journal,title,abstract,year,doi,target,contributor
Organic Process Research & Development,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.",2000,10.1021/op990202j,CC1=C(C(=CC=C1)C)OCC(=O)N[C@@H](CC2=CC=CC=C2)[C@H](C[C@H](CC3=CC=CC=C3)NC(=O)[C@H](C(C)C)N4CCCNC4=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2001,10.1021/op9901994,C#CCOC1=C(C=C(C(=C1)N2C(=O)N3CCCCC3=N2)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2000,10.1021/op990197j,CC(C)(C)C1=CC(=CC(=C1O)C(C)(C)C)CC2C(=O)NCS2,Dmitry Zankov
Organic Process Research & Development,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.",2000,10.1021/op990196r,C1C=C(O)C=CC=1C1N(C2C=CC(F)=CC=2)C(=O)C1C(O)COC1C=CC(F)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9901947,C1C=CC(OC2C=CC=C(C=O)C=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990193e,C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)O[C@H]3[C@H]4COC(=O)[C@@H]4[C@@H](C5=CC6=C(C=C35)OCO6)C7=CC(=C(C(=C7)OC)OP(=O)(O)O)OC)O)O,Dmitry Zankov
Organic Process Research & Development,"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.",1999,10.1021/op990191u,C1C=CC2C(OCC=2C=1)1CCC(N2CCN(C3C=CC(C#N)=C(F)C=3)CC2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990188a,CN(CC1=CC=CC=C1)C(=O)[C@H](CC2=CC3=CC=CC=C3C=C2)NC(=O)[C@@H]4CCCN4C(=O)NC5=CC=CC=C5[N+](=O)[O-],Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990187i,CCC(C)(C)C(=O)O[C@H]1C[C@H](C=C2[C@H]1[C@H]([C@H](C=C2)C)CC[C@@H]3C[C@H](CC(=O)O3)O)C,Dmitry Zankov
Organic Process Research & Development,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.",2000,10.1021/op990185y,C[C@H](CCC1=CC=CC=C1)NC[C@@H](C2=CC(=C(C=C2)O)C(=O)N)O,Dmitry Zankov
Organic Process Research & Development,"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.",1999,10.1021/op990182l,CCOCN1C2=C(C=CC(=C2)F)N3C1=C(C(=O)CC3)C(=O)NC4=CC=CC=C4F,Dmitry Zankov
Organic Process Research & Development,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",2000,10.1021/op990104y,COC1=CC=C(C=C1)CCCCCCCCOC2=C(N=C(C=C2)CSCC3=CC(=CC=C3)C(=O)O)/C=C/C(=O)O,Dmitry Zankov
Organic Process Research & Development,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",2000,10.1021/op990104y,C1=CC=C(C=C1)CCOC2=C(N=C(C=C2)CSC3=C(C=CC=C3Cl)Cl)/C=C/C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2000,10.1021/op9900939,C1=CN(C(=O)N=C1N)[C@H]2/C(=C/F)/[C@@H]([C@H](O2)CO)O,Dmitry Zankov
Organic Process Research & Development,"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.",2000,10.1021/op990081n,CN1C2=C(C=CC(=C2)[C@H](C3=CC=C(C=C3)Cl)N4C=NC=N4)N=N1,Dmitry Zankov
Organic Process Research & Development,"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.",2000,10.1021/op990081n,CN1N=NC2C=CC(C(O)C3C=CC(Cl)=CC=3)=CC1=2,Dmitry Zankov
Organic Process Research & Development,"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.",2000,10.1021/op990081n,CNC1C(N)=CC=C(C(O)=O)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2000,10.1021/op990079w,CC(N)C(NC(C(O)=O)CCC(N)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9900683,CCCC1=NN(C2=C1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N4CCN(CC4)C)OCC)C,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990067a,C1=CSC(=C1)C(=O)C2=C(N(C3=C2C=C(C=C3)Cl)C(=O)N)O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990066i,C1CCC(=C(C1)CC(=O)O)N2C(=O)C=CC(=N2)C3=C4C=CC=CN4N=C3C5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.,1999,10.1021/op9900582,C1CCN([C@H](C1)CCO)C(=O)/C=C/C2=C3C=CC=CN3N=C2C4=CC=CC=C4,Dmitry Zankov
Organic Process Research & Development,"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%.",1999,10.1021/op990052c,CC1(C(C(O)=O)C1/C=C(\Cl)/Cl)C,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990044w,C1CCN([C@H](C1)CCO)C(=O)/C=C/C2=C3C=CC=CN3N=C2C4=CC=CC=C4,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990044w,CCOC(/C=C/C1C(C2C=CC=CC=2)=NN2C=1C=CC=C2)=O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990028z,C1C=CC(OC2C=CC=C(C=O)C=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op990019q,CN1CC[C@@]23C=CC(=O)C[C@@H]2OC4=C(C=CC(=C34)C1)OC,Dmitry Zankov
Organic Process Research & Development,"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.",1999,10.1021/op9900176,CCC(CC)O[C@@H]1C=C(C[C@@H]([C@H]1NC(=O)C)N)C(=O)OCC,Dmitry Zankov
Organic Process Research & Development,"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.",1999,10.1021/op9900176,CCOC(C1CC(OS(C)(=O)=O)C2OC(OC2C=1)(CC)CC)=O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9900075, CC[C@@]1(CCC(=O)NC1=O)C2=CC=C(C=C2)N,Dmitry Zankov
Organic Process Research & Development,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%.",1999,10.1021/op9900030,CCN(CCCCOC(=O)C1=CC(=C(C=C1)OC)OC)C(C)CC2=CC=C(C=C2)OC,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9802172,C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.,1999,10.1021/op980215h,CN1CC[C@@H]([C@@H](C1)O)C2=C(C=C(C3=C2OC(=CC3=O)C4=CC=CC=C4Cl)O)O,Dmitry Zankov
Organic Process Research & Development,"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 .",1999,10.1021/op9802125,CCN[C@H]1CN(S(=O)(=O)C2=C1C=C(S2)S(=O)(=O)N)CCCOC,Dmitry Zankov
Organic Process Research & Development,"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.",1999,10.1021/op980210k,C1CN(CCN1)C2=NSC3=CC=CC=C32,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op980209l,C1C[C@H](O[C@@H]1COC2=CC=C(C=C2)F)C#CCCN(C(=O)N)O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9802071,CC(C(O)CN1CCCCC1)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op9802069,C1CCC(=O)CC(=O)C1,Dmitry Zankov
Organic Process Research & Development,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.,1999,10.1021/op980201b,C1C=CC2C(N(C(=O)C=2C=1)C1C(=O)NC(=O)CC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800966,CCCCC(N1C(=O)C(CC2C=CC=CC=2)NC(=O)C1C(C)C)C(NC1CCCCC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800966,COC1C=CC(C/C(/O)=C2/C(=O)N(CC3C=CC(OC)=CC=3)C(CC3C=CC=CC=3)C/2=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800966,CC(C(N1C(=O)C(OC2C=CC=CC=2)C1C1C=CC=CC=1)C(O)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800865,C1C=C(OCCNCC(C2C=CC=CC=2)O)C=CC=1CC(N)=O,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800820,CC(=O)NCCC1=CNC2=C1C=C(C=C2)OC,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op980079g,CC1C(C2C=CC(C(O)=O)=CC=2)=CC=C(N2C(=O)CCC2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op980068n,CN1CC2=C(C=CC(=C2)C(=O)N3CCC(CC3)C4CCNCC4)N[C@H](C1=O)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op980067v,CC(C)(C)C(=O)OCOP(=O)(COCCN1C=NC2=C(N=CN=C21)N)OCOC(=O)C(C)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800663,CC12CCC(=O)C1CC2,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800663,CC12CCC(O)(C)C1CC2,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op9800663,CC12CCC1(S(C1C=CC=CC=1)(=O)=O)C(O)(C)CC2,Dmitry Zankov
Organic Process Research & Development,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.",1999,10.1021/op980060d,CC(=O)CCC1=CC2=C(C=C1)C=C(C=C2)OC,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op980050c,C1C=C2SC(N(CC(N3CCN(N)CC3)=O)C2=CC=1Cl)=O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op9800414,C1C[C@@H](C2=C(C1)C3=C(C=C2)OCO3)CN4CC[C@H](C4)C5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op980039c,CC(C1C(C2C=CC=CC=2)=NN2C=1C=CC=C2)=O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op980038k,CC1=C(C2=C3[C@@H](CN(C3=CC(=C2N1)OC(=O)N4CCN(CC4)C)C(=O)C5=CC6=CC(=C(C(=C6N5)OC)OC)OC)CBr)C(=O)OC,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op9800313,C1C=C(O)C=CC=1CC(N)=O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op980018i,CC(C1C(C)2C(C3C(CC2)C(C)2C(CC(OC(C)=O)CC2)=CC3)CC1)CCCC(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op980006x,COC1C=C2C=C(NC2=CC=1)C(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op9800055,CCCC1N(CC2C=CC(N3C(C4NN=NN=4)=CC=C3C)=CC=2)C2C(=C(C=CN=2)C)N=1,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op9800055,CCOC(C1C=CC(N2C(C#N)=CC=C2C)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op970244c,C1C(F)=C(F)C=C(F)C=1C(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op970242s,CCOC(C(NC(C(NC(C(SC(C)=O)C(C)C)=O)1CCCC1)=O)CC1C=CC(OC)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op970217m,C1C2=CC(OC)=C(OC)C3=C2C(CC2C=C(OC)C(OC)=CC=23)N(C)C1,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9702152,C1C(=O)NC2=C(C=C(C=C2)[N+](=O)[O-])C(=N1)C3=CC=CC=C3Cl,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op970212p,C1=CC2=C(C3=C(C2(CC4=CC=NC=C4)CC5=CC=NC=C5)C=CC=N3)N=C1,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9702105,CCC(=O)O[C@H](C(C)C)O[P@](=O)(CCCCC1=CC=CC=C1)CC(=O)N2C[C@@H](C[C@H]2C(=O)O)C3CCCCC3,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op9702049,CC(NC(CN1C(=O)C(NC(NC2C=C(Cl)C=CC=2)=O)CC(C2C=CC=CC=2)C2C1=CC(C)=CC=2)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op970202o,CCC(=O)OC(C(C)C)OP(=O)(CCCCC1=CC=CC=C1)CC(=O)N2C[C@@H](C[C@H]2C(=O)[O-])C3CCCCC3,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op970126p,CC1=CN(C(=O)NC1=O)[C@H]2C=C[C@H](O2)CO,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op9701245,C1C[C@H](C[C@H]1N2C=NC3=C(N=CN=C32)N)O,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op9701191,CCC(C(N1SC2C=CC=CC=2C1=O)C(O)=O)C,Dmitry Zankov
Organic Process Research & Development,"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%).",1998,10.1021/op970116o,CC(CC1=CC=C(C=C1)OC)NCC(C2=CC(=C(C=C2)O)NC=O)O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op970113b,C(O)(C(O)=O)C(C1C=CC=CC=1)NC(C1C=CC=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op970111r,COC1C=CC2C(CCCC=2C=1OC)=O,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op970110z,C1=CC=C2C=C(C=CC2=C1)C3=NC4=CC=CC=C4C(=C3)Cl,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9701090,CC1=CC2=C(C=C1)OC(=N2)N[C@@H](CC3CCCCC3)C4=CC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op970106n,CC(C#CC1=CC(=CC=C1)OC2=CC=C(C=C2)F)N(C(=O)N)O,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op9701043,COC1=CC(=C(C=C1)OC)CCC2=CC(=C(C=C2)O)C(=O)OC,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op970101q,CC1(CC2=C(O1)C(=CC(=C2)Cl)C(=O)NC3C[C@H]4CC[C@@H](C3)N4C)C,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op970060y,C1C=C(F)C=CC=1CC1C=C(CCC(O)=O)C=C(CCN=S([O-])(C2C=CC(Cl)=CC=2)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op970039x,CC(=O)C1=CC(=C(C=C1)NS(=O)(=O)C)OC2=C(C=C(C=C2)F)F,Dmitry Zankov
Organic Process Research & Development,"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.",1998,10.1021/op9700385,COC1=C(C=C(C=C1)C(=O)NC2=C(C=NC=C2Cl)Cl)OC3CCCC3,Dmitry Zankov
Organic Process Research & Development,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.",1998,10.1021/op970037c,CCCN(CCC)CCC1=C2CC(=O)NC2=CC=C1,Dmitry Zankov
Organic Process Research & Development,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).",1997,10.1021/op9700338,CC1C(O)(C(COC(C)=O)=O)C(C)2C(C3C(CC2)C(C)2C(=CC(C=C2)=O)CC3)C1,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op970026j,CCNC(C1C2OC(OC2C(N)C1)(C)C)=O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op970024z,C1C=C(C(F)(F)F)NC(=O)C=1,Dmitry Zankov
Organic Process Research & Development,"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",1997,10.1021/op970019v,CC(CO)CC(OC(C)(C)C)=O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9700035,CCCC(C1C=NC2C(OC)=CC=CC=2C=1NC1C=CC=CC=1C)=O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9700035,CCCC(C1C=NC2C(OCCO)=CC=CC=2C=1NC1C=CC=CC=1C)=O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9700035,CCCC(C1C=NC2C(O)=CC=CC=2C=1NC1C=CC=CC=1C)=O,Dmitry Zankov
Organic Process Research & Development,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 ).,1997,10.1021/op960043t,CC(C)NC[C@H](C1=CC=C(C=C1)NS(=O)(=O)C)O,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op9600419,CC(C1C=C(C(C)C)C(CC(NS(OC2C(C(C)C)=CC=CC=2C(C)C)(=O)=O)=O)=C(C(C)C)C=1)C,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960040g,CC(CN(C(NC(C)(C)C)=O)CC(O)C(N(CC1C=CC=CC=1)CC1C=CC=CC=1)CC1C=CC=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960038p,C1CCN(C1)C2=NC(=NC3=C2C4=CC=CC=C4N3CCN5CCOCC5)N6CCCC6,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960034k,CCCCCNC(=O)C1=COC(=N1)C2C3CCC(C2CC4=CC=CC=C4CCC(=O)O)O3,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op9600320,CC(C)C[C@@H](CC(=O)O)CN,Dmitry Zankov
Organic Process Research & Development,"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.",1997,10.1021/op9600318,CCNC1C(N2CCNCC2)=NC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960029g,C[C@H]1C[C@](CCO1)(C2=CSC(=C2)SC3=CC4=C(C=C3)N(C(=O)C4)C)O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9600264,C1C=CC(C(O)CN)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960025b,COCC1=C(N2[C@@H]([C@@H](C2=O)NC(=O)/C(=N\\O)/C3=CSC(=N3)N)SC1)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960024j,CCCCCCCCCCCO,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960010d,CC(=O)NC1=C(NC(=O)N(C1=O)C)N,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op960004h,C[C@@H](C(=O)[C@]1(CC[C@@H]2[C@@]1(CCC3=C4CCC(=O)C=C4CC[C@@H]23)C)C)O,Dmitry Zankov
Organic Process Research & Development,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.",1997,10.1021/op9600015,CCCN1C[C@@H](C[C@H]2[C@H]1CC3=CNC4=CC=CC2=C34)CSC,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op9003357,CC1C(COC(C)=O)=NC=CC=1OCC(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op900330e,CCOC(=O)[C@H](CC1=CC=C(C=C1)NC2=NC=CC3=C2C=NC=C3)NC4=C(C(=O)C45CCCCC5)Br,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op9003289,CC1=CC(=CC(=C1OC2=NC(=NC(=C2Br)N)NC3=CC=C(C=C3)C#N)C)C#N,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op900322u,C1C(C#N)=CC(Cl)=CC=1O,Dmitry Zankov
Organic Process Research & Development,"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%.",2010,10.1021/op900319p,C1CN(CCN1)C2=C3CNC(=O)N(C3=CC=C2)CC4=CC(=CC=C4)F,Dmitry Zankov
Organic Process Research & Development,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%.,2010,10.1021/op9003168,CN1C(=O)N(C(=O)[C@]12CN(C[C@H]2C3=CC=C(C=C3)C#N)CC4=CC(=CS4)C(=O)O)C5=CC(=CC(=C5)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op900315j,CC12C(O)CCC1C1C(C3C=CC(O)=CC=3CC1CCCCCCCCC[S+]([O-])CCC(F)(F)C(F)(F)F)CC2,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op900311z,C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)[C@@H](CC4=C3C=CC(=C4)O)CCCCCCCCCS(=O)CCCC(C(F)(F)F)(F)F,Dmitry Zankov
Organic Process Research & Development,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 .",2010,10.1021/op900310v,C1C=CC(NC(NC2C=CC(C3C=CC(C(C4C(C(O)=O)CCC4)=O)=CC=3)=CC=2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,<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.",2010,10.1021/op900299c,C1C=C(S(NC(C(C(F)(F)F)C2C=C(F)C=C(F)C=2)CO)(=O)=O)SC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.,2010,10.1021/op900292j,COC1C=C2C(CCN(C(C(F)(F)F)=O)CC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.,2010,10.1021/op900292j,COC1C=CC(Br)=C(CCNCC(OC)OC)C=1,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op900284w,CC1=CC=C(C=C1)C(=O)C2=CC=C(N2C)CC(=O)NCC(=O)O,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op900284w,CC1=CC=C(C=C1)C(=O)C2=CC=C(N2C)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900265h,C[C@]12CCC(=O)C([C@@H]1CC[C@@]3([C@@H]2CC=C4[C@]3(CC[C@@]5([C@H]4CC(CC5)(C)C)C(=O)[O-])COC(=O)/C=C/C6=C(C=CC(=C6)[O-])NC(=O)/C=C/C(=O)O)C)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op9002642,C1CC2CNCC1O2,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900263b,CC1OC2C(=C(O)C=C(C(OC)=O)C=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.,2009,10.1021/op900260k,CC1C2C(=NC=CC=2OC2C(F)=CC(NC3C=C(Cl)N=C(N)N=3)=CC=2F)NC=1,Dmitry Zankov
Organic Process Research & Development,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.)",2009,10.1021/op900258b,CC1=C(C=CN=C1CS(=O)C2=NC3=CC=CC=C3N2)OCC(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900255k,CC1=NC2=CC=CC=C2C(=C1)COC3=CC=C(C=C3)[C@@]4(CCN(C4=O)[C@H](CC(C)C)C(=O)NO)N,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9002533,CN1C(=O)CC2C(=CC(Br)=CC=2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op9002517,CC1=C(C2=C(C=C1)N=C(NC2=O)N)SC3=CC=NC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9002505,CC1N(C)C2C(=C(O)C=C(C(N(C)C)=O)C=2)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900243c,COC(=O)[C@H](C1=CC=CC=C1Cl)N2CCC3=C(C2)C=CS3,Dmitry Zankov
Organic Process Research & Development,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).",2009,10.1021/op900235p,CCCC1=NC(=C2N1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N4CCN(CC4)CC)OCC)C,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9002328,CC(C)[C@]1(C(=O)NC(=N[C@H]2C[C@@H]3CC[C@H]2C3)S1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900231j,C1C[C@H](N(C1)CCCC(=O)O)COC2=CC=C(C=C2)OC3=CC=C(C=C3)Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900231j,CC(OC(N1C(COC2C=CC(OC3C=CC(Cl)=CC=3)=CC=2)CCC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2009,10.1021/op900230r,C1[C@@H]([C@H](CN1CC2=CC=CC=C2)C(=O)O)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op900228u,CC[C@@H]1[C@@]([C@H]2[C@H](C(=NC(=O)C)[C@@H](C[C@]([C@@H]([C@H](C(=O)[C@H](C(=O)O1)C)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(OC/C(=N/OCC4=CN=C(C=C4)N5C=CC=N5)/CO2)C)C)C)(C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900226j,C1[C@@H]2C[C@@H]2N([C@@H]1C#N)C(=O)[C@H](C34CC5CC(C3)CC(C5)(C4)O)N,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9002246,CCCC(CO)C,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900216v,C1C=C(S(NC(C(C(F)(F)F)C2C=C(F)C=C(F)C=2)CO)(=O)=O)SC=1Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op9002104,CC1=C(N=C(O1)C2=CC=CC=C2)CCOC3=CC=C(C=C3)CN(CC(=O)O)C(=O)OC4=CC=C(C=C4)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900208y,CC1=CC(=C(C=C1)F)NC(=O)NC2=CC=C(C=C2)C3=C4C(=CC=C3)NN=C4N,Dmitry Zankov
Organic Process Research & Development,"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 ).",2009,10.1021/op9002054,CC(C)OC1=C(C=C(C=C1)C(=O)NC2=CC(=C3CCNCC3=C2Cl)Cl)C(=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op9002032,CC1=C(C=CC(=C1)F)[C@H]2CNCCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900202b,C1C=C(NC2N=C(NC3C=CC(CCNC4N=C(NCCO)N=C(NC5C=C(N)C=CC=5)N=4)=CC=3)N=C(NCCC3C=CC(N)=CC=3)N=2)C=C(N)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900197r,CC1(CCN(CC1)C2=NC=CC(=C2)C(=O)O)NCC(=O)N3[C@H](CC[C@H]3C#N)C#C,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900195w,CC(OC(NC1CCC(C(O)=O)CC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.,2009,10.1021/op900188v,C#CCOC1C(C(OC)=O)=CC(Cl)=C(NC(Cl)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9001824,C1C=C2/C(/CC(NC2=CC=1Cl)C(O)=O)=C1/C(=O)N(C2C=CC=CC=2)CC/1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900172t,CC(NC1C(OCC(O)(CNC2CCN(CC3C=CC(Cl)=CC=3)CC2)C)=CC(O)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900163a,C[C@H]1C[C@](CCO1)(C2=CSC(=C2)SC3=CC4=C(C=C3)N(C(=O)C4)C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op9001577,CC1C=CSC=1C1N(C)N=C(C2C(F)=CC=CC=2Cl)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op9001577,CC1C(Br)=CSC=1C1N(C)N=C(C2C(F)=CC=CC=2Cl)N=1,Dmitry Zankov
Organic Process Research & Development,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.,2009,10.1021/op900148x,CC1C(CS(C2NC3C=CC=CC=3N=2)=O)=NC=CC=1OCCCOC,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900141r,CC1(C(=O)N(C(C(O)CNC)C2C=C(F)C=CC=2)C2C(F)=CC=CC1=2)C,Dmitry Zankov
Organic Process Research & Development,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.,2009,10.1021/op900131m,CCC1=CN=C(C=C1)CCOC2=CC=C(C=C2)CC3C(=O)NC(=O)S3,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900127v,C1C2=CC=CC=C2N(C3=CC=CC=C3C1=O)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9001142,C1[C@@H]([C@H](CN1CC2=CNC3=C2N=CNC3=O)O)CO,Dmitry Zankov
Organic Process Research & Development,"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.,2009,10.1021/op900113b,C1C=CC2S(N(C(=O)C=2C=1)CC(NC1C=CC(O)=CC=1)=O)(=O)=O,Dmitry Zankov
Organic Process Research & Development,"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 .",2009,10.1021/op900110k,CC1C=C(OC2C(C3CC3)=NN(CS(C)(=O)=O)C=2C)C=C(C)C=1C#N,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op9001092,CC1(C2CC1CC(C2N)CCO)C,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900097q,CC1C=CC(C(NC2CC2)=O)=CC=1C1C=CC2C(N3CCOCC3)=NN=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900092h,CNC(C1C=CC(C2C(Cl)=C(Cl)C=C(Cl)C=2)=C(N)N=1)=O,Dmitry Zankov
Organic Process Research & Development,New and Improved Manufacturing Process for Valsartan,"A new and improved industrially viable manufacturing process for valsartan, an antihypertension drug, is described.",2009,10.1021/op9000912,CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NNN=N3)[C@@H](C(C)C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900070c,CCOC(=O)C1=C(NC(=C(C1C2=CC=CC=C2Cl)C(=O)OC)C)COCCN,Dmitry Zankov
Organic Process Research & Development,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.,2009,10.1021/op9000687,C1C=C(CCC(O)COC2C=CC(C3SC(S(N)(=O)=O)=CC=3)=CC=2)C=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op9000675,CN1CCN(CC1)C2=CC=CC3=NC(=C(N32)CO)CN(C)[C@H]4CCCC5=C4N=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900065c,C[C@@H](C1=NC(=CS1)C2=CC=C(C=C2)C#N)[C@](CN3C=NC=N3)(C4=C(C=C(C=C4)F)F)O,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900064x,CC(C)C[C@@H](CC(=O)O)CN,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900063e,C(O)C1CSC2N(C(C2NC(CC2C=CC=CC=2)=O)=O)C=1C(OCC1C=CC=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900062p,CC(N1C(=O)C2C=CC(C3N=NN(C4C(F)=CC(F)=CC=4)C=3C)=CC=2C1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900060u,C1C(OC2N=CC(F)=C(N)N=2)CCNC1,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900055u,CCOC(=O)C1=C(NC(=C(C1C2=CC=CC=C2/C=C/C(=O)OC(C)(C)C)C(=O)OCC)C)C,Dmitry Zankov
Organic Process Research & Development,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%.",2009,10.1021/op900053j,C=CC1=C(N2[C@@H]([C@@H](C2=O)N)SC1)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op9000498,C1C(N)=C(N)C=C(C(F)(F)F)C=1C#N,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900039z,C1=CC(=CC=C1[C@@H]2[C@H](C(=O)N2C3=CC=C(C=C3)F)CC[C@@H](C4=CC=C(C=C4)F)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op900015g,CN(CC(O)=O)C/C=C(\C1C=CSC=1)/C1C=CC(C2OC=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op900008a,C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@H](NC(CC[C@H](N(CCN(CC([O-])=O)CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O)C([O-])=O)=O)C[C@H]4CC[C@H]3[C@@H]2CC1)CCC([O-])=O,Dmitry Zankov
