Development of a Streamlined Manufacturing Process for the Highly Substituted Quinazoline Core Present in KRAS G12C Inhibitor Divarasib

A streamlined process for the synthesis of a highly functionalized quinazoline that enabled late-stage preparation of KRAS G12C inhibitor divarasib is presented herein. The highlights of the synthesis are a telescoped four-step preparation of the key 2-amino-4-bromo-3-fluorobenzonitrile intermediate, a critical aromatic chlorination using NCS and catalytic HCl, a cyclization to a quinazoline dione employing CO2 and DBU, and a DABCO-MsOH-catalyzed Halex reaction to form target quinazoline fluoride 2. In the chlorination step, we encountered an unusual halogen scrambling, resulting in critical 4,5-dichloro and 4,5-dibromo impurities that needed to be controlled down to low levels due to minimal purging power in downstream chemistry. The manufacturing process was demonstrated by the preparation of >500 kg of quinazoline 2 in 39% overall yield and 99.5 area % HPLC purity over nine chemical steps and five isolations.