CN101914052A - Oxiracetam compound and new method thereof - Google Patents
Oxiracetam compound and new method thereof Download PDFInfo
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- CN101914052A CN101914052A CN 201010241328 CN201010241328A CN101914052A CN 101914052 A CN101914052 A CN 101914052A CN 201010241328 CN201010241328 CN 201010241328 CN 201010241328 A CN201010241328 A CN 201010241328A CN 101914052 A CN101914052 A CN 101914052A
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- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 14
- -1 Oxiracetam compound Chemical class 0.000 title claims abstract description 9
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 claims abstract description 17
- IOGISYQVOGVIEU-UHFFFAOYSA-N 4-hydroxypyrrolidin-2-one Chemical compound OC1CNC(=O)C1 IOGISYQVOGVIEU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- NWQXZIZIZSQPHR-UHFFFAOYSA-N 4-chloro-3-hydroxybutanamide Chemical compound NC(=O)CC(O)CCl NWQXZIZIZSQPHR-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- AYVAMARJVPYPCO-UHFFFAOYSA-N C(C)(=O)OCC.OC1CC(NC1)=O Chemical compound C(C)(=O)OCC.OC1CC(NC1)=O AYVAMARJVPYPCO-UHFFFAOYSA-N 0.000 claims description 12
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 claims description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 9
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229960004756 ethanol Drugs 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 4
- RDXMEUDCEWSFDP-UHFFFAOYSA-N 3-chloro-2-hydroxypropanenitrile Chemical compound ClCC(O)C#N RDXMEUDCEWSFDP-UHFFFAOYSA-N 0.000 abstract 1
- REJSTDZKZITPBI-UHFFFAOYSA-N 4-amino-1-chlorobutan-2-ol Chemical compound NCCC(O)CCl REJSTDZKZITPBI-UHFFFAOYSA-N 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 5
- IHLAQQPQKRMGSS-BYPYZUCNSA-N 2-[(4s)-4-hydroxy-2-oxopyrrolidin-1-yl]acetamide Chemical compound NC(=O)CN1C[C@@H](O)CC1=O IHLAQQPQKRMGSS-BYPYZUCNSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical class NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
Abstract
The invention relates to an oxiracetam compound and a new method thereof. In the method, 3-chloro-2-hydroxy propionitrile is used as an initial raw material. The method comprises the following steps of: synthesizing 4-hydroxyl-2-pyrrolidone through 4-chloro-3-hydroxyl-butylamide; and then synthesizing oxiracetam. The invention overcomes the defects of complicated preparation process, trouble steps, high cost, low product purity and difficult purification of the prior art.
Description
Technical field
The present invention relates to a kind of oxiracetam compound and novel method thereof, belong to medical technical field.
Background technology
Oxiracetam, chemistry is by name: 4-hydroxyl-2-OXo-1-pyrrolidine ethanamide, molecular formula: C
6H
10N
2O
3Molecular weight: 158.16, structural formula is:
Oxiracetam is the analogue of piracetam, can improve senile dementia and dysmnesia disease patient's memory and learning functionality.Mechanism result of study prompting, oxiracetam can promote Phosphorylcholine and phosphatidyl ethanolamine synthetic, improve the ratio of ATP/ADP in the brain, make the synthetic increase of protein and nucleic acid in the brain.
Oxiracetam is more synthetic first in 1974 than Qie Mu company by Italian SmithKline, listing in 1984, by two kinds of isomer (S)-oxiracetam and (R)-raceme that oxiracetam is formed.At present, the synthetic route of bibliographical information has multiple:
Chinese patent CN1513836A discloses the method for a kind of 4-of preparation hydroxy pyrrolidone-2-acetamine (oxiracetam), with 4-halo acetoacetate derivative is starting raw material, at first the trinitride with basic metal or alkaline-earth metal reacts, after obtaining 4-nitrine acetoacetate derivative, through steps such as hydrogenation, cyclisation, ammonifications, finally obtain oxiracetam again.Synthetic route is:
Disclosing improving one's methods of a kind of oxiracetam among the Chinese patent CN101121688A, is that starting raw material prepares oxiracetam with the ketene dimer, and through the chlorination open loop, resterification makes oxiracetam.Synthetic route is:
Above-mentioned two patent synthetic routes are comparatively complicated, consuming time longer, cause the finished product yield very low, increased cost greatly, are not suitable for suitability for industrialized production.
Chinese patent CN101575309A discloses a kind of method of synthetic (S)-oxiracetam, is starting raw material with the glycine, with chiral reagent (S)-4-halogen-3-butyric ester reaction, carry out esterification with ethanol again, product reacts with ammoniacal liquor again, and ammonia is separated, and obtains product (S)-oxiracetam.Synthetic route is:
Chinese patent CN1956953A discloses the preparation method of a kind of 4-hydroxyl-2-oxidation-1-pyrrolidine acetamide, and synthetic route is:
Above-mentioned two patent steps are simple, but used intermediate is difficult for purchase, costs an arm and a leg, the cost height, and also the final product purity that obtains is lower, and be not easy purifying.
