Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I

A kind of technology of clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in the field of preparation of high melting point crystal form I of clopidogrel hydrogen sulfate, and can solve the problems of harsh process conditions, easy crystal transformation, long storage time, etc. question

Active Publication Date: 2008-01-09
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0009] The low melting point crystalline form I of clopidogrel bisulfate with a melting point range of 180-186°C prepared by the disclosed patented process in the prior art has defects such as low purity of the crystalline form I and easy crystal transformation after long storage time; while the international patent Although WO2005/012300 can produce crystal form I with a high melting point, the yield is relatively high, but its process conditions are...

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  • Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I
  • Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I
  • Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I

Examples

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Embodiment 1

[0018] Put 5 g of clopidogrel free base and 35 ml of methyl ethyl ketone into a 100 ml three-necked flask, stir to dissolve and clarify, control the temperature at 25 ± 2 ° C, slowly add 1.5 g of concentrated sulfuric acid (mass fraction is 98%), after a small amount of crystals are precipitated, Add 0.5ml of methanol, stir and crystallize at this temperature for 12 hours. After the crystallization is completed, filter, wash with a small amount of butanone, and drain as much as possible to ensure that the residual amount of butanone in the filter cake is less than 10%. The filter cake was dried under vacuum at 30°C for 2-4 hours. 5.6 g of white powder solid was obtained, namely clopidogrel bisulfate crystal form I, with a yield of 86%. Melting point: 198-200°C.

Embodiment 2

[0020] Put 5g of clopidogrel free base and 35ml of acetone into a 100ml three-necked flask, stir to dissolve and clarify, control the temperature at 25±2°C, slowly add 1.5g of concentrated sulfuric acid (mass fraction is 98%) dropwise, after a small amount of crystals are precipitated, add Methanol 0.5ml, stirred and crystallized at this temperature for 12 hours, after the crystallization was completed, filtered, washed with a small amount of acetone, and drained as much as possible to ensure that the residual amount of acetone in the filter cake was less than 8%. The filter cake was dried under vacuum at 30°C for 2-4 hours. 5.5 g of white powder solid was obtained, which was the crystalline form I of clopidogrel bisulfate, and the yield in this step was 85%. Melting point: 198-200°C.

Embodiment 3

[0022] Put 5 g of clopidogrel free base and 35 ml of methyl ethyl ketone into a 100 ml three-necked flask, stir to dissolve and clarify, control the temperature at 25 ± 2 ° C, slowly add 1.5 g of concentrated sulfuric acid (mass fraction is 98%), after a small amount of crystals are precipitated, Add 0.5ml of absolute ethanol, stir and crystallize at this temperature for 12 hours, after the crystallization is completed, filter, wash with a small amount of butanone, and drain as much as possible to ensure that the residual amount of butanone in the filter cake is less than 10%. The filter cake was dried under vacuum at 30°C for 2-4 hours. 5.4 g of white powder solid was obtained, which was the crystalline form I of clopidogrel bisulfate, and the yield of this step was 83%. Melting point: 198-200°C.

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Abstract

Preparation of (+)-(S)-chlorpyrroline hydrogen sulfate high-smelting point crystal Iis carried out by dissolving chlorpyrroline free alkali into ketone solvent, adding into concentrated sulfuric acid, eluting crystal out, adding into alcohol solvent, agitating while crystallizing, filtering, washing for filter cake by ketone solvent, pumping and vacuum drying to obtain final product. It's simple and efficient, has gentle reactive condition and can be used for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and pharmacy, and relates to a preparation method of (+)-(S-)-clopidogrel bisulfate high melting point crystal form I (formula one). [0002] Formula 1: [0003] Background technique [0004] Polymorphism exists widely in organic medicines. For medicines with the same chemical structure, due to different crystallization conditions, such as solvents, temperatures, cooling rates, etc., the molecular arrangement and lattice structure are different when crystallization is formed, thus forming different crystal forms. Different crystal forms lead to different lattice energies, as well as different melting points, dissolution rates, and solubility of drugs. [0005] (+)-(S-)-Clopidogrel bisulfate is a platelet aggregation inhibitor. Scientific research has found that it is more effective than aspirin in inhibiting platelet aggregation, and has little side effects on the intestinal tract. ...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 李昌龙楼科侠秦靖张达
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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