CN103724326B - A kind of preparation method of High-purity fasudil hydrochloride - Google Patents
A kind of preparation method of High-purity fasudil hydrochloride Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of High-purity fasudil hydrochloride, the method be with homopiperazine and isoquinoline 99.9-5-sulfonyl chloride hydrochloride for raw material, use anhydrous alcohol solution homopiperazine; Methylene dichloride dissolves isoquinoline 99.9-5-sulfonyl chloride hydrochloride, and add anhydrous sodium sulphate and solid sodium bicarbonate, reacted by homopiperazine ethanolic soln and isoquinoline 99.9-5-chloride solution, repeatedly concentrating under reduced pressure crystallization, eventually pass filtration, dry obtained High-purity fasudil hydrochloride.The Fasudil Hydrochloride foreign matter content utilizing the inventive method obtained is lower than 0.1%, and purity reaches more than 99.9%.The advantages such as this preparation method has safety, environmental protection, production cost is low, quality product is high, easy to operate.
Description
Technical field
The present invention relates to a kind of preparation method of High-purity fasudil hydrochloride, belong to medical art.
Background technology
Fasudil Hydrochloride, chemical name is: fasudil hydrochloride, and 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) the isoquinoline 99.9 sulfa drugs developed the eighties in last century of Co., Ltd., it is a kind of protein kinase RHO inhibition (intracellular calcium antagonist), by blocking the final stage of vasoconstriction process, also namely by increasing the activity of myosin hydrogen chain Phosphoric acid esterase, vasodilation (suppression vasospasm), the tension force reducing endotheliocyte plays drug effect, thus improves cerebral tissue microcirculation, does not produce and increase the weight of robber's blood of brain.It is mainly used in improving and brain spasm after prevention subarachnoid hemorrhage and the symptoms of cerebral ischemia that causes clinically, simultaneously also can neuroprotective anti-apoptotic, promotes neurotization.
About the preparation method of Fasudil Hydrochloride, the method as CN200910075350.3, US4678783, US5942505 synthetic hydrochloric acid fasudil is mainly made solvent with methylene dichloride and is dissolved homopiperazine and isoquinoline 99.9-5-sulfonyl chloride hydrochloride respectively.Isoquinoline 99.9-5-sulfonyl chloride hydrochloride dichloromethane solution obtains isoquinoline 99.9-5-SULPHURYL CHLORIDE dichloromethane solution after adopting sodium hydrogen carbonate solution alkalization, is separated removing aqueous phase also dry.Isoquinoline 99.9-5-SULPHURYL CHLORIDE dichloromethane solution is added dropwise to homopiperazine dichloromethane solution, react under low temperature, first add excessive concentrated hydrochloric acid dissolving fasudil after reacting completely and proceed to aqueous phase, aqueous phase is alkalized in organic solvent and proceeds to organic phase, acidifying obtains Fasudil Hydrochloride crude product again, finally carries out refining obtaining Fasudil Hydrochloride.All there is following shortcoming in this kind of technology:
1. meet water electrode after the alkalization of isoquinoline 99.9-5-sulfonyl chloride hydrochloride unstable, be easily hydrolyzed, affect product yield and impurity can be brought in finished product;
2. homopiperazine is easily degraded and is produced a small amount of impurity in put procedure, when making dissolution with solvents homopiperazine solid with methylene dichloride, is easy to violent polyreaction occurs, and releasing amount of heat sets off an explosion and causes security incident occurs;
3. isoquinoline 99.9-5-SULPHURYL CHLORIDE dichloromethane solution and homopiperazine react a step produce impurity and be difficult to remove; Although as Chinese patent CN102020636A relates to the method for purification of Fasudil Hydrochloride in prior art, namely first 5-isoquinoline 99.9 sulphonic acid chloride hydrochloride is prepared by processing 5-isoquinoline 99.9 sulfonic acid under SOCl2/DMF condition, regulate pH to neutral rear dichloromethane extraction with the NaHCO3 aqueous solution, dichloromethane solution and homopiperazine are obtained by reacting the dichloromethane solution of fasudil.This solution by acid solution adjust ph to 4.5-5.5, then dichloromethane extraction aqueous phase is used, discard the organic phase being dissolved with dimer impurity, gained aqueous phase solution alkali lye adjust ph is 9.5-10.5, then dichloromethane extraction aqueous phase is used, discard the aqueous phase being dissolved with homopiperazine impurity, then solution is by becoming hydrochloride to obtain Fasudil Hydrochloride after chromatography column purified on silica gel.Chinese patent CN102002036, CN101812051, CN101962379, CN1183782, CN101092413, US5942505 etc. relate to how purification refine Fasudil Hydrochloride, specifically comprise and change column chromatography purification eluent, method such as change recrystallization solvent, resin absorption etc., 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 such as CN201010558960.1 adopts the feed ratio improving homopiperazine to prevent the dimeric generation of side reaction product, the mass ratio that feeds intake of homopiperazine and isoquinoline 99.9-5-SULPHURYL CHLORIDE is up to 2-4:1, the homopiperazine amount dropped into is very large, but homopiperazine price is higher, cause production cost high.
