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Type I clopidogrel hydrogen sulfate salt preparation method

A technology of clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in the field of preparation of type I clopidogrel hydrogen sulfate, and can solve the problems of uncontrollable crystal form purity, inability to prepare, and increased toxic and side effects

Active Publication Date: 2015-05-13
YABAO PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In WO03051362AZ of Israel Teva Pharmaceutical Industry Co., Ltd., other 4 kinds of crystalline forms of clopidogrel hydrogen sulfate have been reported, namely crystalline form III, crystalline form IV, crystalline form V, crystalline form V1 and amorphous form, wherein only crystalline form I and II can be used as medicine, and each of the other crystal forms contains about 7% of solvent molecules, resulting in increased toxic and side effects of these crystal forms of drugs, and cannot be used as raw materials for the preparation of corresponding preparations.
The existing method for preparing crystal form I is difficult to obtain a stable type I clopidogrel sulfate product, and the purity of the crystal form is uncontrollable

Method used

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  • Type I clopidogrel hydrogen sulfate salt preparation method
  • Type I clopidogrel hydrogen sulfate salt preparation method
  • Type I clopidogrel hydrogen sulfate salt preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Mix clopidogrel salt with dichloromethane, add water, add ammonia water to the solvent, and stir for 0.5 hours to generate the free base of clopidogrel, measure the pH value of the aqueous phase to be 7 to 8, and let it stand for stratification. The aqueous phase was extracted once more with dichloromethane, the organic phases were combined, and the solvent was recovered to dryness after washing with water; 5 times the amount of a mixed solvent of ethyl acetate and acetone was added to the clopidogrel free base obtained after concentration, and ethyl acetate and acetone The volume ratio of clopidogrel is 15:1, stir to completely dissolve the clopidogrel free base, cool down to -15°C, add 10% of the theoretically generated clopidogrel hydrogen sulfate amount as a seed crystal, according to the moles of sulfuric acid and clopidogrel free base The ratio is 0.9-1.05:1, add the solution of sulfuric acid diluted with organic solvent (diluted by 10 times with sulfuric acid) dro...

Embodiment 2

[0031] Mix clopidogrel salt with dichloroethane, add water, add sodium carbonate aqueous solution to the solvent, and stir for 1 hour to generate clopidogrel free base, measure the pH value of the aqueous phase to be 7-8 when static Separate the layers, extract the aqueous phase once with an aqueous solution of sodium carbonate, combine the organic phases, and recycle the solvent to dryness after washing with water; add 10 times the amount of a mixed solvent of ethyl acetate and acetone to the clopidogrel free base obtained after concentration, The volume ratio of ethyl acetate to acetone is 5:1, stir to completely dissolve the clopidogrel free base, cool down to 15°C, add 0.5% of the theoretically generated clopidogrel hydrogen sulfate seed crystals, follow the sulfuric acid and clopidogrel The molar ratio of the free base is 0.9~1.05:1. Add the solution of sulfuric acid (diluted 20 times by sulfuric acid) diluted with organic solvent to the solution dropwise. After dropping, ...

Embodiment 3

[0033] Mix clopidogrel salt with chloroform, add water, add an aqueous solution of potassium carbonate to the solvent, and stir for 0.8 hours to generate the free base of clopidogrel, measure the pH value of the water phase to 7-8 and let it stand Separate the layers, extract the aqueous phase once with chloroform, combine the organic phases, wash with water and recover the solvent to dryness; add 8 times the amount of a mixed solvent of ethyl acetate and acetone to the clopidogrel free base obtained after concentration, ethyl acetate The volume ratio of ester to acetone is 8:1, stir to completely dissolve the clopidogrel free base, cool down to 0°C, add 1% of the theoretically generated clopidogrel bisulfate amount as seed crystals, follow the formula of sulfuric acid and clopidogrel free base The molar ratio of the solution is 0.9~1.05:1, add dropwise the sulfuric acid solution diluted by organic solvent (10 times dilution of sulfuric acid) into the solution, after dropping, ...

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Abstract

The invention discloses a type I clopidogrel hydrogen sulfate salt preparation method which comprises the following steps: (1) mixing clopidogrel salt with an organic solvent, adding water, adding an acid binding agent or an acid binding agent water solution to the solvent, stirring for reaction to generate clopidogrel free alkali, standing for layering, extracting aqueous phase with the same organic solvent, combining the organic phase, washing with water, recovering the solvent to dry; and (2) adding an organic solvent into the concentrated clopidogrel free alkali, stirring to fully dissolve the clopidogrel free alkali, cooling, adding seed crystal, according to the molar ratio of sulfuric acid to clopidogrel free alkali of 0.9-1.05:1, dropwise adding sulfuric acid solution into the solution, standing, filtering, and drying to obtain the type I clopidogrel hydrogen sulfate. The type I clopidogrel hydrogen sulfate obtained by the method has the advantages of high purity and stable property.

Description

technical field [0001] The invention relates to a preparation method of type I clopidogrel hydrogen sulfate. Background technique [0002] Clopidogrel bisulfate, the chemical structural formula is as follows: [0003] [0004] Clopidogrel hydrogen sulfate is the sulfate salt of clopidogrel, which is a drug that inhibits platelet aggregation in medicine. In the early original patent EP281459, the crystal form of clopidogrel hydrogen sulfate was not pointed out, but in Sanofi’s later patents FR9807464 and FR2779726Al, two crystal forms of clopidogrel hydrogen sulfate were reported, crystal form I and crystal Type II. In WO03051362AZ of Israel Teva Pharmaceutical Industry Co., Ltd., other 4 kinds of crystalline forms of clopidogrel hydrogen sulfate have been reported, namely crystalline form III, crystalline form IV, crystalline form V, crystalline form V1 and amorphous form, wherein only crystalline form I and II can be used as medicine, and each of the other crystal for...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P7/02
CPCC07D495/04
Inventor 姚勇敢王大明任武贤禹玉洪
Owner YABAO PHARMA GRP CO LTD
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