CN102603603B - Method for preparing (S)-oxiracetam - Google Patents

Method for preparing (S)-oxiracetam Download PDF

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Publication number
CN102603603B
CN102603603B CN201110024485.4A CN201110024485A CN102603603B CN 102603603 B CN102603603 B CN 102603603B CN 201110024485 A CN201110024485 A CN 201110024485A CN 102603603 B CN102603603 B CN 102603603B
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ethyl ester
glycine ethyl
oxiracetam
ester hydrochloride
exchange resin
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CN102603603A (en
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叶雷
陈宇瑛
荣祖元
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Chongqing Runze Pharmaceutical Co Ltd
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Chongqing Runze Pharmaceutical Co Ltd
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Abstract

A method for preparing (S)-oxiracetam comprises the steps of conducting a reaction of a glycine ethyl ester hydrochloride with (S)-4-halogen-3-hydroxy-ethyl butyrate in an alcohol solvent in an alkaline condition, wherein the glycine ethyl ester hydrochloride and the (S)-4-halogen-3-hydroxy-ethyl butyrate are adopted as raw materials, filtering, washing filtrate with inorganic alcohol, concentrating, then extracting, separating and introducing ammonia water to prepare a crude product, and purifying the crude product; and dissociating the glycine ethyl ester hydrochloride into glycine ethyl ester by diethyl ether and ammonia gas firstly. Purification treatment comprises the steps that the crude product of (S)-oxiracetam is dissolved in a benign solvent to prepare a saturated solution, and then the saturated solution is dispersed in a closed environment by a poor solvent. According to the method, the main raw materials are low in cost, easy to obtain and environment-friendly; the glycine ethyl ester hydrochloride is adopted for dissociation, so that the using amount of the materials in the reaction is reduced effectively, the cost is lowered, and in addition, the glycine ethyl ester hydrochloride plays an active role in the reaction yield. The HPLC (high-performance liquid chromatography) purity of the prepared (S)-oxiracetam reaches up to more than 99.0%, the yield is high and reaches up to 36%, the reaction condition is moderate, the operation is simple, and the industrialized scale production is facilitated.

