Kalidindi S,
Gangu AS,
Kuppusamy S,
Sathasivam S,
Shekarappa V,
Murugan S,
Bondigela S,
Kandasamy M,
Ghanta K,
Vinodini A,
Shrikant A,
Ramachandran R,
Gallagher WP,
Kopp N,
González-Bobes F,
*,
Eastgate MD,
Vaidyanathan R.
*
Bristol-Myers Squibb, New Brunswick, USA and Bristol-Myers Squibb Research and Development Center, Bangalore, India
Development of a Scalable Synthetic Route to BMS-986251, Part 2: Synthesis of the Tricyclic Core and the API.
Org. Process Res. Dev. 2021;
25: 1556-1572
DOI:
10.1021/acs.oprd.1c00125
Key words
BMS-986251 - halogen–metal exchange - deoxyfluorination - annulation
Significance
RORγt is a nuclear receptor that regulates the production of proinflammatory cytokines, such as IL-17 and IL-22. BMS-986251 is a RORγt inverse agonist that is of interest for the treatment of immunological disorders. For syntheses of related analogues, see: D. Marcoux et al. J. Med. Chem.
2019, 62, 9931; A. Karmakar et al. Org. Process Res. Dev.
2021, 25, 1001.
Comment
Highlights of the synthesis of BMS-986251 depicted are (1) a high-yielding four-step aza-Michael addition/mesylation/annulation sequence to form the tricyclic core, and (2) installation of the heptafluoroisopropyl moiety through a three-step carboxylation–bistrifluoromethylation–deoxyfluorination sequence.
