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

A practical synthesis of (2R,3S)- and (2S,3R)-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-[(1R,2S)-1-({5-[(dimethylamino)methyl]-2-ethoxyphenyl}aminocarbonyl)-2-(1H-indol-3-yl)propyl]-4-phenyl-1-piperidinecarboxamide to be prepared in good yield with high quality.