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 l-tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyc...

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Bibliographic Details
Published in:Organic process research & development 1998-07, Vol.2 (4), p.238-244
Main Authors: Johnson, Erik P, Cantrell, William R, Jenson, Todd M, Miller, Scott A, Parker, David J, Reel, Noela M, Sylvester, Leo G, Szendroi, Robert J, Vargas, Kevin J, Xu, Jean, Carlson, John A
Format: Article
Language:English
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/op970242s