce 3 was replaced with a more scalable stepwise imidazole synthesis. Key rationale for the new routes are discussed.",10.1021/op0502396,1
Towards an Information-Rich Process Development. Part I:  Interfacing Experimentation with Qualitative/Semiquantitative Modelling,"In today's competitive environment, the low-tonnage chemicals industry (fine and effect chemicals) is under increasing pressure to deliver more products to the market quicker and more cost effectively. Process development is a critical phase in bringing a fine chemical product from discovery to the market and requires the provision of an efficient framework for the capture of process knowledge and understanding. This is traditionally done by somewhat indirect means either through building understanding in individuals or the construction of a mathematical or physical model of the process. Such approaches suffer from two defects: first they do not collect understanding in a form that is readily shared by all the technologists involved, and second they do not collect understanding early enough in design. For example, the data required for the detailed modelling of a process is often only available well after the process configuration is fixed and properties can be measured under relevant conditions. Considering a liquid biphase reaction system, this paper demonstrates the interaction of targeted experimentation and qualitative/semiquantitative reaction evaluation to allow capture, testing, and sharing of understanding much earlier in design. The resultant qualitative predictions are tested against experimental observations to identify aspects where the qualitative model needs refinement. Recommendations for using more rigorous process analysis tools to explain these so-called anomalous observations are thus made.",10.1021/op050236t,0
"Regioselective Synthesis of an Imidazo[4,5-<i>c</i>]pyridine through Selective Acylation of 3,4-Diaminopyridine:  Synthesis of CP-885,316","CP-885,316 ( 1 ), an imidazo[4,5- c ]pyridine, 4, was prepared from 3,4-diaminopyridine ( 9 ). Two routes were demonstrated using the regioselective introduction of either an acetamide at the 3-position or a tert -butylcarbamate at the 4-position.",10.1021/op0502250,1
"Process Development of the Synthesis of 3,4,5-Trimethoxytoluene","3,4,5-Trimethoxytoluene (TMT) was synthesized, starting from p -cresol, through bromination followed by methylation to give 3,5-dibromo-4-methoxytoluene (DBMT). The methoxylation of the latter with sodium methoxide in methanol was studied under pressure and by continuous distillation of the solvent, methanol. The O-methylation reaction preceding the methoxylation was advantageous from the point of view of separation, purification, and isolation of the desired product and also in reducing the tar formation. The residue obtained was minimized to 0.6−0.7 wt % of the DBMT. The methoxylation reaction with distillative removal of methanol gave a conversion of 98% of DBMT to the mixture of methoxylated products, and the conversion to TMT was 86.5% as compared to 93% and 70.81%, respectively, when the reaction was carried out under pressure in a sealed reactor. However, the overall conversion to TMT based on p -cresol is 64.27% for the methoxylation reaction under pressure and 78.46% for the reaction by continuous removal of methanol calculated as isolated yield. The advantages of the methoxylation of the DBMT over the published literature procedures involving direct methoxylation of 3,5-dibromo- p -cresol followed by methylation of the dimethoxy- p -cresol are the ease of separation, purification, and isolation by vacuum fractionation of the desired product TMT.",10.1021/op0502248,0
A High Yield and Pilot-Scale Process for the Preparation of Adapalene,Strategies that were adopted during the process development of adapalene to achieve a cost-effective commercial-scale synthesis are described herein. These included (1) the use of AcOH/H 2 SO 4 to afford 2-(1-adamantyl)-4-bromophenol in quantitative yield; (2) the dimethyl sulfate methylation to enhance the yield of methylation to 95%; (3) direct conversion of the Grignard reagent into methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthoate by the catalysis of both PdCl 2 (PPh 3 ) 2 and ZnCl 2 in high yield; (4) the use of EDTA-disodium salt dihydrate to ensure the heavy metal's content within acceptable limits; (5) the use of toluene to simplify the original chromatographic purification to recrystallization. The pilot-scale synthesis of adapalene is described in detail in the Experimental Section.,10.1021/op050223f,1
"A Concise, Efficient and Production-Scale Synthesis of a Protected <scp>l</scp>-Lyxonolactone Derivative:  An Important Aldonolactone Core","A multikilogram-scale synthesis of l -lyxonolactone-2,3- O -isopropylidene is reported. It proceeds efficiently from an optimized, large-scale, aqueous bromine oxidation of d -ribose to d -ribonolactone including a one-pot isopropylidene formation, and subsequent conversion of the d -ribonolactone-2,3- O -isopropylidene to l -lyxonolactone-2,3- O -isopropylidene via the derived C 5 -mesylate and intramolecular relactonization of the product of aqueous potassium hydroxide cleavage of the d -ribonolactone ring. The inversion of configuration at the C 4 -chiral center is understood in terms of an intermediating C 4 −C 5 -epoxide. The overall process is noteworthy for its operational simplicity, stereochemical integrity, and use of inexpensive chemicals.",10.1021/op050222n,0
Parameters Controlling the One-Step Derivatization of Controlled Pore Glass with a Diol for Solid-Phase Synthesis of 3‘-Modified Oligonucleotides,"The one-step adsorption of oligoethylene glycol (OEG) affords an efficient derivatization of controlled pore glass (CPG) to perform oligonucleotide (ODN) solid-phase synthesis. This strategy leads to the synthesis of high-quality ODN-3‘-OEG. We have investigated various parameters that could influence the adsorption process to improve our understanding of the diol-anchoring mechanism. Diol concentration, solvent, temperature, and reaction time have been studied. Similarly, desorption of ODN-3‘-OEG was realized successfully in both weakly basic or neutral conditions. We assumed that the adsorption mechanism involves hydrogen bond-type interactions between diol hydroxyls and silanols from the silica surface.",10.1021/op050221v,0
Practical Synthesis of 2-Amino-5-fluorothiazole Hydrochloride,"The first synthesis of 2-amino-5-fluorothiazole hydrochloride is reported from 2-aminothiazole. The synthesis proceeds in 35% overall yield, involves no chromatographic purification, and has been employed to prepare multikilogram quantities of the title compound. The key fluorine-introducing step comprises the reaction of dilithiated 2- tert -butoxycarbonylaminothiazole with N -fluorobenzenesulfonimide.",10.1021/op0502194,0
"Selective Hydrolysis of Ethyl 5,6-Dihydro-4H-pyrrolo[1,2-<i>b</i>]pyrazole-2-carboxylate and Ethyl 5,6-Dihydro-4H-pyrrolo[1,2-<i>b</i>]pyrazole-3-carboxylate as a Key Step in the Large-Scale Synthesis of Bicyclic Heteroaryl Carboxyaldehydes","The isomeric mixture of ethyl 5,6-dihydro-4H-pyrrolo[1,2- b ]pyrazole-2- and −3-carboxylates ( 14 and 15 ), derived from a proline meso-ionic synthon, demonstrated remarkably different stabilities towards alkaline hydrolysis. On that basis, a nonchromatographic, highly efficient method for their large-scale separation was developed. The desired isomer 14 was converted into 5,6-dihydro-4H-pyrrolo[1,2- b ]pyrazole-2-carbaldehyde, a key intermediate in the synthesis of bicyclic heteroaryl-substituted 6-alkylidene penems.",10.1021/op050218b,1
"The Expedient Synthesis of 4,2‘-Difluoro-5‘-(7-trifluoromethyl- imidazo[1,2<i>-a</i>]pyrimidin-3-yl)biphenyl-2-carbonitrile, a GABA α2/3 Agonist","An expedient regioselective synthesis of a GABA α2/3 agonist 1 is described . The key step is an efficient regioselective palladium-catalyzed coupling of 7-trifluoromethylimidazo[1,2- a ]pyrimidine ( 5 ) to 5‘-chloro-4,2‘-difluorobiphenyl-2-carbonitrile ( 15 ). The efficiency of this step was affected by the choice of solvent, ligand, and tetrabutylammonium salt additive.",10.1021/op050217j,1
(2-Acetoxyphenoxy)ethyl (APOE) as a Phosphate Protecting Group in Solid-Phase Synthesis of Oligonucleotides via the Phosphoramidite Approach,The (2-acetoxyphenoxy)ethyl (APOE) group could be an alternative to the conventional 2-cyanoethyl group for phosphate protection in solid-phase oligonucleotide synthesis to circumvent DNA alkylation by acrylonitrile generated under basic condition. This group is stable during oligonucleotide synthesis and can be removed under mild conditions using aqueous ammonium hydroxide. Multiple phosphorothioate oligodeoxyribonucleotides and 2‘- O -methoxyethyl-modified oligoribonucleotide chimera were synthesized and characterized extensively. The deprotection of this group follows an intramolecular attack on the α-carbon adjacent to phosphate oxygen to liberate the oligonucleotide and an innocuous cyclic ether as side product. No modification of nucleobases was observed during deprotection of this group.,10.1021/op0502147,0
An Efficient Enantiopure Synthesis of a Pivotal Precursor to Substance P Antagonists<sup>1</sup>,"Many substance P antagonists have a core structure based on the quinuclidine skeleton. Manufacture of these drug antagonists proceeds through the advanced intermediate (2 S,3 S )- cis -2-benzhydryl-3-aminoquinuclidine 1, and all previous syntheses of 2 S,3 S - 1 proceed through quinuclidinone 2 . The synthesis described herein provides a 40% improved synthetic yield of (2 S,3 S )- 1 from quinuclidinone 2, when compared to all previously reported syntheses. The key process improvements originate from: (1) dynamic kinetic resolution of ketone rac - 4, producing ketone (2 S )- 4 and (2) the subsequent reductive amination of ketone (2 S )- 4 without epimerization. The former dynamic kinetic resolution, the first demonstrated for this ketone (quinuclidinone) architecture, uses inexpensive (natural) l -tartaric acid to provide ketone (2 S )- 4 in high yield (90%) and enantiopurity (95% ee). The latter demonstrates the first use of Ti(O i Pr) 4 /Pt-C/H 2 for reductive amination and is especially noteworthy for its ability to preserve the α-labile C2 stereocenter of ketone (2 S )- 4 . The new reductive amination method is general in nature and should find broad applicability.",10.1021/op050213e,1
"An Efficient and Economical Synthesis of 5,6-Diethyl-2,3-dihydro-1<i>H</i>-inden-2-amine Hydrochloride","An efficient and economical synthesis of 5,6-diethyl-2,3-dihydro-1 H -inden-2-amine hydrochloride ( 1 ) utilizing 2-aminoindan as a cheap and commercially readily available starting material is described. The newly developed synthesis involves six-steps with 49% overall yield, and it introduces two ethyl groups at the 5- and 6-positions via sequential regioselective Friedel−Crafts acetylations and hydrogenations of N -protected-2-aminoindan. The Friedel−Crafts acetylations can be carried out neat with high regioselectivity using acetyl chloride as the reagent as well as the solvent, thus avoiding the use of halogenated solvents.",10.1021/op0502093,1
Isomerization-Free Sulfonylation and Its Application in the Synthesis of PHA-565272A,FeCl 3 catalyzed an isomerization-free Friedel−Crafts sulfonylation between 1-naphthalenesulfonyl chloride and halobenzenes. The coupled halide was then displaced using 35% hydrazine in DMSO to provide the Fischer indole precursor. Pure 5-chloro-2-pentanone was the key for a successful Grandberg modification of Fischer indole synthesis that effectively constructed both the indole core and side chain of the target molecule. The development of these methods enabled a rapid preparation of kilogram quantities of PHA-565272A.,10.1021/op050208a,1
"Development of a Pilot-Scale Preparation of <i>N</i>-[[(5S)-3-[4-(1,1-Dioxido-4- thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, PNU-288034, an Oxazolidinone Antibacterial Agent","As part of Pfizer's continuing efforts in the oxazolidinone area, we have developed an efficient synthesis of PNU-288034 and successfully implemented it on pilot scale. The key step was a novel, acid-catalyzed, double Michael addition of 2,6-difluoroaniline with divinyl sulfone to install the desired dioxidothiomorpholinyl ring. Regioselective nitration provided the desired para-nitrogen, which was converted to the penultimate carbamate using standard chemistry. The resulting carbamate proved to be an excellent substrate for the recently reported oxazolidinone synthesis. As is normally the case, removing impurities to achieve our quality targets for API was a challenge, but unexpectedly, some impurities also caused significant processing difficulties as well. In the end, a safe and robust process was developed which provided clinical-quality material in five linear steps with an overall yield of 41% and was proven reproducible in multiple pilot-plant campaigns.",10.1021/op050207i,1
Simple Preparation of Highly Pure Monomeric <i>ω</i>-Hydroxycarboxylic Acids,"Highly pure monomeric ω -hydroxycarboxylic acids (HCAs) with ≥C 6 are prepared from their corresponding lactones or alkyl ω -hydroxycarboxylates through saponification followed by H 2 SO 4 acidification and treatment at 35−40 °C/8−12 mbar or by freeze-drying. The HCA is being formed through its sodium or potassium salt and is obtained in 80−85% yield with >99.5% purity, uncontaminated with dimers. This simple procedure excludes chromatographic purification.",10.1021/op0502046,0
Stereoselective Process for a CCR3 Antagonist,"A convergent, multikilogram, stereoselective synthesis of 1 is described. A key fragment, ( S )-3-(4-fluorobenzyl)piperidine ( 2 ) was synthesized from valerolactam in three steps using our recently discovered Ir−BDPP-catalyzed asymmetric hydrogenation. Another key fragment, (1 R,2 R )-2-(benzyloxycarbonylamino)cyclohexanecarboxaldehyde ( 3 ) was synthesized from meso -hexahydrophthalic anhydride in seven steps. The stereochemistry was set in the first step of this sequence via a quinidine-mediated desymmetrization of the meso -anhydride. Coupling of the fragments 2 and 3 followed by deprotection provided the penultimate 23 . The active pharmaceutical ingredient (API) free base 1 was obtained by treatment of 23 with the aminothiazole fragment 4 under mild conditions.",10.1021/op050202l,1
<i>Special Feature Section:  <u>Safety of Chemical Processes</u></i>Safety Feature,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSpecial Feature Section: Safety of Chemical ProcessesSafety FeatureTrevor LairdView Author Information Editor Cite this: Org. Process Res. Dev. 2005, 9, 6, 951Publication Date (Web):October 26, 2005Publication History Published online26 October 2005Published inissue 1 November 2005https://pubs.acs.org/doi/10.1021/op050197lhttps://doi.org/10.1021/op050197leditorialACS PublicationsCopyright © 2005 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views701Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (11 KB) Get e-AlertscloseSUBJECTS:Anions,Manufacturing,Safety,Solvates Get e-Alerts",10.1021/op050197l,0
"On Using Tree Analysis to Quantify the Material, Input Energy, and Cost Throughput Efficiencies of Simple and Complex Synthesis Plans and Networks:  Towards a Blueprint for Quantitative Total Synthesis and Green Chemistry","Synthetic plans or networks may be depicted as trees in a graph-theoretical sense. When drawn in a systematic way according to a defined convention key “green” metrics relating to the efficiency of performance of a synthesis to a target molecule may be easily obtained by inspection, that is, by a “connect-the-dots” approach. Example metrics include the cumulative and overall reaction mass efficiency (RME), the overall raw materials cost (RMC), and the fraction of total energy input directed to product (FTE). Throughout this paper kernel metrics are used to determine and compare the intrinsic efficiencies of synthetic plans since these depend directly on the nature of the chemical transformations and not on ancillary variables such as solvent usage, etc. Histograms of these metrics versus reaction stage allow for the easy determination of the mass-, cost-, and input energy-determining steps for a given synthesis plan. Other useful parameters that can be determined from a synthesis tree include the degree of convergence, the degree of asymmetry, the optimum time to complete a synthesis, and the degree of building to target structure with respect to reaction stage (molecular weight first moment). All of these metrics allow for easy comparison and ranking of synthetic plans. It is demonstrated that the tree analysis is robust and is applicable to any synthetic plan or network of any degree of complexity. The concept of “overall reaction yield” is shown to be applicable only to linear synthesis plans or networks and is replaced by the more general overall RME metric for syntheses involving mixed linear and convergent segments. The synthesis of the antibacterial agent triclosan is used as a tutorial exercise to introduce key concepts. Further example synthetic plans analyzed by the present tree analysis illustrating various plan types include quinine (Woodward−Doering−Rabe, Stork, Jacobsen, and Acharya−Kobayashi methods), sildenafil (asymmetric convergent), absinthin (symmetric convergent), papaverine (convergent using common intermediates), bupleurynol (multicomponent convergent), and polypeptide syntheses (Fischer, Bergmann−Zervas, Merrifield, azide, anhydride, and segment doubling methods). Example synthetic networks examined include industrial syntheses of veronal (5,5-diethylbarbituric acid) (complex branching to target node) and feedstock products derived from phthalic anhydride (complex branching from source node).",10.1021/op0501904,1
Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the 3-(4-Fluorophenyl)morpholine Moiety of NK<sub>1</sub> Receptor Antagonist Aprepitant,"An efficient and highly stereoselective one-pot Grignard addition/hydrogenation procedure is a key step in the synthesis of the NK 1 receptor antagonist aprepitant. The critical influence of pH on the nature and stability of the intermediate Grignard adducts, along with their reactivity in the hydrogenation reaction, is described. The observation of a defluorinated impurity under hydrogen-starved conditions led to mechanistic studies that revealed unusual kinetics in the hydrogenation reaction. Detailed analysis of the kinetic profiles under hydrogen-starved conditions indicated the two steps of the reaction, debenzylation of the Grignard adducts and reduction of the incipient imine, occurred in near perfect stepwise fashion wherein the debenzylation reaction was essentially complete before any imine reduction took place. Under hydrogen-saturated conditions the inhibition of the imine reduction was less complete, but the partial buildup of reactive imine intermediate led to a dramatic spike in reaction rate toward the end of reaction. Possible mechanistic rationales to explain these observation are discussed.",10.1021/op0501895,1
"Handbook of Reagents for Organic Synthesis:  Reagents for Glycoside, Nucleotide and Peptide Synthesis Edited by D. Crich. Wiley:  New York. 2005. 770 + xiv pp. £80. ISBN 0-470-02304-X.",,10.1021/op050187k,0
"Calcium Pantothenate. Part 2.<sup>1</sup> Optimisation of Oxynitrilase-Catalysed Asymmetric Hydrocyanation of 3-Hydroxy-2,2-dimethylaldehyde:  Synthesis of (<i>R</i>)-Pantolactone","The synthesis of ( R )-pantolactone via oxynitrilase-catalysed asymmetric hydrocyanation of 3-hydroxy-2,2-dimethylaldehyde has been investigated. ( R )-Oxynitrilases from almonds as well as from apple and plum kernels were employed as catalysts in the form of defatted meal. A number of factors influencing the hydrocyanation process have been studied and the conditions optimised using statistical methods. ( R )-Pantolactone with 74% yield and 30% ee has been synthesised.",10.1021/op050186s,1
"A New and Direct Asymmetric Synthesis of a Hindered Chiral Amine via a Novel Sulfinate Ketimine Derived from <i>N</i>-Tosyl-1,2,3-oxathiazolidine-2-oxide:  Practical Asymmetric Synthesis of (<i>R</i>)-Sibutramine","A novel and direct approach for the asymmetric synthesis of ( R )-sibutramine via chiral amine 5 using N -tosyl-1,2,3-oxathiazolidine-2-oxide ( 13 ) as a recyclable chiral auxiliary is described. Chiral sulfinate imine 16e was obtained by treatment of 13e with the imine intermediate formed from the reaction of a nitrile 1 and i BuMgCl that, upon reduction, provides an optically active amine 5 with high enantiopurity.",10.1021/op050182n,1
Safety Improvement of Chemical Processes Involving Azides by Online Monitoring of the Hydrazoic Acid Concentration,"Hydrazoic acid (HN 3 ) is formed during the synthesis of tributyltin azide and in the following cycloaddition to prepare a tetrazole ring compound. The formation of this substance is inherent to many azide processes because small amounts of protic components cannot be avoided. Hydrazoic acid is a very toxic volatile compound, which has highly explosive properties. Under certain conditions (presence of impurities in the reaction mixture), the gas concentration can come close to the decomposition limit. Therefore, online monitoring of this gas concentration is essential to ensure the process safety. FT-IR and FT-NIR experiments were performed in the laboratory scale to calibrate the spectrometers. Due to the possibility of using quartz light fiber cables, a FT-NIR spectrometer was installed to monitor the hydrazoic acid concentration in the industrial scale.",10.1021/op0501803,0
Development of a Practical High-Yield Industrial Synthesis of Pergolide Mesylate,"The development of a high-yield and low environmental impact synthesis able to deliver highly pure pergolide mesylate 1 is described. The process [seven chemical steps (four telescoped), three steps of isolation of intermediate, and only one drying] affords pergolide mesylate 1 in 75−81% overall yield from dihydrolysergic acid 4 with >99.8% purity.",10.1021/op0501747,1
A “Second-Generation Process” for the Synthesis of <scp>l</scp>-Neopentylglycine:  Asymmetric Reductive Amination Using a Recombinant Whole Cell Catalyst,"A “second-generation process” for the enantioselective synthesis of l -neopentylglycine has been developed, realizing the first whole cell-catalyzed approach to this pharmaceutically interesting, bulky amino acid. The synthesis of this nonnatural amino acid proceeds highly efficiently via a reductive amination of the corresponding α-keto acid in the presence of a recombinant whole cell catalyst, bearing a leucine dehydrogenase and formate dehydrogenase. The desired l -neopentylglycine was obtained with >95% conversion and a high enantioselectivity of >99% ee at substrate concentrations of up to 88 g/L.",10.1021/op0501702,0
Trouble with Potassium Carbonate and Centrifuges:  Mass Transfer and Scale-Up Effects in the Manufacture of ZD9331 POM Quinacetate,"Manufacture of ZD9331 pivaloyloxymethyl (POM) quinacetate, was progressively scaled up from large-scale lab to pilot plant to full-scale production. The specific surface area of the potassium carbonate used for the deprotonation was found to be critical as successive increases in the mass transfer area were counteracted by the reduced mass transfer efficiency, linked to the reactor size and impeller effectiveness. Furthermore, a change from a pressure filter to a centrifuge meant that the washing efficiency was similarly limited by mass transfer, with the rate of dissolution of the undesired regioisomer on the centrifuge being too low for the shorter wash time. These problems were overcome, resulting in two successful manufacturing campaigns with over 1 tonne of POM quinacetate produced well within specification in eight batches.",10.1021/op0501693,0
Development of a Scalable Process for a Key Intermediate of (<i>R</i>)-Metalaxyl by Enzymatic Kinetic Resolution,"A scale-up study was carried out for the enzyme-catalyzed kinetic resolution of 2-methoxyethyl N -(2, 6)-dimethylphenyl)alaninate rac - 3 for the preparation of ( R )-metalaxyl at 20-L scale. Immobilization of lipase PS on a polymeric support enabled the reuse of the enzyme. The unreacted enantiomer was racemized by means of acid/aldehyde catalyzed Schiff base intermediate formation. The combination of lipase PS-catalyzed hydrolytic kinetic resolution and racemization of the remaining ester gave a satisfactory reaction yield (> 80%) and high enantiomeric excess (96% ee) for one recycle.",10.1021/op050166q,0
A Practical Enantioselective Synthesis of a Novel Peptide Deformylase Inhibitor,"A practical synthesis of the peptide deformylase inhibitor LBM415, (2 S )- N -(5-fluoro-1-oxido-2-pyridinyl)-1-[(2 R )-2-[(formylhydroxyamino)methyl]-1-oxohexyl]-2-pyrrolidinecarboxamide, magnesium salt 11, is described. The key chiral intermediate, (2 S )- N -(5-fluoro-2-pyridinyl)-1-[(2 R )-2-[[formyl(phenylmethoxy)amino]methyl]-1-oxohexyl]-2-pyrrolidinecarboxamide 8, was made by coupling the corresponding amino acid 7 with the carboxamide 25 prepared from l -proline and 2-amino-5-fluoropyridine. Following oxidation of the pyridine nitrogen, selective hydrogenolysis of the benzyl group afforded the free acid of the drug substance, which was converted to the magnesium salt in situ with magnesium chloride. The product was obtained in an overall yield of 16% with an ee > 99%.",10.1021/op050165y,1
Process Analytical Technology Edited by Katherine A. Bakeev. Blackwell Publishing:  Oxford. 2005. 451 pp. £109. ISBN 1-4051-2103-3.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTProcess Analytical Technology Edited by Katherine A. Bakeev. Blackwell Publishing: Oxford. 2005. 451 pp. £109. ISBN 1-4051-2103-3.Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 6, 1023Publication Date (Web):October 8, 2005Publication History Published online8 October 2005Published inissue 1 November 2005https://pubs.acs.org/doi/10.1021/op0501646https://doi.org/10.1021/op0501646book-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views196Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Crystallization,Infrared light,Infrared spectroscopy,Pharmaceuticals,Pharmaceutics Get e-Alerts",10.1021/op0501646,0
Handbook of Reagents for Organic Synthesis:  Reagents for High-Throughput Solid-Phase and Solution-Phase Organic Synthesis Edited by Peter Wipf. John Wiley &amp; Sons Ltd:  Chichester. 2005. 380 pp. £75. ISBN 0-470-86298-X (hardbound).,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTHandbook of Reagents for Organic Synthesis: Reagents for High-Throughput Solid-Phase and Solution-Phase Organic Synthesis Edited by Peter Wipf. John Wiley & Sons Ltd: Chichester. 2005. 380 pp. £75. ISBN 0-470-86298-X (hardbound).Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 6, 1022–1023Publication Date (Web):October 7, 2005Publication History Published online7 October 2005Published inissue 1 November 2005https://pubs.acs.org/doi/10.1021/op050163dhttps://doi.org/10.1021/op050163dbook-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views181Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysts,Organic synthesis,Peptides and proteins,Reagents Get e-Alerts",10.1021/op050163d,0
The Synthesis of a Novel Inhibitor of B-Raf Kinase,"A scaleable synthetic route to [4,7‘]bis-isoquinolinyl-1-yl-(2- tert -butyl-pyrimidine-5-yl)amine ( 1 ), an inhibitor of B-Raf kinase is described. The key step in the synthesis is the Pd-catalyzed Negishi coupling of 4-bromo-1-chloroisoquinoline with trifluoromethanesulfonic acid isoquinoline-7-yl ester to yield 1-chloro[4,7‘]bis-isoquinolinyl. This intermediate is transformed to the desired drug substance in one additional step, by reaction with 2- tert -butyl-5-aminopyrimidine in the presence of NaH. A special focus was put on the finally successful removal of traces of Zn and Pd in the drug substance, which came from the Negishi coupling.",10.1021/op0501601,1
A Practical Method for the Synthesis of a Cyclosporine−Fluorescein Conjugate,"A straightforward synthesis of a cyclosporine−fluorescein conjugate through the MeBmt hydroxyl group was developed. Reaction of cyclosporine A in phosgene/toluene solution with added triethylamine, followed by subsequent reaction with 4‘-aminomethylfluorescein, produces good yields of the cyclosporine−fluorescein conjugate.",10.1021/op0501592,0
"Oxazoles:  Synthesis, Reactions and Spectroscopy, Part A Edited by D. C. Palmer. Wiley-Interscience:  Hoboken, NJ. 2003. 640 + xviii pp. £195. ISBN 0-473-39494-7.",,10.1021/op050158+,0
Experiences with Commercial Production Scale Operation of Dissolving Metal Reduction Using Lithium Metal and Liquid Ammonia,"The final step which generates free base in the synthesis of Sumanirole Maleate (PNU-95666E) consists of a cryogenic dissolving metal reduction using lithium metal and liquid ammonia. This chemistry was new to the Pfizer API production plant. Due to the hazards associated with the handling of lithium metal and ammonia gas at cryogenic reaction temperature, special challenges were encountered related to the design of the equipment, choice and handling of materials, operations, waste treatment, and both safety and economic issues. The topics discussed in this article include the use of Li instead of Na or K, impact of the choice of physical form of lithium metal, design of the lithium addition apparatus, and problems experienced during the addition. We also discuss techniques for addition of ammonia to the reactor, evaporation of ammonia from the reaction mixture, options for ammonia disposal, and internal reuse of ammonia. Comments on hazards for this reaction are also provided. It is hoped that this document will be of benefit to other professionals who may want to develop and scale-up dissolving metal reduction processes.",10.1021/op050155x,0
One-Pot Preparation of 7-Hydroxyquinoline,"An efficient one-pot procedure for the four-step preparation of 7-hydroxyquinoline ( 1 ) from 3- N -tosylaminophenol ( 4 ) in 60% isolated yield, that reduces the risk of exposure to acrolein ( 2 ), is described.",10.1021/op0501545,0
A New Efficient Stereoselective Debromination Reaction with Trialkylgermanium Hydrides Useful in the Design of Short Synthetic Routes to β-Lactamase Inhibitor Prodrugs,"Prodrugs derived from the β-lactamase inhibitor 6-β-hydroxymethylsulbactam can be synthesized efficiently in a three-step process by making use of the highly stereoselective radical debromination utilizing tri- n -butylgermanium hydride. This reagent is capable of abstracting bromine from the C-6 position of pairs of epimers 6-hydroxymethyl-6-bromo-penicillate-1,1-dioxide esters and functionalized esters suitable for prodrug use in high yields. The bromine abstraction usually results in favoured formation of the 6-β-hydroxymethyl epimer relative to the 6-α-hydroxymethyl epimer in ratios that exceed 97:3. Reaction of pure 6-α-hydroxymethyl-6-β-bromo-penicillate-1,1-dioxide ester results in almost exclusive formation of 6-β-hydroxymethylsulbactam ester. This methodology conserves the C−C bond formation at C-6 by making use of both epimers resulting from formylation, which is difficult and nonstereoselective in the β-hydroxymethylsulbactam prodrug synthesis.",10.1021/op050151s,1
"Contemporary Drug Synthesis By Jie Jack Li, Douglas S. Johnson, Drago R. Sliskovic, and Bruce D. Roth. Wiley-Interscience:  New Jersey. 2004. 221 pp. £51.50. ISBN 0-471-21480-9.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTContemporary Drug Synthesis By Jie Jack Li, Douglas S. Johnson, Drago R. Sliskovic, and Bruce D. Roth. Wiley-Interscience: New Jersey. 2004. 221 pp. £51.50. ISBN 0-471-21480-9.Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 6, 1020Publication Date (Web):September 7, 2005Publication History Published online7 September 2005Published inissue 1 November 2005https://pubs.acs.org/doi/10.1021/op0501489https://doi.org/10.1021/op0501489book-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views1546Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Organic synthesis,Pharmaceuticals,Salts,Sodium,Students Get e-Alerts",10.1021/op0501489,0
"Transition Metals for Organic Synthesis:  Building Blocks and Fine Chemicals. Second Revised and Enlarged Edition. (2-Volume Set.) Edited by Matthias Beller and Carsten Bolm. Wiley-VCH:  Weinheim. 2004. 662 pp. (Vol. 1), 652 pp (Vol. 2). £270. ISBN 3-527-30613-7.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTTransition Metals for Organic Synthesis: Building Blocks and Fine Chemicals. Second Revised and Enlarged Edition. (2-Volume Set.) Edited by Matthias Beller and Carsten Bolm. Wiley-VCH: Weinheim. 2004. 662 pp. (Vol. 1), 652 pp (Vol. 2). £270. ISBN 3-527-30613-7.Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 6, 1017–1018Publication Date (Web):September 3, 2005Publication History Published online3 September 2005Published inissue 1 November 2005https://pubs.acs.org/doi/10.1021/op050145whttps://doi.org/10.1021/op050145wbook-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views521Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Cyclization,Hydrocarbons,Oxidation,Oxidation reactions Get e-Alerts",10.1021/op050145w,0
Process Development and Pilot Plant Synthesis of Methyl 2-Bromo-6-chlorobenzoate,"A scalable process for a pilot plant synthesis of methyl 2-bromo-6-chlorobenzoate ( 1 ) is described. The strategy employed for the synthesis hinged on the esterification of the sterically encumbered parent acid produced through an o -lithiation/carboxylation approach. Vigilant temperature control was paramount for the success of this synthetic pathway. Initiation of an exothermic benzyne decomposition pathway during the o -lithiation step occurred at −70 °C. In the pilot plant, cooling via the jacket service was suitable to provide batch temperatures of −75 °C. However, control of reaction heat required liquid nitrogen injection into the process vessel simultaneously with the exothermic reagent charges. Esterification of the carboxylic acid was accomplished with potassium carbonate/methyl iodide, and subsequent crystallization resulted in 79% overall yield of the title compound from inexpensive starting materials.",10.1021/op0501444,0
"Fieser's Reagents for Organic Synthesis By Tse-Lok Ho. 2004. Wiley-Interscience:  Hoboken, New Jersey. Volume 22. 608 + xiv pp. £54.50. ISBN 0-471-285515-3.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTFieser's Reagents for Organic Synthesis By Tse-Lok Ho. 2004. Wiley-Interscience: Hoboken, New Jersey. Volume 22. 608 + xiv pp. £54.50. ISBN 0-471-285515-3.Cite this: Org. Process Res. Dev. 2005, 9, 6, 1017Publication Date (Web):August 20, 2005Publication History Published online20 August 2005Published inissue 1 November 2005https://doi.org/10.1021/op050141rCopyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views90Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (57 KB) Get e-AlertsSUBJECTS:Catalysts,Organic synthesis,Reagents,Selectivity Get e-Alerts",10.1021/op050141r,0
"Amines:  Synthesis, Properties and Applications By S. A. Lawrence. Cambridge University Press:  Cambridge. 2004. 371 + x pp. £100/$180. ISBN 0-521-78284-8.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTAmines: Synthesis, Properties and Applications By S. A. Lawrence. Cambridge University Press: Cambridge. 2004. 371 + x pp. £100/$180. ISBN 0-521-78284-8.Cite this: Org. Process Res. Dev. 2005, 9, 6, 1016Publication Date (Web):August 20, 2005Publication History Published online20 August 2005Published inissue 1 November 2005https://doi.org/10.1021/op0501390Copyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1038Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (57 KB) Get e-AlertsSUBJECTS:Amines,Molecular structure,Monomers,Peptides and proteins,Salts Get e-Alerts",10.1021/op0501390,0
"Efficient Total Synthesis of Lycophyll (ψ,ψ-Carotene-16,16‘-diol)","A practical procedure is described for the total synthesis of lycophyll (16,16‘-dihydroxy-lycopene; ψ,ψ-carotene-16,16‘-diol), based on a C10 + C20 + C10 synthetic methodology using the commercially available materials geraniol (C10) and crocetindialdehyde (C20). A late-stage double Wittig olefination on crocetindialdehyde was used to form the desired lycophyll scaffold in eight linear synthetic steps, while generating a mixture of polyenic geometric isomers that could be effectively separated using HPLC. All- trans lycophyll was subsequently separated to >95% purity by semipreparative chromatography using a C30 carotenoid column.",10.1021/op050137f,1
"Still Going Wrong! Case Histories of Process Plant Distasters and How They Could Have Been Avoided By Trevor Kletz. Gulf Professional Publishing, Butterworth-Heinemann, Elsevier:  Amsterdam, Boston. 2003. £29.95. 230 pp. ISBN 0-7506-7709-0.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTStill Going Wrong! Case Histories of Process Plant Distasters and How They Could Have Been Avoided By Trevor Kletz. Gulf Professional Publishing, Butterworth-Heinemann, Elsevier: Amsterdam, Boston. 2003. £29.95. 230 pp. ISBN 0-7506-7709-0.Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 6, 1015Publication Date (Web):September 8, 2005Publication History Published online8 September 2005Published inissue 1 November 2005https://pubs.acs.org/doi/10.1021/op050135vhttps://doi.org/10.1021/op050135vbook-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views141Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Manufacturing,Organic reactions,Process chemistry,Safety Get e-Alerts",10.1021/op050135v,0
Scalable Reactor Design for Pharmaceuticals and Fine Chemicals Production. 1:  Potential Scale-up Obstacles,"A comprehensive review of factors that inhibit scalability of fine chemicals and pharmaceuticals, from the chemical engineering point of view, is presented. These potential scale-up obstacles are generated by the fact that chemical rate constants are scale-independent, whereas physical parameters and phenomena are not. The paper identifies the most common factors that interact with chemistry to cause a fall in performance on scale-up and suggests ways in which these issues can be analysed in order to generate appropriate solutions. A hierarchy of the importance of the potential scale-up obstacles as perceived in industry is presented based on information collected from chemical companies, while the merits of scale-out as opposed to scale-up are addressed.",10.1021/op050133a,0
"Microwave Assisted Organic Synthesis Edited by J. P. Tierney and P. Lidstrom. Blackwell Publishing:  Oxford. 2005. 280 pp. £89.50. ISBN 1-4051-1560-2. (Also published by CRC Press in U.S.A. and Canada, ISBN 0-8493-2371-1.)","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTMicrowave Assisted Organic Synthesis Edited by J. P. Tierney and P. Lidstrom. Blackwell Publishing: Oxford. 2005. 280 pp. £89.50. ISBN 1-4051-1560-2. (Also published by CRC Press in U.S.A. and Canada, ISBN 0-8493-2371-1.)Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 5, 697Publication Date (Web):August 16, 2005Publication History Published online16 August 2005Published inissue 1 September 2005https://pubs.acs.org/doi/10.1021/op050132ihttps://doi.org/10.1021/op050132ibook-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views297Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Electromagnetic radiation,Organic chemistry,Organic synthesis,Safety Get e-Alerts",10.1021/op050132i,0
A Practical and Efficient Synthesis of Thalidomide via Na/Liquid NH<sub>3</sub> Methodology<sup>1</sup>,"A facile, efficient, concise, cost-effective, and scalable synthesis of thalidomide in high overall yield (55%) is presented. Treatment of Boc-protected l -glutamic acid diester via Na/liquid (liq.) NH 3 (−33 °C) mediated cyclization methodology produces a corresponding glutarimide ring which was subsequently condensed with phthalic anhydride in the presence of glacial acetic acid to afford thalidomide.",10.1021/op050129z,1
Process Development Challenges to Accommodate A Late-Appearing Stable Polymorph:  A Case Study on the Polymorphism and Crystallization of a Fast-Track Drug Development Compound,The case of disappearing/late-appearing stable polymorphs and their impact is well-understood by scientists in the pharmaceutical industry. This paper discusses an instance where a more stable crystal form was discovered during the development of a fast-track drug candidate. Challenges in adapting to the discovery of the new crystal form during this accelerated drug development program and approaches to develop a robust crystallization process are discussed.,10.1021/op0501287,1
"Active Pharmaceutical Ingredients; Development Manufacturing and Regulation Edited by S. H. Nusim. Taylor and Francis:  Boca Raton, FL, 2005. £79.99. xiv + 337 pp. ISBN 0-8247-0293-X","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTActive Pharmaceutical Ingredients; Development Manufacturing and Regulation Edited by S. H. Nusim. Taylor and Francis: Boca Raton, FL, 2005. £79.99. xiv + 337 pp. ISBN 0-8247-0293-XCite this: Org. Process Res. Dev. 2005, 9, 5, 698–699Publication Date (Web):August 5, 2005Publication History Published online5 August 2005Published inissue 1 September 2005https://doi.org/10.1021/op050125uCopyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views191Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (23 KB) Get e-AlertsSUBJECTS:Amorphous materials,Chemical engineering and industrial chemistry,Industrial manufacturing,Manufacturing,Solvents Get e-Alerts",10.1021/op050125u,0
Utilization of Lithium Amide in the Synthesis of <i>N</i>-Arylanthranilic Acids and <i>N</i>-Arylanthranilamides,"A procedure for the preparation of N -arylanthranilic acids and N -arylanthranilamides was developed. Lithium amide promoted coupling of anilines with 2-fluorobenzoic acids or 2-fluorobenzamides lead to the desired compounds in good yield. Both primary and N -substituted anilines were effective partners for the reaction. In the reaction of 2,3,4-trifluorobenzoic acid with various anilines, selectivity for ortho substitution was observed exclusively.",10.1021/op0501242,0
Concise Synthesis of a Selective α<sub>1</sub>-Adrenoceptor Antagonist,"An efficient synthesis of an adrenoceptor antagonist has been developed and demonstrated in a pilot plant. A linear synthesis that relied on a catalytic reduction of a rather insoluble nitroaromatic proved to be a viable route. The active pharmaceutical ingredient (API) that contained an amidine functional group was generated from the amino-containing precursor by activation of dimethylacetamide (DMA) with phosphorus oxychloride (POCl 3 ). The reaction between DMA and POCl 3 was studied using ReactIR and was found to be a fast but not instantaneous reaction. The iminium salt generated from DMA and POCl 3 had acceptable stability to allow for its use on a pilot-plant scale; however, a trend towards decomposition was revealed on the basis of in situ FTIR data. Formation of the complex was evaluated in a reaction calorimeter (RC-1), and the stability of the complex was probed with an Advanced Reactive System Screening Tool (ARSST).",10.1021/op050122h,1
Assessment of a Reductive Amination Route to Methyl(3-nitrobenzyl)amine Hydrochloride,"During the development of a sodium borohydride mediated reductive amination of 3-nitrobenzaldehyde with methylamine, studies revealed that partial reduction of the nitro group occurred, and potentially dangerous azo- and azoxy-containing products were generated. Borane- tert -butylamine activated with methanesulfonic acid was determined to be a safer reducing agent, and abuse tests on the reduction stage of the process have demonstrated that partial reduction of the nitro group did not occur. Conditions were developed that were suitable for scale-up to a pilot plant.",10.1021/op050120x,0
Developing Processes for Crystallization-Induced Asymmetric Transformation,"Crystallization-induced dynamic resolution (CIDR) is an adaptation of dynamic resolution, a process that can afford in principle a quantitative yield of chiral product from a racemic starting material through in situ resolution. Crystallization-induced asymmetric transformation (CIAT) includes CIDR and the preparation of diastereomers and olefins that are driven by crystallization. The history of CIAT and CIDR processes is reviewed, along with key observations made by researchers. Recommendations are made for identifying opportunities for and developing CIAT processes.",10.1021/op050119y,0
Chemoenzymatic Synthesis of <i>N</i>-Trifluoroacetyl Doxorubicin-14-Valerate (Valrubicin),"An efficient two-step, chemoenzymatic synthesis of N -trifluoroacetyl doxorubicin-14-valerate (Valrubicin) from doxorubicin hydrochloride salt is reported. The key step is a lipase-catalyzed regioselective esterification of N -trifluoroacetyl doxorubicin using commercially available valeric acid as the acyl donor. The overall yield for the process is 79%.",10.1021/op0501186,0
Process Development and Large-Scale Synthesis of a PDE4 Inhibitor,"An efficient, scalable synthesis of the PDE4 inhibitor, 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{( E )-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl)quinoline benzenesulfonate ( 10 ) is described. The synthesis is highly convergent, generating the penultimate 9 by coupling aldehyde 7 and oxadiazole 8 in a Knoevenagel reaction. The process consists of a total of nine chemical steps, five of which comprise the sequence to prepare aldehyde 7 via Skraup reaction, bromination, sulfone formation, methylation and Suzuki−Miyaura cross-coupling, and a two-step sequence for the synthesis of oxadiazole 8 that includes the methylamidoxime and oxadiazole steps. The final two steps are Knoevenagel coupling and salt formation. The process produced the drug candidate 10 in 46% overall yield from 2-bromo-4-methylaniline ( 1 ) on multikilogram scale.",10.1021/op050116l,1
"Design and Optimization in Organic Synthesis, 2nd revised and enlarged edition Rolf Carlson and Johan E. Carlson. Elsevier:  Dordrecht, The Netherlands. 2005. 574 pp (+ CD). Price:  £180, $290, 265 Euro. ISBN 0-444-51527-5.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTDesign and Optimization in Organic Synthesis, 2nd revised and enlarged edition Rolf Carlson and Johan E. Carlson. Elsevier: Dordrecht, The Netherlands. 2005. 574 pp (+ CD). Price: £180, $290, 265 Euro. ISBN 0-444-51527-5.Derek RobinsonView Author Information 38 Millbrook Court, Little Mill, Pontypool, Monmouthshire, NP4 0HT, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 5, 699–700Publication Date (Web):July 22, 2005Publication History Published online22 July 2005Published inissue 1 September 2005https://pubs.acs.org/doi/10.1021/op050112ghttps://doi.org/10.1021/op050112gbook-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views213Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Component analysis,Kinetics,Organic synthesis,Software,Solvents Get e-Alerts",10.1021/op050112g,0
Development of a Scalable Process for 1-β-Methyl Azetidinone: A Carbapenem Key Intermediate,"An optimized process for the stereoselective synthesis of 1-β-methyl carbapenem key intermediate (3 S,4 S )-[( R )-1‘-(( tert -butyldimethylsilyl)oxy)ethyl]-4-[( R )-1-carboxyethyl]-2-azetidinone ( 1 ) and (3 R,4 R )-4-acetoxy-3-[( R )-1‘-(( tert -butyldimethylsilyl)oxy)ethyl]-2-azetidinone has been developed employing commercially available chiral 4-phenyl-2-oxazolidinone. This method provides an efficient and cost-effective process with improved selectivity and higher yield.",10.1021/op0501085,1
A Preparative Route to Methyl 3-(Heteroaryl)acrylates Using Heck Methodology,Methyl 3-(heteroaryl)acrylates were prepared using Heck coupling of heteroarene halides with methyl acrylate mediated by Pd(OAc) 2 /P(OCH 3 ) 3 . Reactions were highly efficient (reaction times between 60 and 120 min) and scalable to 100 g of heteroarene halide. The isolated yields are from 76 to 99%.,10.1021/op050106k,1
Catalytic Mesylation of Alcohols:  A Highly Productive Process for Trifluoroethyl Mesylate,"“Intermediate” Lewis acids are efficient catalysts for mesylation of trifluoroethanol (TFE) by mesyl chloride at 80 °C. In the absence of solvent, trifluoroethyl mesylate (TFEMes) is obtained in a chemical yield of 98% with total conversion of TFE. The only coproduct of the reaction, hydrochloric acid, simply distills from the reaction mixture. Distillation of TFEMes allows for recycle of the catalyst without any treatment.",10.1021/op050105s,0
"An Efficient and Scalable Synthesis of the Endothelin Antagonists UK-350,926 and UK-349,862 Using a Dynamic Resolution Process","The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N -sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with ( S )-(−)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N -carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.",10.1021/op050102f,1
Process Design and Scale-Up Elements for Solvent Mediated Polymorphic Controlled Tecastemizole Crystallization,"Tecastemizole, an active metabolite of the histamine H 1 -receptor antagonist Astemizole (Hismanal), crystallizes out in two polymorphic forms (form A and form B). Thermodynamic stability screening results show that form A is more stable and form B is kinetically favorable (metastable) in the temperature range of process interest. A process design switch from a seed controlled growth approach to a solvent mediated interconversion based approach was adopted for reasons of simplicity and robustness during early Phase II development. The effects of dissolution, mass transfer, and surface-controlled growth on the observed interconversion rate were studied under well-defined seeding conditions. The experimental results show a significant effect of operating temperature on the interconversion rate and also show that the rate-limiting step is the growth of form A. Growth controlled kinetic parameters were estimated and are reported here. A nonlinear cooling profile was developed to take advantage of the temperature rate effect on form interconversion. Scale-up of the modified procedure was performed at both pilot and full-scale manufacturing, and the results confirmed the laboratory findings.",10.1021/op050101n,0
"A New Process for Synthesis of the Astrocyte Activation Suppressor, ONO-2506","Development of a new process for the synthesis of ONO-2506, an agent that suppresses astrocyte activation, is described. Previous processes that involved asymmetric synthesis with a chiral auxiliary were unsatisfactory from a cost perspective because the relatively expensive chiral auxiliaries were not recyclable. To develop a more cost-effective process, we designed a new process starting from chiral 1,2-epoxyoctane, which was readily prepared catalytically by Prof. Jacobsen's method. The new five-step process was developed with the establishment of a modified cyanation condition, in which lithium cyanide was prepared in situ by combining lithium hydroxide with acetone cyanohydrin. Then the mechanisms for racemization and the side reaction until the cyanation step were clarified, and these problems were solved. The main features of this process are crystallization of the amide intermediate, since its optical purity is readily improved by recrystallization up to 100% ee in addition to formation of the dibenzylamine salt with ONO-2506 that leads to improved chemical and optical purity of the final product. The shorter synthesis, including a one-pot reaction was ruled out because of the hazardous nature of the Katriztky hydrolysis conditions for the conversion of nitrile to amide in the presence of sodium cyanide.",10.1021/op0500988,1
Improved and High Yield Synthesis of the Potent Arginase Inhibitor:  2(<i>S</i>)-Amino-6-boronohexanoic Acid,"A simple three-step synthesis of the potent arginase inhibitor 2( S )-amino-6-boronohexanoic acid (ABH) has been developed. The key step was alkylation of the Ni II complex of the Schiff base derived from glycine and ( S )-2-[ N ‘-( N -benzylprolyl)amino]benzophenone (BPB) with pinacol 4-bromobutylboronate. Acidic hydrolysis afforded ABH in 50% overall yield, high enantiomeric excess, and quantitative recovery of the chiral auxiliary.",10.1021/op050096n,1
"Refined Synthesis of 2,3,4,5-Tetrahydro-1,3,3-trimethyldipyrrin, a Deceptively Simple Precursor to Hydroporphyrins","2,3,4,5-Tetrahydro-1,3,3-trimethyldipyrrin (1) is a crucial building block in the rational synthesis of chlorins and oxochlorins. The prior 5-step synthesis of 1 from pyrrole-2-carboxaldehyde (2) employed relatively simple and well-known reactions yet suffered from several drawbacks, including limited scale (>/= 0.5 g of 1 per run). A streamlined preparation of 1 has been developed that entails four steps: (i) nitro-aldol condensation of 2 and nitromethane under neat conditions to give 2-(2-nitrovinyl)pyrrole (3), (ii) reduction of 3 with NaBH(4) to give 2-(2-nitroethyl)pyrrole (4), (iii) Michael addition of 4 with mesityl oxide under neat conditions or at high concentration to give gamma-nitrohexanonepyrrole 5, and (iv) reductive cyclization of 5 with zinc/ammonium formate to give 1. Several multistep transformations have been established, including the direct conversion of 2 --> 1. The advantages of the new procedures include (1) fewer steps, (2) avoidance of several problematic reagents, (3) diminished consumption of solvents and reagents, (4) lessened reliance on chromatography, and (5) scalability. The new procedures facilitate the preparation of 1 at the multigram scale.",10.1021/op050087e,1
Process Development of an Inherently Safer Oxidation:  Synthesis of 2-Chloro-6-methylbenzoic Acid in the R411 Manufacturing Process,"Many oxidation reactions can be hazardous when run on large scale. The manufacturing process for the production of R411, a developmental compound indicated for the treatment of asthma, includes the oxidation of 2-chloro-6-methylbenzaldehyde to the corresponding carboxylic acid. The use of sodium chlorite in this transformation was efficient and economical, but there were safety concerns regarding the use of hydrogen peroxide to scavenge unwanted hypochlorite, which was generated as a byproduct of the reaction. During the development of the R411 manufacturing process, an inherently safer oxidation system was discovered using a stoichiometric quantity of dimethyl sulfoxide (DMSO) as scavenger. The new process provided equivalent yields and purities to the hydrogen peroxide procedure, thus maintaining the economic viability of the process. The developed process was demonstrated in fixed equipment on a 300 gal scale.",10.1021/op050083+,0
"Development and Semicommercial Implementation of an Environmentally Benign, Hydrogen Peroxide Mediated Oxidation of Aliphatic Alcohols","A process for the oxidation of an aliphatic alcohol (primary alcohol in C12−C15 region, substrate selected on the basis of a customer requirement) was developed and scaled up from laboratory (100 mL and 1 L scale) to bench (CR26 reactor) and to semicommercial scale (1000 litre) for toll manufacturing purposes. This oxidation was performed using hydrogen peroxide and a transition metal catalyst under phase transfer conditions. Although hydrogen peroxide mediated oxidation is a potentially hazardous process, the process was successfully scaled up using additional experimental data (from laboratory and bench scale), simple mathematical modelling, and simulation of the hydrodynamics of the multiphase system. The product acid from a C13 primary alcohol could be obtained at alcohol conversions exceeding 95% in selectivities approaching 100%.",10.1021/op050082h,0
A Practical and Efficient Process for the Preparation of Tazarotene,"We describe an efficient process for the preparation of tazarotene starting from 4,4-dimethyl-6-bromothiochromane S -oxide ( 9 ), 2-methyl-3-butyn-2-ol ( 10 ), and 6-chloronicotinic acid ethyl ester ( 8 ). Our synthetic pathway compares favorably over the previously reported procedures since tazarotene was prepared straightforwardly using cheap reagents and without the employment of hazardous organometallic compounds. The process is based on the use of sulfoxide 9 as key starting material. The C-15 framework of the target was built up by means of two different approaches based on a palladium-mediated coupling reaction. The molecular structure of compound has been confirmed by X-ray crystallography.",10.1021/op050080x,1
"An Efficient Process for Synthesis of 3-(<i>R</i>)-3-(2,3-Dihydrobenzofuran-5-yl)- 1,2,3,4-tetrahydropyrrolo[3,4-<i>b</i>]quinolin-9-one","3-( R )-3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4- b ]quinolin-9-one ( 1 ) is a key intermediate in the synthesis of pyrroloquinolone analogues, a series of highly potent and selective phosphodiesterase 5 (PDE5) inhibitors. Racemic 1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H -β-carboline ( 6, Scheme 2) was prepared by Pictet−Spenger condensation in 84% isolated yield with >97% chemical purity. The desired intermediate, 1-( R )-1-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-1 H - β -carboline N -acetyl- d -leucine salt ( 8 ), was obtained in 35% isolated yield with high chiral purity (≥ 97% ee) from the chemical resolution of 6 with N -acetyl- d -leucine ( 7 ). A racemization step was developed for recycling enriched 1-( S) -β-carboline 9 freebase ( 8 / 9, 25 ± 3%/75 ± 3%) to a near racemic mixture ( 8 / 9, 47 ± 1%/53 ± 1%). Furthermore, the resolving reagent 7 was recovered in >76% yield, which, together with the recycled racemic mixture ( 8 / 9, 47 ± 1%/53 ± 1%), afforded 35% more salt 8 after two recycles (≥97.0% ee). The salt 8 was converted to 1-( R )-1-(2,3-dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1 H -β-carboline ( 10 ) in excellent yield (94%). A modified Winterfeldt oxidation of compound 10 using Aliquat 175 as a phase transfer catalyst produced 3-( R )-2-benzyl-3-(2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydropyrrolo[3,4- b ]quinolin-9-one ( 12 ) in moderate 42% yield. Hydrogenolysis of compound 12 gave the desired compound 1 in quantitative yield with retention of chiral purity (≥97.0% ee). This efficient, reproducible, economical, and nonchromatography scale-up process could be used to make multikilogram quantities of compound 1 .",10.1021/op050079y,1
First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin,"A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N -benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N -benzyloxy group and salt formation. The overall yield was 52% over eight steps.",10.1021/op0500786,1
Nucleosidic Phosphoramidite Synthesis via Phosphitylation:  Activator Selection and Process Development,"Nucleosidic phosphoramidites are key building blocks for the automated, solid supported syntheses of oligonucleotide-based drugs. A safe, industrially viable process for preparing nucleosidic phosphoramidites 5-Me-MOE-U and MOE-A has been developed and utilized on multikilogram scales. The optimization of this process is described in detail. Emphasis is placed on the search for activators to replace the hazardous 1 H -tetrazole, the development of an extractive workup, and the advancement of a precipitation method to avoid both chromatographic purification and product foaming issues.",10.1021/op050077d,0
"Practical, Scalable, Enantioselective Synthesis of (2<i>R</i>,3<i>R</i>)-<i>N</i>-Boc-2-amino-3- cyclohexyl-3-hydroxypropanoic Acid","An enantioselective synthesis of (2 R,3 R )-2-( tert -butoxycarbonyl)amino-3-cyclohexyl-3-hydroxypropanoic acid has been described starting from enantiomerically enriched ethyl 3-cyclohexyl-2,3-dihydroxypropanoate, easily available by Sharpless asymmetric dihydroxylation. The key reaction is the direct preparation of a sulfate by diol treatment with sulfuryl chloride, thus avoiding ruthenium-catalyzed sulfite oxidation.",10.1021/op050076l,1
"Diastereomeric Salt Resolution Based Synthesis of LY503430, an AMPA (α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid) Potentiator",This article describes the development and optimization of chemical reactions and subsequent preparation of the API LY503430 under cGMPs to fund first human dose (FHD) clinical evaluation as a potential therapeutic agent for Parkinson's disease. Reasons and rationale are presented for changes in solvents and reagents. One of the major developments presented here is the replacement of a chiral chromatography with a diastereomeric salt resolution. This article also discusses a preferred orientation issue with LY503430 which complicated the XRPD analysis.,10.1021/op0500741,1
"Regioselective Synthesis of 2,6-Dimethyltetralin:  Key Precursor to 2,6-Dimethylnaphthalene","A novel regioselective synthesis for 2,6-dimethyltetralin (2,6-DMT), a key precursor to 2,6-dimethylnaphthalene (2,6-DMN), is described. The synthesis comprises the following three steps; the Heck reaction between commercially available 4-bromotoluene and 3-methyl-3-buten-1-ol, the catalytic reduction of the coupling products, and the acid-catalyzed cyclization of the alcohol intermediate. The process has an advantage over the established processes in that 2,6-DMT is obtained as the only isomer, and the isomerization and/or the complicated separation and purification steps are not required to produce pure 2,6-DMT. 2,6-DMN could be also obtained as a major product depending on the cyclization conditions.",10.1021/op050072g,1
A Practical Synthesis of the Dual Matrix Metalloprotease/Tumor Necrosis Factor Inhibitor MMP090,"A practical 9-step synthesis of the dual matrix metalloprotease/tumor necrosis factor inhibitor MMP090, trans -( R )-[[ N -(4-ethoxyphenylsulfonyl)- N -(4-pyridinylmethyl)]amino]- N -hydroxy-4-propoxy cyclohexaneacetamide 10, was accomplished in 12% overall yield from d -4-hydroxyphenylglycine. Highlights include: (1) selective hydrogenation of d -hydroxyphenylglycine to afford predominantly the trans isomer without racemization; (2) virtually complete removal of the undesired cis diastereoisomer by fractional recrystallization of a TBS ether derivative of the functionalized cyclohexylglycine; (3) direct conversion of the TBS ether into the n -propyl ether in the presence of a catalytic amount of bismuth bromide in high yield; and (4) conversion of the carboxylic acid into the hydroxamic acid using an aqueous solution of hydroxylamine.",10.1021/op050066k,1
Efficient Synthesis of a 5-HT<sub>2C</sub> Receptor Agonist Precursor,"A short, scaleable, synthetic approach toward the tricyclic indole derivative 2, an intermediate in the synthesis of the 5-HT 2C agonist 1, is described. The synthesis started with Williamson etherification of inexpensive 4-nitro-3-methylphenol ( 11 ) followed by reduction to the corresponding aniline 13 and subsequent Boc protection. Acylation of the methyl group in 14 via lithiation furnished γ-chloroketone 16, which was subjected to acid promoted indole formation to afford 17 . In the final step, NaOH induced hydrolytic cleavage of the Boc protecting group followed by direct intramolecular nucleophilic substitution gave rise to target molecule 2 in an overall yield of 65% over six steps.",10.1021/op050065s,1
A Continuous Reactive Separation Process for Ethyl Lactate Formation,"The continuous formation of ethyl lactate (L 1 E) from aqueous lactic acid solution and ethanol is carried out in a reactive separation column. Nearly complete conversion of lactic acid can be achieved with L 1 E yield exceeding 85%; byproduct lactate oligomer esters and acids formed can be further converted to additional L 1 E. Concentrated (88 wt % in water) lactic acid feedstock gives the best results, with as little as 40% excess ethanol required to achieve >95% conversion of lactic acid. Similar conversion can be obtained using 50 wt % lactic acid feed solution, but with much higher ethanol feed rates. Optimal column operation in both cases is observed with no reflux, so that operation is as a reactive stripping column. Limiting the quantity of ethanol added or vaporizing feed ethanol makes it possible to eliminate ethanol and water from the bottom stream of the column, thus simplifying recovery and purification of L 1 E product and facilitating the recycle of byproduct oligomers. Reaction of oligomeric byproducts with excess ethanol over Amberlyst 15 cationic exchange resin in a batch reactor gives a high yield of L 1 E, indicating that process yields of L 1 E approaching 100% are feasible.",10.1021/op0500640,0
Development of a Scalable Synthesis of Gastrazole (JB95008):  A Potent CC<i>K</i><sub>2</sub> Receptor Antagonist,"A practical and scalable synthesis was developed that was used to prepare multikilogram batches of gastrazole, a selective cholecystokinin-2 receptor antagonist. In addition, evidence was found to indicate an amide bond-forming reaction proceeded via the isoimide of a benzimidazoleamide acid derivative.",10.1021/op0500638,1
"A Scalable Process for the Synthesis of 2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-<i>d</i>][1]benzazepine Monohydrate and 4-[(Biphenyl-2-ylcarbonyl)amino]benzoic Acid:  Two New Key Intermediates for the Synthesis of the AVP Antagonist Conivaptan Hydrochloride","A process for the multikilogram synthesis of the dual vasopressin-receptor antagonist, conivaptan hydrochloride, has been developed. This method relies on the introduction of operationally simple chemistry during the final stages of the process when two key intermediates, isolated by crystallization, are reacted to assemble the final molecule. A three-stage sequence has been developed for the synthesis of the first key amine hydrate intermediate, and modifications of the original process are described here. Major strategic improvements have been made in defining the final route to the “side chain” precursor molecule, which is the second key intermediate. These advances revolve around the acylation of an unprotected amino benzoic acid and subsequent high-yield telescoped processes for the synthesis of 4-[(biphenyl-2-ylcarbonyl)amino]benzoic acid. This novel method leads to a 4-fold increase in the overall yield of the target materials, circumvents the restricted synthetic intermediates, and constitutes a safe, reliable, adaptable, environmentally friendly, and cost-effective approach with improved manipulability.",10.1021/op050061n,1
"Process Development of CP-481715, a Novel CCR1 Antagonist","Process development for the synthesis of 2-quinoxalinecarboxamide, N -[(1 S,2 S,4 R )-4-(aminocarbonyl)-1-[(3-fluorophenyl)methyl]-2,7-dihydroxy-7-methyloctyl] is described. An optimized and streamlined process starting from lactone 2 was developed: Lactone 2 was alkylated diastereoselectively with prenyl bromide, followed by deprotection of the N -Boc group and concomitant hydration of the olefin. Aminolysis of the lactone in methanolic ammonia afforded the titled compound.",10.1021/op050059w,1
Process Development:  From the Initial Idea to the Chemical Production Plant By G. Herbert Vogel. Wiley VCH:  Weinheim. 2005. 478 pp. $195. ISBN 3-527-31089-4.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewProcess Development: From the Initial Idea to the Chemical Production Plant By G. Herbert Vogel. Wiley VCH: Weinheim. 2005. 478 pp. $195. ISBN 3-527-31089-4.Francis McConvilleView Author Information FXM Engineering & Design Worcester, Massachusetts 01602Cite this: Org. Process Res. Dev. 2005, 9, 3, 374Publication Date (Web):April 13, 2005Publication History Published online13 April 2005Published inissue 1 May 2005https://pubs.acs.org/doi/10.1021/op0500537https://doi.org/10.1021/op0500537book-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views224Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Manufacturing,Safety,Separation science,Thermodynamics Get e-Alerts",10.1021/op0500537,0
"Synthesis of Methyl 1-(2,3,5-Tri-<i>O</i>-acetyl-β-<scp>l</scp>-ribofuranosyl)-1,2,4- triazole-3-carboxylate from <scp>l</scp>-Ribose:  From a Laboratory Procedure to a Manufacturing Process","A two-step manufacturing process for methyl 1-(2,3,5-tri- O -acetyl-β- l -ribofuranosyl)-1,2,4-triazole-3-carboxylate ( 1 ) was developed. In step 1, l -ribose was converted to a β/α mixture of 1,2,3,5-tetra- O -acetyl- l -ribofuranoses ( 2 and 4 ). The step contained four chemical transformations and was completed in “one-pot” in approximately 95% yield. The crude step 1 product was reacted with methyl 1,2,4-triazole-3-carboxylate ( 3 ) in step 2 to produce 1 . The successful utilization of both isomers ( 2 and 4 ) in step 2 offered advantages of higher overall yield and a much simplified process by eliminating the isolation of pure 2 . The process was successfully scaled up to the pilot plant and subsequently in a manufacturing campaign using commercial production facilities.",10.1021/op050051m,0
Control of Product Quality in Batch Crystallization of Pharmaceuticals and Fine Chemicals. Part 1:  Design of the Crystallization Process and the Effect of Solvent,"The product quality in a crystallization process refers to the crystal size distribution (CSD), crystal morphology, polymorphic outcome and the degree of crystallinity, and purity. In addition, the product yield is also important. Properties such as the filterability and solid bulk density are directly related to the CSD. To obtain the desired product quality, attention should be paid to the various operating conditions such as the local and average levels of supersaturation, the type of the solvent, the operating temperature and pressure, the type and concentration of impurities and tailor-made additives, degree of mixedness, geometry and the mode of operation of the crystallizer, and seeding and feeding policies. In addition to these variables, the implementation of external control either in the form of a feedback controller or an optimal control policy can further improve the product quality. In Part 1 of the present communication, an attempt is made to present a systematic approach to investigate the effect of various operating conditions, i.e., the design of the crystallization processes, on the product quality. In particular the effect of the solvent in terms of the solubility and its ability to participate in forming hydrogen bonds with the solute molecules will be studied. The effect of mixing, the seeding policy, and the design of the feed system on the product quality will also be discussed. Experimental results are presented to demonstrate the effect of the operating conditions in improving the filterability and solid bulk density of ranitidine hydrochloride and another pharmaceutical compound. In Part 2, the effect of the “external control” on the product quality will be discussed.",10.1021/op050049v,0
Process Enabling and the Scale-Up of 6β-Hydroxymethylsulbactam and Its Esters,The optimization of the synthesis of 6β-hydroxymethylsulbactam is described. The primary challenge in this synthesis is the installation of the 6β-hydroxymethyl group with the proper stereochemistry. Engineering challenges associated with the addition of gaseous formaldehyde to a Grignard reagent at low temperature and a number of approaches to achieving the appropriate β-stereochemistry are presented.,10.1021/op050047a,0
"Aqueous Kolbe−Schmitt Synthesis Using Resorcinol in a Microreactor Laboratory Rig under High-p,T Conditions","The aqueous Kolbe−Schmitt synthesis using resorcinol to yield 2,4-dihydroxy benzoic acid was performed in a microreactor rig. This small-scale plant was equipped initially with one capillary reactor and one microstructured cooler only. Later, two upgraded versions were constructed, having in addition a microstructured cooler and a microstructured mixer, respectively. The chemical protocol was significantly varied as compared to standard laboratory operation as described in the literature. Higher temperatures (up to 220 °C) and pressures (up to 74 bar) were employed in a facile manner, termed high-p,T processing. In this way, the reaction time could be shortened by orders of magnitude, from about 2 hours to less than one minute, in some cases to some seconds. This resulted in a remarkable increase of the space-time yield by a factor of 440 at best. Productivity was in the L/h range and yielded at best 111 g/h product, corresponding to 4 t/a. Scale-out solutions are indicated. Drawbacks of the microreactor operation were also identified such as high sensitivity to fouling and delicate regulation of the system pressure, leading to partly unstable plant operation. Possibly even a considerable part of the product was rearranged to 2,6-dihydroxybenzoic acid and then thermally decomposed under the harsh reaction conditions. Solutions to overcome or at least diminish these restrictions are envisaged, and in the hope that this may be achieved, a process innovation and business perspective for the high-p,T microreactor processing is depicted.",10.1021/op050045q,0
"Development of a Novel Synthetic Process for 2-Deoxy-3,5-di-<i>O</i>-<i>p</i>-toluoyl-α-<scp>l</scp>-ribofuranosyl Chloride:  A Versatile Intermediate in the Synthesis of 2‘-Deoxy-<scp>l</scp>-ribonucleosides","A novel synthetic route to 2-deoxy-3,5-di- O - p -toluoyl-α- l -ribofuranosyl chloride ( 1 ) from inexpensive d -xylose ( 3 ) is described. 1 is a key intermediate in the synthesis of the antiviral agent 1-(2-deoxy-β- l -ribofuranosyl)thymine (β- l -thymidine) (2) and other 2 ‘-deoxy- l -ribonucleosides. This seven-step synthesis employs a key conversion of the d to the l configuration of the sugar moiety ( 6 to 7 in Scheme 1) using simple reagents and reaction conditions. The entire process involves only three isolation steps. The key compound ( 1 ) was produced in 11% overall yield without chromatography.",10.1021/op0500436,1
"Evaluation of Kilogram-Scale Sonagashira, Suzuki, and Heck Coupling Routes to Oncology Candidate CP-724,714","The synthesis of the anti-cancer compound 2-methoxy- N -(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}- E -allyl)acetamide (CP-724,714) ( 1 ) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.",10.1021/op050039u,1
"BP Process Safety Series. IChemE:  Rugby, 2004 (A) Hazards of Water. £15. ISBN 0-85295-466-2. (B) Hazards of Steam. £15. ISBN 0-85295-468-9. (C) Hazards of Air and Oxygen. £15. ISBN 0-85295-467-0. (D) Hazards of Nitrogen and Catalyst Handling. £15. ISBN 0-85295-469-7.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBP Process Safety Series. IChemE: Rugby, 2004 (A) Hazards of Water. £15. ISBN 0-85295-466-2. (B) Hazards of Steam. £15. ISBN 0-85295-468-9. (C) Hazards of Air and Oxygen. £15. ISBN 0-85295-467-0. (D) Hazards of Nitrogen and Catalyst Handling. £15. ISBN 0-85295-469-7.Cite this: Org. Process Res. Dev. 2005, 9, 4, 520Publication Date (Web):April 6, 2005Publication History Published online6 April 2005Published inissue 1 July 2005https://doi.org/10.1021/op0500382Copyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views126Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (12 KB) Get e-AlertsSUBJECTS:Atmospheric chemistry,Lipids,Nitrogen,Safety,Water Get e-Alerts",10.1021/op0500382,0
"Chemical Process Equipment:  Selection and Design, 2nd edition By J. R. Couper, W. R. Penney, J. R. Fair, S. M. Walas. Elsevier/Gulf Professional Publishing:  Oxford. 2005. 814 + xvii pp. £125. ISBN 0-7506-7510-1.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTChemical Process Equipment: Selection and Design, 2nd edition By J. R. Couper, W. R. Penney, J. R. Fair, S. M. Walas. Elsevier/Gulf Professional Publishing: Oxford. 2005. 814 + xvii pp. £125. ISBN 0-7506-7510-1.Cite this: Org. Process Res. Dev. 2005, 9, 3, 373–374Publication Date (Web):April 6, 2005Publication History Published online6 April 2005Published inissue 1 May 2005https://doi.org/10.1021/op050036hCopyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views688Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (21 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Crystallization,Fluids,Heat transfer,Separation science Get e-Alerts",10.1021/op050036h,0
Side Reactions in Organic Synthesis:  A Guide to Successful Synthesis Design By F. Zaragoza Dörwald. Wiley VCH:  Weinheim. 2005. 374 pp. £65.00 (Paperback). ISBN 3-527-310215.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTSide Reactions in Organic Synthesis: A Guide to Successful Synthesis Design By F. Zaragoza Dörwald. Wiley VCH: Weinheim. 2005. 374 pp. £65.00 (Paperback). ISBN 3-527-310215.Cite this: Org. Process Res. Dev. 2005, 9, 3, 372–373Publication Date (Web):March 12, 2005Publication History Published online12 March 2005Published inissue 1 May 2005https://doi.org/10.1021/op0500281Copyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views143Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (21 KB) Get e-AlertsSUBJECTS:Organic reactions,Organic synthesis,Physical and chemical processes,Post-translational modification,Selectivity Get e-Alerts",10.1021/op0500281,0
"Organometallics in Process Chemistry Edited by R. D. Larsen. Springer-Verlag:  Heidelberg, Germany. 2004. 299 pp. $229.00. ISBN 3-540-01603-1 (also available in electronic version via springerlink.com)","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTOrganometallics in Process Chemistry Edited by R. D. Larsen. Springer-Verlag: Heidelberg, Germany. 2004. 299 pp. $229.00. ISBN 3-540-01603-1 (also available in electronic version via springerlink.com)Cite this: Org. Process Res. Dev. 2005, 9, 3, 372Publication Date (Web):March 12, 2005Publication History Published online12 March 2005Published inissue 1 May 2005https://doi.org/10.1021/op0500279Copyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views181Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (21 KB) Get e-AlertsSUBJECTS:Cross coupling reaction,Organometallic chemistry,Palladium,Process chemistry Get e-Alerts",10.1021/op0500279,0
The Preparation of Single Enantiomer 2-Naphthylalanine Derivatives Using Rhodium−Methyl <i>BoPhoz</i>-catalyzed Asymmetric Hydrogenation,"The single enantiomers of 2-naphthylalanine and N - tert -butoxycarbonyl 2-naphthylalanine were prepared from 2-naphthaldehyde. The sequence has been optimized and run on multikilogram scale, with the key step the asymmetric hydrogenation of methyl 2-acetamido-3-(2-naphthyl)propenoate using the rhodium complex of the methyl BoPhoz ligand, which proceeded smoothly at scale with 97.9% ee. Enhancement to >99.5% ee was achieved by crystallization of the methyl 2-amino-3-(2-naphthyl)propanoate methanesulfonic acid addition salt, the product of acidic deacylation of the hydrogenation product. This protocol for enantiomeric purity enhancement appears to be general for these types of amino acid derivatives. Subsequent transformations did not effect the enantiomeric purity, affording the desired products in >99.5% ee.",10.1021/op050026g,1
"An Improved, Scalable, and Impurity-Free Process for Tolterodine Tartrate","Tolterodine tartrate is an anticholinergic muscle relaxant used to treat urinary frequency, urinary urgency, and incontinence in people with unstable bladders. An improved, cost-effective, and impurity-free process for tolterodine tartrate suitable for large-scale commercial production is described here by addressing various scale-up and impurity issues.",10.1021/op050024w,1
Two-Step Catalytic Oxidative Dehydrogenation of Propane:  An Alternative Route to Propene,"The use of solid oxygen carriers (SOCs) in catalytic dehydrogenation may provide a more efficient production process for small alkenes by shifting the equilibrium to the product side. In this paper we use dynamic simulations to investigate the feasibility of two-step oxidative dehydrogenation of propane to propene using a SOC. The proposed process is carried out in a cyclically operated fixed-bed reactor, filled with a mixture of a dehydrogenation catalyst and a SOC. In the first step (the dehydrogenation), propane is fed to the reactor. The SOC oxidises the hydrogen produced during the dehydrogenation. In the second step, the SOC is regenerated and the accumulated coke burned off by allowing oxygen into the reactor. We determine the cyclic steady states by simulating the process for different feed temperatures and SOC concentrations, and we show that addition of a SOC to a reactor filled with dehydrogenation catalyst increases the conversion of propane and enhances the selectivity towards propene.",10.1021/op050020r,0
"Synthesis of a Substance P Antagonist:  An Efficient Synthesis of 5-Substituted-4-<i>N,N</i>-dimethylamino-1,2,3-triazoles","A highly efficient synthesis of the substance P antagonist 1 is reported starting from the optically pure morpholine acetal derivative 2 . The 5-dimethylaminomethyl-1,2,3-triazole moiety is elaborated via a 1,3-dipolar cycloaddition between an activated acetylenic intermediate and sodium azide. Two approaches to the construction of the triazole moiety of 1 have been designed. The first approach is linear affording the side chain in four steps and 85−92% overall yield. The reactive acetylenic aldehyde 5 allowed for a mild azide cyclization. A simple reductive amination of the triazole aldehyde completed the synthesis of 1 . An alternative, more efficient, convergent synthesis using analogous methodology developed from the linear synthesis was designed to improve the overall efficiency of the process as well as remove the concerns with the handling of azide. The triazole adduct was prepared offline in a two-step, one-pot operation as the building block 4- N,N -dimethylaminomethyl-1,2,3-triazole-aldehyde 3 . Formylation of N,N -dimethylaminopropyne and azide cyclization were carried out as a through process to afford the triazole aldehyde 3 in 90% assay yield. The product was isolated in overall yields ranging from 67 to 81% depending on method. The aldehyde group of 3 was used for coupling to the morpholine building block through a reductive amination with NaBH(OAc) 3 in near quantitative yield to afford the substance P antagonist 1 as a hydrochloride salt in 95% yield from 2 .",10.1021/op050019s,1
Ion-Exchange Resin Catalysis in Benign Synthesis of Perfumery Grade <i>p</i>-Cresylphenyl Acetate from <i>p</i>-Cresol and Phenylacetic Acid,"p-Cresyl phenyl acetate is a very important perfume that finds wide applications and possesses an organoleptic character similar to those of honey, nuts, and butter. It is produced by mineral acid-catalyzed esterification of p -cresol with phenylacetic acid. Use of homogeneous acid catalysts leads to posttreatment pollution problems apart from the quality-related issues. The current work is focused with an eco-friendly and benign catalytic process, employing the solid acid catalysts such as dodecatungstophosphoric acid (DTP) supported on K-10 clay, ion-exchange resins, sulfated zirconia, etc. for esterification of p -cresol with phenylacetic acid to p -cresylphenyl acetate. The order of catalytic activity was found to be Amberlyst-15 ≈ Indion-125 > 20% w/w DTP/K-10 > sulfated zirconia. Indion-125 was used for further experiments. It was observed that the catalyst has excellent reusability and that the reaction was 100% selective towards p -cresylphenyl acetate. A pseudo-first-order kinetic model was built up to fit the experimental data, and the apparent activation energy was found to be 9.56 kcal/mol.",10.1021/op0500133,0
"Efficient and Scalable Synthesis of Ethyl 2,6-Dichloro-5-Fluoronicotinoyl Acetate Using the Blaise Reaction as a Key Step<sup>1</sup>","An efficient synthesis of 2,6-dichloro-5-fluoronicotinoyl acetate ( 1 ) has been accomplished in a single step using the Blaise reaction of ethyl bromoacetate with 3-cyano-2,6-dichloro-5-fluoropyridine ( 4 ). Use of methanesulfonic acid as an in situ activator of zinc removed the induction period of the Blaise reaction to render it safe and viable for a large-scale operation.",10.1021/op050012a,1
"Selective Crystallization of an Allylic 7α-Bromide:  A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol Diacetate","An efficient synthesis of (3β)-7-dehydro-1α,25-diacetoxycholesterol ( 1 ) is described. When acetonitrile was used as the crystallizing solvent, only the 7α-bromide 6a was isolated and bromide 6a was prepared in a 69% yield starting from 3β-TBDMS-1α,25-diacetoxycholesterol ( 5 ). Dehydrobromination with sym -collidine led to the regioselective formation of only the 5,7-diene 7 . After deprotection with concentrated hydrochloric acid, the diene diacetate 1 was obtained in an overall yield of 44% without chromatographic separations. When tetrabutylammonium fluoride trihydrate was used as the base, the 7β-fluoride 10 was isolated.",10.1021/op050009r,1
Towards a PAT-Based Strategy for Crystallization Development,"A strategy for the rapid, material-efficient development of crystallization processes centred around the use of process analytical technology (PAT) is presented and demonstrated on an active pharmaceutical ingredient (API) currently in development at Pfizer's Sandwich laboratories. PAT is implemented at scales as small as 1 mL in high-throughput equipment, enabling the early acquisition of key data to select the best crystallization approach. At a larger scale, PAT offers a window into process kinetics and, for the case study discussed in this contribution, highlighted vulnerabilities of the process arising from the formation of a labile solvate. A combination of on-line and off-line analyses provided the basis for a full assessment of the process.",10.1021/op0500077,0
Synthesis of Alkyl Aryl Ethers by Catalytic Williamson Ether Synthesis with Weak Alkylation Agents,"For almost 70 years, there have been attempts to advance the Williamson ether synthesis process to allow the use of low-cost, noncarcinogenic, weak alkylating agents and avoid salt production. These attempts to produce a “green” version of Williamson ether synthesis have been based on the use of weak alkylating agents such as carboxylic acid esters at relatively high temperatures (approximately 200 °C) and pressures. However, none of the processes considered was suitable for industrial application because of the high concentration of the alkali metal carboxylates required. By increasing the temperature to above 300 °C, it has now proved possible to carry out Williamson ether synthesis as a homogeneous catalytic process. The large temperature increase significantly boosts the alkylating power of weak alkylating agents such as alcohols, carboxylic acid esters, and ethers derived from weak Brönsted acids, which are only weak alkylating agents at room temperature. At such temperatures, carboxylic acid esters such as benzoic acid methyl ester or acetic acid methyl ester demonstrate the alkylating power usually expected of alkylating agents derived from strong acids. In the catalytic cycle of this new process, for example, the low-cost alcohol methanol and phenol were converted into anisole and water at 320 °C via the intermediate methyl benzoate in the presence of catalytic quantities of alkali metal benzoate and phenolate. The catalytic Williamson ether synthesis (CWES) at high temperatures is especially well-suited for the production of alkyl aryl ethers such as anisole, neroline, and 4-methyl anisole which are of industrial importance. Selectivity values of up to 99% have been reached.",10.1021/op050001h,0
Alternate Synthesis of a β-3 Adrenergic Receptor Agonist,"Previously our group reported synthetic efforts used to synthesize kilogram quantities of the β-3 receptor agonist ( R )-(4-(2-(2-(6-aminopyridin-3-yl)-2-hydroxyethylamino)ethoxy)phenyl)acetic acid, 1 . Additional research was conducted to explore an alternate chiral route with a streamlined protecting group scheme. The alternate asymmetric process and synthetic rationale are described.",10.1021/op0499775,1
Practical One-Pot Synthesis of <i>N</i>-(<i>tert</i>-Butoxycarbonyl)sulfamide from Chlorosulfonyl Isocyanate via <i>N</i>-(<i>tert</i>-Butoxycarbonyl)aminosulfonylpyridinium Salt,"An efficient and practical process for the one-pot synthesis of N -( tert -butoxycarbonyl)sulfamide ( 4 ), a raw material for the aminosulfamoyl-containing side chain 3 of a novel carbapenem antibiotic doripenem hydrate (S-4661: 1 ), is described. In the previous process, chlorosulfonyl isocyanate was converted to N -( tert -butoxycarbonyl)aminosulfonyl chloride ( 7 ), an extremely unstable intermediate against moisture, which afforded the target compound 4 using liquid ammonia at cryogenic temperatures in 90% isolated yield. The use of liquid ammonia required cryogenic reaction temperatures because of heat generated from the highly exothermic reaction and the low boiling point of ammonia. In the improved process, the deactivation of the sulfonyl chloride 7 with pyridine at 0 °C afforded water-resistant N -( tert -butoxycarbonyl)aminosulfonylpyridinium salt ( 8 ) which was converted in situ to the target compound 4 in the presence of water at 0 °C in 90−96% isolated yields. Aqueous ammonia can be used, and no cryogenic temperatures are necessary for this new one-pot process.",10.1021/op0499728,1
Online Spectroscopy and Multivariate Data Analysis as a Combined Tool for Process Monitoring and Reaction Optimization,"Multivariate modeling and spectroscopy taken together constitute a powerful tool applicable to both process monitoring and to process and reaction optimizing. The present article establishes how near-IR spectroscopy utilizing a fiber-optical transmission probe can be combined with principal component analysis to extract concentration profiles from a set of spectra recorded during the course of a reaction. Moreover, it is demonstrated how to easily determine the end-point (optimized reaction time, that is, the minimized time) of a reaction, and a simple calibration for quantitative analysis is demonstrated.",10.1021/op049971f,0
Novel Innovation Systems for a Cellular Approach to Continuous Process Chemistry from Discovery to Market,"Continuous processing of liquid/liquid synthesis and microreaction technology are shown to reduce the cost of process development and manufacturing of active pharmaceutical ingredients and other functional molecules on a commercial scale. Combinatorial synthesis systems for continuous chemistry are introduced, and their applications are described. Reactions within these systems scale seamlessly in standardized commercial continuous synthesis equipment allowing rapid access to kilogram quantities of advanced intermediates. Chemical and process development within such systems are illustrated by a case study of a continuous multistep process. Additionally, another case study shows the benefit of microreaction technology in the manufacture of high value added functional chemicals.",10.1021/op049970n,0
Process Research and Scale-Up for a β-3 Adrenergic Receptor Agonist,"A scaleable synthesis of the β-3 adrenergic receptor agonist, (4-{2-[2-(6-aminopyridin-3-yl)-(2 R )-hydroxy-ethylamino]ethoxy}phenyl)acetic acid is presented. The key coupling step utilizes a silyl-protected β-hydroxy tosylate to alkylate a primary amine, thus avoiding water-soluble intermediates and reducing unwanted side products. Deprotection strategies and isolation of a zwitterionic species are described.",10.1021/op049969o,1
"Pilot-Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist. Part 2. Synthesis of <i>N</i>-[2-(5-Hydroxy-4,6-tetrahydropyrimidine)]-3-amino-5-hydroxybenzoic Acid","Studies directed toward the process research and development of a scalable method for preparing tetrahydropyrimidine 2, a key intermediate to the α v β 3 integrin antagonist 1, are described. A linear approach employing 3-amino-5-hydroxybenzoic acid, methyl isothiocyanate, and 1,3-diaminopropan-2-ol as key reagents is detailed. The results of process development research, a successful pilot run, and a production campaign are explained.",10.1021/op049968w,1
"An Improved Synthesis of the Selective Matrix Metalloproteinase Inhibitor, Ro 28-2653","An efficient synthesis of Ro 28-2653, a selective matrix metalloproteinase inhibitor, has been developed. The title compound was prepared in four steps and 76% overall yield from 4-biphenylacetic acid. The key, barbituric acid formation step was significantly improved by using 2-propanol and potassium tert -butoxide as the solvent and base, respectively, instead of the typical ethanol and sodium ethoxide combination.",10.1021/op049965j,1
Efficient Fast Screening Methodology for Optical Resolution Agents:  Solvent Effects Are Used To Affect the Efficiency of the Resolution Process,"An efficient and fast screening methodology for optical resolution agents through the classical crystallization of the corresponding diastereomeric salts is described. In this contribution, we demonstrate that the determination of the eutectic composition by chiral analysis of the corresponding mother liquor (ML) obtained under appropriate experimental conditions provides us with a very fast screening methodology. We also demonstrate that solvent can have a profound effect not only on the efficiency of the resolution process by modifying the eutectic composition but also on the ease of crystallization.",10.1021/op0499627,0
"The Highly Selective Equatorial Hydride Delivery by Biocatalysis:  Chemoenzymatic Synthesis of <i>trans</i>-2-(4-Propylcyclohexyl)-1,3-propanediol via <i>cis</i>-4-Propylcyclohexanol","4-Propylcyclohexanone 10a (69 g/L) is reduced by the catalysis of Galactomyces geotrichum JCM 6359 using i -PrOH (4.0 equiv) as an auxiliary substrate for recycling externally supplemented NAD + (0.001 equiv) in 40 mM potassium phosphate buffer (pH 7.5) for 20 h to provide a mixture of cis -4-propylcyclohexanol 3a [ cis / trans (99:0.5); 74%] and unconsumed 10a (22%). Practically pure 3a can be isolated in 69% yield after removing the entailed ketone 10a via bisulfite adduct formation. In the meantime, the crude reduction product [ 3a / 10a (74:22)], without further purification, can be elaborated into trans -2-(4-propylcyclohexyl)-1,3-propanediol 1a, a compound deemed versatile in liquid-crystals development, in 30% overall yield from 10a in four steps.",10.1021/op049961e,1
Drying an Organic Monohydrate:  Crystal Form Instabilities and a Factory-Scale Drying Scheme to Ensure Monohydrate Preservation,"This contribution discusses the laboratory results and factory-scale drying of an organic monohydrate with therapeutic qualities. The crystal form instabilities of this monohydrate are discussed with respect to undesired dehydrated crystalline species and an IPA solvate. To reproducibly determine the end-of-drying while ensuring deliverable monohydrate is produced, a factory-scale drying scheme in which a dew-point hygrometer is used to measure the water content of the dryer vapor effluent online was shown to be effective. This online measurement technique obviates the need for repeated sampling from the dryer and is a low-cost alternative to near-infrared (NIR) spectroscopy monitoring systems. This novel factory-scale drying scheme was successful in determining the end-of-drying while ensuring preservation of the desired monohydrate for four 20−30 kg batches. Also, drying curves were produced from the recorded dew-point data by an iterative approach.",10.1021/op049956a,0
Approaches to a Scaleable Synthesis of CH8757:  A Potent Inhibitor of Matrix Metalloproteinases,"The synthesis of the matrix metalloproteinase (MMP) inhibitor CH8757 is described. The discovery route has been modified to incorporate a three-stage one-pot sequence using α,α,α-trifluorotoluene as solvent. The formation of the hydroxamic acid using oxalyl chloride is catalysed by DBU, thus avoiding the use of DMF, which may form the highly toxic byproduct, dimethylcarbamoyl chloride.",10.1021/op049954q,1
"Development of a Manufacturing Process for Sibenadet Hydrochloride, the Active Ingredient of Viozan","A process for commercial manufacture of the dual D 2 -β 2 receptor agonist sibenadet hydrochloride has been developed. The process relies upon introduction of operationally simple chemistry at the final stages where two key intermediates are reacted to assemble the final molecule, isolated by crystallization. A nine-stage sequence for synthesis of the key amine hydrochloride intermediate was developed, and modifications to the original process are described. Major strategic improvements were made in definition of the final route to the “side chain” precursor molecule, the second key intermediate, hinging around a thiyl radical addition and subsequent high-yielding telescoped processes for synthesis of this highly crystalline benzoate ester. Development of these chemistries is discussed, together with some issues surrounding definition of the final validated commercial processes.",10.1021/op049953y,1
Demethylation of 4-Methoxyphenylbutyric Acid Using Molten Pyridinium Hydrochloride on Multikilogram Scale,"4-Methoxyphenylbutyric acid ( 2 ) is smoothly demethylated in 3 h at 180 °C when melted with pyridinium hydrochloride (Pyr·HCl), affording 4-hydroxyphenylbutyric acid ( 3 ), a key starting material for the preclinical candidate LY518674 ( 1 ). The adaptation of this chemistry to 22-L and pilot-plant scale is described, including findings to facilitate product isolation, selection of a compatible extraction solvent, and observation of an unusual relationship between the number of solvent extractions and the Pyr·HCl stoichiometry. To the best of our knowledge, this represents the first literature report of the use of this classic demethylation chemistry on multikilogram scale.",10.1021/op0499526,0
An Efficient Synthesis of 2-Quinoxalinecarboxylic Acid,"Development of a cost efficient and scaleable process for 2-quinoxalinecarboxylic acid is described. The primarily goals of the development work were to improve the overall yield of the process, to minimize the use of environmentally unacceptable materials, and to obtain a material with a high level of purity. A variety of approaches were examined, and the most efficient method was a condensation of o -phenylenediamine with a monosaccharide followed by a mild peroxide oxidation.",10.1021/op049951d,1
A Practical Building Block for the Synthesis of Discodermolide,"A new highly diastereoselective and practical route to the lactone 6a which is used as a key building block for the total synthesis of the microtubule-stabilizing anticancer agent discodermolide is reported. This exploits the chiral auxiliary (4 R )-4-isopropyl-5,5-diphenyloxazolidin-2-one ( 7 ) which conveys crystallinity to the synthetic intermediates throughout the entire process. Purifications can thus be performed by recrystallization, avoiding chromatography to afford the final product in high enantiomeric purity. The overall efficiency is augmented by the facile recovery of the auxiliary by precipitation at the end of the sequence.",10.1021/op049950l,1
First Safe and Practical Synthesis of 2-Amino-8-hydroxyquinoline,"The first safe and efficient synthesis of the important building block 2-amino-8-hydroxyquinoline ( 1 ) is described. Starting from the readily available N -oxide 3 of the cheap bulk chemical 8-hydroxyquinoline ( 2 ), the target compound is obtained in a two-step one pot procedure in good overall yield (53−66%) and purity (>98%) on a kilogram scale without chromatography.",10.1021/op049944p,0
Development of an Efficient Synthesis for a Nipecotate-Containing Immunopotentiator,The preparation of Elanco Animal Health immunopotentiator ( S )-ethyl-1-(2-thiopheneacetyl)-3-piperidinecarboxylate ( 1 ) is described. The synthesis includes a new resolution of racemic ethyl nipecotate with dibenzoyl- l -tartaric acid. The resolved salt is found to couple directly with commercially available 2-thiopheneacetyl chloride under environmentally friendly Schotten−Baumann conditions to afford the amide in high yield. The final product is an oil which is purified by wiped film evaporative distillation.,10.1021/op049941c,0
Lawesson's Reagent:  A New Entry in the Preparation of 2-Azetidinones,Lawesson's reagent is found to be a unique reagent that provides a convenient route for the synthesis of β-lactams from Schiff's bases and alkoxy/aryloxy acetic acids. The process involves the formation of a titanium enolate of a mixed anhydride followed by condensation with imine to afford β-lactam.,10.1021/op049939l,0
"A Practical Synthesis of 3,4-Dimethoxy-<i>o</i>-toluic Acid","A streamlined, telescoped process has been developed for the preparation of 3,4-dimethoxy- o -toluic acid, starting with economical and readily available 2,3-dimethoxybenzaldehyde. Catalytic reduction of the aldehyde functional group generated dimethoxytoluene, which was brominated in situ. The resultant aryl bromide was isolated, converted into a Grignard reagent, and transformed into a carboxylic acid with dry ice. The process was demonstrated on a pilot-plant scale.",10.1021/op049938t,0
An Efficient Amination Method for Manufacturing Cytidines,A novel method for amination of uridine derivatives was developed and applied to the syntheses of cytidines. The method consists of an activation step with 1-methylpiperidine at the C 4 -position of a uracil base. Large-scale preparation of 2‘-deoxycytidine was performed using this method.,10.1021/op0499371,1
Successful Development and Scale-up of a Palladium-Catalysed Amination Process in the Manufacture of ZM549865,"Key steps in the synthesis of ZM549865 (a 5-HT receptor antagonist) are the palladium-catalysed amination of ethyl 8-bromo-6-fluoro-4-oxo-4 H -2-chromenecarboxylate and subsequent hydrolysis of the ester group. The development of a simple, robust process capable of making multikilogram amounts of the required intermediate is described. Performing the amination step at 125 °C instead of 80 °C and optimising the hydrolysis conditions led to an increase in overall yield from 44% to about 70% as well as reducing the reaction time from days to hours. The chromone ring was initially constructed by reaction of 2-bromo-4-fluorophenol with dimethyl acetylenedicarboxylate followed by cyclisation. A potentially cheaper route was developed that involved formation of a substituted acetophenone via the Fries rearrangement, followed by condensation with diethyl oxalate and cyclisation.",10.1021/op0499369,1
Streamlined Processes for the Synthesis of a Farnesyl Transferase Inhibitor Drug Candidate,"As part of a fast-paced oncology program, quinolinone 1 was discovered and developed as a potent inhibitor of farnesyl transferase for the treatment of cancer. The initial synthesis, which suffered from a lengthy linear sequence and a late-stage chromatographic resolution, was deemed not amenable to large-scale production. While investigating alternate routes to address these issues, the original synthesis was successively improved and streamlined. This enabled route supplied the timely production of drug substance required to support early toxicological and clinical studies. Several iterations of the process were made, and as a result of these improvements, an efficient four-step sequence was developed for the synthesis of quinolinone d -tartrate 2 starting from readily available outsourced intermediate 5 in 26% overall yield, including a classical resolution. The key features of the synthesis include a Castro−Stevens coupling, an imidazole Grignard addition, and a concomitant classical resolution/final salt formation with d -(−)-tartaric acid.",10.1021/op049935g,1
"ChemProject:  A Valuable, Easy-To-Use Tool for COGS Calculations in Chemical Process Research and Development","In this paper, we describe the software “ChemProject” which is used to perform cost of goods (COGS) calculations. Then, we exemplify its use by comparing the COGS of a synthesis before and after process development.",10.1021/op049933w,1
Reinvestigation of Phase-Transfer-Catalyzed Chlorpyrifos Synthesis,"Production of chlorpyrifos via the phase-transfer-catalyzed reaction of O, O -diethylphosphorochloridothioate and the sodium salt of 3,5,6-trichloropyridin-2-ol was reinvestigated. The formation of sulfotep (the major byproduct) and the yield are influenced by the nature and concentration of the catalysts, temperature, stirring rate, and time of the reaction. The elucidation of the roles of different parameters influencing the end of the reaction have permitted us to perform the synthesis of chlorpyrifos on bench scale (0.3 M scale) under optimized conditions using the minimum amounts of catalysts (0.5 mol %) with 92% yield and 98.5% purity.",10.1021/op049929k,0
<i>SPECIAL FEATURE SECTION:  <u>NEW TECHNOLOGIES IN PROCESS RESEARCH</u></i>,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: NEW TECHNOLOGIES IN PROCESS RESEARCHUlf TilstamView Author Information Lilly Development Centre S.A.,B-1348 Mont-Saint-Guibert, Belgium Cite this: Org. Proc. Res. Dev. 2004, 8, 3, 421Publication Date (Web):April 21, 2004Publication History Published online21 April 2004Published inissue 1 May 2004https://pubs.acs.org/doi/10.1021/op049928shttps://doi.org/10.1021/op049928seditorialACS PublicationsCopyright © 2004 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views410Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (12 KB) Get e-AlertscloseSUBJECTS:Catalysts,Chemical reactions,Industrial manufacturing,Microreactors,Pharmaceutics Get e-Alerts",10.1021/op049928s,0
"Practical Large-Scale Synthesis of Cefmatilen, A New Cephalosporin Antibiotic","A practical large-scale process for the synthesis of cefmatilen hydrochloride hydrate ( 1 ), a new oral cephalosporin antibiotic, is described. Several impurities are isolated from a bulk drug and identified. Side reactions are discussed in order to prevent them. The conditions were optimized to control the formation of impurities. The process is amenable to a multikilogram-scale preparation. Several kilograms of compound 1 for clinical trials were successfully prepared by this process from the three starting materials (7-aminocephem hydrochloride 4, triethylammonium acetate 5, and triazole 7 ) on a pilot scale in overall yields of 61−65% (10−14% higher than those for the previous process).",10.1021/op049920i,1
Development of a Safe and Scalable Oxidation Process for the Preparation of 6-Hydroxybuspirone:  Application of In-Line Monitoring for Process Ruggedness and Product Quality,The development of a safe and scalable oxidation process for the hydroxylation of the azapirone psychotropic agent buspirone ( 1 ) to furnish 6-hydroxybuspirone ( 2 ) is described. A mechanistic understanding of how key process factors affected product quality led to the successful application of FTIR as a process analytical technology (PAT) tool. This enabled real time quality assurance and the development of an effective and efficient manufacturing process. The identification of impurities and the development of recrystallization methods to provide active pharmaceutical ingredients (API) with optimal purity will also be addressed.,10.1021/op049918r,0
“One-Pot” Preparation of<i>N</i>-Carbamate Protected Amino Acids via the Azide,"A convenient and efficient method for the preparation of fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Alloc) amino acids is proposed. This method is particularly attractive due to the fact that the reaction sequence Fmoc/Alloc-chloride to Fmoc/Alloc-azide to Fmoc/Alloc-amino acid can readily be carried out in one pot. A further advantage is the minimization of byproducts, which are easily removed during the workup. Most important, this strategy minimizes the formation of dipeptides that are difficult to remove by crystallization. Thus, Fmoc and Alloc amino acids are obtained in high yield (60−90%) and purity as evidenced by thin-layer chromatography, reversed-phase high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance. 1",10.1021/op049917z,0
Process Development and Pilot-Scale Synthesis of Cefotetan,Strategies that were adopted during the process development of Cefotetan in order to achieve a cost-effective commercial-scale synthesis are described herein. These included replacement of the trifluoroacetic acid used for cleavage of the benzhydryl ester and the development of an alternative synthetic route. This work led to improvement of both the impurity profile and the yield of the process. The pilot-scale synthesis of Cefotetan is described in detail in the Experimental Section. The scaled-up process has been successfully used for the commercial manufacture of Cefotetan since 1983.,10.1021/op049914m,1
Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(<i>N</i>-<i>tert</i>-butoxycarbonyl)pyrrolidine. Part 1. Screening of Metal Catalysts,"A novel synthetic route was devised for 4-aminomethyl-3- Z -methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-( N - tert -butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing ( t -Boc) 2 O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-aminomethyl-3-amino-1-( N - tert -butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in over-reduction of the desired intermediate, 4-aminomethyl-3- Z -methoxyimino 1-( N - tert -butoxycarbonyl)pyrrolidine ( Z -AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-( N - tert -butoxycarbonyl)aminomethyl-3- Z -methoxyimino-1-( N - tert -butoxycarbonyl)pyrrolidine ( Z -BAMBP) rose to as high as 91% over Raney cobalt by suppressing the over-reduction of Z -AMBP to AABP. On the basis of these observations, a CMBP hydrogenation process over Raney cobalt was proposed. Among noble metal catalysts, only Pd was found to show a high activity. Over Pd catalyst, 4-cyano-3-amino-1-( N - tert -butoxycarbonyl)-3,4-pyrroline (CABP) was found to be a major byproduct, while the formation of AABP or 4-( N - tert -butoxycarbonyl)aminomethyl-3-( N - tert -butoxycarbonyl)amino-1-( N - tert -butoxycarbonyl)pyrrolidine (BABABP) was greatly suppressed. The byproduct CABP formed by hydrogenolysis of the methyl group in the methyloxime group in CMBP could be recycled to the original substrate, 1-( N - tert -butoxycarbonyl)-4-cyano-pyrrolidine-3-one (BCPO) by an acid-catalyzed hydrolysis.",10.1021/op049913u,1
Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(<i>N</i><i>-tert</i>-butoxycarbonyl)pyrrolidine. Part 2. The Palladium Catalysts in Acidic Media,"Chemoselective hydrogenation of 4-cyano-3-methoxyimino-1-( N - tert -butoxycarbonyl)pyrrolidine (CMBP) to 4-aminomethyl-3- Z -methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate for gemifloxacin, was investigated over Pd catalysts with in situ acid protection. Addition of more than 1.6 equiv of acidic protons for CMBP was found to drastically elevate both the reaction rate and selectivity to 4-aminomethyl-3- Z -methoxyimino-1-( N - tert -butoxycarbonyl)pyrrolidine ( Z -AMBP) over Pd catalyst with a complete suppression of the major side reaction to 4-cyano-3-amino-1-( N - tert -butoxycarbonyl)-3,4-pyrroline (CABP). Methanol as the organic solvent was found to increase the hydrogenation rate greatly compared to other solvents with a negligible decrease of selectivity. The leaching of Pd by acid and consequent accumulation of Pd ion in the reaction mixture was negligible in CMBP hydrogenation. The novel process of chemoselective CMBP hydrogenation in acidic media over Pd catalyst was thus much simpler yet more efficient compared to the conventional one. The whole AMPM process time starting from 1-( N - tert -butoxycarbonyl)-4-cyanopyrrolidine-3-one (BCPO) could be reduced by at least approximately 15 h which would result in a great reduction of materials such as catalysts, ( t -Boc) 2 O, and solvent. Additionally, reduction of reaction steps improved the overall yield of AMPM significantly. Employment of methanesulfonic acid as an acidic agent in the hydrogenation step allowed an environmentally benign pathway to AMPM by omission of a neutralization step with an extra reduction in process time and materials consumed.",10.1021/op0499122,0
Investigation into the Acidification Process of Zafirluskast Nitroacid Leads to a Surprising Improvement in Product Quality,"An investigation into the acidification step of the zafirlukast nitroacid process was conducted by varying a range of parameters, including acid molarity, addition time, final pH, and temperature. A significant and unexpected improvement in product quality was achieved by using dilute rather than concentrated acid, independent of the final pH, and without a reduction in yield. The change to the dilute-acid process could be accommodated within the constraints of the existing registered process.",10.1021/op049911+,0
Integrated Approach to the Development and Understanding of the Borane Reduction of a Carboxylic Acid,"A delayed exotherm was recorded during the reduction of a carboxylic acid with BH 3 ·THF. This article will describe our efforts to explain and control the observed exotherm using a reactor integrated with a mass-flow meter, a reaction calorimeter, and an in situ FT-IR probe. In the end, a kinetic model is proposed that allows control of the addition rate of the reagent based on the known cooling capacity of the reaction vessel.",10.1021/op049910h,0
The Efficient Synthesis of Disodium Disuccinate Astaxanthin (Cardax),"A practical procedure is described for the multigram preparation of disodium disuccinate derivatives of synthetic astaxanthin (Cardax) [from all- trans -(all- E )-3 S,3‘ S-, meso -(3 R,3‘ S )-, and 3 R,3‘ R -dihydroxy-β,β-carotene-4,4‘-dione) in a 1:2:1 statistical mixture of stereoisomers, as well as from the individual component stereoisomers]. Process development eliminated chromatographic separations, controlled geometric isomerization, and improved the overall yield of the two-step process, with significant improvements in both the yield and purity of Cardax. Bulk chromatographic separation of the diastereomeric dicamphanic acid ester of synthetic astaxanthin was performed by modifications of the published procedure to subsequently generate multigram quantities of each stereoisomer of disodium disuccinate of astaxanthin.",10.1021/op049909i,1
Process Control Limits from a Laboratory Study on the Ni(0)-Mediated Coupling of Ethyl Acrylate with a C-22 Steroidal Iodide:  A Case Study on the Role of Experimental Design in Highly Developed Processes,"An experimental design was used to assess the process robustness in the Ni(0)-mediated coupling of the C-22 steroidal iodide 15 with ethyl acrylate to yield the coupled product 16 . Although the reaction conditions were optimized by empirical means, an experimental design was employed to assess the process sensitivity to certain key factors. Within the experimental space defined by the experimental parameters: moles of ethyl acrylate, moles of water, and moles of nickel chloride hexahydrate, moles of ethyl acrylate was the only significant factor, and no interactive effects were found. The selection of factors was based on mechanistic considerations and from an analysis of competing pathways. The design demonstrated that a potentially capricious reaction was very robust. The predictive equation from the experimental design was used to determine the control limits of the process with respect to the design response, the corrected yield. Process control limits determined from the predictive equation in an experimental design can be used to set realistic process specifications.",10.1021/op049908q,1
"Molar-Scale Synthesis of 1,2:5,6-Di-<i>O</i>-isopropylidene-α-<scp>d</scp>-allofuranose:  DMSO Oxidation of 1,2:5,6-Di-<i>O</i>-isopropylidene-α-<scp>d</scp>-glucofuranose and Subsequent Sodium Borohydride Reduction","Two variants of oxidation with DMSO followed by sodium borohydride reduction have been investigated to make the synthesis of 1,2:5,6-di- O -isopropylidene-α- d -allofuranose ( 4 ) suitable for large-scale manufacturing.",10.1021/op049903t,0
Multi-Kiloscale Enantioselective Synthesis of a Vitronectin Receptor Antagonist,"The development of a novel, cost-effective synthesis of the vitronectin receptor antagonist SB-273005 became necessary as the compound proceeded to Phase 1. A practical synthesis of the compound presented challenges to the process chemist. Chief among the challenges was developing an enantioselective route to the compound. Second was either developing a scalable Mitsunobu coupling of the side chain to the main body or finding alternate chemistry. In this paper we will describe the chemistry we developed which allowed us to make over a hundred kilograms of SB-273005 by a process that we believe is suitable for even larger scale manufacturing.",10.1021/op0499021,1
A Pressure-Resistant Small-Scale Reaction Calorimeter That Combines the Principles of Power Compensation and Heat Balance (CRC.v4),"An improved version of a small-scale reaction calorimeter fitted with an integrated infrared-attenuated total reflection (IR-ATR) probe has been developed. The new device has a sample volume of 20−50 mL, a metal block as an intermediate thermostat and is applicable to higher pressure up to 30 bar. Isothermal conditions are maintained using the power compensation principle. Peltier elements are implemented to compensate the change of the heat-transfer coefficient during the measurement, making time-consuming calibrations unnecessary.The Hastelloy reactor vessel is easily exchangeable and is available with and without the IR-ATR probe. The new combined reaction calorimeter (CRC.v4) has been characterized by using test reactions such as neutralization of NaOH, hydrolysis of acetic anhydride, and acetylation of a substituted benzopyranol. The characteristics of the new equipment and those of an earlier published version are compared.",10.1021/op049900g,0
Development of an Efficient and Scalable Process of a Respiratory Syncytial Virus Inhibitor,"An improved process has been developed for compound 1, a respiratory syncytial virus (RSV) inhibitor. This improved process is convergent, safe, efficient, and useful to prepare compound 1 in kilogram quantities.",10.1021/op049899l,1
Ortho Lithiation of <i>N</i>-Pivaloylfluoroanilines as a Useful Tool for Either Selective Methylation or Benzoxazole Synthesis,"Lithiation of N- pivaloyl-3,4-difluoroaniline ( 1a ) with a slight excess of 2 mole equiv of n -butyllithium followed by methylation was studied. The reaction was found to be useful for either the selective methylation of 3,4-difluoroaniline or the synthesis of benzoxazole derivatives, depending on the reaction temperature. In the reaction of N- pivaloyl-3-chloro-4-fluoroaniline ( 1b ) and N- pivaloyl-3-fluoroaniline ( 1c ), the reaction proceeded rather sluggishly but benzoxazole formation predominated.",10.1021/op0498969,0
Intelligent Electronic Laboratory Notebooks for Accelerated Organic Process R&amp;D,"Pharmaceutical companies are being forced to find methods to dramatically improve their research and development productivity and efficiency. One approach is replacing the paper laboratory notebooks that have been used in the same way for centuries with an electronic system. An intelligent electronic laboratory notebook (ELN) solution that enables better planning, recording, process optimization, and reporting can enable scientists and engineers to make better decisions throughout organic process research and development, while developing enterprise-wide intellectual capital. The intelligent ELN solution supports the workflow of organic process research and development from route selection through process optimization and validation; process engineering and manufacturing; kilo-lab and pilot-plant operations; and to the creation, review, and approval of product specifications. By implementing best practices learned over the past several years, pharmaceutical companies can now achieve successful intelligent ELN deployments that will provide the gains they so desperately need for their employees and shareholders.",10.1021/op049890j,0
A Scaleable Synthesis of Fiduxosin,"Fiduxosin ( 1 ) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4- cis -disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner. A [3+2] cycloaddition of an enantiopure azomethine ylide followed by a diastereoselective crystallization was employed to prepare the benzopyranopyrrolidine in high diastereomeric and enantiomeric purity. Conditions for reduction of an O-aryl lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished in high yield. The thienopyrazine was prepared by condensation of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen substitutive deamination to prepare regiospecific trisubstituted pyrazines will be described.",10.1021/op049889k,1
A New Process for Antineoplastic Agent Clofarabine,"Clofarabine is a promising DNA polymerase inhibitor currently in clinical trials for a variety of liquid and solid tumor indications. The efforts for development of a new manufacturing process for clofarabine are presented. This new process allows for the reliable and efficient production of drug substance in high anomeric excess and high overall purity, without using chromatography. The high anomeric selectivity is achieved by reacting 2-chloroadenine with 1-bromo-2-deoxy-2-fluoro-3,5-di- O -benzoyl-α- d -ribofuranose ( 4 ) and potassium ter t -butoxide in a mixture of three solvents. Following crystallization, anomeric ratios exceeding 50 (β/α) are achieved. Deprotection and additional crystallization afford a clofarabine drug substance containing less than 0.1% of the α-anomer.",10.1021/op049884n,0
Scale-Up and Safety Evaluation of a Sandmeyer Reaction,"A scale-up of a new process for the production of 2-chloro-5-trifluoromethyl-benzonitrile by a Sandmeyer reaction of 2-Chloro-5-trifluoromethylaniline with copper cyanide/sodium cyanide is described. To ensure a safe implementation, a safety evaluation of the process was carried out, which is described in the following. The new process gives a better working environment and better productivity due to shorter reaction time.",10.1021/op0498823,0
Green Engineering:  Environmentally Conscious Design of Chemical Processes By David T. Allen and David R. Shonnard. Prentice Hall PTR:  New Jersey. 2002. 552 pp. £51.99. ISBN 0-13-061908-6.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTGreen Engineering: Environmentally Conscious Design of Chemical Processes By David T. Allen and David R. Shonnard. Prentice Hall PTR: New Jersey. 2002. 552 pp. £51.99. ISBN 0-13-061908-6.Peter L. SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, UKCite this: Org. Proc. Res. Dev. 2004, 8, 6, 1083Publication Date (Web):July 8, 2004Publication History Published online8 July 2004Published inissue 1 November 2004https://doi.org/10.1021/op049881aCopyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views556Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (31 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Environmental pollution,Green chemistry,Physical and chemical processes,Physicochemical properties Get e-Alerts",10.1021/op049881a,0
"Facile and Practical Synthesis of 2,6-Dichloropurine","A facile and industrially viable process for preparation of 2,6-dichloropurine is reported. The process involves direct chlorination of xanthine with phosphorus oxychloride and a weak nucleophilic organic base, such as amidine, guanidine base, or Proton-Sponge.",10.1021/op049878r,0
Regioselective Synthesis of 1-Aklyl-4-(3-pyridyl)-Substituted Imidazole,"A practical and regioselective synthesis of 1-alkyl-4-(3-pyridyl) imidazole via a Suzuki coupling reaction employing 3-pyridylboronates has been investigated. The use of sec -butyllithium in place of n -butyllithium for complete selectivity in removing bromines on tribromoimidazole to provide a key bromoimidazole coupling unit is described. For effective Suzuki coupling reaction, the nature of pyridylboronates and the conditions employed are discussed. The factors affecting the outcome of the Suzuki coupling reaction are presented.",10.1021/op0498767,0
High-Throughput Experimentation in Pharmaceutical Process R&amp;D:  Developing a New Software Workflow to Overcome Downstream Data-Analysis Bottlenecks and Improve Productivity,"A new software workflow is described to overcome our data analysis, data-modification, and visualisation bottlenecks. Through a combination of in-house and external supplier expertise, a software workflow has been developed to tackle the mass of data generated from high-throughput experimentation. Also described is our solution to high-throughput HPLC reaction analysis. In overcoming these bottlenecks, the productivity of our screening technology has dramatically increased.",10.1021/op049873u,0
A Novel and Efficient Route to Zafirlukast,"Zafirlukast, an important drug for allergic pulmonary disorders such as asthma, is synthesized by a five-step, high-yielding, and inexpensive process.",10.1021/op049869i,1
An Improved Process for the Large-Scale Preparation of Antirheumatic Agent MX-68,"A large-scale preparation route of MX-68, a novel MTX derivative bearing a dihydro-2 H -1,4-benzothiazine moiety and l -homogulutamic acid, is described. The original route that is a laboratory-scale synthesis for preclinical study has been improved. The improved process involves the following features: each step does not use haloalkane solvents, corrosive reagents, and chromatographic purification, and the formation of the major impurity at the final step is minimized. This improvement has enabled us to supply sufficient quantities of MX-68, which is required for both the toxicity test and the clinical study.",10.1021/op049867y,1
Process R&amp;D:  Past and Present,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTProcess R&D: Past and PresentTrevor LairdView Author Information Editor Cite this: Org. Proc. Res. Dev. 2004, 8, 5, 689Publication Date (Web):August 11, 2004Publication History Published online11 August 2004Published inissue 1 September 2004https://pubs.acs.org/doi/10.1021/op0498666https://doi.org/10.1021/op0498666editorialACS PublicationsCopyright © 2004 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views469Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (14 KB) Get e-AlertscloseSUBJECTS:Agrochemicals,Industrial manufacturing,Pharmaceuticals,Physical and chemical processes,Solvents Get e-Alerts",10.1021/op0498666,0
DioRaSSP:  Diosynth Rapid Solution Synthesis of Peptides,"We have developed a novel method for the large-scale manufacturing of peptides in solution called DioRaSSP. It combines the advantages of the homogeneous character of classical solution-phase synthesis with the generic character and the amenability to automation inherent to the solid-phase approach. DioRaSSP is characterized by the fact that intermediates are not isolated. Processes according to this highly efficient synthesis method are easy to scale-up and yield products of reproducible high purity. Moreover, we have recently implemented the first fully automated solution-phase peptide synthesizer for application in processes according to DioRaSSP.",10.1021/op049864l,0
Selective Synthesis of <i>p</i>-Hydroxybenzaldehyde by Liquid-Phase Catalytic Oxidation of <i>p</i>-Cresol,"Liquid-phase oxidation of p -cresol over insoluble cobalt oxide (Co 3 O 4 ) catalyst under elevated pressure of air gave 95% selectivity to p -hydroxybenzaldehyde, an important flavoring intermediate. The selectivity to p -hydroxybenzaldehyde could be enhanced by manipulating the concentrations of p -cresol, sodium hydroxide, and catalyst and the partial pressure of oxygen in such a way that the byproducts normally encountered in this oxidation process were eliminated or minimized significantly.",10.1021/op0498619,0
Acrylate as an Efficient Dimethylamine Trap for the Practical Synthesis of 1-<i>tert</i>-Butyl-4-piperidone via Transamination,"Efficient trapping of dimethylamine was the key to success in the transamination of 1,1-dimethyl-4-oxopiperidinium iodide with tert -butylamine to afford 1- tert -butylpiperidin-4-one in high yield. The use of sodium acrylate was found to provide an elegant way to both trap dimethylamine and provide a convenient method to allow purification in the subsequent extraction.",10.1021/op049860g,1
Synthesis of Methyl Phenyl Glyoxylate via Clean Oxidation of Methyl Mandelate over a Nanocatalyst Based on Heteropolyacid Supported on Clay,"Oxidation is an important class of reaction from both industrial and academic points of view. In recent years, a large number of oxidizing agents have been used for a variety of industrial reactions, but many of them are polluting, giving poor yields. Mandelates have played an important role in organic synthesis and are used in artificial flavoring and perfumes. Methyl phenyl glyoxylate, which contains two carbonyl groups, is an important intermediate used in fine chemical industry. Oxidation of methyl mandelate was carried out to prepare methyl phenyl glyoxylate, with 85% selectivity, by using hydrogen peroxide in the presence of a novel catalyst, namely, 20% w/w Cs 2.5 H 0.5 PW 12 O 40 /K-10 catalyst, which is partly substituted dodecatungstophosphoric acid supported on clay. The catalyst is a nano material and reusable. The workup is easy.",10.1021/op049858p,0
Solid-Supported Continuous Flow Synthesis in Microreactors Using Electroosmotic Flow,"This paper reports the fabrication of a microreactor suitable for use with supported reagents. We demonstrate that the electroosmotic flow can be used to move the reagents over a solid-supported catalyst bed. It is demonstrated that it is important that the support should not swell in organic solvents to obtain reproducible flow, and it is shown that silica supports fulfill this criteria. Silica-functionalised piperazine is used in a variety of Knoevenagel reactions to give the product in high conversion.",10.1021/op049857x,0
Scaleable Syntheses of Isomeric Limonene Aziridines from the Commercially Available Mixture of <i>cis</i>- and <i>trans</i>-Limonene Oxides,A short and efficient route to both isomers of limonene aziridine is described. The process is amenable to scale-up and allows easy access to multigram quantities of these highly useful chiral building blocks.,10.1021/op0498464,0
Practical Process for the Air Oxidation of Cresols:  Part A. Mechanistic Investigations,"The catalytic air oxidation of p -cresol and 2,6-di- tert -butyl-4-methylphenol to the corresponding benzaldehydes was investigated to determine the mechanism at work in these oxidation reactions. A number of intermediates and byproducts, mainly in the form of dimers, were observed during the course of the reactions, and their structures were elucidated by spectroscopic and chromatographic methods. The existence of these compounds in the reaction mixtures, and their proposed methods of formation, provided further insight into the mechanism involved in these oxidations.",10.1021/op049845b,0
Practical Process for the Air Oxidation of Cresols:  Part B. Evaluation of the Laboratory-Scale Oxidation Process,"Mechanistic proposals and predictions made in a preceding paper (Part A) were evaluated by carrying out the catalytic air oxidation of p -cresol in an alternative solvent system, comprising either a mixture of ethylene glycol and acetic acid (for oxidations under acidic conditions) or ethylene glycol and water (for oxidations under basic conditions). The results obtained in these experiments confirmed that ethylene glycol acts as a nucleophile in these solvent systems, thereby stabilizing the quinomethide intermediate and resulting in highly efficient oxidations in both alkaline and acidic media. 4-Hydroxybenzaldehyde, the desired product, was thus obtained in isolated yields of up to 98% and purities >99%. The inherent drawbacks associated with alkaline methanol and aqueous acetic acid solutions were thus circumvented, and the result is a highly efficient process for the production of 4-hydroxybenzaldehyde.",10.1021/op049844j,0
Large Scale Deprotection of a <i>tert</i>-Butoxycarbonyl (Boc) Group Using Aqueous HCl and Acetone,A procedure for tert -butoxycarbonyl (Boc) group removal using concentrated HCl and acetone was developed and utilized on multi-kilogram scale in the synthesis of LY544344·HCl ( 1 ). The details surrounding this procedure and the advantages offered by it are described herein.,10.1021/op049842z,0
"Chemical Process Research:  The Art of Practical Synthesis Edited by Ahmed F. Abdel-Magid and John A. Ragan. ACS Symposium Series 870. American Chemical Society:  Washington, DC. 2004. 211 pp. Price $125. ISBN 0-8412-3824-3.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTChemical Process Research: The Art of Practical Synthesis Edited by Ahmed F. Abdel-Magid and John A. Ragan. ACS Symposium Series 870. American Chemical Society: Washington, DC. 2004. 211 pp. Price $125. ISBN 0-8412-3824-3.W. J. WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Proc. Res. Dev. 2004, 8, 6, 1086Publication Date (Web):September 21, 2004Publication History Published online21 September 2004Published inissue 1 November 2004https://pubs.acs.org/doi/10.1021/op049840ehttps://doi.org/10.1021/op049840ebook-reviewACS PublicationsCopyright © 2004 American Chemical SocietyRequest reuse permissionsArticle Views141Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Addition reactions,Alcohols,Materials,Pharmaceuticals,Photochemical reactions Get e-Alerts",10.1021/op049840e,0
An Efficient Catalytic Asymmetric Route to 1-Aryl-2-imidazol-1-yl-ethanols,"The asymmetric hydrogenation of 1-aryl-2-imidazol-1-yl-ethanones offers a concise route to homochiral 1-aryl-2-imidazol-1-yl-ethanols. Catalytic asymmetric transfer hydrogenation with formic acid using [( R, R )-TsDPEN]Ru(Cymene)Cl as precatalyst was shown to be effective in this transformation. Preliminary process development showed that the hydrogenation could be carried out under mild conditions at a molar substrate-to-catalyst ( S / C ) ratio of 1000−2000.",10.1021/op049838n,0
Minimizing Isobutylene Emissions from Large Scale<i>tert</i>-Butoxycarbonyl Deprotections,"Isobutylene off-gas amounts liberated during the methanesulfonic acid-catalyzed deprotection of N -BOC−pyrrolidine in THF, methanol, ethanol, 2-propanol, toluene, and dichloromethane were measured using on-line gas-phase mass spectroscopy. While one full equivalent of isobutylene was released as an off-gas when THF was used as the reaction solvent, emissions were reduced by 65−95% in other solvents. In alcohol solvents, the corresponding alkyl tert -butyl ethers are formed as byproducts of the reaction as expected. In dichloromethane and toluene, oligomers of isobutylene can be formed under the reaction conditions. These results provided the basis for developing an effective acid/toluene scrubber for isobutylene that was successfully employed on the pilot plant scale.",10.1021/op049837v,0
An Expeditious Scalable Synthesis of (<i>S</i>)-2-Amino-5-methoxytetralin via Resolution,"The first resolution of (±)-2-amino-5-methoxytetralin 1 is achieved via diastereomeric salt formation with ( S )-mandelic acid to give ( S )- 1 ·HCl of 99.7% ee in 29% overall yield from (±)- 1 ·HCl, ( S )- 1 ·HCl being a chiral intermediate to assemble N-0923 2, a potent dopamine D 2 agonist effective against Parkinson's disease. Preparation of (±)- 1 ·HCl involves the Birch reduction of 1,6-dimethoxynaphthalene 3b and reductive amination of 5-methoxy-2-tetralone 4 with aqueous NH 3 over Raney Ni under a hydrogen atmosphere (2.9−3.9 bar) between 70 and 80 °C. With the off-enantiomer ( R )- 1 arising from the resolution, its xylene solution is heated at 130 °C over Raney Co under a hydrogen atmosphere (2.0−2.7 bar) to regenerate (±)- 1 ·HCl in 95% yield, which should enhance the overall throughput of the resolution process.",10.1021/op0498363,1
An Efficient and Safe Procedure for the Large-Scale Pd-Catalyzed Hydrazonation of Aromatic Chlorides Using Buchwald Technology,"A convenient, optimized and safe synthesis of N -arylhydrazines, useful as intermediates for active ingredients in agricultural and pharmaceutical applications, is reported. Starting from aryl halides (chlorides and bromides), a palladium-catalyzed carbon−nitrogen coupling reaction followed by an acidic treatment afforded the target molecules in good to excellent yields using low catalyst loadings. This technology has then been successfully applied on a large scale in a pilot plant. This contribution also describes the major improvements in ligand synthesis and the thermal data required to develop a process on a pilot scale.",10.1021/op049832y,0
"Process Development of (1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>)- Spiro[bicyclo[3.1.0]hexane-2‘,5‘-dioxo-2,4‘-imidazolidine]-6-carboxylic Acid, (<i>R</i>)-α-Methylbenzenemethanamine Salt (LSN344309)","Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1 S,2 S,5 R,6 S )-spiro[bicyclo[3.1.0]hexane-2‘,5‘-dioxo-2,4‘-imidazolidine]-6-carboxylic acid, ( R )-α-methylbenzenemethanamine salt ( 5 ) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Bücherer−Berg's reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with ( R )-(+)-α-methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.",10.1021/op049829e,1
A Novel Eco-Friendly Process for the Synthesis of 2-Chlorobenzylidenemalononitrile and ITS Analogues Using Water As a Solvent,A simple and novel eco-friendly process for the synthesis of 2-chlorobenzylidene malononitrile (CS) and their analogues in water using 1-methyl imidazole (catalyst) has been developed. The reaction conditions for the preparation of CS are optimized for large scale applications.,10.1021/op0498262,0
"Industrial Synthesis of Maxacalcitol, the Antihyperparathyroidism and Antipsoriatic Vitamin D<sub>3</sub> Analogue Exhibiting Low Calcemic Activity","Maxacalcitol, the 22-oxa-derivative of 1α,25-dihydroxyvitamin D 3 and used currently as an antihyperparathyroidism and antipsoriatic drug, has been synthesized in seven chemical steps from 1α-hydroxydehydroepiandrosterone on the basis of our previously developed route. The present synthesis allows the production of the protected form of the penultimate intermediate in 26% overall yield in a kilogram scale reaction employing neither difficult reaction conditions nor chromatographic purification, having overcome all the difficulties involved in the previous route.",10.1021/op049822x,1
<i>SPECIAL FEATURE SECTION:  <u>SOFTWARE FOR APPLICATION IN CHEMICAL DEVELOPMENT AND SCALE-UP</u></i>,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: SOFTWARE FOR APPLICATION IN CHEMICAL DEVELOPMENT AND SCALE-UPDavid LathburyView Author Information AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK Cite this: Org. Proc. Res. Dev. 2004, 8, 6, 964Publication Date (Web):October 21, 2004Publication History Published online21 October 2004Published inissue 1 November 2004https://pubs.acs.org/doi/10.1021/op0498215https://doi.org/10.1021/op0498215editorialACS PublicationsCopyright © 2004 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views393Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (9 KB) Get e-AlertscloseSUBJECTS:Interfaces,Power,Software Get e-Alerts",10.1021/op0498215,0
"Chemical Micro Process Engineering:  Fundamentals, Modelling and Reactions, 10th ed by V. Hessel, S. Hardt, and H. Löwe. Kluwer Academic Publishers:  Dordrecht. 2003. Wiley-VCH:  Weinheim. 2004. xxxviii + 674 pp. £135. ISBN 3-527-30741-9.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTChemical Micro Process Engineering: Fundamentals, Modelling and Reactions, 10th ed by V. Hessel, S. Hardt, and H. Löwe. Kluwer Academic Publishers: Dordrecht. 2003. Wiley-VCH: Weinheim. 2004. xxxviii + 674 pp. £135. ISBN 3-527-30741-9.Cite this: Org. Process Res. Dev. 2005, 9, 1, 122–123Publication Date (Web):November 4, 2004Publication History Published online4 November 2004Published inissue 1 January 2005https://doi.org/10.1021/op0498161Copyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views353Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (20 KB) Get e-AlertsSUBJECTS:Crystallization,Microreactors,Organic reactions,Physical and chemical processes Get e-Alerts",10.1021/op0498161,0
"Development of a Scalable Process for 1-(3,5-Dichlorophenyl)-5-iodo-3-methyl- (4-methylbenzyl)-1<i>H</i>-imidazo[1,2-<i>a</i>]imidazol-2-one:  A Key Intermediate for the Synthesis of LFA-1 Inhibitors","A safe, robust, chromatography-free and reproducible process for the multi-kilogram synthesis of vinyl iodide 2, a key intermediate for the synthesis of LFA-1 inhibitors, was developed and implemented at the pilot plant. Execution of the above process allowed us to support preclinical activities in the LFA-1 program.",10.1021/op049813o,0
Process Development and Scale-up of a Selective α<sub>1</sub>-Adrenoceptor Antagonist,A synthetic route to a potent and selective α-1-adrenergic receptor antagonist has been developed and demonstrated in a pilot plant. The route has been used in two pilot plant campaigns and has produced RO3203546 in 2.3 and 12.0 kg batch sizes. The first pilot plant campaign focused primarily on the end-game of the process with particular emphasis on the development of a method to isolate the active pharmaceutical ingredient (API). The second pilot plant campaign allowed front-end process improvements to be demonstrated. The reiterative process improvements resulted in an economical process with improved throughput and product quality when compared to the original discovery synthesis.,10.1021/op0498114,1
"A Facile and Scaleable Synthesis of ABT-239, A Benzofuranoid H<sub>3</sub> Antagonist","A facile and scaleable synthesis of a potent and selective histamine H 3 receptor antagonist, ABT-239 ( 1 ), was developed starting from commercially available 4‘-hydroxy-biphenyl-4-carbonitrile ( 2 ). The synthesis comprised four chemical steps and a salt formation step with an overall yield of 40%. A highly selective monoiodination of a phenol was developed and used to prepare iodophenol ( 3b ) in near quantitative yield using NIS in AcOH in the presence of a small amount of H 2 SO 4 . A Pd-catalyzed cross coupling reaction of the iodophenols ( 3b ) with butyn-3-ol ( 4a ) provided benzofuran ( 5 ) in one step in >80% yield, en route to 1 . The new process required no chromatographic purification throughout the synthesis and was successfully demonstrated on scale-up to prepare 1.7 kg of the target ABT-239 ( 1 ).",10.1021/op049809c,1
Investigation of Practical Routes for the Kilogram-Scale Production of <i>cis</i>-3-Methylamino-4-methylpiperidines,"Two routes for the synthesis of cis - N -protected-3-methylamino-4-methylpiperidine ( 3 ) were examined: a route hinging on the electrochemical oxidation of carbamate 1 to install a ketone at the 3 position of the piperidine followed by reductive amination (disconnection A), and a route involving the hydrogenation of an appropriately functionalized pyridine (disconnection B). While both routes to the desired compound were ultimately successful, the pyridine hydrogenation approach proved to be more amenable to kilogram-scale preparations due to the crystallinity and purity of intermediates in that route.",10.1021/op049808k,1
A Formal Synthesis of (+)-Discodermolide,"Herein, we report the formal synthesis of (+)-discodermolide ( 1 ), a promising anticancer agent of sponge origin, in 24 linear steps, with 35 steps in total. The route proceeds from lactone 2, a building block containing the common 1,2- anti -2,3 -syn stereotriad found in each of the three subunits, methyl ketone 4 (C 1 −C 6 ), vinyl iodide 7 (C 9 −C 14 ), and iodide 8 (C 15 −C 24 ) utilized for the construction of 1 . The key fragment union was achieved by a Suzuki cross-coupling between 7 and 8 .",10.1021/op049807s,1
"Practical Synthesis of Triethylammonium (<i>Z</i>)-2-[2-(Boc-amino)thiazol-4-yl]-2-(trityloxyimino)acetate, the Side Chain of Cefmatilen","A practical synthesis of triethylammonium ( Z )-2-[2-( N - tert -butoxycarbonylamino)thiazol-4-yl]-2-(triphenylmethyloxyimino)acetate ( 1 ) which is the C-7 side chain of cefmatilen, a new cephalosporin antibiotic, is described. The conditions were optimized to control the impurity and to increase the yield. Selective acetylation of oxime group before tert -butoxycarbonylation reduced the amount of Boc 2 O. Compound 1 was synthesized from compound 6 by this improved process in 80% overall yield (12% higher than that for the medicinal process) via a four-reaction sequence (95% per reaction).",10.1021/op049804f,1
"Profiling the Formation of 2-Chloro-<i>N,N</i>-dimethylamino Trimethinium Chloride Salt, a Key Intermediate in the Manufacturing Process of Etoricoxib","2-Chloro- N, N -dimethylamino trimethinium chloride salt (CDT-chloride) is a key intermediate in the synthesis of Etoricoxib, a selective COX-2 inhibitor developed by Merck & Co., Inc. The formation of CDT-chloride from a mixture of chloroacetic acid and POCl 3 in DMF was monitored by in situ IR and in situ NIR. The buildup of transient intermediates, starting material disappearance, and product/byproduct formation were effectively followed during the course of the reaction using both techniques. The observations confirmed the intermediacy of both chloroacetyl chloride and a Vilsmeier type reagent as well as document the evolution of carbon dioxide.",10.1021/op049802v,0
Determination of the Source of the <i>N</i>-Methyl Impurity in the Synthesis of Pemetrexed Disodium Heptahydrate,"The synthesis of Pemetrexed Disodium Heptahydrate has consistently resulted in a very low level (ca. 0.02%) unknown impurity. To ensure long-term control, the identity and source of the impurity were desired. Isolation and characterization identified the impurity as the N -methyl derivative. The source was identified as the methyl groups on the peptide coupling agent, 2,6-Dimethoxy-1,3,5-triazine (CDMT). Further work assured the current conditions provide adequate control.",10.1021/op0498013,1
A Study of the Paterson Boron Aldol Reaction as Used in the Large-Scale Total Synthesis of the Anticancer Marine Natural Product (+)-Discodermolide,"This note discusses an optimisation study of a key reagent-controlled enantioselective boron enolate aldol reaction forming the C 6 −C 7 bond and the C 7 hydroxyl-bearing stereocenter in (+)-discodermolide. Conditions were found which increased the yield, decreased the excess of enolate necessary, and increased product stability with respect to the published procedure.",10.1021/op049800a,1
Chemistry Development of a Convergent Route to Trecetilide Hemi-Fumarate,"A novel, efficient, stereoselective synthetic route for N -(4-{4-[ethyl(6-fluoro-6-methylheptyl)amino]-1-( S )-hydroxybutyl}phenyl)methanesulfonamide hemi-fumaric acid salt (trecetilide hemi-fumarate, Figure 1) has been developed. The process features a convergent approach, which assembles two key intermediates in the last step to form the final molecule, which is then isolated by pH-controlled extraction. The new route offers significant yield and purity advantages over the previous route. However, the solvent volume and cycle time were not fully optimized due to the termination of the project.",10.1021/op049799f,1
The Chemistry of Process Development in Fine Chemical &amp; Pharmaceutical Industry By C. Someswara Rao. Asian Books Private Limited:  New Delhi. 2004. 1277 pp. ISBN 81-86299-50-5.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewThe Chemistry of Process Development in Fine Chemical & Pharmaceutical Industry By C. Someswara Rao. Asian Books Private Limited: New Delhi. 2004. 1277 pp. ISBN 81-86299-50-5.Cite this: Org. Process Res. Dev. 2005, 9, 1, 123Publication Date (Web):December 24, 2004Publication History Published online24 December 2004Published inissue 1 January 2005https://doi.org/10.1021/op049792yCopyright © 2005 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views292Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (7 KB) Get e-AlertsSUBJECTS:Industrial manufacturing,Organic chemistry,Organic reactions,Reagents,Solvents Get e-Alerts",10.1021/op049792y,0
"Practical Synthesis of an Orally Active CCR5 Antagonist, 7-{4-[2-(Butoxy)- ethoxy]phenyl}-<i>N</i>-(4-{[methyl(tetrahydro-2<i>H</i>-pyran-4-yl)amino]methyl}phenyl)- 1-propyl-2,3-dihydro-1<i>H</i>-1-benzazepine-4-carboxamide","A practical method of synthesizing 7-{4-[2-(butoxy)ethoxy]phenyl}- N -(4-{[methyl(tetrahydro-2 H -pyran-4-yl)amino]methyl}phenyl)-1-propyl-2,3-dihydro-1 H -1-benzazepine-4-carboxamide ( 8 ), an orally active CCR5 antagonist, has been developed. Methyl 7-bromo-1-propyl-2,3-dihydro-1 H -1-benzazepine-4-caboxylate ( 14a ) was synthesized in good yield by the esterification of 4-[(4-bromo-2-formylphenyl)(propyl)amino]butanoic acid ( 13 ) followed by an intramolecular Claisen type reaction with 28% sodium methoxide in dimethyl carbonate as a solvent in one pot. The Suzuki−Miyaura reaction of 14a and 1-bromo-4-(2-butoxyethoxy)benzene ( 10 ) followed by hydrolysis and amidation gave 8 . A new inexpensive method without chromatographic purification was established.",10.1021/op0497916,1
A New Purification Process for Pharmaceutical and Chemical Industries,"A novel separation and purification process suitable for pharmaceutical and chemical industries has been developed. The process is based on the difference in adsorption and solubility of organic compounds. The process was carried out under mechanical stirring, and individual components were isolated in short time with excellent purity. The process can be suitably adopted for the purification of organic compounds in large scale.",10.1021/op049790d,0
Improvement of Dye Properties of the Azo Pigment Yellow 12 Using a Micromixer-Based Process,"The properties of coloured pigments are primarily affected by the particle size as well as the size distribution. As both are influenced by the production process, the pigment synthesis of Yellow 12 was investigated using a micromixer apparatus. The micromixer ensures fast mixing by multilamination of thin lamellae and thereby a faster complete mixing of the reactants compared to batch processes. It was found that the micromixer-based process leads to a smaller pigment size distribution. This results in an improvement of the pigment properties. Compared to a commercially available Yellow 12 standard the glossiness was increased by 73% and the transparency by 66% with unchanged tinctorial power.",10.1021/op049789e,0
Development of the One-Carbon Homologation of a 4-Methylcoumarin Assisted by In-Line FTIR,In-line FTIR was applied as a suitable PAT (process analytical technology) to monitor and control the enolate formation step in the one-carbon homologation process of a 4-methylcoumarin with chloromethyl pivalate. The techniques to determine the endpoint of the reaction and to obtain kinetic and stability data both in THF and DMF as reaction solvent are presented. The valuable chemical data obtained by this PAT was used to support the scale-up of the homologation process.,10.1021/op049787u,0
"Practical Synthesis of FR195752, the Side Chain of Micafungin, Utilizing a Regioselective Conversion of Diaryl-β-diketone to 3,5-Diarylisoxazole","The practical synthesis of FR195752, the side chain of Micafungin, was established utilizing a highly regioselective conversion of diaryl-β-diketone to 3,5-diarylisoxazole via the corresponding β-keto enamine intermediate whose disfavored regioisomer could be recycled efficiently after its hydrolysis. In addition, the related substance of FR195752 could be strictly controlled by the purification of its intermediate.",10.1021/op0497862,1
Straightforward Preparation of Highly Enantioselective Anchored Chiral Homogeneous Catalysts,"A new method of anchoring homogeneous catalysts onto basic carbons is presented. The ease of the preparation is particularly remarkable, and the method proved to be suitable for scale-up. In the case of asymmetric heterogeneous catalysts for hydrogenation reactions, enantioselective improvement was observed in all cases where a comparison was made with the homogeneous species. Cationic rhodium catalysts are more suitable for this technology, but loading of other types of catalysts based on a variety of metals is also possible.",10.1021/op049785+,0
A Review of the Use of Process Analytical Technology for the Understanding and Optimization of Production Batch Crystallization Processes,"Crystallization at production scale is typically a poorly understood unit operation, with little implementation of the first principles aspect of crystallization in its design, optimization, and control. Problems with production crystallizers include the following: (1) inconsistencies of batch-to-batch in terms of the size and number of crystals produced and (2) the purity profile (residual impurities in crystals, or wrong polymorph or chiral purity). This can have a significant impact both on product quality and downstream process unit operations including filtration, drying, milling, and product formulation. This contribution reviews typical problems encountered in production crystallization, with case studies, advice, and strategies to understand and avoid these problems through the use of in situ crystallization characterization tools.",10.1021/op049783p,0
Selectivity Control by Use of Near-IR for a Hydrogenation Process,"We applied process analytical technologies to solve the problem of selectivity in the hydrogenation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride ( 1 ) to (±)3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2- a ]pyrimidin-4-one monohydrochloride ( 2 ). We showed that both mid-IR and near-IR (NIR) were suitable for in-line analysis of the hydrogenation. We chose to use NIR in the production environment due to easier implementation. We developed a NIR model by correlation of NIR results with HPLC results for a laboratory-scale hydrogenation reactor, and we used production batch data to adjust and confirm this model.",10.1021/op049782x,0
An Efficient Commercial Process for the Preparation of Isotretinoin,"We describe an efficient process for the preparation of isotretinoin (13-cis isomer of vitamin A acid) in a single step starting from β-ionylidene acetaldehyde ( 5 ). The process conditions are convenient to operate on a commercial scale and afford isotretinoin of excellent quality; levels of related isomeric impurities such as tretinoin (all trans retinoic acid) and 9,13-di- cis -retinoic acid are extremely low. Thus, condensation of dienolate of methyl 3,3-dimethylacrylate with β-ionylidene acetaldehyde ( 5 ) followed by aqueous acidic workup afforded isotretinoin in >95% purity. The condensation reaction proceeds via in situ formation of lactone ( 8 ); furthermore, the reaction conditions have been optimized to exploit in situ generated methoxide anion for lactone ring opening to afford the desired product. Distinct advantages of this process are that it does not require isolation of intermediate lactone and utilizes in situ generated methoxide for lactone ring opening, thus obviating the need for an additional step and base. We also describe an optimized process for the preparation of β-ionylidene acetaldehyde ( 5 ), a key intermediate for isotretinoin.",10.1021/op0497815,1
Preparation of Optically Pure Esomeprazole and Its Related Salt,"The magnesium salt of ( S )-isomer of omeprazole, with a trade name of Nexium, is the first proton-pump inhibitor developed as a single isomer for the treatment of acid-related diseases. A process for the preparation of the optically pure ( S )-isomer of omeprazole through transition metal complex is described.",10.1021/op049779d,1
Scale-Up of a Reformatsky Reaction to an Indenyl Butanoate,A safe process for the Reformatsky reaction of 5-methoxy-1-indanone and methyl 2-bromo butyrate giving an indenyl butanoate was developed. It was scaled-up from the lab to the pilot plant. The results from two campaigns on pilot-plant scale are presented.,10.1021/op049778l,0
"An Improved Large Scale Synthesis of the Schöllkopf Chiral Auxiliaries:  (2<i>R</i>)- and (2<i>S</i>)<i>-</i>2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine","Syntheses of the Schöllkopf chiral auxiliaries have been carried out on large scale in high overall yields from d - and l -valine. This method avoids the use of highly toxic phosgene or triphosgene, low-temperature reactions, and unstable intermediates.",10.1021/op049777t,1
A Practical and One-Pot Procedure for the Synthesis of 3-Amino-2-cyclohexen-1-one from 3-Aminophenol,"A simple, totally catalytic, and environmentally benign process for the synthesis of 3-amino-2-cyclohexen-1-one using 10% Pd/C-catalyzed hydrogenation has been developed.",10.1021/op0497761,0
"A Practical Large-Scale Synthesis of (3<i>R</i>,4<i>R</i>)-4-(Hydroxymethyl)pyrrolidin-3-ol via Asymmetric 1,3-Dipolar Cycloaddition","(3 R,4 R )-4-(Hydroxymethyl)pyrrolidin-3-ol ( 1 ), which is a useful intermediate for the synthesis of various bioactive molecules, has been synthesized in 51% overall yield by 1,3-dipolar cycloaddition reaction from the dipolarophile, ( E )-3-benzyloxypropenoyl-(2‘ S )-bornane-10,2-sultam ( 5 ), and the achiral ylide precursor, N -(benzyl)- N -(methoxymethyl)- N -(trimethylsilylmethyl)amine ( 6 ), without using chromatography and the subsequent reduction with LAH and catalytic hydrogenation. The diastereomers 7 and 8 were separated by crystallization, and efficient procedures were developed for the subsequent reactions to afford 1 .",10.1021/op049768k,1
Adsorbent Screening for Metal Impurity Removal in Pharmaceutical Process Research,A microtube screening approach affords simple and convenient assessment of the selective adsorption of metal impurities by a variety of different process adsorbents. This approach is helpful in identifying rapid solutions to metal impurity problems in pharmaceutical process research. Several examples illustrating the utility of the approach are presented.,10.1021/op049764f,0
A New Industrial Process for Oxcarbazepine,"A novel industrial process for the antiepileptic drug oxcarbazepine 1 has been developed. Unlike the old process, the new process is free from halogenated solvents and can be performed in standard production equipment. It starts from commercially available 1,3-dihydro-1-phenyl-2H-indol-2-one 10 . In the key step, an electrophilic ring closure reaction of 2-[(methoxycarbonyl)phenylamino] benzeneacetic acid 5 to 10,11-dihydro-10-oxo-5H-dibenz[ b, f ]azepine-5-carboxylic acid methyl ester 6 in poly phosphoric acid was applied. For the manufacture of 5, a highly efficient process using a dianion strategy was developed.",10.1021/op049760a,1
Process Analytical Technology:  An Investment in Process Knowledge,"Process analytical technology (PAT) is fast becoming an integral part of many active pharmaceutical ingredient (API) production facilities. The incorporation of early PAT devices, such as pH probes for example, was shown to increase process efficiency and safety by acting on data in real time and by eliminating sampling. PAT applications, such as online redox, NIR, and sophisticated particle size analysis, increase (in real time) detailed knowledge of processes, thus affording increased robustness and greater straight-through processing (right-first-time) opportunities. Modern developments in analytical technologies provide chemical and analytical insights for all types of chemical reactions and process monitoring such as drying, distillations, crystallizations, hydrogenations, and others. This article will discuss two applications; each is very different from the other. The first application, redox monitoring, is a traditional PAT application used to monitor differences in the oxidation state of two reaction constituents. Our discussion will describe an oxidation/reduction (redox) application used to monitor the reduction of excess bromine with sodium bisulfite using an online probe. The second application is crystallization and granulation monitoring using a Lasentec Focused Beam Reflectance Measurement (FBRM) instrument for the optimization of a crystallization and granulation process in manufacturing (reference information is publicly available on this equipment; visit the Mettler-Toledo website at: http:// www.lasentec.com/method_of_measurement.html).",10.1021/op0402127,0
Viral Clearance Issues Associated with the Use of an Animal-Derived Enzyme in the Synthesis of Emtricitabine,"Emtricitabine, the active ingredient in the antiviral drug Coviracil, has been prepared by a process using pig liver esterase to resolve optical isomers of an intermediate. Since this enzyme was derived from an animal source, potential existed for viral contamination of the product and the multipurpose equipment in which the product was prepared. To address these issues, the potential risk of viral contamination was assessed, and the potential for the process to clear viruses from the process stream was determined.",10.1021/op040210m,0
Reply to Comment on “Optimisation of the Linear Alkyl Benzene Sulfonation Process for Surfactant Manufacture” and “Sulfonation Technology for Anionic Surfactant Manufacture”:  Falling Film SO<sub>3</sub> Sulfonation - Laminar or Turbulent Flow Controversy,"ADVERTISEMENT RETURN TO ISSUEPREVCommunication to Edi...Communication to EditorNEXTReply to Comment on “Optimisation of the Linear Alkyl Benzene Sulfonation Process for Surfactant Manufacture” and “Sulfonation Technology for Anionic Surfactant Manufacture”: Falling Film SO3 Sulfonation - Laminar or Turbulent Flow ControversyDavid W. RobertsView Author Information C. Chem. Eur. Chem., FRSC, Manufacturing Chemistry and Toxicology Consultant, 63 Poulton Road, Bebington, Wirral, Merseyside CH63 9LD, UK Cite this: Org. Proc. Res. Dev. 2004, 8, 6, 1081–1082Publication Date (Web):September 24, 2004Publication History Published online24 September 2004Published inissue 1 November 2004https://doi.org/10.1021/op040209nCopyright © 2004 American Chemical SocietyRequest reuse permissionsArticle Views244Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (23 KB) Get e-AlertscloseSUBJECTS:Aromatic compounds,Chemical calculations,Liquids,Manufacturing,Thickness Get e-Alerts",10.1021/op040209n,0
Comment on “Optimisation of the Linear Alkyl Benzene Sulfonation Process for Surfactant Manufacture” and “Sulfonation Technology for Anionic Surfactant Manufacture”:  Falling Film SO<sub>3</sub> Sulfonation - Laminar or Turbulent Flow Controversy,"ADVERTISEMENT RETURN TO ISSUEPREVCommunication to Edi...Communication to EditorNEXTComment on ""Optimisation of the Linear Alkyl Benzene Sulfonation Process for Surfactant Manufacture"" and ""Sulfonation Technology for Anionic Surfactant Manufacture"": Falling Film SO3 Sulfonation - Laminar or Turbulent Flow ControversyEdward A. KnaggsView Author Information 715 Colwyn Terrace, Deerfield, Illinois 60015-3111, U.S.A.% Cite this: Org. Proc. Res. Dev. 2004, 8, 6, 1079–1080Publication Date (Web):September 24, 2004Publication History Published online24 September 2004Published inissue 1 November 2004https://pubs.acs.org/doi/10.1021/op0402073https://doi.org/10.1021/op0402073rapid-communicationACS PublicationsCopyright © 2004 American Chemical SocietyRequest reuse permissionsArticle Views431Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Amorphous materials,Chemical reactions,Industrial manufacturing,Physical and chemical processes,Surfactants Get e-Alerts",10.1021/op0402073,0
"Use of DOE for Rapid Development of a Red-Al Reduction Process for the Synthesis of 3,4-Isopropylidenedioxypyrrolidine Hydrotosylate","Statistical design of experiments (DOE) was used to rapidly optimize Red-Al reduction of an imide to produce, after deprotection and salt formation, 3,4-isopropylidenedioxypyrrolidine hydrotosylate ( 1 ), an intermediate in the synthesis of Ingliforib. A Red-Al reduction process was successfully scaled to produce multikilogram quantities of 1, thus demonstrating a safer and more economical process. Further development resulted in an optimized procedure, which not only avoided borane reduction but also allowed the three-step procedure to be performed without isolation of the intermediates, solvent exchange, or distillation.",10.1021/op040204q,1
Development of an Efficient Process for the Preparation of Sch 39166:  Aziridinium Chemistry on Scale,A large-scale synthesis of a tricyclic D1/D5 dopamine antagonist based on regio- and stereoselective ring opening of an aziridinium ion with a Grignard reagent was optimized and scaled up.,10.1021/op0402026,1
Canonical Analysis of Response Surfaces:  A Valuable Tool for Process Development<sup>1</sup>,"The principles of response surface modelling are briefly described. The computations involved in the canonical analysis of response surface models are given in detail. Three examples of canonical analysis in the context of organic synthesis development are discussed. These examples treat enamine synthesis by a modified titanium tetrachloride procedure, kinetic modelling, and the synthesis of the trimethylsilyl enol ether from methyl vinyl ketone.",10.1021/op040023o,0
Synthesis of Commercial Phosphodiesterase(V) Inhibitors,"The literature syntheses (including patents) of three commercial phosphodiesterase(V) (PDE5) inhibitors (sildenafil, vardenafil, and tadalafil) are reviewed with particular emphasis on large-scale manufacture. For each of these compounds, some impressive chemical development work has been reported.",10.1021/op040019c,1
Synthetic Process Development and Scale-Up of the Oxidative Cleavage of a Double Bond Catalyzed by Ruthenium Trichloride,"Using statistical experimental tools, a relatively complex process for the oxidative cleavage of a double bond catalyzed by a ruthenium catalyst was studied. A good understanding of the influence of the reaction parameters led to the development of a technically feasible process which was successively scaled up to kilogram-laboratory facilities and finally to the launch plant facilities.",10.1021/op040014f,0
Application of Process Modelling Tools in the Scale-Up of Pharmaceutical Crystallisation Processes,"Crystallisations are frequent process steps in the manufacture of active pharmaceutical ingredients (APIs). They are the primary means of intermediate or product formation and separation to achieve the desired purity and form. These unit operations are complex processes which are difficult to control due to the interlinked chemical and physical effects. For example, chemical aspects such as salt and polymorph concerns are in the forefront of process research, but physical effects manifesting themselves on scale-up, due to equipment influences, can be equally important for the successful outcome of a campaign. Several operational parameters, such as temperature or impeller speed, need to be understood and controlled to achieve constant desupersaturation, consistent narrow particle size distribution around the desired mean, minimal attrition, and homogeneous growth conditions. This paper focuses on the equipment influence on crystallisations, relating it to first principles with respect to heat and momentum transfer, analysing it with computational fluid dynamics (CFD), and demonstrating its process impact using examples from recent development work. Dynamic process modelling and CFD are state-of-the-art engineering tools to identify process requirements and match them with equipment capabilities. The work reported here demonstrates how a semiquantitative application of these tools can lead to a controllable, robust process in an existing plant despite the time and resource limitations usually encountered in the industry.",10.1021/op040013n,0
Sanofi-Synthelabo Chemical Development and the Development of an Electronic Laboratory Notebook,"Past attempts to develop electronic laboratory notebooks (ELN) have not always met with the success expected of them. This may have been due to job aspects and the difficulties encountered in their practical application, insufficient support provided to users during the learning phase, application complexity, interfacing problems with preexisting information systems, and the necessary integration of regulatory and legal aspects. Sanofi-Synthelabo adopted a different approach by emphasizing practical application and user support while putting the regulatory aspects to one side. An ELN model was developed on the basis of initial user-derived specifications, and a prototype was then produced, known as Kalabie (Klee business software). This ELN is sufficiently flexible to be shaped for different specialized chemical development sectors (synthesis, automates, preparative chromatography) and interfaces with preexisting in-house Oracle and MDL databases, thus supporting multisite extensions as a user-friendly intranet application. Technicians, scientists, and managers were happy with Kalabie when it entered service. Work is ongoing to extend the use of the ELN and to integrate the regulatory aspects.",10.1021/op040012v,0
Synthesis of Trifluoromethanesulfonic Acid from CHF<sub>3</sub>,Trifluoromethane is transformed to trifluoromethanesulfonic acid (TFMSA) at low temperature in a liquid-phase reaction in a strong acid such as fuming sulfuric acid as well as in a strong basic solution such as t -BuOK/DMF.,10.1021/op040007r,0
Claisen Condensation as a Facile Route to an α-Alkoxy-cinnamate:  Synthesis of Ethyl (2<i>S</i>)-2-Ethoxy-3-(4-hydroxyphenyl)propanoate,The title compound was prepared from p -anisaldehyde and ethyl ethoxyacetate via a racemic synthetic route. The synthesis involves a Claisen-type condensation in which the elimination was unexpectedly promoted by an excess of the ester. The process has been successfully performed on a 2000-L scale with a total yield over seven steps of 19%.,10.1021/op040006z,1
An Improved Process for the Preparation of Trimethylhydrazine and Its Coupling with an Activated Acid Intermediate,"Trimethylhydrazine (TMH) was prepared in two steps from 1,1-dimethylhydrazine, using an easy to scale-up procedure that avoided difficult acid−base extractions. The procedure provided TMH as a solution in 1,4-dioxane, in a form that was easy and safe to handle in a coupling with an enantiomerically pure, sterically hindered, Boc-protected-amino acid, 1 . This key coupling reaction in the preparation of 3 was accomplished through the corresponding acid chloride, thereby avoiding the use of expensive coupling reagents.",10.1021/op0342022,1
<i> SPECIAL FEATURE SECTION: <u>SAFETY OF CHEMICAL PROCESSES</u> </i> Are MSDs Safe? Reflections at the MSDS's 20th Birthday <sup>1</sup>,"ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSES Are MSDs Safe? Reflections at the MSDS's 20th Birthday1Giora AgamView Author Information Pi2Chim Ltd., Consultation Services in Chemical and Biotechnological R&D, Beer-Sheva, Israel E-mail: [email protected]Cite this: Org. Proc. Res. Dev. 2004, 8, 6, 1042–1044Publication Date (Web):October 5, 2004Publication History Published online5 October 2004Published inissue 1 November 2004https://doi.org/10.1021/op034201+Copyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views438Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (27 KB) Get e-AlertsSUBJECTS:Granular materials,Manufacturing,Materials,Redox reactions,Safety Get e-Alerts",10.1021/op034201+,0
Continuous Microflow Synthesis of Butyl Cinnamate by a Mizoroki−Heck Reaction Using a Low-Viscosity Ionic Liquid as the Recycling Reaction Medium,"A continuous microflow system was developed with efficient catalyst recycling for a Mizoroki−Heck reaction of iodobenzene with butyl acrylate, using a low-viscosity ionic liquid ([bmim]NTf 2 ) as the reaction medium. Using a CPC CYTOS Lab System as the microreaction apparatus, in combination with an originally developed microextraction/catalyst recycling system, the reaction medium, which contained Pd catalyst could be continuously recycled to provide a total of 115.3 g (80%, 10 g/h) of the desired product.",10.1021/op034200h,0
Re-engineering the Chemical Processing Plant:  Process Intensification Edited by Andrzej Stankiewicz and Jacob A. Moulijn. Marcel Dekker:  New York. 2004. $165. 529 pp. ISBN 0-8247-4302-4.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTRe-engineering the Chemical Processing Plant: Process Intensification Edited by Andrzej Stankiewicz and Jacob A. Moulijn. Marcel Dekker: New York. 2004. $165. 529 pp. ISBN 0-8247-4302-4.Cite this: Org. Proc. Res. Dev. 2004, 8, 2, 299Publication Date (Web):January 28, 2004Publication History Published online28 January 2004Published inissue 1 March 2004https://doi.org/10.1021/op034199mCopyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views447Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (46 KB) Get e-AlertsSUBJECTS:Chemical engineering and industrial chemistry,Computational chemistry,Pharmaceuticals,Pharmaceutics,Physical and chemical processes Get e-Alerts",10.1021/op034199m,0
A Practical Synthesis of a Potent δ-Opioid Antagonist:  Use of a Modified Knorr Pyrrole Synthesis,A modified Knorr pyrrole reaction is described which may have practical benefits for the large-scale synthesis of SB-342219. The use of zinc to reduce a phenylhydrazone is replaced by the hydrogenation of the corresponding oxime to provide a common aminoketone intermediate. The modifications have practical benefit with respect to carrying out the reaction and isolating the product. A modified N-demethylation procedure is also described. The use of zinc to reduce an intermediate trichloroethylcarbamate is replaced with the aqueous hydrolysis of the corresponding 1-chloroethylcarbamate.,10.1021/op034198u,0
"Asymmetric Catalysis on Industrial Scale:  Challenges, Approaches and Solutions Edited by H. U. Blaser and E. Schmidt. Wiley-VCH:  Weinheim. 2004. £115. 454 pp. ISBN 3-527-30631-5.",,10.1021/op034196+,0
Microwaves in Organic Synthesis Edited by Andre Loupy. Wiley-VCH:  Weinheim. 2002. 159 euro. 499 pp. ISBN 3-527-30514-9.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTMicrowaves in Organic Synthesis Edited by Andre Loupy. Wiley-VCH: Weinheim. 2002. 159 euro. 499 pp. ISBN 3-527-30514-9.Peter SpargoView Author Information Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex, TN20 6EW, UKCite this: Org. Proc. Res. Dev. 2004, 8, 2, 298Publication Date (Web):January 15, 2004Publication History Published online15 January 2004Published inissue 1 March 2004https://doi.org/10.1021/op034195hCopyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views266Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (46 KB) Get e-AlertsSUBJECTS:Catalysis,Electromagnetic radiation,Organic chemistry,Organic reactions,Organic synthesis Get e-Alerts",10.1021/op034195h,0
Application of Microreactor Technology in Process Development,"The microreactor technology is an efficient tool for kilogram-scale syntheses in continuous mode and is particularly effective for hazardous reactions that do not allow scale-up in conventional reactors. Applications to several classes of reactions including highly exothermic reactions, high-temperature reactions, reactions with unstable intermediates, and reactions involving hazardous reagents are described herein.",10.1021/op034193x,0
Example of Finishing Technologies as Key Elements for Successful Active Pharmaceutical Ingredient Process Development,"Little has been published so far to emphasize the role of finishing technologies (crystallization, filtration, drying) as crucial elements for successful process development of active pharmaceutical ingredients (APIs). In the presented example high marketing forecasts stressed the objective for the process to be robust, simple, and tailor-made for high-volume production. The major hurdle was the purification of the reaction mixture of an intermediate containing inorganic salts, polymers, isomers, and colored byproducts that needed to be separated. Systematic application of finishing technologies paved the way to a commercial process. Removal of colored byproducts and isomers was found to be the most challenging task after separation of inorganic salts by quench and of polymers by charcoal treatment. The problem was resolved in three steps. First, solvent screening for the crystallization yielded toluene to be most efficient to separate colored byproducts. Second, solubility measurements of product and isomers provided an operating range of the process parameters for an economic crystallization at an unusually high concentration (60% w/w). Isomers could be separated since they remain soluble at endpoint temperature. To avoid the problem of wall crusts during scale-up, the metastable range was estimated experimentally. And third, near-infrared spectroscopy was implemented as an on-line measurement method for the product concentration in toluene to determine the endpoint of evaporation and thus to facilitate robustness and yield optimization. As further result of proper elaboration of crystallization conditions the crystals exhibited compact cubic morphology and large size. Consequently, filtration and washing of the wet product cake were efficient, and the drying process could be eliminated before continuing with the next synthesis step.",10.1021/op034188t,0
Process Development on an Efficient New Convergent Formal Synthesis of MIV-150,"Starting from a known linear route and a proposed convergent route, we have successfully developed a new hybrid convergent route to MIV-150 that takes advantage of the robust chemistry for the preparation of a fluoroketal and the stereospecific Negishi coupling of an iodocyclopropane moiety to a benzene ring. Stereoselective β- and cis- iodination chemistry was developed for the preparation of an enantiomerically pure iodocyclopropanecarboxylate. Following the Negishi coupling, proven chemistry from the linear route was incorporated, thus ensuring a similar high-purity profile for the final active pharmaceutical ingredient (API). In addition, we have prepared and evaluated a series of basic inorganic and organic MIV-150 salts that have drastically increased water solubility over the parent compound.",10.1021/op0341871,1
"Process Development of a Scaleable Route to (2<i>R</i>)-[3-(2-Aminopropyl)-1<i>H</i>-indol-7-yloxy]-<i>N,N</i>-diethylacetamide:  A Key Intermediate for AJ-9677, a Potent and Selective Human and Rat β<sub>3</sub>-Adrenergic Receptor Agonist","(2 R )-[3-(2-Aminopropyl)-1 H -indol-7-yloxy]acetic acid ( 2 ) is the left-hand side segment of AJ-9677, which is a potent and selective human and rat β 3 -adrenergic receptor agonist. Herein, we describe the process development of a scaleable synthetic route to the corresponding N,N -diethylacetamide derivative 3 of 2 from 7-benzyloxy-1 H -indole ( 4 ). Reaction of the indole Grignard reagent 12 generated from 4 and methylmagnesium bromide with the N -Fmoc- d -alanyl chloride 22, followed by reduction of the resulting crude 3-acylindole 26 with NaBH 4 in a mixture of MeCN and 2-PrOH at refluxing temperature and subsequent treatment with oxalic acid gave the oxalate of the N -deprotected product, (2 R )-3-(2-aminopropyl)-7-benzyloxy-1 H -indole [( R )- 7 ] as a crystalline material in 60% yield. After N -protection of the ( R )- 7 by Boc group, the (2 R )-3-[2-(Boc-amino)propyl]-1 H -indole 30 was hydrogenated to provide the (2 R )-3-(2-aminopropyl)-7-hydroxy-1 H -indole 31, which was subsequently alkylated with ClCH 2 CONEt 2 to give 32 in 91% yield. Finally, treatment of 32 with oxalic acid afforded the desired 3 in 79% in >99% ee.",10.1021/op0341869,1
Process Development of a Large-Scale Synthesis of TKA731:  A Tachykinin Receptor Antagonist,"An efficient and chromatography-free large-scale synthesis of a tachykinin receptor antagonist TKA731 ( 1 ), utilizing the coupling of dipeptide 7 and 2-chloro-4( 3H )-quinazolinone ( 13 ) as the key step, is described. The overall yield of 1 from BOC- l -3-(2-naphthyl)alanine ( 2 ) in six linear steps (total of eight steps) is 63%. This new convergent approach avoided the use of methyl iodide and the formation of methanethiol byproduct in the last step involving the construction of the quinazolinone ring in the original discovery synthesis. Four chromatographies were also eliminated. The main cause of the side reaction, leading to the urethane byproduct ( I ) formation and starting amino acid ( 2 ) liberation during the coupling of 2 with N -benzylmethylamine using well-known isobutyl chloroformate mediated mixed carboxylic-carbonic anhydride method, was found to be the symmetrical anhydride ( III ) formation from 2 as determined by the CO 2 offgas formation. A new procedure for the coupling of 2 with N -benzylmethylamine involving a reverse addition of 2 and the base to the coupling agent isobutyl chloroformate, followed by the addition of the amine, was developed that minimized the symmetrical anhydride formation. A novel, water-assisted N -methylation of 5 with dimethyl sulfate in the presence of sodium hydride in THF was also developed that eliminated the use of methyl iodide, silver oxide, and KCN. Deprotection of the BOC group in 6 with sulfuric acid circumvented the formation of diketopiperazine and tetrapeptide observed with HCl and trifluoroacetic acid, respectively.",10.1021/op0341824,1
Development and Applications of a Practical Continuous Flow Microwave Cell,"A series of synthetic transformations were successfully and safely scaled up to multigram quantities using focused microwave irradiation with a continuous flow reaction cell that was developed in-house and which can be easily adapted to commercially available instrumentation. The representative reactions that were investigated included aromatic nucleophilic substitution (S N Ar), esterification, and the Suzuki cross-coupling reaction. In general, the product yields were equivalent to or greater than those run under conventional thermal heating conditions.",10.1021/op034181b,0
Development of a Practical Multikilogram Production of (<i>R</i>)-Seudenol by Enzymatic Resolution,"Different enzymatic routes for the production of ( R )-seudenol were investigated. The Novozym 435-catalyzed reaction of racemic seudenol with vinyl butyrate proved to be the most promising route. By using vinyl laurate as an acyl donor, ( R )-seudenol laurate could be separated from ( S )-seudenol by an extractive work-up procedure. A nonaqueous hydrolysis allowed the isolation of pure ( R )-seudenol. Scaling up to 7 kg resulted in a robust reproducible process.",10.1021/op034179k,0
Selectivity Gains and Energy Savings for the Industrial Phenyl Boronic Acid Process Using Micromixer/Tubular Reactors,"An industrial production-scale process currently conducted at Clariant site/Frankfurt, termed Phenyl Boronic Acid Process from here on, was investigated at laboratory-scale using two micromixer/tubular reactor configurations, being equipped with either a glass interdigital (for details see (1) Ehrfeld, W.; Golbig, K.; Hessel, V.; Löwe, H.; Richter, T. Characterization of mixing in micromixers by a test reaction: single mixing units and mixer arrays. Ind. Eng. Chem. Res. 1999, 38, (3), 1075−1082; (2) Hessel, V.; Hardt, S.; Löwe, H.; Schönfeld, F. Laminar mixing in different interdigital micromixers - Part I: Experimental characterization. AIChE J. 2003, 49, 566−577; (3) Hardt, S.; Schönfeld, F. Laminar Mixing in Different Interdigital Micromixers - Part 2: Numerical Simulations. AIChE J. 2003, 49, 578−584; (4) Herweck, T.; Hardt, S.; Hessel, V.; Löwe, H.; Hofmann, C.; Weise, F.; Dietrich, T.; Freitag, A. Visualization of Flow Patterns and Chemical Synthesis in Transparent Micromixers. In Topical Conference Proceedings; IMRET 5, 5th International Conference on Microreaction Technology, AIChE Spring National Meeting; Matlosz, M., Ehrfeld, W., Baselt, J. P., Eds.; Springer-Verlag: Berlin, 2001; pp 215−229) or a steel split-recombine mixer (for details see Schönfeld, F.; Hessel, V.; Hofmann, C. An Optimised Split-and-Recombine Micro Mixer with Uniform ‘Chaotic' Mixing. Lab Chip 2004, 4, 65−69). The best yield of the microreactor investigations was 89%, exceeding the performance of the industrially employed stirred-tank process by nearly 25%. Moreover, the total amount of side and consecutive products was decreased from 10−15% to 5−10%. In addition to these yield improvements, the energy expenditure of the microreactor processing was also notably reduced, first of all because of carrying out the reaction at favorable ambient temperature. In contrast, the former batch process had to be carried out at cryogenic temperatures of −35 °C. Even at temperatures as high as 50 °C, a high selectivity was maintained when using the microreactor. As a further cause for energy savings, the higher purity of the product eliminated the need for distillation; in total therefore, only one heating−cooling cycle with reduced temperature difference was required for the microreactor process in contrast to the three cycles with large temperature differences used in conventional processing. Facing production and process liability issues, a specially made pilot-scale configuration was constructed entirely out of stainless steel components, among them a split−recombine caterpillar mixer having larger internal fluid channels than the interdigital glass mixer. The new configuration allowed one to perform scale-up studies at throughputs as high as 10 L/h.",10.1021/op0341768,0
A Simple Procedure for the Isolation of γ-Oxobenzenebutanoic Acid Derivatives:  Application to the Synthesis of Fenbufen,"A simple, convenient, and industrially viable process for the isolation of 4-oxobutanoic acid derivatives resulting from Friedel−Crafts acylation products of aromatic hydrocarbons with succinic anhydride is reported. The isolation procedure involves simple quenching of the reaction mixture followed by filtration of the product in good yield and with excellent purity. The generality of the procedure has been demonstrated with representative examples of aromatic hydrocarbon precursors and has also been applied to the isolation of fenbufen. The quantity of aluminum chloride used in the reaction has also been optimized to reduce the load on effluent.",10.1021/op034173v,0
Accelerated Process Development of Pharmaceuticals:  Selective Catalytic Hydrogenations of Nitro Compounds Containing Other Functionalities,"The hydrogenation of three different pharmaceutical nitro-containing compounds has been studied using high-throughput experimentation (HTE) methods. Significant improvements to the existing reactions were obtained for two of the examples. Each reaction exhibits distinct features regarding activity and chemoselectivity. The best catalyst and reaction conditions found were remarkably different for each of the reactions. For one of the reactions, larger-scale studies are presented, which show that the screening reactions provided a fast and reliable indicator of the most promising reaction conditions.",10.1021/op0341667,0
Assessing the Benefits of Direct Isolation Processes,"Direct isolation processes are often used in pilot-plant and manufacturing operations. The primary benefit of a direct isolation process over a process using a conventional extractive workup and crystallization is the decreased cost of goods (COG) due to decreased processing time. Direct isolation processes may be beneficial even when the yield is 5−15% below the yield from a conventional extractive workup and crystallization. The costs of scaling up both direct isolation and extraction processes can be calculated by a mathematical model, and the proportional costs of raw materials, labor, and waste disposal can be assessed. Although direct isolation processes are generally more economical than extraction processes, the direct isolation option is not suitable for all strategies. A perspective is offered on when to develop a direct isolation process over an extractive workup and crystallization process.",10.1021/op034165e,0
"Industrial Synthesis of 4-Chloro,11β-arylestradiol: How to Circumvent a Poor Diastereoselectivity","An industrial synthesis of 11β-arylestrone derivatives is described, based on the conjugate opening of a mixture of allylic 5(10)-α and -β epoxides by an aryl cuprate generated catalytically, followed by hydrolysis and subsequent aromatisation of the isomeric mixture of arylation products. An original method for selective 4-chlorination of estrone derivatives is also described.",10.1021/op0341622,1
Efficient Synthesis of Pyropheophorbide-<i>a</i> and Its Derivatives,"A new and simplified method of preparing hexyloxy pyropheophorbide- a (HPPH), a promising agent used in photodynamic therapy, is described. This method is carried out in two processing steps, replacing an older method requiring five steps. This is accomplished by means of a Dieckmann condensation and subsequent thermal decarboxylation, both occurring in the same high-boiling solvent, thus reversing the long-standing trend in which naturally occurring chlorin derivatives with exocyclic rings are often subjected to conditions that open this ring to obtain chlorin derivatives. In the new process, a raw material without an exocyclic ring is used to construct a product containing the exocyclic ring. The new method does not require cryogenic processing or chromatography, removing the most significant obstacles to large-scale preparation of HPPH and its homologues.",10.1021/op034160h,1
An Improved and Single-Pot Process for the Production of Pantoprazole Substantially Free from Sulfone Impurity,"Pantoprazole ( 1 ), a substituted benzimidazole derivative, is an irreversible proton pump inhibitor, essentially used for the prevention and treatment of gastric acid-related diseases. The process for its preparation generally suffers from the drawback of producing a potential sulfone impurity ( 5 ). The present work details a report of the journey towards the development of a simple, single-pot process for the production of pantoprazole, substantially free from sulfone impurity ( 5 ). The detailed study of the different parameters affecting the purity and yield of the compound has been presented.",10.1021/op034157y,0
Organic Synthesis Highlights V Edited by Hans-Günther Schmalz and Thomas Wirth. Wiley VCH:  Weinheim. 2003. 440 pp. £55. ISBN 3-527-30611-0.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTOrganic Synthesis Highlights V Edited by Hans-Günther Schmalz and Thomas Wirth. Wiley VCH: Weinheim. 2003. 440 pp. £55. ISBN 3-527-30611-0.Cite this: Org. Proc. Res. Dev. 2004, 8, 2, 294–295Publication Date (Web):November 20, 2003Publication History Published online20 November 2003Published inissue 1 March 2004https://doi.org/10.1021/op0341566Copyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views81Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (46 KB) Get e-AlertsSUBJECTS:Chemical synthesis,Organic synthesis,Pharmaceuticals,Phase transitions,Solid phase synthesis Get e-Alerts",10.1021/op0341566,0
A Novel Process of Autoxidation of Cyclohexane Using Pure Oxygen,"Autoxidation of liquid cyclohexane utilizing pure oxygen to produce cyclohexanone, cyclohexanol, and their precursors is achieved in a medium of cyclohexane/water mixture. The addition of water, which acts as an inert component, permits the use of pure oxygen without forming the potentially explosive oxygen/cyclohexane mixtures in the overhead vapor space as well as in the oxygen bubbles. The result is an inherently safer process for cyclohexane oxidation with increased yield and selectivity to the desired products. The use of pure oxygen improves not only the productivity and safety but also reduces the emission and benefits the environment.",10.1021/op0341521,0
"A New and Simplified Process for Preparing <i>N</i>-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine and a Telescoped Process for the Synthesis of (1<i>S</i>-<i>cis</i>)-4-(3,4-Dichlorophenol)-1,2,3,4-tetrahydro-<i>N</i>-methyl-1-naphthalenamine Mandelate:  Key Intermediates in the Synthesis of Sertraline Hydrochloride","N -[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, sertraline imine ( 3 ), is an intermediate for the synthesis of Zoloft, sertraline hydrochloride ( 1 ). A cleaner, simpler, and more efficient alternative to the Schiff base-mediated formation of sertraline imine has been developed and is presented in this paper. The condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalone, sertraline tetralone ( 2 ), and monomethylamine was carried out in ethanol, without the need for classical dehydrating agent, such as TiCl 4, or more novel approaches, such as molecular sieves, both of which produce hazardous byproducts and solid wastes. The low solubility of the imine 3 in this type of solvent is exploited, such that the reaction equilibrium favorably enhances the imine formation. Furthermore, an improved and highly selective catalytic reduction of 3 with Pd/CaCO 3 catalyst in ethanol as the reaction solvent, followed by the resolution of the racemic cis isomer ( 6 ) with d -(−)-mandelic acid results in a more efficient telescoped commercial process to (1 S - cis )-4-(3,4-dichlorophenol)-1,2,3,4-tetrahydro- N -methyl-1-naphthalen-amine mandelate, sertraline mandelate ( 4 ). This new process has been implemented commercially and eliminates the use of hazardous material such as TiCl 4, significantly reduces undesirable byproducts, reduces the number of intermediate isolations, and improves the overall process yield and productivity on industrial scale.",10.1021/op0341465,1
Development of a Scaleable Synthesis of a 3-Aminopyrazinone Acetamide Thrombin Inhibitor,"A scaleable route to 2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)amino]-6-chloro-2-oxohydropyrazinyl}- N -[(3-fluoro(2-pyridyl))methyl]acetamide 1 is described in which various scaleup issues were addressed to provide a safe, efficient, and robust route for the preparation of multi-kilo amounts of the compound. The use of expensive and toxic reagents, notably sodium azide, TMS-cyanide, and Deoxo-Fluor, and the need for specialist equipment were overcome in the preparation of the key fluorinated intermediates 2,2-difluoro-2-(2-pyridyl)ethylamine 3 and 2-aminomethyl-3-fluoropyridine 2 . With minimal isolations and through processing of intermediates, the thrombin inhibitor 1 was isolated in 36% overall yield.",10.1021/op0341420,1
<i>SPECIAL FEATURE SECTION: <u>SAFETY OF CHEMICAL PROCESSES</u></i>,"ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSESTrevor LairdView Author Information Editor Cite this: Org. Proc. Res. Dev. 2003, 7, 6, 1028Publication Date (Web):October 11, 2003Publication History Published online11 October 2003Published inissue 1 November 2003https://pubs.acs.org/doi/10.1021/op034138ohttps://doi.org/10.1021/op034138oreview-articleACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views242Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Safety Get e-Alerts",10.1021/op034138o,0
"Solvent and Temperature Effects in the Free Radical Aerobic Oxidation of Alkyl and Acyl Aromatics Catalysed by Transition Metal Salts and <i>N</i>-Hydroxyphthalimide:  New Processes for the Synthesis of <i>p</i>-Hydroxybenzoic Acid, Diphenols, and Dienes for Liquid Crystals and Cross-Linked Polymers","The aerobic oxidation of 4,4‘-diisopropyldiphenyl and 2,6-diisopropylnaphthalene, catalysed by N -hydroxyphthalimide and Co(II) salts, leads to the corresponding tertiary benzyl alcohols with high conversion and selectivity under mild conditions (temperature 30−60 °C and atmospheric pressure). Solvent and temperature effects, as resulting from the pioneering work of C. Walling, and more recently from the conclusive resolution of K. U. Ingold and co-workers on a quantitative kinetic basis, strongly affect the selectivity of the aerobic oxidation. This is related to the ratio between the rate of β-scission of the alkoxyl radical, which leads to acetophenone derivatives, and the rate of hydrogen atom abstraction, leading to tertiary benzyl alcohols. These latter are efficiently converted either to diphenols for the production of liquid crystals, by reaction with H 2 O 2, or to dienes, useful as cross-linking agents, by dehydration. The aerobic oxidation of p -hydroxyacetophenone catalysed by Mn(NO 3 ) 2 and Co(NO 3 ) 2 leads with high selectivity to p -hydroxybenzoic acid, a useful monomer for liquid crystals.",10.1021/op034137w,0
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5:  Linkage of Fragments C<sub>1</sub><sub>-</sub><sub>6</sub> and C<sub>7</sub><sub>-</sub><sub>24</sub> and Finale,"The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide ( 1 ), using a hybridized Novartis−Smith−Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3- anti -diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide ( 1 ). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials.",10.1021/op034134j,1
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 4:  Preparation of Fragment C<sub>7</sub><sub>-</sub><sub>24</sub>,"Coupling of C 9 - 14 ( 4 ) and C 15 - 21 ( 5a ) fragments to produce the cis -trisubstituted olefin was achieved using Suzuki-type coupling conditions employed by Marshall ( 5a / tert -BuLi/B-OMe-9-BBN added to 4 /Cs 2 CO 3 /Pd(dppf) 2 ). The terminal ( Z )-diene moiety was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield. In the oxidation of alcohols 12 and 16 to 13 and 7, respectively, using iodobenzene diacetate and TEMPO, addition of a trace of water was found to be crucial for complete conversion. The C 8 - 9 ( Z )-olefin functionality was introduced on to aldehyde 13 using a Still−Gennari HWE reaction. Subsequent carbamate installation at C-19 followed by a reduction/oxidation sequence gave the title fragment C 7 - 24 ( 7 ) ready to be coupled with the C 1 - 6 fragment, which is described in Part 2 of this series.",10.1021/op034133r,1
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 3:  Synthesis of Fragment C<sub>15</sub><sub>-</sub><sub>21</sub>,Smith's procedure of preparing fragment C 15 - 21 ( 5 ) from common precursor 3 was optimized. The ease of plant operations made this six-step route successful for the production of several kilograms of this fragment with high purity.,10.1021/op034132z,1
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 2:  Synthesis of Fragments C<sub>1</sub><sub>-</sub><sub>6</sub> and C<sub>9-14</sub>,Kilogram-scale syntheses of fragments C 1 - 6 ( 6 ) and C 9 - 14 ( 4 ) of (+)-discodermolide from common precursor 3 are described. Improved procedures for each step of both fragments were developed by minimizing or eliminating the formation of byproducts that were isolated and characterized in Smith's synthesis.,10.1021/op0341317,1
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 1:  Synthetic Strategy and Preparation of a Common Precursor,"The synthetic strategy for producing multigram quantities of (+)-discodermolide ( 1 ) using a hybridized Novartis−Smith−Paterson synthetic route via common precursor 3 is described. In the first part of this five-part series, we present a multikilogram preparation of α-methyl aldehyde 10 from Roche ester, its syn- aldol reaction with Evans boron enolate, removal of the chiral auxiliary, and the preparation of Weinreb amide 3 (Smith common precursor). The common precursor was produced without any chromatography.",10.1021/op034130e,1
Environmentally Friendly and Efficient Process for the Preparation of β-Hydroxyl Ketones,"An environmentally benign and efficient process for the preparation of β-hydroxyl ketones was developed by the practical cross-aldol reactions of 2-acetylpyridine, acetophenone, and cyclohexanone with 4-nitro-, 3-nitro-, and 2-nitrobenzaldehydes in water catalyzed by Na 2 CO 3 in very high yields.",10.1021/op0341263,0
"The Application of Microreactor Technology for the Synthesis of 1,2-Azoles","We demonstrate the successful synthesis of an array of 1,2-azoles within a borosilicate glass microreactor whereby conversions in the range of 98−100% were obtained. In terms of large-scale production, this corresponds to 0.339 g day - 1 per microreactor when employing reagent concentrations of 1.0 M.",10.1021/op034125a,0
"Process Research, Development, and Pilot-Plant Preparation of Clofencet, a Novel Wheat Hybridizing Agent:  Lewis Acid-Catalyzed Reaction of Ethyl Diazoacetate with 4-Chlorophenyl Hydrazonoacetaldehyde","Described are studies directed toward the chemical research and development of an alternative synthesis to 9, the penultimate intermediate of clofencet ( 1 ), a novel wheat-hybridizing agent. Retrosynthetic analyses as well as the results obtained from feasibility studies are detailed, leading to the successful development of an alternative process. The key features of the novel route are a method for preparing on-scale ethyl diazoacetate ( 28 ) in a safe and effective manner, and the Lewis acid-catalyzed reaction of 28 with hydrazonoacetaldehyde 29, affording β-ketoester 30 . The synthesis is completed via propionylation of 30, acid-catalyzed cyclization of 31 to pyridazinecarboxylic acid ester 32, followed by saponification and isolation of carboxylic acid 9 . The results and challenges of eight pilot-plant runs are reported. The baseline process developed produced over 45 kg of 9 in 43−45% yield.",10.1021/op034123q,1
Synthesis and Characterisation of Impurities of Manufacture in Support of Certificate of the European Pharmacopoeia Applications Part 1 (Clobetasone Butyrate),"Established pharmaceutical products often have complex supply chains and regulatory histories. In Europe the European Directorate for the Quality of Medicine (EDQM) (information from European Pharmacopoeia website, http://www.pheur.org/ ) have promoted the use of certificates of suitability of the European Pharmacopoeia to ensure the quality of medicines by a commonly recognised set of standards, allowing the free movement of medicinal products in member states. This contribution describes the analytical and synthetic chemistry required to synthesise the impurities of manufacture of clobetasone butyrate.",10.1021/op0341216,0
Handbook of Reagents for Organic Synthesis:  Chiral Reagents for Asymmetric Synthesis Edited by L. Paquette. Wiley:  Chichester. 2003. 594 pp. £75. ISBN 0-4708-5625-4.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTHandbook of Reagents for Organic Synthesis: Chiral Reagents for Asymmetric Synthesis Edited by L. Paquette. Wiley: Chichester. 2003. 594 pp. £75. ISBN 0-4708-5625-4.Cite this: Org. Proc. Res. Dev. 2003, 7, 6, 1085Publication Date (Web):September 6, 2003Publication History Published online6 September 2003Published inissue 1 November 2003https://doi.org/10.1021/op034118mCopyright © 2003 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views134Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (19 KB) Get e-AlertsSUBJECTS:Organic synthesis,Reagents Get e-Alerts",10.1021/op034118m,0
Synthesis of T2288:  From Bench Synthesis to Pilot Production,"A practical process to make N -(2,6-dimethylphenyl)-2-piperazin-1-yl-acetamide 1 is described, starting from piperazine 2 and N -chloroacetyl-2,6-xylidine 3 . The unwanted N, N ‘-bis-alkylated product 4 can be removed by simple filtration of the reaction mixture, while the excess of piperazine remains in the aqueous phase after extracting the filtrate with toluene at 70 °C. The product precipitates from the organic phase with 68% active yield.",10.1021/op034117u,1
"An Expedient Synthesis of LAF389, a Bengamide B Analogue","An optimized, convergent, safe synthesis of LAF389 ( 9 ), an anti-cancer agent analogous to bengamide B, is described. Starting from α- d -glucoheptonic ( d -glycero- d -gulo-heptonic acid) γ-lactone ( 10 ), the lactone 15 was constructed in five steps. Major improvements were made in the preparation of the aldehyde precursor 14 and subsequent olefination to yield 15 via a modified Julia protocol. This olefination was significantly improved by using TMSCl as an additive. The second fragment of the drug substance, ε-caprolactam 7, was obtained in two one-pot operations from (5 R )-5-hydroxy- l -lysine ( 1 ). Finally, opening 15 with 7 using sodium 2-ethyl hexanoate (Na-EH) gave 8, which on deprotection yielded LAF389.",10.1021/op0341162,1
"A New Practical Route for the Manufacture of (4aR,10aR)-9-Methoxy-1-methyl-6-trimethylsilanyl- 1,2,3,4,4a,5,10,10a-octahydrobenzo[<i>g</i>]quinoline","Different synthetic routes to the enantiomerically pure octahydrobenzo[ g ]quinoline derivative JNZ092 were evaluated for their suitability to rapidly prepare a first clinical batch on a kilogram scale. On the basis of the experience of previous octahydrobenzo[ g ]quinoline projects a new linear synthesis of JNZ092 was established and scaled up successfully. The overall yield was increased by a factor 10 and the preparation time shortened significantly as compared to those of the medicinal chemistry route. As the key strategy all atoms of the octahydrobenzo[ g ]quinoline skeleton were introduced early by the reaction of the 6-lithiated 1,7-dimethoxynaphthalene with ethyl-2-cyano-3-ethoxyacrylate. As a valuable technological refinement the practicability of a chromatographic technique with repetitive feed injection for the problematic separation of the enantiomers was demonstrated.",10.1021/op034112x,1
"The Synthesis of the High-Potency Sweetener, NC-00637. Part 3:  The Glutamyl Moiety and Coupling Reactions","The synthesis of the high-potency sweetener, NC-00637 ( 1 ), required selective preparation of the γ-protected glutamic acid. Coupling of the three components could be performed in any order, but the final route involved N -acylation of the protected l -glutamic acid with the acid chloride derived from ( S )-2-methylhexanoic acid. Activation of the α-carboxyl group allowed condensation with 5-amino-2-cyanopyridine ( 4 ). Saponification of the γ-ester 19 then provided the sweetener 1 .",10.1021/op0341115,1
"The Synthesis of the High-Potency Sweetener, NC-00637. Part 2:  Preparation of the Pyridine Moiety","The pyridine moiety within the high-potency sweetener, NC-00637 ( 1 ), 5-amino-2-cyanopyridine ( 4 ), was prepared from 2-hydroxy-5-nitropyridine ( 10 ). The sequence involved the conversion of the hydroxy group to bromide followed by substitution with cyanide to give 2-cyano-5-nitropyridine ( 8 ). Reduction of the nitro group proved to be troublesome when catalytic hydrogenation was used. Iron with an acid gave a reproducible reaction that could be used at scale.",10.1021/op034110c,1
Crystallization Process Development of an Active Pharmaceutical Ingredient and Particle Engineering via the Use of Ultrasonics and Temperature Cycling,"Process development of a Bristol-Myers Squibb drug substance candidate involved the development of crystallization and particle engineering protocols to address polymorphism, oiling out, and particle size control issues. Two monotropic polymorphs were evaluated, and one was determined to be thermodynamically more stable. The oiling problem was solved by adjusting the polarity of the solvent system and conducting controlled nucleation at low supersaturation. Two protocols were developed to produce the desired form consistently in high quality and yield with a short processing time. Slow crystallization was required to ensure product quality since the final crystallization served as an important purification step, but slower crystallization led to larger crystals. To avoid dry milling, ultrasound was used for particle size reduction in the crystal slurry post-crystallization. Temperature cycling followed for particle size uniformity. The scale-up involved use of an ultrasonic tube through which the crystal slurry was passed continuously. The protocol was successfully executed in multikilogram-scale GMP batches.",10.1021/op034107t,0
"Synthesis and Purification of 6-Ethoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic Acid Benzylamide","The synthesis of 6-ethoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid benzylamide ( 1 ) on multikilogram scale is described. The major challenge for the synthesis of this quinolone GABA partial agonist was in the isolation of product of acceptable purity for clinical studies due to the insolubility of this compound. Also described are efforts to circumvent a high-temperature cyclization required for the synthesis of the quinolone ring system.",10.1021/op0341061,1
Safety vs Efficiency in the Development of a High-Energy Compound,"A scalable route to 5-(2-carboxy-pyridin-2-yloxy)-benz[1,2,5]oxadiazole ( 3 ) is demonstrated. The synthesis was designed to minimize potential safety issues with a previously practiced route and, in particular, to avoid the handling of 5-hydroxybenzofurazan, which was found to decompose with a large energy release at relatively low temperatures. The new route builds the benzofurazan moiety onto a nicotinonitrile core to avoid high-energy intermediates with low onset temperatures of decomposition.",10.1021/op0341059,1
"Development of a Scalable Process for CI-1034, an Endothelin Antagonist","A concise, convergent multikilogram synthesis of CI-1034 (1 ), a potent endothelin receptor antagonist, is described. A 15-step preparation from commercially available o -vanillin and benzenesulfonyl chloride employs a remarkably robust Suzuki coupling between a boronic acid and an aromatic sulfonate ester as the key synthetic step. A scalable route capable of producing multikilogram quantities of CI-1034 with no chromatographic steps is described in this contribution. Improvements to the process included using a 4-fluorobenzenesulfonate ester as a suitable substitute for the triflate group in the Suzuki reaction and the use of MgCl 2 as a substitute for TiCl 4 in a Dieckmann condensation to provide the benzothiazine dioxide core.",10.1021/op034104g,1
"A Practical Synthesis of the Platelet Fibrinogen Antagonist, Elarofiban","Elarofiban is a novel, nonpeptide, orally active fibrinogen receptor antagonist useful for the treatment of platelet mediated thrombotic disorders (Costanzo, M. J.; Hoekstra, W. J.; Maryanoff, B. E. WO, 97/41102, 1997). Herein we describe the process research that was carried out for the synthesis of elarofiban that eventually led to the development of a safe and cost-effective commercial scale process.",10.1021/op034103o,1
A Comparison between Kinetic Parameters from the Synthesis of Tris(<i>p</i>-nitrophenyl)phosphite and Tris(<i>p</i>-nitrophenyl)phosphate Using Reaction Calorimetry,"Tris( p -nitrophenyl)phosphite was prepared by a modification of a “one-pot” methodology developed for the preparation of triaryl phosphates. This exothermic reaction was performed in a Mettler RC-1 calorimeter. The principal aim of this work was to compare the reactivity of phosphorus trichloride and phosphorus oxychloride in their reactions with sodium p -nitrophenoxide. The reaction rate and the reaction rate constant for the synthesis of tris( p -nitrophenyl)phosphite were evaluated and compared to the obtained values for the tris( p -nitrophenyl)phosphate synthesis. Phosphorus trichloride was found to react faster than phosphorus oxychloride, but the reaction with the phosphorus oxychloride proved to be more exothermic.",10.1021/op034100b,0
"Pilot Plant Preparation of an α<sub>v</sub>β<sub>3</sub> Integrin Antagonist. Part 1. Process Research and Development of a (<i>S</i>)-β-Amino Acid Ester Intermediate:  Synthesis via a Scalable, Diastereoselective Imino-Reformatsky Reaction","Described are four process research investigations directed toward discerning a scalable, enantioselective method for preparing ( S )-β-amino acid ester 3, a key intermediate to the α v β 3 integrin antagonist 1 . Reported are an asymmetric Michael reaction approach, attempts to enantioselectively hydrogenate an enamine, resolution of (±)- 3 via diastereomeric salt formation, and a synthetic route employing a novel, diastereoselective imino-Reformatsky reaction. This last research initiative proved successful and was employed as the enabling route to initial API supply. Process development of this enabling chemistry is reported. The technical issues researched and optimized were (1) the necessity of employing MEM-protection for high yield and diastereoselectivity in the imino-Reformatsky reaction, (2) the reaction kinetics of MEM chloride hydrolysis and the application of these data to an on-scale quench procedure, (3) the efficient formation of the ( S )-phenylglycinol imine 15 in NMP and a dehydration of this product solution on-scale, employing molecular sieves, (4) a calorimetric study of the Reformatsky reaction and the application of these data, (5) the replacement of Pb(OAc) 4 with NaIO 4 and the use of methylamine to sequester competing oxazolidine formation, and (6) further development of the isolation and purification protocol for the ethyl ester, p -TsOH salt of ( S )- 3 . The results and challenges associated with two campaigns in which the potential commercial process was practiced are discussed.",10.1021/op034094j,1
Practical Large-Scale Synthesis of Doripenem:  A Novel 1β-Methylcarbapenem Antibiotic,"A practical large-scale process for the synthesis of doripenem hydrate ( 1 ), a novel parenteral 1β-methylcarbapenem antibiotic, from p -nitrobenzyl-protected enolphosphate 2b and N -( p -nitrobenzyloxycarbonyl)-protected aminomethylpyrrolidine 3c is described. We found effective extraction conditions to remove p -toluidine and most other organic impurities using a THF/water system containing an inorganic salt. Significant improvements have been made to the previous synthesis using a medicinal chemical procedure. The new process requires no chromatographic purification and affords the target compound 1 as a sterile crystalline powder. Several kilograms of compound 1 were successfully prepared by this process.",10.1021/op034088n,1
Electrostatic Hazards in Liquids and Relevance to Process Chemistry,"Wherever there is flow of a liquid, there is the possibility of generating a static charge within it. The rate of flow, the conductivity of the liquid, and the diameter of the vessel/pipe have a dramatic effect on the electrostatic build up. Even though the system may be grounded, static charge can still accumulate and can often discharge in the form of a spark. This can lead to a number of problems in terms of process manufacture from the pitting of the vessel to the possibility of a fire where a flammable atmosphere is present. This report aims to highlight a number of issues with static buildup in liquids and the techniques, which can be used to minimise these hazards.",10.1021/op0340863,0
CO<sub>2</sub> Offgas as a Mechanistic Probe and Scale-up Tool in N-Acylations Using Mixed Anhydrides from Amino Acids and Isobutyl Chloroformate,"The reaction pathways of an N-acylation reaction, involving a mixed anhydride intermediate produced from reaction of an amino acid with isobutyl chloroformate, were analyzed using a novel technique involving the quantitation of CO 2 evolved during various parts of the process. Under the normal mode of addition, in which chloroformate is added to a carboxylate anion solution, the dominant mode of yield loss to undesired product was shown to be the formation of a symmetric anhydride, implying that byproduct urethane formation was almost exclusively due to reaction of unreacted chloroformate with amine. This result suggests that inferred high concentrations of carboxylate anion present with the normal addition mode should be minimized to decrease yield loss. This hypothesis was confirmed by demonstrating that symmetric anhydride formation is almost eliminated when the reverse addition (viz., addition of carboxylate anion solution to chloroformate) was carried out. These results, in conjunction with the relative temperature insensitivity of the pathways occurring after amine addition, were used to deduce that the higher amounts of remaining starting acid observed on scale-up were due to slower mixing at larger scales, resulting in greater symmetric anhydride yields. The reverse addition, although forming much lower symmetric anhydride amounts, is nevertheless a rapid reaction whose selectivity could be impacted adversely on scale-up due to slower mixing. The offgas methodology presented here can be used to quantify reaction selectivity as a function of scale and thus serve as a diagnostic tool for assessing mixing efficiency at larger scales.",10.1021/op034085a,0
A Scalable Synthesis of Meso-Substituted Dipyrromethanes,"A one-flask synthesis of meso-substituted dipyrromethanes has been refined. The procedure entails reaction of an aldehyde in 100 equiv of pyrrole as the solvent containing a mild Lewis acid (e.g., InCl 3 ) at room temperature. Following removal and recovery of excess pyrrole, the dipyrromethane is obtained by crystallization. The procedure generates minimal waste and does not require aqueous/organic extraction, chromatography, or distillation. The procedure has been scaled linearly to obtain >100 g of 5-phenyldipyrromethane. The utility of various analytical methods for characterizing dipyrromethanes has been investigated.",10.1021/op034083q,0
"A Convenient Synthesis of High-Purity 1-Chloro-2,6-difluorobenzene","A convenient preparation of high-purity 1-chloro-2,6-difluorobenzene has been developed. The key to the isolation of the desired isomer, without contamination of the difficult-to-separate isomer 1-chloro-2,3-difluorobenzene, is the use of sulfonyl chloride to direct fluorine substitution to the ortho and para positions of the aryl ring. Although activation with sulfonyl chloride requires additional reaction steps, the process results in good overall yield and requires only low-cost commodity chemicals. The high-purity 1-chloro-2,6-difluorobenzene is useful as an intermediate for active ingredients in agricultural and pharmaceutical applications.",10.1021/op0340816,1
