Preparation method of fasudil hydrochloride semihydrate

A technology for fasudil hydrochloride and hemihydrate, applied in the field of medicine, can solve the problems of complicated operation, unavoidable environmental pollution, unfavorable production and the like, and achieve the effect of improving drying efficiency

Pending Publication Date: 2022-01-25
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Dichloromethane and chloroform have low boiling points, low concentration recovery rate, and inevitable environmental pollution
In the patent US5942505, the crystalline hydrate of Fasudil hydrochloride in water was dried at 25°C for 6 hours to obtain Fasudil hydrochloride trihydrate, and then dried at 25°C (humidity 75%) for 10 hours to obtain Fasudil hydrochloride Hemihydrate (water content 2.5-3.1%), complex operation, not conducive to production

Method used

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  • Preparation method of fasudil hydrochloride semihydrate
  • Preparation method of fasudil hydrochloride semihydrate
  • Preparation method of fasudil hydrochloride semihydrate

Examples

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Effect test

Embodiment 1

[0048] A preparation method of fasudil hydrochloride hemihydrate, comprising the steps of:

[0049] Referring to Example 3 of US4678783, 55 g of isoquinoline-5-sulfonyl chloride hydrochloride was dissolved in 500 ml of ice water, adjusted to pH 6 with saturated aqueous sodium bicarbonate solution, extracted with 1000 ml of dichloromethane, and the extract was extracted within 20 minutes Add it dropwise to 500ml of dichloromethane solution containing 50g of homopiperazine, cool down in an ice bath, and after the addition is complete, stir the reaction solution at 15-20°C for 2 hours to obtain a fasudil base reaction solution;

[0050] Stir and wash the Fasudil alkali reaction solution with water twice, each water consumption is 1500ml; then take the organic layer, extract with 660ml of 0.35mol / L hydrochloric acid aqueous solution, take the acid extraction water layer; stir and wash the acid with 660ml of dichloromethane Extract the water layer, then use 5mol / L sodium hydroxide ...

Embodiment 2

[0055] A preparation method of fasudil hydrochloride hemihydrate, comprising the steps of:

[0056] With reference to the embodiment 1 of US5942505, 88g homopiperazine is dissolved in 400ml chloroform, cooling in ice bath, the chloroform solution of isoquinoline-5-sulfonyl chloride is added dropwise (50g isoquinoline-5-sulfonyl chloride is dissolved in 400ml chloroform ), added dropwise in 1h, added, and continued to stir in an ice bath for 1h to obtain a fasudil base reaction solution;

[0057] Stir and wash the Fasudil alkali reaction solution with water twice, each water consumption is 800ml; then take the organic layer, extract with 580ml of 0.4mol / L hydrochloric acid aqueous solution, take the acid extraction water layer; stir and wash the acid with 580ml of dichloromethane Extract the water layer, then use 10mol / L sodium hydroxide aqueous solution to adjust the pH of the acid-extracted water layer to 11, cool down to -3~3°C, stir and crystallize for 2h, filter, wash the ...

Embodiment 3

[0060] A preparation method of fasudil hydrochloride hemihydrate, comprising the steps of:

[0061] Referring to Example 2 of CN103450157, in 440ml of dichloromethane, add 7g of potassium carbonate and 25g of homopiperazine, stir to dissolve, control the temperature below 0°C, slowly and continuously add 22g of 5-isoquinolinesulfonyl chloride hydrochloride, and finish adding , stirring at 0-15°C for 3h to obtain a fasudil base reaction solution;

[0062] Stir and wash the Fasudil alkali reaction solution with water twice, each water consumption is 220ml; then take the organic layer, extract with 200ml of 0.45mol / L hydrochloric acid aqueous solution, take the acid extraction water layer; stir and wash the acid with 200ml of dichloromethane Extract the water layer, then use 10mol / L sodium hydroxide aqueous solution to adjust the pH of the acid-extracted water layer to 10, cool down to -3~3°C, stir and crystallize for 2h, filter, wash the filter cake with 40ml of water, and dry i...

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Abstract

The invention discloses a preparation method of a fasudil hydrochloride semihydrate. The preparation method comprises the following steps: S1, synthesizing fasudil base in a hydrophobic aprotic solvent to obtain a fasudil base reaction solution; washing the fasudil alkali reaction liquid with water, and then extracting with a hydrochloric acid aqueous solution to obtain an acid-extracted water layer; washing the acid-extracted water layer with dichloromethane, then adjusting the pH value to 10-11, and crystallizing to obtain a fasudil alkali wet product; and S2, carrying out salt forming reaction on the fasudil alkali wet product and hydrochloric acid in water, crystallizing, and drying to obtain the fasudil hydrochloride semihydrate. The method is simple in process operation, short in production period, environment-friendly, low in cost, high in yield, pure in product and more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of fasudil hydrochloride hemihydrate. Background technique [0002] Fasudil Hydrochloride, the chemical name is hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine Hydrochloride hemihydrate, an isoquinoline sulfonamide derivative developed by Asahi Kasei Co., Ltd., is a Rho kinase inhibitor, which can not only inhibit the activity of free calcium ions in cells, but also inhibit smooth muscle myosin light chain phosphate Dilation of vascular smooth muscle and dilation of blood vessels. It is clinically used to improve and prevent cerebral vasospasm and subsequent cerebral ischemia after subarachnoid hemorrhage. [0003] There are many patents for the synthesis of Fasudil hydrochloride, such as: US4678783, US5942505, CN103450157, CN102020635, CN102070612, but the synthesis method is to condense isoquinoline-5-sulfonyl chloride or its hydrochloride with ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/13
Inventor 吴标凌林朱先锋李前进王周红
Owner HEFEI JIUNUO MEDICAL TECH
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