CN103739538B - A kind of preparation method of (S)-Olaxiracetam - Google Patents
A kind of preparation method of (S)-Olaxiracetam Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
Abstract
A kind of preparation method of (S)-Olaxiracetam, it is characterized in that: adopt glycine ethyl ester hydrochloride and (S)-4-halogen-3-hydroxy-butyric acid ethyl ester to be that raw material reacts under alcoholic solvent and alkaline condition, filter, through inorganic alkoxide washing, concentrated again through extraction, be separated and pass into the purification process that ammoniacal liquor obtains (S)-Olaxiracetam crude product and crude product, wherein glycine ethyl ester hydrochloride first adopts ether to dissociate into glycine ethyl ester with ammonia; The described purification process to crude product comprises that to adopt weight part ratio to be the water of 1:5 ~ 20 and acetone be that solvent carries out recrystallization process.The yield height of (S)-oxiracetam prepared by the present invention can up to 36%, (the S)-oxiracetam product HPLC purity obtained can up to more than 99.4%, and simultaneous reactions mild condition, cycle be short, simple to operate is beneficial to commercial scale production.
Description
The present patent application is application number 201110024010.5, the applying date on 01 21st, 2011, the divisional application of denomination of invention " preparation method of (S)-Olaxiracetam ".
Technical field
The present invention relates to the preparation of oxiracetam, be specifically related to the preparation method of (S)-Olaxiracetam.
Background technology
Oxiracetam (oxiracetam), it is the nootropics synthesized first in 1974 than Qie Mu company by Italian SmithKline, this medicine went on the market in 1987 in Italy, the raceme that oxiracetam is made up of two kinds of isomer (S)-oxiracetams ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam).About the report of oxiracetam, hydroxy-amino-butyric acid (GABOB) cyclic derivatives that it is a kind of synthesis is disclosed, ATP in brain can be promoted, promote that vagusstoff synthesizes and strengthens the conduction of nervous excitation, improved action is had to the antidromicity caused by anoxic is forgetful, can hypermnesis, improving learning capacity, is one of active drug of the illnesss such as treatment dementia of the Alzheimer type (AD), vascular dementia (VD).
About the report of synthesis (S)-oxiracetam ((S)-4-hydroxyl-2-oxo-N-pyrrolidin ethanamide), United States Patent (USP) 4,824,966,4,843,166 and 5,276,164 preparation methods disclosing oxiracetam and intermediate thereof, method disclosed in these patents comprises makes 4-(C
1-C
2)-alkoxyl group-3-pyrroline-2-one-l-base-acetic acid (C
l-C
4)-alkyl ester and trichloromethyl silane react to protect hydroxyl, then carry out hydrogenation and amidation to products therefrom, according to the method, obtain racemize oxiracetam through hydrogenation reduction; Therefore, the method has the shortcoming not being suitable for preparation optically-active pure oxiracetam, in addition, 4-(C1-C2)-alkoxyl group-3-pyrroline-2-one-1-base-acetic acid (C1-C4)-alkyl ester to prepare yield low.The open 2000-9456 of Korean Patent discloses the method preparing optically-active pure (s)-oxiracetam, in the method, first from optically-active pure (s)-3-HBL synthesis (s)-3,4-epoxy butyrate is as the intermediate under aqueous conditions, then, under aqueous conditions with G-NH2 by this midbody compound amidation, with cyclisation; Although this technology seems industrially have advantage in yield and purity compared with above-mentioned method, but its shortcoming is because purity low the causing of (s)-3-HBL produces a lot of impurity, and prepare highly purified (s)-3-HBL and can't reach, therefore, the method does not obtain having the oxiracetam being suitable for purity needed for medicinal application.
Summary of the invention
The object of the present invention is to provide that a kind of yield is high, the high (S)-Olaxiracetam preparation method being suitable for purity needed for medicinal application of purity.
The present invention seeks to be achieved through the following technical solutions:
A kind of preparation method of (S)-Olaxiracetam, it is characterized in that: adopt glycine ethyl ester hydrochloride and (S)-4-halogen-3-hydroxy-butyric acid ethyl ester to be that raw material reacts under alcoholic solvent and alkaline condition, filter, wash through inorganic alkoxide, concentrated again through extraction, be separated and pass into the purification process that ammoniacal liquor obtains (S)-Olaxiracetam crude product and crude product, wherein glycine ethyl ester hydrochloride first will add in ether, under the low temperature of 0 ~-10 DEG C, pass into ammonia again make it to dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride, it is 1mol:1000 ~ 1500ml:1 ~ 1.5mol that the usage ratio of ether and ammonia is closed, the described purification process to crude product is collected after thick product water dissolution by storng-acid cation exchange resin, pass through in strongly basic anion exchange resin again and the solution collected, make the pH value of the solution of described collection for completing time neutral, it is that solvent carries out recrystallization process that the thick product after then being concentrated by the solution that neutralization is collected adopts weight part ratio to be the water of 1:5 ~ 20 and acetone.
