CN1216035C - Method for preparing amantadine sulfate - Google Patents
Method for preparing amantadine sulfate Download PDFInfo
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- CN1216035C CN1216035C CN 200310106041 CN200310106041A CN1216035C CN 1216035 C CN1216035 C CN 1216035C CN 200310106041 CN200310106041 CN 200310106041 CN 200310106041 A CN200310106041 A CN 200310106041A CN 1216035 C CN1216035 C CN 1216035C
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- water
- sulfate
- described preparation
- contenton
- amantadine
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Abstract
The present invention discloses a novel method for preparing amantadine sulfate (I) used for treating influenza A. Amantadine hydrochloride is used as raw material and is dissolved in water or mixed solvent of water and polar organic solvent, sulfate solution is dripped during stirring to generate precipitates of amantadine sulfate, and the precipitates are filtered and dried to obtain the amantadine sulfate (I). The amantadine sulfate (I) prepared by the method has the advantages of favorable product quality, simple operation, high yield, low cost, no use of organic solvent, little environmental pollution, easy realization of industrialized production, etc.
Description
The preparation method of the medicine contenton (I) that technical field the present invention relates to.
Background technology contenton (I) is widely used in the dysthymia disorders due to treatment influenza A, Parkinson's disease and the borna disease virus.
Routinely, the method for preparing contenton is as follows: amantadine (2mol) is dissolved in appropriate solvent (as: ethanol) back and sulfuric acid (1mol) salify, wishes to obtain required contenton (I).Synthetic route is as follows:
Amantadine I
Because contenton is slightly soluble in water, be insoluble to most of organic solvents such as ethanol, therefore verify through ultimate analysis with the contenton (I) (1: 2) of method for preparing gained, the percentage composition of nitrogen element and the error of calculated value are more than 0.5%, analyze reason, may contain 1: 1 salt of part in the product with this method gained, i.e. C
10H
17NH
2SO
4
Summary of the invention the objective of the invention is to seek that a kind of synthesis technique is simple, the preparation method of the contenton (I) of constant product quality.
By analysis and grope, we utilize amantadine hydrochloride solubleness in water better, and the relatively poor characteristics of contenton solubleness in water directly are raw material with the amantadine hydrochloride, behind the mixed solvent of it is water-soluble or water and polar organic solvent, drip vitriol (as sodium sulfate) solution, preferably under agitation carry out, along with the dropping of sulfate liquor, the contenton of generation (I) is constantly separated out from reaction solution, suction filtration, the dry product that gets.Vitriol is example with sodium sulfate, and reaction formula is as follows:
Amantadine hydrochloride sodium sulfate sodium-chlor
One or more of above-mentioned vitriol preferably sulfuric acid sodium, vitriolate of tartar, Lithium Sulphate, sal epsom, calcium sulfate, Tai-Ace S 150, ammonium sulfate.
Above-mentioned vitriol is the preferred composite salt that forms of any two or more and the sulfuric acid in sodium, potassium, lithium, magnesium, calcium, aluminium and the ammonium ion also.
Above-mentioned sulfate liquor is water-soluble or water-soluble by vitriol and the solution of the mixed solution gained of polar organic solvent.
The preferred C of above-mentioned polar organic solvent
1～5Alcohol, acetone, DMF or DMSO.
The content range of water can be 0.1%～100% in the mixed solvent, is preferably 10～100%, is more preferably 50%～100%.
The used amount of amantadine hydrochloride is 1: 2～1 with the feed ratio that reacts total solvent: 500g/ml.Be more preferably 1: 5～1: 20g/ml.
The temperature that drips vitriol can be a room temperature, preferred 5～80 ℃, and further preferred 10～50 ℃.
Dripping sulfate liquor is to carry out under the condition that stirs amantadine hydrochloride solution.
Contenton (I) with the method for preparing gained, through the ultimate analysis checking, the percentage composition of its C, H and N element and the error of calculated value are all in 0.3%, record content greater than 99.0% with nonaqueous titrations, record related substance less than 0.5% with vapor-phase chromatography, this shows, prepare contenton with this law, good product quality, and have simple to operate, yield is high (general＞90%), cost is low, to advantages such as little, the easier realization suitability for industrialized production of the pollution of environment.
Utilize aforesaid method,, can make other insoluble salt of amantadine by changing the acid group of above-mentioned inorganic salt, as: carbonate, sulphite, phosphoric acid salt, phosphite etc.
Utilize aforesaid method, also can be with other water-soluble acid salt preferably, the solution by to the sour an alkali metal salt of the mixed solution and dripping another kind of its aqueous solution or water and some organic solvents changes into its water-soluble relatively poor another kind of acid salt.
Embodiment
Embodiment 1
Amantadine hydrochloride 84.5g (0.45mol) is dissolved in the 400ml distilled water, under stirring at room, drip metabisulfite solution (the 32g anhydrous sodium sulphate is dissolved in the 400ml distilled water), there are a large amount of white precipitates to separate out, drip and finish suction filtration, washing, dry white powder solid (I) 85.2g, yield 94.5%, mp:364.6 ℃ of getting, content 99.80%, related substance 0.007%.
