CN102603595A - Preparation method of (S)-oxiracetam - Google Patents
Preparation method of (S)-oxiracetam Download PDFInfo
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- CN102603595A CN102603595A CN2011100236190A CN201110023619A CN102603595A CN 102603595 A CN102603595 A CN 102603595A CN 2011100236190 A CN2011100236190 A CN 2011100236190A CN 201110023619 A CN201110023619 A CN 201110023619A CN 102603595 A CN102603595 A CN 102603595A
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Abstract
A preparation method of (S)-oxiracetam is characterized in that the preparation method comprises the steps of conducting a reaction of a glycine ethyl ester hydrochloride with a (S)-4-halogen-3-hydroxy-ethyl butyrate in an alcohol solvent under an alkaline condition, wherein the glycine ethyl ester hydrochloride and the glycine ethyl ester hydrochloride are taken as raw materials, filtering, washing with inorganic alcohol, concentrating, then extracting, separating, and introducing ammonia water to prepare a crude product of the (S) oxiracetam, and purifying the crude product. The glycine ethyl ester hydrochloride is dissociated into glycine ethyl ester by diethyl ether and ammonia gas firstly, and the purification of the crude product comprises recrystallization treatment by use of water and acetone as solvents, wherein a weight ratio of the water to acetone is 1:(5-20). According to the (S)-oxiracetam prepared by the preparation method, the yield is high and reaches up to 36%, the HPLC (high performance liquid chromatography) purity of the prepared (S)-oxiracetam reaches up to more than 99.4%, in addition, the reaction condition is moderate, the period is short, the operation is simple, and the industrialized scale production is facilitated.
Description
Technical field
The present invention relates to the preparation of oxiracetam, be specifically related to the preparation method of (S)-oxiracetam.
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 ((S)-4-hydroxyl-2-oxo-N-pyrrolidine acetamide), USP 4,824; 966,4,843,166 and 5; 276,164 disclose oxiracetam and intermediates preparation thereof, and disclosed method comprises and makes 4-(C in these patents
1-C
2)-alkoxyl group-3-pyrroline-2-one-1-base-acetate (C
1-C
4)-alkyl ester and trichloromethyl silane reaction are carried out hydrogenation and amidation to products therefrom then with the protection hydroxyl, according to this method, obtain racemize oxiracetam through the two key reduction of hydrogenation; Therefore, this method has the shortcoming that is not suitable for the pure oxiracetam of preparation optically-active, and in addition, the preparation yield of 4-(C1-C2)-alkoxyl group-3-pyrroline-2-one-1-base-acetate (C1-C4)-alkyl ester is low.The open 2000-9456 of Korean Patent discloses the method for preparing pure (the s)-oxiracetam of optically-active; In the method; At first from synthetic (s)-3 of pure (the s)-3-of optically-active hydroxybutyrolactone, 4-epoxy butyrates is as the midbody under the aqueous conditions, then; Under aqueous conditions with G-NH2 with this midbody compound amidation, follow cyclisation; In industry, has advantage aspect yield and the purity though as if this technology compared with above-mentioned method; But its shortcoming be because (s)-purity of 3-hydroxybutyrolactone is low to cause producing a lot of impurity; And prepare highly purified (s)-3-hydroxybutyrolactone and can't reach; Therefore, this method does not obtain having the oxiracetam that is suitable for the required purity of medicinal application.
Summary of the invention
The object of the present invention is to provide a kind of yield height, high (the S)-oxiracetam preparation method who is suitable for the required purity of medicinal application of purity.
The present invention seeks to realize through following technical scheme:
A kind of preparation method of (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; Filter, through the inorganic alkoxide washing, concentrate again through extraction, separate and feed the purification process that ammoniacal liquor makes (S)-oxiracetam bullion and bullion, wherein glycine ethyl ester hydrochloride earlier the employing ether dissociate into glycine ethyl ester with ammonia; Said purification process to bullion 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; The pH value of the solution of said collection is accomplished when neutral, and the thick product after the solution concentration of the collection that will neutralize then is dissolved in water, is added dropwise to acetone under 2～5 ℃; Stir 1～4h; Carry out the recrystallization processing and obtain crystallized product, the weight part ratio of said bullion and water is 1: 0.5～0.6, and the weight part ratio of water and acetone is 1: 6～10.
Above-mentioned passing through used water dissolution with thick product before the ion exchange resin, wherein thick product: water=1 gram: 1.0 milliliters.
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: 10 milliliters.
In order to improve the purity of the finished product, recrystallization process of the present invention carries out under-10～10 ℃.
