The development of a scalable continuous flow process to synthesize a densely functionalized quinazoline organozinc intermediate toward KRAS G12C inhibitor divarasib (GDC-6036) is reported herein. A traditional cryogenic batch metalation process was initially employed, but instability of the quinazoline organomagnesium species above −60 °C presented a logistical roadblock, with limited flexibility for its implementation as the manufacturing scale increased. An investigation of the underlying component reaction kinetics in batch mode using PAT was followed by process modeling to develop a practical continuous flow process. Challenges relating to reactor fouling caused by precipitation of inorganic solids were addressed through the combination of plug flow and continuous stirred tank reactors in the final production system. Initial laboratory proof-of-concept experiments translated successfully to a multikilogram scale, with excellent yield and performance in the subsequent atroposelective Negishi cross-coupling.

• Genentech, Inc.
• F. Hoffmann-La Roche AG

• Intermediate
• Process Analytical Technologies

1. Divarasib
2. halogen−metal exchange
3. HPLC
4. Intermediate
5. KRAS G12C Inhibitor
6. Negishi coupling
7. Process analytical technologies
8. Research Article