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

• Published in: Organic process research & development Vol. 24; no. 8; pp. 1393 - 1404
• Main Authors: Hill, David R, Abrahamson, Michael J, Lukin, Kirill A, Towne, Timothy B, Engstrom, Kenneth M, Reddy, Rajarathnam E, Kielbus, Angelica B, Pelc, Matthew J, Mei, Jianzhang, Nere, Nandkishor K, Chen, Shuang, Henry, Rodger, Chemburkar, Sanjay, Ding, Chen, Zhang, Hongqiang, Cink, Russell D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.08.2020; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; HCV; Knoevenagel; ABT-493; chiral resolution; glecaprevir; ESTERS; INHIBITORS
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.0c00245

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.