Summary of the invention
The object of the present invention is to provide a kind of novel method of synthesizing oxiracetam compound, solved preparation process complexity in the prior art, complex steps, the cost height, product purity is low, is difficult for the shortcoming of purifying.
The technical scope that the present invention solves comprises:
The synthetic method of the oxiracetam compound shown in a kind of formula (I),
Synthesis step is:
(1), makes intermediate (III) 4-chloro-3-hydroxyl-butyramide with 3-chloro-acetaldehyde cyanhydrin and vitriol oil stirring reaction under heating condition of formula (II);
(2) condensation reaction generation intermediate (IV) 4-hydroxyl-2-Pyrrolidone takes place in 4-chloro-3-hydroxyl-butyramide in the presence of sodium hydroxide;
(3) under solvent and sodium methylate existence condition, with ethyl chloroacetate prepared in reaction intermediate (VI) 4-hydroxyl-2-Pyrrolidone ethyl acetate of 4-hydroxyl-2-Pyrrolidone and formula V;
(4) under the dehydrated alcohol existence condition, place autoclave to react 4-hydroxyl-2-Pyrrolidone ethyl acetate and liquefied ammonia, make oxiracetam.
Synthetic route is:
Wherein, (II) be 3-chloro-acetaldehyde cyanhydrin; (III) be 4-chloro-3-hydroxyl-butyramide; (IV) be 4-hydroxyl-2-Pyrrolidone; (V) be ethyl chloroacetate; (VI) be 4-hydroxyl-2-Pyrrolidone ethyl acetate; Et represents ethyl.
Preferably, the solvent of step (3) is selected from a kind of in isopropyl ether, ether, ethylene dichloride, santochlor, acetonitrile, hexanaphthene, sherwood oil, ethyl acetate, dimethylol propionic acid, methylene dichloride, trifluoroacetic acid, the methyl-phenoxide in the above-mentioned described method, is preferably isopropyl ether.
As the present invention's one preferred embodiment, the preparation method of described oxiracetam compound specifically comprises the steps:
(1) the 3-chloro-acetaldehyde cyanhydrin and the vitriol oil are mixed, stir, be warmed up to 50-60 ℃, reaction 2-3h, cool to room temperature is poured reactant in the mixture of ice and water into then, stir, use ethyl acetate extraction, the anhydrous sodium sulfate drying organic phase, concentrating under reduced pressure gets oily matter product 4-chloro-3-hydroxyl-butyramide;
(2) will go up step intermediate 4-chloro-3-hydroxyl-butyramide and dehydrated alcohol, sodium hydroxide mixing, be warmed up to 50-60 ℃, reaction 10-15h, ethanol is reclaimed in underpressure distillation then, in residuum, add ethyl acetate, stir 20-30min, filter, concentrating under reduced pressure, residue gets 4-hydroxyl-2-Pyrrolidone with the Virahol recrystallization;
(3) 4-hydroxyl-2-Pyrrolidone and sodium methylate, isopropyl ether are mixed, be stirred and heated to backflow, stirring reaction 4-5h, slowly drip the solution that ethyl chloroacetate and isopropyl ether form then, keep simultaneously being reflected at reflux state, continue reaction 4-5 hour after dripping, cool to room temperature then, cross and filter out residue, underpressure distillation gets 4-hydroxyl-2-Pyrrolidone ethyl acetate;
(4) in autoclave, add dehydrated alcohol and 4-hydroxyl-2-Pyrrolidone ethyl acetate, and feeding liquefied ammonia, stirring reaction 20-24 hour under certain condition, after reaction finishes, with the reaction solution cool to room temperature, reclaim ammonia, the underpressure distillation solvent is to doing, use ethyl alcohol recrystallization again, get white crystals product oxiracetam.
Wherein step (4) reactor pressure remains on 7atm, and temperature of reaction maintains 55-60 ℃.
Embodiment
Synthesizing of embodiment 1 4-chloro-3-hydroxyl-butyramide
In three mouthfuls of reaction flasks, add 478g (4mol) the 3-chloro-acetaldehyde cyanhydrin and the 500ml vitriol oil, stir, be warmed up to 50 ℃, reaction 2h, cool to room temperature then, reactant is poured in the mixture of ice and water of 2000ml, stir, use the ethyl acetate extraction three times of 800ml respectively, the anhydrous sodium sulfate drying organic phase, concentrating under reduced pressure gets oily matter product 495g product, yield 90%.
