Stereochemical Investigations on Intermediates for the Synthesis of Histamine H_2 Receptor Agonists and Neuropeptide Y Y_1 Antagonists: Chiral Separation of Phenyl(pyridyl)alkanoic Acids by HPLC and CE

Abstract

The enantiomeric building blocks for the prepn. of histamine H2 receptor agonists and NPY Y1 antagonists (3-(3,4-difluorophenyl)-3-(2-pyridyl)propanoic acid, 4-(3,4-difluorophenyl)-4-(2-pyridyl)butanoic acid and 4-(3,4-dichlorophenyl)-4-(2-pyridyl)butanoic acid (I)) have been sepd. by HPLC and capillary electrophoresis (CE). On a Chiralpak AD column resolns. of at least 1.5 and selectivities of at least 1.11 were obtained. CE sepn. was achieved with (2-hydroxypropyl)-alpha-cyclodextrin or (2-hydroxypropyl)-beta-cyclodextrin as chiral selector. After an optimization procedure, including selection of the best suited cyclodextrin, variation of buffer pH, cyclodextrin concn. and capillary temp., the enantiomers were sepd. with resolns. of at least 1.3. CD measurements at different pH values were used for the characterization of the enantiomers and for the elucidation of their abs. configurations using (R)-(-)-I as ref. The anal. enantioselective HPLC and CE were integrated in studies on the detn. of the abs. configuration of several stereoisomeric NPYY1 antagonists, which were sepd. into diastereomers by HPLC on a semi-preparative scale.