Preparation method of alectinib

Abstract

The invention discloses a preparation method of alectinib. The preparation method comprises the following steps of using 2-(4-bromo-3-hydroxyphenyl)ethyl acetate as a raw material; performing trifluoromethanesulfonic acid etherification with trifluoromethyl sulfonic anhydride, so as to obtain a trifluoromethanesulfonic acid etherification compound; performing substitution reaction with the other raw material, namely 4-(4-piperidyl)morpholine, so as to obtain 2-{4-bromo-3-[4-morpholine-4-yl]piperidine-1-yl]phenyl}ethyl acetate, then performing dimethylation reaction and hydrolysis reaction to obtain 2-{4-bromo-3-[4-morpholine-4-yl]piperidine-1-yl]phenyl}-2-methyl propionate to be subjected to condensation reaction with malonic acid mono-tert-butyl ester, so as to obtain the 4-{4-bromo-3-[4-morpholine-4-yl]piperidine-1-yl]phenyl}-4-methyl-3-oxopentanoate tert-butyl; utilizing a typical Fischer indole synthesis method, enabling carbonyl and phenylhydrazine to cyclize under the acid catalyzing action to form indole nuclear parent; finally, performing cyclizing reaction, boric acidifying and catalytic coupling reaction, so as to prepare the alectinib. The preparation method has the advantages that the design of route method is reasonable, the price of raw material is low, the obtaining is easy, and the reaction condition is easily and effectively controlled.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of alectinib. Background technique [0002] The chemical name of Alectinib, a novel anaplastic lymphoma kinase (ALK) inhibitor, is 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidine -1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, its chemical structure is: [0003] [0004] Alectinib is an innovative drug invented by Chugai Pharmaceutical, a subsidiary of Roche Pharmaceuticals. It has been approved as a breakthrough drug by the US FDA and has been approved for accelerated approval as a new oral anti-lung cancer drug for the treatment of advanced (metastatic) ALK gene mutations. Non-small cell lung cancer (NSCLC), or the treatment of patients resistant to crizotinib. [0005] Patents US20130143877 and WO2012023597A1 disclose a synthetic route for the preparation of Alectinib: starting from 7-methoxy-...

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Problems solved by technology

[0014] The starting materials of the above two synthetic routes are relatively expensive and difficult to obtain, so they need to be synthesized and prepared; because the intermediate products and final products of the two synthetic routes contain many impurities and by-products, a large amount of solvents are required for purification, and the operation is cumbersome , the yield is low, which is not conducive to the promotion of industrial production. Therefore, it is necessary to explore the preparation method of Alectinib which is suitable for industrial production due to its short process flow, simple operation and low cost.

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