CN103724326A - High-purity fasudil hydrochloride preparation method - Google Patents

High-purity fasudil hydrochloride preparation method Download PDF

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CN103724326A
CN103724326A CN201310685211.9A CN201310685211A CN103724326A CN 103724326 A CN103724326 A CN 103724326A CN 201310685211 A CN201310685211 A CN 201310685211A CN 103724326 A CN103724326 A CN 103724326A
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solution
homopiperazine
isoquinoline
fasudil
hydrochloric acid
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CN103724326B (en
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廖远征
黄筱萍
陈开军
武琴
李涛
姚欣
刘建廷
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SICHUAN SUNNYHOPE PHARMACEUTICAL CO Ltd
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SICHUAN SUNNYHOPE PHARMACEUTICAL CO Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a high-purity fasudil hydrochloride preparation method which comprises the following steps: using homopiperazine and isoquinoline-5-sulphonyl chloride hydrochloride as raw materials, and using absolute ethyl alcohol to dissolve homopiperazine; using dichloromethane to dissolve isoquinoline-5-sulphonyl chloride hydrochloride, adding anhydrous sodium sulfate and solid sodium bicarbonate, reacting on a homopiperazine ethanol solution with an isoquinoline-5-sulfonyl chloride solution, performing concentration and crystallization under reduced pressure for many times, and finally performing filtration and drying to prepare high-purity fasudil hydrochloride. The high-purity fasudil hydrochloride prepared through the preparation method disclosed by the invention has an impurity content less than 0.1% and a purity more than 99.9%. The preparation method has the advantages of safety, environmental protection, low production cost, high production quality, convenience in operation and the like.

