CN103351322B - A kind of synthetic method of oxiracetam - Google Patents
A kind of synthetic method of oxiracetam Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of oxiracetam, this synthetic method take ketene dimer as raw material, prepares oxiracetam through bromination, esterification, reduction, pass ring four-step reaction.Synthetic method of the present invention has simple to operate, safety, environmental protection, and raw material is cheap and easy to get, and reaction conditions is gentle, and productive rate is high, significantly reduces the cost of product, therefore, is more suitable for suitability for industrialized production.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of oxiracetam synthetic method.
Background technology
Oxiracetam, English name Oxiracetam, chemistry Esomeprazole by name, molecular formula is C
6h
10n
2o
3(158.16); Be that one acts on the cholinergic nootropics of reticular formation of brain stem, within 1974, first synthesized by Italian ISF company, within 1987, go on the market in Italy with Neuromet first, within 1991, go on the market in Portugal with Neupan.
Oxiracetam was widely used since Discussion on Chinese Listed from 1998, had the kind such as capsule, injection (little liquid drugs injection) at present.Oxiracetam bulk drug synthetic route is numerous, causes its yield and quality also to have bigger difference.
Chinese patent application CN1513836A discloses a kind of preparation technology of oxiracetam, its with 4-haloacetyl acetogenin for starting raw material, first react with the trinitride of basic metal or alkaline-earth metal, obtain 4-nitrine acetoacetate derivative, again through steps such as hydrogenation, cyclization, ammonifications, obtain oxiracetam, its route is as follows:
The method that this route adopts sodiumazide introducing azido-to restore amino, there is larger potential safety hazard aborning, in addition, products obtained therefrom purity is low, is only 97%, does not possess industrialization advantage.
Japanese patent application JP53101367 discloses with 4-amino-3-hydroxybutyrate for starting raw material, after hydroxyl protection, cyclization, replaces with 2-ethyl bromoacetate, deprotection, the again step of ammonia solution obtain target product.The shortcoming of this route is raw materials used and amino protecting agent is expensive, and production cost is high, is not suitable for suitability for industrialized production.
It is raw material that Chinese patent application CN101121688A discloses with ketene dimer, after chlorine reaction, through esterification, forms double bond methyl ether with sulfur oxychloride; Again with Formation of glycine amidate, Guan Huan obtains intermediate 4-methoxyl group-pyrroline-2-one-1-guanidine-acetic acid.This intermediate obtains oxiracetam through esterification, ammonia solution, salify, reduction four step again.This route is in starting raw material, and total recovery can reach 22.5%, but the salt remained in target product not easily removes, and in addition, the side reactions such as the hydrolysis that reduction reaction is adjoint while carrying out also impact yield and final product quality.
Therefore, explore new oxiracetam synthesis technique, reduce production cost, applicable suitability for industrialized production is the emphasis of oxiracetam technical study.We launch exploratory development accordingly, to find the synthesis technique of optimization.
Summary of the invention
The present inventor has found a kind of novel synthesis being suitable for industrialized oxiracetam in the research of oxiracetam synthesis technique.
The object of the invention is to provide a kind of novel synthesis being suitable for industrialized oxiracetam.