Description

One is prepared the method for (S)-oxiracetam
Technical field
The present invention relates to prepare the method for oxiracetam, be specifically related to the method that one is prepared (S)-oxiracetam, belong to the field of chemical synthesis.
Background technology
Oxiracetam (oxiracetam), be by Italian SmithKline Bi Qiemu company in 1974 synthetic nootropics first, this medicine went on the market in Italy in 1987, the raceme that oxiracetam is made up of two kinds of isomer (S)-oxiracetam ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam).About the report of oxiracetam, disclosing it is a kind of synthetic hydroxy-amino-butyric acid (GABOB) cyclic derivatives, can promote ATP in brain, promote vagusstoff to synthesize and strengthen the conduction of nervous excitation, there is an improved action to the antidromicity due to anoxic is forgetful, can hypermnesis, improve learning capacity, be one of active drug of the illnesss such as treatment dementia of the Alzheimer type (AD), vascular dementia (VD).
About the report of synthetic (S)-oxiracetam; United States Patent (USP) 4; 797; 496 and the method for preparing oxyracetam that discloses of WO 93/06826; in the document, disclosed method comprises from chiral beta-hydroxy butyrolactone and obtains chirality alkyl 3; 4-epoxy butyric ester; make products therefrom react and make products therefrom carry out N deprotection with the G-NH2 of N protection; then obtain the pure oxyracetam of optically-active through cyclisation; the step of the method is relatively less; but due to chirality alkyl 3,4-epoxy butyric ester synthesis yield is extremely low and cause the method cost high.US Patent No. 4173569 has been addressed the synthetic method of another kind of (s)-oxiracetam: (s)-GABOB is starting raw material, through sillylation reagent protection hydroxyl, product after cyclization reacts with halogenated acetic acids ethyl ester, reaction product is through Deprotection, ammonia solution, finally obtains target compound; This kind of preparation method is not suitable for commercial scale production, and using protecting group to carry out protection to hydroxyl can increase reactions steps, wastes raw material, consuming time longer, increases cost, and total recovery is reduced.
Summary of the invention
The object of the present invention is to provide that a kind of yield is high, purity is high, be particularly suitable for the preparation method of required (the S)-oxiracetam of medicinal application.
The present invention seeks to be achieved through the following technical solutions:
One is prepared the method for (S)-oxiracetam, it is characterized in that: adopting glycine ethyl ester hydrochloride is that raw material reacts under alcoholic solvent and alkaline condition with (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, with inorganic alkoxide washing, concentrated again through extraction, separate the purification process that passes into ammoniacal liquor and make (S)-oxiracetam crude product and crude product, described glycine ethyl ester hydrochloride first will adopt ether to dissociate into glycine ethyl ester with ammonia; Described purification process comprises (S)-oxiracetam crude product is dissolved in its optimum solvent, and at room temperature makes saturated solution, then under closed environment with its poor solvent diffusion.
The purification process of the thick product of the present invention is that thick product is also collected with passing through storng-acid cation exchange resin after water dissolution, then passes through in strongly basic anion exchange resin and the solution of collection, and the pH value that makes the solution of described collection completes while being neutral; Then the thick product after the solution of neutralization being collected concentrates is dissolved in its optimum solvent, and at room temperature makes saturated solution, then under closed environment, spreads with its poor solvent.
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 further to improve the present invention (S)-oxiracetam product yield 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: 6 milliliters.
The optimum solvent of the present invention refer to (S)-oxiracetam therein solubleness be greater than 10 grams/100 grams solvents, poor solvent refer to (S)-oxiracetam therein solubleness at 1 gram/solvent below 100 grams, be that those skilled in the art all know for optimum dissolving (easily broad dose) and the definition of poor solvent (slightly soluble or indissoluble solvent).
For (the S)-oxiracetam purity that makes to make is higher, the optimum solvent of the present invention is preferably dehydrated alcohol or propyl carbinol; Poor solvent of the present invention is preferably anhydrous diethyl ether, sherwood oil or normal hexane; Wherein agents useful for same all can be analytical pure or chemical purity rank.
For (S)-oxiracetam purity of further making to make is higher, crystallisate is more stable, the consumption of poor solvent of the present invention be (S)-oxiracetam saturated solution volume 3-8 doubly, preferable amount be 5-6 doubly.
The present invention adopts the temperature of poor solvent diffusion to be preferably 21-23 DEG C, is preferably 5-7 days diffusion time.
Specifically, purification process of the present invention is with also collecting by 732# storng-acid cation exchange resin after water dissolution by thick product, pass through again in 711# strongly basic anion exchange resin and the solution of collecting, the pH value that makes the solution of described collection completes while being neutral, the described laggard row ion exchange resin treatment of water dissolution for thick product, wherein thick product: water=1 gram: 0.6 milliliter, described thick product: described 732# storng-acid cation exchange resin=1 gram: 6 milliliters; Then the thick product after the solution of neutralization being collected concentrates is dissolved in dehydrated alcohol or propyl carbinol, at 18 DEG C, stir and make saturated solution, under closed environment, at 22 DEG C, spread 6 days with the anhydrous diethyl ether of 5.8 times of amounts of described saturated solution volume, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