Description

A kind of preparation method of high-purity hydrochloric acid fasudil
Technical field
The present invention relates to a kind of preparation method of high-purity hydrochloric acid fasudil, belong to medical technical field.
Background technology
Fasudil Hydrochloride, chemical name is: fasudil hydrochloride, molecular formula is: C 14h 17n 3o 2sHCl, molecular weight is 327.83, English by name: Fasudil Hydrochloride.
Its chemical structural formula is as follows:
Fasudil Hydrochloride is Japanese Asahi Kasei(Asahi Chemical Industry) Co., Ltd. is in the isoquinoline 99.9 sulfa drugs of the exploitation eighties in last century, it is a kind of protein kinase RHO inhibition (intracellular calcium antagonist), by the final stage of blocking-up vasoconstriction process, also by increasing the activity of myosin hydrogen chain Phosphoric acid esterase, vasodilation (inhibition vasospasm), reduce the tension force performance drug effect of endotheliocyte, thereby improve cerebral tissue microcirculation, do not produce and increase the weight of robber's blood of brain.It is mainly used in clinically improving and prevention subarachnoid hemorrhage after brain spasm and the symptoms of cerebral ischemia causing, simultaneously also can the anti-apoptosis of neuroprotective, promote neurotization.
The preparation method of relevant Fasudil Hydrochloride, if the method for CN200910075350.3, US4678783, US5942505 synthetic hydrochloric acid fasudil is mainly to make solvent with methylene dichloride to dissolve respectively homopiperazine and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride.Isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride dichloromethane solution obtains isoquinoline 99.9-5-SULPHURYL CHLORIDE dichloromethane solution after adopting sodium hydrogen carbonate solution alkalization, and water dry is removed in separation.Isoquinoline 99.9-5-SULPHURYL CHLORIDE dichloromethane solution is added dropwise to homopiperazine dichloromethane solution, under low temperature, react, after reacting completely, first add excessive concentrated hydrochloric acid to dissolve fasudil and proceed to water, water is alkalized and proceeds to organic phase in organic solvent, acidifying obtains Fasudil Hydrochloride crude product again, finally refines and obtains Fasudil Hydrochloride.All there is following shortcoming in this kind of technology:
1. after the alkalization of isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, meet water electrode unstable, easily hydrolysis, affects product yield and can in finished product, bring impurity into;
Homopiperazine in put procedure easily degraded produce a small amount of impurity, while making dissolution with solvents homopiperazine solid with methylene dichloride, be easy to violent polyreaction occurs, emit amount of heat and set off an explosion and cause occurring security incident;
3. isoquinoline 99.9-5-SULPHURYL CHLORIDE dichloromethane solution and homopiperazine react an impurity that step produces and are difficult to and remove; Although relate to the method for purification of Fasudil Hydrochloride in prior art as Chinese patent CN102020636A, first by processing 5-isoquinoline 99.9 sulfonic acid under SOCl2/DMF condition, prepare 5-isoquinoline 99.9 sulphonic acid chloride hydrochloride, with the NaHCO3 aqueous solution, regulate pH to use dichloromethane extraction after neutral, dichloromethane solution and homopiperazine reaction obtain the dichloromethane solution of fasudil.This solution regulates pH value to 4.5-5.5 by acid solution, then use dichloromethane extraction water, discard the organic phase that is dissolved with dimer impurity, it is 9.5-10.5 that gained aqueous phase solution regulates pH value with alkali lye, then use dichloromethane extraction water, discard the water that is dissolved with homopiperazine impurity, then solution becomes hydrochloride to obtain Fasudil Hydrochloride after purifying by chromatography column silica gel.How Chinese patent CN102002036, CN101812051, CN101962379, CN1183782, CN101092413, US5942505 etc. relate to purification refine Fasudil Hydrochloride, specifically comprise methods such as changing column chromatography purification eluent, change recrystallization solvent, resin absorption, but these methods all can increase man-hour and produce a large amount of organic liquid wastes;
4. in Fasudil Hydrochloride building-up process, generate side reaction product dimer, prior art prevents the dimeric generation of side reaction product as CN201010558960.1 adopts the feed ratio that improves homopiperazine, the mass ratio that feeds intake of homopiperazine and isoquinoline 99.9-5-SULPHURYL CHLORIDE is up to 2-4:1, the homopiperazine amount dropping into is very large, but homopiperazine price is higher, cause production cost high.
Summary of the invention
The object of the invention is to overcome the shortcoming of prior art, a kind of preparation method of high-purity hydrochloric acid fasudil is provided, the advantage such as the method has safety, environmental protection, production cost is low, quality product is high, easy to operate.
Object of the present invention is achieved through the following technical solutions: a kind of preparation method of high-purity hydrochloric acid fasudil, and it comprises the following steps:
S1. weigh: the ratio that is 1:1.5~2 in mole weight ratio takes isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and homopiperazine;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 10~50mg/ml anhydrous sodium sulphate in dichloromethane solution, after stirring 25~35min, add isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, add again solid sodium bicarbonate to alkalize, extremely without filtering after Bubble formation, gained liquid cooling is to temperature≤10 ℃, standby; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is 5~20:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to solution temperature≤10 ℃; The weight ratio of described dehydrated alcohol and homopiperazine is 5~20:1;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep temperature of reaction≤10 ℃, after stirring reaction 1~5h, adding concentrated hydrochloric acid regulator solution pH is 5.0~6.5, filter, gained filtrate is for next-step operation, filter residue is for further reclaiming homopiperazine, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 2~3 times, at 50~80 ℃, dry;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, and reinforcing body volume is the water dissolution solid of 1~10 times, filters, and collects filtrate;
