CN103724250B - A kind of preparation method of (S)-Olaxiracetam - Google Patents
A kind of preparation method of (S)-Olaxiracetam Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/26—2-Pyrrolidones
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Abstract
A kind of preparation method of (S)-Olaxiracetam, adopting glycine ethyl ester hydrochloride and (S)-4-halogen-3-hydroxy-butyric acid ethyl ester is that raw material reacts under alcoholic solvent and alkali condition, filter, through washing with inorganic alkoxide, concentration then through extracting, aqueous phase concentration, pass into strong aqua ammonia reaction and prepare the purification process of (S)-Olaxiracetam crude product and crude product；Described glycine ethyl ester hydrochloride first mix with alkali, alcoholic solvent, more wherein dropping (S)-4-halogen-3-hydroxy-butyric acid ethyl ester raw material and gradation addition alkali with the pH that controls to react for 8-9；Described purification process includes being dissolved in its good solvent (S)-Olaxiracetam crude product, and at room temperature makes saturated solution, then spreads with its poor solvent under closed environment.(S)-oxiracetam HPLC purity prepared by the present invention reaches more than 99.0%, and yield height may be up to 33%, and reaction condition gentleness is simple to operate is beneficial to industrial-scale production.
Description
The present patent application is application number 201110023874.5, the applying date on 01 21st, 2011, the divisional application of denomination of invention " preparation method of (S)-oxiracetam ".
Technical field
The present invention relates to the method preparing oxiracetam, be specifically related to the method that one prepares (S)-oxiracetam, belong to the field of chemical synthesis.
Background technology
Oxiracetam (oxiracetam), it it is the nootropics synthesized first in 1974 than Qie Mu company by Italy SmithKline, this medicine listed in Italy in 1987, the raceme that oxiracetam is made up of two kinds of isomer (S)-oxiracetams ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam).Report about oxiracetam, hydroxy-amino-butyric acid (GABOB) cyclic derivatives that it is a kind of synthesis is disclosed, ATP in brain can be promoted, promote that acetylcholine synthesizes and strengthens the conduction of neural excitation, improvement effect is had to the antidromicity caused by anoxia is forgetful, can hypermnesis, improve learning capacity, be one for the treatment of dementia of the Alzheimer type (AD), the active drug of disease such as vascular dementia (VD).
Report about synthesis (S)-oxiracetam; United States Patent (USP) 4; 797; 496 and the method preparing oxyracetam that discloses of WO93/06826; method disclosed in the document include from chirality retouch-hydroxybutyrolactone obtains chirality alkyl 3; 4-epoxy butyrate; products therefrom is made to react with the N Aminoacetamide protected and make products therefrom carry out N deprotection; then the pure oxyracetam of optically-active is obtained through cyclisation; the step of the method is relatively fewer; but owing to chirality alkyl 3,4-epoxy butyrate synthesis yield is extremely low and cause the method cost high.US Patent No. 4173569 has addressed the synthetic method of another kind of (s)-oxiracetam: (s)-carry-amino-retouch-hydroxybutyric acid is initiation material; hydroxyl is protected through sillylation reagent; product after cyclization reacts with halogenated acetic acids ethyl ester; product is through Deprotection; aminolysis, finally obtains target compound；This kind of preparation method is not suitable for industrial-scale production, and using protection base that hydroxyl is carried out protection can increase reactions steps, wastes raw material, consuming time longer, increases cost, makes total recovery reduce.
Summary of the invention
It is an object of the invention to provide that a kind of yield is high, purity high, be suitable to the preparation method of (S)-oxiracetam needed for medicinal application.
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 and (S)-4-halogen-3-hydroxy-butyric acid ethyl ester is that raw material react under alcoholic solvent and alkali condition, filter, through washing with inorganic alkoxide, concentration is then through extracting, separate the purification process passing into prepared (the S)-oxiracetam crude product of strong aqua ammonia reaction and crude product；Described glycine ethyl ester hydrochloride is first mix with alcoholic solvent with alkali, then drips (S)-4-halogen-3-hydroxy-butyric acid ethyl ester raw material and gradation addition alkali wherein with the pH that controls to react for 8-9；The described purification process to crude product includes carrying out ion exchange resin treatment and being dissolved in its good solvent by (S)-oxiracetam crude product, and at room temperature makes saturated solution, then spreads with its poor solvent under closed environment.
