Enantioselective synthesis of brivaracetam and intermediates thereof

A process for enantioselective synthesis of the compound of formula I and key intermediates thereof comprising the steps of:

• (a) condensing a pentanal with a glycoxylic acid in presence of a condensing agent to form Intermediate 1
• (b) reducing said Intermediate 1 with a reducing agent to form Intermediate 2
• (c) treating said Intermediate 2 with 0.1-1 mol % of a chiral ligand in presence of a metal based catalyst;
• followed by enantio-selectively reducing the unsaturated lactone of said Intermediate 2 in presence of a reductant and an additive in order to form Intermediate 3
• (d) reacting the said Intermediate 3 with a chiral amine in a solvent to produce a diastereomeric mixture of Intermediate 4
• wherein R1 is a substituted or unsubstituted aryl or heteroaryl;
• and
• R2 is a substituted or unsubstituted alkyl or cycloalkyl;
• (e) purifying said Intermediate 4 by crystallization in order to form Intermediate 5 having 99.90-100% chiral purity
• wherein R1 is a substituted or unsubstituted aryl or heteroaryl;
• and
• R2 is a substituted or unsubstituted alkyl or cycloalkyl;
• (f) cyclizing said Intermediate 5 with a cyclizing agent in order to form intermediate 6 having an enantiomeric purity of 99.90-100%
• (g) reacting said intermediate 6 with a suitable ring-opening agent to produce the compound intermediate 7A
• wherein R1 is selected from saturated or unsaturated C1-20 alkyl, substituted or unsubstituted C1-10 aryl, a metal of Group I of the Periodic table;
• and
• X is CI, Br, I, OH, OMs, OTs, ONs;
• with a proviso that X is OH only when R1 is a metal of Group I of the Periodic table;
• OR
• the compound intermediate 7B:
• wherein X is selected from a group consisting of CI, Br, I, OMs, OTs, ONs;
• followed by
• (h) reacting the said intermediate 7A OR intermediate 7B with a chiral amide to produce the compound Brivaracetam of formula I with chiral purity of 99-100%.