CN102603600A - Method for preparing (S)-oxiracetam - Google Patents
Method for preparing (S)-oxiracetam Download PDFInfo
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- CN102603600A CN102603600A CN2011100240088A CN201110024008A CN102603600A CN 102603600 A CN102603600 A CN 102603600A CN 2011100240088 A CN2011100240088 A CN 2011100240088A CN 201110024008 A CN201110024008 A CN 201110024008A CN 102603600 A CN102603600 A CN 102603600A
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- ethyl ester
- glycine ethyl
- oxiracetam
- ester hydrochloride
- butyrate
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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 under 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
Technical field
The present invention relates to prepare the method for oxiracetam, be specifically related to the method for a kind of preparation (S)-oxiracetam, belong to the field of chemical synthesis.
Background technology
Oxiracetam (oxiracetam); Be by Italian SmithKline than Qie Mu company in 1974 synthetic nootropics first; This medicine in 1987 in Italy listing, oxiracetam by two kinds of isomer (S)-oxiracetam ((S)-oxiracetam) with (R)-oxiracetam (raceme of (R)-oxiracetam) form.Report about oxiracetam; Disclosing it is a kind of synthetic hydroxy-amino-butyric acid (GABOB) cyclic derivatives, can promote ATP in the brain, promotes vagusstoff to synthesize and strengthen the conduction of nervous excitation; To the antidromicity due to the anoxic is forgetful improved action arranged; Can hypermnesis, improve learning capacity, be one of active drug of treatment DAT (AD), vascular dementia illnesss such as (VD).
About the report of synthetic (S)-oxiracetam, USP 4,797; 496 methods that prepare oxyracetam that disclose with WO 93/06826; Disclosed method comprises from chiral beta-hydroxy GBL acquisition chirality alkyl 3 in the document, and 4-epoxy butyric ester makes the G-NH2 reaction of products therefrom and N protection and makes products therefrom carry out the N deprotection; Obtain the pure oxyracetam of optically-active through cyclisation then; The step of this method is less relatively, but because chirality alkyl 3, and 4-epoxy butyric ester synthesis yield is extremely low and cause this method cost high.U.S. Pat 4173569 has been addressed the compound method of another kind of (s)-oxiracetam: (s)-and GABOB is a starting raw material; Through sillylation reagent protection hydroxyl; Product after the cyclization and the reaction of halogenated acetic acids ethyl ester; Reaction product is through the deprotection base, and ammonia is separated, and obtains target compound at last; This kind preparation method is not suitable for commercial scale prodn, and using the protection base that hydroxyl is protected can increase reactions step, 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 the preparation method that a kind of yield is high, purity is high, be particularly suitable for required (the S)-oxiracetam of medicinal application.
The present invention seeks to realize through following technical scheme:
The method of a kind of preparation (S)-oxiracetam; It is characterized in that: adopt glycine ethyl ester hydrochloride with (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is that raw material reacts under alcoholic solvent and alkaline condition; Filtration, inorganic alkoxide wash filtrate, the concentrated purification process that makes (S)-oxiracetam bullion and bullion again through extraction, separation feeding ammoniacal liquor, said glycine ethyl ester hydrochloride will adopt ether to dissociate into glycine ethyl ester with ammonia earlier; Said purification process be earlier with thick product with water dissolution after through strongly acidic cationic exchange resin and collect; Pass through in the strongly basic anion exchange resin again and the solution of collecting; When being neutral, the pH value that makes the solution of said collection accomplishes; Thick product after the solution concentration of collecting that will neutralize then is dissolved in its optimum solvent; And at room temperature process saturated solution, and under closed environment, spreading then with its poor solvent, the consumption of said poor solvent is 3-8 a times of (S)-oxiracetam saturated solution volume; The temperature of said employing poor solvent diffusion is 21-23 ℃, and be 5-7 days diffusion time.
