Method for improving resolution yield of clopidogrel camphorsulfonate

A technology of clopidogrel camphorsulfonate and camphorsulfonate, which is applied in the field of synthesis to improve the yield of dexclopidogrel camphorsulfonate, and can solve the problem of complex resolution steps and low yield of clopidogrel resolution and other issues, to achieve the effect of simple operation

Active Publication Date: 2013-03-20
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to solve the shortcomings of low clopidogrel resolution yield and complex resolution steps in the prior art, the invention provides a method for improving the resolution yield of clopidogrel camphorsulfonate, and the resolution steps are improved , to increase the resolution yield to more than 90%, its enantiomers are less than 0.1%, and the operation is simple and practical. Compared with other methods, it has very obvious advantages

Method used

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  • Method for improving resolution yield of clopidogrel camphorsulfonate
  • Method for improving resolution yield of clopidogrel camphorsulfonate
  • Method for improving resolution yield of clopidogrel camphorsulfonate

Examples

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Effect test

Embodiment 1

[0024] Step 1: Dissolve 90g (0.28mol) of clopidogrel racemate in 450ml of dichloromethane / acetone mixed solvent (1 / 10 by volume), and add 64.5g (0.28mol) of L-camphor-10-sulfonic acid , stirred and dissolved, stirred and crystallized between 15-20°C for 12 hours, suction filtered (the mother liquor was continued to be used in step 2), and dried to obtain 46.5g of the target product, D-clopidogrel camphorsulfonate B, with an ee value> 99.8%.

[0025] Step 2: Control the temperature of the mother liquor in step 1 to 5-10°C, stir for 4 hours, suction filter and dry to obtain 64g of clopidogrel camphorsulfonate C, and add 4.1g of dextroclopidogrel camphorsulfonate B to C, and add dichloromethane / acetone mixed solvent (volume ratio is 1 / 10) 340ml, heating makes it dissolve, stirring crystallization, stirring crystallization 12 hours between the control temperature 15-20 ℃, then through suction filtration ( The mother liquor was continued to be used in Step 3), and dried to obtain ...

Embodiment 2

[0029] Step 1: Dissolve 180 g (0.56 mol) of clopidogrel racemate in 900 ml of dichloromethane / acetone mixed solvent (1 / 10 by volume), add 129 g (0.56 mol) of L-camphor-10-sulfonic acid, Stir to dissolve, stir and crystallize at 15-20°C for 12 hours, filter with suction (the mother liquor will continue to be used in step 2), and dry to obtain the target product dextroclopidogrel camphorsulfonate solid B is 95g, ee value > 99.8 %.

[0030] Step 2: Control the temperature of the mother liquor in step 1 to 0-5°C, stir for 4 hours, suction filter and dry to obtain 130 g of clopidogrel camphorsulfonate C, and add 8 g of dextroclopidogrel camphorsulfonate B to C , and add 690ml of dichloromethane / acetone mixed solvent (1 / 10 in volume ratio), heat to dissolve, stir and crystallize at 15-20°C for 18 hours, then filter with suction (the mother liquor will continue to be used in step 3), and dry to obtain The solid B' of clopidogrel camphorsulfonate is 44.1 g, and the ee value is >99.8%...

Embodiment 3

[0034] Step 1: Dissolve 180 g (0.56 mol) of clopidogrel racemate in 900 ml of dichloromethane / acetone mixed solvent (1 / 10 by volume), add 129 g (0.56 mol) of L-camphor-10-sulfonic acid, Stir to dissolve, stir and crystallize at 15-20°C for 18 hours, filter with suction (the mother liquor will continue to be used in step 2), and dry to obtain the target product, D-clopidogrel camphorsulfonate B, which is 95.6g, and the ee value is >99.8 %.

[0035]Step 2: Control the temperature of the mother liquor in step 1 to 0-5°C, stir for 8 hours, suction filter, and dry to obtain 141 g of clopidogrel camphorsulfonate C, and add 10 g of dextroclopidogrel camphorsulfonate B to C and add 755ml of dichloromethane / acetone mixed solvent (volume ratio is 1 / 10), heat to dissolve, stir and crystallize, control the temperature between 15-20°C to stir and crystallize for 18 hours, then suction filter (mother liquor Continue to use in step 3), dry to obtain dexclopidogrel camphorsulfonate solid B' ...

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Abstract

The invention discloses a synthesis method capable of improving the yield of dextro-clopidogrel camphorsulfonate. In the method, racemate of clopidogrel is used as a raw material, the dextro-clopidogrel camphorsulfonate is obtained by repeatedly performing the steps of resolution with the resolving agent, crystallization, vacuum filtration and drying, and the obtained dextro-clopidogrel camphorsulfonate is dissociated by a dissociating agent to obtain the dextro-clopidogrel camphorsulfonate with a yield of over 90 percent. The enantiomer of the clopidogrel dextroisomer product obtained by the method is less than 0.1 percent, and the ee value of the clopidogrel dextroisomer product obtained by the method is over 99.5 percent. Compared with other methods, the method has the advantage of simple operation.

Description

technical field [0001] The invention relates to an improvement of a clopidogrel resolution method, in particular to a synthesis method for increasing the yield of dextroclopidogrel camphorsulfonate. Background technique [0002] Clopidogrel is a platelet inhibitor, which was successfully developed by the French company Sanofi in 1986. Its clinical drug is its sulfate. Clopidogrel can selectively inhibit adenosine diphosphate (ADP) and its platelet receptors. The binding of ADP and the secondary activation of the glycoprotein GPIIIb / IIIa complex mediated by ADP can inhibit platelet aggregation. Clopidogrel must be biotransformed to inhibit platelet aggregation. In addition to ADP, clopidogrel can also inhibit platelet aggregation. Interrupts the expansion of platelet activation caused by released ADP and inhibits platelet aggregation induced by other agonists. Clopidogrel acts by irreversibly modifying platelet ADP receptors. Its chemical formula is as follows: [0003] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
Inventor 金晓峰殷学治
Owner CHANGZHOU PHARMA FACTORY
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