CN104098547A - Refining method for hydroxyfasudil - Google Patents
Refining method for hydroxyfasudil Download PDFInfo
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- CN104098547A CN104098547A CN201410364481.4A CN201410364481A CN104098547A CN 104098547 A CN104098547 A CN 104098547A CN 201410364481 A CN201410364481 A CN 201410364481A CN 104098547 A CN104098547 A CN 104098547A
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- fasudil 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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Abstract
The invention relates to a refining method for hydroxyfasudil. The refining method is characterized in that the hydroxyfasudil is dissolved in a heated solvent A, and a solvent B is added dropwise at a certain temperature; the combination is cooled to be below 10 DEG C, stood for devitrification, filtered, washed by the mixed liquor of A and B with the proportion the same as that of the added A and B, and dried to a hydroxyfasudil refined product. According to the invention, a high purity hydroxyfasudil crystal can be obtained, the content is greater than 99.8%, and the single impurity of the hydroxyfasudil can be stably controlled not to be greater than 0.1%.
Description
Technical field
The present invention relates to a kind of process for purification of Fasudil Hydrochloride, be specifically related to the process for refining of the medicine Fasudil Hydrochloride production of raw medicine process that a kind of ischemic cerebrovascular symptom causing for cerebral vasospasm after subarachnoid hemorrhage etc. improves.
Background technology
Fasudil Hydrochloride is a kind of sulfonyl isoquinoline derivative, its English Fasudil Hydrochloride by name, and chemistry six hydrogen-1-(5-alkylsulfonyl isoquinoline 99.9)-1-(H)-Isosorbide-5-Nitrae-diazepine hydrochloride by name, molecular formula is C
14h
17n
3o
2..HCl, chemical structural formula is as follows:
Be a kind of intracellular calcium antagonist of Japanese Asahi Kasei Corporation exploitation, have the effects such as cerebral vasodilators, for the caused brain spasm of subarachnoid hemorrhage, go on the market June nineteen ninety-five in Japan, is widely used at present clinical clinically.
The preparation technology of Fasudil Hydrochloride mainly passes through following steps at present:
The Fasudil Hydrochloride finished product that this synthesis technique is produced all contains three class impurity: pigment, excessive raw material homopiperazine and by product dimer, the compound of structural formula as shown in (II).The existence of these impurity has certain influence to the drug effect of Fasudil Hydrochloride, and the purity that therefore improves this medicine has very important meaning to medicine.
At present, the process for refining of Fasudil Hydrochloride mainly contains two kinds:
The one, by silicagel column, carry out the purification of crude product, as US4678783, CN201010558960, CN201010100169 etc., this method adopts chloroform-methanol system wash-out, bad to the impurity dimer effect that polarity is less, and adopt post method of purification complicated operation, production cycle is long, is not suitable for producing in enormous quantities;
The 2nd, the method for employing recrystallization.The recrystallization of fasudil is basic only relevant with two kinds of factors, and the one, solvent (solvent species and solvent multiple etc.), the 2nd, temperature (recrystallization temperature and rate of temperature fall etc.).CN103030629A, CN102020635A adopt the method for methyl alcohol+poor solvent to adopt room temperature to drip poor solvent, bad to the dimeric effect of removing.
Publication number is that water-methanol, water-ethanol, the methyl alcohol-ether system that the patent application of CN101973981A points out to adopt bibliographical information carried out recrystallization to Fasudil Hydrochloride crude product, all do not obtain satisfied effect, cannot be stable by the single Control of Impurities of Fasudil Hydrochloride in 0.1%.In 0007 section of file, from stating application water-methanol, water-ethanol, methyl alcohol-ether system, Fasudil Hydrochloride crude product is carried out to recrystallization, does not all obtain satisfied effect, cannot be stable by the single Control of Impurities of Fasudil Hydrochloride in 0.1%.We by experiment condition grope, according to the system in documents, carry out fasudil recrystallization, discovery is by relaxing ground thereafter to the control of temperature in Crystallization Process-be mainly in solvent orange 2 A dissolution method, at a certain temperature, add B solvent, cooling crystallization, can obtain highly purified Fasudil Hydrochloride crystallization again, and content is greater than 99.8%, the single impurity of control Fasudil Hydrochloride that can be stable is not more than 0.1%.The solvent using with respect to documents, what we invented employing is all conventional usual vehicle, cost has superiority.