In order to improve exchange capacity, exchange velocity, strongly acidic cationic exchange resin of the present invention is preferably the 732# strongly acidic cationic exchange resin; Strongly basic anion exchange resin of the present invention is preferably the 711# strongly basic anion exchange resin.
In order further to improve the present invention (S)-oxiracetam product yield and purity, in the purification process process of the present invention, the consumption of said strongly acidic cationic exchange resin is: said thick product: said strongly acidic cationic exchange resin=1 gram: 6 milliliters.
The optimum solvent of the present invention be meant (S)-oxiracetam within it solubleness greater than 10 the gram/100 the gram solvents; Poor solvent is meant (the S)-oxiracetam solvent of solubleness below 1 gram/100 grams within it, is that those skilled in the art all know for the optimum dissolving (being prone to broad dose) and the definition of poor solvent (slightly soluble or indissoluble solvent).
In order to make (the S)-oxiracetam purity that makes higher, the optimum solvent of the present invention is preferably absolute ethyl 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.
(the S)-oxiracetam purity that makes is higher, crystallisate is more stable in order further to make, and the consumption of poor solvent of the present invention is preferably 5-6 times of (S)-oxiracetam saturated solution volume.
Specifically; Purification process of the present invention be with thick product with water dissolution after through the 732# strongly acidic cationic exchange resin and collect; Pass through in the 711# strongly basic anion exchange resin again and the solution of collecting, completion when the pH value that makes the solution of said collection is neutral, said thick product is with the laggard capable ion exchange resin treatment of water dissolution; Wherein thick product: water=1 gram: 0.6 milliliter, said thick product: said 732# strongly acidic cationic exchange resin=1 gram: 6 milliliters; Thick product after the solution concentration of collecting that will neutralize then is dissolved in absolute ethyl alcohol or propyl carbinol; Under 18 ℃, stir and process saturated solution; Anhydrous diethyl ether with 5.8 times of amounts of said saturated solution volume under closed environment spread 6 days down at 22 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
In order to make reactant and product be easy to dissolve and react the convenient processing after accomplishing that alcoholic solvent of the present invention is preferably anhydrous methanol or absolute ethyl alcohol; Because destructible product under the highly basic condition is beneficial to the stable environment of product in order in reaction process, to form, the alkaline condition in the reaction process of the present invention is through adding the mineral alkali regulation and control, preferably adding sodium hydrogencarbonate; The present invention (S)-4-halogen-3-hydroxyl-ethyl n-butyrate preferably adopts (S)-4-chloro-3-hydroxyl-ethyl n-butyrate.
Because the unsettled characteristic of glycine ethyl ester; Therefore raw material is to adopt glycine ethyl ester hydrochloride but come down to glycine ethyl ester participating in reaction; For the consumption that reduces reaction raw materials in the reaction process of the present invention reduces cost, more fully glycine ethyl ester hydrochloride is dissociated into glycine ethyl ester to improve yield simultaneously; The present invention preferably adds glycine ethyl ester hydrochloride in the ether the free of glycine ethyl ester hydrochloride, feeds ammonia more at low temperatures.
In the free treating processes of the present invention to glycine ethyl ester hydrochloride; Obtain glycine ethyl ester in order further to dissociate fully; Its temperature that feeds ammonia is 0～-5 ℃; Further be preferably-4 ℃～-5 ℃, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia relation is 1mol: 1000～1500ml: 1～1.5mol.
In order further to improve yield; The usage ratio of each material of the present invention is preferably glycine ethyl ester with molar ratio computing: sodium hydrogencarbonate: (S)-and 4-chloro-3-hydroxyl-ethyl n-butyrate=1: 0.8～1.3: 1～1.5; The consumption of said anhydrous methanol is 5～10 times of sodium hydrogencarbonate, in weight part; Further be preferably glycine ethyl ester: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.3: 1.5, the consumption of anhydrous methanol is 9 times of sodium hydrogencarbonate.
