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.

中文翻译：

---

生产掺入脱羧 sp2-sp3 交叉偶联的局部 Pan-Trk 抑制剂的工艺开发


针对局部 pan-Trk 抑制剂 1 的合成路线的开发被描述为从可用起始材料进行八阶段合成。工艺改进包括开发脱羧 sp^{2-sp 3} 交叉偶联，这在以前从未进行过大规模验证。探索了参数，平衡了安全性与转化率和选择性，逐步扩大到多个成功的 0.7 kg 批次。交叉偶联显示出高非对映选择性，在粗制 ¹⁹F NMR 中未观察到相反的非对映异构体。通过在 Boc 脱保护后结晶下游吡咯烷盐进一步提高选择性，通过 UPLC 得到 99.5：0.5 的非对映异构体比。该路线已在两次 GMP 活动中得到可重复的证明，通过 HPLC 以 >98% 的峰面积纯度提供千克级 API。通过关注交付速度，路线设计、实体形式筛选、工艺研究和制造使关键的首次人体 （FIH） 临床研究成为可能。