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Title: An asymmetric synthesis of Levetiracetam
Authors: Raju, Veeramalla
Somaiah, Sripathi
Sashikanth, Suthrapu
Laxminarayana, Eppakayala
Mukkanti, Kagga
Keywords: Asymmetric synthesis;Heterocycles;Strecker reaction;Chiral auxiliaries;Stereoselective synthesis
Issue Date: Sep-2014
Publisher: NISCAIR-CSIR, India
Abstract: 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
Page(s): 1218-1221
ISSN: 0975-0975(Online); 0376-4710(Print)
Appears in Collections:IJC-B Vol.53B(09) [September 2014]

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