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Process for preparing I-clopidogrel hydrogen sulfate

A technology of clopidogrel sulfate and clopidogrel salt, which is applied in the field of preparation of type I clopidogrel sulfate, and can solve problems such as inability to provide stability

Inactive Publication Date: 2005-11-02
上海开特生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The object of the present invention is to overcome the defect that existing methods cannot provide stable type I clopidogrel sulfate, thereby providing a method for preparing type I clopidogrel sulfate with high purity and stable properties

Method used

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  • Process for preparing I-clopidogrel hydrogen sulfate
  • Process for preparing I-clopidogrel hydrogen sulfate
  • Process for preparing I-clopidogrel hydrogen sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Under argon protection, 12.6 grams of clopidogrel sulfate (0.03mol) and 300 milliliters of chloroform were added into a 500 milliliter three-necked flask, and under stirring and cooling with ice water, 4.5 grams of potassium carbonate (0.045mol) and An aqueous solution composed of 40 ml of ionic water was stirred until the pH value of the upper layer was greater than 9; the layers were left to stand, the lower organic phase was separated, the upper aqueous layer was extracted once with 150 ml of chloroform, the organic phases were combined, dried with potassium sulfate, and concentrated to dryness , to obtain free clopidogrel base; add tert-butyl methyl ether 300ml to this free clopidogrel base, stir for 1 hour, and completely dissolve the solid residue; 40% sulfuric acid solution, so that clopidogrel and sulfuric acid are salified to generate clopidogrel bisulfate, and the temperature of the mixed solution is controlled between -15 and -5°C during the dropwise addition;...

Embodiment 2

[0025] Under nitrogen protection, 5.39 g (0.01 mol) of clopidogrel camphorsulfonate was added to a 250 ml three-necked flask together with 50 ml of ethylene dichloride, and under stirring and cooling with ice water, 1.48 g of potassium carbonate ( 0.015mol) and 30 ml of ionic water, stirred for one hour, and the pH value of the upper layer was measured to be greater than 9; the lower organic phase was separated after standing for stratification, and the upper aqueous layer was extracted once with 30 ml of dichloroethane, and the organic phases were combined , after being dried with sodium sulfate, concentrated to dryness to obtain free clopidogrel base; add ethyl acetate 100ml to this free clopidogrel base, stir for 1 hour, the solid residue is completely dissolved; the mixture is cooled to -5°C, start to drop 2.2 grams of 90% sulfuric acid to make clopidogrel and sulfuric acid salt into clopidogrel bisulfate, and control the temperature of the mixed solution during the dropwis...

Embodiment 3

[0027] Under nitrogen protection, 7.15 grams of clopidogrel hydrochloride (0.02mol) and 100 milliliters of dichloromethane were added into a 250 milliliter three-necked flask, and under stirring and cooling with ice water, 2.5 grams of sodium carbonate (0.023 mol) were added dropwise. ) and 30 milliliters of ionized water, stirred for one hour, and the pH value of the upper layer was measured to be greater than 9; the layered organic phase was separated, and the upper aqueous layer was extracted once with 50 milliliters of dichloromethane, and the combined organic phases were washed with sulfuric acid After sodium drying, concentrate to dryness to obtain free clopidogrel base; add 150ml of ethyl formate to the free clopidogrel base, stir for 1 hour to completely dissolve the solid residue; cool the mixture to -10°C , start to drop 2 grams of concentrated sulfuric acid to make clopidogrel and sulfuric acid salify to generate clopidogrel bisulfate, and control the temperature of ...

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Abstract

The invention relates to a method for producing sulfuric acid chlorogray of styleó±, containing the following steps: under the protection of inert gas and cooled with iced water, adding aqueous solution with sodium carbonate / potassium into organic solvent comprising chlorogray salt until the pH is higher than 9; and demixing the liquid, extracting the water layer with the same organic solvent, after combining with organic phase, drying and concentrating it to get free chlorogray alkali; then dissolving it in solvent, dropping in stoichiometric sulfate liquor, and the chlorogray formed, with the temperature controlled between minus 20 Deg.C to 5 Deg.C; then filtering the mixed solution, vacuum drying it, and then the sulfuric acid chlorogray of styleó±can be collected. The sulfuric acid chlorogray produced in such way is proved to beó±morph crystal system confirmed by X-ray diffraction, infrared spectrum and DSC spectrogram, and the fusible point is 181~186 Deg.C, and the specific rotation is 52.0í½55.0 deg. (c=1, carbinol). The method can produce sulfuric acid chlorogray of styleó±steadly.

Description

technical field [0001] The invention relates to a method for preparing type I clopidogrel sulfate. Background technique [0002] The structural formula of clopidogrel (methyl alpa-5(4,5,6,7-tetrahydro(3,2-c)thieno pyridyl)-acetate) is shown in formula I: [0003] [0004] Formula I [0005] Clopidogrel sulfate is the sulfate salt of clopidogrel, which is an antiplatelet drug in medicine. There are various crystal forms of clopidogrel sulfate, such as amorphous form, type I, type II or other crystal forms discovered recently. Wherein as medical use, people hope to obtain type I clopidogrel sulfate more. Most of the clopidogrel sulfate crystals obtained by the existing preparation method are amorphous, type II or a mixture of type I and type II. A method for preparing type I clopidogrel sulfate is disclosed in the patent US281459, but in actual synthesis, people cannot obtain stable type I clopidogrel sulfate products according to this method, but often a mixture of typ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 毛海舫钱宏光陈晨
Owner 上海开特生物科技有限公司
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