A kind of preparation method of alectinib

Abstract

The invention discloses a preparation method for alectinib. The preparation method comprises the following steps: with 2-{4-bromo-3[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-2-methylethyl propionate as a raw material, carrying out a reduction reaction to reduce the raw material into aldehyde; then subjecting the prepared aldehyde and tert-butyl 2,2-dichloroacetate to an addition-rearrangement reaction; then subjecting obtained 3-chloro-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-tert-butyl 2-oxovalerate to a substitution reaction; carrying out a cyclization reaction and a hydrolysis reaction on prepared 3-(3-cyanophenylamino)ethyl-4-{4-bromo-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-tert-butyl 2-oxovalerate; subjecting obtained 6-cyano-2-{2-[4-bromo-3-(4-(morpholin-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H-indole-3-carboxylic acid to a cyclization reaction; and successively carrying out a boric acid reaction and a catalytic coupling reaction on obtained 9-bromo-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-formonitrile so as to obtain alectinib. The method has the advantages of simple operation and low cost, and is a green environment-friendly process suitable for industrial production.

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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