CN101812051B - High purity fasudil hydrochloride compound - Google Patents
High purity fasudil hydrochloride compound Download PDFInfo
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- CN101812051B CN101812051B CN2010101001696A CN201010100169A CN101812051B CN 101812051 B CN101812051 B CN 101812051B CN 2010101001696 A CN2010101001696 A CN 2010101001696A CN 201010100169 A CN201010100169 A CN 201010100169A CN 101812051 B CN101812051 B CN 101812051B
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- fasudil
- fasudil hydrochloride
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Abstract
The invention relates to high purity fasudil hydrochloride compound; the method can obtain high purity fasudil hydrochloride finished goods and belongs to the technical field of medicine. The purity of the fasudil hydrochloride is greatly increased by acid-base reaction, silicagel column elution and activated carbon adsorption. The method has simple technique, low cost and high yield and is suitable for industrialization production.
Description
Technical field
The present invention relates to a kind of fasudil hydrochloride compound, can obtain highly purified Fasudil Hydrochloride, belong to medical technical field by this method.
Background technology
Fasudil Hydrochloride, chemical name are six hydrogen-1-(5-isoquinolinesulfonylcompounds)-1H-1,4-diazepine hydrochloride, molecular formula C
14H
17N
3O
2SHCl, molecular weight 327.83 is the compound of following graphic (I) structure:
Fasudil Hydrochloride is that a kind of kinases inhibitor is the intracellular calcium antagonist, and by the terminal stage of blocking-up vasoconstriction process, the myosin light chain phosphorylation is come vasodilation, suppresses vasospasm.Brain spasm after being applicable to improvement clinically and preventing subarachnoid hemorrhage and the symptoms of cerebral ischemia that causes.
The preparation method of Fasudil Hydrochloride reports seldom that both at home and abroad domestic have only Tianjin red sun pharmaceutcal corporation, Ltd to produce without competition, and its product purity is relatively poor, causes the quality of the pharmaceutical preparations defective, has influenced clinical application.
Summary of the invention
Usually, Fasudil Hydrochloride be by isoquinoline 99.9 through the oleum sulfonation, the sulfonic acid of generation is converted into SULPHURYL CHLORIDE, with phenodiazine leather reaction, obtains product again.Its reaction scheme is as follows:
Wherein when 5-isoquinoline 99.9 SULPHURYL CHLORIDE and the condensation of phenodiazine leather, be easy to generate the by product of a small amount of dimerization, reacted product purity is not high, detected impurity contains not raw material of complete reaction of above-mentioned substance and other usually, not easily separated, cause product purity relatively poor easily, thereby make the quality of the pharmaceutical preparations defective, influenced clinical application.
In order to remove above-mentioned impurity, taked multiple purification process, methods such as for example underpressure distillation, recrystallization, one-tenth salt extraction, products obtained therefrom purity does not still reach requirements for clinical application, has complex process, reagent cost problem of higher in addition.By chromatography method repetition tests such as silicagel column, aluminum oxide, macroporous resin, polymeric amide are relatively contrasted, we find, utilize silica gel column chromatography method, can effectively address the aforementioned drawbacks, if further find to adopt the MeOH/CHCl of specified proportion
3It is good especially to separate effect during as eluent.In suitability for industrialized production, cost is low because silica gel column chromatography separates, handle easily, and be the selection approach of using always.In fact, separate the finished product that obtain of purifying by aforesaid method and pass through the medical requirement of the detected purity accords of HPLC, so become optimized technical scheme of the present invention.
Therefore, the invention provides a kind of process for purification of fasudil hydrochloride compound, comprise the steps:
(1) pass through to add aqueous ethanolic solution to the Fasudil Hydrochloride crude product, heated and stirred slowly adds alkali to separating out the insolubles fasudil;
(2) insolubles is packed into silicagel column (Silica gel), eluent MeOH/CHCl
3, collect isolating first component of pillar wash-out, this component concentration is maximum;
(3) then described component is dissolved in the solvent, the charcoal absorption purifying filters, and collects filtrate;
(4) to filtrate dripping hydrochloric acid solution, finally obtain highly purified fasudil hydrochloride compound.