Summary of the invention
We find the Fasudil Hydrochloride of the preparations such as water-methanol, water-ethanol, methyl alcohol+ether solvent system, in treating process, by the control to temperature in Crystallization Process, can obtain highly purified Fasudil Hydrochloride crystallization.
The invention provides a kind of process for purification of Fasudil Hydrochloride, through great many of experiments, we find, after Fasudil Hydrochloride being dissolved with a kind of solvent orange 2 A, at a certain temperature, drip the poor solvent B crystallization of Fasudil Hydrochloride, drip Bi Jiangwen crystallization, can obtain highly purified Fasudil Hydrochloride crystallization, content is greater than 99.8%, and the single impurity of control Fasudil Hydrochloride that can be stable is not more than 0.1%.And the method is simple, the cycle is short, is suitable for industrialized production.
For achieving the above object, technical solution of the present invention is as follows:
Fasudil Hydrochloride is dissolved in the solvent orange 2 A of heating, drips solvent B under certain temperature, be cooled to below 10 ℃, standing crystallization, filters, and with the solvent wash of the solubilizing agent A of institute, B ratio, after being dried, can obtain refining fasudil hydrochloride product.
The process for purification of Fasudil Hydrochloride of the present invention, wherein solvent orange 2 A is methyl alcohol, ethanol, water one or both mixing solutions wherein, is preferably methyl alcohol;
The process for purification of Fasudil Hydrochloride of the present invention, Fasudil Hydrochloride is dissolved in hot solvent orange 2 A, temperature be 40 ℃ to the boiling point of this solvent, be preferably reflux state;
The process for purification of Fasudil Hydrochloride of the present invention, while dripping solvent B the temperature of system be 30 ℃ to reflux state, be preferably reflux state;
The process for purification of Fasudil Hydrochloride of the present invention, the solvent B adding is one or both the mixing solutions in ether, acetone, ethyl acetate, methylene dichloride, methyl tertiary butyl ether, dioxane, is preferably ether.
The process for purification of Fasudil Hydrochloride of the present invention, the volume ratio of the solvent orange 2 A adding and solvent B is 1:1～1:10, is preferably: 1:1～1:5.
The most preferred method of the present invention:
Fasudil Hydrochloride is dissolved in the methyl alcohol of heating, under reflux state, drips solvent ether, be cooled to below 10 ℃, standing crystallization, filters, with institute's solubilizing agent methyl alcohol: the solvent wash of ether (1:1) ratio, can obtain refining fasudil hydrochloride product after dry.
The present invention, with respect to prior art, has mainly done improvement to following aspect:
To dripping the temperature of solvent B, done research, solvent B is 30 ℃ or drips to reflux state in temperature, and solvent B can reduce the content of dimer impurity in Fasudil Hydrochloride greatly.
Compared to the prior art, the present invention is by the screening of processing parameter, obtain a kind of simple and practical, the process for purification of the Fasudil Hydrochloride that effect is good, it is 99.9% that its content is up to its content, single impurity is 0.01%, yield is up to 91%.
Embodiment
Embodiment is only described further summary of the invention, is not limited to the content of embodiment.
