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Method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form

A technology of clopidogrel hydrogen sulfate and clopidogrel camphor sulfonate, applied in the direction of organic chemistry and the like, can solve the problems of low crystal form purity, difficult control of technological process, difficult to meet the requirements of industrialized scale-up production, etc. High purity, good crystal quality stability, not easy to agglomerate

Inactive Publication Date: 2012-11-28
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to provide a method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form, to overcome the easy agglomeration existing in the prior art, the crystal form purity is not high, and the process is difficult control, it is difficult to meet the defects of industrial scale-up production requirements

Method used

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  • Method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form
  • Method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form
  • Method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form

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Embodiment 1

[0029] Add (+)-(S-)-clopidogrel camphorsulfonate 118g and dichloromethane 200ml in the reaction flask, stir and drop the temperature to below 5°C and control the temperature below 5°C and dropwise add sodium bicarbonate aqueous solution (20.2g Sodium bicarbonate and 300ml of water), after the dropwise addition, stir for another 10 minutes, let it stand for 5 minutes, separate the lower organic phase, extract the aqueous phase with 200ml of dichloromethane once, combine the organic phases, and use 100ml of purified water for the combined phases ×2 was washed twice, concentrated under reduced pressure to obtain an equivalent amount of (+)-(S-)-clopidogrel (free base) (64.2 g).

Embodiment 2

[0031] Inhale 100Kg of dichloromethane into the reaction kettle, add 26.2Kg of (+)-(S-)-clopidogrel camphorsulfonate, cool down to below 5°C in an ice-salt bath under stirring, and add dropwise under temperature control below 5°C Aqueous solution of sodium bicarbonate (4.8Kg sodium bicarbonate and 70Kg water), after dropwise addition, stir for 15 minutes, let stand for 10 minutes, separate the lower organic phase, extract the aqueous phase once with 100Kg of dichloromethane, and combine the organic phases , the combined phase was washed twice with purified water 35Kg×2, and concentrated under reduced pressure to obtain an equivalent amount of (+)-(S-)-clopidogrel (free base) (15.2Kg).

Embodiment 3

[0033] Dissolve the (+)-(S-)-clopidogrel prepared in Example 2 with 137Kg of ethyl acetate and add it to a stirred reactor, control the temperature at 20°C, add 1.0Kg of (+)-(S- -)-Clopidogrel bisulfate 1 crystal seed, slowly dropwise add 15.2Kg of 98% sulfuric acid ethyl acetate solution prepared in advance (the amount of 98% concentrated sulfuric acid is 5.1Kg, 0.051Kmol), drop for 1 hour After the addition is completed, stir at 25°C for 1.5h, filter, wash twice with 21Kg ethyl acetate, centrifuge, vacuum greater than 0.09Mpa, and dry at 40-50°C to obtain free (+)-(S-)-clopidogrel hydrogen sulfate Salt (1 crystal form) 19.9Kg, yield 95.1%, content of 1 crystal form 100%.

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Abstract

The invention provides a new method for preparing a (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form. The method comprises the following steps of: dissolving (+)-(S-)-clopidogrel (free alkali) into an organic solvent, stirring, controlling the temperature to be between 15 and 40 DEG C, adding seed crystal, dripping 5 to 40 percent concentrated sulfuric acid solution, stirring for certain time at a constant temperature, filtering, washing, drying, and thus obtaining the crystal form. The preparation method is mild in reaction conditions and suitable for temperature change of any season, does not require special temperature control equipment, avoids caking in the sulfuric acid dripping process, and is easy to operate, high in controllability, short in process time and suitable for the requirement for industrialized mass production; and the yield of the crystal form is over 85 percent, the crystal form is high in purity and high in quality stability, and the content of the 1 crystal form can reach over 99 percent.

Description

technical field [0001] The present invention relates to a method for preparing (+)-(S-)-clopidogrel hydrogen sulfate, namely (+)-(S-)-α-(2-chlorophenyl)-4,5,6,7- The invention discloses a method for crystal form 1 of methyl tetrahydrothieno[3,2-C]pyridyl-5-acetate bisulfate, belonging to the technical field of chemical medicine preparation. Background technique [0002] Clopidogrel bisulfate is an antithrombotic drug with a molecular structural formula as shown in Formula 2: [0003] [0004] The drug was originally developed by the French company Samofi and was successfully developed in 1980; it is clinically used in the treatment of atherosclerotic diseases, acute coronary syndrome, prevention of in-stent restenosis and thrombotic complications after coronary stent implantation disease etc. [0005] Clopidogrel bisulfate currently used as a drug in the market mainly has two crystal forms, 1 crystal form and 2 crystal form. Patent ZL99807458.6 described the characteri...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 华长华金志平
Owner ZHEJIANG JINGXIN PHARMA
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