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Method for preparing dabigatran etexilate hydrolysis impurity

A technology of dabigatran etexilate and impurities, applied in the field of preparation of dabigatran etexilate hydrolyzed impurities, to achieve the effect of high purity

Inactive Publication Date: 2015-01-21
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN102964307A discloses a dabigatran etexilate related substance 2-{[4-(amino-n-hexaneoxyimide-methylene)-phenylimine]-methylene}-1-methyl-1 Hydrogen-benzimidazole-5-carboxylic acid ethyl ester and its synthesis method, but the impurity is not a hydrolysis impurity
At present, the method for preparing high-purity impurity C has not been reported

Method used

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  • Method for preparing dabigatran etexilate hydrolysis impurity
  • Method for preparing dabigatran etexilate hydrolysis impurity
  • Method for preparing dabigatran etexilate hydrolysis impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Prepare dabigatran etexilate hydrolysis impurities according to the following steps:

[0046] (1) In a 100ml single-necked flask, sequentially add 2g of dabigatran etexilate, 30ml of absolute ethanol, and 30ml of 0.5mol / L hydrochloric acid, heat to 40°C, and stir for 20h;

[0047] (2) The reaction solution obtained in step (1) is distilled under reduced pressure until oily matter is produced, the solvent is removed, 60ml of dichloromethane is added for extraction, and the extract is collected;

[0048] (3) separate and purify step (2) gained extract with medium pressure preparative chromatography, mobile phase is the aqueous solution of the acetonitrile of volume ratio 60:40 and pH4.4, and described aqueous solution is the ammonium acetate aqueous solution of concentration 0.2%, uses Acetic acid was used to adjust the pH value to 4.4, and the stationary phase was octadecyl silica gel. The components with a retention time of 17 to 20 minutes were collected under the cond...

Embodiment 2

[0052] Prepare dabigatran etexilate hydrolysis impurities according to the following steps:

[0053] (1) In a 100ml single-necked flask, sequentially add 2g of dabigatran etexilate mesylate, 50ml of anhydrous acetonitrile, and 30ml of 0.02mol / L sulfuric acid, heat to 50°C, and stir for 8 hours;

[0054] (2) The reaction solution obtained in step (1) is distilled under reduced pressure until oily matter is produced, the solvent is removed, 50ml of dichloromethane is added for extraction, and the extract is collected;

[0055] (3) separate and purify the extract obtained in step (2) with medium pressure preparative chromatography, mobile phase is the aqueous solution of the acetonitrile of volume ratio 55:40 and pH 4.0, and described aqueous solution is the ammonium acetate aqueous solution of concentration 0.3%, with acetic acid Adjust its pH value to 4.0, use octadecyl silica gel as the stationary phase, collect components with a retention time of 17-20 min at a detection wave...

Embodiment 3

[0058] Prepare dabigatran etexilate hydrolysis impurities according to the following steps:

[0059] (1) In a 100ml single-necked flask, add 2g of dabigatran etexilate, 30ml of anhydrous isopropanol, and 30ml of 2mol / L p-toluenesulfonic acid successively, heat to 10°C, and stir for 36h;

[0060] (2) The reaction solution obtained in step (1) is distilled under reduced pressure until oily matter is produced, the solvent is removed, 40ml of dichloromethane is added for extraction, and the extract is collected;

[0061] (3) separate and purify step (2) gained extract with medium pressure preparative chromatography, mobile phase is the aqueous solution of the acetonitrile of volume ratio 60:40 and pH 5.0, and described aqueous solution is the ammonium acetate aqueous solution of concentration 0.1%, with acetic acid Adjust its pH value to 5.0, the stationary phase is octadecyl silica gel, collect the components with a retention time of 17 to 20 min at a detection wavelength of 315 ...

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Abstract

The invention relates to a method for preparing a dabigatran etexilate hydrolysis impurity C. The method comprises the following steps: (1) sufficiently dissolving dabigatran etexilate or dabigatran etexilate mesylate as a raw material in a mixed medium consisting of an organic solvent and an acid solution, and performing hydrolysis reaction at 10-50 DEG C, thereby obtaining a mixed liquid after the reaction is completed; (2) performing reduced pressure distillation on the obtained mixed liquid obtained in the step (1) till an oily matter is generated, removing the solvent, adding dichloromethane into the oily matter to extract, and collecting the extract; (3) purifying the extract of the step (2) by using a medium-pressure preparative chromatography method, performing pressure reduction distillation to remove the solvent so as to obtain an oily matter, and washing the oily matter with distilled water, wherein alkyl silica gel is adopted as the solid phase, and an organic solvent and an aqueous solution with the pH value of 4.0-5.0 are adopted as the flow phase; and (4) adding ethyl acetate into the oily matter obtained in the step (3), heating till the oily matter is completely dissolved, cooling, separating out crystals, performing suction filtration, and drying in vacuum, thereby obtaining a product, that is, the dabigatran etexilate hydrolysis impurity C.

Description

technical field [0001] The invention relates to the quality control of dabigatran etexilate, in particular to a method for preparing dabigatran etexilate by hydrolyzing impurities. Background technique [0002] Dabigatran etexilate mesylate is an oral thrombin inhibitor whose chemical structure is: [0003] [0004] Its preparation, dabigatran etexilate capsules, was approved for marketing in Europe in March 2008, becoming the first new category of oral anticoagulant drugs to be marketed after warfarin in more than 50 years. Dabigatran etexilate can be converted into dabigatran in the body, which can inhibit thrombin activity to achieve anticoagulant effect. This drug is mainly used for postoperative venous thromboembolism and specific patient groups. The launch of the drug is a major advance in the field of anticoagulant therapy and the prevention of potentially fatal thrombosis, and it is another major newcomer in the field of cardiovascular therapy. [0005] At prese...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 孙建华李立标王艳
Owner BENGBU BBCA MEDICINE SCI DEV
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