In embodiments of the invention, the invention provides a kind of synthetic method of oxiracetam, it is characterized in that comprising the steps:
(1) by ketene dimer, methylene dichloride mixing, add bromine, after question response completes, underpressure distillation removing methylene dichloride obtains 4-bromo-3-oxo butyryl bromide (i.e. Compound I);
(2) in 4-bromo-3-oxo butyryl bromide (i.e. Compound I), C1-C4 alkanol (i.e. ROH is dripped, here R is the alkyl of C1-C4), after question response completes, decompression steams C1-C4 alkanol (i.e. ROH), obtain 4-bromo-3-oxobutanoic acid esters (i.e. Compound II per, wherein R is C1-C4 alkyl);
(3) by 4-bromo-3-oxobutanoic acid esters (i.e. Compound II per, wherein R is C1-C4 alkyl) use dissolve with methanol, add reductive agent, after having reacted, regulating pH=5.0-6.5, continuing reaction to completing, steaming desolventizes, again with water-insoluble organic solvent extraction, get organic layer evaporated under reduced pressure and obtain 4-bromo-3-hydroxybutyrate ester (i.e. compound III, wherein R is C1-C4 alkyl);
(4) by mineral alkali, glycyl amide hydrochloride, ethanol mixing, 4-bromo-3-hydroxybutyrate ester (i.e. compound III, wherein R is C1-C4 alkyl) is dripped, post-heating backflow 20-30 hour, filtered while hot, concentrated, then obtain oxiracetam crude product by methanol crystallization; Oxiracetam crude product is refluxed in C1-C4 alkanol solvent, after activated carbon decolorizing recrystallization, obtains oxiracetam fine work;
In a preferred embodiment, the invention provides a kind of synthetic method of oxiracetam, it is characterized in that comprising the steps:
(1) by ketene dimer, methylene dichloride mixing, to add after bromine 20-30 DEG C of reaction, react 6-8 hour, underpressure distillation removes after methylene dichloride must 4-bromo-3-oxo butyryl bromide (i.e. Compound I);
(2) in 4-bromo-3-oxo butyryl bromide (i.e. Compound I), C1-C4 alkanol (i.e. ROH is dripped, here R is C1-C4 alkyl), 20-30 DEG C of reaction, react rear decompression and steam C1-C4 alkanol (i.e. ROH, here R is C1-C1 alkyl) solvent, obtain 4-bromo-3-oxobutanoic acid esters (i.e. Compound II per, wherein R is C1-C4 alkyl);
(3) by 4-bromo-3-oxobutanoic acid esters (i.e. Compound II per, wherein R is C1-C4 alkyl) use dissolve with methanol, add reductive agent, after 15-20 DEG C of reaction completes for 3-4 hour, regulate pH=5.5-6.5, after continuing 15-20 DEG C of reaction 0.5-1h, extract with water-insoluble organic solvent, get organic layer evaporated under reduced pressure and obtain 4-bromo-3-hydroxybutyrate ester (i.e. compound III, wherein R is C1-C4 alkyl);
(4) by mineral alkali, glycyl amide hydrochloride, ethanol mixing, rear dropping 4-bromo-3-hydroxybutyrate ester (i.e. compound III, wherein R is C1-C4 alkyl), reflux 22-24h, filtered while hot, concentrated, then obtain oxiracetam crude product by methanol crystallization; Oxiracetam crude product refluxes in C1-C4 alkanol (i.e. ROH, R is C1-C4 alkyl here) solvent, obtains oxiracetam fine work after activated carbon decolorizing recrystallization.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, C1-C4 alkanol (the i.e. ROH that step (2), step (4) use, here R is C1-C4 alkyl), for methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol or the trimethyl carbinol, be more preferably methyl alcohol, ethanol, propyl alcohol or butanols, particularly preferably methyl alcohol.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, C1-C4 alkanol solvent (i.e. ROH in step (4), here R is C1-C4 alkyl), for methyl alcohol, ethanol, propyl alcohol, Virahol, one or more mixture in butanols, isopropylcarbinol or the trimethyl carbinol, be more preferably one or more the mixture in methyl alcohol, ethanol, propyl alcohol or butanols, a kind of particularly preferably in methyl alcohol or ethanol or their mixture.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, in step (3), reductive agent is red aluminium, POTASSIUM BOROHYDRIDE or sodium borohydride, preferably, is sodium borohydride.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, water-insoluble organic solvent described in step (3) is selected from methylene dichloride, chloroform, 1, one or more mixture in 2-ethylene dichloride, ethyl acetate or methyl acetate, most preferably, be the one in methylene dichloride or ethyl acetate.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, in step (4), mineral alkali is alkali metal hydroxide or alkaline carbonate, and described alkali metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide; Described alkaline carbonate is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus; Preferably, described mineral alkali is sodium carbonate.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, in step (1), the mol ratio that the rare ketone of two second and bromine feed intake is 1: 2 ~ 1: 3, is preferably, 1: 2.5-2.8.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, in step (3), the mol ratio that reductive agent and Compound II per feed intake is 2.5 ~ 3.5: 1, preferably, is 2.5 ~ 3.0: 1.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, preferably in step (3), regulates the pH to 5.5-6.5 of reaction solution with acetic acid.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, in step (4), the mol ratio that described glycyl amide hydrochloride and 4-bromo-3-hydroxybutyrate ester (i.e. compound III, wherein R is C1-C4 alkyl) feed intake is 1.1 ~ 1.5: 1.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, in step (4), the time that 4-bromo-3-hydroxybutyrate ester (i.e. compound III, wherein R is C1-C4 alkyl) drips is 1.0h.
