Preparation method of type I clopidogrel hydrogen sulfate

A technology of clopidogrel bisulfate and clopidogrel base, which is applied in the field of preparation of type I clopidogrel bisulfate, which can solve the problems of human poisoning, ether flammability, unsafety, etc., and achieves little harm to human body and mild reaction conditions Effect

Inactive Publication Date: 2012-10-03
SHANDONG QIDU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, through experiments, according to the reported literature, most of the methods cannot obtain the product, but obtain other crystal forms or amorphous products or mixed crystal forms
[0007] The method for preparing the type I product reported in U.S. Patent US20030114479 is relatively simple, directly dissolving clopidogrel hydrogen sulfate in methanol, then evaporating the solvent, adding solvent ether or tert-butyl methyl ether and stirring for a certain period of time, thereby obtaining the type I product, but We have proved through experiments that it is difficult to obtain the pure target product with tert-butyl methyl ether, but the effect is very good with diethyl ether
However, ether is a strong anesthetic, highly volatile, and has many toxic effects on the human body; moreover, ether is flammable, which brings great unsafe factors to industrialized large-scale production

Method used

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  • Preparation method of type I clopidogrel hydrogen sulfate
  • Preparation method of type I clopidogrel hydrogen sulfate
  • Preparation method of type I clopidogrel hydrogen sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Put 11.00 g of clopidogrel hydrogen sulfate into a 250 mL round bottom flask, then add 40.0 mL of dichloromethane and 40.0 mL of purified water, control the temperature at 8°C, and adjust the pH to 7 with sodium bicarbonate. The reaction was stirred for 2 hours at 8°C. After the reaction was completed, the layers were separated, the aqueous phase was extracted with 10 mL of dichloromethane, the organic phases were combined, and the organic phase was washed with 10 mL of purified water. Add 1.50 g of anhydrous magnesium sulfate to the organic phase, stir and dry for 5 h. After drying, filter and evaporate the solvent at 40±3°C and -0.08~-0.1MPa to obtain 7.90g of clopidogrel base as an oil. After the distillation is complete, add 135mL of isopropyl ether and 15mL of isopropanol, and cool down to 6°C. After the clopidogrel base is completely dissolved, slowly add 2.65g of concentrated sulfuric acid at this temperature. After the dropwise addition, stir the reaction for 1...

Embodiment 2

[0038]Take 27.50 g of clopidogrel hydrogen sulfate and put it in a 500 mL round bottom flask, then add 100.0 mL of dichloromethane and 100.0 mL of purified water, cool down to 8°C, and adjust the pH to 9 with sodium carbonate. The reaction was stirred for 2 hours at 8°C. After the reaction was completed, the liquids were separated, the aqueous phase was extracted with 30 mL of dichloromethane, the organic phases were combined, and the organic phases were washed with 30 mL of purified water. Add 3.80g of anhydrous magnesium sulfate to the organic phase, stir and dry for 5h. After drying, filter and distill off the solvent at 40±3°C, -0.08~-0.1MPa to obtain 20.40 g of clopidogrel base as an oil. After the distillation is complete, add 165mL of isopropyl ether and 165mL of isopropanol, and cool down to 6°C. After the clopidogrel is completely dissolved, slowly add 6.69g of concentrated sulfuric acid at this temperature. After the dropwise addition, stir the reaction for 16 hours...

Embodiment 3

[0044] Put 46.2 g of clopidogrel hydrogen sulfate into a 1000 mL round bottom flask, then add 168.0 mL of dichloromethane and 168.0 mL of purified water, cool down to 8°C, and adjust the pH to 8 with sodium bicarbonate. The reaction was stirred for 2.5 hours at 8°C. After the reaction was completed, the liquids were separated, the aqueous phase was extracted with 50 mL of dichloromethane, the organic phases were combined, and the organic phases were washed with 50 mL of purified water. Add 6.00g of anhydrous magnesium sulfate to the organic phase, stir and dry for 5h. After drying, filter and evaporate the solvent at 40±3°C and -0.08~-0.1MPa to obtain 32.50g of oily clopidogrel base. After the distillation is complete, add 63.0mL of isopropyl ether and 567.0mL of isopropanol, and cool down to 6°C. After the clopidogrel is completely dissolved, slowly add 9.90g of concentrated sulfuric acid at this temperature. After the dropwise addition, stir for 16 hours to complete the rea...

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Abstract

The invention relates to a preparation method of type I clopidogrel hydrogen sulfate, belonging to the technical field of preparation of medical substances. The preparation method of the type I clopidogrel hydrogen sulfate comprises the following steps of: reacting clopidogrel hydrogen sulfate with an alkali in an organic solvent and water to obtain clopidogrel alkali; adding clopidogrel alkali into a mixed solvent of isopropyl ether and isopropanol, and acidifying to obtain a suspension; and filtering and drying to obtain the type I clopidogrel hydrogen sulfate. The method has the advantages of mild reaction conditions, small damages of used solvent to human bodies, safety, reaction yield of 85-93 percent and suitability for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of type I clopidogrel hydrogen sulfate, which belongs to the technical field of preparation of medical substances. Background technique [0002] The chemical name of clopidogrel is S(+)-2-(2-chlorophenyl)-2(4,5,6,7-tetrahydrothiophene[3,2-c]pyridine-5)methyl acetate The bisulfate, the structural formula is as follows: [0003] [0004] Clopidogrel bisulfate is the sulfate salt of clopidogrel, which is a platelet aggregation inhibitor because it selectively inhibits the binding of adenosine diphosphate (ADP) to its receptor and the subsequent ADP-mediated Activation of the glycoprotein GPⅡb / Ⅲa complex, thus inhibiting platelet aggregation. In addition to ADP, clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the expansion of platelet activation caused by released ADP. It was first invented by the French pharmaceutical company Sanofi. Since 2005, clopidogrel has been c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 贡肖巍朱建益赵波于长安
Owner SHANDONG QIDU PHARMA
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