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Preparation method for clopidogrel hydrogen sulphate

A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in the field of preparation of clopidogrel bisulfate to achieve the effects of convenient operation, simple post-processing, and avoiding double-tethering

Inactive Publication Date: 2014-07-30
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The traditional preparation method of adding sulfuric acid to free base often contains a large amount of residual solvent

Method used

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  • Preparation method for clopidogrel hydrogen sulphate
  • Preparation method for clopidogrel hydrogen sulphate
  • Preparation method for clopidogrel hydrogen sulphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Dissolve 10 g of concentrated sulfuric acid in 990 g of methyl isobutyl ketone solution, cool the solution to 20° C. after completely dissolving, then slowly add clopidogrel free base methyl isobutyl ketone with a mass concentration of 50% The solution was 63g, and the addition time was 0.5h. Stir while adding, and a white solid was precipitated. After the addition, the reaction solution was heated to 15°C, and stirred at this temperature for 3h, filtered, and dried to obtain clopidogrel hydrogen sulfate, which was obtained by XRD It was detected as clopidogrel bisulfate crystal form I, the yield was 88%, the purity was 99.8%, mp: 184~186°C, [α] D =55.0°, residual solvent (GC): 450 ppm.

Embodiment 2

[0027] Example 2: Dissolve 10 g of concentrated sulfuric acid in 323 g of methyl isobutyl ketone solution, cool the solution to 20° C. after completely dissolving, then slowly add clopidogrel free base methyl isobutyl ketone with a mass concentration of 40% The solution was 75g, and the dropwise addition time was 1h, stirring while adding, and a white solid was precipitated. After the addition, the reaction solution was heated to 20°C, and continued to stir at this temperature for 5h, filtered, and dried to obtain clopidogrel hydrogen sulfate, which was obtained by XRD It was detected as clopidogrel bisulfate crystal form I, the yield was 90%, the purity was 99.6%, mp: 184~186℃, [α] D =55.0°, residual solvent (GC): 500 ppm.

Embodiment 3

[0028] Example 3: Dissolve 10 g of concentrated sulfuric acid in 24 g of methyl isobutyl ketone solution, cool the solution to 20° C. after completely dissolving, then slowly add clopidogrel free base methyl isobutyl ketone with a mass concentration of 30% The solution was 73g, and the dropwise addition time was 2h. Stirring while adding, precipitated a white solid. After the addition, the reaction solution was heated to 30°C, and continued to stir at this temperature for 10h, filtered, and dried to obtain clopidogrel hydrogen sulfate, which was obtained by XRD It was detected as clopidogrel bisulfate crystal form I, the yield was 85%, the purity was 99.8%, mp: 184~186℃, [α] D =55.0°, residual solvent (GC): 460 ppm.

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Abstract

The invention provides a preparation method for clopidogrel hydrogen sulphate. The preparation method for clopidogrel hydrogen sulphate comprises the following steps: dissolving clopidogrel free alkali in an organic solvent to obtain a solvent system mixture, adding the solvent system mixture in a concentrated sulphuric acid organic solvent at a temperature of minus 20 to 20 DEG C, stirring to separate out solids, then heating to 15-50 DEG C and continuing to stir for 3-20 hours, and filtering and drying to obtain the clopidogrel hydrogen sulphate. The preparation method provided by the invention is convenient to operate, simple in aftertreatment and especially has a remarkable effect of reducing the residual solvent of clopidogrel hydrogen sulphate; the obtained product is high in yield, good in purity, stable in quality, and suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to a high-purity clopidogrel bisulfate compound with low solvent residue and a preparation method thereof. technical background [0002] Cardiovascular and cerebrovascular thrombotic disease is a major disease that seriously affects human health, but inhibiting platelet aggregation is an effective way to treat this disease. Clopidogrel Hydrogen Sulfate (Clopidogrel Hydrogen Sulfate, such as formula I) is a new generation of platelet aggregation inhibitors, the chemical name is (S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3 , 2-c] pyridine-5 (4H) - methyl acetate hydrogen sulfate, trade name Plavix (Plavix). The product was developed by Sanofi in France, and it was first launched in the United States in March 1998, and entered the Chinese market in August 2001. The drug has the advantages of strong curative effect, high safety, few side effects, and low cost, and has become the first-line drug for the treatment of thrombotic diseases...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 刘洋吴进泉张文灵王鹏陈健陈曦
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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