Structure-Retention Behavior of a Morpholine Hydrochloride Pharmaceutical Intermediate

Summary A vant Hoff plot of the retention factor of (2R, 3S)-2-({(1R)-1-3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl) morpholine hydrochloride (I), on a C-18 stationary phase, was found to exhibit significant non-linearity. Similar plots for II and III, which are structurally-related to compound I, displayed a smaller degree of non-linearity and were driven by predominately enthalpic and entropic retention processes, respectively. It was hypothesized that the retention behavior of I could be a combination of interactions rising from the shared functional groups of II and III. In addition, it was found that the curvature in the plot for I was enhanced for the homologous compounds IV and V which have extended aromaticity at the 3-position of the morpholine ring. In general, it was observed that as the size of the molecule increased, more entropic retention character was exhibited. However, molecular geometry was also found to play a key role in governing the retention properties of this class of compounds.