Stereoselective homonucleophilic substitution of 3- O-methyl and 3- O-ethyloxazepam enantiomers by chiral stationary phase high-performance liquid chromatography

Abstract

Enantiomers of 3- O-methyloxazepam and 3- O-ethyloxazepam were resolved by chiral stationary phase high-performance liquid chromatography (CSP-HPLC). Temperature-dependent and acid-catalysed racemization of 3- O-methyloxazepam enantiomers in methanol and 3- O-ethyloxazepam enantiomers in ethanol were studied by quenching reaction products at various times by neutralization. Enantiomeric contents of reaction product were determined by CSP-HPLC. Thermodynamic parameters in the formation of the activated complex ( E act, Δ H‡, Δ S‡ and Δ G‡) were consistent with those determined by a spectropolarimetric method. A nucleophilically solvated and transient C3 carbocation intermediate resulting from an N4-protonated enantiomer is proposed to be an intermediate and responsible for the acid-catalysed stereoselective homonucleophilic substitution and the resulting racemization.