Above-mentioned described process for purification, the concentration of wherein said aqueous ethanolic solution are 10-75% (V/V), and the weight ratio of Fasudil Hydrochloride crude product and aqueous ethanolic solution is 3-20.
Above-mentioned described process for purification, wherein said alkali is highly basic or strong base-weak acid salt, is selected from sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, S-WAT, sodium-acetate, is preferably sodium hydroxide.
Above-mentioned described process for purification, wherein said eluent MeOH/CHCl
3Between ratio be 2: 100-5: 100 (V/V).
Above-mentioned described process for purification, wherein said silica gel consumption are 10-30 times of fasudil crude product weight.
Above-mentioned described process for purification, wherein said solvent is selected from chloroform, methylene dichloride, normal hexane, acetonitrile, acetone, methyl alcohol, Virahol, propyl carbinol, is preferably acetonitrile.
Above-mentioned described process for purification, Fasudil Hydrochloride and alkali reaction to pH value of solution value is 9-11, is preferably 9.5-10.5.
Above-mentioned described process for purification, fasudil and hydrochloric acid reaction to pH value of solution value is 3-6, is preferably 4-5.
Above-mentioned described process for purification, wherein purge process was heated to 30-60 ℃ of whip attachment 15-30 minute for adding the gac of overall solution volume 0.1-0.2 (g/ml).
As the present invention's one preferred embodiment, the process for purification of described fasudil hydrochloride compound comprises the steps:
(1) be 3-20 10-75% aqueous ethanolic solution (V/V) doubly to the Fasudil Hydrochloride crude product by adding weight ratio, heated and stirred 10-20 minute, slowly add alkali to separating out the insolubles fasudil, filter, 40-50 ℃ of drying under reduced pressure gets the fasudil crude product;
(2) insolubles is packed into silicagel column (Silica gel), eluent MeOH/CHCl
3, its proportioning is 2: 100-5: 100 (V/V), wash-out obtain three components, collect the first maximum component of pillar wash-out separation component content;
(3) then described component is dissolved in the solvent, adds the gac of overall solution volume 0.1-0.2 (g/ml), be heated to 60 ℃ of whip attachment 15-30 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 0.5-2mol/L is 4-5 in filtrate, separates out insolubles, and stirring at room reaction 20-30 minute is filtered, and 40-50 ℃ of drying under reduced pressure gets the refining fasudil hydrochloride product.
The process for purification of fasudil hydrochloride compound provided by the invention, by acid-base reaction, the silicagel column wash-out, charcoal absorption has improved the purity of Fasudil Hydrochloride greatly, has optimized the quality of formulation products, has ensured safety of clinical administration; Present method technology is simple, and cost is low, and the yield height is suitable for suitability for industrialized production.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
The preparation of silicagel column takes by weighing 20-50 times of weight 200-300 order silica gel, selects methyl alcohol fully to stir as solvent, selects suitable pillar to adorn post then, according to method compacting commonly used in order to test.The high performance liquid chromatograph that the present invention uses is LC-VP (day island proper Tianjin), and other reagent all is analytical pure.Measure the purity of final product according to the method for routine.
Making with extra care of embodiment 1 Fasudil Hydrochloride
(1) 100g Fasudil Hydrochloride crude product is dissolved in 15% aqueous ethanolic solution of 1000ml, heated and stirred 10 minutes, slowly adding 5% sodium hydroxide solution to pH value is 9.5, separate out insolubles, stirring reaction 20 minutes filters, 50 ℃ of drying under reduced pressure get fasudil 84.7g;
(2) fasudil 20g is packed into silicagel column (400g, eluent), MeOH/CHCl
3, its proportioning is 2: 100 (V/V), crude product is faint yellow, can be divided into 3 faint yellow colour bands on pillar, collects on the pillar and tells the first maximum elution fractions;
(3) component of collecting is dissolved in 200ml and adds in the methylene dichloride, add the gac of 0.3g, be heated to 60 ℃ of whip attachment 15 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 0.5mol/L is 4 in filtrate, separates out insolubles, and stirring at room reaction 30 minutes is filtered, and 50 ℃ of drying under reduced pressure get refining fasudil hydrochloride product 18.9g, and total recovery is 84.0%, and it is 99.96% that HPLC detects purity.