Organic Process Research & Development,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%.",2009,10.1021/op8003184,CC(NC(C(O)(C(F)(F)F)C)=O)C1C(F)=CC(C2C=C(Cl)C=C(F)C=2C2N=C(C)ON=2)=CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800313t,CC(C(C(OC)=O)CNC(C1C=CC=CC=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800308t,CC1=NC2=CC=CC=C2C(=C1)COC3=CC=C(C=C3)[C@@]4(CCN(C4=O)[C@H](CC(C)C)C(=O)NO)N,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800307k,C(CN1CCN(C2C3C=C(F)C=CC=3C=CC=2)CC1)CCOC1N=C2C(CCNC(N2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op8003037,CC(OC(N1CC=CC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op8002932,CC(C)(C)OC(=O)CN1CCN(CCN(CCN(CC1)CC(=O)OC(C)(C)C)[C@H](CCC(=O)O)C(=O)OC(C)(C)C)CC(=O)OC(C)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800292b,C=CC1C=CC(S(CCO)(=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800290t,C1CC2NN=C(C3NN=NN=3)C=2C1,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800289h,CNCC[C@@H](C1=CC=CS1)OC2=CC=CC3=CC=CC=C32,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op8002882,CCC(OC1C=CC=C(CN2C3C=C(OC(F)(F)F)C=CC=3C(C(C3C=CC(Cl)=CC=3)=O)=C2C)C=1)C(O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800285t,COC1=CC2=C(C=C1)C(=CC=C2)OC,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800284k,CC[C@H](CO)NC1=NC(=C2C(=N1)N(C=N2)C(C)C)NCC3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800284k,CC[C@H](CO)NC1=NC(=C2C(=N1)N(C=N2)C(C)C)NCC3=CC=C(C=C3)C4=CC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op8002823,CC1=C(C=CC(=C1)F)[C@H]2CNCCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.,2009,10.1021/op8002745,CC(NC/C=C\CCC(N)(C(O)=O)C)=N,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800270e,C[C@@H]([C@@H](CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op8002689,CC(C1=NCCN1)OC2=C(C=CC=C2Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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 ).",2009,10.1021/op800266x,CC1C=C(Cl)C=C(C)C=1OC1C(C(OC)=O)=C(NC(CO)CC)C=C(C)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800265e,C1C(CCl)=CC(C(F)(F)F)=CC=1C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op8002618,CN1C[C@@H]2C[C@H]1CN2C3=C(C=C4C(=C3)N(C=C(C4=O)C(=O)O)C5CC5)F,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800260j,CCC(C(C(O)=O)CC)C,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800257u,CCCC1C(OC2C=CC=CC=2C(O)=O)=CC=CC=1OCCCOC1C=C(O)C(C2C=CC(F)=CC=2)=CC=1CC,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800255j,CCNC1(CCN(CC1)C2=NC=NC3=C2N=C(N3C4=CC=C(C=C4)Cl)C5=CC=CC=C5Cl)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op8002536,C1C(S(C2C=C(F)C=C(F)C=2)(=O)=O)=CC2C(N)=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800250v,CC1C=CC(C(NC2CC2)=O)=CC=1C1C=CC2C(OC(C(F)(F)F)C)=NN=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800250v,CC1C=CC(C(O)=O)=CC=1B(O)O,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op800250v,CC(OC1C2C=CC(Cl)=CC=2C=NN=1)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2009,10.1021/op8002486,CC1=CC=C(C=C1)CN2C(=O)NC(=N2)CCCC3=CC=C(C=C3)OC(C)(C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800247w,C1C=CC(CN2CC(C(C3CCOCC3)=O)OCC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800245v,C(C(N)CCO)CO,Dmitry Zankov
Organic Process Research & Development,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.,2009,10.1021/op800243q,C/C(/N(CC1C=CC(F)=CC=1)C)=N\C1C=C2C(CC(O)C2NC(C2C=CC(C3C=CC=CC=3)=CC=2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800238q,C1C2C(C(C(O)=O)=CN(C3C(F)=CC(F)=C(N)N=3)C=2C(Cl)=C(N2CC(OCC(O)CNC3C(Cl)=C4N(C5C(F)=CC(F)=C(N)N=5)C=C(C(O)=O)C(=O)C4=CC=3F)C2)C=1F)=O,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800231b,C/C(/C1C=C(N)C=CC=1)=C1/C2C=CC=CC=2OCC2C=C(Br)C=CC/1=2,Dmitry Zankov
Organic Process Research & Development,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 ).",2008,10.1021/op8002294,CC1=C(C=CC(=C1)SCC2=C(N=C(S2)C3=C(C=C(C=C3)C(F)(F)F)F)C)OC(C)(C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800228h,C1[C@H](O[C@H](S1)CO)N2C=CC(=NC2=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800215a,CCOC1C=CC(CCNC(COC2C=CC(CC(OC)C(O)=O)=CC=2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800211c,CC(C)(C)C1=CC=C(C=C1)C2=C(N(C3=CC=CC=C32)CC4=CC(=CC(=C4)OCCOC)OCCOC)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2009,10.1021/op800210x,C1=CC(=C(C=C1Cl)Cl)C(=O)[N-]S(=O)(=O)C2=CC=C(S2)Br,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op8002085,CC(CNCC1OC2C(=CC=C3N=C(C)C=CC3=2)OC1)CC1C2C=C(F)C=CC=2NC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op8002079,CN(C)CCC[C@@]1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,"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.,2009,10.1021/op800203p,C1C=C2C(CC(N2CC(N)=O)=O)=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800198b,COC1C=C2C=C(F)C=NC2=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800182x,C1=NC2=C(N=C(N=C2N1[C@H]3[C@H]([C@@H]([C@H](O3)CO)O)F)Cl)N,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800181e,CC1=C(C2=C(C=C1)N=C(NC2=O)N)SC3=CC=NC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op8001799,CC(CC(C(O)=O)1N(C(C2C=CC(C(C)(C)C)=C(OC)C=2)=O)C(C2SC=CN=2)C(CC(O)=O)C1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800177x,CC1C(C(CCC2C(C(N(C)C)=O)=CC3N(C(C)=NC=3C=2O)C)=O)=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800177x,CC1N(C)C2C(=C(O)C=C(C(N(C)C)=O)C=2)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800177x,CC1C(C(C2COC3C4N=C(C)N(C)C=4C=C(C(N(C)C)=O)C=3C2)=O)=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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 .",2008,10.1021/op800176e,CCOC1C=C(N2C(C3C=CC(C)=CC=3)=NC(C(N3CCN(C4C=C(C(O)=O)C5C=CC=CC=5C=4)CC3)=O)=C2)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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 .",2008,10.1021/op800176e,CCOC1C=C(N2C(C3C=CC(C)=CC=3)=NC(C(O)=O)=C2)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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 .",2008,10.1021/op800176e,COC(C1C2C=CC=CC=2C=C(N2CCNCC2)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800173u,CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C(N2)C=CC(=N3)OC,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800169s,CC1(OB(C2C=C(Cl)C=CC=2OCC2C=CC(Cl)=CC=2F)OC1(C)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800158w,CC1=CC=C(C=C1)C2=CC(=NN2C3=CC=C(C=C3)S(=O)(=O)N)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800157z,CCC(CC)O[C@@H]1C=C(C[C@@H]([C@H]1NC(=O)C)N)C(=O)OCC,Dmitry Zankov
Organic Process Research & Development,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 .",2008,10.1021/op800153y,CN(C(C(N(C1C2=NC(C(NCC3C=CC(F)=CC=3)=O)=C(O)C(=O)N2CCCC1)C)=O)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800146d,CC1=C(C=CC(=C1)F)[C@H]2CNCCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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%.,2008,10.1021/op800144h,CCCOC1C=CC2C=C(CCC(N)(CO)C)C=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800142b,CCN1C2C=C3C(C)(C)CCC(C)(C)C3=CC=2/C(/C2C(F)=CC(C(O)=O)=CC=2)=N\C2C=C(C(C)=O)C=CC1=2,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800137b,CC1=CC=CC=C1S(=O)(=O)NC(=O)C2=CC(=C(C=C2)CC3=CN(C4=C3C=C(C=C4)NC(=O)OC5CCCC5)C)OC,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op8001195,CN1C2C(=CC(N3C(=O)OC(CNC(OC)=O)C3)=CC=2F)CC1=O,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800113s,C1C=CC(N2N=C(OCC3CNCCC3)C3C=C(F)C=CC2=3)=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800108s,C1C(O)CCS(=O)(=O)C1,Dmitry Zankov
Organic Process Research & Development,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.,2008,10.1021/op800105j,C1CN(CCN1CCC2=C(C=C3C(=C2)CC(=O)N3)Cl)C4=NSC5=CC=CC=C54,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800104r,C1=CN(C(=O)N=C1N)[C@H]2C([C@@H]([C@H](O2)CO)O)(F)F,Dmitry Zankov
Organic Process Research & Development,"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.,2008,10.1021/op8000993,C1C[C@@H](C2=C(C1)C=CC=N2)N(CCCCN)CC3=NC4=CC=CC=C4N3,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800098a,CC1N(C2C=CC(SC3C=CC=C(C(C(N)=O)4CCOCC4)C=3)=CC=2)C=CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800092e,CC(C1N(CCC(O)CC(O)CC(O)=O)C(C2C=CC(F)=CC=2)=NC=1C(NCC1C=CC=CC=1)=O)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2008,10.1021/op800090s,CC1N=C2C(C=CC=C2)=C(COC2C=CC(S(NC3C(C(NO)=O)CCC3)(=O)=O)=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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).",2008,10.1021/op800076r,CC(C1OC(C(C2N(C(CNC(CO)(C)C)=O)CC(F)C2)=O)=NN=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op8000756,CCN1C2N=CC(CCOC3C4C=CC=CC=4[N+](O)=CC=3)=CC=2C(=O)N(C)C2C1=NC=CC=2,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800073z,COC1C(N2CCC(NC3NCCCN=3)CC2)=CC=C(C(NCC(NS(C2C=CC=CC=2)(=O)=O)C(O)=O)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800071m,C[C@@H](C1=CC=CC=N1)C2=C(SC3=CC=CC=C32)CCN(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800067v,CC1OC2C=CC(N/C(/NC3C(=O)N(CC(N4CCCC4)=O)CCCC3)=N/C(C3C=NC(C(N(C)C)=O)=CC=3)=O)=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800066m,COC1C=C2CC(C(=O)C2=CC=1OC)CC1CCN(CC2C=CC=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800065q,CC(N1CCN(C2N=CC(C(F)(F)F)=CC=2)CC1)(C(NC1C2CC(C(N)=O)3CC1CC(C3)C2)=O)C,Dmitry Zankov
Organic Process Research & Development,"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).",2008,10.1021/op800062d,CC1=NN=C(N1C2C[C@H]3CC[C@@H](C2)N3CC[C@@H](C4=CC=CC=C4)NC(=O)C5CCC(CC5)(F)F)C(C)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2008,10.1021/op8000614,CC1=NN=C(N1C2C[C@H]3CC[C@@H](C2)N3CC[C@@H](C4=CC=CC=C4)NC(=O)C5CCC(CC5)(F)F)C(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800060h,COC1=C(C=CC(=C1)NC(=O)NC2=CC=CC(=C2)CNC(=O)O[C@H]3CCOC3)C4=CN=CO4,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800059y,C1C[C@H]([C@@H]2[C@@H]([C@@H](CN2C1)O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800042a,CC1CN(CCN1)C2=C(C=C3C(=C2OC)N(C=C(C3=O)C(=O)O)C4CC4)F,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op8000355,CCS(C1C=CC(NC(C(O)(C(F)(F)F)C)=O)=C(Cl)C=1N1CCN(C)CC1)(=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op800033c,C[C@@](C(=O)NC1=C(C=C(C=C1)S(=O)(=O)C2=CC=C(C=C2)C(=O)N(C)C)Cl)(C(F)(F)F)O,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800025p,C1CC=C(CCNC(C2C=CC(Br)=CC=2)C#N)C=C1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op8000178,C1(C=C(OC)C=CC=1)C(OC1C(OC(CCC(O)=O)=O)C2OC1C1C(=O)N(C3C=CC=CC=3)C(=O)C12)(C1C=CC=CC=1)C1C=CC(OC)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op8000146,CC1=C2CC[C@H](CC2=C(C=C1)N3CCN(CC3)C)NC(=O)C4=CC=C(C=C4)N5CCOCC5,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op800008w,CCN1CCC(=CC2=CC(=C(C(=C2)C(C)(C)C)O)C(C)(C)C)S1(=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700295x,C1C2CC3CC1CC(C2)(C3)COCCCCCN4[C@@H]([C@H]([C@@H]([C@H](C4O)O)O)O)CO,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op700288p,C[C@@H]1CC[C@@H](C(=O)CN1S(=O)(=O)C2=CC=CC=N2)NC(=O)[C@H](CC(C)C)NC(=O)C3=CC4=CC=CC=C4O3,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700286u,CC(C(NC(OCC1C2C=CC=CC=2C2C=CC=CC1=2)=O)(C(O)=O)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op7002858,CC(C)(C)P(C1=CC=NN1C2=C(N(N=C2C3=CC=CC=C3)C4=CC=CC=C4)C5=CC=CC=C5)C(C)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700281w,COC1=CC(=NC2=NC(=NN12)NS(=O)(=O)C3=C(C=CN=C3OC)C(F)(F)F)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op7002776,CC(C)(C)NCC1=C(C=C(C=C1)NC2=C3C=CC(=CC3=NC=C2)Cl)O,Dmitry Zankov
Organic Process Research & Development,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.,2008,10.1021/op700270n,CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700265n,O=C(CC1CCC1)C=C([C@@H](COCC2=CC=CC=C2)NO)N,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700259d,COC(C(N)C(CC(F)(F)F)CC(F)(F)F)=O,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op7002584,CC(N(CCCC(C1C=CC(Cl)=CC=1)1C2C(=CC(Cl)=CC=2)CC1)C)C(O)=O,Dmitry Zankov
Organic Process Research & Development,"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 .",2008,10.1021/op700248t,C1C=CC(C(C2C=CC=CC=2)CNC2C3N=CN(C4OC(CO)C(O)C4O)C=3N=C(C(NCCN3CCCCC3)=O)N=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op700246g,C1C(C)CCN(CCC(C2C=CC=CC=2)C2C=C(F)C=C(F)C=2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700240c,CN1C[C@H]2[C@H](C1)C3=C(C=CC(=C3)Cl)OC4=CC=CC=C24,Dmitry Zankov
Organic Process Research & Development,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 .",2008,10.1021/op700235c,CC(NC(C1C=CC(C(F)(F)F)=NC=1CC(O)C(N)CC1C=C(F)C=CC=1F)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700227p,CNC(=O)C1=CC=CC=C1SC2=CC3=C(C=C2)C(=NN3)/C=C/C4=CC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op7002248,CC(C)C[C@@H](CC(=O)O)CN,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700222r,CC1N=C(NC(C)=O)SC=1C1C=C(N2C=NC=C2)C(S(C)(=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op700218j,CC(C)OC(=O)[C@H](CCSC)NC(=O)C1=C(C=CC(=C1)NC[C@@H]2C[C@@H](CN2)SC(=O)C3=CN=CC=C3)CCC4=CC=C(C=C4)F,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700198s,CC1OC=C(C(OC)=O)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700195j,CN1C(C2CC2)=NC=C1Br,Dmitry Zankov
Organic Process Research & Development,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 ).",2007,10.1021/op7001886,C[C@@]1(C2=CC(=C(C=C2CCO1)OC)CN[C@H]3CCCN[C@H]3C4=CC=CC=C4)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700186z,CN(C(SC1C=CC=CC=1)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700183q,CN1CC(C2C=CC(SC)=CC=2)C2C(=CC(OCCCN3CCC(F)CC3)=CC=2)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700181n,CC1C=CC2C3OC(CNCC4CC5C6C=C(F)C=CC=6NC=5CC4)COC=3C=CC=2N=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700178q,C1C2C3C(CC=2C(Cl)=C(O)C=1)1CC(CC1)C(=O)C=3Cl,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op7001722,CC(NC1C([N+](O)=O)=CC(/C=C/C2C=CC=CC=2)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700164t,CC1=C(C=CC(=C1)CNC(=O)C2=NN(C(=C2)C3=CC=C(C=C3)C(C)(C)C)C)OC(C)(C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op7001613,CC1=CC(=C(N1)/C=C\\2/C(=C/C(=C/3\\C=C4C=CC=CC4=N3)/N2)OC)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700160a,C1C2C(O)COC2OC1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op7001563,CC(C)(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)[C@H](CN(CC2=CC=C(C=C2)C3=CC=CC=N3)NC(=O)[C@H](C(C)(C)C)NC(=O)OC)O)NC(=O)OC,Dmitry Zankov
Organic Process Research & Development,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 ).",2007,10.1021/op7001535,C1C=C2C=CC=C(N3CCNCC3)C2=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2008,10.1021/op7001479,CCCCCC1C2C=CC=CC=2C2C=CC=CC1=2,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700146c,C1CC(C#N)C(OC2C=C(C(F)(F)F)C(C#N)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700141u,C1C=C(C(F)(F)F)C=CC=1C1N=C(CO)SN=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op7001326,COC(C1C(N)=CC(CC2C=CC(F)=CC=2)=CN=1)=O,Dmitry Zankov
Organic Process Research & Development,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%.",2008,10.1021/op700126w,CN(CC1C(C2C3C(=CC=C(C#N)C=3)NC=2)C1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700122q,C1C=CC(SCCSC2C=CC=CC=2N2C(=O)C=CC2=O)=C(N2C(=O)C=CC2=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700121y,CC(OC1C=CC(C2C=C3C4C(N5CCCOC(=C35)C=2)CCNC4)=C(C(F)(F)F)C=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700120n,CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NNN=N3)[C@@H](C(C)C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700117q,C1=CC(=CC=C1CC2=CC=C(O2)C(=O)/C=C(/C3=NC=NN3)\\O)F,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700116y,C1=CC(=CC=C1CC2=CC=C(O2)C(=O)/C=C(/C3=NC=NN3)\\O)F,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700114d,CC1C(Br)=CN=C(N)C=1[N+](O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op7001134,CC1=CC(=C(C=C1)O)[C@H](CCN(C(C)C)C(C)C)C2=CC=CC=C2,Dmitry Zankov
Organic Process Research & Development,"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).",2008,10.1021/op7001112,CC(OC(N1C(C(O)=O)C(C)(C)C(F)(F)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700110b,CC1=C(N(N=C1C(=O)NN2CCCCC2)C3=C(C=C(C=C3)Cl)Cl)C4=CC=C(C=C4)Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700107h,CC1=CN(C2=C(C=C(C=C12)F)/C=C/C(=O)NS(=O)(=O)C3=CC(=C(S3)Cl)Cl)CC4=C(C=C(C=C4)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700107h,CC1C2C=C(F)C=C(/C=C/C(OC)=O)C=2NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700102k,CC1N(CCC2C=C3C(C=C(N4N=CC=CC4=O)C=C3)=CC=2)CCC1,Dmitry Zankov
Organic Process Research & Development,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.,2007,10.1021/op700093y,CC(NC(C(OC)=O)CC1C=CC=C(O)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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 .",2007,10.1021/op700091d,C1COC(C2CSC3N(C(C3N)=O)C=2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)C1.CC.CC,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700088y,C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)C(=O)N(C)C)C(=O)O)[C@@H](C)O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700086d,CC1C(NC(CN2CCN(C3CC(CC4C=CC=CC=4)N(C(C4C=C(C(F)(F)F)C=C(C(F)(F)F)C=4)=O)CC3)CC2)=O)=C(C)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700084h,CCCC1C(Cl)=NC=NC=1CN1C(C2C(F)=CC=CN=2)=NC=C1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700074k,COC1C=CC(N2CCOCC2)=CC=1[N+]([O-])=O,Dmitry Zankov
Organic Process Research & Development,"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 .",2007,10.1021/op700073g,C1C=CC(CCN2CC3C(CCN3)CC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700068g,C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NC4=C(C=CC(=C4)C(F)(F)F)C(F)(F)F)CC[C@@H]5[C@@]3(C=CC(=O)N5)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op7000639,CC(N)C1CN(C2C(F)=CC3C(N(N)C(N(C4CC4)C=3C=2OC)=O)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700062c,CC(NCC1OC(=O)N(C2C=CC(I)=CC=2)C1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700061x,C1CCN(CCOC2C=CC(C3OC4C(=CC=C(O)C=4)C4CCOC5C=C(O)C=CC=5C3=4)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op7000589,C1C=CC2C(N)CCC(C3C=C(Cl)C(Cl)=CC=3)C=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700054p,COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700054p,COCCOC1=C(C=C2C(=C1)C(=NC=N2)NC3=CC=CC(=C3)C#C)OCCOC,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700052u,C1CN(C1)CC2CC(C2)N3C=C(C4=C(N=CN=C43)N)C5=CC(=CC=C5)OCC6=CC=CC=C6,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700052u,C1C=CC(COC2C=C(C3C4C(N)=NC=NC=4NC=3)C=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700052u,COC(C1CC(OS(C)(=O)=O)C1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op7000518,CC1NC2C(=CC=CC=2)C=1CCN,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op7000468,COC1C=C2C(CNCC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700042w,C1C2C(C2)C(=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700041z,C1C=C(C#N)C(C2C=CC(CNC3C(C(OC)=O)=CC=CC=3N)=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700040v,CC1=CC=C(C=C1)CN2C(=O)NC(=N2)CCCC3=CC=C(C=C3)OC(C)(C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op7000386,CC1N(C(COC2C(CS(O)(=O)=O)=CC(Cl)=CC=2)=O)CC(C)N(CC2C=CC(F)=CC=2)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700026n,C[C@@H]([C@@H](CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700025d,COC(=O)[C@H](C1=CC=CC=C1Cl)N2CCC3=C(C2)C=CS3,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700020f,CC(C(OC1C=CC2C3C(C4C=CC(OCCN5CCCCC5)=CC=4)OC4C(=CC=C(OC(C(C)(C)C)=O)C=4)C=3COC=2C=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op7000194,CCCN1CCC(CC1)C2=NC3=C(C=CC=C3N2)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700014t,CC1C=C(C2C(F)=CC3C(C4C(=O)NSC=4N(C4CC4)C=3C=2OC)=O)C=CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700010a,CC1C=CC(S(CC(O)(C(F)(F)F)CC(C2C=C(F)C=CC=2OC)(C)C)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700009t,CC1C2N=C(N)C3C=NC4C(=CC(OC)=C(OC)C=4)C=3C=2C=CC=1N,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op700007g,CCOC1=CC=CC=C1O[C@H]([C@@H]2CNCCO2)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op7000063,CCOC1=CC=CC=C1O[C@@H]([C@H]2CNCCO2)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op700001c,CCN(C1=CC=CC=C1)C(=O)C2=C(C3=C(C=CC=C3Cl)N(C2=O)C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op6002852,CC1=NSC(=C1)NC(=O)C(=O)C2=C3C=CC=CN3C(=C2)CC4=CC=C(C=C4)C#N,Dmitry Zankov
Organic Process Research & Development,"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.",2008,10.1021/op600280g,CNC(=O)C1=CC(=CC=C1)SC2=CC3=C(C=C2)C(=NN3)/C=C/C4=CC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500412a,CN1C(=CC=N1)C2=CC=C(C=C2)SC3=CC=CC(=C3)C4(CCOCC4)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500395b,C1=CC(=CC=C1CN)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500394f,CCNC(=O)N(CCCN(C)C)C(=O)[C@@H]1C[C@H]2[C@@H](CC3=CNC4=CC=CC2=C34)N(C1)CC=C,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500394f,CCCN1C[C@@H](C[C@H]2[C@H]1CC3=CNC4=CC=CC2=C34)CSC,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500394f,COC(C1CNC2C(C3C4C(C2)=CNC=4C=CC=3)C1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op5003903,CC1C=NC(CN2C3N=C(N=C(Cl)C=3N=C2)N)=C(C)C=1OC,Dmitry Zankov
Organic Process Research & Development,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 .",2015,10.1021/op500386g,CCC(=O)NCC[C@@H]1CCC2=C1C3=C(C=C2)OCC3,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op5003837,C[C@]1([C@@H]([C@H](O[C@H]1N2C=NC3C2N=C(NC3=O)N)COP(=O)(NCC4=CC=CC=C4)OCCSC(=O)C(C)(C)CO)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500379a,CC(NC(OC1C2CCN(CC2)C1)=O)(C1N=C(C2C=CC(F)=CC=2)SC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2015,10.1021/op5003769,CCC1C2C(=NC=CN=2)NC=1C1C=CC(C(O)(C)C)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500367p,C1CCC(CC1)N2C3=C(C=CN=C3)C4=CN=C(N=C42)NC5=NC6=C(CN(CC6)C(=O)CO)C=C5,Dmitry Zankov
Organic Process Research & Development,"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.,2015,10.1021/op500366s,CC1=C(SC2=C1N=C(N=C2N3CCOCC3)C4=CN=C(N=C4)N)CN5CCN(CC5)C(=O)[C@H](C)O,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500357r,CCOC1=NC2=CC=CC(=C2N1CC3=CC=C(C=C3)C4=CC=CC=C4C5=NOC(=O)N5)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500351q,C1[C@H]2CSC(=N[C@]2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5003402,CN1C(CCC2C=CC=CC=2NC(/C=C/C2C=CC=CC=2)=O)CCCC1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500334b,C1C=C2C3C(OC(=O)C2=CC=1N)=CC(O)=CC=3,Dmitry Zankov
