Nucleophilic Substitution and Racemization of 3-Ethoxy-N-desmethyldiazepam Enantiomers in Acidic Ethanol

SHEN K. YANG AND XIANG-LIN LU

Department of Pharmacology, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda , Maryland 20814-4799, USA

ABSTRACT

   pKal values of 3-ethoxy-N-desmethyldiazepam (3-EtO-NDZ) in ethanol and acetonitrile containing various concentrations of sulfuric acid,determined by spectrophotometry and spectropolarimetry, were found to be 3.4 and 0.63 respectively. Temperature dependent racemization of enantiomeric 3-EtO-NDZ in ethanol containing various acid concentrations was studied by monitoring changes of ellipticity at 365nm as a function of time on a spectropolarimeter. The racemization reactions were found to follow apparent first order kinetics. Thermodynamic parameters of the racemization reaction were: Eact = 16.7k cal/mol,and at 25℃:  ΔH≠ = 16.1 kcal/ mol, ΔS≠ = -22.0 cal/K/mol, and ΔG≠ = 22.6 kcal/mol, respectively. The racemization had an isotope effect (kH/kD) Of 1.9 at 42℃. Based on the results of this report and the results of literature reports on the preferred conformation of enantiomeric 3-substituted-1,4-benzodiazepines ,a nucleophilically solvated C3 carboniun ion intermediate resulting from either a P (plus) or a M (minus) conformation is proposed to be an intermediate. This intermediate is responsible for the stereoselective nucleophilic substitution and the subsequent racemization of 3-EtO-NDZ enantiomers in acidic ethanol.

Key Words: 3-ethoxy-N-desmethyldiazepam, stereoselective nucleophilic substitution, racemization.