Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly

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.