A Highly Atroposelective Negishi Coupling Enables the Commercial Manufacturing Process of Divarasib

Abstract

In this publication, we highlight our development efforts that resulted in the commercial manufacturing route of divarasib (1), a highly potent KRAS G12C inhibitor currently undergoing phase III clinical trials. Most prominently, our process landmarks, the first example of a highly atroposelective Negishi coupling at scale, allowing isolation of the step product (R_a)-4 as a single isomer without chromatography. The implementation of a continuous process for the metalation steps of the atroposelective Negishi coupling allowed for the elimination of the cryogenic reaction conditions from the manufacturing process. Furthermore, we detail improvements for the other chemical steps resulting in an impressive yield increase (factor of 6) and process mass intensity (PMI) reduction (factor of 39) for this sequence.