CN103509002A - Purification decolorization method of fasudil hydrochloride - Google Patents
Purification decolorization method of fasudil hydrochloride Download PDFInfo
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- CN103509002A CN103509002A CN201210203958.1A CN201210203958A CN103509002A CN 103509002 A CN103509002 A CN 103509002A CN 201210203958 A CN201210203958 A CN 201210203958A CN 103509002 A CN103509002 A CN 103509002A
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- fasudil
- fasudil hydrochloride
- dichloromethane solution
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- hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic 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
- C07D401/02—Heterocyclic 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
- C07D401/12—Heterocyclic 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
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- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a crude drug processing method, particularly relates to a purification decolorization method of a crude drug, and more particularly relates to a purification decolorization method of fasudil hydrochloride. Aiming at the problem that in the prior art a fasudil hydrochloride product is purified and decolored by organic solvent recrystallization, the new purification decolorization method of the fasudil hydrochloride is provided, through direct pH adjusting of a fasudil dichloromethane solution and matched filtering operation, the fasudil hydrochloride product is separated from pigments and water soluble impurities, a new idea that a crude drug hydrochloride can be crystallized in an aqueous solution is developed, so that the problem of organic compound recrystallion in an organic solution in the prior art is solved.
Description
Technical field
The present invention relates to a kind for the treatment of process of bulk drug, particularly relate to a kind of purifying decoloring method of bulk drug, more specifically relate to a kind of purifying decoloring method of Fasudil Hydrochloride.
Background technology
Fasudil Hydrochloride is that a kind of kinases inhibitor is intracellular calcium antagonist, and its pharmacological action is for passing through the terminal stage of blocking-up vasoconstriction process, and this process of sphaeroprotein light chain phosphorylation, carrys out vasodilation, thereby suppresses vasospasm.Its pharmacy goods are applicable to improve and prevent the brain spasm after subarachnoid hemorrhage and the symptoms of cerebral ischemia causing clinically.
The clinical common formulations of Fasudil Hydrochloride is injection, therefore all very strict to the requirement of its color and purity, how the Fasudil Hydrochloride purifying that decolours is seemed to particularly important.
In existing technique, the method for purifying can be divided into two steps substantially, the first step adopts organic solvent recrystallization method if US5942505 etc. is to the product purifying that decolours, the free alkali that second step utilizes compound to organic phase and water two-phase rejecting effect as EP1726306 and patent CN101723934A etc., or by silica gel column chromatography if US5942505, EP187371 and patent CN101812051A etc. are to the product purifying that decolours.Inevitably, first all to adopt organic solvent recrystallization method to carry out the purifying decolorization of the first step and the rejecting of the two-phase of organic basic bulk drug to product, but problem is that the result of so doing is often unsatisfactory, and constantly repeat these two processes, not only allow operation more complicated, outside loss is larger, result is also barely satisfactory.
Summary of the invention
The present invention is directed to current Fasudil Hydrochloride and utilize organic solvent recrystallization the problem existing in product decolouring purifying to be provided to a kind of purifying decoloring method of new Fasudil Hydrochloride, comprise the following steps:
(1) make the dichloromethane solution of fasudil;
(2) pH value to 4.5～5.5 of fasudil dichloromethane solution in regulating step (1);
(3) reduce below system temperature to 0 ℃, stir, insulation half hour;
(4) mixture obtaining in step (3) is filtered, collect filter cake, obtain Fasudil Hydrochloride decolouring purifying product.
As a kind of improvement, in described step (2), adopt dilute hydrochloric acid to regulate the pH value of fasudil dichloromethane solution.
As another, improve, in described step (1), the preparation method of fasudil dichloromethane solution is: the dichloromethane solution that the dichloromethane solution of 5-isoquinoline 99.9 SULPHURYL CHLORIDE is dropped to homopiperazine.
The present invention is by the direct pH regulator to fasudil dichloromethane solution, complement filter operation, pigment and water-soluble impurity is separated with Fasudil Hydrochloride Realization of Product, opened up the new approaches of hydrochloride crystallization in the aqueous solution of bulk drug, the organic compound problem that recrystallization can't resolve in organic solution is in the past resolved.