Embodiment 2
Amantadine hydrochloride 84.5g (0.45mol) is dissolved in 200ml distilled water and the 200ml ethanol mixed solvent, stir and drip metabisulfite solution (the 32g anhydrous sodium sulphate is dissolved in the 300ml distilled water) down, there are a large amount of white precipitates to separate out, drip and finish, suction filtration, washing, dry white powder solid (I) 86.3g that gets, yield 95.7%, content 99.56%, related substance 0.012%.
Embodiment 3
Amantadine hydrochloride 37.5g (0.2mol) is dissolved in the 200ml distilled water, stir the mixing solutions (7.1g anhydrous sodium sulphate and 8.7g anhydrous potassium sulfate are dissolved in the 150ml distilled water) that drips sodium sulfate and vitriolate of tartar down, there are a large amount of white precipitates to separate out, drip and finish suction filtration, washing, dry white powder solid (I) 37.2g, yield 92.8%, mp:363.8 ℃ of getting, content 99.63%, related substance 0.016%.
Embodiment 4
(a) the sulfuric acid composite salt (as; Potassium sodium sulfate) preparation (annotate: also available other method of sulfuric acid composite salt obtains)
Get sodium sulfate at random and vitriolate of tartar is an amount of, after being dissolved in water, evaporation moisture content, dry potassium sodium sulfate composite salt.Record with the barium sulfate precipitate method and to contain 0.6205g sulfate ion (SO in the above-mentioned composite salt of every gram
4 2-).
(b) amantadine hydrochloride 37.5g (0.2mol) is dissolved in the 200ml distilled water, stir and drip potassium sodium sulfate solution (the 15.47g potassium sodium sulfate is dissolved in the 120ml distilled water) down, there are a large amount of white precipitates to separate out, drip and finish, suction filtration, washing, dry white powder solid (I) 36.4g that gets, yield 90.8%, content 99.48%, related substance 0.009%.
Embodiment 5
Amantadine hydrochloride 8.45g (0.045mol) is dissolved in 200ml distilled water and the 400ml ethanol mixed solvent, under stirring at room, drip metabisulfite solution (the 3.2g anhydrous sodium sulphate is dissolved in the 250ml distilled water), separate out white precipitate, drip and finish, suction filtration, washing, dry white powder solid (I) 7.8g that gets, yield 86.5%, content 99.68%, related substance 0.006%.
Embodiment 6
Amantadine hydrochloride 18.8g (0.1mol) is dissolved in the 200ml distilled water, stirs down and drip sodium carbonate solution (5.3g yellow soda ash is dissolved in the 100ml distilled water), separate out precipitation, drip and finish, cooling, suction filtration, washing, dry white powder crystal (carbonic acid amantadine) 17g, the yield 93.4% of getting.
Claims (8)
1, the preparation method of contenton (I):
In the mixed solvent of amantadine hydrochloride is water-soluble or water and polar organic solvent, drip sulfate liquor under when temperature is 10～50 ℃, stirring, generate contenton (I), suction filtration, dry contenton (I).
2, the described preparation method of claim 1, vitriol wherein is selected from one or more of sodium sulfate, vitriolate of tartar, Lithium Sulphate, sal epsom, calcium sulfate, Tai-Ace S 150, ammonium sulfate.
3. the described preparation method of claim 1, wherein vitriol is the composite salt that any two or more and sulfuric acid in sodium, potassium, lithium, magnesium, calcium, aluminium and the ammonium ion form.
4. the described preparation method of claim 1, wherein sulfate liquor is water-soluble or water-soluble by vitriol and the solution of the mixed solution gained of polar organic solvent.
5. claim 1 or 4 described preparation methods, wherein polar organic solvent is C
1～5Alcohol, acetone, N, dinethylformamide or methyl-sulphoxide.
6. the described preparation method of claim 1, wherein the content range of water is 50%～100% in the mixed solvent.
7. the described preparation method of claim 1, wherein the used amount of amantadine hydrochloride is 1: 2～1 with the feed ratio of reaction total solvent: 500g/ml.
8. the described preparation method of claim 7, wherein amantadine hydrochloride is 1: 5～1 with the feed ratio of reaction total solvent: 20g/ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310106041 CN1216035C (en) | 2003-10-10 | 2003-10-10 | Method for preparing amantadine sulfate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310106041 CN1216035C (en) | 2003-10-10 | 2003-10-10 | Method for preparing amantadine sulfate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1528736A CN1528736A (en) | 2004-09-15 |
| CN1216035C true CN1216035C (en) | 2005-08-24 |
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| CN 200310106041 Expired - Fee Related CN1216035C (en) | 2003-10-10 | 2003-10-10 | Method for preparing amantadine sulfate |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100351225C (en) * | 2004-10-28 | 2007-11-28 | 中国医学科学院医药生物技术研究所 | Symmetrel derivatives and synthesis method thereof and their use as neuron damage protective agent |
| CN102174116B (en) * | 2011-03-24 | 2013-03-20 | 华南理工大学 | 1-amantadine hydrochloride carboxylic acid cellulose ester and method for preparing same |
| CN108152422A (en) * | 2018-01-30 | 2018-06-12 | 上海信谊万象药业股份有限公司 | The analysis method that drug content measures in a kind of amantadine hydrochloride solid pharmaceutical preparation |
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2003
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