CN101200451B - Method for preparing hydrochloride urapidil - Google Patents
Method for preparing hydrochloride urapidil Download PDFInfo
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- CN101200451B CN101200451B CN2006100952984A CN200610095298A CN101200451B CN 101200451 B CN101200451 B CN 101200451B CN 2006100952984 A CN2006100952984 A CN 2006100952984A CN 200610095298 A CN200610095298 A CN 200610095298A CN 101200451 B CN101200451 B CN 101200451B
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Abstract
The invention relates to a preparation method of the urapidil hydrochloride. The method comprises the following procedures, the urapidil is dissolved in the alcohols or/and the ketones solvent, the organic solution of the hydrogen chloride is slowly added after the heating dissolution for controlling pH at the range of 2.0 to 4.0, then the mixture is crystallized by decreasing the temperature into the range of 20 to 70 DEG C, and the urapidil hydrochloride is filtrated and dried by the decompression drying. The content is not lower than 99.5 percent, the clarity and the pH meet the purity requirement of the raw material used in the injection. The invention has the advantages of simple method, stable quality, easy operation and being suitable for the industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of Urapidil hydrochloride.
Background technology
The chemical name of Urapidil hydrochloride be 6-[[3-[4-(the 2-anisole is taken out-the 1-piperazinyl] propyl group] amino]-1,3-dimethyl-2,4 (1H, 3H) pyrimidine dione hydrochloride, English name are Urapidil Hydrochloride, and English chemical name is 6-[[3-[4-(2-Methoxyphenyl)-1-piperazinyl] propyl] amino]-1,3-dimethyl-2,4 (1H, 3H)-pyrimi dinedione Hydrochloride, its chemical structural formula:
The Urapidil hydrochloride commodity are called erbanin, Urapidil Hydrochloride (Ebrantil), sharp happiness is decided, and is the uridylic that benzene azoles piperazine replaces, and this product has periphery and the dual hypotensive effect of maincenter.Periphery is mainly blocked postsynaptic α 1 acceptor, distends the blood vessels significantly to reduce Peripheral resistance.More weak presynaptic α 2 retardations are also arranged, the vasoconstriction effect (peripheral action that is different from Prazosin) of blocking-up catecholamine simultaneously; Mainly (HTla) acceptor reduces the sympathetic feedback regulation of oblongata cardiovascular center and step-down (central action that is different from clonidine) by exciting serotonin-1A to central action for it.In the hypotensive while, this product generally can not cause reflex tachycardia.In clinical open research, can reduce systolic pressure and diastolic pressure 3.1% and 2.1% respectively during individual event anesthesia, the hypertensive patient is reduced to 12% and 6.7% respectively.This medicine is remarkable to the essential hypertension effect.And the normotensive is not had antihypertensive effect.During spinal anesthesia, can reduce about 32%, the diastolic pressure 27% of systolic pressure significantly.In the patient of cardiac insufficiency, use urapidil and can reduce oxygen consumption of myocardium, reduce lung wedge pressure and Peripheral resistance, improve left ventricular function, increase cardiac output.
In existing production technology, the source of Urapidil hydrochloride is mainly dissolved under solvent system by urapidil, feed hydrochloric acid gas salify, crystallization gained, and there are notable difference in Urapidil hydrochloride and urapidil aspect solubility property, the example hydrochloric acid urapidil is easily molten in water, slightly soluble in ethanol or chloroform, (China national drug standard WS1-(X-116)-2003Z) almost insoluble in ether, urapidil is in hot ethanol, chloroform, benzene, acetone, chloroform and dithiocarbonic anhydride dissolving, be slightly soluble in petroleum hydrocarbon, almost insoluble in water.Therefore, aspect pharmacology, Urapidil hydrochloride is water-soluble stronger than urapidil, is easier to be absorbed by the body, and has increased the drug effect of urapidil significantly.Since Urapidil hydrochloride in water easily molten and in organic solvent (as ethanol) slightly soluble, urapidil is insoluble and at a certain temperature and dissolving in the organic solvent (as hot ethanol), make with extra care purification so Urapidil hydrochloride is very difficult by the method for recrystallization in water.At disclosed document, " the urapidil powder injection and preparation method thereof " Chinese patent (CN200310117368.8) of Guangdong Qifang Pharmaceutical Co., Ltd.'s application is arranged; " urapidil high-capacity injection, its preparation method and application thereof " Chinese patent (CN 200410049988.7) of Yang Lixin application is the preparation method of injecting drug use.Simultaneously, clinically, the formulation that has obtained registration in China has Xi'an Lijun pharmaceutical Co., Ltd and SHANDONG LUOXIN PHARMACY STOCK Co., LTD. etc. to produce Urapidil hydrochloride injection liquid and hydrochloride for injection urapidil, be injecting drug use, the security of medication is extremely important, so the purity of Urapidil hydrochloride is most important.Because the preparation of Urapidil hydrochloride is mainly injection.In order to control the remaining quantity of urapidil in the Urapidil hydrochloride finished product effectively, therefore adopt a suitable preparation technology, it is extremely important once to prepare qualified Urapidil hydrochloride.