Embodiment 1: take 10 grams of Fasudil Hydrochloride crude products, be dissolved in the methyl alcohol of 80ml backflow, drip ether 80ml under reflux state, be cooled to 10 ℃, standing crystallization 1 hour, filters, with the washing of methyl alcohol-ether 1:1 mixed solution, after being dried, obtain refining fasudil hydrochloride product 9.1g.Its content is 99.90%, and single impurity is 0.01%.Yield 91%
Embodiment 2: take 10 grams of Fasudil Hydrochloride crude products, be dissolved in the methyl alcohol of 80ml backflow, under reflux state, drip acetone 240ml, dropwise, be cooled to 10 ℃, standing crystallization 1 hour, filters, with the washing of methanol-acetone 1:3 mixed solution, after vacuum-drying, obtain refining fasudil hydrochloride product 9.1g.Its content is 99.89%, and single impurity is 0.01%.Yield 91%
Embodiment 3: take 10 grams of Fasudil Hydrochloride crude products, be dissolved in the anhydrous methanol of 80ml backflow, under reflux state, drip acetone 400ml, dropwise, be cooled to 10 ℃, standing crystallization 1 hour, filters, with the washing of methanol-acetone 1:5 mixed solution, after vacuum-drying, obtain refining fasudil hydrochloride product 9.0g.Its content is 99.82%, and single impurity is 0.02%, yield 90%.
Embodiment 1-3 content and impurity detected result:
| ? | Content | Single impurity | Yield |
| Embodiment 1 | 99.90％ | 0.01％ | 91％ |
| Embodiment 2 | 99.89％ | 0.01％ | 91％ |
| Embodiment 3 | 99.82％ | 0.02％ | 90％ |
Embodiment 4, solvent orange 2 A are methyl alcohol, and solvent B is ether, the impact experiment of the temperature of reaction system on Fasudil Hydrochloride dimer impurity content while dripping solvent B
| Dropping temperature | 10℃ | 20℃ | 30℃ | 40℃ | 50℃ | 60℃ | Reflux state |
| Dimer content | 0.25％ | 0.22％ | 0.02％ | 0.03％ | 0.03％ | 0.02％ | 0.01％ |
The impact experiment of the volume ratio of embodiment 5, solvent methanol and solvent ether on Fasudil Hydrochloride stability.
From above experimental data, show, solvent systems is at the amount ratio of solvent methanol and solvent ether at 1:1～1:10, and dimer impurity content can be controlled in 0.1%.
The impact experiment of the selection of embodiment 6, different solvent orange 2 A and solvent B on Fasudil Hydrochloride stability
From above experimental data, solvent systems is at the amount ratio of solvent orange 2 A and solvent B at 1:1～1:10, and dimer impurity content can be controlled in 0.1%.
The detection method of embodiment 7, impurity of the present invention.
HPLC testing conditions: chromatographic column: C18 post; Detect wavelength: 275nm; Flow velocity: 1ml/min.
Moving phase condition: A: methyl alcohol B:1.0 triethylamine (phosphoric acid is adjusted pH6.0).
| Time (min) | A | B |
| 0 | 20 | 80 |
| 10 | 20 | 80 |
| 20 | 25 | 75 |
| 40 | 55 | 45 |
| 55 | 55 | 45 |
| 56 | 20 | 80 |
| 60 | 20 | 80 |
Claims (9)
1. the process for purification of a Fasudil Hydrochloride, the method comprises the following steps: Fasudil Hydrochloride is dissolved in the solvent orange 2 A of heating, under certain temperature, drip solvent B, be cooled to below 10 ℃, standing crystallization, filter, with the solvent wash of the solubilizing agent A of institute, B ratio, after being dried, can obtain refining fasudil hydrochloride product; Wherein, solvent orange 2 A is selected from: the mixing solutions of one or both in methyl alcohol, ethanol, water; Solvent B is selected from: the mixing solutions of one or both in ether, acetone, ethyl acetate, methylene dichloride, methyl tertiary butyl ether, dioxane, the volume ratio of the solvent orange 2 A adding and solvent B is 1:1～1:10.
2. the process for purification of Fasudil Hydrochloride according to claim 1, is characterized in that: solvent orange 2 A is methyl alcohol.
3. the process for purification of Fasudil Hydrochloride according to claim 1, is characterized in that: solvent B is ether.
