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.
NSTL