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Preparation method of fasudil hydrochloride

A technology of fasudil hydrochloride and isoquinolinesulfonyl chloride hydrochloride, which is applied in the field of medicine, can solve the problems that fasudil hydrochloride is difficult to pass through suction filtration, etc., so as to reduce the probability of acylation, the experimental operation is simple, and the reaction fast effect

Inactive Publication Date: 2013-04-17
成都天翼医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, the method of evaporating the water phase to directly obtain Fasudil hydrochloride solves the problem that Fasudil hydrochloride is difficult to obtain by suction filtration

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0045] A preparation method of Fasudil hydrochloride, comprising the following steps:

[0046] (1) Preparation of 5-isoquinolinesulfonyl chloride hydrochloride

[0047]

[0048] Weigh 2250g of 5-isoquinolinesulfonic acid, add it to a 30L glass reaction kettle, add 18000ml of thionyl chloride, stir for 10min, add 450ml of N,N-dimethylformamide, stir for 10min, pass into the interlayer of the reaction kettle Heat conduction oil, stir and heat up to reflux, reflux reaction for 2 hours, after the reaction is completed, the reaction solution is evaporated to dryness under reduced pressure, 2000ml of dichloromethane is added to the reaction kettle, and the solvent is evaporated to dryness under reduced pressure, and then stirred with 10Kg of dichloromethane Wash 4 times, filter, and vacuum-dry the filter cake at 40°C for 4 hours to obtain a white solid, namely 2480.01 g of 5-isoquinolinesulfonyl chloride hydrochloride, yield: 87.31%.

[0049] (2) Preparation of Fasudil Hydrochlo...

Embodiment 2

[0056] (1) Preparation of 5-isoquinolinesulfonyl chloride hydrochloride

[0057] Weigh 2250g of 5-isoquinolinesulfonic acid, add it to a 30L glass reaction kettle, add 18000ml of thionyl chloride, stir for 10min, add 450ml of N,N-dimethylformamide, stir for 10min, pass into the interlayer of the reaction kettle Heat conduction oil, stir and heat up to reflux, reflux reaction for 1 hour, after the reaction is complete, evaporate the reaction solution to dryness under reduced pressure, add 2000ml of dichloromethane, then evaporate the solvent to dryness under reduced pressure, then add 10Kg of dichloromethane to stir wash twice, After filtration, the filter cake was vacuum-dried at 40°C for 4 hours to obtain a white solid, namely 2449.90 g of 5-isoquinolinesulfonyl chloride hydrochloride, yield: 86.25%.

[0058] (2) Preparation of Fasudil Hydrochloride Crude Product

[0059] Weigh 1706.48g of homopiperazine, add it into a glass reactor, add 30.4L of dichloromethane, stir and di...

Embodiment 3

[0063] (1) Preparation of 5-isoquinolinesulfonyl chloride hydrochloride

[0064] Weigh 2250g of 5-isoquinolinesulfonic acid, add it to a 30L glass reaction kettle, add 18000ml of thionyl chloride, stir for 10min, add 450ml of N,N-dimethylformamide, stir for 10min, pass into the interlayer of the reaction kettle Heat conduction oil, stir and heat up to reflux, reflux reaction for 5 hours, after the reaction is completed, the reaction solution is evaporated to dryness under reduced pressure, 2000ml of dichloromethane is added, and the solvent is evaporated to dryness under reduced pressure, then 10Kg of dichloromethane is added to stir wash 3 times, After filtration, the filter cake was vacuum-dried at 40°C for 4 hours to obtain a white solid, namely 2481.15 g of 5-isoquinolinesulfonyl chloride hydrochloride, yield: 87.35%.

[0065] (2) Preparation of Fasudil Hydrochloride Crude Product

[0066] Weigh 3412.96g of homopiperazine, put it into a glass reaction kettle, add 30.4L of...

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to a preparation method of a protein kinase inhibitor fasudil hydrochloride. According to the method, as 5-isoquinoline sulfuryl chloride hydrochloride is adopted to react with homopiperzine directly, the problem that 5-5-isoquinoline sulfuryl chloride is easy to hydrolyze is avoided; and as fasudil hydrochloride is obtained by a direct water phase evaporating method, the problem that the extraction filtration of fasudil hydrochloride is difficult is solved. The preparation method is simple to operate, and higher in product yield and product purity.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a protein kinase inhibitor fasudil hydrochloride: hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride Preparation. Background technique [0002] Fasudil hydrochloride, chemical name: hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, molecular formula: C 14 h 17 N 3 o 2 S·HCl, molecular weight 327.83, English name: Fasudil Hydrochloride. [0003] Its chemical structure is as follows: [0004] [0005] (I) [0006] Fasudil is a new type of isoquinoline sulfonamide derivatives jointly developed by Asahi Kasei Co., Ltd. and Nagoya University Pharmacology Laboratory. Fasudil and its salts, such as Fasudil hydrochloride, as a new and highly effective vasodilator, can effectively relieve cerebral vasospasm, improve subarachnoid hemorrhage (SAH), and prevent chronic ischemic cerebrovascular spasms. In recent years, the research on its pharm...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 崔翼罗邻涛周定康刘三勇
Owner 成都天翼医药科技有限公司
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