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.
This manuscript describes the control strategy for the commercial process to manufacture brivanib alaninate. The active pharmaceutical ingredient is a prodrug which is susceptible to hydrolysis. In addition to controlling hydrolysis, a robust strategy was required in order to control input and process-related impurities. Three significant aspects of control include understanding of the reaction parameters in order to minimize the regioisomer during the alkylation with (R)-propylene oxide, development of a design space through statistical models to control impurity formation, and the use of in situ FT-IR to monitor the hydrogenolysis of the Cbz protecting group.
BMS-813160 is a pharmaceutical entity
currently in development
at Bristol Myers Squibb. Its defining structural feature is a unique
chiral all cis triamino cyclohexane core. Medicinal
and process chemistry groups at BMS have previously published synthesis
strategies for chemotypes similar to the target molecule, but a streamlined
approach amenable for longer-term supply was necessary. A new synthetic
route was conceptualized, experimentally investigated, and determined
to meet the criteria for efficiency that addressed key limitations
of previous approaches. Adopting/optimizing the Trost asymmetric allylic
amination desymmetrization methodology was a key tool used to produce
a synthesis intermediate with high optical purity. In addition, developing
a tandem Mannich–aza-Michael reaction to obviate the need for
a Curtis/acylation sequence and a novel reductive amination/thermal
lactamization to circumvent Freidinger-type pyrrolidone preparation
are some of the synthesis improvements that enabled access to the
target molecule to fulfill long-term supply requirements.
The development of a multi-kilogram-scale synthetic route to enantiomerically pure ((2S,3S,4S)-3-ethyl-4-fluoro-5oxopyrrolidin-2-yl)methyl methanesulfonate (BMT-415200) 1 is described in this work. In this sequence, a safe and robust process of nine linear steps with four isolations was implemented. The synthesis features highly diastereoselective hydrogenation of enones 12, diastereoselective reduction of ketone 13, and deoxyfluorination of the corresponding secondary alcohol 8 followed by C−H oxidation of 9 to lactam 10. The target compound 1 was prepared in 19% overall yield with >99% purity from commercially available di-tert-butyl (S)-4-oxopyrrolidine-1,2-dicarboxylate 7.
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