Development of analytical and preparative chromatographic separations of novel growth hormone secretagogue compounds

Chromatographic separations of new growth hormone secretagogue compounds we re developed to support structure-activity relationship (SAR) studies in co njunction with lead optimization. These new compounds differed from Merck's MK-677 by having two chiral centers and thus diastereomeric mixtures were generated. Separation of initial compounds in the SAR was achieved on a Kro masil C-18 column using an ammonium acetate buffer and acetonitrile. Howeve r, additional candidates were not separable on C-18 columns and a chiral Kr omasil CHI-DMB column was used to resolve the diastereomeric compounds. The Kromasil CHI-DMB packing was also used in a preparative chromatographic sy stem to resolve multigram quantities of secretagogue candidates for testing . Chiral separations of different intermediates were also developed in supp ort of evolution of an asymmetric synthetic route. This report summarizes d evelopment of the preparative chromatographic system used to purify diaster eomeric mixtures and chiral separations of intermediates in the synthesis. (C) 2000 Elsevier Science B.V. All rights reserved.