Above by before ion exchange resin by thick product water dissolution, wherein thick product: water=1 gram: 1.0 milliliters.
In order to improve exchange capacity, exchange velocity, storng-acid cation exchange resin of the present invention is preferably 732# storng-acid cation exchange resin; Strongly basic anion exchange resin of the present invention is preferably 711# strongly basic anion exchange resin.
In order to further improve (S)-Olaxiracetam product yield of the present invention and purity, in purification process process of the present invention, the consumption of described storng-acid cation exchange resin is: described thick product: described storng-acid cation exchange resin=1 gram: 10 milliliters.
In order to improve the purity of the finished product, recrystallization process of the present invention carries out at-10 ~ 10 DEG C.
In order to improve the purity of the finished product of the present invention further, recrystallization process of the present invention is by dissolving crude product in water, at-10 ~ 10 DEG C, be added dropwise to acetone, stirs 0.5 ~ 12h, obtains crystallized product; The weight part of described crude product and water is 1:0.4 ~ 0.7, and the weight part ratio of water and acetone is 1:5 ~ 20; More preferably, at 2 ~ 5 DEG C, be added dropwise to acetone, stir 1 ~ 4h, obtain crystallized product; The weight part of described crude product and water is 1:0.5 ~ 0.6, and the weight part ratio of water and acetone is 1:6 ~ 10.
Purification process of the present invention, more preferably before crystallisation process, is first refined obtained crude product, and the ethanol specifically adding 2 ~ 8 times of above-mentioned crude product weight stirs, and leaches, obtained refined products; Or/and carry out recrystallize (secondary crystal) after above-mentioned recrystallization process.In order to be distinguished by above-mentioned crystallisation process, recrystallize is here called secondary crystal, and above-mentioned recrystallization process is called primary crystallization.
Secondary crystal of the present invention is by water-soluble for above-mentioned primary crystallization product, at-10 ~ 10 DEG C, be added dropwise to acetone, stirs 0.5 ~ 12h, obtains secondary crystal product; The weight part ratio of described primary crystallization product and water is 1:0.4 ~ 0.7, and the weight part ratio of water and acetone is 1:5 ~ 20.
In order to further improve the purity of final product, refinement treatment of the present invention is that the ethanol adding its weight 4.5 times in the crude product after being concentrated by ion exchange resin treatment is stirred, and leaches, obtained refined products; Primary crystallization of the present invention is that at 2 DEG C, be added dropwise to acetone, stir 2h, obtain crystallized product, the weight part of described crude product and water is 1:0.4, and the weight part ratio of water and acetone is 1:6 by water-soluble through refining or after being concentrated by ion exchange resin treatment crude product; Secondary crystal of the present invention is by water-soluble for primary crystallization product, at 8 DEG C, be added dropwise to acetone, and stir 5h, obtain secondary crystal product, the weight part ratio of described primary crystallization product and water is 1:0.7, and the weight part ratio of water and acetone is 1:15.
In order to reduce reaction raw materials in reaction process of the present invention consumption, reduce costs, simultaneously that glycine ethyl ester hydrochloride is free to improve yield and to be beneficial to purification process more fully, glycine ethyl ester hydrochloride preferably adds in ether to the free of glycine ethyl ester hydrochloride by the present invention, pass into ammonia at low temperatures again, described in pass into ammonia temperature be preferably 0 ~-5 DEG C.
Specifically, the free process of the present invention to glycine ethyl ester hydrochloride adds in anhydrous diethyl ether by glycine ethyl ester hydrochloride, ice-cold to-2 DEG C ~-3 DEG C, pass into ammonia, filter, filtrate is concentrated to obtain glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia is closed is 1mol:1200ml:1.5mol.