Organic Process Research & Development,"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.",2015,10.1021/op500327t,C1[C@H]2CSC(=N[C@]2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5003165,CCOC(C1(N(C)C(=O)C2C=CC=CC1=2)COC(CC1C=C(C(N(C)C)=O)C(NC(C2C=CC=C(C)C=2C2C=CC(C(F)(F)F)=CC=2)=O)=CC=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500314c,CC1=C2CC[C@@]3(CCC=C([C@H]3C(=O)[C@@H](C2(C)C)CC1)C)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2014,10.1021/op5002885,COC1=C(C=C2CN(CCC2=C1)C(=O)[C@@H]3CCCN(C3)CCNC(=O)C4=CC=C(C=C4)F)OC,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500277s,CC1C=C(C)C=C(NC(C2N(S(C3C=CC(OC)=CC=3)(=O)=O)CCC2)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500274j,C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500271w,CC1C2C(=NC=NC=2N2CCN(C(OC(C)(C)C)=O)CC2)C(=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500270z,C[C@@H]1C[C@H](C2=C1C(=NC=N2)N3CCN(CC3)C(=O)[C@H](CNC(C)C)C4=CC=C(C=C4)Cl)O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500266w,COC1C(NC2CC(C(N3CC4C=C(C(F)(F)F)C=NC=4CC3)=O)3CCOC3C2)CCOC1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500265z,CC(OC(NC1CC(C(O)=O)2C(CCC2)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500264v,C1C=CC(C(O)C2NCCCC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2015,10.1021/op500264v,C1CCN[C@@H](C1)[C@H](C2=CC=CC=C2)NC(=O)C3=C(C(=CC=C3)C(F)(F)F)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500263m,CCOC(C1C2C(N(C(=O)C12)CC1C=CC=CC=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500250b,CN1CC(C(NC2C=CC(Cl)=CC=2)=O)C(C2C=CC(/C=C/C(NC3C=CC=CC=3N)=O)=CC=2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500247h,C1=CC(=CC=C1N)S(=O)(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5002353,C1C=CC(C2C=CC(C=O)=CC=2)=C(C#N)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500222p,C1=CC(=C(C=C1OC2=C(C=C(C=C2I)C[C@@H](C(=O)[O-])N)I)I)OS(=O)(=O)[O-],Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500210w,CCCC(NC(C1N(C(C(NC(CC2CCCCC2)=O)C(C)(C)C)=O)CC2(ON=C(C3C=C(C)C(OC)=C(C)C=3)C2)C1)=O)C(C(NC1CC1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500204z,C1[C@H]2CSC(=N[C@]2(CO1)C3=C(C=CC(=C3)NC(=O)C4=NC=C(C=C4)F)F)N,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500193s,CC(C)(C)C[C@H]1C[C@H](CCN1)C2=CC(=O)NO2,Dmitry Zankov
Organic Process Research & Development,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.,2014,10.1021/op500173q,CN(C(N(C1C=CC(OC)=CC=1)C1CCCC=C1)=O)C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500166n,C1=CC(=C(C(=C1)F)CN2C=C(N=N2)C(=O)N)F,Dmitry Zankov
Organic Process Research & Development,"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 .",2014,10.1021/op5001644,C1COC(C(O)=O)CNC1,Dmitry Zankov
Organic Process Research & Development,"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 .",2014,10.1021/op5001644,COC(C1OCCC(=O)NC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500152g,C#CCN[C@@H]1CCC2=CC=CC=C12,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5001513,CCC(N)C1C=C(S(C)(=O)=O)N=CC=1,Dmitry Zankov
Organic Process Research & Development,"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%.",2014,10.1021/op500148k,C1C(C)=C2NC(C(N)C)=NC2=C(C)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op5001463,CC(C)(C)C1=C(C=NN1C2=CC=C(C=C2)C(=O)O)C(=O)NC3C4CC5CC(C4)CC3C5,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5001435,C(N)1C(O)C(N)C(O)C(N)C1O,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500135x,CC1OC=CC(=O)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500135x,C=CC(CC(O[Si](C(C)(C)C)(C)C)C)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500134e,C1C=C(F)C=CC=1C(O)C(N1N=CCC1C(NCC1C(N2N=NN=C2)=CC=C(Cl)C=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500128p,CN1N=C(C(F)F)C(C(O)=O)=C1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500128p,CCOC(C1C(C(F)F)=NN(C)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5001226,CCC(=O)O[C@@]1([C@@H](C[C@@H]2[C@@]1(C[C@@H]([C@]3([C@H]2C[C@@H](C4=CC(=O)C=C[C@@]43C)F)F)O)C)C)C(=O)SCF,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500121w,CC(C1C(N2C(Cl)=[N+](C3C(C(C)C)=CC=CC=3C(C)C)C=C2)=C(C(C)C)C=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500116w,CCOCC(NC(C1C(O)C(C(N(C2N=CC(C(C)C)=CC=2)C2CC2)=O)CNC1)=O)CC(C)C,Dmitry Zankov
Organic Process Research & Development,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.,2014,10.1021/op500114v,CC(C1C=CC(CNC(C2N(C)N=C(C=O)C=2Cl)=O)=CC=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.,2014,10.1021/op500105n,CC1=C(C(=NO1)C)C2=CC(=C(C=C2)C3=CC(=C(S3)NC(=O)N)C(=O)N)O[C@H]4CCNC4,Dmitry Zankov
Organic Process Research & Development,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",2014,10.1021/op5001034,CC1C(C2C=CC(C3SC(NC(N)=O)=C(C(N)=O)C=3)=C(OC3CN(C(OC(C)(C)C)=O)CC3)C=2)=C(C)ON=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500102h,CCOC(C1C(C(F)F)=NN(C)C=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op5001012,CCOC(C(C#C)(OCC)OCC)OCC,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500096j,C=CC1COC(=O)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500084q,CCCCCCOC(=O)NC(=N)C1=CC=C(C=C1)NCC2=NC3=C(N2C)C=CC(=C3)C(=O)N(CCC(=O)OCC)C4=CC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500083y,C1CN2CCC1[C@H](C2)OC(=O)N3CCC4=CC=CC=C4[C@@H]3C5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500074h,C1C=C2C3C=CSC=3NC(=O)C2=CC=1,Dmitry Zankov
Organic Process Research & Development,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.,2014,10.1021/op500072b,CCO[C@@H]([C@H]1C[C@H]([C@H]2[C@@H](O1)[C@@H]([C@@]3([C@@]2(CC[C@]45[C@H]3CC[C@@H]6[C@]4(C5)CC[C@@H](C6(C)C)O[C@H]7CN(CCO7)C8CN(C8)C(C)C)C)C)O)C)C(C)(C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500070t,C1CN(CCN1CCCCC2=CNC3=C2C=C(C=C3)C#N)C4=CC5=C(C=C4)OC(=C5)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500066f,CC(C)(C)OP(=O)(OCCl)OC(C)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500065t,CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)NC(C)(C)C)C(=O)NC(CC3CCC3)C(=O)C(=O)N)C,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op500063g,C1C(OCC2OC(=O)NC2)=NOC=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5000545,CC=CC1=C(N2[C@@H]([C@@H](C2=O)NC(=O)[C@@H](C3=CC=C(C=C3)O)N)SC1)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op5000489,C1C2C3C(CC=2C2N=NNC=2C=1)1CC(CC1)C(=O)C=3C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500044p,CC(=O)O[C@H]1CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3CC=C2C1)CC=C4C5=CN=CC=C5)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500042u,CC(C(SCCOP(OCC1OC(N2C(=O)N=C(N)C=C2)C(O)(C)C1O)(NCC1C=CC=CC=1)=O)=O)(CO)C,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500038s,OP(OC(C(NC(C(Cl)Cl)=O)CF)C1C=CC(S(C)(=O)=O)=CC=1)(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500032w,C1C=C2C(C(C3CCC(C4C=CC(Cl)=CC=4)CC3)=C(O)C(=O)C2=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500031z,C1CC1NC2CC2,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500030v,CC(NCC1OC(=O)N(C2C=C(F)C(N3N=CC(C4C=CC=CN=4)=C3)=CC=2)C1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500030v,C1C=CN=C(C2C=NNC=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500030v,C1=CC(C2C(N)=NNC=2)=NC=C1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500030v,C1C=C(C2C=NN(C3C(F)=CC([N+]([O-])=O)=CC=3)C=2)N=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op500025v,CC1=CC(=C2C(=C1)[C@H](CCCN2CC3CCC(CC3)C(=O)O)N(CC4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)C5=NN(N=N5)C)C,Dmitry Zankov
Organic Process Research & Development,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.,2014,10.1021/op5000094,CC1C(CN2CCC3(OCC(F)(F)C4C=C(SC3=4)Cl)CC2)=CN(C2C(CO)=CC=CN=2)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op4003642,COC1=CC=C(C=C1)C2=CC(=O)C3=C(C(=C(C=C3O2)OC)O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op4003642,CC(C1C(OC)=C(O)C(OC)=CC=1O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400357f,COC1=NC2=C(C3=C(C=C(C=C3)Cl)N=C2C=C1)NC4=CC(=C(C(=C4)CN5CCCC5)O)CN6CCCC6,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400354g,C1C=C(S(C2CC2)(=O)=O)C=CC=1C(C(NC1N=CC=NC=1)=O)CC1CCOCC1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op4003533,CC1=C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@H]4C1=CC(=O)CC4,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op4003505,CC1=C2[C@H](C(=O)[C@@]3([C@H](C[C@@H]4[C@]([C@H]3[C@@H]([C@@](C2(C)C)(C[C@@H]1OC(=O)[C@@H]([C@H](C5=CC=CC=C5)NC(=O)C6=CC=CC=C6)O)O)OC(=O)C7=CC=CC=C7)(CO4)OC(=O)C)O)C)OC(=O)C,Dmitry Zankov
Organic Process Research & Development,"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%.",2014,10.1021/op4003467,CC1(C2C(=C(N3C(=O)NC(=O)C=C3)C=C(C=2OC)C2C=CC3C(=CC=C(NS(C)(=O)=O)C=3)C=2)OC1)C,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400335p,CC(=O)C1=CC(=C(C=C1)OCCCN2CCC(CC2)C3=NOC4=C3C=CC(=C4)F)OC,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400331j,CC1(CCCC2=C(C=C3C=CN=C(C3=C2)O[C@@H]4C[C@H](N(C4)C(=O)[C@@H](NC(=O)OC1)C5CCCCC5)C(=O)N[C@@]6(C[C@H]6C=C)C(=O)NS(=O)(=O)C7CC7)OC)C,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400331j,COC1C(Br)=CC2C(Cl)=NC=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,"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 .",2014,10.1021/op400325r,CN1CC(F)C(N2C(=O)S/C(=C\C3C=CC4N(N=CC=4C=3)CC3C(C(F)(F)F)=CC(Cl)=CC=3)/C2=O)CC1,Dmitry Zankov
Organic Process Research & Development,"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 .",2014,10.1021/op400325r,C1C(C=O)=CC2C=NN(CC3C=CC(Cl)=CC=3C(F)(F)F)C=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400317z,CN1N=CC2C=C(OC3C(F)=CC([N+]([O-])=O)=CC=3)C(Br)=CC1=2,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400317z,CC1=CC=C(C(=O)N1C2=CC=C(C=C2)F)C(=O)NC3=CC(=C(C=C3)OC4=C(C=C5C(=C4)C=NN5C)C6=CNN=C6)F,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op400313y,C[C@@H](CC1=CC=CC=C1)N(C)CC2=CC=CC=C2,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400309q,CN1CC[C@@]23CCCC[C@@H]2[C@@H]1CC4=C3C=C(C=C4)OC,Dmitry Zankov
Organic Process Research & Development,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 .",2013,10.1021/op400304h,C1C=C(NC2C3N=CC(C4N=CC(C(N)=O)=CC=4C(F)(F)F)=NC=3N=CC=2)N=CC=1C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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 .",2013,10.1021/op400304h,CCOC(OCC)C(C1C(C(F)(F)F)=CC(C(N)=O)=CN=1)=O,Dmitry Zankov
Organic Process Research & Development,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 .",2013,10.1021/op400304h,C1C=C(NC2C=CN=C(N)C=2N)N=CC=1C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400300t,CC(C1C(O)=C(C(C)C)C=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4002966,CC(N(C(OC(C)(C)C)=O)/C=C(/C(O)=O)\C1C=CC(Cl)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2014,10.1021/op400294z,CC(C)[C@@H](CC1=CC(=C(C=C1)OC)OCCCOC)C[C@@H]([C@H](C[C@@H](C(C)C)C(=O)NCC(C)(C)C(=O)N)O)N,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400292m,CCCNC(C(NCCC)C1N=CC=CC=1)C1C=CC=CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400289z,CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)[C@@]34[C@@H]([C@H]([C@@H]([C@@](O3)(CO4)CO)O)O)O)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400288v,CCOC(=O)C1=C(N=C(C(=C1)C#N)N2CCC(CC2)C(=O)NS(=O)(=O)CC3=CC=CC=C3)C,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400285y,CC(C(NC(OC1CCCC1)=O)C(N1C(C(O)=O)CC(O)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op4002824,CC1C=C(C(NC2C=C(OC3C=CC4=NC(NC(C5CC5)=O)=NN4C=3)C=CC=2F)=O)N(C)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op4002824,C1C(O)=CC(N)=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4002802,CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)[C@@]34[C@@H]([C@H]([C@@H]([C@@](O3)(CO4)CO)O)O)O)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400279n,CNCCC(OC1C=CC(C(F)(F)F)=CC=1)C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4002774,CC(C)C[C@@H](CC(=O)O)CN,Dmitry Zankov
Organic Process Research & Development,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).",2014,10.1021/op400269b,CC(C)C(=O)O[C@]1(C[C@H]2CC[C@@H]1C=C2C3=CC=CC=C3)CCN(C)CCCC4=NC5=C(C=CC(=C5N4)OC)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400268f,C1C=C(C(F)(F)F)C=CC=1CCC1C2C(=CC(OC)=C(OC)C=2)CCN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400268f,CNC(=O)[C@@H](C1=CC=CC=C1)N2CCC3=CC(=C(C=C3[C@@H]2CCC4=CC=C(C=C4)C(F)(F)F)OC)OC,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400266k,C1[C@@H](C=CC1=O)O,Dmitry Zankov
Organic Process Research & Development,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%).",2013,10.1021/op4002593,C1C(CC(O)C(OC(C)C)=O)=CC(O)=C(O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400250s,CC1=C(C(=[N+](C=C1)[O-])C)C(=O)N2CCC(CC2)(C)N3CCC(CC3)N(C4=CC=CC=C4)C5=CN=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400242j,CC1=CC2=C(N1)C=CC(=C2F)OC3=NC=NN4C3=C(C(=C4)OC[C@@H](C)OC(=O)[C@H](C)N)C,Dmitry Zankov
Organic Process Research & Development,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).",2013,10.1021/op400237j,CCC1=CC(=CC(=N1)CC)CC[C@@]2(CC(=C(C(=O)O2)CC3=NN4C(=CC(=NC4=N3)C)C)O)C5CCCC5,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400236r,CCC1=CC(=CC(=N1)CC)CC[C@@]2(CC(=C(C(=O)O2)CC3=NN4C(=CC(=NC4=N3)C)C)O)C5CCCC5,Dmitry Zankov
Organic Process Research & Development,"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 .",2013,10.1021/op4002356,CCC1=CC(=CC(=N1)CC)CC[C@@]2(CC(=C(C(=O)O2)CC3=NN4C(=CC(=NC4=N3)C)C)O)C5CCCC5,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400233z,C1C[C@H](CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400233z,CC(C(CCC(C1C=CC(Br)=CC=1)C=O)=O)C,Dmitry Zankov
Organic Process Research & Development,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",2013,10.1021/op400230q,CC(OC(N1CC(C2C=CC(Br)=CC=2)CCC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400228z,CN1S(=O)(=O)CCCCCNC(C2C=C(F)C=C(CNC(=O)C3=C(O)C4C(C1=N3)=CC=CN=4)C=2)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400228z,CCOC(C1N=C(Br)C2C(=NC=CC=2)C=1O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400228z,CNS(CCCCCN)(=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400219y,CC[C@H](C[C@H](O)[C@@H](N)CN1CC(=O)N(CC1(C)C)c1ccccc1Cl)C(=O)N[C@@H]1[C@H]2C[C@H]3C[C@@H]1C[C@](O)(C3)C2,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4002164,CS(C1C=CC(C(C(NC2N=CC(C(O)CO)=NC=2)=O)CC2CCCC2)=CC=1Cl)(=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400215h,COC1N=C2CCN(C(=O)C2=C(N)N=1)C1C=CC(C(C#N)2CCC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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%.",2013,10.1021/op400211t,COC(C1CCCCC1)1CCN(C2C=CC(C3SC(C4CCC(C(=O)[H])CC4)=NN=3)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op4002092,CN1CCN(C(C2CCN(C3C=C(C4N(C)C5C=CC=CC=5N=4)C=CC=3)CC2)=O)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400205k,CC(C(CC(N)C(O)=O)CC1C=CC(OC)=C(OCCCOC)C=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400204g,CC(C1C=CC=CC=1)N1CC(C2C=CC(C#N)=CC=2)OCC1,Dmitry Zankov
Organic Process Research & Development,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.",2014,10.1021/op400184f,CC1N=CC2C=CC=C(NC(NC3C4C=CC(Cl)=CC=4OC(CF)(CF)C3)=O)C=2C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400181g,COC(=O)C12C3C4C1C5C2C3C45C(=O)OC,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400179f,CN1C2=C(C=C(C=C2)N(CCCl)CCCl)N=C1CCCC(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op4001753,C1C=C(Cl)C(Cl)=C(C2C(N)=NC(N)=NC=2CF)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4001737,C1C2NC(C(O)=O)=CC=2OC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4001687,CC1N=CC(CO)=C(CO)C=1O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400162p,CC1=C(C=CC2=C1CCN(C2)CCC(=O)O)C3=NOC(=N3)C4=CC(=C(C=C4)OC(C)C)C#N,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400155u,C1C=CC(COC(N2NC(C(O)=O)CCC2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400150w,C1CC2(NCC(C3C=C(F)C=C(F)C=3)N(CC(O)=O)C2=O)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400145w,CN1C2=C(C=C(C=C2)OC)C(=O)N(C1=O)CC3CCC(CC3)C(=O)N4CCN(CC4)C(=O)COC,Dmitry Zankov
Organic Process Research & Development,"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 .",2013,10.1021/op400144z,CC1C(C2C=CC=C(O)C=2)(C)CCNC1,Dmitry Zankov
Organic Process Research & Development,"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 .",2013,10.1021/op400144z,C[C@H]1CN(CC[C@@]1(C)C2=CC(=CC=C2)O)C[C@H](CC3=CC=CC=C3)C(=O)NCC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400137m,CC(C)C1=NOC(=C1)CNC2=NC(=CC(=N2)N3CCN(CC3)C)NC4=NNC(=C4)C5CC5,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400133d,CC1NN=C(NC2N=C(NC(C3N=CC(F)=CN=3)C)N=CC=2Cl)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400133d,CC(N)C1N=CC(F)=CN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400119b,CN(CCOC1C=CC(CC(NC(C2C=CC=CC=2)=O)C(NC(CO)CC2C=CC=CC=2)=O)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op400115g,CC1NCCC2(N(C3C=C(F)C=CC=3)C(=O)C=C2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400113a,CN(CCOC1C=CC(CNC(C2C=C(OC)C(OC)=C(OC)C=2)=O)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4001077,CN(C1C=C2CCN(C(=O)C2=CC=1)C1C=CC=C(C2C=C(NC3N=CC(C(N4CCOCC4)=O)=CC=3)C(=O)N(C)C=2)C=1CO)C,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400101p,CC1OCC(C2C=CC=CC=2)NC1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400101p,CC1OCC(C2C=CC=CC=2)N(C2N=C3NC(COC3=CC=2)=O)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400100s,CC1C=CC(S(NC2N=C(C3N=CC=CN=3)N=C(OCCO)C=2OC2C(OC)=CC=CC=2)(=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400095f,C1NC(Br)=NC=1[N+]([O-])=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400088k,CNC(=O)C1=CC=CC=C1SC2=CC3=C(C=C2)C(=NN3)/C=C/C4=CC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400061w,COC(C1C=C(I)C(Cl)=NC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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%.",2013,10.1021/op400060z,C(/C(O)CC(O)CC(O)=O)=C\C1C=NC2C(=CC(F)=C(F)C=2F)C=1SC1C=CC(F)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400046y,CC(OC1C=CC(N)=NC=1)(CN1CCC1)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400039d,CC1(CC(=NNC1=O)C2=CC3=C(C=C2)OC4(CCN(CC4)C5CCC5)OC3)C,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op4000384,CC[C@H](/C=C/C=C\\C[C@H](/C=C/C=C/C=C\\[C@H](CCCC(=O)O)O)O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400034f,CC1=CC(=C(C=C1)C)OCCCC(C)(C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400024a,CCCN(CCC)CCC1=C2CC(=O)NC2=CC=C1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op4000237,CCN(C(OC1C=C(C(N(C)C)C)C=CC=1)=O)C,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op4000219,CN(C)[C@H]1[C@@H]2C[C@@H]3CC4=C(C=C(C(=C4C(=C3C(=O)[C@@]2(C(=C(C1=O)C(=O)N)O)O)O)O)NC(=O)CN5CCCC5)F,Dmitry Zankov
Organic Process Research & Development,"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",2013,10.1021/op4000187,C1C=C(C(Cl)CCl)C(Cl)=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op4000169,CC1N(C2C=C(Br)C=CC=2O)N=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400013e,C1C=C(S(NC(C(N)=O)CCC(F)(F)F)(=O)=O)C=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op400012p,COC1=CN=C(C2=C1C(=CN2)C(=O)C(=O)N3CCC(=C(C#N)C4=CC=CC=C4)CC3)C5=NC=CN=C5,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400010u,B([C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)C1=CC=CC(=N1)C2=CC=CC=C2)(O)O,Dmitry Zankov
Organic Process Research & Development,"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%.",2013,10.1021/op400008e,CCCCC1=C(C2=C(O1)C=CC(=C2)NS(=O)(=O)C)C(=O)C3=CC=C(C=C3)OCCCN(CCCC)CCCC,Dmitry Zankov
Organic Process Research & Development,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",2013,10.1021/op400007p,COC1=C(C=C2C(=C1)CC(C2=O)CC3CCN(CC3)CC4=CC=CC=C4)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op400002r,CN1CC2CC(C=C(C3C=CC=NC=3)C2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300367c,CO[C@@H]1[C@@H]([C@H]([C@@H]([C@H](O1)COS(=O)(=O)[O-])O[C@H]2[C@@H]([C@H]([C@@H]([C@@H](O2)C(=O)[O-])O[C@@H]3[C@@H]([C@H]([C@@H]([C@H](O3)COS(=O)(=O)[O-])O[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)C(=O)[O-])O[C@@H]5[C@@H]([C@H]([C@@H]([C@H](O5)COS(=O)(=O)[O-])O)O)NS(=O)(=O)[O-])O)O)OS(=O)(=O)[O-])NS(=O)(=O)[O-])O)OS(=O)(=O)[O-])O)NS(=O)(=O)[O-],Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300365e,CN1CCN(CC1)C(=O)C2=CC=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C(N4C5CCOCC5)C(F)(F)F)F,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300365e,C1C(N2C(C(F)(F)F)=NC=C2)CCOC1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300352w,C(=O)=NC1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300352w,C1C=CC(O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op300345v,CC(OC1N=CC(C2ON=C(C3C=CC(NC4CC(C(O)=O)CC4)=CC=3)N=2)=CC=1Cl)C,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op300345v,CC(OC1N=CC(C2ON=C(C3C=CC(OC4CC(C(O)=O)C4)=CC=3Cl)N=2)=CC=1Cl)C,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op300344m,CC1=CC(=NN1)NC2=NN3C(=C(N=C3C(=C2)CN4CCOCC4)C)CC5=C(C=C(C=C5)Cl)F,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op300344m,CC1N=C2C(CN3CCOCC3)=CC(Cl)=NN2C=1CC1C(F)=CC(Cl)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op300343q,C1CN2CCC1[C@H](C2)OC(=O)N3CCC4=CC=CC=C4[C@@H]3C5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300342y,CC(C)(CC1=CC=CC(=C1)CC(=O)NCC2=CC(=CC=C2)C3=CC=C(C=C3)O)NC[C@@H](C4=CC(=C(C=C4)O)NS(=O)(=O)C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op300337y,CN1CC[C@@]23C=C[C@@H](C[C@@H]2OC4=C(C=CC(=C34)C1)OC)O,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op300335d,CC(OC1C(OC(C)=O)C(N2C(=O)SC3C=NC(N)=NC2=3)OC1CO)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300331b,CC(N1CCC(C2C=CC(C(NC(N)=N)=O)=CC=2C(F)(F)F)CC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300330f,CC12C(=O)N(CC(F)(F)C)C3C(=NC(C4C=CC(NC(NC5CC5)=O)=CC=4)=NC=3)N1CCOC2,Dmitry Zankov
Organic Process Research & Development,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).",2013,10.1021/op300326b,CC(C)(C#N)C1=CC(=CC(=C1)CN2C=NC=N2)C(C)(C)C#N,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300325f,CC1=C(C=CN=C1CS(=O)C2=NC3=CC=CC=C3N2)OCC(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300323k,CN1CCC(C2C=CC(F)=CC=2)(COCC2C=C(C(F)(F)F)C=C(C3CC3)N=2)CC1,Dmitry Zankov
Organic Process Research & Development,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 .",2013,10.1021/op3003213,CC(CC1NC(C(NC2C(OC)=CC(C(N)=O)=CC=2)=O)C(C2C=CC=C(Cl)C=2F)C11C(=O)NC2C1=CC=C(Cl)C=2)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op3003147,CCN(C)C(=O)OC1=CC=CC(=C1)[C@H](C)N(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3003129,COC1=CC(=NC(=C1SC)/C=N/O)C2=CC=CC=N2,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3003097,CC1C2NN=CC=2C=C(CC(N)C(OC)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3003097,CC1C2NN=CC=2C=C(/C=C(\O)/C(O)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3003097,CC1C2NN=CC=2C=C(CC(NC(N2CCC(C3C(=O)NC4C=CC=CC=4C=3)CC2)=O)C(N2CCN(C3CCN(C)CC3)CC2)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op3003085,C(OCC(O)=O)1C2CCC(O)(COC(N(C3C=CC=CC=3)C3C=CC=CC=3)=O)CC=2C=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op3003085,C1C=CC(COC2C3CCC(O)(CO)CC=3C=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300306c,CC1C(CC(O)=O)=CC2C(=CC(F)=CC=2)C=1CC1C=CC(S(C)(=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300306c,CC(COC(CC1C(C)=C(O)C2C(=CC=C(F)C=2)C=1)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300303p,COC(C1C=C2NC(C3C=CC=CC=3O)=C(C3CCCCC3)C2=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300302s,C1C(C2C=C(O)C=C(C3C=CSC=3)C=2)=CC2OCOC=2C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300302s,CCOC(CCCOC1C=CC=C(CCCCCCBr)C=1CCC(OCC)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2013,10.1021/op300301u,C1CCC(CC1)NC(=O)OC2=CC(=C(C=C2)O)C3=CC(=CC=C3)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.,2012,10.1021/op3002992,CS(=O)(=O)N1CCN(CC1)CC2=CC3=C(S2)C(=NC(=N3)C4=C5C=NNC5=CC=C4)N6CCOCC6,Dmitry Zankov
