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.
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