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.

中文翻译：

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TRPA1 抑制剂 GDC-6599 第一代立体控制制造工艺的开发


我们报告了一种针对 TRPA1 抑制剂 GDC-6599 (1) 的适合用途、立体控制且无色谱法的第一代制造工艺，以实现首次人体临床试验。该过程中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-恶二唑形成和后期嘌呤酮 N-烷基化。该 13 步工艺成功生产了 4.39 kg GDC-6599 (1)，总产率为 11%，HPLC 纯度为 99.6 A%，er 大于 99.9:0.1，dr 大于 99.9:0.1。