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

Abstract

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.

A Radical Addition Approach to a Heptafluoroisopropyl Substituted Arene, Combined with a Highly Diastereoselective Annulation Reaction To Synthesize the Tricyclic Core of BMS-986251

“…Namely: (1) the cost and lead time of 6-iodotetralone; 4 (2) the introduction of the sulfur at the wrong oxidation state, which had to be adjusted in the synthetic linear sequence; (3) the need for a classical resolution approach which reduced overall yield and impacted material throughput; and (4) the multistep installation of the heptafluoroisopropyl group including an unproductive protection/deprotection sequence. 5 As we set to explore route options which would enable meeting the program goals, we considered several synthetic strategies and prioritized those which would result in (1) use of readily available starting materials; (2) an asymmetric synthesis which would not require classical resolution; and (3) simple, ideally one-step, incorporation of the challenging heptafluoroisopropyl group.…”

“…Specifically, this new route benefited from a 4fold increase in overall yield, a 66% reduction in cycle time, an 87% reduction in PMI (process mass intensity), and a projected 4-fold reduction of raw material cost when compared to our previous approach (Table 2). 2 ■ EXPERIMENTAL SECTION General Information. All reactions were performed under a nitrogen atmosphere.…”

“…We have recently described our initial synthetic route to intermediate 10 , which was crucial to enable the preparation of 12 and support early development and clinical activities. Compound 10 was synthesized through a 10-step sequence (Scheme ). This sequence was based on the initial discovery route that utilized 6-iodo-tetralone as starting material .…”

“…Isolation of 9 as the HCl salt was challenging due to slow filtration caused by the needle crystal morphology and its hygroscopicity, which complicated long-term storage and handling. We decided to target a different salt for isolation and selected l -tartaric acid, as a well-behaved salt and ideal for isolation and storage. The tartrate salt also provided an additional purge of the minor enantiomer to <0.5%.…”

Radical Perfluoroalkylation of Arenes via Carbanion Intermediates

“…Perfluoroalkyl-substituted arenes have received significant interest from the synthetic chemistry community over the past few decades due to the prevalence of these moieties within a large array of clinical drug candidates. − One such clinical candidate recently reported by Bristol Myers Squibb was the heptafluoroisopropyl-substituted (HFP) 1 , which is shown to be a promising inverse agonist of RORγt (Figure ). …”