A ceritinib preparing method

Abstract

The invention relates to a ceritinib preparing method. The method includes (1) reacting 4-bromo-2-isopropoxy-5-methylaniline and acetic anhydride to generate N-(4-bromo-2-isopropoxy-5-cresyl) acetamide, (2) reacting 4-piperidone to generate N-benzyl-4-piperidone, (3) subjecting the N-(4-bromo-2-isopropoxy-5-cresyl) acetamide and the N-benzyl-4-piperidone to a docking reaction, (4) subjecting a product of the former step to dehydroxylation and (5) generating a finally product that is ceritinib from N-(4-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-cresyl) acetamide under the existence of a catalyst. The novel ceritinib preparing method is provided. The synthesis route is low in cost, reaction conditions are mild and easy to control, and the method is suitable for large-scale industrial production.

Description

technical field

[0001] The invention relates to a method for synthesizing organic compounds, in particular to a method for preparing ceritinib. Background technique

[0002] Ceritinib is an anticancer drug approved by the FDA on April 29, 2014. Ceritinib is an ALK inhibitor (Anaplastic Lymphoma Kinase), indicated for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed after crizotinib treatment or who are intolerant to crizotinib. The trade name is Zykadia, developed by Novartis Pharmaceuticals.

[0003] The synthesis of ceritinib uses the convergence method, first synthesizing two fragments with similar molecular weights, and then splicing the two fragments (JMC, 2013, 5675). The first fragment starts from compound 1, after nitration by SNAr reaction with isopropanol to give 2, 2 and 3 PtO after Suzuki coupling 2 Fragment 4 was obtained by catalytic hydrogenation to reduce the nitro g...

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