Allen Y. Hong*, Katarzyna A. Piechowicz, Jacob C. Timmerman, Haiming Zhang, Carmela Molinaro and Francis Gosselin,
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Development of a First-Generation Stereocontrolled Manufacturing Process of TRPA1 Inhibitor GDC-6599
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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