CN101914052B - Oxiracetam compound and new method thereof - Google Patents
Oxiracetam compound and new method thereof Download PDFInfo
- Publication number
- CN101914052B CN101914052B CN2010102413284A CN201010241328A CN101914052B CN 101914052 B CN101914052 B CN 101914052B CN 2010102413284 A CN2010102413284 A CN 2010102413284A CN 201010241328 A CN201010241328 A CN 201010241328A CN 101914052 B CN101914052 B CN 101914052B
- Authority
- CN
- China
- Prior art keywords
- hydroxyl
- pyrrolidone
- reaction
- chloro
- ethyle acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 16
- -1 Oxiracetam compound Chemical class 0.000 title claims abstract description 9
- IOGISYQVOGVIEU-UHFFFAOYSA-N 4-hydroxypyrrolidin-2-one Chemical compound OC1CNC(=O)C1 IOGISYQVOGVIEU-UHFFFAOYSA-N 0.000 claims abstract description 26
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 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
- 239000002904 solvent Substances 0.000 claims description 9
- 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
- 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
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 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
- LHBPNZDUNCZWFL-UHFFFAOYSA-N 4-chloro-3-hydroxybutanenitrile Chemical compound ClCC(O)CC#N LHBPNZDUNCZWFL-UHFFFAOYSA-N 0.000 claims 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 6
- 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
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 6
- 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 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
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali 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
- 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
- 235000013905 glycine and its sodium salt Nutrition 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
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000003786 synthesis reaction 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 that Phosphorylcholine and phosphatidyl ethanolamine are synthetic, and the ratio of ATP/ADP in the raising brain makes 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 with (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 earth alkali 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 glycocoll, 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 midbody is difficult for purchase, costs an arm and a leg, and cost is high, and the final product purity that obtains is lower, and is 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 complicacy in the prior art, complex steps, cost is high, and product purity is low, is difficult for the shortcoming of purifying.
The technical scope that the present invention solves comprises:
The compound method of the oxiracetam compound shown in a kind of formula (I),
Synthesis step is:
(1), makes midbody (III) 4-chloro-3-hydroxyl-yulocrotine with 3-chloro-acetaldehyde cyanhydrin and vitriol oil stirring reaction under heating condition of formula (II);
(2) condensation reaction generation midbody (IV) 4-hydroxyl-2-Pyrrolidone takes place in 4-chloro-3-hydroxyl-yulocrotine in the presence of sodium hydroxide;
(3) under solvent and sodium methylate existence condition, with ethyl chloroacetate prepared in reaction midbody (VI) 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE of 4-hydroxyl-2-Pyrrolidone and formula V;
(4) under the absolute ethyl alcohol existence condition, place autoclave to react in 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE and liquefied ammonia, make oxiracetam.
Synthetic route is:
Wherein, (II) be 3-chloro-acetaldehyde cyanhydrin; (III) be 4-chloro-3-hydroxyl-yulocrotine; (IV) be 4-hydroxyl-2-Pyrrolidone; (V) be ethyl chloroacetate; (VI) be 4-hydroxyl-2-Pyrrolidone ETHYLE 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, ETHYLE 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-yulocrotine;
(2) will go up step midbody 4-chloro-3-hydroxyl-yulocrotine and absolute ethyl alcohol, sodium hydroxide mixing, be warmed up to 50-60 ℃, reaction 10-15h; Ethanol is reclaimed in underpressure distillation then; In residuum, add ETHYLE 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 ETHYLE ACETATE;
(4) in autoclave, add absolute ethyl alcohol and 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE, and feed 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) reaction kettle pressure remains on 7atm, and maintain is at 55-60 ℃.
Embodiment
Synthesizing of embodiment 1 4-chloro-3-hydroxyl-yulocrotine
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 is poured reactant in the mixture of ice and water of 2000ml then; 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 midbody 275g (2mol) 4-chloro-3-hydroxyl-yulocrotine and 2L absolute ethyl alcohol, the mixing of 85g sodium hydroxide, be warmed up to 50 ℃, reaction 15h; Ethanol is reclaimed in underpressure distillation then, in residuum, adds 1000ml ETHYLE ACETATE, stirs 30min; Filter, remove insolubles, concentrating under reduced pressure ETHYLE 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 ETHYLE 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 drips the solution that 122g (1mol) ethyl chloroacetate and 500ml isopropyl ether form then, keeps being reflected at reflux state simultaneously; Continue reaction 5h after dripping; Cool to room temperature is crossed and is filtered to remove the solid residue in the reaction solution, decompression and solvent recovery then; The underpressure distillation product gets the 147g colourless liquid again, yield 79%.
Synthesizing of embodiment 4 oxiracetams
In autoclave, add absolute ethyl alcohol 600ml with on the product 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE 93g (0.5mol) in step, and in reaction kettle, feed liquefied ammonia 350g, the pressure of reaction kettle is remained on 7atm; Maintain is at 55-60 ℃, and stirring reaction 24h is after reaction finishes; With the reaction solution cool to room temperature, with the ammonia of regenerating column absorbing redundant, the underpressure distillation solvent is to doing; The ethyl alcohol recrystallization of adding 90% gets 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 (5)
1. the compound method of the oxiracetam compound shown in the formula (I),
It is characterized in that may further comprise the steps:
(1) with 4-chloro-3-hydroxybutyronitrile and vitriol oil stirring reaction under heating condition, makes 4-chloro-3-hydroxyl-yulocrotine;
(2) condensation reaction generation 4-hydroxyl-2-Pyrrolidone takes place in 4-chloro-3-hydroxyl-yulocrotine 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 ETHYLE ACETATE;
(4) under the absolute ethyl alcohol existence condition, place autoclave to react in 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE and liquefied ammonia, make oxiracetam;
Synthetic route is:
In the synthetic route, (II) be 4-chloro-3-hydroxybutyronitrile; (III) be 4-chloro-3-hydroxyl-yulocrotine; (IV) be 4-hydroxyl-2-Pyrrolidone; (V) be ethyl chloroacetate; (VI) be 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE; Et represents ethyl.
