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Method for preparing alectinib

A technology of alectinib and dihydrogen, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of unfavorable industrial production promotion, expensive starting materials, and the use of a large amount of solvents, and achieves easy and effective control of reaction conditions, reasonable and unique design, and reagents Easy to get effect

Inactive Publication Date: 2017-09-05
HUNAN BOAODE BIOPHARML TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 requir

Method used

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  • Method for preparing alectinib

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0043] Example 1

[0044] A) Preparation of 6-bromo-7-hydroxy-3,4-dihydro-2-naphthone:

[0045] 6-Bromo-7-methoxy-3,4-dihydro-2-naphthone (6.0g, 23.5mmol) and a mass percentage concentration of 48% hydrobromic acid aqueous solution (39.6g, 234.9mmol) were added to the reaction flask, The reaction mixture was added to 100°C, refluxed and stirred for 24 hours. TLC spot plate confirmed the reaction was completed, the reaction solution was reduced to 0-5°C, 50% sodium hydroxide solution was slowly added to adjust the pH to 2, and the solution was precipitated at 0-5°C. Crystallize for 3h, filter, and recrystallize the filter cake with a mixed solvent of ethyl acetate and n-hexane to obtain 6-bromo-7-hydroxy-3,4-dihydro-2-naphthone, an off-white solid (5.4g). The rate is 95%.

[0046] B) Preparation of 6-bromo-1,2,3,4-tetrahydro-2-oxo-7-naphthyl triflate:

[0047] 6-Bromo-7-hydroxy-3,4-dihydro-2-naphthone (5.0g, 20.7mmol) was dissolved in triethylamine (4.2g, 41.5mmol), and trifluorometh...

Example Embodiment

[0058] Example 2

[0059] A) Preparation of 6-bromo-7-hydroxy-3,4-dihydro-2-naphthone:

[0060] 6-Bromo-7-methoxy-3,4-dihydro-2-naphthone (5.0g, 19.6mmol) and a mass percentage concentration of 48% hydrobromic acid aqueous solution (49.6g, 294.2mmol) were added to the reaction flask, The reaction mixture was added to 105°C, refluxed and stirred for 20 hours. TLC spot plate confirmed that the reaction was completed. The reaction solution was reduced to 0-5°C, and 50% sodium hydroxide solution was slowly added to adjust the pH to 2, and it was precipitated at 0-5°C. Crystallize for 3h, filter, and recrystallize the filter cake with a mixed solvent of ethyl acetate and n-hexane to obtain 6-bromo-7-hydroxy-3,4-dihydro-2-naphthone, an off-white solid (4.7g). The rate is 99%.

[0061] B) Preparation of 6-bromo-1,2,3,4-tetrahydro-2-oxo-7-naphthyl triflate:

[0062] 6-Bromo-7-hydroxy-3,4-dihydro-2-naphthone (4.5g, 18.7mmol) was dissolved in N,N-diisopropylethylamine (6.0g, 46.4mmol), slowly...

Example Embodiment

[0073] Example 3

[0074] A) Preparation of 6-bromo-7-hydroxy-3,4-dihydro-2-naphthone:

[0075] 6-Bromo-7-methoxy-3,4-dihydro-2-naphthone (2.5g, 9.8mmol) and a mass percentage concentration of 48% hydrobromic acid aqueous solution (8.3g, 49.2mmol) were added to the reaction flask, The reaction mixture was added to 95°C, stirred and reacted under reflux for 30 hours. TLC spot plate confirmed that the reaction was completed. The reaction solution was reduced to 0-5°C, and 50% sodium hydroxide solution was slowly added to adjust the pH to 2, and it was precipitated at 0-5°C. Crystallize for 3h, filter, and recrystallize the filter cake with a mixed solvent of ethyl acetate and n-hexane to obtain 6-bromo-7-hydroxy-3,4-dihydro-2-naphthone, an off-white solid (2.2g). The rate is 93%.

[0076] B) Preparation of 6-bromo-1,2,3,4-tetrahydro-2-oxo-7-naphthyl triflate:

[0077] 6-Bromo-7-hydroxy-3,4-dihydro-2-naphthone (2.2g, 9.1mmol) was dissolved in pyridine (1.1g, 13.9mmol), and trifluoromet...

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Abstract

The invention discloses a method for preparing alectinib. The method comprises the following steps: firstly, by taking 6-bromine-7-methoxy-3,4-dihydro-2-naphthalenone as a raw material, performing hydrolysis so as to obtain methoxyl, performing deprotection, further performing trifluoromethanesulfonic acid esterification reaction on trifluoromethanesulfonic anhydride so as to obtain a trifluoromethanesulfonie ester compound, performing bimethylation reaction, performing substitution reaction on 1,1-dimethyl-6-bromine-2-oxo-3,4-dihydro-7-trifluoromethanesulfonate and another raw material, namely 4-(4-piperidyl) morpholine, implementing a classical reaction Fisher indole synthesis method, performing cyclization on carbonyl and phenylhydrazine under acid catalysis so as to form indole parent nucleus, and finally performing oxidation reaction, boric acid formation and catalytic coupling reaction, thereby obtaining the alectinib. The method is simple to operate and relatively low in cost, is a green and environmental-friendly process method, and is applicable to 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-...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 林开朝黄伟张建国
Owner HUNAN BOAODE BIOPHARML TECH DEV
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