Chiral HPLC Separations of 1-Azabicyclo[2.2.1]Heptan-3-One and 1-Alkoxycarbonylalkyl-Pyrrolidine-3-Carboxylic Acid Alkyl Ester Enantiomers on Polysaccharide-Based Stationary Phases

Abstract

Chiralcel OD-H, OJ, Chiralpak AD and AS columns were screened for the enantiomeric separation of 1-azabicyclo-[2.2.1]heptan-3-one (5) and 1-alkoxycarbonylalkyl-pyrrolidine-3-carboxylic acid alkyl ester intermediates (1, 2, 3 & 4, see Figure 1 for structures) during the large-scale synthesis of PD 151832. PD 151832 is a highly potent ml subtype selective muscarinic agonist expected to be useful for patients with Alzheimer's disease. Cellulose-based columns such as Chiralcel OD-H and OJ are in general less efficient than amylose-based columns such as Chiralpak AD and AS for separation of these types of compounds. The optimal column for separation of compounds 3 and 5 is a Chiralpak AD column using hexane/2-propanol/diethylamine as mobile phase, while a Chiralpak AS column works the best for compounds 1, 2 and 4 using the same solvent mixture.