CONFORMATIONAL-ANALYSIS OF CYPROHEPTADINE HYDROCHLORIDE

A nuclear magnetic resonance and theoretical study on the conformations and molecular flexibility of cyproheptadine hydrochloride (1) is reported. In the 1H NMR spectrum of 1 in CDCI3, two conformational forms are observed to occur in an approximate ratio of 1:4. In both forms, NOE and coupling constant measurements suggested that the terminal N-methyl group is equatorial. NOE experiments identified the more populated conformer (labeled D) as similar to the form seen in the X-ray crystal structure of cyproheptadine. The other form observed (A) may in principle be converted to D via either inversion of the central ring (Tinv) or concerted nitrogen (Ninv) and piperidine ring inversion (Pinv). Chemical-exchange peaks in the 400-MHz 2D NOESY/chemical-exchange spectrum suggested that the latter mechanism is responsible for interconversion between the two forms. A theoretical study of the various interconversion processes using both molecular mechanics (MM2) and molecular orbital (AM1) approaches is also reported. © 1990, American Chemical Society. All rights reserved.