The process development for the synthesis of BMS-986020 (1) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient 1. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation.

We report research and development conducted to enable the safe implementation of a highly enantioselective palladium-catalyzed desymmetrization of a meso−bis-ester using trimethylsilylazide (TMSN 3 ) as the nucleophile. This work is used as a case example to discuss safe practices when considering the use of azide reagents or intermediates, with a focus on the thermodynamic and quantitative analysis of the hazards associated with hydrazoic acid (HN 3 ).

Many active pharmaceutical ingredients (APIs) display poor powder properties and cannot be directly compressed into tablets with sufficient strength. The desired powder properties are often difficult to achieve through conventional particle engineering approaches, such as particle size and habit modification during crystallization. Co-processing of API with excipients can significantly improve the functional properties to overcome these difficulties. Herein, a co-processing technology was developed to improve powder properties in which the polymer is precipitated and coats the crystalline API particles resulting in discrete, nearly spherical agglomerates. Critical process parameters were identified and scalability up to 50 kg scale was demonstrated in the pilot plant. The co-processed APIs generated under various process conditions were formulated into blends at 50−90 wt % loading and successfully processed by direct compression.

BMS-986251, a potent and efficacious RORγt inverse agonist, was synthesized starting from 6-iodotetralone using 13 chemical transformations with only eight isolated intermediates. The synthesis involved a four-step telescoped diastereoselective aza-Michael reaction-annulation sequence followed by installation of the heptafluoro-iso-propyl side chain and final amidation to furnish the desired API.

The cyclohexane dicarboxylate unit of BMS-986251 (1), a potent and efficacious RORγt inverse agonist, was synthesized starting from Hagemann’s ester in seven chemical transformations with five isolated intermediates. The synthesis involved an enzymatic kinetic resolution, a two-step telescoped enol tosylation followed by carboxylation using a benign CO surrogate for the installation of the second carboxylate functionality, and a Crabtree catalyst-mediated diastereoselective olefin hydrogenation. This process was successfully demonstrated to produce 3.6 kg of compound 3.