- Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam
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In this contribution, we demonstrate that it is possible to obtain the lactol tautomer of alpha-ketoglutaric acid (AKGA) in the solid state by cocrystallizing it with Leviteracetam, a chiral nootropic drug used to treat epilepsy. In addition, we show that a cocrystal can be isolated with the racemic equivalent of Levetiracetam, Etiracetam (Eti), in which AKGA stays in the keto-form. We also report the existence of a cocrystal conglomerate in the Etiracetam-AKGA system, which is more stable than the racemic cocrystal at room temperature. The existence of a stable conglomerate is put in relation to the enantiospecificity of the Levetiracetam cocrystals, which is likely related to the ability of the Etiracetam enantiomers to stabilize one lactol tautomer at a time in solution or to promote its formation by hydrogen bonding. By comparing the peculiarities of the system in hand to the general behavior of cocrystallizing chiral systems with and without zwitterionic coformers, we suggest that for a pseudoquaternary cocrystal (made up of two racemate compounds) to exist the pseudoternary combinations (made up of one racemate and an enantiomer of the second compound) should exist and the enantiomers of the two compounds should form a diastereomeric pair at the binary level, rather than behave enantiospecifically.
- George, Fanny,Norberg, Bernadette,Robeyns, Koen,Wouters, Johan,Leyssens, Tom
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- Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams
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We report the synthesis of racetams, a diverse class of small molecule drugs, by means of the Ugi four-center three-component reaction (U4C-3CR). For the first time, γ-aminobutyric acid is employed as bifunctional input in the Ugi reaction. This protocol is simple, general, and allows one-pot access to a range of drugs and bioactive small molecules.
- Cioc, R?zvan C.,Schaepkens van Riempst, Lola,Schuckman, Peter,Ruijter, Eelco,Orru, Romano V. A.
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- A Short Enantioselective Synthesis of (S)-Levetiracetam through Direct Palladium-Catalyzed Asymmetric N -Allylation of Methyl 4-Aminobutyrate
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An exceedingly short and enantioselective synthesis of the antiepileptic drug (S)-levetiracetam was elaborated. As the chirogenic key step, a Pd-catalyzed asymmetric N -allylation of methyl 4-aminobutyrate was achieved in the presence of only 1 mol% of a catalyst prepared in situ from [Pd(allyl)Cl] 2 and a tartaric acid-derived C 2 -symmetric diphosphine ligand.
- Albat, Dominik,Neud?rfl, J?rg-Martin,Schmalz, Hans-Günther
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- Ionic Cocrystals of Etiracetam and Levetiracetam: The Importance of Chirality for Ionic Cocrystals
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A striking variety of anhydrous and hydrated ionic cocrystals (ICCs) of the enantiopure antiepileptic drug (AED) levetiracetam and of its racemic intermediate etiracetam with the pharmaceutically acceptable salts CaCl2 and MgCl2 was synthesized and structurally characterized. The difference in the interaction of enantiopure and racemic compounds of interest with the inorganic salts was investigated. Variable-temperature X-ray powder diffraction (VT-XRPD) and calorimetric analyses (TGA and DSC) of all obtained ICCs showed a significant improvement in thermal stability with respect to pure racetams.
- Song, Lixing,Shemchuk, Oleksii,Robeyns, Koen,Braga, Dario,Grepioni, Fabrizia,Leyssens, Tom
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- Solid-state chiral resolution mediated by stoichiometry: Crystallizing etiracetam with ZnCl2
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Chiral resolution of racemic etiracetam was achieved via co-crystallization with ZnCl2. Depending on the amount of ZnCl2 either a stable racemic compound or a stable conglomerate can be obtained. Excess ZnCl2 triggers the quantitative conversion of the racemate into the conglomerate solid; this unprecedented behaviour was investigated through a racetam/ZnCl2/solvent phase diagram.