Inventor finds that in R&D process the addition sequence of raw material is worthy of careful study very much, due to the characteristic that glycine ethyl ester is unstable, therefore raw material is adopt glycine ethyl ester hydrochloride but substantially glycine ethyl ester is participating in reaction, and charging sequence decides whether glycine ethyl ester hydrochloride can dissociate into glycine ethyl ester thus decide the height of product yield in the reaction fully；Simultaneously, product (S)-oxiracetam has characteristic easily destroyed under basic conditions, and reacting is that requirement carries out in the basic conditions, alkali is again indispensable reaction raw materials simultaneously, and the mode therefore adding alkali in the reaction having product to produce has special being particular about with condition.
In order to improve the yield of end product, the present invention, after above-mentioned extraction, aqueous phase concentration, also carries out column chromatography for separation, then passes into strong aqua ammonia and prepare (S)-oxiracetam.
It is beneficial to the carrying out of reaction to make glycine ethyl ester hydrochloride raw material of the present invention fully dissociate into glycine ethyl ester, improves the yield of final products, described glycine ethyl ester hydrochloride first mix with alkali, alcoholic solvent be 68-73 DEG C, stir 1-3 hour under pH8-9, it is further preferred that 68-70 DEG C, stirring 2 hours under pH8.7.
In order to further make glycine ethyl ester hydrochloride dissociate into glycine ethyl ester, alkali of the present invention preferably employs sodium carbonate or sodium bicarbonate, alcoholic solvent preferably employs dehydrated alcohol, wherein glycine ethyl ester hydrochloride is 1: 1 with the mol ratio of sodium carbonate, or the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, the consumption of dehydrated alcohol is 5-8 times of alkali weight, more preferably 6 times.
It is beneficial to the environment that product is stable to be formed in course of reaction, after glycine ethyl ester hydrochloride mixes with alkali, alcoholic solvent, it is that point 2-4 time (preferably 2 times) add alkali with pH in control system for 8-9 that gradation adds alkali, it is simultaneously added dropwise (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, time for adding is 2.5 hours, is 60-65 DEG C at system temperature and reacts 22-26 hour.
The present invention (S)-4-halogen-3-hydroxy-butyric acid ethyl ester preferably employs (S)-4-chloro-3-hydroxyl-ethyl n-butyrate.；(S) consumption of-4-halogen-3-hydroxy-butyric acid ethyl ester is preferably glycine ethyl ester hydrochloride: (S)-4-halogen-3-hydroxy-butyric acid ethyl ester=1mol:0.8-1.3mol.
More specifically, the present invention (S)-oxiracetam crude product be prepared by glycine ethyl ester hydrochloride first with alkali, alcoholic solvent 68-73 DEG C, stirring 1-3 hour under pH8-9, wherein alkali preferably employs sodium carbonate or sodium bicarbonate, alcoholic solvent preferably employs dehydrated alcohol, the mol ratio of glycine ethyl ester hydrochloride and sodium carbonate is 1: 1, or the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, the consumption of dehydrated alcohol is 5-8 times of alkali weight；Then it is add alkali for 2-4 time with pH in control system for 8-9, it is simultaneously added dropwise (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, time for adding is 2.5 hours, being 60-65 DEG C at system temperature to react 22-26 hour, wherein glycine ethyl ester hydrochloride is 1: 0.8-1.3 with the mol ratio of (S)-4-halogen-3-hydroxy-butyric acid ethyl ester；Filtering, filtrate methanol or ethanol are fully washed, concentrated, concentrate is soluble in water, and the chloroform adding 4 times of filtrate weight extracts, and after aqueous phase concentration, column chromatography for separation obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethyl acetate；Finally add strong aqua ammonia, react 5～7 hours at 23～26 DEG C.
The yield of (S)-oxiracetam is prepared in order to further improve the present invention, the present invention (S)-oxiracetam crude product be prepared by glycine ethyl ester hydrochloride first with alkali, alcoholic solvent 68-70 DEG C, stirring 2 hours under pH8.7, wherein alkali preferably employs sodium bicarbonate, alcoholic solvent preferably employs dehydrated alcohol, the mol ratio of glycine ethyl ester hydrochloride and sodium bicarbonate is 1: 2, and the consumption of dehydrated alcohol is 6 times of alkali weight；Then divide 2 times and add alkali with pH in control system for 8.5-9, it is simultaneously added dropwise (S)-4-chloro-3-hydroxyl-ethyl n-butyrate., time for adding is 2.5 hours, being 62-64 DEG C at system temperature to react 24-25 hour, wherein glycine ethyl ester hydrochloride is 1: 1.1 with the mol ratio of (S)-4-chloro-3-hydroxyl-ethyl n-butyrate.；Filtering, filtrate methanol or ethanol are fully washed, concentrated, concentrate is soluble in water, and the chloroform adding 4 times of filtrate weight extracts, and after aqueous phase concentration, column chromatography for separation obtains (S)-4-hydroxyl-2-OXo-1-pyrrolidine ethyl acetate；Finally add the ammonia that mass percentage concentration is 23%, react 5～7 hours at 23～26 DEG C.
