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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