- Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly
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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 (1R,2R)-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.
- Abrahamson, Michael J.,Chemburkar, Sanjay,Chen, Shuang,Cink, Russell D.,Ding, Chen,Engstrom, Kenneth M.,Henry, Rodger,Hill, David R.,Kielbus, Angelica B.,Lukin, Kirill A.,Mei, Jianzhang,Nere, Nandkishor K.,Pelc, Matthew J.,Reddy, Rajarathnam E.,Towne, Timothy B.,Zhang, Hongqiang
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- Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis
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Glecaprevir was identified as a potent HCV NS3/4A protease inhibitor, and an enabling synthesis was required to support the preclinical evaluation and subsequent Phase I clinical trials. The enabling route to glecaprevir was established through further development of the medicinal chemistry route. The key steps in the synthesis involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key amino acid. The enabling route was successfully used to produce 41 kg of glecaprevir, sufficient to support the preclinical evaluation and early clinical development.
- Cink, Russell D.,Lukin, Kirill A.,Bishop, Richard D.,Zhao, Gang,Pelc, Matthew J.,Towne, Timothy B.,Gates, Bradley D.,Ravn, Matthew M.,Hill, David R.,Ding, Chen,Cullen, Steven C.,Mei, Jianzhang,Leanna, M. Robert,Henle, Jeremy,Napolitano, José G.,Nere, Nandkishor K.,Chen, Shuang,Sheikh, Ahmad,Kallemeyn, Jeffrey M.
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p. 183 - 200
(2020/02/04)
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- Method for Producing Fluorine-Containing Cyclopropane Carboxylic Acid Compound
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The present invention provides an industrially applicable method for production of a fluorine-containing cyclopropane carboxylic acid compound useful as an intermediate for pharmaceutical and agrichemical products. A fluorine-containing cyclopropane monoester is obtained by: forming a fluorine-containing cyclic sulfate with the use of a fluorine-containing dial compound and sulfuryl fluoride (as a cyclic sulfuric esterification step); reacting the fluorine-containing cyclic sulfate with a malonic diester, thereby forming a fluorine-containing cyclopropane diester (as a cyclopropanation step); and hydrolyzing the fluorine-containing cyclopropane diester (as a hydrolysis step). The fluorine-containing cyclopropane carboxylic acid compound, such as fluorine-containing cyclopropane monoester or its salt, can be obtained with high chemical and optical purity by mixing the fluorine-containing cyclopropane monoester with an amine and subjecting the resulting salt of the fluorine-containing cyclopropane monoester and amine to recrystallization purification.
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- Difluoroalkylcyclopropyl amino acids and esters, and syntheses thereof
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The invention provides methods of synthesizing compounds in an asymmetric or enantioenriched fashion, wherein the compounds are useful intermediates in the synthesis of viral protease inhibitors.
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- Synthetic route to anti-viral agents
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The invention provides methods of synthesizing a viral protease inhibitor in high yield, without using expensive catalysts or challenging reaction conditions.
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- Class of large ring heterocyclic compound restraining HCV and manufacturing and uses thereof
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The invention relates to a class of compounds that inhibit HCV. The compounds are represented by Formula A. The invention also relates to preparation and pharmaceutical use of the compounds.
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- Hepatitis C Virus Inhibitors
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Hepatitis C virus inhibitors having the general formula are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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Page/Page column 12
(2010/06/22)
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- QUINOXALINE-CONTAINING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS
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The present invention discloses compounds of formula I and II or pharmaceutically acceptable salts, esters, or prodrugs thereof which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, t
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Page/Page column 183
(2009/06/27)
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