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Fasudil hydrochloride compound and novel method thereof

A technology of fasudil hydrochloride, compound, applied in the field of fasudil hydrochloride compound and its new method

Inactive Publication Date: 2012-08-01
HAINAN LINGKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the defects of the above-mentioned prior art, we have further improved the sulfonation reaction of isoquinoline. We have found that chlorosulfonic acid can overcome the above-mentioned defects as a sulfonating agent through a large number of tests. This reaction condition is relatively mild. Reaction can occur at room temperature, reducing the risk

Method used

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  • Fasudil hydrochloride compound and novel method thereof
  • Fasudil hydrochloride compound and novel method thereof
  • Fasudil hydrochloride compound and novel method thereof

Examples

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Effect test

Embodiment 1

[0026] The synthesis of embodiment 1 5-isoquinolinesulfonic acid

[0027] The isoquinoline of 258g (2mol) is joined in the reaction bottle of 5L, then add the carbon tetrachloride solvent of 1L and stir to dissolve, cool to below 10 ℃ with ice water, then slowly add 256g (2.2mol) chlorosulfonic acid, Control the temperature of the reaction system below 25°C, stir and react for 8-10 hours, distill off the carbon tetrachloride solvent under reduced pressure, pour the residue into 2L of ice-water mixture, stir at below 10°C for 2-3 hours, and precipitate a solid , filtered, washed with a small amount of water first, and then washed with a small amount of methanol, and dried under vacuum at 40-50° C. to obtain 372 g of off-white solid, with a yield of 89%.

Embodiment 2

[0028] The synthesis of embodiment 2 5-isoquinolinesulfonyl chloride hydrochloride

[0029] Add 209g of 5-isoquinolinesulfonic acid, 1700ml of thionyl chloride and 1ml of dimethylformamide into a 3L reaction flask, heat to 80°C-85°C for 3-5 hours, and distill off the remaining di Chlorothionyl, then add 500ml of dichloromethane, stir, precipitate solid, filter, wash with 150ml of dichloromethane, and vacuum dry at 40-50°C to obtain 248g of solid, yield 94%.

Embodiment 3

[0030] The synthesis of embodiment 3 Fasudil hydrochloride

[0031] In a 5L reaction flask, dissolve 132g (0.5mol) of 5-isoquinolinesulfonyl chloride hydrochloride in 1200ml of ice water, then adjust the pH to 6 with saturated sodium bicarbonate solution, and then use 2.5L of dichloromethane Extract, then add 1.2L of dichloromethane solution containing 200g homopiperazine dropwise to the dichloromethane extraction solution, react at 15°C-20°C for 2-3 hours, wash twice with 500ml of purified water, no Dry over sodium sulfate, distill the solvent off under reduced pressure to obtain an oily substance, then add 500ml of methanol to dissolve it, adjust the pH to 6 with 1-2M hydrochloric acid solution, stir for 1-2 hours, concentrate to dryness under reduced pressure, then add methanol and ether (2:1) mixed solvent recrystallization, obtain 123g of Fasudil hydrochloride, yield 75%.

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Abstract

The invention relates to a fasudil hydrochloride compound and a novel method thereof. The method comprises the following steps of: in the presence of a solvent, performing sulfonation reaction on a chlorosulfonic acid serving as a sulfonating agent and isoquinoline to generate a 5-isoquinolinesulfonic acid; reacting the 5-isoquinolinesulfonic acid with thionyl chloride under a heating condition to generate isoquinoline-5-sulfonyl chloride hydrochloride; and dissolving the isoquinoline-5-sulfonyl chloride hydrochloride with ice water, adjusting the pH value of the solution with sodium bicarbonate, reacting the solution with homopiperazine, adjusting the pH value again with a hydrochloric acid, and concentrating under reduced pressure and recrystallizing to prepare the fasudil hydrochloridecompound. The synthesis method of the invention has the advantages of mild reaction conditions, high yield and easy industrial production.

Description

technical field [0001] The invention relates to a fasudil hydrochloride compound and a new method thereof, belonging to the technical field of medicine. Background technique [0002] Fasudil hydrochloride, chemical name is 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, structural formula: [0003] [0004] Fasudil hydrochloride is a protein kinase inhibitor, that is, an intracellular calcium ion antagonist. It dilates blood vessels and inhibits vasospasm by blocking the phosphorylation of myosin light chain, the final stage of the vasoconstriction process. It is clinically suitable for improving and preventing cerebral spasm after subarachnoid hemorrhage and the symptoms of cerebral ischemia caused by it. [0005] The preparation method of Fasudil hydrochloride is seldom reported at home and abroad, in the existing method, 60% oleum has been used in the process of synthesizing 5...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
Inventor 陶灵刚
Owner HAINAN LINGKANG PHARMA CO LTD
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