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

被引：13

作者：

Hill, David R. ^{[1
]}

Abrahamson, Michael J. ^{[2
]}

Lukin, Kirill A. ^{[1
]}

Towne, Timothy B. ^{[1
]}

Engstrom, Kenneth M. ^{[1
]}

Reddy, Rajarathnam E. ^{[2
]}

Kielbus, Angelica B. ^{[2
]}

Pelc, Matthew J. ^{[1
]}

Mei, Jianzhang ^{[1
]}

Nere, Nandkishor K. ^{[1
]}

Chen, Shuang ^{[1
]}

Henry, Rodger ^{[1
]}

Chemburkar, Sanjay ^{[2
]}

Ding, Chen ^{[3
]}

Zhang, Hongqiang ^{[3
]}

Cink, Russell D. ^{[1
]}

机构：

[1] AbbVie Inc, Proc Res & Dev, N Chicago, IL 60064 USA

[2] AbbVie Inc, Operat Sci & Technol, N Chicago, IL 60064 USA

[3] AbbVie Inc, Analyt Res & Dev, N Chicago, IL 60064 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2020年 / 24卷 / 08期

关键词：

glecaprevir; ABT-493; HCV; Knoevenagel; chiral resolution; INHIBITORS; ESTERS;

D O I：

10.1021/acs.oprd.0c00245

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

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.

引用

页码：1393 / 1404

页数：12

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