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

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC

ACS Applied Electronic Materials Pub Date : 2024-05-23 DOI:10.1021/acs.oprd.4c00134

Allen Y. Hong*, Katarzyna A. Piechowicz, Jacob C. Timmerman, Haiming Zhang, Carmela Molinaro and Francis Gosselin,

引用次数: 0

Abstract

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.

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开发 TRPA1 抑制剂 GDC-6599 的第一代立体可控制造工艺

我们报告了 TRPA1 抑制剂 GDC-6599 (1) 的适合目的、立体可控和无色谱的第一代生产工艺，以实现首次人体临床试验。该工艺的关键步骤包括连续的 KRED 介导的不对称酮还原、亲核氰化、1,2,4-噁二唑形成和后期的嘌呤酮 N-烷基化。该 13 步工艺成功制备了 4.39 千克 GDC-6599 (1)，总收率为 11%，HPLC 纯度为 99.6A%，ER 值为 99.9:0.1，DR 值为 99.9:0.1。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Applied Electronic Materials Multiple-

CiteScore

7.20

自引率

4.30%

发文量

567