Influence of chemical structure of tricyclic tertiary dimethylamines on chiral separation by reversed-phase high-performance liquid chromatography after derivatization with (−)-menthylchloroformate

Abstract

In the present study (−)-menthylchloroformate was used as a chiral derivatizing agent for promethazine, trimeprazine, trimipramine and N-(2-dimethylaminopropyl)iminodibenzyl. (−)-Menthylchloroformate reacted with the tertiary dimethylamine moiety in these tricyclic antihistamines and antidepressants, resulting in the formation of diastereoisomers. Owing to the reaction conditions, during the derivatization with (−)-menthylchloroformate, the possibility of racemization had to be established. For this purpose different ratios of (+) and (−)-promethazine were prepared. Enantiomeric separation of these mixtures took place on a Chiral α AGP column or, after derivatization with (−)-menthylchloroformate, on a C 18 column. The results from these two independent separation systems were compared with trace racemization. No racemization was found during the experiments. To study the effects of changes in the molecular structures of the tertiary dimethylamines on the chromatographic behavior of the derivatization products, four tertiary dimethylamines [promethazine, trimipramine, trimeprazine and N-(2-dimethylaminopropyl) iminodibenzyl] were derivatized and analyzed. With these amines the effects on resolution and capacity factor of replacing a phenothiazine ring by an iminodibenzyl ring or insertion of a carbon molecule between the chiral centre in the chain and the place where (−)-menthylchloroformate reacts were studied. Not only the distance between the chiral centres in the diastereoisomers (a longer distance caused less resolution and higher capacity factors) but also the kind of ring influenced resolution and capacity factor. Finally, the influence of eluent composition on resolution and capacity factor was studied. Three different mixtures of methanol and acetic acid were tested. More acetic acid in the eluent caused a better resolution and higher capacity factor. The higher capacity factor, however, resulted in unacceptable retention times.