Epimerization and hydrolysis of 3,6-dimethyl-2,3,5,6-tetrahydro[1,2,4]thiadiazino[6,5,4- hi]indole 1,1-dioxide

Abstract

In this study, configurational and chemical stability of (R,R),(S,S),(R,S),(S,R)-3,6-dimethyl-2,3,5,6-tetrahydro[1,2,4]thiadiazino[6,5,4- hi]indole 1,1-dioxide ( 1) were investigated by dynamic and stopped-flow HPLC methods. Single epimeric mixtures (R,R),(R,S)- 1 and (S,S),(S,R) -1 were obtained combining synthetic and chromatographic strategies. Separation of (R,R) -1 and (R,S)- 1 was achieved by chiral chromatography and absolute configuration of eluted epimers has been assigned basing on molecular modelling calculations. Epimerization and hydrolysis of (R,R),(R,S)- 1 have been studied by classical off-column, dynamic HPLC and stopped-flow HPLC methods. The influence of different parameters, such as temperature, pH and dielectric constant was evaluated. The data obtained indicate that (R,R),(R,S)- 1 undergoes to a rapid epimerization in aqueous solvent and hydrolysis in acidic conditions. Moreover, epimerization and hydrolysis were investigated in presence of an artificial membrane and in physiological buffers (pH 2.2 and 7.0 at 37.5 °C) to simulate in vivo conditions.