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, step (4) is described obtains oxiracetam crude product with methanol crystallization, refers in residue after concentration the methyl alcohol adding 3.5-5.5 times (quality in 4-bromo-3-hydroxybutyrate ester).
In embodiments of the invention, the synthetic method of oxiracetam provided by the invention, wherein, step (4) is described with C1-C4 alkanol (i.e. ROH, here R is C1-C4 alkyl) solvent recrystallization obtains oxiracetam highly finished product, refer to C1-C4 alkanol (the i.e. ROH adding 3.5-5.5 times (quality in 4-bromo-3-hydroxybutyrate ester) in oxiracetam crude product, here R is C1-C4 alkyl), be preferably 3.8-4.5 doubly (quality in 4-bromo-3-hydroxybutyrate ester), reaction solution is warming up to 45 ~ 55 DEG C, add 5-18% weight, preferably, it is the activated carbon decolorizing of 10% weight (in 4-bromo-3-hydroxybutyrate ester quality), rear cooling crystallization.
The invention provides a kind of brand-new synthetic method of oxiracetam, the method is simple to operate, and reaction conditions is gentle, and safety, environmental protection, raw material is cheap and easy to get, and productive rate is high, significantly reduces production cost, therefore, is more suitable for suitability for industrialized production.
Embodiment
Further illustrate of the present invention below by way of specific embodiment.It should be noted that the following example is not limiting the scope of the present invention.
Embodiment 1
(1) in reaction flask, add ketene dimer 100g, 500g methylene dichloride, control temperature is at 20-30 DEG C.Slowly drip 476g bromine, holding temperature 20-30 DEG C, drip and finish, reaction solution stirs 6 hours.Water pump reclaim under reduced pressure methylene dichloride, until steam (control temperature≤30 DEG C) without obvious liquid.
(2) the 4-bromo-3-oxo butyryl bromide control temperature 20-30 DEG C above-mentioned steps (1) obtained, in residual solution, drip methyl alcohol 45g, finish, reaction solution stirs 30 minutes.Temperature control≤50 DEG C ,-0.08MPa, namely evaporated under reduced pressure methyl alcohol obtain 4-bromo-3-oxobutyrate 204g, two step yields 87.9%.
(3) 200g4-bromo-3-oxobutyrate and 400g methyl alcohol are dropped in 2000ml reaction flask, be cooled to 15-17 DEG C, temperature control 15-20 DEG C, slowly add sodium borohydride 14g, add rear insulation reaction 3.0 hours.In reduction reaction liquid, add a small amount of glacial acetic acid, adjustment pH is slightly acidic (PH=6), stirring reaction 0.5 hour, and intensification concentrating under reduced pressure steams methanol solution (50 ~ 60 DEG C ,-0.08MPa), after having concentrated, is cooled to 15-20 DEG C.In concentrated solution, slowly add saturated brine 400.0g (temperature control 15-20 DEG C), stirring reaction 1.0 hours, after having reacted, layering, collects upper strata, and lower floor extracts once by 300g ethyl acetate again.Merge the washing of organic phase 300.0g half saturated brine once.Organic phase concentrating under reduced pressure reclaims ethyl acetate (-0.08Mpa, 50 ~ 70 DEG C), obtains 4-bromo-3-hydroxybutyrate methyl esters 181g, yield 89.8%.