Because in the prior art, the preparation of Urapidil hydrochloride is dissolved under solvent system by urapidil and is fed hydrochloric acid gas salify, crystallization gained, and in this preparation process, the pH of product is wayward, misoperation is arranged slightly, can cause the index such as content, pH, clarity of product defective.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of high-purity hydrochloric acid urapidil, to satisfy the purity requirement of injection bulk drug.
The objective of the invention is to realize that by such technical scheme promptly a kind of preparation method of Urapidil hydrochloride comprises the steps:
Urapidil is dissolved in alcohols or/and in the ketones solvent, after heating for dissolving is complete, slowly drip the organic solution of hydrogenchloride, and control pH value slowly is cooled to 20 ℃～70 ℃ crystallizatioies in 2.0～4.0 scopes, filter, and drying under reduced pressure promptly gets Urapidil hydrochloride.
In the above-mentioned technology, the control of pH is key of the present invention in the reaction process, can adopt the control of accurate pH test paper or pH meter.In the time of in the scope of pH value at 2.0-4.0 when reaction, the pH value of finished product Urapidil hydrochloride fluctuates in the scope of 4.0-6.0, conforms to quality requirements.The pH value of finished product directly influences the clarity of product, if pH control is careless slightly, then the clarity of Urapidil hydrochloride is much larger than No. 2 standard turbidity solutions.
The organic solution of described hydrogenchloride, its organic solvent are that alcohols is or/and ketones solvent.Described alcoholic solvent comprises methyl alcohol, ethanol, Virahol and butanols; Described ketones solvent comprises acetone, butanone, methyl iso-butyl ketone (MIBK).
Because Urapidil hydrochloride is insoluble to some organic solvent (as methyl alcohol, ethanol, Virahol, butanols, acetone etc.), in entire reaction course, very easily separate out white hydrochloride urapidil solid, if expect that it is 20 ℃～70 ℃ that the Urapidil hydrochloride crystal is then controlled recrystallization temperature.
The Urapidil hydrochloride that aforesaid method obtains, adopt the method for China national drug standard WS-(X-116)-2003Z to measure, its purity can reach more than 99.5%, and related substance is not higher than 0.02%, clarity＜No. 2 standard turbidity solution can reach the purity requirement of injection bulk drug.
In the present invention, urapidil is commercially available, as the product of the triumphant peaking worker in Shanghai company limited production.The Urapidil hydrochloride reference substance derives from the drug inspection reference material that Sigma company provides.
Compared with prior art, the present invention adopts the organic solution that drips hydrogenchloride to replace directly feeding hydrogen chloride gas, it is advantageous that and can control reaction pH value more effectively and accurately.In addition, control suitable recrystallization temperature, can effectively suppress separating out of urapidil, the clarity that has guaranteed Urapidil hydrochloride can reach the purity requirement of injection bulk drug less than No. 2 standard turbidity solutions.The inventive method is easy, steady quality, and easy handling is suitable for industrialized production.
Description of drawings
Fig. 1 is the HPLC collection of illustrative plates of urapidil related substance
Fig. 2 is the HPLC collection of illustrative plates of embodiment 1 gained Urapidil hydrochloride related substance
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
In being furnished with the 250mL there-necked flask of reflux exchanger, add the 160ml dehydrated alcohol, 8.1g urapidil highly finished product, be heated to 90 ℃ under stirring, the ethanolic soln (feeding gained in the alcohol solvent by hydrogen chloride gas) that drips hydrogenchloride makes pH value of solution adopt accurate pH test paper to be controlled at about 3-4, continued stirring and insulation reaction 30 minutes, system still is the solution of clear, slowly be cooled to about 40 ℃ then, constant temperature crystallization 1 hour, heat filtering, filter cake with a small amount of absolute ethanol washing once, suction filtration.Filter cake decompression,＜60 ℃ of conditions under dry 2 hours, white crystalline Urapidil hydrochloride 6.6g, yield 75.4%, total recovery 61.1% (theoretical value 10.9g) is 100.5% in dry product content, and related substance is 0.02%, pH=4.76, clarity＜No. 2 standard turbidity solution.
