Efficient Large Scale Preparation of Neutral Endopeptidase/Angiotensin-Converting Enzyme Dual Inhibitor CGS30440

The development and piloting of a potential manufacturing process for ACE/NEP dual inhibitor CGS30440 is described. The synthesis proceeds sequentially from 1-aminocyclopentanecarboxylic acid via N-protection, peptide coupling with <SCP>l</SCP>-tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]-<SCP>l</SCP>-tyrosine ethyl ester, N-deprotection, peptide coupling of [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-<SCP>l</SCP>-tyrosine ethyl ester with <SCP>d</SCP>-2-bromo-3-methylbutyric acid, and final displacement of bromide with thioacetate. This approach is superior to shorter Discovery routes based upon final peptide coupling of <SCP>l</SCP>-2-(acetylthio)-3-methylbutanoic acid to [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-<SCP>l</SCP>-tyrosine ethyl ester.