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Preparation method of imatinib

A technology of imaamine and halomethylbenzoic acid, which is applied in the field of imatinib preparation, can solve the problems of large environmental pollution, cumbersome operation, and many impurities, and achieve high product yield, simple operation, and easy-to-obtain raw materials Effect

Active Publication Date: 2013-06-12
CHENGDU BAIYU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Method 3 is feasible in production, but p-chloromethylbenzoyl chloride is extremely easy to hydrolyze, and the reaction is not complete, thereby causing an increase in production cost, and adopting pyridine as an alkali has serious environmental pollution
[0018] In order to overcome many shortcomings of the existing preparation method, such as many reaction steps, many impurities, cumbersome operation, large environmental pollution and high cost, the inventors of the present invention intend to provide a new method for preparing imatinib

Method used

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  • Preparation method of imatinib

Examples

Experimental program
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Effect test

Embodiment 1

[0054] In a 100ml three-necked flask equipped with a stirring and thermometer, add 50ml of dichloromethane and 3.4g of p-chloromethylbenzoic acid, stir at room temperature, add 1.6g of sodium hydroxide and stir, and add 2.4g of pivaloyl chloride dropwise under control of 30°C. React for 0.5 hours. After the reaction is complete, add a DMF solution of imamamine (2.77g / 50ml), keep stirring for 3 hours, filter, rinse with 10ml of dichloromethane, rinse once with 10ml of purified water, and dry under reduced pressure at 40-60°C to obtain Intermediate 2 is 7.74g, and the yield is 90.00%.

Embodiment 2

[0056] In a 100ml three-necked flask equipped with a stirring and thermometer, add 50ml of dichloromethane and 4.3g of p-bromomethylbenzoic acid, stir at room temperature, add 2.3g of triethylamine until it dissolves, and add dropwise at -30~-25℃ 1.9 g of pivaloyl chloride was reacted for 1.5 hours. After the reaction is completed, add imamamine in DMF (11.1g / 50ml), heat up to 0-25°C and stir for 3 hours, filter, rinse with 10ml of dichloromethane, rinse once with 10ml of purified water, and reduce the temperature at 40-60°C. After vacuum drying, 8.1 g of Intermediate II was obtained with a yield of 94.19%.

Embodiment 3

[0058] In a 100ml three-necked flask equipped with a stirring and thermometer, add 50ml of dichloromethane and 3.4g of p-chloromethylbenzoic acid, stir at room temperature, add 2.3g of triethylamine until it dissolves with stirring, and dropwise add pentapentyl at 0-20°C Acyl chloride 4.8g, reacted for 1 hour. After the reaction is completed, add a DMF solution of imamamine (4.4g / 50ml), keep stirring for 3 hours, filter, rinse with 10ml of dichloromethane, rinse once with 10ml of purified water, and dry under reduced pressure at 40-60°C to obtain Intermediate 2 is 8.2g, and the yield is 95.34%.

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Abstract

The invention relates to a preparation method of imatinib. The preparation method provided by the invention has simple steps and can be used for preparing imatinib in two steps. The preparation method comprises the following steps: A, reacting p-Toluic acid serving as a raw material with halogenated phthalate esters or acyl chlorides in an organic solvent under catalytic action of alkali at -30 DEG C to 100 DEG C to obtain mixed anhydride; B, condensing the mixed anhydride and N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine under the action of alkali to obtain amide, and then further reacting amide with N-methyl piperazine to obtain imatinib. The method disclosed by the invention has the advantages that the reaction steps are simplified and only two reaction steps are needed; and the raw material is easily available, the operation is simple, the cost is low, the product yield is high and the product quality is good; therefore, the method is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of imatinib. Background technique [0002] Imatinib is the precursor for the preparation of imatinib mesylate, which is clinically used to treat various tumors, especially for the treatment of chronic myelogenous leukemia. It was originally successfully developed by Swiss Novartis, and It was approved by the FDA in 2001. In 2002, the FDA approved the drug as a drug for the treatment of gastrointestinal stromal tumors. [0003] The chemical name of imatinib is: 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine ] amino] phenyl] benzamide, its chemical structural formula is as follows: [0004] [0005] Following is the preparation method of reported imatinib: [0006] method 1 [0007] US20060223817, US20080103305, WO2008051597, etc. adopt the method shown in the following formula or a similar method to prepare imatinib. [0008] [0009] The common shortcoming that exi...

Claims

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Application Information

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IPC IPC(8): C07D401/04
Inventor 雷朗邹涛施智锋孙毅田阿娟
Owner CHENGDU BAIYU PHARMA CO LTD
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