Deucravacitinib (BMS-986165) is a small molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route.  Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability.  Key accomplishments include: 1) the development of a novel cyclocondensation under mild conditions to afford a 1,2,4-triazole, 2) the development of safe, homogeneous conditions to quench POCl<sub>3</sub> following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, 3) the discovery of a robust, scalable “dual-base” palladium-catalyzed C-N coupling reaction, and 4) mechanistic understanding to inform control strategies for a number of process-related impurities in an EDC coupling API step.  Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.

Design and development of the commercial process to Deucravacitinib

ACS Spring 2022

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