Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate

A technology of clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in the preparation of type I clopidogrel hydrogen sulfate and the field of preparation of type I clopidogrel hydrogen sulfate, which can solve the problem of short storage time and product crystal form Problems such as low purity and complex preparation process of type I clopidogrel bisulfate have achieved the effect of easy industrial production and high crystal purity

Inactive Publication Date: 2012-05-02
JIANGNAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The main purpose of the present invention is to overcome the existing complex preparation process of type I clopidogrel bisulfate, the problems of low crystal form purity and short storage time, etc., and provide a type I clopidogrel with high crystal form purity The preparation method of bisulfate

Method used

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  • Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate
  • Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate
  • Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate

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Effect test

Embodiment 1

[0032] Under the protection of nitrogen, add 5 grams of clopidogrel bisulfate type II, 50 milliliters of dichloromethane and 50 milliliters of water into a 250 milliliter three-neck flask, stir, cool down to 0~5 °C, and dropwise add 30 milliliters of 10% sodium carbonate aqueous solution. React until the pH value of the aqueous phase of the solution reaches 7-8, let stand to separate the layers, separate the organic phase, and extract the aqueous phase once with 50 ml of dichloromethane. The organic phases were combined and evaporated to dryness of dichloromethane to obtain 3.5 g of clopidogrel free base. Add 94.5 ml of ethyl acetate to the free base (ρ=0.9 g / cm 3 ), stirred to dissolve the free base completely, and filtered to obtain a clear solution. Control the temperature of the solution at 23°C, add 0.05 g of clopidogrel hydrogensulfate type I to the solution, mix well, and start to add 10.5 ml of 10% sulfuric acid ethyl acetate solution dropwise (control the amount of ...

Embodiment 2

[0034] Under nitrogen protection, add 6.5 g of clopidogrel camphorsulfonate, 50 ml of dichloromethane and 50 ml of water into a 250 ml three-neck flask, stir, cool down to 0~5°C, and dropwise add 30 ml of 10% sodium carbonate aqueous solution . React until the pH value of the aqueous phase of the solution reaches 7-8, let stand to separate the layers, separate the organic phase, and extract the aqueous phase once with 50 ml of dichloromethane. The organic phases were combined and evaporated to dryness of dichloromethane to obtain 3.6 g of clopidogrel free base. Add 97.2 ml of ethyl acetate to the free base (ρ=0.9g / cm 3 ), stirred to dissolve the free base completely, and filtered to obtain a clear solution. Control the temperature of the solution at 23°C, add 0.05 g of clopidogrel type I bisulfate to the solution, mix well, and start to add 10.8 ml of 10% ethyl sulfate acetate solution dropwise, and control the temperature of the solution at 23~25°C during the dropwise addit...

Embodiment 3

[0036]Under the protection of nitrogen, 4.8 grams of clopidogrel hydrobromide, 50 milliliters of dichloromethane and 50 milliliters of water were added to a 250 milliliter three-neck flask, stirred, cooled to 0~5 °C, and 30 milliliters of 10% sodium carbonate was added dropwise aqueous solution. React until the pH value of the aqueous phase of the solution reaches 7-8, let stand to separate the layers, separate the organic phase, and extract the aqueous phase once with 50 ml of dichloromethane. The organic phases were combined and evaporated to dryness of dichloromethane to obtain 3.4 g of clopidogrel free base. Add 91.8 ml of ethyl acetate to the free base (ρ=0.9 g / cm 3 ), stirred to dissolve the free base completely, and filtered to obtain a clear solution. Control the temperature of the solution at 23°C, add 0.05 g of clopidogrel type I bisulfate to the solution, mix well, and start to add 10.2 ml of 10% ethyl sulfate acetate solution dropwise, and control the temperature...

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Abstract

The invention discloses a method for preparing high-purity I-type clopidogrel hydrogen sulfate, belonging to the technical field of finding and preparing of drug crystal forms. The method comprises the following four steps of: (A) transforming a clopidogrel salt into free alkali thereof at a lower temperature; (B) dropwise adding sulfuric acid into aqueous alkali at 20 to 25 DEG C, reacting and crystallizing; (C) growing crystals for 1 to 2 hours at the same temperature; and (D) washing an obtained solid by using ethyl acetate, and performing vacuum drying. An I-type clopidogrel hydrogen sulfate crystal prepared by using the method is determined to be the high crystal form purity I-type clopidogrel hydrogen sulfate after being subjected to X-ray powder diffraction, infrared spectrum and thermal analysis. An appropriate amount of seed crystal is added during crystallization, the crystallization speed is obviously increased, and the crystallization can be completed within about 5 hours.

Description

technical field [0001] The present invention relates to a method for preparing clopidogrel hydrogen sulfate type I with high crystal purity, more specifically, the present invention relates to a method for preparing type I clopidogrel hydrogen sulfate using clopidogrel salt as a raw material, belonging to Drug crystal form discovery and preparation technology field. Background technique [0002] Clopidogrel hydrogen sulfate (clopidogrel hydrogen sulfate, the structural formula is shown below), the chemical name is (+)-( S )-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2- c ]pyridyl-5(4 H )-methyl acetate bisulfate is a new type of highly effective anti-platelet aggregation drug. The drug was first developed by the French company Sanofi-Aventis in 1987. Since it was first launched in the United States in 1998, it has been launched in Europe, Canada, Australia, Singapore and other countries, and entered the Chinese market in 2001. The drug has good tolerance and few adverse reac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 陆杰汪晶李祯舒亮曾德利
Owner JIANGNAN UNIV
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