Axial Chirality in the Sotorasib Drug Substance, Part 2: Leveraging a High-Temperature Thermal Racemization to Recycle the Classical Resolution Waste Stream

The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate atropisomer M-1 from a racemic precursor (rac-1). In parallel, the team sought to develop a racemization process to enable recycling of the classical resolution waste stream and maximize productivity and sustainability. Computational and experimental methods revealed a high barrier to rotation (ca. 42 kcal/mol) prompting the design of a high-temperature (>300 °C) racemization protocol for recovery of the racemic compound. Described herein are the determination of the barrier to rotation, optimization of conditions to enable racemization, proof-of-concept for a continuous-flow process to execute the process, and kilogram-scale demonstration, including (1) recovery of the undesired atropisomer as a crystalline solid from the classical resolution waste stream, (2) thermal racemization by a high-temperature continuous-flow process, and (3) isolation of the racemic compound by crystallization directly from the reaction stream.