Purification process of the present invention further was preferably before crystallisation process, and the bullion that makes is made with extra care earlier, specifically was that 2～8 times the ethanol that adds above-mentioned bullion weight stirs, and leached, and made refined products; Or/and after above-mentioned recrystallization process, carry out recrystallize (secondary crystal).For above-mentioned crystallisation process is distinguished, the recrystallize here is called secondary crystal, and above-mentioned recrystallization process is called primary crystallization.
Secondary crystal of the present invention is that above-mentioned primary crystallization product is water-soluble, under-10～10 ℃, is added dropwise to acetone, stirs 0.5～12h, obtains the secondary crystal product; The weight part ratio of said 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 further to improve the purity of final product, refinement treatment of the present invention is that the ethanol that adds 4.5 times of its weight in the bullion after concentrating through ion exchange resin treatment stirs, and leaches, and makes refined products; Primary crystallization of the present invention is with water-soluble through bullion refining or that pass through after ion exchange resin treatment concentrates, under 2 ℃, is added dropwise to acetone, stirs 2h, obtains crystallized product, and the weight part of said bullion and water is 1: 0.4, and the weight part ratio of water and acetone is 1: 6; Secondary crystal of the present invention is that the primary crystallization product is water-soluble, under 8 ℃, is added dropwise to acetone, stirs 5h, obtains the secondary crystal product, and the weight part ratio of said primary crystallization product and water is 1: 0.7, and the weight part ratio of water and acetone is 1: 15.
For the consumption that reduces reaction raw materials in the reaction process of the present invention, reduce cost; Simultaneously that glycine ethyl ester hydrochloride is free more fully to improve yield and to be beneficial to purification process; The present invention preferably adds glycine ethyl ester hydrochloride in the ether the free of glycine ethyl ester hydrochloride; Feed ammonia more at low temperatures; The temperature of said feeding ammonia is 0～-10 ℃, further is preferably 0～-5 ℃, and wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia relation is 1mol: 1000～1500ml: 1～1.5mol.
Specifically; The present invention is that glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether to the free processing of glycine ethyl ester hydrochloride; Ice-cold to-2 ℃～-3 ℃; 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: 1200ml: 1.5mol.
In order further to improve yield and purity, the present invention (S)-4-halogen-3-hydroxyl-ethyl n-butyrate preferably adopts (S)-4-chloro-3-hydroxyl-ethyl n-butyrate, and alcoholic solvent preferably adopts anhydrous methanol, and alkali is preferably sodium hydrogencarbonate; The usage ratio of each material of the present invention is preferably glycine ethyl ester with 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; Further be preferably glycine ethyl ester: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.2: 1.5, the consumption of anhydrous methanol is 7 times of sodium hydrogencarbonate.
Specifically; The preparation of the present invention (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-2 ℃～-3 ℃; 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: 1200ml: 1.5mol; Add sodium hydrogencarbonate and anhydrous methanol or absolute ethyl alcohol then; Drip (S)-4-chloro-3-hydroxyl-ethyl n-butyrate, the time of said dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate is 2～3 hours, and control pH is 8～9; Temperature of reaction is 65～70 ℃, reacts 25～30 hours; Filter, filtrate, concentrate with the ethanol thorough washing, enriched material is water-soluble, and the chloroform that adds 2～4 times of filtrating weight again extracts, water concentrates column chromatography for separation; Add strong aqua at last, reacted 5～8 hours down at 20～30 ℃; Said glycine ethyl ester: 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 weight.
In order further to improve the yield of the present invention's preparation (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide; The preparation of the present invention (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethanamide bullion is earlier glycine ethyl ester hydrochloride to be added in the anhydrous diethyl ether; Ice-cold to-2 ℃～-3 ℃; 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: 1200ml: 1.5mol; Add described (the S)-4-of sodium hydrogencarbonate, anhydrous methanol and dropping chloro-3-hydroxyl-ethyl n-butyrate then, dripped 3 hours, control pH is 8, and temperature of reaction is 68 ℃, reacts 28 hours; Filter, filtrate, concentrate with the ethanol thorough washing, the chloroform that adds 4 times of filtrating weight again extracts, concentrates column chromatography for separation; Add mass percentage concentration at last and be 28% ammoniacal liquor, 21 ℃ of reactions 8 hours down; Said glycine ethyl ester: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.2: 1.5, with molar ratio computing, the consumption of anhydrous methanol or absolute ethyl alcohol is 7 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 has also played very positive effect simultaneously.
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.Adopt acetone and water as the solvent in the crystallisation process; Effectively reduce foreign matter content, significantly improved the quality of the finished product; The most of organic solvent toxicity that uses among the present invention 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.
3, the yield height of (the S)-oxiracetam of the present invention preparation can be up to 36%, and (the S)-oxiracetam product HPLC purity that makes can be up to more than 99.4%, and gentle, cycle of reaction conditions shortly, simple to operate is beneficial to commercial scale prodn simultaneously.
