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https://lnkd.in/gYY28Q-K This study presents the development of a scalable continuous flow process for synthesizing a densely functionalized quinazoline organozinc intermediate for the KRAS G12C inhibitor Divarasib (GDC-6036). Initially, a cryogenic batch metalation process faced logistical challenges due to the instability of the quinazoline organomagnesium species above −60 °C. Investigation of reaction kinetics in batch mode, followed by process modelling, led to a practical, continuous flow approach. Addressing reactor fouling issues, a combination of plug flow and continuous stirred tank reactors was implemented in the final production system. Laboratory experiments successfully translated to a multikilogram scale, yielding excellent performance in subsequent atroposelective Negishi cross-coupling.