In order to improve yield and purity further, the present invention (S)-4-halogen-3-hydroxy-butyric acid ethyl ester preferably adopts ATS-4, and alcoholic solvent preferably adopts anhydrous methanol, and alkali is preferably sodium bicarbonate; The usage ratio of each material of the present invention is preferably glycine ethyl ester with molar ratio computing: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1:0.8 ~ 1.3:1 ~ 1.5, the consumption of described anhydrous methanol is 5 ~ 10 times of sodium bicarbonate, with parts by weight; More preferably, glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1:1.2:1.5, the consumption of anhydrous methanol is 7 times of sodium bicarbonate.
Specifically, the preparation of (S)-oxiracetam crude product of the present invention first adds in anhydrous diethyl ether by glycine ethyl ester hydrochloride, ice-cold to-2 DEG C ~-3 DEG C, pass into ammonia, filter, filtrate is concentrated to obtain glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia is closed is 1mol:1200ml:1.5mol; Then sodium bicarbonate and anhydrous methanol or dehydrated alcohol is added, drip (S)-4-chloro-3-hydroxyl-ethyl butyrate, the time of described dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate is 2 ~ 3 hours, control pH is 8 ~ 9, temperature of reaction is 65 ~ 70 DEG C, reacts 25 ~ 30 hours; Filter, with the abundant wash filtrate of ethanol, concentrated, enriched material is water-soluble, then the chloroform adding 2 ~ 4 times of filtrate weight carries out extracting, aqueous phase concentrates, column chromatography for separation; Finally add strong aqua, react 5 ~ 8 hours at 20 ~ 30 DEG C; Described glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1:0.8 ~ 1.3:1 ~ 1.5, the consumption of described anhydrous methanol is 5 ~ 10 times of sodium bicarbonate weight.
The yield of (S)-oxiracetam is prepared in order to further improve the present invention, the preparation of (S)-oxiracetam crude product of the present invention first adds in anhydrous diethyl ether by glycine ethyl ester hydrochloride, ice-cold to-2 DEG C ~-3 DEG C, pass into ammonia, filter, filtrate is concentrated to obtain glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia is closed is 1mol:1200ml:1.5mol; Then add (the S)-4-chloro-3-hydroxyl-ethyl butyrate described in sodium bicarbonate, anhydrous methanol and dropping, drip 3 hours, control pH is 8, and temperature of reaction is 68 DEG C, reacts 28 hours; Filter, with the abundant wash filtrate of ethanol, concentrate, then the chloroform adding 4 times of filtrate weight carries out extracting, concentrating, column chromatography for separation; Finally add the ammoniacal liquor that mass percentage concentration is 28%, react 8 hours at 21 DEG C; Described glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1:1.2:1.5, with molar ratio computing, the consumption of anhydrous methanol or dehydrated alcohol is 7 times of sodium bicarbonate weight.
The present invention has following beneficial effect:
1, the main raw material that the present invention uses is (S)-4-halogen-ethyl 3-hydroxybutanoate and glycine ethyl ester hydrochloride, is commercial goods, the cheap and easy to get and environmental protection of raw material, pollution-free; Meanwhile, the present invention first glycine ethyl ester hydrochloride carries out described free process, effectively reduces the consumption of material in reaction, reduces cost, also serves very positive effect to the yield of reaction simultaneously.
2, the present invention have employed ion exchange resin treatment in purifying the finished product (S)-oxiracetam; with adopt compared with silica gel column chromatography method in prior art; although treatment effect is suitable; but ion exchange resin repeatedly can regenerate and reuse on the one hand, reduces cost; ion exchange resin uses pure water to carry out wash-out on the other hand; avoid with an organic solvent, pollution-free, simultaneously preferably for the large production of large-scale industrial.Adopt acetone and water as the solvent in crystallisation process, effectively reduce foreign matter content, significantly improve the quality of the finished product, the majority of organic solvent toxicity used in the present invention is little, it is low to pollute, the water used in last handling process is pollution-free avirulent especially, so the present invention is not only suitable for suitability for industrialized production, also meet national requirements for environmental protection.
3, the yield height of (S)-oxiracetam that prepared by the present invention can up to 36%, (the S)-oxiracetam product HPLC purity obtained can up to more than 99.4%, and simultaneous reactions mild condition, cycle be short, simple to operate is beneficial to commercial scale production.
Embodiment
Below by embodiment, the present invention is specifically described; what be necessary to herein means out is that following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make some nonessential improvement and adjustment according to the invention described above content to the present invention.