"Software for Process Research, Development, and Scale-up","ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSoftware for Process Research, Development, and Scale-upTrevor LairdView Author Information EditorCite this: Org. Proc. Res. Dev. 2003, 7, 4, 449Publication Date (Web):June 28, 2003Publication History Published online28 June 2003Published inissue 1 July 2003https://pubs.acs.org/doi/10.1021/op034080dhttps://doi.org/10.1021/op034080deditorialACS PublicationsCopyright © 2003 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views651Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (17 KB) Get e-AlertscloseSUBJECTS:Crystallization,Kinetics,Safety,Software Get e-Alerts",10.1021/op034080d,0
"Practical Synthesis of <i>N</i>-{4-[(2-Methyl-4,5-dihydroimidazo[4,5-<i>d</i>][1]benzazepin- 6(1<i>H</i>)-yl)carbonyl]phenyl}biphenyl-2-carboxamide Monohydrochloride:  an Arginine Vasopressin Antagonist","A novel, reliable, and cost-effective synthetic route to N -{4-[(2-methyl-4,5-dihydroimidazo[4,5- d ][1]benzazepin-6(1 H )-yl)carbonyl]phenyl}biphenyl-2-carboxamide monohydrochloride ( 1, YM087), a potent Arginine vasopressin antagonist, has been developed. Using moisture-controlled potassium carbonate, imidazole formation from α-bromoketone furnished imidazobenzazepine, avoiding potential oxazole-ring formation. Catalytic reduction of nitro imidazobenzazepine afforded the corresponding amine in high yields. Treatment of the imidazole-containing amine directly, with a carbonyl chloride, afforded the target amide circumventing protection of the imidazole.",10.1021/op034079e,1
Rapid Scale-Up of the Matrix Metalloproteinase Inhibitor CH5902:  Process Safety and Route Development Considerations,"The synthesis of the novel MMP inhibitor CH5902 is described. In this approach, the original discovery route has been streamlined and telescoped into a four-stage sequence, which has been demonstrated on a multikilogram scale. A number of issues arising from both process development and process safety concerns are discussed.",10.1021/op0340762,1
Scalability of Microwave-Assisted Organic Synthesis. From Single-Mode to Multimode Parallel Batch Reactors,"The direct scalability of microwave-assisted organic synthesis (MAOS) in a prototype laboratory-scale multimode microwave batch reactor is investigated. Several different organic reactions have been scaled-up typically from 1 mmol to 100 mmol scale. The transformations include multicomponent chemistries (Biginelli dihydropyrimidine and Kindler thioamide synthesis), transition metal-catalyzed carbon−carbon cross-coupling protocols (Heck and Negishi reactions), solid-phase organic synthesis, and Diels−Alder cycloaddition reactions using gaseous reagents in prepressurized reaction vessels. A range of different solvents (high and low microwave absorbing), Pd catalysts (homogeneous and heterogeneous), and varying reaction times and temperatures have been explored in these investigations. In all cases, it was possible to achieve similar isolated product yields on going from a small scale (ca. 5 mL processing volume) to a larger scale (max 500 mL volume) without changing the previously optimized reaction conditions (direct scalability). The prototype, benchtop multimode microwave reactor used in the present study allows parallel processing in either quartz or PTFE-TFM vessels with maximum operating limits of 300 °C and 80 bar of pressure. The system features magnetic stirring in all vessels, complete on-line monitoring of temperature, pressure and microwave power, and the ability to maintain inert or reactive gas atmosphere.",10.1021/op034075+,0
Process for Developing 3β-[4-(<i>S</i>)-Arylacetylamino-4β-(2-(2-furyl)ethyl]azetidin-2-one:  A Carbacephem Key Intermediate,An optimized process for the stereospecific synthesis of carbacephem key intermediates 3β-[4-( S )-phenoxyacetylamino-4β-[2-(2-furyl)ethyl]azetidin-2-one ( 1 ) and 3β-[4-( S )-phenyl-acetylamino-4β-[2(2-furyl)ethyl)]azetidin-2-one] ( 2 ) is described. This report provides an efficient and cost-effective process for achieving a consistent yield and quality of intermediates 1 and 2 via Birch reduction employing a sodium/ammonia instead of lithium/ammonia system.,10.1021/op034074h,1
"Reaction Safety:  An Improved Procedure for the Preparation of 1,3,4,12a-Tetrahydro-11<i>H</i>-[1,4]-oxanio[3,4-<i>c</i>][1,4]benzodiazepine-6,12-dione with Iron in Acetic Acid","This contribution describes the development of an improved scaleable process to prepare 1,3,4,12a-tetrahydro-11 H -[1,4]-oxanio[3,4- c ][1,4]benzodiazepine-6,12-dione, 2, in a safe and operationally simple procedure using iron powder in acetic acid. The original procedure being used to prepare initial quantities of this material also involves the use of iron with acetic acid. However, these original reaction conditions are not amenable to scale-up due to safety and operational issues. Reaction calorimetry is used to evaluate modifications to the original conditions that result in an improved procedure that has been developed and scaled to produce multikilogram amounts of material for initial development studies.",10.1021/op034073p,0
"A Practical Synthesis of 6-[2-(2,5-Dimethoxyphenyl)ethyl]-4-ethylquinazoline and the Art of Removing Palladium from the Products of Pd-Catalyzed Reactions","A concise large-scale synthesis of 1, a new antimitotic agent is described. The key step was a one-pot Sonogashira cross-coupling of an aryl halide with a heteroaryl halide through an acetylene using the readily available 2-methyl-3-butyn-2-ol ( 7 ). An innovative approach for palladium removal was designed and successfully scaled-up on a multikilogram scale. The product was crystallized from the crude reaction mixture while keeping the residual palladium in the mother liquor by using Pd-scavenging agents such as N -acetylcysteine or thiourea.",10.1021/op034072x,1
"Evaluation and Optimisation of the Reagent Addition Sequence during the Synthesis of Atrazine (6-Chloro-<i>N</i><sup>2</sup>-ethyl-<i>N</i><sup>4</sup>-isopropyl-1,3,5-triazine-2,4-diamine) Using Reaction Calorimetry","The sequence of reagent addition and associated heats of reaction during the synthesis of the important herbicide atrazine (6-chloro- N 2 -ethyl- N 4 -isopropyl-1,3,5-triazine-2,4-diamine) from cyanuric chloride, isopropylamine, and ethylamine have been investigated by means of calorimetric and analytical methods. Sodium hydroxide was used as proton scavenger in this procedure. The best addition sequence found was the concurrent addition of amine and NaOH, keeping the amine in slight excess at all times. Using this feed sequence, the reaction becomes feed-controlled, and provided that a proper level of mixing can be maintained in the reactor, a high degree of control over reaction selectivity is obtained.",10.1021/op0340715,0
"A Scalable Synthesis of (<i>R</i>)-3,5-Dihydro-4<i>H</i>-dinaphth[2,1-<i>c</i>:1‘2‘-<i>e</i>]azepine","Environmentally benign scalable procedures are developed to supply enantiomerically pure ( R )-3,5-dihydro-4 H -dinaphth[2,1- c:1‘2‘- e ]azepine 1 as its hydrogen oxalate salt in a five-step overall yield of 41%, which consist of the following: (1) bis O -triflation of ( R )-1,1‘-bi-2-naphthol 8 [(CF 3 SO 2 ) 2 O, pyridine, PhMe; quantitative yield]; (2) Kumada's cross-coupling [MeMgI, NiCl 2 (dppp), tert -BuOMe; 96% yield]; (3) radical bromination [ N -bromosuccinimide, 2,2‘-azobisisobutyronitrile, cyclohexane; 54% yield]; (4) cyclization [allylamine, Et 3 N, THF, 86%]; (5) N -deallylation [1,3-dimethylbarbituric acid, Pd(OAc) 2, Ph 3 P, PhMe] followed by crystalline salt formation with oxalic acid (overall 92% yield).",10.1021/op034067t,0
"The Process Development of a Novel Aldose Reductase Inhibitor, FK366. Part 1. Improvement of Discovery Process and New Syntheses of 1-Substituted Quinazolinediones","This contribution describes part 1 of process development of a novel aldose reductase inhibitor FK366 ( 1 ). The original process applied on a laboratory scale was improved from the safety viewpoint to manufacture materials on 500-L scale suitable for toxicological and pharmacological evaluations. A new process, including regioselective alkylation of silylated quinazolinedione, provided a practical and cost-effective synthesis of FK366 in a dramatically increased yield.",10.1021/op0340661,1
The Chemical Development of LB71350,An efficient synthesis of the HIV-1 protease inhibitor LB71350 ( 1 ) is described. High diastereoselective epoxidation of the cis -allylic carbamate fragment of (5 S )-[ N -(benzyloxycarbonyl)-amino]- N -[2-methyl-(1 R )-[(phenyl)carbonyl]-propyl]-6-phenylhex-( Z )-enamide ( 16 ) and one-pot preparation of N -[(1-methylethoxy)carbonyl]-3-(methylsulfonyl)- l -valine ( 4 ) are the key features of the synthesis.,10.1021/op034062w,1
An Efficient and Cost-Effective Synthesis of Pagoclone,"The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3 S -(5-methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA A receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a β-keto phosphonium salt was prepared by selectively reacting a primary α-bromo ketone with triphenylphosphine in the presence of a secondary α-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a γ-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.",10.1021/op034060b,1
"Process Development and Pilot Plant Scale Synthesis of Spiro[3.5]nonane-6,8-dione","A two step synthesis of spiro[3.5]nonane-6,8-dione is reported which allows the production of the target molecule on a pilot plant scale. The first step of the process comprises the epoxidation of spiro[3.5]non-7-en-6-one mediated by sodium perborate. Here, the use of sodium perborate proved beneficial over the standard protocols employing hydrogen peroxide since a much safer process was accomplished. The resulting crude epoxide was subsequently submitted to a palladium-catalyzed rearrangement to afford spiro[3.5]nonane-6,8-dione in 26% overall yield.",10.1021/op0340560,1
"Safety Aspects of the Under-Pressure Reaction of Trichloroacetyl Chloride and Acrylonitrile in the Preparation of 3,5,6-Trichloro-2-pyridinol","The under-pressure reaction of trichloroacetyl chloride ( 1 ) with acrylonitrile ( 2 ) in the preparation of 3,5,6-trichloro-2-pyridinol becomes explosive in certain circumstances. The studies of the reaction's enthalpy, the instability of the 2-chloropropionitrile ( 8 ), and the observation of the unexpected increase of pressure have helped us to point out that the above feature is due to the exothermic nature of the reactions and the HCl released by the 2-chloropropionitrile decomposition at elevated temperature. So, controlling the temperature and well-done stirring of the reaction mixture is very important in large-scale production to avoid the explosion nature of the reaction.",10.1021/op0340558,0
"An Efficient One-Pot Process for 10-Bromo-8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-<i>b</i>]pyridin-11-one, an Intermediate to SCH 66336","An efficient process for the preparation of 10-bromo-8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2- b ]pyridin-11-one ( 7), an intermediate to an antitumor agent SCH 66336, is described. This one-pot method consists of a selective reduction of 8-chloro-7(9)-nitro-5,6-dihydro-benzo[5,6]cyclohepta[1,2- b ]pyridin-11-one ( 4 ) with Sn(II) bromide (generated in situ from Sn(II) sulfate and HBr), followed by bromination at the 10 position, and deamination. The desired product ( 7 ) is isolated in 75% overall yield.",10.1021/op034054f,1
Solvent-Free Organic Synthesis By K. Tanaka. Wiley−VCH:  Weinheim. 2003. 433 pp. £80. ISBN 3-527-30612-9.,,10.1021/op034052v,0
Process Development and Scale-Up of the PPAR Agonist NNC 61-4655,"A scalable synthetic route of the nonselective but PPARα-preferring potent PPAR agonist NNC 61 - 4655 aimed for treatment of type 2 diabetes was developed. The synthetic pathway comprises the convergent synthesis and coupling of the two key intermediates E -5-(chloropent-3-en-1-ynyl)benzene 8 (prepared in a five-step synthesis in 18% overall yield) and ( S )-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid isopropyl ester 9 . The 2-aminoethanol salt of NNC 61 - 4655 was selected in a preclinical salt selection program as the appropriate salt form for further development. More than 900 g of NNC 61 - 4655, 2-aminoethanol was finally synthesized under GMP in 98.7% purity. In comparison to the original medicinal chemistry route, starting from phenylpropargyl aldehyde 1, the overall yield towards NNC 61 - 4655 could be enhanced from 24 to 37%. An improved scalable two-step synthesis for 8 was developed on a laboratory scale (≥33−35% overall yield) shortly after the GMP batch.",10.1021/op034048j,1
"Cross-Coupling Methods for the Large-Scale Preparation of an Imidazole−Thienopyridine:  Synthesis of [2-(3-Methyl-3H-imidazol-4-yl)- thieno[3,2-<i>b</i>]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine","The multihundred-gram synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2- b ]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine ( 1 ) is described utilizing a Stille cross-coupling of an iodothienopyridine ( 3 ) with 5-(tributylstannyl)-1-methylimidazole ( 11 ). Several cross-coupling methods were evaluated for the conversion of thienopyridine 3 to imidazole−thienopyridine 2, but only two were effective: the Stille coupling and a Negishi cross-coupling of the organozinc reagent derived from 2-( tert -butyldimethylsilyl)-1-methylimidazole and iodothienopyridine ( 3 ). The latter procedure worked well on laboratory scale (<50 g), but was capricious upon scale-up. The issues with scale-up of an organostannane reagent are discussed, including control and analysis of organotin levels.",10.1021/op0340457,1
Catalysts and Process for the Production of Benzyl Toluenes,"A method for the synthesis of benzyl toluenes from toluene and using molecular bromine as catalytic operator is reported here. The process can be carried out in one of two ways: the first method involves the simultaneous bromination/alkylation of toluene, followed by recycling of the liberated HBr to an oxidation reactor to form molecular bromine; the second method involves the formation of benzyl bromide in a separate step with in situ bromine recycling, followed by alkylation of toluene. HBr liberated during the alkylation step is recovered and recycled in the bromination reactor. Solid catalysts that maximize side-chain bromination over ring bromination, whilst at the same time catalysing the Friedel−Crafts condensation of toluene with benzyl bromide, are key to the success of the process.",10.1021/op034043m,0
Practical Large-Scale Synthesis of the 2-Aminomethylpyrrolidin-4-ylthio-Containing Side Chain of the Novel Carbapenem Antibiotic Doripenem,"The first synthesis using an original procedure and a practical large-scale process using an improved procedure for the synthesis of the N -PNZ-protected 2-aminomethylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate (S-4661), a novel parenteral 1β-methylcarbapenem antibiotic, are described. trans -4-Hydroxy- l -proline ( 4 ) was converted in an efficient process to (2 S,4 S )-4-acetylthio-2-( N -sulfamoyl- tert -butoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine ( 3 ) in 55−56% overall yield via a six-step sequence, which includes the two alternative routes to intermediate 13 . This process requires no chromatographic purifications, no cryogenic temperatures, no haloalkane solvents, and short operating times and is amenable to a multikilogram-scale preparation. Several kilograms of the side chain 3 were successfully prepared by this process.",10.1021/op0340412,1
"Developing an Industrial Chemical Process:  An Integral Approach By J. Mizrahi. CRC Press:  Boca Raton, FL. 2002. 229 pp. $140 (Paperback). ISBN 0-8493-1360-0.",,10.1021/op034039a,0
Organolithiums:  Selectivity for Synthesis By J. Clayden. Elsevier:  the Netherlands. 2002. 384 pp. $125. ISBN 0-08-043262X. $45 (Paperback). ISBN 0-08-0432611.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewOrganolithiums: Selectivity for Synthesis By J. Clayden. Elsevier: the Netherlands. 2002. 384 pp. $125. ISBN 0-08-043262X. $45 (Paperback). ISBN 0-08-0432611.Cite this: Org. Proc. Res. Dev. 2003, 7, 3, 448Publication Date (Web):April 9, 2003Publication History Published online9 April 2003Published inissue 1 May 2003https://doi.org/10.1021/op034038iCopyright © 2003 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views142Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (13 KB) Get e-AlertsSUBJECTS:Substitution reactions Get e-Alerts",10.1021/op034038i,0
Chemical Development on the Chiral Auxiliary (<i>S</i>)-4-(Phenylmethyl)-2-oxazolidinone Utilizing Automated Synthesis and DoE,"Enantiopure 4-substituted oxazolidinones are well-known chiral auxiliaries for asymmetric synthesis of carboxylic acid derivatives. The 4-(phenylmethyl)-substituted oxazolidinones derived from d - or l -phenylalanine are known to be particularly useful. We have conducted chemical development studies toward an efficient and scaleable “one-pot” process for production of ( S )-4-(phenylmethyl)-2-oxazolidinone 2 . The first step in the process employed a sodium borohydride reduction of phenylalanine mediated by an additive. The second step utilized triphosgene as a phosgene source to effect cyclization of the intermediate amino alcohol. Both chemical steps and workup procedures were screened and optimized utilizing statistical design of experiments (DoE) and parallel synthesis. The procedure was further characterized in an automated reactor system that provided heat flow measurements and modeled production at the plant scale. The efficiency of this process was compared to those of others previously reported on the basis of raw material cost, time requirements, safety, and hazardous waste generation.",10.1021/op034033l,0
Scale-Up of the Synthesis of a Pyrimidine Derivative Directly on Solid Support,"The solid-phase synthesis of 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide, a compound obtained through combinatorial chemistry and parallel synthesis, can be scaled up directly on solid support in excellent yields and high purity. By applying highly loaded aminomethyl polystyrene as solid support, a good ratio between the product and the starting resin is achieved. For comparison, the synthesis was also performed in solution. The solid-phase synthesis approach has the advantage that the desired compound is easily and quickly accessible in sufficient quantities for early development demands.",10.1021/op034032t,1
Concepts of Nature in Organic Synthesis:  Cascade Catalysis and Multistep Conversions in Concert,"The development of cascade conversions (i.e. combined (catalytic) reactions without intermediate recovery steps as taking place in living cells) is considered as one of the important future directions for carrying out sustainable organic syntheses with inherently safer designs. It will drastically reduce operating time and costs as well as consumption of auxiliary chemicals and use of energy. Production of waste for multistep syntheses might ultimately reach the level of well below 1 kg per kg of product. The concept of cascade conversions is demonstrated by a representative selection of illustrative, mostly catalytic, examples on laboratory as well as on pilot or industrial scale and discussed within the strategic context of new synthesis methodology as required by present developments in life sciences industries. Full exploitation of such multistep syntheses and catalysis will require the development of novel, mutually compatible, organic and biosynthetic methods and procedures. Eventually a full integration of organic synthesis and biosynthesis can be envisaged. Syntheses requiring a smaller range of reaction parameters and reagents but a more intricate array of efficient catalysts might be expected. Integration with in situ product separation techniques will become mandatory, preferably by continuous processing.",10.1021/op0340311,0
"A Practical Synthesis of 3-<i>n</i>-Propylphenol, a Component of Tsetse Fly Attractant Blends",A practical synthesis of the tsetse fly attractant 3- n -propylphenol involves the Grignard reaction of 3-hydroxybenzaldehyde and ethylmagnesium bromide affording a benzylic alcohol-type phenol derivative that upon catalytic hydrogenation gives the title product in 75% overall yield. Selection of the right solvent mixture and temperature range for the Grignard reaction is crucial for the kilogram-scale preparation of the target compound.,10.1021/op0340309,1
"Strictly “Pair”-Selective and Economical Synthesis of Conjugated Diynes via Pd-Catalyzed Reaction of Terminal Alkynes with 1,1-Dichloroethylene, Elimination with LDA, and Subsequent Transformations","Various unsymmetrically substituted conjugated diynes can be synthesized in a completely “pair”-selective manner via Pd-catalyzed reaction of terminal alkynes with 1,1-dichloroethylene in the presence of Pd(PPh 3 ) 4 followed by elimination with 2 equiv of lithium diisopropylamide (LDA), zincation with ZnBr 2 or ZnCl 2, and Pd-catalyzed cross-coupling with aryl and alkenyl iodides and bromides. The desired unsymmetrically substituted conjugated diynes have been obtained in >80% yields except in two cases where an alkenylzinc reagent generated in situ from ( E )-3-iodo-2-propenol was used. The use of 1,1-dichloroethylene renders this method more economical than those involving 1,2-dihaloethylenes previously reported.",10.1021/op034029+,0
The Synthesis of <i>N</i>-Aryl-5(<i>S</i>)-aminomethyl-2-oxazolidinone Antibacterials and Derivatives in One Step from Aryl Carbamates,"Since 1993, a significant process research and development effort directed towards the large-scale synthesis of oxazolidinone antibacterial agents has been ongoing in both Early Chemical Process Research and Development, and Chemical Process Research and Development at Pharmacia. This work has led to the successful development of the current commercial process to produce Zyvox (linezolid), recently approved by the FDA as an antibacterial. While this synthesis is appropriate for the preparation of linezolid in particular, a more convergent and versatile synthesis was developed for the rapid preparation of numerous other oxazolidinone analogues. Toward this end, economical methods for the large-scale preparation of N -[(2 S )-2-(acetyloxy)-3-chloropropyl]acetamide 3 and tert -butyl [(2 S )-3-chloro-2-hydroxypropyl]carbamate 27 from commercially available ( S )-epichlorohydrin via the common intermediate (2 S )-1-amino-3-chloro-2-propanol hydrochloride 2a were developed. Also, general methods for coupling these reagents with N -aryl carbamates to give N -aryl-5( S )-aminomethyl-2-oxazolidinone derivatives in one step were developed. These reagents and procedures have proven widely applicable in the preparation of a diverse array of oxazolidinone analogues such as 23 and 28 in both process and medicinal chemistry research.",10.1021/op034028h,1
Identification and Control of a Process-Related Impurity in the Chlorination of 3-Hydroxy-3-carbacephem,"A process for the synthesis of carbacephem key intermediate (4-nitrophenyl)methyl,7-amino-1-carba(dethia)-3-chloro-3-cephem-4-carboxylate, monohydrochloride (1 ) via chlorination and deacylation employing chlorotriphenoxyphosphonium chloride [(PhO) 3 P + ClCl - ] has been described. The most difficult problem encountered during the process development was the formation of an impurity 2, which has been isolated, identified, and controlled by modifying the reaction conditions.",10.1021/op034026x,0
"The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 1:  Synthesis of the Key Intermediate 2,3,4,5-Tetrahydro-4-methyl-3-oxo-1<i>H</i>-1,4-benzodiazepine-2-acetic Acid Methyl Ester, SB-235349","The development of an efficient manufacturing route to 2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid methyl ester SB-235349, a key intermediate in the synthesis of lotrafiban is described. The synthesis starts with 2-nitrobenzyl alcohol which is mesylated, reacted with methylamine and then dimethylacetylene dicarboxylate followed by reduction of the nitro group. Treatment of the resultant aniline with acid gives an intermediate quinazoline which rearranges on treatment with base to give a 1,4-benzodiazapine. Reduction of the exocyclic double bond affords SB-235349. The process can be run without isolation of any of the intermediates and has been used to prepare several tons of SB-235349.",10.1021/op034024c,1
The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 2:  Conversion of the Key Intermediate SB-235349 to SB-214857-A,"The process development to the manufacturing route to (2 S )-7-([4,4‘-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid hydrochloride (SB-214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2 RS )-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2 S )-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2 S )-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid. The unreacted ( R )-enantiomer of the starting ester is recovered and recycled to the racemate by treatment with sodium methoxide. The next stage describes the palladium-catalysed aminocarbonylation of the aryl iodide with 4,4‘-pyridylpiperidine to give (2 S )-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1 H -1,4-benzodiazepine-2-acetic acid dihydrate. The third stage is the hydrogenation of the pyridine subunit over palladium on charcoal to obtain the zwitterionic (2 S )-7-([4,4‘-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1 H -1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.",10.1021/op034023k,1
Ionic Liquids in Synthesis Edited by P. Wasserscheid and T. Welton. Wiley-VCH:  Weinheim. 2003. xvi + 364 pp. £80. ISBN 3-527-30515-7.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewIonic Liquids in Synthesis Edited by P. Wasserscheid and T. Welton. Wiley-VCH: Weinheim. 2003. xvi + 364 pp. £80. ISBN 3-527-30515-7.Cite this: Org. Proc. Res. Dev. 2003, 7, 2, 223–224Publication Date (Web):February 26, 2003Publication History Published online26 February 2003Published inissue 1 March 2003https://doi.org/10.1021/op0340210Copyright © 2003 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views791Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (25 KB) Get e-AlertsSUBJECTS:Catalysts,Physical and chemical processes,Purification,Salts,Solvents Get e-Alerts",10.1021/op0340210,0
A Scalable Asymmetric Synthesis of (<i>R</i>)-2-Amino-1-(3-pyridinyl)ethanol Dihydrochloride via an Oxazaborolidine Catalyzed Borane Reduction,This report describes a scalable process for the asymmetric synthesis of ( R )-2-amino-1-(3-pyridinyl)ethanol dihydrochloride. The stereochemistry of the product is set via a reduction of 3-chloroacetyl pyridine with 2 equiv of borane-dimethyl sulfide and a catalytic amount of an in situ generated oxazaborolidine. The enantiomeric excess (ee) of the reductive step depends on the addition rate of the substrate and the temperature. The authors hypothesize that the low ee observed during a fast addition of the substrate or at low temperatures is due to the slow regeneration of the active catalyst from the catalyst−product complex.,10.1021/op0340208,1
SYNPHOS: a New Atropisomeric Diphosphine Ligand. From Laboratory-scale Synthesis to Scale-up Development,"A new optically active diphosphine ligand, [(5,6),(5‘,6‘)-bis(ethylenedioxy)biphenyl-2,2‘-diyl]bis(diphenylphosphine) (SYNPHOS) has been synthesized. Laboratory-scale synthesis and scale-up development of this ligand are described herein. This new atropisomeric diphosphine was also used in ruthenium-catalyzed asymmetric hydrogenation.",10.1021/op034016w,1
There's No Industrial Biocatalyst Like Hydrolase:  Development of Scalable Enantioselective Processes Using Hydrolytic Enzymes<sup>1</sup>,"Chiral, racemic esters, ethyl (±)-tetrahydrofuran-2-carboxylate 4c, methyl (±)-α-phenylpropionate 9b, methyl (±)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate 12a, 2-methoxyethyl (±)-1-(4- tert -butylphenyl)-2-oxopyrrolidine-4-carboxylate 15a, (±)-1-benzyloxy-3-chloropropan-2-yl hydrogen succinate 18c, and (±)-3-butyryloxyquinuclidinium butyrate [(±)- 20b · n -PrCO 2 H], are resolved kinetically by enantioselective hydrolysis catalyzed by an Aspergillus melleus protease [ E = 60; 93.9% ee and 35% yield for ( R )-tetrahydrofuran-2-carboxylic acid 4a ], a Klebsiella oxytoca hydrolase [ E > 200; 99.5% ee and 36% yield for ( S )-α-phenylpropionic acid 9a ], a K . oxytoca hydrolase [ E = 145; 97.7% ee and 34% yield for ( R )-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid 12b ], a Bacillus brevis protease [ E = 77; 99% ee and 45% yield for ( S )- 15a ], a Serratia marcescence esterase [ E = 49; 99% ee and 43% yield for ( S )- 18c ], and an A . melleus protease [ E = 96; 96% ee and 42% yield for ( R )- 20b ], respectively. Each enzymatic process is discussed with focus on the following tactical issues: (1) identification of a hydrolase with high enantioselectivity, (2) substrate concentrations not less than 1 M that allow for industrially viable volume efficiency (space−time yield), (3) product separation by partition between organic and aqueous phases, and (4) alleviation of a hydrolysate inhibiting the enzymatic activity.",10.1021/op034014b,1
"The Pilot Plant Real Book - A Unique Handbook for the Chemical Process Industry By Francis X. McConville. FXM Engineering and Design:  Worcester, MA (http://www.pprbook.com). 2002. 312 pp. Price $89.95. ISBN 0-9721769-1-8.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTThe Pilot Plant Real Book - A Unique Handbook for the Chemical Process Industry By Francis X. McConville. FXM Engineering and Design: Worcester, MA (http://www.pprbook.com). 2002. 312 pp. Price $89.95. ISBN 0-9721769-1-8.Will WatsonView Author Information Scientific Update, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, United KingdomCite this: Org. Proc. Res. Dev. 2003, 7, 2, 223Publication Date (Web):February 13, 2003Publication History Published online13 February 2003Published inissue 1 March 2003https://pubs.acs.org/doi/10.1021/op034013jhttps://doi.org/10.1021/op034013jbook-reviewACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views756Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Amorphous materials,Elastomers,Manufacturing,Materials,Separation science Get e-Alerts",10.1021/op034013j,0
Process Development of ONO-2506:  A Therapeutic Agent for Stroke and Alzheimer's Disease,"A process for the synthesis of ONO-2506, an agent that suppresses astrocyte activation, has been developed. Significant improvement of the level of impurities in the final product has been achieved compared with the laboratory-scale procedure. Kilogram quantities of the compound have been supplied for preclinical studies by this improved process, with both a high quality (99.8%) and a high optical purity (99.6% ee). This was achieved by formation of a crystalline salt of an intermediate which could be recrystallized to give high purity. Toward the future launch of this product, residual problems such as byproduct formation during stereoselective allylation and removal of chiral auxiliary steps were also solved by further investigation.",10.1021/op034008f,1
Practical Preparation and Resolution of 1-(2‘-Diphenylphosphino-1‘-naphthyl)isoquinoline:  A Useful Ligand for Catalytic Asymmetric Synthesis,"A practical synthesis of the atropisomerically chiral ligand QUINAP is described, followed by its efficient resolution into enantiomers by employing a deficiency of the chloropalladium complex derived from 1‘ -(R)- 1‘-(dimethylamino)-1-ethylnaphthalene. The X-ray structure of the ligand, which crystallises as a conglomerate, is reported.",10.1021/op034007n,1
Efficient Enantioselective Synthesis of the NMDA 2B Receptor Antagonist Ro 67-8867,"An efficient, enantioselective, and scalable eight-step synthesis for the NMDA 2B receptor antagonist Ro 67-8867 ( S, S )- 1 selected for the treatment of acute ischemic stroke is described based on the coupling reaction of the amino alcohol ( S, S )- 6 with the sulfone building block 7. The synthesis of the amino alcohol ( S, S )- 6 was achieved by the highly selective asymmetric hydrogenation of the piperidinone 4*HCl proceeding with concomitant dynamic kinetic resolution to ( S, S )- 5 . Subsequent debenzylation afforded the enantiomerically pure amino alcohol ( S, S )- 6 after ee-enhancement by simple crystallization in good yield. The hydrogenation substrate 4*HCl was prepared as a stable hydrochloride in two steps from ethyl N -benzyl-3-oxo-4-piperidinecarboxylate hydrochloride ( 2 ) for which a new, short, efficient, and cheap synthesis was developed. To bypass a mutagenic intermediate, a revised safe protocol for the sulfone building block 7 was established. The new synthesis allows the access to Ro 67-8867 ( S, S )- 1 in an overall yield of 53% compared to 3.5% of the Discovery Chemistry approach.",10.1021/op034006v,1
Asymmetric Synthesis of an MMP-3 Inhibitor Incorporating a 2-Alkyl Succinate Motif,"An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 ( 1 ) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the biarylpropanal equivalent ( 11 ), which was reacted with the phosphonosuccinate ( 10 ) to selectively afford the trans- β-substituted itaconate ( 12 ). Catalytic asymmetric hydrogenation of the itaconate ( 12 ) was achieved in good conversion and with 86−96% enantiomeric excess with a range of phosphine-modified rhodium and ruthenium cationic complexes. The resulting enantiomerically enriched 2-alkyl succinate ( 2 ) was elaborated to the desired drug substance ( 1 ) in two steps. The synthesis benefits from several crystalline intermediates, allowing control of process impurities, and can be operated safely within parameters readily achievable on scale. Investigations into the polymorphic forms of ( 1 ) have shown that the compound crystallizes in planar sheets, based on a backbone of hydrogen-bonding amide and acid functionalities, with large hydrophobic pockets formed by the biarylpropyl groups. An understanding of this crystal-packing arrangement has aided the development of crystallization processes allowing complete control over solid form.",10.1021/op034001y,1
Overcoming Backpressure Problems during Solid-Phase Synthesis of Oligonucleotides,"During solid-phase synthesis of oligonucleotides in packed-bed reactors a substantial pressure build-up is observed during acid deprotection and subsequent solvent washing as the length of the support-bound oligonucleotide increases. Maintaining high flow rates of reagents and wash solvents is crucial to achieving the necessary short acid-exposure times during these steps. Exceeding the maximum system pressure limit, especially likely to occur in the latter part of the synthesis, may lead to shutdown of the automated synthesis. Addition of inert filling materials (e.g., glass microspheres, quartz sand) to the polymeric polystyrene-based solid support reduces pressure build-up, allowing automated synthesis to go to completion without reducing flow rates or manual intervention.",10.1021/op030213j,0
Preparation of Guanine PDE Inhibitors:  Development of the Common Synthetic Route Strategy. A Case Study,"A single synthetic route, called the chloropurine route, capable of quickly delivering initial kilogram quantities of several chiral as well as achiral guanine phosphodiesterase inhibitors of increasing complexity is described. During the course of this work, unraveling the formation mechanism of chloropurines allowed for the scale-up of the key intermediates. The mechanism for the cyclization of the chiral five-membered amino alcohols and its implication on the enantiomeric purity needed for this step are also described.",10.1021/op030212r,1
"Research and Development of a Second-Generation Process for Oseltamivir Phosphate, Prodrug for a Neuraminidase Inhibitor","A second-generation manufacturing process from a shikimic acid-derived epoxide to oseltamivir phosphate features a magnesium chloride−amine complex-catalyzed ring opening of the epoxide by tert -butylamine, a selective O-sulfonylation of the resulting tert -butylamino alcohol, a surprisingly efficient cleavage of a tert -butyl group from an aliphatic tert -butylamide, and the isolation of oseltamivir phosphate from a palladium-catalyzed allyl transfer reaction mixture. The overall yield from the epoxide to oseltamivir phosphate has been increased from 27 to 29% or 35−38% for two previous processes, respectively, to 61%.",10.1021/op0302107,1
"Process Research on [(2<i>S</i>)-(3-Fluorophenyl)-(1<i>S</i>)-(5-oxotetrahydrofuran- 2-yl)ethyl]carbamic Acid <i>tert</i>-Butyl Ester, a Lactone Intermediate for an Aspartyl Protease Inhibitor","Two processes for the preparation of lactone [2 S -(3-fluorophenyl)-1 S -(5-oxotetrahydrofuran-2-yl)ethyl]carbamic acid tert -butyl ester 1 starting from S -BOC-(3-fluorophenyl)alanine 3 are described. ( S )-(3-Fluorophenyl)alanine N -methyl- N -methoxy amide 10, the Weinreb amide of 3, was reacted with 2-(2-1,3-dioxanyl)ethylmagnesium bromide to provide key intermediate ketoacetal 11 . To achieve high yields for this conversion, the N−H of the BOC group in Weinreb amino acid amide 10 was deprotonated first with a simple Grignard reagent (methyl or benzylmagnesium halide) followed by Barbier reaction with magnesium metal and 2-(2-bromoethyl)-1,3-dioxane. The acetal group in 11 was opened oxidatively with ozone, and the resulting ester 15 was reduced selectively at low temperature with N -Selectride. Alternatively, the ketone moiety in 11 was reduced diastereoselectively with aluminum triisopropoxide in 2-propanol to give the undesired ( R, S )-diastereomeric alcohol. The alcohol was converted to the mesylate which was heated in solution to cause formation of oxazolidinone 19 through displacement of the mesylate group by the carbonyl moiety of the BOC group with loss of tert -butyl alcohol. This intramolecular reaction provided the desired ( S, S )-diastereomer. Finally, acetal 19 was converted to nitrile 20 with hydroxylamine hydrochloride in ethanol with catalytic toluenesulfonic acid at reflux. Basic aqueous hydrolysis of nitrile 20 followed by treatment with di- tert -butyl dicarbonate provided 1 . While the second process was longer, the inexpensive reagents, simple reaction conditions, and high yields made it the process of choice. Both processes have been run on a multikilogram scale.",10.1021/op030207n,1
Process Research of (<i>R</i>)-Cyclohexyl Lactic Acid and Related Building Blocks:  A Comparative Study,"( S )-Cyclohexyl lactic acid is a component of the selective E-selectin inhibitor 2 (( S )-cHexLact-2- O -(3-Galβ(1→3)ddGlc(4→1)αFuc). We describe the evaluation of various synthetic routes to this building block: ( A ) diazotation of phenylalanine followed by phenyl ring hydrogenation; ( B ) phenyl ring hydrogenation of phenyl alanine followed by diazotation; ( C ) acidic hydrolysis of the cyanohydrin derived from phenylacetaldehyde, enantiomeric resolution of the resulting, racemic phenyl lactic acid via diasteromeric salt formation and phenyl ring hydrogenation; ( D ) enantioselective dihydroxylation of a cinnamate ester, followed by hydrogenation of the benzylic hydroxy group and the aromatic nucleus; ( E ) enantioselective biocatalytic reduction of phenylpyruvic acid, followed by phenyl ring hydrogenation. The development of (2 R )-2- O -(4-nitrophenyl)sulfonyl-cyclohexyl lactic acid p -bromobenzylester 21 as a buidling block with improved crystallinity and stability is also described.",10.1021/op030202q,1
"A Practical Pilot-Scale Synthesis of 4-Vinyl-2,3-dihydrobenzofuran Using Imidate Ester Chemistry and Phase-Transfer Catalysis","A two-step telescoped synthesis of 4-vinyl-2,3-dihydrobenzofuran ( 2 ) was demonstrated using imidate ester chemistry and phase-transfer catalysis. Treatment of 2,3-bis(2-hydroxyethyl)phenol ( 1 ) with the Vilsmeier reagent resulted in an in situ generation of a bis-imidate intermediate 4, which was converted to 4-(2-chloroethyl)-2,3-dihydrobenzofuran ( 6 ) via a sequential ring closure and chloride displacement reactions. Further dehydrohalogenation of 6 using a phase-transfer catalyst provided an excellent, cost-effective method to prepare high quality 4-vinyl-2,3-dihydrobenzofuran ( 2 ). The yields for the two-step telescoped process ranged from 83 to 90%.",10.1021/op030201y,1
Polymeric Materials in Organic Synthesis and Catalysis Edited by Michael R. Buchmeiser. Wiley Interscience:  Weinheim. 2003. xxxiii + 559 pp. 159 Euro/235 SFR. ISBN 3-527-30630-7.,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTPolymeric Materials in Organic Synthesis and Catalysis Edited by Michael R. Buchmeiser. Wiley Interscience: Weinheim. 2003. xxxiii + 559 pp. 159 Euro/235 SFR. ISBN 3-527-30630-7.Philip HodgeView Author Information Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United KingdomCite this: Org. Process Res. Dev. 2005, 9, 1, 121–122Publication Date (Web):December 18, 2004Publication History Published online18 December 2004Published inissue 1 January 2005https://pubs.acs.org/doi/10.1021/op030052jhttps://doi.org/10.1021/op030052jbook-reviewACS PublicationsCopyright © 2005 American Chemical SocietyRequest reuse permissionsArticle Views147Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Catalysts,Chemical reactions,Polymers,Reagents,Solid phase synthesis Get e-Alerts",10.1021/op030052j,0
The Merck Bile Acid Cortisone Process:  The Next-to-Last Word,"A personal account of the process research and development effort at Merck and Company, leading to the first commercial process for the manufacture of cortisone acetate, is described.",10.1021/op030050z,1
"A Practical Synthesis of 2,3,4,6-Tetra-<i>O</i>-acetyl-1-<i>O</i>-(2-propenyl)-β-<scp>d</scp>-glucopyranoside Using ZnCl<sub>2</sub>","2,3,4,6-Tetra- O -acetyl-1- O -(2-propenyl)-β- d -glucopyranoside ( 1a ), which is a useful raw material in the synthesis of a bioactive agent, has been synthesized in 50% yield by reacting β- d -glucose pentaacetate and 3 mol equiv of an allyl alcohol with 0.9 mol equiv of ZnCl 2 in toluene at 80 °C for 2 h followed by recrystallization from diisopropyl ether. This method is suitable for the large-scale preparation of 1a due to its efficiency, safety, and cost-effectiveness.",10.1021/op0300488,0
Chromatography as an Enabling Technology in Pharmaceutical Process Development:  Expedited Multikilogram Preparation of a Candidate HIV Protease Inhibitor,"Chromatography plays a vital role in supporting preclinical pharmaceutical development, whether in providing assays for purity determinations, preparative separation of small amounts of intermediates for route selection studies, or purification of bulk drug substances on multikilogram scale. All three approaches are illustrated in the recent development of a candidate HIV protease inhibitor in these laboratories. Chiral supercritical fluid chromatography (SFC) on the hundreds-of-milligrams scale afforded an enantiopure intermediate to facilitate early synthetic studies, HPLC on the tens-of-grams scale provided purified material for use in salt form investigations, and HPLC using a 30 cm column was used to purify 5.6 kg of a key intermediate to provide material for early preclinical evaluations.",10.1021/op0300443,0
Calorimetric Approach and Simulation for Scale-Up of a Friedel−Crafts Reaction,"The present study, on the optimisation of the scale-up of a Friedel−Crafts acylation, joins together experimental calorimetric techniques and simulation techniques. The adopted methodology involved the execution of isothermal tests at different temperatures, using the reaction calorimeter RC1, to obtain the heat flow versus time data. These data were used to perform a kinetic study of the reaction by using the simulation software BatchCAD. The reliability of the adopted kinetic model was confirmed by comparing the experimental data obtained by operating the desired reaction in adiabatic mode (in a Phi-Tec II calorimeter) with the predictions of the kinetic model in the same conditions. Using this kinetic equation it was possible to simulate the process under pilot-plant conditions. The good agreement between the model predictions and the experimental data confirmed the accuracy of the kinetic equations. Finally several large-scale production-plant simulations were carried out varying both dosing time and reaction temperature to maximise the space/time yield and minimise the thermal risks. This led to a high quality and safe process, saving a large part of the time (and money) usually spent in traditional scale-up procedures.",10.1021/op030043a,0
A New Approach to the Rapid Parallel Development of Four Neurokinin Antagonists. Part 5. Preparation of ZM374979 Cyanoacid and Selective Crystallisation of ZM374979 Atropisomers,"ZM374979 cyanoacid was prepared from ZD4974 cyanoester by a selective Grignard reaction followed by selective ester hydrolysis. On conversion of ZM374979 cyanoacid to ZM374979 free base, atropisomerism was observed, necessitating the development of a process for the selective crystallisation of a single atropisomer.",10.1021/op030041q,1
A New Approach to Rapid Parallel Development of Four Neurokinin Antagonists. Part 4. Synthesis of ZD2249 Methoxy Sulfoxide,"The manufacture of ZD2249 methoxy sulfoxide ( 1 ) using a new project approach is described. Research department processes were scaled up to 100 L if process safety and robustness were not compromised; other factors were treated according to the new approach. Using this strategy, we were able to manufacture a key intermediate on sufficient scale to support delivery of 1 kg quantities of bulk drug within 6 months of the start of lab work.",10.1021/op030039z,1
Evaluation of Kinetic Parameters from the Synthesis of Triaryl Phosphates Using Reaction Calorimetry,"ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionEvaluation of Kinetic Parameters from the Synthesis of Triaryl Phosphates Using Reaction CalorimetryCarlos F. Pinto Machado e Silva and Joao F. Cajaiba da SilvaCite this: Org. Proc. Res. Dev. 2003, 7, 6, 1083Publication Date (Web):October 9, 2003Publication History Published online9 October 2003Published inissue 1 November 2003https://pubs.acs.org/doi/10.1021/op0300387https://doi.org/10.1021/op0300387correctionACS PublicationsCopyright © 2003 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views371Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (14 KB) Get e-Alertsclose Get e-Alerts",10.1021/op0300387,0
"An Efficient Synthesis of a Key Intermediate for the Biologically Active Vitamin D Analogue, Seocalcitol","In the key synthetic step in the manufacture of the key intermediate for the biologically active vitamin D analogue, seocalcitol, a more practical and attractive procedure is achieved using the commercially available EtMgBr and CeCl 3, resulting in 79% yield. The key intermediate is synthesised from vitamin D 2 in 10 steps with only three isolations, giving 21% overall yield.",10.1021/op030037e,1
Stereoselective Synthesis of Alkylphosphonates:  A Facile Rearrangement of Cyanoethyl-Protected Nucleoside Phosphoramidites,"Cyanoethyl-protected nucleoside phosphoramidites undergo a facile Michaelis−Arbuzov reaction upon addition of acrylonitrile to afford cyanoethyl phosphonates. This rearrangement is stereoselective at room temperature, but racemization is observed at high temperatures, indicating two different pathways. A plausible mechanism is proposed for this reaction.",10.1021/op030035u,0
A New Multipurpose Microreactor for Process Safety Studies,"A new glass-lined microreactor for SETARAMs Calvet Calorimeters BT 2.15 and C 80 is described, which allows fast and simple characterization of thermal properties of chemical reactions and reaction mixtures. Application examples are presented, and the special features of this reactor are outlined.",10.1021/op030030x,0
Optimisation of Ethyl(2-phthalimidoethoxy)acetate Synthesis with the Aid of DOE,"We investigated the reaction of alkylation of 2-phthalimidoethanol with ethyl chloroacetate leading to ethyl(2-phthalimidoethoxy)acetate. The synthesis was successfully optimised by applying factorial design. Major side products have been separated, identified, and characterised. The yield level was increased from 25% to 52%, and a method of decreasing the amount of side products has been proposed.",10.1021/op030029y,0
"Optimization of the Reduction of a 5-Benzylidenethiazolidine-2,4-dione Derivative Supported by the Reaction Response Surface Analysis:  Synthesis of Pioglitazone Hydrochloride","A reaction response surface analysis was applied to a series of experiments carried out under various conditions (temperature, time, amount of a catalyst and reduction reagents, purification of the substrate). Significant improvements were made in the C C bond reduction in the benzylidene−thiazolidinedione intermediate in the synthesis of pioglitazone hydrochloride.",10.1021/op0300286,0
Efficient Preparation of a Key Intermediate in the Synthesis of Roxifiban by Enzymatic Dynamic Kinetic Resolution on Large Scale,"Additional information is presented for the transformation of a kinetic resolution into a dynamic kinetic resolution of the isobutyl ester 5b to form the acid 2 in high yield and ee via the intermediacy of a thioester 6c, (Pesti, J. A.; Yin, J.; Zhang, L.-H; Anzalone, L. J. Am. Chem. Soc. 2001, 123, 11075−11076.). The development of optimized reaction conditions for the preparation of 6c, its dynamic kinetic resolution to 2, and the scale-up of both reactions into a pilot plant are described.",10.1021/op0300239,0
Combined Effect of Polymorphism and Process on Preferential Crystallization:  Example with (±)-5(4‘-Methylphenyl)-5-methylhydantoin,"The structural data of two varieties of the title compound as well as the corresponding irreversible polymorphic transition are detailed. Although extensive structural analogies are pointed out, the transition is of destructive/reconstructive type with a poor rate requiring days or even weeks for completion. Without seeding, evidence of epitaxial nucleation is given. The genuine impact of polymorphism on the preferential crystallization is highlighted. The greater the departure from thermodynamic equilibrium the greater the differences between the courses of the entrainments initiated with a given polymorph. The best result in terms of robustness, yield, and conditions for up-scaling is obtained by using a combination of (i) a smooth crystallization process (auto-seeded and polythermic: AS3PC), (ii) the use of the stable polymorph, (iii) a pretreatment of the solid particles designed to enlarge the surface of the solid phase ready for the crystal growth as soon as the cooling program is launched.",10.1021/op030022g,0
Online Spectroscopic Investigations (FTIR/Raman) of Industrial Reactions:  Synthesis of Tributyltin Azide and Hydrogenation of Chloronitrobenzene,"The utilization of online spectroscopic methods (FTIR/Raman) for the development and the monitoring of chemical processes was demonstrated with two important chemical reaction types. The synthesis of tri- n -butyltin azide takes place at the solid−liquid interface and is therefore very sensitive to changes of reaction conditions or surface properties. Traditional offline analysis should be avoided due to the high toxicity of the compounds. The concentration variations of all involved compounds were determined. In the same way, the synthesis of 2-chloroaniline was studied to detect the formation of an unstable intermediate (the hydroxylamine) which can lead to uncontrolled decomposition reactions. Online spectroscopy is an opportunity to obtain the information about a reaction system faster and more efficiently than with conventional methods. This allows the rapid optimization of safe chemical processes and provides information for process control.",10.1021/op030009w,0
Continuous Process for the Production of Aromatic Hydrocarbons from <i>n</i>-Hexane and C<sub>5+</sub> Natural Gas Liquid over Pd-Loaded ZSM-5 Zeolite,"A continuous process for the production of aromatic hydrocarbons from n -hexane and C 5+ natural gas liquid (C 5+ NGL) over Pd-loaded ZSM-5 zeolite in a tubular reactor was developed. The optimal conditions for continuous aromatization of n -hexane and C 5+ NGL were found at 400 °C reaction temperature and 0.4 cm 3 /min reactant feeding rate, employing ZSM-5 (0.5% Pd content) as a catalyst; under these conditions, n -hexane conversion and aromatic contents in reaction product were found to be 99.7% and 92.3%, respectively. GC and GC/MS analysis revealed that this continuous process for n -hexane aromatization yielded both benzene derivatives and naphthalene derivatives, including benzene (5.7%), toluene (23.6%), xylenes (25.0%), 4-ethyltoluene (3.5%), 1,3,5-trimethylbenzene (4.9%), 1-methylnaphthalene (4.3%), and 1,5-dimethylnaphthalene (3.6%). Under the same reaction conditions, C 5+ NGL gave 94.3% conversion and 92.6% aromatic contents in reaction product. The composition of product included benzene (8.1%), toluene (23.3%), xylenes (22.8%), 4-ethyltoluene (4.3%), 1,3,5-trimethylbenzene (3.7%), 1-methylnaphthalene (4.1%), and 1,5-dimethylnaphthalene (2.9%).",10.1021/op030007b,0
Efficient Synthesis of Antisense Phosphorothioate Oligonucleotides:  Evaluation of Dichloroacetic Acid at Higher Concentration to Reduce Cycle Time,Efficiency of phosphorothioate oligonucleotide syntheses could be improved by increasing the concentration of dichloroacetic acid in toluene to 10% from 3% (v/v) during the detritylation step. It was also found that dichloroacetic acid is better than dichloropropionic acid when compared at similar concentrations.,10.1021/op030006j,0
Development of the Juliá−Colonna Asymmetric Epoxidation Reaction:  Part 1. Preparation and Activation of the Polyleucine Catalyst,The preparation of silica-supported poly- l -leucine has been studied under a variety of reaction conditions leading to an efficient procedure for the preparation of material suitable for use in the Juliá−Colonna asymmetric epoxidation reaction.,10.1021/op0300037,0
"Synthesis and Chemistry of Agrochemicals VI Edited by D. R. Baker, J. G. Fenyes, G. P. Lahm, T. P. Selby, and T. M. Stevenson. ACS Symposium Series 800. American Chemical Society:  Washington, DC (Distributed by Oxford University Press). 2002. xii + 364 pp. £95/$135.00. ISBN 0-8412-3783-2.","ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTSynthesis and Chemistry of Agrochemicals VI Edited by D. R. Baker, J. G. Fenyes, G. P. Lahm, T. P. Selby, and T. M. Stevenson. ACS Symposium Series 800. American Chemical Society: Washington, DC (Distributed by Oxford University Press). 2002. xii + 364 pp. £95/$135.00. ISBN 0-8412-3783-2.Cite this: Org. Proc. Res. Dev. 2003, 7, 2, 223Publication Date (Web):January 23, 2003Publication History Published online23 January 2003Published inissue 1 March 2003https://doi.org/10.1021/op030001mCopyright © 2003 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views153Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (25 KB) Get e-AlertsSUBJECTS:Agrochemicals,Insecticides,Manufacturing,Vinyl Get e-Alerts",10.1021/op030001m,0
Development of Jacobsen Asymmetric Epoxidation and Sharpless Asymmetric Dihydroxylation Methods for the Large-Scale Preparation of a Chiral Dihydrobenzofuran Epoxide,"Two well-known methodologies, the Jacobsen asymmetric epoxidation (AE) and the Sharpless asymmetric dihydroxylation (AD) followed by epoxidation, were evaluated for the large-scale preparation of a chiral dihydrobenzofuran epoxide. The AE method was improved by substituting ethanol for dichloromethane for the dissolution of meta -chloroperbenzoic acid ( m -CPBA). This change in solvent had a significant impact on scaleability of the AE procedure by preventing crystallization of the m -CPBA during addition to the cold reaction mixture. Factors affecting the enantiomeric excess and yield of the chiral epoxide resulting from AD followed by epoxidation were studied. The Sharpless AD reaction provided the intermediate chiral diol as a solid with high ee (>98.5%). The Sharpless−Kolb conversion of the chiral diol to a chiral epoxide was modified to potassium tert -butoxide/tetrahydrofuran to obtain the product in good yield (74−84%) and high ee (>98%). Both the AE and AD processes were scaled up to prepare large quantities of the chiral epoxide.",10.1021/op025622e,0
Process Development for a Herbicide Intermediate via Catalytic Carboxylation of an Aromatic Diazonium Compound,"A laboratory process is described for the preparation of 2-sulfo-4-methoxybenzoic acid (SMBA) via diazotization of 2-amino-4-methoxy-sulfonic acid followed by Pd-catalyzed carbonylation in the presence of water. The most important process parameters were the catalyst precursor and water content. Both a two-step procedure using isolated diazonium compound as well as a one-pot reaction proved to be feasible. A yield of >95% SMBA was obtained after 3−4 h, using 1 mol % PdCl 2 at 8 bar and 60 °C. This is the first technically feasible catalytic carbonylation of an arene diazonium compound.",10.1021/op025621m,1
"The Synthesis of OSU 6162:  Efficient, Large-Scale Implementation of a Suzuki Coupling","The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU 6162 ( 1 ), a potential CNS agent from Pharmacia Corporation, is presented. The key construction in the described synthesis is a palladium-catalyzed aryl cross-coupling reaction between bromosulfone ( 4 ) and pyridyl borane ( 14 ). Initially developed conditions for this Suzuki reaction, conducted in tetrahydrofuran/aqueous hydroxide, delivered free base ( 6 ) or hydrochloride salt ( 15a ) in reproducible 80% yield. However, by changing the solvent to toluene and the base to carbonate, significant decreases in catalyst requirement were realized, and the methane sulfonate salt ( 15b ) of the coupled product could be obtained in reproducible 92−94% yield on 200-kg input. The success of the Suzuki reaction was critically dependent on a bulk source of the pyridyl borane coupling partner. Cryogenic conditions were developed for its generation via lithium−halogen exchange to generate thermally labile 3-lithiopyridine followed by transmetalation with diethylmethoxy borane. This highly exothermic series of transformations yielded crystalline diethyl-3-pyridyl borane in reproducible 75−80% yield on scales ranging up to 200-kg input. Selective reduction of the biaryl, classical resolution and introduction of the propyl group via the Gribble reductive amination procedure completed the synthesis of OSU 6162 free base. This route was employed to deliver over 35 kg of clinical-quality bulk drug in short order.",10.1021/op025620u,1
"Process Optimization and Synthesis of 3-(4-Fluorophenyl)-4,5-dihydro-<i>N</i>-[4-(tri- fluoromethyl)phenyl]-4-[5-(trifluoromethyl)-2-pyridyl]-1<i>H</i>-pyrazole-1-carboxamide","ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProcess Optimization and Synthesis of 3-(4-Fluorophenyl)-4,5-dihydro-N-[4-(tri- fluoromethyl)phenyl]-4-[5-(trifluoromethyl)-2-pyridyl]-1H-pyrazole-1-carboxamideJames M. Renga, Kevin L. McLaren, and Michael J. RicksView Author Information Discovery Process Research, Dow AgroSciences, 9410 Zionsville Road, Indianapolis, Indiana 46268-1053, U.S.A. Cite this: Org. Proc. Res. Dev. 2003, 7, 3, 267–271Publication Date (Web):April 2, 2003Publication History Received18 December 2002Published online2 April 2003Published inissue 1 May 2003https://pubs.acs.org/doi/10.1021/op025619vhttps://doi.org/10.1021/op025619vreview-articleACS PublicationsCopyright © 2003 American Chemical SocietyRequest reuse permissionsArticle Views938Altmetric-Citations4LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Chemical synthesis,Isolation,Process optimization,Rearrangement,Solvents Get e-Alerts",10.1021/op025619v,1
Thermochemical Scale-Up of a Mesylation Reaction,"The scale-up of the synthesis of a very expensive key pharmaceutical intermediate requires a very accurate knowledge of the overall heat-transfer coefficient of the plant reactors. Those data allow the optimization of the safety, quality, and yield of the process. Starting from the accurate and reliable measurements determined by reaction calorimetry, the overall heat-transfer coefficient of the plant reactor can be evaluated, and the reaction performance can be simulated with a computer program. Here is reported an example of a reaction successfully scaled up to 1500-fold with excellent yield and high product quality.",10.1021/op025617a,0
"The Synthesis of the High-Potency Sweetener, NC-00637. Part 1:  The Synthesis of (<i>S</i>)-2-Methylhexanoic Acid","The synthesis of the high potency sweetener candidate NC-00637 ( 1 ) required large quantities of ( S )-2-methylhexanoic acid ( 2 ). This acid was first prepared in small quantities by the use of chiral auxiliaries. For large quantities, resolution by classical means and an enzymatic method were investigated. Asymmetric hydrogenation provided a workable solution.",10.1021/op025616i,1
"Large-Scale Negishi Coupling as Applied to the Synthesis of PDE472, an Inhibitor of Phosphodiesterase Type 4D","5-[2-Methoxy-5-(4-pyridinyl)phenyl]-2,1,3-benzoxadiazole (PDE472) is a selective inhibitor of the phosphodiesterase PDE4D isoenzyme, which is a recognised drug target for the treatment of asthma. Different synthetic routes to PDE472 were investigated, and the research synthesis was optimised to prepare a phase I batch on pilot-plant scale with the focus on the elimination or minimization of inherent process risks. An important refinement of the key Negishi aryl−aryl coupling involved preforming the arylpalladium complex, which was then added to the arylzinc intermediate. Residual palladium was removed from PDE472 via crystallization of the hemi-maleate salt, which afforded drug-substance containing <2 ppm Pd.",10.1021/op025615q,1
May <i>Organic Process Research &amp; Development</i> Keep Growing!,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTMay Organic Process Research & Development Keep Growing!View Author Information EditorCite this: Org. Proc. Res. Dev. 2003, 7, 1, 1Publication Date (Web):December 19, 2002Publication History Published online19 December 2002Published inissue 1 January 2003https://doi.org/10.1021/op025614yCopyright © 2003 American Chemical SocietyRequest reuse permissions This publication is free to access through this site. Learn MoreArticle Views531Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (16 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Crystallization,Quality management Get e-Alerts",10.1021/op025614y,0
"The Asymmetric Synthesis of (3<i>S</i>,4<i>R</i>,5<i>S</i>)-3-Amino-4,5-<i>O</i>-isopropylidenedioxycyclopentene","The title amine, an important substructure of nucleoside Q, is available from the 3,4-epoxycyclopentene in five steps. The epoxide is directly converted to the acetonide of cis -3, 4-dihydroxycyclopentene by treatment with boron trifluoride, a ring-opening with retention of configuration, a previously unknown process since known conversions of epoxides directly to acetonides normally involve initiating by nucleophilic opening of the epoxide with inversion of configuration. Two strategies were developed for diastereoselective allylic oxidation to cis -3,4- O -isopropylidenedioxy- trans -5-hydroxycyclopentene direct oxidation with selenium dioxide and a two-step process, epoxidation followed by base. The corresponding carbonate undergoes a palladium-catalyzed deracemization with phthalimide as nucleophile in 98% ee. Recrystallization can increase the ee to >99%. Removal of the phthalimide group to give the title compound occurs smoothly with ethylenediamine. Thus, a most efficient five-step synthesis (six steps from cyclopentadiene) contrasts with two recent asymmetric syntheses that required 12−16 steps.",10.1021/op025611l,1
"Reinvestigation of the Reaction of Trichloroacetyl Chloride and Acrylonitrile in the Preparation of 3,5,6-Trichloropyridin-2-ol","The synthesis of 3,5,6-trichloropyridin-2-ol via the CuCl-catalyzed reaction of trichloroacetyl chloride and acrylonitrile under both pressure and atmospheric conditions and the hydrolysis of the reaction mixture were reinvestigated. The products and byproducts formed in each case, before the hydrolysis step, were characterized, and the factors causing their formation are discussed. It was found that two newly identified byproducts influence the yield of the reaction.",10.1021/op025610t,0
Scale-Up of Polymerization Process:  A Practical Example,"The scale-up/-down of polymerization reactors has to deal with large viscosity changes during the process, addressing mass- and heat-transfer issues. A practical example on scale-up of styrene and methyl methacrylate free radical bulk and solution polymerization is presented. The main critical parameters are mixing at molecular level (micromixing) and heat removal capacity. The operating parameters being kept constant are: reaction conditions (temperature, pressure, chemistry) and thus the reaction time. A pilot plant issued from scale-down of possible industrial sizes was developed to represent, at best, larger scales. The main parameter being scaled-up is the heat removal capacity, which has to be maintained constant among the different sizes. New concepts are adapted to dissipate the mixing energy where it is the most suitable, and the final step is the scale-up/-down strategy. Another issue addressed in this contribution is the need for in-line analytics that could operate at different plant scales and thus give important information for process control. Scale-up/-down strategy must include the whole process, not only the reaction stage but also what happens before, after, and simultaneously, i.e., upstream, downstream, and peripheral operations. Finally the measurable success of a scale-up/-down analysis could only be proved at industrial scale, where a good agreement between pilot- and larger scale should be observed. The concepts in terms of transfer phenomena, analytics, separation, product properties, feasibility, and economics should also be included in this analysis.",10.1021/op025605p,0
Process Development on the Enantioselective Enzymatic Hydrolysis of <i>S</i>-Ethyl 2-Ethoxy-3-(4-hydroxyphenyl)propanoate,"A novel biocatalytic approach for the large-scale production of S -2-ethoxy-3-(4-hydroxyphenyl)propanoic acid S -1 from its racemic ethylester rac -2 by enantioselective hydrolysis has been developed. S -1 is an important building block in the synthesis of PPARα and -γ agonists such as Ragaglitazar [NNC 61-0029 ((−)DRF2725)]. The development history comprises enzyme screening, biocatalyst and process optimization, and scale-up to pilot plant. The project was thereby highly interdisciplinary by combining biotechnology and chemistry technologies. The final process was successfully run on a 44-kg pilot scale in 43−48% yields and with high enantiomeric purities (98.4−99.6% ee).",10.1021/op0256035,1
Process for Purification of 3-Alkenylcephem Carboxylic Acid,The present report describes a novel and efficient method for enrichment of 7-amino-3-[( Z )-propen-1-yl]-3-cephem-4-carboxylic acid ( 1 ) in a mixture of ( Z / E ) 7-amino-3[( Z / E )-propen-1-yl]-3-cephem-4-carboxylic acid via formation of 7-β-isopropylideneammonium salt in acidic conditions. This method provides high yield and 7-amino-3-[( Z )-propen-1-yl]-3-cephem-4-carboxylic acid ( 1 ) having a low E -isomer content from a mixture containing very high proportion of E -isomer. The usage of these isopropylidene ammonium salts provides a method for separation of mixtures of cephalosporins where geometric isomerism about a double bond exists.,10.1021/op025602c,0
SPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSES,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: SAFETY OF CHEMICAL PROCESSESTrevor LairdView Author Information EditorCite this: Org. Proc. Res. Dev. 2002, 6, 6, 876Publication Date (Web):October 30, 2002Publication History Published online30 October 2002Published inissue 1 November 2002https://pubs.acs.org/doi/10.1021/op025601khttps://doi.org/10.1021/op025601keditorialACS PublicationsCopyright © 2002 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1026Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (13 KB) Get e-AlertscloseSUBJECTS:Anions,Mixtures,Physical and chemical processes,Safety,Testing and assessment Get e-Alerts",10.1021/op025601k,0
Development of a Scaleable Route for the Production of<i>cis</i>-<i>N</i>-Benzyl-3-methylamino-4-methylpiperidine,"The synthesis of cis - N -benzyl-3-methylamino-4-methylpiperidine ( 5 ) via hydroboration of tetrahydropyridine 3 followed by oxidation and reductive amination was optimized and scaled up to produce 10-kg quantities of product. Three routes to 3 were identified, and the reduction of pyridinium salt 7 was selected as the most preferable to run on-scale. The hydroboration and oxidative workup were carefully studied to optimize throughput on that transformation, as was the reductive amination.",10.1021/op025599x,1
In Situ Recycling of Chiral Ligand and Surplus Nucleophile for a Noncatalytic Reaction:  Amplification of Process Throughput in the Asymmetric Addition Step of Efavirenz (DMP 266),"The synthesis of efavirenz (DMP 266) involves a highly enantioselective asymmetric reaction of ketone 2a with lithium cyclopropylacetylide 3a in the presence of (1 R,2 S )-pyrrolidinylnorephedrine (PNE) 4b as the chiral mediator to produce 6b, a key advance intermediate bearing a tetrasubstituted chiral carbon. The major drawback of this reaction is that it requires at least 2 mol of cyclopropylacetylene (CPA) 3b, 2 mol of the chiral mediator 4b, and 4 mol of an n -alkyllithium base to generate a 1 mol of addition product 6b . In a program to improve the cost-effectiveness of the process, we have studied this asymmetric addition reaction to reduce the stoichiometry of the chiral moderator and CPA nucleophile. The initial experimental designs to improve the stoichiometry were based on the assumption that the second equivalent of lithium cyclopropylacetylide simply acted as a base to deprotonate the N−H of ketones 2a or 2b, leaving 1 equiv of unlithiated and presumably unreactive CPA. It was reasoned that if we lithiate this CPA in the postreaction mixture, it would complex with the already lithiated ligand in the reaction which could then be used to convert additional 2a or 2b into product thus improving the stoichiometry. After some trial experiments, a dramatic decrease in stoichiometry was achieved and it was found that by simply adding one more equivalent of an n -alkyllithium to the system after the first reaction cycle, it was possible to obtain at least a 14% throughput increase with just a 5% dilution of the reaction volume in this simple and more cost-efficient process. The chiral addition reactions could be run with multiple cycles in the same pot with the sequential addition of n -alkyllithium 5, CPA 3b, and ketone 2a . However, after four cycles, there was some decrease in the enantioselectivities (90.8%) that ultimately places a practical limit on the number of recycles possible. The process throughput increase can be explained in the light of a recent mechanistic investigation by Collum and co-workers. We postulate that the introduction of an n -alkyllithium to the reaction mixture after the completion of the first cycle regenerates the reactive cubic tetrameric aggregate 8 by structural reorganization of the product-incorporated inactive aggregate 9 .",10.1021/op025595s,0
Pilot-Scale Lipase-Catalyzed Regioselective Acylation of Ribavirin in Anhydrous Media in the Synthesis of a Novel Prodrug Intermediate,"The ester 4 was synthesized via Candida antarctica lipase-catalyzed acylation of ribavirin ( 3 ) with the oxime ester of l -Cbz-Ala ( 2 ) in anhydrous THF. The reaction was highly regioselective, resulting in the exclusive acylation of the 5‘-hydroxyl. The process practiced on pilot-plant scale produced 82 kg of 4 in three batches in an average isolated yield of 82%.",10.1021/op0255938,0
"Rapid Development of an Enantioselective Synthesis of (<i>R</i>)-1-Hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic Acid","A two-stage, three-step synthesis of ( R )-1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid from 7-methoxy tetralone is described which employed an optimised Wittig olefination of 7-methoxytetralone and Sharpless asymmetric dihydroxylation followed by platinum-catalysed oxidation.",10.1021/op025590v,1
Synthesis of <i>p</i>-Aminophenol by Catalytic Hydrogenation of <i>p</i>-Nitrophenol,"The catalytic hydrogenation of p -nitrophenol to p -aminophenol was investigated in a laboratory-scale batch-slurry reactor. Pt/C catalyst (1%) was chosen for optimization of reaction conditions and kinetic studies because of its higher catalytic activity compared to that of other heterogeneous transition metal catalysts. The average catalytic activity and initial rate of hydrogenation was found to increase with increase in the solvent polarity. To investigate the intrinsic kinetics of the reaction, the effect of catalyst loading, agitation speed, p -nitrophenol concentration, and hydrogen partial pressure on the initial rate of hydrogenation was studied at different temperatures. The analysis of initial rate data indicated that the mass-transfer resistances were not significant under the prevailing reaction conditions. A simple Langmuir−Hinschelwood (L−H)-type model was found to represent the kinetics of hydrogenation of p -nitrophenol to p -aminophenol satisfactorily. The apparent energy of activation was found to be 61 kJ/mol.",10.1021/op025589w,0
Identification of the Decomposition Products in an Industrial Nitration Process under Thermal Runaway Conditions,"Directive 96/82/EC on the control of major-accident hazards involving dangerous substances, so-called Seveso II Directive, requires inventorying of dangerous substances which are believed might be generated during loss of control of an industrial chemical process. In the present work a nitration process that has underlined a potential risk of thermal runaway has been studied. A kinetic model has been developed and validated using the calorimetric data from a Mettler RC1 and a differential scanning calorimeter, along with the commercial software BatchCAD. The model has been later used to simulate the behaviour of an industrial reactor under abnormal conditions and to evaluate their consequences. Finally, the conditions that lead to thermal runaway scenarios have been reproduced to identify the decomposition products, as Seveso II Directive requires, using thermogravimetry and adiabatic calorimetry coupled with FTIR gas analyser.",10.1021/op0255884,0
A Practical Synthesis of <scp>l</scp>-Valyl-pyrrolidine-(2<i>R</i>)-boronic Acid:  Efficient Recycling of the Costly Chiral Auxiliary (+)-Pinanediol,"A practical synthesis of l -valyl-pyrrolidine-(2 R )-boronic acid ( 1 ) is detailed. A previously disclosed synthesis of 1 (Snow, R.; Kelly, T. R.; Adams, J.; Coutts, S.; Perry, C. (Boehringer Ingelheim Pharmaceuticals, Inc.). WO 93/10127, 1993) was significantly improved by developing an efficient process for recycling the costly chiral auxiliary (+)- pinanediol.",10.1021/op025587b,1
"3,4,5-Tri-Dodecyloxybenzoic Acid:  Combining Reaction Engineering and Chemistry in the Development of an Attractive Tool To Assist Scaling Up Solid−Liquid Reactions","The synthesis of tris- O -dodecyl-gallic acid (3,4,5-tri-dodecyloxybenzoic acid) was selected as a model system in our program to define design tools and a methodology for fine-chemical scale-up. The just-suspended conditions of potassium carbonate in MIBK have been studied to find a scale-up rule for this system from 1 dm 3 lab-scale to an industrial scale of 6000 dm 3 . By adjusting the relation of Zwietering to the values obtained by visual observations of the lowest stirrer speed at which the solid particles are just-suspended on a 1- and a 10-dm 3 scale with different particle sizes and two stirrer types, a scale-up rule was developed which was verified under just-suspended conditions on a 50-dm 3 scale. In addition, a prediction was made using this rule as a minimum criterion for a 6000-dm 3 reactor where no problems regarding off-bottom criteria are expected. The focused beam rotating measurement (FBRM) and photo video measurement (PVM) Lasentec techniques have been used successfully to determine just-suspended stirrer rates and to gain more insight into the dynamic (de)agglomeration behaviour of potassium carbonate during the tri-alkylation of methyl gallate. These techniques proved to be powerful tools in accelerating process development of heterogeneous reaction systems.",10.1021/op020007w,0
A “Bottom-Up” Approach to Process Development:  Application of Physicochemical Properties of Reaction Products toward the Development of Direct-Drop Processes,"The “bottom-up” approach to development of direct-drop processes is a powerful, yet simple, strategy that every process chemist should consider for the development of efficient, cost-effective, and environmentally friendly processes. This approach is aided by a “parallel crystallization” technique, which allows for rapid identification of multiple solvent systems for the crystallization of the desired product using a minimal amount of material and solvent. This “bottom-up” approach is illustrated by several examples where the desired product is crystallized directly from the reaction mixture.",10.1021/op0102114,0
<i>SPECIAL FEATURE SECTION:  <u>PROCESS INTENSIFICATION/CONTINUOUS PROCESSING IN THE FINE CHEMICALS ARENA</u></i>,"ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSPECIAL FEATURE SECTION: PROCESS INTENSIFICATION/CONTINUOUS PROCESSING IN THE FINE CHEMICALS ARENATrevor LairdView Author Information EditorCite this: Org. Proc. Res. Dev. 2001, 5, 6, 612Publication Date (Web):October 18, 2001Publication History Published online18 October 2001Published inissue 1 November 2001https://pubs.acs.org/doi/10.1021/op010083jhttps://doi.org/10.1021/op010083jeditorialACS PublicationsCopyright © 2001 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views709Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (14 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Industrial manufacturing,Materials,Microreactors Get e-Alerts",10.1021/op010083j,0
Urea as an Efficient Reagent for the Synthesis of 3-Ethyl-3-(hydroxymethyl)oxetane:  A Novel Component in Cationic Ring-Opening Polymerisation,"Urea is a very attractive chemical raw material for large-scale production as it combines low cost with virtually unlimited supply and essentially no toxic effects. Here, we present a study on its use in the dehydration of trimethylolpropane with formation of 3-ethyl-3-(hydroxymethyl)oxetane. The reaction consists of carbonylation of trimethylolpropane and subsequent extrusion of carbon dioxide. The first step was run at a temperature of 120−160 °C at a pressure of approximately 300 mmHg for 1−5 h. Most likely, carbamates of TMP constitute the major product. In the latter step, the temperature was increased to 195−215 °C, the pressure was reduced to 10−50 mmHg, and the final product was isolated by distillation. A spiroorthocarbonate of TMP was formed as an unexpected by-product. The process has been demonstrated on a multikilogram scale. Toxicological screening revealed 3-ethyl-3-(hydroxy-methyl)oxetane to be irritating to eye but not to skin.",10.1021/op010037j,0
A Concise Asymmetric Synthesis of A β-Lactam-Based Cholesterol Absorption Inhibitor,"A concise, four-step, asymmetric synthesis of a β-lactam-based\ncholesterol absorption inhibitor, Sch 57939, was developed. The\ndiscovery of a one-step enantio- and diastereoselective synthesis\nof a &lt;i&gt;trans&lt;/i&gt;-β-lactam provided easy access to the desired three\nchiral centers. A novel zinc phenoxide-promoted ether synthesis\nwas reported for the completion of the side chain.",10.1021/op000079s,0
"3,4,5-Tri-dodecyloxybenzoic Acid:  Optimisation and Scale-Up of the Synthesis","The synthesis of tris- O -dodecyl-gallic acid (3,4,5-tri-dodecyloxybenzoic acid) a versatile building block for organic liquid crystalline materials has been selected for fine chemical scale-up. A large-scale procedure of the alkylation of methyl gallate was optimised with experimental design techniques. Apart from the solvent effect, also the temperature, phase-transfer catalyst, stirring speed, and amount of base were found to be most significant for the reaction rate. Reaction calorimetry revealed no excessive exothermic reaction steps in the process. Reaction kinetics on the alkylation reaction was studied as a function of particle size distribution of the base, potassium carbonate, and formation of carbon dioxide. Combination of all experimental results has debouched into a master recipe for kilogram-scale synthesis in a 10 dm 3 fully automated (semi)batchwise operated reactor.",10.1021/op000066e,1
"<i>N</i>(π)-2-Naphthylmethoxymethyl-Protected Histidines: Scalable, Racemization-Free Building Blocks for Peptide Synthesis","Histidine (His) racemizes with relative ease during peptide synthesis. One strategy to suppress this racemization is to protect the nitrogen atom of the imidazole moiety in His with a suitable protecting group. Among the numerous protecting groups that have already been tested, the p -methoxybenzyloxymethyl (PMBOM) group on the π-nitrogen atom effectively suppresses the racemization. However, a large-scale synthesis of N (π)-PMBOM-protected derivatives has hitherto been hampered by the requirement of a freshly prepared unstable reagent. Herein we report the synthesis of N (π)-2-naphthylmethoxymethyl (NAPOM)-protected His derivatives, which can be prepared on a gram scale and do not suffer from the aforementioned instability problems. Furthermore, these NAPOM-protected His derivatives suppress the racemization in Boc- and Fmoc-based peptide synthesis.",10.1021/acs.oprd.9b00538,1
A Concise and Efficient Synthesis of Dapagliflozin,"A concise and efficient synthesis of the SGLT-2 inhibitor dapagliflozin ( 1 ) has been developed. This route involves ethyl C -aryl glycoside 9 as the key intermediate, which is easily crystallized and purified as the crystalline n -propanol solvate with high purity (>98.5%). The tetra-O-unprotected compound 9 could be directly reduced to crude dapagliflozin with high diastereoselectivity. The final pure API product 1 was isolated and purified with high purity (>99.7%). The process has been implemented on a multikilogram scale.",10.1021/acs.oprd.9b00141,1
"<i>N</i>-Acyl-5,5-dimethylhydantoin, a New Mild Acyl-Transfer Reagent in Pd Catalysis: Highly Efficient Synthesis of Functionalized Ketones","The palladium-catalyzed Suzuki–Miyaura cross-coupling of N -acyl-5,5-dimethylhydantoins with arylboronic acids has been developed via selective amides C–N bond cleavage. The new reagent is commercially available and air-/moisture-stable, and it offers a variety of ketones in good yields through Suzuki coupling under mild conditions (up to 95%).",10.1021/acs.oprd.8b00182,0
<i>N</i>-Butylpyrrolidinone as Alternative Solvent for Solid-Phase Peptide Synthesis,"High Resolution Image Download MS PowerPoint Slide By means of a systematic approach, several green solvent candidates were tested for their feasibility to replace the reprotoxic dimethylformamide (DMF) as a solvent used in solid-phase peptide synthesis (SPPS). According to the results presented in this paper, it is clear that N -butylpyrrolidinone (NBP) is the best green solvent candidate to replace DMF in SPPS.",10.1021/acs.oprd.7b00389,0
"<i>In Situ</i> Generated Palladium on Aluminum Phosphate as Catalytic System for the Preparation of β,β-Diarylated Olefins by Matsuda–Heck Reaction","In situ generated palladium on aluminum phosphate provides a novel and active catalytic system for the preparation of β,β-diarylated olefins using the Matsuda–Heck reaction. The reaction conditions of this catalytic protocol were optimized by a Response-Surface model.",10.1021/acs.oprd.7b00279,0
A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol,"A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prepare Salbutamol in 49% isolated yield after recrystallization.",10.1021/acs.oprd.7b00261,1
A Comparison between Continuous and Batch Processes to Capture Aldehydes and Ketones by Using a Scavenger Resin,"A low-cost isoniazid-based scavenger resin was previously prepared and successfully used to capture aldehydes and ketones in solution by using a batch approach. The present work compares batch and continuous processes in relation to the preparation of the scavenger resin and the effectiveness of cyclohexanone scavenging. The batch preparation of the resin proved to be the better choice because the resin produced in the continuous flow suffered deformation on its surface that prevented access to the active sites in the internal porous polymer matrix. Conversely, the continuous-flow approach presented higher capturing yields than the batch. The optimized scavenging process was successfully used to remove formaldehyde present in a solution and the carbonyl compounds present in an ethanolic extract of Cymbopogon citratus.",10.1021/acs.oprd.7b00256,0
Use of Catalytic Static Mixers for Continuous Flow Gas–Liquid and Transfer Hydrogenations in Organic Synthesis,"Catalytic static mixers were used for the continuous flow hydrogenation of alkenes, alkynes, carbonyls, nitro- and diazo-compounds, nitriles, imines, and halides. This technique relies on tubular reactors fitted with 3D printed static mixers which are coated with a catalytic metal layer, either Pd or Ni. Additive manufacturing of the metal mixer scaffold results in maximum design flexibility and is compatible with deposition methods such as metal cold spraying which allow for mass production and linear process scale up. High to full conversion was achieved for the majority of substrates, demonstrating the flexibility and versatility of the catalytic static mixer technology. In the example of an alkyne reduction, the selectivity of the flow reactor could be directed to either yield an alkene or alkane product by simply changing the reactor pressure.",10.1021/acs.oprd.7b00180,0
(Chloromethyl)dimethylchlorosilane–KF: A Two-Step Solution to the Selectivity Problem in the Methylation of a Pyrimidone Intermediate en Route to Raltegravir,"The present work describes a two-step process, namely, silylation with (chloromethyl)dimethylchlorosilane and desilylation, to address the selectivity problem in the N -methylation of a pyrimidone intermediate toward the synthesis of the raltegravir active pharmaceutical ingredient. The said methodology delivers the desired drug substance in which the O -methylated impurity content is below the detection limit by high-performance liquid chromatography analysis. Moreover, this two-step, one-pot procedure provides an apparent advantage in terms of environmental impact with respect to the optimum approach described in the literature, while it compares equally well in terms of cost and operational simplicity.",10.1021/acs.oprd.7b00171,1
A Chemoenzymatic Route to Chiral Intermediates Used in the Multikilogram Synthesis of a Gamma Secretase Inhibitor,"A chemoenzymatic route for the production of an intermediate to a gamma secretase inhibitor is described. The route is robust and was run at multikilogram scale. The process employs both a transaminase catalyzed reductive amination of a substituted tetralone and an alcohol dehydrogenase catalyzed reduction of an α-ketoester to generate the two chiral centers in the molecule, with nearly perfect stereoselectivity. The process also features simple isolation schemes, including a direct drop isolation of the aminotetralin phosphate salt.",10.1021/acs.oprd.7b00096,1
A Chlorine Gas-Free Synthesis of Dichloroglyoxime,"A new procedure for the synthesis and isolation of dichloroglyoxime is discussed. This material has historically been synthesized from glyoxime and elemental chlorine gas. Chlorine gas is difficult to handle and control in the laboratory and has a high toxicity profile. Our method for making dichloroglyoxime in high purity uses glyoxime and N -chlorosuccinimide in DMF, with a lithium chloride-based workup. Overall yields are comparable with those obtained using the procedure involving the use of chlorine gas.",10.1021/acs.oprd.6b00252,1
"Kinetic Research of <i>O</i>,<i>O</i>′-Dibenzoyltartaric Anhydride Synthesis: Tartaric Acid and Its <i>O-</i>Acyl Derivatives. Part 12",A kinetic study of dibenzoyl- l -tartaric anhydride synthesis was described. The kinetic equation and the dependence of the reaction rate constant on the temperature were determined. It was shown that the reaction is of the pseudo first order. The kinetic data enable the design of a continuous reactor.,10.1021/acs.oprd.6b00147,1
"Development of an Enantioselective Novozym 435 Mediated Acetylation for the Preparation of (1<i>S</i>,3<i>R</i>)-3-Acetamidocyclohexane-1-carboxylic Acid","Starting from a cheap and readily available starting material, a short and enantioselective route to (1 S,3 R )-3-acetamidocyclohexane-1-carboxylic acid was developed. The key steps were a rhodium catalyzed hydrogenation of 3-aminobenzoic acid and an enantioselective Novozym 435 mediated acetylation of racemic isopropyl 3-aminocyclohexanecarboxylate.",10.1021/acs.oprd.6b00146,1
"A Scalable Synthesis of 2-(1,2,4-Oxadiazol-3-yl)propan-2-amine Hydrobromide Using a Process Safety-Driven Protecting Group Strategy","A safe and scalable synthesis of 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrobromide is described. A process safety-driven synthetic strategy was employed for the selection of thermally stable compounds en route to the target 1,2,4-oxadiazole. Application of process safety principles and tools for predicting the stability of process streams, isolated compounds, and for defining optimum reaction parameters are discussed in detail. The effect of protecting groups on the thermal stability of isolated intermediates is also highlighted.",10.1021/acs.oprd.6b00145,1
Enabling the Scale-Up of a Key Asymmetric Hydrogenation Step in the Synthesis of an API Using Continuous Flow Solid-Supported Catalysis,"High Resolution Image Download MS PowerPoint Slide The development of a continuous flow process for asymmetric hydrogenation with a heterogenized molecular catalyst in a real industrial context is reported. The key asymmetric step in the synthesis of an API (active pharmaceutical ingredient) has been developed on a kilogram scale with constant high single-pass conversion (>95.0%) and enantioselectivity (>98.6% ee) through the asymmetric hydrogenation of the corresponding enamide. This performance was achieved using a commercially available chiral catalyst (Rh/( S,S )-EthylDuphos) immobilized on a solid support via strong interaction resulting from the requirement of electroneutrality. The factors affecting the long-term catalyst stability and enantioselectivity were identified using small-scale continuous flow setups. A dedicated automated software-controlled high-pressure pilot system with a small footprint was then built and the asymmetric hydrogenation on kilogram-scale was realized with a space time yield (STY) of up to 400 g L –1 h –1 at predefined conversion and enantiopurity levels. No catalyst leaching was detected in the virtually metal-free product stream, thereby eliminating costly and time-consuming downstream purification procedures. This straightforward approach permitted an easy and robust scale-up from gram to kilogram scale fully matching the pharmaceutical quality criteria for enantiopurity and low metal content, thus demonstrating the high versatility of fully integrated continuous flow molecular catalysis.",10.1021/acs.oprd.6b00143,1
Concise Cu (I) Catalyzed Synthesis of Substituted Benzofurans via a Tandem SNAr/C–O Coupling Process,A novel and convergent approach to tetrasubstituted benzofurans was developed from ortho -bromo aryl fluorides and keto-amides via one-pot SNAr displacement and subsequent Cu(I) catalyzed C–O coupling on the ortho -bromide. The scope of this methodology was demonstrated on several similar substrates.,10.1021/acs.oprd.6b00141,1
Organic Solvent Nanofiltration (OSN): A New Technology Platform for Liquid-Phase Oligonucleotide Synthesis (LPOS),"Organic solvent nanofiltration (OSN) technology is a membrane process for molecular separation in harsh organic media. However, despite having well-documented potential applications, development hurdles have hindered the widespread uptake of OSN technology. One of the most promising areas of application is as an iterative synthesis platform, for instance for oligonucleotides or peptides, where a thorough purification step is required after each synthesis cycle, preferably in the same working solvent. In this work, we report a process development study for liquid-phase oligonucleotide synthesis (LPOS) using OSN technology. Oligonucleotide (oligo) based drugs are being advanced as a new generation of therapeutics functioning at the protein expression level. Currently, over 100 oligo based drugs are undergoing clinical trials, suggesting that it will soon be necessary to produce oligos at a scale of metric tons per year. However, there are as yet no synthesis platforms that can manufacture oligos at >10 kg batch scale. With the process developed here, we have successfully carried out eight iterative cycles of chain extension and synthesized 5-mer and 9-mer 2′- O -methyl oligoribonucleotide phosphorothioates, all in liquid phase media. This paper discusses the key challenges, both anticipated and unexpected, faced during development of this process and suggests solutions to reduce the development period. An economic analysis has been carried out, highlighting the potential competitiveness of the LPOS-OSN process and the necessity for a solvent recovery unit.",10.1021/acs.oprd.6b00139,0
Two Approaches to the Chemical Development and Large-Scale Preparation of a Pyrimidyl Tetrazole Intermediate,"Two new routes to a pyrimidyl tetrazole intermediate are described. The first-generation route featured an iron-catalyzed cross-coupling between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. A subsequent intramolecular Heck cyclization afforded the desired bicyclic core, which was subsequently converted to the corresponding carboxylic acid via hydroboration and oxidation. This route was rapidly defined and used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate, which supported early toxicology and clinical studies of a drug candidate. A second-generation, eight-step route to the pyrimidyl tetrazole intermediate was defined and demonstrated on multikilogram scale in a 21% overall yield. The key transformation in this sequence was a copper(I) mediated cyclization of an iodopyrimidine, affording the bicyclic core of the target in quantitative yield. Due to the larger scale involved for the second-generation approach, significant process safety evaluation was undertaken for a number of steps in this route, and the highlights of these studies are presented.",10.1021/acs.oprd.6b00136,1
Flow Grignard and Lithiation: Screening Tools and Development of Continuous Processes for a Benzyl Alcohol Starting Material,"Efficient continuous Grignard and lithiation processes were developed to produce one of the key regulatory starting materials for the production of edivoxetine hydrochoride. For the Grignard process, organometallic reagent formation, Bouveault formylation, reduction, and workup steps were run in continuous stirred tank reactors (CSTRs). The lithiation utilized a hybrid approach where plug flow reactors (PFRs) were used for the metal halogen exchange and Bouveault formylation steps, while the reduction and workup steps were performed in CSTRs. Relative to traditional batch processing, both approaches offer significant advantages. Both processes were high-yielding and produced the product in high purity. The two main processes were directly compared from a number of perspectives including reagent and operational safety, fouling potential, process footprint, need for manual operation, and product yield and purity.",10.1021/acs.oprd.6b00131,0
"Evaluation of PAT Methods for Potential Application in Small-Scale, Multipurpose Pharmaceutical Manufacturing Platforms","Small-scale (refrigerator-sized, 1.0 (width) × 0.7 (length) × 1.8 m (height)), multipurpose pharmaceutical manufacturing platforms (PMP) necessitate unique high demands on process analytical technologies (PAT), for instance, in in situ, real-time monitoring of liquid formulations (solution and suspension) to determine the strength prior to the release from PMPs that are not comparable to lab-scale or industrial-scale needs. Commercially available plug-and-play PATs were evaluated for their potential application in PMPs regarding versatility, flexibility, reliability, and physical size (including the control box). The results presented here indicate that single-frequency ultrasounds currently surpass commercially available plug-and-play PATs in ways such as focused beam reflectance measurements, conductivity, and turbidity as well as UV–vis, Fourier transform infrared, near-infrared, and Raman spectroscopy for the purpose of in situ, real-time concentration monitoring of aqueous and alcohol-based solutions and suspension-formulated drugs in one single PAT device, as it is preferred in PMPs to maintain a small footprint.",10.1021/acs.oprd.6b00129,0
A Biocatalytic Route to the Novel Antiepileptic Drug Brivaracetam,"An asymmetric synthesis of the novel antiepileptic drug Brivaracetam 1 is described. The stereochemistry of the 4- n -propyl substituent is introduced by a biocatalytic resolution of ( rac )-methyl 2-propylsuccinate 4- tert -butyl ester 4 . The selection of the resolution substrate and the screening of enzymes were carried out from our in-house screening platform. The development and scale-up of the best conditions, including solvent media, pH control, workup, and enzyme supply, led up to a successful demonstration conducted at 1 kg scale in a 10 L vessel. The chiral intermediate ( R )-2-propylsuccinic acid 4- tert -butyl ester 6 was reproducibly obtained in 42% yield and 97% ee all along the development. The control of the stereochemistry via the biocatalytic resolution allowed the production of Brivaracetam 1 within the required commercial quality specifications.",10.1021/acs.oprd.6b00094,1
Up-Scale Pseudotelescopic Photoinduced Arndt-Eistert α-Amino Acid Homologation in a Flow Reactor Cascade,"We present an efficient, pseudotelescopic synthesis of β-amino acids via the Arndt-Eistert homologation of α-amino acids using a flow reactor cascade. Our system utilizes flow generation of diazomethane, diazoketone preparation, and subsequent photoflow Wolff rearrangement without intermediate isolation. This innovative method enhances safety, improves scalability, and allows access to substrates previously unavailable in thermal/catalytic Wolff rearrangement. Notably, the reaction conditions are mild, which lead to high yields and excellent purity, thereby expanding the synthetic utility of the Wolff rearrangement. This work unveils a versatile and scalable approach to β-amino acid synthesis, opening new synthetic and medicinal chemistry avenues.",10.1021/acs.oprd.5c00061,0
Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products,"High Resolution Image Download MS PowerPoint Slide Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.",10.1021/acs.oprd.5b00325,0
<i>OPR&amp;D</i>: An Exceptional Legacy and Exciting Opportunities for the Future of Process Chemistry,,10.1021/acs.oprd.4c00537,0
A Concise Flow Synthesis of the IKZF2 Glue Degrader DKY709,"DKY709, a protein degrader targeting Helios (IKZF2), was efficiently synthesized via flow chemistry. The synthetic sequence comprised a visible-light-induced benzyl bromination, an amination–cyclization cascade, a photoinduced C(sp 2 )–C(sp 3 ) coupling, and a high-temperature, high-pressure de-Boc/alkylation. Each reaction was systematically optimized under continuous-flow or stop-flow conditions to identify crucial parameters. The overall yield was substantially increased from 4.3% to 22.8% using commercially available starting materials, while the number of synthetic steps was reduced from five to four. The scalability of each reaction step was validated, and the direct use of intermediates in subsequent steps minimized workup complexity.",10.1021/acs.oprd.4c00476,1
"1,2,3-Triazole Synthesis: Development of Safe and Effective Batch and Continuous Manufacturing Processes","In this paper, we present the development of a safe water-based synthesis of 1,2,3-triazole using cheap raw materials. Starting from glyoxal and hydrazine, a safe and efficient three-step end-to-end continuous process was developed. This protocol transforms heterogeneous batch reactions into a homogeneous streamlined continuous flow system. This advancement not only obviated the separation of hazardous intermediates, thereby mitigating potential risks, but also significantly diminished the reaction time of each step. This has ensured a rapid and stable supply of 1,2,3-triazole for downstream product development such as tazobactam. Additionally, the study delves into the insights gained from transitioning from batch reactions to continuous flow processes, highlighting the practical and safety benefits of continuous flow synthesis.",10.1021/acs.oprd.4c00020,1
"2,5-Dihydro-1<i>H</i>-pyrrol-3-yl Boronic Derivatives: Multigram Synthesis and Coupling Reactions","A protocol for the multigram synthesis of 3-substituted 2,5-dihydro-1 H -pyrrole boronic derivatives is reported. The method relied on the triflation of N -Boc-3-oxopyrrolidine and subsequent palladium-catalyzed borylation. Optimization studies demonstrated the high efficiency of t -BuOK as a base for the triflation step and good performance of the one-pot protocol as compared with the conventional step-by-step synthesis. The method allowed the production of up to 60 g of the target compound (as pure trifluoroborate or technical-grade boropinacolate) in one run using commercially available reagents and common laboratory equipment. Application of the obtained building block for the preparation of compounds relevant to medicinal chemistry through C–C coupling reactions is also illustrated. It is suggested that the boropinacolate form of the title building block is advantageous when immediate synthesis of the coupling products is envisaged, whereas trifluoroborate is more convenient for storage and commercialization.",10.1021/acs.oprd.3c00454,0
Use of a Dynamic Flow Platform To Translate a Batch Immobilized Transaminase Process to a Packed Bed Reactor for the Synthesis of an Intermediate of Nemtabrutinib,"Herein we describe the translation of an immobilized transaminase process in batch to a packed bed reactor for the synthesis of cyrene amine, an intermediate of Nemtabrutinib. This change in reactor design provided significant benefits in both robustness of the immobilized enzyme preparation and minimization of the amount of the enzyme required to perform the transformation. The extended residence times required for high conversion led us to investigate a dynamic flow system to quickly survey the reaction kinetics under various conditions and to provide approximate residence times for pseudosteady state runs to determine the lifetime of the enzyme. The immobilized enzyme lifetime was assessed and found to provide high levels of conversion for over 100 h of performance. Ultimately, the process was scaled to provide over a kilogram of the desired amine, isolated as a tosylate salt, and further optimization with an evolved enzyme and translation to larger scales is also discussed.",10.1021/acs.oprd.3c00374,0
Opportunities and Challenges in Mechanochemical Cocrystallization toward Scaled-Up Pharmaceutical Manufacturing,"Recently, pharmaceutical cocrystals have gained immense interest because of their potential to tune mechanical, pharmacokinetic, and physicochemical properties of active pharmaceutical ingredients (APIs) while keeping their therapeutic action intact. In this review, cocrystallization is raised as a viable strategy toward commercialized pharmaceutical manufacturing, where attention has been paid to solid-state cocrystal preparation methods and their opportunities and challenges in overall product and process development. A comparative study of cocrystallization in the form of mechanical energy is demonstrated with the aid of SELECT criteria to qualitatively evaluate the synthetic route selection of scalable mechanochemical cocrystallization methods. Remedies and alternatives for the challenges that arise in mechanochemical synthesis of cocrystals are presented in this review, highlighting the commercial perspectives of sustainable, eco-friendly, and less toxic mechanochemical methods.",10.1021/acs.oprd.2c00314,0
Modified Greener Procedure for the Synthesis of Cucurbit[6]uril,"A modified procedure for the synthesis of cucurbit[6]uril on the kilogram scale was elaborated. The procedure includes reaction of glycoluril with paraformaldehyde in the minimal amount of concentrated sulfuric acid, filtration of the product directly from the reaction mixture, and workup by dissolution and reprecipitation of the product in water, with a yield of up to 65%. The modifications made the procedure more environmentally friendly and suitable for large-scale synthesis.",10.1021/acs.oprd.2c00308,0
Scale-Up Synthesis of 1-Methyladamantane and Its Functionalization as a Key Point for Promising Antiviral Agents,"Methyladamantane and its derivatives are rare chemotypes for industrial and even wide research use. The proposed scalable and inexpensive approach to such compounds opens the door to further extensive study of biologically active derivatives based on this uncommon core. Optimized synthesis of the key precursor, the chiral (1 S,3 R,5 R,7 S )-3-methyl-5-phenyladamantane-1-carboxylic acid, showcases some significant innovations. The main one is very effective and cost-efficient stacked injections in preparative chiral chromatography and showed potential for enantioresolution of chiral cage compounds. Scaling the preparation of (1 S,3 R,5 R,7 S )- trans - N -(4-aminocyclohexyl)-3-methyl-5-phenyladamantane-1-carboxamide, which was recently shown to have notable activity against the Ebola virus, to multigram levels is an excellent example of our elaboration significance. It may push forward further biological investigation of this promising antiviral agent.",10.1021/acs.oprd.2c00305,1
Development of Commercial Manufacturing Processes for Acalabrutinib,"The development of processes to produce the Bruton tyrosine kinase inhibitor, acalabrutinib 1, has resulted in improvements to the yield, cycle time, and operability, to realize a robust commercial manufacturing process. A highly accelerated clinical program meant that numerous key process challenges had to be resolved in a short timeframe. Issues are discussed, such as the uncontrolled epimerization of a chiral center and the control of the acalabrutinib 1 crystallization step, which was prone to oiling. Specifically, work to understand the complex polymorph landscape of a key intermediate (to facilitate resolution of a filtration issue) is described.",10.1021/acs.oprd.2c00304,1
Large-Scale Amide Coupling in Aqueous Media: Process for the Production of Diazabicyclooctane β-Lactamase Inhibitors,"Herein, the amide coupling of six primary amines with the sodium salt of diazabicyclooctane acid in an aqueous medium without an additional base/surfactant or organic solvent is described. The product was efficiently isolated from the reaction through simple filtration and recrystallized using hot water treatment as a swift and cost-effective process. The methodology was implemented on a kilogram scale to produce penultimate intermediates for synthesizing β-lactamase inhibitors such as zidebactam, relebactam, and nacubactam. The comparison of green metrics for several previously reported amide coupling methods was discussed. The developed procedure avoids using hazardous organic solvents and provides a simple isolation method at the operational level with high purity and efficiency.",10.1021/acs.oprd.2c00299,0