Embodiment
Embodiment 1
The purifying decoloring method of Fasudil Hydrochloride, comprises the following steps:
(1) make the dichloromethane solution of fasudil;
(2) pH value to 4.5～5.5 of fasudil dichloromethane solution in regulating step (1);
(3) reduce below system temperature to 0 ℃, stir, insulation half hour;
(4) mixture obtaining in step (3) is filtered, collect filter cake, obtain Fasudil Hydrochloride decolouring product.
Embodiment 2
The purifying decoloring method of Fasudil Hydrochloride, comprises the following steps:
(1) dichloromethane solution of 5-isoquinoline 99.9 SULPHURYL CHLORIDE is dropped to the dichloromethane solution of homopiperazine, make the dichloromethane solution of fasudil;
(2) pH value to 4.5～5.5 of fasudil dichloromethane solution in regulating step (1);
(3) reduce below system temperature to 0 ℃, stir, insulation half hour;
(4) mixture obtaining in step (3) is filtered, collect filter cake, obtain Fasudil Hydrochloride decolouring product.
Embodiment 3
The purifying decoloring method of Fasudil Hydrochloride, comprises the following steps:
(1) make the dichloromethane solution of fasudil;
(2) progressively drip dilute hydrochloric acid to solution system, pH value to 4.5～5.5 of fasudil dichloromethane solution in regulating step (1);
(3) reduce below system temperature to 0 ℃, stir, insulation half hour;
(4) mixture obtaining in step (3) is filtered, collect filter cake, obtain Fasudil Hydrochloride decolouring product.
Embodiment 4
The first step: in reactor, add homopiperazine methylene dichloride mixed solution, frozen cooling to 0 ℃, the dichloromethane solution of dropping 5-isoquinoline 99.9 SULPHURYL CHLORIDE, controls reacting liquid temperature below 5 ℃, and after dropwising, reaction solution is yellow-green colour.
Drip 4mol/L aqueous hydrochloric acid to reaction system, regulate pH to 5.
Cooling starts to separate out white solid when approximately 15 ℃ of system temperatures, continues to be cooled to below 0 ℃, and insulation half hour, filter, filter cake is off-white color solid, filtrate is yellow-green colour, wherein contains pigment and is dissolved in the impurity of acidic aqueous solution.
Second step: further the Fasudil Hydrochloride after decolouring is carried out to purifying according to EP1726306 and the disclosed method of patent CN101723934A.Detailed process is as follows: off-white color solid filter cake is dissolved in the water, adds methylene dichloride, and washing, stratification, discards methylene dichloride organic phase (wherein containing the partial impurities that dissolves in methylene dichloride), fetches water mutually stand-by.More than regulating aqueous solution pH to 10, again add methylene dichloride, extraction, stratification, abandons or adopts the aqueous solution (wherein containing the partial impurities that dissolves in the alkaline aqueous solution), gets methylene dichloride organic phase, in the dichloromethane solution obtaining, add salt-forming reagent, filter, obtain Fasudil Hydrochloride crude product.Approximately 90% aqueous ethanolic solution recrystallization for crude product, obtains Fasudil Hydrochloride sterling, HPLC content: 99.97%, and single maximum contaminant 0.03%, color is lower than yellow No. 0.5.
Compare (CN101812051A column chromatography method obtains 99.96%) with the resulting Fasudil Hydrochloride of method in document, the cost that not only obtains product is lower, and color is completely qualified, content is higher, simple to operate, is applicable to producing.
The disclosed technique means of the present invention program is not limited only to the disclosed technique means of above-mentioned technique means, also comprises the technical scheme being comprised of above technical characterictic arbitrary combination.
The above is the specific embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
Claims (3)
1. a purifying decoloring method for Fasudil Hydrochloride, is characterized in that comprising the following steps:
(1) make the dichloromethane solution of fasudil;
(2) pH value to 4.5～5.5 of fasudil dichloromethane solution in regulating step (1);
(3) reduce below system temperature to 0 ℃, stir, insulation half hour;
(4) mixture obtaining in step (3) is filtered, collect filter cake, obtain Fasudil Hydrochloride decolouring purifying product.
2. the purifying decoloring method of Fasudil Hydrochloride according to claim 1, is characterized in that adopting dilute hydrochloric acid to regulate the pH value of fasudil dichloromethane solution in described step (2).