- Shemchuk, Oleksii,Song, Lixing,Robeyns, Koen,Braga, Dario,Grepioni, Fabrizia,Leyssens, Tom
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- The sustainable synthesis of levetiracetam by an enzymatic dynamic kinetic resolution and an: Ex-cell anodic oxidation
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Levetiracetam is an active pharmaceutical ingredient widely used to treat epilepsy. We describe a new synthesis of levetiracetam by a dynamic kinetic resolution and a ruthenium-catalysed ex-cell anodic oxidation. For the enzymatic resolution, we tailored a high throughput screening method to identify Comamonas testosteroni nitrile hydratase variants with high (S)-selectivity and activity. Racemic nitrile was applied in a fed-batch reaction and was hydrated to (S)-(pyrrolidine-1-yl)butaneamide. For the subsequent oxidation to levetiracetam, we developed a ligand-free ruthenium-catalysed method at a low catalyst loading. The oxidant was electrochemically generated in 86% yield. This route provides a significantly more sustainable access to levetiracetam than existing routes. This journal is
- Arndt, Sebastian,Grill, Birgit,Schwab, Helmut,Steinkellner, Georg,Pogorev?nik, Ur?ka,Weis, Dominik,Nauth, Alexander M.,Gruber, Karl,Opatz, Till,Donsbach, Kai,Waldvogel, Siegfried R.,Winkler, Margit
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- Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction
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Identifying catalyst activation modes that exploit one-electron chemistry and overcome associated deactivation pathways will be transformative for developing first-row transition metal catalysts with performance equal or, ideally, superior to precious metals. Here we describe a zinc-activation method compatible with high-throughput reaction discovery that identified scores of cobalt-phosphine combinations for the asymmetric hydrogenation of functionalized alkenes. An optimized catalyst prepared from (R,R)-Ph-BPE (Ph-BPE, 1,2-bis[(2R,5R)-2,5-diphenylphospholano]ethane) and cobalt chloride [CoCl2·6H2O] exhibited high activity and enantioselectivity in protic media and enabled the asymmetric synthesis of the epilepsy medication levetiracetam at 200-gram scale with 0.08 mole % catalyst loading. Stoichiometric studies established that the cobalt (II) catalyst precursor (R,R)-Ph-BPECoCl2 underwent ligand displacement by methanol, and zinc promoted facile one-electron reduction to cobalt (I), which more stably bound the phosphine.
- Friedfeld, Max R.,Zhong, Hongyu,Ruck, Rebecca T.,Shevlin, Michael,Chirik, Paul J.
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- Ternary and quaternary phase diagrams: Key tools for chiral resolution through solution cocrystallization
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The goal of this contribution is to guide the reader through the construction and the understanding of quaternary phase diagrams in the pursuit of optimal conditions for a chiral resolution through cocrystallization in solution. The overall description will be illustrated by experimental results on a system involving RS-2-(2-oxopyrrolidin-1-yl) butanamide as chiral API to be separated, and S-mandelic acid as chiral coformer.
- Springuel, Geraldine,Collard, Laurent,Leyssens, Tom
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- Total synthesis of levetiracetam
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Total synthesis of levetiracetam, an active ingredient of epilepsy treatment medications, is reported. The reported method is based on a one-pot dehydration/sigmatropic rearrangement of (R,E)-hept-4-en-3-ol carbamate to the corresponding allylamine derivative, an advanced precursor of levetiracetam.
- Narczyk, Aleksandra,Mrozowicz, Micha?,Stecko, Sebastian
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- Theoretical studies on racemization of levetiracetam: Structural movements, character of hydroxide ion and guidelines for efficient control
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Levetiracetam, a novel antiepileptic drug, is administered as the S-enantiomer of etiracetam according to the predominant pharmacodynamic advantage compared to its R-enantiomer. Thus, the content of enantiomer is restricted explicitly, which creates a hotspot focused on the stereochemistry of levetiracetam during synthesis. However, unexpected racemization was observed during our practice. It's important to understand the racemization mechanism for levetiracetam. In this article, the racemization process for levetiracetam is comprehensively explored by means of widely used density functional theory. Firstly, basic structural movements were determined for further description of racemization process. Then, five plausible pathways for isolated levetiracetam were identified with detailed elucidation of structural movements during racemization. Significant energy barriers were observed corresponding to the proton transfer process, which demonstrated the chiral stability of levetiracetam in neutral environment. Further, hydroxide ion was introduced to elucidate the character of it in racemization process. The result indicated that hydroxide ion could facilitate the racemization by dramatically reducing the barriers for proton transfer, which was further confirmed by the experiment. Additionally, several suggestions were proposed according to the theoretical mechanism and experimental observation, resulting in the efficient control of racemization extent during synthesis. Finally, qualified levetiracetam could be prepared in kg-scale.
- Li, Zhen,Wu, Chengjun,Liu, Jiazu,Li, Linwei,Sun, Changshan,Sun, Tiemin
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- Radiosynthesis of 11C-levetiracetam: A potential marker for PET imaging of SV2A expression
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The multistep preparation of 11C-levetiracetam (11C-LEV) was carried out by a one-pot radiosynthesis with 8.3 ± 1.6% (n = 8) radiochemical yield in 50 ± 5.0 min. Briefly, the propionaldehyde was converted to propan-1-imine in situ as labeling precursor by incubation with ammonia. Without further separation, the imine was reacted with 11C-HCN to form 11C-aminonitrile. This crude was then reacted with 4-chlorobutyryl chloride and followed by hydrolysis to yield 11C-LEV after purification by chiral high-performance liquid chromatography (HPLC). Both the radiochemical and enantiomeric purities of 11C-LEV were >98%.
