Development of a Scalable Manufacturing Process for Alectinib with a Concise Preparation of the Indole-Containing Tetracyclic Core

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%.