CN109776497A - A kind of preparation method of hydrochloride Fasudil hemihydrate - Google Patents
A kind of preparation method of hydrochloride Fasudil hemihydrate Download PDFInfo
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- CN109776497A CN109776497A CN201910170677.2A CN201910170677A CN109776497A CN 109776497 A CN109776497 A CN 109776497A CN 201910170677 A CN201910170677 A CN 201910170677A CN 109776497 A CN109776497 A CN 109776497A
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- hydrochloride
- fasudil
- hemihydrate
- preparation
- ethyl alcohol
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Abstract
The present invention provides a kind of preparation methods of hydrochloride Fasudil hemihydrate, specifically includes the following steps: being dissolved in concentration under 1, Fasudic hydrochloride counterflow condition is in 70%~95% ethyl alcohol, solvent usage is that under reflux conditions, entirely molten can be advisable；2, it is cooled to 0~5 DEG C, crystallization；3, it filters；4,40~60 DEG C of forced air dryings or vacuum drying；The method provided by the invention for preparing hydrochloride Fasudil hemihydrate, simple process, operation are easy.
Description
Technical field
The present invention relates to organic synthesis field, especially a kind of new hydrochloride Fasudil hemihydrate preparation method.
Background technique
Fasudic hydrochloride structural formula:
Fasudic hydrochloride Fasudil is that Japanese Asahi Kasei Corporation cooperates with Nagoya University pharmaceutical research room
A kind of novel isoquinoline sulphone amide derivative of exploitation, trade name Eril/ Yi Lilu.As one kind is novel, efficient blood vessel is tight
Medicine is opened, cerebral angiospasm can be effectively relieved in Fasudil, improve the prognosis of Subarachnoid Hemorrhage (SAH) patient.
Chinese patent CN1183782, CN103450157, CN102020635 etc. disclose Fasudic hydrochloride half and are hydrated
The preparation method of object.
The specific method of CN1183782 is that Fasudic hydrochloride anhydride is recrystallized with water, obtains Fasudic hydrochloride
Trihydrate, places 40 DEG C, under 75% damp condition, dry hydrochloride Fasudil hemihydrate.Drying process condition is opposite
It is harsh, it is not easy to realize in the industry.
The specific method of CN103450157 is that Fasudil adds hydrochloric acid hydrochloric acid method in the mixed solution of methanol-water
Relax ground you, filtering, filtrate is added tetrahydrofuran, acetone, glycol dimethyl ether etc., crystallization, filtering, dry Fasudic hydrochloride
Semihydrate.This method introduces more residual solvents, and operates also relatively cumbersome.
The specific method of CN102020635 is that Fasudil dissolves in methyl alcohol, adds hydrochloric acid hydrochloric acid Fasudil, subtracts
Pressure concentration, then ethyl alcohol, methanol, acetone, acetonitrile equal solvent are added into residue, crystallization filters, and it is dry, it obtains hydrochloric acid method and relaxes ground
That semihydrate.This method needs to be evaporated under reduced pressure before adding ethyl alcohol, and group becomes a small amount of methanol, Shao Liangshui, ethyl alcohol, salt after ethyl alcohol is added
Sour Fasudil.Vacuum distillation is related with vacuum degree, vacuum pump discharges amount, vapo(u)rizing temperature etc., and influence factor is more, vacuum distillation
There are more parameters for the quality index of residue.The composition ratio of solution concentration and solvent is variable, and yield, quality are also corresponding
It can change, technology stability is not easy to realize industrialization there are problem.
Using Fasudic hydrochloride anhydride, hydrochloride Fasudil hemihydrate is carried out with 70%~95% ethyl alcohol of concentration
Preparation, through retrieving, this method does not have document report mistake, without patent protection yet.
Summary of the invention
Problem to be solved by this invention is to find a kind of preparation method of hydrochloride Fasudil hemihydrate, simplifies behaviour
Make, and avoids current existing patent protection method.
To solve the above problems, selecting 70%~95% ethyl alcohol of concentration is recrystallisation solvent by experiment, and reflux dissolution, drop
Warm crystallization, filtering, air blast or vacuum drying obtain hydrochloride Fasudil hemihydrate, specifically includes the following steps:
Step 1: it is in 70%~95% ethyl alcohol that Fasudic hydrochloride anhydride is dissolved in concentration under reflux conditions；
Step 2: it is cooled to 0~5 DEG C, crystallization；
Step 3: dehydrated alcohol washs filter cake after filtering；
Step 4: 40~60 DEG C of forced air dryings or being dried under vacuum to constant weight.
The preparation method of a kind of hydrochloride Fasudil hemihydrate, it is characterized in that: Fasudic hydrochloride is anhydrous
Object: 70%~95% ethyl alcohol=1:2~5 (g/ml).
0%~95% ethanol consumption of solvent is under reflux conditions that hydrochloride Fasudil hemihydrate can be complete
It is molten to be advisable.
Hydrochloride Fasudil hemihydrate, simple process are prepared using present invention process, operation is easy.