- Cai, Hancheng,Mangner, Thomas J.,Muzik, Otto,Wang, Ming-Wei,Chugani, Diane C.,Chugani, Harry T.
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- A short enantioselective synthesis of the antiepileptic agent, levetiracetam based on proline-catalyzed asymmetric α-aminooxylation
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An efficient enantioselective synthesis of a new antiepileptic drug, levetiracetam is described, in high optical purity (>99.5% ee), using proline-catalyzed α-aminooxylation of n-butyraldehyde as the key step.
- Kotkar, Shriram P.,Sudalai, Arumugam
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- REGIOSELECTIVE OXIDATION OF HETEROCYCLIC ALPHA-AMINO AMIDES
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The present invention relates to regioselective chemical and electrochemical processes for the preparation of an oxidized heterocyclic alpha-amino amide compounds. By applying specific catalysts or catalyst systems during chemical oxidation or by applying particular electrochemical oxidation conditions the present invention provides access to valuable alpha amino amide compounds, which are oxidized at the heterocyclic amino group by regioselective introduction of either a hydroxyl or a keto group. In a more particular embodiment, the present invention describes a chemical oxidation reaction, which advantageously is applicable in the enantioselective synthesis of valuable oxidized heterocyclic alpha-amino amide compounds, like levetiracetam, brivaracetam or the synthesis of piracetam. Another aspect of the present invention relates to a process for the electrochemical recycling of alkali perhalogenate oxidants as spent during said regioselective oxidation reactions of the invention. Still another aspect of the invention relates to the electrochemical preparation of perhalogenates.
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Page/Page column 87-88
(2021/10/30)
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- Preparation method of levetiracetam
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The invention relates to a preparation method of levetiracetam, and belongs to the technical field of medicine synthesis. In order to solve the problem that resolution is needed due to low chiral purity in the prior art, the invention provides a preparation method of levetiracetam. The method comprises the following steps: reacting 2-halogenated butyramide with 2-pyrrolidone in the presence of an acid-binding agent under the catalytic action of a catalytic amount of chiral BINOL derived phosphoric acid ligand to obtain the levetiracetam, wherein the 2-halogenated butyramide is selected from 2-chlorobutyramide or 2-bromobutyramide. The method has the characteristic of high chiral conversion rate, the effects of high product yield and high chiral purity are achieved, the yield reaches 85% or above, and the chiral purity reaches 99% or above.
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Paragraph 0051-0055
(2021/10/20)
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- Preparation method of levetiracetam
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The invention relates to a preparation method of levetiracetam, which belongs to the technical field of drug intermediate synthesis. In order to solve the problems of need of resolution treatment andserious pollution in the prior art, the invention provides a preparation method of levetiracetam, which comprises the following steps of under the action of concentrated sulfuric acid, carrying out esterification reaction on a compound (S)-2-(4-chlorobutylamide) butyric acid as shown in a formula I and alcohol to obtain corresponding (S)-2-(4-chlorobutylamide) butyrate, enabling (S)-2-(4-chlorobutyramide) butyrate and an ammoniation reagent to be subjected to a reaction to obtain chlorobutyramide, in the presence of a phase transfer catalyst and alkali, enabling chlorobutanamide to be subjected to a cyclization reaction to be converted into levetiracetam. According to the method, the effects of high chiral purity and high yield can be effectively achieved, a complex splitting process is not needed, the conditions of the whole reaction process are mild, and the whole yield is high.
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Paragraph 0025; 0028-0029; 0032-0033; 0036-0037; 0040-0041
(2021/02/06)
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- Method for synthesizing medicine for treating epilepsy by using L-2-aminobutanamide hydrochloride
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The invention discloses a method for synthesizing a medicine for treating epilepsy by using L-2-aminobutanamide hydrochloride, and relates to the technical field of medicine synthesis, and the method comprises the following steps: under the protection of nitrogen, adding L-2-aminobutanamide hydrochloride and 4-chlorobutyrate into isopropyl alcohol, and reacting under the action of an alkaline substance and a catalyst, heating and refluxing to carry out nucleophilic substitution reaction and ring-closure reaction to prepare the levetiracetam. According to the method, the levetiracetam is synthesized by adopting a milder alkaline substance and a one-pot method, the operation is simple, the levetiracetam can be prepared without post-treatment, the levetiracetam obtained by the method is low in impurity content and high in chemical purity, the yield can reach 83.43% or above, and the purity reaches 99.6%.