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
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) glycine ethyl ester hydrochloride 139.6g is added among the anhydrous diethyl ether 1200ml; Ice-cold to-2 ℃; Feeding 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) in above-mentioned glycine ethyl ester, add sodium hydrogencarbonate 100.8g, absolute ethyl alcohol 705ml and dropping (S)-4-chloro-3-hydroxyl-ethyl n-butyrate 250.0g, the said dropping time is 3 hours, is 68 ℃ in pH8.0, temperature and reacts 28 hours down;
(c) filter, filtrate, concentrate with the ethanol thorough washing, the chloroform that adds 4 times of filtrating weight again extracts, concentrates column chromatography for separation; Add 25% strong aqua at last, reaction made (S)-oxiracetam bullion in 8 hours under 21 ℃;
Glycine ethyl ester wherein: sodium hydrogencarbonate: (S)-4-chloro-3-hydroxyl-ethyl n-butyrate=1: 1.2: 1.5, with molar ratio computing, the consumption of absolute ethyl alcohol is 7 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=1.0 grams: 1.0 milliliters, said thick product: said strongly acidic cationic exchange resin=1 gram: 10 milliliters;
(b) adopt ethanol to carry out refinement treatment above-mentioned bullion after concentrating through ion exchange resin then, the ethanol that adds 4.5 times of bullion weight stirs, leaches, and makes refined products; Carry out primary crystallization then and handle, will be water-soluble through the bullion after refining, under 2 ℃, be added dropwise to acetone, stir 2h, obtain crystallized product, the weight part of said bullion and water is 1: 0.4, the weight part ratio of water and acetone is 1: 6; Carry out secondary crystal at last and handle, the primary crystallization product is water-soluble, under 8 ℃, be added dropwise to acetone, stir 5h, obtain the secondary crystal product, the weight part ratio of said primary crystallization product and water is 1: 0.7, the weight part ratio of water and acetone is 1: 15.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.65%, and yield is 36%.
Embodiment 2
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether, ice-cold to 0 ℃, feed ammonia and make glycine ethyl ester hydrochloride fully dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: ether: ammonia=1mol: 1000ml: 1mol;
(b) in above-mentioned glycine ethyl ester, 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;
(c) filter, filtrate, concentrate with the methyl alcohol thorough washing, the ETHYLE ACETATE that adds 5 times of filtrating weight again extracts, concentrates column chromatography for separation; Add strong aqua at last, reaction made (S)-oxiracetam bullion in 5 hours under 20 ℃;
Glycine ethyl ester wherein: yellow soda ash: (S)-4-bromo-3-hydroxyl-ethyl n-butyrate=1: 1: 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 strongly acidic cationic exchange resin, then through strongly basic anion exchange resin neutralization and collection solution, concentrated; Said bullion: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 8 milliliters;
(b) adopt ethanol to carry out refinement treatment above-mentioned bullion after concentrating through ion exchange resin then, the ethanol that adds 2 times of bullion weight stirs, leaches, and makes refined products; Carry out primary crystallization then and handle, will be water-soluble through the bullion after refining, under-10 ℃, be added dropwise to acetone, stir 1h, obtain crystallized product, the weight part of said bullion and water is 1: 0.7, the weight part ratio of water and acetone is 1: 5.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.53%, and yield reaches 33%.
Embodiment 3
A kind of preparation method of (S)-oxiracetam, carry out as follows:
1, the preparation of bullion:
(a) adopt ether to dissociate into glycine ethyl ester glycine ethyl ester hydrochloride with ammonia;
(b) in above-mentioned glycine ethyl ester, add yellow soda ash, absolute ethyl alcohol and dropping (S)-4-iodo-3-hydroxyl-ethyl n-butyrate;
(c) filter, filtrate, concentrate with the ethanol thorough washing, the methylene dichloride that adds 7 times of filtrating weight again extracts, concentrates 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;
(b) then above-mentioned bullion after concentrating through ion exchange resin is carried out recrystallization and handle, bullion is water-soluble, be added dropwise to acetone, stir and obtain crystallized product, the weight part ratio of said water and acetone is 1: 12.
The HPLC purity of (the S)-oxiracetam product that finally makes reaches 99.12%, 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 99.4%～99.7%, and yield reaches 28%～34%.