(4) 131g glycyl amide hydrochloride, 900g dehydrated alcohol, 229g sodium carbonate are added in reaction flask, be warming up to backflow, 180g4-bromo-3-hydroxybutyrate methyl esters is slowly dripped (within about 1.0 hours, dropwising), after dropwising, continue back flow reaction 24.0 hours, after reaction terminates, filtered while hot, filter cake washs once with 180g hot methanol again.Underpressure distillation goes out methyl alcohol and obtains solid sticky thing, adds 720g methyl alcohol, stirred crystallization, obtains oxiracetam crude product.Added by crude product in 720 methyl alcohol and heat up about 50 DEG C, add 18g gac insulation decolouring, decrease temperature crystalline, obtains oxiracetam fine work 93g, yield 64.4%.(
1H-NMR(D
2O)δ2.80(1H，dd，J＝17.8Hz)，2.36(1H，dd，17.8Hz)，4.58(1H，d，J＝6.0Hz)，3.40(1H，d，J＝11.4Hz)，3.80(1H，dd，J＝11.4Hz)，3.96(1H，d，J＝16.0Hz)，4.05(1H，d，J＝16.0Hz)
Embodiment 2
(1) in reaction flask, add ketene dimer 420g, 2730g methylene dichloride, control temperature is at 20-30 DEG C.Slowly drip bromine 1490g, holding temperature 20-30 DEG C, about 8 hours logical complete, and reaction solution stirs 1 hour.Water pump reclaim under reduced pressure methylene dichloride, until steam (control temperature≤30 DEG C) without obvious liquid.The step of oxiracetam fine work is prepared with (2), (3), (4) in example 1, total recovery 49.2% by 4-bromo-3-oxo butyryl bromide.(
1H-NMR(D
2O)δ2.82(1H，dd，J＝17.8Hz)，2.34(1H，dd，17.8Hz)，4.58(1H，d，J＝6.0Hz)，3.45(1H，d，J＝11.4Hz)，3.84(1H，dd，J＝11.4Hz)，3.93(1H，d，J＝16.0Hz)，4.06(1H，d，J＝16.0Hz)
Embodiment 3
(1) synthesis step of (2) (3) is all with example 1.
(4) 73g glycyl amide hydrochloride, 500g anhydrous methanol, 41g sodium hydroxide are added in reaction flask, be warming up to backflow, 100g4-bromo-3-hydroxybutyrate methyl esters is slowly dripped (within about 1.0 hours, dropwising), after dropwising, continue back flow reaction 24.0 hours, after reaction terminates, filtered while hot, filter cake washs once with 100g hot methanol again.Underpressure distillation goes out methyl alcohol and obtains solid sticky thing, adds 400g methyl alcohol, stirred crystallization, obtains oxiracetam crude product.Added by crude product in 400 methyl alcohol and heat up about 50 DEG C, add 10g gac insulation decolouring, decrease temperature crystalline, obtains oxiracetam fine work 53g, yield 66.1%.
Embodiment 4
(1) in reaction flask, add ketene dimer 100g, 500g methylene dichloride, control temperature is at 20-30 DEG C.Slowly drip 476g bromine, holding temperature 20-30 DEG C, drip and finish, reaction solution stirs 6 hours.Water pump reclaim under reduced pressure methylene dichloride, until steam (control temperature≤30 DEG C) without obvious liquid.
(2) the 4-bromo-3-oxo butyryl bromide control temperature 20-30 DEG C above-mentioned steps (1) obtained, in residual solution, drip ethanol 40g, finish, reaction solution stirs 30 minutes.Temperature control≤50 DEG C ,-0.08MPa, namely evaporated under reduced pressure methyl alcohol obtain 4-bromo-ethyl 3-oxobutanoate 204g, two step yields 87.9%.
(3) 200g4-bromo-ethyl 3-oxobutanoate and 400g methyl alcohol are dropped in 2000ml reaction flask, be cooled to 15-17 DEG C, temperature control 15-20 DEG C, slowly add sodium borohydride 12g, add rear insulation reaction 3.0 hours.In reduction reaction liquid, add a small amount of glacial acetic acid, regulate pH to be 6.2, stirring reaction 0.5 hour, intensification concentrating under reduced pressure steams methanol solution (50 ~ 60 DEG C ,-0.08MPa), after having concentrated, is cooled to 15-20 DEG C.In concentrated solution, slowly add saturated brine 400.0g (temperature control 15-20 DEG C), stirring reaction 1.0 hours, after having reacted, layering, collects upper strata, and lower floor extracts once by 300g ethyl acetate again.Merge organic phase 300.0 half saturated brine washings once.Organic phase concentrating under reduced pressure reclaims ethyl acetate (-0.08Mpa, 50 ~ 70 DEG C), obtains 4-bromo-ethyl 3-hydroxybutanoate 178.6g, yield 92.4%.