The purification process of the thick product of the present invention be will by storng-acid cation exchange resin collecting after thick product water dissolution, again through in strong-base anion-exchange resin and the solution collected, making the pH value of solution of described collection for completing time neutral；Then it is dissolved in neutralizing the thick product after the solution collected concentrates in its good solvent, and at room temperature makes saturated solution, then spread with its poor solvent under closed environment.
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；Strong-base anion-exchange resin of the present invention is preferably 711# strong-base anion-exchange resin.
In order to further 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: 8 milliliters.
Good solvent of the present invention refer to (S)-oxiracetam dissolubility within it more than 10 grams/100 grams of solvents, poor solvent refers to that (S)-oxiracetam dissolubility within it is at the solvent of 1 gram/less than 100 grams, and the definition for optimum dissolving (readily soluble solvent) and poor solvent (slightly soluble or indissoluble solvent) is that those skilled in the art all know.
In order to make (the S)-oxiracetam purity prepared higher, good solvent of the present invention is preferably without water-ethanol or n-butyl alcohol；Poor solvent of the present invention is preferably absolute ether, petroleum ether or normal hexane；Wherein agents useful for same can be all analytical pure or chemical purity level.
In order to make further, (the S)-oxiracetam purity prepared is higher, crystal is more stable, and the consumption of poor solvent of the present invention is 6-9 times of (S)-oxiracetam saturated solution volume, it is preferable that consumption is 8 times.
The present invention adopts the temperature that poor solvent spreads to be preferably 24-28 DEG C, and diffusion time is preferably 3-6 days.
Specifically, purification process of the present invention is will to pass through 732# storng-acid cation exchange resin after thick product water dissolution and collect, again through in 711# strong-base anion-exchange resin and collect solution, make the pH value of solution of described collection for completing time neutral, ion exchange resin treatment is carried out after described thick product water dissolution, wherein thick product: water=1 gram: 0.7 milliliter, described thick product: described 732# storng-acid cation exchange resin=1 gram: 8 milliliters；Then it is dissolved in dehydrated alcohol or n-butyl alcohol by neutralizing the thick product after the solution collected concentrates, at 22 DEG C, saturated solution is made in stirring, spread 5 days at 26 DEG C with the absolute ether of described saturated solution volume 8 times amount under closed environment, the crystal of precipitation is obtained (S)-oxiracetam product through filtering, drying.
The present invention has following beneficial effect:
1, the primary raw material that the present invention uses is (S)-4-halogen-ethyl 3-hydroxybutanoate and glycine ethyl ester hydrochloride, is commercial goods, and raw material is cheap and easy to get and environmental protection, pollution-free；Meanwhile, the present invention first glycine ethyl ester hydrochloride carries out described free process, effectively reduces the consumption of material in reaction, reduces cost, the yield of reaction is also functioned to positive effect simultaneously.The yield height of (S)-oxiracetam prepared by the present invention may be up to 33%, and reaction condition is gentle, the cycle short, simple to operate is beneficial to industrial-scale production, and (the S)-oxiracetam product HPLC purity simultaneously prepared reaches more than 99.0%.
2, the present invention have employed ion exchange resin treatment in purification final products (S)-oxiracetam; compared with adopting silica gel column chromatography method with prior art; although treatment effect is suitable; but, ion exchange resin can repeatedly regenerate and reuse on the one hand, reduces cost; ion exchange resin is to use pure water to carry out eluting on the other hand; avoid use organic solvent, pollution-free, simultaneously preferably for the big production of large-scale industrial.The present invention selects the good solvent of suitable (S)-oxiracetam to dissolve, poor solvent method of diffusion, effectively reduce impurity content, significantly improve the quality of final products, and the majority of organic solvent toxicity of use is little, it is low to pollute, the water used in last handling process is pollution-free avirulent especially, so the present invention is not only suitable for industrialized production, also comply with national requirements for environmental protection.