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Paragraph 0057-0058; 0062-0063; 0071-0072; 0076-0077
(2021/11/03)
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- METHOD FOR PREPARING LEVETIRACETAM
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A preparing method for high-purity levetiracetam, comprising: adjusting the pH of an extracted aqueous layer obtained by dissociating (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-methylbenzylamine salt to 5-9; removing water; adding an organic solvent to form a solution and then performing an esterification reaction with ethyl chloroformate or methylchlorofonmate; and carrying out an ammonolysis reaction to obtain the levetiracetam. The method simplifies production process, increases yield, reduces or even avoids the use of triethylamine in the esterification process, and reduces the emission of a great amount of three wastes.
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Paragraph 0027-0045
(2020/06/27)
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- Method for preparing levetiracetam
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The invention relates to a method for preparing levetiracetam. The method comprises the following steps: reacting aminobutyric acid in lower alcohol and thionyl chloride to obtain an intermediate I; adding ammonia water to continue the reaction, and adding hydrochloric acid to adjust the pH value to about 3 to salify to obtain a salified intermediate II refined product; reacting the intermediate II in the presence of KOH in the presence of a catalyst and dichloromethane, and then adding 4-chlorobutyryl chloride to continuously react; adding water to hydrolyze, adjusting the pH to be weakly alkaline by using diluted hydrochloric acid, and crystallizing to obtain a levetiracetam crude product; decolorizing and crystallizing in ethyl acetate to obtain a refined product of levetiracetam. The invention also relates to the levetiracetam prepared by the method and pharmaceutical application thereof, for example, the levetiracetam can be used for treating or preventing epilepsy, Parkinson's disease, dyskinesia, migraine, tremor, idiopathic tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic diseases.
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Paragraph 0079; 0080; 0084-0087; 0090-0093; 0096-0099; 0102
(2020/02/14)
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- Preparation method of levetiracetam and intermediates thereof
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The invention provides a preparation method of levetiracetam and intermediates thereof. The specific steps are as follows: dropwise adding pyrrolidone into a toluene solution of sodium methoxide or sodium hydride, performing concentrating to dryness after a reaction is completed, adding toluene again, dropwise adding ethyl 2-bromobutyrate, and carrying out a reaction by heating to obtain a compound of a formula 3; adding a NaOH aqueous solution to the compound of the formula 3, performing heating until a reaction is completed, and dropwise adding concentrated hydrochloric acid to precipitate acompound of a formula 4; carrying out a reaction of the compound of the formula 4, R-(+)-phenylethylamine, and triethylamine to obtain a compound of a formula 6; performing hydrolysis by a NaOH solution, acidification by concentrated hydrochloric acid, and purification to a compound of a formula 7; and performing esterification by TsOH/EtOH to obtain a compound of a formula 8, and then performingammonia hydrolysis to obtain levetiracetam.
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Paragraph 0043; 0056-0057; 0059
(2020/01/08)
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- Method for preparing levetiracetam
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The invention relates to the technical field of drug synthesis, and provides a method for preparing levetiracetam. The method includes the following steps: taking L-2-aminobutyric acid as a starting material, and preforming esterification with thionyl chloride to obtain (S)-2-methyl aminobutyrate hydrochloride; performing aminolysis reaction between the (S)-2-methyl aminobutyrate hydrochloride andammonia water to generate (S)-2-aminobutylamine hydrochloride; preforming acylation reaction between the(S)-2-aminobutylamine hydrochloride and the mixed solution of 4-chlorobutyryl chloride and dichloromethane; directly performing cyclization reaction between the intermediate product with the dichloromethane and tetrabutyl ammonium bromide to obtain a crude product of levetiracetam; and recrystallizing the crude product to generate the levetiracetam. The preparation method uses the easily-obtained starting material to ensure good reproducibility of the synthesis route, simple unit operationand economic accounting. The reaction in each step is easy to purify, the quality is controllable, and the reaction yield is greatly improved.
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Paragraph 0112; 0123-0125; 0129; 0137-0140
(2019/01/23)
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- Method for preparing levetiracetam
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The invention relates to a method for preparing levetiracetam, comprising the following step: enabling L-2-aminobutanamide hydrochloride as material to generate one-pot reaction with 4-chlorobutyic acid ester under an alkaline condition, so as to complete nucleophilic substitution and ring closing reaction, thus obtaining a finished product of levetiracetam. The method disclosed by the invention is simple in operation, low in cost, simple in equipment requirement, safe and environment-friendly, and suitable for industrial large-scale production.
