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Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

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journal contribution
posted on 20.02.2019, 17:19 by Yuji Takahama, Kazuyoshi Obitsu, Kazuhiro Takeguchi, Shun Hirasawa, Koji Kobayashi, Takahiro Akiba, Norihiro Ueda, Ryoki Orii, Atsushi Ohigashi, Takumi Takahashi, Minoru Okada, Shigeru Ieda
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.