For make reactant and product be easy to dissolve and react after processing facilitate, alcoholic solvent of the present invention is preferably anhydrous methanol or dehydrated alcohol; Due to destructible product under highly basic condition, in order to form and to be beneficial to the stable environment of product in reaction process, the alkaline condition in reaction process of the present invention is by adding mineral alkali regulation and control, preferably adding sodium bicarbonate; The present invention (S)-4-halogen-3-hydroxy-butyric acid ethyl ester preferably adopts (S)-4-chloro-3-hydroxyl-ethyl butyrate.
Due to the unsettled characteristic of glycine ethyl ester, therefore raw material is employing glycine ethyl ester hydrochloride but is in fact that glycine ethyl ester is participating in reaction, reduce costs, more fully glycine ethyl ester hydrochloride dissociated into glycine ethyl ester in order to reduce the consumption of reaction raw materials in reaction process of the present invention to improve yield simultaneously, the present invention preferably adds glycine ethyl ester hydrochloride in ether the free of glycine ethyl ester hydrochloride, then passes into ammonia at low temperatures.
The present invention is in the free treating processes of glycine ethyl ester hydrochloride, in order further to dissociate and to obtain glycine ethyl ester fully, its temperature that passes into ammonia is 0~-5 DEG C, more preferably-4 DEG C~-5 DEG C, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 1mol: 1000~1500ml: 1~1.5mol.
In order further to improve yield, the usage ratio of the 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, in weight part; More preferably, glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1: 1.3: 1.5, the consumption of anhydrous methanol is sodium bicarbonate 9 times.
Specifically, the preparation of the present invention (S)-oxiracetam crude product is first glycine ethyl ester hydrochloride to be added in anhydrous diethyl ether, ice-cold to-4 DEG C~-5 DEG C, pass into ammonia, filter, filtrate concentrating obtained to glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 1mol: 1000~1500ml: 1~1.5mol; Then add sodium bicarbonate and anhydrous methanol, dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate, the time of described dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate is 2~3 hours, controlling pH is 8~9, reacts 25~27 hours, and temperature of reaction is 65~70 DEG C; Filter, with the abundant wash filtrate of ethanol, concentrated, enriched material is water-soluble, add the chloroform of 4 times of filtrate weight to extract, water is concentrated, column chromatography for separation again, finally adding concentration expressed in percentage by weight is 25%~28% ammoniacal liquor, reacts and within 5~8 hours, make (S)-oxiracetam crude product 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, with molar ratio computing; The consumption of described anhydrous methanol is 5~10 times of sodium bicarbonate weight.
In order further to improve the yield of the present invention's preparation (S)-oxiracetam product, the preparation of the present invention (S)-oxiracetam crude product is first glycine ethyl ester hydrochloride to be added in anhydrous diethyl ether, ice-cold to-4 DEG C~-5 DEG C, pass into ammonia, filter, filtrate concentrating obtained to glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 1mol: 1150ml: 1.1mol; Then add anhydrous methanol, sodium bicarbonate and dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate, described time for adding is 2.8 hours, and controlling pH is 8.5, and temperature of reaction is 65 DEG C, reacts 27 hours; Filter, with the abundant wash filtrate of ethanol, concentrated, enriched material is water-soluble, add the chloroform of 4 times of filtrate weight to extract, water is concentrated, column chromatography for separation again, finally adding concentration expressed in percentage by weight is 27% ammoniacal liquor, reacts and within 5 hours, make (S)-Esomeprazole crude product at 22 DEG C; Described glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1: 1.3: 1.5, with molar ratio computing; The consumption of described anhydrous methanol is 9 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, pollution-free of raw material; Meanwhile, the present invention first glycine ethyl ester hydrochloride carries out described free processing, has effectively reduced the consumption of material in reaction, has reduced cost, the yield of reaction is also played a positive role simultaneously.The yield of (S)-oxiracetam prepared by the present invention is high, can be up to 36%, reaction conditions gentleness, cycle be short, simple to operate is beneficial to commercial scale production, and (the S)-oxiracetam product HPLC purity simultaneously making reaches more than 99.0%.
2, the present invention has adopted ion exchange resin treatment in purifying the finished product (S)-oxiracetam; compared with available technology adopting silica gel column chromatography method; although treatment effect is suitable; but ion exchange resin can repeatedly be regenerated and reuse on the one hand, has reduced cost; ion exchange resin is to carry out wash-out with pure water on the other hand; avoid with an organic solvent, pollution-free, simultaneously preferably for the large production of large-scale industrial.The present invention selects optimum dissolution with solvents, the poor solvent method of diffusion of suitable (S)-oxiracetam, effectively reduce foreign matter content, significantly improved the quality of the finished product, and use majority of organic solvent toxicity little, pollute low, the water using 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.
