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Method for refining fasudil hydrochloride

A technology of fasudil hydrochloride and a refining method, which is applied in the refining process field of the production process of the drug fasudil hydrochloride raw material, can solve the problems of side reactions, difficult to remove, etc., achieves strong adaptability, ensures product quality, and is heavy good effect

Active Publication Date: 2010-06-09
TIANJIN CHASE SUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Fasudil hydrochloride, English name: Fasudil, chemical name: hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine hydrochloride, is a protein Kinase inhibitors are intracellular calcium ion antagonists, which are used to treat ischemic encephalopathy. In the existing production and refining process of fasudil hydrochloride, 5-sulfonic acid isoquinoline is generally used after chlorination, and then reacted with homopiperazine. Substitution reaction, after being adsorbed by the resin column, it is acidified with hydrochloric acid to form a salt, and the crude product is repeatedly recrystallized and refined. Some side reactions inevitably occur during the preparation process. The by-products produced by the side reactions are difficult to remove because they are similar in structure to the main drug.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1. Take away 500ml of the feed liquid after the column, add 2.5‰ (g / ml) activated carbon, mix well and filter.

[0030] 2. After adding 7.5% purified water to the filtrate and fully stirring (12.5 min), stop stirring, let stand to separate the layers, and separate the water phase and the oil phase.

[0031] 3. Take the oil phase, add 7.5% purified water, then adjust the pH of the feed solution to 6.75 with hydrochloric acid under stirring, separate the water phase, and set aside.

[0032] 4. Add n-butanol of 3.5 times the volume of the water phase to the water phase obtained in the previous step, start vacuum distillation after fully stirring, control the vacuum degree above 0.008Mpa, add n-butanol appropriately during the distillation process, and distill The resulting mixture of n-butanol and water was collected. In the mid-term of distillation, crystals will begin to separate out. When the water content of the reaction solution drops to 6.5%, the distillation is sto...

Embodiment 2

[0041] 1. Take away 1000ml of the feed liquid after the column, add 2‰ (g / ml) activated carbon, mix well and filter.

[0042] 2. After adding 7.5% purified water to the filtrate and stirring fully, stop stirring, let stand to separate the layers, and separate the water phase and the oil phase.

[0043] 3. Take the oil phase, add 7.5% purified water, then adjust the pH of the feed solution to 5.5 with 6M hydrochloric acid under stirring, separate the water phase, and set aside.

[0044] 4. Add n-butanol of 3.5 times the volume of the water phase to the water phase obtained in the previous step, start vacuum distillation after fully stirring, control the vacuum degree above 0.008Mpa, add n-butanol appropriately during the distillation process, and distill The resulting mixture of n-butanol and water was collected. In the mid-term of distillation, crystals will begin to separate out. When the water content of the reaction solution drops to 6.5%, the distillation is stopped, filt...

Embodiment 3

[0053] 1. Take away 500ml of the feed liquid after the column, add 1‰ (g / ml) activated carbon, mix well and filter.

[0054] 2. After adding 5% purified water to the filtrate and fully stirring (10 min), stop stirring, let stand to separate the layers, and separate the water phase and the oil phase.

[0055] 3. Take the oil phase, add 5-10% purified water, then adjust the pH of the feed solution to 5.0 with hydrochloric acid under stirring, separate the water phase, and set aside.

[0056] 4. Add n-butanol twice the volume of the water phase to the water phase obtained in the previous step, start vacuum distillation after fully stirring, control the vacuum degree above 0.008Mpa, add n-butanol appropriately during the distillation process, and distill The resulting mixture of n-butanol and water was collected. Crystals will begin to separate out in the middle of the distillation. When the water content of the reaction solution drops to 5%, the distillation is stopped, filtered...

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Abstract

The invention relates to a method for refining fasudil hydrochloride. The method comprises the following steps: 1, discoloring, namely adding active carbon into fasudil after resin adsorption, fully mixing the active carbon and the fasudil, filtering the mixture, removing the active carbon, and collecting the filtered solution for later use; 2, washing, namely adding purified water into the discolored solution, fully mixing the solution, separating the solution to remove water phase, and collecting the oil phase for later use; 3, acidifying and salifying, namely adding the purified water intothe oil phase, adjusting pH value of the solution by hydrochloric acid to fully acidify and salify the oil phase, and collecting the water phase for later use; and 4, crystallization, namely, adding n-butyl alcohol into the water phase, fully mixing the solution, then decompressing and azeotropic-crystallizing the solution, duly replenishing the n-butyl alcohol to keep the consistency of the solution, stopping crystallization till the moisture content in the mother solution is reduced to a certain value, and filtering and drying the crystals to obtain a refined fasudil hydrochloride product.

Description

Technical field: [0001] The present invention relates to a process for refining and extracting raw materials, in particular to the refining of the production process of the drug Fasudil hydrochloride used for improving the symptoms of ischemic cerebrovascular diseases caused by cerebral vasospasm after subarachnoid hemorrhage. craft. technical background: [0002] Fasudil hydrochloride, English name: Fasudil, chemical name: hexahydro-1-(5-sulfonylisoquinoline)-1(H)-1,4-diazepine hydrochloride, is a protein Kinase inhibitors are intracellular calcium ion antagonists, which are used to treat ischemic encephalopathy. In the existing production and refining process of fasudil hydrochloride, 5-sulfonic acid isoquinoline is generally used after chlorination, and then reacted with homopiperazine. Substitution reaction, after being adsorbed by a resin column, it is acidified with hydrochloric acid to form a salt, and the crude product is repeatedly recrystallized and refined. Some ...

Claims

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Application Information

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IPC IPC(8): C07D401/12
Inventor 许素法李学改
Owner TIANJIN CHASE SUN PHARM CO LTD
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