cis/trans Isomerization Rate of Oxazolam in Organic Solvents Measured by High-Performance Liquid Chromatography

Abstract

Diastereoisomers of oxazolam (2R-cis, 2R-trans, 2S-cis, and 2S-trans isomers) were resolved and assigned by high-performance liquid chromatography (HPLC). By means of HPLC the cis/trans isomerization rates of oxazolam in some organic solvents could be measured, although such rate measurements had previously been attempted only by an nuclear magnetic resonance (NMR) method and it was reported that in most organic solvents the isomerization was too fast to allow the rates to be measured. In some cases (depending on the lot number of the solvent), rapid isomerization was observed in chloroform-d (the ratio of cis isomer to trans isomer (2 : 3) did not change with time, that is, the isomerization was at equilibrium immediately after dissolution of oxazolam in the CDCI₃). This fast isomerization was suggested to be catalyzed by an acid contaminant, since the iminium intermediate of oxazolam was detected in the reaction solution by fluorescence spectroscopy.