Early Process Development and Scale-Up of Orally Active Apomorphine Drug Candidates,"The manufacturing route to a novel apomorphine Parkinson’s drug candidate (MCL-509) has been developed from a mg laboratory scale to that suitable for use on a 20–50 L scale. While the synthetic sequence could not be bettered, all six reaction steps required significant improvement for scale-up. Hazardous and toxic reagents and hazardous steps were removed; all concentrations to dryness and chromatographic purifications were eliminated; isolations were operationally simplified, and plant cycle times were shortened. Two pairs of steps (1 and 2; 5 and 6) were successfully telescoped, and steps 3, 4, and 5 were re-imagined such that all three steps were substantially redeveloped with alternative reagents. Now relying solely on crystallizations for isolation, the yield, purity, and color of each intermediate was greatly improved. All six process steps were easily transferred to the pilot plant with only minimal accommodation work required prior to manufacture on a 20–50 L scale per batch. Thus, the manufacturing campaign performed essentially as expected and without issues while delivering an approximate 10-fold increase in material yield alongside the requisite quality improvements.",10.1021/acs.oprd.2c00297,1
Toward the Development of a Manufacturing Process for the Insecticide Tyclopyrazoflor. Part I. Evaluation of Strategies using Ullmann Coupling of Pyrazole Derivatives,"Synthetic strategies based on Ullmann coupling of functionalized pyrazoles and 3-halopyridine to access the insecticide tyclopyrazoflor ( 1 ) were evaluated. A five-step route featuring a middle-stage Ullmann coupling approach was selected as the lead route for optimization and was scaled up in a pilot plant at more than 50 kg scale of each step. This route started from reductive chlorination of 4-nitropyrazole followed by acetylation to provide N -(3-chloro-1 H -pyrazol-4-yl)acetamide as the key coupling nucleophile, which readily coupled with 3-bromopyridine in the presence of copper(I) chloride as catalyst and 1,2-dimethylethylenediamine (DMEDA) as ligand. Subsequent NaBH 4 reduction afforded the corresponding ethyl amine, which was coupled with 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride to furnish tyclopyrazoflor ( 1 ). This highly concise route offered a critical foundation for development of a scalable manufacturing process.",10.1021/acs.oprd.2c00296,1
A Review of Tangential Flow Filtration: Process Development and Applications in the Pharmaceutical Industry,"Tangential flow filtration is an efficient membrane separation technology utilized across a wide range of industries for separation and purification applications. The requirement of telescoped manufacturing to produce high-volume drugs in the pharmaceutical industry has led to increased adoption of membrane separation for drug substance synthesis. Particularly, for noncrystalline molecules with limited product stability and significant thermal liabilities, TFF is a powerful alternative to traditional isolation techniques. This Review discusses the various considerations during the development of a TFF process and highlights applications of TFF to produce pharmaceutically relevant molecules such as proteins, peptides, monoclonal antibodies, and so on. Finally, a future perspective on the technology is shared for improved performance.",10.1021/acs.oprd.2c00291,0
Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation,"We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4 . Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford–Stevens diazo-generating flow process at 30 °C, well below the thermal onset temperature ( T onset = 57 °C), while also minimizing accumulation of the highly energetic diazo intermediate (Δ H D = −729 J/g). The Bamford–Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid–liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels <100 ppm in the final aryldiazoacetate solution, thereby ensuring acceptable reactivity, selectivity, and purity in the water sensitive cyclopropanation reaction. The full process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale.",10.1021/acs.oprd.2c00288,0
"Process Research for ZG1077, a KRAS G12C Inhibitor","A novel, efficient, and robust synthetic route to ZG1077 with an atropisomer structure for KRAS G12C inhibitors was designed. The critical process parameters were optimized and established to reduce or avoid process-related impurities. The formation mechanism, purge pathways, and control strategy for these impurities are discussed. Compared with the medicinal chemistry route, the single atropisomer drug substance was obtained with chiral resolution rather than the supercritical fluid chromatogram purification technique, and it was obtained in 3.01% overall yield with >99.5% purity and 99.8% e.e. in the novel route. However, the overall yield is only 0.56%, and the purity and chiral purity were less than 99.0% in the medicinal chemistry route. The process is suitable to obtain enough active pharmaceutical ingredients for preclinical and clinical studies.",10.1021/acs.oprd.2c00284,1
Process Development of a Triphasic Continuous Flow Suzuki–Miyaura Coupling Reaction in a Plug Flow Reactor,"We have successfully adapted a Suzuki–Miyaura coupling reaction to a continuous flow process. The reaction was a triphasic mixture involved with two liquid phases that are only partially miscible in addition to the presence of an insoluble catalyst as a solid phase. The reaction required very rapid reaction heat up and mixing, which were difficult to achieve under batch conditions. A plug flow reactor (PFR) equipped with a static mixer was implemented in this continuous flow process, and the heterogenous reaction mixture was well handled, which is attributed to the high velocity flow rates and fast reaction kinetics. The reaction was successfully carried out on a 1.6 kg scale to give 80% isolated yield of the product with superior reaction high-performance liquid chromatography profile to the batch process.",10.1021/acs.oprd.2c00278,0
Targeting Particle Size Specification in Pharmaceutical Crystallization: A Review on Recent Process Design and Development Strategies and Particle Size Measurements,"Obtaining a particle size within the specifications for a pharmaceutical compound in an industrial crystallization can be a challenging task. The events affecting the final particle size of the product include nucleation, growth, breakage, and agglomeration, which are often convoluted. Secondary nucleation may significantly influence the particle size distribution. The strategies and techniques relevant to obtaining an in-spec particle size in crystallization are summarized and discussed from a perspective of process parameters. The effect of cooling profiles, seeding strategies, as well as mixing by agitation are reviewed, and an efficient and controlled crystallization process may be achieved using an optimized combination of these conditions. Multiple characterization methods for particle size and distribution are compared, and the discrepancies associated with the measurements are addressed.",10.1021/acs.oprd.2c00277,0
Commercially Viable Synthesis of Medetomidine Using a Classical Approach to the Imidazole Ring Formation,"A commercially viable and efficient method for the synthesis of medetomidine hydrochloride ( 1 ) was developed combining two reliable synthetic approaches: the modern method for C–C bond formation through the sp 2 –sp 3 Kumada cross-coupling and the classical method for the imidazole ring formation based on the Weidenhagen reaction. The latter was earlier limited by the high toxicity of hydrogen sulfide used to recover imidazoles from the copper complexes and difficulties in working up the reaction mixture. We achieved a remarkable advance in the Weidenhagen reaction through the use of nonhazardous complexons providing less than a 10 ppm residual level of metals in the final product. In the developed method, 3-(2,3-dimethylphenyl)butan-2-one ( 7 ) is synthesized in a one-step and one-pot manner by the cross-coupling of 2-(1-bromoethyl)-2-methyl-1,3-dioxolane ( 14 ) and 2,3-dimethylphenyl magnesium bromide ( 10 ), followed by one-pot deprotection of the resulting ethylene ketal 8, and several intermediates at the next steps can be used without additional purification; these benefits enable medetomidine hydrochloride ( 1 ) to potentially be produced on a multikilogram scale.",10.1021/acs.oprd.2c00273,1
Pd-Catalyzed Cyanation of a Bromoaryl Carboxylate En Route to Etrumadenant: Robust Process with Low Catalyst Loading Enabled by Preactivation,"Palladium-catalyzed cyanation of aryl bromides is a powerful approach to install a functional group commonly found in active pharmaceutical ingredients starting from readily available precursors. The development of a robust cyanation of a bromo benzoic acid to generate an intermediate en route to etrumadenant is described. Full conversion with catalyst loading as low as 0.13 mol % was enabled by study of the catalyst preactivation step, which was affected by trace water levels. Details of the scale-up of this process to the hundred-kilogram batch size are included.",10.1021/acs.oprd.2c00272,1
Scale-Up of a Rh-Catalyzed Asymmetric sp<sup>3</sup>–sp<sup>2</sup> Suzuki–Miyaura-Type Reaction,"High Resolution Image Download MS PowerPoint Slide Csp 2 –Csp 2 Suzuki–Miyaura couplings (SMCs) are ubiquitous in the synthesis of small molecules, but analogous Csp 2 –Csp 3 bond-forming SMCs are rare, especially asymmetric variants. Recently, we developed a series of Rh-catalyzed couplings between racemic sp 3 -hybridized allyl chlorides and heteroaryl boronic acids. Here, we demonstrate that these catalytic asymmetric reactions can be scaled-up to give over 100 g of a product. The reaction we chose to test couples a heteroaromatic boronic acid derivative and a racemic bicyclic electrophile to give a product with three contiguous stereogenic centers. The SMC product was obtained as a single diastereomer in 90% yield and 98% ee. Kinetic analysis of the reaction reveals two exothermic steps in the reaction setup and revealed the means by which to prevent the generation of heat spikes detrimental to the stability of the catalyst.",10.1021/acs.oprd.2c00268,0
“On-Water” Reaction of (Thio)isocyanate: A Sustainable Process for the Synthesis of Unsymmetrical (Thio)ureas,"We describe a facile, sustainable, and chemoselective process for the synthesis of unsymmetrical (thio)ureas through the “on-water” reaction of (thio)isocyanates with amines. Detailed mechanistic studies revealed that the physical nature and solubility of reagents in water are responsible for the observed reaction rate and selectivity. Significant efforts have been made to design a scalable process to achieve the “zero waste” “water-mediated” protocol for the synthesis of (thio)ureas from (thio)isocyanates and amines. The decisive advantages of the process are the simple product isolation through filtration and the recycling of the water effluent. It also avoids the use of sensitive anhydrous reaction conditions and toxic volatile organic solvents. The developed process ensures that chemoselectivity and robustness and are successfully scaled-up to produce 100 g of isoproturon in high yield and purity. Green chemistry parameters such as process mass intensity, reaction mass efficiency, and molar efficiency values (with and without solvent) were calculated and compared.",10.1021/acs.oprd.2c00266,0
Enantioselective Synthesis of <i>trans</i>-Disubstituted Cyclopropyltrifluoroborate Building Blocks through Ru-Catalyzed Cyclopropanation,"Enantioselective synthesis of trans -1,2-disubstituted cyclopropanes containing Lewis basic nitrogen functionalities remains a challenge to metal-catalyzed cyclopropanation reactions. Herein, we reported an alternative strategy to access similar products by a sequence of enantioselective cyclopropanation of potassium vinyltrifluoroborate, followed by cross-coupling of the cyclopropyl boronate product. The cyclopropanation process was readily performed in a 50 g scale from commercially available starting materials. An interesting enrichment of product enantiomeric purity by simple crystallization is also noted.",10.1021/acs.oprd.2c00265,1
Cost and Energy Saving Process for the Laboratory-Scale Production of Chloroform-<i>d</i>,"Deuterochloroform (CDCl 3 ), a commonly deuterated solvent in research and undergraduate laboratories and widely employed for nuclear magnetic resonance analyses, could be prepared using a more sustainable and efficient catalytic process. The synthesis includes a one-pot reaction of hexachloroacetone with deuterium oxide (D 2 O) in the presence of poly( N -vinylimidazole). The catalyst is more sustainable, highly recyclable, highly chemical and thermally stable, soluble in D 2 O, and high in efficiency.",10.1021/acs.oprd.2c00260,0
"Large-Scale Synthesis of Chiral Tetrahydropyran via Asymmetric Allylation Catalyzed by (<i>S</i>)-3,3′-Cl<sub>2</sub>-BINOL","Asymmetric synthesis of chiral tetrahydropyran 3, a key intermediate of PDE2 inhibitor 1, has been achieved in five linear steps with a 49% overall yield and >99:1 er on a large scale. The whole chemical process was realized without silica gel chromatography purification, starting from tert -butyl 2-chloro-5-(2-chloroacetyl)benzoate 7 . The key features of current synthesis include asymmetric allylation catalyzed by an organocatalyst ( S )-3,3′-Cl 2 -BINOL under solvent-free conditions.",10.1021/acs.oprd.2c00258,1
Understanding Chemical Processes with Entropic Sampling,"High Resolution Image Download MS PowerPoint Slide Kinetic models are widely used in simulating the relationship between the input space and the outcome space of a chemical process. Ignoring the computational cost, complete profiling, i.e., performing simulations at all grid points in the input space, would be the best way to understand the model because it provides us with a complete picture of intervariable relationships. Optimization methods that sample favorable input points can only provide narrower views. In this paper, we employ entropic sampling, a statistical physics method, to approximate complete profiling. It is cost-effective and provides a holistic picture of the model, where one can perform post hoc exploratory analyses across any region of the outcome space. Using a kinetic model of the nucleophilic aromatic substitution reaction, we analyze how the failure rate is related to process parameters and elucidate different ways to achieve low failure rates.",10.1021/acs.oprd.2c00254,0
Continuous-Flow Supercritical CO<sub>2</sub> Platform for In-Situ Synthesis and Purification of Small Molecules for Drug Discovery,"The use of supercritical CO 2 (scCO 2 ) as an enabling technology paves the way for an efficient in-line integration of the synthesis and purification of organic molecules. The scCO 2 platform presented here provides a streamlined process to produce a diverse family of triazoles, common drug precursors, by 1,3-dipolar copper-catalyzed azide-alkyne cycloaddition (CuAAC, Huisgen reaction), also decreasing the environmental impact by significantly reducing the use of traditional solvents. To further exemplify the potential of this scCO 2 platform, the synthesis and purification of rufinamide, a drug used to treat seizures associated with Lennox–Gastaut syndrome, is also reported.",10.1021/acs.oprd.2c00253,0
"Safer and Convenient Synthesis of 3,4-Bis(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole-2-oxide (BNFF/DNTF)","A safer, convenient, and scalable synthesis for 3,4-bis(4-nitro-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole-2-oxide (BNFF or DNTF) is described. The obtained products were fully characterized and further confirmed by single-crystal X-ray diffraction. The reaction process of tandem nitration–cyclization was optimized, and the thermal stability of the optimal reaction system was studied. 3-Amino-4-(carboxymethyl)furazan is oxidized and then treated with dilute mixed acid (HNO 3 and H 2 SO 4 ) to obtain BNFF in a yield of 52% and a purity of 99% after liquid chromatography analysis. Compared with some previously reported multistep methods that relied on high-concentration hydrogen peroxide solutions and suffered from dangerous exothermic profiles, this new method used to synthesize BNFF promises to be safer and more efficient.",10.1021/acs.oprd.2c00250,1
"Development of a Commercial Manufacturing Process for Sotorasib, a First-in-Class KRAS<sup>G12C</sup> Inhibitor","A commercial process to manufacture sotorasib (AMG 510), a first-in-class KRAS G12C inhibitor, is described. Development efforts focused on rendering a fit-for-purpose early-phase route into a viable long-term commercial process through the reduction of side reactions to improve yield and product quality, as well as reducing cycle times of crystallization processes by improving particle properties and filtration times. These improvements were key to ensuring clinical supply and commercial launch. The final route consists of five synthetic operations from starting material M- 1, including a telescoped two-step sequence, and a final form-setting crystallization.",10.1021/acs.oprd.2c00249,1
"Unique Superbase TBD (1,5,7-Triazabicyclo[4.4.0]dec-5-ene): From Catalytic Activity and One-Pot Synthesis to Broader Application in Industrial Chemistry","TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) is an organic superbase with unique catalytic effects due to its bifunctionality. It is already successfully used as a versatile catalyst, e.g., for transesterification, amidation, Michael addition, and aldol reactions, in technical silicone chemistry and even for enantioselective transformations. Currently, main applications are in innovative polymer chemistry (vitrimers, nonisocyanate polyurethanes, and polyureas). Restrictions of a broader application of TBD in technical processes due to its limited market availability and the complicated handling of its crystalline delivery form are now overcome by a simple one-pot synthesis of TBD, which generates an easy-to-make, ready-to-apply liquid formulation.",10.1021/acs.oprd.2c00248,0
"Development of an Efficient Process to Prepare Methyl 4,5,6-Trichloropicolinate Using Highly Selective C–H Borylation/Chlorodeborylation Reactions","This report details the development of an efficient process to prepare methyl 4,5,6-trichloropicolinate using Ir-catalyzed C–H borylation followed by CuCl 2 -mediated chlorodeborylation under optimized conditions. The process featured extremely low loadings (as low as 0.0005 equiv) of an [Ir(OMe)cod] 2 precatalyst with outstanding reactivity and regioselectivity (>150:1) during C–H borylation. The impurity from product dechlorination can be significantly reduced by >30-fold to <0.4%. The excellent reactivity and control of the protodeborylation impurity in subsequent copper-mediated chlorodeborylation was also highlighted. This enabled successful demonstration of a highly efficient process at a 46 mmol scale with an excellent overall yield (75%). Furthermore, it was showcased that the Ir catalyst and 4,4′-di- tert -butyl-2,2′-bipyridyl (dtbpy) ligand can be directly recycled and reused after filtration of the product. All these developments would offer significant economic benefits as well as process simplification for applying Ir chemistry.",10.1021/acs.oprd.2c00247,1
Development of a Telescoped Alkylation/Reduction Reaction Sequence and an Asymmetric Hydrogenation to Enable the Kilogram Synthesis of ABBV-3748,"Challenges in the synthesis of the cystic fibrosis transmembrane receptor corrector ABBV-3748 were addressed to enable a multikilogram-scale GMP sequence. Implementation of an early-stage telescoped titanium-mediated alkylation and palladium-catalyzed hydrogenation limited the formation of a dimerization impurity and provided consistent yields across reaction scales. Development of late-stage enantioselective hydrogenation installed the stereocenter present in the active pharmaceutical ingredient. Aspects of reagent and catalyst selection, reaction optimization, and crystallization in these two key synthetic steps are described herein.",10.1021/acs.oprd.2c00245,1
"Improved Synthesis of the Selected Serine Protease uPA Inhibitor UAMC-00050, a Lead Compound for the Treatment of Dry Eye Disease","The α-aminophosphonate UAMC-00050, a newly developed trypsin-like serine protease inhibitor, is a lead compound for the treatment of dry eye syndrome and ocular inflammation. The medicinal chemistry route developed at the University of Antwerp possessed several problems hampering the scale-up such as poor yields for some of the steps, hazardous reagents, and environmental footprint. Herein, we report an optimized route for the UAMC-00050, in which environmental unfriendly solvents were excluded, hazardous reagents were replaced with safer alternatives, and are more efficient in terms of atom economy. Every reaction step was optimized to reach a higher yield, and design of experiment was used to find the optimum conditions in the last step. Furthermore, all the flash chromatography purifications of intermediates were replaced with plug filtration, slurry purifications, or crystallization. The overall yield was increased from 3% in the medicinal chemistry route to 22% in the process development route.",10.1021/acs.oprd.2c00244,1
Practical Process for synthesizing<i>R</i>-Tetrahydropapaverine─A Key Intermediate of Cisatracurium Besylate (Nimbex),"In this paper, a practical process to synthesize the key intermediate R -tetrahydropapaverine of cisatracurium besylate was proposed. First, tetrahydropapaverine hydrochloride ( 1 .HCl) was prepared from inexpensive and commercially available 2-(3,4-dimethoxyphenyl)ethanamine ( 2 ) and 3,4-dimethoxybenzeneacetic acid ( 3 ) through a one-pot process. The yield and purity of the product were up to 85.4 and 98.1% on a 150 g scale, respectively. Then, a new resolution process was developed to prepare R -tetrahydropapaverine by using a half equivalent of N -acetyl- d -phenylalanine, and the obtained R -tetrahydropapaverine had a yield of 28.1% and 98.0% ee on a 120 g scale. Furthermore, the S -isomer was racemized to 1 .HCl in the one-pot process with 77.7% isolated yield and 99.0% purity.",10.1021/acs.oprd.2c00243,1
Development of a Robust and Scalable Synthetic Route for a Potent and Selective Isoindolinone PI3Kγ Inhibitor,"We recently described the structure-guided optimization of a series of pyrazolopyrimidine isoindolinone PI3Kγ inhibitors, which resulted in the identification of an advanced lead compound ( 1 ) with favorable potency, selectivity, and drug-like properties. To support preclinical characterization of 1, a robust and scalable synthesis was required. Herein, we report the development of an optimized synthesis of 1, which features a scalable difluoromethylation protocol and a one-pot borylation/Suzuki–Miyaura cross-coupling reaction to access the biaryl core of the molecule. A method was developed for the efficient removal of residual palladium following Pd-catalyzed cross-coupling, which provided access to 1 in high purity without the use of any chromatographic purifications. A comprehensive investigation of solid-state polymorphism identified a thermodynamically stable crystalline form of 1, greater than 200 g of which were prepared using our optimized synthesis.",10.1021/acs.oprd.2c00240,1
"Efficient Process for Obeticholic Acid: Synthesis, Structural Assignment, and Control Strategy for Diastereoisomeric Impurities","An efficient process for the preparation of chirally pure obeticholic acid [ 1, (6α, 7α), OCA] with an overall yield of 30.78% from compound 5 (CDCA) is presented in this article. During the process development, there is a requirement for characterization of physical samples of all the possible diastereomers of 1 such as 2 (6β, 7α), 3 (6β, 7β), and 4 (6α, 7β) to designate the peaks for the quantitative measurement of their contents in high-performance liquid chromatography (HPLC). All these diastereomers ( 2, 3, and 4 ) are synthesized, separated using preparative HPLC, and characterized using various spectroscopic techniques. This paper describes the fate and control mechanism of the diastereomeric and process- and degradation-related impurities in detail.",10.1021/acs.oprd.2c00237,1
Development of an Efficient New Route to PPARδ Agonist Fonadelpar: Formation of the C–C Bond by Claisen Condensation,"An efficient new synthesis of a peroxisome proliferator-activated receptor delta agonist fonadelpar was developed. The new process features a more practical approach to construct the ethylene linker of fonadelpar by coupling an advanced aldehyde and a ketone via Claisen–Schmidt condensation, which is followed by hydrogenation and an optimized process to obtain the isoxazole moiety. The convergent synthesis provides a robust and scalable approach to prepare the drug candidate in significantly fewer steps and with a higher yield.",10.1021/acs.oprd.2c00235,1
Process Development and Optimization of Linagliptin Aided by the Design of Experiments (DoE),"A design of experiments (DoE) approach was applied to the development and optimization of the manufacturing process to prepare linagliptin. DoE techniques such as a central composite face-centered design and a fractional factorial design were applied to obtain the critical process parameters and establish the optimal reaction conditions. With process-related impurities determined and successfully removed, a robust high-yielding and high-purity procedure was identified, which has been successfully demonstrated at a 100 g scale level to prepare the desired product in a 68% overall isolated yield and high-performance liquid chromatography (HPLC) purity of around 99.9%.",10.1021/acs.oprd.2c00230,1
Direct Construction of Chiral Ether via Highly Efficient Heck Reaction and N-Directed Asymmetric Hydrogenation for Large-Scale Synthesis of MALT1 Inhibitor RGT-068A,"Chemical process development efforts leading to the large-scale production of RGT-068A are discussed. Process optimization resulted in (1) successful replacement of the Stille coupling reaction involving toxic stannane reagent via highly efficient Heck reaction of methyl vinyl ether, (2) construction of the chiral ether unit through N-directed Ru-catalyzed asymmetric hydrogenation avoiding super-critical fluid chromatography (SFC) chiral separation, and (3) a streamlined process with a significantly improved overall yield of about 25%, 5-fold higher than the original discovery synthetic route, which enabled the delivery of high-quality material for IND-enabling studies.",10.1021/acs.oprd.2c00229,1
Safety Considerations and Proposed Workflow for Laboratory-Scale Chemical Synthesis by Ball Milling,"High Resolution Image Download MS PowerPoint Slide Chemical reactions that take place in a ball mill and in the absence of a bulk reaction solvent present different safety profiles to stirred solution reactions. Herein, we present and describe steps that a researcher may take to better ensure that they have considered some of the hazards and measures that emerge and minimize the risk to themselves and their colleagues.",10.1021/acs.oprd.2c00226,0
Optimized Synthesis of a Key Intermediate of Nirmatrelvir,"In this study, the development of a concise alternative process for synthesis of a key nirmatrelvir intermediate cyclic glutamine analog is described. The process proceedes via α-cyanomethylation of dimethyl N -BocGlu in the presence of NdCl 3, followed by one-pot Raney nickel-catalyzed hydrogenation of the cyano group with concomitant cyclization and ammonolysis and subsequent deprotection of N -Boc to deliver the target intermediate cyclic glutamine analog in three steps with an 82% overall yield and 99.4 A% high-performance liquid chromatography (HPLC) purity. This study resulted in improved synthetic efficiency and stereoselectivity of α-cyanomethylation for production of a key nirmatrelvir intermediate cyclic glutamine analog.",10.1021/acs.oprd.2c00225,1
"Scalable Process of Spiro(cyclopropane)oxazepane Pyridine Carboxylic Acid through Kulinkovich, Mitsunobu, and Pd-Catalyzed Intramolecular C–N Coupling","The oxazepane pyridine intermediate, an important fragment of active pharmaceutical ingredients, is of great interest in the pharmaceutical industry. In this manuscript, a scalable and economical process for the synthesis of a fused 2′,3′-dihydro-5’ H -spiro[cyclopropane-1,4′-pyrido[3,2-b][1,4]oxazepine]-8′-carboxylic acid 1 on multikilogram scales is described. The synthesis features a streamlined isolation process from the Mitsunobu reaction by using one solvent system for a two-step process. Furthermore, a robust palladium-catalyzed intramolecular amination for the seven-membered heterocycle was developed. The reproducible reaction rate was established by adding the catalyst and ligand as solids without preparing the palladium complex under nitrogen. The residual palladium was effectively reduced by recrystallization of the carboxylic ester intermediate 2 . The synthesis of key intermediate 5 was realized via the Kulinkovich reaction from readily available simple building blocks. The regulatory starting material compound 1 was isolated in a high-purity profile after saponification of the ester 2 with an overall yield of 70% over five steps.",10.1021/acs.oprd.2c00221,1
<i>tert</i>-Butylethylcarbodiimide as an Efficient Substitute for Diisopropylcarbodiimide in Solid-Phase Peptide Synthesis: Understanding the Side Reaction of Carbodiimides with OxymaPure,"The undesired reaction between carbodiimides (peptide coupling reagent) and OxymaPure (peptide coupling additive), which takes place in very low extension during peptide bond formation, is dependent on the steric hindrance around the carbodiimide backbone. Carbodiimides containing tertiary substituents on N such as di- tert -butylcarbodiimide do not activate the carboxylic group properly; the presence of secondary substituents such as in the case of diisopropylcarbodiimide (DIC) leads to the formation of oxadiazole and HCN; finally, primary substituents render an adduct of oxadiazine and no formation of HCN. tert -Butylethylcarbodiimide (TBEC), which is a hybrid of primary and tertiary substituents, leads to the formation of oxadiazine with no concomitant formation of HCN. Furthermore, TBEC outperforms DIC in terms of yield and minimization of racemization as it is demonstrated herein.",10.1021/acs.oprd.2c00220,0
Efficient and Improved Solution-Phase Synthesis of Modified RNA Dinucleotides: Versatile Synthons in Cap 1 mRNA Therapeutics,"An efficient and improved chemical method for the gram-scale synthesis of RNA dinucleotides such as pA m pA, pA m pG, and pA m pU is described that utilizes phosphoramidite chemistry using a solution-phase strategy. The first step involves the coupling between 5′- O -MMT protected nucleoside-3′- O -phosphoramidite and protected nucleoside containing the free 5′-OH group in the presence of tetrazole, followed by the oxidation of phosphite triester using tert -butyl hydroperoxide to afford the corresponding protected N m pN. Then, the 5′- O -MMT is cleaved under 3% TCA/DCM conditions. Finally, the 5′-hydroxyl group is phosphorylated by the use of an activated bis(2-cyanoethyl)- N, N -diisopropyl phosphoramidite using tetrazole, followed by the oxidation of trivalent to pentavalent phosphorus using tert -butyl hydroperoxide and subsequent deprotection using ammonium hydroxide to afford the corresponding RNA dinucleotide, pN m pN, in good yields with high purity (>99.5%).",10.1021/acs.oprd.2c00218,0
Antibody–Drug Conjugate Synthesis Using Continuous Flow Microreactor Technology,"Continuous flow reactors enable chemical reactions to occur within shielded pipes and tubes. This synthetic process is considered to overcome some limitations of commonly used batch reactors. Many successful examples of the synthesis of small molecules by continuous flow processes have been reported; however, their application in bioconjugation reactions, such as antibody–drug conjugate (ADC) syntheses, is extremely limited in the scientific literature. To our knowledge, we herein report the first continuous flow process-mediated ADC synthesis in the peer-reviewed literature. The optimized mixer type, reaction time, and mixer diameter are discussed. From these results, ADCs with clinically relevant drug–antibody ratios were produced. All of the flow reaction steps were conducted using a scaled-down manufacturing approach utilizing a stepwise mixing system to perform sequential reduction/conjugation processes. Furthermore, the established continuous flow methodology could be applied to combinations of three different antibodies and three different payloads, and the same trends were observed for each of the nine attempted ADC syntheses. These results demonstrate that continuous flow chemistry can be employed to develop reliable and robust processes for producing ADCs.",10.1021/acs.oprd.2c00217,0
Computer Vision for Kinetic Analysis of Lab- and Process-Scale Mixing Phenomena,"A software platform for the computer vision-enabled analysis of mixing phenomena of relevance to process scale-up is described. By bringing new and known time-resolved mixing metrics under one platform, hitherto unavailable comparisons of pixel-derived mixing metrics are exemplified across non-chemical and chemical processes. The analytical methods described are applicable using any camera and across an appreciable range of reactor scales, from development through to process scale-up. A case study in nucleophilic aromatic substitution run on a 5 L scale in a stirred tank reactor shows how camera and offline concentration analyses can be correlated. In some cases, it can be shown that camera data hold the power to predict reaction progress.",10.1021/acs.oprd.2c00216,0
Synthesis of Thiomorpholine via a Telescoped Photochemical Thiol–Ene/Cyclization Sequence in Continuous Flow,"A procedure for the continuous flow generation of thiomorpholine in a two-step telescoped format was developed. The key step was the photochemical thiol-ene reaction of cysteamine hydrochloride and vinyl chloride as low-cost starting materials. This reaction could be conducted under highly concentrated (4 M) conditions using a low amount (0.1-0.5 mol %) of 9-fluorenone as the photocatalyst, leading to the corresponding half-mustard intermediate in quantitative yield. Thiomorpholine was subsequently obtained by base-mediated cyclization. The robustness of the process was demonstrated by performing the reaction for 7 h (40 min overall residence time), isolating the desired thiomorpholine via distillation.",10.1021/acs.oprd.2c00214,0
"Novel, Practical, and Efficient Process for the Preparation of 4,5-Dichloroindole","A novel, practical, and efficient three-step process for the preparation of 4,5-dichloroindole 5, an important starting material for a wide range of fine chemicals and pharmaceuticals has been developed. The process comprises nitration of commercially available 2,3-dichlorobenzaldehyde 1, a telescopic process for the Henry reaction, and subsequently reductive cyclization of resulting o,β-dinitrostyrene intermediate 4 into 4,5-dichloroindole using iron powder in methanol and acetic acid by the Nenitzescu reaction. The large-scale applicability of this novel and improved process has been successfully demonstrated on a multikilogram scale by carrying multiple batches to produce 5 in 67–70% yields and 96–98% purity without column chromatography. The reactions are facile, safe, and easy to scale up.",10.1021/acs.oprd.2c00212,1
Streamlined Synthesis of Aminoacridinium Photocatalysts with Improved Photostability,"The efficient synthesis of photocatalysts with improved photostability from readily available resources is a requirement for more sustainable and scalable photocatalysis. Herein, we describe a strategy utilizing a high-yielding threefold C–N cross-coupling selective for three out of six arylbromide sites to avoid alkyl groups in the final catalyst structure. A subsequent triple metalation to form 1,5,5′-trifunctional organometallic reagents enables the coupling and cyclization with simple esters, whereas a third unreacted functionality is hydrolyzed upon acidic quench. This short reaction sequence results in bis(diarylamino)acridiniums with dramatically increased photostability, allowing us to lower the catalyst loading to 0.10 mol % without loss in yield.",10.1021/acs.oprd.2c00209,1
Mathematical Modeling and Optimization to Inform Impurity Control in an Industrial Active Pharmaceutical Ingredient Manufacturing Process,"Mathematical modeling of pharmaceutical manufacturing processes can provide insights and understanding regarding the key factors impacting product quality. In this study, we describe the development of a dynamic model for a stage in an active pharmaceutical ingredient (API) manufacturing process, its calibration and validation versus industrial experimental data, and its use to address three objectives: (1) assessment of process operating parameter criticality on key performance indicators (KPIs); (2) confirming whether the considered process operating space safely respected limits of critical quality attribute (CQA) impurities; and (3) finding process setpoints that can potentially improve the KPIs. Objective 1 used global sensitivity analysis (GSA) to find that only operating parameters associated with the reactor were significant. Objectives 2 and 3 used nonlinear optimization, confirming that impurity limits are respected at any point in the considered process operating space and suggesting a shifted process setpoint that could allow enhanced yield (∼4% absolute increase) and reduced impurity content (∼0.5 mol % absolute reduction).",10.1021/acs.oprd.2c00208,0
Development of a Robust and Scalable Process for the Large-Scale Preparation of Vilazodone,"A robust and scalable synthesis for vilazodone was developed to avoid the formation of impurities derived from N-detosylation reactions under alcoholic conditions. During our research, these impurities, potentially genotoxic alkyl tosylate and out-of-specification indole N-alkylated vilazodones, were identified as process impurities that have never been reported. Through adjusting the functionality transformations, this process successfully prevented the tosyl group from encountering any alkoxides, which would inevitably lead to the generation of alkyl tosylate and indole N-alkylated vilazodone byproducts. In addition, this manufacturing process has also been demonstrated on a kilogram scale, delivering 1.05 kg of vilazodone hydrochloride with an overall yield of 71% (calculated from ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate hydrochloride 7·HCl ). HPLC purity of the product was detected >99.5%, with any single impurity <0.1% HPLC area percentage. Indole N-alkylated vilazodones were not detected, and the yield was 10% higher than the previous Friedel–Crafts acylation route.",10.1021/acs.oprd.2c00206,1
Refractive Index to Monitor Solid-Phase Oligonucleotide Synthesis,"Automated solid-phase oligonucleotide synthesis (SPOS) is a highly developed and efficient process, which has been used in academia and industry since decades. Still, some chemical transformations as well as all washing steps are run in a black box modus as only a few process analytical technology tools are available, namely, UV–vis spectroscopy and conductivity. To ensure high yields and efficiencies in each of the numerous steps, the process is usually performed using an excess of building blocks, reagents, and solvents. The reaction conditions are defined according to standard procedures and not necessarily to the real or optimal need of the reaction. As a result, SPOS suffers from generating large amounts of toxic waste, and its reduction is a must from the perspective of sustainability. One approach to make the process more sustainable is to add more complementary monitoring tools that provide online information about the progress of the process. Herein, we disclose our promising preliminary results in the use of refractive index to monitor SPOS.",10.1021/acs.oprd.2c00203,1
Practical Asymmetric Synthesis of a Bicyclic Pyrrolidinol,"The “butterfly-shaped” bicyclic pyrrolidinol ((2 R,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)-methanol ( 1 ) is a key building block for drug candidates, and its practical chemical synthesis remains elusive. As such, an asymmetric synthesis for ((2 R,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)-methanol ( 1 ) that is amenable for scale-up has been developed. The newly optimized process utilizes readily available N -Boc- trans -4-hydroxy- l -proline methyl ester ( 8 ) to establish the challenging stereogenic center bearing the fluoride. Subsequent diastereoselective α-alkylation was achieved by leveraging Seebach’s self-regeneration of stereochemistry (SRS) methodology, which has been exploited for the synthesis of proline derivatives. Finally, intramolecular cyclization/deprotection cascade and carbonyl reduction afford the bicyclic pyrrolidinol 1 in nine linear steps from compound 8 . This process significantly reduces the overall production sequence and allows the preparation of product 1 on a multikilo scale with a 40% overall yield and perfect control of chirality (>99% ee and de).",10.1021/acs.oprd.2c00200,1
Advancing Scalable Chemistry toward Novel CELMoDs: Process Development for the Synthesis of CC-90009,"CC-90009 ( 1 ) is a cereblon E3 ligase modulating drug (CELMoD) in clinical trials for the treatment of acute myeloid leukemia (AML). An efficient synthesis of 1 was required to support drug substance supply for clinical trials. The structure features an isoindolinone core, an α,α-difluorophenylacetamide, and a chemically sensitive α-amidoglutaramide moiety prone to hydrolysis or ring opening under basic or Lewis acidic conditions. A key feature of the synthesis was the transformation of a phthalide to the corresponding o -(chloromethyl)benzoate ester while managing the tendency of intermediates to relactonize. The realization of this transformation under mild conditions also serves as a model for a broadly applicable strategy to access these valuable motifs. Optimization of the nitrile hydrogenation and the amide bond formation to form 1 afforded the API in significantly improved yield and with high purity. This route was scaled up to supply early clinical trials and served as the basis for commercial route development.",10.1021/acs.oprd.2c00199,1
Multigram Synthesis of Pure HMF and BHMF,"5-Hydroxymethylfurfural (HMF) is a bio-based platform chemical that can be used as a building block to produce several compounds with diverse applications. Even though HMF synthesis holds promise for a greener future, the current state of technology and the high production cost limit its competitiveness on an industrial scale. In this prospect, we have developed a multigram-scale procedure for HMF by reacting d-fructose with Purolite CT275DR-an acidic resin-in a dimethyl carbonate (DMC)/tetraethyl ammonium bromide (TEAB) biphasic system. Reactions performed in an autoclave for 2 h at 110 °C using up to 40 gram of d-fructose resulted in an overall HMF yield of 70%. HMF was purified by a custom-made procedure leading to ca 50% of the pure crystalline product; meanwhile, the residual HMF-rich oil was directly reduced to bis(hydroxymethyl)furan (BHMF). Green metrics and the Ecoscale algorithm were used to evaluate the sustainability of the herein-proposed procedure in comparison with previously reported works.",10.1021/acs.oprd.2c00196,0
Synthesis of MDM2-p53 Inhibitor BI-0282 via a Dipolar Cycloaddition and Late-Stage Davis–Beirut Reaction,"Herein, we report the structure and synthesis of the potent MDM2-p53 inhibitor BI-0282. The complex spirooxindole scaffold bearing four stereocenters embedded in a rigid polycyclic ring-system was effectively prepared on a multi-gram scale in only five synthesis steps employing a three-component 1,3-dipolar cycloaddition and a late-stage Davis-Beirut reaction as key steps.",10.1021/acs.oprd.2c00192,1
Manufacturing Process Development for Uprifosbuvir (MK-3682): A Green and Sustainable Process for Preparing Penultimate 2′-Deoxy-α-2′-Chloro-β-2′-Methyluridine,"A simple and efficient process to prepare Uprifosbuvir intermediate, 2′-deoxy-α-2′-chloro-β-2′-methyluridine ( 1 ), from bis-pivaloyl tertiary alcohol 5a is described. The key discoveries are a novel BSA-promoted anhydrouridine formation catalyzed by HCl as an additive and a milder safe Me 2 SiCl 2 -promoted chlorination of anhydrouridine. These discoveries collectively enabled the establishment of a robust process toward compound 1, which was demonstrated successfully at the plant scale.",10.1021/acs.oprd.2c00191,1
Addition Reaction of Alcohol to Isocyanate Catalyzed by Copper Present in Tap Water: Robust Manufacturing Process of Naldemedine Tosylate,"We discovered that copper present in laboratory tap water could catalyze an addition reaction of the hydroxyl group of acetylnaltrexone to isocyanate. The first pilot manufacturing of naldemedine tosylate encountered an unexpected problem in which the addition reaction was seriously delayed. Detailed investigations showed that the low copper content in pilot tap water led to a reduced reaction rate. This discovery allowed us to establish a robust manufacturing process by adding a copper catalyst. Since unintended contamination by metal catalysts can confuse chemists, we share our experience with the hope that our findings will raise awareness of contamination issues among researchers.",10.1021/acs.oprd.2c00187,1
Scalable Process of Methimazole,"Base hydrolysis of imidazole carboxylate was observed to be an efficient route for the scalable synthesis of the antithyroid drug methimazole. Ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate ( 12 ) was produced as a key intermediate in the reaction of 1-methyl-1H-imidazole ( 4 ) with ethyl chloroformate ( 11 ) and sulfur. Compound 12 undergoes hydrolysis in two steps in the presence of a base to give methimazole ( 1 ) with an overall yield of 78%. The process was studied through the Quality by Design (QbD) concept and observed to be robust.",10.1021/acs.oprd.2c00185,1
Development of a Continuous Flow Synthesis of Lorazepam,"Lorazepam, a widely used sedative that appears on the World Health Organization list of essential medicines, experiences periodic shortages. Using a workflow involving route scouting, high-throughput experimentation, and impurity profiling to develop an optimal sequence, we report a novel 5-step route for synthesis of lorazepam in flow. The five steps comprise N-acylation, diazepine ring closure, imine N-oxidation, Polonovski-type rearrangement, and ester hydrolysis to give lorazepam. Each step was optimized and translated to continuous flow. The mean residence times for each of the individual flow reactions summed to a total of 72.5 min for the 5-step sequence. We also report a comprehensive analysis of the purity and byproduct profile to maximize the desired product purity in each step, leading to over 99% pure lorazepam.",10.1021/acs.oprd.2c00184,1
Efficient Synthesis of a Key Intermediate for Moxifloxacin Via Intramolecular Double Stereodifferentiation,"An intramolecular double stereodifferentiation methodology was developed during the synthetic process development of ( S, S )-2,8-diazobicylo[4.3.0] nonane ( 1 ), the key intermediate of the fourth-generation fluoroquinolone Moxifloxacin. The dual chiral-auxiliary strategy employed in this process guaranteed high stereoselectivity of the hydrogenation reaction to build the cis-[5,6] bicyclic system with desired stereochemistry. 1,6-Bis(( R )-1-phenylethyl)-3,4,6,7-tetrahydro-1 H -pyrrolo[3,4- b ]pyridine-2,5-dione ( 11f ), the precursor of the hydrogenation reaction, was prepared from commercially available and affordable chemicals ethyl acetoacetate, ( R )-(+)-1-methylbenzylamine, and acryloyl chloride, and the process was further facilitated by telescoping the first three steps into one pot. Moreover, this process has been proven robust at a hectogram scale, providing 450 g of intermediate 1 with a total yield of 56.2% over seven steps and enantiomeric excess of more than 99%, demonstrating the potential for commercial-scale applicability.",10.1021/acs.oprd.2c00183,1
Novel Analytical Approach to Quantify Reactive Potentially Mutagenic Sulfonate Ester Impurities in Pharmaceutical Compounds and Its Application in the Development of a Control Strategy for Nonaflate Impurities in Belzutifan Synthesis,"Sulfonate esters are encountered frequently as impurities that are potentially mutagenic in different manufacturing processes producing active pharmaceutical ingredients (APIs) due to the widespread use of sulfonyl halide/anhydride or sulfonic acid as reagents in the processes. While a scientific risk assessment, based on the formation and predicted purge of sulfonate esters, can justify the absence of these impurities in the final API for some cases, for other cases, analytical testing data showing the levels of sulfonate ester impurities in the API is required to support the risk assessment. The detection and quantitation of a subset of sulfonate esters that are reactive and unstable are challenging using the existing gas chromatography–mass spectrometry (GC–MS) or Liquid chromatography–MS (LC–MS) methods. We reported here a new approach to quantify reactive sulfonate esters at low levels in pharmaceutical compounds by taking advantage of the reactivity of the sulfonate ester. With this approach, an unstable sulfonate ester is intentionally hydrolyzed to the corresponding sulfonate anion and alcohol. The resulting stable sulfonate anion can then be measured readily using an LC–MS method as a way to quantify the sulfonate ester indirectly. The specificity, sensitivity, precision, and accuracy of the analytical method were validated with three stable sulfonate esters as the model compounds. The method was successfully applied to the belzutifan synthesis to analyze the amounts of several reactive nonaflate impurities formed in the final step of the synthesis. These data, in combination with a purge-based scientific risk assessment, supported a control strategy for these mutagenic impurities that centers around process control without the need to perform routine analytical testing.",10.1021/acs.oprd.2c00182,0
"Scalable Synthesis of CVN424, an Inverse Agonist of the GPR6 Receptor","CVN424 is a drug candidate, which is being investigated in clinical trials for the treatment of motor fluctuations associated with Parkinson’s disease. We herein describe the process development of an efficient synthetic route that delivered several kilograms of the drug substance. The synthesis included diacylation of commercially available 3,4-diaminopyridine 1 with diethyl oxalate to give 2 and chlorination with POCl 3 to give pyrido[3,4- b ]pyrazine 3, followed by two sequential nucleophilic aromatic substitutions. A final hydrogenation and acetylation of intermediate 7 provided CVN424. Overall, a safe and robust synthesis was developed, which occurred in five linear steps with an overall yield of 15%.",10.1021/acs.oprd.2c00181,1
Tunable Microwave Flow System for Scalable Synthesis of Alkyl Imidazolium-type Ionic Liquids,"A continuous flow auto-frequency tuning single-mode microwave reactor is disclosed as a powerful platform to synthesize alkyl imidazolium salts as ionic liquids/ionic liquid precursors in up to near-quantitative yields, 100–600 g h –1 productivities and record space-time yields. Challenges faced, including viscosity changes, dielectric property changes, and phase separations, were addressed by different operation modes of the reactor without reactor redesigning. Depending on the purpose, this highly productive method could prove to be useful for intensive applications of ionic liquids.",10.1021/acs.oprd.2c00180,0
Biocatalysis: Improving Enzymatic Processes through Protein and Reaction Engineering,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTBiocatalysis: Improving Enzymatic Processes through Protein and Reaction EngineeringCarlos A. Martinez*Carlos A. MartinezBiocatalysis Center of Excellence (BCE) and Chemical R&D, Pharmaceutical Sciences, Small Molecules, Pfizer Inc., Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, United States*Phone: 860-5018743. Email: [email protected]More by Carlos A. Martinez, Nicholas J. TurnerNicholas J. TurnerDepartment of Chemistry and Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, U.K.More by Nicholas J. Turnerhttps://orcid.org/0000-0002-8708-0781, and Zhi LiZhi LiDepartment of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585More by Zhi Lihttps://orcid.org/0000-0001-7370-2562Cite this: Org. Process Res. Dev. 2022, 26, 7, 1855–1856Publication Date (Web):July 15, 2022Publication History Published online15 July 2022Published inissue 15 July 2022https://doi.org/10.1021/acs.oprd.2c00179Copyright © Published 2022 by American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1239Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (482 KB) Get e-AlertsSUBJECTS:Alcohols,Amines,Biocatalysis,Peptides and proteins,Reaction engineering Get e-Alerts",10.1021/acs.oprd.2c00179,0
"Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate","Described herein is the discovery and development of a process to prepare an atropisomeric intermediate in the synthesis of the KRAS G12C inhibitor sotorasib. Using high-throughput experimentation, (+)-2,3-dibenzoyl- d -tartaric acid [(+)-DBTA] was identified as an inexpensive and readily available resolving agent that enables separation and isolation of the desired atropisomer through a classical resolution. Subsequent optimization and characterization studies led to a highly selective process, providing the desired atropisomer as a unique three-component cocrystal solvate with a selectivity of >2000:1. This classical resolution has been performed successfully on >500 kg scale and was critical to the commercialization of the sotorasib manufacturing process.",10.1021/acs.oprd.2c00176,1
Transformation of the Manufacturing Process from Discovery to Kilogram Scale for AWZ1066S: A Highly Specific Anti-<i>Wolbachia</i> Drug Candidate for a Short-Course Treatment of Filariasis,"Anti- Wolbachia therapy has been clinically proven to be a safe approach for the treatment of onchocerciasis and lymphatic filariasis. AWZ1066S, a first-in-class highly specific anti- Wolbachia drug candidate developed for a short-course treatment of human filariasis, has advanced into clinical development. An improved, cost-efficient, and scalable process for the manufacture of this clinical candidate is described. Presented herein is the process development work for the active pharmaceutical ingredient (API) and its two key starting materials [2-(trifluoromethyl)-3-pyridyl]methanamine and ( S )-3-methylmorpholine, starting from 2,4-dichloropyrido[2,3- d ]pyrimidine, which is capable of delivering high-purity (>99%) API consistently. The optimized production route was used in the manufacture of the clinical candidate at the kilogram scale to support the ongoing clinical development.",10.1021/acs.oprd.2c00167,1
Accelerated Multiphosphorylated Peptide Synthesis,"Preparing phosphorylated peptides with multiple adjacent phosphorylations is synthetically difficult, leads to β-elimination, results in low yields, and is extremely slow. We combined synthetic chemical methodologies with computational studies and engineering approaches to develop a strategy that takes advantage of fast stirring, high temperature, and a very low concentration of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produce multiphosphorylated peptides at an extremely rapid time and high purity.",10.1021/acs.oprd.2c00164,0
Synthesis and Applications of Periodate for Fine Chemicals and Important Pharmaceuticals,"An emerging interest for the application of periodate in the synthesis of active pharmaceutical ingredients (APIs) and for the valorization of renewable feedstock is eminent. However, periodate exhibits a high molecular mass, is expensive compared to other common bulk-oxidizers and is used only reluctantly in technical applications. Recently, a new and green electrochemical synthesis was established. The preparation and regeneration method for periodate lowers costs and enables the use of periodate in the synthesis of regulated products. This review will briefly introduce the key innovations in the electrochemical synthesis of periodate and will survey the most important applications of periodate in the production of fine chemicals.",10.1021/acs.oprd.2c00161,1
Process Development and Scale-Up of a Protease Inhibitor for the Treatment of HIV Featuring the Preparation of a Neopentyl Grignard Reagent and Development of a One-Pot Curtius Reaction,"Compound 1 is a densely functionalized iminohydantoin that possesses a quaternary stereocenter and is under development as an HIV protease inhibitor. Key challenges that are discussed include the preparation of a neopentyl Grignard reagent via magnesium insertion, development of a one-pot Curtius reaction that generated a volatile isocyanate and was trapped with an alcohol, and removal of a CBz protecting group to isolate a succinate salt. This study describes process development efforts that enabled the first scale-up of 1 .",10.1021/acs.oprd.2c00153,1
"Preparation of Enantiopure 3-Aminopiperidine and 3-Aminoazepane Derivatives from Ornithine and Lysine. Consecutive Syntheses of Pharmacologically Active Analogs, Such as Besifloxacin",,10.1021/acs.oprd.2c00152,0
Development of an Optimized Synthetic Process for an Antiobesity Drug Candidate (S-234462) Featuring Mild Chlorination of Benzoxazolone and In Situ IR Monitoring of a Mitsunobu Reaction,"Here, we outline the manufacturing process history of S-234462. For the optimized process, 6-fluorobenzoxazolone, ((1r,4r)-4-aminocyclohexyl)methanol, and ethyl( tert -butylsulfonyl)carbamate were selected as starting materials. The first key to successful process development was the discovery of mild chlorination conditions of 6-fluorobenzoxazolone using phosphorus pentachloride and polyphosphoric acid. The second key was the establishment of N -alkylation by the Mitsunobu reaction, which did not require excess ethyl( tert -butylsulfonyl)carbamate. In addition, kinetic study of the Mitsunobu reaction using in situ IR analysis enabled control of the reaction conversion.",10.1021/acs.oprd.2c00150,1
An Alternative Route to the Anticancer Agent: 2-Fluorofucose from Readily Available L-(−)Rhamnose and Mechanistic Insights into a Zinc/Ammonium Iodide-Mediated Elimination Reaction,"2-Fluorofucose ( 6 ) is a fucosylation inhibitor administered orally to patients with advanced solid tumors. 6 exhibits antitumor activity, putatively via multiple mechanisms. Herein, we report a robust formal synthetic route for obtaining 6 ( SGD-2083 ) from L-(−)rhamnose as a starting material. This provides an alternative expedient route toward its commercial-scale production for a First in Human (FIH) campaign. In this work, we have optimized a linear synthesis constituting a sequential, strategic protection, oxidation, reduction, and bromination. Importantly, we biased the reactivity of an organozinc intermediate toward an ionic pathway by inclusion of salt additives. Computational insights and mechanistic studies highlighting the role of relative configuration and the reactivity of these protected sugars are the key toward the success of this efficient and scalable route. The efficiency of this eight-step linear synthesis was demonstrated on multigram scale, furnishing key intermediate 4 in 32% overall yield.",10.1021/acs.oprd.2c00146,1
Synthesis of a Pyridoazepine Scaffold via Rhodium-Catalyzed Ring Expansion and Nitroacetamide Condensation,"Pyridoazepines are privileged structures in the search for novel drug candidates. We present the synthesis of a versatile pyridoazepine scaffold employing a precedented rhodium(II)-catalyzed ring expansion and subsequent double-condensation-cyclization with nitroacetamide. The reactions applied several potentially hazardous reagents and intermediates, including p -toluenesulfonyl azide and nitroacetamide, the latter of which was determined to be potentially explosive and shock-sensitive. Reactions employed were derisked for laboratory scale work through DSC and TS U analysis in concert with optimization of reaction conditions. The key rhodium-catalyzed ring expansion was shown by TS U analysis to occur in a controllable manner with manageable nitrogen evolution. A new procedure is presented that enables preparation of nitroacetamide without excessive manipulation (i.e., extractive isolation) or isolation of dry solid. This article describes early safety studies used to derisk the preparation of multi-gram quantities of the target pyridoazepine.",10.1021/acs.oprd.2c00145,1
Suppression of Simultaneous Fmoc-His(Trt)-OH Racemization and <i>N</i><sup>α</sup>-DIC-Endcapping in Solid-Phase Peptide Synthesis through Design of Experiments and Its Implication for an Amino Acid Activation Strategy in Peptide Synthesis,"Coupling Fmoc-His(Trt)-OH in solid-phase peptide synthesis is frequently accompanied by significant racemization. Histidine is among the most susceptible amino acid residues inclined to racemize in peptide syntheses. In this study, the His racemized impurity could not be effectively purged by the applied chromatographic purification. Consequently, a Taguchi design of experiment (DOE) was first applied to screen the critical process parameters affecting the histidine racemization. Optimization of the DOE is subsequently performed to search for the optimum. The derived DOE models reveal that the conditions of Fmoc-His(Trt)-OH carboxylate pre-activation prior to its coupling to growing peptide chains are critical for the subject histidine racemization. Intensive Fmoc-His(Trt)-OH pre-activation stimulates this side reaction. On the other hand, without the amino acid pre-activation, by adopting the in situ Fmoc-Xaa-OH activation, another side reaction, that is, peptide N α endcapping by N,N -diisopropylcarbodiimide, is boosted. A conflicting relationship between histidine racemization and peptide N α endcapping has been detected through the DOE investigation. Significant models are established for the histidine racemization and peptide N α endcapping, and reconciliation to balance these two side reactions is accomplished on this basis.",10.1021/acs.oprd.2c00144,0
Route Design and Development of Tetrachlorantraniliprole: Copper-Catalyzed Cyclization and One-Pot Preparation of Pyrazole Acid Chloride,"Synthetic strategies for preparing insecticide tetrachlorantraniliprole ( 1 ) were explored. Target compound 1 was synthesized from 2,3,5-trichloropyridine ( 2 ) using a six-step process. The obtained yield of 51.7% was considerably higher than the 4.7% yield of the initial seven-step process. Process highlights include copper-catalyzed cyclization of 3-chloro-2-hydrazinopyridine ( 3 ) for forming the key intermediate 2-(3,5-dichloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate ( 4 ), one-pot preparation of pyrazole acid chloride ( 9 ) from thionyl chloride, and a coupling reaction of pyrazole acid chloride ( 9 ) with benzamide ( 10 ) to afford target compound 1 without an acid scavenger. The process represents a reliable alternative for large-scale manufacturing of tetrachlorantraniliprole ( 1 ).",10.1021/acs.oprd.2c00141,1
Optimization of Nitrosation Reaction for Synthesis of 4-Aminoantipyrine by Response Surface Methodology and Its Reaction Mechanism,"A small-scale process of nitrosation reaction for the preparation of 4-aminoantipyrine (AA) is optimized. Response surface methodology combined with Box–Behnken design is used to build the model and optimize parameters. AT-SO 4 /sodium nitrite molar ratio, antipyrine (AT)/sulfuric acid molar ratio, reaction time, and reaction temperature are selected as independent variables, and the purity and yield of AA are the response values. The optimized reaction conditions are as follows: n (AT-SO 4 )/ n (NaNO 2 ) = 0.84, n (AT)/ n (H 2 SO 4 ) = 1.72, the reaction temperature is 17 °C, and the reaction time is 2 min. The AA yield and purity reach 90.60 and 75.19%, respectively. In addition, IR and liquid chromatography–mass spectrometry analyses are used to study the reaction mechanism. Secondary nitrosation reaction products are discovered to be formed, and an unprecedented reaction mechanism is proposed.",10.1021/acs.oprd.2c00132,1
Development of Dual Practical Manufacturing Routes to Cognate Pyrrolobenzodiazepine-Based Linker-Drugs,"The synthetic strategies for two distinct but related linker-toxins 1 and 2 were reconfigured in order to devise an efficient and unified supply chain for both compounds. This involved establishing novel chemical routes to crystalline, monomeric building blocks that could be combined in a unique way for each molecular target. This streamlined approach avoided challenging desymmetrization efforts en route to each target molecule as well as a drastically reduced need for multiple chromatographic purifications throughout the syntheses. In the final instance, the shared-building-block concept enabled access to advanced intermediates from which the optimized endgames were implemented, ultimately resulting in robust synthetic processes to both 1 and 2 .",10.1021/acs.oprd.2c00129,0
"Development, Validation, and Application of a Custom-Made Mini-Reaction Calorimeter for Thermal Safety Screening","Before scaling up to production, it is of high importance to evaluate the potential of a reaction to lead to an undesired thermal degradation event. The use of a large amount of compounds is usually required for a reliable calorimetry study. In this work, we report the development of a milliliter-scale reaction calorimeter for reaction screening applications. The setup was designed using laboratory equipment and characterized and validated with routine experiments. The results were sufficiently accurate enabling us to observe trends in the measured reaction enthalpies of a family of compounds reacting with strong bases as a function of the compounds' structures.. The use of the microscale tailor-made calorimeter is considered very valuable for potentially highly energetic reactions since reaction calorimetry studies can be performed accurately and safely with small amounts of valuable materials.",10.1021/acs.oprd.2c00128,0
Minimizing Material Consumption in Flow Process Research and Development: A Novel Approach Toward Robust and Controlled Mixing of Reactants,"Scarce availability of chemical starting materials is a crucial challenge in the development of flow chemical processes. This is particularly important for organometallic reactions, which typically require high flow rates and hence high material consumption, to generate sufficiently short mixing and residence times. To address this issue, micromixers that mix efficiently even at small Re numbers and that have a low tendency of clogging are necessary. Here, we propose the usage of microannular gear pumps as active mixers, which allow the reduction of material consumption by >10-fold while achieving fast mixing times for common organometallic reactions. This novel approach is benchmarked against several commercially available mixers with respect to the mixing time at low flow rates, showing that the gear pumps can achieve fast mixing (< 50 ms) even at <1 mL/min. To assess the crucially important factor of time to blockage in a consistent manner, a novel protocol is developed based on the controlled precipitation of lithium salts during the mixing process. This shows that the gear pump is significantly more robust than common mixers as operation can be maintained for over 2 h. Lastly, we highlight that the microannular gear pump approach allows the manipulation of mixing time at equal residence time, by tuning the rotation speed, thus allowing for characterization of the mixing sensitivity of reactions. Taken together, our multiparametric analysis of common mixing approaches highlights that the usage of microannular gear pumps for active mixing of fast organometallic reactions presents a powerful alternative able to address current limitations of organic process development.",10.1021/acs.oprd.2c00123,1
"Racemic Synthesis of a Key 1,4-Dihydro-2<i>H</i>-spiro[isoquinoline-3,4′-piperidin]-3′-ol Building Block",The synthesis of a key spiroamine building block for a medicinal chemistry program is described. Key innovations were a regioselective epoxide ring opening and a late-stage Pictet–Spengler reaction that was quickly optimized using Design of Experiments.,10.1021/acs.oprd.2c00121,1
Co-immobilized Multienzyme System for the Cofactor-Driven Cascade Synthesis of (<i>R</i>)<i>-</i>2-Amino-3-(2-bromophenyl)propanoic Acid: A Model Reaction,"d -Amino acids are important intermediates for the synthesis of β-lactam antibiotics and other vital pharmaceuticals, which can be synthesized by various methods including biocatalysis. In this work, we have demonstrated using immobilized multienzyme cofactor-driven cascade reaction for the synthesis of a model d -amino acid, ( R )-2-amino-3-(2-bromophenyl)propanoic acid. In the present study, three enzymes, namely, d -amino acid amino transaminase from Bacillus cereus ( bc DAAT), a d -lactate dehydrogenase ( lh D-LDH) from Lactobacillus helveticus, and a formate dehydrogenase ( cb FDH) from Candida boidinii, were successfully demonstrated in a practical and scalable immobilization protocol on glutaraldehyde-activated amino polymer beads LX1000HA. From the results, it was evident that the sequentially co-immobilized cb FDH along with the other two enzymes exhibited excellent stability at >90% for 10 cycles (150 h). Pilot-scale batches conducted at 50 g scale using the above immobilized multienzyme resulted in an overall isolated yield of 65% of ( R ) - 2-amino-3-(2-bromophenyl)propanoic acid (∼33 g white powder; HPLC purity, >99%; ee, 99.0%). The application of the immobilized enzyme was also evaluated in PBR continuous-flow reaction, in which a stable conversion of >95% for 36 h was achieved (space–time yield, 323.3 g L –1 day –1 ]. d -Amino acids are vital building blocks used in pharmaceuticals and fine chemicals. Hence, we believe that immobilized multienzyme cofactor-driven cascade reaction could be a potential manufacturing platform for d -amino acids.",10.1021/acs.oprd.2c00119,0
Reactor Design for the Direct Electrosynthesis of Periodate,"A reactor design to continuously produce sodium paraperiodate under strongly alkaline conditions is presented. The target compound is generated by direct electrosynthesis. The approach combines the concepts of cyclic flow electrolysis and a continuous stirred tank reactor (e-CSTR), which is operated in a steady-state mode. It enables fully continuous operation and allows the flexible and independent use of various iodine sources as starting materials. Further developments are the use of either dissolved or solid starting materials, the inline separation of the product, and the recycling of electrolytes. This enables a cost-efficient synthesis of metaperiodate from sodium iodide in Ph. Eur. quality.",10.1021/acs.oprd.2c00116,0
Development of a New Synthetic Route of the Key Intermediate of Irbesartan,"Herein, we describe a new synthetic route to prepare 4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile ( 5 ), an intermediate of irbesartan. Compared with leucine or its derivatives as the starting material to synthesize irbesartan in many previous reports, the intermediate 5 could be obtained in four steps from low-cost and commercially available glycine methyl ester as the starting material, which also avoided the use of highly toxic cyanide. The spirocycle structure in the intermediate 5 was constructed with dihaloalkanes via a simple alkylation reaction. The related impurities and process parameters were studied in detail. Finally, the scale-up of this route was successfully performed on a 200 g scale, affording 332 g of the intermediate 5 with 98.4% purity and 54.2% overall yield in four steps. Meanwhile, process mass intensity and yield stability were demonstrated. The current synthetic route provides an alternative strategy for the production of irbesartan.",10.1021/acs.oprd.2c00113,1
Kilo-Scale Electrochemical Oxidation of a Thioether to a Sulfone: A Workflow for Scaling up Electrosynthesis,"Organic electrosynthesis is a rapidly evolving field, providing powerful methods to assemble targets of interest in organic synthesis. Concerns around the scalability of electrochemical methods remain the biggest reason behind their scarce implementation in manufacturing routes for the pharmaceutical industry. To fill this gap, we report a workflow describing the key reaction parameters toward the successful scale-up of an organic electrosynthetic method from milligram to kilogram scale. The reaction used to demonstrate our workflow and scale-up in a flow setting was the oxidation of a thioether to its corresponding sulfone, a fragment of interest in an active pharmaceutical ingredient under development. The use of online flow nuclear magnetic resonance spectroscopy, offline ion chromatography, cyclic voltammetry, and density functional theory calculations provided insight into the reaction mechanism and side reactions.",10.1021/acs.oprd.2c00111,0
"Direct Synthesis of Methylchlorosilanes: Catalysts, Mechanisms, Reaction Conditions, and Reactor Designs","Silicone polymers are produced commercially mainly from methylchlorosilanes prepared by direct synthesis. The yield and selectivity of this synthetic process depend not only on chemical reactions but also on transfer phenomena, leading to conflicting results and controversial interpretations within this research field. This review highlights recent advances in synthesis mechanisms, including catalysts and promoters, especially the effect of process parameters and reactor form on the reactivity and selectivity of the reaction. This review shows that different catalysts and their structures and promoters lead to significant differences in reaction rates and product distributions. Process parameters such as feed gas velocity and composition, reaction temperature, reaction pressure, silica fume, etc., as well as synthesis reactor structure have influenced the reaction rate and yield distribution. Although there is some consensus on understanding the influence of operating parameters, synthesis reactor structure, and reaction kinematics, further studies are still needed to elucidate the catalytic mechanism and synergistic mechanism between the reaction and transfer processes. It also reviews recent trends in these response characteristics in previously reported studies and offers important directions for future research in this field.",10.1021/acs.oprd.2c00107,0
"Continuous-Flow Synthesis of <i>syn</i>-2-Amino-1,3-diol via Catalytic Hydrogenation: A Vital Intermediate of (+)-Thiamphenicol and (+)-Florfenicol","In this paper, an expeditious and efficient continuous-flow process is reported for the synthesis of syn -2-amino-1,3-diol. The starting material syn -2-nitro-1,3-diol reacts with hydrogen gas in a micro fixed-bed reactor packed with a Raney Ni catalyst to provide syn -2-amino-1,3-diol in 93% isolated yield. The reaction time in the flow system was markedly reduced (from 36 h in batch to 5 min in flow) due to enhanced mass transfer. The effects of the catalyst, solvent, reaction temperature, reaction time, pressure, and H 2 flow rate have been investigated successively. The optimum conditions for the continuous-flow reaction are described as follows when using Raney Ni as a catalyst at a reaction temperature of 25 °C, a reaction pressure of 10 bar, a reaction solvent of 3% AcOH in methanol, an H 2 flow rate of 25 sccm, and a liquid flow rate of 0.6 mL/min. The reaction kinetics in the temperature range of 10–40 °C were investigated. The reaction rate constants and activation energy were determined. The continuous flow system allows for an efficient hydrogenation of syn -2-nitro-1,3-diol on the hectogram scale, corresponding to an overall productivity of 73.6 g/d after continuous operation for over 240 h.",10.1021/acs.oprd.2c00100,1
"Cost-Efficient, Multigram Scalable Synthesis of Shelf-Stable Electrophilic (Phenylsulfonyl)difluoromethylating Reagents","An easy-to-handle protocol for the synthesis of an efficient electrophilic (phenylsulfonyl)difluoromethylating reagent, namely, the S -([phenylsulfonyl]difluoromethyl)-dibenzothiophenium salt I, is depicted. The latter was synthesized on approximately 40 g scale in a three-step/one-purification sequence from commercially available or easy-to-synthesize starting materials with an estimated global prize of about 10.6 €/g. The bench-stable reagent I was found to be air- and moisture-tolerant. By changing the counter anion, a small library of electrophilic sources (reagents I – III ) is now available for the (phenylsulfonyl)difluoromethylation reaction. Differential scanning calorimetry (DSC) measurements have been also carried out on the different salts ( I – III ) along with a key intermediate to ensure a safe process.",10.1021/acs.oprd.2c00099,1
Development of a Practical Process for the Large-Scale Preparation of the Chiral Pyridyl-Backbone for the Crabtree/Pfaltz-Type Iridium Complex Used in the Industrial Production of the Novel Fungicide Inpyrfluxam,"Herein, we report the development activities leading to an efficient process for the large-scale production of the key intermediate to a crabtree/pfaltz-type iridium complex for industrial application. The process employs a highly efficient Suzuki coupling and a highly enantioselective transfer hydrogenation.",10.1021/acs.oprd.2c00097,1
Development of an Ene Reductase-Based Biocatalytic Process for the Production of Flavor Compounds,"Ene reductases catalyze the biocatalytic reduction of activated alkenes, offering a powerful biobased alternative to metal-catalyzed and organocatalyzed double-bond reductions. With the aim to utilize the natural catalysts for the development of sustainable industrial processes for the flavor and fragrance (F&F) industry, we investigated the synthetic potential of a wild-type ene reductase library consisting of 20 enzymes to produce flavor compounds, including decanal. In our library screening, we identified several ene reductases that could efficiently reduce 2 E -decenal as well as other investigated target substrates. Five of the characterized enzymes exhibited high reduction activities even at increased substrate concentrations (10 g/L). By analyzing additional enzyme characteristics (thermostability, solubility, and activity at 10 °C), enzyme Pbr-ER from Pseudomonas brassicacearum was chosen for further characterization and process optimization. Using optimized reaction conditions, the Pbr-ER-catalyzed reduction of 2 E -decenal was performed at 100 mL scale at 40 g/L substrate concentration, achieving a high conversion yield (>93%) within 24 h.",10.1021/acs.oprd.2c00096,0
Side-Chain Unprotected Fmoc-Arg/His/Tyr-OH Couplings and Their Application in Solid-Phase Peptide Synthesis through a Minimal-Protection/Green Chemistry Strategy,"Conventional SPPS (solid-phase peptide synthesis) requires protecting the nucleophilic side-chains of amino acids to prevent undesired modifications. A large volume of TFA (trifluoroacetic acid) is generally needed to remove these protecting groups after the peptide assembly. Such a process significantly lowers the productivity of the subject peptide manufacture due to handling large volumes of TFA and the resultant anti-solvent for precipitating and isolating the crude products. Enabling the side-chain unprotected amino acid couplings should break through such a bottleneck in peptide production and drastically increase productivity. Fmoc-Arg-OH, Fmoc-His-OH, and Fmoc-Tyr-OH are utilized in this study as substrates to investigate their couplings to peptide molecules. Side reactions induced by these side-chain unprotected amino acids have been elucidated, and solutions addressing these side reactions are developed. The processes of the side-chain unprotected amino acid couplings have been successfully implemented in peptide synthesis through a minimal-protection SPPS (MP-SPPS) strategy. Significantly reduced TFA concentration was enabled to quantitatively detach the peptide from the solid support and obtain the crude peptide product in high yield. In this process, trifluorotoluene, an alternative solvent to DCM (dichloromethane) with low toxicity, was employed as the medium for TFA-mediated peptide cleavage and side-chain global deprotection. A crude peptide product with high purity was obtained from the MP-SPPS process, and a 5.3-fold productivity increase was accomplished.",10.1021/acs.oprd.2c00083,0
Fit-for-Purpose Synthesis of an Aza-Cryptophycin Analogue as the Payload for an Antibody–Drug Conjugate,"The synthesis of an aza-cryptophycin analogue is described, featuring a highly trans-selective ring-closing metathesis reaction and an asymmetric Corey–Chaykovsky-type reaction to install the epoxide function. This latter reaction is an answer to the long-standing synthetic challenged posed by the efficient formation of the epoxide function of the cryptophycin family of compounds in a diastereoselective manner. It allows for a one-third reduction in the number of steps compared with the previously used synthesis (27 to 19 steps) and increases the overall yield of the longest linear sequence by a factor of 27 (0.6% to 16%). This fit-for-purpose synthesis allowed the production of a steady supply of the material for the early phase of a cryptophycin-based antibody–drug conjugate program.",10.1021/acs.oprd.2c00080,0
A Novel and Practical Synthesis of Mavorixafor,"A novel and practical synthesis of mavorixafor ( 1 ) is reported. The novelty of this synthetic route is the use of 8-chloro-5,6,7,8-tetrahydroquinoline ( 9 ) and 1,4-diaminobutane as the materials, instead of 8-amino-5,6,7,8-tetrahydroquinoline ( 4 ) and N,N-diprotected aminobutyraldehyde ( 6a or 6b ). The preparation of ( S )-8-(4-aminobutylamino)-5,6,7,8-tetrahydroquinoline ( 13 ) by resolution with N -acetyl- l -leucine was first achieved. Then the one-pot synthesis of 1 from 13 involving protection, condensation, and subsequent hydrolysis was successfully developed. In addition, the final product with a satisfactory purity (>99.5%, detected by both achiral and chiral HPLC) was obtained by a simple operation (salification) without column chromatographic purification.",10.1021/acs.oprd.2c00076,1
Recent Advances in the Solid- and Solution-Phase Synthesis of Peptides and Proteins Using Microflow Technology,"Peptides have become increasingly important as drugs and drug candidates. In particular, specialty peptides have garnered considerable attention in recent years because of their improved metabolic stability, higher affinity, and biological target selectivity; some of them have the ability to enable cell membrane permeation and oral administration. Despite its long history, peptide synthesis has various limitations, such as high cost, generation of large amounts of waste, and the requirement for hazardous reagents and solvents. Microflow synthesis, wherein the inner diameter of the reaction tube is ≤1 mm, presents several advantages compared with conventional batch synthesis, such as precise control of the reaction time on a short scale, precise reaction temperature control, and facile scale-up with high reproducibility. Microflow technology has been utilized for peptide synthesis since the beginning of the 21st century. The advantages of microflow synthesis enable the use of highly active and unstable chemical species or high-temperature conditions that accelerate peptide synthesis. The combined use of microflow technology, automated synthesis, and online monitoring technologies has emerged in recent years. This approach not only improved the synthetic efficiency but also afforded large amounts of reliable data that can be used to train machine learning models. This review summarizes the solid- and solution-phase syntheses of α-peptides and specialty peptides, including N-methylated peptides, β-peptides, and cyclic peptides, reported mainly after 2017. The recently reported mesoflow peptide syntheses (inner diameter of the reaction channels > 1 mm), the microflow automated syntheses, and in-line analysis are covered in this review.",10.1021/acs.oprd.2c00074,1
Flow Toolkit for Measuring Reaction Enthalpy and Application to Highly Exothermic Synthesis of Alkylaluminoxanes,"We present a flow strategy to characterize reaction enthalpy and showcase the application in synthesis of alkylaluminoxanes from the fast and exothermic alkylaluminum hydrolysis. Our platform mainly encompasses a three-dimensional printed micromixer and a tubular reactor in an adiabatic vacuum box, aided by a thermal imaging camera to record temperature profiles. The temperature increase at steady state is used to calculate the released heat, which is further decoupled to quantify the reaction enthalpy and enthalpy of mixing. We validate the concept with the classic neutralization reaction between sulfuric acid and sodium hydroxide, with less than 2% deviation from theoretical values. In application, we determine the exothermic reaction enthalpy and the endothermic enthalpy of mixing to be −143.13 and +7.66 kJ/mol for triisobutylaluminum hydrolysis and −164.63 and +5.03 kJ/mol for trimethylaluminum hydrolysis, respectively. The presented platform, on the one hand, yields new insights into the microreactor scale-up for alkylaluminoxane synthesis and, on the other hand, can be readily used to measure reaction enthalpies of other reactions.",10.1021/acs.oprd.2c00072,0
Discovery and Process Development of a Scalable Biocatalytic Kinetic Resolution toward Synthesis of a Sterically Hindered Chiral Ketone,"Sterically hindered chiral ketones are useful intermediates in the synthesis of active pharmaceutical ingredients. Here, we report a scalable and highly enantioselective synthesis through a kinetic resolution process promoted by a wild-type ketoreductase (KRED) enzyme. The process was investigated thoroughly, including DoE optimizations and a kinetic study. Scale-up demonstrations on up to 0.8 kg revealed an enzyme aggregation/deactivation challenge, and solutions were provided to obtain the desired enantiomer in high yields and enantiomeric excesses with relatively low enzyme loadings (2–4 wt %).",10.1021/acs.oprd.2c00067,0
Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC,"The development of an efficient synthetic process for a clinical candidate Larotinib ( 4 ), which is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of esophageal squamous cell carcinoma (ESCC), is reported for scale-up. The process used 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate ( 12 ) as the regulatory starting material and provided a stable and industrializable intermediate chloroquinazoline 11 under the process control. Further optimization of the process obviously improved the reaction yield and reduced the impurity level including alkyl halide potential genotoxic impurities (PGIs), at the same time avoiding the use of laborious and time-consuming column chromatography. More than 110 kg of Larotinib ( 4 ) in one batch can be finally produced stably for clinical research. Compared to our initial synthetic route in preclinical research, the overall yield of this optimized process increased significantly from 16.2 to 55.6%.",10.1021/acs.oprd.2c00059,1
"Development of a Process to a 4-Arylated 2-Methylisoquinolin-1(2<i>H</i>)-one for the Treatment of Solid Tumors: Lessons in Ortho-Bromination, Selective Solubility, Pd Deactivation, and Form Control","We here present an optimized, scalable synthesis of bromodomain and extra-terminal (BET) inhibitor BMS-986378 (CC-90010). The original route and process 1A was 7 steps with 33.8% yield and featured numerous problematic solvents, process safety concerns, difficult to scale unit operations, and challenging to control impurities. Reaction optimization to remove or mitigate these challenges resulted in our first scale-up route and process, 2A. Subsequent challenges encountered on scale-up of route and process 2A warranted the creation and implementation of an enhanced process, which eliminated dichloromethane from a phenol bromination, improved catalyst performance in the penultimate cross-coupling, and finally developed a concomitant solvent charging process for form control in the final API crystallization. The resulting scale-up route and process, 2B, was demonstrated on a >50 kg scale and afforded the final product in 49% yield over 7 steps in >99.9% assay and area purity, meeting all ICH requirements for quality.",10.1021/acs.oprd.2c00057,1
"Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes","Cu-mediated Ullmann-type cross-coupling has experienced significant advances over the last century since the seminal publication by Ullmann in 1901. These advances have significantly expanded the scope of the original classical Ullmann coupling of aryl halides for formation of diaryl compounds to include the formation of carbon–heteroatom and other carbon–carbon bonds. The introduction of bidentate ligands drastically improved the performance of this class of transformations to enable milder reaction conditions that can tolerate a wide range of sensitive functional groups. Recent development of more powerful second-generation bidentate ligands has further allowed the coupling of less reactive aryl chlorides to proceed smoothly and realized low catalyst and ligand loadings for a broad scope of Ullmann-type cross-coupling reactions. As a result of these breakthrough advances in the past decades, Cu-mediated Ullmann-type cross-coupling reactions have been frequently implemented in academic research and have found ubiquitous industrial applications including the preparation of pharmaceutical and agrochemical products. This review provides an overview of selected general Cu-mediated Ullmann-type transformations for the formation of carbon–carbon and carbon–heteroatom (C–N, C–O, C–S, and C–P) bonds and their applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes.",10.1021/acs.oprd.2c00050,1
Multigram Scale Synthesis of Piperarborenines C-E,"We report the multigram scale synthesis of heterodimeric β-truxinic imides piperarborenines C-E using a catechol-tethered diastereoselective intramolecular [2 + 2] photocycloaddition. Key innovations lie in the use of catechol as a practical auxiliary for the synthesis of homo- and heterodimeric β-truxinates and the use of a UV-LED flow photoreactor in the [2 + 2] step. This approach is highly scalable, requiring a single column purification, no photocatalysts, and no cryogenic conditions.",10.1021/acs.oprd.2c00049,1
Use of Phosphazene Base BTPP for Phosphorylative Activation in the Scale-Up of BET Inhibitor GSK525762,"In this article, an improved synthesis of a key triazole intermediate in the synthesis of bromo- and extra-terminal domain (BET) inhibitor GSK525762 ( 1 ) is described, which avoids the need for the formation of a thioamide intermediate for the key methyltriazolo[1,4]benzodiazapine formation. Conditions for a phosphorylative activation of lactam 4 were identified through the extensive screening of reagents and solvents, where a number of phosphazene bases were found to have unmatched activity. Development efforts focused on the use of phosphazene base P1- t -Bu-tris(tetramethylene) (BTPP) with diethyl chlorophosphoridate (DECP) and culminated in the demonstration of the new process at a 750 g scale. The resulting synthetic route avoids the use of thiolating agent P 2 S 5 and isolation of the resulting thioamide while delivering 1 in exceptional purity with a reduced number of steps, resulting in a higher yield and improved throughput over the previous process.",10.1021/acs.oprd.2c00048,1
Highly Efficient and Selective Hydrogenation of Sugars Catalyzed by Ru-MACHO-BH: Practical Synthesis of Sugar Alcohols,"A highly efficient synthesis of sugar alcohols was achieved by selective hydrogenation with a homogeneous catalyst. Ru-MACHO-BH, the PN H P-ruthenium catalyst, promoted the hydrogenation with extremely high reactivity and selectivity. The reaction could be applied to various kinds of mono- and disaccharides and has been successfully run on a scale of several tens of grams.",10.1021/acs.oprd.2c00047,0
Excellence in Industrial Organic Synthesis 2021,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTExcellence in Industrial Organic Synthesis 2021John A. Ragan*John A. RaganChemical Research & Development, Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States*Email: [email protected]More by John A. Ragan, Ke ChenKe ChenProcess Research & Development, WuXi Apptec, Fute Zhong Road, Waigaoqiao, Shanghai 20013, ChinaMore by Ke Chen, Donna G. BlackmondDonna G. BlackmondDepartment of Chemistry, Scripps Research, La Jolla, California 92037, United StatesMore by Donna G. Blackmond, and Pamela M. TadrossPamela M. TadrossPharmaceutical Technical Operations, Technical Product Stewardship, Merck & Co., 10 Lakewood Road, Natick, Massachusetts 01760, United StatesMore by Pamela M. TadrossCite this: Org. Process Res. Dev. 2022, 26, 3, 479Publication Date (Web):February 18, 2022Publication History Published online18 February 2022Published inissue 18 March 2022https://pubs.acs.org/doi/10.1021/acs.oprd.2c00038https://doi.org/10.1021/acs.oprd.2c00038editorialACS PublicationsCopyright © Published 2022 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views5798Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (398 KB) Get e-AlertscloseSUBJECTS:Catalysis,Cross coupling reaction,Drug discovery,Organic synthesis,Therapeutics Get e-Alerts",10.1021/acs.oprd.2c00038,0
"Synthesis Optimization, Scale-Up, and Catalyst Screening Efforts toward the MGAT2 Clinical Candidate, BMS-963272",This paper describes the efficient scale-up synthesis of 1 (BMS-963272) which relies upon a highly selective Mannich-type alkylation strategy to stereospecifically install a quaternary carbon center. An intramolecular cyclization reaction is also used to form the aryl dihydropyridone (ADHP) core. The optimized route has been demonstrated to provide more than 100 g of active pharmaceutical ingredient for preclinical toxicology evaluation. A catalyst screening effort is also discussed as part of a complimentary convergent approach which will facilitate a more expedient assessment of back-up molecules bearing aryl diversity at the C4-position of the ADHP core.,10.1021/acs.oprd.2c00036,1
Synthesis of 5-Substituted Tetrazoles: Reaction of Azide Salts with Organonitriles Catalyzed by Trialkylammonium Salts in Non-polar Media,"An efficient synthesis of 5-substituted tetrazole derivatives via the addition of azide ions to an organonitrile is presented. This new protocol minimizes the potential generation of hydrazoic acid by employing a catalytic amount of an activating proton source (trialkylammonium chloride) in combination with a phase transfer agent (tetraalkylammonium salt). Both aromatic and aliphatic nitriles are successfully reacted to produce the corresponding 5-substituted-1 H -tetrazole products. The superiority of choline chloride as a phase transfer agent, the recyclability of both the catalytic proton source and the phase transfer agent, and the proposed mechanistic role of each of the reaction components are also presented.",10.1021/acs.oprd.2c00032,1
Development of an Improved Synthetic Process of Clonazepam by Preventing the Formation of a Trimeric Compound in the Presence of HCl,"An improved synthesis process of clonazepam was developed with the key parameters determined. The trimer intermediate ( 9 ) of clonazepam prepared by using the one-pot method was isolated and identified for the first time. It was further confirmed that the depolymerization of 9 at high temperature was the rate-determining step for the preparation of clonazepam by using the one-pot method, which results in a low yield and purity. 2-Amino- N -(2-(2-chlorobenzoyl)-4-nitrophenyl) acetamide hydrochloride (7·HCl) was a key intermediate separated in the improved process, and the method of its synthesis with high purity to avoid the production of 9 was further reported. The improved process performed better in terms of efficiency and robustness. Besides, the high-performance liquid chromatography purity and total yield of clonazepam obtained by using the improved method were 99.98% and 57%, respectively.",10.1021/acs.oprd.2c00023,1
An Efficient Synthesis of the Bicyclic Darunavir Side Chain Using Chemoenzymatic Catalysis,"Herein, we describe a chemoenzymatic synthesis of the bicyclic fragment of Darunavir. A ketoreductase was identified using metagenomic mining to catalyze a highly enantio- and diastereoselective dynamic kinetic resolution of a β-ketolactone. Subsequent lactone reduction with diisobutylaluminum hydride and phase transfer cyclization affords the bicyclic acetal fragment in 39% yield over four steps.",10.1021/acs.oprd.2c00017,1
Scale-Up of Diazonium Salts and Azides in a Three-Step Continuous Flow Sequence,"Rapid synthesis and scale-up of active molecules to support the development process of new drug candidates is key in the pharmaceutical industry. Herein, we describe the development of a scalable continuous flow procedure for three key steps in the synthesis of 2H-indazoles, which were identified as highly potent and selective TLR7 and TLR8 antagonists. Transformation of hazardous diazonium salt and azide chemistries from the batch mode to continuous flow mode helped mitigate and limit the risks associated with the handling of large amounts of hazardous reagents and intermediates in the batch mode. In a two-step approach, we first screened and optimized the reaction parameter for a diazotization─azidation─cyclization three-step sequence using a commercial research-scale plug flow reactor. In the second step, we demonstrated the robustness and scalability of this reaction sequence, which finally enabled us to rapidly prepare and deliver the required amount of material in high quality.",10.1021/acs.oprd.2c00016,0
"Efficient Divergent Synthesis of 2′-<i>O</i>,4′-<i>C</i>-Ethylene-Bridged Nucleic Acid (ENA) Phosphoramidites","2′- O,4′- C -Ethylene-bridged nucleic acid (ENA) phosphoramidites are highly promising modified nucleic acid monomers discovered by Daiichi Sankyo. To increase the productivity of manufacturing, we have developed a highly efficient synthetic method for ENA phosphoramidites. The basic concept of the new synthetic route is “divergent synthesis” for the preparation of four types of monomers such as A, G, C, and T. We applied stereoselective glycosylation reactions without utilizing neighboring group participation to set a common intermediate in the downstream of the route.",10.1021/acs.oprd.2c00013,0
Scale-Up of a Heterogeneous Photocatalytic Degradation Using a Photochemical Rotor–Stator Spinning Disk Reactor,"High Resolution Image Download MS PowerPoint Slide Many chemical reactions contain heterogeneous reagents, products, byproducts, or catalysts, making their transposition from batch to continuous-flow processing challenging. Herein, we report the use of a photochemical rotor–stator spinning disk reactor (pRS-SDR) that can handle and scale solid-containing photochemical reaction conditions in flow. Its ability to handle slurries was showcased for the TiO 2 -mediated aerobic photodegradation of aqueous methylene blue. The use of a fast rotating disk imposes high shear forces on the multiphase reaction mixture, ensuring its homogenization, increasing the mass transfer, and improving the irradiation profile of the reaction mixture. The pRS-SDR performance was also compared to other lab-scale reactors in terms of water treated per reactor volume and light power input.",10.1021/acs.oprd.2c00012,0
Stereoselective Synthesis of a Tubulysin Core for Antibody–Drug Conjugate Studies,"An expeditious synthesis of an advanced tripeptide intermediate en route to a tubulysin antibody–drug conjugate payload is described. The efficient formation of an N -propyl tertiary amide required tailoring the amine component to reduce steric demand. Additionally, double activation of the carboxylate was required via an aluminum–Lewis acid coupled activated ester strategy to enable the formation of the highly congested amide bond with superior retention of stereochemical integrity. Other permutations of reactant structure and reagents met with failure. The realization of this key direct bond construction enabled a convergent solution-phase synthesis of the unnatural tubulysin tripeptide in a highly convergent manner from three simple building blocks in eight steps and 22.4% overall yield utilizing only a single silica gel chromatographic purification.",10.1021/acs.oprd.2c00010,1
Process Safety from Bench to Pilot to Plant,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTProcess Safety from Bench to Pilot to PlantQiang Yang*Qiang YangEli Lilly and Company, Indianapolis, Indiana 46285-0001, United States*E-mail: [email protected]More by Qiang YangView Biographyhttps://orcid.org/0000-0003-3762-5015, S. Camille PeresS. Camille PeresEnvironmental and Occupational Health, Texas A&M University, College Station, Texas 77843, United StatesMore by S. Camille PeresView Biographyhttps://orcid.org/0000-0002-3679-9171, Qingsheng WangQingsheng WangDepartment of Chemical Engineering, Texas A&M University, College Station, Texas 77843, United StatesMore by Qingsheng WangView Biographyhttps://orcid.org/0000-0002-6411-984X, and Ashok G. DastidarAshok G. DastidarFauske & Associates, Burr Ridge, Illinois 60527-5802, United StatesMore by Ashok G. DastidarView BiographyCite this: Org. Process Res. Dev. 2022, 26, 2, 235–238Publication Date (Web):February 18, 2022Publication History Published online18 February 2022Published inissue 18 February 2022https://pubs.acs.org/doi/10.1021/acs.oprd.2c00008https://doi.org/10.1021/acs.oprd.2c00008editorialACS PublicationsCopyright © Published 2022 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views4573Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (3 MB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Chemical reactions,Manufacturing,Organic reactions,Safety Get e-Alerts",10.1021/acs.oprd.2c00008,0
Continuous Processing of Concentrated Organolithiums in Flow Using Static and Dynamic Spinning Disc Reactor Technologies,"High Resolution Image Download MS PowerPoint Slide Organometallic reactions involving highly reactive organolithium reagents are widely used in organic synthesis. However, the use of such organometallics in batch mode on a pilot and industrial scale is challenging for safety reasons and frequently requires expensive cryogenic process conditions. A change to continuous processing in flow mode can provide major advantages for process safety and economics. In this study, we compare static and dynamic flow reactor technologies for two important organolithium (butyllithium and hexyllithium)-enabled transformations: deprotonations and bromine/lithium exchange reactions. Using higher concentrated (≥3 M) butyllithium (BuLi) solutions, that is, reaction mixtures with reduced hydrocarbon content, decreases the risk of reactor fouling and allows for increased space/time yields. In the flow mode, the observed reactions could be carried out under more convenient conditions, that is, at higher temperatures compared to the batch mode, and the deprotonation reaction even at ambient temperature instead of −78 °C. The formation of precipitates with the risk of clogging can be further reduced by changing from static flow to dynamic spinning disc reactor technology. The SpinPro reactor system from Flowid has been identified to ensure robust performance, as it tolerates salt precipitations and can provide excellent mass transfer conditions. Flow process technology using concentrated organolithium products can provide unique benefits for the manufacturing of pharmaceutical intermediates, agrochemical products, and specialty chemicals.",10.1021/acs.oprd.2c00007,0
Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution,"This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients.",10.1021/acs.oprd.2c00005,0
"Mapping Polymorphic Behavior of Process Intermediates, an Often-Overlooked Exercise","Presented are two case studies where polymorphic behavior of a process intermediate was identified and the relationship was investigated for form control. Case study I: 1 is a process intermediate for a novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor that was isolated as an unsolvated hydrochloride salt ( 1-HCl ). Initial research lots and the first delivery batch yielded form I of 1-HCl; however, during process optimization to support a second delivery, form II was identified. This discovery left limited time to map the thermodynamic relationship between the two phases prior to the second production, and based on limited knowledge at the time, form I was selected and successfully scaled even though it was determined to be the room temperature metastable phase. Case study II: 2 is a process intermediate for a novel toll-like receptor 8 (TLR8) agonist. Applying lessons learned from case study I, polymorph screening identified unsolvated forms I and II, whose relative stabilities were mapped so that a crystallization could be designed to ensure phase control for the thermodynamically most stable form at room temperature prior to production, which ultimately benefited superior impurity rejection.",10.1021/acs.oprd.2c00003,0
"Identification, Synthesis, and Comprehension of an Imidazole N-3 Regioisomeric Impurity of Olmesartan Medoxomil Key Intermediate","Trityl olmesartan ethyl ester (TOEE), a key intermediate of the launched angiotensin II receptor blocker olmesartan medoxomil, was built using two blocks via an N -alkylation reaction, wherein the imidazole N -1 isomer of this intermediate was the only isomeric product reported previously. Unexpectedly, from a sample of laboratory trials, an undesired impurity (a level of 0.2–0.3%) sharing the same molecular mass with TOEE was detected and assumed to be an N-3 regioisomeric impurity of TOEE. Accordingly, a five-step lactone ring-opening synthetic route was designed and successfully used to obtain this impurity, whose structure perfectly matched the NMR and mass spectra. Subsequent characterization by SCXRD directly confirmed the initial speculation of it being an N-3 regioisomer, which was reported for the first time. Next, two downstream impurities toward the active pharmaceutical ingredient (API) were synthesized, in which the N-3 impurity of API proved to be inseparable with the API molecule under the European Pharmacopoeia chromatography method, introducing a risk of impurity identification. Sequential investigations focusing on impurity tracing and control strategies of the downstream impurities were conducted to meet the quality control requirements.",10.1021/acs.oprd.2c00002,1
"High-Yield Synthesis of Enantiopure 1,2-Amino Alcohols from <scp>l</scp>-Phenylalanine via Linear and Divergent Enzymatic Cascades",")-phenylethanolamine was isolated in a 92% yield and >99.9% ee starting from ca. 100 mg of the diol intermediate. In summary, l-phenylalanine was converted into enantiomerically pure 2-phenylglycinol and phenylethanolamine in overall yields of 61% and 69%, respectively. This work exemplifies how linear and divergent enzyme cascades can enable the synthesis of high-value chiral molecules such as amino alcohols from a renewable material such as l-phenylalanine with high atom economy and improved sustainability.",10.1021/acs.oprd.1c00490,1
"Review of Synthetic Approaches toward the Synthesis of Cariprazine, an Antipsychotic Drug","Schizophrenia is a chronic and severe mental disorder affecting 20 million people worldwide. Research has not identified the causes of schizophrenia as one single factor. It is thought that interactions between genes and a range of environmental factors may cause schizophrenia. The majority of schizophrenia cases are controlled by the use of antipsychotic drugs, such as aripiprazole, asenapine, olanzapine, quetiapine, risperidone, and cariprazine. Gedeon Richter and Forest Laboratories developed an antipsychotic drug known as cariprazine that contains a piperazine ring, and it is manufactured by Actavis under the trade name Vraylar. This review provides a brief background of the synthetic approaches to cariprazine.",10.1021/acs.oprd.1c00488,1
