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A kind of preparation method of alectinib

A technology of alectinib and ethyl, 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, less impurities, and easy reagents. The effect

Active Publication Date: 2019-09-20
湖南润星制药有限公司
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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.

Method used

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  • A kind of preparation method of alectinib
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  • A kind of preparation method of alectinib

Examples

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Effect test

Embodiment 1

[0032] A) Preparation of 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoic acid tert-butyl ester:

[0033] 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (10.0g, 24mmol) was dissolved in N,N-dimethylformamide (200mL), 4-(4-piperidinyl)morpholine (9.2g, 54mmol) and sodium methoxide (3.2g, 59mmol) were added, the reaction mixture was stirred at 100°C for 12 hours, the reaction solution was cooled to room temperature, water (40mL) was added, and cooled Crystallize at -10°C for 3 hours and filter to obtain 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3 -Tert-Butyl oxovalerate, white solid (9.6g), yield 87%.

[0034] B) Preparation of 6-cyano-2-{2-[4-ethyl-3-(4-(morpholin-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H -Indole-3-carboxylic acid:

[0035] 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate tert-butyl ester (9.0g, 20mmol), 3-cyanophenylhydrazine (3.3g, 25mmol) and trifluoroaceti...

Embodiment 2

[0039] A) Preparation of 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoic acid tert-butyl ester:

[0040] 4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (5.0g, 12mmol) was dissolved in toluene (100mL), and 4-(4-piperidine was added Yl)morpholine (5.5g, 32mmol), sodium ethoxide (2.4g, 35mmol), the reaction mixture was stirred at 110°C for 6 hours, the reaction solution was cooled to room temperature, water (50mL) was added, and cooled to -10°C for 4 hours to crystallize , Filter to obtain 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate tert-butyl ester , White solid (5.0g), yield 91%.

[0041] B) Preparation of 6-cyano-2-{2-[4-ethyl-3-(4-(morpholin-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H -Indole-3-carboxylic acid:

[0042] 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate tert-butyl ester (5.0g, 11mmol), 3-cyanophenylhydrazine (2.0g, 15mmol) and acetic acid (45.8g, ...

Embodiment 3

[0046] A) Preparation of 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoic acid tert-butyl ester:

[0047] 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (13.5g, 32mmol) was dissolved in 1,4-dioxane (250mL) and added 4-(4-piperidinyl)morpholine (10.0g, 59mmol), sodium tert-butoxide (6.2g, 65mmol), the reaction mixture was stirred at 90°C for 18 hours, the reaction solution was cooled to room temperature, and water (120mL) was added. Cool to -5°C and crystallize for 4 hours and filter to obtain 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl- Tert-Butyl 3-oxopentanoate, white solid (12.6 g), yield 86%.

[0048] B) Preparation of 6-cyano-2-{2-[4-ethyl-3-(4-(morpholin-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H -Indole-3-carboxylic acid:

[0049] 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoic acid tert-butyl ester (12.5g, 27mmol), 3-cyanophenylhydrazine (4.0g, 30mmol) and formic acid (5...

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Abstract

The invention discloses a preparation method of Alectinib. The method comprises the steps that tert-butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate and 4-(piperidin-4-yl)-morpholine are subjected to a substitution reaction; obtained tert-butyl 4-{4-ethyl-3-[4-(morpholine-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate is subjected to a cyclization reaction and hydrolysis reaction, obtained 6-cyano-2-{2-[4-ethyl-3-(4- morpholine-4-yl)piperidin-1-yl)phenyl]prop-2-yl}-1H-indole-3-carboxylic acid is subjected to the cyclization reaction, and the Alectinib is obtained. According to the method, the operation is simplified, the cost is low, and the method is an environment-friendly technical method and suitable for industrial production.

Description

Technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a preparation method of alectinib. Background technique [0002] The chemical name of the new anaplastic lymphoma kinase (ALK) inhibitor Alectinib 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 certified as a breakthrough therapy drug by the US FDA, and has accelerated approval as a new oral anti-lung cancer drug for the treatment of advanced (metastatic) ALK gene mutations. Treatment of non-small cell lung cancer (NSCLC) or patients who are resistant to crizotinib. [0005] Patent US20130143877 and WO2012023597A1 disclose a synthetic route for preparing alectinib: starting with 7-methoxy-3,4-dihydro-2-naphthone, throu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
Inventor 林开朝张建国童明
Owner 湖南润星制药有限公司
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