Development of a Scalable Synthetic Route to BMS-986251, Part 2: Synthesis of the Tricyclic Core and the API

• DOI: 10.1021/acs.oprd.1c00125
• Publication Date: 2021-06-15T14:37:31Z
• Authors: Srinivas Kalidindi; Aravind S. Gangu; Sankar Kuppusamy; Shunmugaraj Satha...; Vijaykumar Shekar...; Saravanan Murugan; Sivasankar Bondigela; Moorthy Kandasamy; Kishore Ghanta; Arun Vinodini; Abhishek Shrikant; Ravikumar Ramacha...; William P. Gallagher; Nathaniel Kopp; Francisco Gonzále...; Martin D. Eastgate; Rajappa Vaidyanathan
• Keywords: Annulation; Tricyclic; Side chain; Sequence (biology)

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 four-step telescoped diastereoselective aza-Michael reaction-annulation sequence followed by installation of the heptafluoro-iso-propyl side chain final amidation to furnish desired API.