Toward a Telescoped Batch-Continuous Process for the KRAS G12C Inhibitor GH35: Controlling a Critical Dimeric Impurity during Acryloylation

A combined batch-continuous-flow process was devised for the synthesis of the covalent KRASG12C inhibitor GH35 (1), specifically designed to address the challenging dimerization of its acrylamide warhead during the acryloylation reaction. By the use of flow chemistry, the formation of the critical dimeric impurity GH35-IM03 was effectively suppressed, enabling a scalable and robust manufacturing process. This approach reduced GH35-IM03 to 0.22% in the free base of GH35, significantly facilitating downstream purification and improving the overall yield. At the 58.6 kg scale for the drug substance (mesylate salt), the optimized process achieved an overall yield of 66.4%, representing a 24.7% increase over the conventional first-in-human batch process. The methodology establishes a reference strategy for managing reactive impurity formation in the synthesis of Michael-acceptor-based covalent inhibitors.