A kind of preparation method of alectinib

A technology of alectinib and ethyl, applied in the field of medicinal chemical synthesis, can solve the problems of unfavorable industrialized production and promotion, use a large amount of solvents, expensive starting materials, etc., and achieves easy and effective control of reaction conditions, easy availability of reagents, and impurities. less effect

Active Publication Date: 2019-09-20
湖南润星制药有限公司
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  • Claims
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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
  • A kind of preparation method of alectinib
  • A kind of preparation method of alectinib

Examples

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Embodiment 1

[0032] A) Preparation of 6-cyano-2-[2-(4-ethyl-3-iodophenyl)propan-2-yl]-1H-indole-3-carboxylic acid:

[0033] 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (6.3g, 15mmol), 3-cyanophenylhydrazine (2.5g, 19mmol) and three Fluoroacetic acid (94.9g, 832mmol) was mixed, the reaction mixture was stirred and reacted at 100°C for 9 hours, the reaction solution was lowered to 60°C, water (50mL) was added, and the reaction was kept for 3 hours, concentrated by rotary evaporation to dryness, and added to saturated sodium bicarbonate solution And, add ethyl acetate to extract, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, recrystallize with ethyl acetate and n-hexane mixed solvent to get 6-cyano-2-[2-(4-ethyl-3-iodo Phenyl)propan-2-yl]-1H-indole-3-carboxylic acid, off-white solid (6.2g), yield 90%.

[0034] B) Preparation of 9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile:

[0035] 6-cyano-2-[2-(4-...

Embodiment 2

[0039] A) Preparation of 6-cyano-2-[2-(4-ethyl-3-iodophenyl)propan-2-yl]-1H-indole-3-carboxylic acid:

[0040]4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (11.0g, 26mmol), 3-cyanophenylhydrazine (4.8g, 36mmol) and acetic acid (103.1g, 1717mmol) were mixed, the reaction mixture was stirred and reacted at 115°C for 6 hours, the reaction solution was lowered to 70°C, water (110mL) was added, and the reaction was kept for 2 hours, concentrated by rotary evaporation to dryness, neutralized by adding saturated sodium bicarbonate solution, Add ethyl acetate for extraction, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, and recrystallize with a mixed solvent of ethyl acetate and n-hexane to obtain 6-cyano-2-[2-(4-ethyl-3-iodophenyl )prop-2-yl]-1H-indole-3-carboxylic acid, off-white solid (9.6g), yield 81%.

[0041] B) Preparation of 9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile:

[0042] 6-cya...

Embodiment 3

[0046] A) Preparation of 6-cyano-2-[2-(4-ethyl-3-iodophenyl)propan-2-yl]-1H-indole-3-carboxylic acid:

[0047] 4-(4-Ethyl-3-iodophenyl)-4-methyl-3-oxopentanoic acid tert-butyl ester (3.6g, 9mmol), 3-cyanophenylhydrazine (1.4g, 11mmol) and formic acid (16.9g, 367mmol) were mixed, the reaction mixture was stirred and reacted at 90°C for 12 hours, the reaction solution was lowered to 50°C, water (45mL) was added, and the reaction was kept for 4 hours, concentrated by rotary evaporation to dryness, neutralized by adding saturated sodium bicarbonate solution, Add ethyl acetate for extraction, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, and recrystallize with a mixed solvent of ethyl acetate and n-hexane to obtain 6-cyano-2-[2-(4-ethyl-3-iodophenyl )prop-2-yl]-1H-indole-3-carboxylic acid, off-white solid (3.3g), yield 80%.

[0048] B) Preparation of 9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile:

[0049] 6-cyano-2...

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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 is subjected to a cyclization reaction and a hydrolysis reaction; obtained 6-cyano-2-[2-(4-ethyl-3-iodophenyl) prop-2-yl]-1H-indole-3-carboxylic acid is subjected to the cyclization reaction; obtained 9-ethyl-6,6-dimethyl-8-iodo-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile and 4-(piperidin-4-yl)-morpholine are subjected to a substitution 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
Inventor 林开朝钟云健李涛
Owner 湖南润星制药有限公司
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