Investigation into the Formation of Impurities during the Optimization of Brigatinib

[Image: see text] During the process development of brigatinib, we have made an unusual observation about some impurities. Detailed investigation has led to the conclusion that impurity A is formed via the raw material 2 oxidation, impurity B is formed via the pyrolysis of DMF, impurity C is formed via raw material 4, and impurity D is formed via HCl-catalyzed decomposition of intermediate 3. The present work details a report of the journey toward the development of an efficient process for the commercial production of brigatinib substantially free from all the impurities.