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Production method of fasudil hydrochloride

A technology of fasudil hydrochloride and its production method, which is applied in the direction of organic chemistry, can solve the problems of incomplete utilization, easy formation of impurities, high cost, etc., and achieve the effects of full utilization, increased reaction yield, and simple and convenient treatment

Inactive Publication Date: 2011-02-16
河南省健康伟业生物医药研究股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

1. Since 1,4-diazepine has no selectivity at all, both ends of the reaction may participate in the reaction easily, and impurities are easily generated
2. In the reaction, the expensive raw material 1,4-diazepine must be excessive, which cannot be fully utilized, resulting in waste, so that the cost is relatively high
3. The yield is low, and the single-step yield reported in the literature is the highest in dichloromethane, which is only 72%.

Method used

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  • Production method of fasudil hydrochloride
  • Production method of fasudil hydrochloride

Examples

Experimental program
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Effect test

example 1

[0026] Example 1 The preparation of 1-tert-butylcarbonate group-1,4-diazepine (compound 3)

[0027] (1) In a single-necked bottle equipped with magnetic stirring, add ethanol and ethyl acetate with a volume ratio of 1:1 mixed solvent (100ml), and slowly add thionyl chloride (17g, 0.143mol) dropwise under cooling in a water bath to obtain An acidic alcoholic solution.

[0028] (2) In a three-necked flask equipped with mechanical stirring, add 1,4-tert-butyl dicarbonate-1,4-diazepine (compound 2) (41.5g, 0.138mol), then add ethanol and ethyl acetate A mixed solvent (200ml) with an ester volume ratio of 1:1; slowly add the acidic solution obtained in step (1) dropwise at room temperature, stir for 2 hours, and filter to obtain 1-tert-butylcarbonate-1,4-di The yield of azepine (compound 3) (15 g, 0.064 mol) was 46.4%. The filtrate was concentrated to obtain 20.6 g of unreacted 1,4-tert-butyldicarbonate-1,4-diazepine (compound 2), with a recovery rate of 49.5%.

example 2

[0029] Example 2 Preparation of 1-(5-isoquinolinesulfonyl)-4-tert-butylcarbonate-1,4-diazepine (compound 5)

[0030] In the there-necked flask equipped with mechanical stirring, add sodium hydroxide (2g, 0.0500mol), water (60ml) and ethanol (60ml), add 1-tert-butylcarbonate group-1,4-diazepine ( Compound 3) (10 g, 0.0427 mol), isoquinoline-5-sulfonyl chloride (compound 4) (9.7 g, 0.0426 mol). Stir at room temperature for 2 hours, concentrate to remove ethanol, extract with ethyl acetate, and concentrate the extract to obtain 1-(5-isoquinolinesulfonyl)-4-tert-butylcarbonate-1,4-diazepine (compound 5), as light yellow sticky substance.

example 3

[0031] Example 3 Preparation of hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride (fasudil hydrochloride)

[0032] The viscous material obtained in Example 2 was dissolved in ethanol, thionyl chloride was added dropwise, filtered, and dried. Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride (fasudil hydrochloride) (13 g, 0.0397 mol) was obtained with a yield of 93%.

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Abstract

The invention discloses a production method of fasudil hydrochloride and relates to the field of medicament synthesis. According to the method, the traditional process is improved. The fasudil hydrochloride is prepared by protecting homopiperazine with di-tert-butyl dicarbonate to generate 1-Boc-homopiperazine and then reacting the 1-Boc-homopiperazine with isoquinolin-5-sulphonyl chloride. The improvement can greatly improve the reaction yield, simultaneously avoid the use of first kind or second kind of solvent and benefit the safety production and the industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to isoquinoline sulfonamide derivatives of antiangina pectoris and cardiovascular and cerebrovascular drugs, in particular to the improvement of the production method of fasudil hydrochloride. Background technique [0002] Fasudil hydrochloride (fasudil hydrochloride), its chemical name: hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, its English name: 1-( 5-isquinoline-sulfonyl)-homopiperazine hydrochloride or 5-(1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride is a new type of isoquinoline sulfonamide derivatives. As a new and highly effective vasodilator, fasudil can effectively relieve cerebral vasospasm, improve the prognosis of patients with subarachnoid hemorrhage (SAH), and prevent and treat chronic ischemic cerebral vasospasm. In recent years, the research on its pharmacological effects and clinical application has been in-depth, and a lot of results ha...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 闫东海叶乾堂张红雨张静芳
Owner 河南省健康伟业生物医药研究股份有限公司
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