Making with extra care of embodiment 2 Fasudil Hydrochloride
(1) 100g Fasudil Hydrochloride crude product is dissolved in 75% aqueous ethanolic solution of 1000ml, heated and stirred 20 minutes, slowly adding 20% sodium hydrogen carbonate solution to pH value is 9.8, separate out insolubles, stirring reaction 10 minutes filters, 40 ℃ of drying under reduced pressure get fasudil 84.1g;
(2) fasudil 15g is packed into silicagel column (400g, eluent), MeOH/CHCl
3, its proportioning is 5: 100 (V/V), crude product is faint yellow, can be divided into 3 faint yellow colour bands on pillar, collects on the pillar and tells the first maximum elution fractions;
(3) component of collecting is dissolved in 150ml and adds in the methylene dichloride, add the gac of 0.5g, be heated to 60 ℃ of whip attachment 30 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 2mol/L is 3 in filtrate, separates out insolubles, and stirring at room reaction 20 minutes is filtered, and 40 ℃ of drying under reduced pressure get refining fasudil hydrochloride product 13.7g, and total recovery is 81.0%, and it is 99.97% that HPLC detects purity.
Making with extra care of embodiment 3 Fasudil Hydrochloride
(1) 100g Fasudil Hydrochloride crude product is dissolved in 30% aqueous ethanolic solution of 1000ml, heated and stirred 20 minutes, slowly adding 10% potassium hydroxide solution to pH value is 10.5, separate out insolubles, stirring reaction 15 minutes filters, 45 ℃ of drying under reduced pressure get fasudil 82.8g;
(2) fasudil 10g is packed into silicagel column (300g, eluent), MeOH/CHCl
3, its proportioning is 3: 100 (V/V), crude product is faint yellow, can be divided into 3 faint yellow colour bands on pillar, collects on the pillar and tells the first maximum elution fractions;
(3) component of collecting is dissolved in 100ml and adds in the methylene dichloride, add the gac of 0.2g, be heated to 50 ℃ of whip attachment 20 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 1mol/L is 4.5 in filtrate, separates out insolubles, and stirring at room reaction 25 minutes is filtered, and 45 ℃ of drying under reduced pressure get refining fasudil hydrochloride product 9.8g, and total recovery is 87.0%, and it is 99.97% that HPLC detects purity.
Making with extra care of embodiment 4 Fasudil Hydrochloride
(1) 100g Fasudil Hydrochloride crude product is dissolved in 15% aqueous ethanolic solution of 1000ml, heated and stirred 20 minutes, slowly adding 8% sodium acetate soln to pH value is 9.3, separate out insolubles, stirring reaction 20 minutes filters, 50 ℃ of drying under reduced pressure get fasudil 82.2g;
(2) fasudil 25g is packed into silicagel column (500g, eluent), MeOH/CHCl
3, its proportioning is 4: 100 (V/V), crude product is faint yellow, can be divided into 3 faint yellow colour bands on pillar, collects on the pillar and tells the first maximum elution fractions;
(3) component of collecting is dissolved in 300ml and adds in the methylene dichloride, add the gac of 0.5g, be heated to 50 ℃ of whip attachment 20 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 2mol/L is 4.0 in filtrate, separates out insolubles, and stirring at room reaction 20 minutes is filtered, and 45 ℃ of drying under reduced pressure get refining fasudil hydrochloride product 23.1g, and total recovery is 82.0%, and it is 99.90% that HPLC detects purity.
Making with extra care of embodiment 5 Fasudil Hydrochloride
(1) 100g Fasudil Hydrochloride crude product is dissolved in 10% aqueous ethanolic solution of 1000ml, heated and stirred 20 minutes, slowly adding 6% sodium sulfite solution to pH value is 9.7, separate out insolubles, stirring reaction 15 minutes filters, 45 ℃ of drying under reduced pressure get fasudil 83.8g;
(2) fasudil 15g is packed into silicagel column (300g, eluent), MeOH/CHCl
3, its proportioning is 5: 100 (V/V), crude product is faint yellow, can be divided into 3 faint yellow colour bands on pillar, collects on the pillar and tells the first maximum elution fractions;
(3) component of collecting is dissolved in 200ml and adds in the acetonitrile, add the gac of 0.5g, be heated to 60 ℃ of whip attachment 15 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 0.5mol/L is 4.2 in filtrate, separates out insolubles, and stirring at room reaction 20 minutes is filtered, and 45 ℃ of drying under reduced pressure get refining fasudil hydrochloride product 15.39g, and total recovery is 91.2%, and it is 99.95% that HPLC detects purity.
