Analytical and Preparative Enantiomeric Separation of a Series of C5-Cycloalkylamine-L,4-Benzodiazepin-2-one CCK_B Receptor Antagonists by Chiral HPLC

Abstract

A series of C5 cycloalkyl benzodiazepin-2-one CCK_B receptor antagonists are reported in which substitution by tolyl-urea at C3 has generated a chiral centre. As only one of these enantiomers is selective for the CCK_B receptor an analytical separation of the enantiomers was developed to monitor the resolution of compounds by chemical means. It was shown that such compounds may be resolved using a Pirkle-type 3,5-(dinitrobenzoyl)-leucine (DNBL) chiral stationary phase (CSP) to give high a and R_s values. Such high enantioselectivities allowed the separation to be scaled-up sufficiently such that gram quantities of each enantiomer could be isolated by preparative chiral HPLC. An investigation is described in which the effect of substituent, mobile phase composition, temperature and the alternate CSP 3,5-(dinitrobenzoyl)-phenylglycine (DNPBG) is discussed for such compounds.