Organic Process Research & Development,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.,2012,10.1021/op3002992,C1C2N=C(N=C(N3CCOCC3)C=2SC=1)Cl,Dmitry Zankov
Organic Process Research & Development,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.,2012,10.1021/op3002992,CS(N1CCN(CC2SC3C(N4CCOCC4)=NC(Cl)=NC=3C=2)CC1)(=O)=O.CC.CC,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300296t,CC1C2N=C(C3SC=C(C(F)(F)F)N=3)C=C(O[C@H]3CN4C(=O)N(C)CCCCC=C[C@H]5[C@@](C(NS(C6(C)CC6)(=O)=O)=O)(C5)NC(=O)[C@@H]4C3)C=2C=CC=1OC |c:29|,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300294g,CCOC1C=C(C(C)(C)C)N=CC=1C1N(C(N2CCC(CC(N)=O)CC2)=O)C(C2C=CC(Cl)=CC=2)(C)C(C2C=CC(Cl)=CC=2)(C)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op3002883,C1CCN(C2CC(C3SC4C=C(N5N=CC=CC5=O)C=CC=4N=3)C2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3002867,CCOC1=NC2=CC=CC(=C2N1CC3=CC=C(C=C3)C4=CC=CC=C4C5=NOC(=O)N5)C(=O)OCC6=C(OC(=O)O6)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300278c,CC1=NC2=C(C(=N1)N3CCN(CC3)C)N=C(N2C4CCOCC4)C5=CC=CC=C5Cl,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3002728,C1C2=C(CN1C(=O)C3=CC(=C(C=C3)OC(F)F)C#CC4=CC=CC=N4)N=CC=C2,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3002728,C1C=C2C(CNC2)=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300270r,CN1CC2=CC(NC3C(=O)N(C)N=C(Cl)C=3)=NN2CC1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300270r,CN1CC2=CC(N)=NN2CC1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3002678,CC1N(C(C2C(C3N=CC=CN=3)=CC=C(C)C=2)=O)CC(COC2N=CC(F)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.,2012,10.1021/op300263w,C1CN2CCC1(CC2)S,Dmitry Zankov
Organic Process Research & Development,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.,2012,10.1021/op300262z,CC1(CC(=O)C2C(C(F)(F)F)=NN(C3C=CC(C(N)=O)=C(NC4CCC(OC(CN)=O)CC4)C=3)C=2C1)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300260m,CCOC1C=C2N=CC(C#N)=C(Cl)C2=CC=1NC(C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op3002596,CN(CCCC1(OCC2C1=CC=C(C#N)C=2)C1C=CC(F)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2012,10.1021/op300258w,CCCCC(N1CCN(CC2C=CC=CC=2)CC1)C(O)C1C=CC2C(=CC=C(OC)C=2Cl)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300257z,C1CCN(CCCOC2C=CC(CCCCCl)=CC=2)CCC1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300252n,COC1=CC=CC(=C1)NC2=NC=NN3C2=C(C=C3)CN4CC[C@H]([C@@H](C4)O)N,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300252n,COC1C=C(NC2C3N(C=CC=3CO)N=CN=2)C=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300249q,CCCC(C(C1C2C=C(C=C(F)C=2NC=1)C)C1C=CC(Cl)=CC=1)C1C=CC(C(NCCC(O)=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op300237b,CC1C=CC=CC=1N1N=C(C2C(C3C=CC(F)=CC=3)=NN3C=2NCC(CO)C3)C=CC1=O,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op300237b,CC1C=CC=CC=1N1N=C(C(Br)C(C2C=CC(F)=CC=2)=O)C=CC1=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300235t,CC(C(N1CC(OC2N(C)C3N=C(N4C(CC)=NC5C=CC=CC4=5)N=C(N4CCOCC4)C=3N=2)C1)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op3002273, CC1=C(C=CC=C1OC2=CC(=C(C=C2CNC)F)Cl)OC,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300212u,CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300209p,CC1N(C2C=C(Br)C=CC=2O)N=CC=1,Dmitry Zankov
Organic Process Research & Development,"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 .",2012,10.1021/op300198a,CN1C2=C(C(=C(C1=O)F)NC3=C(C=C(C=C3)I)F)C(=O)N(C=N2)C[C@H](CO)O,Dmitry Zankov
Organic Process Research & Development,"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 .",2012,10.1021/op300198a,CN1C(=O)C2C(Cl)=C(F)C(N(C)C=2N=C1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300194c,C1CC(CC(N2C=NC(C(F)(F)F)=C2)C(NC2N=CC(C(O)=O)=CC=2)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300194c,CC(C)(COC(C(N1C=NC(C(F)(F)F)=C1)CC1CCCC1)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2013,10.1021/op300192e,C1=NC(=NC(=O)N1[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O)N,Dmitry Zankov
Organic Process Research & Development,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.,2013,10.1021/op300190s,C(NCC1N=CC(C)=NC=1N)=O,Dmitry Zankov
Organic Process Research & Development,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%.",2012,10.1021/op300188x,CC([Si](OC(C1OC=CC=1)CC=O)(C)C)(C)C,Dmitry Zankov
Organic Process Research & Development,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%.",2012,10.1021/op300188x,CC(C(CCC/C=C/C(O)C1OC=CC=1)=O)C,Dmitry Zankov
Organic Process Research & Development,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%.",2012,10.1021/op300188x,CC(C(CCC/C=C\CC1C(=O)CC(O[Si](C(C)(C)C)(C)C)C=1)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300186p,C1C=CC(COC2C(=O)C=COC=2CC(O)C2C=CC=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op300185s,CC1=NC2=C(C=C1)C(=CC=C2)OCCN3CCC(CC3)CC4=CC5=C(C=C4)OCC(=O)N5,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op300185s,C1C=C2OCC(NC2=CC=1Br)=O,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op300185s,C1C=C2OCC(NC2=CC=1CC1CCNCC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300181r,CCNC(C1C(C)=C2C(NC3C(C)=CC=C(C(NOC)=O)C=3)=NC=NN2C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300181r,CCOC(C1C(C)=C(C(OCC)=O)NC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300179u,CCCCC1N(CC2C=CC(C3C=CC=CC=3C3N=NNN=3)=CC=2)C(CO)=C(Cl)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300174w,C1C=CC(CNC2C(O)CN(CC3C=CC=CC=3)CC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300173z,CC1=C(C2=C(C=CC=C2N1CC(=O)O)NC(=O)C)SC3=CC=C(C=C3)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300171m,C1CN(CCN1CCCCC2=CNC3=C2C=C(C=C3)C#N)C4=CC5=C(C=C4)OC(=C5)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300170q,CC1C=NC(C2C=C(N3CCC(C(N4CCN(C)CC4)=O)CC3)C=CC=2Cl)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300165q,COC1=C(C(=O)C2=CC=CC=C2C1=O)C3CCC(CC3)C4=CC=C(C=C4)Cl,Dmitry Zankov
Organic Process Research & Development,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 ).",2012,10.1021/op300164y,CC(NCCCC1C=C(C(F)(F)F)C=CC=1)C1C2C=CC=CC=2C=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300163n,CC#CCOC1C=CC(C(NC(C(NO)=O)C(C)(N)C)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op3001542,C=CCN(C(C(C1SC=CC=1)1C(CN)C1)=O)CC=C,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op3001492,C1C=CC(C(C2C=CC(=O)N(CCCC3C=C(OCCCC(O)=O)C=CC=3)N=2)C2C=CC=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300147f,C1C=CC(P(S)(C2C=CC=CC=2)=S)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300139g,C1C=C(S(C2CC2)(=O)=O)C=CC=1C(C(NC1N=CC=NC=1)=O)CC1CCOCC1,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op3001383,CC([Si](OCC(CO)CN)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3001355,C1C=C2C(C(CC3C=CC(C4CC4)=CC=3)=CN2C2OC(CO)C(O)C(O)C2O)=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300131e,C[C@H]([C@@H]1[C@@H]2N(C1=O)C(=C(S2)S[C@H]3CC[S@@](=O)C3)C(=O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300130p,C[C@H]([C@@H]1[C@@H]2N(C1=O)C(=C(S2)S[C@H]3CC[S@@](=O)C3)C(=O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300128c,CC1=NC(=NO1)[C@]2(C3=C(C[C@@H](N2)C4=NC=C(N4)C5=CC=C(C=C5)F)C6=CC=CC=C6N3)C7=CN(N=C7)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300126e,CC1C=CC2C(=CC=CC=2N2CCN(CCC3C=C(N4C(=O)NCC4)C=CC=3)CC2)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300120r,CC1C=C(NC2N=C(N3C(C4ON=C(C5N=CC=CN=5)C=4)CCC3)N=C(OC)C=2)NN=1,Dmitry Zankov
Organic Process Research & Development,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 ).",2012,10.1021/op300119s,C1CN(C[C@@H]1C(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)N)CCC4=CC5=C(C=C4)OCC5,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300116j,C/C=C/C1C=C([N+]([O-])=O)C=CC=1OC(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op3000916,C1=CC=C(C=C1)C(C2=CC=C(C=C2)F)(C3=CC=C(C=C3)F)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300084z,C1C2CC3CC1CC(C2)C3(C(=O)O)N,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300077m,CC1=NN=C(O1)C(=O)NC(C)(C)C2=NC(=C(C(=O)N2C)O)C(=O)NCC3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300069n,C=C1OC2(CCCCC2)OC1=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300069n,C1CCC(C(N)CC(O)=O)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300069n,CC(CC(N)CC(O)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300059b,CC(NC(OC(C)(C)C)=O)C(NC(C1N=CC=CC=1)1CC1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300056k,CC1=C(C(=CC=C1)C)NC(=O)CN2CCN(CC2)CC(COC3=CC=CC=C3OC)O,Dmitry Zankov
Organic Process Research & Development,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).",2012,10.1021/op3000543,C1CN2CCC1[C@H](C2)OC(=O)N3CCC4=CC=CC=C4[C@@H]3C5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300053a,C1C=C(S(C2CC2)(=O)=O)C=CC=1C(C(NC1N=CC=NC=1)=O)CC1CCOCC1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300039c,CN(C)CCCC1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300034u,CN(C(C1C=CC=CC=1)CCOC1C2C=CC=CC=2C=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op300031r,CC(O)1CC(N)(C2C=CC(C3C(C4C=CC=CC=4)=CC4N5C(C(F)F)=NN=C5C=CC=4N=3)=CC=2)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op3000306,CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NNN=N3)[C@@H](C(C)C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300026r,CC1=C(C(=CC=C1)C)NC(=O)CN2CCN(CC2)CC(COC3=CC=CC=C3OC)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300021m,C1C=C(N)C(NC(C2C=CC(C3C(C#N)=CC(CN([H])[H])=CN=3)=CC=2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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 .",2012,10.1021/op300017v,CCCCC1=C(C2=C(O1)C=CC(=C2)NS(=O)(=O)C)C(=O)C3=CC=C(C=C3)OCCCN(CCCC)CCCC,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300012d,C1[C@H](COC2=C1C=C(C=C2F)F)N3C(=CNC3=S)CCN,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300012d,C1C(F)=CC(F)=C2C=1CC(N)CO2,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op300009y,C1CN(CCN1CCOCC(=O)O)C(C2=CC=CC=C2)C3=CC=C(C=C3)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op3000064,CN1CC(C2C=CC3SC=CC=3C=2)C2C(=CC(N3CCOCC3)=CC=2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200387s,C1=CC2=C3C4=C1C=CC5=C4C6=C(C=C5)C=CC(=C36)C=C2,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200381w,C1CNC[C@H]([C@@H]1C2=CC=C(C=C2)F)COC3=CC4=C(C=C3)OCO4,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200380z,C1C=CC2C(C3C=C(C(/N=C(\N)/N)=O)C=CC=3C=2C=1)1OCCC1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200378r,C1C=CC(C(NC(C2C(Cl)=CC=C(C(F)(F)F)C=2Cl)=O)C2N3CCC(CC3)C2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op200369v,C(O)C1OC(=O)OC1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op200368m,CCOC(C1C=C(C#N)C(Cl)=NC=1C)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op200368m,CCOC(C1C=C(C#N)C(=O)NC=1C)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op200365n,CCNC(=O)[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=NC3=C(N=C(N=C32)C(=O)NCCNC(=O)NC4CCN(CC4)C5=CC=CC=N5)NCC(C6=CC=CC=C6)C7=CC=CC=C7)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op2003634,C1C=C2N(C(NC2=NC=1)=O)C1CCNCC1,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op200362h,C1C[C@H]2[C@@H](C1)C3=C(C=CC(=C3)O)O[C@H]2C4=CC=C(C=C4)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200360b,C/C=C/1\\[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200357h,C1C=C2C(C(CCO2)=O)=CC=1CCOS(C(F)(F)F)(=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op2003562,COCC(N)C1CC1,Dmitry Zankov
Organic Process Research & Development,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.,2012,10.1021/op200354f,C1CCNC(C1)C(C2=CC(=NC3=C2C=CC=C3C(F)(F)F)C(F)(F)F)O,Dmitry Zankov
Organic Process Research & Development,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).",2012,10.1021/op200351g,CN1C(C2CCNCC2)=NC(C2C=CC(F)=C(C(F)(F)F)C=2)=C1,Dmitry Zankov
Organic Process Research & Development,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).",2012,10.1021/op200351g,C1C=C(C(F)(F)F)C=C(C2N=C(C3CCNCC3)NC=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200346g,C[C@H](/C=C/[C@H](C)C(C)C)[C@H]1CC[C@@H]\\2[C@@]1(CCC/C2=C\\C=C/3\\C[C@H](C[C@@H](C3=C)O)O)C,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200344a,C1=CC(=C(C=C1Cl)Cl)C(=O)NS(=O)(=O)C2=CC=C(S2)Br,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op2003419,C[C@@](C(=O)NC1=C(C=C(C=C1)S(=O)(=O)C2=CC=C(C=C2)C(=O)N(C)C)Cl)(C(F)(F)F)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200340c,C(N)C(CP(O)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2012,10.1021/op200334x,C1=CC2=C(NN=C2N=C1)CN3C4=C(C=N3)C(=C(C=C4)Cl)OC5=CC(=CC(=C5)C#N)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200332p,CNC(C1C=C2CC(N(C3CCN(CC(N4CC5C(CCC5)C4)=O)CC3)C2=CC=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200331s,C1C=C(C)C=CC=1C(OCC1C=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200326s,CCC1=C(C(=CC(=C1)C2=NOC(=N2)C3=CC(=NC(=C3)C)N(CC)CC)C)OC[C@H](CNC(=O)CO)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200326s,CCN(C1C=C(C(O)=O)C=C(C)N=1)CC,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200326s,CCC1C(O)=C(C)C=C(/C(/N)=N/O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200325u,CC(=O)OC1=CC2=C(S1)CCN(C2)C(C3=CC=CC=C3F)C(=O)C4CC4,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2003198,C[C@@H](C1CC1)N2C=C(N=C(C2=O)NC3=C(C=C(C=C3Cl)OC(F)F)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200314z,C1CCC(CC(NC(CNC(COC2C=CC(C3N(C4C=CC(F)=CC=4)C(=O)C3SCC(O)C3C=CC(F)=CC=3)=CC=2)=O)=O)C([O-])=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200313v,COC1=C(C=CC2=C1CC[C@H](CC2)N3CCOCC3)NC4=NC=C(C(=N4)N[C@@H]5[C@@H]6C[C@H]([C@@H]5C(=O)N)C=C6)Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200312m,CN(C)CC/C=C\\1/C2=CC=CC=C2COC3=C1C=C(C=C3)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200310y,C1C=CC2CN(CC(N3CCN(C4C5C(=CC(F)=CC=5)NN=4)CC3)CO)CC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200310y,[H]C(N1CCC(C2C3C(=CC(F)=CC=3)ON=2)CC1)(CO)CN1CC2C=C(F)C=CC=2C1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200309z,C1CN(CC1(F)F)C(=O)[C@@H]2C[C@@H](CN2)N3CCN(CC3)C4=NC=CC=N4,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200306q,CCC1C=CC(CC2C=CC=C(C3OC(O)C(O)C(O)C3O)C=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200305y,C1CC2C=C(C1CC2=O)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200301h,CC1C(NC(COC2C(C(C3C=C(C(F)(F)F)C=C(F)C=3)=O)=CC(Cl)=CC=2)=O)=CC=C(C(O)=O)C=1F,Dmitry Zankov
Organic Process Research & Development,"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.,2012,10.1021/op200299p,CCC(O)(C(F)(F)F)C1N=NN(CC2C=C3C(C(C4C=C(F)C=CC=4)=CC(O3)=O)=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200284m,CN(CCC1NC2C(=CC(CN3N=CN=C3)=CC=2)C=1)C,Dmitry Zankov
Organic Process Research & Development,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%.",2012,10.1021/op2002744,C1C=C(S(Cl)(=O)=O)C(S(C)(=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200264t,CCOC1N2C(=NC(S(Cl)(=O)=O)=N2)C=C(F)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op2002613,CC(C)C[C@@H](/C=C/[C@H](CC1=CC=CC=C1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(=O)OCC3=CC=CC=C3)C(=O)NC4CC(N(C(C4)(C)C)[O])(C)C)NC(=O)OC(C)(C)C,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200259t,CC1C(C(NCCC(N2CCC(N(C(NOC)=O)CC3C=CSC=3)CC2)C)=O)=C(C)N=C(Cl)C=1,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200259t,CC(N1CCC(=O)CC1)CC#N,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200259t,CC1C(C(O)=O)=C(C)N=C(Cl)C=1,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200259t,CONC(OC1C=CC([N+]([O-])=O)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200257g,CC12C(F)3C(C4C(CC3O)(C)C3(OC(OC3C4)C3C=CC(SC4C=C(SC)C=CC=4)=CC=3)C(CO)=O)CC(F)C1=CC(=O)C=C2,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200257g,CSC1C=CC=C(SC2C=CC(C(=O)[H])=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200251c,C1C=C2N(C(C3C=COC=3)=NC2=CC=1C(O)=O)C1CCCCC1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2002497,C#CCCCC1C(O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2002479,CCCC1C(OCC2C=CC(C(O)C3C=C(C#N)C=CC=3)=CC=2)=CC=C(C(C)=O)C=1O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2002408,CC(C)(CC1=CC=CC(=C1)CC(=O)NCC2=CC(=CC=C2)C3=CC=C(C=C3)O)NC[C@@H](C4=CC(=C(C=C4)O)NS(=O)(=O)C)O,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200238p,CNCC1=CC=C(C=C1)C2=C3CCNC(=O)C4=C3C(=CC(=C4)F)N2,Dmitry Zankov
Organic Process Research & Development,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.",2012,10.1021/op200233r,CC(C)(CCC(C1=CC=CC=C1)(C2=CC=CC=C2)C(=O)N)N3CC(C3)OC4=CC=CC(=C4)O,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2002326,CCC[C@@H](C)C[C@@H](CC(=O)O)N,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200229j,CC1=CC(=NN1)NC2=NN3C(=C(N=C3C(=C2)CN4CCOCC4)C)CC5=C(C=C(C=C5)Cl)F,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200229j,CC1N=C2C=CC(Cl)=NN2C=1C(C1C(F)=CC(Cl)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.,2011,10.1021/op200221y,CN(C)CC(C1=CC=C(C=C1)OC)C2(CCCCC2)O,Dmitry Zankov
Organic Process Research & Development,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%.",2011,10.1021/op200207h,C1[C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC2=C(C=CC(=C2)C3=CC1=C(C=C3)O)O)C(=O)O)C[C@H](CN)O)N,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2002003,CC1N=CC(CN)=C(N)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001996,CCc1noc(C2CN=CNC2)n1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200197z,CC(C)(C)C1=CC=C(C=C1)S(=O)(=O)NC2=C(C(=NC(=N2)C3=NC=CC=N3)OCCO)OC4=CC=CC=C4OC,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001904,CC(C)(CC1=CC=CC(=C1)CC(=O)NCC2=CC(=CC=C2)C3=CC=C(C=C3)O)NC[C@@H](C4=CC(=C(C=C4)O)NS(=O)(=O)C)O,Dmitry Zankov
Organic Process Research & Development,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.,2011,10.1021/op200186d,C1CN(CCC1OC2=C(C=CC(=C2)F)Br)C3=NOC(=C3)C4=NN(N=N4)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001854,C1C=CC2ON=C(N3CC4N(CC(COC5C=CC=CC=5)CC4)CC3)C=2C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2001832,CCC[C@@H](C)C[C@@H](CC(=O)O)CN,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200181f, CCOC1=CC=CC=C1O[C@H]([C@@H]2CNCCO2)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200180t,CC1(OB(CC#C[Si](C)(C)C)OC1(C)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200177b,CC(NC(C1C(C2C=CC(C(F)(F)F)=NC=2)(C)C1)=O)C1C=C(F)C(NS(C)(=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200176f,CN1C2=C(C=C(C=C2)N(CCCl)CCCl)N=C1CCCC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200175t,C[C@@H](C(=O)N)NS(=O)(=O)C1=CN=C2N1[C@](C(=O)N2C3=CC(=CC(=C3)Cl)Cl)(C)CC4=CC=C(C=C4)OC(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200174k,CN1C[C@@H]2[C@H](C1)C2CN(CC3=CC(=C(C=C3)F)Cl)C(=O)C4=CN(C=N4)C,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200173g,CN1C(=CC=N1)C2=CC=C(C=C2)SC3=CC=CC(=C3)C4(CCOCC4)C(=O)N,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2001723,C1CN(C(CCOC2C=C(CC(O)=O)C=C(Cl)C=2)2CCN(C3SC4C(C=CC(C(F)(F)F)=N4)N=3)CC2)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200171a,C1C=C(F)C=C(SC2C3C(=CC=CN=3)N([H])C=2C(N)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001673,CC(=O)OCC(C)(C)CN1C2=C(C=C(C=C2)Cl)[C@H](O[C@@H](C1=O)CC(=O)N3CCC(CC3)CC(=O)O)C4=C(C(=CC=C4)OC)OC,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001639,CCC[C@@H](C)C[C@@H](CC(=O)O)N,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200153s,C[C@@H](C(=O)OC[C@@H]1[C@H](C[C@@H](O1)N2C=NC3=C2N=C(NC3=O)N)F)OC(=O)[C@H](C(C)C)N,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2001518,CC(C)NCC(COC1=CC=CC2=CC=CC=C21)O,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2001518,CC(C)NCC(COC1=CC=C(C=C1)CCOC)O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200145j,CC1N(CS(C)(=O)=O)N=C(C2CC2)C=1OC1C=C(C)C(C#N)=C(C)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200140v,CC1C=CC2C(N3CCN(CCC4C=C(N5C(=O)NCC5)C=CC=4)CC3)=CC=CC=2N=1,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200139r,C1CC2C=C(C1CC2=O)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200131n,C[C@H](C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op200129m,CC1N(CC2C=CC(CC(NC(OC(C)(C)C)=O)C(O)=O)=CC=2)C(C)CCC1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001222,C(CCOCC12CC3CC(C1)CC(C3)C2)CCN1C(CO)C(O)C(O)C(O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001194,CC(N1N=C2C(CCNCC2)=C1C1C=CC(F)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.,2011,10.1021/op200112g,CC1(C=CC2=C(O1)C=CC3=C2OC[C@@]4([C@H]3OC5=C4C=CC(=C5)O)O)C,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200108k,CC(N)(CC1C=C(CC(OC)=O)C=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200107g,CC(C)C(=O)OC1=C(C=C(C=C1)CO)[C@H](CCN(C(C)C)C(C)C)C2=CC=CC=C2,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001063,CN1C(=O)C=C(C2C(C(N(C3CC3)CC3C=C(Br)C(C)=C(CCCOC)C=3)=O)CNCC2)C=C1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2001047,CC(CCC1C=CC=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200087f,C[C@]1(C(=O)N(C(=O)N1C)C2=CC(=CC(=C2)Cl)Cl)CC3=CC=C(C=C3)Br,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200087f,C=CCC(N)(C1C=C(C)C=C(C)C=1)C1C=C(C)C=C(C)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200087f,CCOC(C(NC(OC(C)(C)C)=O)C(C1C=CC=CC=1)O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200085k,CCO[C@@H](CC1=CC=C(C=C1)OC)C(=O)OCC,Dmitry Zankov
Organic Process Research & Development,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",2011,10.1021/op200084g,C(C(O)=O)C(C1C=CC=CC=1)N,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200082a,C1CC(NCC2N=CC=CC=2)C(NCC2C=CC=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.,2011,10.1021/op2000805,CC1=CN(C(=O)NC1=O)[C@H]2C[C@@H]([C@H](O2)COC(=O)C3=CN(C=CC3)C)N=[N+]=[N-],Dmitry Zankov
Organic Process Research & Development,"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",2011,10.1021/op200079g,CN1CCN(CC1)CCOC2=CC3=C(C(=C2)OC4CCOCC4)C(=NC=N3)NC5=C(C=CC6=C5OCO6)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2000783,C1C=C(C(N)=O)C2C(=CN(N=2)C2C=CC(C3CNCCC3)=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2000755,C(NC1CC1)1CC1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200068c,CCS(=O)(=O)C1=NC=C(C=C1)OC2=CC(=CC(=C2)C(=O)NC3=NN(C=C3)C)O[C@@H](C)CO.CS(=O)(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200065p,CC1C=C(O)C=C(C)C=1CC(N)C(O)=O,Dmitry Zankov
Organic Process Research & Development,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%.",2011,10.1021/op200051v,CC1=C(C(=O)C(=C(C1=O)OC)OC)CCCCCCCCCCO,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200038y,C=CC1C(N)(C(O)=O)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op2000332,C1C(N)=NC(=O)N(C2SC(CO)OC2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200032b,CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NNN=N3)[C@@H](C(C)C)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200030t,C1C(C2SC=CC=2N)=CC=C(Cl)C=1,Dmitry Zankov
Organic Process Research & Development,"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 .",2011,10.1021/op200021a,C1=CC=C(C=C1)CN2C3=CC(=NC(=C3NC2=O)N)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2000207,COC1=C(C=C2[C@@H]3C[C@@H]([C@H](CN3CCC2=C1)N4C[C@H](CC4=O)CF)N)OC,Dmitry Zankov
