- 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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supporting information
p. 2601 - 2607
(2021/05/06)
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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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- 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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- Treatment of memory impairment using (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
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(R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide, its preparation and pharmaceutical compositions containing the same. It can be prepared either by reacting (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid successively with an alkyl haloformate and with ammonia, or, by cyclizing an (R)-2-amino-butanamide 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 dextrorotatory enantiomer has been found to have significantly higher mnemic activity and lower toxicity than the corresponding racemate.
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