Optimization of Metal Affinity Ketoreductase Immobilization for Application in Batch and Flow Processes,"Protein isolation from fermentation broth or protein mixtures by using cost-effective, scalable, regenerable resins offers a significant increase in value and productivity; hence, many recombinant proteins contain a fused histidine tag to facilitate immobilized metal affinity chromatography purification. A newly developed methacrylic iminodiacetic acid-functionalized resin, capable of attaining metal ion loadings of 0.25 mmol metal/g and high affinity toward His-tagged protein, was studied in the immobilization of a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent His-tagged ketoreductase and in the coimmobilization of the ketoreductase and glucose dehydrogenase. The affinity immobilization was compared to various other resin-enzyme interactions, that is, covalent, ionic, and hydrophobic, showing that the His-tag immobilization provides up to 4 times increase in specific activity due to the high immobilization selectivity and suitable enzyme orientation. Biocatalyst recycling in batch showed excellent stability over 10 cycles in aqueous and 5 cycles in organic media. NADPH cofactor recycling was studied in batch and continuous flow using cosubstrate 2-propanol as well as separately immobilized and coimmobilized ketoreductase and glucose dehydrogenase, in the presence of glucose. The best biotransformation with cofactor regeneration was in the presence of the coimmobilized ketoreductase and glucose dehydrogenase, while the lowest conversion was obtained by using the two enzymes separately immobilized. These studies showed that, by using cofactor regeneration systems, an NADPH concentration 1000 times lower than the substrate concentration can be used while maintaining the enzyme productivity.",10.1021/acs.oprd.1c00483,0
Development and Process Intensification of an Efficient Flow–Cascade Reaction Sequence in the Synthesis of Afizagabar,"Aromatic nitration and catalytic hydrogenation are among the most dangerous reactions in the chemical industry. The traditional, batchwise pilot plant manufacturing process of a key intermediate of our drug candidate afizagabar (S44819) involved these kinds of transformations (besides a Dakin–West-type reaction, a ring closure, and a keto reduction step). To mitigate some of the hazards associated with this sequence, a flow chemical approach was developed. First, a flow–cascade process was elaborated, which furnished the product with a throughput of 1.52 g/h with an HPLC purity of 95.6%. The bottleneck of the procedure in terms of output was the heterogeneous catalytic hydrogenation; therefore, our subsequent process intensification efforts primarily concentrated on this step. Finally, application of higher concentrations and an upscaled hydrogenation reactor combined with the corresponding adjustment of parameters of further reaction steps resulted in an efficient process with an effective product yield of 11.95 g/h and an increased HPLC purity (97.1%). The 4-step uninterrupted process described here is based on a newly developed heterogeneous flow reactor system and a custom-made liquid–liquid extractor, providing an instructive case study on handling hazardous processes in a safe and efficient way.",10.1021/acs.oprd.1c00481,1
Development of Enzymatic Variants for the Synthesis of Bioresorbable Polyesters,"Enzymatic synthesis of polymeric materials is a powerful approach to make these processes greener, more economical, and safer for scale-up. Herein, we characterized new variants of the hyperthermophilic carboxylesterase from the archaeon Archaeoglobus fulgidus with quantum mechanics/molecular mechanics molecular dynamics simulations. The designed variants were expressed and tested for the synthesis of poly(ε-caprolactone) and triblock poly(ε-caprolactone)–poly(ethylene glycol), two important biomaterials. The reactant complexes of the best variants formed stronger hydrogen bonds with the nucleophilic oxygen and the subsequent tetrahedral intermediates formed stronger hydrogen bonds with the leaving lactone oxygen, reflecting the best active site preorganization for stabilization of the two consecutive transition states that involve the same active site machinery. Our findings set the underpinning ground to redesign other enzymes for polyesterification reactions.",10.1021/acs.oprd.1c00480,0
Driving Aspirational Process Mass Intensity Using Simple Structure-Based Prediction,"High Resolution Image Download MS PowerPoint Slide An important metric for gauging the impact that a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step-PMI for a given synthesis from a process description is more and more common across the pharmaceutical industry, especially in process chemistry departments. As with other pharmaceutical companies, our company has established a strong track record of delivering on our Corporate Sustainability goals, being recognized with eight EPA Green Chemistry Challenge Awards in the last 15 years, and we show how these routes help define aspirational PMI targets. While green chemistry principles help in optimizing PMI and developing more sustainable processes, a key challenge for the field is defining what a “good” PMI for a molecule looks like given its structure alone. An existing tool that chemists have at their disposal to predict PMI requires the synthetic route be provided or proposed (e.g., via retrosynthetic analysis) which then enables practitioners to compare predicted PMIs between routes. We have developed SMART-PMI (in-Silico MSD Aspirational Research Tool) to complement existing tools by predicting PMI from molecular structure alone. Using only a 2D chemical structure, we can generate a predicted SMART-PMI from a measure of molecular complexity and molecular weight. We show how these predictions correlate with historical PMI data from our company’s clinical and commercial portfolio of processes. From this SMART-PMI prediction, we have established target ranges which we termed “Successful”, “World Class”, and “Aspirational” PMI. The goal of this range is to set the floor for what is a “good” PMI for a given molecule and provide ambitious targets to drive innovative green chemistry. Using this model, chemists can develop synthetic strategies that make the biggest impact on PMI. As innovation in chemistry and processes leads to better and better PMIs, in turn, this data can drive ever more aggressive targets for the model. The potential of SMART-PMI, in combination with other existing PMI tools, to set industry-wide aspirational PMI targets is discussed.",10.1021/acs.oprd.1c00477,1
Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction,"The plant-scale manufacture of AZD5069 involved the assembly of a pyrimidine sulfonamide (AZD5069 MAPI) via Pd-catalyzed coupling of a chloropyrimidine derivative with an azetidinesulfonamide. This step revealed a number of operational and commercial challenges, in particular the difficulty of removing palladium residues to an acceptably low level and the increasingly prohibitive costs of the metal, ligand, and scavenger used. An alternative, copper-catalyzed Ullmann–Goldberg coupling reaction was investigated, developed, and ultimately successfully operated in four pilot plant batches of >50 kg scale.",10.1021/acs.oprd.1c00475,1
Process Development of Enantioselective Imine Reductase-Catalyzed Syntheses of Pharmaceutically Relevant Pyrrolidines,"Process development and optimization for an enzymatic reduction of 2-aryl-substituted pyrrolines to enantioselectively access the corresponding pyrrolidines have been carried out. Such chiral pyrrolidines are of high pharmaceutical interest and represent structural subunits in, e.g., larotrectinib and MSC2530818. This work enables access to the heterocyclic amine products with full conversion (>99%), excellent enantioselectivity (>99% ee), and good to high yield (up to 91%) in the presence of a readily available recombinant Escherichia coli -type whole-cell catalyst containing an imine reductase from Cupriavidus sp. HPC(L) and a glucose dehydrogenase in recombinant form. The developed processes utilizes cheap d -glucose as an economically favorable and nontoxic reducing agent and runs at a substrate loading of 18 g/L, which is also in an attractive range for larger-scale operations.",10.1021/acs.oprd.1c00471,0
Development of a Continuous Photochemical Bromination/Alkylation Sequence En Route to AMG 423,The development of a photochemical bromination/alkylation sequence as part of a continuous process for the synthesis of an intermediate en route to AMG 423 is discussed. Highlights of this continuous process include a significant reduction in reaction time and the elimination of aqueous waste streams. Also discussed are mechanistic and kinetic studies offering insights into notable features of the photochemical bromination.,10.1021/acs.oprd.1c00469,1
"Development of a Commercial Process for Deucravacitinib, a Deuterated API for TYK2 Inhibition","Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4-triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl 3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable “dual-base” palladium-catalyzed C–N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.",10.1021/acs.oprd.1c00468,1
Development of Scalable Processes with Underutilized Biocatalyst Classes,"Over the past few decades, biocatalysis has become a significant contributor to the manufacture of complex active pharmaceutical ingredients (APIs), agrochemicals, and commodity chemicals. In the context of API synthesis, the biocatalysis community has long relied on three predominant catalyst classes: lipases, ketoreductases, and transaminases. While reactions catalyzed by these enzymes can enable amazing new synthetic routes to the desired compounds, numerous additional enzymatic transformations remain that are not as routinely implemented in process chemistry. Here we discuss a few enzyme classes that are beginning to see increased use in process chemistry and not only highlight the key transformations catalyzed but also take a deeper dive in to how scalable, robust, and cost-effective processes were developed. Aggregate learnings from these case studies will highlight techniques used to bring new catalysts to process scale and, ideally, spark interest developing additional biocatalyst classes to execute scalable biotransformations.",10.1021/acs.oprd.1c00467,1
A Techno-economic Assessment of a Biocatalytic Chiral Amine Production Process Integrated with <i>In Situ</i> Membrane Extraction,"The production of chiral amines through asymmetric synthesis using amine transaminase (ATA) has the potential for high yields in an efficient single-step process. Integrating in situ membrane extraction with this biocatalytic chiral amine production process has been demonstrated to reach higher yields by shifting the equilibrium position through product recovery. To date, however, it is unclear whether the in situ product recovery strategy is economically viable. This study carried out a techno-economic assessment to understand the main drivers of the manufacturing costs and to set quantitative development targets. The chiral amine products under study are ( R )-(+)- or ( S )-(−)-α-methylbenzylamine (MBA) and sitagliptin. Their manufacturing costs were quantified and benchmarked to three alternative production pathways. The results yield an MBA manufacturing cost of €17.8/mol for the integrated process with membrane extraction, which is lower than the cost for the benchmark process using an ion-exchange resin (€23.4/mol). The sitagliptin manufacturing cost is estimated to be €30.9/mol, which is €1.6/mol and €4.6/mol less than the benchmark process with engineered transaminase and the rhodium-catalyzed process, respectively. On the basis of the outcomes of sensitivity analyses, development targets were set for the membrane flux and selectivity and the product concentration, which are the key parameters that influence the manufacturing cost related to the membrane.",10.1021/acs.oprd.1c00464,0
Recent Progress and Developments in Chemoenzymatic and Biocatalytic Dynamic Kinetic Resolution,"Dynamic kinetic resolution (DKR) is a powerful method to construct complex molecules with one or more stereocenters. In light of their exquisite stereospecificity and stereoselectivity, enzymes are becoming widely used as catalysts in DKR. This review summarizes chemoenzymatic and biocatalytic methodologies for DKR that have been developed in the past decade. Additionally, applications of these methodologies in the preparation of active pharmaceutical ingredients and emerging paradigms, including the combined use of biocatalysis and photocatalysis for DKR, are highlighted.",10.1021/acs.oprd.1c00463,1
Application of the Polonovski Reaction: Scale-up of an Efficient and Environmentally Benign Opioid Demethylation,"An environmentally benign iron-catalyzed nonclassical Polonovski reaction has been developed and scaled up to accomplish the challenging N -demethylation of MCL-509 Methyl to secondary amine MCL-509 Amine.HCl, key intermediates on the route to potential Parkinson’s treatment, MCL-509. The optimized reaction proceeded via the N -oxide in 2 h at room temperature in methanol/water using a mild stoichiometric oxidant and iron catalysis to yield the crystalline amine as its HCl salt directly from the reaction solution in typically 84% yield and 96% purity, after requiring only a screening filtration and facile solvent swap. This reaction was a great improvement in every aspect over the chloroformate-mediated and classical von Braun reactions utilized previously, especially for environmental, health, safety, and operability reasons. Robustness on scale was proven by the minimal technical transfer support required and the lack of any issues with all manufacturing batches produced in reproducible yields and consistent quality.",10.1021/acs.oprd.1c00462,0
"Evaluation of the Thermal Hazard of the Oxidation Reaction in the Synthesis of 3,4-Bis(4-nitrofurazan-3-yl)furoxan","Safety evaluation of chemical reactions is very significant before industrial applications are conducted. A lot of thermal hazards are generated in the synthesis of 3,4-bis(4-nitrofurazan-3-yl)furoxan (DNTF) because of the strong exothermicity of the oxidation reaction, unstable hydrogen peroxide, and interactions between the materials. In this article, systematic parameters regarding the safe synthesis of DNTF were studied, including the preparation stage of reaction solution and the oxidation reaction step. A Calvet microcalorimeter and an RC1mx reaction calorimeter were employed for process safety research. Differential scanning calorimetry and adiabatic accelerating rate calorimetry were used to investigate the thermal stabilities of the materials and their thermal hazards. After screening of the thermal stabilities of the materials in the two stages, hazardous materials were identified, and their thermal safety parameters were obtained. Finally, two evaluation methods were applied to evaluate the hazard levels of the preparation process and the oxidation reaction process in the synthesis of DNTF on the basis of thermal safety parameters. This study provides critical safety technical guidance for the DNTF synthesis process and safety design.",10.1021/acs.oprd.1c00458,0
"Development of a Scalable Route with Efficient Stereoisomer Control to YZJ-1139, an Orexin Receptor Antagonist","An effort toward the synthesis and process development of the orexin receptor antagonist YZJ-1139( 1 ) was described in this article. YZJ-1139( 1 ) contains the azabicyclic nortropane structure with three chiral centers. By the original process, highly pure intermediates or API could be obtained by chromatography with a relatively low yield. To remove the undesirable stereoisomers as early as possible, intermediate 13 with ( R )-α-phenethyl was synthesized by the Robinson–Schöpf reaction and easily purified as hydrochloride. The single crystal X-ray study was used to confirm the stereo configuration of 13·HCl and 18·HCl . The protecting group could be easily removed by transfer hydrogenation, resulting in enantiomerically pure intermediate 3 as a d -tartarate. The overall yield for preparing YZJ-1139( 1 ) was significantly increased, and this cost-efficient process might be promising in future commercial productions.",10.1021/acs.oprd.1c00457,1
Optimization of the Everolimus Intermediate Preparation Process: Impurity Identification Followed by One-Pot Transformation to the Desired Product,"An investigation of the everolimus intermediate PG-EVR preparation process resulted in the identification of three impurities PG-D,E,F constantly formed as byproducts in large amounts. Their structures were reliably established based on two-dimensional (2D) NMR and liquid chromatography–high-resolution tandem mass spectrometry (LC–HRMS/MS) data as dialkylated rapamycin derivatives. Finding that one of these impurities PG-E is hydrolyzable to the target everolimus intermediate resulted in optimized technology based on changing the selectivity of byproduct formation to PG-E as the major one followed by its one-pot quantitative transformation to PG-EVR . The yield of the everolimus intermediate increased by 10% under mild conditions, while lower amounts of reagents and solvents were required. The active pharmaceutical ingredient (API) that meets the requirements of the European Pharmacopoeia was prepared from thus obtained intermediate with no need for high-performance liquid chromatography (HPLC) purification, indicating a significant increase in the efficiency of large-scale production using new technology.",10.1021/acs.oprd.1c00456,0
Binary Solvent Swap Processing in a Bubble Column in Batch and Continuous Modes,"A lab-scale bubble column was investigated as an alternative means to achieve a low-temperature binary solvent swap of solutions containing pharmaceutical materials at atmospheric pressure, for batch and continuous configurations. The rate of solvent evaporation was predicted by first-principles vapor-liquid equilibrium (VLE) thermodynamic modeling and compared to experimentally achieved results. For batch configurations, evaporation rates of up to 5 g/min were achieved at gas flow rates up to 2.5 L/min (0.21 m/s superficial velocity) and temperatures up to 50 °C. This achieved 99 mol % purity of the desired solvent within three ""put and take"" evaporations from a 50:50 starting mixture. The evaporation rate profiles for the duration of the experiments were calculated, and the changing concentration profile was predicted within satisfactory error margins of <5%. Continuous process modeling explored a multistage equilibrium configuration and could predict the approach to attaining steady-state operation for various operating conditions. All rates of evaporation and resulting changes in solution concentration were measured, and direct comparison of model predictions fell within instrumentation error margins, as previously. This underlined the capability of the model to provide accurate representations of predicted evaporation rates and binary solution concentration changes during operation.",10.1021/acs.oprd.1c00455,0
"Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib <i>via</i> Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition","An efficient and elegant enantioselective synthesis of the key chiral pyrrolidine fragment of Upadacitinib (ABT-494) has been described. Oppolzer’s chiral sultam-directed asymmetric 1,3-dipolar cycloaddition was employed as a convenient tool to obtain the desired level of concomitant diastereoselectivity and enantioselectivity in the construction of the 3,4- syn substituted pyrrolidine moiety. The synthesis process was demonstrated as a proof of study on a lab scale and was refined during scale-up to allow for easy disengagement of the chiral auxiliary and its subsequent reuse.",10.1021/acs.oprd.1c00454,0
"Development of a Rapid Scale-Up Synthesis of (<i>S</i>)-<i>N</i>-(8-((2-Amino-2,4-dimethylpentyl)oxy)-5<i>H</i>-chromeno[3,4-<i>c</i>]pyridin-2-yl)acetamide, a Potent Adaptor-Associated Kinase 1 Inhibitor","( S )- N -(8-((2-Amino-2,4-dimethylpentyl)oxy)-5 H -chromeno[3,4- c ]pyridin-2-yl)acetamide ( 1 ) is a potent adaptor-associated kinase 1 inhibitor, which may have the potential to treat neuropathic pain and other neurological disorders including schizophrenia, Parkinson’s disease, bipolar disorder, and Alzheimer’s disease. For preclinical studies, a substantial amount of high-quality material was required. The original discovery route for the preparation of this compound suffered from scale-up issues that included a very low-yielding C–O coupling step and the use of expensive and toxic reagents. This paper describes a rapid scale-up synthesis accomplished in eight steps, which involves the coupling of phenol 17 with oxathiazolidine 18 as the key transformation.",10.1021/acs.oprd.1c00452,1
Adsorption of Amine Compounds on the Glass Surface and Their Impact on the Development of Analytical Method and Pharmaceutical Process,"A diamine compound (3-{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propan-1-amine) was demonstrated to impact downstream steps in a pharmaceutical synthetic process, and control of this compound to less than 0.015 wt % (or 150 ppm) was necessary. A novel, simple, and sensitive liquid chromatography/mass spectrometry (LC/MS) method without the derivatization of the diamine was developed for in-process control (IPC) and demonstrated to be suitable for use when experiments were run at a small lab scale. During the development of the LC-MS method, the diamine was found to significantly adsorb to the surface of glassware, and the adsorption constant was estimated to be (5.4–10.4) × 10 8 mL/mol SiOH. This phenomenon impacted the analytical method recovery and the control of the diamine in the process. The diamine adsorption was investigated, and procedures were developed to mitigate adsorption. The addition of 0.1% triethylamine in sample diluent was found to significantly reduce adsorption of the diamine and improve LC-MS method recovery. However, at the kilo plant scale, the impurities that were initially inhibited in development work appeared. It was determined that the diamine adsorbed on glassware more strongly than previously expected, including the reactor. This paper will discuss steps taken to reduce adsorption on glass for both the analytical scale and the plant glass reactor.",10.1021/acs.oprd.1c00451,0
Process Development and GMP Production of a Conjugate Warhead: Auristatin F-HPA-Ala/TFA (XMT-1864/TFA),"An efficient, large-scale manufacturing process is described for XMT-1864/TFA ( 1-TFA ), an auristatin F derivative, used as a novel, highly potent, cytotoxic warhead in Mersana’s oncology antibody–drug conjugate platforms. The process achieves high diastereomeric purity and controls the impurities with all intermediates readily isolated by crystallization or precipitation in high yield and purity. Protecting groups were selected to ensure tolerability, scalability, and stability of the intermediates under various solution-phase peptide coupling conditions. Crystallization of the final product was developed to remove specified impurities and provide a high-purity active warhead molecule for use in the bioconjugation processing. The convergent synthesis involving six non-GMP steps and five GMP steps has been carried out in multiple cGMP productions on 1-kg scale to produce 1-TFA in >98% chemical purity and <1% total diastereomeric contamination with ∼50% overall yield for the GMP steps.",10.1021/acs.oprd.1c00449,0
Leveraging High-Throughput Experimentation to Drive Pharmaceutical Route Invention: A Four-Step Commercial Synthesis of Branebrutinib (BMS-986195),"The invention of a commercial route to the Bruton's tyrosine kinase inhibitor branebrutinib (BMS-986195) in four total chemical steps is described. The execution of high-throughput experimentation (HTE) coupled with a first-principles approach across the proposed synthetic route enabled the identification of a novel indolization reaction that rapidly generated high synthetic complexity, as the centerpiece of the synthesis. A parallel HTE strategy during route design enabled the efficient and rapid evaluation of multiple options within a short timeframe to complete rigorous process development while mitigating the risks associated with implementing new chemistry featuring an aggressive disconnection strategy.",10.1021/acs.oprd.1c00443,1
"Development of an Operationally Simple, Scalable, and HCN-Free Transfer Hydrocyanation Protocol Using an Air-Stable Nickel Precatalyst","Hydrocyanation reactions enable access to synthetically valuable nitriles from readily available alkene precursors. However, hydrocyanation reactions using hydrogen cyanide (HCN) or similarly toxic reagents on laboratory scale can be particularly challenging due to their hazardous nature. In addition, such processes typically require air- and temperature-sensitive Ni(0) precatalysts, further reducing the operational simplicity of this transformation. Herein, we report a HCN-free transfer hydrocyanation of alkenes and alkynes that employs commercially available aliphatic nitriles as sacrificial HCN donors in combination with a catalytic amount of air-stable and inexpensive NiCl 2 as a precatalyst and a cocatalytic Lewis acid. The scalability and robustness of the catalytic process were demonstrated by the hydrocyanation of α-methylstyrene on a 100 mmol scale (11.4 g of product obtained) using 1 mol % of the Ni catalyst. In addition, the feasibility of the dehydrocyanation protocol using the air-stable Ni(II) precatalyst and norbornadiene as a sacrificial acceptor was showcased by the selective conversion of an aliphatic nitrile into the corresponding alkene.",10.1021/acs.oprd.1c00442,0
Continuous-Flow Hofmann Rearrangement Using Trichloroisocyanuric Acid for the Preparation of 2-Benzoxazolinone,"A continuous-flow preparation of 2-benzoxazolinone via the Hofmann rearrangement of salicylamide has been implemented employing trichloroisocyanuric acid as the stable and atom-economic chlorinating agent. The system was optimized to avoid solid accumulation and allow the preparation of hundreds of grams of the pure desired material over a working day. Furthermore, a trichloroisocyanuric acid (TCCA)-based chlorination of 2-benzoxazolone to the corresponding 5-chloro derivative was also carried out under batch conditions.",10.1021/acs.oprd.1c00440,0
Commercial-Scale Visible Light Trifluoromethylation of 2-Chlorothiophenol Using CF <sub>3</sub> I Gas,"Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report, and the mechanism was investigated to define the key scale-up parameters. The mechanistic insight was leveraged in the design and execution of two different reactor designs: an LED-based plug flow photoreactor and a laser-based continuous stirred tank photoreactor. In one of the first examples of commercial-scale photoredox chemistry, the process was scaled to provide over 500 kg of the desired intermediate and amended to fully continuous manufacturing.",10.1021/acs.oprd.1c00436,0
Unleashing the Potential to Electrify Process Chemistry: From Bench to Plant,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTUnleashing the Potential to Electrify Process Chemistry: From Bench to PlantKevin Lam*Kevin LamDepartment of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich, Central Avenue, Chatham Maritime ME4 4TB, United Kingdom*Email: [email protected]More by Kevin LamView Biographyhttps://orcid.org/0000-0003-1481-9212 and Katherine M. P. Wheelhouse*Katherine M. P. WheelhouseChemical Development, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom*Email: [email protected]More by Katherine M. P. WheelhouseView Biographyhttps://orcid.org/0000-0002-1963-1465Cite this: Org. Process Res. Dev. 2021, 25, 12, 2579–2580Publication Date (Web):December 17, 2021Publication History Published online17 December 2021Published inissue 17 December 2021https://pubs.acs.org/doi/10.1021/acs.oprd.1c00434https://doi.org/10.1021/acs.oprd.1c00434editorialACS PublicationsCopyright © Published 2021 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views2015Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (424 KB) Get e-AlertscloseSUBJECTS:Electrochemistry,Manufacturing,Optimization,Process chemistry,Sustainability Get e-Alerts",10.1021/acs.oprd.1c00434,0
Scaling up a C–H Borylation: Addressing the Safety Concerns of an Iridium-Catalyzed Process for Multikilo Scale Manufacture,"Iridium-catalyzed C–H borylation reactions are a rapid and versatile entry into Suzuki coupling partners, but their inherent safety issues can limit their use in large-scale manufacture. The stoichiometric byproduct from this reaction, HBpin, can liberate hydrogen gas on contact with moisture in air, as well as acting as an effective borylating agent in the reaction, resulting in an additional pathway for the generation of hydrogen. Using a targeted, multidisciplinary approach, a C–H borylation process to generate a key intermediate in the synthesis of an API was redesigned in preparation for large-scale manufacture. Through careful evaluation of the existing process and the use of high-throughput experimentation, PAT techniques, NMR, process safety experimentation, and process engineering, the process was constructed so that inherent risks associated with this reaction were minimized and contained to a final controlled quench of the reactive byproducts of the reaction. The final process was transferred to a manufacturing facility, delivering >70 kg of the borylated product over two batches.",10.1021/acs.oprd.1c00432,1
Modified and Scalable Synthesis of <i>N</i> -Tosyl-4-ChlorobenzenesulfonimidoylFluoride (SulfoxFluor):Direct Imidation of Sulfinyl Chlorides with Chloramine-T Trihydrate,"Abstract N-Tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor) has emerged as a new fluorination reagent that can be used in the rapid deoxyfluorination of various alcohols. We disclose in this article a general and practical method for the preparation of SulfoxFluor and its adaption to a large scale. Starting from readily available 4-chlorobenzenesulfonyl chloride, chloramine-T trihydrate, and potassium fluoride, SulfoxFluor was prepared on a hectogram scale in 63% overall yield with simple purification techniques. The use of chloramine-T trihydrate (instead of anhydrous chloramine-T) is a significant improvement over previous work, which streamlines the process and avoids the risk of explosion during drying or heating. This research not only establishes a reliable method for the scale-up synthesis of SulfoxFluor but also provides an insight into the imidation of sulfinyl chlorides with chloramine-T in the presence of water.",10.1021/acs.oprd.1c00431,1
Asymmetric Synthesis of Optically Active 3-Cyclohexene-1-carboxylic Acid Utilizing Lactic Ester as a Chiral Auxiliary in the Diastereoselective Diels–Alder Reaction,"The optically active 3-cyclohexene-1-carboxylic acid was synthesized through a TiCl 4 -catalyzed diastereoselective Diels–Alder reaction utilizing lactic acid ester as a chiral auxiliary, which can be removed by washing with H 2 O. The ( S )- and ( R )-isomers were both derived from easily available ethyl l -lactate.",10.1021/acs.oprd.1c00430,1
Engineering Enzyme Properties for Improved Biocatalytic Processes in Batch and Continuous Flow,"&lt;p&gt;The widespread adoption of biocatalysis by industry to perform highly selective chemical syntheses has been made possible only by the development of highly effective methods in enzyme engineering to overcome the limitations of naturally occurring enzymes. Through these methods we can adapt a broad range of enzyme properties, including interactions between enzymes and their substrates and cofactors and robustness of enzymes toward the nonphysiological environments of industrial processes, and even introduce new to nature chemical reactivities. The trend toward increased reaction complexity through the deployment of multienzyme cascades has also encouraged the development of engineering methods and design principles to improve cascade performance and accelerate their development, including engineering of spatial and temporal compartmentalization of cascades via biocatalyst colocation and immobilization. As the trend toward building reaction complexity continues, it is becoming clear that reaction design and engineering can be accelerated by the adoption of integrated multiscale engineering methods that are built around the concepts of standardization, modularity, and abstraction. &lt;/p&gt;",10.1021/acs.oprd.1c00424,0
Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow,"This article describes two routes toward the synthesis of cis or trans C2,3,5,7-tetrasubstituted dihydrobenzofurans as potent and selective bromodomain and extra-terminal BD2 inhibitors, followed by the optimization of the synthesis of the lead molecule GSK973 to support pre-clinical efficacy and safety studies. The use of flow chemistry for a Claisen rearrangement, extensive optimization of the fluorination step, and high-yielding aminocarbonylation were key to generate the required 50 g of material. The identified new route also represents a robust starting point for further optimization.",10.1021/acs.oprd.1c00422,1
Efficient Multigram-Scale Synthesis of 7-Substituted 3-Methyltetral-1-ones and 6-Fluoromenadione,"Herein, we report a safe and economical multigram synthesis of 6-fluoromenadione, an intermediate in the synthesis of novel biologically active agents. The key to this six-step sequence process involves the condensation of the readily available starting 4′-fluoropropiophenone and glyoxylic acid, a bromination–elimination sequence from 7-fluoro-3-methyltetral-1-one allowing aromatization of the naphthol intermediate, which is then oxidized into the corresponding 6-fluoromenadione. The multigram process has been demonstrated from 25 g of starting material scale with an improved overall yield of 50% and then applied to five other 7-substituted 3-methyltetralones and their corresponding 6-substituted menadiones.",10.1021/acs.oprd.1c00421,1
“One-Pot” Synthesis of Molnupiravir from Cytidine,"High Resolution Image Download MS PowerPoint Slide A one-pot process for preparing molnupiravir from cytidine was developed. The advantages of this synthesis were as follows: (1) The presence of N, N -dimethylformamide dimethyl acetal (DMF-DMA) facilitated the selective protection of 2′,3′-dihydroxyls and amino of cytidine, which eliminated the negative impact of these groups on the following isobutyrylation at 5′-hydroxyl. (2) Degradations of the product in the deprotection stage were avoided since a mild condition was used. (3) The achievement of deprotection and hydroxyamination in one single step improved the synthetic efficiency. (4) Molnupiravir with high purity (purity up to 99.7% analyzed by high-performance liquid chromatography (HPLC)) was obtained in a yield of 63% through crystallization.",10.1021/acs.oprd.1c00419,1
Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry,"A multi-step process using continuous flow chemistry to produce propofol is described. A scale-up of a 5-stage process (two continuous flow chemical steps, two extractions using a semi-batch approach, and one purification) provided propofol in high purity. This process minimizes the number of impurities formed during the double Friedel–Crafts reaction allowing to run two continuous flow chemical steps sequentially. The use of simple, inexpensive, and readily available reagents affords a viable process for this widely employed active pharmaceutical ingredient.",10.1021/acs.oprd.1c00416,1
A Highly Efficient and Sustainable Biocatalytic Oxidation Process toward (<i>R</i>)-Undecavertol,"A biotransformation to produce ( R )-Undecavertol has been developed and demonstrated on the pilot scale. The process is a racemic resolution using a highly ( S )-selective alcohol dehydrogenase in the oxidative direction and an NAD(P)H oxidase for cofactor regeneration. Oxygen limitation is prevented by supplying pure oxygen, achieving a >400 g L –1 substrate concentration and a space-time yield of 14 g L –1 h –1 on the pilot scale and even up to 680 g L –1 and a space-time yield of 21 g L –1 h –1 on the lab scale. In three pilot-plant batches, more than 85 kg of ( R )-Undecavertol was produced biocatalytically.",10.1021/acs.oprd.1c00415,0
Initial Route Scouting and Final Process Development for the Multi-Kg Production of 3-Fluoro-6-methoxyquinoline from <i>p</i>-Anisidine and 2-Fluoromalonic Acid,"A scalable route to 3-fluoro-6-methoxyquinoline needed to be developed as multi-kg amounts of this heterocycle were required. Initial route development focused on the formation of the key C–F bond via a Balz–Schiemann reaction or electrophilic fluorination using Selectfluor. Both routes were developed on laboratory scale and provided gram amounts of 3-fluoro-6-methoxyquinoline. However, due to process safety concerns and high step counts, both routes were not suitable for further scale up. Therefore, a third approach was developed, in which the desired heterocycle was formed via condensation of p -anisidine with 2-fluoromalonic acid, two inexpensive and commercially available starting materials. After intensive optimization and safety studies, this POCl 3 -mediated process was successfully scaled up to a 32 kg scale. After final hydrodechlorination, 12 kg of 3-fluoro-6-methoxyquinoline with excellent purity was produced.",10.1021/acs.oprd.1c00414,1
Recent Advances in Photobiocatalysis for Selective Organic Synthesis,"Photocatalysis has emerged as a powerful tool to generate reactive intermediates under mild reaction conditions. The combination of photocatalysis and biocatalysis, possessing advantages of the reactivity of photocatalysts and the selectivity of enzymes, has received increasing attention for its potential to realize the green synthesis of value-added chemicals. This review provides an overview of recent progress in photobiocatalysis, including the regeneration of cofactors, generation of H 2 O 2 in situ, cascades involving a photobiocatalytic transformation, and the photoinduced enzymatic reactions inspired by the photoactive cofactor within the enzyme.",10.1021/acs.oprd.1c00413,1
Rapid Continuous-Flow Water-Free Synthesis of Ultrapure Ionic Liquids Assisted by Microwaves,"A wide range of imidazole, pyridine including insoluble polymers, and tertiary amine derivatives rapidly reacted with orthoformate using various Brønsted acids or ammonium salts to control the anionic parts. The corresponding ionic liquids were formed in excellent yields under microwave-batch conditions within 10 min. A scale-up synthesis was easily achieved using a microwave flow system. Typically, [BMIM][BF 4 ] was produced at a rate of 26.2 g/h under an Ar atmosphere with an E-factor of 0.8. Both batch and flow experiments were also performed in a domestic microwave oven.",10.1021/acs.oprd.1c00412,0
Transaminase Engineering and Process Development for a Whole-Cell Neat Organic Process to Produce (<i>R</i>)-α-Phenylethylamine,"The production of ( R )-α-phenylethylamine (( R )-α-PEA) from acetophenone is a classic reaction for the characterization of transaminases. However, developing a commercially viable transaminase process to manufacture ( R )-α-PEA usually suffers from two drawbacks. One is related to the biocatalyst itself, since transaminases are easily inhibited by ( R )-α-PEA at low concentrations. The other drawback is a common low space-time yield of typical transaminase processes, because the reaction equilibrium greatly favors the formation of acetophenone over ( R )-α-PEA. In this study, an ( R )-selective amine transaminase (TA) from Aspergillus fumigatus Af293 was engineered by a directed evolution for an efficient process to produce ( R )-α-PEA. The evolved variant showed an over 3000-fold increase in activity and a tolerance with 2.0 M isopropylamine as well as the complete absence of inhibition by ( R )-α-PEA. At the same time, using this evolved TA variant, a continuous neat organic process using whole-cells was developed where the biocatalyst and remaining acetophenone can be efficiently separated from ( R )-α-PEA and reused repetitively. This not only decreases the overall cost and waste generation but also achieves a very high space-time yield of up to 168 g L –1 d –1 of ( R )-α-PEA in an industrial pilot scale setup.",10.1021/acs.oprd.1c00409,0
Simultaneous Preparation of (<i>S</i>)-2-Aminobutane and <scp>d</scp>-Alanine or <scp>d</scp>-Homoalanine via Biocatalytic Transamination at High Substrate Concentration,"( S )-2-Aminobutane, d -alanine, and d -homoalanine are important intermediates for the production of various active pharmaceutical ingredients and food additives. The preparation of these small chiral amine or amino acids with high water solubility still demands searching for efficient methods. In this work, we identified an ω-transaminase (ω-TA) from Sinirhodobacter hungdaonensis ( Shd TA) that catalyzed the kinetic resolution of racemic 2-aminobutane at a concentration of 800 mM using pyruvate as the amino acceptor, leading to the simultaneous isolation of enantiopure ( S )-2-aminobutane and d -alanine in 46% and 90% yield, respectively. In addition, ( S )-2-aminobutane (98% ee ) and d -homoalanine (99% ee ) were isolated in 45% and 93% yield, respectively, in the kinetic resolution of racemic 2-aminobutane at a concentration of 400 mM coupled with deamination of l -threonine by threonine deaminase. We thus developed a biocatalytic process for the practical synthesis of these valuable small chiral amine and d -amino acids.",10.1021/acs.oprd.1c00408,0
High Yielding Continuous-Flow Synthesis of Norketamine,"High Resolution Image Download MS PowerPoint Slide A new continuous-flow process is presented for synthesis of the pharmaceutical intermediate norketamine ( 5 ). Our approach has been to take the well-established and industrially applied batch synthetic route to this promising antidepressant precursor and convert it to a telescoped multi-stage continuous-flow platform. This involves the α-bromination of a ketone, an imination/rearrangement sequence with liquid ammonia, and a thermally induced α-iminol rearrangement. Our approach is high yielding and provides several processing advantages including the reduction of many of the hazards conventionally associated with this route, particularly in the handling of liquid bromine, hydrogen bromide gas, and liquid ammonia. Each of these presents serious operational challenges in a batch process at scale.",10.1021/acs.oprd.1c00407,1
Tetrahydro-4<i>H</i>-pyran-4-one: From the Laboratory Scale to Pilot Plant Manufacture,This study describes our recent efforts to find an efficient and scalable route to tetrahydro-4 H -pyran-4-one using the commercially available starting materials. The route scouting work and the full development of an efficient access to the target are described. This work culminated in the preparation of above 20 kg of the title compound in our pilot plant facility.,10.1021/acs.oprd.1c00403,0
"Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19","Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.",10.1021/acs.oprd.1c00400,1
Asymmetric Organocatalysis and Continuous Chemistry for an Efficient and Cost-Competitive Process to Pregabalin,"High Resolution Image Download MS PowerPoint Slide Herein, we present the scale up development of an innovative synthetic process to pregabalin. The process is underpinned by two enabling technologies critical to its success; continuous chemistry allowed a safe and clean production of nitroalkene, and asymmetric organocatalysis gave access to the chiral intermediate in an enantioenriched form. Crucial to the success of the process was the careful development of a continuous process to nitroalkene and optimization of the organocatalyst and of the reaction conditions to attain remarkably high turn-over frequency in the catalytic asymmetric reaction. Successful recycle of the organocatalysts was also developed in order to achieve a cost-competitive process.",10.1021/acs.oprd.1c00394,1
Industrial-Scale Continuous Vacuum Drying of Active Pharmaceutical Ingredient Paste: Determination of the Process Window,"Many efforts have been made in recent years to adopt and implement continuous processing into the pharmaceutical production chain, driven by the desire to optimize the process efficacy and cost as well as the product quality. In the current challenging times, the need for fast adaptable processes to enlarge and facilitate the drug production on short notice is even more immanent than before. Suitable equipment for some unit operations is still missing. Drying is one of those and one of the most complex processes in the active pharmaceutical ingredient (API) manufacturing chain. Drying can influence the surface structure, particle size, as well as the morphology, in the worst case even causing degradation, especially in heat-sensitive substances. When producing APIs by proper design of the crystallization process to the desired target properties, it is key to have a drying process that can remove residual liquids without changing the particles. Practically, this means not changing particle size distribution by neither agglomeration nor particle attrition. In this work, the process window of a process, enabling full-scale continuous drying of a crystalline API after crystallization and washing, was investigated. An Ibuprofen paste containing water and ethanol as a liquid phase has been dried in a continuous vacuum dryer. The particles undergo no change during the process, and the needle-shaped particle form as well as the volume mean diameter of ∼80 μm was maintained until the end of the process for a large process window. Furthermore, it was shown that this continuous process can be run successfully in a semicontinuous mode, which enables implementing this new process into the existing batch operating manufacturing plants. The process time is much faster as for conventional batch drying technology, and the product volume can be scaled via run time or the throughput, therefore enabling a fast response to change in drug demand.",10.1021/acs.oprd.1c00393,0
"Development of a Practical and Scalable Synthetic Route for the Adenosine Monophosphate-Activated Protein Kinase Activator, ASP4132","This paper describes the research and development of a practical and efficient process for making the adenosine monophosphate-activated protein kinase (AMPK) activator, ASP4132 ( 1 ). The newly developed process includes an efficient telescoping process consisting of Suzuki–Miyaura coupling and hydrogenation, effective removal of palladium using N -acetyl cysteine and silica gel, and reductive amination with the stable and mild reducing reagent, 2-picoline borane. The need for chromatographic purification was removed from all steps. The overall yield improved from 18% in the medicinal synthetic route to 43% using the new procedure. This highly efficient process was successfully demonstrated on a pilot scale to yield ASP4132 ( 1 ) with high quality.",10.1021/acs.oprd.1c00392,1
Quantum Mechanical Methods for Thermal Hazard Risk Assessment in Early Phase Pharmaceutical Development,"Quantum mechanical (QM) applications to predict heat of reaction (Δ H r ) and thermal stability of strained aminocarbocylic salts, diazo compounds, and nitroalkanes for early phase thermal hazard risk assessment is presented. We provide examples on the use of explicit solvation to predict accurate Δ H r . Based on the QM calculations, the criticality class of a copper-catalyzed C–N coupling reaction is determined according to Stoessel’s reaction criticality class and the predictions are consistent with RC1 calorimetric experiment. We emphasize that to predict accurate Δ H r, it is important to consider the roles of reagents and solvents in QM calculations rather than simply considering the bond formation and bond breaking steps involved with reactants and products. Further, the use of predicted Δ H r for salt formation is applied to predict the thermal stability of bromoacetylene azetidine compounds to establish structure–stability relationship which would be useful to identify stable salt intermediates for safe reaction design. A strong correlation between Δ H r and the left limit of the DSC onset temperature ( T init, °C) of the of exothermic peak is identified ( T init = −2.85 Δ H r − 99.5). We propose that this model can be used as a prediction tool for novel azetidine salts to provide an estimate of thermal stability before synthesis. In this paper, for the first time we report molecular electrostatic potential (MESP) descriptor for the prediction of T init of diazo compounds. The deepest MESP minimum ( V min ) on the diazo group is considered as a probe to quantify the variation in structural effects. A strong correlation between V min and T init is found which would provide a new way of interpreting the thermal stability of novel diazo molecules just based on chemical structure. Further, the applicability of V min is verified on another set of compounds (nitroalkanes) and a good correlation is obtained. The structure–stability relationships that involves V min can be a useful QM descriptor for thermal stability prediction of a variety of molecules.",10.1021/acs.oprd.1c00391,0
"Development of a Practical and Greener Process for the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two S<sub>N</sub>Ar Reactions, Oxidation and Suzuki Coupling","A sustainable second-generation process for GDC-0134 was developed with a particular focus on safety and greenness, while complying with strong specifications to supply pivotal clinical studies. Through these efforts, we discovered solvents to replace the solvents classified as substances of very high concern by the REACH regulation in two S N Ar steps. We further established a safer and faster way to oxidize the sulfanyl to the sulfonyl intermediate by dosing H 2 O 2 at higher temperatures, reducing accumulation while minimizing uncontrolled H 2 O 2 decomposition. The reaction conditions for the Suzuki coupling and the second S N Ar were modified to increase the selectivity in these two steps. A change in the solvent for the final crystallization allowed operation at higher concentrations and delivery of a highly pure active pharmaceutical ingredient (API). The new improved process reduced the process mass intensity by approximately 40% and was successfully used to produce 150 kg of GDC-0134.",10.1021/acs.oprd.1c00389,1
Scale-Up and Development of Synthesis 2-Ethylhexyl Nitrate in Microreactor Using the Box–Behnken Design,"In this study, kilogram-scale synthesis of 2-ethylhexyl nitrate in a microreactor was reported. Using Box–Behnken experimental design, the effects of process parameters such as temperature, molar ratio, total flow rate, and mass fraction of sulfuric acid on the yield of the target product were systematically investigated. The experimental design was studied at four factors and three levels. The results revealed that the sulfuric acid mass fraction and temperature significantly affected the yield of the product. There was a good agreement between the experimental results and predicted results by the proposed regression model. Subsequently, the mixing effect of the liquid–liquid heterogeneous system in microreactor was simulated by using computational fluid dynamics. The results provide solid evidence that the microreactor has excellent mixing efficiency in mass and heat transfer compared with the conventional reactor. Consequently, based on the results of process parameter optimization, an enlarged microreactor was designed to intensify the preparation of 2-ethylhexyl nitrate by a throughput of 16 kg/h.",10.1021/acs.oprd.1c00388,0
"Convenient, Large-Scale Synthesis of (<i>S</i>)-TRIP Using Suzuki Cross-Coupling Conditions","A three-step synthesis of ( S )-TRIP enabled by efficient Suzuki cross-coupling conditions using commercial starting materials was developed and demonstrated on a kilogram scale. These novel Suzuki reaction conditions feature Pd 2 (dba) 3 /CataCXium A in the presence of TBAB and KOH and provide conversions up to 90% while minimizing the formation of common byproducts. Following an improved demethylation protocol and a powerful methanol purification protocol during step 2, high-quality catalyst of up to 99% purity was isolated in 52% yield over three steps.",10.1021/acs.oprd.1c00386,0
Concise Process for Pyriftalid Synthesis by Introducing the Mercapto Group Directly from a Nitro Group,"A concise and efficient process for the synthesis of pyriftalid is described herein. The improved process features the direct introduction of the mercapto group by one-step substitution of a nitro group using sodium sulfide and elemental sulfur. A systematic study of the key step is also carried out in this article. Compared with previous routes, the optimized route is shorter and avoids a hazardous catalytic reduction and a subsequent diazotization reaction. Salt waste generated in workup is reduced as well. Pyriftalid is obtained in 68% overall yield and 99.88% purity in five steps with 3-nitrophthalic acid as the starting material.",10.1021/acs.oprd.1c00384,1
"Kilogram-Scale Preparation of the Easily Available, Low-Cost Electrophilic Trifluomethylating Reagent YlideFluor","A kilogram-scale process for the preparation of a potentially broadly applicable electrophilic trifluoromethylating reagent, (trifluoromethyl)(4-nitrophenyl)bis(carbomethoxy)methylide (YlideFluor), was reported. The reagent was prepared in three steps from a cheap, commercially available starting material, and the price of the reagent is estimated to be as low as $1.5/g. Application of the reagent in the preparation of trifluoromethylated derivatives of two drug molecules in the gram scale was demonstrated.",10.1021/acs.oprd.1c00381,0
Engineering a Transaminase for the Efficient Synthesis of a Key Intermediate for Rimegepant,"Transaminases have been increasingly utilized as efficient biocatalysts in the synthesis of pharmaceutical intermediates, but a major drawback is their poor substrate acceptance, especially the limitation for the synthesis of sterically hindered chiral amines. Herein we report the engineering of a transaminase that can convert the ketone (6 S,9 R )-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5 H -cyclohepta[ b ]pyridin-5-one to (5 S,6 S,9 R )-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5 H -cyclohepta[ b ]pyridin-9-ol, a key intermediate for the synthesis of rimegepant, a CGRP antagonist for the treatment of migraine. Starting from an enzyme backbone with no detectable activity toward the desired ketone, a rational design approach enabled us to produce an enzyme variant with detectable trace activity. Then, by following various evolution strategies, including iterative saturation mutagenesis focused on a key loop and random mutagenesis of the whole sequence, further improvement of the activity was achieved. The resultant variant showed 99.0% conversion and >99.5% de for the desired reaction at the gram scale as well as at the kilogram scale to afford the product (5 S,6 S,9 R )-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5 H -cyclohepta[ b ]pyridin-9-ol in 80.2% yield with 99.9% HPLC purity, thus showcasing promising potential for industrial application.",10.1021/acs.oprd.1c00376,0
Development of an Improved Route to a Human Immunodeficiency Virus Maturation Inhibitor by Chromium-Free Allylic Oxidation and an Efficient Asymmetric Henry Reaction,"Development of an improved route to a human immunodeficiency virus maturation inhibitor is described. Key features of the chemistry that was developed include avoidance of chromium reagents by use of a novel allylic oxidation with NBS/water and an aldehyde oxidation using either bleach/TEMPO under flow conditions or dichlorodimethylhydantoin in batch. It was demonstrated that an imine could be used for in situ protection of a labile aldehyde, and the mixed anhydride for the acetylation was optimized. A highly enantioselective Henry reaction was developed, and it was demonstrated that hazardous Raney nickel could be replaced by hydrogenation over platinum.",10.1021/acs.oprd.1c00374,1
An Optimized Safe Process from Bench to Pilot cGMP Production of API Eptifibatide Using a Multigram-Scale Microwave-Assisted Solid-Phase Peptide Synthesizer,"High Resolution Image Download MS PowerPoint Slide A growing industrial interest toward the peptide drug market fueled the need for the development of effective and cGMP compliant manufacturing methods for these complex molecules. Solid-phase strategies are considered methods of election for medium-length peptide syntheses not only on the research scale but for multigram-scale production, as well. The possibility to use microwave-assisted technology on the multigram scale, recently introduced, prompted us to evaluate the possibility to conveniently set up a safe and fully cGMP-compliant pilot process to produce eptifibatide, a generic peptide active pharmaceutical ingredient. Accordingly, we developed an optimized process on the laboratory scale (1–5 mmol), which was subsequently successfully scaled up to 70 mmol, obtaining all the information required by regulatory agencies to validate the process and qualify the pilot scale plant. The process consists of 5 steps: (1) automated microwave-assisted solid-phase synthesis of eptifibatide linear precursor; (2) cleavage from the resin with concomitant amino acid side-chains deprotection; (3) disulfide-bond formation in solution; (4) purification by flash column chromatography; (5) ion-exchange solid-phase extraction. Since the direct scale-up of a multigram-scale cGMP compliant peptide API production procedure is a challenge that requires an accurate understanding of each involved step, we initially performed a quality management risk assessment, which enabled a smooth and effective achievement of a successful final result.",10.1021/acs.oprd.1c00368,1
Stereoselective Nickel(II)-Catalyzed Addition of Aryl Grignards to Diphenylacetylene in the Synthesis of Zuclomiphene,"Stereoselective synthesis of zuclomiphene was developed using nickel-catalyzed addition of 4-fluorophenylmagnesium bromide to 1,2-diphenylacetylene, followed by quenching with a chlorinating reagent. Since the aryl fluoride addition and chlorination reactions occur consecutively in one pot, the cis orientation of the two phenyl groups of 1,2-diphenylacetylene is conserved, leading to the highly selective synthesis of zuclomiphene. The use of the Grignard reagent resulted in the presence of bromide ions in the reaction mixture, which led to the formation of the bromo-analog of zuclomiphene. Alternative routes were then explored to overcome this issue to yield high-purity zuclomiphene.",10.1021/acs.oprd.1c00366,1
"Scalable Synthesis of <i>N</i>,<i>N</i>′-Di(2,3-dihydroxy-propyl)-1,4-naphthalenedipropanamide and Its 1,4-Endoperoxide as a Singlet Oxygen-Releasing Molecule","We report a greatly improved, operationally simple, and scalable three-step synthesis of the nonionic and water-soluble singlet oxygen ( 1 O 2 ) carrier molecule N, N ′-bis(2,3-dihydroxypropyl)-1,4-naphthalenedipropanamide-1,4-endoperoxide (DHPNO 2 ). Starting from 1,4-dibromonaphthalene, the developed sequence involves (1) a ligand-free Pd-catalyzed double Heck reaction with methyl acrylate, (2) Pd/C-catalyzed hydrogenation, and (3) amide formation by simple methyl ester aminolysis using 3-amino-1,2-propanediol to give N, N ′-bis(2,3-dihydroxypropyl)-1,4-naphthalenedipropanamide (DHPN) in 70% overall yield (three steps). A solution of the corresponding endoperoxide DHPNO 2 in D 2 O (storable at −20 °C), obtained by sensitized photo-oxidation of DHPN at 4 °C, is a valuable research tool allowing a controlled release of singlet oxygen ( 1 O 2 ) in aqueous biological systems at physiological temperatures.",10.1021/acs.oprd.1c00364,1
Synthesis of 5-Nitrotetrazolate via the Aqueous Oxidation of 5-Aminotetrazole,"The preparation of the important energetic precursor sodium nitrotetrazolate has long been plagued by safety and purity problems. The prevailing synthesis methods utilizing the Sandmeyer reaction proceed via sensitive, explosive intermediates and would be classified as a high-hazard process. In this work, we directly oxidize precursor 5-aminotetrazole to 5-nitrotetrazole in aqueous solution utilizing a heterogeneous titanium superoxide catalyst, skipping the sensitive intermediates inherent in the current industrial Sandmeyer route and providing a vastly safer process with a yield of 50–65%. The prepared sodium nitrotetrazole is of high purity and therefore is directly useful in the synthesis of the primary explosive DBX-1, which is a synthesis that is highly sensitive to impurities. The improved safety and excellent product purity demonstrates the superiority of our route.",10.1021/acs.oprd.1c00361,0
MSD’s Process Safety Scale-Up Methodology for Pilot Plant Scale and Beyond,"Process safety testing is critical for small molecule active pharmaceutical ingredient (API) scale-up and manufacturing by proactively identifying any process safety hazards, including environmental and industrial hygiene issues. The intent of this contribution is to describe how Merck & Co., Inc. Kenilworth, NJ (known as MSD outside of the U.S. and Canada) manages process safety testing for pilot plant and manufacturing scale operations with a stagewise approach. Several case studies will be discussed.",10.1021/acs.oprd.1c00360,0
Impact of Phosphine Featurization Methods in Process Development,"Modern high-throughput experimentation (HTE) has enabled the rapid exploration of large expanses of chemical reaction space to accelerate the development of key synthetic steps in pharmaceutical processes. However, the dimensionality of reaction parameters, the desire to use minimal starting material, and the need to thoroughly analyze reaction outcomes still require the judicious selection of which experiments to perform in which order. Therefore, the development of a capability to quantify reagent diversity and analyze reaction outcomes in HTE holistically is paramount. A method to address this goal would combine computational featurization of key reaction components with the use of multivariate linear regression modeling to correlate the reaction performance outputs. In this context, we describe a process of establishing a computational featurization platform for monodentate phosphine ligands and considerations for its implementation at GSK. We demonstrate that the choice of computational method has an impact on phosphine descriptor values, ligand selection for experiments, and the development of linear regression models of reaction outcomes.",10.1021/acs.oprd.1c00357,0
Development of a Scalable Route to a Pyrrolidone Compound via a Hydroxyfuranone,"Herein, we describe the preparation of pyrrolidone compound 1 as a potential antiepileptic drug. The key steps of this synthetic route are based on the preparation of a heterocyclic amine and its condensation with a hydroxyfuranone in a three-step one-pot process. The development of the synthesis led to decreased route complexity and removal of chromatographic purifications. These improvements were demonstrated at scale by the production of 700 g of this pyrrolidone.",10.1021/acs.oprd.1c00350,1
Comparison of One-Dimensional and Two-Dimensional Population Balance Models for Optimization of a Crystallization Process for a Needle-Shaped Active Pharmaceutical Ingredient,"The two-dimensional population balance model (2D PBM) introduces the enhanced capability of modeling two different sets of growth kinetics, which can offer advantages to modeling crystallization processes that generate needle-like particles, a commonly encountered active pharmaceutical ingredient (API) morphology. Although one-dimensional population balance model (1D PBM) can be utilized effectively to model nonequant morphologies with the selection of appropriate shape factors, it cannot account for morphology or aspect ratio changes that can occur during the crystallization process. In this work, the advantage of the 2D PBM for an industrial crystallization process that generates needle-shaped API is highlighted by comparing the 1D PBM and 2D PBM results. The API utilized for this work had extremely slow desupersaturation and was not able to achieve solubility concentration despite an ∼50 h seed bed age. While the 1D PBM is useful in optimizing the crystallization process to enhance desupersaturation behavior, the 1D PBM did not match the particle size quantiles and, thus, could not be utilized to probe the impact of crystallization process parameters on the particle aspect ratio (AR). The 2D PBM was necessary to model the particle size quantiles and was utilized to further optimize process conditions for minimizing the particle aspect ratio. Simulations utilizing the 2D PBM indicated that, regardless of antisolvent addition rate or seed morphology, the final material would still have a high aspect ratio. This knowledge saved the investment of much time and effort in trying to minimize particle AR with changes in crystallization processing parameters alone and, thus, highlights the utility of the 2D PBM to the pharmaceutical industry.",10.1021/acs.oprd.1c00344,0
Automated High-Throughput Partition Coefficient Determination with Image Analysis for Rapid Reaction Workup Process Development and Modeling,"With this work, we explore the application of a novel image analysis algorithm in combination with a high-throughput automated workflow to extract partition coefficient measurements and full mass balance from small-scale samples. An image analysis algorithm was developed in MATLAB R2018b to determine the volume of the aqueous and organic phases of the biphasic samples with 95% accuracy. The automated workflow used less than 1% of the typical reagent amounts and provided up to 94% time savings when compared with the conventional partition coefficient determination studies. This approach also proves that it is possible to build thermodynamic models for liquid–liquid equilibrium process steps using small-scale vessels (8 mL) and identify the impact of varying process parameters in silico. The model could predict the system behavior at a kilo scale and resulted in an optimized set of process conditions that increased the product recovery from 88 to 94% theoretical. The good agreement between the model and the experimental data also enabled the impact of process parameters on a critical impurity to be determined, supporting risk assessment and quality by design activities for the case study highlighted.",10.1021/acs.oprd.1c00343,0
Asymmetric Synthesis of the Cyclohexyl Fragment in RORγt Inhibitor (BMS-986251) Enabled by a Dynamic Kinetic Resolution of Hageman’s Ester,"The cyclohexyl fragment 1 in BMS-986251 was synthesized starting from Hagemann’s ester 2 in 7 steps and 5 isolations. The route is highlighted by a dynamic kinetic resolution (DKR), a telescoped enol nonaflation followed by a palladium-catalyzed carbonylation, and a rhodium-catalyzed directed diastereoselective olefin hydrogenation. The optimized process was demonstrated on 1 kg scale, with an overall 51% yield and >99% ee and dr.",10.1021/acs.oprd.1c00339,1
"Continuous Flow Synthesis of a Blocked Polyisocyanate: Process Intensification, Reaction Monitoring Via In-Line FTIR Analysis, and Comparative Life Cycle Assessment","The traditional batch production of blocked polyisocyanates, key components in the preparation of self-cross-linking resins, has significant drawbacks associated with the exothermic character of the reaction and the high viscosity of some of the materials involved. We have developed a continuous flow strategy for the generation of a methyl ethyl ketoxime-blocked polyisocyanate. The neat oxime and the viscous polyisocyanate were pumped and mixed in continuous flow using a Kenics static mixer. The homogeneous mixture obtained was fully converted to the target blocked polyisocyanate in a residence time unit downstream of the mixer. Real-time reaction monitoring, via in-line Fourier-transform infrared analysis at the reactor outlet, has been implemented, enabling fast optimization of the reaction conditions and providing a sensitive and reliable method to control product quality. The process has been intensified in flow by stepwise increase of the temperature of the residence time unit. Full conversion after only 15 s of overall residence time has been achieved at 155 °C, providing a productivity of ca. 1 kg per hour for a reactor of only 4.5 mL volume. The ecological impacts of a conceptualized upscaled flow process compared to the industrial batch procedure have been evaluated by a comparative life cycle assessment (LCA) according to the ISO 14040/44 LCA framework. The LCA results illustrate the capabilities of continuous processing to enable more sustainable production of blocked polyisocyanates.",10.1021/acs.oprd.1c00329,0
"Design, Development, and Analysis of an Automated Sampling Loop for Online Monitoring of Chiral Crystallization",of both the liquid and the solid. This work demonstrates a proof of concept of both the experimental and theoretical aspects of the new system.,10.1021/acs.oprd.1c00320,0
"Development of the Enabling Route for a Novel HCV NS3/4A Inhibitor, Furaprevir","Furaprevir demonstrated adequate safety and effectiveness in clinical phases I and II, which was identified as a potent Hepatitis C virus (HCV) NS3/4A protease inhibitor. Research on the synthesis process of Furaprevir is insufficient, so a reliable manufacturing procedure is required to support subsequent clinical trials. There were two challenging steps in the synthesis process, which involved an amide-bond formation and a ring-closing metathesis (RCM) reaction to form the product active pharmaceutical ingredient (API). The optimized process conditions were successfully used to produce 25 kg per batch of Furaprevir, which was sufficient to support the subsequent clinical development and onward.",10.1021/acs.oprd.1c00315,1
Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-<i>N</i>-(1-methyl-1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine,"Route evaluation, process development, and large-scale manufacturing of 4-chloro- N -(1-methyl-1 H -pyrazol-4-yl)pyrimidin-2-amine ( 1 ) are described. The improved route consists of two linear chemical steps: oxidation of 4-chloro-2-(methylthio)pyrimidine ( 11 ) to 4-chloro-2-(methylsulfonyl)pyrimidine ( 7 ) and displacement of the sulfonyl with N -(1-methyl-1 H -pyrazol-4-yl)formamide ( 10 ) under basic conditions followed by in situ hydrolysis of the N -formyl intermediate to deliver compound 1 . N -(1-Methyl-1 H -pyrazol-4-yl)formamide ( 10 ) was readily prepared from 1-methyl-1 H -pyrazol-4-amine ( 4 ) via reaction with formic acid. The route allows for large-scale production of 4-chloro- N -(1-methyl-1 H -pyrazol-4-yl)pyrimidin-2-amine ( 1 ). Density functional theory (DFT) calculations were carried out to better understand the observed reactivity and selectivity.",10.1021/acs.oprd.1c00314,1
High-Throughput Experimentation Enabling Rapid Process Optimization of an RSV Drug Candidate,The process optimization for the synthesis of an RSV antiviral agent is described. Key to the identification of these optimal conditions was the use of high-throughput experimentation to greatly reduce the development time and realize significant process improvements in key steps such as the telescoped pyrazolopyrimidine core assembly and the borylation/Suzuki sequence.,10.1021/acs.oprd.1c00313,1
"Scalable Synthesis of (<i>R</i>,<i>R</i>)-<i>N</i>,<i>N</i>-Dibenzyl-2-fluorocyclohexan-1-amine with CsF under Hydrogen Bonding Phase-Transfer Catalysis","Hydrogen bonding phase-transfer catalysis offers a convenient solution to activate safe and economical metal alkali fluorides for enantioselective nucleophilic fluorination. Herein, we demonstrate the scalability of this protocol with the fluorination of 200 g of racemic trans - N, N -dibenzyl-2-bromocyclohexan-1-amine in a mechanically stirred 1 L glass reactor using 0.5 mol % of a bis-urea organocatalyst. In these experiments, full conversions were obtained for high mixing intensities (impeller average shear rate >10 000 s –1; maximum energy dissipation per unit of mass >300 W/kg). The thermal safety of the reaction was assessed by differential scanning calorimetry and reaction calorimetry, assigning the reaction to Stoessel’s critical class 3.",10.1021/acs.oprd.1c00312,0
Deracemization via Periodic and Non-periodic Temperature Cycles: Rationalization and Experimental Validation of a Simplified Process Design Approach,"Solid-state deracemization via temperature cycles is a promising technique that combines crystallization and racemization in the same batch process to attain enantiomer purification. This method is particularly attractive because the target enantiomer can be isolated with a 100% yield, and a large number of operating parameters can be adjusted to do this effectively. However, this implies that several choices need to be made to design the process for a new compound. In this work, we provide a solution to this dilemma by suggesting a simplified model-free design approach based on a single dimensionless parameter, that is, the dissolution factor, that represents the cycle capacity. This quantity is obtained from a novel rescaling of the model equations proposed in previous work and acts as a handy design parameter because it only depends on the operating conditions, such as the suspension density, the enantiomeric excess, and the difference in solubility between high and low temperatures in the cycle. With extensive modeling studies, supported by experimental results, we demonstrate the primary and general effect of the dissolution factor on the deracemization process and thus its relevance for the process design. Through both experiments and simulations, we rationalize and evaluate the process performance when periodic and non-periodic temperature cycles are applied to the deracemization of virtual and real compounds with different properties, that is, growth rate and solubility. Based on the approach proposed here, we clarify how the combined effect of more operating conditions can be exploited to obtain quasi-optimal process performance, which results superior when deracemization via periodic temperature cycles is performed.",10.1021/acs.oprd.1c00310,0
"Multidecagram Scale Synthesis of an Endoperoxide, Precursor of Anti-malarial and Anti-leishmanial Agents, <i>via</i> Free-Radical [2 + 2 + 2] Annulation with Molecular Oxygen","From screening experimental parameters to scaling up, a safe approach is reported for the multidecagram scale preparation of methyl ester of 6,6-dibutyl-3-hydroxy-3-methyl-1,2-dioxane-4-carboxylic acid ( 7 ), a flexible common intermediate for the synthesis of a variety of anti-malarial and/or anti-leishmanial compounds. The critical feature of the reaction is the use of a pure oxygen flow under batch conditions using methyl acetoacetate and 2-butyl-1-hexene as reagents, and a mixture of Mn(II) and Mn(III) acetates as catalysts, in acetic acid. Once the best solvent, catalyst loading, temperature, and reaction time in the small-scale procedure (10 mL vial) were defined, the process was adapted up to a 3 L flask, eventually resulting in the production of about 70 g of 7 . The developed reaction protocol gives a satisfactory result considering: (i) the inexpensive starting materials used, (ii) the 100% atom economy of the [2 + 2 + 2]-annulation reaction, (iii) the stoichiometric ratio of the two reagents (only oxygen is used in excess) coupled with low catalyst loading, and (iv) the mild conditions adopted. The calorimetric studies allow us to classify this reaction as an inherently safe process. On a larger scale, the possible formation of a flammable vapor mixture in the reactor headspace was minimized using two parallel continuous flows of oxygen and argon, thus ensuring a constant headspace vapor phase renewal.",10.1021/acs.oprd.1c00309,0
Development of a Kilogram-Scale Route for Clinical Sample Production of the Intravenous Anesthetic Cipepofol,"Propofol has been widely used as a clinical anesthetic for a few decades. Its derivative with a three-membered ring, Cipepofol, was found to be equally effective and with less side effects. Here, we report a process for the scale-up total synthesis of Cipepofol . It could be obtained in five steps from the commercially available 2-isopropylphenol. The key reactions involved Claisen rearrangement, Simmons–Smith cyclopropanation, and chiral resolution through carbamate formation/crystallization, followed by hydrolysis and wiped-film distillation. The reaction conditions were mild, and the involved reagents were easily accessible. With this process, the final product was synthesized in a 14% overall yield, without column chromatographic purification. The synthetic route offered a shorter, robust, and economical production of Cipepofol (chemical purity > 99.5%, 99.5% ee) in kg scale.",10.1021/acs.oprd.1c00306,1
Stirring Peptide Synthesis to a New Level of Efficiency,"Accelerating solid-phase synthesis is crucial for accessing a large number of peptides in a short time. Since standard peptide synthesis is usually done under poor diffusion conditions with slow or no mixing of the solid support, acceleration of the process is achieved by applying a large excess of reagents. In this work, overhead stirring and heating were combined to provide accelerated solid-phase peptide synthesis without using an excess of reagent. A new setup that allows both heating and fast stirring was designed specifically for research laboratory-scale peptide synthesis. By increasing the diffusion of both reagents and beads in a narrow dimension reactor, solid-phase reactions were done in seconds and medium-size peptides were synthesized in minutes.",10.1021/acs.oprd.1c00304,0
"Efficient, Protecting Group Free Kilogram-Scale Synthesis of the JAK1 Inhibitor GDC-4379","The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of a 3-substituted-4-aminopyrazole employing a telescoped oximation and hydrazine condensation of a 1,3-dielectrophile to generate nitrosopyrazole and a novel copper-catalyzed NaBH 4 reduction of the nitroso group. The endgame process features an amidation of aminopyrazole with acid chloride under Schotten–Baumann conditions to provide access to the penultimate intermediate. A selective N-1 alkylation of the pyrazole moiety was accomplished under phase-transfer conditions, which delivered GDC-4379 with a defined particle-size distribution suitable for micronization after recrystallization and wet milling.",10.1021/acs.oprd.1c00302,1
PAT Implementation on a Mobile Continuous Pharmaceutical Manufacturing System: Real-Time Process Monitoring with In-Line FTIR and Raman Spectroscopy,"The strategies and experimental methods for implementation of process analytical technology (PAT) on the mobile pharmaceutical manufacturing system, Pharmacy on Demand (PoD), are discussed. With multiple processes to be monitored on the PoD end-to-end continuous manufacturing process, PAT and its real-time process monitoring capability play a significant role in ensuring final product quality. Here, we discuss PAT implementation for real-time monitoring of an intermediate and API concentrations with in-line Fourier-transformed infrared and Raman spectroscopy for the five-step continuous synthesis of ciprofloxacin on the PoD synthesis unit. Two partial least squares regression models were built and verified with flow chemistry experiments to obtain a root-mean-square error of prediction (RMSEP) of 2.2 mg/mL with a relative error of 2.8% for the step 2 FlowIR model and a RMSEP of 0.9 mg/mL with a relative error of 2.8% for the step 5 Raman model. These models were deployed during an 11 h step 1–3 and a 5 h step 4–5 continuous ciprofloxacin synthesis run performed on the PoD system. In these runs, the real-time prediction of intermediate and product concentration was achieved with an online model processing software (Solo_Predictor) and a PAT data collection and management software (synTQ).",10.1021/acs.oprd.1c00299,0
Synthesis of the C1–C13 Fragment of Eribulin on a Kilogram Scale,"An improved kilogram-scale synthesis of the C1–C13 fragment of eribulin is disclosed. Rh-mediated 6- endo - tet cyclization of a vinyl epoxide provides a crystalline tetrahydropyran intermediate, which was transformed to a lactol intermediate having the bicyclic motif of the C3–C12 fragment. This intermediate was further elaborated into the C1–C13 fragment of eribulin following the precedent sequence of reactions.",10.1021/acs.oprd.1c00295,0
Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter,"A novel apparatus concept for integrated, small-scale continuous filtration, washing, and drying is presented. The continuous vacuum screw filter (CVSF) allows obtaining dried and free-flowing product particles from the continuously fed suspension. While the first study presented the CVSF concept in detail and focused on the characterization with respect to the product quality control and solid-phase residence time distribution (RTD S ) during sole filtration, the modular extension with washing modules and a vacuum-induced (pre-) drying setup is now presented here. For this purpose, a wash module was designed and implemented. The influence of single-stage and two-stage washing on the particle size distribution (PSD) and RTD S was investigated for the L -alanine/water model system. Single-stage washing increased the particle size of d 90,3 by 120 μm (+19%) due to a higher agglomeration degree, while using two-stage washing could completely preserve the particulate properties of the inlet suspension. To identify favorable operating conditions for efficient (pre-) drying, the effect of varying throughputs and mean residence times on the residual moisture of the product particles was quantified. High filling degrees (>30%) and increased mean residence times (>11 min), in combination with two-stage washing and efficient vacuum-induced airflow, ensured completely isolated, free-flowing, and almost dry particles with residual moistures of 1% and an entire maintenance of the PSD. Measurements of the RTD S showed a slight broadening due to the wash liquid used, still ensuring a narrow RTD S and thus almost plug-flow-like behavior. In summary, the CVSF offers unique features, such as its modularity and rapid start-up behavior, providing a promising concept for integrated continuous particle isolation from suspensions.",10.1021/acs.oprd.1c00294,0
"Study on the Safety Design of 3-Amino-6-Bromo-1,2,4-Triazine Drying Process Based on Thermal Analysis Technology","The thermal decomposition behavior of 3-amino-6-bromo-1,2,4-triazine (ABTA) with different moisture contents was studied with a differential scanning calorimeter (DSC). It was found that the thermal stability of the original wet ABTA was worse than that of the qualified dry ABTA. As the drying process proceeded and water was removed from ABTA, the first exothermic shoulder of the original wet ABTA disappeared gradually, and the thermal stability of ABTA improved accordingly. It was verified by the interruption and rescanning method that the decomposition behavior of the qualified dry ABTA followed the N-order reaction, while that of the original wet ABTA had obvious autocatalytic characteristics. The multistep series model was used to fit the thermal decomposition behaviors of the original wet ABTA and the qualified dry ABTA to obtain their decomposition kinetic parameters and predict their heat release behaviors under ideal adiabatic conditions. It was shown that the qualified dry ABTA was safe at 40–50 °C within 48 h, while the original wet ABTA had a great risk of a thermal runaway at 40–50 °C. The Thomas model was used to predict the heat release behavior of the original wet ABTA, which further confirmed the risk of a thermal runaway of the original wet ABTA in the drying process of production. Based on the relevant research results, the safety design requirements and safety operation precautions of the ABTA production drying process were determined.",10.1021/acs.oprd.1c00293,0
"Large-Scale Enantioselective Reduction of 2,3-Disubstituted Indenopyridine Enables a Practical Manufacturing Process for an 11β-HSD-1 Inhibitor","An economical and practical manufacturing process for an 11β-HSD-1 inhibitor is reported. The key feature of the synthesis is the identification of a unique and effective MeO-BoQPhos ligand for the Ir-catalyzed asymmetric hydrogenation of a fused tricyclic indenopyridinium salt. It is the first highly reactive chiral P,N ligand system to be utilized in asymmetric pyridine reduction. The enantioenriched indanopiperidine was produced with a low catalyst loading of 1000 ppm [Ir(COD)Cl] 2 . The challenges and solutions for final active pharmaceutical ingredient (API) physicochemical properties are also described. This asymmetric synthesis of the API was accomplished in 38% overall yield with >99.8% ee and >99.5 area % purity. This overall process results in a much shorter production cycle and significant waste reduction on the manufacturing scale.",10.1021/acs.oprd.1c00290,1
Synthesis of 1-Chloronaloxone and 2-Chloronaloxone,"This paper describes the unambiguous synthesis of authentic samples of 1-chloronaloxone and 2-chloronaloxone to support the unequivocal assignment of impurities observed in a drug product containing a combination of buprenorphine hydrochloride and naloxone hydrochloride. The key step in the synthesis of 1-chloronaloxone was the C-1-selective chlorination of (5α)-6-(1,3-dioxolan-2-yl)-4,5-epoxy-14-hydroxy-3-methoxy-17-(2-propenyl)morphinan using the Palau’Chlor reagent. The key step in the synthesis of 2-chloronaloxone was the C-2-selective chlorination of (5α)-3-diethylcarbamate-6-(1,3-dioxolan-2-yl)-4,5-epoxy-14-hydroxy-17-(2-propenyl)morphinan using a directed ortho metalation approach.",10.1021/acs.oprd.1c00288,0
Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib,"Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.",10.1021/acs.oprd.1c00287,1
Scalable Synthesis of β-Lactamase Inhibitor QPX7728 by Sequential Nickel-Catalyzed Boron Insertion into a Benzofuran Substrate and Enantioselective Cyclopropanation of the Resulting Vinylboronate,"We report the scalable, high-yielding, and highly selective synthesis of the β-lactamase inhibitor QPX7728 featuring two key synthetic steps: nickel-catalyzed boron insertion of benzofuran 1 followed by enantioselective cyclopropanation of the resulting cyclic vinylboronate 2 . The identification of the key reagents (catalyst and chiral auxiliary) for both steps relied on the use of high-throughput experimentation. Further optimization allowed for the cost-effective and scalable production of QPX7728.",10.1021/acs.oprd.1c00285,1
"Process Development, Manufacture, and Understanding of the Atropisomerism and Polymorphism of Verinurad","The manufacturing route toward verinurad, an amphoteric, class II atropisomer that readily forms solvates, has proven to be highly complex. This previously required the isolation of intermediates with challenging physical properties and the application of cryogenic processes. New processes were designed and optimized, enabling the manufacture of 113 kg of verinurad in its desired polymorphic form. An interdisciplinary approach involving the synthesis, high-throughput experimentation, analytical chemistry, crystallization science, in silico modeling, and engineering was employed. Kinetic measurement of enantiomerically enriched verinurad salts confirmed that racemization occurred within the clearance time frame, thus mitigating safety concerns associated with inherent axial chirality in verinurad.",10.1021/acs.oprd.1c00284,1
Expedited Kilolab Development of AZD7624 Using Kulinkovich-de Meijere Cyclopropanation,"AZD7624 is a small molecule compound developed for the treatment of chronic obstructive pulmonary disease. This study describes the lab development and kilolab manufacture of the drug substance. A small number of route options were evaluated using lab proof-of-concept and predictive studies, before a Kulinkovich-de Meijere cyclopropanation of an aromatic nitrile with little precedent was explored as a means of shortening the medicinal chemistry route. In the synthesis of the cyclopropanation substrate, an S N Ar-carbamoylation telescope sequence was used. The lab development activities devised procedures to make two of the reagents in the kilolab facility, addressed critical safety concerns, and prevented the coating of the reactor with titanium dioxide. Although cyclopropanation only proceeded in 37% yield, it still made the manufacturing target for its subunit, enabling 5.3 kg of in-specification AZD7624 to feed preclinical testing and phase 1 studies.",10.1021/acs.oprd.1c00283,1
"Review of Synthetic Routes and Crystalline Forms of the Oncology Drugs Capmatinib, Selpercatinib, and Pralsetinib","This article reviews the synthetic routes and final crystalline forms of the recently approved oncology drugs capmatinib, selpercatinib, and pralsetinib. The patent literature served as the primary source of information.",10.1021/acs.oprd.1c00282,1
A Scalable Synthesis of Roxadustat (FG-4592),"A scalable five-step protocol for synthesis of roxadustat, an orally administered hypoxia-inducible factor-propyl hydroxylase inhibitor (HIF-PHI), was developed with an emphasis placed on aspects of medicinal chemistry. The isoquinoline core of the molecule was prepared using a purposefully designed cyclocondensation in which both the cyclocondensation and demasking of the groups being condensed is promoted by a common acid agent in one step. Roxadustat was obtained pure in a very competitive overall yield across all reaction steps and in compliance with permissible residual Pd level in API.",10.1021/acs.oprd.1c00281,1
Using Oxygen as the Primary Oxidant in a Continuous Process: Application to the Development of an Efficient Route to AZD4635,"An aerobic oxidation operated in continuous flow is described as the key step in an efficient three-step route to AZD4635. By implementing this technique for the oxidation step, safety concerns in batch mode were addressed and an improved yield and quality of the product were obtained. Moreover, a PAT method (Fourier transform infrared (FTIR)) was employed to obtain a real-time analysis during the optimization in flow. The optimized three-step sequence was demonstrated on a multigram scale to give AZD4635 in 32% overall yield.",10.1021/acs.oprd.1c00279,1
An Efficient Second-Generation Manufacturing Process for the pan-RAF Inhibitor Belvarafenib,"Herein, the development of a streamlined manufacturing process for the pan-RAF inhibitor belvarafenib (GDC-5573) is reported. The process to belvarafenib features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access the penultimate intermediate 3 . The final amide coupling was accomplished by a mild and safe protocol employing N,N,N ′,N ′-tetramethylchloroformamidinium hexafluorophosphate as the coupling reagent, which afforded belvarafenib on a multikilogram production scale after recrystallization.",10.1021/acs.oprd.1c00277,1
Hybrid Flow-Batch Model for the Efficient Synthesis of 2-(Dimethylamino)-6-methylpyridin-4-ol,"A practical and scalable method for the synthesis of 2-(dimethylamino)-6-methylpyridin-4-ol is described. Despite its structural simplicity, the synthesis and isolation of this molecule in useful yields has proven to be challenging. A hybrid-flow (flow–batch–flow) mode approach was designed to circumvent issues associated with the safety and technical limitations of some of the steps in the process. The synthesis was successfully implemented to generate multigram quantities of a key intermediate for a drug candidate.",10.1021/acs.oprd.1c00264,1
Efficient Manufacturing Process for the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven Diastereoselective Pictet–Spengler Condensation,"GDC-9545 is a selective estrogen receptor degrader that is being developed as a treatment for ER+/HER2– breast cancer. A robust, convergent manufacturing process for GDC-9545 was developed. The process features a Wenker aziridine synthesis to produce the key starting material tryptamine 11, a highly efficient C–N coupling between aminoazetidine 9 and 2,6-difluoro-4-bromobenzaldehyde diethyl acetal ( 33 ) to construct key intermediate 10, and a crystallization-driven diastereoselective Pictet–Spengler reaction to furnish the active pharmaceutical ingredient GDC-9545·tartrate.",10.1021/acs.oprd.1c00263,1
First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet–Spengler Reaction and a C–N Coupling Reaction,"An asymmetric synthesis of the selective estrogen receptor degrader GDC-9545 ( 1 ) is described. The synthesis features a Friedel–Crafts indole functionalization and a strain-release aminoazetidine formation to construct the two key starting materials 2 and 4, respectively, a diastereoselective Pictet–Spengler reaction (98% yield, 95:5 dr) to assemble the tetrahydrocarboline core, and a highly efficient Pd-catalyzed C–N coupling (90% yield) using [ t -BuBrettPhos Pd(allyl)]OTf as the catalyst and DBU as the base to furnish the final C–N bond. This expedient route produces GDC-9545·tartrate active pharmaceutical ingredient in a longest linear sequence of six steps in 37% overall yield with 99.0 area % HPLC purity without chromatographic purification.",10.1021/acs.oprd.1c00262,1
Development of an Intrinsically Safer Methanolysis/Aromatic Nitro Group Reduction for Step 1 and 2 of Talazoparib Tosylate,"A change in facility for the synthesis of the step 2 intermediate for talazoparib tosylate ( 1 · TsOH ) required the development of an alternative, intrinsically safer process. Rapid route scouting and considerations of process safety enabled the development of a telescoped two-step process that was demonstrated on a multikilogram scale.",10.1021/acs.oprd.1c00259,1
Catalytic Static Mixer-Enabled Hydrogenation of a Key Fenebrutinib Intermediate: Real-Time Analysis for a Stable and Scalable Process,"Catalytic static mixer (CSM) technology is presented as an industrially viable solution for aromatic nitro group reduction in the synthesis of fenebrutinib. Factors affecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR and UHPLC). This facilitated the development of stable and optimal conditions in a system with four CSMs positioned inside a thermostated shell-and-tube reactor. Additional care was taken to ensure the control of three key impurities to low levels (<0.10 area% by offline UHPLC analysis). The optimal conditions (0.4 M concentration, 20 bar, 120 °C, 3.3 equiv H 2 ) were then scaled up to a reactor with eight CSMs, whereby an improvement in the space–time yield was achieved. Over 16 h of processing, a stable impurity profile was observed, without metal leaching. Finally, the reaction was performed in a system with 16 CSMs, which also provided an increase in the space–time yield (to 26.2 mol L –1 h –1 or 6.5 kg L –1 h –1 ), resulting in 174 g h –1 throughput, while maintaining an excellent impurity profile.",10.1021/acs.oprd.1c00258,0
Safety Assessments Supporting Scale-up of Chemistry Involving Hydrogen,"Asymmetric transfer hydrogenation (ATH) is a commonly used transformation in the pharmaceutical industry for the reduction of ketones to establish key stereocenters. Yet, the potential for hydrogen gas generation during reaction, workup, and waste handling processes could be overlooked, resulting in serious safety issues such as waste container overpressurization or fire. In this study, multiple module calorimeter (MMC) testing along with micro-GC tests of small scale (1–2 mL) representative lab samples were performed to detect and predict the potential safety hazards associated with the scale-up of an ATH process. Due to the safety concern discovered in the early safety screening tests, methanesulfonic acid (MSA) quench was implemented at the end of the ATH reaction to suppress hydrogen generation, avoiding possible overpressurizing the waste drum and the need to use special hydrogen-rated equipment at pilot- and production-scale. A safety assessment was performed to ensure that the subsequent vacuum distillation poses no risk of hydrogen combustion caused by using a standard pump/system. The process improvements and rigorous safety assessments enable the ATH reaction to be scaled-up using standard pilot plant equipment without the need for special handling and monitoring requirements for hydrogen gas. This study provides useful guidance and recommendations for safer scaling-up of similar organic synthetic reactions which may also generate flammable gas.",10.1021/acs.oprd.1c00256,1
Application of Biocatalytic Reductive Amination for the Synthesis of a Key Intermediate to a CDK 2/4/6 Inhibitor,"Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone to introduce the chiral secondary amine with high diastereoselectivity. The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed reductive cyclization and the process development for two S N Ar reactions en route to 3 are also presented.",10.1021/acs.oprd.1c00255,1
A Study on the Reaction Mechanisms and Process Safety of Pyrisoxazole Synthesis,"Understanding the kinetics and thermodynamic parameters of main reactions is critical for identifying the optimal operating conditions for chemical processes. The reaction mechanism and process safety for the synthesis of pyrisoxazole from 3-acetylpyridine, p -chloroprene, and n -methylhydroxylamine sulfate with sodium acetate as the buffer were researched in this study. The reaction mechanism was investigated by the combined analysis of molecular spectrum and liquid chromatography, and the molecular spectral data of the characteristic functional groups and their changes during the reaction were obtained. The apparent thermodynamic and kinetic data of the synthesis reaction were obtained by chemical reaction hazards study. The apparent reaction heat was −1298.7 kJ·kg –1, the adiabatic temperature rise of the runaway system was 59.4 K, the maximum reaction rate arrival time of the runaway system was 24 h, which corresponded to the temperature TD 24 of 116.8 °C, and the maximum temperature MTSR of the runaway system was 135.9 °C.",10.1021/acs.oprd.1c00254,0
Fully Continuous Flow Synthesis of 5-(Aminomethyl)-2-methylpyrimidin-4-amine: A Key Intermediate of Vitamin B<sub>1</sub>,"Herein, we demonstrate an expeditiously fully continuous flow synthesis of 5-(aminomethyl)-2-methylpyrimidin-4-amine, a key intermediate for vitamin B 1 . The process is accomplished via three chemical transformations in six sequential continuous flow devices from an economical starting material, 2-cyanoacetamide. First, single step continuous flow synthesis is demonstrated in a certain type of flow reactor for each reaction step, with a yield of 94, 90, and 99%, respectively. Then, fully continuous flow synthesis of 5-(aminomethyl)-2-methylpyrimidin-4-amine is demonstrated in 84% total yield with a total residence time of 74 min and 0.92 g/h throughput.",10.1021/acs.oprd.1c00253,1
Enzyme Optimization and Process Development for a Scalable Synthesis of (<i>R</i>)-2-Methoxymandelic Acid,"The rational protein engineering of wild type BCJ2315 nitrilase and its use in the development of a one-pot, enantioselective, dynamic kinetic resolution for ( R )-2-methoxymandelic acid is reported. Through a combination of molecular docking and B -factor analyses, a focused library of mutants was identified and screened to improve nitrilase selectivity, activity, and stability. Initial optimization revealed that the addition of sodium bisulfite prevented enzyme deactivation by the aldehyde starting material, removing the need to isolate the cyanohydrin and allowing for development of a one-pot process for mutant screening. Further optimization of the process with the preferred mutants revealed subtle interactions between temperature, pH, substrate loading, and enzyme source which ultimately led to development of a suitable lyophilized whole cell process for scale-up, affording ( R )-2-methoxymandelic acid in 97% ee and 70% isolated yield on multigram scale.",10.1021/acs.oprd.1c00250,1
Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates,"Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes. Reactions with high exothermicity or otherwise hazardous in nature, as well as reactions involving the formation of unstable intermediates, can benefit from continuous processing. This technology has been broadly adopted across the pharmaceutical industry due to its intrinsic ability to operate at low reaction volumes, facilitate improved temperature control, and safely accommodate higher pressures. Two such industrially relevant examples are aromatic nitration and regioselective aryl ring metalation, followed by trapping with an electrophile. Both reaction classes commonly face scale-up challenges when performed in batch processing. The nitration reaction usually features a multiphase, mixing-sensitive reaction associated with a large exotherm that can lead to the formation of potentially hazardous overnitrated byproducts. Similarly, metalation reactions of aryl rings often require cryogenic conditions, which are challenging to achieve on scale. In this study, a mixing-limited solid–liquid–liquid (S–L–L) nitration reaction was evaluated to understand the transport phenomena. The determination of the Hatta number and impact of the impeller power on the kinetics enabled the design of a safe, scalable, high-yielding, and robust continuous stirred tank (CSTR) flow process. A study of critical formylation reaction parameters led to a first-generation tubular flow reactor design to process >10 kg of a substrate in the pilot plant. A more practical CSTR reactor system in series was developed to support a resupply delivery. This reactor configuration enabled superior temperature control, alleviated the risks associated with salt formation, and increased the throughput and yield.",10.1021/acs.oprd.1c00249,0
Synthesis of Fingolimod Employing Regioselective Aziridine Ring-Opening Reaction as a Key Step,"An efficient and scalable synthesis of the immunomodulating drug fingolimod hydrochloride has been developed with the aziridine regioselective ring-opening reaction as a key step. This manuscript describes design, detailed synthetic route scouting, and optimization study of the aziridine ring-opening reaction. As a starting material for the polar part of the fingolimod molecule, cheap, common, and widely commercially available tris(hydroxymethyl)aminomethane was used. n -Octyl group was introduced into the molecule either via Kumada or Negishi cross-couplings, or alternatively by Sonogashira cross-coupling followed by hydrogenation. The final step consists of a one-pot acidic deprotection both of the acetonide and Boc group, providing thus highly pure fingolimod hydrochloride from the crude reaction mixture directly. The described process is highly effective, is industrially applicable, and has been successfully applied to 500 g scales of the target product.",10.1021/acs.oprd.1c00248,1
Development and Scale-Up of a Novel Photochemical C–N Oxidative Coupling,"A visible light promoted C–N-coupling of a functionalized pyridazinone with veratrole was developed to forge the central C–N bond of an agrochemical intermediate. Dosing aqueous NaOCl and 4% O 2 in N 2 under blue light irradiation (460 nm) was key to promote the desired transformation while generating benign wastes. Mechanistic studies suggest the formation of a N-chloro species that undergoes selective coupling via a radical pathway induced by the combination of light and oxygen. Further development led to an optimized semi-batch process, which was successfully scaled up to an initial 20 L and then 1.2 m 3 .",10.1021/acs.oprd.1c00244,1
"Manufacturing Process Development for Belzutifan, Part 5: A Streamlined Fluorination–Dynamic Kinetic Resolution Process",Here we report the fluorination–dynamic kinetic resolution (DKR) process for the commercial supply of belzutifan (MK-6482). Key process safety and robustness issues in the Selectfluor fluorination reaction were identified and addressed on the basis of increased mechanistic understanding. Aggressive process optimization enabled a single-pot direct isolation process that allowed delivery of the fluorodiol product with low process mass intensity.,10.1021/acs.oprd.1c00242,0
"Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination","We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical approach circumvents the need for azo radical initiators and proceeds at room temperature. Implementation of continuous flow technology allowed tight control of irradiation and residence time, resulting in a robust process with minimized byproduct formation. This method was selected for the manufacturing process for belzutifan and represents the first commercial continuous flow photochemical process in our company, laying the foundation for the utilization of photochemistry in the pharmaceutical industry.",10.1021/acs.oprd.1c00240,0
"Manufacturing Process Development for Belzutifan, Part 6: Ensuring Scalability for a Deoxyfluorination Reaction","The development of a regio- and stereoselective deoxyfluorination process for the manufacture of belzutifan (MK-6482) was challenging because of a combination of particular reaction and engineering sensitivities. These aspects were addressed through a series of mechanistic, range-finding, and mixing studies that enabled a robust process to be established. In particular, mixing studies led to the discovery of a second phase of perfluoro-1-butanesulfonyl fluoride in the reaction at cryogenic temperature, requiring the liquid–liquid dispersion to be controlled sufficiently to minimize the formation of side products. The changes implemented as a result of these investigations culminated in a process executed successfully on the pilot and commercial scales.",10.1021/acs.oprd.1c00239,0
Development of a Commercial Process for Odalasvir,"Odalasvir is a selective inhibitor of hepatitis C virus NS5A protein, a key target for combination therapies. This paper describes the chemical process development for the synthesis of this active pharmaceutical ingredient and the improvements that were achieved over the medicinal chemistry route. Optimization of all of the reaction conditions and crystallizations resulted in higher throughput and a highly improved process mass intensity. The process is robust and has been scaled up to ∼100 kg batches without issues.",10.1021/acs.oprd.1c00237,1
"Manufacturing Process Development for Belzutifan, Part 1: A Concise Synthesis of the Indanone Starting Material","A four-step synthesis of the indanone core of belzutifan (MK-6482) is described. This route starts from the commodity raw material dihydrocoumarin and was successfully demonstrated on a large scale to produce indanone 11 in the synthesis of belzutifan, an FDA-approved first-in-class therapy for the treatment of patients with certain types of Von Hippel–Lindau disease-associated tumors.",10.1021/acs.oprd.1c00236,0
"Manufacturing Process Development for Belzutifan, Part 3: Completing a Streamlined Through-Process with a Safe and Scalable Oxidation","We report the development of a modified Kornblum oxidation mediated by 2-picoline N -oxide for the synthesis of belzutifan that circumvented safety and stench problems associated with the original clinical supply route conditions. A robust quench for the crude bromination stream with 1,3-dimethoxybenzene and 2,6-lutidine enabled a single-solvent through-process that avoided the isolation of a mutagenic intermediate and resulted in a significantly lower process mass intensity. A ternary-solvent, constant-volume distillation was then used to crystallize the ketone product directly from the reaction mixture.",10.1021/acs.oprd.1c00232,0
"Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control","A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO 2 byproduct. Special effort was required to design a scale-insensitive process for the removal of CO 2 with active nitrogen headspace sweeping, supported by process modeling and verification with process analytical technology data. Automated sampling facilitated data-rich experimentation via kinetic profiling, culminating in enhanced understanding and further robustness-based optimization for the reduction reaction. Herein we report the development of a one-pot through-process with direct isolation of 3 in high yield (>90%) and purity (>99 LCAP, >99 ee) at commercial scales. The newly developed process ensures process robustness and improves cycle times and process mass intensity.",10.1021/acs.oprd.1c00231,1