Specifically; The preparation of the present invention (S)-oxiracetam bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-4 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 1mol: 1000～1500ml: 1～1.5mol; Add sodium hydrogencarbonate and anhydrous methanol, dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate then, the time of said dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate is 2～3 hours, and control pH is 8～9, reacts 25～27 hours, and temperature of reaction is 65～70 ℃; Filter, filtrate, concentrate with the ethanol thorough washing; The chloroform that enriched material is water-soluble, add 4 times of filtrating weight again extracts, water concentrates, column chromatography for separation; Add concentration expressed in percentage by weight at last and be 25%～28% ammoniacal liquor, 20～30 ℃ down reaction made (S)-oxiracetam bullion in 5～8 hours; Said glycine ethyl ester: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 0.8～1.3: 1～1.5, with molar ratio computing; The consumption of said anhydrous methanol is 5～10 times of sodium hydrogencarbonate 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 bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-4 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 1mol: 1150ml: 1.1mol; Add anhydrous methanol then, sodium hydrogencarbonate and dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate, the said dropping time is 2.8 hours, and control pH is 8.5, and temperature of reaction is 65 ℃, reacts 27 hours; Filter, filtrate, concentrate with the ethanol thorough washing; The chloroform that enriched material is water-soluble, add 4 times of filtrating weight again extracts, water concentrates, column chromatography for separation; Add concentration expressed in percentage by weight at last and be 27% ammoniacal liquor, 22 ℃ down reaction made (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide bullion in 5 hours; Said glycine ethyl ester: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.3: 1.5, with molar ratio computing; The consumption of said anhydrous methanol is 9 times of sodium hydrogencarbonate weight.
The present invention has following beneficial effect:
1, the main raw material of the present invention's use is (S)-4-halogen-ethyl 3-hydroxybutanoate and glycine ethyl ester hydrochloride, is the commercial goods, the cheap and easy to get and environmental protection, pollution-free of raw material; Simultaneously, the present invention at first glycine ethyl ester hydrochloride carries out described free processing, has effectively reduced the consumption of material in the reaction, has reduced cost, and the yield to reaction also plays a positive role simultaneously.The yield of (the S)-oxiracetam of the present invention preparation is high, can be up to 36%, reaction conditions is gentle, the cycle shortly, simple to operate is beneficial to commercial scale prodn, (the S)-oxiracetam product HPLC purity that makes simultaneously reaches more than 99.0%.
2, the present invention has adopted ion exchange resin treatment in purifying the finished product (S)-oxiracetam, compares with the available technology adopting silica gel column chromatography method, though treatment effect is suitable; But the on the one hand ion exchange resin repeated use of can repeatedly regenerating has reduced cost; Ion exchange resin is to use pure water to come wash-out on the other hand; Avoided with an organic solvent, pollution-free, simultaneously preferablyly be used for the big 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 the most of organic solvent toxicity that uses is little, pollution is low; It is avirulent that the water that uses in the last handling process is pollution-free especially, so the present invention not only is suitable for suitability for industrialized production, also meets national requirements for environmental protection.
Embodiment
Through embodiment the present invention is carried out concrete description below; Be necessary to be pointed out that at this following examples only are used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present 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
The method of a kind of preparation (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) earlier glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether; Ice-cold to-4 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 139.6g: 1150ml: 18.7g; Add sodium hydrogencarbonate 109.2g, anhydrous methanol 983ml and dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate 250.0g, the said dropping time is 2.8 hours, keeps pH8.5 and temperature to be 65 ℃, to react 27 hours;
(b) filter, with ethanol thorough washing filtrating, concentrate, the chloroform that enriched material is water-soluble, add 4 times of filtrating weight again extracts, water is concentrated, column chromatography for separation; Add mass concentration at last and be 27% ammoniacal liquor, 22 ℃ down reaction made (S)-oxiracetam bullion in 5 hours;
Glycine ethyl ester wherein: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.3: 1.5, with molar ratio computing, the consumption of anhydrous methanol is 9 times of sodium hydrogencarbonate weight;
2, the purifying of bullion:
(a) with the above-mentioned bullion that makes of water dissolution, through the 732# strongly acidic cationic exchange resin, then through neutralization of 711# strongly basic anion exchange resin and collection solution, concentrated; Said bullion: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 6 milliliters;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in absolute ethyl alcohol; Under 18 ℃, stir and process saturated solution; Anhydrous diethyl ether with 5.8 times of amounts of said saturated solution volume under closed environment spread 6 days down at 22 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.22%, and yield is up to 36%.
