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Method for preparing I-type clopidogrel hydrogen sulfate

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

Inactive Publication Date: 2013-10-23
HEILONGJIANG FUHE HUAXING PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to overcome the defect that existing methods cannot provide stable type I clopidogrel bisulfate, thereby providing a method for preparing type I clopidogrel bisulfate with high purity and stable quality

Method used

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  • Method for preparing I-type clopidogrel hydrogen sulfate
  • Method for preparing I-type clopidogrel hydrogen sulfate
  • Method for preparing I-type clopidogrel hydrogen sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Add 12.6g (0.03mol) of clopidogrel sulfate and 200mL of dichloromethane into a 500mL three-neck flask, control the room temperature, add a saturated solution of sodium bicarbonate deionized water under stirring, until the pH of the organic phase is greater than 8, and let it stand The organic phase was separated, and the aqueous phase was extracted once with 150 mL of dichloromethane. The organic phases were combined, dried and concentrated to obtain free clopidogrel base; 300 mL of isobutyl ketone was added to the free clopidogrel base, and stirred for 1 hour. It is completely dissolved; 50% stoichiometric isobutyl ketone sulfate solution is added dropwise at 30°C to make clopidogrel and sulfuric acid salt into clopidogrel bisulfate; after the dropwise addition, stir at room temperature for 12 hours; filter to obtain a solid Wash 3 times with isobutyl ketone 10mL, dry under reduced pressure at 50°C to obtain 10.5g of type I clopidogrel bisulfate, specific optical rotati...

Embodiment 2

[0024] Add 42.0g (0.1mol) of clopidogrel sulfate and 600mL of dichloromethane into a 2L three-neck flask, control the room temperature, add a saturated solution of sodium bicarbonate deionized water under stirring, until the pH of the organic phase is greater than 8, and let it stand Separate the organic phase, and extract the aqueous phase once with 500 mL of dichloromethane, combine the organic phases, dry and concentrate to obtain free clopidogrel base; add 1 L of isobutyl ketone to the free clopidogrel base, and stir for 1 hour to make It is completely dissolved; 50% stoichiometric isobutyl ketone sulfate solution is added dropwise at 30°C to make clopidogrel and sulfuric acid salt into clopidogrel bisulfate; after the dropwise addition, stir at room temperature for 12 hours; filter to obtain a solid Washed 3 times with 50 mL of isobutyl ketone, dried under reduced pressure at 50° C. to obtain 35.7 g of type I clopidogrel hydrogen sulfate, specific optical rotation: 52.0° (...

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Abstract

The invention relates to a method for preparing I-type clopidogrel hydrogen sulfate. The method comprises the following steps: dripping a sodium bicarbonate aqueous solution into a clopidogrel salt organic solvent solution until the pH value is 8 under the condition of room temperature; standing to layer, extracting the water layer by the same organic solvent, combining with the organic phase, and drying and concentrating to obtain free clopidogrel; dissolving the clopidogrel in the organic solvent, and dripping stoichiometric sulfuric acid solution, leading the clopidogrel and the sulfuric acid to generate clopidogrel hydrogen sulfate, and controlling the temperature of the mixed solution to be between 20 and 40 DEG C when solutions are dripped; and filtering and drying to obtain the I-type clopidogrel hydrogen sulfate. X-diffraction and infrared ray and other methods confirm that the clopidogrel hydrogen sulfate prepared by the method which is provided by the invention is an I-type crystal form with the melting point of between 182 and 186 DEG C and the specific rotation of between 52.0 and 55.0 degrees (c equals to 1, methanol). The method can be used for preparing the I-type clopidogrel hydrogen sulfate stably and conveniently.

Description

technical field [0001] The invention relates to a method for preparing type I clopidogrel bisulfate. Background technique [0002] The structural formula of clopidogrel (methyl alpa-5(3,2-c)thieno pyridyl)-acetate) is shown in formula I: [0003] [0004] Clopidogrel hydrogen sulfate is the hydrogen sulfate salt of clopidogrel, and its structural formula is as shown in formula II: [0005] [0006] It is an antiplatelet drug in medicine. There are various crystal forms of clopidogrel bisulfate, such as amorphous, type I, type II and so on. Clopidogrel bisulfate type I is more desirable in pharmaceutical production. A method for preparing type I clopidogrel hydrogen sulfate is disclosed in the patent US281459, but in actual synthesis, the reproducibility is poor (less than 30%), and stable type I products cannot be obtained, and type I and type II are often obtained mixture, and mainly type II products. Contents of the invention [0007] The object of the present...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 吴光彦
Owner HEILONGJIANG FUHE HUAXING PHARMA GROUP
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