op9b00469_si_001.pdf (1.04 MB)
Development of the Enabling Route for Glecaprevir via Ring-Closing Metathesis
journal contributionposted on 2020-01-14, 20:07 authored by Russell D. Cink, Kirill A. Lukin, Richard D. Bishop, Gang Zhao, Matthew J. Pelc, Timothy B. Towne, Bradley D. Gates, Matthew M. Ravn, David R. Hill, Chen Ding, Steven C. Cullen, Jianzhang Mei, M. Robert Leanna, Jeremy Henle, José G. Napolitano, Nandkishor K. Nere, Shuang Chen, Ahmad Sheikh, Jeffrey M. Kallemeyn
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.