A practical synthesis of enantiopure β-methyltryptophan ethyl ester for a preparation of diabetes drug

Abstract

A practical synthesis of (2 R,3 S)- and (2 S,3 R)-β-methyltryptophan ethyl ester (β-MeTrp-OEt) has been developed. Racemic threo-β-MeTrp-OEt was diastereoselectively prepared via crystallization-induced diastereomer transformation (CIDT) of the α-nitro equivalent of β-MeTrp-OEt. The enantiomers were resolved via diastereomeric salt formation using a half equivalent of ( R)-2-(4-hydroxyphenoxy)propionic acid. The process allowed a diabetes drug candidate N-[(1 R,2 S)-1-({5-[(dimethylamino)methyl]-2-ethoxyphenyl}aminocarbonyl)-2-(1 H-indol-3-yl)propyl]-4-phenyl-1-piperidinecarboxamide to be prepared in good yield with high quality.