Summary of the invention
The object of the invention is to the shortcoming overcoming prior art, a kind of preparation method of High-purity fasudil hydrochloride is provided, the advantages 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 fasudil hydrochloride, and it comprises the following steps:
S1. weigh: the ratio being 1:1.5 ~ 2 in mole weight ratio takes isoquinoline 99.9-5-sulfonyl 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, isoquinoline 99.9-5-sulfonyl chloride hydrochloride is added after stirring 25 ~ 35min, add solid sodium bicarbonate again to alkalize, filter after bubble-free produces, gained liquid cooling is to temperature≤10 DEG C, for subsequent use; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-sulfonyl chloride hydrochloride is 5 ~ 20:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to solution temperature≤10 DEG C; 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 DEG C, adding concentrated hydrochloric acid regulator solution pH after stirring reaction 1 ~ 5h is 5.0 ~ 6.5, filter, gained filtrate is used for next-step operation, filter residue is used for reclaiming homopiperazine further, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 2 ~ 3 times, dries at 50 ~ 80 DEG C;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, reinforcing body volume is the water dissolution solid of 1 ~ 10 times, filters, and collects filtrate;
S6. secondary pressure concentrates: the filtrate reduced in volume collected by step S5, to 1/10 ~ 1/2 of filtrate original volume, is cooled to less than 10 DEG C crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refine: by Fasudil Hydrochloride crude product by adding the anhydrous alcohol solution that weight ratio is 1 ~ 10 times, add the gac of overall solution volume 0.1 ~ 2g/ml again, whip attachment 25 ~ 35min, filter decarburization, collect filtrate, filtrate is cooled to less than 10 DEG C crystallizations, again filters, the vacuum-drying at 40 ~ 90 DEG C of gained solid, obtained High-purity fasudil hydrochloride.
The present invention has the following advantages:
1. the molal weight that feeds intake of isoquinoline 99.9-5-sulfonyl chloride hydrochloride of the present invention and homopiperazine is than being 1:1.5 ~ 2, lower than the isoquinoline 99.9-5-sulfonyl chloride hydrochloride of traditional method and the feed ratio of homopiperazine, significantly reduces production cost;
2. use dehydrated alcohol as dissolution with solvents homopiperazine, avoid the danger that set off an explosion when traditional method adopts methylene dichloride to dissolve homopiperazine solid, safer;
3. first add siccative anhydrous sodium sulphate in the solution when dissolving isoquinoline 99.9-5-sulfonyl chloride hydrochloride, add solid sodium bicarbonate again to alkalize, prevent because of the unstable generation causing being hydrolyzed in aqueous of isoquinoline 99.9-5-SULPHURYL CHLORIDE, significantly reduce the generation of by-product impurities, improve product purity;
4., owing to adding the pH value (5.0 ~ 6.5) that isoquinoline 99.9-5-sulfonyl chloride hydrochloride solution and homopiperazine ethanolic soln react, homopiperazine directly can be precipitated, just use the recycling of homopiperazine, reduce production cost; Avoid the excessive acidifying of side reaction product, reduce the dissolving of side reaction product in water, be beneficial to the direct removal of side reaction product, further increase product purity, compared 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 fasudil hydrochloride, it comprises the following steps:
S1. weigh: the ratio being 1:1.5 in mole weight ratio takes isoquinoline 99.9-5-sulfonyl 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, isoquinoline 99.9-5-sulfonyl chloride hydrochloride is added after stirring 25min, add solid sodium bicarbonate again to alkalize, filter after bubble-free produces, gained liquid cooling is to temperature 10 DEG C, for subsequent use; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-sulfonyl chloride hydrochloride is 5:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, is cooled to solution temperature 10 DEG C; 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 temperature of reaction 10 DEG C, adding concentrated hydrochloric acid regulator solution pH after stirring reaction 1h is 5.0, filter, gained filtrate is used for next-step operation, filter residue is used for reclaiming homopiperazine further, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 2 times, dries at 50 DEG C;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, reinforcing body volume is the water dissolution solid of 1 times, filters, and collects filtrate;
S6. secondary pressure concentrates: the filtrate reduced in volume collected by step S5, to 1/10 of filtrate original volume, is cooled to 9 DEG C of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refine: by Fasudil Hydrochloride crude product by adding the anhydrous alcohol solution that weight ratio is 1 times, add the gac of overall solution volume 0.1g/ml again, whip attachment 25min, filter decarburization, collect filtrate, filtrate is cooled to 9 DEG C of crystallizations, again filters, the vacuum-drying at 40 DEG C of gained solid, obtained High-purity fasudil hydrochloride.