Synthesizing of embodiment 2 4-hydroxyl-2-Pyrrolidones
To go up step intermediate 275g (2mol) 4-chloro-3-hydroxyl-butyramide and 2L dehydrated alcohol, the mixing of 85g sodium hydroxide, be warmed up to 50 ℃, reaction 15h, ethanol is reclaimed in underpressure distillation then, adds the 1000ml ethyl acetate in residuum, stir 30min, filter, remove insolubles, the concentrating under reduced pressure ethyl acetate, residue adopts the Virahol recrystallization to get white solid 4-hydroxyl-2-Pyrrolidone 161g, yield 80%.
Synthesizing of embodiment 3 4-hydroxyl-2-Pyrrolidone ethyl acetate
In reaction flask, add isopropyl ether 1000ml and 101g (1mol) 4-hydroxyl-2-Pyrrolidone, 60g sodium methylate, be stirred and heated to backflow, stirring reaction 5h, solution becomes clear liquid, slowly drip the solution that 122g (1mol) ethyl chloroacetate and 500ml isopropyl ether form then, keep being reflected at reflux state simultaneously, continue reaction 5h after dripping, cool to room temperature then, cross the solid residue that filters to remove in the reaction solution, decompression and solvent recovery, the underpressure distillation product gets the 147g colourless liquid again, yield 79%.
Synthesizing of embodiment 4 oxiracetams
In autoclave, add dehydrated alcohol 600ml and on the product 4-hydroxyl-2-Pyrrolidone ethyl acetate 93g (0.5mol) in step, and in reactor, feed liquefied ammonia 350g, the pressure of reactor is remained on 7atm, temperature of reaction maintains 55-60 ℃, stirring reaction 24h, after reaction finishes, with the reaction solution cool to room temperature, absorb unnecessary ammonia with recovery tower, the underpressure distillation solvent adds 90% ethyl alcohol recrystallization to doing, get white crystals product oxiracetam 71g, yield 90%, purity 99.9%, MP:168 ℃.
Structural identification
1HNMR(CDCl
3，300MHz)δ1.33(t，3H，J＝7.2Hz)，2.38(dd，1H，J＝17.5，J＝2.8Hz)，2.69(dd，1H，J＝17.2，J＝6.7Hz)，3.36(dd，1H，J＝10.1，J＝1.7Hz)，3.72(dd，1H，J＝10.0，J＝5.2Hz)，3.94(d，1H，J＝17.7Hz)，4.22(d，1H，J＝17.1Hz)，4.33(q，2H，J＝7.2Hz)，4.35(bs，1H)，4.57(m，1H)。
Claims (4)
1. oxiracetam compound and the novel method thereof shown in the formula (I),
It is characterized in that may further comprise the steps:
(1) stirring reaction under heating condition with the 3-chloro-acetaldehyde cyanhydrin and the vitriol oil makes 4-chloro-3-hydroxyl-butyramide;
(2) condensation reaction generation 4-hydroxyl-2-Pyrrolidone takes place in 4-chloro-3-hydroxyl-butyramide in the presence of sodium hydroxide;
(3) under solvent and sodium methylate existence condition, with 4-hydroxyl-2-Pyrrolidone and ethyl chloroacetate prepared in reaction 4-hydroxyl-2-Pyrrolidone ethyl acetate;
(4) under the dehydrated alcohol existence condition, place autoclave to react 4-hydroxyl-2-Pyrrolidone ethyl acetate and liquefied ammonia, make oxiracetam;
Synthetic route is:
In the synthetic route, (II) be 3-chloro-acetaldehyde cyanhydrin; (III) be 4-chloro-3-hydroxyl-butyramide; (IV) be 4-hydroxyl-2-Pyrrolidone; (V) be ethyl chloroacetate; (VI) be 4-hydroxyl-2-Pyrrolidone ethyl acetate; Et represents ethyl.
2. method according to claim 1, it is characterized in that solvent in the step (3) is selected from a kind of in isopropyl ether, ether, ethylene dichloride, santochlor, acetonitrile, hexanaphthene, sherwood oil, ethyl acetate, dimethylol propionic acid, methylene dichloride, trifluoroacetic acid, the methyl-phenoxide, is preferably isopropyl ether.