Embodiment 2
The method of a kind of preparation (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) adopt anhydrous diethyl ether glycine ethyl ester hydrochloride to be dissociated into glycine ethyl ester with ammonia; Add yellow soda ash, anhydrous methanol and dropping (S)-4-bromo-3-hydroxyl-ethyl n-butyrate; The said dropping time is 2.5 hours, is 70 ℃ in pH8.0, temperature and reacts 25 hours down;
(b) filter, with ethanol thorough washing filtrating, concentrate, the methylene dichloride that enriched material is water-soluble, add 5 times of filtrating weight again extracts, water is concentrated, column chromatography for separation; Add ammoniacal liquor at last, reaction made (S)-oxiracetam bullion in 7 hours under 20 ℃;
Glycine ethyl ester wherein: yellow soda ash: (S)-4-bromo-3-hydroxyl-ethyl n-butyrate=1: 0.5: 1, with molar ratio computing, the consumption of anhydrous methanol is 6 times of yellow soda ash weight;
2, the purifying of bullion:
(a) with the above-mentioned bullion that makes of water dissolution, through the 732# strongly acidic cationic exchange resin, then through neutralization of 711# strongly basic anion exchange resin and collection solution, concentrated; Said bullion: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 10 milliliters;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in propyl carbinol; Under 25 ℃, stir and process saturated solution; Sherwood oil with 4 times of amounts of said saturated solution volume under closed environment spread 5 days down at 21 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.01%, and yield reaches 35%.
Embodiment 3
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) adopt ether glycine ethyl ester hydrochloride to be dissociated into glycine ethyl ester, drip (S)-4-iodo-3-hydroxyl-ethyl n-butyrate, add absolute ethyl alcohol and sodium hydrogencarbonate with ammonia;
(b) then with ethanol thorough washing, concentrated, the ETHYLE ACETATE that add 6 times of amount filtratings again extract, concentrate column chromatography for separation; Add strong aqua at last, reaction made (S)-oxiracetam bullion in 8 hours under 30 ℃;
2, the purifying of bullion:
(a) with the above-mentioned bullion that makes of water dissolution, through 001 * 7 strongly acidic styrene type cation exchange resin, then through neutralization of 201 * 7 basicity styrene series anion exchange resins and collection solution, concentrated;
The thick product that (b) will neutralize then after the solution concentration of collecting is dissolved in propyl carbinol; At room temperature stir and process saturated solution; Under closed environment, spread down at 21-23 ℃ with said saturated solution volume 3-8 normal hexane doubly; Spread after 5-7 days, the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.2%, and yield reaches 26%.
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 (5)
1. method for preparing (S)-oxiracetam; It is characterized in that: adopt glycine ethyl ester hydrochloride with (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is that raw material reacts under alcoholic solvent and alkaline condition; Filtration, inorganic alkoxide wash filtrate, the concentrated purification process that makes (S)-oxiracetam bullion and bullion again through extraction, separation feeding ammoniacal liquor, said glycine ethyl ester hydrochloride will adopt ether to dissociate into glycine ethyl ester with ammonia earlier; Said purification process be earlier with thick product with water dissolution after through strongly acidic cationic exchange resin and collect; Pass through in the strongly basic anion exchange resin again and the solution of collecting; When being neutral, the pH value that makes the solution of said collection accomplishes; Thick product after the solution concentration of collecting that will neutralize then is dissolved in its optimum solvent; And at room temperature process saturated solution, and under closed environment, spreading then with its poor solvent, the consumption of said poor solvent is 3-8 a times of (S)-oxiracetam saturated solution volume; The temperature of said employing poor solvent diffusion is 21-23 ℃, and be 5-7 days diffusion time.