Organic Process Research & Development,"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.,2011,10.1021/op200019k,C1C(=O)OCC1CF,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op200016a,C[C@H](C1=CC=CC2=CC=CC=C21)NCCCC3=CC(=CC=C3)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op2000095,CCCCCCCCOC1=C(C=C(C=C1)C2=NN=C(S2)[C@](C)(CO)N)C(F)(F)F.C(=O)(C(F)(F)F)O.C(=O)(C(F)(F)F)O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op200002u,CN(CCN(C1COC2C=CC=CC=2C2N(C3C(C=2C2CCCCC2)=CC=C(C(O)=O)C=3)C1)C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op100335q,CC1N(C2C=CC(F)=CC=2)C(C)=NC=1C#CC1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op100325h,COC(C1C2S(CC(N)(C(OC)=O)C12)(=O)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op100323b,C(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)O/N=C(\C(O)=O)/C1N=C(N)SN=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op100318b,C(C(F)(F)F)(OC(F)F)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op1003117,C1C[C@@H]2C=C(C[C@H]1[NH2+]2)C3=CC4=CC=CC=C4S3,Dmitry Zankov
Organic Process Research & Development,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.,2011,10.1021/op1003083,CCC1=C2C(=CC=C1)C(=CN2)CCO,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op1003055,CC#C[C@@H](CC(=O)O)C1=CC=C(C=C1)OCC2=CC(=CC=C2)C3=CC=C(C=C3)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op1003055,CC#CC(C1C=CC(O)=CC=1)CC(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op1003055,C1C=C(CBr)C=C(C2C=CC(C(F)(F)F)=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op100299d,CC(OC(N1C(C(O)=O)(C)COC1(C)C)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op1002984,C1C=C(Cl)C(CC2SC3C(=C(NC4C=CC(C(F)(F)F)=CC=4)N=CN=3)N=2)=C(Cl)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op100291g,CC1=C(C(=O)C2=C(C1=O)N3CC4C(C3(C2COC(=O)N5CC5)OC)N4C)N,Dmitry Zankov
Organic Process Research & Development,"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.",2011,10.1021/op100288t,COC1C=CC(C(CC2C(Cl)=CN=CC=2Cl)=O)=C2OC(OC=12)1CCCC1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op100286g,C1C(Cl)=CC(Cl)=C(C2C(C#N)=C(N3CCOCC3)SC=2C2NN=CN=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op100286g,CCOC(C1SC(N2CCOCC2)=C(C#N)C=1I)=O,Dmitry Zankov
Organic Process Research & Development,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 .",2011,10.1021/op1002853,C[C@@H]1CCN(CCN1C(=O)C2=C(C=CC(=C2)C)N3N=CC=N3)C4=NC5=C(O4)C=CC(=C5)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op1002775,COCC(N)CCO,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op100270u,CCC(NC1N2C(=C(C3C=CC(OC)=NC=3C)C(C)=N2)N=C(C)N=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100268e,CC1=CC=C(C=C1)CNC(=O)C2=NN(C(=C2C(C)C)CC[C@H](C[C@H](CC(=O)O)O)O)C3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2011,10.1021/op100267p,C1CN(C(C2C=C(F)C(B(O)O)=CC=2)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.,2010,10.1021/op1002598,CC1(CN(CCCOC2C=CC(C3CCN(C(C4C5C=CC=CC=5C(CCC(O)=O)=CC=4)=O)CC3)=CC=2)CCC1)C,Dmitry Zankov
Organic Process Research & Development,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.,2010,10.1021/op1002598,CC(C)1CNCCC1,Dmitry Zankov
Organic Process Research & Development,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.,2010,10.1021/op1002598,C1C(/C=C/C(OCC2C=CC=CC=2)=O)C2C=CC=CC=2C(C(O)=O)=C1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100258j,C1OC(CCCC(N)C(O)=O)OC1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100257r,CC1=NN=C(O1)C(=O)NC(C)(C)C2=NC(=C(C(=O)N2C)[O-])C(=O)NCC3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100251q,CN1CCC[C@@H]1CC2=CNC3=C2C=C(C=C3)CCS(=O)(=O)C4=CC=CC=C4,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100249z,CN1C(CC2C3C=C(Br)C=CC=3NC=2)CCC1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100249z,CN1C(CCC2OCCCO2)CCC1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100249z,CC1(COC(CCC2N(C)CCC2)OC1)C,Dmitry Zankov
Organic Process Research & Development,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.,2011,10.1021/op100247m,CS(OC1CN(CC2C=CC=CC=2)C1)(=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100233f,C1C2CC(OC=2C(C2C(Cl)=CC=CC=2Cl)=CC=1F)CN,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100226k,CC1C=C(C2C3C(=CC=CC=3)C(=O)NN=2)SC=1,Dmitry Zankov
Organic Process Research & Development,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 ).",2010,10.1021/op100225g,CN1C(=O)N(C(=O)[C@]12CN(C[C@H]2C3=CC=C(C=C3)C#N)C4=NC=C(C=C4)C(=O)O)C5=CC(=CC(=C5)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.,2010,10.1021/op100210s,CC1=CN(C=N1)C2=CC=C(C=C2)C3=NC4(CCCC4)N(C3=O)CC(=O)NC5=CC=C(C=C5)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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 .",2010,10.1021/op100205s,CC1C(C2C(=O)N(C)C3N(N=CC=3C=2)C2C(F)=CC=CC=2F)=CC(C(NC2CC2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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 .",2010,10.1021/op100205s,CN1C(=O)C(Br)=CC2C=NN(C3C(F)=CC=CC=3F)C1=2,Dmitry Zankov
Organic Process Research & Development,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 .",2010,10.1021/op100205s,C1C=C(F)C(N2N=CC(C#N)=C2N)=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1002038,CCOC(C)(C(OCCl)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100199t,CCN1C2C(=CC(I)=CC=2)C(=O)C(C(O)=O)=C1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op1001947,C1=CC=C2C(=C1)C(=CN2)C[C@](C[C@@H](C(=O)O)N)(C(=O)O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100186c,C[C@@H](C1=CC=CN2C1=NC(=C2)C3=CC=C(C=C3)C[C@@H](CNC(=O)CN(C)C)NC(=O)C4=CC(=C(C=C4)OC(C)C)Cl)O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100186c,C1C=CC(CC(N)CN2C(=O)C3C=CC=CC=3C2=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100186c,CCCCC[N-]CC(NC(C1C=CC(OC(C)C)=C(Cl)C=1)=O)CC1C=CC(C2N=C3N(C=CC=C3C(O)C)C=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001808,COC(C1NC2C(=C(F)C(Cl)=CC=2)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001808,C1C=C2NC(OC2=C(I)C=1Cl)=O,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100174j,C=CC(NC(OC(C)(C)C)=O)CC1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100174j,CC(OC(NC(C1OC1)CC1C=CC=CC=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100164v,CC(OC(N1C(CO)CC2C(C2)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100164v,CC(OC(C1NC(=O)C2C(C2)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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%.",2010,10.1021/op100163m,CN1CCN(CC1)CCOC2=CC3=C(C(=C2)OC4CCOCC4)C(=NC=N3)NC5=C(C=CC6=C5OCO6)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100161y,CN1CCN(CC1)CCOC2=CC3=C(C(=C2)OC4CCOCC4)C(=NC=N3)NC5=C(C=CC6=C5OCO6)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001512,CC1=CC(=C(N=C1OC(F)F)C)NC2=NC(=CN(C2=O)[C@H](COC)C3CC3)C#N,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001512,CC1=CC(=C(N=C1OC(F)F)C)NC2=NC(=CN(C2=O)[C@H](COC)C3CC3)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001512,CC1C(OC(C(F)(F)F)=O)=NC(C)=C(N)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001512,COCC(N1C(=O)C(Cl)=NC(Cl)=C1)C1CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100147h,CC1C(N2C3C(=C(N4N=C(C)C=C4)C=C(N=3)C)CC2)=CC=C(OC)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100147h,C1C(C2SC=CN=2)=NNC=1,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op1001462,CC1ON=C(NC(CC2C=CC(CC(NCC(O)C3C=NC=CC=3)(C)C)=CC=2)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op1001462,CC1ON=C(NC(CC2C=CC(CC(NCC(O)C3N=CC=CC=3)(C)C)=CC=2)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op1001462,CC(O)(CC1C=CC(CC(O)=O)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op1001462,CC(C1ON=C(NC(CC2C=CC(CC(N)(C)C)=CC=2)=O)C=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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 .,2010,10.1021/op1001462,C1C=CN=C(C2OC2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100141g,CCC1=C2C(=NN1CCOC)C(=O)NC(=N2)C3=C(N=CC(=C3)S(=O)(=O)N4CCN(CC4)CC)OCC,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100139f,COC[C@@]12C[C@@]1(CCNC2)C3=CC(=C(C=C3)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001337,C[C@H](CN1C=NC2=C(N=CN=C21)N)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op1001319,[H][C@]12CC[C@]3(C)[C@@H](O)CC[C@@]3([H])[C@]1([H])[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)Cc4cc(O)ccc24,Dmitry Zankov
Organic Process Research & Development,"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.,2010,10.1021/op1001287,COC1=C2C(=C(C=C1)C3(CCC(CC3)C(=O)O)C#N)OCCO2,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100124x,C1C=C(C2C3C(=CC=CN=3)C=C(C3CCC(C(O)=O)CC3)N=2)C=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100121s,CC1=C(C=CC(=C1)F)[C@H]2C[C@H](CCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C(=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1001148,CCN1C2=NC=C(C(=C2C=N1)NC3CCOCC3)C4=NN=C(O4)CC5=C(N=C(S5)C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100113j,C1C=C2N(S(N(C3C(F)=CC=CC=3F)C2=CC=1)(=O)=O)CCN1CCN([H])CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100112r,CC/C(/C1C=CC=CC=1)=C(/C1C=CC(/C=C/C(O)=O)=CC=1)\C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100104z,CN1C2(C(C3C=CC(C#N)=CC=3)CN(C3C=CC(C(O)=O)=CN=3)C2)C(=O)N(C2C=C(Cl)C=C(Cl)C=2)C1=O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100103v,CC1N=C2C=CC=C(N3CCN(CCC4C5OCC6N(C=5C=CC=4)C=NC=6C(N)=O)CC3)C2=CC=1,Dmitry Zankov
Organic Process Research & Development,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).",2010,10.1021/op100101q,CN1N=CC(C2C=NC3/C=C\C4C=CC(NS(N(CC5OCCOC5)C)(=O)=O)=CC=4C(=O)C=3C=2)=C1,Dmitry Zankov
Organic Process Research & Development,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).",2010,10.1021/op100101q,CN(S(N)(=O)=O)CC1OCCOC1,Dmitry Zankov
Organic Process Research & Development,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).",2010,10.1021/op100101q,CNCC1OCCOC1,Dmitry Zankov
Organic Process Research & Development,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).",2010,10.1021/op100101q,C1C2/C=C\C3C(C(=O)C=2C=C(Br)C=1)=CC(Cl)=CN=3,Dmitry Zankov
Organic Process Research & Development,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).",2010,10.1021/op100101q,CC1(OB(C2C=NN(C)C=2)OC1(C)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1000989,CCCN[C@H]1CCC2=C(C1)SC(=N2)N,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100097c,CC(O)C1C(=O)N2C1C1C(=C2C(O)=O)/C(=C/C2C=CN=CC=2)/CCC1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100090j,CC(C)(C1=CC=C(C=C1)C(CCCN2CCC(CC2)C(C3=CC=CC=C3)(C4=CC=CC=C4)O)O)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100084r,CN(CC1CNC2C(=CC(Cl)=CC=2)C1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100084r,CN(CC1CN(C(C(NC(C2CCN(C(C3N(C)C4C=CC=CC=4C=3)=O)CC2)=O)CC2C3C=CC=CC=3NC=2)=O)C2C(=CC(Cl)=CC=2)C1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100084r,CN(CC1CN(C(C(N)CC2C3C=CC=CC=3NC=2)=O)C2C(=CC(Cl)=CC=2)C1)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100082w,CC1(OC2C3C(C=CC=2C1)=CC=CC=3)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100072y,C1C=C(CC2C=C(Cl)C=CC=2OCC2C(F)=CC(Cl)=CC=2)N=C(C(O)=O)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100070d,C=CC1C(N)(C(OC)=O)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op1000622,CC1=C(C=CC(=C1)F)[C@H]2C[C@H](CCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CCN(CC4)C(=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op1000594,CCOC(C(P(OC)(OC)=O)NC(C)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100055f,CC(CCC1C=C(C(F)(F)F)C=CC=1CNC(NC1C2C=NN(C)C=2C=CC=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100053k,COC1=CC=C(C=C1)CC2=C(NN=C2O[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)F)O)O)C(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100049t,C1C=C2C(COC2=O)=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,"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) .",2010,10.1021/op1000447,COC(C1C(C2C=CC(F)=CC=2)CC(=O)NC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100036c,CC1=C(C2=CC3=NC(=CC4=NC(=CC5=C(C(=C(N5)C=C1N2)C=C)C)C(=C4CCC(=O)[O-])C)C(=C3C)CCC(=O)[O-])C=C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100036c,CC1C(C(C)=O)=C(I)NC=1CC1NC(I)=C(C)C=1C(C)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100020z,CC1C(C(N2CC3C(CN(C3)CCC(NC(C3COCC3)=O)C3C=C(F)C=CC=3)C2)=O)=C(C)N=CN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100020z,CC(OC(NC(C1C=C(F)C=CC=1)CC=O)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100020z,CCOC(CC(N)C1C=C(F)C=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2010,10.1021/op100020z,CC1C(C(N2CC3C(=CNC=3)C2)=O)=C(C)N=CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100018r,CNS(=O)(=O)CCC1=CC2=C(C=C1)NC=C2C3CCN(CC3)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100010n,CC(C)C1=NC(=NC(=C1/C=C/[C@H](C[C@H](CC(=O)O)O)O)C2=CC=C(C=C2)F)N(C)C3=NC=NN3C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100010n,CC(C)C1N=C(Cl)N=C(C2C=CC(F)=CC=2)C=1C(OC)=O,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100008m,CC(C1N=CC=C2N3C(=C(SC4C=C(Cl)C(Cl)=CC=4)C=12)C(CC(O)=O)CC3)C,Dmitry Zankov
Organic Process Research & Development,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.",2010,10.1021/op100008m,CC(/C(/C1C=C(C(OC)=O)NC=1)=N\CC(OC)OC)C,Dmitry Zankov
Organic Process Research & Development,"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",2006,10.1021/op068010t,C(/N)(\N)=C(\[N+]([O-])=O)/[N+]([O-])=O,Dmitry Zankov
Organic Process Research & Development,"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).",2006,10.1021/op068009u,C1=CC=C(C=C1)C2=NC(C(=O)NC3=C2C=C(C=C3)Cl)O,Dmitry Zankov
Organic Process Research & Development,"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).",2006,10.1021/op068009u,C1=CC=C(C(=C1)C2=NC(C(=O)NC3=C2C=C(C=C3)Cl)O)Cl,Dmitry Zankov
Organic Process Research & Development,"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%.,2007,10.1021/op060245h,CC1NC2C=CC3OC45N(CCCC4)CCCC5CC=3C=2C=1C(OC(C1C=CC(F)=CC=1)C)=O,Dmitry Zankov
Organic Process Research & Development,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 .",2007,10.1021/op060244p,CCCCN(CCCC)CC(C1=CC(=CC\\2=C1C3=C(/C2=C/C4=CC=C(C=C4)Cl)C=C(C=C3)Cl)Cl)O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060241c,C1C=C(C2C=NC(Cl)=NC=2)N=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op060239l,CC1=C(ON=C1N)C,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op0602371,C1CCN(CC(C2C=CC=CC=2)NCCCNC(C2C=CC=CC=2)CN2CCCCC2)CC1,Dmitry Zankov
Organic Process Research & Development,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%.",2007,10.1021/op060231b,C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C)O)CC[C@@H]4[C@@]3(COC(=O)C4)C,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060228s,COC1C=CC2C(N)CCC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060228s,CC(C)(C)C1=CC2=C(C=C1)[C@@H](CC2)NC(=O)NC3=CC=CC4=C3C=NN4,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op0602268,CCCC1C(OCC2C=CC(C(O)C3C=C(C#N)C=CC=3)=CC=2)=CC=C(C(C)=O)C=1O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op0602268,CCCC1C(OCC2C=CC(C(OC(C)=O)C3C=C(C#N)C=CC=3)=CC=2)=CC=C(C(C)=O)C=1O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op0602268,CC([Si](OCC1C=CC(C(O)C2C=C(C#N)C=CC=2)=CC=1)(C)C)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op060225f,C1[C@H]([C@H]2[C@@H]([C@H]2[C@@]1(C(=O)O)N)C(=O)O)F,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op060223v,C1C=CN=C(C(NC2C3NC4C(C=3CCC2)=CC(Cl)=CC=4)=O)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0602223,COC1=CN=C(N2C1=NC(=N2)NS(=O)(=O)C3=C(C=CC=C3OCC(F)F)C(F)(F)F)OC,Dmitry Zankov
Organic Process Research & Development,"<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 ).",2006,10.1021/op060210h,C1C=C(O)C2NC=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,"<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 ).",2006,10.1021/op060210h,CC(N)CC1C2C=CC=C(OCC3C=CC=CC=3)C=2NC=1,Dmitry Zankov
Organic Process Research & Development,"<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 ).",2006,10.1021/op060210h,CC1C([N+]([O-])=O)=C(O)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"<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 ).",2006,10.1021/op060210h,CCN(C(COC1C2NC=C(CC(N)=C)C=2C=CC=1)=O)CC,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060208q,CCCCCCCCCCC[C@@H](C[C@H]1[C@@H](C(=O)O1)CCCCCC)OC(=O)[C@H](CC(C)C)NC=O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060207y,CC1C2C(NC=NC=2NC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060207y,C(C(N)=O)/C(/N)=C(\C(O)=O)/C#N,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060204l,CC(=C)[C@H]1C(=O)C2=C3N1C4=C(C3=CC5=C2[C@H]([C@H]6C5=CC(OC6(C)C)(C)C)O)C[C@H]7[C@]4([C@]8(CC[C@@H]([C@@]([C@@H]8CC7)(C)/C=C/C=C(\\C)/C(=O)O)O)C)C,Dmitry Zankov
Organic Process Research & Development,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).",2006,10.1021/op060200g,CCCC1=NC2=C(N1CC3=CC=C(C=C3)C4=CC=CC=C4C(=O)O)C=C(C=C2C)C5=NC6=CC=CC=C6N5C,Dmitry Zankov
Organic Process Research & Development,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.,2006,10.1021/op060199l,CCCC[C@H](CO)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op0601924,CC(C)NC1=NC(=CS1)C2=NC3=C(C=CC(=C3)OC)C(=C2)O[C@@H]4C[C@H]5C(=O)N[C@@]6(C[C@H]6/C=C\\CCCCC[C@@H](C(=O)N5C4)NC(=O)OC7CCCC7)C(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op0601924,C=CCCCCCC(NC(C)=O)C(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060191b,CC(C)N1C2=CC=CC=C2C(=C1/C=C/[C@@H](C[C@@H](CC(=O)O)O)O)C3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060180i,C[C@@H](CNS(=O)(=O)C(C)C)C1=CC=C(C=C1)C2=CC=C(C=C2)CCNS(=O)(=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2007,10.1021/op060171+,CC(C(O)(C1N=CNC=1)C1C=CC2C=C(OC)C=CC=2C=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0601621,CC1=C(N=C(O1)C2=CC=CC=C2)CCOC3=CC=CC4=C3C=NN4CCC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060158p,CC1CC(=O)NC2=NN(C(=O)C=12)C1C=CC(C(O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.,2006,10.1021/op0601565,C1C=CC2N(C(N(CCCN)C=2C=1)=O)C1CCN(C(NC(C2C=CC=CC=2)C2C=CC=CC=2)=S)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0601518,COC1C=C(OC)N2C(=NC(N)=N2)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op0601464,CC1C=C(O)C=C(C)C=1CC(NC(OC(C)(C)C)=O)C(NC(CO)CNCCCC1C=CC=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060130d,CCCCC1OC(C(Br)2CC2)=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060130d,CCCCC1OC(C(C(CP(OC)(OC)=O)=O)2CC2)=NC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060128m,CC1C(C2C=C(N3CCOCC3)N=CC=2N(C(C(C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(C)C)=O)C)=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060128m,CC1C(C2C=C(N3CCOCC3)N=CC=2N(C(C(C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(C)C)=O)C)=CC=C(NC)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060128m,CC1C(C2C(C(N)=O)=CN=C(N3CCOCC3)C=2)=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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 .",2006,10.1021/op060118l,CN(CCC(O)C1SC=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060114g,CN1CC(C(OC)=O)C(C2C=CC(Cl)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060104f,CCC1N(C)C(C(OCC)=O)=C(C2C=CC(Br)=CC=2)C=1C#N,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060104f,CCOC(C1C(C2C=CC=CC=2)=C(C(OCC)=O)NC=1C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060104f,CCOC(/C(/C(C1C=CC(Br)=CC=1)=O)=N\O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060104f,CCC(CC1N=C(N)C(C(CC)=O)=C(CC)C=1C#N)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060104f,CC/C(/CC#N)=N/NC1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060099f,C1C=C2C3CCNC(C4C=C5CCOC5=CC=4)C=3NC2=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060099f,C1C=C2C(C3CN(C4N=CC(C5N=CC=CC=5)=CN=4)C(C4C=C5CCOC5=CC=4)C=3NC2=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060099f,C1C=CC2NC3C(C4C=C5CCOC5=CC=4)N(C4N=CC=CC=4)CC=3C(=O)C=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600963,C1C=CC2C(OC(=O)C=2C=1)1CCN(C(NC2C=NC(C3C=CC=CC=3)=CN=2)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600916,CCOC(=O)/C=C/[C@H](C[C@@H]1CCNC1=O)NC(=O)[C@H](CC#C)N2C=CC=C(C2=O)NC(=O)C3=NOC(=C3)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600916,C#CCC(N1C(=O)C(NC(C2C=C(C)ON=2)=O)=CC=C1)C(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2007,10.1021/op060087u,CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC,Dmitry Zankov
Organic Process Research & Development,"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 .",2006,10.1021/op060083p,CN(C1CCCC1)C(=O)[C@H](CC2=CC=C(C=C2)/C(=N/N)/N)NS(=O)(=O)C3=CC4=CC=CC=C4C=C3,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600761,CC1C=C(C)N2C(=NC(CC3C(=O)OC(C4CCCC4)(CCC4C=C(F)C(C(C#N)(C)C)=CC=4)CC=3O)=N2)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600761,CC(C1C(F)=CC(C#CC(O)(C2CCCC2)CC2OC(C)(C)OC(=O)C=2)=CC=1)(C#N)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600714,C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)CNS(=O)(=O)N)C(=O)O)[C@@H](C)O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060068k,C1C=CC2N(C3CCN(CC4N=CC=CC=4)CC3)C=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060057r,C1C=C(C#N)C=C(C2C(C(OCC=C)=O)C(O)(C(F)(F)F)NC3CCCC(=O)C2=3)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600557,C1C(CN1C2=C(C=C3C(=C2Cl)N(C=C(C3=O)C(=O)O)C4=C(C=C(C(=N4)N)F)F)F)O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600557,CCOC(C1C(=O)C2C(=CC(N3CC(OC(C(C)C)=O)C3)=C(F)C=2)N(C2C(F)=CC(F)=C(N)N=2)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060054e,CCOC(C1C(=O)C2C(=CC(N3CCC3)=C(F)C=2)N(C2C(F)=CC(F)=C(N)N=2)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060049a,CC1C(CBr)=CC2C(N(C(C)=NC=2C=1)COC(C(C)(C)C)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060044d,CC(COC(C1C=CC2N=C(N)C=CC=2C=1)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060042t,CC(S(N1C(N)=NC2C1=CC(C1N=C(C3C(F)=CC=CC=3F)NC=1C1C=CC=CC=1)=CC=2)(=O)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0600299,COC1C(NC(N)=O)C2C(C(O)C(O2)N2C(=O)N=C(N)C=C2)OC1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060016v,CC(C)(CCOC1=C(C=NN(C1=O)C2=CC(=C(C=C2)F)F)C3=CC=C(C=C3)S(=O)(=O)C)O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060014a,CC[C@@H]1C[C@@H](C2=C(N1C(=O)OCC)C=CC(=C2)C(F)(F)F)N(CC3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C(=O)OC,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op060013i,CC[C@@H]1C[C@@H](C2=C(N1C(=O)OCC)C=CC(=C2)C(F)(F)F)N(CC3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C(=O)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op060003h,C1CN(CC=C1C2=C(C=C(C=C2F)N3C[C@@H](OC3=O)COC4=NOC=C4)F)C(=O)[C@H](CO)O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op058000c,C1C[C@@H](C(=O)N(C1)[P@](=O)(N)NS(=O)(=O)O)N,Dmitry Zankov
Organic Process Research & Development,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.,2006,10.1021/op050264b,C1=COC(=C1)[C@@H](CN)O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op050263j,C(C1C=CC=CC=1)1OC(C2C=CC=C3C=2C=CC=C3)OC1=O,Dmitry Zankov