Claims (6)
1. the preparation method of (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; Filter, through the inorganic alkoxide washing, concentrate again through extraction, separate and feed the purification process that ammoniacal liquor makes (S)-oxiracetam bullion and bullion, wherein glycine ethyl ester hydrochloride earlier the employing ether dissociate into glycine ethyl ester with ammonia; Said purification process to bullion 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; The pH value of the solution of said collection is accomplished when neutral, and the thick product after the solution concentration of the collection that will neutralize then is dissolved in water, is added dropwise to acetone under 2～5 ℃; Stir 1～4h; Carry out the recrystallization processing and obtain crystallized product, the weight part ratio of said bullion and water is 1: 0.5～0.6, and the weight part ratio of water and acetone is 1: 6～10.
2. preparation method as claimed in claim 1 is characterized in that: before said recrystallization process, also bullion is made with extra care earlier, said making with extra care is that 2～8 times the ethanol that adds said bullion weight stirs, leaches, and makes refined products; Or/and after said recrystallization process, carry out secondary crystal; Said secondary crystal is that said primary crystallization product is water-soluble; Under-10～10 ℃, be added dropwise to acetone, stir 0.5～12h, obtain the secondary crystal product; The weight part ratio of said primary crystallization product and water is 1: 0.4～0.7, and the weight part ratio of water and acetone is 1: 5～20.
3. preparation method as claimed in claim 2; It is characterized in that: said is that glycine ethyl ester hydrochloride is added in the ether to the free of glycine ethyl ester hydrochloride; Under 0～-10 ℃ low temperature, feed ammonia again, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia relation is 1mol: 1000～1500ml: 1～1.5mol.
4. preparation method as claimed in claim 3; It is characterized in that: said free processing to glycine ethyl ester hydrochloride is that glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether; Ice-cold to-2 ℃～-3 ℃; 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: 1200ml: 1.5mol.
5. preparation method as claimed in claim 4 is characterized in that: said (S)-4-halogen-3-hydroxyl-ethyl n-butyrate adopts (S)-4-chloro-3-hydroxyl-ethyl n-butyrate, and alcoholic solvent adopts anhydrous methanol, and alkali is sodium hydrogencarbonate; The usage ratio of said each material is preferably glycine ethyl ester with 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.
6. preparation method as claimed in claim 1 is characterized in that: it is to carry out as follows: the preparation of (1), bullion:
(a) glycine ethyl ester hydrochloride is added in the anhydrous diethyl ether, ice-cold to 0 ℃, feed ammonia and make glycine ethyl ester hydrochloride fully dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: ether: ammonia=1mol: 1000ml: 1mol;
(b) in said glycine ethyl ester, 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;
(c) filter, filtrate, concentrate with the methyl alcohol thorough washing, the ETHYLE ACETATE that adds 5 times of filtrating weight again extracts, concentrates column chromatography for separation; Add strong aqua at last, reaction made (S)-oxiracetam bullion in 5 hours under 20 ℃;
Glycine ethyl ester wherein: yellow soda ash: (S)-4-bromo-3-hydroxyl-ethyl n-butyrate=1: 1: 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 strongly acidic cationic exchange resin, then through strongly basic anion exchange resin neutralization and collection solution, concentrated; Said bullion: water=1 gram: 0.6 milliliter, said thick product: said strongly acidic cationic exchange resin=1 gram: 8 milliliters;
(b) adopt ethanol to carry out refinement treatment said bullion after concentrating through ion exchange resin then, the ethanol that adds 2 times of bullion weight stirs, leaches, and makes refined products; Carry out primary crystallization then and handle, will be water-soluble through the bullion after refining, under-10 ℃, be added dropwise to acetone, stir 1h, obtain crystallized product, the weight part of said bullion and water is 1: 0.7, the weight part ratio of water and acetone is 1: 5.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554108A (en) * | 2013-10-29 | 2014-02-05 | 安徽万邦医药科技有限公司 | Improved tadalafil preparation method |
| CN103554000A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| CN103965090A (en) * | 2014-05-31 | 2014-08-06 | 江苏诚信制药有限公司 | Refining method of oxiracetam |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554108A (en) * | 2013-10-29 | 2014-02-05 | 安徽万邦医药科技有限公司 | Improved tadalafil preparation method |
| CN103554000A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| CN103554000B (en) * | 2013-11-06 | 2015-03-11 | 重庆润泽医药有限公司 | (S)-oxiracetam crystal form III, and preparation method and application thereof |
| US9670156B2 (en) | 2013-11-06 | 2017-06-06 | Chongqing Ruzer Pharmaceutical Company Limited | Crystal form III of (S)-oxiracetam, preparation method and use thereof |
| CN103965090A (en) * | 2014-05-31 | 2014-08-06 | 江苏诚信制药有限公司 | Refining method of oxiracetam |
| CN103965090B (en) * | 2014-05-31 | 2015-11-18 | 江苏诚信药业有限公司 | A kind of process for purification of oxiracetam |
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