Investigation into the Formation of Impurities during the Optimization of Brigatinib

Aofeng Guo; Qiankun Zhang; Junming Zhang; Jiale Chen; Jiaqi Chen; Yu Sha

doi:10.1021/acsomega.0c03816

Investigation into the Formation of Impurities during the Optimization of Brigatinib

ACS Omega. 2020 Nov 3;5(45):29265-29271. doi: 10.1021/acsomega.0c03816. eCollection 2020 Nov 17.

Authors

Aofeng Guo¹, Qiankun Zhang¹, Junming Zhang¹, Jiale Chen¹, Jiaqi Chen¹, Yu Sha¹

Affiliation

¹ Key Laboratory of Structure-Based Drug Design& Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, P. R. China.

Abstract

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.