A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary

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.

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(αS,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-(2-oxopyrrolidin-1-yl)butyrateC20H26N2O4Dr > 98:2Ee > 99%[α]D20=-42.3 (c 0.96, CHCl3)Source of chirality: (S)-N-phenylpantolactamAbsolute configuration: αS,3S

(αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-(2-oxopyrrolidin-1-yl)butyrateC20H26N2O4Dr > 98:2Ee > 99%[α]D20=+50.3 (c 1.03, CHCl3)Source of chirality: (S)-N-phenylpantolactamAbsolute configuration: αR,3S

(αS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-chlorobutyrateC16H20ClNO3Dr = 85:15Ee > 99%Source of chirality: (R)-N-phenylpantolactamAbsolute configuration: αS,3R

(αR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl 2-bromobutyrateC16H20BrNO3Dr > 98:2Ee > 99%[α]D20=-36.6 (c 1.19, CHCl3)Source of chirality: (S)-N-phenylpantolactamAbsolute configuration: αR,3S