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Paragraph 0040; 0041; 0051
(2018/07/30)
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- Improvement method of levetiracetam synthesis process
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The invention provides an improvement method of a levetiracetam synthesis process. The method comprises steps as follows: (S)-2-aminobutanamide (I) is taken as a starting material, firstly, (S)-N-[1(aminocarbonyl) propyl]-4-bromo-butanamide (II) is prepared from (S)-2-aminobutanamide (I) and 4-bromobutyrylbromide under the action of sodium hydrogen carbonate, and is subjected to cyclization underthe action of potassium carbonate, and levetiracetam (II) is obtained. According to the method, by means of adjustment of the starting material and alkali, effects of mild reaction conditions, safe operation and effective control for any individual impurity, especially enantiomers are achieved, and ee is higher than or equal to 99.6%.
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Paragraph 0014; 0020; 0021
(2018/04/28)
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- Synthesis process of levetiracetam
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The invention relates to the technical field of pharmaceutical preparation, in particular to a preparation method of an antiepileptic drug. The synthesis process of levetiracetam designed by the invention takes (S)-2-(4-chlorobutyramide) butyric acid as an initial raw material, pyridine as an alkali and (Boc)2O as an activating reagent of carboxylic acid, an ammonium salt is added to prepare (S)-2-(4-chlorobutyramide) butyramide, and finally a cyclization reaction is carried out in the presence of alkali to obtain levetiracetam. The process does not need chemical resolution, does not use highly toxic or corrosive chemical reagents, is simple to operate, mild in conditions, environment-friendly and high in finished product quality, and is suitable for industrial production.
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Paragraph 0031; 0034-0036; 0039-0040
(2019/01/14)
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- A method for purification of levetiracetam
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The invention discloses a purifying method of levetiracetam. The method includes: adding crude levetiracetam into a crystallization system, adding activated carbon and weak base accounting for greater than 1% of weight of the crude levetiracetam, performing heating to 50-100 DEG C, and performing decolorizing, filtering, cooling, crystallizing, filtering, rinsing and drying to obtain finished levetiracetam. The levetiracetam purified by the purifying method is not less than 99.8% in purity and not less than 99.8% in chiral purity; yield is high, operating is simple, and the solvent is simple to recycle; the purifying method is suitable for large-scale industrial application.
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Paragraph 0026; 0027; 0036
(2018/10/19)
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- Sequential ruthenium catalysis for olefin isomerization and oxidation: Application to the synthesis of unusual amino acids
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How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is capable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging α-tri- and tetrasubstituted α-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam.
- Liniger, Marc,Liu, Yiyang,Stoltz, Brian M.
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p. 13944 - 13949
(2017/11/06)
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- Levetiracetam and pharmaceutical composition containing the same
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The invention provides high-purity levetiracetam and a pharmaceutical composition comprising high-purity levetiracetam. The high-purity levetiracetam is prepared with a one-pot method. According to the invention, (S)-2-aminobutyryl hydrochloride is adopted as an initial material, and is subjected to condensation and cyclization with 4-chlorobutyryl chloride, such that levetiracetam with a purity higher than 99.5% and with unknown individual impurity lower than 0.05% is obtained. Further, the levetiracetam obtained with the above method is dissolved in an organic solvent; the solution is filtered with a filter of 0.22-0.45mum while still hot, such that a chloride-qualified product with a chloride impurity amount lower than 0.02% can be obtained with high conversion rate. According to the invention, levetiracetam purity can be substantially improved, and a raw material and a pharmaceutical composition with excellent qualities can be further obtained.
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Paragraph 0070; 0071
(2017/08/25)
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- A preparation method of levetiracetam (by machine translation)
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The invention relates to a preparation method of levetiracetam, comprises the following steps: in an inert solvent, in the presence of a strong alkali and catalyst of the (S)- 2 - amino - d amide hydrochloride and 4 - chlorobutyryl chloride to carry out the reaction, the reaction temperature is maintained at - 15 °C -15 °C between, reaction time is 5 - 8 hours, to obtain the crude levetiracetam; through the levetiracetam crude product from the organic solvent or organic solvent mixture is purified by crystallization or recrystallization, to get the object product; wherein catalyst is selected from polyethylene glycol, sodium dodecyl benzene sulfonate, betaine, dodecyl betaine, cetyl betaine, alkyl betaine in eighteen of the one or more. Preparation method of this invention to avoid the use of gene toxicity quaternary ammonium salt catalyst as the catalyst, the method for the production of the levetiracetam more safe, and reliable. (by machine translation)
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Paragraph 0021; 0022; 0023; 0024; 0025; 0026
(2017/08/28)
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- Novel method for preparing levetiracetam
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The invention discloses a novel method for preparing levetiracetam. The method employs L-threonine as a raw material and is used to prepare levetiracetam through steps of amidation of carboxyl, acylation of amino, cyclization, sulfonylation, reduction and the like. The provided method for preparing levetiracetam employs the raw material natural amino acid L-threonine, the raw material source is wide and low in price, the reaction demanded conditions and the reaction process are simple, the total yield is relatively high, and the method is suitable for industrialized production.
