Development and Demonstration of an Ultra-High-Temperature Continuous Racemization Process

Herein we describe a continuous flow process for the thermal racemization of an undesired atropisomer to facilitate recovery of the desired form from the racemic mixture. A kinetic model was developed with the ability to predict the degree of racemization at varying temperatures. The high activation energy for the process required it to be carried out over 300°C under continuous flow conditions using a superheated solvent stream. Process safety was a key factor in the reactor design due to the operating conditions and a potential thermal event observed during the characterization work. The process was demonstrated in a lab-scale (~100 mL) tubular reactor before being scaled up to a pilot-scale (~1 L) reactor that processed >15 L of feed in a day. Following the reaction, the product was recovered via cooling crystallization as a high purity racemic material suitable for further processing.