Claims (5)
1. the process for purification of the fasudil hydrochloride compound shown in the formula (I) is characterized in that comprising the steps:
(1) be the aqueous ethanolic solution of 3-20 10-75%V/V doubly with the Fasudil Hydrochloride crude product by the adding weight ratio, heated and stirred 10-20 minute, slowly add alkali to separating out the insolubles fasudil, filter, 40-50 ℃ of drying under reduced pressure gets the fasudil crude product;
(2) insolubles is packed into silicagel column, eluent is 2: the MeOH/CHCl of 100-5: 100V/V
3, wash-out obtains three components, collects the first maximum component of pillar wash-out separation component content;
(3) then described component is dissolved in the solvent, adds the gac of overall solution volume 0.1-0.2g/ml, be heated to 60 ℃ of whip attachment 15-30 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value to filtrate dropping 0.5-2mol/L is 4-5, separates out insolubles, and stirring at room reaction 20-30 minute is filtered, and 40-50 ℃ of drying under reduced pressure finally obtains highly purified fasudil hydrochloride compound.
2. process for purification according to claim 1 is characterized in that described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, S-WAT or sodium-acetate.
3. process for purification according to claim 1 is characterized in that described solvent is methylene dichloride or acetonitrile.
4. process for purification according to claim 1, it is characterized in that with alkali reaction to pH value of solution value be 9-11.
5. process for purification according to claim 4, it is characterized in that with alkali reaction to pH value of solution value be 9.5-10.5.
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| CN2010101001696A CN101812051B (en) | 2010-01-25 | 2010-01-25 | High purity fasudil hydrochloride compound |
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| CN2010101001696A CN101812051B (en) | 2010-01-25 | 2010-01-25 | High purity fasudil hydrochloride compound |
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| CN101812051B true CN101812051B (en) | 2011-08-24 |
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Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199123B (en) * | 2010-03-24 | 2014-09-03 | 天津红日药业股份有限公司 | New crystal form and pharmaceutical application of fasudil |
| CN101962379B (en) * | 2010-09-28 | 2013-02-27 | 山西普德药业股份有限公司 | Method for refining sulfonyl isoquinoline derivative |
| CN101973981B (en) * | 2010-10-09 | 2013-01-02 | 南京优科制药有限公司 | Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride |
| CN102060845B (en) * | 2010-12-28 | 2013-07-03 | 天津红日药业股份有限公司 | Fasudil crystal formation III as well as preparation method and application thereof |
| CN102060844B (en) * | 2010-12-28 | 2014-05-28 | 天津红日药业股份有限公司 | Fasudil crystal formation IV as well as preparation method and application thereof |
| CN102250066B (en) * | 2011-03-02 | 2013-05-01 | 武汉启瑞药业有限公司 | Fasudil derivative and preparation method thereof |
| CN102138901B (en) * | 2011-03-30 | 2012-12-19 | 天津红日药业股份有限公司 | Nasal spray or aerosol containing Fasudil |
| CN102229601B (en) * | 2011-05-12 | 2013-07-03 | 天津市汉康医药生物技术有限公司 | Hexahydro-1-(5-isoquinoline sulfonyl)-1 (H)-1, 4- diazepine hydrochloride amorphous compound |
| CN102516179B (en) * | 2011-11-23 | 2015-07-22 | 北京美迪康信医药科技有限公司 | Method for refining nizofenone fumarate and intermediate synthesizing method |
| CN102924436B (en) * | 2012-11-30 | 2014-03-19 | 南京正大天晴制药有限公司 | Refining method of fasudil hydrochloride |
| CN103113352A (en) * | 2013-03-09 | 2013-05-22 | 山东方明药业集团股份有限公司 | Method for preparing fasudil impurity-homopiperazine disulfone |
| CN103896873B (en) * | 2013-10-23 | 2015-11-25 | 山东诚创医药技术开发有限公司 | A kind of process for purification of acotiamide hydrochloride hydrate |
| 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 |
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