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Method for refining fasudil

A refining method and fasudil technology, which are applied in the refining process field of crude fasudil, can solve the problems of affecting drug quality, high toxicity of reagents, unfavorable large-scale production, etc., and achieve good refining effect, low production cost and low cost low effect

Active Publication Date: 2011-04-06
JIANGSU CAREFREE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As reported in US 5942505, a mixed solution of chloroform containing methanol volume fraction of 5% is used as an eluent for the crude product synthesized; methanol and chloroform (1:5, V / V) are used as an eluent for the crude product synthesized in CN101092413A report reagent; CE'DRIC LOGE et al. (Journal of Enzyme Inhibition and Medicinal Chemistry, 2003Vol.18 (2), pp.127-138) said that the synthetic crude product was washed with a mixture of methanol and dichloromethane as an eluent gradient These methods can purify the crude product, but the cost is too high, the toxicity of the reagents used is relatively large, which is not conducive to large-scale industrial production, and the yield is only 40% to 80%, which is relatively low, and the solvent residue of the eluent used Seriously affect the quality of medicines

Method used

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  • Method for refining fasudil

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Experimental program
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Effect test

Embodiment 1

[0025] The refining method of embodiment 1 Fasudil, proceed as follows:

[0026] a. Add 500 g of the crude product of fasudil to ethyl acetate at 30° C., fully stir to dissolve it, the mass concentration is 5%, and filter while it is hot to obtain filtrate A1;

[0027] b. Heat A1 to 30°C, stir, add dropwise n-hexane whose volume is 1.5 times the volume of ethyl acetate, and stir to obtain B1;

[0028] c. Naturally cool B1 to room temperature, then transfer to a 0°C refrigerator to freeze overnight, filter to obtain a solid, and vacuum-dry to obtain 440 g of finished product Fasudil with a purity of 99.4% and a yield of 88%.

Embodiment 2

[0029] The refining method of embodiment 2 Fasudil, proceed as follows:

[0030] a. 500 g of the crude product of fasudil was added into ethyl acetate at 30° C., fully stirred to make it dissolve, and the mass concentration was 25%, and filtered while it was hot to obtain filtrate A2;

[0031] b. Heat A2 to 30°C, stir, add dropwise n-hexane that is 1 times the volume of the added ethyl acetate, and stir to obtain B2;

[0032] c. Naturally cool B2 to room temperature, then transfer to -20°C refrigerator to freeze overnight, filter to obtain a solid, and vacuum-dry to obtain 460 g of finished product Fasudil with a purity of 99.5% and a yield of 92%.

example 3

[0033] The refining method of example 3 Fasudil, proceeds in the following steps:

[0034] a. 500 g of the crude product of fasudil was added into ethyl acetate at 70° C., fully stirred to make it dissolve, and the mass concentration was 25%, and filtered while it was hot to obtain filtrate A3;

[0035] b. Heat A3 to 70°C, stir, add dropwise n-hexane 0.5 times the volume of ethyl acetate added, and stir to obtain B3;

[0036] c. Naturally cool B3 to room temperature, then transfer to a 0°C refrigerator to freeze overnight, filter to obtain a solid, and vacuum-dry to obtain 425 g of finished product Fasudil with a purity of 99.6% and a yield of 85%.

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Abstract

The invention discloses a method for refining fasudil. In the method, recrystallization by ethyl acetate and normal hexane can be used for removing some polar small impurities from coarse fasudil, and the obtained product contains less than 0.05 percent of small polar impurities and can meet requirements of standards completely. Compared with the conventional column chromatography, the method hasthe characteristics of simple operation, low production cost and high finished product purity, and can be used in the industrial production of coarse fasudil.

Description

technical field [0001] The invention relates to a refining process for crude fasudil, in particular to removing less polar impurities in fasudil. Background technique [0002] Fasudil (hexahydro-1-(5-sulfonylisoquinoline)-1H-1,4-diazepine, molecular structure below) is a Rho-kinase inhibitor with potent vasodilator effects and Bao [0003] [0004] protection of ischemic brain tissue. The crude product obtained by the current synthesis process contains some ammonia and less polar impurities, which are difficult to remove. The removal of impurities in the traditional process is achieved by column chromatography, but the eluents used are different. As reported in US 5942505, a mixed solution of chloroform containing methanol volume fraction of 5% is used as an eluent for the crude product synthesized; methanol and chloroform (1:5, V / V) are used as an eluent for the crude product synthesized in CN101092413A report reagent; CE'DRIC LOGE et al. (Journal of Enzyme Inhibitio...

Claims

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Application Information

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IPC IPC(8): C07D403/12A61P9/08A61P9/00
Inventor 秦引林
Owner JIANGSU CAREFREE PHARM CO LTD
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