In being furnished with the 250mL there-necked flask of reflux exchanger, add the 160ml dehydrated alcohol, 8.1g urapidil highly finished product, be heated to 80 ℃ under stirring, the ethanolic soln (feeding gained in the alcohol solvent by hydrogen chloride gas) that drips hydrogenchloride makes pH value of solution adopt accurate pH test paper to be controlled at 2-3, continued stirring and insulation reaction 30 minutes, system still is the solution of clear, slowly be cooled to about 70 ℃ then, add an amount of Urapidil hydrochloride crystal seed, constant temperature crystallization 1 hour, heat filtering, filter cake with a small amount of absolute ethanol washing once, suction filtration.Filter cake decompression,＜60 ℃ of conditions under dry 2 hours, white crystalline Urapidil hydrochloride 4.1g, yield 37.6% is 101.0% in dry product content, related substance is 0.05%, pH=4.39, clarity＜No. 2 standard turbidity solution.
In being furnished with the 250mL there-necked flask of reflux exchanger, add the 160ml dehydrated alcohol, 8.1g urapidil highly finished product, be heated to 60 ℃ under stirring, the ethanolic soln (feeding gained in the alcohol solvent by hydrogen chloride gas) that drips hydrogenchloride makes pH value of solution adopt accurate pH test paper to be controlled at about 3-4, continued stirring and insulation reaction 30 minutes, system still is the solution of clear, slowly be cooled to about 40 ℃ then, add a spot of Urapidil hydrochloride crystal seed, constant temperature crystallization 1 hour, heat filtering, filter cake with a small amount of absolute ethanol washing once, suction filtration.Filter cake decompression,＜60 ℃ of conditions under dry 2 hours, white crystalline Urapidil hydrochloride 7.7g, yield 70.6% is 99.9% in dry product content, related substance is 0.02%, pH=5.12, clarity＜No. 2 standard turbidity solution.
In being furnished with the 250mL there-necked flask of reflux exchanger, add the 160ml dehydrated alcohol, 8.1g urapidil highly finished product, be heated to 40 ℃ under stirring, the aqueous isopropanol (feeding gained in the isopropanol solvent by hydrogen chloride gas) that drips hydrogenchloride makes solution PH adopt accurate pH test paper to be controlled at about 2-3, continued stirring and insulation reaction 30 minutes, system still is the solution of clear, slowly be cooled to about 20 ℃ then, constant temperature crystallization 1 hour, heat filtering, filter cake with a small amount of absolute ethanol washing once, suction filtration.Filter cake decompression,＜60 ℃ of conditions under dry 2 hours, white crystalline Urapidil hydrochloride 6.9g, total recovery 63.3% is 99.5% in dry product content, related substance is 0.03%, pH=4.87, clarity＜No. 2 standard turbidity solution.
In being furnished with the 250mL there-necked flask of reflux exchanger, add 160ml acetone, 8.1g urapidil highly finished product, be heated to 60 ℃ under stirring, the acetone soln (feeding gained in the acetone solvent by hydrogen chloride gas) that drips hydrogenchloride makes pH value of solution adopt accurate pH test paper to be controlled at about 3-4, continued stirring and insulation reaction 30 minutes, system still is the solution of clear, slowly be cooled to about 40 ℃ then, add a spot of Urapidil hydrochloride crystal seed, constant temperature crystallization 1 hour, heat filtering, filter cake with a small amount of absolute ethanol washing once, suction filtration.Filter cake decompression,＜60 ℃ of conditions under dry 2 hours, white crystalline Urapidil hydrochloride 6.4g, total recovery 58.7% is 100.6% in dry product content, related substance is 0.04%, pH=4.75, clarity＜No. 2 standard turbidity solution.
Embodiment 6
In being furnished with the 250mL there-necked flask of reflux exchanger, add 160ml methyl alcohol, 8.1g urapidil highly finished product, be heated to 60 ℃ under stirring, the methanol solution (feeding gained in the methanol solvate by hydrogen chloride gas) that drips hydrogenchloride makes pH value of solution adopt accurate pH test paper to be controlled at about 3-4, continued stirring and insulation reaction 30 minutes, system still is the solution of clear, slowly be cooled to about 40 ℃ then, add a spot of Urapidil hydrochloride crystal seed, constant temperature crystallization 1 hour, heat filtering, filter cake with a small amount of absolute ethanol washing once, suction filtration.Filter cake decompression,＜60 ℃ of conditions under dry 2 hours, white crystalline Urapidil hydrochloride 6.7g, total recovery 61.5% is 99.8% in dry product content, related substance is 0.06%, pH=4.69, clarity＜No. 2 standard turbidity solution.
The comparative example 1
In the 500ml reaction flask, (content is 95.4% to add Urapidil hydrochloride crude product 10.0g, pH=2.91, clarity〉No. 2 standard turbidity solutions), be suspended in the 400ml ethanol, fully stir into suspension liquid, warming-in-water stirs 30min to 75-85 ℃ of backflow constant temperature, and heat filtering, filter cake place＜and 60 ℃ drying under reduced pressure case carries out vacuum-drying 2h, promptly get Urapidil hydrochloride sample 8.8g, yield 88.0% is 97.4% in dry product content, and related substance is 0.03%, pH=3.42, clarity〉No. 2 standard turbidity solutions.
