Alectinib (marketed as Alecensa) is an oral, highly potent ALK inhibitor for the treatment of ALK-positive, non–small-cell lung cancer (NSCLC). This paper describes the evolution from a medicinal chemistry synthetic process to a process enabling the scaled-up supply of a high-quality drug substance. A characteristic structural feature of alectinib is its indole-containing tetracyclic core, the construction of which was effectively achieved through intramolecular reductive cyclization and an intramolecular Friedel–Crafts reaction. Furthermore, the optimized synthetic route and conditions were designed to suppress the formation of impurities containing the same tetracyclic scaffold that are difficult to purge in downstream processes. The established manufacturing process could consistently produce alectinib on a multikilogram scale, typically with an overall yield of 29% and purity exceeding 99.9 area%.

中文翻译：

---

开发一种可扩展的 Alectinib 生产工艺，简明制备含吲哚的四环核心


Alectinib （商品名称为 Alecensa） 是一种口服高效 ALK 抑制剂，用于治疗 ALK 阳性非小细胞肺癌 （NSCLC）。本文描述了从药物化学合成工艺到能够扩大高质量原料药供应的工艺的演变。alectinib 的一个典型结构特征是其含吲哚的四环核心，其构建是通过分子内还原环化和分子内 Friedel-Crafts 反应有效实现的。此外，优化的合成路线和条件旨在抑制含有相同四环支架的杂质的形成，这些杂质在下游工艺中难以清除。已建立的生产工艺可以持续生产数公斤规模的 alectinib，通常总产率为 29%，纯度超过 99.9 面积。