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- Compositions and methods for the treatment of epilepsy
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The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II; and methods for treating or preventing neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, partial seizures, adjunctive therapy for partial, myoclonic, tonic-clonic seizures and schizophrenia, neuropathic pain, seizures, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder.
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- An asymmetric synthesis of Levetiracetam
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An asymmetric synthesis of (S)-levetiracetam has been developed through application of a Strecker reaction using [(1S)- 1-(4-methoxyphenyl)ethyl]amine hydrochloride as a chiral auxiliary. Addition of propanaldehyde to a solution of sodium cyanide and [(1S)-1-(4-methoxyphenyl)ethyl]amine hydrochloride in the mixture of methanol and water at 25-30°C afforded diastereomerically pure 2-[2-(4-methoxyphenyl)-(S)-methylethyl-amino]-( S )-butyronitrile hydrochloride compound 4 . In this reaction cyanide group attack at less hindered side that is re-face of the imine intermediate gave the diastereomerically pure nitrile 4. Which upon hydrolysis in the presence of 6 M aqueous hydrochloride solution obtained enantiomerically pure (S )-2- aminobutyric acid hydrochloride 5, is a key intermediate for the (S)-levetiracetam. This intermediate further react with SOCl2 in presence of methanol formed S-2-amino methyl butyrate as in situ intermediate which on further ammonalysis in the presence of methnaolic ammonia as a solvent under ammonia pressure provided S-2-amino butyramide hydrochloride 6 which further condensed with 4-chlorobutyryl chloride 7 and followed by cyclization in the presence of potassium hydroxide, dichloromethane solvent used catalytic amount of tetra butyl ammonium bromide afforded crude (S)-levetiracetam 1, further recrystalization in the presence of ethyl acetate obtained pure (S)-levetiracetam 1.
- Raju, Veeramalla,Somaiah, Sripathi,Sashikanth, Suthrapu,Laxminarayan, Eppakayala,Mukkanti, Kagga
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p. 1218 - 1221
(2014/12/10)
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- Does chirality influence the tendency toward cocrystal formation?
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We performed a systematic cocrystal search for the enantiopure and racemic version of a selected active pharmaceutical ingredient, expecting that a coformer giving a cocrystal with a single enantiomer will also interact with the racemic mixture since they present identical functional groups prone to cocrystallization. We identified several novel cocrystals of levetiracetam and its racemic equivalent, etiracetam, using a wide variety of nonchiral coformers. Fourteen novel cocrystals of the enantiopure compound were obtained, whereas 18 of the racemic compound were identified. Out of these, 13 share a common coformer. A structural analysis indicates that in most cases the strongest hydrogen bonding interactions occur both in the enantiopure, as well as the racemic cocrystal, whereas van der Waals interactions, or less strong secondary hydrogen bonding interactions, lead to a differentiation of the final structure. On the basis of our work, we suggest an approach that could lead to a more optimal cocrystal screening of an enantiopure compound, especially when a limited amount of this compound is available. Starting with a screen of the racemic compound, the set of possible coformers for the enantiopure screen can be limited to those yielding a positive hit in the former screen. Doing so, our example shows an increase in efficiency from 10% to 72%.
- George, Fanny,Tumanov, Nikolay,Norberg, Bernadette,Robeyns, Koen,Filinchuk, Yaroslav,Wouters, Johan,Leyssens, Tom
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p. 2880 - 2892
(2014/06/23)
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- An alternate synthesis of enantiomerically pure levetiracetam (Keppra)
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A simple and efficient synthesis of levetiracetam has been achieved with high enantiopurity (>99%) starting from commercially available benzyl glycidyl ether. The method is amenable for industrial scale-up.
- Mujahid, M.,Mujumdar, P.,Sasikumar, M.,Kunte, S. S.,Muthukrishnan, M.
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p. 1512 - 1515,4
(2012/12/12)
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- An alternate synthesis of enantiomerically pure levetiracetam (Keppra)
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A simple and efficient synthesis of levetiracetam has been achieved with high enantiopurity (>99%) starting from commercially available benzyl glycidyl ether. The method is amenable for industrial scale-up.
- Mujahid,Mujumdar,Sasikumar,Kunte,Muthukrishnan
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p. 1512 - 1515
(2013/01/15)
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- Process for the preparation of Levetiracetam
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A process for the manufacturing of levetiracetam, wherein said process comprises the steps of: (1) reacting the (?)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid with a substoichiometric amount of an activating agent in an alcoholic solvent, and (2) subjecting the resulting reaction solution of step (1) to an ammonolysis process with gaseous ammonia.