Detailed description of the invention
By the examples below the present invention is specifically described; be necessary it is pointed out here that be that following example are served only for the present invention is further described; it is not intended that limiting the scope of the invention, the present invention can be made some nonessential improvement and adjustment according to the invention described above content by the person skilled in the art in this field.
Embodiment 1
The preparation method of a kind of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) by glycine ethyl ester hydrochloride 139.6g and sodium bicarbonate 84.0g, dehydrated alcohol 1008ml 70 DEG C, pH be that 8.7 times stirrings mix for 2 hours, drip (S)-4-chloro-3-hydroxyl-ethyl n-butyrate. 183.3g again, the pH of point 2 addition sodium bicarbonate 84.0g control reaction systems is 9, reacts 24～25 hours at 62～64 DEG C, and the time of described dropping (S)-4-halogen-3-hydroxy-butyric acid ethyl ester is 2.5 hours；Wherein glycine ethyl ester hydrochloride is 1: 2 with the mol ratio of sodium bicarbonate, and dehydrated alcohol consumption is 6 times of alkali weight, and the mol ratio of glycine ethyl ester hydrochloride and (S)-4-chloro-3-hydroxyl-ethyl n-butyrate. is 1: 1.1；
B () then filters, with the abundant wash filtrate of inorganic alkoxide, concentration, concentrate is dissolved in water, add the chloroform of 4 times of filtrate weight carry out extracting, aqueous phase concentration, column chromatography for separation；It is eventually adding the strong aqua ammonia that mass percentage concentration is 23% at 23～26 DEG C, reacts 5～7 hours prepared (S)-oxiracetam crude products.
2, the purification of crude product:
A (), with the above-mentioned prepared crude product of water dissolution, by 732# storng-acid cation exchange resin, then passes through 711# strong-base anion-exchange resin and neutralizes and collect solution, concentration；
B () is then dissolved in n-butyl alcohol by neutralizing the thick product after the solution collected concentrates, at 22 DEG C, saturated solution is made in stirring, spread 5 days at 26 DEG C with the normal hexane of described 8 times of volumes of saturated solution under closed environment, the crystal of precipitation is obtained (S)-oxiracetam product through filtering, drying.
The HPLC purity of final (the S)-oxiracetam product prepared reaches 99.30%, and yield reaches 35%.
Embodiment 2
The preparation method of a kind of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) by glycine ethyl ester hydrochloride and alkali, alcoholic solvent 68～73 DEG C, pH be that 8～9 times stirrings mix for 1～3 hour, then drip (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, gradation adds alkali to control the pH of reaction system is that 8-9 fully reacts；
B () then filters, with the abundant wash filtrate of inorganic alkoxide, concentration, concentrate is dissolved in water, add the dichloromethane of 5 times of filtrate weight carry out extracting, aqueous phase concentration；It is eventually adding strong aqua ammonia reaction and prepares (S)-oxiracetam crude product.
2, the purification of crude product:
A (), with the above-mentioned prepared crude product of water dissolution, by 732# storng-acid cation exchange resin, then passes through 711# strong-base anion-exchange resin and neutralizes and collect solution, concentration；Described crude product: water=1 gram: 0.8 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 12 milliliters；
B () is then dissolved in n-butyl alcohol by neutralizing the thick product after the solution collected concentrates, at 22 DEG C, saturated solution is made in stirring, spread 3 days at 25 DEG C with the petroleum ether of described saturated solution volume 7 times amount under closed environment, the crystal of precipitation is obtained (S)-oxiracetam product through filtering, drying.
The HPLC purity of final (the S)-oxiracetam product prepared reaches 99.1%, and yield reaches 30%.
Embodiment 3
The preparation method of a kind of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
(a) by glycine ethyl ester hydrochloride and sodium bicarbonate, absolute methanol 68～73 DEG C, pH be that 8 times stirrings mix for 3 hours, then drip (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, gradation adds sodium bicarbonate and controls the pH of reaction system and 8.8 fully react；Wherein glycine ethyl ester hydrochloride is 1: 2 with the mol ratio of sodium bicarbonate, and dehydrated alcohol consumption is 5～8 times of alkali weight；
B () then filters, with the abundant wash filtrate of inorganic alkoxide, concentration, concentrate is dissolved in water, adds ethyl acetate and carries out extracting, aqueous phase concentration, separates；It is eventually adding strong aqua ammonia reaction and prepares (S)-oxiracetam crude product；
2, the purification of crude product:
A (), with the above-mentioned prepared crude product of water dissolution, by 001 × 7 strongly acidic styrene type cation exchange resin, then passes through 201 × 7 basicity styrene series anion exchange resins and neutralizes and collect solution, concentration；
B then thick product after neutralizing the solution concentration collected is dissolved in n-butyl alcohol by (), saturated solution is made at room temperature stirring, spreads with normal hexane under closed environment, by the crystal of precipitation through filtering, dry obtain (S)-oxiracetam product.
