Process Development for the Manufacture of a Topical\nPan-Trk Inhibitor Incorporating Decarboxylative sp<sup>2</sup>–sp<sup>3</sup> Cross-Coupling

The\ndevelopment of a synthetic route toward topical pan-Trk inhibitor <b>1</b> is described as an eight-stage synthesis from available\nstarting materials. Process improvements include the development of\na decarboxylative sp<sup>2</sup>–sp<sup>3</sup> cross-coupling\nwhich had not previously been demonstrated on scale. Parameters were\nexplored, balancing the safety aspects with conversion and selectivity,\nscaling up in a stepwise fashion to multiple successful 0.7 kg batches.\nThe cross-coupling showed high diastereoselectivity, with the opposite\ndiastereomer not observed in the crude <sup>19</sup>F NMR. Selectivity\nwas further improved by crystallizing the downstream pyrrolidine salt\nafter Boc deprotection, to give a diastereomer ratio of 99.5:0.5 by\nUPLC. This route has been reproducibly demonstrated in two GMP campaigns\ndelivering API on kilogram scale, in >98% area purity by HPLC.\nThe\nroute design, solid-form screening, process research, and manufacture\nhave enabled crucial first-in-human (FIH) clinical studies, through\nfocus on speed of delivery.