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.
Cink, Russell D.,Ding, Chen,Engstrom, Kenneth M.,Fickes, Michael G.,Henle, Jeremy,Kallemeyn, Jeffrey M.,Lukin, Kirill A.,Marren, James,Morrill, Westin H.,Nere, Nandkishor K.,Pelc, Matthew J.,Ravn, Matthew M.,Shekhar, Shashank,Towne, Timothy B.,Vinci, John C.,Wei, Haojuan,Welch, Dennie S.,Zhao, Gang
Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis
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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(2020/02/04)
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