A Practical Telescoped Three-Step Sequence for the Preparation of (1R,2R)-2-(4-Bromobenzoyl)cyclohexanecarboxylic Acid: A Key Building Block Used in One of Our Drug Development Projects

A large-scale, robust telescoped process involving acid chloride generation and Friedel–Crafts acylation followed by hydrolysis of an ester was developed for the manufacture of a homochiral disubstituted cyclohexane. Chromatography was avoided, and instead, crystallization was employed to furnish the pure carboxylic acid. This acid was further used as a key building block for the synthesis of drug candidates via amide bond formation using various amines followed by a Suzuki coupling with a pyrazole pinacol ester. The total synthesis of one of the drug candidates on a multihundred gram scale is described.