Embodiment 1
A preparation method for (S)-Olaxiracetam, carries out as follows:
1, the preparation of crude product:
A glycine ethyl ester hydrochloride 139.6g adds in anhydrous diethyl ether 1200ml by (), ice-cold to-2 DEG C, passing into ammonia 25.5g makes glycine ethyl ester hydrochloride fully dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: ether: ammonia=1mol:1200ml:1.5mol;
B () adds sodium bicarbonate 100.8g, dehydrated alcohol 705ml and drips ATS-4 250.0g in above-mentioned glycine ethyl ester, described time for adding is 3 hours, reacts 28 hours at pH8.0, temperature are 68 DEG C;
C () filters, with the abundant wash filtrate of ethanol, concentrated, then the chloroform adding 4 times of filtrate weight carry out extracting, concentrated, column chromatography for separation; Finally add 25% strong aqua, at 21 DEG C, react 8 hours obtained (S)-Olaxiracetam crude products;
Wherein glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1:1.2:1.5, with molar ratio computing, the consumption of dehydrated alcohol is 7 times of sodium bicarbonate weight;
2, the purifying of crude product:
A (), with water dissolution above-mentioned obtained crude product, by 732# storng-acid cation exchange resin, is then neutralized by 711# strongly basic anion exchange resin and collects solution, concentrated; Described crude product: water=1.0 gram: 1.0 milliliters, described thick product: described storng-acid cation exchange resin=1 gram: 10 milliliters;
B then crude product after concentrating above by ion exchange resin adopts ethanol to carry out refinement treatment by (), the ethanol adding crude product weight 4.5 times stirs, leaches, obtained refined products; Then carry out primary crystallization process, by water-soluble for the crude product after refining, at 2 DEG C, be added dropwise to acetone, stir 2h, obtain crystallized product, the weight part of described crude product and water is 1:0.4, and the weight part ratio of water and acetone is 1:6; Finally carry out secondary crystal process, by water-soluble for primary crystallization product, at 8 DEG C, be added dropwise to acetone, stir 5h, obtain secondary crystal product, the weight part ratio of described primary crystallization product and water is 1:0.7, and the weight part ratio of water and acetone is 1:15.
The HPLC purity of final obtained (S)-Olaxiracetam product reaches 99.65%, and yield is 36%.
Embodiment 2
A preparation method for (S)-Olaxiracetam, carries out as follows:
1, the preparation of crude product:
A glycine ethyl ester hydrochloride adds in anhydrous diethyl ether by (), ice-cold to 0 DEG C, passes into ammonia and makes glycine ethyl ester hydrochloride fully dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: ether: ammonia=1mol:1000ml:1mol;
B () adds sodium carbonate, anhydrous methanol and the bromo-3-hydroxy-butyric acid ethyl ester of dropping (S)-4-in above-mentioned glycine ethyl ester, described time for adding is 2.5 hours, reacts 25 hours at pH8.0, temperature are 70 DEG C;
C () filters, with the abundant wash filtrate of ethanol, concentrated, then the ethyl acetate adding 5 times of filtrate weight carry out extracting, concentrated, column chromatography for separation; Finally add strong aqua, at 20 DEG C, react 5 hours obtained (S)-Olaxiracetam crude products;
Wherein glycine ethyl ester: sodium carbonate: the bromo-3-hydroxy-butyric acid ethyl ester=1:1:1 of (S)-4-, with molar ratio computing, the consumption of anhydrous methanol is 6 times of sodium carbonate weight;
2, the purifying of crude product:
A (), with water dissolution above-mentioned obtained crude product, by storng-acid cation exchange resin, is then neutralized by strongly basic anion exchange resin and collects solution, concentrated; Described crude product: water=1 gram: 0.6 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 8 milliliters;
B then crude product after concentrating above by ion exchange resin adopts ethanol to carry out refinement treatment by (), the ethanol adding crude product weight 2 times stirs, leaches, obtained refined products; Then carry out primary crystallization process, by water-soluble for the crude product after refining, at-10 DEG C, be added dropwise to acetone, stir 1h, obtain crystallized product, the weight part of described crude product and water is 1:0.7, and the weight part ratio of water and acetone is 1:5.
The HPLC purity of final obtained (S)-Olaxiracetam product reaches 99.53%, and yield reaches 33%.
