Joseph H. Kennedy

Comparison of chiral separations on polysaccharide chiral stationary phases to an improved Pirkle phase

Polysaccharide chiral stationary phases (CSPs) Chiralcel OD, OJ, Chiralpak AD, AS, and a chemically derived Whelk-O 1 were evaluated for separation of different types of racemic compounds. When possible, small differences in a structure such as conversion of ketone to alcohol were compared to investigate differences in chiral separation capabilities of a given CSP. Comparison of separations on the Whelk-O 1 and polysaccharide CSPs are presented. Correlations between aromatic bulk of a molecule and chiral recognition as well as functional groups on molecules which enhance chiral recognition are discussed.

Investigation of perchlorate, phosphate and ion-pairing eluent modifiers for the separation of cephalosporin epimers

The retention behavior of several pairs of 7 alpha- and 7 beta-cephalosporin epimers was investigated using perchlorate, phosphate and ion-pairing eluent modifiers. At pH 2.5, sodium perchlorate, sodium phosphate and sodium pentanesulfonate all provided separation of epimers with free 7-amino groups. When the 7-amino group was blocked, as in cephalexin and cefaclor, sodium perchlorate gave the best separation at pH 2.5. A tetrabutylammonium ion-pairing system at pH 7.0 provided separation of all epimer pairs containing a free carboxylic acid at the 3 position. Hydrophobic, residual silanol and ionic interactions were factors in the retention mechanism of the cephalosporins under the conditions investigated. An ionic interaction of perchlorate with the protonated amine of the cephalosporin was postulated as an explanation of the retention and selectivity effects observed with perchlorate as an eluent modifier.

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

Chromatographic separations of new growth hormone secretagogue compounds were developed to support structure-activity relationship (SAR) studies in conjunction with lead optimization. These new compounds differed from Mercks MK-677 by having two chiral centers and thus diastereomeric mixtures were generated. Separation of initial compounds in the SAR was achieved on a Kromasil C18 column using an ammonium acetate buffer and acetonitrile. However, additional candidates were not separable on C18 columns and a chiral Kromasil CHI-DMB column was used to resolve the diastereomeric compounds. The Kromasil CHI-DMB packing was also used in a preparative chromatographic system to resolve multigram quantities of secretagogue candidates for testing. Chiral separations of different intermediates were also developed in support of evolution of an asymmetric synthetic route. This report summarizes development of the preparative chromatographic system used to purify diastereomeric mixtures and chiral separations of intermediates in the synthesis.

Development of Preparative Chiral Separations Using an Intelligent Chiral Resolution System

Abstract Chiral preparative chromatography is a technology increasingly used in the pharmaceutical industry to deliver enantiomerically pure drug candidates. A strategy for rapid screening of conditions on polysaccharide chiral stationary phases (CSPs) has been developed with an emphasis on preparative applications. Sample solubility is a major limiting factor in preparative chromatography. Most reported analytical chiral separations on polysaccharide CSPs are with eluent systems consisting of mainly hexane and small amounts of alcohol as a modifier. The intelligent chiral resolution system (ICRS) was developed to emphasize polar solvents as the first choice for eluent systems. Examples of this approach, and details on the screening procedure are presented. Using the system, chiral preparative procedures can be developed for most compounds in approximately 3 hours.