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(2011/04/18)
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- Process for the preparation of levetiracetam
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A process for the manufacturing of levetiracetam, wherein said process comprises the steps of: (1) reacting the (-)-(S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid with a substoichiometric amount of an activating agent in an alcoholic solvent, and (2) subjecting the resulting reaction solution of step (1) to an ammonolysis process with gaseous ammonia.
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Page/Page column 5
(2010/02/17)
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- A NOVEL POLYMORPH OF LEVETIRACETAM AND A PROCESS FOR ITS PREPARATION
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The invention relates to Form IV of Levetiracetam and a process for its preparation.
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Page/Page column 3
(2009/05/28)
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- PROCESS FOR THE PREPARATION OF LEVETIRACETAM
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The present invention relates to a process for the preparation of levetiracetam and, more particularly, to an improved process for the preparation of levetiracetam characterized by a crystallization-induced dynamic resolution of a diastereoisomeric mixture of an (±)-alpha-ethyl-2-oxo-l -pyrrolidine acetamide derivative.
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Page/Page column 19-22
(2008/06/13)
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- PROCESSES FOR THE PREPARATION OF LEVETIRACETAM
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Provided are processes for preparing levetiracetam of the Formula (I):Various aspects and embodiments are provided.
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Page/Page column 15
(2008/12/06)
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- Asymmetric synthesis of the antiepileptic drug levetiracetam
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Palladium-catalyzed asymmetric synthesis of levetiracetam of antiepileptic drug was expediently accomplished.
- Imahori, Tatsushi,Omoto, Keisuke,Hirose, Yumi,Takahata, Hiroki
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experimental part
p. 1627 - 1632
(2009/07/17)
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- A METHOD FOR THE PURIFICATION OF LEVETIRACETAM
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The present invention relates to an improved process for the preparation of Levetiracetam of formula (I). More particularly, the present invention relates to a method for the purification of crude Levetiracetam using a solvent mixture of ethyl acetate and water.(I).
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Page/Page column 4
(2008/06/13)
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- Process for the preparation of 2-oxo-1-pyrrolidine derivatives
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The present invention relates to alternative processes for the preparation of 2-oxo-1-pyrrolidine derivatives of formula (I) Particularly, the present invention relates to alternative processes for the synthesis of levetiracetam, brivaracetam and seletracetam.
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Page/Page column 17
(2010/11/27)
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- 3-CARBOXY- 2-OXO-1 -PYRROLIDINE DERIVATIVES AND THEIR USES
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The present invention relates to 3-carboxy-2-oxo-l -pyrrolidine derivatives of formula (I), geometrical isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and all possible mixtures thereof, and processes using them.
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Page/Page column 16-17
(2008/06/13)
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- PROCESS FOR PREPARING LEVETIRACETAM AND RACEMIZATION OF (R) AND (S)-2-AMINO BUTYNAMIDE AND THE CORRESPONDING ACID DERIVATIVES
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Process for the preparation of (S)-(-)-α --ethyl-2-oxo-1-pyrrolidineacetamide of Formula (I), comprising the steps of (i) resolution of racemic 2-amino butynamide with L-(+)-tartaric acid either in alcoholic solvents like methanol, isopropanol , ethanol or in water or mixture of water-alcohol to provide (S)-(+)-2-amino butynamide tartarate salt ; and ii)direct conversion of (S)-(+)-2-amino butynamide tartarate salt and 4-halobutryl chloride in presence of inorganic or organic base in suitable solvent and drying agents yielded the desired (S)-(-)- α--ethyl-2-oxo-1-pyrrolidineacetamide (I). Further (S)-(+)-2-aminlo butynamide tartarate salt is converted to (S)-(+)-2-amino butynamide hydrochloride salt, by reacting with an inorganic or organic base in a suitable solvent followed by reaction with HCl gas in an appropriate solvent . The preparation of (S)-(+)-2-amino butynamide hydrochloride salt, which is an intermediate for Levetiracetam, is prepared from (S)-(+)-2-amino butynamide tartarate salt in presence of inorganic base selected from potassium carbonate or hydroxide, sodium carbonate or hydroxide, ammonia gas, and organic base selected from triethyl amine, DMAP, and the like and a suitable solvent selected from methanol, isopropanol , ethanol or in water or mixture of water-alcohol.
