CN102924357A - Preparation method for oxiracetam intermediate - Google Patents
Preparation method for oxiracetam intermediate Download PDFInfo
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- CN102924357A CN102924357A CN2011102266966A CN201110226696A CN102924357A CN 102924357 A CN102924357 A CN 102924357A CN 2011102266966 A CN2011102266966 A CN 2011102266966A CN 201110226696 A CN201110226696 A CN 201110226696A CN 102924357 A CN102924357 A CN 102924357A
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- Prior art keywords
- ethanamide
- preparation
- oxiracetam
- alkoxyl group
- pyrroline
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- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- NOICVUZFTAVDNM-UHFFFAOYSA-N acetamide;pyrrolidin-2-one Chemical compound CC(N)=O.O=C1CCCN1 NOICVUZFTAVDNM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000012188 paraffin wax Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- -1 chloracetyl acetic ester Chemical compound 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
Abstract
The present invention relates to a new preparation method for an oxiracetam intermediate. According to the preparation method, 4-alkoxy-3-pyrrolin-2-one-1-acetamide is adopted as a raw material, and the following synthetic route is adopted to prepare an oxiracetam intermediate 4-alkoxy-3-pyrrolidine-2-one-1-acetamide. The preparation method for the oxiracetam intermediate has characteristics of easy operation, high yield, high product purity and low cost, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of oxiracetam intermediate.
Background technology
Oxiracetam, chemical name is 4-hydroxyl pyrrolidine-2-ketone-1-ethanamide, commodity are called neuromet, neupan, strong youth's magnitude, be a kind of novel medicine for central nervous system that promotes ability of learning and memory, be drugs approved by FDA be used for the treatment of one of medicine of senile dementia, be mainly used in clinically treating senile dementia, block that the neural official of dull-witted agent can demonstrate,prove, cerebral trauma more, the brain function that the diseases such as encephalitis cause is incomplete, memory disorder.At present such medicine has caused that people note and interest widely, and the demand of such medicine is also increased severely with day.This compound is synthetic in 1974 by Italian history Bick Qie Mu company first, listing in 1987.
For many years; the report synthetic about oxiracetam is a lot; main route is as raw material take ketene dimer; open loop chlorination under the effect of chlorine obtains the chloracetyl acetic ester, and this intermediate is through polystep reaction; obtain the finished product oxiracetam [JP9026267 through different approach; EP216325, US5276164, US4118396].But the common issue with that these syntheti c routes exist is that total recovery is low, the intermediate product purification difficult.
Patent CN1011211688A proposes a kind of improving one's methods (preparation flow is as follows), take ketene dimer as starting raw material, through the chlorination open loop, methylate, cyclization esterification ammonia solution makes intermediate 4-methoxyl group-3-pyrroline-2-one-1-ethanamide, this centre is through demethylation under acidic conditions, and potassium borohydride reduction obtains oxiracetam.This route slightly is improved for the route yield of front, but final step reduction yield is still lower, and product cost is high.
WO2005/115978, disclose among the CN101575309B with (S)-4-halo-3-hydroxybutyrate ester and prepared (S)-Olaxiracetam (preparation flow is as follows) as starting raw material, such preparation method's route is shorter, but raw materials cost is higher, long reaction time, product purity is low, purification difficult.
Summary of the invention
The objective of the invention is to solve the defective on the existing oxiracetam intermediate synthetic method, provide a kind of high yield to prepare the method for the high oxiracetam intermediate of purity.
The object of the present invention is achieved like this: press the method among the patent documentation CN1011211688A, prepare raw material 4-alkoxyl group of the present invention-3-pyrroline-2-one-1-ethanamide (I).My I of chemical combination under pressurized conditions, in alcohols or the varsol, under the catalysis of metal catalyst Raney nickel, preparation 4-alkoxyl group pyrrolidin-2-one-1-ethanamide (II).Compound ii can take off alkyl through aluminum chloride and obtain oxiracetam (III) (preparation flow is as follows).
R in the chemical compounds I of selecting is C
1 ~ 4Alkyl, preferable methyl.
