Synthesis of 1-(-Butyl) 4-Methyl (1,2,4)-2-Methylcyclohexane-1,4-dicarboxylate from Hagemann's -Butyl Ester for an Improved Synthesis of BMS-986251.

We describe an efficient synthetic route to differentially protected diester, 1-(-butyl) 4-methyl (1,2,4)-2-methylcyclohexane-1,4-dicarboxylate (+)-, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester as a critical component.