CN101885697A - Preparation method of Oxiracetam, product of Oxiracetam and use of product - Google Patents
Preparation method of Oxiracetam, product of Oxiracetam and use of product Download PDFInfo
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- CN101885697A CN101885697A CN2009100688769A CN200910068876A CN101885697A CN 101885697 A CN101885697 A CN 101885697A CN 2009100688769 A CN2009100688769 A CN 2009100688769A CN 200910068876 A CN200910068876 A CN 200910068876A CN 101885697 A CN101885697 A CN 101885697A
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Abstract
The invention provides a method for preparing Oxiracetam, which comprises the following steps: performing alkaline treatment of 4-hydroxy-2-pyrrolidone under a water-free condition; reacting the treated 4-hydroxy-2-pyrrolidone with 2-chloroacetamide in an organic solvent in the presence of a catalyst; and after the reaction is finished, performing filtration, distillation and recrystallization to obtain the Oxiracetam. In the method, the final product can be obtained by a one-step reaction, the operation is simple and convenient, and large scale production can be realized. The invention also provides the Oxiracetam obtained by the method, which has the characteristics of high yield, high purity and good treatment effect. The invention also provides the use of the Oxiracetam obtained by the method in the preparation of medicaments for treating brain dysfunction, impaired memory and senile dementia.
Description
Technical field
The present invention relates to the medical chemistry field, the product that particularly, the present invention relates to a kind of method for preparing oxiracetam, obtains by this method and the purposes of this product.
Background technology
Oxiracetam (Oxiracetam), its chemistry 4-hydroxyl-pyrrolidin-2-one by name-1-yl acetamide, chemical structural formula be as the formula (1):
This product pharmaceutically is being used as the brain function activator.1984, by the exploitation listing of Italian ISF company, 1977 synthetic first, referring to U.S.4118396.
Up to now, the synthetic route and the preparation method that report this product are more, some exists, and reactions steps is many, loaded down with trivial details, the intermediate purity difference of operation, some must be with behind the method purifying of chromatography eluant, just can carry out next step reaction, be not suitable for commercial scale production, oxiracetam (Oxiracetam) synthetic route of wherein being put down in writing in the prior art is as follows:
Particularly, see also US 1978,4118396 (DE, 1977,2635853), EP 1985,154490, piffer:C et al.Farmaco Ed Sci, 1977,32:602, DE 1978,2758937, ibid 1978,2759033, EP 1987,224256, ibid 1987,216325, day disclosure special permission 87-72661, EP1985,156655, day disclosure special permission 87-26267, EP 1987,223328, day disclosure special permission 91-181458, ibid 1987,286964, ES 1985,537842, day disclosure special permission 88-132872 and EP 1987,249018.
In the past reactions steps is many, impurity is many in order to overcome, need the separating for several times purifying, complex operation, many shortcomings that cost is high, the invention provides a kind of new method for preparing oxiracetam, this method adopts single step reaction can obtain final product, oxiracetam.
Summary of the invention
One object of the present invention is, a kind of new method for preparing oxiracetam is provided, and adopting 4-hydroxyl-2-Pyrrolidone is starting raw material, reacts direct synthesizing oxiracetam with the 2-Haloacetamide.
Another object of the present invention is, the oxiracetam that is obtained by method for preparing is provided.
Another purpose of the present invention is, the purposes of the oxiracetam that is obtained by method for preparing is provided.
On the one hand, the invention provides the preparation method of the oxiracetam shown in a kind of formula (1), this method comprises reacts the 2-Haloacetamide shown in 4-hydroxyl-2-Pyrrolidone shown in the formula (2) and the formula (3), obtain the oxiracetam shown in the formula (1), the reaction formula of described reaction is as follows:
Wherein, the X in the formula (3) is a halogen atom, is preferably chlorine or bromine;
Preferably, the 2-Haloacetamide shown in the described formula (3) is 2-monofluoroacetamide, 2-chlor(o)acetamide, 2-bromoacetamide, 2-iodo-acid amide, or its mixture, more preferably 2-chlor(o)acetamide and/or 2-bromoacetamide.
4-hydroxyl-2-Pyrrolidone shown in its Chinese style (2) is available from Nanjing Chemlin chemical industry company limited and Shanghai rapid development chemical industry company limited, and the 2-Haloacetamide shown in the formula (3) steps female chemical industry company limited available from Shanghai.