4. according to claim 1 hydrochloric acid, state the process for purification of fasudil, it is characterized in that: Fasudil Hydrochloride is dissolved in hot solvent orange 2 A, temperature be 40 ℃ to the boiling point of this solvent.
5. the process for purification of Fasudil Hydrochloride according to claim 1, is characterized in that: the temperature that drips solvent B be 30 ℃ to reflux state.
6. the process for purification of Fasudil Hydrochloride according to claim 1, is characterized in that: the volume ratio of the solvent orange 2 A adding and solvent B is 1:1～1:5.
7. the process for purification of Fasudil Hydrochloride according to claim 1, it is characterized in that: Fasudil Hydrochloride is dissolved in the methyl alcohol of heating, under reflux state, drip solvent ether, be cooled to below 10 ℃, standing crystallization, filter, with institute's solubilizing agent methyl alcohol: the solvent wash of ether (1:1) ratio, can obtain refining fasudil hydrochloride product after dry.
8. the process for purification of Fasudil Hydrochloride according to claim 1, it is characterized in that: take 10 grams of Fasudil Hydrochloride crude products, be dissolved in the methyl alcohol of 80ml backflow, under reflux state, drip ether 80ml, be cooled to 10 ℃, standing crystallization 1 hour, filters, with the washing of methyl alcohol-ether 1:1 mixed solution, after being dried, obtain refining fasudil hydrochloride product.
9. the process for purification of Fasudil Hydrochloride according to claim 1, it is characterized in that: take 10 grams of Fasudil Hydrochloride crude products, be dissolved in the methyl alcohol of 80ml backflow, under reflux state, drip acetone 240ml, dropwise, be cooled to 10 ℃, standing crystallization 1 hour, filter, with the washing of methanol-acetone 1:3 mixed solution, after vacuum-drying, obtain refining fasudil hydrochloride product.
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| CN201410364481.4A CN104098547B (en) | 2014-07-28 | 2014-07-28 | A kind of process for purification of Fasudic hydrochloride |
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| CN201410364481.4A CN104098547B (en) | 2014-07-28 | 2014-07-28 | A kind of process for purification of Fasudic hydrochloride |
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| CN104098547A true CN104098547A (en) | 2014-10-15 |
| CN104098547B CN104098547B (en) | 2016-08-24 |
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Cited By (2)
| 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 |
| CN110441449A (en) * | 2019-08-14 | 2019-11-12 | 昆药集团股份有限公司 | In relation to the detection method of substance in Fasudic hydrochloride raw material or injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973981A (en) * | 2010-10-09 | 2011-02-16 | 南京新港医药有限公司 | Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride |
| CN102924436A (en) * | 2012-11-30 | 2013-02-13 | 南京正大天晴制药有限公司 | Refining method of fasudil hydrochloride |
| CN103030629A (en) * | 2011-10-10 | 2013-04-10 | 南京亿华药业有限公司 | Method for preparing fasudil hydrochloride |
-
2014
- 2014-07-28 CN CN201410364481.4A patent/CN104098547B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973981A (en) * | 2010-10-09 | 2011-02-16 | 南京新港医药有限公司 | Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride |
| CN103030629A (en) * | 2011-10-10 | 2013-04-10 | 南京亿华药业有限公司 | Method for preparing fasudil hydrochloride |
| CN102924436A (en) * | 2012-11-30 | 2013-02-13 | 南京正大天晴制药有限公司 | Refining method of fasudil hydrochloride |
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 |
| CN110441449A (en) * | 2019-08-14 | 2019-11-12 | 昆药集团股份有限公司 | In relation to the detection method of substance in Fasudic hydrochloride raw material or injection |
| CN110441449B (en) * | 2019-08-14 | 2021-06-29 | 昆药集团股份有限公司 | Method for detecting related substances in fasudil hydrochloride raw material or injection |
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| CN104098547B (en) | 2016-08-24 |
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