Organic Process Research & Development,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 .",2006,10.1021/op0502607,CC(C(NC(C(NC(NCCC1C=CC=CC=1)=O)1CC2C3C=CC=CC=3NC=2CC1)=O)C(N)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op050257n,CCOC(CC(O)CC#N)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op0502553,CC1C=CC(C(C2NC(C(O)C3C=CC(C)=CC=3)=CC=2)C2NC(C(O)C3C=CC(C)=CC=3)=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op050251y,C1COCCN1CC2=CC3=C4C(=C2)C(=O)C(=CN4C(=C3)CCO)C(=O)NCC5=CC=C(C=C5)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0502506,CC(C)(C(=O)N[C@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@](C3)(CC4=CC=CC=C4)C(=O)N(C)N(C)C)N,Dmitry Zankov
Organic Process Research & Development,"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 .",2006,10.1021/op050242p,CC1C2C(=CC(OC)=CC=2)OC(=O)C=1C1C=CC(OC)=CC=1OC,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0502396,CC1=C(C2=C(S1)C=C(C=C2)OC3=C4C(=NC=C3)C=C(S4)C5=NC=CN5C)C(=O)NC,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op0502250,CCN1C(CN2C(C3SC=CN=3)=NC=C2)=NC2C=CN=CC1=2,Dmitry Zankov
Organic Process Research & Development,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.,2006,10.1021/op050223f,COC1=C(C=C(C=C1)C2=CC3=C(C=C2)C=C(C=C3)C(=O)O)C45CC6CC(C4)CC(C6)C5,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op050218b,C1CN2C(=CC(C=O)=N2)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op050217j,CC1(OB(C2C=CC(F)=C(C3C=CC(F)=CC=3C#N)C=2)OC1(C)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050213e,C1C2C(N)C(C(C3C=CC=CC=3)C3C=CC=CC=3)N(CC2)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op0502093,CCC1C=C2C(CC(N)C2)=CC=1CC,Dmitry Zankov
Organic Process Research & Development,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.,2006,10.1021/op050208a,CC1=C(C2=C(N1)C=CC(=C2)S(=O)(=O)C3=CC=CC4=CC=CC=C43)CCN,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op050207i,CC(=O)NC[C@H]1CN(C(=O)O1)C2=CC(=C(C(=C2)F)N3CCS(=O)(=O)CC3)F,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op050202l,CC1N=C(NC(NC2C(CN3CC(CC4C=CC(F)=CC=4)CCC3)CCCC2)=O)SC=1C(C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op050202l,C1C=CC(C(NC2C(C=O)CCCC2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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).",2006,10.1021/op0501904,C1C=C(OC2C=CC(Cl)=CC=2O)C(Cl)=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0501895,C[C@H](C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)O[C@@H]2[C@@H](N(CCO2)CC3=NNC(=O)N3)C4=CC=C(C=C4)F,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050186s,CC1(COC(=O)[C@@H]1O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2006,10.1021/op050182n,CC(C)C[C@H](C1(CCC1)C2=CC=C(C=C2)Cl)N(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2006,10.1021/op0501747,CCCN1C[C@@H](C[C@H]2[C@H]1CC3=CNC4=CC=CC2=C34)CSC,Dmitry Zankov
Organic Process Research & Development,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%.",2005,10.1021/op050165y,CCCC[C@@H](CC(=O)NC(=O)[C@H]1CCCN1C2=[N+](C=C(C=C2)F)[O-])N(C=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0501601,CC(C1C=CC(NC2N=CC(C3C=C4C(C=CN=C4)=CC=3)=C3C=2C=CC=C3)=CC=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0501601,CC(C1N=CC(N)=CN=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0501601,CC(C1N=CC(NC2N=CC(C3C=C4C(C=CN=C4)=CC=3)=C3C=2C=CC=C3)=CN=1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050151s,CC1(S(=O)(=O)C2N(C(C2CO)=O)C1C(OCOC(OC1CCOCC1)=O)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050151s,CC(OC(C1N2C(C(C2=O)CO)S(=O)(=O)C1(C)C)=O)OC(C1C=CC=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050137f,C/C(=C\\C=C\\C(=C\\C=C\\C(=C\\C=C\\C=C(\\C=C\\C=C(\\C=C\\C=C(\\CC/C=C(/CO)\\C)/C)/C)/C)\\C)\\C)/CC/C=C(/CO)\\C,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050137f,C/C(/CC/C=C(/C(OC)=O)\C)=C\CP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050129z,C1CC(=O)NC(=O)C1N2C(=O)C3=CC=CC=C3C2=O,Dmitry Zankov
Organic Process Research & Development,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.,2005,10.1021/op0501287,C1C(C#CC(C(F)(F)F)2NC(=O)NC3C2=CC(Cl)=CC=3)C1,Dmitry Zankov
Organic Process Research & Development,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).",2006,10.1021/op050122h,C/C(/N(C)C)=N\C1C=C(CNC)C=CC=1,Dmitry Zankov
Organic Process Research & Development,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).",2006,10.1021/op050122h,CC1C(OC)=C(OC)C=C2NC(N(CC3C=CC=C(/N=C(/N(C)C)\C)C=3)C)=NC(=O)C=12,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050116l,CC(S(C)(=O)=O)(C1C=C(C2C=C(C=O)C=CC=2)C2N=CC=CC=2C=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050116l,CC1N=C(/C(/C2C=CC(S(C)(=O)=O)=CC=2)=C/C2C=CC=C(C3C4C(=CC=CN=4)C=C(C(S(C)(=O)=O)(C)C)C=3)C=2)ON=1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0501085,CC(C(O)=O)C1NC(=O)C1C(O[Si](C(C)(C)C)(C)C)C,Dmitry Zankov
Organic Process Research & Development,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%.,2005,10.1021/op050106k,COC(/C=C/C1C=NC=NC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050102f,CC1C=CC(S(NC(C(C2C3C(=CC(C(=O)O)=CC=3)N(C)C=2)C2C=C3OCOC3=CC=2)=O)(=O)=O)=C(OC)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050102f,CC1C=CC(S(NC(C(C2C3C(=CC(CO)=CC=3)N(C)C=2)C2C=C3OCOC3=CC=2)=O)(=O)=O)=C(OC)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op0500988,CCCCCC[C@@H](CCC)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050096n,C(CC(N)C(O)=O)CCB(O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050087e,CC1CC(C)(C)C(CC2NC=CC=2)N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050087e,CC(CC(C([N+]([O-])=O)CC1NC=CC=1)(C)C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050080x,CCOC(=O)C1=CN=C(C=C1)C#CC2=CC3=C(C=C2)SCCC3(C)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2005,10.1021/op050079y,C1C=CC2NC3C(C4C=C5CCOC5=CC=4)NCC=3C(=O)C=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0500786,C1CN2C(=NN=C2C(F)(F)F)CN1C(=O)C[C@@H](CC3=CC(=C(C=C3F)F)F)N,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0500786,C1NCC2=NN=C(C(F)(F)F)N2C1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0500786,COC(CC(NOCC1C=CC=CC=1)CC1C(F)=CC(F)=C(F)C=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050076l,CC(OC(NC(C(O)=O)C(O)C1CCCCC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.,2005,10.1021/op0500741,CC(C)S(=O)(=O)NC[C@@](C)(C1=CC=C(C=C1)C2=CC=C(C=C2)C(=O)NC)F,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050072g,CC1C=CC2C(=CC=C(C=2)C)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050066k,CCCOC1CCC(C(N(S(C2C=CC(OCC)=CC=2)(=O)=O)CC2C=CN=CC=2)C(NO)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050065s,COC1C=C2C=C3N(C2=CC=1)CCC3,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050065s,CCOC1C=C2C=C3N(C2=CC=1)CCC3,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0500638,C1CCCC(CC1)CNC(=O)C2=CC3=C(C=C2C(=O)N[C@@H](CC4=CC=CC=C4F)C(=O)NC5=CC(=CC(=C5)C(=O)[O-])C(=O)[O-])N=CN3,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050061n,CC1=NC2=C(N1)CCN(C3=CC=CC=C32)C(=O)C4=CC=C(C=C4)NC(=O)C5=CC=CC=C5C6=CC=CC=C6,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050059w,CC(C)(CC[C@H](C[C@@H]([C@H](CC1=CC(=CC=C1)F)NC(=O)C2=NC3=CC=CC=C3N=C2)O)C(=O)N)O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op0500436,CC1C=CC(C(OCC2OC(Cl)CC2OC(C2C=CC(C)=CC=2)=O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050039u,CC1=NC=C(C=C1)OC2=C(C=C(C=C2)NC3=NC=NC4=C3C=C(C=C4)/C=C/CNC(=O)COC)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op050026g,CC(OC(NC(C(O)=O)CC1C=CC2C(=CC=CC=2)C=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050024w,CC1=CC(=C(C=C1)O)[C@H](CCN(C(C)C)C(C)C)C2=CC=CC=C2,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050024w,CC(N(CCC(C1C(O)=CC=C(C)C=1)C1C=CC=CC=1)CCC(C1C(O)=CC=C(C)C=1)C1C=CC=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2005,10.1021/op050019s,CC(OC1OCCN(CC2NN=NC=2CN(C)C)C1C1C=CC(F)=CC=1)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050012a,CCOC(CC(C1C(Cl)=NC(Cl)=C(F)C=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op050009r,CC(C1C(C)2C(C3C(CC2)C(C)2C(CC(O)CC2OC(C)=O)=CC=3)CC1)CCCC(OC(C)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0499775,C1C=C(OCCNCC(O)C2C=NC(N)=CC=2)C=CC=1CC([O-])=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0499728,C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)CNS(=O)(=O)N)C(=O)O)[C@@H](C)O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049969o,C1C=C(OCCNCC(O)C2C=NC(N)=CC=2)C=CC=1CC([O-])=O,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op049968w,C1C(C(O)=O)=CC(O)=CC=1NC1NCC(O)CN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op049965j,C1CN(CCN1C2=CC=C(C=C2)[N+](=O)[O-])C3(C(=O)NC(=O)NC3=O)C4=CC=C(C=C4)C5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op049961e,CCCC1CCC(C(CO)CO)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049954q,CC(C(C(NO)=O)CS(N1CC/C(=N/OC2C=CC(C#N)=CC=2)/CC1)(=O)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op049953y,C1=CC=C(C=C1)CCOCCCS(=O)(=O)CCNCCC2=C3C(=C(C=C2)O)NC(=O)S3,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op049953y,C1C(CCN)=C2SC(NC2=C(O)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049951d,C1=CC=C2C(=C1)N=CC(=N2)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049950l,CC1C(O)C(C)C(=O)OC1,Dmitry Zankov
Organic Process Research & Development,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.,2004,10.1021/op0499371,C1[C@@H]([C@H](O[C@H]1N2C=CC(=NC2=O)N)CO)O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0499369,CCOC(C1OC2C(=CC(F)=CC=2Br)C(=O)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0499369,CN1CCN(C2C=C(F)C=C3C(C=C(OC=23)C(O)=O)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049935g,C#CC1C=C(C2C3C=C(C(O)(C4N(C)C=NC=4)C4C=CC(Cl)=CC=4)C=CC=3N(C)C(=O)C=2)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op049933w,CC1C(NC(CN2CCN([H])CC2)=O)=C(C)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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).",2004,10.1021/op049920i,C1C(=C(N2[C@H](S1)[C@@H](C2=O)NC(=O)/C(=N\O)/C3=CSC(=N3)N)C(=O)O)SCSC4=NNN=C4,Dmitry Zankov
Organic Process Research & Development,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.,2004,10.1021/op049914m,CN1C(=NN=N1)SCC2=C(N3[C@@H]([C@@](C3=O)(NC(=O)C4SC(=C(C(=O)N)C(=O)[O-])S4)OC)SC2)C(=O)[O-],Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049913u,CO/N=C1/C(CN)CNC/1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049909i,CC1=C(C(C[C@@H](C1=O)O)(C)C)/C=C/C(=C/C=C/C(=C/C=C/C=C(/C=C/C=C(/C=C/C2=C(C(=O)[C@H](CC2(C)C)O)C)\C)\C)/C)/C,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049908q,CC(C1C(C)2C(C3C(CC2)C(C)2C(CC(O)CC2O)=CC3)CC1)CCCC(O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0499021,CNC1=CC=CC(=N1)CCOC2=CC3=C(C[C@H](C(=O)N(C3)CC(F)(F)F)CC(=O)O)C=C2,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049899l,C1C=CC2N(C(CN3C(=O)N(C4CC4)C4C3=CN=CC=4)=NC=2C=1)CCCCO,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049899l,C1C(NC2C=CN=CC=2[N+]([O-])=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049889k,COC1=CC=CC2=C1[C@@H]3CN(C[C@@H]3CO2)CCCCN4C(=O)C5=C(C6=NC(=CN=C6S5)C7=CC=CC=C7)NC4=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049889k,COC(C1SC2C(=NC(C3C=CC=CC=3)=CN=2)C=1N=C=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049869i,CC1=CC=CC=C1S(=O)(=O)NC(=O)C2=CC(=C(C=C2)CC3=CN(C4=C3C=C(C=C4)NC(=O)OC5CCCC5)C)OC,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049867y,C1CSC2=C(N1CC3=CN=C4C(=N3)C(=NC(=N4)N)N)C=CC(=C2)C(=O)N[C@@H](CCCC(=O)O)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op049860g,CC(N1CCC(=O)CC1)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0498363,COC1C2CCC(N)CC=2C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op049829e,C[C@@H](C(=O)N[C@]1(CC[C@@H]2[C@H]1[C@H]2C(=O)O)C(=O)O)N,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op049822x,C[C@@H]([C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H](C[C@@H](C3=C)O)O)C)OCCC(C)(C)O,Dmitry Zankov
Organic Process Research & Development,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.,2004,10.1021/op0498114,COC1C=C2C(N=C(N3CC4N=CN=C(N5CCOCC5)C=4CC3)NC2=CC=1OC)=O,Dmitry Zankov
Organic Process Research & Development,"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 ).",2004,10.1021/op049809c,CC(C1N(CCC2OC3C=CC(C4C=CC(C#N)=CC=4)=CC=3C=2)CCC1)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op049808k,CC1C(NC)CN(CC2C=CC=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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 .",2005,10.1021/op049807s,C[C@H]1[C@@H](OC(=O)[C@@H]([C@H]1O)C)C[C@@H](/C=C\[C@H](C)[C@@H]([C@@H](C)/C=C(/C)\C[C@H](C)[C@H]([C@H](C)[C@H]([C@@H](C)/C=C\C=C)OC(=O)N)O)O)O,Dmitry Zankov
Organic Process Research & Development,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 .",2005,10.1021/op049807s,CC(C(O[Si](C(C)(C)C)(C)C)C(C(N(OC)C)=O)C)C(C)=O,Dmitry Zankov
Organic Process Research & Development,"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).",2004,10.1021/op049804f,CC(OC(NC1SC=C(/C(/C([O-])=O)=N/OC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0498013,C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-],Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op049800a,C[C@H]1[C@@H](OC(=O)[C@@H]([C@H]1O)C)C[C@@H](/C=C\[C@H](C)[C@@H]([C@@H](C)/C=C(/C)\C[C@H](C)[C@H]([C@H](C)[C@H]([C@@H](C)/C=C\C=C)OC(=O)N)O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op049799f,CCN(CCCCCC(C)(C)F)CCC[C@@H](C1=CC=C(C=C1)NS(=O)(=O)C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op0497916,CCCCOCCOC1=CC=C(C=C1)C2=CC3=C(C=C2)N(CCC(=C3)C(=O)NC4=CC=C(C=C4)CN(C)C5CCOCC5)CCC,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op0497862,CCCCCOC1C=CC(C2ON=C(C3C=CC(C(ON4N=NC5C=CC=CC4=5)=O)=CC=3)C=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op0497815,CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C\C(=O)O)/C)/C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op049779d,CC1=CN=C(C(=C1OC)C)C[S@](=O)C2=NC3=C(N2)C=C(C=C3)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2005,10.1021/op049777t,CC(C1N=C(OC)CN=C1OC)C,Dmitry Zankov
Organic Process Research & Development,"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 .",2005,10.1021/op049768k,C1NCC(O)C1CO,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op049760a,C1C2=CC=CC=C2N(C3=CC=CC=C3C1=O)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op049760a,COC(N(C1C=CC=CC=1CC(O)=O)C1C=CC=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op040204q,CC1(OC2C(CNC2)O1)C,Dmitry Zankov
Organic Process Research & Development,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.,2004,10.1021/op0402026,CN1CCC2=CC(=C(C=C2[C@@H]3[C@@H]1CCC4=CC=CC=C34)O)Cl,Dmitry Zankov
Organic Process Research & Development,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.,2004,10.1021/op0402026,CNC1C(O)CCC2C1=CC=CC=2,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op040019c,CCCC1=NN(C2=C1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N4CCN(CC4)C)OCC)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op040019c,CCCC1=NC(=C2N1N=C(NC2=O)C3=C(C=CC(=C3)S(=O)(=O)N4CCN(CC4)CC)OCC)C,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op040019c,CN1CC(=O)N2[C@@H](C1=O)CC3=C([C@H]2C4=CC5=C(C=C4)OCO5)NC6=CC=CC=C36,Dmitry Zankov
Organic Process Research & Development,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.",2005,10.1021/op040019c,CCCC1C([N+]([O-])=O)=C(C(N)=O)N(C)N=1,Dmitry Zankov
Organic Process Research & Development,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%.,2004,10.1021/op040006z,CCOC(C(OCC)=O)CC1C=CC(O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0342022,CNN(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0341871,CCC(=O)C1=C(C(=C(C=C1)F)[C@@H]2C[C@@H]2NC(=O)NC3=NC=C(C=C3)C#N)O,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op0341869,CC(N1C(=O)OC(C2C=CC=C(Cl)C=2)C1)CC1C2C=CC=C(OCC3C=CC=CC=3)C=2NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0341824,CN(CC1=CC=CC=C1)C(=O)[C@H](CC2=CC3=CC=CC=C3C=C2)N(C)C(=O)[C@@H]4CCCN4C5=NC6=CC=CC=C6C(=O)N5,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op0341622,CCN(CCOC1C=CC(C2C3C(CCC4C(Cl)=C(O)C=CC=43)C3CCC(O)C3(C)C2)=CC=1)CC,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op034160h,CCC1=C(C2=NC1=CC3=C(C4=C(CC(=C5[C@H]([C@@H](C(=CC6=NC(=C2)C(=C6C)C=C)N5)C)CCC(=O)O)C4=N3)O)C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op0341465,CNC1C2C=CC=CC=2C(C2C=C(Cl)C(Cl)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0341420,C1C=CN=C(C(F)(F)CN)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0341420,C1C=C(F)C(CN)=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0341420,CCOC(CN1C(=O)C(O)=NC=C1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op0341420,C1C=CN=C(C(F)(F)CNC2C(=O)N(CC(NCC3N=CC=CC=3F)=O)C(Cl)=CN=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034134j,C[C@H]1[C@@H](OC(=O)[C@@H]([C@H]1O)C)C[C@@H](/C=C\[C@H](C)[C@@H]([C@@H](C)/C=C(/C)\C[C@H](C)[C@H]([C@H](C)[C@H]([C@@H](C)/C=C\C=C)OC(=O)N)O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034133r,[13CH2]=C/C=C\C(C(OC(N)=O)C(C(O[Si](C(C)(C)C)(C)C)C(C(/C(/C)=C\C(C(O[Si](C(C)(C)C)(C)C)C(/C=C\C=O)C)C)C)C)C)C,Dmitry Zankov
Organic Process Research & Development,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.,2003,10.1021/op034132z,CC1C(C(C(O[Si](C(C)(C)C)(C)C)C(CI)C)C)OC(C2C=CC(OC)=CC=2)OC1,Dmitry Zankov
Organic Process Research & Development,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.,2003,10.1021/op0341317,CC(C(O[Si](C(C)(C)C)(C)C)C(C(N(OC)C)=O)C)C(C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034130e,C[C@H]1[C@@H](OC(=O)[C@@H]([C@H]1O)C)C[C@@H](/C=C\[C@H](C)[C@@H]([C@@H](C)/C=C(/C)\C[C@H](C)[C@H]([C@H](C)[C@H]([C@@H](C)/C=C\C=C)OC(=O)N)O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034130e,CC(C(O)C(C(N(OC)C)=O)C)COCC1C=CC(OC)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op034123q,CCC1=C(C(=O)C=NN1C2=CC=C(C=C2)Cl)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034117u,CC1C(NC(CN2CCNCC2)=O)=C(C)C=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0341162,CC(C)(C)/C=C/[C@H]([C@@H]([C@H]([C@H](C(=O)N[C@H]1CC[C@H](CNC1=O)OC(=O)C2CCCCC2)OC)O)O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034112x,CN1C2C(CC3C(C2)=C(OC)C=CC=3[Si](C)(C)C)CCC1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034112x,CCCN1C2C(CC3C(C2)=CC=CC=3OC)CC(C(OC)=O)C1,Dmitry Zankov
Organic Process Research & Development,"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 .",2003,10.1021/op0341115,CCCCC(C(NC(C(NC1C=NC(C#N)=CC=1)=O)CCC(O)=O)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034110c,C1C=C(N)C=NC=1C#N,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0341061,CCOC1N=C2C(C(C(NCC3C=CC=CC=3)=O)=CNC2=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op0341059,C1C=C(C#N)C(OC2C=CC3C(=NON=3)C=2)=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op0341059,C1C=NC(OC2C=CC3C(=NON=3)C=2)=C(C(O)=O)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2004,10.1021/op034104g,CCC1=C2C(=CC(=C1)C3=C(N(S(=O)(=O)C4=CC=CC=C43)C5=CC=CC=C5C(F)(F)F)C(=O)[O-])OCO2,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034103o,C1C[C@H](CN(C1)C(=O)CCC2CCNCC2)C(=O)N[C@@H](CC(=O)O)C3=CN=CC=C3,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034103o,COC(CC(N)C1C=CC=NC=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034094j,C1C(Cl)=CC(C(N)CC(O)=O)=C(O)C=1Br,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034094j,C1C(C(NCC(NC(C2C=C(Cl)C=C(Br)C=2O)CC(O)=O)=O)=O)=CC(O)=CC=1NC1NCC(O)CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034088n,C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)CNS(=O)(=O)N)C(=O)O)[C@@H](C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0340816,C1C=C(F)C(Cl)=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034079e,CC1=NC2=C(N1)CCN(C3=CC=CC=C32)C(=O)C4=CC=C(C=C4)NC(=O)C5=CC=CC=C5C6=CC=CC=C6,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op0340762,C1C=C(N2CCN(S(CC(C=O)3CCOCC3)(=O)=O)CC2)C=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.,2003,10.1021/op034074h,C1C=C(CCC2NC(=O)C2NOC(CC2C=CC=CC=2)=O)OC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034072x,CCC1C2C(=CC=C(C=2)C#CC2C=C(OC)C=CC=2OC)N=CN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034072x,CCC1C2C(=CC=C(C=2)CCC2C=C(OC)C=CC=2OC)N=CN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0340661,C1=CC2=C(C=C1Cl)N(C(=O)N(C2=O)CC3=C(C=C(C=C3)Br)F)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.,2003,10.1021/op034062w,CC(C)[C@H](C(=O)C1=CC=CC=C1)NC(=O)C[C@@H]2[C@H](O2)[C@H](CC3=CC=CC=C3)NC(=O)[C@H](C(C)(C)S(=O)(=O)C)NC(=O)OC(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034060b,CC(C)CCC(=O)CC1C2=CC=CC=C2C(=O)N1C3=NC4=C(C=C3)C=CC(=N4)Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0340560,C1CC2(C1)CC(=O)CC(=O)C2,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034054f,C1C=C2CCC3C=C(Cl)C=C(Br)C=3C(=O)C2=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op034048j,CCOC(C(O)=O)CC1C=CC(OC/C=C/C#CC2C=CC=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0340457,CC1NC2C=CC(NC3C=CN=C4C=C(SC=34)C3N(C)C=NC=3)=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op0340457,C1C=NC2C=C(SC=2C=1Cl)I,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op0340412,CC(SC1CN(P(C(OCC2C=CC=CC=2)=O)CC2C=CC=CC=2)C(CN(S(N)(=O)=O)C(OC(C)(C)C)=O)C1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034032t,C1C=CC(C2C=C(C3C=CC(C(N)=O)=CC=3)N=C(N)N=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.,2003,10.1021/op0340309,CCCC1C=C(O)C=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034028h,CC1OC(CO)CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034028h,CC(NCC(OC(C)=O)C(Cl)C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034028h,CC(=O)NC[C@H]1CN(C(=O)O1)C2=CC(=C(C=C2)N3CCOCC3)F,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034024c,CN1CC2=C(C=CC(=C2)C(=O)N3CCC(CC3)C4CCNCC4)N[C@H](C1=O)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op034024c,C(C(O)=O)C1NC2C(=CC=CC=2)CN(C)C1=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034023k,CN1CC2=C(C=CC(=C2)C(=O)N3CCC(CC3)C4CCNCC4)N[C@H](C1=O)CC(=O)O,Dmitry Zankov
Organic Process Research & Development,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.,2003,10.1021/op0340208,C1C=C(C(O)CN)C=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034016w,C1COC2=C(O1)C=CC(=C2C3=C(C=CC4=C3OCCO4)P(C5=CC=CC=C5)C6=CC=CC=C6)P(C7=CC=CC=C7)C8=CC=CC=C8,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034014b,C(OCC1C=CC=CC=1)C1OC1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034008f,CCCCCC[C@@H](CCC)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034007n,C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=NC=CC6=CC=CC=C65,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034006v,C1CN(C[C@H]([C@H]1CC2=CC=CC=C2)O)CCS(=O)(=O)C3=CC=C(C=C3)O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op034001y,CC1=C(C=CC(=C1)CCC[C@H](CC(=O)O)C(=O)N[C@H](C(=O)N[C@H](COC)C2=CC=CC=C2)C(C)(C)C)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op030212r,C(C)1NC2C(N(C3N(C=2N=1)C1C(CCC1)N=3)C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op030212r,CN1C(=O)C2=C(N=C(N2)CC3=CC=C(C=C3)C(F)(F)F)N4C1=N[C@H]5[C@@H]4CCC5,Dmitry Zankov
