102767-28-2Relevant articles and documents
Peculiar Case of Levetiracetam and Etiracetam α-Ketoglutaric Acid Cocrystals: Obtaining a Stable Conglomerate of Etiracetam
George, Fanny,Norberg, Bernadette,Robeyns, Koen,Wouters, Johan,Leyssens, Tom
, p. 5273 - 5282 (2016)
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.
A Short Enantioselective Synthesis of (S)-Levetiracetam through Direct Palladium-Catalyzed Asymmetric N -Allylation of Methyl 4-Aminobutyrate
Albat, Dominik,Neud?rfl, J?rg-Martin,Schmalz, Hans-Günther
, p. 1089 - 1092 (2021)
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.
Solid-state chiral resolution mediated by stoichiometry: Crystallizing etiracetam with ZnCl2
Shemchuk, Oleksii,Song, Lixing,Robeyns, Koen,Braga, Dario,Grepioni, Fabrizia,Leyssens, Tom
, p. 10890 - 10892 (2018)
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.
Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction
Friedfeld, Max R.,Zhong, Hongyu,Ruck, Rebecca T.,Shevlin, Michael,Chirik, Paul J.
, p. 888 - 893 (2018)
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.
Total synthesis of levetiracetam
Narczyk, Aleksandra,Mrozowicz, Micha?,Stecko, Sebastian
, p. 2770 - 2775 (2019)
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.
Radiosynthesis of 11C-levetiracetam: A potential marker for PET imaging of SV2A expression
Cai, Hancheng,Mangner, Thomas J.,Muzik, Otto,Wang, Ming-Wei,Chugani, Diane C.,Chugani, Harry T.
, p. 1152 - 1155 (2014)
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%.
REGIOSELECTIVE OXIDATION OF HETEROCYCLIC ALPHA-AMINO AMIDES
-
Page/Page column 87-88, (2021/10/30)
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.
Preparation method of levetiracetam
-
Paragraph 0025; 0028-0029; 0032-0033; 0036-0037; 0040-0041, (2021/02/06)
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.