ENANTIOMERIZATION OF AN ATROPISOMERIC DRUG

The antipsoriatic -(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b][1,8] n aphthyridin-5(7H)-one, Sch 40120, is chiral only because it lacks plan arity and possesses a stereogenic axis. It comprises short-lived, inte rconverting atropisomeric enantiomers distinguished by the chlorine su bstitutent. The atropisomers form diastereomeric complexes with the sh ift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl) ethanol, which were detected by H-1 NMR spectroscopy. Liquid chromatography on an ovomucoi d chiral column isolated each enantiomer from the racemic mixture. Re- injections of the separated enantiomers onto the same column held cons tant at 10 degrees C established that each enantiomer formed the other . Under identical chromatographic conditions, both stereoisomers indep endently recreated the racemic mixture. The calculated enantiomer half -life lasted 1.6 min at the physiological temperature of 37 degrees C. Simulations of dynamic liquid chromatograms acquired with a chiral st ationary phase indirectly yielded values of the half-lives. The chroma tograms were modeled with the computer program SIMUL. Also determined were the rate constants for enantiomerization and the corresponding Gi bbs free energies of activation, all at varying temperatures. At 37 de grees C, the rate constant and activation energy respectively equaled 0.213 min(-1) and 21.6 kcal mole(-1). An Arrhenius plot was linear. Th e intractably brief life spans necessitated development of the racemic drug, rather than advancement of one enantiomer only. The pharmacolog ical, biological, and chemical consequences of molecular asymmetry inh erent to the drug were therefore nil. (C) 1996 Wiley-Liss, Inc.