2. the method for claim 1; It is characterized in that: said purification process be with thick product with water dissolution after through strongly acidic cationic exchange resin and collect; Pass through in the strongly basic anion exchange resin again and the solution of collecting, completion when the pH value that makes the solution of said collection is neutral, said thick product is with the laggard capable ion exchange resin treatment of water dissolution; Wherein thick product: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 6 milliliters; Thick product after the solution concentration of collecting that will neutralize then is dissolved in absolute ethyl alcohol or propyl carbinol; Under 18 ℃, stir and process saturated solution; Anhydrous diethyl ether with 5.8 times of amounts of said saturated solution volume under closed environment spread 6 days down at 22 ℃, and the crystal of separating out is obtained (S)-oxiracetam product through filtration, drying.
3. according to claim 1 or claim 2 method; It is characterized in that: said alcoholic solvent is anhydrous methanol or absolute ethyl alcohol; Alkaline condition in the said reaction process is through adding the sodium hydrogencarbonate regulation and control, and said (S)-4-halogen-3-hydroxyl-ethyl n-butyrate is (S)-4-chloro-3-hydroxyl-ethyl n-butyrate; The usage ratio of said each material is glycine ethyl ester with the molar ratio computing: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 0.8～1.3: 1～1.5, the consumption of said anhydrous methanol is 5～10 times of sodium hydrogencarbonate, in weight part.
4. method as claimed in claim 3 is characterized in that: said is that glycine ethyl ester hydrochloride is added in the ether to the free of glycine ethyl ester hydrochloride, feeds ammonia more at low temperatures; The temperature of said feeding ammonia is-4 ℃～-5 ℃, and the usage ratio relation of said glycine ethyl ester hydrochloride, ether and ammonia is 1mol: 1000～1500ml: 1～1.5mol.
5. method as claimed in claim 3; It is characterized in that: the preparation of said (S)-oxiracetam bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-4 ℃～-5 ℃; Feed ammonia, filter, will filtrate concentrate glycine ethyl ester, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia concerns to be 1mol: 1000～1500ml: 1～1.5mol; Add sodium hydrogencarbonate and anhydrous methanol, dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate then, the time of said dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate is 2～3 hours, and control pH is 8～9, reacts 25～27 hours, and temperature of reaction is 65～70 ℃; Filter, filtrate, concentrate with the ethanol thorough washing; The chloroform that enriched material is water-soluble, add 4 times of filtrating weight again extracts, water concentrates, column chromatography for separation; Add concentration expressed in percentage by weight at last and be 25%～28% ammoniacal liquor, 20～30 ℃ down reaction made (S)-oxiracetam bullion in 5～8 hours; Said glycine ethyl ester: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 0.8～1.3: 1～1.5, with molar ratio computing; The consumption of said anhydrous methanol is 5～10 times of sodium hydrogencarbonate weight.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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 |
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| 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 |
| 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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| 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 |
| 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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| 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 |
| 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 |
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Address after: 400042 Chongqing city Yubei District Qinye Road No. 9 Applicant after: Chongqing Runze Pharmaceutical Co., Ltd. Address before: 401120 Chongqing city Yubei District Shuangfeng Bridge Street Airport Road No. 296 Building 1 yuan and 7 2- store Applicant before: Chongqing Runze Medical Instruments Ltd. |
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| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: CHONGQING RUNZE MEDICAL INSTRUMENTS LTD. TO: CHONGQING RUNZE PHARMACEUTICAL CO., LTD. |
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| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120725 |