Prepared by chemical compounds I in the shortening process of compound ii, select pressure range at 0.1 ~ 10MPa, accelerate because of pressure augmenting response speed, also easily produce by product simultaneously, so the preferable range of hydrogen pressure is 2 ~ 6MPa.Temperature is another important factor of impact reaction, and temperature raises, and speed of response improves, and product purity descends simultaneously, purification difficult, so the temperature general control at 20 ~ 70 ℃, preferred 30 ~ 50 ℃.The alcohols of selecting in this reaction or varsol are C
1 ~ 6Monohydroxy-alcohol or C
4 ~ 6Straight-chain paraffin, polar solvent more easily makes reaction carry out fully, when other conditions of reaction are identical, as being solvent with methyl alcohol, reacting and namely reacted completely in 6 hours, be that solvent then need react 50 hours if select normal hexane, particular methanol in the present invention.
The mass ratio of the 4-alkoxyl group that drops in the hydrogenation reaction-3-pyrroline-2-one-1-ethanamide (I) and Raney nickel is 1:0.02 ~ 2, preferred 1:0.05 ~ 0.15; The alcohols that adds or the volume of varsol and the mass ratio of 4-alkoxyl group-3-pyrroline-2-one-1-ethanamide (I) are 2 ~ 50:1, and preferable range is 10 ~ 15:1.
After obtaining the midbody compound II of oxiracetam, under the catalysis of sodium iodide or potassiumiodide, slough alkyl R on the compound ii by taking off alkyl reagent aluminum chloride, namely obtain oxiracetam, the reaction solvent in this step can be selected dimethyl formamide, acetonitrile, methylene dichloride, tetrahydrofuran (THF), toluene equal solvent.Namely by after the midbody compound II that obtains oxiracetam, can obtain the target product oxiracetam.
The method for preparing oxiracetam intermediate (II) provided by the invention, cost is low, and operation and subsequent purification are easy, yield and purity are more than 98%, further can make oxiracetam through simple reaction, and very high yield and purity are also arranged, be fit to be applied to suitability for industrialized production.
In order to make feature of the present invention clear, some non-limiting embodiments of the present invention are described now.
Embodiment
The preparation of embodiment 1 4-methoxyl group-3-pyrrolidin-2-one-1-ethanamide
In autoclave, add successively 4-methoxyl group-3-pyrroline-2-one-1-ethanamide 34g(200 mmol), methyl alcohol 400 mL, and Raney Ni 3.0 g, water 4mL, the hydrogen pressure of 6.0 MPa, reaction is 12 hours under the room temperature.After reaction is finished, give off hydrogen, filtered and recycled Raney nickel.Decompression is removed organic solvent and is got product, 4-methoxyl group-3-pyrrolidin-2-one-1-ethanamide 33.9g, and yield 98.4%, purity is 98.5%, sample obtains white solid with the Virahol crystallization, purity is the 99.5%(HPLC normalization method).
The preparation of embodiment 2 4-oxyethyl group-3-pyrrolidin-2-one-1-ethanamide
In autoclave, add successively 4-oxyethyl group-3-pyrroline-2-one-1-ethanamide 36.8g(200 mmol), ethanol 400 mL, and Raney Ni 2.4 g, water 3mL, the hydrogen pressure of 4.0 MPa, reaction is 20 hours under the room temperature.After reaction is finished, give off hydrogen, filtered and recycled Raney nickel.Decompression is removed organic solvent and is got product, 4-oxyethyl group-3-pyrrolidin-2-one-1-ethanamide 36.9g, and yield 99.2%, purity is 98.9%, sample obtains white solid with the Virahol crystallization, purity is the 99.6%(HPLC normalization method).
The preparation of embodiment 3 oxiracetams (compound III)
With 4-methoxyl group-3-pyrrolidin-2-one-1-ethanamide (17.2g, 100 mmol) and sodium iodide solid (14.9g, 100 mmol) be suspended in 400 mL acetonitriles in, be cooled to 0 ℃.Add aluminum chloride (13.3 g; 100 mmol) slowly raise temperature to 20 ℃, and stirred 3 hours.The reaction solution dilute with water, and with ethyl acetate extraction 3 times.Organic phase merges with the saturated sodium-chloride water solution washing and uses anhydrous sodium sulfate drying, the compound III 15.0g of evaporate to dryness, yield 95%, purity 98.1%(HPLC normalization method).Product 10g obtains oxiracetam product 9.3g with the 100mL recrystallizing methanol, and purity is the 99.5%(HPLC normalization method).