Preferably, the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the no more than formula of molar weight (2) of the 2-Haloacetamide shown in the described formula (3), for example, the molar weight of the 2-Haloacetamide shown in the described formula (3) equates with the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the formula (2).
Preferably, described method is carried out alkaline purification to the 4-hydroxyl-2-Pyrrolidone shown in the formula (2) before also being included in reaction, the material that described alkaline purification is used is selected from potassium hydride KH, sodium hydride, sodium amide, n-Butyl Lithium, tert-butyl lithium, diethylin lithium, alkoxide and composition thereof, be preferably alkoxide, because their prices are low, combustibility is little, more preferably sodium methylate and/or sodium ethylate.
Preferably, the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the no more than formula of the molar weight of described alkaline purification materials used (2), for example, the molar weight of this material equates with the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the formula (2), if excessive meeting causes side reaction.
Preferably, described alkaline purification is carried out in anhydrous system, because the existence of water can cause side reaction.
Preferably, described being reflected in the organic solvent carried out, and when described method comprised alkali treatment, described alkaline purification was also carried out in organic solvent; Described organic solvent is selected from benzene-like compounds: for example, and benzene,toluene,xylene; Hydrocarbon derivative: for example chloroform, methylene dichloride, ethylene dichloride; Non-protonic solvent: for example, N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO); Ester compound: for example ethyl acetate, butylacetate; Ether compound: for example, tetrahydrofuran (THF), 1,4-dioxane, 1,2-glycol dimethyl ether, diglyme, triglyme, single ethyl ether; Ketone compounds: for example, acetone, methylethylketone, methyl iso-butyl ketone (MIBK); Nitrile compounds, for example, acetonitrile; Cyanides, for example, second cyanogen; Alcohol compound, for example, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ethylene glycol; And composition thereof, be preferably non-protonic solvent, for example, dimethyl sulfoxide (DMSO) (DMSO) and/or N, dinethylformamide (DMF); Further preferably, employed organic solvent was identical during described reaction neutralization bases was handled.
Preferably, described method also comprise to the reaction in add catalyzer, described catalyzer is selected from Tetrabutyl amonium bromide (TBAB), benzyltriethylammoinium chloride (TEBA), tri-n-octyl methyl ammonium chloride, 4-butyl ammonium hydrogen sulfate, ethylenediamine tetraacetic acid (EDTA) (EDTA) and composition thereof, it adds molar weight and two kinds of reactants: the molar ratio with the molar weight sum 2-Haloacetamide shown in the formula (3) the 4-hydroxyl-2-Pyrrolidone shown in the formula (2) is 1: 100-1: 1, be preferably 1: 40-1: 20.
Preferably, the temperature of reaction of described method is 0-150 ℃, is preferably 20-100 ℃, more preferably 30-80 ℃.
On the other hand, the invention provides oxiracetam by method for preparing.
Another aspect the invention provides the application in oxiracetam by method for preparing is used for the treatment of encephalopathy such as brain function deficiency, memory disorder and senile dementia in preparation the medicine.
Compared with prior art, advantage of the present invention is:
Method of the present invention has been simplified reactions steps, and raw material is easy to get, and is simple to operate, and cost is low, the product yield height, and quality is good, is adapted to scale operation.
Embodiment
Followingly the present invention is described with reference to specific embodiment.It will be appreciated by those skilled in the art that these embodiment only are used to illustrate purpose of the present invention, the scope that it does not limit the present invention in any way.
Embodiment 1
In being furnished with the 500ml four-hole boiling flask of stirring, thermometer, reflux exchanger and drying tube, add methyl alcohol 90ml, gradation slowly adds sodium Metal 99.5 9.4g, after the stirring at room dissolving, adds 4-hydroxyl-2-Pyrrolidone of 40.4g (0.4mol), is heated to backflow.Stirring and refluxing 1h steams and removes methyl alcohol, adds the dry toluene of 100ml, continues distillation, treats that toluene steams to the greatest extent, is chilled to room temperature.The dimethyl sulfoxide (DMSO) that adds 100ml, the benzyltriethylammoinium chloride of 4.6g, 0.02mol (TEBA) is in 30 ℃ of 2-chlor(o)acetamides that drip 41.2g, 0.4mol down, make in its dimethyl sulphoxide solution that is dissolved in 200ml, after waiting to dropwise, be warming up to 80 ℃, reaction 2h.After question response finishes, filter, filtrate decompression is steamed and is desolventized, and with 100ml residue Virahol recrystallization, gets the 18.5g white crystals.Through YRT-3 fusing point instrument (Precision Instrument Factory, Tianjin Univ.) test, m.p.166～169 ℃.Therefore as can be known, the white crystals that obtains is an oxiracetam, and yield is 58.5%.
