1360828-80-3Relevant articles and documents
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly
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
, p. 1393 - 1404 (2020/10/15)
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.
Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis
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.
, p. 183 - 200 (2020/02/04)
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.
Synthetic route to anti-viral agents
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Page/Page column 74, (2017/11/27)
The invention provides methods of synthesizing a viral protease inhibitor in high yield, without using expensive catalysts or challenging reaction conditions.
MACROCYCLIC AND BICYCLIC INHIBITORS OF HEPATITIS C VIRUS
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Page/Page column 89, (2014/09/29)
Compounds of formula (I):or pharmaceutically acceptable salts thereof, wherein the various substituents are defined herein, methods of using said compounds, and pharmaceutical compositions containing said compounds.