Claims (6)
1. the preparation method of an oxiracetam intermediate, it is characterized in that selecting 4-alkoxyl group-3-pyrroline-2-one-1-ethanamide (I) is raw material, through under pressurized conditions, in alcohols or the varsol, the hydrogenation reaction of Raney nickel catalysis, reduction makes 4-alkoxyl group pyrrolidin-2-one-1-ethanamide (II), and reaction formula is as follows.
2. method according to claim 1 is characterized in that the R in the raw material 4-alkoxyl group selected-3-pyrroline-2-one-1-ethanamide (I) is C
1 ~ 4Alkyl, preferable methyl.
3. method according to claim 1 and 2 is characterized in that the mass ratio of the 4-alkoxyl group that drops in the hydrogenation reaction-3-pyrroline-2-one-1-ethanamide (I) and Raney nickel is 1:0.02 ~ 2, preferred 1:0.05 ~ 0.15.
4. method according to claim 1, when it is characterized in that hydrogenation reaction the pressure of hydrogen at 0.1 ~ 10 MPa, preferred 2 ~ 6 MPa; Temperature is at 20 ~ 70 ℃, preferred 30 ~ 50 ℃.
5. method according to claim 1 is characterized in that alcohols or varsol that hydrogenation reaction is selected are C
1 ~ 6Monohydroxy-alcohol or C
4 ~ 6Straight-chain paraffin, monohydroxy-alcohol particular methanol wherein.
6. method according to claim 1 or 5 is characterized in that alcohols that hydrogenation reaction adds or the volume of varsol and the mass ratio of 4-alkoxyl group-3-pyrroline-2-one-1-ethanamide (I) are 2 ~ 50:1, and preferable range is 10 ~ 15:1.
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| CN2011102266966A CN102924357A (en) | 2011-08-09 | 2011-08-09 | Preparation method for oxiracetam intermediate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011102266966A CN102924357A (en) | 2011-08-09 | 2011-08-09 | Preparation method for oxiracetam intermediate |
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| CN102924357A true CN102924357A (en) | 2013-02-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022023839A1 (en) * | 2020-07-30 | 2022-02-03 | Latvian Institute Of Organic Synthesis | 2-(2-oxo-3-pyrolin-1-yl)acetamides as anticonvulsants |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0224256A1 (en) * | 1985-11-26 | 1987-06-03 | Lonza Ag | Alkyl-4-alkoxy-2-oxo-pyrrolidin-1-yl acetate |
| EP0538505A1 (en) * | 1990-06-26 | 1993-04-28 | Lonza Ag | Process for the preparation of 4-hydroxy-2-oxo-pyrrolidinyl-1-acetamide |
| CN102134212A (en) * | 2010-01-27 | 2011-07-27 | 重庆圣华曦药业股份有限公司 | Preparation method of Oxiracetam |
-
2011
- 2011-08-09 CN CN2011102266966A patent/CN102924357A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0224256A1 (en) * | 1985-11-26 | 1987-06-03 | Lonza Ag | Alkyl-4-alkoxy-2-oxo-pyrrolidin-1-yl acetate |
| EP0538505A1 (en) * | 1990-06-26 | 1993-04-28 | Lonza Ag | Process for the preparation of 4-hydroxy-2-oxo-pyrrolidinyl-1-acetamide |
| CN102134212A (en) * | 2010-01-27 | 2011-07-27 | 重庆圣华曦药业股份有限公司 | Preparation method of Oxiracetam |
Non-Patent Citations (1)
| Title |
|---|
| DAVID D.P.LAFFAN等: "An Efficient Synthesis of Racemic 4-Hydroxy-2-oxo-1-pyrrolidineacetamide (Oxiracetam) Using Tetramic-Acid Intermediates", 《HELVETICA CHIMICA ACTA》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022023839A1 (en) * | 2020-07-30 | 2022-02-03 | Latvian Institute Of Organic Synthesis | 2-(2-oxo-3-pyrolin-1-yl)acetamides as anticonvulsants |
| DK181768B1 (en) * | 2020-07-30 | 2024-12-05 | Latvian Inst Organic Synthesis | 2-(2-oxo-3-pyrolin-1-yl)acetamides as anticonvulsants |
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Application publication date: 20130213 |