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Preparation method of I type clopidogrel hydrogen sulfate

A technology for clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in the field of pharmaceutical compound preparation, can solve the problems of poor reproducibility of the preparation method, reduced production cost and high production cost, and achieves that the operation method is simple and feasible, The effect of reducing production cost and high crystal purity

Inactive Publication Date: 2010-08-18
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a method for stably preparing high-purity I-type clopidogrel hydrogen sulfate for the defects of high production cost, cumbersome operation, and poor reproducibility of the preparation method in the existing preparation method of type I clopidogrel hydrogen sulfate. A new method of type clopidogrel hydrogen sulfate, the biggest feature of this method is that each operation can stably obtain type I clopidogrel hydrogen sulfate, and at the same time, the low-cost tetrahydrofuran solvent is used in the preparation process instead of the one used in the patent CN 1903859A Expensive solvents such as five-carbon ketone and hexa-carbon ketone, and no steps such as nitrogen protection are required in the preparation process, which reduces production costs and is simple and easy to operate

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Put 0.536 g of clopidogrel free base and 5 ml of tetrahydrofuran into a 100 ml flask, stir at -14°C until the solution is clear, slowly add 0.165 g of concentrated sulfuric acid with a mass fraction of 98%, and react at -14°C for 1-2 hours , slowly raised the temperature to 20°C, and continued to stir and crystallize at this temperature for 10-12 hours. After the crystallization was completed, filter, wash with tetrahydrofuran, and drain as much as possible. Vacuum-dry the filter cake for 3 to 4 hours to obtain 0.538 grams of white powder solid, which is type I clopidogrel bisulfate, with a yield of 77% and a crystal form purity of 100% ( Figure 1~2 It shows that the obtained clopidogrel bisulfate is pure type I).

Embodiment 2

[0027] Put 0.551 g of clopidogrel free base and 5 ml of tetrahydrofuran into a 100 ml flask, stir at -12°C until the solution is clear, slowly add 0.175 g of concentrated sulfuric acid with a mass fraction of 98%, and react at -12°C for 1-2 hours , slowly raised the temperature to 20°C, and continued to stir and crystallize at this temperature for 10-12 hours. After the crystallization was completed, filter, wash with tetrahydrofuran, and drain as much as possible. The filter cake was vacuum-dried for 3 to 4 hours to obtain 0.521 g of white powder solid, which was type I clopidogrel bisulfate, with a yield of 73% and a crystal form purity of 100%.

Embodiment 3

[0029] Put 0.502 g of clopidogrel free base and 5 ml of tetrahydrofuran into a 100 ml flask, stir at 0°C until the solution is clear, slowly add 0.166 g of concentrated sulfuric acid with a mass fraction of 98%, react at 0°C for 1-2 hours, slowly Raise the temperature to 20°C, and continue to stir and crystallize at this temperature for 10-12 hours. After the crystallization is completed, filter, wash with tetrahydrofuran, and drain as much as possible. The filter cake was vacuum-dried for 3-4 hours to obtain 0.514 g of a white powder solid, namely type I clopidogrel bisulfate, with a yield of 79% and a crystal form purity of 100%.

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Abstract

The invention discloses a preparation method of I type clopidogrel hydrogen sulfate. The method comprises the following steps: (1) dissolving clopidogrel free base in tetrahydrofuran, and adding concentrated sulfuric acid at the temperature of minus 14-0 DEG C; (2) leading the mixture to react for 1-2 hours, then slowly increasing the reaction temperature to 20-40 DEG C, continuing the reaction for 10-12 hours, and fully precipitating crystals; and (3) filtering after obtaining the crystals, washing a filter cake with the tetrahydrofuran, draining, vacuum-drying and obtaining the I type clopidogrel hydrogen sulfate. The I type clopidogrel hydrogen sulfate prepared through the method is not doped with II type clopidogrel hydrogen sulfate and has high crystal phase purity, and the preparation process does not need the steps of nitrogen production and the like, thereby reducing the production cost, leading the operation method to be simple and easy, realizing high repeatability and being easy to realize mass production.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical compounds, in particular to a preparation method of type I clopidogrel bisulfate. Background technique [0002] Clopidogrel bisulfate is an antithrombotic drug, clinically used to prevent and treat heart, brain and other arterial circulation disorders caused by high platelet aggregation. Clopidogrel was originally successfully developed by the French company Sanofi in 1980. On November 17, 1997, the U.S. Food and Drug Administration approved clopidogrel bisulfate (Plavix) for post-myocardial infarction, post-stroke and confirmed peripheral artery disease. disease, clopidogrel bisulfate entered my country in 2001 and was mainly used for the treatment and prevention of patients with myocardial infarction. [0003] The structural formula of the clopidogrel bisulfate molecule is shown below: [0004] [0005] Existing research results show that the molecule has six different crystal fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 鲁统部闫岩王子舟张伟雄誉智豪
Owner SUN YAT SEN UNIV
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