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Preparation method of fasudil hydrochloride

A technology of fasudil hydrochloride and amine group, applied in the field of preparation of pharmaceutical compounds, can solve the problems of difficulty in separation, high commercial price, affecting the production cost of final products, etc., and achieve the effects of improving yield and high product purity

Inactive Publication Date: 2011-07-13
CHENGDU XINJIE HIGH TECH DEV CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0006] The above-mentioned synthetic route is short and has few steps, but there are certain defects: first, the commercial price of the raw material of the compound of formula 7 (homopiperazine) is too high, directly affects the production cost of the final product, and does not have market competitiveness; second, According to the above method, the reaction of formula 2 and formula 7 compounds (homopiperazine), the reaction product is not a single compound, as shown in the following reaction formula, its product is a mixture, including the hexahydro-1-(5 -isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride (fasudil hydrochloride) and the compound shown in formula 10 are difficult to separate, resulting in low yield of fasudil hydrochloride

Method used

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  • Preparation method of fasudil hydrochloride

Examples

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Embodiment 1

[0032] Embodiment 1 prepares 1-benzyloxycarbonyl-4-(5-isoquinoline sulfonamide) homopiperazine

[0033] Add 1-benzyloxycarbonylhomopiperazine (1.23 kg), 5-isoquinolinesulfonyl chloride (1 kg) and potassium carbonate (0.88 kg), add dichloromethane (5 liters), and stir vigorously at 15-30°C 5 hours. After completion of the reaction, add water (5 liters), separate the layers, extract the aqueous phase with ethyl acetate (5 liters each time, extract 3 times), combine the organic layers, dry with anhydrous sodium sulfate for 3 hours, and filter off the solids. The filtrate was concentrated under reduced pressure to obtain 1-benzyloxycarbonyl-4-(5-isoquinolinesulfonamide)homopiperazine as a pale yellow solid. It can be used directly without purification.

Embodiment 2

[0034] Example 2 Preparation of Hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride

[0035] Using the 1-benzyloxycarbonyl-4-(5-isoquinolinesulfonamide) homopiperazine (1 kg) prepared as shown in Example 1, add 10 liters of water, carefully add concentrated hydrochloric acid (10 liter), after the exotherm stabilizes, heat to 100-110°C for reflux reaction for 3 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, extracted with ethyl acetate (2 liters each time, extracted 3 times in total), collected the aqueous phase, adjusted to pH=10-13 with 5M sodium hydroxide solution, and extracted with dichloromethane (3 liters each time, total extraction 4 times), the organic phases were combined, dried with anhydrous sodium sulfate for 3 hours, the solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain a light yellow solid and the crude product of Fasudil. The obtained pale yellow s...

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Abstract

The invention discloses a preparation method of fasudil hydrochloride. The preparation method comprises the following steps of: performing sulfonylation on 5-isoquinoline sulfonyl chloride and amino-protected homopiperazine, and removing an amino protective group of a reaction product. The amino-protected homopiperazine is taken as a raw material for the sulfonylation, so that two amino groups are prevented from being subjected to the sulfonylation to generate a byproduct; therefore, the yield of a target product (namely the fasudil hydrochloride) is improved, and the obtained product has high purity.

Description

technical field [0001] The present invention relates to the preparation of a pharmaceutical compound, especially the preparation of hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride (commonly known as: Fasudil hydrochloride) Preparation. Background technique [0002] Fasudil (Fasudil), chemical name: hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine, also known as HA1077, is a pharmacological agent of Asahi Kasei Co., Ltd. and Nagoya University. A new type of isoquinoline sulfonamide derivatives developed in cooperation with the research laboratory. Fasudil and its salts, such as Fasudil hydrochloride, as a new type of high-efficiency vasodilator, can effectively relieve cerebral vasospasm, improve subarachnoid hemorrhage (SAH), and prevent and treat chronic ischemic cerebrovascular disease. spasms. In recent years, the research on its pharmacological effects and clinical application has been in-depth, and a lot of results have been obtained. [000...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCY02P20/55
Inventor 高建王晓玲李有章叶丁谢成莲
Owner CHENGDU XINJIE HIGH TECH DEV CO LTD
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