Alternative Synthesis of Cobimetinib

A novel approach for synthesis of Cobimetinib was reported, avoiding usage of a strong base in any of the steps with a chiral substrate. An efficient kinetic resolution of racemic key intermediate - tert-butyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate with L-tartaric acid was developed, by which enantiopure S-enantiomer was obtained as the corresponding diastereomeric tartrate salt, followed by peptide coupling with 3,4-difluoro-2-(2-fluoro-4-iodo-anilino) benzoic acid in mild conditions and avoiding the use of corresponding haloanhydrides, affording Boc-protected Cobimetinib. In the end, Cobimetinib was obtained in a total yield of 28.2%, calculated based on the S-enantiomer of the racemic key intermediate, via acid-mediated removal of Boc-protective group.