Development of a First-Generation Stereocontrolled Manufacturing Process of TRPA1 Inhibitor GDC-6599

被引：0

作者：

Hong, Allen Y. ^{[1
]}

Piechowicz, Katarzyna A. ^{[1
]}

Timmerman, Jacob C. ^{[1
]}

Zhang, Haiming ^{[1
]}

Molinaro, Carmela ^{[1
]}

Gosselin, Francis ^{[1
]}

机构：

[1] Genentech Inc, Dept Synthet Mol Proc Chem, South San Francisco, CA 94080 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2024年 / 28卷 / 06期

关键词：

TRPA1; inhibitor; 1,2,4-oxadiazole; chiral tetrahydrofuran; stereoselective synthesis; biocatalysis; nucleophiliccyanation; RECEPTOR; IDENTIFICATION;

D O I：

10.1021/acs.oprd.4c00134

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

We report a fit-for-purpose, stereocontrolled, and chromatography-free first-generation manufacturing process for GDC-6599 (1), a TRPA1 inhibitor, to enable first-in-human clinical trials. Key steps in the process include consecutive KRED-mediated asymmetric ketone reductions, nucleophilic cyanation, 1,2,4-oxadiazole formation, and late stage purinone N-alkylation. The 13-step process successfully produced 4.39 kg of GDC-6599 (1) in 11% overall yield with 99.6 A% HPLC purity, >99.9:0.1 er, and >99.9:0.1 dr.

引用

页码：2325 / 2333

页数：9

共 21 条

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