Structure and conformation of (1S,2R)-cis-2-[hydroxyaminocarbonylmethyl(N-methyl)aminocarbonyl]cyclohexanecarboxylic acid: X-ray, NMR and molecular mechanics studies

Abstract

The structural characterization of idrapril, (1S,2R)-cis-2-[hydroxyaminocarbonylmethyl(N-methyl)aminocarbonyl]cyclohexanecarboxylic acid (4), a novel ACE inhibitor and its related benzyloxy derivative (3) has been carried out by NMR studies. The crystal structure of 3 has been determined by X-ray diffraction. The NMR spectra indicate the presence of two cis and trans isomers with respect to the amide bond at room temperature, with rotational barriers of 70 kJ mol^–1. The preferred conformation of these compounds is the trans rotamer with the carboxylic moiety in the equatorial orientation.

Conformational studies in aqueous solution have been reported for idrapril as a function of pH and the equilibrium constant has been determined. The results suggest the presence of intramolecular hydrogen bonds, as is confirmed by molecular mechanics calculations.