op0c00245_si_002.cif (379.35 kB)
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly
dataset
posted on 2020-07-28, 16:27 authored by David
R. Hill, Michael J. Abrahamson, Kirill A. Lukin, Timothy B. Towne, Kenneth M. Engstrom, Rajarathnam E. Reddy, Angelica B. Kielbus, Matthew J. Pelc, Jianzhang Mei, Nandkishor K. Nere, Shuang Chen, Rodger Henry, Sanjay Chemburkar, Chen Ding, Hongqiang Zhang, Russell D. CinkThe 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.