Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed. READ ARTICLE
Organic Process Research & Development DOI:10.1021/acs.oprd.8b00427
Authors: Yuji Takahama, Kazuyoshi Obitsu, Kazuhiro Takeguchi, Shun Hirasawa, Koji Kobayashi, Takahiro Akiba, Norihiro Ueda, Ryoki Orii, Atsushi Ohigashi, Takumi Takahashi, Minoru Okada, Shigeru Ieda