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Abstract
Two differing approaches to the liquid chromatographic analysis of active esters used in pharmaceutical processing were developed. Selection of methodology was dictated by the intrinsic chemistries involved and the processing requirements.
The first approach (chromatographic systems A and B) described was employed to monitor a mesylation reaction with a relatively simple HPLC impurity profile to a minimum of 99.0% conversion. Chromatographic conditions, designed as a compromise to achieve adequate analyte solubility, specificity, and minimized on-column decomposition within a short analysis time cycle, included an aprotic mobile phase used with a Zorbax SB-CN column at ambient temperature.
The second approach (chromatographic system C) described was employed to monitor a triflation reaction to a minimum 97.0% conversion. The impurity profile of this reaction was far more complex than the former reaction, and as a result a more sophisticated analysis method was necessary. A chemical derivatization using tetrabutylammonium bromide in sieve-dried acetonitrile was developed to stabilize the reaction product as its bromo analog, permitting longer column residence times to achieve the necessary method specificity.
ACKNOWLEDGEMENTS
The authors would like to thank Peter Skrdla and Jean Wyvratt for reviewing the manuscript and providing helpful suggestions, as well as Dave Lieberman and Ross Miller of Merck Research Laboratories for preparing the active ester samples used for the completion of this work.