op0c00244_si_004.cif (3.45 MB)
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Macrocycle via Intramolecular Etherification
dataset
posted on 2020-07-28, 16:26 authored by Jeffrey
M. Kallemeyn, Kenneth M. Engstrom, Matthew J. Pelc, Kirill A. Lukin, Westin H. Morrill, Haojuan Wei, Timothy B. Towne, Jeremy Henle, Nandkishor K. Nere, Dennie S. Welch, Shashank Shekhar, Matthew M. Ravn, Gang Zhao, Michael G. Fickes, Chen Ding, John C. Vinci, James Marren, Russell D. CinkGlecaprevir 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.