The comparative example 2
In the 50ml reaction flask, (content is 95.4% to add the urapidil crude product 20.0g that feels sad, pH=91, clarity〉No. 2 standard turbidity solutions), be dissolved in the 10ml deionized water, fully stir and be warming up to 50 ℃, slowly be cooled to normal temperature after, place the cold compartment of refrigerator crystallization that spends the night, filter, filter cake places＜and 60 ℃ drying under reduced pressure case carries out vacuum-drying 5h, promptly gets Urapidil hydrochloride sample 7.8g, yield 39.0%, in dry product content is 98.5%, related substance is 0.07%, pH=3.87, clarity〉No. 2 standard turbidity solutions.
Brief summary:
Because Urapidil hydrochloride is soluble in water, is insoluble to some organic solvent (as methyl alcohol, ethanol, Virahol, butanols, acetone etc.); Urapidil is soluble in some organic solvent (as methyl alcohol, ethanol, Virahol, butanols, acetone etc.), and is water insoluble.Therefore Urapidil hydrochloride is not easy to be made with extra care by general purifying techniques such as recrystallizations, Urapidil hydrochloride quality after it is refining can not reach China national drug standard WS-(X-116)-2003Z requirement, clarity wherein particularly〉No. 2 standard turbidity solutions, quality can not satisfy the purity requirement (referring to comparative example 1,2) of injecting drug use.
Claims (1)
1. the preparation method of a Urapidil hydrochloride is characterized in that: comprise the steps:
Urapidil is dissolved in alcohols or/and in the ketones solvent, after heating for dissolving is complete, slowly drip the organic solution of hydrogenchloride, and control pH value slowly is cooled to 20 ℃ of-70 ℃ of crystallizatioies in the 2.0-4.0 scope, filter, and drying under reduced pressure promptly gets Urapidil hydrochloride; The organic solvent of the organic solution of described hydrogenchloride is an alcohols or/and ketone, and described alcoholic solvent is selected from methyl alcohol, ethanol, Virahol or butanols; Described ketones solvent is selected from acetone, butanone or mibk.
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| CN2006100952984A CN101200451B (en) | 2006-12-15 | 2006-12-15 | Method for preparing hydrochloride urapidil |
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| CN2006100952984A CN101200451B (en) | 2006-12-15 | 2006-12-15 | Method for preparing hydrochloride urapidil |
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| CN101200451B true CN101200451B (en) | 2010-12-15 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102295607B (en) * | 2011-06-16 | 2013-04-17 | 郑州大学 | Inverse phase transfer catalysis preparation method for urapidil |
| CN105111152A (en) * | 2015-09-24 | 2015-12-02 | 青岛华之草医药科技有限公司 | Anti-hypertension urapidil medicine compound |
| CN111116491A (en) * | 2018-11-01 | 2020-05-08 | 罗欣药业(上海)有限公司 | Urapidil hydrochloride crystal form and preparation method thereof |
| CN109516960B (en) * | 2018-12-26 | 2021-07-02 | 河北一品制药股份有限公司 | Preparation method of urapidil hydrochloride |
| CN114685380A (en) * | 2020-12-25 | 2022-07-01 | 燃点(南京)生物医药科技有限公司 | Novel crystal form A of urapidil hydrochloride and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957786A (en) * | 1969-08-20 | 1976-05-18 | Byk Gulden | Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production |
| DE4130918A1 (en) * | 1991-09-17 | 1993-03-18 | Juergen Dr Huhnt | Alpha-sympatholytic and beta-sympathomimetic contg. solns. - for injection after dental anaesthesia to relieve vasoconstriction and reduce anaesthetic effect |
| CN1626086A (en) * | 2003-12-12 | 2005-06-15 | 广东奇方药业有限公司 | Urapidil powder and injection preparation and preparing method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3957786A (en) * | 1969-08-20 | 1976-05-18 | Byk Gulden | Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production |
| DE4130918A1 (en) * | 1991-09-17 | 1993-03-18 | Juergen Dr Huhnt | Alpha-sympatholytic and beta-sympathomimetic contg. solns. - for injection after dental anaesthesia to relieve vasoconstriction and reduce anaesthetic effect |
| CN1626086A (en) * | 2003-12-12 | 2005-06-15 | 广东奇方药业有限公司 | Urapidil powder and injection preparation and preparing method |
Non-Patent Citations (1)
| Title |
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| column8,line14-24 和column23,line60-63. |
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