Embodiment 2: a kind of preparation method of High-purity fasudil hydrochloride, it comprises the following steps:
S1. weigh: the ratio being 1:2 in mole weight ratio takes isoquinoline 99.9-5-sulfonyl 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, isoquinoline 99.9-5-sulfonyl chloride hydrochloride is added after stirring 35min, add solid sodium bicarbonate again to alkalize, filter after bubble-free produces, gained liquid cooling is to temperature 8 DEG C, for subsequent use; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-sulfonyl chloride hydrochloride is 20:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, is cooled to solution temperature 7 DEG C; 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 temperature of reaction 5 DEG C, adding concentrated hydrochloric acid regulator solution pH after stirring reaction 5h is 6.5, filter, gained filtrate is used for next-step operation, filter residue is used for reclaiming homopiperazine further, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 3 times, dries at 80 DEG C;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, reinforcing body volume is the water dissolution solid of 10 times, filters, and collects filtrate;
S6. secondary pressure concentrates: the filtrate reduced in volume collected by step S5, to 1/2 of filtrate original volume, is cooled to 7 DEG C of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refine: by Fasudil Hydrochloride crude product by adding the anhydrous alcohol solution that weight ratio is 10 times, add the gac of overall solution volume 2g/ml again, whip attachment 35min, filter decarburization, collect filtrate, filtrate is cooled to 5 DEG C of crystallizations, again filters, the vacuum-drying at 90 DEG C of gained solid, obtained High-purity fasudil hydrochloride.
Embodiment 3: a kind of preparation method of High-purity fasudil hydrochloride, it comprises the following steps:
S1. weigh: the ratio being 1:1.6 in mole weight ratio takes isoquinoline 99.9-5-sulfonyl 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, isoquinoline 99.9-5-sulfonyl chloride hydrochloride is added after stirring 28min, add solid sodium bicarbonate again to alkalize, filter after bubble-free produces, gained liquid cooling is to temperature 5 DEG C, for subsequent use; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-sulfonyl chloride hydrochloride is 10:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, is cooled to solution temperature 7 DEG C; 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 temperature of reaction 4 DEG C, adding concentrated hydrochloric acid regulator solution pH after stirring reaction 2h is 5.5, filter, gained filtrate is used for next-step operation, filter residue is used for reclaiming homopiperazine further, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 2 times, dries at 60 DEG C;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, reinforcing body volume is the water dissolution solid of 4 times, filters, and collects filtrate;
S6. secondary pressure concentrates: the filtrate reduced in volume collected by step S5, to 1/4 of filtrate original volume, is cooled to 5 DEG C of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refine: by Fasudil Hydrochloride crude product by adding the anhydrous alcohol solution that weight ratio is 4 times, add the gac of overall solution volume 1g/ml again, whip attachment 28min, filter decarburization, collect filtrate, filtrate is cooled to less than 8 DEG C crystallizations, again filters, the vacuum-drying at 55 DEG C of gained solid, obtained High-purity fasudil hydrochloride.
Embodiment 4: a kind of preparation method of High-purity fasudil hydrochloride, it comprises the following steps:
S1. weigh: the ratio being 1:1.8 in mole weight ratio takes isoquinoline 99.9-5-sulfonyl 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, isoquinoline 99.9-5-sulfonyl chloride hydrochloride is added after stirring 32min, add solid sodium bicarbonate again to alkalize, filter after bubble-free produces, gained liquid cooling is to temperature 3 DEG C, for subsequent use; Wherein, the weight ratio of described methylene dichloride and isoquinoline 99.9-5-sulfonyl chloride hydrochloride is 15:1;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, is cooled to solution temperature 6 DEG C; 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 temperature of reaction 8 DEG C, adding concentrated hydrochloric acid regulator solution pH after stirring reaction 3.5h is 6.2, filter, gained filtrate is used for next-step operation, filter residue is used for reclaiming homopiperazine further, and the method for described recovery homopiperazine is: by filter residue absolute ethanol washing 3 times, dries at 70 DEG C;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, reinforcing body volume is the water dissolution solid of 8 times, filters, and collects filtrate;
S6. secondary pressure concentrates: the filtrate reduced in volume collected by step S5, to 1/8 of filtrate original volume, is cooled to 5 DEG C of crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refine: by Fasudil Hydrochloride crude product by adding the anhydrous alcohol solution that weight ratio is 7 times, add the gac of overall solution volume 1.8g/ml again, whip attachment 32min, filter decarburization, collect filtrate, filtrate is cooled to 6 DEG C of crystallizations, again filters, the vacuum-drying at 75 DEG C of gained solid, obtained High-purity fasudil hydrochloride.