"Preparative Synthesis of an <i>R</i><sub>P</sub>-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations","High Resolution Image Download MS PowerPoint Slide Cyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′- H -phosphonate monoester, which affords the desired R P -3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired S P -diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity.",10.1021/acs.oprd.1c00230,1
"Scalable Process for Making 5,7-Dichlorotetrahydroisoquinoline-6-carboxylic Acid Using Methylene as the Protecting Group","The development of an industrially scalable synthetic route for 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid ( 1 ), a key starting material for lifitegrast, is described. This route includes the following features: (1) tetrahydroisoquinoline 19 was prepared in three steps from readily commercially available 3,5-dichlorobenzoyl chloride and 2-aminoethanol in a high total yield of 76%; (2) formaldehyde instead of triphenylmethyl chloride was employed in the protection of the secondary amine, resulting in much higher atom economy; (3) the target compound 1 was produced in an overall yield of 66% with an HPLC purity of 99% by area.",10.1021/acs.oprd.1c00229,1
Scale-Up of a Continuous Manufacturing Process of Edaravone,"Edaravone belongs to a class of brain-protective agents, which can scavenge free radicals. To reduce impurities and improve the yield, a continuous flow production process of edaravone was developed. The synthesis is continuously carried out in two steps. The throughput can reach 11.328 kg/day and the purity of the final product is 99.95%, which are in accordance with the needs of production. This is an efficient and quick production process suitable for industrial production.",10.1021/acs.oprd.1c00228,0
"Homocoupling of a Grignard Reagent toward the Synthesis of 2,2′-Bis(trifluoromethyl)-4,4′-diaminobiphenyl","A new process for the synthesis of 2,2′-bis(trifluoromethyl)-4,4′-diaminobiphenyl (TFMB) comprising three steps has been industrially developed. The first step is the homocoupling of the Grignard reagent derived from 1-chloro-2-(trifluoromethyl)benzene with iron chloride(III) in the presence of an oxidizing agent to afford 2,2′-bis(trifluoromethyl)biphenyl. The second step is the nitration of this biphenyl to 2,2′-bis(trifluoromethyl)-4,4′-dinitrobiphenyl, and the third step is the reduction of this dinitrobiphenyl using hydrogen over Pd/C to afford TFMB. This process has been demonstrated on an industrial scale.",10.1021/acs.oprd.1c00227,0
Finkelstein Reaction in Non-polar Organic Solvents: A Streamlined Synthesis of Organic Iodides,The Finkelstein reaction of organic halides was found to proceed smoothly in non-polar organic solvents other than acetone when operated in the presence of a catalytic amount of tetra- n -butylammonium bromide and water. The new protocol was successfully applied to a preparation of ethyl 5-iodopentanoate from the corresponding bromide which was used directly for zinc reagent formation and Fukuyama coupling to enable the formation of the (+)-biotin side chain in a streamlined manner. Rate acceleration by microwave irradiation and an application to the synthesis of trimethylsilyl iodide will be described as well.,10.1021/acs.oprd.1c00226,0
Crystallization-Based Synthetic Route to Antimalarial Agent BRD5018: Diazocene Ring Formation via a Staudinger-aza-Wittig Reaction on an Azetidine-Ribose Template,"The development of an entirely crystallization-based synthetic route to the antimalarial BRD5018 is described, which assembles a structurally complex bicyclic azetidine scaffold adorned with five stereogenic centers without the need for any chromatographic separations. A diastereoselective glycine ester Claisen rearrangement, diastereomeric salt resolution, and diastereoselective iodo-lactonization are utilized to provide an efficient access to three contiguous stereogenic centers on an acyclic template with the desired relative and absolute configurations. A tandem aziridine ring-opening/azetidine ring-closure on the derived 2-amino-1,4-diol template was developed to efficiently establish the all- cis trisubstituted azetidine scaffold with the proper ancillary functionality for end-game maneuvers. d -Ribose-2,3-acetonide provided a conveniently differentiated vicinal syn -diol suitable for the planned reductive amination/periodate cleavage/Staudinger-aza-Wittig sequence to form the eight-membered diazocene ring. An early quantitative installation of the diaryl acetylene moiety via a Sonogashira coupling on an electronically matched methyl 4-bromocinnamate circumvented a low-yielding, late-stage reaction in the first-generation synthesis. Multiple crystalline intermediates enabled the complete removal of chromatography from the synthesis resulting in a substantially reduced cost and waste generation with enhanced throughput and quality control.",10.1021/acs.oprd.1c00225,1
Synthesis of BACE1 Inhibitors <b>E2609</b>/<b>E2071</b> via Oxime–Olefin Cycloaddition Following a Process Risk Mitigation Strategy,"Process development of E2609 from the preclinical stage to the clinical stage following a process risk mitigation strategy is described here. Key features include a turbo Grignard reaction monitored by in-situ IR, [3 + 2] cycloaddition in water, chemoselective amide coupling via in-situ protection, and a Reformatsky/decarboxylation approach to install a difluoromethyl group. Toward safe and scalable manufacture of E2071, an analog of E2609, a flow-reaction process for trifluoromethylation of aldehydes is presented here.",10.1021/acs.oprd.1c00223,1
"Toward a Practical, Nonenzymatic Process for Investigational COVID-19 Antiviral Molnupiravir from Cytidine: Supply-Centered Synthesis","A scalable four-step synthesis of molnupiravir from cytidine is described herein. The attractiveness of this approach is its fully chemical nature involving inexpensive reagents and more environmentally friendly solvents such as water, isopropanol, acetonitrile, and acetone. Isolation and purification procedures are improved in comparison to our earlier study as all intermediates can be isolated via recrystallization. The key steps in the synthesis, namely, ester formation, hydroxyamination, and deprotection were carried out on a multigram scale to afford molnupiravir in 36-41% yield with an average purity of 98 wt % by qNMR and 99 area% by HPLC.",10.1021/acs.oprd.1c00219,1
Efficient Synthesis of (<i>S</i>)-1-Boc-3-aminopiperidine in a Continuous Flow System Using ω-Transaminase-Immobilized Amino-Ethylenediamine-Modified Epoxide Supports,"We developed a continuous flow system using ω-transaminase covalently immobilized on an epoxy resin modified with ethylenediamine (EDA) to synthesize ( S )-1-Boc-3-aminopiperidine, which is a key intermediate for several novel inhibitors. A second functional group (−NH 3 + ) was introduced to rapidly adsorb ω-transaminase, which was further rigidified by multipoint covalent attachment to the modified resin with high binding efficiency (>95%) and activity recovery (75%). The resulting immobilized ω-transaminase was stable with 90% residual activity after 15 reuse cycles. We synthesized ( S )-1-Boc-3-aminopiperidine using this continuous flow system, and 95% conversion was obtained within 10 min of residence. The system was continuously operated for 24 h and achieved a space–time yield of 930.73 g·L –1 ·day –1, indicating outstanding reaction efficiency. This efficient continuous bioprocess has potential for large-scale production of ( S )-1-Boc-3-aminopiperidine.",10.1021/acs.oprd.1c00217,0
Development of a High-Throughput Kinetics Protocol and Application to an Aza-Michael Reaction,"High-throughput experimentation (HTE) has become integral to the pharmaceutical industry with most major pharmaceutical companies investing in automation and high-throughput screening technologies. Testing hundreds of reactions in parallel has distinct advantages; however, one clear disadvantage is that performing a reaction on micromolar scale is not always indicative of the reaction’s performance on multikilogram scale. Additionally, a great deal of information is lost by looking at a single time point. Valuable data around intermediates, over-reaction, catalyst induction periods, and so forth are invisible to a typical HTE workflow, which involves analyzing reactions at a single time point (e.g., 18 h). We envisioned a workflow in which time courses for each well of a high-throughput screen were collected. With this change in strategy, it could then become possible to complete high-throughput screening, select reaction conditions, gather kinetic information, and successfully build a kinetic model in less than 1 week. A kinetic model consisting of scale-independent parameters allows for virtual reaction optimization where the input concentrations, catalyst loading, and temperature can all be simulated and adjusted to understand their impact on yield or quality in a matter of seconds. A case study is presented with a transition metal salt/TMSCl-catalyzed aza-Michael reaction to showcase the performance and robustness of the high-throughput kinetic platform. A reaction progress kinetic analysis approach is utilized to quickly screen the rates of 48 catalyst/solvent combinations and create a mechanistic model. The first-principles kinetic model provides support for a proposed mechanism of dual activation by TMSCl.",10.1021/acs.oprd.1c00213,0
"Practical Kilogram Synthesis of (<i>S</i>)-1-Benzyl-4-Bromo-3-Methyl-1,2,3,6-Tetrahydropyridine","Despite chiral piperidines being a commonly found motif in approved drugs and drug candidates, the synthesis of these compounds occasionally suffers from challenges of scalability and stereochemical control. As part of a medicinal chemistry program, we sought access to a series of stereochemically pure 3,4-disubstituted piperidines. A classical ammonium salt resolution was investigated to furnish chiral ( S )-1-benzyl-4-bromo-3-methyl-1,2,3,6-tetrahydropyridine as a valuable chiral precursor to C-3,4 di-substituted piperidines, which may have broader utility for other pharmaceutical intermediates. Specifically, in this work, in support of scale-up efforts for toxicology studies, we describe a practical synthesis to access kilogram quantities of enantiopure ( S )-1-benzyl-4-bromo-3-methyl-1,2,3,6-tetrahydropyridine, utilizing a Shapiro reaction, followed by a classical salt resolution with an inexpensive chiral acid in high yield and enantioselectivity.",10.1021/acs.oprd.1c00212,0
Unconventional Synthetic Process of Fasudil Hydrochloride: Costly Homopiperazine Was Avoided,"An efficient, robust, and cost-effective synthetic process of fasudil hydrochloride 1 was developed. Starting from readily available ethylenediamine and 5-isoquinoline sulfonyl chloride, the target product 1 was prepared through a six-step reaction, including sulfonamidation, protection, nucleophilic substitution, deprotection, cyclization, and salification. The process afforded 1 in 67.1% overall yield (based on 5-isoquinoline sulfonyl chloride) with 99.94% purity. Compared to the earlier published methodologies, the use of homopiperazine or its derivatives as intermediates was avoided. The salient features of this environmentally friendly synthetic route include easily available starting materials and operational simplicity, which could be suitable for large-scale industrial production.",10.1021/acs.oprd.1c00211,1
Advancing Base-Metal Catalysis: Development of a Screening Method for Nickel-Catalyzed Suzuki–Miyaura Reactions of Pharmaceutically Relevant Heterocycles,Interest in replacing palladium catalysts with base metals resulted in the development of a 24-reaction screening platform for identifying nickel-catalyzed Suzuki–Miyaura reaction conditions. This method was designed to be directly applicable to process scale-up by employing homogeneous reaction conditions alongside stable and inexpensive nickel(II) precatalysts and has proven to be broadly suitable for complex heterocyclic substrates relevant to bioactive molecules. These advances were enabled by the key discovery that a methanol additive greatly improves the reaction performance and enables the use of organic-soluble amine bases. The screening platform and scale-up workflow were applied to a representative cross-coupling using the antipsychotic perphenazine and enabled the rapid development of a gram-scale synthesis that highlighted the utility of this method and the advantages of nickel catalysis for metal remediation.,10.1021/acs.oprd.1c00210,0
Synthesis of Enantiopure Unnatural Amino Acids by Metallaphotoredox Catalysis,"We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.",10.1021/acs.oprd.1c00208,0
Practical Gas Cylinder-Free Preparations of Important Transition Metal-Based Precatalysts Requiring Gaseous Reagents,"A simple and safe setup for the synthesis of a selection of important transition metal-based precatalysts is reported, all requiring low-molecular weight gaseous reagents for their preparation. Hydrogen, carbon monoxide, ethylene, and acetylene are each liberated in a controlled manner from a corresponding easy-to-handle precursor in a closed two-chamber reactor. Gas cylinders and elaborate setups/techniques connected to handling toxic and/or flammable gases as reported in the literature can thus be avoided. The corresponding precatalysts are of high relevance in the active research fields of C–H bond activation, dehydrogenation, hydrogenation, and coupling reactions. The selection of complexes shown is meant to serve as examples for the usefulness and broadness of the presented methods, allowing precatalysts requiring gaseous reagents to become available for the research community.",10.1021/acs.oprd.1c00205,0
"Accelerated Development of a Scalable Synthesis of CY6463, a CNS-Penetrant sGC Stimulator for the Treatment of Neurodegenerative Diseases","High Resolution Image Download MS PowerPoint Slide Soluble guanylate cyclase (sGC) stimulators are small molecules that increase nitric oxide (NO) signaling by binding to sGC, leading to an increase in cyclic guanosine monophosphate production. Such compounds have previously been studied clinically for noncentral nervous system (CNS) disorders. CY6463 is the first CNS-penetrant sGC stimulator to enter clinical trials and has the potential to positively impact a range of neurodegenerative diseases. In this paper, we present the development of an efficient, robust, and scalable synthesis of this compound that allowed for rapid generation of larger quantities of material, thereby accelerating advancement into early clinical studies, while minimizing the use of resources. The synthesis features a palladium-catalyzed one-pot Negishi coupling/cyanation sequence and a novel triazole formation from a Boc-protected amidrazone. Optimization of the reactions, safety considerations, and control of impurities, as well as a mechanistic study of the triazole formation reaction, are discussed.",10.1021/acs.oprd.1c00204,1
Hydrogen Evolution from Telescoped Miyaura Borylation and Suzuki Couplings Utilizing Diboron Reagents: Process Safety and Hazard Considerations,"The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis(pinacolato)diboron (BisPin), used in the developmental synthesis of an intermediate for abemaciclib, led to the observation of hydrogen being generated. Quantitative headspace GC and solution 11 B NMR were used to show that the rapid decomposition of the excess BisPin from the borylation under the aqueous basic conditions of the Suzuki reaction was responsible for H 2 generation. The moles of H 2 observed were found equal to the BisPin excess, which is rationalized by mass balance and a stoichiometric reaction. The possible generation of the stoichiometric levels of H 2 should be considered in hazard assessments of this class of reaction. Kinetic and process modeling was used to minimize the risk upon scale-up, and results for commercial manufacturing batches are presented, which showed good agreement with the lab scale data. Furthermore, the hydrogen evolution potentials of other common borylating agents including bisboronic acid (BBA) and pinacol borane were demonstrated.",10.1021/acs.oprd.1c00198,0
Practical Synthesis of (+)-Biotin Key Intermediate by Calcium Borohydride Reduction and Temperature-Dependent Purity Upgrade during Crystallization,An expedient synthesis of a key intermediate for (+)-biotin has been accomplished through high-yielding reduction of chiral imide with calcium borohydride and efficient isolation of the desired isomer by crystallization at a specific temperature where only undesired isomer was converted to soluble anhydrate while the desired isomer kept unchanged as a less soluble monohydrate.,10.1021/acs.oprd.1c00196,1
Investigating the Activation Kinetics of Phosphoramidites for Oligonucleotide Synthesis,"Solid-phase synthesis of oligonucleotides relies on a repeating cycle of rapid and well-defined synthetic steps to generate the target sequence. It is recognized that the underlying skeleton of the nucleotide influences the rates of the coupling reactions when the phosphoramidite coupling method is used. Using both in-line mid-IR spectroscopy and rapid NMR spectroscopy, we studied the rates of activation of traditional deoxyribonucleoside phosphoramidites and their chemically modified constrained ethyl (cEt) ribose locked nucleic acid analogues. This article reports our findings, which demonstrate a striking difference in the kinetics of activation for the two nucleotide structures. It was found that the cEt phosphoramidites required a larger excess of activator to achieve complete activation compared with their deoxyribonucleoside analogues. However, even with double the relative activator charge, the observed rate was over 10 times lower.",10.1021/acs.oprd.1c00195,0
Early Development and Kilogram Scale-Up of a Non-steroidal FXR Agonist for the Treatment of Non-alcoholic Steatohepatitis (NASH),"Non-alcoholic steatohepatitis (NASH) is a serious chronic liver disease characterized by progressive fibrosis that can lead to cirrhosis, liver failure, and death. Compound 1 is a farnesoid X receptor (FXR) agonist that was investigated for use as a treatment for NASH. This paper describes process development efforts enabling the first multikilogram scale-up.",10.1021/acs.oprd.1c00193,1
Development of a Scalable Lanthanide Halide/Quaternary Ammonium Salt System for the Nucleophilic Addition of Grignard Reagents to Carbonyl Groups and Application to the Synthesis of a Remdesivir Intermediate,"This manuscript describes the development and implementation of a scalable additive system, consisting of a lanthanide salt and a solubilizing quaternary ammonium salt, to improve the yield and robustness of the addition of an organomagnesium reagent to a ribonolactone en route to remdesivir. This system was found to be generally applicable in enhancing other challenging organomagnesium additions to enolizable and hindered carbonyl-containing compounds.",10.1021/acs.oprd.1c00191,0
"Efficient Biocatalytic Synthesis of (<i>R</i>)-2-Chloro-1-(3,4-difluorophenyl)ethanol by the Short-Chain Dehydrogenase <i>Pp</i>KR8 from <i>Paraburkholderia phymatum</i> STM815","Bioreductions catalyzed by ketoreductases play an important role in the synthesis of chiral alcohols. However, the synthesis of ( R )-2-chloro-1-(3,4-difluorophenyl)ethanol (24b), an important chiral intermediate for the synthesis of the anticoagulant ticagrelor, poses significant challenges in terms of high substrate concentration requirements that limit its production. In this study, a novel NADH-dependent, short-chain dehydrogenase, Pp KR8, from Paraburkholderia phymatum STM815, exhibited excellent enantioselectivity and high activity for the production of ( R )-CFPL (24b) through the reduction of 2-chloro-1-(3,4-difluorophenyl)ethanone (24a). The coexpression of Pp KR8 and glucose dehydrogenase from Bacillus subtilis in Escherichia coli allowed up to 300 g/L (1.57 M) CFPO (24a) to be completely converted into 24b with 99.9% enantiomeric excess and a high space–time yield (728 g/(L day)). Substrate specificity assays demonstrated a broad substrate spectrum for Pp KR8, which included 35 α/β-ketoesters, aromatic ketones, and heterocyclic ketones. Moreover, three additional optically pure chiral alcohols that are used as important drug intermediates were synthesized at high substrate concentrations (150–330 g/L), demonstrating the excellent industrial potential of Pp KR8-mediated bioreductions.",10.1021/acs.oprd.1c00189,0
Daisy-Chaining Photo- and Thermal Chemistry: Multistep Continuous Flow Synthesis of Visible-Light-Mediated Photochemistry with a High-Temperature Cascade Reaction,"A highly efficient visible-light-mediated photochemical [2 + 2] cycloaddition is coupled with an atom economic thermal cascade reaction in a continuous flow process. By moving the photochemistry from ultraviolet (UV) to visible, it is made more energy-efficient and can be conducted with readily available equipment. The application of high-temperature flow chemistry to the thermal cascade step allows for safe and reliable scale-up with short reaction times. Thus, we demonstrate a rare example of a photo/thermal daisy-chained process and, specifically, the first visible-light-mediated excited state to the thermal cascade reaction as a fully continuous process (20 g/h). The synthetic utility of flow chemistry is further showcased by the isolation of a reactive intermediate at quantities not possible under batch conditions.",10.1021/acs.oprd.1c00187,0
Discovery and Development of an Unusual Organocatalyst for the Conversion of Thymidine to Furanoid Glycal,"Our work required a reliable efficient preparation of 2-trimethylsilyloxymethyl((2 R,3 S )-3-(trimethylsilyloxy)-2,3-dihydrofuran (glycal 1 ). The best literature protocol for the preparation of this dihydrofuran glycal is the treatment of thymidine with 20 mol % (NH 4 ) 2 SO 4 in (TMS) 2 NH (HMDS) at reflux. Unfortunately, this procedure was found to be extremely unreliable and messy on scale-up. The need for removal of ammonia formed during reactions using HMDS was identified as critical to the success of these reactions. A high throughput screening prototype setup enabling release of the gaseous ammonia byproduct was developed, allowing rapid screening of reaction conditions. Extensive high throughput screening initially identified 1 mol % (PhSO 2 ) 2 NH ( DBSI ) in heptane at reflux gave more reliable and improved results. Despite this, this improvement still suffered from disadvantages such as the formation of a bisglycosylated byproduct, the need for a wiped film distillation to isolate the glycal, and the need to expel the formed NH 3 gas from the reaction mixture. Further screening revealed an unprecedented catalyst 1 mol % (Ph 2 PS) 2 NH ( PTPI ) with bistrimethylsilylacetamide (BSA) in heptane–toluene at 100 °C gave rapid and virtually quantitative conversion to the glycal. Throughout, process analytical technology (PAT) was extensively employed to improve process understanding and inform development from bench scale through over 3 orders of magnitude scale-up.",10.1021/acs.oprd.1c00186,0
A Holistic Strategy for Cyanide Control and Safety for Pharmaceutical Manufacturing,"The manufacturing route toward gefapixant citrate generates a trace amount of cyanide as a byproduct of a reaction employing the reagent chloroacetonitrile. In the development of a cyanide control strategy, conventional process and analytical approaches fell short because of challenges and incompatibilities with the matrices of the process and waste streams. To overcome these, we identified and adapted specific procedures for cyanide control. Our strategy ensured safety for patients, operators, and waste management.",10.1021/acs.oprd.1c00185,1
Facile and Cost-Effective Route for the Synthesis of Simmerafil,"An improved synthesis of simmerafil, a potent PDE5 inhibitor as a clinical candidate, is described with a 38.1% overall yield and 99.7% purity. Starting from the safe and inexpensive salicylamide ( 15 ), the key intermediate 2-propoxybenzimidamide ( 21 ), which is also a potential precursor for the preparation of pyrimidinone derivatives, was effectively and conveniently obtained. The subsequent process from 21 to simmerafil was optimized, which makes it more amenable to scale-up.",10.1021/acs.oprd.1c00184,1
Kilogram-Scale Synthesis of 2′-<i>C</i>-Methyl-<i>arabino</i>-Uridine from Uridine via Dynamic Selective Dipivaloylation,"We report a practical 3′,5′-diprotection strategy suitable for the kilogram-scale preparation of 2′- C -methyl- arabino -uridine, a key intermediate in the synthesis of the HCV NS5B inhibitor uprifosbuvir. Starting from uridine, dipivaloylation afforded an ∼2:1 mixture of 3′,5′- and 2′,5′-dipivaloyluridine. Subjecting this mixture to TEMPO/bleach oxidation promoted a dynamic acylation migration–selective oxidation to afford the 2′-ketone in 65% yield. Alternatively, treatment with 1 equiv of BF 3 etherate led to the crystallization-driven equilibration and precipitation of 3′,5′-dipivaloyluridine·BF 3 complex in a >50:1 ratio. After salt break, this mixture was oxidized in the presence of TEMPO/AcOOH to afford the 2′-ketone in 90% yield. Subsequent α-facial-selective methylation with MeMgBr/MnCl 2 afforded 3′,5′-dipivaloylated 2′- C -methyl- arabino -uridine 12 . This three-step process was successfully demonstrated on a multikilogram scale to afford the key intermediate for the manufacture of uprifosbuvir.",10.1021/acs.oprd.1c00175,1
Experiment and Simulations for the Thermal Safety of the Nitration Reaction Liquid of the Final State in the Synthesis Process of <i>N</i>-Nitrodihydroxyethyl Dinitrate (DINA),"In the synthesis process of N -nitrodihydroxyethyl dinitrate (DINA) with the HNO 3 –Mg(NO 3 ) 2 method, the thermal stability of the nitration reaction liquid of the final state is poor, which leads to the thermal runaway of the entire reaction system easily. The research on the thermal runaway reaction under actual reaction conditions indicates high consumption and high risk. In this article, thermal decomposition behavior and isothermal thermal decomposition kinetics of the nitration reaction liquid of the final state in the synthesis process of DINA were investigated by differential scanning calorimetry (DSC) and microcalorimetry. The mechanism of the stability of the nitration reaction liquid was explored. The thermal safety of the material in a large-scale reactor was simulated and predicted by a thermal simulation software on the basis of kinetic parameters including activation energy, pre-exponential factors, and mechanistic functions. These findings not only avoid the risk and consumption of large-size materials but also guide their application in process optimization, inherent safety design, and handling.",10.1021/acs.oprd.1c00172,0
Large-Scale Cyclopropanation of Butyl Acrylate with Difluorocarbene and Classical Resolution of a Key Fluorinated Building Block,"To address challenges in the preparation of a key building block containing a difluorocyclopropane moiety, we have developed a new protocol for difluorocarbene generation that relies on a Krapcho-type dealkylation of ethyl bromodifluoroacetate (EBDFA), an inexpensive and readily available fluorinated feedstock. Application of DoE and kinetic modeling was used to understand key reaction parameters and identify an optimal process. We report two variants of this procedure that offer different processing advantages and that have both been scaled successfully multiple times to deliver hundreds of kilograms of the resulting difluorocyclopropane. To access a single enantiomer of the target compound, we have also developed a classical resolution strategy and recycling protocol for the undesired enantiomer to replace previous chromatographic methods for separation.",10.1021/acs.oprd.1c00171,0
Nitrosamine Reactivity: A Survey of Reactions and Purge Processes,"Drug recalls have led to increased regulatory scrutiny into the formation and presence of nitrosamine ( N -nitrosoamine) impurities in medicines. This review aims to assist the development of risk mitigation strategies by summarizing known reactions of nitrosamines, with a focus on reactions useful within the context of complex molecule synthesis. This review should serve as a useful reference and help lead to the development of chemical processes which effectively control nitrosamines.",10.1021/acs.oprd.1c00162,0
From Screening to Scale-Up: The DoE-Based Optimization of Electrochemical Reduction of <scp>l</scp>-Cystine at Metal Cathodes,"Design of experiment (DoE) is a powerful statistical tool in establishing improved chemical processes. An optimization and scale-up of the electrochemical reduction of l -cystine to l -cysteine is presented. Subsequent to an electrode screening of 17 metals and alloys in divided batch-type cells, the lead electrode was selected for a systematic optimization in flow cells with a geometric cathodic surface area ranging from 10 to 100 cm 2 . Using two consecutive factorial designs, parameters like substrate concentration, current density, electrode gap, amount of applied charge, and number of cell passages were screened for significant effects onto the l -cystine conversion. A multiresponse optimization combining the product conversion and Faradaic efficiency was performed to account for economic considerations.",10.1021/acs.oprd.1c00153,0
"DMF-Assisted Iodination Side Reaction during the Preparation of Disulfide Peptides, Its Substrate/Solvent/pH Dependence, and Implications on Disulfide-Peptide Production","Severe iodination of a disulfide peptide molecule (peptide D) was detected from the on-resin disulfide cyclization process. LC/MS/MS results indicated that iodination occurred on the Thi (thienylalanine) residue. Systematic investigation revealed that the iodination reaction occurred predominantly in the I 2 /DMF-mediated on-resin disulfide formation reaction. The iodination side reaction was strongly solvent-dependent and favored in DMF and NMP. A tentative mechanism similar to that of the Vilsmeier–Haack reaction was proposed. A variety of amino acid/peptide substrates were tested as iodination substrates. The results indicated the susceptibility of amino acids with electron-rich aromatic groups to iodination. Additionally, various solutions were proposed for preventing peptide iodination based on the findings in this study. This study demonstrates the applicability of the on-resin disulfide production of peptides bearing electron-rich aromatic residues.",10.1021/acs.oprd.1c00151,0
"Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator","Adenosine 5′-monophosphate-activated protein kinase (AMPK) activator YLF466D is a promising preclinical drug candidate to treat metabolic diseases and myocardial ischemia-reperfusion injury (MIRI). Herein, we report our efforts on optimization and development of a practical and scalable process for the preparation of YLF466D in kilogram scale. The process features a palladium-catalyzed C–H activation under mild reaction conditions, geometry selectivity, effective impurities purging, and low levels of residual solvents in the final active pharmaceutical ingredient (API). We applied this process successfully to prepare more than 17 kg (3.0–3.6 kg per batch) of YLF466D to support its preclinical study.",10.1021/acs.oprd.1c00150,0
Development of a Practical Manufacturing Process to Relebactam via Thorough Understanding of the Origin and Control of Oligomeric Impurities,"The development of a robust manufacturing process to relebactam, a potent β-lactamase inhibitor, is described. The origin and control strategy of oligomer impurities formed during hydrogenolysis of benzyl urea intermediate 9 and deprotection of Boc-sulfate intermediate 11 have been thoroughly studied and developed. The optimal manufacturing process has been successfully implemented for commercialization, preparing relebactam ( 1 ) in >99% purity with a non-detectable level of oligomers.",10.1021/acs.oprd.1c00149,1
Application of a Statistical Approach to Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 3: Development of Design Space for Control of Particle Size Distribution,"This study constructs a control strategy with a design space of the particle size distribution for futibatinib using a design of experiment and statistical approach without an additional milling process to save resources for validating consistency and equivalence. First, an L 12 orthogonal experiment of the Plackett–Burman type is designed to identify the risk of whether 11 potential critical process parameters in the recrystallization process are in fact critical process parameters. Next, the effect of particle size distribution is confirmed by changing the levels of the process parameters of agitated drying in the two-trial manufacturing; we find that the agitated drying time is a critical process parameter. Then, we prove that there is little out-of-specification risk of the particle size distribution considering manufacturing error and analytical error using the Monte Carlo approach. Finally, this study confirms the reimplementation of failure mode and effect analysis as risk evaluation improves the understanding of the manufacturing process and reduces the particle size distribution risk of futibatinib by clarifying the process. Based on the quality-by-design concept, we construct a design space and control strategy for the particle size distribution, focusing on experimental design and statistical analysis. This study clarifies that the agitated drying process affects the particle size more than other parameters do. By examining the overall process, this study demonstrates that particle size can be controlled sufficiently without the milling process. It proves that the commercial manufacturing method is a robust process, and futibatinib can be stably produced.",10.1021/acs.oprd.1c00147,0
Application of a Statistical Approach to the Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 2: Development of Design Space for Impurities Using the Response Surface Methodology,"This study aims to construct a design space of impurities for risk assessment based on the quality-by-design concept through focusing on the design of experiment and statistical analysis. First, we identify multiple regression equations for critical process parameters of impurities using face-centered composite design, which is a type of response surface methodology. Next, a design space is constructed by these prediction models for analyzing the risk of the impurities. Finally, this risk is evaluated by process understanding and control ranges in the construction of a control strategy. This study proves that the commercial manufacturing method is a robust process and futibatinib can be stably produced.",10.1021/acs.oprd.1c00146,0
Application of a Statistical Approach to Process Development of Futibatinib by Employing Quality-by-Design Principles. Part 1: Identification of Critical Process Parameters for Impurities,"We focus on a novel experimental design and statistical analysis to identify the critical process parameters (CPPs) of impurities in futibatinib, which is a fibroblast growth factor receptor inhibitor. First, using failure mode and effects analysis, we identify 11 potential CPPs as the process parameters to be investigated. Next, an L 12 orthogonal experiment of the Plackett–Burman type is designed for risk analysis to check whether the 11 potential CPPs are in fact CPPs. Finally, for each impurity, analysis of variance, regression analysis, and regression diagnosis are carried out, enabling the CPPs to be analyzed correctly. Based on the quality-by-design concept, we identify three impurities that impact the impurity profile of the active pharmaceutical ingredient and five CPPs of the impurities, focusing on design of experiment and statistical analysis. We also clarify the process parameters to be examined in more detail for commercial production.",10.1021/acs.oprd.1c00145,0
High-Flux Continuous-Flow Synthesis of C.I. Pigment Yellow 12 from Clear Alkaline Solutions of the Coupling Component,"In this study, a continuous-flow azo-coupling reaction for the synthesis of C.I. Pigment Yellow 12 (PY12), a common commercial azo pigment, was developed using an impinging mixer at high fluxes. The coupling component was pumped into the mixer as a clear alkaline aqueous solution to overcome the blocking issue from unexpected big particles during a long-time running. It was revealed that the local pH at the azo-coupling reaction center could be precisely regulated with negligible variation over time by the addition of sodium acetate. Fast heat transfer resulted in no accumulation of heat in the mixer together with the following delay loop reactor. The acetoacetaniline solution temperature, reactant flux, and post-treatment temperature were optimized. The flux can reach 40 L/h. PY12 with a hue similar to that of commercial batch products could be achieved with a yield above 98%. Furthermore, the PY12 samples exhibited transparency and tinting strength higher than those of the commercial batch products. In comparison with the batch process, the continuous-flow process presented in this work displays advantages of decreased energy consumption, a reduced amount of wastewater, as well as chemical oxygen demand of wastewater, showing great potential for industrial production.",10.1021/acs.oprd.1c00144,0
"Development of a Stereoselective and Scalable Synthesis for the Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor, BMT-297376; <i>N</i>-((<i>R</i>)-1-((<i>cis</i>)-4-(3-(Difluoromethyl)-2-methoxypyridin-4-yl)cyclohexyl)propyl)-6-methoxynicotinamide","The current work describes a stereoselective and scalable route to N -(( R )-1-(( cis )-4-(3-(difluoromethyl)-2-methoxypyridin-4-yl)cyclohexyl)propyl)-6-methoxynicotinamide ( 1 ) from readily available 1,4-dioxaspiro[4.5]decan-8-one. The developed process encompasses an efficient 1,4-trans-selective synthesis of ( trans )-4-(3-(difluoromethyl)-2-methoxypyridin-4-yl)cyclohexyl methanesulfonate as the key intermediate and the use of Ellman sulfinamine methodology to install an alkyl amine in a stereoselective manner. Various synthetic routes were screened to accomplish a stereoselective and scalable protocol to access the title compound ( 1 ). This advancement enabled a competent route to the title compound in an enantioselective, safe, cost-effective, and scalable manner.",10.1021/acs.oprd.1c00142,1
Efficient Synthesis of a Key Intermediate for Baloxavir Marboxil from a Greener Starting Material: Ethylene Glycol,"In this article, a robust and scalable process to prepare the key intermediate 7-(benzyloxy)-3,4,12,12a-tetrahydro-1 H -[1,4]oxazino[3,4- c ]pyrido[2,1- f ][1,2,4]triazine-6,8-dione ( 1 ) for the synthesis of the influenza antiviral drug baloxavir marboxil is described. The process is based on a novel preparation of 2-(2,2-dimethoxyethoxy)ethanamine 5 employing inexpensive and readily available ethylene glycol as the starting material with more convenient manipulation and fewer environmental hazards compared with the original routes starting with ethanolamine or its derivatives. Large-scale applicability of this new route has been successfully demonstrated on kilogram-scale production to afford 700 grams of 1 with 99.3% purity in 31% yield over six steps. With such satisfactory quality, baloxavir marboxil is eventually furnished with excellent purity (>99.5%, single impurity < 0.1%). Meanwhile, the corresponding impurity profile is studied in detail.",10.1021/acs.oprd.1c00141,1
Six-Step Gram-Scale Synthesis of the Human Immunodeficiency Virus Integrase Inhibitor Dolutegravir Sodium,"A short and practical synthesis for preparing the active pharmaceutical ingredient dolutegravir sodium was developed. The convergent strategy starts from ( R )-3-amino-1-butanol and establishes the BC ring system in a 76% isolated yield over four steps. Ring A was constructed by a one-pot 1,4-addition to diethyl-(2 E / Z )-2-(ethoxymethylidene)-3-oxobutandioate and subsequent MgBr 2 ·OEt 2 -mediated regioselective cyclization. Amide formation with 2,4-difluorobenzylamine was either performed from the free carboxylic acid or through aminolysis of the corresponding ethyl ester. Final salt formation afforded dolutegravir sodium in a 48–51% isolated yield (HPLC purity of 99.7–99.9%) over six linear steps.",10.1021/acs.oprd.1c00139,1
<i>In Situ</i> Imaging Combined with Deep Learning for Crystallization Process Monitoring: Application to Cephalexin Production,"The online detection of a trace amount of an undesired solid phase within a crystal slurry can enable feedback control to improve product purity, decrease batch rejection, and increase process performance. Systems involving the production of one crystalline solid while suppressing the nucleation of a second solid are common, with applications to polymorphs, hydrates/solvates, chiral resolution, and byproducts. Several process analytical technologies (PATs) have already been established for system-specific detection of an undesired solid phase; this study adds to that PAT suite an image-based technique with greater generality and sensitivity than common tools such as Raman spectroscopy and focused beam reflectance measurement. In situ microscope images are analyzed with a convolutional neural network (CNN) to extract image features and classify cropped regions obtained by a sliding window as containing a single particle type or multiple particle types. As an experimental case study, the performance of the technique is evaluated using a system involving contamination of reactive crystallization of cephalexin with phenylglycine, the sparingly soluble byproduct in the enzymatic synthesis of cephalexin. A CNN, ResNet, was retrained for the classification task at hand and showed >98% accuracy on the test data, highlighting the distinct features of different crystal classes used as the basis of process monitoring.",10.1021/acs.oprd.1c00136,0
Continuous Synthesis and Separation of <i>p</i>-Bromobenzyl Bromide Using Atom-Efficient Bromination of <i>p</i>-Bromotoluene without Any Organic Effluent: Potential for Green Industrial Practice,"This work focuses on the bromination of p -bromotoluene (PBT) using different brominating agents such as liquid Br 2, NaBr–NaBrO 3, NaBr–NaBrO 3 –NaCl, NaBr–H 2 O 2, and HBr–H 2 O 2 . NaBr–NaBrO 3 –NaCl is an eco-friendly brominating agent obtained from a bromine recovery plant. Both NaBr–NaBrO 3 and NaBr–NaBrO 3 –NaCl were found to be nonhazardous and efficient brominating agents. Pure NaBr–NaBrO 3 resulted in the best PBT conversion with 79.7% Br atom efficiency in water and 98.2% average Br atom efficiency using dichloroethane as a solvent. Dichloroethane is de facto no longer used in the US and Europe and is not eco-friendly; the process with water as a solvent is the best. The substrate to active bromine molar ratio of 3:1 was found to be sufficient to get the maximum selectivity of p- bromobenzyl bromide (PBBB). The low-temperature crystallization method was used for separation cum purification of the product. Unreacted PBT was recycled along with the dibromo byproduct obtained. The dibromo product, which was built up gradually in the reaction mixture over 10 successive batches, was converted back into PBBB/PBT through NaBH 4 treatment of the mother liquor. This continuous process is highly sustainable and produces zero organic waste, making it potentially attractive toward green industrial implementation.",10.1021/acs.oprd.1c00135,0
Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction,"A large-scale asymmetric synthesis has been developed for the kilo-lab manufacture of AZD8186. The process initially employs a regioselective Heck coupling in water to provide the starting aromatic ketone. This ketone is reduced asymmetrically under ruthenium-catalyzed transfer hydrogenation conditions to provide a chiral alcohol in high enantiomeric purity. The key synthetic step then requires the reaction of this chiral alcohol with the activated derivative of 3,5-difluoroaniline under the Mitsunobu reaction conditions. The common issues associated with the use of the Mitsunobu reaction, such as removal of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate (DIAD) by-products, have been eliminated through crystallization of the relevant intermediates.",10.1021/acs.oprd.1c00133,1
Development of a Recycling Process for an Industrial-Scale Production of Tipifarnib,"Current production of tipifarnib involves a late-stage chiral resolution where the mother liquor containing ∼2/3 of the product is disposed of as waste. As part of an effort to develop an efficient recycling process, a NaNO 2 -mediated racemization was initially devised and successfully implemented at kilogram scale. However, formation of a new hard-to-purge impurity and concerns about potential N -nitrosamine contamination prompted exploration of a NaNO 2 -free process. Additional experimentation with acidic conditions at elevated temperatures afforded a highly efficient, robust recycling process that was seamlessly incorporated into the original process. The resulting production output of tipifarnib increased over 60%, and waste disposal was dramatically decreased.",10.1021/acs.oprd.1c00132,1
Hazard Evaluation and Safety Considerations for Scale-Up of a Fuming Nitric Acid Mediated Nitration of Aryl Boronic Acids,"Our laboratory has recently reported the highly efficient and chemoselective ipso nitration of aryl boronic acids using fuming nitric acid as the nitrating agent. Herein, we disclose and discuss the hazards associated with this reaction and the safety considerations that must be accounted for when increasing the scale of this process. Reaction Calorimetry was used to accurately determine reaction progress and revealed that careful, substrate-dependent selection of an appropriate reaction and reagent concentration and accurate titration of HNO 3 are required to allow for safe and scalable use of this nitration process.",10.1021/acs.oprd.1c00131,0
Catalyst-Free and Scalable Process for Synthesis of Novel MAP4K4 Inhibitor DMX-5804 and Its Glyco-Conjugates,"DMX-5804 is a potent and selective mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) inhibitor, which is currently under evaluation for the treatment of myocardial infarction. Here, we report the process development of scalable and practical synthesis of DMX-5804. Process optimization resulted in the following: (1) removal of transition metals from the process and reduced duration of reactions, (2) a streamlined process with significantly improved yields using low-cost raw materials, (3) importantly, microwave-assisted reactions were removed, (4) column purification avoided throughout the process, and (5) crystallized products showed over 95% purity in each step.",10.1021/acs.oprd.1c00130,1
Development of a Safe Continuous Process to Sodium Nitrotetrazolate via Solid Phase “Catch and Release”,"Sodium nitrotetrazolate (NaNT) is a key intermediate to copper(I) nitrotetrazolate (DBX-1), a material of interest as a replacement for lead based primary explosives. Historical syntheses of NaNT were plagued with safety issues that prevented the large-scale manufacturing of NaNT. In this article, we detail the development of a safe process to generate NaNT in a continuous flow reactor via solid phase “catch and release”; a process that also reduces the formation of the most detrimental impurities that inhibit the synthesis of DBX-1. Furthermore, we discuss the demonstration of this process in 100 and 1000 mL continuous stirred tank reactors (CSTRs) and implications of scale-up of this process for robust production of NaNT at the manufacturing scale.",10.1021/acs.oprd.1c00129,0
Harnessing the Power of Catalysis for the Synthesis of CRTH2 Antagonist MK-1029,"The synthetic strategy utilized to prepare clinical supplies of CRTH2 antagonist MK-1029 is described. Specifically, the approach communicated is predicated on the intervention of five distinct catalytic methods, using three separate metals and an enzyme, to enable successful construction of this complex active pharmaceutical ingredient.",10.1021/acs.oprd.1c00128,1
Application of Continuous Flow in Tazobactam Synthesis,"Tazobactam is a β-lactamase inhibitor. In this work, a combination of continuous flow and batch experiments for the synthesis of tazobactam has been developed. The first three steps and the preparation of the peroxyacetic acid are continuously carried out in the microreactors, which improves the procedure safety and efficiency. There is also a final step of the deprotection reaction in the microreactor, which can increase the yield and reduce the formation of impurities. Under optimized process conditions, the total yield of the target product reached 37.09% (30.93% in batch). The continuous flow method not only greatly reduces the reaction time but also significantly improves procedure safety and increases the yield.",10.1021/acs.oprd.1c00127,1
Process Development of a Second Generation β-Amyloid-Cleaving Enzyme Inhibitor—Improving the Robustness of a Halogen-Metal Exchange Using Continuous Stirred-Tank Reactors,"Process development for the synthesis of a second generation β-amyloid-cleaving enzyme (BACE1) inhibitor ( 1 ) is described. The lithiothiazole addition to the isoxazolene ( 5 ) under batch conditions was not scalable because of reaction gelling and anion instability. A continuous stirred-tank reactor flow process was developed and successfully executed on the 70 kg scale in multiple runs. In a head-to-head comparison between the continuous and batch processes, the former was clearly superior as it gave a higher yield (80 vs 63%) of the adduct ( 4 ) and better reaction control for handling the unstable lithiothiazole as a reaction intermediate. Subsequently, 4 underwent Pd-catalyzed amination with t -butyl carbamate, reductive cleavage of the N–O bond, thioamidine cyclization, and deprotection of the Boc group to provide hydropyranothiazine 2 . The synthesis of 1 was completed by amidation with 5-(difluoromethoxy)picolinic acid and the successive deprotection of the benzamide group with either Silicycle-diamine or l -lysine.",10.1021/acs.oprd.1c00126,1
"Development of a Scalable Synthetic Route to BMS-986251, Part 2: Synthesis of the Tricyclic Core and the API","BMS-986251, a potent and efficacious RORγt inverse agonist, was synthesized starting from 6-iodotetralone using 13 chemical transformations with only eight isolated intermediates. The synthesis involved a four-step telescoped diastereoselective aza-Michael reaction-annulation sequence followed by installation of the heptafluoro- iso -propyl side chain and final amidation to furnish the desired API.",10.1021/acs.oprd.1c00125,0
Development of a Scalable Synthetic Route to BMS-986251. Part 1: Synthesis of the Cyclohexane Dicarboxylate Fragment,"The cyclohexane dicarboxylate unit of BMS-986251 ( 1 ), a potent and efficacious RORγt inverse agonist, was synthesized starting from Hagemann’s ester in seven chemical transformations with five isolated intermediates. The synthesis involved an enzymatic kinetic resolution, a two-step telescoped enol tosylation followed by carboxylation using a benign CO surrogate for the installation of the second carboxylate functionality, and a Crabtree catalyst-mediated diastereoselective olefin hydrogenation. This process was successfully demonstrated to produce 3.6 kg of compound 3 .",10.1021/acs.oprd.1c00124,1
Leveraging AQbD Principles for Development of Challenging Drug Substance Stability-Indicating Methods,"Drug substance stability-indicating methods (SIMs) must undergo a litany of optimization and robustness stresses to ensure that the methods can be successfully validated, transferred, and routinely executed within a variety of different laboratories. These studies typically expose limitations with the methods that require flexibility and strategic development to address. Incorporation of an analytical quality by design (AQbD) strategy leverages risk assessments and a thorough evaluation of critical method parameters to achieve the desired goal—a method that delivers robust, high-quality data. Herein, we describe the development, challenges, and solutions implemented for a pair of pharmaceutical drug substance liquid chromatography SIMs. In this case study, the analytical target profile was defined, followed by an iterative approach to method development, which consisted of automated stationary phase and mobile phase screenings, followed by software-based optimization and robustness evaluations. Aspects of the collective tracked components (e.g., low UV-response, poor solute retention, and amine-rich compounds) presented several challenges for this case study, but were addressed through nontraditional method conditions, such as divided primary and supplemental methods and carefully controlled concentration of a chaotropic mobile phase modifier. Due to timeline constraints, impurities designated as critical were refined in parallel with analytical method development. New information from a forced degradation study (i.e., coelution of an oxidative degradant with the active pharmaceutical ingredient) triggered a method redesign, which was rapidly achieved by leveraging the knowledge gained during earlier method development. The optimized methods were then tested empirically through validation-level chromatographic robustness experiments and critical method parameters were identified. Altogether, this workflow enabled thorough characterization of many possible conditions so robust, validatable, and easily transferrable methods could be generated to support long-term stability studies and commercial manufacturing.",10.1021/acs.oprd.1c00121,0
Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form,"We describe a series of improvements to the synthesis of a 3,8-diazabicyclo[3.2.1]octane derivative that result in a reduced step count and higher overall efficiency compared to previously published syntheses. Our method includes optimization and mechanistic understanding of a key diastereoselective cyclization to achieve a >95:5 diastereomeric ratio, as well as demonstration of a unique enzyme-catalyzed amidation reaction using hexamethyldisilazane as both an ammonia source and scavenger. Finally, we identify a novel cocrystal solid form of the target compound that provides improved purity and material properties. Demonstration of the new chemistry to prepare >100 kg of the target compound serves to illustrate the robustness of the new process.",10.1021/acs.oprd.1c00120,1
On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin,"The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with necessary process changes identified and implemented before scaling for longer runs. These changes included implementing a continuous liquid–liquid extraction (CLLE) step and eliminating and replacing the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) initially used in the ring-closure step due to DBU plausibly forming a decomposition side product that negatively impacted the final product purity. Process conditions were scaled 1.5–2-fold in order to enable the ultimate project goal of producing enough crude ciprofloxacin within 24 h to manufacture 1000 250 mg tablets. Working toward this goal, several production-scale runs were carried out to assess the reproducibility and robustness of the finalized process conditions, with the first three steps being run continuously up to 22 h and the last two steps being run continuously up to 10 h. The end result is a process with a throughput of ∼29 g/h (∼700 g/24 h) with a crude product stream profile of 94 ± 2% and 34 ± 3 mg/mL after five chemical transformations across four reactors and one continuous CLLE unit operation with each intermediate step maintaining a purity >95% by HPLC.",10.1021/acs.oprd.1c00118,1
On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Implementation and <i>In Situ</i> Control of Downstream Production,"Traditional pharmaceutical manufacturing operates around a supply chain that is subject to complex logistics and is vulnerable to spikes in demand and interruptions. In this context, continuous pharmaceutical manufacturing in portable, refrigerator-sized factories is a promising solution with applications in battlefield medicine, pandemic response, and mitigation of local medical emergencies. A new iteration of the pharmacy on demand initiative is hereby presented, involving the development of equipment and processes for the manufacture of ciprofloxacin HCl with commercialization in mind. This article covers the implementation and the feedback control strategies for downstream manufacturing, as well as the results of the first end-to-end continuous manufacturing campaign. The results involve a significant leap from prior iterations, consistently attaining drug substance specifications in a fully automated process and with a 4-fold increase in the process throughput over the most recent iteration.",10.1021/acs.oprd.1c00117,0
Pilot-Scale Production of Peroxygenase from <i>Agrocybe aegerita</i>,"High Resolution Image Download MS PowerPoint Slide The pilot-scale production of the peroxygenase from Agrocybe aegerita (r Aae UPO) is demonstrated. In a fed-batch fermentation of the recombinant Pichia pastoris, the enzyme was secreted into the culture medium to a final concentration of 0.29 g L –1 corresponding to 735 g of the peroxygenase in 2500 L of the fermentation broth after 6 days. Due to nonoptimized downstream processing, only 170 g of the enzyme has been isolated. The preparative usefulness of the so-obtained enzyme preparation has been demonstrated at a semipreparative scale (100 mL) as an example of the stereoselective hydroxylation of ethyl benzene. Using an adjusted H 2 O 2 feed rate, linear product formation was observed for 7 days, producing more than 5 g L –1 ( R )-1-phenyl ethanol. The biocatalyst performed more than 340.000 catalytic turnovers (942 g of the product per gram of r Aae UPO).",10.1021/acs.oprd.1c00116,0
Solid Form Selection and Process Development of KO-947 Drug Substances,"KO-947 is a potent, selective extracellular signal-regulated kinases (ERK) inhibitor that was investigated in the clinic for the treatment of various solid tumors. KO-947 free base, form E, was originally recommended out of 10 identified crystalline forms for the development of an oral solid dosage product. Change of clinical need shifted the focus to aqueous solubility enhancement through salt formation. Mesylate salt demonstrated remarkably increased aqueous solubility and also profound polymorphism. Anhydrous form III was initially recommended but later dropped, primarily due to the manufacturing difficulties. In the end, form IX was discovered through close collaboration between preformulation and process scientists. An elaborate manufacturing process was then devised to successfully produce mesylate salt, form IX in kilogram scale supplied for the clinical use.",10.1021/acs.oprd.1c00113,0
Multigram Synthesis of Trioxanes Enabled by a Supercritical CO<sub>2</sub> Integrated Flow Process,"Photochemical synthesis of highly reactive hydroperoxides and their conversion into useful products, such as 1,2,4-trioxanes, are of wide interest for synthetic organic chemistry and pharmaceutical manufacturing particularly because of their relevance as potential antimalarial and anticancer treatment drugs, for example, Artemisinin. One class of antimalarial drugs is based on 1,2,4-trioxane scaffolds although production of such compounds on a gram scale is challenging due to their instability in oxidizable solvents. Furthermore, current methods employ either solid oxidants, which make continuous processing problematic, or molecular oxygen, requiring long reaction times of up to 48 h. Here, we report a new multigram continuous approach using a custom-built high-pressure sapphire photoreactor to synthesize trioxanes via the dearomatization of para -substituted phenols by photogenerated singlet oxygen in supercritical CO 2 . CO 2 also facilitates mixing with O 2 and has lower viscosity, thereby improving penetration into the pores of the solid acid catalyst used for the formation of trioxanes. We show the capabilities of a 5.2 mL reactor to scale up the reaction to 67 g/day. This synthetic approach provides a platform to rapidly access high-value compounds under flow conditions, with high atom efficiencies, excellent yields, short reaction times, and without the need for isolation of hazardous intermediates.",10.1021/acs.oprd.1c00111,0
Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing,"The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.",10.1021/acs.oprd.1c00108,0
"A Review on Synthetic Advances toward the Synthesis of Apremilast, an Anti-inflammatory Drug","Psoriasis and psoriatic arthritis are immune-mediated chronic inflammatory disorders which predominantly involve skin and joints. Around the world, it has affected nearly 38 million people worldwide. In 2014, Celgene Corporation’s ( S )-apremilast was introduced to treat patients suffering from the different types of psoriasis. In this review, we discuss the different strategies for the synthesis of ( S )-apremilast which will help further develop novel routes for its synthesis.",10.1021/acs.oprd.1c00107,1
Progress and Opportunities for Utilizing Seeding Techniques in Crystallization Processes,"Seeding is a significant but challenging task for optimizing crystallization process operation, product quality, and process efficiency. With the development of modern crystallization technology, there have been considerable advancements in seeding techniques in recent years. This article elaborates on how seeds affect the crystallization process, clarifies the qualitative connection between seeding parameters, defines the variables and product quality attributes based on a variable-based causal graph, and analyzes various possible factors that result in seeding-technique failure based on an Ishikawa diagram. The development of seeding-technique studies and existing problems are then systematically reviewed and discussed based on the qualitative and quantitative characteristics of seeds and the factors that influence seeding efficiency. Based on extensive research accomplishments, the challenges and opportunities for utilizing seeding techniques are analyzed, and potentially valuable seeding-technique topics and directions for improving crystallization are presented. In addition, a framework to guide seed recipe design and optimization is defined by combining simulation and experimental verification.",10.1021/acs.oprd.1c00103,0
A Continuous-Flow Electrochemical Taylor Vortex Reactor: A Laboratory-Scale High-Throughput Flow Reactor with Enhanced Mixing for Scalable Electrosynthesis,"We report the development of a small footprint continuous electrochemical Taylor vortex reactor capable of processing kilogram quantities of material per day. This report builds upon our previous development of a scalable photochemical Taylor vortex reactor ( Org. Process Res. Dev. 2017, 21, 1042; 2020, 24, 201–206). It describes a static and rotating electrode system that allows for enhanced mixing within the annular gap between the electrodes. We demonstrate that the size of the annular gap and the rotation speed of the electrode are important for both conversion of the substrate and selectivity of the product exemplified using the methoxylation of N -formylpyrrolidine. The employment of a cooling jacket was necessary for scaling the reaction in order to manage the heat generated by electrodes at higher currents (up to 30 A, >270 mA cm –2 ) allowing multimole productivity per day of methoxylation product to be achieved. The electrochemical oxidation of thioanisole was also studied, and it was demonstrated that the reactor has the performance to produce up to 400 g day –1 of either of the corresponding sulfoxide or sulfone while maintaining a very high reaction selectivity (>97%) to the desired product. This development completes a suite of vortex reactor designs that can be used for photo-, thermal-, or electrochemistry, all of which decouple residence time from mixing. This opens up the possibility of performing continuous multistep reactions at scale with flexibility in optimizing processes.",10.1021/acs.oprd.1c00102,0
Proof-of-Concept Design of an In-Line pH Neutralization System with Coarse and Fine Adjustments for the Continuous Manufacturing of Pharmaceuticals,"In the continuous manufacturing of pharmaceuticals, in-line monitoring and control are essential. Many pharmaceutical manufacturing processes require pH adjustment. Here, an in-line pH neutralization system with both coarse and fine adjustments was designed, and promising results were obtained. In nonbuffered conditions, the proposed two-pump system was able to control the fluctuations within approximately 2 pH units near the equivalence point, for both aqueous solutions and organic–H 2 O mixtures with strong acid.",10.1021/acs.oprd.1c00101,0
"New Scalable Synthetic Routes to <b>ELQ-300</b>, <b>ELQ-316</b>, and Other Antiparasitic Quinolones","The endochin-like quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised, which would lower costs and be amenable to large-scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad–Limpach reaction to produce 3-substituted 4(1 H )-quinolones such as ELQ-300 and ELQ-316 . This synthetic route, the first described to be truly amenable to industrial-scale production, is relatively short (five reaction steps), does not require palladium, chromatographic separation, or protecting group chemistry, and may be performed without high vacuum distillation.",10.1021/acs.oprd.1c00099,1
"Development of a Stereoselective Synthesis of (1<i>R</i>,4<i>R</i>)- and (1<i>S</i>,4<i>S</i>)-2-Oxa-5-azabicyclo[2.2.2]octane","Despite the prevalence of morpholine derivatives and bridged heterocycles in medicinally relevant compounds, bridged bicyclic morpholines remain scarce because of the challenges associated with their synthesis. MRK A, an IDH1 mut inhibitor for the treatment of glioma, derives its potency in part from substitution of a zigzag 2,5-bicyclic morpholine, 2-oxa-5-azabicyclo[2.2.2]octane, at C8. While existing entries suffered from low yields and lack of stereochemical control, we developed concise stereospecific routes toward both enantiomers of the zigzag morpholine antipode. The key common intermediate in the two routes was a chiral bicyclic lactone, which was readily synthesized following our previous synthesis of relebactam from optically pure (2 S,5 S )-5-hydroxypiperidine-2-carboxylic acid (HPA). The desired ( R, R ) enantiomer for incorporation into MRK A required inversion of both stereocenters of the bicyclic lactone intermediate, which was accomplished by epimerization via a crystallization-induced diastereomer transformation process followed by a key Ti(O i Pr) 4 -mediated intramolecular S N 2 ring closure. By this method, the ( R, R )-zigzag morpholine was synthesized in six steps from HPA in 25% overall yield.",10.1021/acs.oprd.1c00098,1
"Intensified Continuous Flow Synthesis and Workup of 1,5-Disubstituted Tetrazoles Enhanced by Real-Time Process Analytics","Continuous flow processing presents a solution for the safe and effective formation of 1,5-tetrazoles due to the small reactive inventory and absence of a reactor headspace. This has been exemplified using a model amide, 2-chloro- N -methylacetamide, activated using POCl 3 to its corresponding imidoyl chloride, which reacts with trimethylsilyl azide. Initial scoping revealed that an excess of azide is vital to facilitate a clean reaction but also that a high concentration would dramatically accelerate the reaction without the need for greatly elevated temperature. In a short residence time of 10 min, complete conversion was achieved, resulting in 77–86% yield of the desired product in high purity (>99.7%) after recrystallization, omitting any chromatographic purification. The developed process reached an excellent space–time yield (1.16 kg L –1 h –1 ) due to its high concentration and short residence time. Successful technology transfer included development of a continuous workup, with pH-controlled quench in a CSTR, followed by extraction. During flow optimization, two orthogonal PAT methods were separately employed, NMR and FTIR, enabling real-time starting material and product quantification. Finally, the developed reaction protocol was demonstrated on a number of other substrates, achieving high yields in most cases, up to quantitative.",10.1021/acs.oprd.1c00096,0
"Scale-Up and Optimization of a Continuous Flow Carboxylation of <i>N</i>-Boc-4,4-difluoropiperidine Using <i>s</i>-BuLi in THF","We report a large-scale carboxylation of N -Boc-4,4-difluoropiperidine ( 1 ) enabled by a continuous flow process. The flow process involved N -Boc-directed α-deprotonation using s -BuLi in THF and subsequent trapping with CO 2 gas. Flow chemistry enabled the safe and scalable preparation of 400 g of carboxylic acid 2 over the course of a day to support our medicinal chemistry research program.",10.1021/acs.oprd.1c00092,0
Investigation of Lithium Acetyl Phosphate Synthesis Using Process Analytical Technology,"Acetyl phosphate salts are common phosphate donors for enzymatic phosphorylation with kinases and are used in a variety of industrial biocatalytic processes. Due to their ever-increasing demand, synthesis of high-quality acetyl phosphate salts is critical for pharmaceutical process development, especially given that common impurities such as acetic acid and phosphate can inhibit the intended reaction. Current offline analytical methodologies for investigating the acetyl phosphate reagent quality are limited due to the hydrolytically unstable nature of the chemical species, resulting in its potential degradation before complete analysis may occur. It is therefore advantageous to synthesize high-purity acetyl phosphate using process analytical technology (PAT) tools to monitor reaction progress in real time. In this work, several PAT tools were employed specifically for the investigation of lithium acetyl phosphate synthesis, including in situ Fourier transform infrared spectroscopy, pH and temperature sensing, online optical microscopy, and focused beam reflectance measurements. These PAT tools offer a significant benefit by providing insights into reaction optimization, through observing the timing of temperature and pH changes, realizing a particle size target, and directly monitoring the consumption of reagents and formation of products. Results indicate that these online in situ methods are successful in detailed reaction monitoring and process characterization for the production of quality lithium acetyl phosphate, allowing for real-time reaction understanding.",10.1021/acs.oprd.1c00091,0
Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-<i>ortho-</i>Substituted Biaryl Pyridone,"The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine cyclization to construct the pyridone core; however, the overall efficiency of this route was limited by the linear synthesis of the hindered biaryl pyridone. This lack of convergence is solved in a second-generation route that minimizes low-temperature lithiation chemistry, replaces costly Pd coupling with scalable nucleophilic arylation, and reduces step count. The improved synthesis was enabled by a new Negishi coupling method that addresses limitations of the Suzuki–Miyaura literature for tetra- ortho -substituted biaryl pyridones.",10.1021/acs.oprd.1c00088,1
In-line Monitoring of Microgel Synthesis: Flow versus Batch Reactor,"In-line monitoring of polymerization via Raman spectroscopy is standard for batch reactors but yet to be manifested for flow reactors. When transferring the in-line Raman spectroscopy from batch to flow reactors, the aim is to maintain the measurement precision. We present a customized Raman measurement cell for in-line monitoring in a tubular flow reactor and a systematic accuracy analysis of the obtained measurement. The accuracy analysis involves comparing three calibration models and measurements of flowing solvent, monomer solution, and microgel solution. The evaluation of the measurements reveals that multimolecular analyte solutions most significantly influence the quantification accuracy. From these investigations, we derive a quality criterion for the Raman measurements based on the root mean square error, and apply the criterion to the monitoring of precipitation polymerization of poly( N -iso-propylacrylamide) (PNIPAM) microgels. The results compare the predictions from the Raman measurements of the microgel synthesis in the flow and batch reactor. Applying the quality criterion enables high-quality measurements and allows the functional detection of outliers during the synthesis. The identification and exclusion of outliers eliminate several potential errors to cause the difference in measurement results from the flow and batch reactors. This contribution serves as a guideline for transferring in-line monitoring from batch to flow reactors as the example of precipitation polymerization.",10.1021/acs.oprd.1c00087,0
"Evaluation, Method Development, and Validation for Content Determination of Potential Genotoxic Impurities (PGIs) at the TTC Level in Telmisartan API","Telmisartan is an angiotensin II receptor antagonist used in the cure of hypertension and other heart diseases. In the current research work, the synthetic route of Telmisartan, including those of starting materials, was evaluated to identify nine potential genotoxic impurities (PGIs) (impurities I–IX) by making use of the literature-, statistical-, and rule-based methods. To date, no suitable methods have been developed for the separation and quantification of these nine impurities in Telmisartan at the threshold of toxicological concern (TTC) level. Based on the identified impurities, four chromatographic methods were developed and validated as per the International Council on Harmonisation (ICH) guidelines. The developed methods are practical and efficient in the detection as well as quantification of PGIs and may be adopted to guarantee the safe use of Telmisartan.",10.1021/acs.oprd.1c00086,1
Consolidating and Managing Data for Drug Development within a Pharmaceutical Laboratory: Comparing the Mapping and Reporting Tools from Software Applications,"We present a perspective on drug development for the synthesis of an active pharmaceutical ingredient ( e.g., agomelatine) within a commercial technology called Luminata and compare the results to the current method of consolidating the reaction data into Microsoft Excel. The Excel document becomes the ultimate repository of information extracted from multiple sources such as the electronic lab notebook, the laboratory information management system, the chromatography data system, in-house databases, and external data. The major needs of a pharmaceutical company are tracking the stages of multiple reactions, calculating the impurity carryover across the stages, and performing structure dereplication for an unknown impurity. As there is no standardized software available to link the different needs throughout the life cycle of process development, there is a demand for mapping tools to consolidate the route for an API synthesis and link it with analytical data while reducing transcription errors and maintaining an audit trail.",10.1021/acs.oprd.1c00082,0
Improved Multigram Route to a Tricyclic Key Intermediate for Dibenzosuberone-Based p38 Inhibitors via an Optimized Early-Stage Heck Coupling,"The p38α MAP kinase has been a heavily investigated target in the last two decades. The structural class of dibenzosuberone-based p38 inhibitors, exemplified by the promising candidate skepinone-L, was already successfully validated in several in vivo models of inflammatory as well as oncologic indications. The increasing demand of key intermediates and final compounds caused by the ongoing development of this inhibitor class urged the conception of an optimized route for the preparation of the core dibenzosuberone scaffold in multigram quantities. Rerouting of the initial discovery route resulted in an almost 4-fold increase of overall yield to 46%, the elimination of chromatographic purification, and the substitution of two critical reaction steps, which hindered a feasible scale-up. The key modification was the introduction and optimization of an early-stage Heck coupling based on Buchwald precatalysts allowing consistently high yields (ca. 90%) at multigram scales with a favorably low Pd loading of 0.1 mol %. This newly developed synthetic access to the dibenzosuberone intermediate 2-chloro-7-hydroxy-10,11-dihydro-5 H -dibenzo[ a, d ][7]annulen-5-one is capable of ensuring the supply of skepinone-L and other candidates during further development.",10.1021/acs.oprd.1c00081,1
Extended Solution-phase Peptide Synthesis Strategy Using Isostearyl-Mixed Anhydride Coupling and a New C-Terminal Silyl Ester-Protecting Group for <i>N</i>-Methylated Cyclic Peptide Production,"Herein, we present a new and efficient convergent solution-phase synthetic strategy for producing peptides containing N -methyl amino acids. Specifically, we have synthesized a model cyclic octapeptide with two N -methyl amino acids, utilizing an isostearyl-mixed anhydride coupling methodology and a novel silyl ester-protecting group, cyclohexyl di- tert -butyl silyl (cHBS). This newly developed method uses an isostearic acid chloride (ISTA-Cl) and silylation reagent that allows coupling between N- and C-terminally unprotected amino acids with sterically hindered N -methyl amino acids. High yields of four dipeptide fragments are efficiently synthesized by omitting the traditional C-terminal deprotection step. The silyl ester-protecting group at the C-terminus is stable during general peptide synthesis, and is selectively cleaved by fluoride ions. This group further suppresses diketopiperazine formation during the deprotection of the N α -amino-protecting group. The linear octapeptide precursor is convergently synthesized utilizing protection and selective deprotection of the silyl ester-protecting group, and the cyclic octapeptide can be obtained with high purity using this novel methodology, via a route shorter than conventional solution-phase peptide synthesis strategies.",10.1021/acs.oprd.1c00078,1
Development of the Late-Phase Manufacturing Process of ZPL389: Control of Process Impurities by Enhanced Process Knowledge,"The development of the late-phase manufacturing process of the drug candidate ZPL389 and the strategies for the control of impurities are outlined in detail. Selective salt formation at several stages was pivotal to controlling the process impurities. The extensive optimization of the N-methylation of a Boc-protected amine with dimethyl sulfate and of a nucleophilic aromatic substitution without the use of metal catalysts led to a robust, scalable process. The process was demonstrated on a >100 kg scale. Overall, improved drug substance quality, higher yield, and reduction of the process mass intensity were achieved.",10.1021/acs.oprd.1c00077,1
Development of a Safe and Scalable Process for the Production of a High-Purity Thiocarbamate-Based Ionizable Lipid as an Excipient in mRNA-Encapsulating Lipid Nanoparticles,"Thiocarbamate lipid 2 was prepared on a 25–50 g scale by coupling a carbamoyl chloride with 3-(dimethylamino)-1-propanethiol. Chromatography, activated charcoal treatment, and washing were required to obtain 2 (57%, light yellow oil) in >98% purity. Lipid 2 was successfully prepared on a 1 kg scale by replacing the carbamoyl chloride with an acyl imidazolium intermediate and coupling with the lipophilic amine salt 8 to give 2 in a higher yield (68%) and greater purity (99.8%, colorless oil) using an improved, chromatography-free, purification protocol. In addition, mutagenic impurities in 2 could be controlled well below required specifications.",10.1021/acs.oprd.1c00076,1
Application of Flow and Biocatalytic Transaminase Technology for the Synthesis of a 1-Oxa-8-azaspiro[4.5]decan-3-amine,"Spirocyclic ring systems are useful intermediates in the design and synthesis of medicinally active agents and commonly found as cores in natural products. Recently, syntheses of a key intermediate Boc-protected-1-oxa-8-azaspiro[4.5]decan-3-amine 1 were examined. While multigram quantities of the racemic material could be made from the reduction of an energic azide intermediate, larger scale reactions and a chiral synthesis required further investigations. Herein, we describe the use of a continuous three-step flow process to scale the formation and reduction of an azide intermediate, and the use of a transaminase to prepare the desired enantiomer in high yield and enantiomeric excess.",10.1021/acs.oprd.1c00075,1
Safe Scale-Up of an<i>N</i>-Bromosuccinimide Involved Bromination Reaction,"A hazardous side reaction between N -bromosuccinimide (NBS) and 2-methyltetrahydrofuran (2-MeTHF) was identified during the thermal safety analysis toward a bromination process. A delay reaction owing to a preferred free-radical initiation was observed. The progress of the side reaction and influence of NBS concentration on the reaction heat were studied by means of different calorimeters. The heat flow of the desired reaction was measured by the reaction calorimeter (RC1), indicating the bromination could be controlled under a semibatch mode with appropriate feeding program of NBS. On the basis of these investigations, two consecutive brominating processes with 106 kg starting material were safely scaled up in the pilot plant with expected yields.",10.1021/acs.oprd.1c00074,0
Practical and Scalable Manufacturing Process for a Novel Dual-Acting Serotonergic Antidepressant Vilazodone,"Vilazodone combines the effects of a selective serotonin reuptake inhibitor with the 5-HT 1A receptor partial agonist activity. Here, we report the development of a viable and scalable process for manufacturing vilazodone that features a convergent synthetic approach, with low cost and high purity. The key indole synthesis was improved to first make up the hydrazone intermediate and then modify a pendant hydroxy group to realize a much increased overall yield. This process was successfully used to prepare >2 kg of vilazodone hydrochloride with a total yield of 56.2% and purity of 99.93%.",10.1021/acs.oprd.1c00069,1
Kilogram-Scale Preparation of an Aminopyrazole Building Block via Copper-Catalyzed Aryl Amidation,"We describe a scalable method for preparing an aminopyrazole building block using copper-catalyzed amidation with acetamide as an ammonia surrogate. This procedure provides an alternative to the standard nitration/reduction sequence and avoids energetic intermediates, specialized hydrogenation equipment, and potentially genotoxic impurities that arise from nitro reduction. The chemistry has been successfully scaled to produce >50 kg of the target compound and demonstrate the viability of this alternative route.",10.1021/acs.oprd.1c00066,1
Fully Continuous Flow Synthesis of 3-Chloro-4-oxopentyl Acetate: An Important Intermediate for Vitamin B1,"A fully continuous flow synthesis of 3-chloro-4-oxopentyl acetate ( 2 ), an important intermediate for vitamin B 1 ( 1 ), was developed. This continuous flow manufacturing included two chemical transformations and an inline extraction step without intermediate purification and solvent exchange. In this work, the traditional synthetic route for batch operation was efficiently simplified via a series of separated screening tests in flows under various conditions. We found that the chlorination reaction can be carried out in only 30 s at room temperature by flow. We also simplified the decarboxylation/acylation step by using a cross-mixer, so that acetic anhydride was no longer required in the acylation reaction. A computational fluid dynamics simulation was carried out to study the improved micromixing of liquid–liquid two-phase streams. Finally, 3-chloro-4-oxopentyl acetate ( 2 ) was obtained in a 90% isolated yield with a product purity of 96% and a total residence time of approximately 32 min. This fully continuous process was operated smoothly for 12 h, and approximately 19.1 g of the desired product was generated with a production rate of 1.79 g h –1 .",10.1021/acs.oprd.1c00065,1
Impurity Identification and Scale-Up of a Novel Glycopeptide Antibiotic,"A variety of novel glycopeptide antibiotics have been developed to combat the drug-resistant bacterial strains. Previously, we reported a series of vancomycin derivatives that are modified with lipid tails and extra sugars. SM-V-61, as one of the vancomycin analogues with a trifluoromethyl-biphenyl fragment and galactose, showed enhanced antibacterial activity, improved PK/PD, better water solubility, and safety. However, the deficient synthetic procedure, lower yield, and complicated impurities hindered the further development of the drug candidate SM-V-61. Herein, we reported a further study on SM-V-61 impurity analysis and process optimization. We first synthesized and identified a variety of impurities and established the analytical method for quality analysis and control of SM-V-61. Based on the defined analytical method, we optimized the synthetic procedure for SM-V-61 and operated the synthesis on 30–40 and 500–600 g scales in the laboratory and manufacturing workshop, respectively.",10.1021/acs.oprd.1c00064,0
"Synthesis of Rovafovir Etalafenamide (Part I): Active Pharmaceutical Ingredient Process Development, Scale-Up, and Impurity Control Strategy","This manuscript describes the chemical process development and multi-kilogram synthesis of rovafovir etalafenamide (GS-9131), a phosphonamidate prodrug nucleotide reverse transcriptase inhibitor under investigation for the treatment of HIV-1 infection. Rovafovir etalafenamide is assembled in a four-step sequence beginning from the nucleoside core and an elaborated phosphonamidate alcohol. The assembly starts with a decarboxylative elimination of a β-hydroxyacid to yield the corresponding cyclic enol ether, which is subsequently coupled to a functionalized phosphonamidate alcohol in an iodoetherification reaction. Oxidative syn elimination then installs the required fluoroalkene, after which a final deprotection reaction yields the active pharmaceutical ingredient (API). Understanding the genesis, fate, and purge of the des -fluoro analog of the API, a mitochondrial toxin, proved to be a central driver in the development of the manufacturing route and impurity control strategy. Initial control strategies revolved around the use of silica gel chromatography or simulated moving bed chromatography to purge the des -fluoro impurity to an acceptable level, but ultimately a chromatography-free approach to mitigate the formation of this impurity was devised that expanded manufacturing flexibility. Design of experiments was used to improve the iodoetherification fragment coupling reaction and to reduce the level of the des -fluoro impurity formed in this step. Furthermore, several new crystalline intermediate forms were discovered and implemented as isolation points to bolster the overall impurity control strategy for standard, diastereomeric, and potentially mutagenic impurities as well as for the des -fluoro impurity. These processes were executed on multi-kilogram scale to produce API for clinical studies.",10.1021/acs.oprd.1c00059,1
Refractive Index: The Ultimate Tool for Real-Time Monitoring of Solid-Phase Peptide Synthesis. Greening the Process,"Peptides are the basis of many drugs currently on the market and of more in advanced studies. Most peptides are synthesized using solid-phase peptide synthesis (SPPS). A characteristic of this strategy is that synthetic intermediates are not isolated. In this context, the development of a real-time monitoring method would assure an optimal synthetic process. The refractive index (RI) of a liquid provides key information about its physical properties and the composition of any solution. Here, we provide the first demonstration that the RI is a process analytical tool (PAT) suitable for the real-time monitoring of SPPS. This strategy comprises three steps: coupling, deprotection, and washes, which can be monitored online by refractometry. Given that monitoring capacity helps in the determination of the endpoint of the reactions and the optimization of all synthetic steps, it has a direct impact on the consumption of reagents, solvents, and time, thereby contributing to greener SPPS.",10.1021/acs.oprd.1c00051,0
Tetramethylammonium Fluoride Tetrahydrate for S<sub>N</sub>Ar Fluorination of 4-Chlorothiazoles at a Production Scale,"This article describes the use of tetramethylammonium fluoride tetrahydrate (TMAF·4H 2 O) for the large-scale preparation of a challenging 4-fluorothiazole. Commercially available TMAF·4H 2 O was procured on a large scale and rigorously dried by distillation with isopropyl alcohol and then dimethylformamide at elevated temperature. This method of drying provided anhydrous TMAF [TMAF (anh)] containing <0.2 wt % water and <60 ppm isopropanol. The use of TMAF (anh) was essential for production of the 4-fluorothiazole. When the chlorothiazole starting material was treated with other anhydrous fluoride sources, poor conversion of the starting material or potential safety issues were observed. S N Ar fluorination using dried TMAF·4H 2 O was carried out at a 45.1 kg scale at 95–100 °C to produce 36.8 kg of 4-fluorothiazole 1b .",10.1021/acs.oprd.1c00042,0
Integrating Continuous-Flow Electrochemistry and Photochemistry for the Synthesis of Acridinium Photocatalysts Via Site-Selective C–H Alkylation,"Acridinium dyes are among the most frequently studied classes of organic photocatalysts because of their favorable excited-state properties such as high reduction potential and good lifetime. However, it remains challenging to modulate their catalytic performance by a structural modification. Here, we report a two-step continuous-flow system for the synthesis of functionalized acridinium photocatalysts through a site-selective late-stage C(aryl)–H functionalization of the acridinium core. The alkylation is achieved by pumping the parent acridinium dye sequentially through a photoreactor to achieve cross-coupling with an organotrifluoroborate and an electrochemical reactor for electrocatalytic dehydrogenation. The two-step automatic system allows the introduction of a diverse range of alkyl groups at the 3-position of the acridinium dye. Subjecting 3-alkylated acridinium salts to the flow system for a second alkylation forms 3,6-disubstituted acridinium dyes.",10.1021/acs.oprd.1c00038,0
Scalable Flow Electrochemical Alcohol Oxidation: Maintaining High Stereochemical Fidelity in the Synthesis of Levetiracetam,"An electrochemical flow process has been developed for an alcohol oxidation step in the synthesis of the generic epilepsy drug levetiracetam. A crucial metric in this process is the retention of high enantiomeric purity as the oxidation of the primary alcohol to the carboxylic acid proceeds via an epimerizable aldehyde intermediate. Here, three different reactor configurations are compared: undivided batch, undivided flow, and divided flow cells. The divided flow cell accesses the highest rate, throughput, and enantiomeric fidelity among the three configurations. This approach is showcased in a 200-gram scale process that retains ≥97% enantiomeric purity and highlights a unique advantage of flow electrolysis.",10.1021/acs.oprd.1c00036,0
"Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification","A two-step synthesis of molnupiravir ( 1 ) is presented. This work focuses on the development of practical reaction and purification conditions toward a manufacturing route. The sequence commences from highly available cytidine ( 2 ), and molnupiravir is formed through direct hydroxamination of the cytosine ring and esterification of the sugar’s primary alcohol without use of protecting or activating groups. A highly crystalline hydrate of N -hydroxycytidine ( 3 ) resulted in an easily purified intermediate, and a practical, off-the-shelf enzyme was selected for the acylation. The yield was increased through a chemically promoted, selective ester cleavage, which converted a byproduct, molnupiravir isobutyryl oxime ester ( 4 ), into the final API. Both reactions proceed in >90% assay yield, and crystallization procedures are used to afford intermediates and active pharmaceutical ingredients in purities above 99% with an overall yield of 60%. Excellent throughput and sustainability are achieved by limiting the total concentration to 7 volumes of solvent in the course of the two reactions with an overall PMI of 26 including work-up and isolation. Environmentally friendly solvents, water and 2-methyl tetrahydrofuran, enhance sustainability of the operation.",10.1021/acs.oprd.1c00033,1
"Stereocontrolled Synthesis of Delgocitinib, a JAK Inhibitor for the Treatment of Atopic Dermatitis","Herein is reported the nine-step commercial synthesis of delgocitinib, a Janus kinase inhibitor approved for the treatment of atopic dermatitis in 2020. Its chiral spirodiamine core was selectively constructed by an intramolecular S N 2 reaction of the suitably designed γ-lactone substrate and a few subsequent steps including a selective γ-lactone ring-opening reaction with potassium phthalimide, hydrazine-free mild dephthaloylation, and one-pot reduction of β- and γ-lactams. The route affords chemically and stereochemically pure delgocitinib in 39% yield.",10.1021/acs.oprd.1c00031,0
Synthesis of Rovafovir Etalafenamide (Part IV): Evolution of the Synthetic Process to the Fluorinated Nucleoside Fragment,"Fluorinated nucleoside 1 is a key starting material in the synthesis of rovafovir etalafenamide ( 2 ), a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV. While an initial manufacturing route enabled the production of 1 to support clinical development, alternative approaches were explored to further enhance manufacturing effectiveness, improve processing time, reduce cost, and minimize the environmental impact. Toward this end, two new routes were developed to a key synthetic intermediate, which was converted to 1 using a new protecting group strategy. The new chemistry led to improvements in the manufacturing process while reducing the overall process mass intensity (PMI).",10.1021/acs.oprd.1c00026,1
Highly Efficient and Practical Synthesis of the Key Intermediate of Telmisartan,"We reported herein an efficient and practical method to access 1,7′-dimethyl-2′-propyl-2,5′-bi(1 H -benzimidazole) 1, a key intermediate for the synthesis of telmisartan. The synthetic route was based on readily available o -methylaniline as the starting material, and the target product 1 was prepared through a six-step process, including amidation, formylation, cyclization, hydrolysis, amidine, and oxidation. The overall yield for the preparation of 1 was 51.5% on the 100 g scale, with a purity of 99.91%. The salient features of this method include economic and easily available starting materials, operational simplicity, and environmentally friendly, which is suitable for the industrial production.",10.1021/acs.oprd.1c00025,1
Flash Chemistry Approach to Organometallic <i>C</i>-Glycosylation for the Synthesis of Remdesivir,"High Resolution Image Download MS PowerPoint Slide In a rapidly changing environment, such as the current COVID-19 pandemic, continuous flow reactors bear the potential to increase the production of urgently needed active pharmaceutical ingredients (APIs) on demand. In the synthesis of remdesivir, the organometallic C -glycosylation step was identified as a limitation for the large-scale production, requiring long addition periods and cryogenic temperatures. Previous studies have focused on a Grignard-based protocol, but a flash chemistry approach, using organolithium reagents, has facilitated significant improvements. After gaining further understanding of the C -glycosylation, this step was successfully transferred to a five-stream continuous flow process, achieving 60% yield at a moderate temperature (−30 °C) in a total residence time of just 8 s. Stable processing was demonstrated for 2 h, providing an exceptionally high space–time yield of 10.4 kg L –1 h –1, in a scalable flow reactor system.",10.1021/acs.oprd.1c00024,1
Copper(II) Lysinate and Pseudoproline Assistance in the Convergent Synthesis of the GLP-1 Receptor Agonists Liraglutide and Semaglutide,"A growing interest in peptides as active pharmaceutical ingredients (APIs) requires the development of efficient strategies for their preparation. This is particularly challenging in the case of long peptides with a strong tendency for aggregation and folding. Here, we describe the pseudoproline-assisted convergent synthesis of GLP-1 receptor agonist lipopeptides liraglutide and semaglutide, which involves the stepwise condensation of three fragments in the solid phase. The insertion of a pseudoproline residue at the site of fragment coupling prevents aggregation and allows obtaining these peptides with excellent purity and high yield. In addition, for the synthesis of lipidated side chains, we developed a novel approach that involves copper(II) lysinate intermediates and can be particularly suitable for the industrial preparation of both liraglutide and semaglutide and other peptides with a similar branched structure.",10.1021/acs.oprd.1c00021,1
"Practical Synthesis of (3a<i>R</i>, 9b<i>R</i>)-8-Fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1<i>H</i>-benzo[e]indole: An Advanced Intermediate to Access the RORγt Inverse Agonist <b>BMT-362265</b>","A practical and scalable route to (3a R, 9b R )-8-fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1 H -benzo[e]indole 10, an advanced intermediate en route to the synthesis of the RORγt inverse agonist, BMT-362265, is described starting from fluorobenzene. The synthesis involved the screening of multiple synthetic routes for their feasibility and scalability. We also demonstrate the utility of an annulating reagent, ( R )- N -(2-chloroethyl)-2-methylpropane-2-sulfinamide, for the diastereoselective synthesis of tricyclic pyrrolidine intermediates 24 and 36 on a multigram scale.",10.1021/acs.oprd.1c00019,1
Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale,"A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scale-up when transferring from batch to flow are highlighted. During the rapid process development, unexpected and expected issues concerned with the use of 1 M and 2 M lithium diisopropylamide in flow were encountered and overcome as they arose. Organolithium chemistry was operated in continuous flow mode; a reaction sequence of sp 3 deprotonation and in-line acetone quench, followed by a semibatch workup was scaled up to multigram quantities in a rapid, fit-for-purpose manner for early-phase project delivery.",10.1021/acs.oprd.1c00015,1
Development of a One-Step Synthesis of 5-Amino-1<i>H</i>-imidazole-4-carboxamide,An innovative and efficient synthesis of 5-amino-1 H -imidazole-4-carboxamide (AIC) from commercially available hypoxanthine (∼$30/kg) is described. The development of the key hydrolysis step and a practical isolation enables a highly efficient one-step manufacturing process for AIC with minimal environmental impact and significant reduction of production cost.,10.1021/acs.oprd.1c00013,1
Process Development of Tacalcitol,"A highly convergent, gram-scale synthesis of vitamin D3 analogue tacalcitol 1 is disclosed, starting from L -valine and Inhoffen–Lythgoe diol. Key features of the synthesis include modified Julia olefination reaction of β-oxybenzothiazol-2-yl sulfone with C/D ring containing aldehyde to access decagrams of fully functionalized C/D ring synthon. The Horner–Wadsworth–Emmons (HWE) reaction between the C/D ring fragment and commercially available phosphonate completes the carbo-skeleton, which is elaborated into tacalcitol 1 in a gram-scale synthesis.",10.1021/acs.oprd.1c00010,1
Scale-Up of Ozonolysis using Inherently Safer Technology in Continuous Flow under Pressure: Case Study on β-Pinene,,10.1021/acs.oprd.1c00008,0
Development of a Robust and Scalable Process for the Large-Scale Preparation of Vadadustat,"A novel and scalable process is developed for the industrial synthesis of vadadustat. The four-step process is one step shorter compared to the reported routes with an increase in total yield to 49.1%. Detailed optimizations furnish vadadustat with a purity of >99.5% through cross-coupling, aromatic substitution and nitrile hydrolysis, amidation, and ester-ether deprotection. The process is also robust and was demonstrated in a kilogram laboratory. Meanwhile, the corresponding impurity profile was thus studied in detail and well documented.",10.1021/acs.oprd.1c00004,1
Synthesis of the Lipophilic Amine Tail of Abediterol Enabled by Multiphase Flow Transformations,"High Resolution Image Download MS PowerPoint Slide The development of a continuous-flow sequence for the synthesis of an important drug candidate precursor is reported. Abediterol is a β 2 -adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of respiratory disease. A flow sequence is developed for the preparation of the lipophilic amine tail portion of abediterol. The sequence comprises of a phase-transfer-catalyzed liquid/liquid O-alkylation, a rhodium-catalyzed hydroformylation, and a ruthenium-catalyzed reductive amination. The reactions were optimized separately within continuous-flow environments to identify important parameter effects. The strongly basic O-alkylation operates with greater than 90% conversion within a 23 min residence time. The hydroformylation uses 1 mol % Rh(acac)(CO) 2 (acac = acetylacetone) as a catalyst and 6 mol % Xantphos as a ligand with 1.1 equiv of hydrogen and carbon monoxide. The optimized O-alkylation and hydroformylation telescoped flow process was successfully operated over 6 h. The protocol is shown to be high yielding for the desired linear aldehyde (75% gas chromatography yield, ∼2.5 g/h). The sequence requires a solvent switch prior to the reductive amination. The final step is a high-pressure (40 bar) and high-temperature (150 °C) Ru-catalyzed reductive amination using ammonia and hydrogen to afford the amine tail. The solution yield for the formation of the amine tail was 78%. The yield of the reductive amination with an unoptimized isolation was 50%, resulting in an overall isolated yield for the three-step sequence of 38%. This compares favorably against the batch yield of 26% using a different synthetic route.",10.1021/acs.oprd.1c00002,1
Research on the Risk of Thermal Runaway in the Industrial Process of Styrene Solution Polymerization,"Polymerization reactions are exothermic processes that are often accompanied by viscosity changes, and they can pose hazards due to thermal runaway. This paper describes an investigation of the potential for thermal runaway in the industrial process of styrene solution polymerization, in which particular focus was devoted to the effects of the monomer concentration and the solvent. As the monomer concentration increased from 20.0 to 50.0 wt %, the heat of reaction Q r and the adiabatic temperature rise Δ T ad increased in a linear manner from 19.0 ± 0.2 to 58.1 ± 0.6 kJ and 21.7 ± 0.1 to 64.8 ± 0.6 K, respectively, and the maximum temperature attained by the synthesis reaction ( MTSR ) was also increased from 86.1 ± 0.2 to 101.5 ± 0.2 °C. In addition, the molecular weight distribution of polystyrene was around 1.9, and the distribution was broad. The risk of a potential runaway reaction was evaluated using the Stoessel assessment criteria and Zurich Hazard Analysis. The criticality of runaway polymerization remained constant with increasing concentration, and class 1 risk was observed. However, the severity of a potential runaway reaction was increased from negligible to medium class. It was found that the solvent had an important effect on the risk of thermal runaway during polymerization. The criticality of the high-boiling solvents toluene and cyclohexanone used in this work was class 1, while that of the low-boiling solvent ethyl acetate was class 3. This work provides valuable insight that can help to control thermal risk in the chemical industry.",10.1021/acs.oprd.0c00554,0
Concise and Efficient Synthesis of [6]-Paradol,"An efficient synthesis of [6]-paradol ( 1 ) has been performed in four steps with a 72.0% overall yield. The present method highlights commercially available materials, convenient isolation with multiple crystallization without involving column chromatography, and a high-purity product (more than 99.2%), and it is amenable to large-scale synthesis.",10.1021/acs.oprd.0c00553,1
Characterization of a Modular Continuous Vacuum Screw Filter for Small-Scale Solid–Liquid Separation of Suspensions,"A key enabler for the future success of continuous manufacturing in pharmaceutical and fine chemical production processes is the control of product quality. Since approx. 90% of all small molecular active pharmaceutical ingredients produced involve a crystallization step, a holistic view on its process chain is crucial in order to ensure a defined particle size distribution, high purity, and specific polymorphic form. Different concepts for small-scale continuous crystallization are available, improving the product qualities in comparison to batch. Continuous solid–liquid separations, on the other hand, are rather scarce. Therefore, we designed and characterized an innovative continuous vacuum screw filter (CVSF) for solid–liquid separation, washing, and drying of suspensions in a small scale (up to 10 g of solid per minute). This contribution shows the general working principle of the CVSF as well as a systematic investigation of varying operating parameters on the particle size distribution (PSD), residual moisture, and residence time distribution of the solid phase. As a model system, l -alanine/water is used. The results show that the PSD can be entirely maintained while ensuring a narrow residence time distribution of the solid phase with axial dispersion numbers between 18.7 and 76.2. The residual moisture is for all experiments in a good range of 20–25%. Furthermore, it could be shown that the operability is possible over 8 h. Summarizing, the modular setup of the CVSF offers a maximized flexibility and thus rapid adaptability to changing market demands and product requirements.",10.1021/acs.oprd.0c00550,0
Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin,"High Resolution Image Download MS PowerPoint Slide Alogliptin ( 1 ) benzoate is a potent, highly selective inhibitor of serine protease dipeptidyl-peptidase IV, approved by US FDA for the treatment of type 2 diabetes. Herein, we report a more cost-effective process that includes ruthenium-catalyzed asymmetric hydrogenation followed by Hofmann rearrangement of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2 H )-yl)methyl)benzonitrile ( 10 ) to introduce a chiral amino moiety at a late stage. Use of an inexpensive and readily available nicotinamide ( 6 ) for a chiral aminopiperidine core and iodobenzene diacetate (PIDA) under mild and specific conditions allowed us to access 1 with excellent total yield and comparable quality to that manufactured by the original process.",10.1021/acs.oprd.0c00544,1
Continuous Flow Process for the Synthesis of Betahistine via Aza-Michael-Type Reaction in Water,"A continuous flow process for the preparation of betahistine with a 90% isolated yield has been reported. 2-Vinylpyridine and saturated methylamine hydrochloride aqueous solution were used as starting materials to achieve excellent results in the silicon carbide flow reactor, which can tolerate the corrosion of chloride ions at high temperature (170 °C) and pressure (25 bar). In the continuous flow process, the product can be obtained in 2.4 min with excellent conversion (>99%) and product selectivity (94%). The throughput can reach 1.06 kg h –1, and the purity of the final product was greater than 99.9% by distillation, which were in accordance with the needs of production. This new process using environmentally friendly water as the solvent is energy-efficient, time- and cost-economic, and offers a 50% reduction in process mass intensity compared to the batch process.",10.1021/acs.oprd.0c00543,1