Embodiment 2
In being furnished with the 500ml four-hole boiling flask of stirring, thermometer, reflux exchanger and drying tube, add methyl alcohol 90ml, gradation slowly adds sodium Metal 99.5 9.4g, after the stirring at room dissolving, adds 4-hydroxyl-2-Pyrrolidone of 40.4g (0.4mol), is heated to backflow.Stirring and refluxing 1h steams and removes methyl alcohol, adds the 100ml dry toluene, continues distillation, treats that toluene steams to the greatest extent, is chilled to room temperature.The N that adds 100ml, dinethylformamide, the benzyltriethylammoinium chloride of 4.6g, 0.02mol (TEBA), in the 2-bromoacetamide of 30 ℃ of following Dropwise 5 5.2g, 0.4mol, make its N that is dissolved in 200ml, in the solution of dinethylformamide, after waiting to dropwise, be warming up to 80 ℃, reaction 2h.After question response finishes, filter, filtrate decompression is steamed and is desolventized, and residue gets the 18g white crystals with 100ml Virahol recrystallization.Through YRT-3 fusing point instrument (Precision Instrument Factory, Tianjin Univ.) test, m.p.166～169 ℃.Therefore as can be known, the white crystals that obtains is an oxiracetam, and yield is 57%.
Embodiment 3
In being furnished with the 500ml four-hole boiling flask of stirring, thermometer, reflux exchanger and drying tube, add methyl alcohol 90ml, gradation slowly adds sodium Metal 99.5 9.4g, after the stirring at room dissolving, adds 4-hydroxyl-2-Pyrrolidone of 40.4g (0.4mol), is heated to backflow., stirring and refluxing 1h steams and removes methyl alcohol, adds dry toluene (100ml), continues distillation, treats that toluene steams to the greatest extent, is chilled to room temperature.Add the 100ml dry toluene, the Tetrabutyl amonium bromide of 6.4g, 0.02mol (TBAB) drips 41.2g, 0.4mol 2-chlor(o)acetamide down in 50 ℃, makes in its solution that is dissolved in 200ml toluene, after waiting to dropwise, is warming up to 100 ℃, reaction 2h.After question response finishes, filter, filtrate decompression is steamed and is desolventized, and residue gets the 13g white crystals with 100ml Virahol recrystallization.Through YRT-3 fusing point instrument (Precision Instrument Factory, Tianjin Univ.) test, m.p.166～169 ℃.Therefore as can be known, the white crystals that obtains is an oxiracetam, and yield is 41%.
Claims (10)
1. the preparation method of the oxiracetam shown in the formula (1), it is characterized in that, this method comprises reacts the 2-Haloacetamide shown in 4-hydroxyl-2-Pyrrolidone shown in the formula (2) and the formula (3), obtains the oxiracetam shown in the formula (1), and the reaction formula of described reaction is as follows:
Wherein, the X in the formula (3) is preferably chlorine or bromine for being selected from halogen atom;
Preferably, the 2-Haloacetamide shown in the described formula (3) is 2-monofluoroacetamide, 2-chlor(o)acetamide, 2-bromoacetamide, 2-iodo-acid amide or its mixture, more preferably 2-chlor(o)acetamide and/or 2-bromoacetamide.
2. method according to claim 1, it is characterized in that, the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the no more than formula of molar weight (2) of the 2-Haloacetamide shown in the described formula (3), preferably, the molar weight of the 2-Haloacetamide shown in the described formula (3) equates with the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the formula (2).
3. method according to claim 1 and 2, it is characterized in that, described method is carried out alkaline purification to the 4-hydroxyl-2-Pyrrolidone shown in the formula (2) before also being included in reaction, the material that described alkaline purification is used is selected from potassium hydride KH, sodium hydride, sodium amide, n-Butyl Lithium, tert-butyl lithium, diethylin lithium, alkoxide and composition thereof, be preferably alkoxide, more preferably sodium methylate and/or sodium ethylate.
