Process Development for the Manufacture of a Topical Pan-Trk Inhibitor Incorporating Decarboxylative sp2–sp3 Cross-Coupling

The development of a synthetic route toward topical pan-Trk inhibitor 1 is described as an eight-stage synthesis from available starting materials. Process improvements include the development of a decarboxylative sp2–sp3 cross-coupling which had not previously been demonstrated on scale. Parameters were explored, balancing the safety aspects with conversion and selectivity, scaling up in a stepwise fashion to multiple successful 0.7 kg batches. The cross-coupling showed high diastereoselectivity, with the opposite diastereomer not observed in the crude 19F NMR. Selectivity was further improved by crystallizing the downstream pyrrolidine salt after Boc deprotection, to give a diastereomer ratio of 99.5:0.5 by UPLC. This route has been reproducibly demonstrated in two GMP campaigns delivering API on kilogram scale, in >98% area purity by HPLC. The route design, solid-form screening, process research, and manufacture have enabled crucial first-in-human (FIH) clinical studies, through focus on speed of delivery.