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Preparation method of fasudil hydrochloride

A technology for fasudil hydrochloride and isoquinoline sulfonyl chloride hydrochloride, which is applied in the field of preparation of fasudil hydrochloride, can solve the problems of poor color, high solubility, large consumption and the like

Active Publication Date: 2011-11-16
吉林省博大伟业制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high solubility of fasudil hydrochloride in water, we tested that the yield of the finished product was 36.3%, and the color was not good, as light yellow lumps
[0011] Comprehensive above-mentioned literature and patent all use column chromatography to separate and purify, and its drawback is: (1) preparation chromatographic column troublesome, drop into 5.0kg5-isoquinolinesulfonyl chloride, must use 150kg silica gel (Wakogel C-200)
(2) Need to consume a large amount of organic solvent chloroform to elute
(3) There are many decompression and concentration processes in the process, which do not meet the requirements of energy saving
(5) High cost of finished products
(6) The operation is cumbersome and time-consuming
(7) Using a large amount of ether does not comply with safe production

Method used

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  • Preparation method of fasudil hydrochloride

Examples

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Effect test

Embodiment 1

[0033] One, the preparation of 5-isoquinolinesulfonyl chloride hydrochloride

[0034] Under stirring, put 1kg of 5-isoquinolinesulfonic acid in a 10L reaction tank, add 8.19kg of thionyl chloride and 40g of DMF to heat, stir and reflux at 75-80°C for 3h, then distill off the thionyl chloride under reduced pressure . After cooling, add 4kg of dichloromethane, filter, wash the precipitate twice with dichloromethane (2.7kg×2), and drain it to obtain the obtained product.

[0035] Two, the preparation of 1-(5-isoquinolinesulfonyl) homopiperazine

[0036] Under agitation, place 1.14kg of 5-isoquinolinesulfonyl chloride hydrochloride, which was converted into pure after the determination of moisture by the Karl-Fisher method, in a 50L reaction tank, add 10kg of purified water and 13.3kg of dichloromethane, and place in an ice bath Cool down to 0°C, add sodium bicarbonate to adjust the pH to 6, then add 13.3 kg of dichloromethane, and separate layers. Separate the 5-isoquinolinesu...

Embodiment 2

[0042] One, the preparation method of 5-isoquinolinesulfonyl chloride hydrochloride is the same as above.

[0043] Two, the preparation of 1-(5-isoquinolinesulfonyl) homopiperazine

[0044]Dissolve 57g of the above 5-isoquinolinesulfonyl chloride hydrochloride in 500ml of purified water, stir in an ice bath and cool down to 0°C, add sodium bicarbonate to adjust the pH to 6, add 1000ml of dichloromethane, and separate layers. Separate the solution of 5-isoquinolinesulfonyl chloride in dichloromethane and add it dropwise to 500ml of dichloromethane containing 52g of homopiperazine for 20 minutes. The temperature was maintained at 15-20°C for 2 hours. After the reaction was completed, water was added to wash twice (300ml×2). 1N hydrochloric acid solution was added dropwise to the dichloromethane phase to adjust the pH to 5-6, and the acidic aqueous layer was separated. Add 250ml of purified water to the lower layer and extract once more, and combine the acid aqueous layer solu...

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Abstract

The invention relates to a preparation method of fasudil hydrochloride. In the method, 1-(5-isoquinoline sulfonyl) homopiperazine does not undergo chromatographic column separation and purification, lots of organic solvent for elution is omitted, and multiple concentration under reduced pressure becomes unnecessary, thus the process is no longer tedious and time consuming. The crude product of fasudil hydrochloride adopts methanol as the recrystallization solvent, so that the preparation steps are reduced, the energy can be saved and the cost can be reduced. The undried 5-isoquinoline sulfonyl chloride hydrochloride that is subjected to a Karl Fischer moisture test and purified solved in water and dichloromethane, and sodium bicarbonate is added for neutralization followed by layering. The split dichloromethane solution of 5-isoquinoline sulfonyl chloride and the dichloromethane solution of homopiperazine are condensed, and water is added for washing. When the dichloromethane layer isseparated and dried, dry hydrogen chloride gas is introduced into the dichloromethane, so that the fasudil hydrochloride crude product can be obtained. The crude product is then recrystallized in methanol, thus obtaining a competitive product which is white or almost white crystalline powder. The yield of 5-isoquinoline sulfonic acid as the competitive product is calculated as 66.3%.

Description

technical field [0001] The invention relates to a preparation method of fasudil hydrochloride. Compared with the existing preparation method, the yield of fasudil hydrochloride is improved. Background technique: [0002] 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride is an isoquinolinesulfonamide compound developed by Asahi Chemical Industry Co, Ltd. This product can not only inhibit the activity of free calcium ions in cells, but also inhibit protein kinase A, G, C and myosin light chain kinase, that is, inhibit the phosphorylation of myosin light chain in the final stage of smooth muscle contraction, and make vascular smooth muscle Dilates, dilates blood vessels. By inhibiting RHO kinase, fasudil can increase the expression of NOS, promote the production of NO, and exert its protective effect on tissue damage. [0003] It is clinically used to improve and prevent cerebral vasospasm after subarachnoid hemorrhage and subsequent cerebral ischemic symptoms. [0004...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 苏焕臣谢文博李旭毛铭李晓东
Owner 吉林省博大伟业制药有限公司
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