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Preparation method of clopidogrel hydrogen sulfate I

A technology of clopidogrel bisulfate and clopidogrel free base, which is applied in organic chemistry and other fields, and can solve problems such as difficulty in obtaining a stable crystal form of clopidogrel bisulfate, relatively high requirements, and long reaction time, etc. Effects of shortening time, overcoming external conditions, and high purity

Inactive Publication Date: 2011-05-25
TIANJIN CHASE SUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Clopidogrel hydrogen sulfate type I crystal form was first disclosed in EP281459 and described, but in the actual synthesis process, it is difficult to obtain stable type I clopidogrel hydrogen sulfate crystal form
[0004] The current preparation methods of clopidogrel bisulfate type I crystal form are mostly synthesized in the environment of dry air or other inert gases, which have relatively high requirements on the environment, and the reaction time is relatively long. The inventors are constantly experimenting. In this process, a new method for preparing clopidogrel hydrogen sulfate type I crystal form was obtained, a simple method for preparing clopidogrel hydrogen sulfate type I crystal form, which saves reaction time and improves product purity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: 220g of clopidogrel hydrochloride and 1400mL of chloroform and water mixed solution (4:3) was added in a 3L four-neck flask, stirred, and 30g of sodium bicarbonate was added after cooling down in an ice-water bath to below 15 degrees Celsius, Stir for 20 minutes, measure the pH value of the water layer to 7-8, let stand to separate the layers, and separate the dichloromethane layer; extract the water layer once with 200 mL of chloroform, combine the organic phases, and distill the chloroform to dryness under reduced pressure. Add 1200mL of ethyl acetate / acetone (volume ratio = 1:5‰) to the free base, stir to dissolve, heat to 15 degrees Celsius, start to add 10mL of 98% sulfuric acid solution dropwise, control the temperature and stirring speed during the dropwise addition, respectively At 15 degrees centigrade and 50 rpm, after the dropwise addition is complete, keep warm for reaction, and the stirring speed is adjusted to 150 rpm. After 8 hours, filter, and...

Embodiment 2

[0027] Embodiment 2: 220g clopidogrel bisulfate and the mixed solution (4:3) of 1400mL ethylene dichloride and water are added in the 3L four-neck flask, stir, add 30g potassium carbonate after cooling down in an ice-water bath below 15 degrees Celsius, Stir for 20 minutes, measure the pH value of the water layer to 7~8, let it stand and separate the layers, and separate the dichloroethane layer; extract the water layer with 200 mL of dichloroethane once, combine the organic phases, and distill the dichloroethane to dryness under reduced pressure. . Add 1200mL of ethyl acetate / acetone (volume ratio = 1:10‰) to the free base, stir to dissolve, heat to 45 degrees Celsius, start to add 12.5mL of 80% sulfuric acid solution dropwise, and control the temperature and stirring speed during the dropwise addition Respectively at 45 degrees Celsius and 50 rpm, after the dropwise addition is complete, keep warm for reaction, and adjust the stirring speed to 150 rpm. After 3 hours, filter...

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Abstract

The invention relates to a preparation method of a drug compound, in particular to a preparation method of clopidogrel hydrogen sulfate I. The method provided by the invention comprises the following steps: 1, mixing clopidogrel salt with an organic solvent and water, adding an acid binding agent to react to generate free alkali of clopidogrel, extracting the water layer with the organic solvent, combining the organic phases and carrying out concentration; and 2. adding the organic solvent into the free alkali of clopidogrel obtained after concentration, dropwise adding sulfuric acid into the solution for reaction based on the molar ratio of the sulfuric acid to the free alkali of clopidogrel, filtering the reactant and drying the filtrate to obtain the crystal form of clopidogrel hydrogen sulfate I, wherein the molar ratio is (0.8-1.05):1.

Description

technical field [0001] The present invention relates to a kind of preparation method of pharmaceutical compound, specifically the present invention relates to a kind of preparation method of clopidogrel bisulfate type I crystal form. Background technique [0002] Clopidogrel hydrogen sulfate (Clopidogrel hydrogen sulfate) is an anti-platelet coagulant drug that can selectively inhibit the binding of ADP (adenosine diphosphate) to platelet receptors, and then inhibit the activation of ADP and glycoprotein GPIIb / IIIa complexes, thereby inhibiting platelet aggregation. Clopidogrel bisulfate can also inhibit non-ADP-induced platelet aggregation without affecting the activity of phosphodiesterase. Since 2005, clopidogrel as an anticoagulant drug has been used clinically for the treatment and prevention of myocardial infarction and has been widely used in clinical heart disease patients. Taking clopidogrel can significantly reduce the incidence of myocardial infarction. Clopidogr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 姚小青孙长海张存彦董凯李学洁王承睿李俊侠刘乃娜韩梅王瑞卿
Owner TIANJIN CHASE SUN PHARM CO LTD
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