We report herein the development and scale up of an Ir-catalyzed N-alkylation reaction between a 4-bromopyridin-2-amine (1) and (4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanol (2) proceeding via a borrowing hydrogen process. The traditional approach of alcohol oxidation followed by reductive amination posed challenges that are attributed to the poor nucleophilicity of the 2-aminopyridine derivative (1) resulting in lower isolated yields. Several catalysts and bases were evaluated for the successful N-alkylation of 1 with 2, and an Ir (III) catalyst in combination with LiOt-Bu as a base was found to provide optimal conversion. The borrowing hydrogen process was successfully demonstrated on a 1.5 kg scale and afforded >70% yield of 3 without the need for a sealed reactor or any other specialized equipment.

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.

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.

We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCI) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.