Book Review of <i>Advances in Organoboron Chemistry towards Organic Synthesis</i>,"ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTBook Review of Advances in Organoboron Chemistry towards Organic SynthesisMartin Juhl*Martin JuhlProcess Chemistry R&D, H Lundbeck A/S, 2500 Valby, Denmark*Email: [email protected]More by Martin JuhlCite this: Org. Process Res. Dev. 2021, 25, 1, 163–165Publication Date (Web):December 24, 2020Publication History Published online24 December 2020Published inissue 15 January 2021https://pubs.acs.org/doi/10.1021/acs.oprd.0c00540https://doi.org/10.1021/acs.oprd.0c00540book-reviewACS PublicationsCopyright © Published 2020 by American Chemical SocietyRequest reuse permissionsArticle Views1058Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Boron,Coupling reactions,Hydrocarbons,Organic compounds,Process chemistry Get e-Alerts",10.1021/acs.oprd.0c00540,0
Prediction of <i>N</i>-Nitrosamine Partition Coefficients for Derisking Drug Substance Manufacturing Processes,"The risk assessment and control of N -nitrosamine impurities in medicines is a topic of great concern for patients, regulators, and the pharmaceutical industry. This paper discusses a modeling approach to predict the solvent–water partition coefficient of 28 N -nitrosamines in 134 water immiscible solvents, including those solvents typically used in pharmaceutical manufacturing. The Conductor-like Screening Model for Real Solvents model has been used because its implementation from first principles does not require regressing specific interaction parameters for the N -nitrosamine functional group. It is proposed that predicted partition coefficients combined with partition modeling should be used to support the industry and regulators in making scientifically justified predictions of the control of N -nitrosamine impurities potentially formed during the manufacture of pharmaceutical products.",10.1021/acs.oprd.0c00535,0
Route Design to Manufacture: Synthesis of the Heterocyclic Fragment of AZD5718 Using a Non-cryogenic Lithiation-Alkoxycarbonylation Reaction,"Route design and process development of the small nitrogen heterocycle 2·HCl, a constituent of AZD5718 ( 1 ), is described. The novel synthetic sequence to 2.HCl involves a desymmetrizing alkylation of 4-nitropyrazole, a non-cryogenic lithiation-alkoxycarbonylation, and a global reduction-cyclization. This new synthetic route was implemented in the manufacture of 2.HCl and was able to deliver over 1000 kg of product with a yield of 77% over the three stages.",10.1021/acs.oprd.0c00533,1
"Thermal Risk Analysis Based on Reaction Mechanism: Application to the 2,6-Diaminopyrazine-1-oxide Synthesis Process","Thermal risk analysis is essential for the development of chemical reactions. This work should be carried out on the basis of a thorough comprehension of the reaction mechanism. In this article, the synthesis process for 2,6-diaminopyrazine-1-oxide (DAPO), an important intermediate in the synthesis of the famous explosive 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105), was employed to show the importance of understanding the reaction mechanism for thermal risk analysis. First, we investigated the reaction mechanism of DAPO synthesis. The reaction mechanism was divided into two stages on the basis of the amount of triethylamine dosed: the first half of triethylamine dosing and the second half of triethylamine dosing until the end of the reaction. Then the thermal properties of DAPO synthesis and the thermal stability of the materials involved were experimentally studied using a reaction calorimeter (RC1) and a differential scanning calorimeter (DSC), respectively. The results show that the temperature corresponding to the maximum reaction rate reached in a time of 24 h under adiabatic conditions ( T D24 ) is higher than the maximum temperature of the synthesis reaction (MTSR) for both of these stages, indicating that once cooling failure occurs, immediately stopping addition of triethylamine could prevent the occurrence of secondary decomposition.",10.1021/acs.oprd.0c00529,1
Trace-Level Determination of Acrylonitrile Generated in the Manufacturing Process of Oligonucleotides by Static Headspace Gas Chromatography with an Electron Impact(+) Mass Detector,"A static headspace capillary gas chromatography (HS-GC) method featured with a short run time, a wide calibration range, and a diluent with strong buffering and stabilizing capability has been developed for the quantitative analysis of trace levels of acrylonitrile, a known genotoxic impurity and potential byproduct of oligonucleotide manufacturing. This GC method was achieved on a commercially available fused silica capillary column, and the total run time including GC oven temperature re-equilibration is 20 min. The method employs a split injection (5:1) and a programmed temperature ramp and was qualified in terms of specificity, accuracy, repeatability/precision, quadratic calibration range, limit of quantitation (0.40 ppm), limit of detection (0.10 ppm), solution stability, and robustness. The method was demonstrated to be quadratic over the range of four orders of magnitude from 0.40 to 4000 ppm with a correlation coefficient greater than 0.99 with average recoveries between 86 and 101%. Method performance was also evaluated using sample matrices of different pH values and compositions, and the method was demonstrated to be suitable as a platform test method for the determination of acrylonitrile in the manufacturing process of oligonucleotides. Finally, the degradation kinetics of acrylonitrile in backbone deprotection (1:1 acetonitrile/triethylamine) and ammonolysis (30% NH 3 aqueous) matrices was assessed. Acrylonitrile was demonstrated to degrade quantitatively and quickly in the ammonolysis sample matrix.",10.1021/acs.oprd.0c00527,0
Large Scale Practical Synthesis of Enantiomerically Pure <i>cis</i>-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene,"The development of multikilogram scale green and economical synthetic route of enantiomerically pure cis -4-amino-3-fluoro-1-methylpiperidine 1 is described. The synthesis features a highly regio-, chemo-, and enantioselective asymmetric hydrogenation of N -benzyl-4-(( tert -butoxycarbonyl)amino)-5-fluoro-tetrahydropyridinium chloride 3 . No purification or chiral enrichment is necessary due to the high selectivity resulting from proper selection of the catalyst system Rh(NBD) 2 (BF 4 ) and Walphos 003. The crude product N -benzylpiperidine 4 was carried directly to N -methylpiperidine utilizing a highly effective one-pot debenzylation and reductive amination protocol. The target compound 1·2HCl was prepared in 66–68% overall yield with >99% ee and >98.5% purity from available compound 3-fluoropyridin-4-amine 2 with a process mass intensity of 150.",10.1021/acs.oprd.0c00525,1
Process Development of a Sonogashira Cross-Coupling Reaction as the Key Step of Tirasemtiv Synthesis Using Design of Experiments,"Palladium-catalyzed coupling reactions represent an important tool for modern organic synthesis and have been extensively used in the pharmaceutical industry for the past 30 years to produce active pharmaceutical ingredients (APIs) with complex structures. A case study is discussed in which Hovione studied a palladium-catalyzed Sonogashira coupling reaction using Design of Experiments with the goal of developing an efficient, economical, and robust process to manufacture an API (tirasemtiv) at commercial scale. The most significant factors were studied, and normal operational ranges were defined, supporting risk assessment activities prior to manufacturing campaigns. As a result, API with critical quality attributes always within the required limits was obtained. Removal of residual metals was determined to be critical for the final API quality, leading to the development of an efficient strategy for residual metal removal.",10.1021/acs.oprd.0c00524,0
Development and Scale-Up of a Direct Asymmetric Reductive Amination with Ammonia,"Direct asymmetric reductive amination represents an efficient means of converting ketones to α-chiral primary amines, but reported examples are very limited. We describe the development of two sets of Ru-catalyzed conditions for the direct conversion of an aryl methyl ketone to a pharmaceutically relevant chiral primary amine. In the presence of NH 3, NH 4 Cl, and H 2, a readily available dtbm-Segphos ruthenium catalyst can be used to prepare the desired chiral primary amine with >93% ee on multikilogram scale.",10.1021/acs.oprd.0c00522,0
Crystallization Process Development for the Final Step of the Biocatalytic Synthesis of Islatravir: Comprehensive Crystal Engineering for a Low-Dose Drug,"Islatravir (MK-8591), a highly potent nucleoside reverse transcriptase translocation inhibitor, is being developed to stem the spread of global HIV infections. Following a nine-enzyme in vitro synthesis of islatravir from 2-ethynylglycerol without intermediate isolation, a crude active pharmaceutical ingredient with high levels of biological and chemical impurities must be purified through recrystallization. With efficacy at sub-milligram doses, islatravir requires a robust crystallization method for consistent particle size to meet content uniformity requirements in a tablet. Herein, we outline the development of two robust crystallization methods that deliver purified islatravir with a controlled particle size distribution (PSD) and impurity profile. We present the development and scale-up of a crystallization using a jet-milled seed to control particle size. We also present the development and scale-up of a novel shear-induced nucleation and thermal annealing crystallization (SINTAX) that avoids the use of dry milling. The impacts of the two crystallization processes on impurity rejection, PSD, and processability are highlighted. Thermal annealing of a slurry after secondary nucleation in the SINTAX process is shown to provide substantial purification benefits.",10.1021/acs.oprd.0c00520,0
"Development of a Synthesis Process for a Novel HCV NS5A Inhibitor, Emitasvir","A new approach to the synthesis of Emitasvir (DAG181), a small molecule hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, is described. Enantioselective enzymatic desymmetrization with hydrolases in the synthetical approach can significantly avoid the loss of chiral raw materials in the resolution process. The synthesis route is further optimized and scaled-up to establish a new process that is applied to the preparation of kilogram scales of target active pharmaceutical ingredients (APIs). Compared with our initial process, the overall yield of target API was dramatically improved from 17 to 40%.",10.1021/acs.oprd.0c00519,1
Development of a Robust Scale-Up Synthetic Route for BPR1K871: A Clinical Candidate for the Treatment of Acute Myeloid Leukemia and Solid Tumors,"High Resolution Image Download MS PowerPoint Slide Herein, a robust and scalable procedure for the synthesis of multikinase inhibitor BPR1K871 ( 1, a quinazoline compound bearing a substituted thiazoline side chain), which is a clinical candidate for the treatment of acute myeloid leukemia and solid tumors, is reported. The previously reported medicinal chemistry synthetic route A with seven steps had encountered several issues during scale-up syntheses such as low yields (7.7% overall yield), the formation of inseparable impurities, particularly in the chlorination step, use of hazardous reagents (NaH/DMF), and laborious column chromatography steps for the purification of the products. A step-by-step approach to overcome the above issues was planned and implemented through two similar routes (B1 and B2) on a gram scale and finally through route B3 on a kilogram scale to synthesize 1 . The final optimized synthetic route B3 does not require column chromatography purification steps. It is one step shorter than the original route A and avoided hazardous reagents for the alkylation reaction in step 2. Furthermore, the highlights of the new route B3 include liquid–liquid continuous extraction of compound 13 in step 2, the use of POCl 3 instead of SOCl 2 to minimize the formation of impurities in the chlorination step 3, and telescoped synthesis of key Boc-protected amino intermediate 15 from 13, in high purity. Using the scale-up route B3, the final product 1 (3.09 kg, yield of 16.5% over six steps with an HPLC purity of 97.8%) was obtained in a single batch for preclinical testing and facilitated clinical testing of 1, which is underway.",10.1021/acs.oprd.0c00515,1
Loss on Drying Using Halogen Moisture Analyzer: An Orthogonal Technique for Monitoring Volatile Content for In-Process Control Samples during Pharmaceutical Manufacturing,"Organic solvents and water are routinely used during the synthetic pathway of an active pharmaceutical ingredient (API) and extraction work up, respectively. Residual amounts of solvents and water tend to be strictly controlled at each step of a process as carryover can often negatively affect crystallization or the reactivity of catalysts and/or activating agents. A rapid, accurate, and precise measurement of these attributes is an important part of this overall control strategy. Here, we have developed a loss on drying (LOD) method for measuring total volatile matter for in-process control liquid and solid samples during a small molecule API manufacturing process, which relies on a halogen moisture analyzer with an integrated mass balance. Mixtures of lactose and microcrystalline cellulose with varying water content were prepared and used for evaluating the precision of the LOD technique with varying sample sizes. We have successfully demonstrated here that not only are the moisture measurements using this LOD method comparable to the traditional methods like Karl Fischer (KF) titration and/or gas chromatography (GC) for volatile solvents but also the LOD measurement process is much faster and requires little to no sample preparation. Further, we present a case study of using LOD and KF together to obtain the ratio of water and DMA (a high boiling point solvent), enabling a more efficient manufacturing process as it obviates the need for specialized HPLC or GC methods needed for measuring high boiling solvents such as DMA.",10.1021/acs.oprd.0c00512,0
"Three-Step One-Pot Process of 3-Methyl-5-Benzofuranol from Amine, Aldehydes, and <i>p</i>-Benzoquinone","3-Methyl-5-benzofuranol was prepared by a one-pot process from morpholine, propionaldehyde, and p -benzoquinone in 85–87% isolated yields. Avoiding the tedious multistep isolation and purification operations, this practical and efficient process dramatically enhanced the production efficiency as well as reduced the amount of chemical wastes of reaction. The scale-up results showed that the performance was maintained, suggesting potential large-scale applications. Furthermore, the synthesis strategy showed high efficiency for a wide range of aliphatic aldehydes and ketone derivatives.",10.1021/acs.oprd.0c00507,1
Dimethyl Fumarate: Heterogeneous Catalysis for the Development of an Innovative Flow Synthesis,"The present work describes the development of an improved synthesis of the active pharmaceutical ingredient (API) dimethyl fumarate. The use of continuous flow technology and the newly developed methylation conditions solve some of the issues of previous commercial production strategies, e . g ., reaching complete conversion and avoiding the formation of toxic impurities. The optimization was carried out using the design of experiment approach and afforded a very efficient, sustainable process, suitable for the industrial application.",10.1021/acs.oprd.0c00503,0
"Early Development, Scale-Up, and Reverse-Phase Purification of a Highly Potent Pyrrolobenzodiazepine Dimer, SG3259, for Use in Antibody–Drug Conjugates","Pyrrolobenzodiazepine (PBD) dimers, such as that found in SG3259, are fully synthetic highly potent (subnanomolar) small molecules currently being developed as warheads for antibody–drug conjugates (ADCs). The complete synthetic route toward the linker drug SG3259 has 17 steps, and 10–20 g of drug was needed prior to antibody conjugation for IND-enabling toxicological studies and Phase I clinical trials. Herein, we disclose the enabling route to SG3259, with the final four steps being conducted under GMP conditions. Significant effort was spent developing the preparatory scale reverse-phase HPLC purification of the final linker drug. SG3259 suffers from poor solubility; acid-, light-, and oxygen-sensitivity; and extremely high potency, factors which make this a challenging target for gram-scale development.",10.1021/acs.oprd.0c00497,0
Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development,"Automated reactor and sampling technologies were used in process characterization studies of a cyclization reaction using gaseous ammonia. These data-rich experiments were structured according to a 2 4 full factorial design of experiment, with each experiment having 12 reaction samples at equal time intervals. Data-driven models were established for key reaction responses to create a process fingerprint, to identify the optimal operating conditions under various constraints, and to evaluate the stability of the process. Leveraging these technologies in late-stage reaction characterization enabled significant improvements in efficiency and experimental reproducibility compared to conventional methods.",10.1021/acs.oprd.0c00496,0
Process Development toward a Pro-Drug of <i>R</i>-Baclofen,"This paper describes the process development conducted toward the multi-kilogram synthesis of a novel transported pro-drug of R -baclofen. The key steps in the synthesis were the enzyme-catalyzed kinetic resolution of isopropyl(methylthiocarbonyloxy)methyl-2-methylpropionate using Candida antarctica lipase A to provide the desired ( S )-enantiomer. This was followed by the reaction with sulfuryl chloride and N -hydroxysuccinimide to produce ( S ) 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate. The synthesis of ( S ) 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl 2-methylpropanate enabled the efficient use of R -baclofen in the final coupling stage of the synthesis. The new route reported here is more efficient and sustainable than those reported previously and had the potential to become the commercial route of manufacture.",10.1021/acs.oprd.0c00491,1
An Optimized Scalable Fully Automated Solid-Phase Microwave-Assisted cGMP-Ready Process for the Preparation of Eptifibatide,"High Resolution Image Download MS PowerPoint Slide We investigated several strategies, based on the use of microwave-assisted solid-phase peptide synthesis (MW-SPPS) and scalable to kilogram-scale manufacturing, for the preparation of Eptifibatide, a disulfide-bridged cyclo-heptapeptide drug approved as an antithrombotic agent. Following the very fast microwave-assisted Fmoc/tBu synthesis of the linear precursor, we explored both the solution (off-resin) and the solid-phase (on-resin) disulfide formation. In order to optimize the oxidation in solution, we focused our attention on the mild disulfide formation procedure based on the use of air, observing some drawbacks, such as the formation of unwanted oxidation byproducts, such as dimers, or the use of large volumes of an environmentally unfriendly solvent (CH 3 CN). In order to overcome these difficulties, we studied four different on-resin strategies, with the final aim to develop a fully automated, single reactor procedure, exploring different strategies to protect the thiol side-chain functional group on the C-terminal Cys residue and to form the Eptifibatide ring. The main difference among these strategies is represented by the final cyclization mode that was obtained either by direct formation of an S–S disulfide bridge or by head to MPA on cysteine side-chain amide bond formation. In conclusion, the optimization of the latter strategy enabled us to devise an optimized scalable fully automated solid-phase microwave-assisted cGMP-ready process to prepare Eptifibatide.",10.1021/acs.oprd.0c00490,0
Development and Demonstration of a Co-feed Process to Address Form and Physical Attribute Control of the Gefapixant (MK-7264) Citrate Active Pharmaceutical Ingredient,"The final chemical transformation and isolation in the synthesis of an active pharmaceutical ingredient (API), referred to as the Pure Step, is often chemically simple but scientifically, operationally, and strategically the most challenging. Pure Step development is critical because it is used to determine and support the critical quality attributes (CQAs) for the API, which will have lasting impacts on both the drug substance and drug product processes. This paper will detail specific challenges for the gefapixant (MK-7264) API, which is isolated as a citrate salt crystallized out of methanol and isopropanol. This citrate salt is then formulated via direct compression to make the final dosage form for the patient. This salt crystallization is particularly challenging due to (1) the propensity of the citrate salt crystal to form solvates, (2) the particle size control requirements, and (3) the variability in crude API purity during development (crude API is the starting material for the Pure Step). The project team had to simultaneously execute targeted, rapid process development to support pilot plant API batches, which supplied clinical trials, tech transfer the process to the manufacturing site overseas, and provide requisite experimental data to support characterization and mechanistic understanding. This work has required technical excellence, streamlined collaboration, and flawless communication across the integrated drug substance/drug product space. The comprehensive process development work resulted in the development of a thermodynamically controlled Pure Step crystallization that yields quality gefapixant API for successful and robust drug product processing.",10.1021/acs.oprd.0c00488,0
Development and Implementation of an Aluminum-Promoted Phosphorylation in the Uprifosbuvir Manufacturing Route,"A novel application of the synthesis of pronucleotide (ProTide) 5′-phosphoramidate monoesters promoted by aluminum-based Lewis acids is described. In the multikilogram synthesis of uprifosbuvir (MK-3682, 1 ), a clinical candidate for the treatment of hepatitis C, this methodology provided >100:1 diastereoselectivity at the phosphorus stereocenter and >100:1 selectivity for the 5′-mono phosphorylation over undesired bisphosphorylation side products. The high diastereoselectivity and mono/bis ratio achieved enabled elimination of the tedious workup associated with the tert -butyl magnesium chloride protocol commonly used to install this functionality in similar nucleotide prodrugs, achieving a near doubling of the isolated yield from 45% to 81%. The process development and purity control strategy of MK-3682, as well as handling of the pyrophoric reagent on scale, will also be discussed.",10.1021/acs.oprd.0c00487,1
Application of C–H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib,"This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed C–H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.",10.1021/acs.oprd.0c00486,1
Palladium-Catalyzed C–O Cross-Coupling as a Replacement for a Mitsunobu Reaction in the Development of an Androgen Receptor Antagonist,"A scalable and efficient synthesis of N -{ trans -4-[(8-cyanoquinolin-4-yl)oxy]cyclohexyl}-3-fluorobenzamide (BAY 1161116), an androgen receptor antagonist, is reported. The original synthesis included a low-yielding Mitsunobu reaction and employed cis -aminocyclohexanol, which is accessible only via a troublesome synthesis, as a key building block. The novel synthetic pathway starts from readily available trans -aminocyclohexanol and features a palladium-catalyzed etherification reaction in place of the Mitsunobu reaction as the key step. This four-step synthesis can be performed reliably on a multikilogram scale, and purification of all intermediates as well as the final product can be achieved by simple extraction and crystallization procedures.",10.1021/acs.oprd.0c00484,1
Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction,"New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern–Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proof-of-concept data for the future application of this technology in the clinical manufacture of ceralasertib.",10.1021/acs.oprd.0c00483,1
Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib,"Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An S N Ar reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer–Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.",10.1021/acs.oprd.0c00482,1
Synthesis of Isotopically Labeled Anti-HIV Nucleoside Islatravir through a One-Pot Biocatalytic Cascade Reaction,"We report the synthesis of the carbon-14-labeled unnatural nucleoside islatravir, an investigational HIV drug, through a one-pot biocatalytic cascade starting from acetaldehyde- 2 - 14 C . Combining enzymatic reactions into multistep biocatalytic cascades accelerates delivery and increases the yield, and in this synthesis it has the added benefits of eliminating handling of radioactive intermediates and minimizing radioactive waste.",10.1021/acs.oprd.0c00476,1
Robust Process Scale-Up Leveraging Design of Experiments to Map Active Pharmaceutical Ingredient Humid Drying Parameter Space,"Sugammadex is a modified γ-cyclodextrin active pharmaceutical ingredient (API) that is used as a reversal agent for neuromuscular blockade drugs in general anesthesia. The open structure of the cyclodextrin molecule yields a multitude of solid forms, and to date, more than 12 different mixed methanol solvate/hydrate forms have been characterized. Historically, the kinetic form (type 1) was manufactured to ensure that the solids could be dried successfully using only heat and vacuum to meet the specifications for residual solvents. Isolation of the thermodynamic form (type 2) was avoided due to the inability to remove process solvents to desired levels during drying and the subsequent need to rework the solids. To meet increasing product demand through improved robustness, the process was redesigned to manufacture the thermodynamic form (type 2). Therefore, an improved drying process had to be developed to enable meeting residual solvent levels of the final API at a large scale. Small-scale drying experiments were performed using a custom, in-house, process analytical technology-enabled drying platform to visualize the real-time evolution of the process solvents and water from the solids and to monitor form change. The mechanism for solvent removal in this case was found to be unique since it was independent of API crystallinity. The key element for successful drying was the displacement of solvent by water molecules, regardless of whether the crystal structure remained intact or collapsed. A predictive model was developed through design of experiments including three-factor interactions of drying humidity, temperature, and pressure, and the model was used to define the operating space to ensure successful drying. The humid drying conditions identified in this study were implemented across scales to ensure that residual solvent specifications were achieved regardless of the crystalline form generated.",10.1021/acs.oprd.0c00475,0
"Large-Scale Production of C<sub>9</sub> Aromatic Hydrocarbon Resin from the Cracked-Petroleum-Derived C<sub>9</sub> Fraction: Chemistry, Scalability, and Techno-economic Analysis","Conversion of olefin-rich side streams of petroleum distillate cracking operations, pyrolysis gasoline (pygas), to hydrocarbon resins (HRs) represents a promising technology to upgrade the pygas byproduct and facilitate pygas valorization. Several methods have been reported for the synthesis of C 9 HRs on a laboratory scale, but none has been implemented on a commercial scale. Owing to the lack of information on C 9 -HR production know-how, the current publicly available technical and financial performance analyses regarding industrial-scale C 9 HR manufacturing are insufficient to justify its feasibility. Herein, the large-scale synthesis of C 9 HR from the steam-cracked petroleum-derived C 9 fraction by two proposed catalytic polymerization processes has been developed. Two C 9 -HR manufacturing processes are divided into two processing areas, which include synthesis and purification/product recovery sections. The P-HO process is based on the catalytic co-oligomerization of the C 9 fraction as the feed, which ends after the alkali decomposition of the catalyst followed by product recovery by vacuum distillation. The P-HE process uses the same reactor, which ends after catalyst filtration followed by product recovery using vacuum distillation. The laboratory-scale experiments were performed to collect inputs for process simulation. A set of targeted experiments including the increase of the scale from the laboratory ( V L = 0.0005 m 3 ) to pilot plant ( V P = 0.1 m 3 ) were performed and the impact of scaling up the processes from the lab and bench to the pilot scale at equal process conditions was investigated. The differences in the HR production rate between the two scale types for the P-HO scenario are slightly greater than for the P-HE scenario. On the basis of data derived from the experimental work, a model of a large-scale installation for the production of C 9 HR with the production rate of 160 metric ton (MT)/year was developed using the Aspen Hyprotech System (HYSYS) v8.8 simulation program. The obtained data from the relevant literature and vendor were used for process equipment design and pricing. Economic feasibility showed that the P-HO scenario has more efficiency and less risk-taking than the P-HE scheme (because of valuable net present value (NPV) $10 977 billion, larger internal rate of return (IRR) 44.01% at $1900/T HR selling price, and less fluctuation against sensitivity analysis parameters).",10.1021/acs.oprd.0c00474,0
Di- <i>tert</i> -butyl Phosphonate Route to the Antiviral Drug Tenofovir,"Di- tert -butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di- tert -butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(O t Bu) 2 as the base for the alkylation of ( R )-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di- tert -butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale).",10.1021/acs.oprd.0c00473,1
Case-Based Thermal Safety Evaluation on a Pharmaceutical Process Using Dimethyl Sulfoxide as a Solvent,"A rupture disc burst was recorded when conducting a calorimetric test by sensitive detection of exothermic reaction. The tested sample was a reaction mixture from a hydroamination process containing the solvent dimethyl sulfoxide (DMSO). Subsequent investigation indicated that the event was caused by the strong autocatalytic decomposition of DMSO. The hazardous decomposition of DMSO that could be initiated by an inadvertent contact with substances involved in the process was studied. Furthermore, risk evaluation on the process thermal runaway was carried out based on the cooling failure scenario. In this particular case, although Stoessel criticality class 2 was assigned, the boiling point of DMSO could not serve as the safety barrier. On the basis of the thermal safety evaluation, the hydroamination process was safely scaled up in the Novartis pilot plant and successfully launched in a commercial production unit. This investigation highlights that every scale-up process involving DMSO as a solvent should be carefully evaluated owing to the potential safety concern caused by its autocatalytic behavior.",10.1021/acs.oprd.0c00472,0
Development of a Scalable and Sublimation-Free Route to MTAD,"The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation.",10.1021/acs.oprd.0c00470,1
Development of a Scalable Method for Manufacturing the Central Core of CD73 Inhibitor AB680,"AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the manufacturing of the azaindazole central core. This synthesis features an N -oxide formation followed by an α-chlorination with POCl 3 leading to the formation of 4,6-dichloro-1 H -pyrazolo[3,4- b ]pyridine 1 in high yield and 99.5% UV purity. This method was successfully performed on multikilogram scale to support the synthesis of AB680.",10.1021/acs.oprd.0c00469,1
Heterogeneous Crystallization as a Process Intensification Technology in an Integrated Continuous Manufacturing Process for Pharmaceuticals,"Continuous heterogeneous crystallization processes in mixed-suspension mixed-product removal (MSMPR) crystallizers of different configurations (e.g., single-stage cooling, multistage cooling, and multistage evaporative cooling) are developed, in which an active pharmaceutical ingredient (acetaminophen, APAP) is crystallized directly on the surfaces of both porous and nonporous polymer excipient substrates (poly(vinyl alcohol), PVA). The heterogeneous crystallization step is part of an integrated continuous manufacturing (ICM) processing train, which starts from raw materials and includes chemical synthesis, crystallization, filtration, and drying. The product from this ICM process is a stream of dried composite particles (i.e., APAP on PVA substrates) that are directly compressed into tablets, eliminating the need for any further processing steps (e.g., milling, sieving, blending, and granulation). The dried composite particles are characterized with scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction. The use of porous polymer substrates (instead of nonporous substrates) increased the crystallization yield by >4× in one set of experiments. In subsequent experiments, the use of porous polymer substrates reduced the risk of bulk nucleation (due to increased internal free volume and surface area) in an evaporative-cooling MSMPR crystallization system. Yields as high as 71% and drug loadings as high as 61.1 ± 2.8% were observed with this evaporative-cooling MSMPR system. Furthermore, it is shown that by altering the suspension density of the excipient particles, the drug loading of the composite particles can be controlled. Finally, the design of the ICM process is discussed. The use of heterogeneous crystallization as a process intensification technology (e.g., incorporation into an end-to-end ICM pharmaceutical production process) has the potential to reduce overall system complexity, capital investment, and operating costs on the commercial scale by reducing the number of downstream processing steps that are required.",10.1021/acs.oprd.0c00468,0
Explosive Hazard Identification in Pharmaceutical Process Development: A Novel Screening Method and Workflow for Shipping Potentially Explosive Materials,"When a material is identified as potentially capable of explosive propagation by the Yoshida correlation, process safety scientists have few options for semiquantitatively assessing the hazards associated with the use of that material. Oxygen balance calculations, the Rule of 6, and the United Nations (U.N.) explosive functional group list are commonly employed qualitative/semiquantitative methods to assess explosivity without requiring additional experimental data. In contrast, a full United Nations Transportation of Dangerous Goods testing regimen requires, at a minimum, 2 kg of material for Test Series 1 alone, an excessive amount that is rarely available in early pharmaceutical development. A new assessment, called the O.R.E.O.S. method, has been developed that combines the three traditional methods for screening of explosive properties ( O xygen balance calculations, the R ule of 6, and the E xplosive functional group list) with the O nset of decomposition determined by differential scanning calorimetry and the proposed S cale. This new assessment has been applied to known energetic materials that are flagged as potentially capable of explosive propagation by the Yoshida correlation and has been shown to be effective at classifying materials in a scale-dependent manner. The tool is customizable to fit any organization’s internal guidance on handling energetic materials. This assessment should find wide utility in both pharmaceutical development groups and contract research organizations as a means to classify compounds that may require further testing before scale-up or to steer project teams to discover safer alternatives. A brief description of the challenges associated with transporting materials for U.N. Series Testing is also presented with the aim of demystifying the process for obtaining such valuable data.",10.1021/acs.oprd.0c00467,0
Process Development and Protein Engineering Enhanced Nitroreductase-Catalyzed Reduction of 2-Methyl-5-nitro-pyridine,"Reduction of aromatic nitro compounds to anilines is of great interest to the chemical industry. Biocatalytic reduction of nitroarenes has made it possible to effectively produce anilines by applying nitroreductase enzymes (NR) in combination with vanadium pentoxide. Herein, the NR-catalyzed reduction of 2-methyl-5-nitro-pyridine ( 2 ) to give the desired aniline ( 1 ) was studied as a model reaction. It demonstrates the importance of process development and enzyme engineering as key approaches to overcome scale-up issues and improve yield and productivity. Moving to fed-batch allowed controlling the feeding rate of 2 to prevent the accumulation of intermediates and formation of undesired side products. Starting with a substrate ( 2 ) concentration of 200 mM (28 g/L) and enzyme loading of 5 mg/mL (18% w/w), it was possible to achieve complete conversion and 1 in 95% yield by high-performance liquid chromatography (89.1% isolated yield) over 18 h, whereas, with 500 mM (69 g/L) 2 and an enzyme loading of 10 mg/mL (14.5% w/w), the same conversion and yield were achieved in 26 h. A rational engineering of NR-4 yielded faster variants, including NR-5, in only one round. The improved rate of the new variants allowed increasing the feeding rate of 2 to shorten the reaction time to less than a day as well as decreasing the enzyme loading to 3.6%.",10.1021/acs.oprd.0c00464,0
"An Easy, Convenient, and Safe Process for the Synthesis of Lofexidine Hydrochloride","A very efficient, cost-effective, and easily scalable process for the synthesis of lofexidine hydrochloride ( 1 ), an alpha 2-adrenergic receptor agonist used for treating opioid withdrawal is presented. Process development allows the preparation of lofexidine hydrochloride ( 1 ) through a one-pot amidation/imidazoline ring formation reaction, starting from ethyl 2-(2,6-dichlorophenoxy)propionate ( 13 ) and ethylenediamine ( 5 ) by the action of titanium isopropoxide. The required intermediate ethyl 2-(2,6-dichlorophenoxy)propionate ( 13 ) can efficiently be obtained through O -alkylation of 2,6-dichlorophenol ( 2 ) with ethyl 2-chloropropionate ( 12 ) using potassium carbonate as an acid-scavenger agent.",10.1021/acs.oprd.0c00453,1
Characterization of Propionyl Phosphate Hydrolysis Kinetics by Data-Rich Experiments and In-Line Process Analytical Technology,"In-depth characterization of reaction kinetics often requires a considerable amount of experimental results under various conditions. Recent advances in data-rich experimentation enable the collection of sufficient data to investigate reactions with only a limited number of experiments. In this study, we developed a cost-efficient, robust approach by utilizing data-rich experimentation to characterize propionyl phosphate hydrolysis reaction kinetics. Specifically, an Fourier transform infrared (FTIR)-based process analytical technology (PAT) and off-line NMR calibration allowed the establishment of a quantitative FTIR multivariant model. This PAT was then integrated with repeated temperature scanning (RTS) to generate a massive database in a single experiment. The data were subsequently used for kinetic analysis, and two key characteristic reaction parameters (the activation energy and pre-exponential factor) were determined on the basis of the assumption of first-order kinetics. We envision that the integrative platform developed in this study can be broadly applied to investigations of the kinetics of a wide range of similar liquid-phase reactions.",10.1021/acs.oprd.0c00451,0
Development of Scalable Routes to 1-Bicyclo[1.1.1]pentylpyrazoles,"The application of bicyclo[1.1.1]pentanes (BCPs) as phenyl bioisosteres has garnered significant attention, as these structural motifs can improve the physiochemical profiles of drug candidates. Despite the potential of using 1-bicyclo[1.1.1]pentylpyrazoles (BCPPs) as 1-phenylpyrazole bioisosteres, this area remains underexplored because of the relative lack of reliable synthetic methods for the preparation of BCPPs. Herein we address this synthetic gap and report the development of novel and scalable routes to generate a host of BCPPs.",10.1021/acs.oprd.0c00446,0
"Preparation of Carbamates, Esters, Amides, and Unsymmetrical Ureas via Brønsted Acid-Activated <i>N</i>-Acyl Imidazoliums","We report the application of Brønsted acid–activated N- acyl imidazoliums as versatile intermediates in carbonyl transformations. The efficient and scalable procedure was validated on a diverse set of carbamates, esters, amides, and unsymmetrical ureas (21 examples, up to 91% yield). Additionally, we exemplify this method on multikilogram scale for the synthesis of an electron-deficient carbamate.",10.1021/acs.oprd.0c00445,0
Development of a Scalable Synthesis of <i>trans</i>-4-Fluorocyclohexylamine via Directed Hydrogenation,"Herein, a scalable and practical process to prepare trans -4-fluorocyclohexylamine hydrochloride ( 1a ) is described. By exploitation of the embedded gem -difluoride motif in the commercially available 4,4-difluorocyclohexanecarboxylic acid, a derived orthoester-masked acid underwent dehydrofluorination to provide the requisite vinyl fluoride for a directed hydrogenation event, enabling selective access to the trans -configuration of 1a .",10.1021/acs.oprd.0c00444,1
Implementing Continuous Manufacturing for the Final Methylation Step in the AMG 397 Process to Deliver Key Quality Attributes,"In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and detailed NMR analysis of the final step identified that rapid base addition and the presence of stoichiometric water were critical to ensure consistent levels of reaction conversion and to obtain the desired active pharmaceutical ingredient (API) in high purity. As a result, a continuous process was developed to facilitate the rapid base addition and short deprotonation residence time, ensuring reliable process performance on a multi-kilogram scale. The AMG 397 GMP manufacture, comprised of the continuous reaction process and semi-batch isolation, delivered the final API in high purity (>99%) and yield (76%), exceeding the API specifications. The lessons learned from the manufacturing campaign, which include equipment clogging and loss of tubing integrity, are discussed and drove the development of a second-generation continuous process to improve reaction processing for future deliveries. The second-generation process has not encountered the challenges of the GMP campaign due to the implementation of important equipment modifications, and the improved process has been successfully demonstrated on a 100 g scale.",10.1021/acs.oprd.0c00440,0
Synthesis of Rovafovir Etalafenamide (Part II): Dynamic Control for Successful Scale-Up of an Oxygen-Releasing Elimination Reaction Mediated by Oxone,"As part of the synthesis of rovafovir etalafenamide, the development and manufacturing-scale demonstration of a dioxirane-mediated oxidative elimination is described. The reaction presented multiple control challenges, including simultaneous addition of two reagent streams, with monitoring and control of temperature and pH in a biphasic mixture, and preventing explosive oxygen levels from building in the reactor headspace. The manuscript describes our evaluation of these challenges and our approach for performing this chemistry at pilot and manufacturing scale, including the development of a cyclic processing strategy that allowed us to substantially reduce processing volumes and improve reaction throughput.",10.1021/acs.oprd.0c00439,0
Large-Scale Synthesis of Eldecalcitol,"Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p -methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-3 positions of the A-ring fragment. Selective protecting group manipulation followed by palladium-catalyzed cyclization then provides the A-ring synthon. The C/D-ring fragment is obtained by (1) direct C-H hydroxylation of Grundman’s ketone using in situ prepared trifluoropropanone dioxirane and (2) protection. Finally, the coupling of the A-ring with the C/D-ring fragment, global deprotection, and recrystallization provide the highly crystalline eldecalcitol.",10.1021/acs.oprd.0c00436,1
Safe and Expeditious Preparation of Ni(cod)<sub>2</sub>for Same-Day High-Throughput Screening,"There is an ongoing effort in the catalysis community to replace precious metal catalysts with their base-metal congeners, especially by applied chemists. This is particularly true in the case of nickel and palladium, the latter of which has experienced supply shortages and a concomitant rise in price over the past year. Ni(cod) 2 (cod = 1,5-cyclooctadiene) continues to be the flag-bearing precatalyst for nickel-catalyzed transformations on account of its versatility and commercial availability, but is plagued by diseconomies originating from limited shelf life and air/temperature sensitivity. The inconsistent purity of Ni(cod) 2 samples over time introduces an element of uncertainty in small-scale catalytic reaction tests such as those employed in high-throughput experimentation (HTE). We provide herein a method by which high-quality 1-g batches of Ni(cod) 2 can be prepared easily in 20 min using no pyrophoric reagents, allowing HTE studies with this catalyst to be performed directly after its preparation, reducing such uncertainty.",10.1021/acs.oprd.0c00435,0
Synthesis of Rovafovir Etalafenamide (Part III): Evolution of the Synthetic Process to the Phosphonamidate Fragment,"Phosphonamidate 1 is a key fragment in the assembly of rovafovir etalafenamide, a novel nucleotide reverse transcriptase inhibitor under development at Gilead Sciences for the treatment of HIV infection. An early manufacturing route, relying on simulated moving bed (SMB) chromatography for the separation of phosphorus diastereomers, was executed on scale to produce multiple batches of 1 . However, developing alternative synthetic conditions became desirable in consideration of the high production cost, long lead time, and high process mass intensity (PMI) associated with SMB. Several strategies to improve these factors are described herein, including epimerization and recycling of the undesired ( R )-phosphorus diastereomer, design of stereoselective approaches to establish the desired (S)-configuration at phosphorus, and identification of conditions or derivatives to allow for selective crystallization. Ultimately, a second-generation route to 1 was developed and demonstrated on scale. The new route achieves the separation of phosphorus diastereomers by means of selective crystallization, does not require SMB, and offers lower PMI, cost, and lead time.",10.1021/acs.oprd.0c00428,1
"Synthesis of Vixotrigine, a Voltage- and Use-Dependent Sodium Channel Blocker. Part 2: Development of a Late-Stage Process","As vixotrigine ( 1 ) entered a later clinical phase for trigeminal neuralgia ( Zakrzewska, J. M.; et al. Lancet Neurol. 2017, 16, 291−300), the development of a sustainable late-stage process was required to meet the supply needs for formulation optimization, phase 3 clinical trials, and registration stability batches (this is the expected commercial formulation). In this article, we describe how the process was streamlined from the early supply route ( Giblin, G.; et al. Org. Process Res. Dev. 2020, DOI: 10.1021/acs.oprd.0c00382 ) and a comprehensive control strategy was established. Process improvements included improving safety and scalability for a temperature-sensitive Grignard reaction, simplifying unit operations, removal of heterogenous conditions, and route redesign to afford a high yielding, one-pot sequential alkylation and amidation. Improvement in the salt formation step, combined with wet milling, resulted in improved particle properties with enhanced flow properties of the final active pharmaceutical ingredient. The process mass intensity was improved 65% while maintaining drug substance purity at more than 99.8%. This new process has been scaled up to generate metric ton quantities of drug substance.",10.1021/acs.oprd.0c00427,1
Development and Scale-Up of a Continuous Manufacturing Process for a Hydrazine Condensation Reaction,The development of a continuous manufacturing process for a hydrazine condensation reaction at high temperature is reported. This continuous process represents a safer approach to manufacture 3-phenyl-1 H -pyrazol-5-amine at scale and exhibits better impurity control compared to a traditional batch process. A controlled crystallization allowed consistently low levels of residual hydrazine (<20 ppm) in isolated solids for further processing to final drug substance. The scalability and robustness of the continuous process was demonstrated at 3 kg scale with a throughput of 0.5 kg/h.,10.1021/acs.oprd.0c00424,0
"Stereoselective Synthesis of a<i>cis</i>-Cedrane-8,9-diol as a Key Intermediate for an Amber Odorant","The naturally occurring (−)-α-cedrene exhibits a weak woody and cedarlike odor. In contrast, cis -cedrene acetonide, which is a derivative of cedrene, is an extremely powerful semisynthetic aroma molecule. The current process starting from cedrene yields cis -cedrene acetonide in an overall yield of <20%. Herein, we report two synthetic pathways toward this valuable product starting either by isomerization of commercially available cedrene epoxide or by photo-oxidation of (−)-α-cedrene to an allylic intermediate. The key step of the synthesis is the epoxidation of the protected or even unprotected allyl alcohol followed by the reductive opening of the epoxide. This reaction sequence leads to the respective cis -diol with the correct stereochemistry. Subsequent acetalization gives cis -cedrene acetonide in up to 78% overall yield. We also report our attempt to prepare the cis -diol with inverted stereochemistry. In this context, we inverted the configuration of the allylic alcohol via a Mitsunobu reaction. However, only the acetyl-protected alcohol could be epoxidized, leading the undesired trans -product in >99% yield.",10.1021/acs.oprd.0c00423,0
"Process Research and Scale-Up Synthesis of 3-(4-Isobutyl-2-methylphenyl)propanal, a Safe and Uniquely Performing Perfumery Ingredient","Ever since the beginning of modern perfumery, muguet (lily-of-the-valley) notes have been sought after and are now found in varying doses in practically every perfume composition, accounting for the warm, soft, and comforting facets of many fragrances. Over the past decades, Lilial and Bourgeonal have evolved to become popular and inexpensive ingredients to satisfy the high demand of such floral odors. However, the search continues for more performing ingredients, especially in this odor family. Through this effort, 3-(4-isobutyl-2-methylphenyl)propanal (Nympheal) was identified as a modern, more performing, and benign alternative to the traditional ingredients. In particular, it outperforms Lilial in a sense that it has a linden blossom, a floral aldehydic odor considered to be more natural in its character. This paper details the challenge to design an efficient synthesis for the multi-kilogram production of the fragrance ingredient Nympheal. The methyl group, strategically placed in the 2-position to ensure the biological safety of the ingredient, also introduced a level of asymmetry into the molecule resulting in regiochemical challenges to identifying potential synthetic routes. Route scouting for this initial scale-up was performed using 1-isobutyl-3-methylbenzene as a feedstock made by continuous dehydrogenation of a mixture of 3- and 5-isobutyl-1-methylcyclohex-1-ene. Different routes were explored for introduction of the propanal moiety including carbonylation, Heck reaction, and Friedel–Crafts reaction. Ultimately, 3.3 kg of Nympheal was prepared by electrophilic bromination of 1-isobutyl-3-methylbenzene, followed by reaction with magnesium and dimethylformamide to give the corresponding benzaldehyde, which was then reacted with ethyl vinyl ether by the procedure from Muller-Cunradi–Pierroh and hydrogenated to give the desired product.",10.1021/acs.oprd.0c00421,1
Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach,"AMG 176 is a drug candidate in our oncology pipeline. Ring-closing metathesis (RCM) is a key reaction in the AMG 176 synthesis that is used to construct the 16-membered macrocycle. Process intensification was executed on a compressed timeline by combining high-throughput experimentation and computational analysis using density functional theory, which led to the identification of an optimal 4-bromobenzoate protecting group on the allylic alcohol moiety. Comprehensive process improvements led to a reduction in reaction volume from 800 to 50 L/kg with a >20% yield improvement compared with the discovery route. The RCM process developed from these studies was instrumental in the clinical advancement of the AMG 176 program.",10.1021/acs.oprd.0c00416,0
Development of a Scalable Negishi Cross-Coupling Process for the Preparation of 2-Chloro-5-(1-(tetrahydro-2<i>H</i>-pyran-2-yl)-1<i>H</i>-pyrazol-5-yl)aniline,"A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-5-yl)aniline ( 1 ), a key intermediate in the synthesis of an immuno-oncology asset, is described. A Negishi cross-coupling between in situ generated heteroaryl zinc reagent 4 and 5-bromo-2-chloroaniline ( 3 ) catalyzed by Pd(Xantphos)Cl 2 enabled the construction of the key aryl–heteroaryl bond. A scalable first-generation process was developed that delivered 1 in multikilogram quantities. Building upon knowledge from the initial process, a more efficient workup and isolation procedure was developed that controlled levels of residual Pd and Zn to consistent levels that were acceptable for downstream processing. The high-yielding optimized process offers streamlined metals remediation, a 30% reduction in the number of unit operations, and a 34% reduction in process mass intensity (PMI) compared to the initial process.",10.1021/acs.oprd.0c00414,1
Characterization of a Novel Drying Technology for Continuous Processing of Cohesive Materials: An Ibuprofen Case Study,"This work addresses the influence of several process parameters on the performance of a novel drying device (patent NL2020740B1). In the new dryer, the processed substance is conveyed through the grooves of a large rotor via an interlocking screw design. A gentle, forced flow is created, preventing agglomeration and attrition and enabling a new technology of continuous drying for poorly flowing substances, which are often applied in the pharmaceutical industry. Drying test runs are performed using water-wetted ibuprofen, a nonsteroidal anti-inflammatory drug with poor material flow properties. The substances were tested according to their size, shape, and flow properties prior to the test runs. The process parameters in question were the temperature, mass flow, air flow, rotational speed, and initial moisture. Additionally, test runs to estimate the drying mechanism and the long-term process behavior, as well as reprocessing tests of the substance ibuprofen, were executed. It was shown that the dryer’s performance for cohesive materials was optimal (continuous process times of up to 10 h were possible with evaporation rates up to 688 g/h). The process was robust, with a few drawbacks related to materials that are prone to tribocharging.",10.1021/acs.oprd.0c00413,0
"Merging Biocatalysis, Flow, and Surfactant Chemistry: Innovative Synthesis of an FXI (Factor XI) Inhibitor",The scalable synthesis of an FXI (Factor XI) inhibitor employing multiple emerging technologies is described. The reduction of ketone to chiral alcohol was established through a biocatalysis approach. The Suzuki–Miyaura cross-coupling reaction was facilitated by surfactant chemistry. A harsh hydrolysis of the nitrile was performed in a continuous manufacturing mode. Extensive reaction optimization and process development led to a well-controlled protocol for scale-up. The alternative approach described here addressed issues from the discovery route and was utilized to deliver the desired target for preclinical studies.,10.1021/acs.oprd.0c00412,1
Development of a Continuous Crystallization Process of the Spironolactone Hydrate Form with a Turbidity-Based Level Control Method,"In this study, a robust continuous antisolvent crystallization method was developed to produce the hydrate form of spironolactone. Continuous crystallizations were implemented in a one-stage mixed-suspension mixed-product removal crystallizer using a process turbidimeter as a fluid level sensor for the first time. The feed and removal rates were controlled by pumps using the signal of a turbidimeter in noncontact mode to maintain a constant fluid level and long-term steady-state operation. The chord length distribution of the crystal suspension was monitored online with a focused beam reflectance measurement probe in our custom-designed measurement cell in which the withdrawn suspension was representative of the crystallizer’s content. The effects of process parameters on the particle size distribution of the products were investigated by full factorial design of experiments. Crystals were produced with monomodal distribution and with d 90 ranging from 7 to 62 μm. The temperature and antisolvent ratio were found to be significant process parameters. Compared to batch operation, these parameters had a larger effect on particle size; moreover, the antisolvent ratio became a key factor in the design of particle size distribution.",10.1021/acs.oprd.0c00409,0
Precise Preparation of a High-Purity Key Intermediate of Tazobactam,"In situ IR was used to precisely prepare high-purity diphenylmethyl 6α-bromopenicillanate 8, a key intermediate of tazobactam. 8 was obtained when 6α-bromopenicillanic acid 2 reacted with diphenyldiazomethane (DDM). 2 is unstable and must therefore react immediately with DDM upon preparation. DDM is also unstable. As DDM decomposes rapidly upon preparation, the DDM content cannot be precisely determined using high-performance liquid chromatography (HPLC) or gas chromatography (GC). Therefore, good yield and purity are difficult to obtain, resulting in large batch-to-batch variations (yield 69.3–82.8%, purity 89.8–98.4%) for 8 . The developed preparation method for 8 involved the use of in situ IR to monitor the reaction process and achieved good results (82.7–83.1% yield and 97.3–98.5% purity). This method was also used to prepare the key intermediate for the synthesis of cephalosporin derivatives, which have high industrial value.",10.1021/acs.oprd.0c00407,1
Flow Chemistry Enabling Efficient Synthesis,"ADVERTISEMENT RETURN TO ISSUEEditorialNEXTFlow Chemistry Enabling Efficient SynthesisJohn R. Naber*John R. NaberMerck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United StatesInstitute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, AustriaPharma Resource Group Inc., 1005 Pontiac Road, Drexel Hill, Pennsylvania 19026, United States*Email: [email protected]More by John R. Naberhttp://orcid.org/0000-0002-4390-3467, C. Oliver Kappe*C. Oliver KappeMerck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United StatesInstitute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, AustriaPharma Resource Group Inc., 1005 Pontiac Road, Drexel Hill, Pennsylvania 19026, United States*Email: [email protected]More by C. Oliver Kappehttp://orcid.org/0000-0003-2983-6007, and Jaan A. Pesti*Jaan A. PestiMerck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United StatesInstitute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, AustriaPharma Resource Group Inc., 1005 Pontiac Road, Drexel Hill, Pennsylvania 19026, United States*Email: [email protected]More by Jaan A. PestiCite this: Org. Process Res. Dev. 2020, 24, 10, 1779–1780Publication Date (Web):October 16, 2020Publication History Published online16 October 2020Published inissue 16 October 2020https://pubs.acs.org/doi/10.1021/acs.oprd.0c00406https://doi.org/10.1021/acs.oprd.0c00406editorialACS PublicationsCopyright © 2020 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3893Altmetric-Citations6LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (637 KB) Get e-AlertscloseSUBJECTS:Chemical engineering and industrial chemistry,Industrial manufacturing,Molecules,Pharmaceuticals Get e-Alerts",10.1021/acs.oprd.0c00406,0
"Developing a Multistep Continuous Manufacturing Process for (1<i>R</i>,2<i>R</i>)-2-Amino-1-methylcyclopentan-1-ol","A multistep continuous manufacturing process to synthesize (1 R,2 R )-2-amino-1-methylcyclopentan-1-ol ( 2 ) was developed. The step 1/2 flow process mitigated the safety hazard associated with high exothermicity during epoxidation, the epoxide-opening reaction, and the low onset of the epoxide intermediate. Process improvements included a hybrid plug flow reactor (PFR)/continuous stirred tank reactor (CSTR) reaction and a continuous quench/work-up process in step 1; a continuous reaction, extraction, washing, and thin-film distillation work-up in step 2; and a continuous trickle bed hydrogenation in step 3, which provided the desired product with high purity and high ee. The end-to-end continuous process provided significant advantages of cost-saving, minimization of manufacturing space and utilities, and reduction of the cycle time.",10.1021/acs.oprd.0c00405,1
"Development of a Novel Chemoenzymatic Process for (<i>S</i>)-1-(Pyridin-4-yl)-1,3-propanediol","We first developed a novel and efficient chemoenzymatic process to prepare ( S )-1-(pyridin-4-yl)-1,3-propanediol, a vital HepDirect prodrug intermediate, from inexpensive and commercially available isonicotinic acid. Through this process, we provide a creative way to obtain the key chiral intermediate, β-hydroxyester, with ketoreductase (KRED) EA. After optimization of the process, we performed the reaction on a 100 g scale with a substrate concentration of up to 150 g/L, a yield of 93%, and an ee value of up to 99.9%. Additionally, we used a simple and effective NaBH 4 /MgCl 2 reduction system to obtain ( S )-1-(pyridin-4-yl)-1,3-propanediol with >99.9% ee and an 80% yield. This novel chemoenzymatic process has the potential to be a cost-effective and environmentally friendly process suitable for industrial use.",10.1021/acs.oprd.0c00403,1
Scalable Continuous Synthesis of Organozinc Reagents and Their Immediate Subsequent Coupling Reactions,"The continuous synthesis of organozinc reagents and their immediately following subsequent also continuous consumption in catalyzed and noncatalyzed coupling reactions were investigated. In the first step, a bed of Zn turnings at variable liquid throughputs and concentrations of organic halide solutions was used, and the formed Zn organometallics were analyzed for quality control. They were then directly pumped into a second step, namely, Reformatsky, Saytzeff, and Negishi coupling reactions. In the organozinc halides’ formation, a novel process window was employed by using a large molar excess of Zn turnings and investigating mechanical as well as chemical Zn activation. Subsequent couplings of the freshly prepared Zn organometallics were done using examples of a Reformatsky, Saytzeff, and Negishi coupling reaction. For the Zn organometallics’ formation, a laboratory-scale reactor setup previously built for Grignard reagent formation was evaluated including a Zn replenishing unit; the same reactor was also used in the metal-catalyzed subsequent step (Negishi coupling). The main objective of this work was to establish the scalable continuous formation of Zn organometallic reagents enabling fast and safe process optimization, analyze the reagents for their purity, and then immediately consume them in various follow-up steps, always only leaving a very small amount of reactive and sensitive organometallic reagent in the setup. It was found that full conversion of the employed halides could be achieved within a single passage through the reactor with organozinc yields of 82–92%, as well as being able to successfully perform subsequent non- and metal-catalyzed coupling steps with yields of up to 92%. A pilot-scale setup allowing a liquid throughput of up to 3–5 L/h has also been built and is ready to be tested with the synthesis as established here.",10.1021/acs.oprd.0c00399,0
Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review,"This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous crystallizers, their engineering advantages/disadvantages, the introduction of the solid form structuring to continuously oriented chemical production, and the usage of the online process analytical technology (PAT) methodologies in interacting functional systems. Furthermore, mechanistic multiscale modeling, whose understanding is of decisive importance for further control application development, was thoroughly discussed as well. The multiscale modeling section also includes the simulation of processes and the optimization of crystallizers. In the last section, model-based predictive control (MPC) is considered, which also covers the intensification approach methods in the field of crystal formation and the introduction of new, highly potential continuous systems, e.g. the coiled flow inverter (CFI) crystallizer, in industry and academia. In the mentioned main sections, individual theme-related articles are collected, discussed, and compared; therefore, a reader can get acquainted with pieces of research, their found results, which have been developed until now, and various emerging perspectives. With regard to the importance of crystallization in the pharmaceutical industry, a reader can already find literature on continuous crystallization. However, due to the growing tendency toward the synthesis of products with specific properties which cannot be achieved with conventional approaches, more attention has been paid in the present work to the establishment of continuous systems for the production of specific fine chemicals. In addition, continuous crystallization could also enable more efficient and ""on-demand"" production, modeling for optimization, MPC, and intensification approaches. A review of the literature classifying studies according to the choice of a continuous system and their description was omitted in this study, as such reviews are already available in the literature.",10.1021/acs.oprd.0c00398,0
"Scalable, Telescoped Hydrogenolysis–Enzymatic Decarboxylation Process for the Asymmetric Synthesis of (<i>R</i>)-α-Heteroaryl Propionic Acids","Enantiopure α-aryl propionic acids are useful building blocks for pharmaceutical research and can be accessed enzymatically using arylmalonate decarboxylases (AMDases) from the corresponding malonic acids. However, the intrinsic instability of malonic acids is a major drawback to this approach in which spontaneous decarboxylation can occur, subsequently eroding enantioselectivity and giving rise to racemic products. This was particularly evident for a panel of N-heterocyclic propionic acids that we wished to access using the approach. Herein, we describe a process to overcome the spontaneous decarboxylation problem in which hydrogenolysis of the corresponding dibenzyl malonates was performed in a biphasic toluene–basic aqueous buffer mixture and telescoped into the subsequent AMDase step. This procedure enabled compounds to be accessed in high enantioselectivities and was successfully demonstrated on 120 g with high yield (76%) and ee (98%).",10.1021/acs.oprd.0c00397,1
Short Gram-Scale Synthesis of Sulfavant A,"Recently, we reported the promising activity of a novel class of sulfoquinovosyl-diacylglycerols named Sulfavants as molecular vaccine adjuvants. Herein, we describe a modified and improved chemical synthesis of the lead product Sulfavant A ( 1 ), with the aim to produce from milligrams to 10 g of the pure compound that is necessary for the preclinical development. Starting from the versatile synthesis based on the trichloroacetimidate methodology, up-scaled preparation of Sulfavant A ( 1 ) was achieved in 11 steps by elimination and modification of those reactions that negatively affected the overall yield by the previous procedure. The novel strategy gave 17% overall yield of the target compound 1 and also paved the way for the gram-scale preparation of a wide range of other charged and neutral glycoglycerolipids.",10.1021/acs.oprd.0c00393,1
High-Throughput Synthesis of (<i>S</i>)-α-Phellandrene through Three-Step Sequential Continuous-Flow Reactions,"The combination of continuous-flow processing with heterogeneous catalysts allows for efficient, sustainable, multistep synthesis. Here, we report the continuous-flow synthesis of a valuable terpene product, phellandrene, from a readily available natural feedstock. The protocol consists of selective hydrogenation using a highly active and stable supported platinum catalyst, dehydrative hydrazone formation, followed by the Shapiro reaction. Appropriate design of the reactor allowed for high productivity and space–time yield. Phellandrene was synthesized on a 30-g scale over 6 h, giving high yields, purity, and productivity.",10.1021/acs.oprd.0c00391,1
Design and Commercialization of an End-to-End Continuous Pharmaceutical Production Process: A Pilot Plant Case Study,"The pharmaceutical industry faces multiple challenges (e.g., inefficient manufacturing techniques, quality control issues, and supply chain vulnerabilities) because of its current batch-wise approach to manufacturing. Recent regulatory support for continuous manufacturing and advances in continuous process technologies have caused an increase in interest from some drug manufacturers to modernize their production processes. However, many of these companies have focused on hybrid processes, where only certain steps are continuous, while others remain batch. Herein, the quality by design (QbD)-based design strategy and operation of an end-to-end integrated continuous manufacturing (ICM) pilot plant that produces both small-molecule active pharmaceutical ingredient (API) and oral solid dosages (OSDs) are discussed. Additionally, important quality and economic matters pertaining to scale-up and commercialization are addressed. ICM has significant benefits, including better quality control, increased supply chain flexibility, a lower capital investment (in the example provided, a ∼ 90% reduction), and lower operating costs (in the example provided, a 33.6% reduction for API and 29.4% reduction for tablets).",10.1021/acs.oprd.0c00383,0
"Synthesis of Vixotrigine, a Use-Dependent Sodium Channel Blocker. Part 1: Development of Bulk Supply Routes to Enable Proof of Concept","Two syntheses of vixotrigine are reported. Route 1, adapted from the medicinal chemistry route, enabled rapid delivery of drug substance for clinical development. Route 2, which was developed to address many of the limitations of Route 1, was used to manufacture pilot quantities of API. Key features of Routes 1 and 2 are the generation of a chiral ketone intermediate from an ( S )-pyroglutamic acid derivative and catalytic reduction to introduce the second stereogenic center into the API with high stereoselectivity. Route 2 was developed to address the purification burden attributable to “benzyne-derived” impurities generated in Route 1. The improved process eliminated the possibility of the formation of these impurities, substantially improved the stereoselectivity in the reduction of the alternate cyclic imine intermediate 22, and gave a pilot plant process with significantly enhanced yield and throughput.",10.1021/acs.oprd.0c00382,1
"Crystallizing Fats? Development of a Scalable, Chromatography-Free Synthesis of Cationic Lipids","Research on the development of scalable routes to pharmaceutical intermediates typically proceeds from explorations of the chemistry to the identification of robust procedures for isolation. Although this order of investigation works well for typical small molecules possessing favorable physical properties and, therefore, numerous options for isolation, this is not always the case. The synthesis of cationic lipids is an exception to the rule and challenges this logic. Supported by extensive solubility and salt screening, we engaged in a reverse development effort, focusing first on identifying isolation conditions and then using that information to select appropriate chemistry. This strategy allowed for development of a robust, chromatography-free route to the cationic lipids of interest that was implemented at kilogram scale with quantifiable improvements to yield and efficiency when compared to the original route.",10.1021/acs.oprd.0c00374,0
"Design of a Kilogram Scale, Plug Flow Photoreactor Enabled by High Power LEDs","A simple and inexpensive photoreactor with a throughput of kilograms of material per day has been developed. This achievement was enabled by using high-power Light Emitting Diodes (LEDs) to provide high light density, leading to minimization of the footprint of the reactor. A study of the impact of tube diameter enabled maximization of the photon absorbance without increasing photocatalyst loading. Further optimization of reaction conditions using a design of experiments (DoE) elucidated reaction sensitivities that allowed the reaction rate, yield, and productivity to be maximized upon scale-up. The reactor has been operated continuously for 6 h leading to reaction performance that provided 12 kg of material per day at 90% conversion.",10.1021/acs.oprd.0c00373,0
Continuous Flow <i>C</i>-Glycosylation via Metal–Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir,"High Resolution Image Download MS PowerPoint Slide As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of high-volume active pharmaceutical ingredients and is considered for use in this synthetic sequence. In particular, the challenging C -glycosylation of a pyrrolotriazinamine via metal–halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric analysis of each reaction step. Multiple simplifications of this process were attempted in batch but in general were found to be unfruitful. The five-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing. Detailed optimization of stoichiometries provided an improvement upon batch conditions with a total residence time of <1 min.",10.1021/acs.oprd.0c00370,0
"Efficient Method for the Synthesis of Amino-1,3-Oxazines from Thioureas","The synthesis of a subtype-selective inhibitor BACE-1 inhibitor is presented. One of the key transformations in this sequence is the conversion of a thiourea to the bicyclic 1,3-aminooxazine. This article outlines the development and application of this method to the target molecule as well as further exploration of its scope and mechanism.",10.1021/acs.oprd.0c00369,1
Risk-Based Operation of a Continuous Mixed-Suspension-Mixed-Product-Removal Antisolvent Crystallization Process for Polymorphic Control,"Innovations in the continuous crystallization field are required for the pharmaceutical industry to go through the paradigm shift from batch to continuous processing. To do so, different risks associated with the continuous crystallization have to be identified and discussed. In this work, a continuous antisolvent crystallization of the model compound indomethacin (IMC) from a ternary solvent system in a mixed-suspension-mixed-product-removal (MSMPR) to produce the desired polymorphic γ-form is evaluated, and potential risks for process failure are identified. One of the main risks identified with the continuous crystallization is gaining a balance between the inlet and outlet flows. Two novel and different level controls are proposed in this work to overcome this risk, an ultrasonic sensor and image analysis based on a video recording of the level. These two methods demonstrate improved process robustness upon implementation. Additionally, different process parameters were investigated and showed that the seed load has a significant effect on maintaining the desired polymorph and avoiding process failure. To the best of our knowledge, this is the first study on continuous crystallization of IMC for the polymorphic control of γ-IMC.",10.1021/acs.oprd.0c00368,0
Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib,"The development of a commercial route toward the JAK1 inhibitor abrocitinib is described. The application of a late-stage Lossen rearrangement provided the desired cis -diaminocyclobutane, which was subsequently sulfonylated using a novel water-tolerable triazole sulfonylating reagent to provide the active pharmaceutical ingredient.",10.1021/acs.oprd.0c00366,1
Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow,"The scale-up of a chiral bicyclic homopiperazine of pharmaceutical interest was investigated. The outcome and safety profile of a key batch ring-expansion step via Schmidt rearrangement was improved using continuous-flow chemistry. The selectivity of nitrogen insertion for the ring expansion was improved via an alternative photochemical oxaziridine rearrangement under mild conditions, which when converted to continuous-flow in a simple and efficient flow reactor allowed the first photochemical scale-up of a homopiperazine.",10.1021/acs.oprd.0c00361,0
"Process Development of Sotagliflozin, a Dual Inhibitor of Sodium–Glucose Cotransporter-1/2 for the Treatment of Diabetes","The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium–glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagliflozin features five contiguous chiral centers on the carbohydrate core flanked by a thioether group and a biaryl moiety. Three chiral centers are obtained from the starting material l -xylose, while the other two were established (or modified) via three highly stereoselective transformations: Luche reduction (dr: 97/3), dynamic kinetic resolution of anomeric hemiacetal (dr: 95/5), and Lewis acid-promoted thiolation (dr: 1000/1). Global deprotection of the resulting penultimate intermediate with catalytic sodium methoxide followed by recrystallization furnishes sotagliflozin. The longest linear sequence consists of 10 steps from l -xylose with an overall yield of 40%. This process has been performed on multi-hundred kilogram batches to satisfy the drug substance development demands.",10.1021/acs.oprd.0c00359,1
Development of a Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl Building Block,"A robust and scalable route toward key heterocyclic building block 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride from cyclopropanated starting material 1-amino-1-cyclopropanecarbonitrile hydrochloride was successfully developed. The key to success was the construction of a pyrimidine ring via cyclization from an amidine intermediate and a bench-stable 2-chloro vinamidinium hexafluorophosphate salt. The cyclization was performed under mild conditions, and the resulting 4-cloropyrimidine derivative was isolated in high yield and purity. The final hydrogenation was intensively optimized: A combination of Pd(OH) 2 /C as a catalyst and NaOMe as a base at 1 bar H 2 pressure in MeOH simultaneously cleaved the Cbz group and dechlorinated the pyrimidine ring while at the same time suppressing the over-reduction of the pyrimidine ring to below 1.0%. After acidification with HCl, followed by removal of the catalyst and NaCl by filtration, the final product was isolated in high yield and purity as a bench-stable off-white solid. The overall yield of the five-step sequence was 57%.",10.1021/acs.oprd.0c00358,1
API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing,"Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, combined cooling and antisolvent crystallization using three stirred tank crystallizers in series. Conversion of the batch process to a continuous process was beneficial to kinetically purge a key impurity. The conversion also allowed for the direct integration of the crystallization process with upstream continuous chemistry sections. A robust control strategy was developed from early research scale all the way to cGMP manufacturing. The authors will share the tools, techniques, modeling, and equipment used and challenges overcome to ensure a safe and reliable manufacturing process. A new intermittent flow technique transferred hot solution from a continuous evaporator into the first crystallizer with no solids bearding at the end of the inlet tubing. The continuous distillation, crystallization, and slurry-off filters were a key part of a broader continuous process and new building that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation.",10.1021/acs.oprd.0c00345,0
A Primer for Pharmaceutical Process Development Chemists and Analysts in Relation to Impurities Perceived to Be Mutagenic or “Genotoxic”,"Regulatory guidance on impurities is becoming increasingly comprehensive and complex. The advent of ICH M7(R1) on mutagenic impurities has introduced a significant and sophisticated toxicological component that can easily be underestimated by the unwary. The term “genotoxic impurity” was used in guidelines that predated the current guidance but is now outdated, although it is still often (mis)used in publications on impurities. ICH M7(R1) applies only to mutagenic impurities, which are defined as compounds that are DNA-reactive and test positive in a bacterial reverse mutation assay or are predicted to do so using appropriate in silico structure–activity software. A tentative indication of mutagenic activity is provided by so-called structural alerts, which are certain electrophilic moieties within a chemical structure. It is now well-established that many conventional alerts are associated with a significant number of false-positive predictions of mutagenic potential. Consequently, caution is required when an alert is used to tag a particular impurity as “genotoxic” with no further checks. Such an approach might lead to the development of unnecessarily sensitive impurity assays, which may or may not be a deliberate choice, and possibly to wasted additional process development costs. This review is intended to provide pragmatic guidance on the evaluation of the mutagenicity status of impurities, on the basis of which it is possible to determine appropriate limits. In addition, a series of published examples are reviewed where analytical method development has been compromised by mistakes concerning mutagenicity status and where incorrect mechanistic assumptions have been made regarding the potential for the formation of particular impurities.",10.1021/acs.oprd.0c00343,0
Development of a Quality Risk Based Tool for the Selection of Regulatory Starting Materials for Commercial Drug Substance Manufacturing Processes,"The selection of regulatory starting materials (RSMs) is a critical step in determining where the drug substance manufacturing process begins as it relates to the submission and approval of the commercial marketing application and with it the formal expectations for Good Manufacturing Practice (GMP) processing. The determination of RSMs can be very challenging and is often subject to significant debate both within pharmaceutical manufacturing organizations and with regulatory bodies that review the commercial marketing application. The use of quality risk management (QRM) as described in ICH Q9 can help provide a process for assessing the RSM attributes and their relationship to the critical quality attributes (CQAs) of both the final drug substance and the drug product. This publication presents a standardized risk assessment tool developed by Merck & Co., Inc., Kenilworth, NJ, USA (MSD) that facilitates the RSM decision-making process on the basis of principles described in ICH Q10 and ICH Q11. The MSD RSM tool was designed to take into account the current regulatory landscape, evolved over time as the landscape dictates, while providing a systematic evaluation of the suitability of proposed RSMs to enable their judicious selection. The MSD RSM tool can be used for new chemical entities (NCEs) submitted for commercial approval or for in-line products going through postapproval changes. The MSD RSM tool provides a total score that is used to assess the alignment with the starting material selection principles in ICH Q11 and the EMA reflection paper, which was retracted by EMA after the ICH Q11 Q&A was issued. The level of alignment should generally correspond with the likelihood that an RSM will be accepted by regulatory agencies in the commercial marketing application.",10.1021/acs.oprd.0c00341,0
Continuous Industrial-Scale Centrifugal Partition Chromatography with Automatic Solvent System Handling: Concept and Instrumentation,"Centrifugal partition chromatography (CPC) is an emerging separation technology in pharmaceutical and natural product purifications, reaching recently industrial-scale solutions. Because both the stationary and mobile phases are liquids in CPC, the solvent consumption of such separation processes is considered significant. Thus, automation is highly required in the preparation and recycling of the solvent mixtures for economical (i.e., continuous) CPC operation. Here, we report a feasible solution for this industrial issue, including the concept, algorithm, and instrumentation of solvent system handling. For majority of ternary solvent systems used in CPC separations, the linear correlation between the density and composition of the phases was recognized and utilized during the continuous solvent recycling. Hence, an efficient density-based composition adjustment algorithm was established in a mixer-settler unit using Coriolis flow meters for precise density monitoring of the upper and lower phases of the biphasic liquid system (BLS). In addition, a complete cascade consisting of a buffer, waste, a recycler (evaporator), and mixer-settler units was designed around the industrial-scale CPC device. The proof of concept was demonstrated by sequential industrial-scale CPC separations of a binary model mixture in the n -hexane/methanol/water (5/4/1, v/v/v) solvent system, followed by the purification of a crude steroid active pharmaceutical ingredient performed in the methyl iso butyl ketone/acetone/water (2/2/1, v/v/v) solvent system. The reproducibility of chromatographic performance and the productivity of the mixer-settler and evaporator units were satisfactory, enabling a robust and continuous operation of the developed separation process.",10.1021/acs.oprd.0c00338,0
"Development of Scalable Synthesis of 5-Butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a Dual Inhibitor of Nitric Oxide and Prostaglandin E<sub>2</sub> Production","We report a scalable efficient synthesis of 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (WQE-134), a dual inhibitor of nitric oxide and prostaglandin E 2 production with potent anti-inflammatory properties. The original five-step synthesis (40% overall yield) was based on two Suzuki–Miyaura reactions and required chromatographic purification of both the intermediate and final products. The novel synthetic pathway is based on cyclization of 2-butyl-1-(4-methoxyphenyl)-3-phenylpropane-1,3-dione with guanidinium methanesulfonate using Eaton’s reagent (P 2 O 5 /MsOH) at 50 °C. The two-step synthesis (34% overall yield) can be performed on a multigram to kilogram scale, and purification of the final product consists of simple extraction (dichloromethane) and crystallization (ethyl acetate and methanol).",10.1021/acs.oprd.0c00324,1
One-Pot Process for Synthesis of Nalbuphine Hydrochloride and Impurity Control Strategy,"An improved kilogram-scale process of synthesis of nalbuphine was developed by investigating the critical parameters. Ten process-related impurities were identified, of which the source and control strategy was elucidated. Moreover, tetramethylammonium triacetoxyborohydride (Me 4 NBH(OAc) 3 ) was developed to reduce the imine and ketone in one pot. As a result, 6-β-epimer was significantly controlled to only 0.08% in the crude nalbuphine. The improved process was robust at kilogram scale in 60.4% overall yield with 99.95% high-performance liquid chromatography (HPLC) purity.",10.1021/acs.oprd.0c00321,0
"Development of a Practical, Biocatalytic Synthesis of <i>tert</i>-Butyl (<i>R</i>)-3-Hydroxyl-5-hexenoate: A Key Intermediate to the Statin Side Chain","The HMG-CoA reductase inhibitors, statins, are one of the most effective and bestselling cholesterol-lowering drugs. The use of statins has greatly extended people’s lives and improved the quality of their life. Development of a more efficient, stereoselective, and sustainable synthesis of statins is continuingly of utmost importance. In the present study, through screening of ketoreductases (KREDs) and reaction optimization, we have successfully performed a highly stereoselective reduction of ketoester 1a catalyzed by KRED-06 at a pilot-plant scale without the addition of exogenous NADP +, generating 3.21 kg of enantiomerically pure tert -butyl ( R )-3-hydroxyl-5-hexenoate (( R )- 2a ) (96.2% yield, >99.9% enantiomeric excess (ee)). This newly developed biocatalytic process alleviates the cryogenic conditions (−40 °C) employed in our first-generation synthesis of ( R )- 2a using NaBH 4 and ( l )-tartaric acid. Coupled with our previously established synthesis of bromocarbonate 3a via a one-pot diastereoselective carboxylation/bromocyclization of ( R )- 2a, we have developed an innovative, practical synthesis route to statin side chain, possessing great potential to be implemented into industrial production of statins.",10.1021/acs.oprd.0c00320,1
Bio- and Chemocatalysis for the Synthesis of Late Stage SAR-Enabling Intermediates for ROMK Inhibitors and MK-7145 for the Treatment of Hypertension and Heart Failure,"A synthetic strategy to provide two late-stage intermediates for the synthesis of diverse analogues of ROMK inhibitors for the treatment of hypertension and heart failure is described. Key transformations include carbonylation of a bromoarene, regioselective vinyl ether Heck coupling and bromination, and asymmetric enzyme-mediated ketone reduction and epoxide ring closure. On selection of MK-7145 ( 1 ) as clinical candidate, conditions were developed to convert 2 equiv of the epoxide intermediates to the C 2 -symmetric active pharmaceutical ingredient.",10.1021/acs.oprd.0c00314,1
Development of Manufacturing Processes for the Carboxylic Acid Key Intermediate of Lusutrombopag: One-Pot Reaction Process of Formylation and the Horner–Wadsworth–Emmons Reaction,"We describe the development of a one-pot preparation process of ( E )-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid ( 3 ), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N -formylmorpholine, followed by olefination employing the Horner–Wadsworth–Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.",10.1021/acs.oprd.0c00311,0
Improvement of the <i>C</i>-glycosylation Step for the Synthesis of Remdesivir,"High Resolution Image Download MS PowerPoint Slide The bulk supply of the antiviral C -nucleoside analogue remdesivir is largely hampered by a low-yielding C -glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transformation. By utilizing diisopropylamine as a cost-effective additive, the addition reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatographic operations.",10.1021/acs.oprd.0c00310,1
"Chemoenzymatic Process for the Preparation of (<i>S</i>)-7-((<i>tert</i>-Butyldiphenylsilyl)oxy)hept-1-yn-4-ol in a Continuous Packed-Bed Reactor, a Key Intermediate for Eribulin Synthesis","A practical chemoenzymatic process has been developed for the preparation of optically pure ( S )-7-(( tert -butyldiphenylsilyl)oxy)hept-1-yn-4-ol, ( S )- 4 . This was prepared via enantioselective acylation of racemic homopropargylic alcohol (+/−)- 4 catalyzed by Amano lipase from Pseudomonas fluorescens . The acylation reaction was studied in a packed-bed reactor (PBR) for the production of optically pure alcohol ( S )- 4 in a continuous mode. The estimated kinetic parameters were V max 3.46 (±0.17) mM/h/g and apparent K m value, K m,app = 582.10 (± 29.10) mM (correlation coeff. r = 0.96). At a substrate concentration of 100 mg/mL (272 mM) and a flow rate of 0.1 mL/min, both the isomers are obtained in >95% theoretical yield and > 99% e.e. at steady state in a PBR with 3.6 g enzyme. The advantage of this protocol is that the enzyme can be recycled many times. Finally, this was converted to ( R )- tert -butyl((4-chloro-6-iodohept-6-en-1-yl)oxy)diphenylsilane, 3, which is the key building block for the synthesis of the C14-C19 intermediate of eribulin.",10.1021/acs.oprd.0c00308,0
"Development of a Commercial Manufacturing Route to 2-Fluoroadenine, The Key Unnatural Nucleobase of Islatravir","We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorporated into MK-8591 via a biocatalytic aldol-glycosylation cascade, which imposes stringent requirements for its synthesis and isolation. Presented herein is the development work leading to a practical, scalable route from guanine, featuring a dual fluorination approach to a novel 9-THP-2,6-difluoropurine intermediate that enables a mild, highly selective, direct amination. This one-pot fluorination/amination sequence utilizes a direct isolation to deliver high purity 9-THP-2-fluoroadenine, which features ideal properties with respect to reactivity, solubility, and crystallinity. An acid-catalyzed liberation of 2-fluoroadenine in aqueous buffer delivers the appropriate purity profile to facilitate the enzymatic cascade to access MK-8591.",10.1021/acs.oprd.0c00304,1
Simple Synthesis of Amides via Their Acid Chlorides in Aqueous TPGS-750-M,"The technology of surfactant chemistry is employed for amide bond construction via the reaction of acyl chlorides with amines in 2 wt % TPGS-750-M aqueous solution. Specifically, this highly efficient method enables a chromatography-free scalable process and recycling of the TPGS-750-M solution.",10.1021/acs.oprd.0c00303,0
Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow,"Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogenation, debenzylation, and reduction of other unsaturated functional groups were inhibited eminently. Moreover, catalytic hydrogenation of ( R )-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (compound I ) afforded the desired product ( R )-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (compound II ) with high selectivity (99.9%) and high conversion (99.5%). Finally, high-quality crizotinib was synthesized from intermediate II .",10.1021/acs.oprd.0c00302,1
Practical Synthesis of a Stable Precursor for Positron Emission Tomography Imaging Agent <sup>18</sup>F-GTP1,"18 F-GTP1 is a deuterated small molecule positron emission tomography (PET) imaging agent used to visualize tau tangles in Alzheimer’s disease patients. The first-generation synthesis of 18 F-GTP1 ’s nonradiolabeled alkyl tosylate precursor was plagued by low-yielding steps, inefficient chromatographic purifications, and variable product quality. Due to these limitations, a more robust second-generation route was developed and successfully executed on kilogram scale. A reduction with LiAlD 4 incorporated geminal deuterium atoms, while an efficient amidation reaction accessed the key acrylamide coupling partner. Moreover, the tricyclic imidazo[1,2- a ]pyrimidine core was assembled via a novel, convergent, and highly selective phosphoramidate-directed annulation. The improved synthesis eliminated all chromatography en route to a high-yielding and reproducible acid-promoted tosylation as the final step.",10.1021/acs.oprd.0c00301,0
Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-one via the Acid-Catalyzed Selective Oxidation of 4-(4-Nitrophenyl)morpholine by Sodium Chlorite as the Sole Oxidant,"4-(4-Nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are the key intermediates for rivaroxaban synthesis. A facile and economically efficient process has been developed for the preparation of these intermediates. Excellent yield of 4-(4-nitrophenyl)morpholine is obtained by condensing 4-chloro nitrobenzene and morpholine, and 4-(4-nitrophenyl)morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield of the corresponding 4-(4-nitrophenyl)morpholin-3-one. Finally, the key intermediate of rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron(III)-catalyzed reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the process did not require column purification.",10.1021/acs.oprd.0c00299,1
Diethanolamine Boronic Esters: Development of a Simple and Standard Process for Boronic Ester Synthesis,"Herein, we disclose the unique physical properties of diethanolamine (DEA) boronic esters that have facilitated the development of a simple and standard process for their synthesis and isolation using environmentally sustainable solvents. Moreover, their preparation is facile, robust, and scalable and can be telescoped from a solution of boronic acid or boronic ester via esterification/transesterification with DEA, therefore providing wide access from a plethora of reaction types. To date, AstraZeneca has successfully manufactured three DEA boronic esters at the kilogram scale (5, 50, and 100 kg batches), with plans to expand this to more examples in 2020.",10.1021/acs.oprd.0c00296,0
Practical and Scalable Manufacturing Process for Plasma Kallikrein Inhibitor ASP5069,"The plasma kallikrein inhibitor ASP5069 is a promising drug candidate for the treatment of edema and hematoma and for the prevention of bleeding during surgery. Here, we report the development of a practical and scalable process for manufacturing ASP5069 that features a convergent synthetic approach, suppression of impurity formation, effective purification of the amine compound by extraction, improved reproducibility of the reductive amination reaction, and a drying process for the dihydrate form. This process was successfully used to prepare >100 g of ASP5069.",10.1021/acs.oprd.0c00291,1
"Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608","Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used to develop the route, including Design of Experiments (DoE), high-throughput experimentation (HTE), and application of desorption electrospray ionization mass spectrometry (DESI-MS) to optimize and telescope the amidation and Sonogashira couplings to prepare the target compound, HSN608, a potent FLT3 inhibitor. Findings from these statistical design and automation studies helped streamline our workflow to achieve 10-fold and 5-fold reductions in the catalyst and cocatalyst loadings, respectively, in the synthesis. The application of high-throughput tools combined with a telescoped continuous synthesis method enabled an efficient and safe synthesis of this lead compound using the hazardous coupling reagent HATU while minimizing byproduct formation.",10.1021/acs.oprd.0c00289,1
A General Kilogram Scale Protocol for Suzuki–Miyaura Cross-Coupling in Water with TPGS-750-M Surfactant,"The development of a kilogram scale protocol for a Suzuki–Miyaura cross-coupling step toward the synthesis of the drug candidate LSZ102 is described. Particularly, the use of the surfactant TPGS-750-M in water as a medium for the transformation and its impact on the selectivity and quality are reported. Minimization of typical impurities generated during the cross-coupling (e.g., dehalogenation) has been in focus during our study. The environmental and cost impacts using such a process are also discussed.",10.1021/acs.oprd.0c00281,0
"Development of an Efficient Scale-Up Synthesis Method for a β<sub>3</sub>-Adrenergic Receptor Agonist, Ritobegron Ethyl Hydrochloride","An efficient route for the multikilogram synthesis of a selective β 3 -adrenergic receptor agonist, ritobegron ethyl hydrochloride ( 1 ), was developed by changing the coupling method of 4-hydroxynorephedrine ( 2 ) with phenoxyacetate 3 . This new method successfully overcame several obstacles in the first-generation method via the use of aldehyde 3b derived from hemiacetal 10 to couple with 2 . The main advantages of the key intermediate 10 were that it was sufficiently stable to enable handling at large scales, it could be synthesized without an exothermic reaction or excessive use of expensive reagents, and it had the ability to reduce impurities by purification prior to coupling with 2 . The resulting second-generation method improved the overall yield from 27 to 43% and the purity from up to 98.5 to 99.5%. Furthermore, it was effective for 69 kg-scale synthesis, representing a major improvement over several hundreds grams scale of the first-generation method.",10.1021/acs.oprd.0c00278,1
Kinetic Parameter Estimation from Spectroscopic Data for a Multi-Stage Solid–Liquid Pharmaceutical Process,"Laboratory and process measurements from spectroscopic instruments are ubiquitous in pharma processes, and directly using the data can pose a number of challenges for kinetic model building. Moreover, scaling up from laboratory to industrial level requires predictive models with accurate parameter values. This means that process identification implies not only kinetic parameter estimation but also the identification of the absorbing species and estimation of variances for both the data and parameters. The recently developed, open-source toolkit KIPET (Short, M.; Schenk, C.; Thierry, D.; Rodriguez, J. S.; Biegler, L. T.; Garcı́a-Muñoz, S. Proceedings of the 9th International Conference on Foundations of Computer-Aided Process Design, 2019, 47, 299; Schenk, C.; Short, M.; Thierry, D.; Rodriguez, J. S.; Biegler, L. T.; Garcı́a-Muñoz, S.; Chen, W. Comput. Chem. Eng. 2020, 134, 106716 ) addresses these topics and provides an alternative to standard parameter estimation packages, in particular for spectroscopic data problems. Moreover, batch processes commonly used in the chemical and pharmaceutical industries involve multiple stages to carry out synthesis operations in a step-by-step manner, often dealing with heterogeneous mixtures, wide operating temperatures, and constant additions and removals of product and waste. For such cases novel modeling approaches are required, as the structure of the kinetic model may vary with time, with model switches that are state dependent. This study presents a new modeling approach and methodology that deals with these practical issues. In developing kinetic models, it approximates the solid dissolution process and deals with multiple stages with different reactor temperatures. Moreover, variances, parameters, concentration, and absorbance profiles are estimated for the process stages using the approach presented by Chen et al. (Chen, W.; Biegler, L. T.; Garcı́a Muñoz, S. J. Chemom. 2016, 30, 506 ). The application of these developed concepts results in realistic profiles as well as reliable kinetic parameter values. The outcomes of this work show that KIPET is a useful toolkit for dealing with pharmaceutical processes with capabilities for dealing with challenging kinetic modeling problems.",10.1021/acs.oprd.0c00277,0
"Kinetics, Thermodynamics, and Scale-Up of an Azeotropic Drying Process: Mapping Rapid Phase Conversion with Process Analytical Technology","Distillation processes with several solid-state phases and dynamic multicomponent liquid-phase compositions can be challenging to understand and scale up because of complexity of the thermodynamics combined with process dynamics and kinetics. Often, development scientists will eschew the most efficient process because of the challenges in generating the necessary information and knowledge required to reproducibly implement it. Herein, we report the robust development of such a process: how it was characterized with in-line process analytical technology, off-line analytics, process modeling, and bench-top experiments and ultimately translated to a manufacturing scale. Through this exercise, we discovered a new solid phase and elucidated a canonical example of kinetic control and pseudoequilibrium. The detailed understanding of the thermodynamics and kinetics of the underlying physicochemical phenomena was used to define a simple control strategy that was implemented on an industrial scale to isolate the desired anhydrous crystal form. In this process, a crystalline dihydrate of a pharmaceutical intermediate was converted into an anhydrous form during distillation drying in a slurry. Water was removed by azeotropic distillation in acetonitrile at atmospheric pressure, while replenishing with dry acetonitrile. Below the critical water activity of conversion, the dihydrate was found to transform reliably and quickly into the anhydrate. Therefore, a concentrated slurry of the anhydrous form was obtained, which was telescoped into the subsequent, water-sensitive reaction. The discovery of an intermediate hemihydrate form added complexity to the system and presented a risk thermodynamically but was found to be kinetically difficult to access. In practice, the dihydrate rapidly converted directly to the anhydrate, and a molecular structural rationale for this behavior is proposed. The characterization and development of this process were enabled by in situ Raman spectroscopy and Fourier-transform infrared spectroscopy for determination of real-time solid-state form and solution water content, respectively. These tools allowed for construction of a process phase map as a function of temperature, water content, and slurry density while at the same time characterizing the kinetics of form transformations between dihydrate, hemihydrate, and anhydrous phases under relevant processing conditions. In addition, multiple off-line analytical techniques were utilized to fully characterize the solid phases, and ternary diagrams were used to explain the thermodynamics of the system and kinetic pathways. Based on this work, the process was transferred to an industrial scale and successfully executed using only a single off-line Karl Fischer measurement as a control strategy.",10.1021/acs.oprd.0c00275,0
Drug Development through Modification of Small Molecular Drugs with Monodisperse Poly(ethylene glycol)s,"Poly(ethylene glycol)s (PEGs) are the most used polymers in biomedicine, and their so-called “stealth” effects are the “gold standard” for biomaterials. However, the polydispersity in regular PEGs hampers their biomedical application, especially in modification of small molecular drugs (SMDs). To address this issue, many synthetic strategies for monodisperse PEGs (M-PEGs) have recently been developed. More importantly, M-PEGs have been successfully employed to modify SMDs, and the crucial roles of M-PEGs in PEGylated SMDs have been discovered in many cases. Herein we summarize the strategies for the synthesis of M-PEGylated SMDs, including Movantik, NKTR-181, polidocanol, propofol, and camptothecin, and the important roles of M-PEGs in optimizing the physicochemical properties, bioavailability, and therapeutic efficacy of SMDs. M-PEGylation is a convenient and effective strategy to develop novel SMDs, especially on the basis of marketed drugs. This review may shed light on the rational design and efficient synthesis of new M-PEGylated SMDs.",10.1021/acs.oprd.0c00273,1
Efficient Processing of Reactions Involving Diazonium Salts: Meerwein Arylation in an Impinging-Jet Reactor,"This work reports a novel approach for performing high-throughput synthesis of Meerwein arylation in an impinging-jet reactor. The multistep reaction was performed in a single reactor via in situ diazonium salt generation followed by Meerwein arylation. The work involves many iterations between experiments and simulations (where we integrate simulating the flow, heat transfer, and reaction simultaneously) for optimization of conditions in an inverted impinging-jet reactor. The effect of design variables viz. catalyst concentration, inlet temperature, and monomer mole ratio on the yield of the desired product was studied in detail, and the simulation results were used to plan the continuous experiments. An infrared camera was used to monitor the transient reactor temperature for steady-state analysis. The lab-scale inverted impinging-jet reactor with over 93% isolated yield can offer a space-time yield of 277.78 tons/m 3 /day. The numbering-up of an inverted impinging-jet reactor can be an effective way for cleaner production of products through typical Meerwein arylation.",10.1021/acs.oprd.0c00271,0