Measure the chromatographic purity of the obtained Fasudil Hydrochloride of embodiment 1, embodiment 2, embodiment 3, embodiment 4, dimer impurity content, other foreign matter contents and total recovery by normal experiment method, result is as following table:
As seen from the above table: the chromatographic purity average of the Fasudil Hydrochloride that the inventive method obtains is 99.9625%, dimer impurity content is 0%, other foreign matter content averages are 0.0375%, total recovery average is 70.8%, and the chromatographic purity of the Fasudil Hydrochloride that traditional technology obtains 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 obtains 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 obtained Fasudil Hydrochloride of traditional technology.
Claims (5)
1. a preparation method for High-purity fasudil hydrochloride, is characterized in that: it comprises the following steps:
S1. weigh: take isoquinoline 99.9-5-sulfonyl chloride hydrochloride and homopiperazine in proportion;
S2. the preparation of isoquinoline 99.9-5-chloride solution: add overall solution volume 10 ~ 50mg/ml anhydrous sodium sulphate in dichloromethane solution, isoquinoline 99.9-5-sulfonyl chloride hydrochloride is added after stirring 25 ~ 35min, add solid sodium bicarbonate again to alkalize, filter after bubble-free produces, gained liquid cooling is to temperature≤10 DEG C, for subsequent use;
S3. the preparation of homopiperazine solution: use anhydrous alcohol solution homopiperazine, be cooled to solution temperature≤10 DEG C;
S4. hybrid reaction: step S2 gained isoquinoline 99.9-5-chloride solution is slowly dropped in homopiperazine solution, keep temperature of reaction≤10 DEG C, after stirring reaction 1 ~ 5h, add concentrated hydrochloric acid regulator solution pH, filter, gained filtrate is used for next-step operation, and filter residue is used for reclaiming homopiperazine further;
S5. a concentrating under reduced pressure: step S4 gained filtrate decompression is distilled to solid, reinforcing body volume is the water dissolution solid of 1 ~ 10 times, filters, and collects filtrate;
S6. secondary pressure concentrates: the filtrate reduced in volume collected by step S5, to 1/10 ~ 1/2 of filtrate original volume, is cooled to less than 10 DEG C crystallizations, then uses the washed cake filtration crystal solution of frozen water, and gained solid is Fasudil Hydrochloride crude product;
S7. refine: by Fasudil Hydrochloride crude product by adding the anhydrous alcohol solution that weight ratio is 1 ~ 10 times, add the gac of overall solution volume 0.1 ~ 2g/ml again, whip attachment 25 ~ 35min, filter decarburization, collect filtrate, filtrate is cooled to less than 10 DEG C crystallizations, again filters, the vacuum-drying at 40 ~ 90 DEG C of gained solid, obtained High-purity fasudil hydrochloride.
2. the preparation method of a kind of High-purity fasudil hydrochloride according to claim 1, is characterized in that: the weight ratio of methylene dichloride described in step S2 and isoquinoline 99.9-5-sulfonyl chloride hydrochloride is 5 ~ 20:1.
3. the preparation method of a kind of High-purity fasudil hydrochloride according to claim 1, is characterized in that: the weight ratio of dehydrated alcohol described in step S3 and homopiperazine is 5 ~ 20:1.
4. the preparation method of a kind of High-purity fasudil hydrochloride according to claim 1, is characterized in that, pH value of solution described in step S4 is 5.0 ~ 6.5.
5. the preparation method of a kind of High-purity fasudil hydrochloride according to claim 1, is characterized in that, the method reclaiming homopiperazine described in step S4 is: by filter residue absolute ethanol washing 2 ~ 3 times, dries at 50 ~ 80 DEG C.
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| CN105866263B (en) * | 2016-03-24 | 2018-06-29 | 四川升和药业股份有限公司 | A kind of method of quality control 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 |
| 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 |
| CN109705096B (en) * | 2019-03-07 | 2023-06-09 | 山东新华制药股份有限公司 | Refining method of fasudil hydrochloride |
| CN111217794A (en) * | 2020-03-14 | 2020-06-02 | 江巨东 | Method for refining fasudil hydrochloride |
| CN114380794B (en) * | 2020-10-22 | 2024-06-28 | 鲁南制药集团股份有限公司 | Preparation method of fasudil |
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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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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