S6. two concentrating under reduced pressure: the filtrate decompression that step S5 is collected is concentrated into 1/10~1/2 of filtrate original volume, are cooled to 10 ℃ of following crystallizations, then use the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refining: by Fasudil Hydrochloride crude product, by adding weight ratio, to be the anhydrous alcohol solution of 1~10 times, the gac that adds again overall solution volume 0.1~2g/ml, whip attachment 25~35min, filter decarburization, collect filtrate, filtrate is cooled to 10 ℃ of following crystallizations, again filters, the vacuum-drying at 40~90 ℃ of gained solid, makes high-purity hydrochloric acid fasudil.
The present invention has the following advantages:
1. the molal weight that feeds intake of isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride of the present invention and homopiperazine, than for 1:1.5~2, lower than isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride of traditional method and the feed ratio of homopiperazine, has significantly reduced production cost;
2. use dehydrated alcohol as dissolution with solvents homopiperazine, the danger having set off an explosion while having avoided traditional method to adopt methylene dichloride to dissolve homopiperazine solid, safer;
3. when dissolving isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, in solution, first added siccative anhydrous sodium sulphate, added again solid sodium bicarbonate to alkalize, prevented because of the unstable generation that causes hydrolysis in the aqueous solution of isoquinoline 99.9-5-SULPHURYL CHLORIDE, significantly reduce the generation of by-product impurities, improved product purity;
4. due to the pH value (5.0~6.5) that has increased isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride solution and homopiperazine ethanolic soln and react, homopiperazine directly can be precipitated, just use the recycling of homopiperazine, reduce production cost; Avoid the excessive acidifying of side reaction product, reduced the dissolving of side reaction product in water, be beneficial to the direct removal of side reaction product, further improved product purity, compare with chromatography removal of impurities, simple to operate, do not produce a large amount of waste liquids, more environmental protection.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, and protection scope of the present invention is not limited to the following stated.
Embodiment 1: a kind of preparation method of high-purity hydrochloric acid fasudil, and it comprises the following steps:
S1. weigh: the ratio that is 1:1.5 in mole weight ratio takes isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and homopiperazine;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 10mg/ml anhydrous sodium sulphate in dichloromethane solution, after stirring 25min, add isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, add again solid sodium bicarbonate to alkalize, extremely without filtering after Bubble formation, gained liquid cooling is to 10 ℃ of temperature, standby; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is 5:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to 10 ℃ of solution temperatures; The weight ratio of described dehydrated alcohol and homopiperazine is 5:1;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep 10 ℃ of temperature of reaction, after stirring reaction 1h, adding concentrated hydrochloric acid regulator solution pH is 5.0, filter, gained filtrate is for next-step operation, filter residue is for further reclaiming homopiperazine, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 2 times, at 50 ℃, dry;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, and reinforcing body volume is the water dissolution solid of 1 times, filters, and collects filtrate;
S6. two concentrating under reduced pressure: the filtrate decompression that step S5 is collected is concentrated into 1/10 of filtrate original volume, is cooled to 9 ℃ of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refining: by Fasudil Hydrochloride crude product, by adding weight ratio, to be the anhydrous alcohol solution of 1 times, the gac that adds again overall solution volume 0.1g/ml, whip attachment 25min, filter decarburization, collect filtrate, filtrate is cooled to 9 ℃ of crystallizations, again filters, the vacuum-drying at 40 ℃ of gained solid, makes high-purity hydrochloric acid fasudil.
Embodiment 2: a kind of preparation method of high-purity hydrochloric acid fasudil, and it comprises the following steps:
S1. weigh: the ratio that is 1:2 in mole weight ratio takes isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and homopiperazine;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 50mg/ml anhydrous sodium sulphate in dichloromethane solution, after stirring 35min, add isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, add again solid sodium bicarbonate to alkalize, extremely without filtering after Bubble formation, gained liquid cooling is to 8 ℃ of temperature, standby; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is 20:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to 7 ℃ of solution temperatures; The weight ratio of described dehydrated alcohol and homopiperazine is 20:1;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep 5 ℃ of temperature of reaction, after stirring reaction 5h, adding concentrated hydrochloric acid regulator solution pH is 6.5, filter, gained filtrate is for next-step operation, filter residue is for further reclaiming homopiperazine, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 3 times, at 80 ℃, dry;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, and reinforcing body volume is the water dissolution solid of 10 times, filters, and collects filtrate;
