Development of a Scalable Synthetic Route to BMS-986251. Part 1: Synthesis of the Cyclohexane Dicarboxylate Fragment

Abstract

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.

Organocatalytic Enantioselective Diels–Alder Reaction of 2‐Trifluoroacetamido‐1,3‐dienes with α,β‐Unsaturated Ketones

“…Reaction of 3 a with 2‐(trimethylsilyl)phenyl trifluoromethanesulfonate ( 13 ) in the presence of TBAT provided phenylated enamide 14 that could in principle be further functionalized [29] . On the other hand, the cycloadduct 3 v was transformed via a sequence of oxidation and hydrolysis to (1 R ,2 S )‐2‐methyl‐4‐oxocyclohexane‐1‐carboxylic acid ( 16 ) {[α] D =−14.1° ( c 0.5, CHCl 3 ), Lit [30] [α] D =−12.8° ( c 1.0, CHCl 3 )}, a key building block used in the synthesis of (+)‐compactin [31] and BMS‐986251 [32] (Scheme 5b). We note that the previous synthesis of the enantioenriched 16 relied on the resolution of the racemates.…”

Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, cis-to-trans Epimerization, and Saponification

“…The projected long duration and high cost for the SMB separation were a clear showstopper for us and necessitated the rapid development of a stereoselective route. With the help of external contract research organizations (CROs), two initial approaches were investigated: (1) the enzymatic kinetic resolution of trans -racemate 5 and (2) the enantioselective hydrogenation of enamide 28 (Scheme ). For the enzymatic resolution, a broad screening of hydrolases resulted in identification of a hit enzyme with high E-value (up to 761).…”