Development of a Commercial Process for Deucravacitinib, a Deuterated API for TYK2 Inhibition

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 1,2,4triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl 3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable "dual-base" palladiumcatalyzed 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.

General Method for Ni-Catalyzed C–N Cross-Couplings of (Hetero)Aryl Chlorides with Anilines and Aliphatic Amines under Homogeneous Conditions Using a Dual-Base Strategy

“…After determining the viability of the Ni-catalyzed C−N coupling, we then investigated the scalability of this reaction by conducting the C−N coupling with >100 mmol starting aryl chloride, 6-chloro-2-methylquinoline (A), and the pharmaceutically relevant aniline B found in the TYK2 inhibitor deucravacitinib 47 (Figure 3) to produce coupling product 32. In this instance, the solvent was switched from 2-MeTHF to 1,2dimethoxyethane to facilitate direct drop isolation by the addition of water containing 2 equiv of potassium bicarbonate.…”

Development of a Scalable Route toward an Alkylated 1,2,4-Triazol, a Key Starting Material for CXCR3 Antagonist ACT-777991

“…Finally, ring closure onto the secondary nitrogen of the hydrazine would complete the formation of the triazole ring . The electrophile 12 could be introduced stepwise or as one single building block built up from a formic acid and an acetic acid derivative …”

Homogenous Iron-Catalysed Deuteration of Electron-Rich Arenes and Heteroarenes

“…8 Earlier this year, the third one was deucravacitinib, approved by the FDA for the treatment of plaque psoriasis. 9…”