2. method according to claim 1 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, ETHYLE ACETATE, methylene dichloride, the methyl-phenoxide.
3. method according to claim 1 is characterized in that the solvent in the step (3) is an isopropyl ether.
4. method according to claim 1 is characterized in that specifically comprising the steps:
(1) the 4-chloro-3-hydroxybutyronitrile 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-yulocrotine;
(2) will go up step midbody 4-chloro-3-hydroxyl-yulocrotine and absolute ethyl alcohol, sodium hydroxide mixing, be warmed up to 50-60 ℃, reaction 10-15h; Ethanol is reclaimed in underpressure distillation then; In residuum, add ETHYLE 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 ETHYLE ACETATE;
(4) in autoclave, add absolute ethyl alcohol and 4-hydroxyl-2-Pyrrolidone ETHYLE ACETATE, and feed 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.
5. method according to claim 4 is characterized in that reaction kettle pressure remains on 7atm in the step (4), and maintain is at 55-60 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102413284A CN101914052B (en) | 2010-08-02 | 2010-08-02 | Oxiracetam compound and new method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102413284A CN101914052B (en) | 2010-08-02 | 2010-08-02 | Oxiracetam compound and new method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101914052A CN101914052A (en) | 2010-12-15 |
| CN101914052B true CN101914052B (en) | 2012-06-27 |
Family
ID=43321729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102413284A Active CN101914052B (en) | 2010-08-02 | 2010-08-02 | Oxiracetam compound and new method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101914052B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603599B (en) * | 2011-01-21 | 2014-06-11 | 温州智创科技有限公司 | 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1190378B (en) * | 1985-06-21 | 1988-02-16 | Isf Spa | PYROLIDONIC DERIVATIVES |
| JPS6226267A (en) * | 1985-07-26 | 1987-02-04 | Denki Kagaku Kogyo Kk | Production of oxiracetam |
| 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 |
-
2010
- 2010-08-02 CN CN2010102413284A patent/CN101914052B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101914052A (en) | 2010-12-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101914052B (en) | Oxiracetam compound and new method thereof | |
| EP2387556B1 (en) | Separation of an enantiomer mixture of (r)- and (s)-3-amino-1-butanol | |
| CN107286086B (en) | Preparation method of N-cyanomethyl bis (trifluoromethyl) nicotinamide and application of N-cyanomethyl bis (trifluoromethyl) nicotinamide | |
| JP2021504418A (en) | Method for producing 2- (5-methoxyisochroman-1-yl) -4,5-dihydro-1H-imidazole and its hydrogen sulfate | |
| SK152998A3 (en) | Racemic separation of ketamine | |
| JP2005507900A (en) | Citalopram manufacturing method | |
| CN109503568B (en) | Preparation method of dasatinib | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| ES2330479T3 (en) | PROCEDURE FOR THE PREPARATION OF DULOXETINE. | |
| CN110423219B (en) | Method for resolving tetrahydroisoquinoline compounds | |
| CN108558715B (en) | Method for preparing enantiopure tert-butyl sulfenamide | |
| CN113024499A (en) | Green synthesis method of coumarin-3-carboxylic acid compounds | |
| CN103086877B (en) | A kind of method for splitting of 2 hydracrylic acid class racemoid | |
| TW201120021A (en) | Process for preparing 2,4-dioxotetrahydrofuran-3-carboxylates | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN109879775A (en) | A kind of environment-friendly preparation method of 5-ALA hydrochloride intermediate | |
| CN104892491B (en) | Method for synthesizing paroxetine chiral intermediate | |
| KR101525296B1 (en) | Lamivudine oxalate and preparation method thereof | |
| HU186528B (en) | Process for producing tetronnoic acid | |
| KR101164424B1 (en) | Manufacturing method for donepezil HCl | |
| WO2010068049A2 (en) | Process for preparing (r)-(+)-lansoprazole and intermediate used therein | |
| CN108484455B (en) | Method for synthesizing chiral optical pure p-toluenesulfinamide | |
| CN109400489B (en) | Preparation method of meclofenoxate hydrochloride | |
| WO2016189463A1 (en) | Ertugliflozin co-crystals and process for their preparation | |
| KR100297802B1 (en) | Method for preparing 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: HAINAN LINGKANG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HU JIANRONG Effective date: 20130725 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 570125 HAIKOU, HAINAN PROVINCE TO: 570216 HAIKOU, HAINAN PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130725 Address after: 570216 Hainan Province, Haikou city Jinpan Industrial Development Zone Industrial Village No. 3-6 building Patentee after: Hainan Lingkang Pharmaceutical Co., Ltd. Address before: The new business building No. 48 570125 Hainan city of Haikou province China World Trade Center Road, room 2601 Patentee before: Hu Jianrong |