Herein we describe a continuous flow process designed 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 using innovative analytical methods. 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 at >20 bar back pressure. Process safety was a key factor due to the extreme 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 custom-built pilot-scale (~1 L) reactor that processed >15 L of feed in a day. Implementation of process controls and PAT tools in the reactor design ensured maximum process safety at each scale, while allowing remote control of the flow equipment. Following the reaction, the product was recovered via cooling crystallization as a high purity racemic material suitable for further processing.
Keywords: Continuous processing, flow chemistry, high temperature, process safety, kinetic modeling, reactor design