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Page/Page column 8
(2010/11/24)
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- IMPROVED PROCESS FOR THE PREPARATION OF (S)-ALPHA-ETYL-2-OXO-1-PYRROLIDINEACETAMIDE AND (R)-ALPHA-ETHYL-2-OXO-1-PYRROLIDINEACETAMIDE
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A process provided for the preparation of the (S)- and (R)- alpha- ethyl-2-oxo-1- pyrrolidineacetamide of formula:(1) from (RS)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid of formula:(2) comprising: i) combining the (RS)-2 with a chiral base (resolving agent) in a resolution solvent and crystallizing from the said mixture the diastereomeric salt of (S)- or (R)-2 and chiral base; ii) regenerating (S)- or (R)-2 from the crystallized diastereomeric salt by treating with a suitable acid or acidic ion-exchange resin; iii) optionally regenerating (R)- or (S)-2 or their mixture (predominantly one enantiomer) from the crystallization mother liquor by treating with a suitable acid or acidic ion-exchange resin; iv) optionally epimerizing (RS)-2 by treating (R)- or (S)-2 or their mixture (predominantly one enantiomer) of step iii with an acid anhydride; V) optionally converting (RS)-2 of step iv into enantiomerically enriched (S)- or (R)-2 through steps i and ii; vi) formation of the mixed anhydride by reacting (R)- or (S)-2 with an alkyl or aryl sulfonyl halogen compound RSO2X in the presence of a suitable base; and vii) reacting the mixed anhydride with ammonia; wherein R represents C 1 to C 15 alkyl or aryl groups such as methyl, ethyl, p-toluenyl, 2,4,6-trimethylbenzyl, 2,4,6-trichloribenzyl, and X represents a halogen atom such as F, Cl and Br atoms.
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Page/Page column 12-13
(2008/06/13)
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- Amino acid esters and amides for reductive amination of mucochloric acid: Synthesis of novel γ-lactams, short peptides and antiseizure agent Levetiracetam (Keppra)
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A simple methodology utilizing mucochloric acid and different α- and β-amino acid esters, amides and short peptides for the synthesis of novel γ-lactam and γ-lactam-based short peptides was developed. The synthesis of an antiseizure agent, Levetiracetam (Keppra) was demonstrated. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Das Sarma, Koushik,Zhang, Ji,Huang, Yun,Davidson, James G.
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p. 3730 - 3737
(2007/10/03)
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- SYNTHESIS OF (S)-α-ETHYL-2-OXO-1-PYRROLIDINEACETAMIDE
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The invention is directed to an improved method of producing (S)-α-ethyl-2- oxo-1-pyrrolidineacetamide (also known as levetiracetam) from (S)-α-ethyl-2-oxo-l- pyrrolidineacetic acid (levo acid) in which (S)-α-ethyl-2-oxo-l-pyrrolidineacetic acid (levo acid) is contacted with di-tert-butyl dicarbonate, ammonium bicarbonate and pyridine in a solvent such as acetonitrile to yield levetiracetam.
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Page/Page column 7
(2008/06/13)
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- A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary
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The synthesis of levetiracetam and its enantiomer by deracemization of (±)-2-bromobutyric acid using either (S)- or (R)-N-phenylpantolactam as chiral auxiliaries, followed by SN2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described.
- Boschi, Francesca,Camps, Pelayo,Comes-Franchini, Mauro,Munoz-Torrero, Diego,Ricci, Alfredo,Sanchez, Laura
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p. 3739 - 3745
(2007/10/03)
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- METHOD OF OBTAINING AN ANTIEPILEPTIC AGENT
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A process for obtaining the pharmaceutical active ingredient, levetiracetam, by means of deaminomethylation of a sufficiently pure enantiomer intermediate (S)-(II), or by means of deaminomethylation of an addition salt thereof with an acid, wherein R1 and R2 are either the same or different (C1-C6)-alkyl radicals, or else R1 and R2 together with the nitrogen atom to which they are bonded form a radical selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-morpholinyl, 1-piperazinyl and 1-[4-(C1-C4)-alkylpiperazinyl]. The invention also comprises preparing the sufficiently pure enantiomer intermediate (S)-(II) by treating the corresponding chemically new racemic intermediate (II) with an amine resolving agent, followed by selective crystallisation of a diastereoisomeric salt thereof. It is useful for obtaining levetiracetam on an industrial scale and involves neither hydrogenation nor chromatography.
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Page/Page column 9
(2008/06/13)
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- PROCESS FOR PREPARING 2-OXO-1-PYRROLIDINE DERIVATIVES
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The present invention relates to a new process for preparing 2-oxo- I -pyrrolidine derivatives of general formula (I) wherein the substituents are as defined in the specification.
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Page/Page column 10
(2008/06/13)
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- Preparation of amino acid amides
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A process for making amino acid amides, comprising reacting an amino acid, or acid salt of an amino acid, with a halogenating agent, or with a substance that reacts with carboxylic acids to form a leaving group, to form an intermediate, then reacting the intermediate with ammonia. When the amino acid or acid salt is enantiomerically pure, the amide will be a stereoisomer. An amide made by the process can be used to form levetiracetam.
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Page/Page column 3
(2008/06/13)
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