Embodiment
Below by embodiment, the present invention is specifically described; be necessary to be pointed out that at this 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 to the present invention according to the invention described above content.
Embodiment 1
One is prepared the method for (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) first glycine ethyl ester hydrochloride is added in anhydrous diethyl ether, ice-cold to-4 DEG C~-5 DEG C, pass into ammonia, filter, filtrate concentrating obtained to glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 139.6g: 1150ml: 18.7g; Add sodium bicarbonate 109.2g, anhydrous methanol 983ml and dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate 250.0g, described time for adding is 2.8 hours, keeps pH8.5 and temperature to be 65 DEG C, to react 27 hours;
(b) filter, with the abundant wash filtrate of ethanol, concentrated, enriched material is water-soluble, add the chloroform of 4 times of filtrate weight to extract again, water is concentrated, column chromatography for separation; Finally adding mass concentration is 27% ammoniacal liquor, reacts and within 5 hours, make (S)-oxiracetam crude product at 22 DEG C;
Wherein glycine ethyl ester: sodium bicarbonate: (S)-4-chloro-3-hydroxyl-ethyl butyrate=1: 1.3: 1.5, with molar ratio computing, the consumption of anhydrous methanol was 9 times of sodium bicarbonate weight;
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 732# storng-acid cation exchange resin, then neutralize and collect solution, concentrated by 711# strongly basic anion exchange resin; Described crude product: water=1 gram: 0.6 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 6 milliliters;
(b) the thick product after the solution of then neutralization being collected concentrates is dissolved in dehydrated alcohol, at 18 DEG C, stir and make saturated solution, under closed environment, at 22 DEG C, spread 6 days with the anhydrous diethyl ether of 5.8 times of amounts of described saturated solution volume, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-4-hydroxyl-2-oxo-N-pyrrolidine acetamide product finally making reaches 99.22%, and yield is up to 36%.
Embodiment 2
One is prepared the method for (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) adopt anhydrous diethyl ether, with ammonia, glycine ethyl ester hydrochloride is dissociated into glycine ethyl ester, add sodium carbonate, anhydrous methanol and dropping (the S)-bromo-3-hydroxy-butyric acid of 4-ethyl ester, described time for adding is 2.5 hours, is at 70 DEG C, to react 25 hours in pH8.0, temperature;
(b) filter, with the abundant wash filtrate of ethanol, concentrated, enriched material is water-soluble, add the methylene dichloride of 5 times of filtrate weight to extract again, water is concentrated, column chromatography for separation; Finally add ammoniacal liquor, at 20 DEG C, react and within 7 hours, make (S)-oxiracetam crude product;
Wherein glycine ethyl ester: sodium carbonate: the bromo-3-hydroxy-butyric acid of (S)-4-ethyl ester=1: 0.5: 1, with molar ratio computing, the consumption of anhydrous methanol was 6 times of sodium carbonate weight;
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 732# storng-acid cation exchange resin, then neutralize and collect solution, concentrated by 711# strongly basic anion exchange resin; Described crude product: water=1 gram: 0.6 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 10 milliliters;
(b) the thick product after the solution of then neutralization being collected concentrates is dissolved in propyl carbinol, at 25 DEG C, stir and make saturated solution, under closed environment, at 21 DEG C, spread 5 days with the sherwood oil of 4 times of amounts of described saturated solution volume, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-oxiracetam product finally making reaches 99.01%, and yield reaches 35%.
Embodiment 3
A kind of preparation method of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) adopt ether, with ammonia, glycine ethyl ester hydrochloride is dissociated into glycine ethyl ester, drip the iodo-3-hydroxy-butyric acid of (S)-4-ethyl ester, add dehydrated alcohol and sodium bicarbonate, described time for adding is 2.3 hours, is at 67 DEG C, to continue to keep 28 hours at pH8.5 and temperature;
(b) then fully wash, concentrate with ethanol, then add 6 times of ethyl acetate of measuring filtrates to extract, concentrate column chromatography for separation; Finally add strong aqua, at 30 DEG C, react and within 8 hours, make (S)-oxiracetam crude product;
Wherein glycine ethyl ester: saleratus: the iodo-3-hydroxy-butyric acid of (S)-4-ethyl ester=1: 1.0: 1.0, with molar ratio computing, the consumption of dehydrated alcohol was 8 times of sodium bicarbonate weight;
2, the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by 001 × 7 strongly acidic styrene type cation exchange resin, then neutralize and collect solution, concentrated by 201 × 7 basicity styrene series anion exchange resins;
(b) the thick product after the solution then neutralization collected is concentrated is dissolved in propyl carbinol, at room temperature stir and make saturated solution, under closed environment with normal hexane diffusion, by the crystal of separating out after filtration, dry (S)-oxiracetam product that obtains.
The HPLC purity of (the S)-oxiracetam product finally making reaches 99.1%, and yield reaches 28%.
Embodiment 4~8:
A kind of preparation method of (S)-oxiracetam, is undertaken by following material and processing parameter, and all the other are with embodiment 1.
The HPLC purity of (S)-oxiracetam product that above embodiment finally makes reaches 99.0%~99.2%, and yield reaches 28%~34%.

