Efficient Large Scale Preparation of Neutral Endopeptidase/Angiotensin-Converting Enzyme Dual Inhibitor CGS30440
Organic Process Research & Development1998Vol. 2(4), pp. 238–244
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Erik P. Johnson, William R. Cantrell, Todd M. Jenson, Scott A. Miller, D.J. Parker, Noela Reel, Leo G. Sylvester, Robert Szendroi, Kevin Vargas, Jean Xu, J. Andrew Carlson
Abstract
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 l-tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]-l-tyrosine ethyl ester, N-deprotection, peptide coupling of [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-l-tyrosine ethyl ester with d-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 l-2-(acetylthio)-3-methylbutanoic acid to [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-l-tyrosine ethyl ester.
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