Axial Chirality in the Sotorasib Drug Substance, Part 1: Development of a Classical Resolution to Prepare an Atropisomerically Pure Sotorasib Intermediate
Andrew T. Parsons, Seb Caille, Marc A. Caporini, Daniel J. Griffin, Michael A. Lovette, William Powazinik, Gabrielle St‐Pierre
Abstract
Described herein is the discovery and development of a process to prepare an atropisomeric intermediate in the synthesis of the KRAS G12C inhibitor sotorasib. Using high-throughput experimentation, (+)-2,3-dibenzoyl-d-tartaric acid [(+)-DBTA] was identified as an inexpensive and readily available resolving agent that enables separation and isolation of the desired atropisomer through a classical resolution. Subsequent optimization and characterization studies led to a highly selective process, providing the desired atropisomer as a unique three-component cocrystal solvate with a selectivity of >2000:1. This classical resolution has been performed successfully on >500 kg scale and was critical to the commercialization of the sotorasib manufacturing process.