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.
Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams
Cioc, R?zvan C.,Schaepkens van Riempst, Lola,Schuckman, Peter,Ruijter, Eelco,Orru, Romano V. A.
, p. 1664 - 1674 (2017)
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.
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.
Ionic Cocrystals of Etiracetam and Levetiracetam: The Importance of Chirality for Ionic Cocrystals
Song, Lixing,Shemchuk, Oleksii,Robeyns, Koen,Braga, Dario,Grepioni, Fabrizia,Leyssens, Tom
, p. 2446 - 2454 (2019)
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.
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.
The sustainable synthesis of levetiracetam by an enzymatic dynamic kinetic resolution and an: Ex-cell anodic oxidation
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
, p. 388 - 395 (2021)
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
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.
Ternary and quaternary phase diagrams: Key tools for chiral resolution through solution cocrystallization
Springuel, Geraldine,Collard, Laurent,Leyssens, Tom
, p. 7951 - 7958 (2013)
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.
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.
Theoretical studies on racemization of levetiracetam: Structural movements, character of hydroxide ion and guidelines for efficient control
Li, Zhen,Wu, Chengjun,Liu, Jiazu,Li, Linwei,Sun, Changshan,Sun, Tiemin
, (2019)
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.