Embodiment 3
A preparation method for (S)-Olaxiracetam, carries out as follows:
1, the preparation of crude product:
A glycine ethyl ester hydrochloride adds in ether by (), under the low temperature of 0 ~-10 DEG C, pass into ammonia make it to dissociate into glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia is closed is 1mol:1000 ~ 1500ml:1 ~ 1.5mol;
B () adds sodium carbonate, dehydrated alcohol and the iodo-3-hydroxy-butyric acid ethyl ester of dropping (S)-4-in above-mentioned glycine ethyl ester;
C () filters, with the abundant wash filtrate of ethanol, concentrated, then the methylene dichloride adding 7 times of filtrate weight carry out extracting, concentrated, column chromatography for separation; Finally add strong aqua, at 30 DEG C, react 8 hours obtained (S)-Olaxiracetam crude products;
2, the purifying of crude product:
A (), with water dissolution above-mentioned obtained crude product, by 001 × 7 strongly acidic styrene type cation exchange resin, then neutralize by 201 × 7 basicity styrene series anion exchange resins and collects solution, concentrates;
B then crude product after concentrating above by ion exchange resin is carried out recrystallization process by (), crude product is water-soluble, is added dropwise to acetone, and stir and obtain crystallized product, the weight part ratio of described water and acetone is 1:5 ~ 20.
The HPLC purity of final obtained (S)-Olaxiracetam product reaches 99.0%, and yield reaches 30%.
Embodiment 4 ~ 8:
A preparation method for (S)-Olaxiracetam, undertaken by following material and processing parameter, all the other are with embodiment 1.
The HPLC purity of the (S)-Olaxiracetam product that above embodiment finally obtains reaches 99.4% ~ 99.7%, and yield reaches 28% ~ 34%.
Claims (1)
1. a preparation method for (S)-Olaxiracetam, is characterized in that, carries out as follows:
(1), the preparation of crude product:
A glycine ethyl ester hydrochloride 139.6g adds in anhydrous diethyl ether 1200ml by (), ice-cold to-2 DEG C, passes into ammonia 25.5g and makes glycine ethyl ester hydrochloride fully dissociate into glycine ethyl ester;
B () adds sodium bicarbonate 100.8g, dehydrated alcohol 705ml and drips ATS-4 250.0g in above-mentioned glycine ethyl ester, described time for adding is 3 hours, reacts 28 hours at pH8.0, temperature are 68 DEG C;
C () filters, with the abundant wash filtrate of ethanol, concentrated, then the chloroform adding 4 times of filtrate weight carry out extracting, concentrated, column chromatography for separation; Finally add 25% strong aqua, at 21 DEG C, react 8 hours obtained (S)-Olaxiracetam crude products;
(2), the purifying of crude product:
A (), with water dissolution above-mentioned obtained crude product, by 732# storng-acid cation exchange resin, is then neutralized by 711# strongly basic anion exchange resin and collects solution, concentrated; Described crude product: water=1.0 gram: 1.0 milliliters, described thick product: described storng-acid cation exchange resin=1 gram: 10 milliliters;
B then crude product after concentrating above by ion exchange resin adopts ethanol to carry out refinement treatment by (), the ethanol adding crude product weight 4.5 times stirs, leaches, obtained refined products; Then carry out primary crystallization process, by water-soluble for the crude product after refining, at 2 DEG C, be added dropwise to acetone, stir 2h, obtain crystallized product, the weight part of described crude product after refining and water is 1:0.4, and the weight part ratio of water and acetone is 1:6; Finally carry out secondary crystal process, by water-soluble for primary crystallization product, at 8 DEG C, be added dropwise to acetone, stir 5h, obtain secondary crystal product, the weight part ratio of described primary crystallization product and water is 1:0.7, and the weight part ratio of water and acetone is 1:15.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4629797A (en) * | 1984-04-02 | 1986-12-16 | I.S.F. Societa Per Azioni | Process for the preparation of pyrrolidone derivatives |
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101239938A (en) * | 2008-03-10 | 2008-08-13 | 苏州凯达生物医药技术有限公司 | Method for preparing (S)-4-hydroxypyrrolidone and derivatives thereof |
| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
-
2011
- 2011-01-21 CN CN2011100240105A patent/CN102603601B/en active Active
- 2011-01-21 CN CN201310699877.XA patent/CN103739538B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4629797A (en) * | 1984-04-02 | 1986-12-16 | I.S.F. Societa Per Azioni | Process for the preparation of pyrrolidone derivatives |
| US4788300A (en) * | 1984-04-02 | 1988-11-29 | I.S.F. Societa Per Azioni | Substituted butanamido acetate compounds for the preparation of pyrrolidone derivatives |
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN101239938A (en) * | 2008-03-10 | 2008-08-13 | 苏州凯达生物医药技术有限公司 | Method for preparing (S)-4-hydroxypyrrolidone and derivatives thereof |
| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
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