Claims (1)

1. prepare the method for (S)-Olaxiracetam for one kind, it is characterized in that: first glycine ethyl ester hydrochloride is added in anhydrous diethyl ether, ice-cold to-4 DEG C~-5 DEG C, pass into ammonia, filter, filtrate concentrating obtained to glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 1mol:1000~1500ml:1~1.5 mol; Then add sodium bicarbonate and anhydrous methanol, dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate, the time of described dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate is 2~3 hours, controlling pH is 8~9, reacts 25~27 hours, and temperature of reaction is 65~70 DEG C; Filter, fully wash filter residue, concentrated with ethanol, enriched material is water-soluble, add the chloroform of 4 times of filtrate weight to extract, water is concentrated, column chromatography for separation again, finally adding concentration expressed in percentage by weight is 25%~28% ammoniacal liquor, reacts and within 5~8 hours, make (S)-Olaxiracetam crude product 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, with molar ratio computing; The consumption of described anhydrous methanol is 5~10 times of sodium bicarbonate weight, in weight part; Described purification process is with also collecting by 732# storng-acid cation exchange resin after water dissolution by thick product, pass through again in 711# strongly basic anion exchange resin and the solution of collecting, the pH value that makes the solution of described collection completes while being neutral, the described laggard row ion exchange resin treatment of water dissolution for thick product, wherein thick product: water=1 gram: 0.6 milliliter, described thick product: described 732# storng-acid cation exchange resin=1 gram: 6 milliliters; Then the thick product after the solution of neutralization being collected concentrates is dissolved in dehydrated alcohol or propyl carbinol, at 18 DEG C, stir and make saturated solution, under closed environment, at 22 DEG C, spread 6 days with the anhydrous diethyl ether of 5.8 times of amounts of described saturated solution volume, by the crystal of separating out after filtration, the dry (S)-Olaxiracetam product that obtains.
CN201110024485.4A 2011-01-21 2011-01-21 Method for preparing (S)-oxiracetam Active CN102603603B (en)

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Families Citing this family (4)

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Publication number Priority date Publication date Assignee Title
WO2013159283A1 (en) * 2012-04-24 2013-10-31 重庆润泽医疗器械有限公司 Method for preparing (s)-oxiracetam
CN105439936A (en) * 2014-08-07 2016-03-30 重庆东泽医药科技发展有限公司 Oxiracetam preparation method
CN105330581A (en) * 2014-08-07 2016-02-17 重庆东泽医药科技发展有限公司 Preparation method for (S)-oxiracetam
CN107021910A (en) * 2016-01-29 2017-08-08 重庆润泽医药有限公司 The method for preparing S-oxiracetam crystal formation II

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5276164A (en) * 1990-06-26 1994-01-04 Lonza Ltd. Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide
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
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5276164A (en) * 1990-06-26 1994-01-04 Lonza Ltd. Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide
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
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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