An improved process for repaglinide via an efficient and one pot process of (1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butan-1-amine -: A useful intermediate

The development of a large-scale synthesis for (1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butan-1-amine (S-(+)-1), a key intermediate of repaglinide (2), is described. The process conditions for S-(+)-1 involving nucleophilic substitution, Grignard reaction, reduction and resolution were optimized and telescoped. The racemization of the undesired enantiomer R-(-)-1 offers a distinctive advantage in terms of cost and overall yield over the existing process. This communication also describes the control of a DCU byproduct obtained during the condensation of S-(+)-1 with phenyl acetic acid derivative 3 in the synthesis of 2.