3. the preparation method of a claim 1 and 2 each described oxiracetam compounds is characterized in that specifically comprising the steps:
(1) the 3-chloro-acetaldehyde cyanhydrin and the vitriol oil are mixed, stir, be warmed up to 50-60 ℃, reaction 2-3h, cool to room temperature is poured reactant in the mixture of ice and water into then, stir, use ethyl acetate extraction, the anhydrous sodium sulfate drying organic phase, concentrating under reduced pressure gets oily matter product 4-chloro-3-hydroxyl-butyramide;
(2) will go up step intermediate 4-chloro-3-hydroxyl-butyramide and dehydrated alcohol, sodium hydroxide mixing, be warmed up to 50-60 ℃, reaction 10-15h, ethanol is reclaimed in underpressure distillation then, in residuum, add ethyl acetate, stir 20-30min, filter, concentrating under reduced pressure, residue gets 4-hydroxyl-2-Pyrrolidone with the Virahol recrystallization;
(3) 4-hydroxyl-2-Pyrrolidone and sodium methylate, isopropyl ether are mixed, be stirred and heated to backflow, stirring reaction 4-5h, slowly drip the solution that ethyl chloroacetate and isopropyl ether form then, keep simultaneously being reflected at reflux state, continue reaction 4-5 hour after dripping, cool to room temperature then, cross and filter out residue, underpressure distillation gets 4-hydroxyl-2-Pyrrolidone ethyl acetate;
(4) in autoclave, add dehydrated alcohol and 4-hydroxyl-2-Pyrrolidone ethyl acetate, and feeding liquefied ammonia, stirring reaction 20-24 hour, after reaction finishes, with the reaction solution cool to room temperature, reclaim ammonia, the underpressure distillation solvent is to doing, use ethyl alcohol recrystallization again, get white crystals product oxiracetam.
4. method according to claim 3 is characterized in that reactor pressure remains on 7atm in the step (4), and temperature of reaction maintains 55-60 ℃.
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| CN2010102413284A CN101914052B (en) | 2010-08-02 | 2010-08-02 | Oxiracetam compound and new method thereof |
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| CN2010102413284A CN101914052B (en) | 2010-08-02 | 2010-08-02 | Oxiracetam compound and new method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321007A (en) * | 2011-07-18 | 2012-01-18 | 石药集团欧意药业有限公司 | Oxiracetam compound and preparation method as well as medicine composition thereof |
| CN102603597A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-oxiracetam |
| CN102603599A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Method for preparing (S)-oxiracetam |
| CN102627596A (en) * | 2012-03-16 | 2012-08-08 | 天津景寅医药生物技术发展有限公司 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN103342673A (en) * | 2013-07-31 | 2013-10-09 | 石药集团欧意药业有限公司 | Oxiracetam crystal form and preparation method thereof |
| CN103588695A (en) * | 2013-11-25 | 2014-02-19 | 石药集团欧意药业有限公司 | Oxiracetam compound adopting crystallization form and preparation method thereof |
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| US4824861A (en) * | 1985-06-21 | 1989-04-25 | Isf Societa Per Azioni | Pyrrolidone derivatives and memory enhancement use thereof |
| CN1513836A (en) * | 2002-06-22 | 2004-07-21 | 张家港浩波化学品有限公司 | Method of preparing 4-hydroxy pyrrolidone-2-acetamine |
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| US4824861A (en) * | 1985-06-21 | 1989-04-25 | Isf Societa Per Azioni | Pyrrolidone derivatives and memory enhancement use thereof |
| JPS6226267A (en) * | 1985-07-26 | 1987-02-04 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603597A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-oxiracetam |
| CN102603599A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Method for preparing (S)-oxiracetam |
| CN102603597B (en) * | 2011-01-21 | 2014-01-22 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam |
| CN102603599B (en) * | 2011-01-21 | 2014-06-11 | 温州智创科技有限公司 | Method for preparing (S)-oxiracetam |
| CN102321007A (en) * | 2011-07-18 | 2012-01-18 | 石药集团欧意药业有限公司 | Oxiracetam compound and preparation method as well as medicine composition thereof |
| CN102321007B (en) * | 2011-07-18 | 2013-05-08 | 石药集团欧意药业有限公司 | Oxiracetam compound and preparation method as well as medicine composition thereof |
| CN102627596A (en) * | 2012-03-16 | 2012-08-08 | 天津景寅医药生物技术发展有限公司 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN102627596B (en) * | 2012-03-16 | 2016-01-27 | 天津景寅医药生物技术发展有限公司 | A kind of preparation method of Esomeprazole |
| CN103342673A (en) * | 2013-07-31 | 2013-10-09 | 石药集团欧意药业有限公司 | Oxiracetam crystal form and preparation method thereof |
| CN103342673B (en) * | 2013-07-31 | 2015-11-18 | 石药集团欧意药业有限公司 | A kind of Oxiracetam crystal form and preparation method thereof |
| CN103588695A (en) * | 2013-11-25 | 2014-02-19 | 石药集团欧意药业有限公司 | Oxiracetam compound adopting crystallization form and preparation method thereof |
| CN103588695B (en) * | 2013-11-25 | 2015-08-05 | 石药集团欧意药业有限公司 | Oxiracetam compound of a kind of crystallized form and preparation method thereof |
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