Crystallization-Induced Dynamic Resolution of a Diarylmthylamine 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.