3. the purifying decoloring method of Fasudil Hydrochloride according to claim 1, is characterized in that the preparation method of fasudil methylene dichloride in described step (1) is: the dichloromethane solution that the dichloromethane solution of 5-isoquinoline 99.9 SULPHURYL CHLORIDE is dropped to homopiperazine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210203958.1A CN103509002B (en) | 2012-06-20 | 2012-06-20 | Purification decolorization method of fasudil hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210203958.1A CN103509002B (en) | 2012-06-20 | 2012-06-20 | Purification decolorization method of fasudil hydrochloride |
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| CN103509002A true CN103509002A (en) | 2014-01-15 |
| CN103509002B CN103509002B (en) | 2015-05-13 |
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| CN201210203958.1A Active CN103509002B (en) | 2012-06-20 | 2012-06-20 | Purification decolorization method of fasudil hydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945381A (en) * | 2015-06-24 | 2015-09-30 | 山东罗欣药业集团股份有限公司 | Fasudil hydrochloride compound and preparation method and medicine composition thereof |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002036A (en) * | 2009-08-31 | 2011-04-06 | 秦引林 | Method for refining fasudil |
| CN102020635A (en) * | 2009-09-10 | 2011-04-20 | 河北凯盛医药科技有限公司 | Preparation method of hydrochloride Fasudil hemihydrate |
| CN102120739A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of fasudil hydrochloride |
| CN102241669A (en) * | 2010-05-13 | 2011-11-16 | 吉林省博大伟业制药有限公司 | Preparation method of fasudil hydrochloride |
-
2012
- 2012-06-20 CN CN201210203958.1A patent/CN103509002B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002036A (en) * | 2009-08-31 | 2011-04-06 | 秦引林 | Method for refining fasudil |
| CN102020635A (en) * | 2009-09-10 | 2011-04-20 | 河北凯盛医药科技有限公司 | Preparation method of hydrochloride Fasudil hemihydrate |
| CN102120739A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of fasudil hydrochloride |
| CN102241669A (en) * | 2010-05-13 | 2011-11-16 | 吉林省博大伟业制药有限公司 | Preparation method of fasudil hydrochloride |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945381A (en) * | 2015-06-24 | 2015-09-30 | 山东罗欣药业集团股份有限公司 | Fasudil hydrochloride compound and preparation method and medicine composition thereof |
| 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 |
| 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 |
| 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 |
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| CN103509002B (en) | 2015-05-13 |
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Effective date of registration: 20160516 Address after: 221004, Jiangsu, Xuzhou Jinshan Development Zone, comprehensive area, the south side of the Cave Hill Patentee after: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Patentee after: CHINA PHARMACEUTICAL University Patentee after: JIANGSU WANBANG BIOPHARMACEUTICALS Co.,Ltd. Address before: 221004 Jiangsu city in Xuzhou Province Economic Development Zone Xuzhou peach Mountain Road No. 7 Patentee before: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Patentee before: CHINA PHARMACEUTICAL University |
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Address after: 221004, Jiangsu, Xuzhou Jinshan Development Zone, comprehensive area, the south side of the Cave Hill Co-patentee after: CHINA PHARMACEUTICAL University Patentee after: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Co-patentee after: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. Address before: 221004, Jiangsu, Xuzhou Jinshan Development Zone, comprehensive area, the south side of the Cave Hill Co-patentee before: CHINA PHARMACEUTICAL University Patentee before: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Co-patentee before: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd. Address after: 221004, Jiangsu, Xuzhou Jinshan Development Zone, comprehensive area, the south side of the Cave Hill Co-patentee after: CHINA PHARMACEUTICAL University Patentee after: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Co-patentee after: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd. Address before: 221004, Jiangsu, Xuzhou Jinshan Development Zone, comprehensive area, the south side of the Cave Hill Co-patentee before: CHINA PHARMACEUTICAL University Patentee before: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Co-patentee before: JIANGSU WANBANG BIOPHARMACEUTICALS Co.,Ltd. |
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Effective date of registration: 20180214 Address after: 221004 Jiangsu city in Xuzhou Province Economic Development Zone Xuzhou peach Mountain Road No. 7 Co-patentee after: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. Patentee after: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Address before: 221004, Jiangsu, Xuzhou Jinshan Development Zone, comprehensive area, the south side of the Cave Hill Co-patentee before: CHINA PHARMACEUTICAL University Patentee before: Xuzhou Wanbang Jinqiao Pharmaceutical Co.,Ltd. Co-patentee before: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. |