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Synthesis and preparation method of fasudil hydrochloride

A technology for fasudil hydrochloride and isoquinoline sulfonyl chloride hydrochloride, applied in the field of medicine, can solve problems such as unpublished yield, and achieve the effects of reducing production cost and usage amount

Inactive Publication Date: 2012-07-25
NOWA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Patents CN101863880A and CN102020635A respectively disclose a method for synthesizing fasudil hydrochloride compound. In the preparation method, 5-isoquinolinesulfonyl chloride hydrochloride and homopiper The equivalent ratio of oxazine used is 1:4, and the yield rate of the step of coupling into fasudil is about 70%; in addition, in the synthesis and purification method of fasudil hydrochloride disclosed in patent CN102020636A, 5-isoquinolinesulfonate The equivalent ratio of acid chloride hydrochloride to homopiperazine is 1:6, but the yield is not published

Method used

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  • Synthesis and preparation method of fasudil hydrochloride
  • Synthesis and preparation method of fasudil hydrochloride
  • Synthesis and preparation method of fasudil hydrochloride

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preparation example Construction

[0023] A kind of synthetic and preparation method of Fasudil hydrochloride, this preparation method comprises the steps:

[0024] (1) In the presence of catalyst N,N-dimethylformamide, 5-isoquinolinesulfonic acid was stirred in thionyl chloride and heated to reflux at a reaction temperature of 75°C-85°C to obtain 5 - Isoquinolinesulfonyl chloride hydrochloride;

[0025] (2) Dissolve 5-isoquinolinesulfonyl chloride hydrochloride in ice water, add dichloromethane solution, slowly add saturated aqueous sodium bicarbonate solution under stirring, adjust the pH value of the solution to neutral and then separate the liquids, and the water phase is dichloromethane After methane extraction once, the organic phases were combined, and the organic phases were washed with water and saturated brine in turn, dried over anhydrous magnesium sulfate, and suction filtered to obtain a dichloromethane solution of 5-isoquinolinesulfonyl chloride;

[0026] (3) Slowly add the dichloromethane soluti...

Embodiment 1

[0031] Example 1 Isoquinoline-5-sulfonyl chloride hydrochloride

[0032] 5-Isoquinolinesulfonic acid (20 g), thionyl chloride (200 mL), and DMF (10 g) were successively added into a 500 mL round-bottomed single-necked flask, and refluxed for 5 hours. The unreacted thionyl chloride was distilled off under reduced pressure to obtain a yellowish solid. 50 mL of dichloromethane was added thereto, and suction filtered. The filter cake was washed with dichloromethane and vacuum-dried to obtain a white solid, namely 5-isoquinolinesulfonyl chloride hydrochloride (22 g, 88%).

Embodiment 2

[0033] Example 2 5-isoquinolinesulfonyl chloride

[0034] Get the hydrochloride (19.4g, 73.4mmol) of 5-isoquinolinesulfonyl chloride obtained in Example 1 and put it into a 1L Erlenmeyer flask containing 300mL of ice-water mixture, then add 150mL of dichloromethane, and stir Neutralize the pH of the mixed liquid system to 7 with saturated aqueous sodium bicarbonate solution, separate and extract, keep the organic phase, extract the aqueous phase with dichloromethane (50mL) again, combine the organic phases, and dry the organic phase over anhydrous magnesium sulfate for half an hour After suction filtration, 200 ml of a dichloromethane solution of 5-isoquinolinesulfonyl chloride was obtained.

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Abstract

The invention discloses a synthesis and preparation method of fasudil hydrochloride, which comprises the steps of taking 5-isoquinoline sulfoacid as raw material, refluxing in thionyl chloride to obtain 5-isoquinoline sulfonyl chloride hydrochloride, adding dichloromethane after dissolving with ice water, adjusting pH value of the solution to be neutral and performing liquid eparation; washing organic phase with water and edible salt, drying and filtering to obtain dichloromethane solution of 5-isoquinoline sulfonyl chloride; performing reaction of the solution with high purity piperazine in the presence of other alkaline reagents, washing the reaction solution with hydrochloric acid aqueous solution and sodium hydroxide aqueous solution after reaction, and extracting the washing solution respectively with dichloromethane; combining organic phases, washing with water, drying and filtering, and dropwise adding saturated hydrogen chloride ethanol solution to separate out crude product of fasudil hydrochloride; and recrystalizing the crude product with ethanol aqueous solution to obtain fasudil hydrochloride. The method provided by the invention greatly reduces the usage amount of high purity piperazine that is expensive by using deacidifying agents that are low in cost so as to reduce the preparation cost of fasudil hydrochloride effectively.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a synthesis and preparation method of fasudil hydrochloride. Background technique [0002] Fasudil hydrochloride, chemical name is hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, molecular formula C 14 h 17 N 3 o 2 S HCl, the molecular weight is 327.83, and the structural formula is: [0003] [0004] Fasudil hydrochloride is a protein kinase inhibitor, that is, an intracellular calcium ion antagonist, which can dilate blood vessels and inhibit vasospasm by blocking the final stage of vasoconstriction process, phosphorylation of muscle protein light chain. It is clinically suitable for improving and preventing cerebral spasm after subarachnoid hemorrhage and the symptoms of cerebral ischemia caused by it. [0005] In the prior art, the main synthetic route of Fasudil hydrochloride is: [0006] [0007] Although the above-mentioned synthetic ro...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 孟俊秀汪艺宁顾大公殷西锋
Owner NOWA PHARMA
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