Effects of Alcohol Modifiers on the Separation of 1-Alkoxycarbonyl-Alkyl-Pyrrolidine-3-Carboxylic Acid Alkyl Ester Enantiomers on Polysaccharide-Based Stationary Phases

Abstract

1-Alkoxycarbonylalkyl-pyrrolidine-3-carboxylic acid alkyl esters (1, 2, 3 and 4, see Figure 1 for structures) are the synthetic intermediates used for the large-scale synthesis of PD 151832. PD 151832 is a highly potent m1 subtype selective muscarinic agonist expected to be useful for patients with Alzheimer's disease. The mobile phase consisting of hexane/2-propanol/diethylamine has been previously shown to resolve the enantiomers of compounds 1, 2 and 4 on a Chiralpak AS column and compound 3 on a Chiralpak AD column.1 In the current study, the nature of the alcohol modifier in mobile phase was varied and the resulting change in stereoselectivity was found to depend on compound and column type. Superior separations can often be achieved by using an alcohol modifier other than the commonly used 2-propanol or ethanol on the same column. The use of different alcohol modifiers in mobile phase to enhance the enantiomeric resolution can provide useful and less expensive alternatives to the approach of using multiple columns in chiral methodology development.