The hydrochloride Fasudil hemihydrate prepared using present invention process has carried out moisture measurement, thermal weight loss point respectively
Analysis, powder X-ray diffraction analysis, as a result as follows:
1. moisture measurement.The sample (experimental method of embodiment 1) that the present invention obtains carries out water by Cattell aquametry
Divide test, moisture result is that the result (theoretical value 2.67%) in 2.77%, with sample containing half of crystallization water is consistent.
2. thermogravimetic analysis (TGA).The sample (experimental method of embodiment 1) that the present invention obtains is the results show that without mistake before 90 DEG C
Reconstructed image, 90~150 DEG C of weightlessness 2.88% are consistent with the result of half of crystallization water is contained in sample.See attached drawing 1.
In heat analysis, hydrochloride Fasudil hemihydrate shows endothermic peak, is the characteristic peak of semihydrate.See attached drawing 1.
3. powder X-ray diffraction is analyzed.
The hydrochloride Fasudil hemihydrate powder X-ray diffraction data (2 θ) that CN1183782 is provided are as follows: about 8.4,12.4,
14.0,16.2,16.8,18.2,19.5,22.4,25.6.The powder for the sample (experimental method of embodiment 1) that the present invention obtains
X- diffraction data (2 θ), and it is reported in the literature almost the same, meet the feature of semihydrate.See attached drawing 2.
Detailed description of the invention
Fig. 1 is the thermogravimetic analysis (TGA) figure for the hydrochloride Fasudil hemihydrate that embodiment 1 obtains；
Fig. 2 is the powder X-ray diffraction analysis chart for the hydrochloride Fasudil hemihydrate that embodiment 1 obtains.
Specific embodiment
By the specific embodiment of following embodiment form, above content of the invention is made further specifically
It is bright.For a person skilled in the art, the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to reality below
Example；The techniques implemented on the basis of the foregoing are all within the scope of the present invention.
Embodiment 1:
20g Fasudic hydrochloride, 40ml ethyl alcohol (75%) are put into clean reaction flask.It is warming up to reflux, is dissolved.Drop
Temperature is to 0~5 DEG C, and crystallization filters, and 10ml dehydrated alcohol washs filter cake.50 DEG C of forced air dryings obtain 17.8g product to constant weight.It receives
Rate: 89%；Moisture (Cattell): 2.77%.
Embodiment 2:
20g Fasudic hydrochloride, 100ml ethyl alcohol (95%) are put into clean reaction flask.It is warming up to reflux, is dissolved.
It is cooled to 0~5 DEG C, crystallization filters, and 10ml dehydrated alcohol washs filter cake.40 DEG C are dried under vacuum to constant weight, obtain 19.4g product.It receives
Rate: 97%；Moisture (Cattell): 2.72%.
Claims (2)
1. a kind of preparation method of hydrochloride Fasudil hemihydrate, it is characterized in that: specifically includes the following steps:
Step 1: it is in 70%~95% ethyl alcohol that Fasudic hydrochloride anhydride is dissolved in concentration under reflux conditions；
Step 2: it is cooled to 0~5 DEG C, crystallization；
Step 3: dehydrated alcohol washs filter cake after filtering；
Step 4: 40~60 DEG C of forced air dryings or being dried under vacuum to constant weight.
2. the preparation method of a kind of hydrochloride Fasudil hemihydrate according to claim 1, it is characterized in that: hydrochloric acid method
Relax ground that anhydride: 70%~95% ethyl alcohol=1:2~5 (g/ml).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910170677.2A CN109776497A (en) | 2019-03-07 | 2019-03-07 | A kind of preparation method of hydrochloride Fasudil hemihydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910170677.2A CN109776497A (en) | 2019-03-07 | 2019-03-07 | A kind of preparation method of hydrochloride Fasudil hemihydrate |
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| CN109776497A true CN109776497A (en) | 2019-05-21 |
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| CN201910170677.2A Pending CN109776497A (en) | 2019-03-07 | 2019-03-07 | A kind of preparation method of hydrochloride Fasudil hemihydrate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113968841A (en) * | 2020-07-23 | 2022-01-25 | 合肥久诺医药科技有限公司 | Preparation method of fasudil hydrochloride hemihydrate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5942505A (en) * | 1995-07-03 | 1999-08-24 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
| 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 |
| CN103450157A (en) * | 2013-08-28 | 2013-12-18 | 合肥久诺医药科技有限公司 | Preparation method for high-purity hydroxyfasudil semihydrate |
-
2019
- 2019-03-07 CN CN201910170677.2A patent/CN109776497A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5942505A (en) * | 1995-07-03 | 1999-08-24 | Asahi Kasei Kogyo Kabushiki Kaisha | 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hydrates |
| 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 |
| CN103450157A (en) * | 2013-08-28 | 2013-12-18 | 合肥久诺医药科技有限公司 | Preparation method for high-purity hydroxyfasudil semihydrate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113968841A (en) * | 2020-07-23 | 2022-01-25 | 合肥久诺医药科技有限公司 | Preparation method of fasudil hydrochloride hemihydrate |
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Application publication date: 20190521 |
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