Process Research for ZG1077, a KRAS G12C Inhibitor

A novel, efficient, and robust synthetic route to ZG1077 with an atropisomer structure for KRAS G12C inhibitors was designed. The critical process parameters were optimized and established to reduce or avoid process-related impurities. The formation mechanism, purge pathways, and control strategy for these impurities are discussed. Compared with the medicinal chemistry route, the single atropisomer drug substance was obtained with chiral resolution rather than the supercritical fluid chromatogram purification technique, and it was obtained in 3.01% overall yield with >99.5% purity and 99.8% e.e. in the novel route. However, the overall yield is only 0.56%, and the purity and chiral purity were less than 99.0% in the medicinal chemistry route. The process is suitable to obtain enough active pharmaceutical ingredients for preclinical and clinical studies.