CN102603595B - Preparation method of (S)-oxiracetam - Google Patents
Preparation method of (S)-oxiracetam Download PDFInfo
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- CN102603595B CN102603595B CN201110023619.0A CN201110023619A CN102603595B CN 102603595 B CN102603595 B CN 102603595B CN 201110023619 A CN201110023619 A CN 201110023619A CN 102603595 B CN102603595 B CN 102603595B
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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 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 ((S)-4-hydroxyl-2-oxo-N-pyrrolidine acetamide), United States Patent (USP) 4,824,966,4,843,166 and 5,276,164 disclose the preparation method of oxiracetam and intermediate thereof, and in these patents, disclosed method comprises and makes 4-(C
1-C
2)-alkoxyl group-3-pyrroline-2-one-1-base-acetic acid (C
1-C
4)-alkyl ester reacts to protect hydroxyl with trichloromethyl silane, then products therefrom is carried out to hydrogenation and amidation, according to the method, obtains racemize oxiracetam through hydrogenation reduction; Therefore, the method has the shortcoming that is not 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 for preparing pure (the s)-oxiracetam of optically-active, in the method, first from synthetic (s)-3 of pure (the s)-3-HBL of optically-active, 4-epoxy butyrate is as the intermediate under aqueous conditions, then, under aqueous conditions with G-NH2 by this midbody compound amidation, follow cyclisation; Although this technology seems to have an advantage industrial aspect yield and purity compared with above-mentioned method, but to be the purity due to (s)-3-HBL low causes producing a lot of impurity for its shortcoming, and prepare highly purified (s)-3-HBL and can't reach, therefore, the 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 that a kind of yield is high, high (the S)-oxiracetam preparation method who is suitable for the required purity of medicinal application of purity.
The present invention seeks to be achieved through the following technical solutions:
A kind of preparation method of (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, filter, through 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, wherein glycine ethyl ester hydrochloride first adopts ether to dissociate into glycine ethyl ester with ammonia; The described purification process to crude product is with also collecting by storng-acid cation exchange resin after water dissolution by thick product, pass through again in strongly basic anion exchange resin and the solution of collecting, 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 water, at 2～5 DEG C, be added dropwise to acetone, stir 1～4h, carry out recrystallization processing and obtain crystallized product, the weight part ratio 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.
Above-mentioned by before ion exchange resin by thick product water dissolution, wherein product slightly: 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 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: 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.
Purification process of the present invention more preferably, before crystallisation process, is first refined the crude product making, and specifically adds the ethanol of 2～8 times of above-mentioned crude product weight to stir, and leaches, and makes refined products; Or/and carry out recrystallize (secondary crystal) after above-mentioned recrystallization process.For above-mentioned crystallisation process is distinguished, the 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 above-mentioned primary crystallization product, at-10～10 DEG C, is 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 further to improve the purity of final product, refinement treatment of the present invention is in the crude product after concentrating by ion exchange resin treatment, to add the ethanol of 4.5 times of its weight to stir, and leaches, and makes refined products; Primary crystallization of the present invention is by water-soluble the crude product after refining or concentrating by ion exchange resin treatment, at 2 DEG C, is added dropwise to acetone, stirs 2h, obtains crystallized product, and 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; Secondary crystal of the present invention is by water-soluble primary crystallization product, at 8 DEG C, is added dropwise to acetone, stirs 5h, obtains secondary crystal product, and 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.
For reduce reaction raw materials in reaction process of the present invention consumption, reduce costs, glycine ethyl ester hydrochloride is dissociated to improve yield and be beneficial to purification process more fully simultaneously, the present invention preferably adds glycine ethyl ester hydrochloride in ether the free of glycine ethyl ester hydrochloride, pass at low temperatures again ammonia, the described temperature that passes into ammonia is 0～-10 DEG C, more preferably 0～-5 DEG C, wherein the usage ratio of glycine ethyl ester hydrochloride, ether and ammonia pass is 1mol: 1000～1500ml: 1～1.5mol.
Specifically, the present invention is that glycine ethyl ester hydrochloride is added in anhydrous diethyl ether to the free processing of glycine ethyl ester hydrochloride, ice-cold to-2 DEG C～-3 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: 1200ml: 1.5mol.
In order further to improve yield and purity, the present invention (S)-4-halogen-3-hydroxy-butyric acid ethyl ester preferably adopts (S)-4-chloro-3-hydroxyl-ethyl butyrate, and alcoholic solvent preferably adopts anhydrous methanol, and alkali is preferably sodium bicarbonate; 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: 1.2: 1.5, the consumption of anhydrous methanol is sodium bicarbonate 7 times.
Specifically, the preparation of the present invention (S)-Esomeprazole crude product is first glycine ethyl ester hydrochloride to be added in anhydrous diethyl ether, ice-cold to-2 DEG C～-3 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: 1200ml: 1.5mol; Then add sodium bicarbonate and anhydrous methanol or dehydrated alcohol, drip (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, 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 add the chloroform of 2～4 times of filtrate weight to extract, water is concentrated, column chromatography for separation; Finally add strong aqua, at 20～30 DEG C, react 5～8 hours; 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.
In order further to improve the yield of the present invention's preparation (S)-Esomeprazole, the preparation of the present invention (S)-Esomeprazole crude product is first glycine ethyl ester hydrochloride to be added in anhydrous diethyl ether, ice-cold to-2 DEG C～-3 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: 1200ml: 1.5mol; Then add (the S)-4-chloro-3-hydroxyl-ethyl butyrate described in sodium bicarbonate, anhydrous methanol and dropping, drip 3 hours, controlling pH is 8, and temperature of reaction is 68 DEG C, reacts 28 hours; Filter, with the abundant wash filtrate of ethanol, concentrated, then add the chloroform of 4 times of filtrate weight to extract, concentrated, column chromatography for separation; Finally adding mass percentage concentration is 28% ammoniacal liquor, reacts 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 was 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, 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 has also been played to very positive effect simultaneously.