The HPLC purity of final (the S)-oxiracetam product prepared reaches 98.5%, and yield is up to 33%.
Embodiment 4
The preparation method of a kind of (S)-oxiracetam, carries out as follows:
1, the preparation of crude product:
A glycine ethyl ester hydrochloride is mixed by () with alkali, alcoholic solvent, then drip (S)-4-halogen-3-hydroxy-butyric acid ethyl ester, gradation add alkali control reaction system pH be that 8-9 fully reacts；
B () then filters, with the abundant wash filtrate of inorganic alkoxide, concentration, concentrate is dissolved in water, add ethyl acetate carry out extracting, aqueous phase concentration；It is eventually adding strong aqua ammonia reaction and prepares (S)-oxiracetam crude product.
2, the purification of crude product:
A (), with the above-mentioned prepared crude product of water dissolution, by 732# storng-acid cation exchange resin, then passes through 711# strong-base anion-exchange resin and neutralizes and collect solution, concentration；Described crude product: water=1 gram: 0.7 milliliter, described thick product: described storng-acid cation exchange resin=1 gram: 8 milliliters；
B () is then dissolved in dehydrated alcohol by neutralizing the thick product after the solution collected concentrates, at 20 DEG C, saturated solution is made in stirring, spread 6 days at 24 DEG C with the absolute ether of described saturated solution volume 6 times amount under closed environment, the crystal of precipitation is obtained (S)-oxiracetam product through filtering, drying.
The HPLC purity of final (the S)-oxiracetam product prepared reaches 99.05%, and yield is 28%.
Embodiment 5～9:
The preparation method of a kind of (S)-oxiracetam, is undertaken by following material and technological parameter, and all the other are with embodiment 1.
The HPLC purity of (S)-oxiracetam product that above example finally prepares reaches 98.5%～99.2%, and yield reaches 28%～34%.
Claims (1)
1. the preparation method of a (S)-Olaxiracetam, it is characterised in that carry out as follows:
(1), the preparation of crude product:
(a) by glycine ethyl ester hydrochloride 139.6g and sodium bicarbonate 84.0g, dehydrated alcohol 1008ml 70 DEG C, pH be 8.7 times stirring 2 hours mix, drip ATS-4 183.3g again, the pH of point 2 addition sodium bicarbonate 84.0g control reaction systems is 9, reacts 24～25 hours at 62～64 DEG C, and the time of described dropping (S)-4-halogen-3-hydroxy-butyric acid ethyl ester is 2.5 hours；
B () then filters, with the abundant wash filtrate of inorganic alkoxide, concentration, concentrate is dissolved in water, add the chloroform of 4 times of filtrate weight carry out extracting, aqueous phase concentration, column chromatography for separation；It is eventually adding the strong aqua ammonia that mass percentage concentration is 23% at 23～26 DEG C, reacts 5～7 hours prepared (S)-Olaxiracetam crude products；
(2), the purification of crude product:
A (), with the above-mentioned prepared crude product of water dissolution, by 732# storng-acid cation exchange resin, then passes through 711# strong-base anion-exchange resin and neutralizes and collect solution, concentration；
B () is then dissolved in n-butyl alcohol by neutralizing the thick product after the solution collected concentrates, at 22 DEG C, saturated solution is made in stirring, spread 5 days at 26 DEG C with the normal hexane of described 8 times of volumes of saturated solution under closed environment, the crystal of precipitation is obtained (S)-Olaxiracetam product through filtering, drying.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005115978A1 (en) * | 2004-05-25 | 2005-12-08 | Ahn-Gook Pharmaceutical Co., Ltd. | 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 |
| US20100125096A1 (en) * | 2008-11-14 | 2010-05-20 | Neurotune Ag | Acetam Derivatives for Pain Relief |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005115978A1 (en) * | 2004-05-25 | 2005-12-08 | Ahn-Gook Pharmaceutical Co., Ltd. | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine 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 |
| US20100125096A1 (en) * | 2008-11-14 | 2010-05-20 | Neurotune Ag | Acetam Derivatives for Pain Relief |
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