4. method according to claim 3, it is characterized in that, the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the no more than formula of the molar weight of described alkaline purification materials used (2), preferably, the molar weight of this material equates with the molar weight of the 4-hydroxyl-2-Pyrrolidone shown in the formula (2).
5. according to claim 3 or 4 described methods, it is characterized in that described alkaline purification is carried out in anhydrous system.
6. according to each described method among the claim 1-5, it is characterized in that described being reflected in the organic solvent carried out, when described method comprised alkali treatment, described alkaline purification was also carried out in organic solvent; Described organic solvent is selected from: benzene,toluene,xylene, chloroform, methylene dichloride, ethylene dichloride, dioxane, N, dinethylformamide, dimethyl sulfoxide (DMSO), ethyl acetate, butylacetate, first hydrogen furan be suitable, 1,4-dioxy, 1,2-glycol dimethyl ether, diglyme, triglyme, single ethyl ether, acetone, methylethylketone, methyl iso-butyl ketone (MIBK), acetonitrile, second cyanogen, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, ethylene glycol and composition thereof, be preferably toluene, dimethyl sulfoxide (DMSO) or N, dinethylformamide; Further preferably, employed organic solvent was identical during described reaction neutralization bases was handled.
7. according to each described method among the claim 1-6, it is characterized in that, described method also comprise to the reaction in add catalyzer, described catalyzer is selected from Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, 4-butyl ammonium hydrogen sulfate, ethylenediamine tetraacetic acid (EDTA) and composition thereof, it adds molar weight and two kinds of reactants: the molar ratio with the molar weight sum 2-Haloacetamide shown in the formula (3) the 4-hydroxyl-2-Pyrrolidone shown in the formula (2) is 1: 100-1: 1, be preferably 1: 40-1: 20.
8. according to each described method among the claim 1-7, it is characterized in that the temperature of reaction of described method is 0-150 ℃, be preferably 20-100 ℃, more preferably 30-80 ℃.
9. require the oxiracetam of each described method preparation among the 1-8 by aforesaid right.
10. the described oxiracetam of claim 9 is used for the treatment of application in the medicine of brain function deficiency, memory disorder and senile dementia in preparation.
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| CN2009100688769A CN101885697B (en) | 2009-05-15 | 2009-05-15 | Preparation method of Oxiracetam |
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| CN2009100688769A CN101885697B (en) | 2009-05-15 | 2009-05-15 | Preparation method of Oxiracetam |
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| CN101885697B CN101885697B (en) | 2012-04-04 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013020390A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | 4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form i and preparation method therefor |
| CN103553997A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
| CN103553998A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
| CN115754113A (en) * | 2022-09-22 | 2023-03-07 | 东北制药集团股份有限公司 | Method for detecting content of catalyst tetrabutylammonium bromide in piracetam intermediate and finished product through high performance liquid chromatography |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1268611C (en) * | 2002-06-22 | 2006-08-09 | 张家港浩波化学品有限公司 | Method of preparing 4-hydroxy pyrrolidone-2-acetamine |
| CN101396358B (en) * | 2007-09-25 | 2011-10-12 | 广东世信药业有限公司 | Oxiracetam injection |
| CN101367757B (en) * | 2008-10-13 | 2012-09-19 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
-
2009
- 2009-05-15 CN CN2009100688769A patent/CN101885697B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013020390A1 (en) * | 2011-08-11 | 2013-02-14 | 重庆润泽医疗器械有限公司 | 4-hydroxy-2-oxo-1-pyrrolidineacetamide racemate crystal form i and preparation method therefor |
| CN103553997A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
| CN103553998A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
| CN103553997B (en) * | 2013-11-06 | 2015-11-25 | 温州智创科技有限公司 | The preparation method of a kind of (S)-Oxiracetam crystal form III |
| CN103553998B (en) * | 2013-11-06 | 2015-11-25 | 温州智创科技有限公司 | (S) preparation method of-Oxiracetam crystal form III |
| CN115754113A (en) * | 2022-09-22 | 2023-03-07 | 东北制药集团股份有限公司 | Method for detecting content of catalyst tetrabutylammonium bromide in piracetam intermediate and finished product through high performance liquid chromatography |
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