Development of a Scalable Synthesis of a HPK1 Inhibitor Featuring a Direct α-Arylation of Boc-Protected N,N-Dimethylamine by Palladium-Mediated Negishi Cross-Coupling

The development of an improved synthesis of the potent HPK1 inhibitor, compound 1, is described. Two primary strategies were explored during this process: metallaphotoredox decarboxylative coupling and Negishi cross-coupling, both focusing on the direct installation of Boc-protected amine in a single step. Through the optimized Pd-catalyzed Negishi cross-coupling, a robust procedure was established for preparing the compound 9 from 3 in a single step on a 20 g scale. This optimization successfully reduced the overall synthesis steps required to produce 1 from 11 to 6, achieving a 28% overall yield.