Method for preparing (+)-(s-)-clopiclogrel hydrogensulfate (I)

A technology for clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in the preparation of hydrogen sulfate type I crystals, and in the field of antithrombotic drugs-clopidogrel hydrogen sulfate, which can solve the flow of clopidogrel hydrogen sulfate. The performance and stability are not ideal, it is unfavorable for large-scale industrial production, and the preparation cycle is long.

Active Publication Date: 2006-10-25
ZHEJIANG HISOAR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since a large amount of heat will be released when the sulfuric acid solution is added dropwise, more energy needs to be removed to keep the temperature at -20-5°C, and the 10-hour stirring time after adding the s...

Method used

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  • Method for preparing (+)-(s-)-clopiclogrel hydrogensulfate (I)
  • Method for preparing (+)-(s-)-clopiclogrel hydrogensulfate (I)
  • Method for preparing (+)-(s-)-clopiclogrel hydrogensulfate (I)

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example 1 Preparation of (+)-(S-)-clopidogrel free base

[0035]Inhalation of methylene chloride 200kg in the free still, add (+)-(S-)-clopidogrel hydrochloride 23kg, under stirring, dropwise add sodium bicarbonate aqueous solution (12kg sodium bicarbonate and 100kg water are made into), dropwise After adding, stir for another 30 minutes, let stand for 10 minutes, separate the lower organic phase, extract the aqueous layer twice with 100Kg×2 dichloromethane, combine the organic phases, wash the combined phase with 5% aqueous sodium bicarbonate solution to pH 7 ~8, washed once with 100kg of water, dried by adding 10kg of anhydrous magnesium sulfate, filtered under pressure, and distilled to recover dichloromethane to obtain 20kg of oily (+)-(S-)-clopidogrel free base.

Embodiment 2

[0036] Example 2 Preparation of (+)-(S-)-clopidogrel free base

[0037] Inhalation of methylene chloride 200kg in the free still, add (+)-(S-)-clopidogrel hydrochloride 23kg, under stirring, drip an aqueous sodium carbonate solution (7kg sodium carbonate and 100kg water), dropwise complete , stir for another 30 minutes, stand for 10 minutes, separate the lower organic phase, extract the aqueous layer twice with 100Kg×2 dichloromethane, combine the organic phases, and wash the combined phase with a 5% aqueous sodium bicarbonate solution to pH 7-8 , washed once with 100kg of water, added 10kg of anhydrous sodium sulfate, dried, filtered under pressure, and distilled to recover dichloromethane to obtain 20kg of oily (+)-(S-)-clopidogrel free base.

Embodiment 3

[0038] Example 3 Preparation of (+)-(S-)-clopidogrel free base

[0039] Inhalation of methylene chloride 200kg in the free still, add (+)-(S-)-clopidogrel sulfate 26.9kg, under stirring, dropwise add sodium carbonate aqueous solution (formed by 7kg sodium carbonate and 100kg water), dropwise complete , stir for another 30 minutes, stand for 10 minutes, separate the lower organic phase, extract the aqueous layer twice with 100Kg×2 dichloromethane, combine the organic phases, and wash the combined phase with a 5% aqueous sodium bicarbonate solution to pH 7-8 , washed once with 100kg of water, added 10kg of anhydrous sodium sulfate, dried, filtered under pressure, and distilled to recover dichloromethane to obtain 20kg of oily (+)-(S-)-clopidogrel free base.

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Abstract

This invention relates to anti thrombus medicine (+)-(S-)-chlorine pyrrole rayl bisulfate preparation method. (+)-(S-)-chlorine pyrrole rayl free alkali shown as formula (I) is added in organic solvent, and weight concentration 10-100 perent sulphuric acid solution is dropwised at 6-20 degree centigrade, then the reaction is kept for 10 minute to 1.5 hours at 50-65 degree centigrade and the temperature is protected, finally formula (II) compound is got after filtration. The sulphuric acid solution is made by sulfuric acid dissolved in organic solvent, the organic solvent is one or more of the following, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, aether, isopropyl ether, tertiary butyl methyl ether or methylene chloride. Mol ratio of compound (I) and sulfuric acid is 1:0.95-1.05. The synthesis in this invention is safe and high efficiency, it is propitious to industrial manufacture, product purity is high, yield is high, and crystal form fluidity is good.

Description

(1) Technical field [0001] The present invention relates to an antithrombotic drug (+)-(S-)-clopidogrel bisulfate (type I) namely (+)-(S-)-α-(2-chlorophenyl)-4,5 , 6,7-tetrahydrothiano[3,2-C]pyridyl-5-methyl acetate hydrogen sulfate type I crystal preparation method. (2) Background technology [0002] Clopidogrel bisulfate is an antithrombotic drug, the molecular formula is as shown in formula (II), and the molecular structural formula is: [0003] [0004] It was originally developed by the French company Sanofi, and it is clinically used in the treatment of atherosclerotic diseases, acute coronary syndrome, and the prevention of in-stent restenosis and thrombotic complications after coronary stent implantation. [0005] The mechanism of action of clopidogrel is to inhibit platelet aggregation by selectively and irreversibly inhibiting the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the GP IIb / IIIa comple...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 张群辉郑志国陈少亭钱绍建胡合飞
Owner ZHEJIANG HISOAR PHARMA
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