S6. two concentrating under reduced pressure: the filtrate decompression that step S5 is collected is concentrated into 1/2 of filtrate original volume, is cooled to 7 ℃ of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refining: by Fasudil Hydrochloride crude product, by adding weight ratio, to be the anhydrous alcohol solution of 10 times, the gac that adds again overall solution volume 2g/ml, whip attachment 35min, filter decarburization, collect filtrate, filtrate is cooled to 5 ℃ of crystallizations, again filters, the vacuum-drying at 90 ℃ of gained solid, makes high-purity hydrochloric acid fasudil.
Embodiment 3: a kind of preparation method of high-purity hydrochloric acid fasudil, and it comprises the following steps:
S1. weigh: the ratio that is 1:1.6 in mole weight ratio takes isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and homopiperazine;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 25mg/ml anhydrous sodium sulphate in dichloromethane solution, after stirring 28min, add isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, add again solid sodium bicarbonate to alkalize, extremely without filtering after Bubble formation, gained liquid cooling is to 5 ℃ of temperature, standby; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is 10:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to 7 ℃ of solution temperatures; The weight ratio of described dehydrated alcohol and homopiperazine is 9:1;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep 4 ℃ of temperature of reaction, after stirring reaction 2h, adding concentrated hydrochloric acid regulator solution pH is 5.5, filter, gained filtrate is for next-step operation, filter residue is for further reclaiming homopiperazine, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 2 times, at 60 ℃, dry;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, and reinforcing body volume is the water dissolution solid of 4 times, filters, and collects filtrate;
S6. two concentrating under reduced pressure: the filtrate decompression that step S5 is collected is concentrated into 1/4 of filtrate original volume, is cooled to 5 ℃ of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refining: by Fasudil Hydrochloride crude product, by adding weight ratio, to be the anhydrous alcohol solution of 4 times, the gac that adds again overall solution volume 1g/ml, whip attachment 28min, filter decarburization, collect filtrate, filtrate is cooled to 8 ℃ of following crystallizations, again filters, the vacuum-drying at 55 ℃ of gained solid, makes high-purity hydrochloric acid fasudil.
Embodiment 4: a kind of preparation method of high-purity hydrochloric acid fasudil, and it comprises the following steps:
S1. weigh: the ratio that is 1:1.8 in mole weight ratio takes isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and homopiperazine;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 40mg/ml anhydrous sodium sulphate in dichloromethane solution, after stirring 32min, add isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, add again solid sodium bicarbonate to alkalize, extremely without filtering after Bubble formation, gained liquid cooling is to 3 ℃ of temperature, standby; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is 15:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to 6 ℃ of solution temperatures; The weight ratio of described dehydrated alcohol and homopiperazine is 15:1;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep 8 ℃ of temperature of reaction, after stirring reaction 3.5h, adding concentrated hydrochloric acid regulator solution pH is 6.2, filter, gained filtrate is for next-step operation, filter residue is for further reclaiming homopiperazine, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 3 times, at 70 ℃, dry;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, and reinforcing body volume is the water dissolution solid of 8 times, filters, and collects filtrate;
S6. two concentrating under reduced pressure: the filtrate decompression that step S5 is collected is concentrated into 1/8 of filtrate original volume, is cooled to 5 ℃ of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refining: by Fasudil Hydrochloride crude product, by adding weight ratio, to be the anhydrous alcohol solution of 7 times, the gac that adds again overall solution volume 1.8g/ml, whip attachment 32min, filter decarburization, collect filtrate, filtrate is cooled to 6 ℃ of crystallizations, again filters, the vacuum-drying at 75 ℃ of gained solid, makes high-purity hydrochloric acid fasudil.
By normal experiment method, measure chromatographic purity, dimer impurity content, other foreign matter contents and the total recovery of the Fasudil Hydrochloride that embodiment 1, embodiment 2, embodiment 3, embodiment 4 make, result is as following table:
As seen from the above table: the chromatographic purity average of the Fasudil Hydrochloride that the inventive method makes is 99.9625%, dimer impurity content is 0%, other foreign matter content averages are 0.0375%, total recovery average is 70.8%, the chromatographic purity of the Fasudil Hydrochloride that traditional technology makes is 99.37%, dimer impurity content is 0.25%, other foreign matter contents are 0.38%, total recovery is 45%.Result shows: the Fasudil Hydrochloride that the inventive method makes is hardly containing dimer impurity, and other foreign matter contents are suitable with traditional technology content, and the purity of product and total recovery are significantly higher than the Fasudil Hydrochloride that traditional technology makes.