(4) 148g glycyl amide hydrochloride, 960g dehydrated alcohol, 229g sodium carbonate are added in reaction flask, be warming up to backflow, 180g4-bromo-ethyl 3-hydroxybutanoate is slowly dripped (within about 1.0 hours, dropwising), after dropwising, continue back flow reaction 24.0 hours, after reaction terminates, filtered while hot, filter cake washs once with 180g hot methanol again.Underpressure distillation goes out methyl alcohol and obtains solid sticky thing, adds 720g methyl alcohol, stirred crystallization, obtains oxiracetam crude product.Added by crude product in 720 methyl alcohol and heat up about 50 DEG C, add 18g gac insulation decolouring, decrease temperature crystalline, obtains oxiracetam fine work 76.7g, yield 65%.
Result and discussion
Data statistics:
| Batch | Four steps mole total recovery | HPLC purity |
| Embodiment 1 | 50.8％ | 99.78％ |
| Embodiment 2 | 49.2％ | 99.82％ |
| Embodiment 3 | 52.1％ | 99.72％ |
| Embodiment 4 | 50.2％ | 99.75％ |
HPLC analytical procedure:
Principle: with high pressure pump, the mixed flow of different ratios is pressed into mutually the chromatographic column that stationary phase is housed, injects trial-product through sampling valve, brings in post by moving phase, in post each composition separated after, enter detector successively, record color atlas, thus measure the impurity level of trial-product.
Instrument: high performance liquid chromatograph
Reagent and solution
Acetonitrile (HPLC)
Potassium primary phosphate (AR)
Phosphoric acid (AR)
Ammoniacal liquor (AR)
Chromatographic condition and system suitability liquid chromatography system adopt UV-detector, are weighting agent with amino bonded silica gel, with mixture of acetonitrile-phosphate buffer (26: 74) for moving phase; Determined wavelength is 210nm, and flow velocity is 1.0ml/min.
The preparation of moving phase: phosphate buffered saline buffer (gets potassium primary phosphate 4.08g, the 500ml that adds water adds the ammoniacal liquor 5ml of 25-28% after dissolving, being diluted with water to 1000ml, after mixing, adjusting pH to 3.5 ± 0.1 with phosphoric acid)-acetonitrile (26: 74) is moving phase, filters degassed for subsequent use.
The preparation of need testing solution: take sample 50mg in 25ml measuring bottle, dissolve by moving phase and be diluted to scale, shaking up.
Determination step: respectively the blank solvent of equal-volume (20ul), need testing solution are injected high performance liquid chromatograph, record color atlas is to 30min.Deduction blank solvent presses area normalization method computer chromatography purity, maximum list is mixed and total impurities.
Sample introduction sequence
| Loading sequence | Solution | Sample introduction needle number |
| 1 | Blank solution | 1 |
| 2 | Trial-product 1 solution | 1 |
| 3 | Trial-product 2 solution | 1 |
Result judges: the obtained oxiracetam fine work purity of method described in the application is high, and its chromatographic purity is not less than 99.7%, maximum contaminant is no more than 0.2%, total impurities is no more than 0.3%.
The application includes but not limited to above embodiment, and every any equivalent alternative or local improvement of carrying out under the principle of the application's spirit, all will be considered as within the protection domain of the application.
