Development of a Commercial Process for Deucravacitinib, a Deuterated API for TYK2 Inhibition
Daniel S. Treitler, Maxime Soumeillant, Eric M. Simmons, Dong Lin, Bahar Inankur, Amanda Rogers, Michael Dummeldinger, Sergei Kolotuchin, Collin Chan, Jun Li, Adam Freitag, Federico Lora Gonzalez, Michael J. Smith, Chris Sfouggatakis, Jianji Wang, Tamas Benkovics, Joerg Deerberg, James H. Simpson, Ke Chen, Steven A. Tymonko
Abstract
Deucravacitinib (BMS-986165) is a deuterated 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 methylated 1,2,4-triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl3 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 API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.