Claims (6)

1. a preparation method for high-purity hydrochloric acid fasudil, is characterized in that: it comprises the following steps:
S1. weigh: take in proportion isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride and homopiperazine;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 10~50mg/ml anhydrous sodium sulphate in dichloromethane solution, after stirring 25~35min, add isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride, add again solid sodium bicarbonate to alkalize, extremely without filtering after Bubble formation, gained liquid cooling is to temperature≤10 ℃, standby;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to solution temperature≤10 ℃;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep temperature of reaction≤10 ℃, after stirring reaction 1~5h, add concentrated hydrochloric acid regulator solution pH, filter, gained filtrate is for next-step operation, and filter residue is for further reclaiming homopiperazine;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, and reinforcing body volume is the water dissolution solid of 1~10 times, filters, and collects filtrate;
S6. two concentrating under reduced pressure: the filtrate decompression that step S5 is collected is concentrated into 1/10~1/2 of filtrate original volume, are cooled to 10 ℃ of following crystallizations, then use the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refining: by Fasudil Hydrochloride crude product, by adding weight ratio, to be the anhydrous alcohol solution of 1~10 times, the gac that adds again overall solution volume 0.1~2g/ml, whip attachment 25~35min, filter decarburization, collect filtrate, filtrate is cooled to 10 ℃ of following crystallizations, again filters, the vacuum-drying at 40~90 ℃ of gained solid, makes high-purity hydrochloric acid fasudil.
2. the preparation method of a kind of high-purity hydrochloric acid fasudil according to claim 1, is characterized in that: the molal weight of the SULPHURYL CHLORIDE hydrochloride of isoquinoline 99.9-5-described in step S1 and homopiperazine is than being 1:1.5~2.
3. the preparation method of a kind of high-purity hydrochloric acid fasudil according to claim 1, is characterized in that: the weight ratio of methylene dichloride described in step S2 and isoquinoline 99.9-5-SULPHURYL CHLORIDE hydrochloride is 5~20:1.
4. the preparation method of a kind of high-purity hydrochloric acid fasudil according to claim 1, is characterized in that: the weight ratio of dehydrated alcohol described in step S3 and homopiperazine is 5~20:1.
5. the preparation method of a kind of high-purity hydrochloric acid fasudil according to claim 1, is characterized in that, pH value of solution described in step S4 is 5.0~6.5.
6. the preparation method of a kind of high-purity hydrochloric acid fasudil according to claim 1, is characterized in that, the method that reclaims homopiperazine described in step S4 is: by filter residue absolute ethanol washing 2~3 times, at 50~80 ℃, dry.
CN201310685211.9A 2013-12-13 2013-12-13 A kind of preparation method of High-purity fasudil hydrochloride Active CN103724326B (en)

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CN105866263A (en) * 2016-03-24 2016-08-17 四川升和药业股份有限公司 Quality control method for fasudil hydrochloride
CN109574992A (en) * 2018-12-06 2019-04-05 河南润弘制药股份有限公司 A kind of preparation method of Fasudic hydrochloride
CN109705096A (en) * 2019-03-07 2019-05-03 山东新华制药股份有限公司 A kind of refining methd of Fasudic hydrochloride
CN109970712A (en) * 2017-12-27 2019-07-05 徐州万邦金桥制药有限公司 A kind of refining methd of Fasudic hydrochloride

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CN102070612A (en) * 2010-12-29 2011-05-25 武汉同源药业有限公司 Method for preparing hydroxyl fasudil compounds
CN102603715A (en) * 2012-03-31 2012-07-25 苏州工业园区南华生物科技有限公司 Synthesis and preparation method of fasudil hydrochloride

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CN102020636A (en) * 2010-11-25 2011-04-20 江苏万邦生化医药股份有限公司 Method for synthesizing and purifying Fasudil hydrochloride
CN102070612A (en) * 2010-12-29 2011-05-25 武汉同源药业有限公司 Method for preparing hydroxyl fasudil compounds
CN102603715A (en) * 2012-03-31 2012-07-25 苏州工业园区南华生物科技有限公司 Synthesis and preparation method of fasudil hydrochloride

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105866263A (en) * 2016-03-24 2016-08-17 四川升和药业股份有限公司 Quality control method for fasudil hydrochloride
CN109970712A (en) * 2017-12-27 2019-07-05 徐州万邦金桥制药有限公司 A kind of refining methd of Fasudic hydrochloride
CN109574992A (en) * 2018-12-06 2019-04-05 河南润弘制药股份有限公司 A kind of preparation method of Fasudic hydrochloride
CN109574992B (en) * 2018-12-06 2020-05-22 河南润弘制药股份有限公司 Preparation method of fasudil hydrochloride
CN109705096A (en) * 2019-03-07 2019-05-03 山东新华制药股份有限公司 A kind of refining methd of Fasudic hydrochloride

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