Electrochemical Cyclobutane Synthesis in Flow: Scale-Up of a Promising Melt-Castable Energetic Intermediate,"The design of a scalable, safe, and robust route to a promising energetic material containing a cyclobutane and four nitric ester groups is described. This route includes a streamlined preparation of a linear cyclobutane precursor, the use of safe methods for tetraester reduction and nitration, and the translation of a small-scale batch electrochemical oxidative cyclization to forge the cyclobutane to a continuous flow setup capable of producing quantities of more than 100 g in a single run. In principle, this scale was limited only by the space considerations of an academic lab, as a larger reservoir would enable kilogram-scale preparations. Lessons learned from an engineering and reaction optimization standpoint in this electrochemical scale-up are also discussed.",10.1021/acs.oprd.0c00270,1
Synthesis of Dipentaerythritol from Pentaerythritol under Acidic Conditions,"The direct synthesis of dipentaerythritol (DPE) from pentaerythritol (PE) was studied under acidic conditions. After optimization of the reaction parameters in a batch reactor, DPE was obtained with 50% selectivity when 50% PE was converted. This process, using PE in suspension in sulfolane (PE/sulfolane ratio = 2333 g/L) at 175 °C for 60 min, required a low amount of sulfuric acid (0.5 mol %). The optimized conditions were transposed to a 140 grams scale process. Finally, DPE was isolated with 16% yield (72% gas chromatography, GC purity) for 28% conversion of PE that corresponds to 57% DPE selectivity.",10.1021/acs.oprd.0c00269,0
"An Improved Process for the Manufacture of 5′-<i>O</i>-(4,4′-Dimethoxytrityl)-<i>N</i><sup>2</sup>-isobutyryl-2′-<i>O</i>-(2-methoxyethyl)guanosine","A revised, optimized process for the manufacture of 5′- O -(4,4′-dimethoxytrityl)- N 2 -isobutyryl-2′- O -(2-methoxyethyl)guanosine (MOE G PNS) that controls critical impurities to less than 0.2% was developed. The 2′- O -alkylation of 2,6-diaminopurine riboside (DAPR) with 1-bromo-2-methoxyethane (MOE-Br) in DMSO was examined using a design of experiments approach, which led to the selection of LiOH as the optimal base choice. Equivalents of base and MOE-Br were optimized to control levels of the critical 3′- O -(2-methoxyethyl) impurity and residual DAPR. DMSO was removed with a solid-phase extraction using SP-207 resin, affording the desired 2′- O -(2-methoxyethyl)-2,6-diaminopurine riboside (MOE DAPR) in an aqueous solution in 53% yield. The methyl bromide impurity commonly found in bulk sourced MOE-Br was controlled using a codistillation with MEK, thereby controlling the resulting critical 2′- O -methyl nucleoside impurity. The aqueous solution was telescoped into the enzymatic conversion of MOE DAPR to 2′- O -(2-methoxyethyl)guanosine (MOE G) using adenosine deaminase. MOE G purity is enhanced at this step due to enzymatic selectivity and crystallization from the reaction mixture, which together significantly reduce levels of the 3′ MOE G isomer. Installation of the isobutyryl and 4,4-dimethoxytrityl protecting groups proceeded similarly to published literature methods, but the workup and isolation conditions were optimized. A series of extractions after isobutyrlation were used to control critical and noncritical impurities, and the final product was crystallized to upgrade purity. The improved process was carried out at the production scale to afford 59 kg of MOE G PNS with no critical impurity over 0.2% in an overall yield of 26%.",10.1021/acs.oprd.0c00261,0
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 6: Development of an Improved Commercial Salt Formation Process,"The development of a sustainable commercial salt formation process for gefapixant citrate (MK-7264), an investigational new P2X3 antagonist for the treatment of chronic cough, is described. Due to the low solubility of the gefapixant free base, the first-generation process for citrate salt formation was a slurry-to-slurry process with poor quality control, wherein impurities were not well rejected and unreacted free base often persisted in the citrate produced. The development of a controlled crystallization from a homogeneous solution, which overcame these deficiencies, was complicated by solubility constraints and a daunting solid form landscape. Herein, we report a novel solution to this problem where the free base is transiently converted to a highly soluble glycolate salt enabling complete dissolution, from which direct crystallization of the final citrate salt occurs in a high yield through salt metathesis. Robust crystallization control was ensured by conducting a comprehensive polymorph screen on the glycolate salt and demonstrating its metastability compared to the desired citrate salt. In addition, process-relevant solvates of the citrate salt were discovered and derisked via a thorough understanding of their stability regions. With this information, a second-generation process salt formation with robust crystalline form and purity control was achieved, utilizing a salt metathesis co-feed process that greatly reduces the amount of solvent required, the overall manufacturing time, and the energy consumption compared to the first-generation conditions.",10.1021/acs.oprd.0c00260,0
Kinetic Investigations To Enable Development of a Robust Radical Benzylic Bromination for Commercial Manufacturing of AMG 423 Dihydrochloride Hydrate,"During development of a radical benzylic bromination, observation of polymerized byproducts and variation in isolated yields warranted an in-depth mechanistic investigation to ensure process understanding and robustness. In situ kinetic studies using multinuclear CryoFree NMR spectroscopy revealed molecular bromine to be the active brominating species and variable time normalization analysis allowed accurate determination of the order of each reagent in this process. These kinetic studies allowed for accurate reaction modeling and were used to demonstrate that adoption of a simple procedural change ensured reliability and reproducibility during manufacturing.",10.1021/acs.oprd.0c00256,1
Optimization and Scale-Up of the Continuous Flow Acetylation and Nitration of 4-Fluoro-2-methoxyaniline to Prepare a Key Building Block of Osimertinib,"High Resolution Image Download MS PowerPoint Slide The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro-2-methoxy-5-nitroaniline, a key building block in the synthesis of osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is used for the treatment of nonsmall-cell lung carcinomas carrying EGFR-TKI sensitizing and EGFR T790M resistance mutations. The hazards associated with nitration of organic compounds, such as thermal runaway and explosivity of intermediates, make it difficult to scale up nitrations to industrial quantities, particularly within large-scale batch reactors. In this study, we investigated an acetic acid/aqueous nitric acid mixture as a predominantly kinetically controlled nitration regime and a water-free mixture of acetic acid, fuming nitric acid, and fuming sulfuric acid (oleum) as a mass-transfer-limited nitration regime. A modular microreactor platform with in-line temperature measurement was utilized for the nitration. Furthermore, we identified that it was necessary to protect the amine functionality through acetylation to avoid side reactions. The process parameters and equipment configuration were optimized at laboratory scale for the acetylation and nitration to improve the product yield and purity. The two steps could be successfully telescoped, and the laboratory-scale flow process was operated for 80 min to afford the target molecule in 82% isolated yield over two steps, corresponding to a throughput of 25 mmol/h. The developed flow process was then transferred to an industrial partner for commercial implementation and scaled up by the use of higher flow rates and sizing-up of the microreactor platform to pilot scale to afford the product in 83% isolated yield, corresponding to a throughput of 2 mol/h (0.46 kg/h).",10.1021/acs.oprd.0c00254,0
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 4: Formylation–Cyclization as a Flow–Batch Process Leads to Significant Improvements in Process Mass Intensity (PMI) and CO Generated versus the Batch–Batch Process,"Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to generate the key intermediate diaminopyrimidine ( 1 ) (AF-072) required a significant excess of ethyl formate (EF), potassium tert -butoxide (KO t- Bu), and guanidine•HCl (G•HCl) when both steps were run as batch processes. It was imperative to develop an alternative process that required less of each reagent and generated less carbon monoxide byproducts, as the annual production of the final active pharmaceutical ingredient (API) is expected to be over 50 MT. In addition, the second generation process was misaligned with our company’s strategy of having the best science in place at the first regulatory filing. The final flow–batch process described herein, which features a flow-based formylation combined with a batch cyclization, has been performed on a 500 kg scale and now requires 35% less EF (leading to a 70% reduction in waste carbon monoxide), 38% less KO t- Bu, and 50% less G•HCl. These improvements, along with a twofold increase in concentration, have resulted in a 54% reduction in the step process mass intensity (step-PMI) from the second generation two-step batch–batch process (PMI of 17.16) to the flow–batch process (PMI of 7.86), without sacrificing reaction performance.",10.1021/acs.oprd.0c00252,0
"Mechanistic Understanding of a Robust and Scalable Synthesis of Per(6-deoxy-6-halo)cyclodextrins, Versatile Intermediates for Cyclodextrin Modification","Cyclodextrin (CD) perfunctionalization reactions are challenging to study because they proceed through a number of regioisomeric intermediates, thus warranting creative approaches to understanding the reaction mechanism. Particularly useful perfunctionalization targets are per(6-deoxy-6-halo)cyclodextrins. Their standard synthesis entails selective S N 2 halogenation at their primary alcohols using a Vilsmeier reagent, but this requires a strongly basic quench to unmask the Vilsmeier-capped secondary alcohols. Herein we present an alternative and simple acidic hydrolytic quench that utilizes existing HX in the end-of-reaction solution and requires only the addition of water. We performed a detailed mechanistic investigation of the new quench, and a central feature was the use of proton sponge to develop an 1 H NMR titration method for HX in organic solvent. This method was used to both quantify and remove HX in the prequenched reaction solution. The HX-free prequenched solution enabled us to (1) identify sensitive intermediates during the quench, (2) quantify all of the reaction byproducts, and (3) determine that HX is critical for hydrolysis. We then studied the halogenation reaction, wherein the new acidic quench facilitated high-throughput experimentation, using mass spectrometry as well as Design of Experiments with automated reaction profiling. Through this, we were able to establish robustness and understand the complex effects of Vilsmeier equivalents and temperature on the reaction outcome.",10.1021/acs.oprd.0c00249,0
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview,"A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced API costs. The key innovations are the implementation of a highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine synthesis in flow, a simplified sulfonamide synthesis, and a novel salt metathesis approach to consistently deliver the correct active pharmaceutical ingredient (API) salt form in high purity.",10.1021/acs.oprd.0c00248,0
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264). Part 5: Completion of the API Free Base via a Direct Chlorosulfonylation Process,"A scalable two-pot sulfonamidation through the process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. Direct conversion of the diaryl ether precursor to a sulfonyl chloride intermediate using chlorosulfonic acid, followed by treatment with aqueous ammonia hydroxide, provided the desired sulfonamide in high yield. A pH-swing crystallization allowed for the formation of a transient acetonitrile solvate that enables the rejection of two impurities. After drying, the desired anhydrous free base form was isolated in high yield and purity.",10.1021/acs.oprd.0c00247,0
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core,"The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic understanding of the cyclization step in the presence of guanidine was established by performing isotopic labeling experiments and identification of impurities. Guided by the mechanistic understanding, further attempts to modify the cyclization reaction by employing additives to reduce the triazine ( 9 ) formation and guanidine loading will also be presented. This newly developed method delivered compound 1 in 88–94% yield on a commercial scale and addressed the shortcomings of the early synthetic route including high PMI, low atom economy, long cycle-time, and multiple purifications to achieve the desired quality.",10.1021/acs.oprd.0c00246,0
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly,"The preceding article described the development of the large-scale synthetic route to macrocycle 3 of glecaprevir ( 1 ), a potent HCV protease inhibitor. This article describes the development of the synthesis of the difluoromethyl-substituted cyclopropyl amino acid 4, its conversion to the fully elaborated side chain, amino sulfonamide 2, and the subsequent final coupling to form glecaprevir. The synthesis of amino acid 4 consists of four key transformations: (a) formation of the difluoromethyl-substituted cyclopropane ring of (±)-diester 15 via Knoevenagel condensation and Corey–Chaykovsky cyclopropanation, (b) diastereoselective hydrolysis of (±)-diester 15 to yield (±)-monoacid 14a – b, (c) conversion of (±)-monoacid 14a – b to (±)-amino ester 10 via a Curtius rearrangement, and (d) resolution of (±)-amino ester 10 followed by saponification to give the desired (1 R,2 R )-amino acid 4 . The large-scale synthetic route to amino acid 4 was successfully used to produce the fully elaborated side chain 2 and ultimately the amount of glecaprevir required to support the late-stage clinical development.",10.1021/acs.oprd.0c00245,1
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Macrocycle via Intramolecular Etherification,"Glecaprevir was identified as a potent hepatitis C virus (HCV) protease inhibitor, and a large-scale synthesis was required to support the late-stage clinical trials and subsequent commercial launch. The large-scale synthetic route to glecaprevir required the development of completely new synthetic approaches to the two key structural features: the 18-membered macrocycle 3 and the difluoromethyl-substituted cyclopropyl amino acid 4 . In this first manuscript, we describe the route development for the macrocycle 3; the second manuscript will describe the development of a new synthetic route to the difluoromethyl-substituted cyclopropyl amino acid 4 and the final assembly of glecaprevir. The large-scale synthetic route to the macrocycle employed a unique intramolecular etherification reaction as the key step in the macrocycle synthesis, avoiding the scalability limitations of the ring-closing metathesis (RCM) reaction of the enabling route. The large-scale synthetic route to the macrocycle was successfully used to produce the amount of glecaprevir required to support the late-stage clinical development.",10.1021/acs.oprd.0c00244,1
Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis,"Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.",10.1021/acs.oprd.0c00241,0
Digital Design of Batch Cooling Crystallization Processes: Computational Fluid Dynamics Methodology for Modeling Free-Surface Hydrodynamics in Agitated Crystallizers,"A framework for the digital design of batch cooling crystallization processes is presented comprising three stages, which are based on different levels of process complexity, integrating crystallizer hydrodynamics with crystallization kinetics and consequently with expected crystal size distribution. In the first stage of the framework, a computational fluid dynamics methodology is developed to accurately assess hydrodynamics in a typical batch crystallizer configuration, comprising a 20 L scale dish-bottom vessel with a single beavertail baffle agitated by a retreat curve impeller, used in the pharmaceutical as well as in the fine chemical industries. The hydrodynamics of crystallizers with such configurations is characterized by vortex formation on the free liquid surface. It is therefore important to model the free surface using the Volume-of-Fluid (VoF) method. Comparison of the predicted mean velocity components with experimental measurements using laser Doppler anemometry reveals that improved predictions are obtained using a differential Reynolds-stress transport model for turbulence coupled with the VoF for modeling the gas-liquid interface compared with those using the Shear-stress transport model and with a flat liquid surface. This study demonstrates that an accurate treatment of the liquid free surface for capturing vortex formation is essential for reliable predictions of the crystallizer’s flow field. While the vortex depth is predicted to increase with increasing impeller Reynolds number, the dependence of hydrodynamic macroparameters, including power number, impeller flow number, and secondary circulation flow number, on Reynolds number reveals that they are essentially constant within the turbulent regime but fluctuate when the flow is in the transitional and laminar regimes as fluid viscosity increases.",10.1021/acs.oprd.0c00240,0
Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy,"High Resolution Image Download MS PowerPoint Slide Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attributed to additional challenges compared to thermal processes, mostly in the homogeneous irradiation of the flow reactor. Here, we detail the process of bringing a previously developed photochemical benzylic bromination, utilizing in situ bromine generation, from lab to pilot scale. The process setup is discussed in detail, alongside a comprehensive risk assessment and discussion of problems encountered in the investigation of key reaction parameters. Ultimately, an assay yield of 88% was obtained in 22 s irradiated residence time, resulting in a productivity of 4.1 kg h –1 (space-time yield = 82 kg L –1 h –1 ) representing a 14-fold scale-up versus the lab-scale process.",10.1021/acs.oprd.0c00239,0
Practical and Efficient Synthesis of 2-Thio-imidazole Derivative—<b>ZY12201</b>: A Potent TGR5 Agonist,"Early scalable process development for the synthesis of ZY12201, a novel TGR5 receptor agonist, as a potential clinical candidate is described. A practical, efficient, and scalable synthetic route provided ZY12201 in seven steps and 32% overall yield. The key step involves an inexpensive acetic acid-mediated cyclization of thiourea 6 for the construction of 2-thio-imidazole derivative 7 . The developed process demonstrated cost-effective, high-yielding, kilogram-scalable, and environmentally friendly synthesis of ZY12201. This high-yielding route enabled us to rapidly synthesize large quantities of ZY12201 in 99% purity to support in vivo and toxicity studies.",10.1021/acs.oprd.0c00234,1
"Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply","The outbreak of the COVID-19 pandemic has spurred an intense global effort to repurpose existing approved drugs for its treatment. In this review, we highlight the development of seven small-molecule drugs that are currently being assessed in clinical trials for the treatment of COVID-19. Three sections are presented for each drug: (1) history, mechanism of action, and status of clinical trials; (2) scalable synthetic routes and final forms; and (3) outlook for supply should clinical trials show treatment efficacy. A brief overview of diagnostic testing and vaccine development is also presented.",10.1021/acs.oprd.0c00233,1
Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor <b>BMS-986260</b>,"A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 ( 1 ) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided access to multikilogram quantities of the key intermediate, 6 . The safety aspects of the synthetic approach to the other fragment of the API (TosMIC 10 ) were critically evaluated, and a robust process for its large-scale synthesis was successfully demonstrated.",10.1021/acs.oprd.0c00232,1
"Development of a Scalable Synthesis of Mevidalen (LY3154207), an Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor","The evolution from early medicinal chemistry to large-scale production of the chemical synthesis of Lilly D1-positive allosteric modulator (PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is outlined. The issues and steps taken to resolve them are outlined across several generations of synthesis, including unexpected issues that arose during cryogenic addition of MeLi to a key imine intermediate and the use of flow chemistry to enable large-scale production. Ultimately, a process that was used to deliver >100 kg of API to support ongoing clinical trials is described.",10.1021/acs.oprd.0c00229,1
3D Printed Reactors for Synthesis of Active Pharmaceutical Ingredients in Continuous Flow,"Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing, is a preferred way for the production of customized reactors. This work presents three examples of 3D printed reactors and their application for the synthesis of API precursors in continuous flow. The first case deals with an aerobic oxidation of Grignard reagents to the corresponding phenols by molecular oxygen. Here, a design concept was utilized; various stainless steel reactors were tested, and their performances were evaluated in continuous flow. Next, another stainless steel reactor was applied for achieving fast mixing in a cascade, leading to a valsartan precursor. The third and final case employed a continuous stirred tank reactor (CSTR) made of a UV-curable resin. It was used for the first step of a multiphase enzymatic decarboxylation followed by a Heck cross-coupling reaction, leading to resveratrol derivatives.",10.1021/acs.oprd.0c00228,0
Process Safety in the Pharmaceutical Industry—Part I: Thermal and Reaction Hazard Evaluation Processes and Techniques,"High Resolution Image Download MS PowerPoint Slide Process safety groups in the pharmaceutical industry are important components of active pharmaceutical ingredient (API) development through its life cycle from discovery to commercial scale. The pharmaceutical process safety laboratory staff conduct a series of tests to identify chemically unstable reagents, intermediates and solvents, and mixtures to ensure that the proposed operating conditions provide a sufficient safety margin from the onset of undesired and potentially catastrophic thermal decomposition. Across several pharmaceutical companies, the methods used for these assessments and how results and conclusions are made are widespread ( vide infra ). A working group was created with members from several pharmaceutical companies within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the goal of precompetitive collaboration and to understand each of the participating companies’ procedures and assessment regarding process safety. Each company was invited to provide input using a blind survey format. This was done in the interest of making this knowledge accessible for the participating companies and the wider community of other pharma and chemical companies and even academic institutions in the US and throughout the world. This article provides the results of this in-depth survey of the members of the IQ Consortium thermal hazard working group. General issues around different tools used to assess thermal hazard risk and questions regarding staffing and tech transfer of process safety data/information from development to manufacturing were addressed. A snapshot of how various assessment strategies are employed as a function of stage of development (early, mid, and late) is also presented.",10.1021/acs.oprd.0c00226,0
Applications of Quantum Chemistry in Pharmaceutical Process Development: Current State and Opportunities,"Application of computational methods to understanding and predicting properties of analogues for drug discovery has enjoyed a long history of success. However, the drug development space (post-candidate selection) is currently experiencing a rapid growth in this arena. Due to the revolution in computing hardware development and improved computational techniques, quantum chemical (QC) calculations have become an essential tool in this space, allowing results from complex calculations to inform chemical development efforts. As a result, numerous pharmaceutical companies are employing QC as part of their drug development workflow. Calculations cover the range of transition state calculations, reaction path determination, and potential energy surface scans, among others. The impact of this rapid growth is realized by providing an in-depth understanding of chemical processes and predictive insight into the outcome of potential process routes and conditions. This review surveys the state of the art in these drug development applications in the pharmaceutical industry. Statistics of computational methods, software, and other metrics for publications in the last 14 years (2005–2019) are presented. Predictive applications of quantum chemistry for influencing experiments in reaction optimization and catalyst design are described. Important gaps in hardware and software capabilities that need to be addressed in order for quantum chemistry to become a more practical and impactful tool in pharmaceutical drug development are discussed. Perspectives for the future direction of application of QC to pharmaceutical drug development are proposed.",10.1021/acs.oprd.0c00222,0
"Toward a Scalable Synthesis and Process for EMA401, Part III: Using an Engineered Phenylalanine Ammonia Lyase Enzyme to Synthesize a Non-natural Phenylalanine Derivative","A process using an engineered phenylalanine ammonia lyase (PAL) enzyme was developed as part of an alternative route to a key intermediate of olodanrigan (EMA401). In the first part of this report, the detailed results from a screening for the optimal reaction conditions are presented, followed by a discussion of several workup strategies investigated. In the PAL-catalyzed reaction, 70–80% conversion of a cinnamic acid derivative to the corresponding phenylalanine derivative could be achieved. The phenylalanine derivative was subsequently telescoped to a Pictet–Spengler reaction with formaldehyde, and the corresponding tetrahydroisoquinoline derivative was isolated in 60–70% yield with >99.9:0.1 er. On the basis of our screenings, carbonate/carbamate-buffered ammonia at an NH 3 concentration of 9–10 M and pH 9.5–10.5 was found to be optimal. Enzyme loadings down to 2.5 wt % (E:S = 1:40 w/w) could be achieved, and substrate concentrations between 3–9 v/w (1.17–0.39 M) were found to be compatible with the reaction conditions. A temperature gradient was applied in the final process: a pre-equilibrium was established at 45 °C, before making use of the temperature dependence of the entropy term with subsequent cooling to 20 °C to achieve maximum conversion. This temperature gradient also allowed balancing of the enzyme stability (low at 45 °C, high at 20 °C) with the activity (high at 45 °C, low at 20 °C) in order to achieve optimal conversion (low at 45 °C, high at 20 °C). From the various workup operations investigated, a sequence consisting of denaturation of the enzyme, NH 3 /CO 2 removal by distillation, acidification, and telescoping to the subsequent Pictet–Spengler cyclization was our preferred approach. The process presented in this study is a more sustainable, shorter, and more cost-effective alternative to the previous process.",10.1021/acs.oprd.0c00217,0
"Toward a Scalable Synthesis and Process for EMA401, Part II: Development and Scale-Up of a Pyridine- and Piperidine-Free Knoevenagel–Doebner Condensation","During route scouting for EMA401 ( 1 ), an angiotensin II type 2 antagonist, we identified the synthesis of key amino acid intermediate 2 via its cinnamic acid derivative 3 as a streamlined option. In general, cinnamic acids can be synthesized from the corresponding aldehydes by a Knoevenagel–Doebner condensation in pyridine with piperidine as an organocatalyst. We aimed to replace both of these reagents and found novel conditions involving toluene as the solvent and morpholine as the organocatalyst. Scale-up of the process allowed the production of 25 kg of cinnamic acid 3 that was of the quality required for process development of the subsequent phenylalanine ammonia lyase-catalyzed step. The modified conditions were found to be widely applicable to alternative aldehydes and thus are of relevance to practitioners of chemical scale-up.",10.1021/acs.oprd.0c00216,0
"Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment","We present the enantioselective synthesis of sodium (3 S )-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet–Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH 2 O in the Pictet–Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.",10.1021/acs.oprd.0c00215,1
Practical and Efficient Approach to the Preparation of Diquafosol Tetrasodium,A scalable and practical route to synthesize the P2Y2 receptor agonist diquafosol tetrasodium has been described. Diquafosol tetrasodium was obtained via a four-step process starting from commercially available 5′-uridylic acid disodium salt. The whole procedure gives the target product in a 45% overall yield with high purity (>99%). Key steps in this process including isolation of impurities and the target product by using anion-exchange resin are discussed in detail. The optimized process has been successfully demonstrated on a large scale to support the development of diquafosol tetrasodium in China.,10.1021/acs.oprd.0c00209,1
Mini-Monoplant Technology for Pharmaceutical Manufacturing,"High Resolution Image Download MS PowerPoint Slide Pharmaceutical production has historically relied on multipurpose batch vessels in order to produce material through scheduled production campaigns. Although this method is flexible, it is becoming less effective in addressing the changing landscape of pharmaceutical production, where more complex and potent molecules are required to be produced more rapidly and can have fluctuations in their demand. This article describes a method for developing intensified and dedicated pharmaceutical processes, known as mini-monoplants. Key value-generating aspects are described at each stage of development, from lab-based development of best-in-class processes to factory-based development for an accelerated time to market and finally to mini-monoplant technology for production at commercial scale.",10.1021/acs.oprd.0c00207,0
Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301,"We report an improved and scalable synthesis of MIDD0301, a positive GABA A receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2′-fluorobenzophenone, which has a nonbasic nitrogen due to electron-withdrawing substituents in the ortho and para positions, reducing its reactivity toward activated carboxylic acids. Investigations of peptide coupling reagents on a multigram scale resulted in moderate yields due to incomplete conversions. Second, the basic conditions used for the formation of the seven-membered 1,4-diazepine ring resulted in racemization of the chiral center. We found that neutral conditions comparable to the p K a of the primary amine were sufficient to support the formation of the intramolecular imine but did not enable the simultaneous removal of the protecting group. Both difficulties were overcome with the application of the N -carboxyanhydride of d -alanine. Activated in the presence of an acid, this compound reacted with nonbasic 2-amino-5-bromo-2′-fluorobenzophenone and formed the 1,4-diazepine upon neutralization with triethylamine. Carefully designed workup procedures and divergent solubility of the synthesic intermediates in solvents and solvent combinations were utilized to eliminate the need for column chromatography. To improve compatibility with large-scale reactors, temperature-controlled slow addition of reagents generated the imidazodiazepine at −20 °C. All intermediates were isolated with a purity of >97% and impurities were identified and quantified. After the final hydrolysis step, MIDD0301 was isolated in a 44% overall yield and a purity of 98.9% after recrystallization. The enantiomeric excess was greater than 99.0%.",10.1021/acs.oprd.0c00200,1
"Multigram Synthesis of BMS-929075, an Allosteric, Palm Site Inhibitor of HCV NS5B Replicase, Involving the Synthesis of a Highly Functionalized Benzofuran through a Telescoped Process","An efficient scale-up synthesis of 4-fluoro-2-(4-fluorophenyl)- N -methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide ( BMS-929075 ), an allosteric, palm site inhibitor of the HCV NS5B replicase, is described. The highlights of the process involve (a) the copper-mediated, one-pot synthesis of 2-(3-bromo-2-fluoro-6-methoxyphenyl)acetic acid ( 21 ) from regiospecifically lithiated 1-bromo-2-fluoro-4-methoxybenzene ( 13 ) and ethyl 2-bromoacetate ( 18 ); and (b) the formation of the highly functionalized benzofuran core 26 through a chromatography-free, telescoped process that proceeds via acylation and a subsequent concomitant demethylation and Boc deprotection using BBr 3, followed by an acid-catalyzed cyclization from Boc-protected 2-(3-bromo-2-fluoro-6-methoxyphenyl)- N -methylacetamide 23 . This process was applied to the preparation of 110 g of high-quality BMS-929075 to enable preclinical toxicology studies.",10.1021/acs.oprd.0c00198,1
Convenient Continuous Flow Synthesis of <i>N</i>-Methyl Secondary Amines from Alkyl Mesylates and Epoxides,"The first continuous flow process was developed to synthesize N -methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N -methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N -methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.",10.1021/acs.oprd.0c00193,0
Short and Easily Scalable Synthesis of the Sex Pheromone of the Horse-Chestnut Leaf Miner (<i>Cameraria ohridella</i>) Relying on a Key Ligand- and Additive-Free Iron-Catalyzed Cross-Coupling,"We describe in this work a short six-step convergent high-scale synthesis of the sex pheromone of the horse-chestnut leaf miner ((8 E,10 Z )-tetradeca-8,10-dienal). This procedure relies on a key stereoselective iron-catalyzed Kumada cross-coupling, which affords the coupling product in high yield in the absence of additional ligands or additives. DFT calculations moreover suggest that ω-alkoxide groups on iron-ligated chains in transient organoiron(II) intermediates can enhance their stability and hamper their decomposition in off-cycle β-hydride elimination reactions.",10.1021/acs.oprd.0c00191,1
"A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration","This article describes the process characterization and development of models to inform a process control strategy to prepare ( R, R )-epoxy ketone 2, an intermediate in the manufacture of carfilzomib. Model calibration for relevant unit operations and the development of a dynamic integrated flowsheet-level model in gPROMS FormulatedProducts software enabled investigation of the impact of process disturbances and model uncertainties on the critical quality attributes (CQAs) and identification of critical process disturbances and failure modes to guide a process control strategy. The model development was similar to that described in the previous parts of this series, but with the added complexity of comparing two distinct kinetic formulations for the epoxidation reaction. The main CQAs for this process were (1) the conversion of enone 1 (target ≥99.0 mol % conversion) and (2) the purity target for solids prior to cake wash (target ≥97.5% purity by weight). Conversion of enone was not always achieved with the expected disturbances: whereas 99.5% conversion was expected for normal operating conditions, 97.2% conversion was predicted for the worst-case combination of disturbances. The chiral purity of crystalline ( R, R )-epoxy ketone 2 was not always achieved with the expected disturbances: 98.2% purity was expected for normal operating conditions, and 96.7% purity was expected for the worst-case combination of disturbances. These analyses allowed for rank ordering of critical process parameters that impact conversion and suitable manipulated variables to develop a robust process control strategy for the manufacturing scheme.",10.1021/acs.oprd.0c00189,0
"A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process","This article details efforts to characterize and develop a process control strategy for the manufacture of enone 2, a carfilzomib drug substance intermediate obtained through a Barbier-type Grignard reaction of morpholine amide 1 . This includes the development of a novel mechanistic model for the heterogeneous Barbier-type Grignard reaction. After the model was characterized with laboratory-scale batch experiments, its performance was compared with experimental data collected under continuous operating conditions. Under nominal operating conditions, the experimentally measured conversion of morpholine amide varied from 94.3% to 96.7%, a range that was encompassed by the model. With a mechanistic model validated under continuous operating conditions, relationships between the magnesium charging interval and the variability in conversion of morpholine amide 1 to enone 2 were determined to further explore the experimental design space. The remaining unit operations were subsequently characterized, and the models developed for the individual operations were integrated into a flowsheet-level dynamic process model implemented in the gPROMS FormulatedProducts software. The impact of various process disturbances and model uncertainties on the critical quality attributes were then investigated, and critical process parameters, failure modes, and control strategies to address these disturbances were identified. The process was found to be most sensitive to operational disturbances in the supplied reactants: morpholine amide 1 and 2-bromopropene (2-BP). As 1 is manufactured upstream by the process described in Part 1 of this series, in silico analysis of potential process control strategies focused on manipulation of the 2-BP concentration and flow rate into the primary reactor. Overall, this work highlights the benefits of using mathematical modeling to deepen the understanding of pharmaceutical manufacturing processes and enable integrated unit operations in a continuous manufacturing setting.",10.1021/acs.oprd.0c00188,1
"A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation","This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3 . Model calibration for relevant unit operations and development of a dynamic integrated flowsheet-level model in gPROMS FormulatedProducts software allowed an investigation of the impact of process disturbances and model uncertainties on critical quality attributes (CQAs) and identification of critical process disturbances and failure modes to guide the process control strategy. The main CQA for this step was the conversion of Boc- d -leucine monohydrate (≥95%). The model was used to ensure that a state of control would be maintained in the presence of disturbances to target process parameters. The process was found to be robust against the analyzed disturbance scenarios, including worst-case combined disturbances. One case study highlights the dynamics of flow blockage for a key reagent, N, N ′-carbonyldiimidazole (CDI), resulting from line clogging and the relationship between blockage duration and reaction conversion. The blockage was studied in silico, and the model demonstrated that the acceptance criteria for reaction conversion were met even with a flow rate reduction of 40%. The detrimental impact on the product concentration in the downstream process, however, required modification of the final distillation operation. The revised distillation column operation was demonstrated to address this concern and tolerated variable concentrations of morpholine amide while achieving the target water specification (<0.25 wt %). The results of this in silico analysis were verified with a production-scale demonstration of morpholine amide synthesis at a throughput of 12 kg/day to experimentally evaluate the impact of disturbances on the control strategy and overall performance of the system.",10.1021/acs.oprd.0c00187,1
Development and Execution of a Production-Scale Continuous [2 + 2] Photocycloaddition,"This article details the approach to large-scale production of cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition of maleic anhydride and ethylene, including (1) focused reaction optimization and development of a robust isolation protocol, (2) the approach to equipment design and process safety, and (3) the results of commissioning tests and production runs delivering the target compound at throughputs exceeding 5 kg/day.",10.1021/acs.oprd.0c00185,0
Optimized Synthesis of 7-Azaindazole by a Diels–Alder Cascade and Associated Process Safety,"Although pyrimidines are not among the most reactive partners in intramolecular inverse-electron-demand [4π s + 2π s ] reactions with alkynes, they can be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-azaindazole by a one-pot Diels–Alder cascade that starts from a pyrimidine substituted at the 2-position by an (alkynyl)hydrazone. The safety of the process and the environmental impact were thoroughly evaluated. Eventually, a selection of cross-coupling reactions of 17 were studied and found to allow the introduction of carbon- and nitrogen-based nucleophiles at the 5-position in good to excellent yields.",10.1021/acs.oprd.0c00184,1
Evaluation and Screening of Spherical Pd/C for Use as a Catalyst in Pharmaceutical-Scale Continuous Hydrogenations,"Over the past several years GSK has been developing the capability to perform continuous hydrogenations within trickle bed reactors. Motivation to develop this technology stems from the ability of trickle bed reactors to perform hydrogenations at high pressures (up to 100 bar within GSK), which is considerably greater than our current hydrogenation batch vessels (5 bar). This allows access to chemistry with improved quality and productivity, with the added benefit of enhanced process control, reduced reactor size, reduced vessel cleaning time, greener processes, and increased safety. To support this ambition a new generation of catalysts for pharmaceutical-scale continuous hydrogenations have been developed with traditional and nontraditional catalyst suppliers. Herein we discuss a procedure to characterize and assess the suitability of the new catalysts from a nontraditional supplier for use in laboratory and pilot plant scale reactors (reactor volume 0.1 to 0.5 L).",10.1021/acs.oprd.0c00183,0
Practical and Scalable Synthesis of a Glucokinase Activator via One-Pot Difluorination and Julia Olefination,"We describe the process research and development of a practical synthesis of glucokinase activator 1 as a potential drug for treating type 2 diabetes mellitus. The key structure, a 3,4- cis -difluorinated cyclopentane moiety, was constructed via diastereoselective epoxidation, followed by one-pot difluorination with Et 3 N·3HF and perfluorobutanesulfonyl fluoride (PBSF). Julia olefination of benzothiazol-2-yl sulfone with glyoxylate furnished an E / Z mixture of acrylate, followed by isomerization of the alkene to the desired E configuration during the formation of the acid chloride in the final step. This development achieved a highly practical process route to 1 (15% overall yield, 12 steps). This process route overcomes the drawbacks of the original medicinal chemistry synthetic route, which used hazardous and costly reagents (LiAlH 4, OsO 4, and Deoxo-Fluor) and had low efficiency (<4% overall yield, 20 steps).",10.1021/acs.oprd.0c00180,1
Cost-Effective Flow Peptide Synthesis: Metamorphosis of HPLC,"We present the further development and fine-tuning of an efficient, economic (≤3 equivalents of activated amino acid ), and environmentally friendly (6 mL organic waste/cycle) procedure for peptide synthesis using a fast amino acid coupling reaction (1.7 min). The designed setup can assist the synthesis of highly pure (>80%) raw materials even for long (up to 30 aa.) and/or difficult sequences. The significant reduction of the coupling time by using the effective PyAOP and N, N ′-diisopropylcarbodiimide/HOBt coupling reagents was achieved, and virtually racemization-free (L-His/D-His <1–5%) peptides can now be synthesized, even at higher column temperature: T = 70 °C. The purity of the product and the efficiency of the synthesis were evaluated using different solid phase supports and protocols. We successfully completed the synthesis of “difficult” sequences [ e.g., insulin B-chain and cecropin A(1–7)-melittin(2–9) hybrid peptide] wasting only a fraction of the organic solvents compared to other methods, furthering peptide chemistry toward a greener approach.",10.1021/acs.oprd.0c00178,0
Development of a Large-Scale Cyanation Process Using Continuous Flow Chemistry En Route to the Synthesis of Remdesivir,"The implementation of cyanation chemistry at manufacturing scales using batch equipment can be challenging because of the hazardous nature of the reagents employed and the tight control of reaction parameters, including cryogenic temperatures, that help to afford acceptable selectivity and conversion for the desired reaction. Application of continuous flow chemistry offers a means to mitigate the risk associated with handling large amounts of hazardous reagents and to better control the reaction parameters. A case study describing the cyanation of a glycoside using continuous flow chemistry toward the synthesis of the drug candidate remdesivir is presented.",10.1021/acs.oprd.0c00172,1
"Development of a Zinc-Mediated Approach to a 2,3-<i>cis</i>-Pyrrolidine Arginase Inhibitor","This manuscript outlines the development activities toward a robust synthesis of cis -2,3-pyrrolidine via tandem zinc-enolate cyclization/Negishi coupling that proceeds with high diastereoselectivity. The methodology facilitated a gram-scale delivery of the target API and eliminated the need for costly chiral resolutions and inefficient protecting group manipulations. A series of DFT experiments provided a transition-state model that agrees closely with the experimental observations and provides a more in-depth understanding of the observed selectivity.",10.1021/acs.oprd.0c00171,1
"Supporting-Electrolyte-Free and Scalable Flow Process for the Electrochemical Synthesis of 3,3′,5,5′-Tetramethyl-2,2′-biphenol","The most efficient electrochemical synthesis of 3,3′,5,5′-tetramethyl-2,2′-biphenol by dehydrogenative coupling is reported. The electrolysis is performed supporting-electrolyte-free in 1,1,1,3,3,3-hexafluoroisopropanol and at carbon electrodes, whereby glassy carbon electrodes turned out to be superior. To provide sufficient conductivity, pyridine is added, and it can easily be recovered by evaporation and reused. This facilitates the downstream process tremendously, making it simple, economical, and technically viable. The scalability was proven by establishing a flow electrolysis in differently sized narrow-gap flow electrolyzers. Carrying out a multistep cascade electrolysis enabled the challenging hydrogen evolution to be successfully addressed. The scaled-up electrolysis provided an isolated yield of 59% biphenol.",10.1021/acs.oprd.0c00170,0
Investigation of On-Resin Disulfide Formation for Large-Scale Manufacturing of Cyclic Peptides: A Case Study,"Peptide molecules bearing disulfide moieties constitute an important category of therapeutics. The establishment of the disulfide structure plays a pivotal role in the production of those peptides. In-solution cyclization is generally adopted in industrial peptide production as a synthetic strategy to build disulfide from the linear deprotected precursor. This methodology is inherently limited by the relatively low productivity, considering the minimizing intermolecular oligomerization by dilution of the overall concentration of the reaction. Alternatively, the disulfide bond could be established from the thiol-protected building blocks directly on the solid support. On-resin disulfide construction was pursued for atosiban process development. Protected linear atosiban resin was treated with I 2 /dimethylformamide (DMF), and the target disulfide was built rapidly and quantitatively within 30 min. The effects of the resin linker and thiol-protecting groups were tested by utilizing Sieber resin, Rink amide resin, and Ramage resin as solid supports and Cys(Trt)/Cys(Acm) as building blocks. The I 2 equivalence, as a potential critical process parameter, was subjected to a proven acceptable range (PAR) study to facilitate the envisioned large-scale manufacturing. Although there was rapid and complete disulfide formation on the solid support in all tested combinations of resin and thiol-protecting groups, a reduction of the disulfide was observed in the processes of a certain peptidyl resin cleavage/global deprotection. A dedicated investigation revealed that hydrosilane, employed as a cation scavenger in peptide synthesis, is responsible for the disulfide degradation in the presence of trifluoroacetic acid (TFA). Eliminating silane from the TFA cleavage solution or subtly controlling its equivalence could effectively suppress the nocuous disulfide reduction in this process. In summary, on-resin disulfide cyclization has been verified to be a viable strategy for atosiban industrial production by this study.",10.1021/acs.oprd.0c00168,0
Preparation of Mono- and Diisocyanates in Flow from Renewable Carboxylic Acids,"Diisocyanates used in polyurethanes are commonly prepared by phosgenation of petroleum-sourced diamines. This involves highly toxic phosgene and produces corrosive HCl, limiting synthetic applications. In our search for a renewable source for diisocyanates, we have developed a practical methodology for the production of isocyanates from algae-biomass-derived fatty acids or other renewable sources. This technique utilizes flow chemistry to prepare and convert high-energy intermediates, thus mitigating safety concerns. By the use of continuous flow, acyl azides are prepared from hydrazides and subsequently heated to undergo Curtius rearrangement, affording isocyanates in one scalable process. The method is efficient, safe, and sustainable, offers an opportunity to prepare isocyanates and diisocyanates from renewable feedstocks, and is amenable to distributed manufacturing processes.",10.1021/acs.oprd.0c00167,1
A Structured Approach To Cope with Impurities during Industrial Crystallization Development,"The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.",10.1021/acs.oprd.0c00166,0
Scalable Synthesis of Esp and Rhodium(II) Carboxylates from Acetylacetone and RhCl<sub>3</sub>·<i>x</i>H<sub>2</sub>O,"Rhodium(II) carboxylates are privileged catalysts for the most challenging carbene-, nitrene-, and oxo-transfer reactions. In this work, we address the strategic challenges of current organic and inorganic synthesis methods to access these rhodium(II) complexes through an oxidative rearrangement strategy and a reductive ligation reaction. These studies illustrate the multiple benefits of oxidative rearrangement in the process-scale synthesis of congested carboxylates over nitrile anion alkylation reactions, and the impressive effect of inorganic additives in the reductive ligation of rhodium(III) salts.",10.1021/acs.oprd.0c00164,0
Chemical Reaction of Carbon Dioxide with Bisepoxides for Synthesis of Organic Cyclic Dicarbonates at Ambient Pressure for Polyhydroxy Urethane Synthesis,"The synthesis of multifunctional cyclic carbonates starting from different epoxides will most likely be an important step to open an alternative way for an isocyanate-free formation of linear and cross-linked polyhydroxy urethanes. Within this contribution, we demonstrate the advantages of a cyclic-performed chemical fixation of carbon dioxide under ambient conditions (normal pressure and temperature in the range of 90 °C). The presented procedure is scalable in contrast to a high-pressure-based system that lacks the possibility to be easily scalable in a cost-effective manner due to safety and construction aspects. Syntheses of different difunctional cyclic carbonates using diglycidyl ester, diglycidyl ethers, and an epoxide within a cyclo-aliphatic ring are performed. During the reaction, the conversion of the epoxides and the formation of the cyclic carbonates are monitored by Fourier transform infrared (FTIR) spectroscopy. Conversions and yields of the reactions are calculated and verified by NMR analysis. The designed circulating gas-flow system even results in high reactivity using the well-known catalyst, tetrabutylammonium bromide, if methyl isobutyl ketone is used as the solvent. This effect is discovered by analyzing experiments in different solvents. Basic model aminolysis experiments are performed to demonstrate that the synthesized cyclic carbonates have the potential to be applicable in an industrial process to produce polyhydroxy urethanes (PHU) and nonisocyanate polyurethanes (NIPU).",10.1021/acs.oprd.0c00163,0
Development of a Versatile Modular Flow Chemistry Benchtop System,"Flow chemistry devices have seen an increase as research tools in recent years. We present a modular system for benchtop continuous flow that allows user flexibility and reliability in the pursuit of challenging chemistry. An oscillating baffle reactor mold-formed in perfluoroalkoxy alkane enables handling reactions forming solids. A LabView control system with help from Omega temperature controllers allows for simple and precise regulation of reaction conditions with real-time monitoring of the temperature and pressure. A new pressurized sample collection vessel allows for inert and pressurized sampling into multiple vials. An array of case studies serves to validate the system by demonstrating the use of interchangeable reactors with in-line heating and cooling, along with the ability to handle highly corrosive and reactive chemical reagents such as white fuming HNO 3 .",10.1021/acs.oprd.0c00160,0
Seeking for Selectivity and Efficiency: New Approaches in the Synthesis of Raltegravir,"The present work describes the development of an improved synthesis of active pharmaceutical ingredient raltegravir. The isolation of a new process intermediate and the newly developed conditions solve the issue of selectivity typical of this production process, with no need for the use of protecting groups, making the present route more efficient and sustainable than what was reported before. Efficiency comparisons with the previous processes confirm the result here obtained.",10.1021/acs.oprd.0c00155,1
Two-Phase Flow in a Coiled Flow Inverter: Process Development from Batch to Continuous Flow,"The transfer of batch processes to continuous flow is a major driver for the application of microreactors. Here, we present a methodology for the transfer of (bio)chemical reactions in batch mode to two-phase continuous flow. For our purposes, the coiled flow inverter (CFI) is a promising reactor design providing enhanced heat and mass transfer, narrow residence time distribution, and rapid mixing. First, this methodology is used for current development of a droplet-based reaction screening system, which was first tested with a Paal–Knorr pyrrole synthesis as model reaction. The reaction was successfully performed in the automated screening system. The yields compared to the batch mode revealed enhanced mass transfer of the product into the continuous phase. Second, we investigated the biocatalyzed oxidation of ABTS by the enzyme laccase in a straight capillary for process development in a CFI. Because of its high flexibility regarding substrate specificity, laccase oxidizes many substrates with a colored product. Hence, an optical evaluation method for determination of reaction rate is used. We compare the Michaelis–Menten kinetic of the batch reaction and the continuous reaction in a capillary. The results show that the batch reaction can be mapped to the capillary setup. However, the capillary in continuous operation enables higher screening capacity of different reaction conditions and simple scale-up procedure.",10.1021/acs.oprd.0c00152,0
Seeding Techniques and Optimization of Solution Crystallization Processes,"Over the past few decades, seeding strategies for solution crystallization processes have been developed for various applications, and significant improvements in crystal quality and process robustness have been achieved. Here a systematic review of seeding techniques from the preparation and characteristics of seed crystals to application instances of seeding strategies is presented. First, the dependence of the seeding strategy on the tuning purpose of secondary nucleation is illustrated and discussed in combination with application instances. Next, seeding crystallization for specific targets such as systems for oiling out, chiral resolution, and tubular crystallization processes is discussed. Finally, opportunities for further study of seeding crystallization are proposed.",10.1021/acs.oprd.0c00151,0
Design and Characterization of a Scaled-up Ultrasonic Flow Reactor,"Ultrasonic microreactors are increasingly applied to particle synthesis, crystallization processes, or organic synthesis involving solids because of the clogging prevention offered by ultrasound irradiation. However, the further application of this technology is limited by the scalability of ultrasonic flow reactors. In this work, we combined experiments and numerical simulations for the design of a scaled-up flow reactor. The reactor consists of a perfluoroalkoxy alkane (PFA) tubing immersed in a box to transmit the ultrasound and provide temperature control, to which six Langevin multifrequency transducers are attached. The acoustic pressure distribution was investigated to characterize the effect of ultrasound frequency and the transducer configurations on particle size distribution for the model reaction of barium sulfate synthesis. Operating the scaled-up reactor with six transducers at a frequency of 40 kHz resulted in an acoustic wave distribution with maximum acoustic pressures in the vicinity of the tubular reactor, thus leading to a small particle size distribution and consequently clogging prevention. The productivity of the scaled-up reactor was 14g/h barium sulfate at a remarkably low applied ultrasound power of 0.48W/mL, highlighting the efficient design and the further scale-up potential.",10.1021/acs.oprd.0c00148,0
A Continuous Flow Sulfuryl Chloride-Based Reaction—Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine,"We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and controlling the temperature led to better outcomes. These reactions are ideal candidates for implementation in a continuous mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein we discuss the flow implementation and the final reactor design that led to a system with a 141 g/h throughput.",10.1021/acs.oprd.0c00146,1
Synthesis of an Oxathiolane Drug Substance Intermediate Guided by Constraint-Driven Innovation,"A new route was developed for construction of the oxathiolane intermediate used in the synthesis of lamivudine (3TC) and emtricitabine (FTC). We developed the presented route by constraining ourselves to low-cost, widely available starting materials-we refer to this as supply-centered synthesis. Sulfenyl chloride chemistry was used to construct the framework for the oxathiolane from acyclic precursors. This bond construction choice enabled the use of chloroacetic acid, vinyl acetate, sodium thiosulfate, and water to produce the oxathiolane.",10.1021/acs.oprd.0c00145,1
Fully Automated Chemical Synthesis: Toward the Universal Synthesizer,"Automated peptide and oligonucleotide synthesizers enabled a revolution in molecular biology and helped pave the way to modern synthetic biology. Similarly, fully automated synthetic chemistry could herald a new wave of innovation in biology and materials sciences by greatly facilitating access to known and novel molecules. Here, we report on an automated multistep chemical synthesizer, AutoSyn, that makes milligram-to-gram-scale amounts of virtually any drug-like small molecule in a matter of hours and demonstrate its versatility with the synthesis of ten known drugs. Of the FDA-approved small-molecule drugs for which we were able to compute a synthetic route, 87% are predicted to be synthesizable on AutoSyn. Moreover, AutoSyn enables digital synthesis protocols that ensure the reproducibility and transferability of synthesis protocols from one lab to another.",10.1021/acs.oprd.0c00143,0
Development and Production of an Enantioselective Tetrahydroisoquinoline Synthesis Enabled by Continuous Cryogenic Lithium–Halogen Exchange,"Route invention, process development, and production of 185 kg of a key tetrahydroisoquinoline intermediate for the dopamine D1 receptor positive allosteric modulator mevidalen are reported. The synthesis leveraged widely commercially available chiral starting materials to build a challenging 1,3- trans -tetrahydroisoquinoline. Two cryogenic lithiations were used to forge C–C bonds, and the heterocycle was formed by an intramolecular nucleophilic displacement. Because of a significant exotherm and instability of the aryllithium intermediate, one lithiation was shown to be scalable only in continuous flow mode. The processes were scaled up using a combination of batch and flow technologies, and the challenges that were encountered during production are described. After the successful pilot-plant campaign, the new route was analyzed from several perspectives to guide future development.",10.1021/acs.oprd.0c00141,1
Cross-Pharma Collaboration on the Development and Evaluation of a New Mid-Scale Preparative Supercritical Fluid Chromatography Instrument,"Precompetitive collaborations on the development of new enabling technologies for conducting pharmaceutical research and development are becoming increasingly popular, as pharmaceutical companies recognize the economic and practical benefits of cross-industry collaborations. We report here one of the first new technology development projects from the recently formed Enabling Technologies Consortium, the creation of a new instrument for carrying out mid-scale preparative supercritical fluid chromatography purifications. Input from a team of experienced separation scientists from 10 pharmaceutical companies helped to define a set of critical product attributes that provided guidance to a team of instrument developers in the creation of a new instrument prototype, with testing and feedback from the group helping to improve and refine the final product features. Two beta test units were placed in laboratories at two ETC member companies, allowing for an in-depth performance testing, following an extensive testing procedures developed by the project team. The evaluation results showed that the system met all required specifications. We describe here the development and testing of the new instrument and provide several examples of its use in carrying out chromatographic purifications in support of pharmaceutical discovery and development research.",10.1021/acs.oprd.0c00136,0
Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate,"We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCl) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.",10.1021/acs.oprd.0c00134,0
Semicontinuous Process for GMP Manufacture of a Carbapenem Intermediate via Carbene Insertion Using an Immobilized Rhodium Catalyst,"A two-stage flow process for cGMP manufacture of a commercially important carbapenem intermediate was developed. Stage 1 featured an intramolecular N–H insertion reaction catalyzed by an immobilized rhodium catalyst. In stage 2, phosphorylation of the resulting keto ester intermediate afforded the target, which was isolated in batch mode. The equipment design and process control strategy leading to validation of the process at the 100 kg scale are discussed.",10.1021/acs.oprd.0c00133,0
Process Intensification for Obtaining a Cannabidiol Intermediate by Photo-oxygenation of Limonene under Continuous-Flow Conditions,"We have investigated the synthesis of p -mentha-2,8-dien-1-ol ( 1 ) as a cannabidiol precursor by photochemical oxidation of ( R )-limonene ( 2 ) with singlet oxygen ( 1 O 2 ) using meso -tetraphenylporphyrin (TPP) as a photosensitizer. Different home-made engineered set-ups were used for reaction intensification. Under optimized conditions, the target compound was obtained at up to 580.8 μmol·min –1 (66.7 g·day –1 ) using a low concentration of TPP (0.1 mM) and requiring 20 min for total conversion. Low-temperature photoreactor approaches made it possible to raise the level of selectivity of the desired limonene derivative up to 66%, with 55% conversion.",10.1021/acs.oprd.0c00131,0
"Development of a Scalable and Practical Synthesis of AB928, a Dual A<sub>2a</sub>/A<sub>2b</sub> Receptor Antagonist","AB928 is a potent and selective dual antagonist of the A 2a and A 2b receptors, which is currently in clinical trials. Here, we report the development of two scalable and practical syntheses of AB928. The first-generation synthesis was used to successfully obtain AB928 in excellent yield and purity to support our preclinical and initial clinical studies. Recently, we have developed a second-generation synthesis of AB928 featuring a palladium-free protocol to access 3-(2-amino-6-chloropyrimidin-4-yl)-2-methylbenzonitrile, a key intermediate in the AB928 synthesis. The new method is scalable, practical, and significantly more cost-effective.",10.1021/acs.oprd.0c00124,1
Ketone Reductase Biocatalysis in the Synthesis of Chiral Intermediates Toward Generic Active Pharmaceutical Ingredients,"A range of generic active pharmaceutical ingredients were examined for potential chiral alcohol motifs and derivatives within their structures that could be employed as key synthetic intermediates. For seven generic active pharmaceutical ingredients (APIs), eight precursor ketones were acquired and then subjected to reduction by >400 commercially available ketone reductases from different suppliers. Positive screening results were achieved for five ketones screened, with multiple ketone reductases available for each successful ketone. Selectivity was typically >99.5% ee in most cases, including for the opposite enantiomer. The three best examples were then optimized and quickly scaled up to 1 L scale in high conversion and isolated yield while retaining selectivity of >99.5% ee for the desired chiral alcohol enantiomer. This work illustrates that where a wide range of enzymes are available, productive enzymes to give either alcohol enantiomer can be readily identified for many ketones and rapidly scaled up to produce chiral alcohols. This approach is particularly applicable to generating chiral API intermediates.",10.1021/acs.oprd.0c00120,0
Enzymatic Preparation of the Chiral (<i>S</i>)-Sulfoxide Drug Esomeprazole at Pilot-Scale Levels,"Esomeprazole is the most popular proton pump inhibitor (PPI) for treating gastroesophageal reflux disease. Enzymatic asymmetric sulfoxidation is a green approach to produce chiral sulfoxides. In this report, we focused on optimizing asymmetric sulfoxidation catalyzed by prazole sulfide monooxygenase ( Ac PSMO). The costly redox cofactor NADPH utilized by Ac PSMO was regenerated by formate dehydrogenase with CO 2 as the coproduct, which can be removed easily. During the scale-up process, oxygen supply was found to be the main limiting factor during the early phase of the reaction, while the instability of Ac PSMO and the lack of the cofactor NADPH hindered progress during the middle and late phases of the 0.6 L reaction. Finally, by adjusting oxygen mass transfer and increasing the dissolved oxygen, the enzymatic reaction was stepwise amplified to a 120 L scale using a 300 L thermostatic stirred reactor, affording 95.9% conversion and 99.9% enantiomeric excess after 12 h. Extraction and refinement of the product resulted in 0.39 kg of the isolated esomeprazole (sodium salt), with 57.8% overall yield (73.4% before the salt-forming reaction) and 99.1% purity. Thus, a green-by-design system was constructed for the efficient and precise oxidation of omeprazole sulfide into esomeprazole with molecular O 2 as the green cosubstrate and CO 2 and H 2 O as byproducts.",10.1021/acs.oprd.0c00115,0
Practical Considerations and Examples in Adapting Amidations to Continuous Flow Processing in Early Development,"Amidation is among the most frequently executed reactions in pharmaceutical research and development. We have explored the feasibility of adapting amidations to plug flow reactor (PFR) process conditions for the preparation of early development compounds. Among coupling reagents possessing good thermal stability, carbodiimides and T3P have been selected, as they are readily soluble, require no preactivation, offer excellent reaction kinetics, and enable convenient product isolation. A carbodiimide/2-hydroxylpyridine oxide (HOPO) protocol was demonstrated in four case studies with homogeneous feed and reaction streams that were readily adaptable to a PFR design. In a head-to-head comparison, T3P was also found to be readily adaptable to a PFR flow process and gave comparable yields. The EDC/HOPO method works well for amidations that do not involve substrates that are highly sensitive to racemization; its water compatibility makes it the reagent of choice when the amine reactant is in a salt form, since water can be added as a cosolvent to aid solubility. For substrates that are extremely sensitive to racemization, we have shown one successful example of peptide coupling using TBTU or COMU under PFR continuous flow conditions.",10.1021/acs.oprd.0c00112,0
Scalable Synthesis of <i>S</i>-Fluoromethyl Benzenesulfonothioate,"A general and practical method for the preparation of S -fluoromethyl benzenesulfonothioate on a 500 g scale in two steps from readily available CH 2 FCl, sulfur, and sodium benzenesulfinate is reported. The reaction was found to be rather sensitive to water and temperature. Furthermore, the main side product of the reaction was identified to be S -phenyl benzenesulfonothioate.",10.1021/acs.oprd.0c00101,0
Design of a Continuous Solvent Recovery System for End-to-End Integrated Continuous Manufacturing of Pharmaceuticals,"Disadvantages of the traditional batch process have encouraged the pharmaceutical industry to explore continuous manufacturing, including end-to-end approaches, such as integrated continuous manufacturing (ICM). As the pharmaceutical industry is relatively solvent-intensive, solvent recovery is necessary to achieve the goal of sustainable manufacturing. A simple vapor–liquid equilibrium (VLE) setup was designed, and its reliability was assessed, from which the VLE data for a two-solvent system were obtained and, accordingly, the distillation columns were designed. The recovered solvent purities were >99.9 wt % for the first solvent (Solvent 1) and >99.8 wt % for the second solvent (Solvent 2), and the recovery yields were 94.9% and 98.3%, respectively. From the E-factor analysis, approximately 30% less waste was generated in the ICM process compared with a corresponding batch process. After integration of the solvent recovery system, the E-factors for both the batch and ICM processes decreased significantly, from 1.63 to 0.29 and from 0.77 to 0.21, respectively.",10.1021/acs.oprd.0c00092,0
Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)<sub>2</sub>Zn(CF<sub>2</sub>H)<sub>2</sub>] and Improved Synthesis of the ICHF<sub>2</sub> Precursor,"Complex [(DMPU) 2 Zn(CF 2 H) 2 ] 1 is a crystalline organometallic reagent with utility in various catalytic difluoromethylation reactions under mild conditions. Unfortunately, this reagent is not commercially available and the procedure for the preparation of this air- and moisture-sensitive zinc complex has only been reported on a small scale. Herein, we report the development of a continuous process for the preparation of reagent 1 on >100 g scale by using a continuous stirred-tank reactor. The key to success is the design of a continuous reactive crystallization process in which the precipitation of the zinc complex 1 is driven by its low solubility in the reaction solvent. The improved synthesis of the iododifluoromethane precursor 2 from readily available bromodifluoroacetic acid further enables the synthesis of complex 1 on a larger scale.",10.1021/acs.oprd.0c00089,0
Efficient Asymmetric Synthesis of Ethyl (<i>S</i>)-4-Chloro-3-hydroxybutyrate Using Alcohol Dehydrogenase <i>Sm</i>ADH31 with High Tolerance of Substrate and Product in a Monophasic Aqueous System,"Bioreductions catalyzed by alcohol dehydrogenases (ADHs) play an important role in the synthesis of chiral alcohols. However, the synthesis of ethyl ( S )-4-chloro-3-hydroxybutyrate [( S )-CHBE], an important drug intermediate, has significant challenges concerning high substrate or product inhibition toward ADHs, which complicates its production. Herein, we evaluated a novel ADH, Sm ADH31, obtained from the Stenotrophomonas maltophilia genome, which can tolerate extremely high concentrations (6 M) of both substrate and product. The coexpression of Sm ADH31 and glucose dehydrogenase from Bacillus subtilis in Escherichia coli meant that as much as 660 g L –1 (4.0 M) ethyl 4-chloroacetoacetate was completely converted into ( S )-CHBE in a monophasic aqueous system with a >99.9% ee value and a high space-time yield (2664 g L –1 d –1 ). Molecular dynamics simulation shed light on the high activity and stereoselectivity of Sm ADH31. Moreover, five other optically pure chiral alcohols were synthesized at high concentrations (100–462 g L –1 ) as a result of the broad substrate spectrum of Sm ADH31. All these compounds act as important drug intermediates, demonstrating the industrial potential of Sm ADH31-mediated bioreductions.",10.1021/acs.oprd.0c00088,0
Process Development and Large-Scale Synthesis of BTK Inhibitor BIIB068,"Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal of transition metal from the process, (2) a streamlined process with significantly improved overall yield, and (3) appropriate impurity control (including potential mutagenic impurities), which enabled delivery of quality material for toxicology studies and clinical trials.",10.1021/acs.oprd.0c00087,1
Continuous-Flow Synthesis of Cationic Lipid SST-01 via Safe and Scalable Aerobic Oxidation and Reductive Amination,"The synthesis of the cationic lipid SST-01, a key component of Kyowa Kirin’s siRNA–lipid nanoparticles, through a two-step homogeneous continuous-flow process is described. Safe and scalable aerobic oxidation with a catalytic Cu I /TEMPO system and diluted oxygen (5% O 2 in N 2 ) was utilized in the first step to provide a lipid aldehyde. Subsequent reductive amination of the first-step eluent with methylamine using tetramethylammonium triacetoxyborohydride provided the target SST-01 in an overall yield of 95%.",10.1021/acs.oprd.0c00084,1
An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly,"An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate's anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2'-deoxynucleoside active pharmaceutical ingredients can be formed.",10.1021/acs.oprd.0c00083,1
Large-Scale Practical Synthesis of Boc-Protected 4-Fluoro-<scp>l</scp>-Proline,A large-scale synthesis process of N -Boc-4-fluoro- l -proline ( 1 ) from N -Boc-4-hydroxy- l -proline methyl ester ( 2 ) using nosyl fluoride ( 13 ) as a deoxyfluorinating agent has been developed. An eco-friendly and large-scale feasible process using a single solvent was developed to afford moderate yields of products with excellent purity >99% by high-performance liquid chromatography . The key feature of the optimization involving chromatography-free purification and isolation on a kilogram-scale at a pilot plant scale is described.,10.1021/acs.oprd.0c00080,1
Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide,"Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline workup and end-of-line crystallization in batch, leading to isolation of α-thio-β-chloroacrylamide Z -3 in pure form from a complex reaction mixture, exploiting the advantage of efficient heat transfer in flow. During development of a continuous flow strategy for production of appreciable quantities of α-thio-β-chloroacrylamides, difficulties surrounding a labor and resource intensive workup followed by final product isolation were addressed. A greener solvent choice was applied to the chemical synthesis, which enabled inline purification and separation, resulting in the crystallization of pure product directly from the reaction mixture. This process was readily scalable and demonstrated control over impurity formation and removal, which is key in an industrial setting.",10.1021/acs.oprd.0c00079,0
An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines,"Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. The key transformation is a convergent one-step procedure from 6 as compared to the current commercial process, with an improved yield from 59% (two steps) to 70%. Further improvements include eliminating the need for problematic magnesium tert -butoxide (MTB) and significant solvent reduction by avoiding an intermediate workup. With the costs of HIV/AIDS treatments remaining a barrier for those most in need, lowering the raw material/processing costs and increasing the security of supply can increase patient access.",10.1021/acs.oprd.0c00078,1
Synthesis Development of the Selective Estrogen Receptor Degrader (SERD) LSZ102 from a Suzuki Coupling to a C–H Activation Strategy,"The development of the synthetic process to the selective estrogen receptor degrader (SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could be significantly improved in regard to overall yield, removal of all chromatographic purifications, and reduction in the number of steps by revisiting the original disconnection strategy. Key features of the final process include construction of the benzothiophene core via Higa cyclization, late-stage phenolation using a Pd-catalyzed hydroxylation of an aryl bromide, and end-game assembly through a Pd-catalyzed C–H activation step. The overall yield could be significantly improved, and the costs could be reduced.",10.1021/acs.oprd.0c00076,1
5-Hydroxymethylfurfural Synthesis in Nonaqueous Two-Phase Systems (NTPS)–PC-SAFT Predictions and Validation,"The condensation reaction of fructose to 5-hydroxymethylfurfural (HMF) is acid-catalyzed, and it suffers from thermodynamic limitation of the conversion, poor kinetics, and consecutive reactions such as formation of humins from HMF. Different approaches exist to overcome these limitations. In this work, the combination of a nonaqueous solvent and a suitable extraction system is presented that ensures high reaction selectivity at full conversion, fast kinetics, and high partition selectivity of the product HMF over reactant fructose, keeping the temperature as low as 70 °C. In the first step of this work, the equation of state PC-SAFT was used to predict solvent effects on the reaction equilibrium of homogenous reaction systems. It was found that the two hydrophilic ionic liquids (ILs) [BMIM]Cl and [MIM]Cl shifted the reaction equilibrium to the product side by factors of 230 and 40, respectively, compared to the reaction in water. The predictions were verified by experimental data, which showed full conversion of fructose to HMF within less than 20 (60) min for the reaction in [MIM]Cl ([BMIM]Cl) with a high selectivity of up to 80%. Even more, the reaction in the [MIM]Cl solvent did not require adding a catalyst due to the acidic character of this IL. In the second step of this work, an in situ extraction of HMF was performed using a nonaqueous two-phase reaction system NTPS that was designed with PC-SAFT. The NTPS contains the reaction phase (either [BMIM]Cl or [MIM]Cl) and the extraction agent, i.e., one of the ketones MEK, MIBK, or ethyl acetate. These IL + organic solvent NTPSs were analyzed and evaluated toward fructose conversion and partitioning of fructose and of HMF. PC-SAFT predicted that, among all systems studied in this work, the NTPS IL + MEK was the most promising for the reaction of fructose to HMF and the in situ removal of HMF from fructose. Experimental results could validate the PC-SAFT predictions, that is, IL + MEK NTPSs allowed efficient conversion of fructose to HMF and a partition selectivity of HMF over fructose of about 100%. This new NTPS does not require an additional catalyst due to the acidity of [MIM]Cl; it allows a high reaction selectivity of 87% at 20 min and 93% conversion, and it moreover provides high separation efficiency. In sum, these results open the door for further developments of in situ extraction systems in the future for efficient and fast fructose conversion and HMF separation from the reacting phase, keeping the temperature as low as possible.",10.1021/acs.oprd.0c00072,0
Scale-Up Synthesis of IID572: A New β-Lactamase Inhibitor,"The new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late-stage functionalization approach. An alternative synthesis was developed to satisfy the short-term material need for toxicological studies in animals. The new synthetic strategy was built on two key features, an intramolecular azomethine ylide [3 + 2] cycloaddition that allowed the efficient formation of molecular complexity from readily available starting materials and an enzymatic resolution that resulted in high optical purity of a key intermediate.",10.1021/acs.oprd.0c00069,0
A Safer Synthesis of the Explosive Precursors 4-Aminofurazan-3-Carboxylic Acid and its Ethyl Ester Derivative,"A safe and efficient one-pot synthesis of 4-aminofurazan-3-carboxylic acid and its hydrogen chloride gas-free conversion to the ethyl ester derivative are described. Previous syntheses of these intermediates were plagued with mischaracterization issues, low yields, and/or dangerous exothermic profiles. The safe scale-up of these materials not only provides benefits to the energetic materials community but may also be of importance to the pharmaceutical and agrochemicals industries.",10.1021/acs.oprd.0c00068,1
Development of a Scalable and Safer Synthesis of Diazeniumdiolates,"Although diazeniumdiolates (DAZDs) and the synthetic methods to access DAZDs were discovered over 50 years ago, the current methodology is not safe, has a limited substrate scope, and is not amenable to large-scale production. For example, a recent investigation utilizing the standard methodology to prepare DAZDs resulted in two unexpected explosions, highlighting the need for safer and more practical chemistry. Recently, we have reported a general, scalable, safer, and high-yielding methodology adaptable to large-scale synthesis of diazeniumdiolates in water using a calcium hydroxide base. Herein, we report the full account for the development of the reaction. The merit of this strategy is evidenced by the highly efficient and safer preparation of a key DAZD intermediate, on the kilogram scale, needed for the preparation of MK-8150 ( 1 ), a novel O 2 -alkylated diazeniumdiolate NO donor under investigation as a potent and significant blood-pressure-lowering drug candidate.",10.1021/acs.oprd.0c00067,1
"Photo-oxidation of Cyclopentadiene Using Continuous Processing: Application to the Synthesis of (1<i>R</i>,4<i>S</i>)-4-Hydroxycyclopent-2-en-1-yl Acetate","(1 R,4 S )-4-Hydroxycyclopent-2-en-1-yl acetate is a chiral small building block that was requested to advance several Pfizer programs into the clinic. Pfizer and Syncom partnered to develop a photo-oxidation process of cyclopentadiene using a flow approach followed by subsequent bis-acetylation of the meso diol and final biocatalytic desymmetrization. This continuous process was demonstrated on a 6 g·h –1 input and is amenable to larger scale. The optimization and scale-up of this sequence is described therein.",10.1021/acs.oprd.0c00066,1
Nontraditional Application of the Photo-Fenton Process: A Novel Strategy for Molecular Construction Using Formamide and Flow Chemistry,"Instead of destroying organic compounds, for the first time the photo-Fenton reaction was employed to construct them. Oxindole and spiro-oxindole scaffolds, which are frequently found in natural products, were selected as molecular targets. The development of a photochemical flow reactor employing the photo-Fenton reaction in formamide resulted in an excellent synthetic methodology for oxindoles. Non-anhydrous conditions are required, and readily available chemicals and mild conditions are employed. Also, novel synthetic approaches for new spiro compounds were efficiently developed using functionalized oxindoles as key intermediates.",10.1021/acs.oprd.0c00057,0
"<i>N</i>-Acyl-5,5-Dimethylhydantoins: Mild Acyl-Transfer Reagents for the Synthesis of Ketones Using Pd–PEPPSI or Pd/Phosphine Catalysts","N -Acyl-hydantoins have emerged as novel acyl-transfer reagents for the synthesis of ketones via selective N–C(O) cleavage. Herein, we report two new protocols for the cross-coupling of N -acyl-5,5-dimethylhydantoins using versatile and readily accessible Pd–PEPPSI or Pd/phosphine catalysts. The acyl Suzuki reactions afford biaryl ketones in good to excellent yields under operationally simple conditions using commercially available, bench- and air-stable twisted N -acyl-hydantoins as acyl donors. The method complements and expands on the previous protocol for the cross-coupling of N -acyl-hydantoins ( Luo, Z. Org. Process Res. Dev. 2018, 22, 1188).",10.1021/acs.oprd.0c00054,0
"Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead","The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.",10.1021/acs.oprd.0c00052,0
"Continuous Process Improvement in the Manufacture of Carfilzomib, Part 1: Process Understanding and Improvements in the Commercial Route to Prepare the Epoxyketone Warhead","Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward the preparation of epoxyketone 4 highlighted several opportunities for process improvement. In this article, three case studies are presented that demonstrate how a detailed understanding of the reaction mechanism led to improvements that increased the overall robustness of the process. In the first case study, the mechanism of racemization of an α-chiral enone was investigated, resulting in the development of an improved aqueous workup procedure. Next, the stability of a bleach/pyridine mixture used for the step 3 epoxidation reaction was studied, leading to the identification of pyridine as a key raw material and improved reaction conditions and control strategy to meet the conversion target. Finally, oxidized butylated hydroxytoluene (oBHT) was identified as an impurity arising from the use of BHT-stabilized tetrahydrofuran in steps preceding the oxidation. The process understanding obtained from these investigations led to the implementation of process improvements that improved the robustness of the process. The development of a second-generation route to 4 is the subject of part 2 in this series (DOI: 10.1021/acs.oprd.0c00052).",10.1021/acs.oprd.0c00051,1
Continuous Safety Improvements to Avoid Runaway Reactions: The Case of a Chloro-Thiadiazole Intermediate Synthesis toward Timolol,"Detailed process safety investigation of an old process revealed hidden, previously unnoticed danger. The synthesis of morpholine-adduct 2 was performed under reaction conditions very close to triggering a potentially dangerous runaway reaction. Process modifications such as dilution with an inert solvent allowed gaining better control of the process. Ultimately, improvement in both quality and yield was obtained.",10.1021/acs.oprd.0c00048,0
Understanding API Static Drying with Hot Gas Flow: Design and Test of a Drying Rig Prototype and Drying Modeling Development,"Developing a continuous isolation process to produce a pure, dry, free-flowing active pharmaceutical ingredient (API) is the final barrier to the implementation of continuous end-to-end pharmaceutical manufacturing. Recent work has led to the development of continuous filtration and washing prototypes for pharmaceutical process development and small-scale manufacture. Here, we address the challenge of static drying of a solvent-wet crystalline API in a fixed bed to facilitate the design of a continuous filter dryer for pharmaceutical development, without excessive particle breakage or the formation of interparticle bridges leading to lump formation. We demonstrate the feasibility of drying small batches on a time scale suitable for continuous manufacturing, complemented by the development of a drying model that provides a design tool for process development. We also evaluate the impact of alternative washing and drying approaches on particle agglomeration. We conclude that our approach yields effective technology, with a performance that is amenable to predictive modeling.",10.1021/acs.oprd.0c00035,0
Where Does the Fluorine Come From? A Review on the Challenges Associated with the Synthesis of Organofluorine Compounds,"Fluorinated organic molecules are increasingly being prepared for a variety of applications, including pharmaceutical products. However, the supply chain to access the necessary raw materials, which originate primarily from calcium fluoride, is often not considered, may be difficult to access at commercial scale, and has become destabilized as more stringent environmental policies are justifiably enforced. This manuscript presents an overview of the preparation and use of simple organofluorinated intermediates and reagents and the challenges associated with them.",10.1021/acs.oprd.0c00030,1
"Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation","Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scale-up challenges, and the solutions implemented are described.",10.1021/acs.oprd.0c00029,1
Development of an Efficient Synthetic Process for Broflanilide,"This article describes the development of an efficient and scalable synthetic route to the novel insecticide broflanilide ( 1 ). This redesigned synthetic sequence starts from 2-fluoro-3-nitrobenzoic acid and 4-(perfluoropropan-2-yl)-2-(trifluoromethyl) aniline and provides the target product in a high overall yield through condensation, nitro group reduction, N -methylation, amidation, and subsequent bromination steps. The desired amide moiety is established under mild conditions, and imide generation is avoided. Using paraformaldehyde and Pt/C for N -methylation and NaBr-NaClO for bromination increased the industrial suitability of this route. Unlike existing routes, this new route requires isolation at only six steps (including the heptafluorination), and the overall yield was 60.3%, representing a significant improvement. Broflanilide ( 1 ) crystals were obtained from recrystallization in 98% aqueous CH 3 OH, and the structure was confirmed by X-ray analysis. This work provides a reliable strategy for the large-scale manufacturing of broflanilide ( 1 ).",10.1021/acs.oprd.0c00028,1
<scp>d</scp>-Serine as a Key Building Block: Enzymatic Process Development and Smart Applications within the Cascade Enzymatic Concept,"An efficient enzymatic method catalyzed by an enzyme from the d -threonine aldolase (DTA) family was developed for d -serine production at industrial scale. This process was used for the synthesis of two valuable ketoses, l -erythrulose and d -fructose, within the cascade enzymatic concept involving two other enzymes. Indeed, d -serine was used as a substrate of d -amino acid oxidase (DAAO) for the in situ generation of the corresponding α-keto acid, hydroxypyruvic acid (HPA), a key donor substrate of transketolase (TK). This enzyme catalyzed the irreversible transfer of the ketol group from HPA to an aldehyde acceptor to form a (3 S )-ketose by stereoselective carbon–carbon bond formation. The compatibility of all enzymes and substrates allowed a sequential three-step enzymatic process to be performed without purification of the intermediates. This strategy was validated with two TK aldehyde substrates to finally obtain the corresponding (3 S )-ketoses with high control of the stereoselectivity and excellent aldehyde conversion rates.",10.1021/acs.oprd.0c00024,0
What Elements Contribute to a High-Quality Continuous Processing Submission for <i>OPR&amp;D</i>?,"This editorial seeks to provide guidance to prospective OPR&D authors with respect to submissions involving continuous processing. Industrially relevant flow drivers are emphasized, along with increased attention to detail and holistic process awareness. Guidelines are provided for topics such as continuous process scale, length of operation, data collection, and claims of benefits. This is intended to improve the quality of manuscripts submitted to OPR&D and to teach the community about industrial success criteria for continuous processing.",10.1021/acs.oprd.0c00020,0
"A Practical Synthesis of the TGFβRI Inhibitor <i>N</i>-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1<i>H</i>-pyrrolo[3,2-<i>b</i>]pyridin-2-yl)pyridin-2-yl)acetamide via One-Pot Sequential Sonogashira and Cacchi Reactions Catalyzed by Pd(OAc)<sub>2</sub>/BINAP","N -(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1 H -pyrrolo[3,2- b ]pyridin-2-yl)pyridin-2-yl)acetamide ( 5 ) is a potent inhibitor of TGFβRI kinase that provides durable antitumor activity when combined with an anti-PD-1 antibody. In order to conduct a full range of preclinical studies, over 150 g of high-quality material was required. The original discovery route through a stepwise copper-mediated Sonogashira reaction, trifluoroacetamide formation, and Cacchi reaction suffered from scale-up issues, mainly associated with tedious chromatographic purification of intermediates. This communication describes a chromatography-free one-pot synthesis of 5 via sequential Sonogashira and Cacchi reactions promoted by the superior catalyst Pd(OAc) 2 /BINAP, which was discovered by catalyst screening.",10.1021/acs.oprd.0c00015,1
Process Development Overcomes a Challenging Pd-Catalyzed C–N Coupling for the Synthesis of RORc Inhibitor <b>GDC-0022</b>,"Process development for a multi-kilogram-scale synthesis of GDC-0022, an inhibitor of retinoic acid receptor-related orphan receptor γ (RORc), is described. Delivery of the active pharmaceutical ingredient (API) relied on diastereoselective preparation of a six-membered sultam building block, as well as execution of its benzylation under heterogeneous conditions. Investigation and optimization of a challenging late-stage palladium-catalyzed C–N coupling of a bicyclic amine were likewise central to synthetic efforts. Understanding of this key reaction, as well as the development of API salt forms and isolations, ultimately enabled a successful reaction at 8.0 kg scale, utilizing 1.0 mol % XantPhos–Pd–G2 as precatalyst and, in turn, preparation of >5.0 kg of GDC-0022 tosylate salt for preclinical needs.",10.1021/acs.oprd.0c00012,1
"One-Pot Enzymatic Synthesis of Enantiopure 1,3-Oxathiolanes Using <i>Trichosporon laibachii</i> Lipase and the Kinetic Model","The dynamic covalent kinetic resolution protocol was efficiently used for the synthesis of the enantiopure (( R )-5-acetoxy-1,3-oxathiolan-2-yl)ethyl benzoate (P R ) from substrates 2-(phenylmethoxy)acetaldehyde (A), 1,4-dithiane-2,5-diol (B), and phenyl acetate (D) by a one-pot process with 99.6% conversion, 97.3% yield, and 96.5% ee through the combination of reversible hemithioacetal transformation and enantiomer-selective lactonization catalyzed by immobilized lipase from Trichosporon laibachii . A proposed kinetic model consisting of transformation and lactonization was developed herein for the first time, fitting the experimental data very well. It was concluded that (1) the transformation in a chemical fashion may follow a power law. (2) The enzymatic lactonization may follow a sequential mechanism with product inhibition. The reaction kinetic data reveal that phenol (P 1 ) would have strong product inhibition, while noncompetitive inhibition, product inhibition of P R, and substrate inhibition were not recognized. The model suggests that there is a common limitation of both enzyme and chemistry in the chemo-enzymatic system, and thus the amount of lipase was increased to accelerate the enzymatic lactonization and to reduce the limitation caused by the enzymatic reaction, resulting in the increase of the yield of P R significantly. The experimental results demonstrate that both the internal and external mass diffusion resistance could be negligible, and thus the kinetic model developed is the inherent kinetic one.",10.1021/acs.oprd.0c00010,1
Total Synthesis of (+)-Oxo-tomaymycin,"(+)-Oxo-tomaymycin, a naturally occurring substance of the pyrrolo-1,4-benzodiazepine family, was synthesized using a short and efficient route. The key construction of the seven-membered ring by amide bond formation was realized via a chemoselective Ar-NO 2 reduction using TiCl 3 under acidic conditions, followed by a spontaneous cyclization. This synthesis was easily scaled up to 80 g, and it should be amenable to the production of larger quantities.",10.1021/acs.oprd.0c00009,1
"Review of Synthetic Routes and Crystalline Forms of the Antiandrogen Oncology Drugs Enzalutamide, Apalutamide, and Darolutamide","This article reviews the synthetic routes and final crystalline forms of the recently approved antiandrogen drugs enzalutamide, apalutamide, and darolutamide, used for the treatment of prostate cancer. The patent literature was the primary source of information.",10.1021/acs.oprd.0c00005,1
Reiterative Chiral Resolution/Racemization/Recycle (RRR Synthesis) for an Effective and Scalable Process for the Enantioselective Synthesis of a Dual IDO1/TDO2 Inhibitor Imidazoisoindole Derivative,"Herein, we report an effective and scalable highly enantioselective synthesis of an 5H-imidazo[5,1- a ]isoindole derivative via an RRR-synthesis approach (resolution–racemization–recycle). Chiral resolution performed with the aid of 2,3-dibenzoyl- d -tartaric acid allowed the obtaining of the desired enantiomer in high enantiopurity (>99% ee) and good yield. The undesired enantiomer was subjected to racemization under basic conditions and again to resolution, improving the efficiency of the entire process. The asymmetric formation of the new stereocenter in an early stage of the synthesis scheme was also investigated by means of organocatalytic systems.",10.1021/acs.oprd.0c00004,1
"New synthetic route to 2,2,6,6-tetraethylpiperidin-4-one: A key-intermediate towards tetraethyl nitroxides",,10.1016/j.tetlet.2019.151207,1
An improved route for the synthesis of Rolloamide B,,10.1016/j.tetlet.2016.07.044,1
"Development of a Practical Synthesis of 4-[6-(Morpholinomethyl)-pyridin-3-yl]naphthalen-1-amine, a Key Intermediate for the Synthesis of BIRB 1017, a Potent p38 MAP Kinase Inhibitor","The development of synthetic routes to 4-[6-(morpholinomethyl)pyridin-3-yl]naphthalen-1-amine, the key intermediate of p38 MAP kinase inhibitor BIRB 1017, via (1) trialkylmagnesium ate complex mediated metalation and borylation followed by Suzuki coupling reactions and (2) pyridine-ring formation from a vinamidinium salt, is described.",10.1055/s-0032-1317790,1
Evolution of the Process for the Preparation of a Selective ErbB VEGF Receptor Inhibitor,"An efficient synthetic route to the potent and selective ErbB VEGF receptor inhibitor, BMS-690514 ( 1 ) is described. Strategic modifications in both approach and procedure addressed several issues, which led to a safe, efficient, and economical process for the preparation of multi-kilogram quantities of 1 . The convergent route involves alkylation of a suitably protected (3 R ,4 R )-4-aminopiperidin-3-ol with the triethyl(alkyl)ammonium salt of a functionalized pyrrolotriazine 3a followed by deprotection to provide 1 as the crystalline free base.",10.1055/s-0032-1317540,1
A scalable and eco-friendly total synthesis of poly(ADP-ribose) polymerase inhibitor Olaparib,A scalable and eco-friendly total synthesis of PARP inhibitor.,10.1039/d3gc02617e,1
"Development of a concise, scalable synthesis of a CCR1 antagonist utilizing a continuous flow Curtius rearrangement",A convergent and robust synthesis of a developmental CCR1 antagonist is described using continuous flow technology.,10.1039/c6gc03123d,1
Practical and scalable one-pot synthesis of arbekacin,An efficient and scalable one-pot production process was developed to prepare arbekacin from dibekacin.,10.1039/d3re00598d,1
Rapid route design of AZD7594,Multidisciplinary collaboration enables the rapid and efficient design and selection of an improved manufacturing route to a new potential medicine for the treatment of asthma.,10.1039/c9re00118b,1
"A Convergent Synthesis of CGS23305, A Thromboxane Synthase Inhibitor","All articles of this category A convergent synthesis of CGS23305 was discovered. The route to the pyridine aldehyde intermediate 5 was reduced from four to two steps. The pyridine aldehyde was converted to the key pyridine aldehyde ester intermediate 7 via Miachel Addition of the N , N -diethylenamine 6 to ethyl acrylate. A Wittig alkenation using the multifunctional moiety 19 completed the carbons keleteon assembly. Hydrogenation and hydrolysis afforded CGS23305 in 44% overall yield from 14 (6 steps). convergent synthesis - pyridine - aldehydes - thromboxane inhibitor",10.1055/s-1999-3458,1
A New and Practical Synthesis of Vortioxetine Hydrobromide,A new and improved synthetic route to vortioxetine hydrobromide is established on a hectogram scale through three simple steps in 63% yield and with 99% purity (HPLC). The key step is the cyclization of the piperazine ring in the final step. Purification methods for the intermediates involved in the route are given.,10.1055/s-0034-1380505,1
Efficient Route to Canagliflozin via Anhydroketopyranose,"The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity.",10.1021/acs.orglett.2c00980,1
Total Synthesis of (+)-Aureol,"A total synthesis of the marine sponge meroterpenoid (+)-aureol has been achieved in 12 steps (6% overall yield) from (+)-sclareolide. Key steps of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimetic cycloetherification reaction.",10.1021/ol301715u,1
Total synthesis of diazonamide A,"A total synthesis of the marine natural product diazonamide A (1) has been accomplished. This work features a highly stereoselective synthesis of the C(10) quaternary center and the central furanoindoline core enabled by an iminium-catalyzed alkylation-cyclization cascade. Additionally, a magnesium-mediated intramolecular macroaldolization and a palladium-catalyzed tandem borylation/annulation were developed to enable the closure of the two 12-membered macrocycles of diazonamide A. This synthesis involves 20 steps in its longest linear sequence and proceeds in 1.8% overall yield.",10.1039/c0sc00577k,1
A synthesis of strychnine by a longest linear sequence of six steps,"Strychnine is synthesized via a longest linear sequence of six steps from commercially available starting materials. Key steps include a base-mediated intramolecular Diels–Alder reaction of a tryptamine-derived Zincke aldehyde, a Ru-catalyzed trans-hydrosilylation of 1,4-butynediol, and a tandem Brook rearrangement/intramolecular conjugate addition reaction that affords the Wieland–Gumlich aldehyde.",10.1039/c1sc00009h,1
The First Total Synthesis of Racemic Chebulic Acid,"Abstract The first total synthesis of racemic chebulic acid is reported, which is the aglycon of several antioxidant ingredients of the fruit of the Terminalia chebula tree. The route started with the straightforward preparation of an indanone‐based β‐oxoester from a benzaldehyde derivative (84 % over the first five steps). The side chain of the target compound was then introduced by conjugated addition of a cuprate reagent derived from dimethyl succinate, which was followed by the first key step of the synthesis: a cerium‐catalyzed α‐hydroxylation of an β‐oxoester. The second key step was the cyanide‐catalyzed ring transformation of the cyclic α‐hydroxy‐β‐oxoester to a δ‐lactone. Finally, chebulic acid was obtained after six‐fold demethylation of three methyl ester moieties and three phenolic ether functions. The overall synthetic route consists of nine consecutive steps and was accomplished in 15 % overall yield.",10.1002/ejoc.202101508,1
Total Synthesis of Indolizidine (+)‐223A,"Abstract We described the diastereoselective total synthesis of indolizidine (+)‐223A in 10 % overall yield over 14 steps starting from 6‐chlorohex‐2‐ynoate. Our strategy involved chain elongation through aldolization, the formation of the indolizidine skeleton by cyclization, and stereocontrolled hydrogenation.",10.1002/ejoc.201101530,1
Second Generation Total Synthesis of (–)‐Preussochromone D,"An improved enantioselective synthesis of the natural product (–)‐preussochromone D ( 3 ) and first insights into a possible route to the trans ‐preussochromones E and F are described. Starting from commercially available 5‐hydroxy‐4 H ‐chromen‐4‐one, two stereocenters are established via auxiliary controlled Michael addition in excellent yield and stereoselectivity. Subsequent build‐up of the five‐membered ring gave access to (–)‐preussochromone D in an improved overall yield and less synthetic steps than previously reported. The total syntheses of preussochromones E and F on a related route were also investigated and first findings are reported herein.",10.1002/ejoc.202000465,1
Asymmetric Total Synthesis of Pinnaic Acid,"Pinned together: Asymmetric total synthesis of pinnaic acid was accomplished through a stereospecific route that features as key steps a Pd-catalyzed trimethylenemethane (TMM) [3+2] cyclization, a four-step tandem hydrogenation–cyclization, and cross-olefin-metathesis reactions (see scheme).",10.1002/anie.200701581,1
Scalable Enantioselective Total Synthesis of (−)‐Goniomitine,"A scalable enantioselective total synthesis of (-)-goniomitine has been developed by using an iridium-catalyzed asymmetric hydrogenation of an exocyclic enone ester to control the configuration of the molecule. The synthesis begins from commercially available starting materials, and proceeds through an integrated asymmetric ketone hydrogenation, Johnson-Claisen rearrangement, and one-pot oxidation/deprotection/cyclization process. With this highly efficient and scalable strategy, (-)-goniomitine was synthesized in eleven steps with 27 % overall yield, and formal enantioselective syntheses of (+)-1,2-dehydroaspidospermidine, (+)-aspidospermidine, and (+)-vincadifformine were also achieved.",10.1002/anie.201812822,1
"Development of a Convergent Large-Scale Synthesis for Venetoclax, a First-in-Class BCL-2 Selective Inhibitor","The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with >99% area purity.",10.1021/acs.joc.8b02750,1
A Practical Synthesis of 5-Lipoxygenase Inhibitor MK-0633,"Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).",10.1021/jo100561u,1
Total Synthesis of the Sphingolipid Biosynthesis Inhibitor Fumonisin B<sub>1</sub>,"The first total synthesis of the sphingolipid biosynthesis inhibitor fumonisin B(1) has been achieved. This convergent synthesis utilizes oxonia Cope rearrangements to prepare two key homoallylic alcohols, which are then functionalized to the primary components A and B for cross-coupling. Other highlights of our approach include a new and efficient synthesis of the diprotected tricarballylic acid C and a global deprotection strategy as the final step.",10.1021/ja9009265,1
Twelve-Step Asymmetric Synthesis of (−)-Nodulisporic Acid C,"A short, enantioselective synthesis of (-)-nodulisporic acid C is described. The route features two highly diastereoselective polycyclizations en route to the terpenoid core and the indenopyran fragment and a highly convergent assembly of a challenging indole moiety. Application of this chemistry allows for a 12-step synthesis of the target indoloterpenoid from commercially available material.",10.1021/jacs.8b09965,1