Organic Process Research & Development,"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%.",2003,10.1021/op0302107,CCC(CC)O[C@@H]1C=C(C[C@@H]([C@H]1NC(=O)C)N)C(=O)OCC,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op030207n,CC(OC(NC(C1OC(=O)CC1)CC1C=C(F)C=CC=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op030202q,C1CCC(CC(OS(C(F)(F)F)(=O)=O)C(OCC2C=CC=CC=2)=O)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op030202q,C1CCC(CC(O)C(O)=O)CC1,Dmitry Zankov
Organic Process Research & Development,"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%.",2003,10.1021/op030201y,C=CC1C2CCOC=2C=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op030050z,CC(C1C(C)2C(C3C4(OC5CCC4(C)C(C5)CC3)C(C2Br)=O)CC1)CCC(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2004,10.1021/op030050z,CC(OCC(C(O)1C(C)2C(C3C(C(C2)=O)C(C)2C(CC(CC2)=O)CC3)CC1)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op030041q,CCC1C(C#N)=CC2C=CC=CC=2C=1C(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op030039z,COC1C=C(S(C)=O)C(C2CCNCC2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op030037e,CCC(CC)(/C=C/C=C/[C@@H](C)[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H](C[C@@H](C3=C)O)O)C)O,Dmitry Zankov
Organic Process Research & Development,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.",2003,10.1021/op025621m,COC1C=C(S(O)(=O)=O)C(C(O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025620u,CCCN1CCC[C@H](C1)C2=CC(=CC=C2)S(=O)(=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025620u,CS(C1C=CC=C(C2CNCCC2)C=1)(=O)=O,Dmitry Zankov
Organic Process Research & Development,"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",2003,10.1021/op025619v,N1=C(C2=CC=CC=C2)C(C2=CC=CC=C2)CN1C(=O)NC1=CC=CC=C1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025616i,CCCCC(C(O)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025615q,COC1=C(C=C(C=C1)C2=CC=NC=C2)C3=CC4=NON=C4C=C3,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025615q,C1C(B(O)O)=CC2C(=NON=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025615q,C1C(C2C(OC)=CC=C(C3C=CN=CC=3)C=2)=CC2C(=NON=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025611l,CC1(OC2C(C=CC2N)O1)C,Dmitry Zankov
Organic Process Research & Development,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).",2002,10.1021/op0256035,CCOC(C(OCC)=O)CC1C=CC(O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2002,10.1021/op025599x,CC1CCN(CC1NC)CC2=CC=CC=C2,Dmitry Zankov
Organic Process Research & Development,"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.",2003,10.1021/op025590v,COC1C=C2C(CCCC2(O)C(O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2002,10.1021/op025587b,CC(C(N)C(N1C(B(O)O)CCC1)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2000,10.1021/op000066e,CCCCCCCCCCOC1C(OCCCCCCCCCC)=C(OCCCCCCCCCC)C=C(C(O)=O)C=1,Dmitry Zankov
Organic Process Research & Development,"<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.",2020,10.1021/acs.oprd.9b00538,CC(OC(NC(C(O)=O)CC1N(COCC2C=CC3C=CC=CC=3C=2)C=NC=1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2019,10.1021/acs.oprd.9b00141,CCOC1=CC=C(C=C1)CC2=C(C=CC(=C2)[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2017,10.1021/acs.oprd.7b00261,CC(C)(C)NCC(C1=CC(=C(C=C1)O)CO)O,Dmitry Zankov
Organic Process Research & Development,(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.",2017,10.1021/acs.oprd.7b00171,CC1=NN=C(O1)C(=O)NC(C)(C)C2=NC(=C(C(=O)N2C)O)C(=O)NCC3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2017,10.1021/acs.oprd.7b00096,CCCC(NC1CC2C(=CC(F)=CC=2F)CC1)C(NC1N=CN(C(CNCC(C)(C)C)(C)C)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2016,10.1021/acs.oprd.6b00252,C(=N\\O)(\\Cl)/C(=N/O)/Cl,Dmitry Zankov
Organic Process Research & Development,"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.,2016,10.1021/acs.oprd.6b00147,C(C1C=CC=CC=1)(OC1C(=O)OC(=O)C1OC(C1C=CC=CC=1)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2016,10.1021/acs.oprd.6b00146,CC(NC1CC(C(O)=O)CCC1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2016,10.1021/acs.oprd.6b00145,CC(N)(C1N=CON=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2016,10.1021/acs.oprd.6b00143,CC(NC(C)=O)C1N=CC(F)=CN=1,Dmitry Zankov
Organic Process Research & Development,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.,2016,10.1021/acs.oprd.6b00141,CNC(C1C2C(=CC(N(S(C)(=O)=O)C)=C(Br)C=2)OC=1C1C=CC(F)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2016,10.1021/acs.oprd.6b00136,C1C(C(O)=O)C2C=NC(N3N=NN=C3)=NC=2C1,Dmitry Zankov
Organic Process Research & Development,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.",2016,10.1021/acs.oprd.6b00094,CCC[C@@H]1CC(=O)N(C1)[C@@H](CC)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2025,10.1021/acs.oprd.4c00476,C1CC(=O)NC(=O)C1N2CC3=C(C2=O)C=CC(=C3)C4CCN(CC4)CC5=CC=CC=C5,Dmitry Zankov
Organic Process Research & Development,"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.",2024,10.1021/acs.oprd.4c00020,C1N=NNC=1,Dmitry Zankov
Organic Process Research & Development,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.",2023,10.1021/acs.oprd.2c00305,CC12CC(C(NC3CCC(N)CC3)=O)3CC(CC(C4C=CC=CC=4)(C3)C1)C2,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00304,CC#CC(=O)N1CCC[C@H]1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00297,Oc1c(Cl)cc(Cl)cc1S(=O)(=O)N(Cc1ccc(F)cc1)Cc1ccc(cc1)C(=O)N1CCCCC1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00296,CCN(C1=CN(N=C1Cl)C2=CN=CC=C2)C(=O)CCSCCC(F)(F)F,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00284,C[C@@H]1CN([C@H](CN1C(=O)C=C)C)C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CC=C5S(=O)(=O)C)C6CCC6,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00273,CC1=C(C(=CC=C1)C(C)C2=CN=CN2)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00273,CC1C(C)=C(Br)C=CC=1C(C1N=CNC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00273,CC1C(C)=C(C(C(CBr)=O)C)C=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00272,CC1=C(C=CC=C1C2=CC(=NC(=N2)N)C3=CN(N=N3)CC4=NC(=CC=C4)C(C)(C)O)C#N,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00265,C1C=C(C2C(CO)C2)C=NC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00258,C(C)1C2N(C(C3C=C(C(O)4COCCC4)C=CC=3Cl)=NN=2)C2N=CC=CC=2N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00250,C(C1C([N+]([O-])=O)=NON=1)1C(C2C([N+]([O-])=O)=NON=2)=[N+]([O-])ON=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00249,C[C@H]1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00247,COC(C1N=C(Cl)C(Cl)=C(Cl)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00245,CC1C=CC2C(S(NC(C3C4C(=C(C5CCC5)C=CC=4OC)OCC3)=O)(=O)=O)=CC=CC=2N=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00244,CC(=O)NC1=CC=C(C=C1)OP(=O)(C(CC2=CC=C(C=C2)N=C(N)N)NC(=O)OCC3=CC=CC=C3)OC4=CC=C(C=C4)NC(=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00243,COC1=C(C=C(C=C1)C[C@@H]2C3=CC(=C(C=C3CCN2)OC)OC)OC,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00240,CC(N1C(=O)C2C(=CC(C3C=CN4C(=C(C(NC5CCC(O)(C)CC5)=O)C(N)=N4)N=3)=CC=2OC(F)F)C1)C1CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00237,CC[C@@H]1[C@@H]2C[C@@H](CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3[C@@H]1O)CC[C@@H]4[C@H](C)CCC(=O)O)C)C)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00235,CC1=CC2=C(C=C1OCC(=O)O)ON=C2CCC3=C(N=C(S3)C4=CC=C(C=C4)C(F)(F)F)C(C)C,Dmitry Zankov
Organic Process Research & Development,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%.",2022,10.1021/acs.oprd.2c00230,CC#CCN1C2=C(N=C1N3CCC[C@H](C3)N)N(C(=O)N(C2=O)CC4=NC5=CC=CC=C5C(=N4)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00229,C[C@@H](C1=C(C=NN2C1=NC=C2)NC(=O)NC3=CC(=C(N=C3)N4N=CC=N4)Cl)OC,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00225,CC(OC(NC(C(N)=O)CC1C(=O)NCC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00221,C1C2(NC3C(=CC(C(O)=O)=CN=3)OCC2)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00212,C1=CC(=C(C2=C1NC=C2)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00209,C1C=C(N(C2C=CC=CC=2)C2C=CC(N(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2Br)C(Br)=CC=1N(C1C=CC=CC=1)C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00206,C1CN(CCN1CCCCC2=CNC3=C2C=C(C=C3)C#N)C4=CC5=C(C=C4)OC(=C5)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00203,CC1C(=O)NC(=O)N(C2OC(COP(OC3C(COP([S-])(OC4C(OC)C(N5C(=O)N=C(N)C=C5)OC4CO)=O)OC(N4C(=O)NC(=O)C(C)=C4)C3)([O-])=O)C(O)C2)C=1,Dmitry Zankov
Organic Process Research & Development,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).",2022,10.1021/acs.oprd.2c00200,C1CN2C(CO)(CC(F)C2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00199,C1CC(=O)NC(=O)C1N2CC3=C(C2=O)C=CC(=C3)CNC(=O)C(C4=CC=C(C=C4)Cl)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00192,C1CC1CN2[C@H]3COC4=C5C=CC(=CC5=NN4[C@H]3[C@@H]([C@@]26C7=C(C=C(C=C7)Cl)NC6=O)C8=C(C(=CC=C8)Cl)F)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00191,C1=CN(C(=O)NC1=O)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00187,CC(C)(C1=NC(=NO1)C2=CC=CC=C2)NC(=O)C3=C([C@H]4[C@@]56CCN([C@@H]([C@@]5(C3)O)CC7=C6C(=C(C=C7)O)O4)CC8CC8)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00185,CN1C=CNC1=S,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00184,C1=CC=C(C(=C1)C2=NC(C(=O)NC3=C2C=C(C=C3)Cl)O)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00183,C1CNC2C(CNC2)C1,Dmitry Zankov
Organic Process Research & Development,"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%.",2023,10.1021/acs.oprd.2c00181,CC(=O)N1CCC2=C(C1)N=C(C(=N2)N3CCC(CC3)OC4=C(C=C(C=C4)F)F)N[C@@H]5CCOC5,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00176,CC(C1N=CC=C(C)C=1N1C(=O)NC(=O)C2C=C(F)C(Cl)=NC1=2)C,Dmitry Zankov
Organic Process Research & Development,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.",2023,10.1021/acs.oprd.2c00167,C1C=C2C(Cl)=NC(Cl)=NC2=NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NC(C)(C)C)CC[C@@H]4[C@@]3(C=CC(=O)N4)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C[C@@]12CCN([C@@H]1N(C3=C2C=C(C=C3)OC(=O)NC)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C[C@@H]([C@@H]([C@H]1CNC2=C(N1)C(=O)NC(=N2)N)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C[C@@H]1[C@@H](CCN1CC2=CC=CC=C2)NC(=O)C3=CC(=C(C=C3OC)NC)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C[C@@H]1CCO[C@@H]2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C[C@H]1[C@@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C2C(=C4C(=C3O)C(=O)C5=C(C4=O)C(=CC=C5)OC)O)(C(=O)CO)O)N)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C1[C@@H]2CNC[C@H]1C3=CC4=NC=CN=C4C=C23,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C1[C@H]2[C@@H]([C@H]2[C@@]([C@@H]1O)(C(=O)O)N)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C1=CC(=CC=C1[C@@H]2[C@H](C(=O)N2C3=CC=C(C=C3)F)CC[C@@H](C4=CC=C(C=C4)F)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C1C[C@H](CNC1)C2=CC=C(C=C2)N3C=C4C=CC=C(C4=N3)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C1CN2C(=NN=C2C(F)(F)F)CN1C(=O)C[C@@H](CC3=CC(=C(C=C3F)F)F)N,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,C1COCC(=O)N1C2=CC=C(C=C2)N3C[C@@H](OC3=O)CNC(=O)C4=CC=C(S4)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC(C)C1=NC(=NC(=C1/C=C/[C@H](C[C@H](CC(=O)O)O)O)C2=CC=C(C=C2)F)N(C)S(=O)(=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC(C1=CN=C(C=C1)C(F)(F)F)S(=NC#N)(=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC(F)1C(=O)OC(CO)C1O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC(NCC(O)COC1C2C(=CC=CC=2)C=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC[C@@H](C(=O)N)N1CCCC1=O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC1=CN(C(=O)NC1=O)[C@H]2C=C[C@H](O2)CO,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CC1=NN=C2N1C3=C(C=C(C=C3)Cl)C(=NC2)C4=CC=CC=C4,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CCCCCCCC(=O)N[C@H](CN1CCCC1)[C@@H](C2=CC3=C(C=C2)OCCO3)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CN[C@H]1CC[C@H](C2=CC=CC=C12)C3=CC(=C(C=C3)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,CN1C2=CC=CC=C2C(=C1O)N=NC(=S)N,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00161,COC1=CC2=C(C=CN=C2C=C1)[C@H]([C@@H]3C[C@@H]4CCN3C[C@@H]4C=C)O,Dmitry Zankov
Organic Process Research & Development,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 .",2022,10.1021/acs.oprd.2c00153,CC(C(F)(F)F)(CC1(NC(=N)N(C(C2C=C(C3N(C(F)F)N=CN=3)C(Cl)=CC=2)COC(NC(C(F)(F)F)2CC2)=O)C1=O)C1C=CC(C2C=NN(C3CC3)N=2)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00150,CC(S(NCC1CCC(NC2OC3C=C(F)C=CC=3N=2)CC1)(=O)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00146,CC1OC(O)C(F)C(O)C1O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00146,CC1OC=CC(OC(C)=O)C1OC(C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2023,10.1021/acs.oprd.2c00145,CC(OC(N1CCC2NC(C([N+]([O-])=O)=CC=2CC1)=O)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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 ).",2022,10.1021/acs.oprd.2c00141,CNC(=O)C1=C(C(=CC(=C1)Cl)Cl)NC(=O)C2=CC(=NN2C3=C(C=C(C=N3)Cl)Cl)Br,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00132,C=C1CN2C(C(O)NC3C=C(OCCCCCOC4C(OC)=CC5C(N6C(C(O)C(C(OCC(SSC7C=CC([N+]([O-])=O)=CN=7)C)=O)C=5C=4)CC(=C)C6)=O)C(OC)=CC=3C2=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00123,COC1C=CC(C(O)C2C=CC(Br)=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.,2022,10.1021/acs.oprd.2c00121,C1C=CC2CNC(CC=2C=1)1C(O)CNCC1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00113,CCCCC1=NC2(CCCC2)C(=O)N1CC3=CC=C(C=C3)C4=CC=CC=C4C5=NNN=N5,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00100,CS(C1C=CC(C(O)C(N)CO)=CC=1)(=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00099,C1C=CC2S(S(CC3C=CC=CC=3)(=O)=O)(C(F)(F)F)C3C(C=2C=1)=CC=CC=3,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00097,CCC1C(C2C=C(C)C3CCC(O)C=3N=2)=C(CC)C=C(C)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00076,C1C[C@@H](C2=C(C1)C=CC=N2)N(CCCCN)CC3=NC4=CC=CC=C4N3,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00074,CC[C@H](C)[C@@H](C(=O)NC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]([C@@H](C)CC)N(C)C(=O)[C@H](C)N(C)C(=O)C1=CC=CC=C1,Dmitry Zankov
Organic Process Research & Development,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%.",2022,10.1021/acs.oprd.2c00059,COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)OCCCN4C[C@@H]5[C@H](C4)OCCO5,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00057,CN1C(=O)C2C=CC=CC=2C(C2C3C=CC=CC=3C(=O)N(C)C=2)=C1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00050,C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2C(=O)NC4=C(C=CC(=C4)C(F)(F)F)C(F)(F)F)CC[C@@H]5[C@@]3(C=CC(=O)N5)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00049,COC1=CC(=CC(=C1OC)OC)/C=C/C(=O)N2CCC=CC2=O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00048,CCNC(=O)C[C@H]1C2=NN=C(N2C3=C(C=C(C=C3)OC)C(=N1)C4=CC=C(C=C4)Cl)C,Dmitry Zankov
Organic Process Research & Development,"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.,2022,10.1021/acs.oprd.2c00036,CC1=CC=C(C=C1)C2=C(C(=O)N[C@@](C2)(C3=CC=C(C=C3)OCCCC(F)(F)F)C(F)(F)F)C4=NNN=N4,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00032,C1C=CC(C2NN=NN=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00023,C1C(=O)NC2=C(C=C(C=C2)[N+](=O)[O-])C(=N1)C3=CC=CC=C3Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00017,C1C2C(O)COC2OC1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.2c00010,CCCN(C(C(NC(C1N(C)CCCC1)=O)C(CC)C)=O)C(C(C)C)CC(C1SC=C(C(OC)=O)N=1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.2c00002,CCCC1=NC(=C(N1CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)C(=O)OCC5=C(OC(=O)O5)C)C(C)(C)O,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00490,C1C=CC(C(N)CO)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00488,CN(C)C(=O)NC1CCC(CC1)CCN2CCN(CC2)C3=C(C(=CC=C3)Cl)Cl,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00481,CC(O)CC1C=C2NC(OC2=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00477,C#C[C@]1([C@H](C[C@@H](O1)N2C=NC3=C(N=C(N=C32)F)N)O)CO,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00475,C[C@H]([C@H](CO)O)OC1=NC(=NC(=C1)NS(=O)(=O)N2CCC2)SCC3=C(C(=CC=C3)F)F,Dmitry Zankov
Organic Process Research & Development,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.,2022,10.1021/acs.oprd.1c00469,COC(N1CCN(CC2C(F)=C([N+]([O-])=O)C=CC=2)CC1)=O.Br,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00468,[2H]C([2H])([2H])NC(=O)C1=NN=C(C=C1NC2=CC=CC(=C2OC)C3=NN(C=N3)C)NC(=O)C4CC4,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00467,C1CN(CCC1CN[C@@H]2C[C@H]2C3=CC=CC=C3)CC4=CC=C(C=C4)C(=O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00463,CNCCC(OC1C2C=CC=CC=2C=CC=1)C1SC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00457,CC1=CC(=C(C=C1)C2=NC=CC=N2)C(=O)N3[C@H]4CC[C@H]([C@@H]3CC4)COC5=NC=C(C=C5)F,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00452,CC(CC(N)(COC1C=C2C(C3C(CO2)=CN=C(NC(C)=O)C=3)=CC=1)C)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00443,CC#CC(=O)N[C@H]1CCCN(C1)C2=C(C=C(C3=C2C(=C(N3)C)C)C(=O)N)F,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00432,CC1=CC(=CC(=N1)Cl)C2=C(N=C(N=N2)N)C3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00431,CC1=CC=C(C=C1)S(=O)(=O)N=S(=O)(C2=CC=C(C=C2)Cl)F,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00430,C1CCC(C(O)=O)CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00422,CC1OC2C(C(NC)=O)=CC(C(NC3C4C3COC4)=O)=CC=2C1C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00421,CC1CC(=O)C2C(=CC=C(C)C=2)C1,Dmitry Zankov
Organic Process Research & Development,“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.",2022,10.1021/acs.oprd.1c00419,CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)NO)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00416,CC(C1C(O)=C(C(C)C)C=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00414,COC1C=CC2N=CC(F)=CC=2C=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00413,CC1C=CC(NCC2C3C=CC=CC=3NC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00407,CNC1(CCCCC1=O)C2=CC=CC=C2Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00400,CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)NO)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00394,CC(C)C[C@@H](CC(=O)O)CN,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00392,COC1C=CC(CN2CCC(C3C=CC4N=C(C(N5CCN(CC6C=CC(C(F)(F)F)=CC=6)CC5)=O)NC=4C=3)CC2)=CN=1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00389,C1CN(CC1(F)F)C2=NC(=CC(=N2)N3C[C@@H]4C[C@H]3CO4)C5=CC(=C(N=C5)N)OC(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00384,CC1C2=C(C(=CC=C2)SC3=NC(=CC(=N3)OC)OC)C(=O)O1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00374,CC(C1C(=O)CC(C(O)CN(CC2C=CC(Cl)=CC=2)CCN(C)C)2C=1C1C(CC2)(C)C(C)2C(C3(C(CC2)C(C)(C)C(OC(CC(C(O)=O)(C)C)=O)CC3)C)CC1)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00368,C1C[C@H]2C(=O)N[C@@H](CSSCCC(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N2C1)CC3=CNC4=CC=CC=C43)CC(=O)O)CCCCN=C(N)N)C(=O)N,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00366,CCN(CC)CCOC1=CC=C(C=C1)C(=C(C2=CC=CC=C2)Cl)C3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00364,C1C=C2C(CCC(NCC(O)CO)=O)=CC=C(CCC(NCC(O)CO)=O)C2=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00350,CC1N=C2SC(COC)=NN2C=1CN1C(=O)C=C(CCC(F)(F)F)C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00339,C(C)1C(C(C2C=CC=CC=2)=O)CCC(C(O)=O)C1,Dmitry Zankov
Organic Process Research & Development,"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.",2022,10.1021/acs.oprd.1c00315,CC(C)OC1=CC=C(C=C1)C2=NC3=C(C(=N2)O[C@@H]4C[C@H]5C(=O)N[C@@]6(C[C@H]6/C=C\\CCCCC[C@@H](C(=O)N5C4)NC(=O)OC7CCCC7)C(=O)NS(=O)(=O)C8(CC8)C)OC9=CC=CC=C93,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00314,CN1N=CC(NC2N=CC=C(Cl)N=2)=C1,Dmitry Zankov
Organic Process Research & Development,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.,2021,10.1021/acs.oprd.1c00313,CC1N(C(C2C=C(C3CC3)N3C(=CC(C4C(F)=CC(C5C(C(O)=O)C5)=CC=4)=N3)N=2)=O)CCC2C=CC=CC1=2,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00306,C[C@H](C1CC1)C2=CC=CC(=C2O)C(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00302,CN(C)C(=O)CN1C=C(C(=N1)C2=C(C=CC(=C2)Cl)OC(F)F)NC(=O)C3=C4N=CC=CN4N=C3,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00290,C1CN(C(C2C=C3N=CNC3=CC=2)=O)C2C(C3C(C2)=CC=C(C#N)C=3)C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00287,CC[C@@H]1CN(C[C@@H]1C2=CN=C3N2C4=C(NC=C4)N=C3)C(=O)NCC(F)(F)F,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00285,B1([C@@H]2C[C@@H]2C3=C(O1)C(=C(C=C3)F)C(=O)O)O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00284,CC(C)(C(=O)O)SC1=C(C=NC=C1)C2=CC=C(C3=CC=CC=C32)C#N,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00283,CC1=C(C=C(C=C1F)C(=O)NC2CC2)N3C=CN=C(C3=O)NC4(CC4)C5=CC=CC=C5OCCNC,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00282,CC(C)(COC1=CN2C(=C(C=N2)C#N)C(=C1)C3=CN=C(C=C3)N4CC5CC(C4)N5CC6=CN=C(C=C6)OC)O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00282,CC1=CC(=NN1)NC2=NC(=NC(=C2)C)C3CCC(CC3)(C(=O)N[C@@H](C)C4=CN=C(C=C4)N5C=C(C=N5)F)OC,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00282,CNC(=O)C1=C(C=C(C=C1)C2=NN3C(=CN=C3N=C2)CC4=CC5=C(C=C4)N=CC=C5)F,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00281,CC1=C2C=C(C=CC2=C(C(=N1)C(=O)NCC(=O)O)O)OC3=CC=CC=C3,Dmitry Zankov
