Crystallization-Induced Dynamic Resolution of a Diarylmethylamine toward the Synthesis of a Potent TRPM8 Inhibitor

The development and demonstration of a crystallization-induced dynamic resolution (CIDR) to prepare a chiral diarylmethylamine, a key intermediate toward the synthesis of a potent TRPM8 inhibitor, is described. Essential to the development of this process was the discovery of (1) efficient classical resolution conditions by a high-throughput screening method, (2) formaldehyde as the optimal racemization agent based on comparison of first-order reaction rate constants, and (3) mechanical grinding as a method to improve solid–liquid mass transfer and facilitate reaction progress. Kinetic analysis of the racemization process and identification of the substrate functional group required for racemization provided the foundation for a mechanistic proposal.