Preparation method of Alectinib

A technology of alectinib and ethyl, which is applied in the field of medicinal chemical synthesis, can solve the problems of short technological process, difficult to obtain, and use a large amount of solvents, and achieves the effects of reasonable technical solution, simplified operation and less impurities

Active Publication Date: 2017-07-07
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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  • Preparation method of Alectinib
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  • Preparation method of Alectinib

Examples

Experimental program
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Embodiment 1

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

[0033] tert-butyl 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate (10.0g, 24mmol) was dissolved in N,N-dimethylformamide (200mL), Add 4-(4-piperidinyl)morpholine (9.2g, 54mmol), sodium methoxide (3.2g, 59mmol), and stir the reaction mixture at 100°C for 12 hours, then cool the reaction solution to room temperature, add water (40mL), and cool Crystallize at -10°C for 3 hours, filter to obtain 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3 - tert-butyl oxopentanoate, white solid (9.6 g), 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] tert-butyl 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate (9.0g, 20mmol), 3-cyanophenylhydrazine (3.3g, 25mmol) and trifluoroacetic acid (123.1g, 1080mmol) were mixed, th...

Embodiment 2

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

[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 base) 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, cooled to -10°C for 4 hours of crystallization , filtered to give tert-butyl 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate , white solid (5.0 g), 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] tert-butyl 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate (5.0g, 11mmol), 3-cyanophenylhydrazine (2.0g, 15mmol) and acetic acid (45.8g, 763mmol) were mixed, a...

Embodiment 3

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

[0047] 4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (13.5g, 32mmol) was dissolved in 1,4-dioxane (250mL), 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 for crystallization for 4 hours, 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] tert-butyl 4-{4-ethyl-3-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}-4-methyl-3-oxopentanoate (12.5g, 27mmol), 3-cyanophenylhydrazine (4.0g, 30mmol) and formic acid (50.2g, 1091mmol)...

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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 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
Inventor 林开朝张建国童明
Owner 湖南润星制药有限公司
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