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Method for preparing hydroxyl fasudil compounds

A technology for fasudil hydrochloride and a compound, applied in the field of drug synthesis, can solve the problems of process limitation, inability to realize large-scale production, labor-intensive and time-consuming, etc.

Active Publication Date: 2011-05-25
珠海晨安医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above two methods for synthesizing Fasudil, in order to remove impurities, require column chromatography and elution after extraction, which is not only labor-intensive and time-consuming, consumes a large amount of eluent, but also cannot realize scale due to the limitation of column chromatography technology. Large-scale production

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  • Method for preparing hydroxyl fasudil compounds
  • Method for preparing hydroxyl fasudil compounds
  • Method for preparing hydroxyl fasudil compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Add 100g (0.38mol) of 5-isoquinolinesulfonyl chloride hydrochloride, 50g (0.60mol) of sodium bicarbonate solid, and 700 ml of dichloromethane into a 2L three-necked flask, cool to -12°C, and Add 600ml of water dropwise at ~-12°C, after dropping, continue to stir for 15 minutes, let stand to separate layers, separate the dichloromethane solution layer containing isoquinolinesulfonyl chloride, and set aside;

[0061] Add 100g (1mol) of homopiperazine to a 2L three-necked flask, add 200ml of dichloromethane, stir mechanically to dissolve into a homogeneous solution, cool to 0°C in ice, and add dropwise isoquinolinesulfonyl chloride dichloromethane solution at 0-5°C , After adding, continue to stir for 5 hours, and detect that the reaction is complete.

[0062] Add 2N hydrochloric acid to adjust the pH to 5-6, separate to remove dichloromethane, go to recovery, add 10% sodium hydroxide solution dropwise to the water layer to adjust the pH to 9-10, add 500ml of dichlorometha...

Embodiment 2

[0068] Add 100 g (0.38 mol) of 5-isoquinolinesulfonyl chloride hydrochloride, 60 g (0.43 mol) of potassium carbonate solid, and 700 ml of dichloromethane into a 2L three-necked flask, add 700 ml of dichloromethane, and cool to -12 ℃, add 500ml of water dropwise at -8℃~-12℃, after dropping, continue stirring for 15 minutes, let stand to separate layers, separate the dichloromethane solution layer containing isoquinolinesulfonyl chloride, and set aside;

[0069] Add 100g (1mol) of homopiperazine to a 2L three-necked flask, add 200ml of dichloromethane, stir mechanically to dissolve into a homogeneous solution, cool to 0°C in ice, and add dropwise isoquinolinesulfonyl chloride dichloromethane solution at 0-5°C , After adding, continue to stir for 5 hours, and detect that the reaction is complete.

[0070] Add 2N hydrochloric acid to adjust the pH to 5-6, remove dichloromethane for recovery, add 10% sodium carbonate solution dropwise to the water layer to adjust the pH to 9-10, ad...

Embodiment 3

[0073] Add 100g (0.38mol) of 5-isoquinolinesulfonyl chloride hydrochloride, 80g (0.75mol) of sodium carbonate solid, and 700 ml of dichloromethane into a 2L three-necked flask, cool to -12°C, and Add 630ml of water dropwise at -12°C, after dropping, continue to stir for 15 minutes, let stand to separate layers, separate the dichloromethane solution layer containing isoquinolinesulfonyl chloride, and set aside;

[0074] Add 100g (1mol) of homopiperazine to a 2L three-necked flask, add 200ml of dichloromethane, stir mechanically to dissolve into a homogeneous solution, cool to 0°C in ice, and add dropwise isoquinolinesulfonyl chloride dichloromethane solution at 0-5°C , After adding, continue to stir for 5 hours, and detect that the reaction is complete.

[0075] Add 2N hydrochloric acid to adjust the pH to 5-6, remove dichloromethane for recovery, add 10% potassium hydroxide solution dropwise to the water layer to adjust the pH to 9-10, add 500ml of dichloromethane for extracti...

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Abstract

The invention relates to a method for preparing hemangiectasis medicine, in particular to the method for preparing hydroxyl fasudil compounds, which belongs to the field of medicine synthesis. In the preparation process, the method of using column chromatography for elution and purification in a hydroxyl fasudil impurity removal method is omitted for realizing large-scale mass production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of a vasodilator drug, in particular to a preparation method of a compound fasudil hydrochloride. Background technique [0002] Fasudil hydrochloride is a vasodilator developed by Japan Asahi Chemicals. The original research manufacturer, Asahi Chemicals, disclosed a synthetic route in its patent US4678783, through the reaction of isoquinoline sulfonic acid with thionyl chloride into an acid chloride, and then with Homopiperazine reaction obtains product Fasudil hydrochloride, and reaction can be expressed as follows: [0003] [0004] In the synthesis reaction, it is very important to control the quality of intermediates, especially the intermediates in the last step. [0005] In order to obtain Fasudil hydrochloride that meets the Pharmacopoeia standard, it is necessary to ensure the high purity of the final intermediate Fasudil, because if Fasudil contains ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 黄毅彭国强张颀黄伟熊骏宇徐敏华
Owner 珠海晨安医药有限公司
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