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Method for preparing dabigatran etexilate hydrolysis impurities

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

Active Publication Date: 2015-02-18
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 A or B has not been reported

Method used

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  • Method for preparing dabigatran etexilate hydrolysis impurities
  • Method for preparing dabigatran etexilate hydrolysis impurities
  • Method for preparing dabigatran etexilate hydrolysis impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Prepare impurity A according to the following steps:

[0067] (1) Take 2g of dabigatran etexilate and dissolve it in 30mL of acetonitrile and 30mL of 0.1mol / L sodium hydroxide aqueous solution, and carry out the hydrolysis reaction at 20°C. After the reaction is complete, a mixed solution is obtained;

[0068] (2) Adjust the mixed solution obtained in step (1) to pH 4.0 with acetic acid, precipitate an oily substance, discard the solvent, and wash the oily substance twice with distilled water;

[0069] (3) Add 20 ml of acetone to the oil obtained in step (2), fully stir to dissolve, stand still to precipitate crystals, remove the solvent by suction, and dry in vacuo to obtain 1.04 g of yellow solid powder with a weight yield of 52%.

[0070] Product detection: After ESI(+)-MS mass spectrometry detection, the product obtained in this example has [M+H] + Is 600.7, [M+Na] + The peak is 622.7, which is related to dabigatran etexilate impurity A (C 32 H 37 N 7 O 5 ) Is consistent wit...

Embodiment 2

[0072] Prepare impurity A according to the following steps:

[0073] (1) Take 2g of dabigatran etexilate and dissolve it in 45mL of acetonitrile and 30mL of 2mol / L sodium carbonate aqueous solution, and carry out the hydrolysis reaction at 50℃. After the reaction is complete, a mixed solution is obtained;

[0074] (2) Adjust the mixed solution obtained in step (1) to pH 3.5 with acetic acid, precipitate an oily substance, discard the solvent, and wash the oily substance twice with distilled water;

[0075] (3) Add 20ml of isopropanol to the oil obtained in step (2), fully stir to dissolve, stand still to precipitate crystals, remove the solvent by suction, and dry in vacuo to obtain 0.74 g of light yellow solid powder, with a weight yield of 37%; After testing, the obtained powder is impurity A, with a purity of 98.5%.

Embodiment 3

[0077] Prepare impurity A according to the following steps:

[0078] (1) Take 2g of dabigatran etexilate and dissolve it in 20mL of ethanol and 40mL of sodium carbonate aqueous solution with a concentration of 0.02mol / L, and carry out the hydrolysis reaction at 10°C. After the reaction is complete, a mixed solution is obtained;

[0079] (2) Adjust the mixed solution obtained in step (1) to pH 4.5 with acetic acid, precipitate an oily substance, discard the solvent, and wash the oily substance twice with distilled water;

[0080] (3) Add 40ml of acetone to the oil obtained in step (2), fully stir to dissolve, leave to stand to precipitate crystals, remove the solvent by suction, and dry in vacuo to obtain 0.83g of light yellow solid powder, with a weight yield of 41.5%; , The resulting powder is impurity A, with a purity of 97.8%.

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Abstract

The invention provides a method for preparing a dabigatran etexilate hydrolysis impurity A. The method comprises steps as follows: (1) dabigatran etexilate or dabigatran etexilate mesylate is used as a raw material and dissolved in a mixed medium of an organic solvent and an alkaline aqueous solution for a hydrolysis reaction; (2) a mixed liquid obtained in Step (1) is adjusted to be acidic, and grease is separated out; (3) the organic solvent is added to the grease, crystals are separated out, and the impurity A is obtained. The invention further provides a method for preparing a dabigatran etexilate hydrolysis impurity B. The method comprises steps as follows: (1) the dabigatran etexilate hydrolysis impurity A is used as a raw material and dissolved in a mixed medium of the organic solvent and an acidic aqueous solution for a hydrolysis reaction; (2) a mixed liquid obtained in Step (1) is depressurized and distilled until grease is produced, and extraction is performed with dichloromethane; (3) an obtained extraction liquid is purified with medium-pressure preparation chromatography, the solvent is removed, and the grease is obtained; (4) ethyl acetate is added, crystals are separated out after dissolution, and the impurity B is obtained.

Description

Technical field [0001] The invention relates to the quality control of dabigatran etexilate, in particular to a method for preparing dabigatran etexilate hydrolyzed impurities. Background technique [0002] Dabigatran etexilate mesylate is an oral thrombin inhibitor, its chemical structure is: [0003] [0004] Its preparation, dabigatran etexilate capsules, obtained marketing approval in Europe in March 2008, becoming the first new class of oral anticoagulant drug to be marketed in more than 50 years after warfarin. Dabigatran etexilate can be converted into dabigatran in the body, which can inhibit thrombin activity to achieve anticoagulant effect. The drug is mainly used for postoperative venous thromboembolism and specific patient populations. The launch of the drug is a major advance in the field of anticoagulation therapy and the prevention of potentially fatal thrombosis, and is another blockbuster rookie in the field of cardiovascular therapy. [0005] At present, the pharm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
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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