- Scalable Flow Electrochemical Alcohol Oxidation: Maintaining High Stereochemical Fidelity in the Synthesis of Levetiracetam
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An electrochemical flow process has been developed for an alcohol oxidation step in the synthesis of the generic epilepsy drug levetiracetam. A crucial metric in this process is the retention of high enantiomeric purity as the oxidation of the primary alcohol to the carboxylic acid proceeds via an epimerizable aldehyde intermediate. Here, three different reactor configurations are compared: undivided batch, undivided flow, and divided flow cells. The divided flow cell accesses the highest rate, throughput, and enantiomeric fidelity among the three configurations. This approach is showcased in a 200-g scale process that retains ≥97% enantiomeric purity and highlights a unique advantage of flow electrolysis.
- Zhong, Xing,Hoque, Md Asmaul,Graaf, Matthew D.,Harper, Kaid C.,Wang, Fei,Genders, J. David,Stahl, Shannon S.
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Read Online
- 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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- 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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p. 2770 - 2775
(2019/03/12)
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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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supporting information
p. 13944 - 13949
(2017/11/06)
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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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Page/Page column 37
(2016/04/20)
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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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- Enantioselective access to chiral drugs by using asymmetric hydrogenation catalyzed by Rh(P-OP) complexes
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P-OP art: Rhodium complexes of P-OP ligands serve as highly efficient and enantioselective catalysts in asymmetric hydrogenation leading to various valuable pharmaceutical building blocks and several direct precursors of chiral drugs such as LY2497282, la
- Etayo, Pablo,Nunez-Rico, Jose Luis,Fernandez-Perez, Hector,Vidal-Ferran, Anton
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supporting information; experimental part
p. 13978 - 13982
(2012/01/06)
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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 18-19
(2008/06/13)
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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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- 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 8; 14-15
(2008/12/06)
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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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p. 6813 - 6815
(2007/10/03)
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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 14
(2008/06/13)
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- PROCESS FOR PREPARING LEVETIRACETAM
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Process for the preparation of (S)-(-)-α-ethyl-2-oxo-l-pyrrolidineacetamide of Formula (I) by the steps of condensation of (S)-2-amino butanol of Formula (II) and 4-halobutryl chloride, where halo group can be chloro, bromo or iodo in solvents to form α-ethyl-2- oxo pyrrolidine ethanol of Formula (III); oxidation of (S)-α-ethyl-2-oxo pyrrolidine ethanol to yield (S)-α-ethyl-2-oxo pyrrolidine acetic acid having the formula (IV); esterification of (S)-α-ethyl-2-oxo pyrrolidine acetic acid (IV) with an alcohol to provide alkyl ester of Formula (V) wherein, R is 1-4 Carbon atom ; ammonolysis of alkyl esters of formula (V) with ammonia to provide (S)-(-)- α-ethyl-2-oxo-l -pyrrolidine acetamide of formula (I).
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Page/Page column 5; 7-8
(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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- (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
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(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide, its preparation and pharmaceutical compositions containing the same. It can be prepared either by reacting (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid successively with an alkyl haloformate and with ammonia, or, by cyclizing an (S)-2-aminobutanamide of the formula X--CH2 CH2 --Y--NHCH(C2 H5)CONH2 wherein Y is a --CH2 -- radical when X represents a ZOOC-- radical and Y is a --CO-- radical when X represents a HalCH2 -- radical, Z being a C1 -C4 alkyl radical and Hal a halogen atom. This laevorotatory enantiomer has been found to have significantly higher protective activity against hypoxia and ischemia than the corresponding racemate.
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