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.Adopt acetone and water as the solvent in crystallisation process, effectively reduce foreign matter content, significantly improved the quality of the finished product, the majority of organic solvent toxicity that uses in the present invention is little, it is low to pollute, 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.
The yield height of (S)-oxiracetam that 3, prepared by the present invention can be up to 36%, (the S)-oxiracetam product HPLC purity making can be 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; 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
A kind of preparation method of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) glycine ethyl ester hydrochloride 139.6g is added in anhydrous diethyl ether 1200ml, 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) in above-mentioned glycine ethyl ester, add sodium bicarbonate 100.8g, dehydrated alcohol 705ml and dropping (S)-4-chloro-3-hydroxyl-ethyl butyrate 250.0g, described time for adding is 3 hours, is at 68 DEG C, to react 28 hours in pH8.0, temperature;
(c) filter, with the abundant wash filtrate of ethanol, concentrated, then add the chloroform of 4 times of filtrate weight to extract, concentrated, column chromatography for separation; Finally add 25% strong aqua, at 21 DEG C, react and within 8 hours, make (S)-oxiracetam crude product;
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 was 7 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=1.0 gram: 1.0 milliliters, described thick product: described storng-acid cation exchange resin=1 gram: 10 milliliters;
(b) then adopt ethanol to carry out refinement treatment above-mentioned crude product after concentrating by ion exchange resin, add the ethanol of 4.5 times of crude product weight to stir, leach, make refined products; Then carry out primary crystallization processing, by water-soluble 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 processing, by water-soluble 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 (the S)-oxiracetam product finally making reaches 99.65%, and yield is 36%.
Embodiment 2
A kind of preparation method of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) glycine ethyl ester hydrochloride is added in anhydrous diethyl ether, ice-cold to 0 DEG C, pass into 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 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;
(c) filter, with the abundant wash filtrate of methyl alcohol, concentrated, then add the ethyl acetate of 5 times of filtrate weight to extract, concentrated, column chromatography for separation; Finally add strong aqua, at 20 DEG C, react and within 5 hours, make (S)-oxiracetam crude product;
Wherein glycine ethyl ester: sodium carbonate: the bromo-3-hydroxy-butyric acid of (S)-4-ethyl ester=1: 1: 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 storng-acid cation exchange resin, then neutralize and collect solution, concentrated by 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: 8 milliliters;
(b) then adopt ethanol to carry out refinement treatment above-mentioned crude product after concentrating by ion exchange resin, add the ethanol of 2 times of crude product weight to stir, leach, make refined products; Then carry out primary crystallization processing, by water-soluble 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 (the S)-oxiracetam product finally making reaches 99.53%, and yield reaches 33%.
Embodiment 3
A kind of preparation method of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) glycine ethyl ester hydrochloride is adopted ether dissociate into glycine ethyl ester with ammonia;
(b) in above-mentioned glycine ethyl ester, add sodium carbonate, dehydrated alcohol and dropping (the S)-iodo-3-hydroxy-butyric acid of 4-ethyl ester;
(c) filter, with the abundant wash filtrate of ethanol, concentrated, then add the methylene dichloride of 7 times of filtrate weight to extract, concentrated, column chromatography for separation; Finally add strong aqua, at 30 DEG C, react and within 8 hours, make (S)-oxiracetam crude product;
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) then above-mentioned crude product after concentrating by ion exchange resin is carried out to recrystallization processing, crude product is water-soluble, be added dropwise to acetone, stir and obtain crystallized product, the weight part ratio of described water and acetone is 1: 12.
The HPLC purity of (the S)-oxiracetam product finally making 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 (1)
1. a preparation method for (S)-Olaxiracetam, is characterized in that: it is to carry out as follows:
(1), the preparation of crude product:
(a) glycine ethyl ester hydrochloride is added in anhydrous diethyl ether, ice-cold to 0 DEG C, pass into ammonia and make glycine ethyl ester hydrochloride fully dissociate into glycine ethyl ester, wherein glycine ethyl ester hydrochloride: ether: ammonia=1mol:1000ml:1 mol;
(b) in described 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;
(c) filter, fully wash filter residue, concentrated with methyl alcohol, then add the ethyl acetate of 5 times of filtrate weight to extract, concentrated, column chromatography for separation; Finally add strong aqua, at 20 DEG C, react and within 5 hours, make (S)-Olaxiracetam crude product;
Wherein glycine ethyl ester: sodium carbonate: the bromo-3-hydroxy-butyric acid of (S)-4-ethyl ester=1:1:1, with molar ratio computing, the consumption of anhydrous methanol is 6 times of sodium carbonate weight;
(2), the purifying of crude product:
(a), with the above-mentioned crude product making of water dissolution, by storng-acid cation exchange resin, then neutralize and collect solution, concentrated by 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: 8 milliliters;
(b) then adopt ethanol to carry out refinement treatment described crude product after concentrating by ion exchange resin, add the ethanol of 2 times of crude product weight to stir, leach, make refined products; Then carry out primary crystallization processing, by water-soluble 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.
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| CN103554108A (en) * | 2013-10-29 | 2014-02-05 | 安徽万邦医药科技有限公司 | Improved tadalafil preparation method |
| 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 |
| 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 |
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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| 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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