A facile, scalable, and sustainable approach to the preparation of the indole-core of alectinib

Abstract Alectinib, which is marketed under the name Alecensa, is an orally administered and highly potent anaplastic lymphoma kinase (ALK) inhibitor used for the treatment of ALK-positive non-small-cell lung cancer. The distinctive structural feature of alectinib is its indole-fused tetracyclic scaffold, for which an efficient synthesis method is crucial in establishing the manufacturing process. While the methodology developed for the first-in-human study has proved to be practical for the preparation of the indole-core on a multi-kilogram scale, continuous improvements of the process for an indole intermediate have been made for reducing environmental impacts in the future manufacturing campaigns as well as sustainable production of alectinib. As a result, the newly established process for the intermediate successfully eliminates the use of harmful solvents restricted under the EU REACH regulation, as well as the need for a rare earth element.