Claims (16)
1. a synthetic method for oxiracetam, is characterized in that comprising the steps:
(1) by ketene dimer, methylene dichloride mixing, add 20-30 DEG C of reaction after bromine, after having reacted, underpressure distillation removes methylene dichloride and obtains 4-bromo-3-oxo butyryl bromide;
(2) in 4-bromo-3-oxo butyryl bromide, drip ROH, in ROH, R is C1-C4 alkyl here, and reducing pressure after 30-50 minute 20-30 DEG C of reaction steams ROH solvent, and obtain Compound II per, wherein in Compound II per, R is C1-C4 alkyl;
(3) by Compound II per dissolve with methanol, reductive agent is added, after 15-20 DEG C of reaction completes, regulate pH=5.5-6.5, maintain 15-20 DEG C of reaction 0.5-1h, extract with water-insoluble organic solvent, get organic layer evaporated under reduced pressure and obtain compound III, wherein in compound III, R is C1-C4 alkyl;
(4) by mineral alkali, glycyl amide hydrochloride, ethanol mixing, rear dropping compound III, reflux 22-24h, filtered while hot, concentrated, then obtain oxiracetam crude product by methanol crystallization; Oxiracetam crude product refluxes in ROH solvent, obtains oxiracetam fine work after activated carbon decolorizing recrystallization; Here in ROH, R is C1-C4 alkyl;
2. synthetic method as claimed in claim 1, wherein, described ROH is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol or the trimethyl carbinol.
3. synthetic method as claimed in claim 2, wherein, described ROH is methyl alcohol, ethanol, propyl alcohol or butanols.
4. synthetic method as claimed in claim 3, wherein, described ROH is methyl alcohol.
5. synthetic method as claimed in claim 1, wherein, in step (3), reductive agent is red aluminium, POTASSIUM BOROHYDRIDE or sodium borohydride.
6. synthetic method as claimed in claim 5, wherein, in step (3), reductive agent is sodium borohydride.
7. synthetic method as claimed in claim 1, wherein, in step (4), mineral alkali is alkali metal hydroxide or alkaline carbonate.
8. synthetic method as claimed in claim 7, wherein, in step (4), mineral alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide.
9. synthetic method as claimed in claim 7, wherein, in step (4), mineral alkali is sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus.
10. synthetic method as claimed in claim 1, wherein, in step (3), the mol ratio that reductive agent and Compound II per feed intake is 2.5 ~ 3.5:1.
11. synthetic methods as claimed in claim 10, wherein, in step (3), the mol ratio that reductive agent and Compound II per feed intake is 2.5 ~ 3.0:1.
12. synthetic methods as claimed in claim 1, wherein, in step (3), regulate the pH to 5.5-6.5 of reaction solution with acetic acid.
13. synthetic methods as claimed in claim 1, wherein, in step (4), the mol ratio that described glycyl amide hydrochloride and compound III feed intake is 1.1 ~ 1.5:1.
14. synthetic methods as claimed in claim 1, wherein, in step (4), the time that compound III drips is 1.0h.
15. synthetic methods as claimed in claim 1, wherein, the water-insoluble organic solvent described in step (3) is selected from one or more the mixture in methylene dichloride, chloroform, 1,2-ethylene dichloride, ethyl acetate or methyl acetate.
16. synthetic methods as claimed in claim 15, wherein, the water-insoluble organic solvent described in step (3) is the one in methylene dichloride or ethyl acetate.
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| CN105330582B (en) * | 2014-08-07 | 2018-08-07 | 重庆润泽医药有限公司 | (R) preparation method of-Esomeprazole |
| CN105820101B (en) * | 2015-01-04 | 2018-12-18 | 哈尔滨三联药业股份有限公司 | A kind of preparation method of the pure 1- of optically-active (carbamoyl) methyl -4- hydroxy-2-pyrrolidinone |
| CN107021906A (en) * | 2016-01-29 | 2017-08-08 | 重庆润泽医药有限公司 | The method for preparing levo-oxiracetam crystal formation II |
| CN106631962B (en) * | 2016-09-30 | 2019-01-22 | 南京帝昌医药科技有限公司 | A kind of preparation method of (S)-Oxiracetam |
| CN112321444A (en) * | 2020-09-17 | 2021-02-05 | 江西邦浦医药化工有限公司 | Synthesis method of 4-bromo-3-oxo-N-phenylbutanamide |
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| CN101121688A (en) * | 2007-09-14 | 2008-02-13 | 南开大学 | Improved method for synthesizing oxiracetam |
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| CN101121688A (en) * | 2007-09-14 | 2008-02-13 | 南开大学 | Improved method for synthesizing oxiracetam |
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| 翟煜翥.4-氯乙酰乙酸乙酯的合成.《辽宁化工》.2001,第30卷(第6期),241-242. * |
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