Organic Process Research & Development,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.",2022,10.1021/acs.oprd.1c00279,CC1=CC(=CC(=N1)Cl)C2=C(N=C(N=N2)N)C3=CC=C(C=C3)F,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00277,CC1=C(C2=C(C=C1)C(=NC=C2)NC3=C(C(=CC=C3)Cl)F)NC(=O)C4=CSC5=C4N=CN=C5N,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00264,CC1C=C(O)C=C(N(C)C)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00263,OCC(F)(F)CN([C@@H]1C2=C(F)C=C(NC3CN(CCCF)C3)C=C2F)[C@H](C)CC4=C1NC5=C4C=CC=C5,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00262,CC(NCC(F)(F)CO)CC1C2C=CC=CC=2NC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00259,CN1N=CN=C1C1C(=O)C2C(C(OC)=O)=CC(F)=CC=2NC1C1C=CC(F)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00256,CS(C1C2C(O)C(F)C(O)C=2C(OC2C=C(C#N)C=C(F)C=2)=CC=1)(=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00255,CC(O)1C(N2C(=O)C(C(F)F)=CC3C=NC(NC4CCN(S(C)(=O)=O)CC4)=NC2=3)CCC1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00253,CC1N=CC(CN)=C(N)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00250,COC1C=CC=CC=1C(O)C(O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00248,CC(OC(N1C2(COC(C)(C)OC2)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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 .",2021,10.1021/acs.oprd.1c00244,CC1C=C(C(C2C(=O)CCCC2=O)=O)C(=O)N(C2C=C(OC)C(OC)=CC=2)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00237,COC(N[C@@H](C(C)C)C(N1[C@H](C2=NC3=CC=C(C4=CC5=CC=C4CCC6=CC=C(CC5)C(C7=CC=C(N=C([C@H]8N([C@]9([H])[C@](CCCC9)([H])C8)C([C@H](C(C)C)NC(OC)=O)=O)N%10)C%10=C7)=C6)C=C3N2)C[C@@]%11([H])[C@]1([H])CCCC%11)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00231,CS(=O)(=O)C1=C2[C@@H]([C@@H]([C@@H](C2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)F)F)O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00230,C1N2C(=NC3N(C4OC5COP(OC5C4O)([O-])=S)C(Br)=NC=3C2=O)NC=1C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00229,C1C2C(=CC(Cl)=C(C(O)=O)C=2Cl)CNC1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00225,CN(C)C[C@@H]1[C@@](C2=CC=C(C=C2)C#CC3=CC=CC=C3)([H])[C@@]4([H])N1C[C@@H]([C@@H](CN(C4)C(NC5=CC=C(C=C5)OC)=O)O)O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00223,FC1=CC=C(NC(C2=NC=C(C(F)F)N=C2)=O)C=C1[C@@]3(N=C(N)SC4)[C@@]4([H])[C@@H](C)OC3,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00219,CC(C(OCC1OC(N2C(=O)N=C(NO)C=C2)C(O)C1O)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00211,C1C=C(S(N2CCNCCC2)(=O)=O)C2C(=CN=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00204,C1C=C(CC2C3N(C=CN=3)C=C(C3NN=C(C(F)(F)F)N=3)N=2)C(F)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.,2021,10.1021/acs.oprd.1c00196,CC(C1C=CC=CC=1)N1C(=O)C2N(C(N(CC3C=CC=CC=3)C2C1=O)=O)CC1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00193,C1C(C2ON=C(C3C(Cl)=CC(F)=CC=3Cl)C=2COC2C=CC(C(O)3CN(C4N=CC(C(O)=O)=CC=4F)C3)=C(Cl)C=2)C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00185,CC([Hg])C1C=C(OC)C(S(N)(=O)=O)=CC=1OC1C=NC(N)=NC=1N,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00184,CCCOC1C(C2NC(=O)C(CC)=C(CC)N=2)=CC(NC(CN2CCN(C)CC2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00175,CC(OC(C(NP(OC1C=CC=CC=1)(OCC1OC(N2C(=O)NC(=O)C=C2)C(C)(Cl)C1O)=O)C)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00149,C1C[C@H](N2C[C@@H]1N(C2=O)OS(=O)(=O)O)C(=O)NC3CCNCC3,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00142,CCC(NC(C1C=CC(OC)=NC=1)=O)C1CCC(C2C(C(F)F)=C(OC)N=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00141,C1C=CC(COC2C(=O)C=CN3C=2C(N2C(=N3)COCC2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00139,CC1N2C(CN3C([S])=C(C(NCC4C(F)=CC(F)=CC=4)=O)C(=O)C(O)=C3C2=O)OCC1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00133,CC(NC1C=C(F)C=C(F)C=1)C1C=C(C(N(C)C)=O)C=C2C(C=C(OC=12)N1CCOCC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00132,CN1C(C(N)(C2C=C3C(C4C=CC=C(Cl)C=4)=CC(N(C)C3=CC=2)=O)C2C=CC(Cl)=CC=2)=CN=C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00130,COCCOC1C=CC(C2C3C(NC=NC=3N(C3C=CC=CC=3)C=2)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00128,C1C=C2C(CC(O)=O)=C3N(C2=C(F)C=1)CC(N1N=NC=C1CC1C=CC(F)=CC=1)CC3,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00127,CC1(S(=O)(=O)C2N(C(C2)=O)C1C(O)=O)CN1N=NC=C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00126,CC1OCC(C2SC=C(N)N=2)2C(CSC(NC(C3C=CC=CC=3)=O)=N2)C1,Dmitry Zankov
Organic Process Research & Development,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 .",2021,10.1021/acs.oprd.1c00124,CC1C(C(N2C3C(S(C4C=CC(F)=CC=4)(=O)=O)(C4C(CC3)=CC(C(F)(C(F)(F)F)C(F)(F)F)=CC=4)CC2)=O)CCC(C(O)=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00120,CCOC(C(Br)CCC(Br)C(OCC)=O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00118,CCOC(/C(/C(C1C(F)=CC(F)=C(F)C=1)=O)=C\NC1CC1)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00107,CCOC1C=C(C(N2C(=O)C3C(=CC=CC=3NC(C)=O)C2=O)CS(C)(=O)=O)C=CC=1OC,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00099,CC1NC2C(=CC(Cl)=C(OC)C=2)C(=O)C=1C1C=CC(OC2C=CC(OC(F)(F)F)=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00098,C1NC2CCC1OC2,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00088,CCOCC1NC(=O)C(C2OC(CC3C=CC(Cl)=CN=3)=NN=2)=C(O)C=1C1C(OC)=CC=CC=1OC,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00086,CCCC1N(CC2C=CC(C3C=CC=CC=3C(O)=O)=CC=2)C2C(=C(C=C(C3N(C)C4C=CC=CC=4N=3)C=2)C)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00081,C1C2C=CC(O)=CC=2C(=O)C2C=CC(Cl)=CC=2C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00078,CCC(C(N(C(C(N(C(C(NC(C(NC(C(NC(CCl)=O)CC1C=CC=CC=1)=O)C)=O)CCCCNC(OC(C)(C)C)=O)=O)C)CC(C)C)=O)C)C(OC)CC(N1C(C(NC(C(N)=O)CS[Tl])=O)CCC1)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00077,CNC1CN(C2N=C(N)N=C(NCC3CC3)C=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00076,CCCCCCCC(OC(CCCN(C(SCCCN(C)C)=O)CCCC(OC(CCCCCCC)CCCCCCC)=O)=O)CCCCCCC,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00075,CC(OC(N1CCC2(OCC(N)C2)CC1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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%.",2021,10.1021/acs.oprd.1c00069,C(CC1C2C(=CC=C(C#N)C=2)NC=1)CCN1CCN(C2C=CC3OC(C(N)=O)=CC=3C=2)CC1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00066,CN1N=CC(N)=C1,Dmitry Zankov
Organic Process Research & Development,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 .",2021,10.1021/acs.oprd.1c00065,CC(OCCC(Cl)C(C)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00059,CCOC(C(NP(OC1C=CC=CC=1)(COC1OC(N2C3N=CN=C(N)C=3N=C2)C(F)=C1)=O)C)=O.[K],Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00033,CC(C(OCC1OC(N2C(=O)N=C(NO)C=C2)C(O)C1O)=O)C,Dmitry Zankov
Organic Process Research & Development,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).",2021,10.1021/acs.oprd.1c00026,C1N=C(N)C2N=CN(C3OC(C(O)=O)C(O)C3F)C=2N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00025,CCCC1NC2C(=C(C=C(C3N(C)C4C(=CC=CC=4)N=3)C=2)C)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00024,CCC(COC(C(NP(OC1C=CC=CC=1)(OCC1OC(C2N3C(C(N)=NC=N3)=CC=2)(C#N)C(O)C1O)=O)C)=O)CC,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00021,CCCCCCCCCCCCCCCC(NC(C(OC(C)(C)C)=O)CCC(NCCCCC(NC(OCC1C2C=CC=CC=2C2C=CC=CC1=2)=O)C(O)=O)=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.1c00019,CC1C(C(N2C3C(S(C4C=CC=CC=4)(=O)=O)(C4C(CC3)=CC(C(F)(C(F)(F)F)C(F)(F)F)=C(F)C=4)CC2)=O)CCC(C(O)=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00015,CC(O)(CC1N=CC(Br)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.,2021,10.1021/acs.oprd.1c00013,C1NC(C(N)=O)=C(N)N=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00010,C[C@H](CC[C@H](C(C)C)O)[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H](C[C@@H](C3=C)O)O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00004,C1C=C(Cl)C=C(C2C=C(O)C(C(NCC(O)=O)=O)=NC=2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.1c00002,C1C=CC(C(F)(F)COCCCCCCN)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00553,CCCCCCCC(CCC1C=C(OC)C(O)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00544,CN1C(=O)N(CC2C=CC=CC=2C#N)C(N2CC(N)CCC2)=CC1=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00543,C1C=CN=C(CCNC)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00533,C1NC(=O)C2=C(N)C=NN2C1,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.0c00529,C(N)1C([N+]([O-])=O)=NC([N+]([O-])=O)=C(N)[N+]=1[O-],Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00525,CN1CC(F)C(N)CC1,Dmitry Zankov
Organic Process Research & Development,"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%.",2021,10.1021/acs.oprd.0c00519,CC(C(NC(OC)=O)C(N1C(C2NC(C3C=CC(C4C=CC(C5C=CC6NC(C7N(C(C(NC(OC)=O)C(C)C)=O)CCC7)=NC=6C=5)=C5C=4C4CC5CC4)=CC=3)=CN=2)CCC1)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00515,CN(CCCOC1C=C2N=CN=C(NCCC3SC(NC(NC4C=CC=C(Cl)C=4)=O)=NC=3)C2=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.0c00507,CC1C2C(=CC=C(O)C=2)OC=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00491,CC(C(OC(NCC(C1C=CC(Cl)=CC=1)CC(O)=O)=O)OC(C(C)C)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00487,CC(OC(C(NP(OC1C=CC=CC=1)(OCC1OC(N2C(=O)NC(=O)C=C2)C(Cl)(C)C1O)=O)C)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00486,CC(N1CCN(CC2OC(C3C=C(C4C5C=CNC=5C=CC=4)C=C4C=3C=NN4)=NC=2)CC1)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00484,C1C=C2C(OC3CCC(NC(C4C=CC=C(F)C=4)=O)CC3)=CC=NC2=C(C#N)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00483,CC1N(C2N=C(C3C=CN=C4C=3C=CN4)N=C(C(S(C)(=O)=N)3CC3)C=2)CCOC1,Dmitry Zankov
Organic Process Research & Development,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%.",2020,10.1021/acs.oprd.0c00482,CC1N(C2N=C(C3C=CN=C4C=3C=CN4)N=C(C(S(C)(=O)=N)3CC3)C=2)CCOC1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00476,C#CC1(OC(N2C3N=C(N=C(N)C=3N=C2)F)CC1O)CO,Dmitry Zankov
Organic Process Research & Development,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).",2021,10.1021/acs.oprd.0c00473,CC(OCP(O)(O)=O)CN1C2N=CN=C(N)C=2N=C1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00470,CN1C(=O)N=NC1=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00469,C1C(Cl)NC2NN=CC=2C=1Cl,Dmitry Zankov
Organic Process Research & Development,"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.",2021,10.1021/acs.oprd.0c00453,CC(OC1C(Cl)=CC=CC=1Cl)C1NCCN=1,Dmitry Zankov
Organic Process Research & Development,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 .",2020,10.1021/acs.oprd.0c00444,C1C(F)CCC(N)C1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00436,C[C@H](CCCC(C)(C)O)[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H]([C@H]([C@@H](C3=C)O)OCCCO)O)C,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00428,CCOC(C(NP(OC1C=CC=CC=1)(COC1OC(N2C3C(=C(N=CN=3)N)N=C2)C(F)=C1)=O)C)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00427,C1C=CC(F)=C(COC2C=CC(C3NC(C(N)=O)CC3)=CC=2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00421,CC(CC1C=C(C)C(CCC=O)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00414,C1CC(N2N=CC=C2C2C=CC(Cl)=C(N)C=2)OCC1,Dmitry Zankov
Organic Process Research & Development,"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.,2020,10.1021/acs.oprd.0c00412,CC(C1C=C(C(O)CN2C3C(C(O)=O)=CC=CC=3C=C2)C=C(C2C=CC3OCC(N)C=3C=2)C=1)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00407,CC1(S(=O)(=O)C2N(C(C2)=O)C1C(O)=O)CN1N=NC=C1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00407,CC1(S(=O)C2N(C(C2Br)=O)C1C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00405,CC(O)1C(N)CCC1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00403,C1C=NC=CC=1C(O)CCO,Dmitry Zankov
Organic Process Research & Development,"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%).",2020,10.1021/acs.oprd.0c00397,CC(C(O)=O)C1C=CC=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00393,CCCCCCCCCCCCCCCCCC(OCC(OC(CCCCCCCCCCCCCCCCC)=O)COCC1OC(CS([O-])(=O)=O)C(O)C(O)C1O)=O,Dmitry Zankov
Organic Process Research & Development,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.",2021,10.1021/acs.oprd.0c00391,CC(C1CC=C(C)C=C1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00382,C1C=C(COC2C=CC(C3NC(C(N)=O)CC3)=CC=2)C(F)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00369,CC(F)(F)C1OCC(C2C(F)=CC=C(NC(C3N=CC(C(F)(F)F)=CC=3)=O)C=2)2C1COC(N)=N2,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00369,CC(F)(F)C1OCC(N)(C2C(F)=CC=C(Br)C=2)C1CO,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00366,CCCS(NC1CC(N(C2N=CN=C3C=2C=CN3)C)C1)(=O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00359,CCOC1C=CC(CC2C(Cl)=CC=C(C3OC(SC)C(O)C(O)C3O)C=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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%.",2020,10.1021/acs.oprd.0c00358,C1C=NC(C(N)2CC2)=NC=1,Dmitry Zankov
Organic Process Research & Development,"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).",2020,10.1021/acs.oprd.0c00324,CCCCC1C(C2C=CC=CC=2)=NC(N)=NC=1C1C=CC(OC)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00320,CC(OC(CC1OC(C)(C)OC(CO)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00314,CC1C(C(O)CN2CCN(CC(O)C3C(C)=C4COC(=O)C4=CC=3)CC2)=CC=C2C=1COC2=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00310,C1C=CC(COCC2OC(O)(C3N4C(C(N)=NC=N4)=CC=3)C(OCC3C=CC=CC=3)C2OCC2C=CC=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00304,C1NC2C(=C(N=C(N=2)F)N)N=1,Dmitry Zankov
Organic Process Research & Development,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 .",2020,10.1021/acs.oprd.0c00302,CC(OC1C=C(C2C=CN(C3CCNCC3)N=2)C=NC=1N)C1C(Cl)=C(F)C=CC=1Cl,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00299,C1C=C(N2C(=O)OC(CNC(C3SC(Cl)=CC=3)=O)C2)C=CC=1N1C(=O)COCC1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00291,CCOC1C(OCC(O)=O)=C(CNC2C(C(NC3C=CC(C(N)=N)=CC=3)=O)=CC(Cl)=CC=2)C=C(CN2CCN(C)CC2)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00289,CN1CCN(CC2C(C(F)(F)F)=CC(NC(C3C=C(C#CC4C=NC(N)=C5C=4C=CC=N5)C=NC=3)=O)=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00278,CCOC(COC1C=C(C)C(CCNC(C(O)C2C=CC(O)=CC=2)C)=CC=1C)=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00273,COCCOCCOCCOCCOCCOCCOCCO[C@H]1CC[C@]2([C@H]3CC4=C5[C@]2([C@H]1OC5=C(C=C4)O)CCN3CC=C)O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00270,C1C(CO[N+]([O-])=O)(CO[N+]([O-])=O)C(CO[N+]([O-])=O)(CO[N+]([O-])=O)C1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00256,CC1C=CC(NC(NC2C(F)=C(CN3CCN(C(OC)=O)CC3)C=CC=2)=O)=CN=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00245,CC(C1NC(=O)OC2C(CCC2)OC/C=C/C(F)(F)C2C(=NC3C=CC=CC=3N=2)OC2CC(C(NC(C(NS(C3(CC3)C)(=O)=O)=O)3C(C(F)F)C3)=O)N(C2)C1=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00244,CC(C1NC(=O)OC2C(CCC2)OC/C=C/C(F)(F)C2C(=NC3C=CC=CC=3N=2)OC2CC(C(NC(C(NS(C3(CC3)C)(=O)=O)=O)3C(C(F)F)C3)=O)N(C2)C1=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00234,CC(C1N(C2C=CC(F)=CC=2)C(SCCOC2C=CC(N3C=NC=C3)=CC=2)=NC=1)(C1C=C(OC)C(OC)=CC=1)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00233,C1N(C2OC(COP(OP(OP(O)(O)=O)(O)=O)(O)=O)C(O)C2O)C(=O)C(C(N)=O)=NC=1F,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00232,C1C(C2N=CN(CCO)C=2C2C=CC3N(C(C#N)=CN=3)N=2)=CC(Cl)=C(F)C=1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00229,CC1N(C(CC2C(Cl)=CC=CC=2Cl)=O)C(CO)CC2C(CCC(O)(C)C)=CC=CC1=2,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00215,COC1C(OCC2C=CC=CC=2)=C2C(CN(C(C(C3C=CC=CC=3)C3C=CC=CC=3)=O)C(C(O)=O)C2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.,2020,10.1021/acs.oprd.0c00209,OP(OP(OP(OP(OCC1OC(N2C(=O)NC(=O)C=C2)C(O)C1O)(O)=O)(O)=O)(O)=O)(OCC1OC(N2C(=O)NC(=O)C=C2)C(O)C1O)=O,Dmitry Zankov
Organic Process Research & Development,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%.",2020,10.1021/acs.oprd.0c00200,CC1/N=C(/C2C(F)=CC=CC=2)\C2C(=CC=C(Br)C=2)N2C1=C(N=C2)C(O)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00198,CC1C=CC(C(NC(C2N=CC=CN=2)2CC2)=O)=CC=1C1C(F)=C2C(C(NC)=O)=C(OC2=CC=1)C1C=CC(F)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00191,CC(CCCCCC/C=C/C=C\CCC(C)(C)C)=O,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00188,CC(CC(NC(OC(C)(C)C)=O)C(C(C)=C)=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00187,CC(CC(NC(OC(C)(C)C)=O)C(C1(OC1)C)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00184,C1C=CC(C2C(I)=CN=C3C=2C(C2CCCCC2)=NN3CC2C=CC=CC=2)=CC=1,Dmitry Zankov
Organic Process Research & Development,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).",2020,10.1021/acs.oprd.0c00180,C1C=C(S(C2CC2)(=O)=O)C=CC=1/C(/C(NC1N=CC(OCCO)=NC=1)=O)=C/C1CC(F)C(F)C1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00172,CCC(COC(C(NP(OC1C=CC=CC=1)(OCC1OC(C2N3C(C(N)=NC=N3)=CC=2)(C#N)C(O)C1O)=O)C)=O)CC,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00171,C(CB(O)O)CC1C(C(O)=O)NCC1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00167,C(=O)=NCN=C=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00155,CC1OC(C(NC(C2N(C)C(=O)C(O)=C(C(NCC3C=CC(F)=CC=3)=O)N=2)(C)C)=O)=NN=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00146,C1N(C2OC(CO)SC2)C(=O)N=C(N)C=1F,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00145,C1C(N)=NC(=O)N(C2OC(CO)SC2)C=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00141,CC1N(C(CC2C(Cl)=CC=CC=2Cl)=O)C(CO)CC2C1=CC=CC=2CCC(O)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00124,CC1C(C2C=C(C3N=NN(CC4N=C(C(O)(C)C)C=CC=4)C=3)N=C(N)N=2)=CC=CC=1C#N,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00087,CC(OC1CN(C(NCC2C(C)=CC(C3N=C(NC4C=NN(C)C=4)N=CC=3)=CC=2)=O)C1)C,Dmitry Zankov
Organic Process Research & Development,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%.",2020,10.1021/acs.oprd.0c00084,CCCCC/C=C\C/C=C\CCCCCCCCN(CCCCCCCC/C=C\C/C=C\CCCCC)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00083,C1C(N)=NC(=O)N(C2OC(CO)SC2)C=1,Dmitry Zankov
Organic Process Research & Development,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.,2020,10.1021/acs.oprd.0c00080,CC(OC(N1C(C(O)=O)CC(F)C1)=O)(C)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00078,C(N1C2C(=C(N=CN=2)N)N=C1)C(OCP(O)(O)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00076,CC(F)(F)C1C=C(F)C=CC=1C1SC2C=C(O)C=CC=2C=1OC1C=CC(/C=C/C(O)=O)=CC=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00068,C(C(O)=O)1C(N)=NON=1,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00067,CC(N/[N+](/[O-])=N\OC1CCN(C2N=CC(C#N)=CC=2)CC1)(C)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00066,CC(OC1CC(O)C=C1)=O,Dmitry Zankov
Organic Process Research & Development,"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).",2020,10.1021/acs.oprd.0c00051,CC(CC(NC(C(NC(C(NC(C(NC(CN1CCOCC1)=O)CCC1C=CC=CC=1)=O)CC(C)C)=O)CC1C=CC=CC=1)=O)C(C1(OC1)C)=O)C,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00030,CC(NC)(F)C(N(P)C)C#N,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00029,C1C(C#N)=CC2N(C(C=CC=2C=1)=O)CCN1CC(F)C(NCC2N=CC3OCCOC=3C=2)CC1,Dmitry Zankov
Organic Process Research & Development,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 ).",2020,10.1021/acs.oprd.0c00028,CN(C(C1C=CC=CC=1)=O)C1C=CC=C(C(NC2C(C(F)(F)F)=CC(C(F)(C(F)(F)F)C(F)(F)F)=CC=2Br)=O)C=1F,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00015,CC(NC1N=CC=C(C2NC3C=CC=NC=3C=2C2C=CC=C(C(F)F)N=2)C=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00012,CC1N(CC2C=C(F)C(N3CC4C(N5C=NN=C5)C4C3)=CC=2F)S(=O)(=O)C(C2C=CC=CC=2)CC1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00010,CC(OC1OC(COC(C2C=CC=CC=2)=O)SC1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00009,C/C=C1/CN2C(C(NC3C(C2=O)=CC(OC)=C(O)C=3)=O)C/1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00005,CC(NC(C1C=C(C(O)C)NN=1)=O)CN1N=C(C2C=C(Cl)C(C#N)=CC=2)C=C1,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00005,CC1(N(C2C=C(F)C(C(NC)=O)=CC=2)C(=S)N(C2C=CC(C#N)=C(C(F)(F)F)C=2)C1=O)C,Dmitry Zankov
Organic Process Research & Development,"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.",2020,10.1021/acs.oprd.0c00005,CNC(C1C(F)=CC(N2C3(CCC3)C(=O)N(C3C=NC(C#N)=C(C(F)(F)F)C=3)C2=S)=CC=1)=O,Dmitry Zankov
Organic Process Research & Development,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.",2020,10.1021/acs.oprd.0c00004,C1C=CC2C3N(C(CCC(F)4CCC(S(N)(=O)=O)CC4)C=2C=1)C=NC=3,Dmitry Zankov
Tetrahedron,"New synthetic route to 2,2,6,6-tetraethylpiperidin-4-one: A key-intermediate towards tetraethyl nitroxides",,2019,10.1016/j.tetlet.2019.151207,CCC1(NC(CC)(CC)CC(=O)C1)CC,Dmitry Zankov
Tetrahedron,An improved route for the synthesis of Rolloamide B,,2016,10.1016/j.tetlet.2016.07.044,CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@H](C(=O)N3CCC[C@H]3C(=O)N1)CC4=CC=CC=C4)CC(C)C)[C@@H](C)CC)CO,Dmitry Zankov
Synlett,"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.",2013,10.1055/s-0032-1317790,C1C=C2C(C3C=CC(CN4CCOCC4)=NC=3)=CC=C(N)C2=CC=1,Dmitry Zankov
Synlett,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.",2012,10.1055/s-0032-1317540,COC1=CC=CC(=C1)NC2=NC=NN3C2=C(C=C3)CN4CC[C@H]([C@@H](C4)O)N,Dmitry Zankov
Synlett,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.",2012,10.1055/s-0032-1317540,COC1C=C(NC2C3N(C=CC=3CO)N=CN=2)C=CC=1,Dmitry Zankov
Green Chemistry,A scalable and eco-friendly total synthesis of poly(ADP-ribose) polymerase inhibitor Olaparib,A scalable and eco-friendly total synthesis of PARP inhibitor.,2023,10.1039/d3gc02617e,C1C(C(N2CCN(C(C3C=C(CC4C5C(=CC=CC=5)C(=O)NN=4)C=CC=3)=O)CC2)=O)C1,Dmitry Zankov
Green Chemistry,"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.,2017,10.1039/c6gc03123d,CC1C(NC(C2C3C=NN(C4C=CC(F)=CC=4)C=3C=NC=2)=O)(C2C=CN=C(S(C)(=O)=O)C=2)C1,Dmitry Zankov
Reaction Chemistry & Engineering,Practical and scalable one-pot synthesis of arbekacin,An efficient and scalable one-pot production process was developed to prepare arbekacin from dibekacin.,2024,10.1039/d3re00598d,C1C[C@H]([C@H](O[C@@H]1CN)O[C@@H]2[C@H](C[C@H]([C@@H]([C@H]2O)O[C@@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)N)O)NC(=O)[C@H](CCN)O)N)N,Dmitry Zankov
Reaction Chemistry & Engineering,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.,2019,10.1039/c9re00118b,C[C@H]([C@H](C1=CC2=C(C=C1)OCCO2)OC3=CC4=C(C=C3)N(N=C4)C5=CC=CC(=C5)C(=O)N[C@@H]6CCOC6)NC(=O)C(C)(F)F,Dmitry Zankov
Synthesis,"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",1999,10.1055/s-1999-3458,C(CC(CCOC1C=NC=CC=1)CCC(O)=O)CCNS(C1C=CC(Cl)=CC=1)(=O)=O,Dmitry Zankov
Synthesis,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.,2015,10.1055/s-0034-1380505,CC1=CC(=C(C=C1)SC2=CC=CC=C2N3CCNCC3)C,Dmitry Zankov
Organic Letters,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.",2022,10.1021/acs.orglett.2c00980,CC1=C(C=C(C=C1)[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)CC3=CC=C(S3)C4=CC=C(C=C4)F,Dmitry Zankov
Organic Letters,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.",2012,10.1021/ol301715u,C1=CC2=C(C=C1O)OC3=C2C(=O)OC4=CC(=CC(=C43)O)O,Dmitry Zankov
Chemical Science,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.",2010,10.1039/c0sc00577k,CC(C)[C@@H]1C2=NC3=C(O2)[C@@]45[C@H](NC6=C(C=CC=C64)C7=C8C(=CC=C7)NC(=C8C9=C(N=C3O9)Cl)Cl)OC2=C5C=C(C[C@@H](C(=O)N1)NC(=O)[C@@H](C(C)C)O)C=C2,Dmitry Zankov
Chemical Science,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.",2011,10.1039/c1sc00009h,C1CN2CC3=CCO[C@H]4CC(=O)N5[C@H]6[C@H]4[C@H]3C[C@H]2[C@@]61C7=CC=CC=C75,Dmitry Zankov
European Journal of Organic Chemistry,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.",2021,10.1002/ejoc.202101508,C1=C2C(=C(C(=C1O)O)O)[C@@H]([C@H](OC2=O)C(=O)O)[C@H](CC(=O)O)C(=O)O,Dmitry Zankov
European Journal of Organic Chemistry,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.",2011,10.1002/ejoc.201101530,CCCC1C(CC(C2N1CCC2)CC)CC,Dmitry Zankov
European Journal of Organic Chemistry,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.",2020,10.1002/ejoc.202000465,C[C@@H]1[C@@H]2[C@@H](C(=O)C3=C(C=CC=C3O2)O)[C@@]([C@@H]1O)(C(=O)OC)O,Dmitry Zankov
Angewandte Chemie International Edition,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).",2007,10.1002/anie.200701581,C[C@@H](/C=C/[C@H](/C=C(/CCO)\Cl)O)[C@H]1CCC[C@]12CCC[C@@H](N2)C/C=C(\C)/C(=O)O,Dmitry Zankov
Angewandte Chemie International Edition,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.",2018,10.1002/anie.201812822,CC[C@]12CCCN[C@H]1N3C(=C(C4=CC=CC=C43)CCO)CC2,Dmitry Zankov
Journal of Organic Chemistry,"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.",2019,10.1021/acs.joc.8b02750,CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C,Dmitry Zankov
Journal of Organic Chemistry,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).",2010,10.1021/jo100561u,CC[C@](C1=NN=C(O1)NCC2=CC3=C(C=C2)C(=CC(=O)O3)C4=CC=C(C=C4)F)(C(F)(F)F)O,Dmitry Zankov
Journal of the American Chemical Society,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.",2009,10.1021/ja9009265,CCCC[C@@H](C)[C@H]([C@H](C[C@@H](C)C[C@@H](CCCC[C@H](C[C@@H]([C@H](C)N)O)O)O)OC(=O)C[C@@H](CC(=O)O)C(=O)O)OC(=O)C[C@@H](CC(=O)O)C(=O)O,Dmitry Zankov
Journal of the American Chemical Society,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.",2018,10.1021/jacs.8b09965,CC(=CCC1=C2C(=CC3=C1[C@H]([C@H]4C3=CC(OC4(C)C)(C)C)O)C5=C(N2)[C@]6([C@H](C5)CC[C@@H]7[C@@]6(CC[C@@H]([C@@]7(C)/C=C/C=C(\C)/C(=O)O)O)C)C)C,Dmitry Zankov