Vol. 29, Issue 8, 1114-1122, August 2001

Carbinolamines, Imines, and Oxazolidines from Fluorinated Propranolol Analogs. ¹⁹F NMR and Mass Spectral Characterization and Evidence for Formation as Intermediates in Cytochrome P450-Catalyzed N-Dealkylation

Alana L. Upthagrove and Wendel L. Nelson

Department of Medicinal Chemistry, University of Washington, Seattle, Washington

Formation of carbinolamine, imine, and oxazolidines from the reactions of desisopropylpropranolol (5), its O-methyl ether (10), and 3-(1-naphthoxy)propylamine (11) with trifluoroacetone and trifluoroacetaldehyde methyl hemiacetal was investigated by ¹⁹F NMR and tandem mass spectrometry. Products from the metabolism of the related secondary amine substrates trifluoropropranolol (7), its O-methyl ether (23), and its N-trifluoroethyl-O-methyl ether analog (24) in the presence of rat liver microsomes and CYP1A2 were examined to determine whether these species were formed. The ¹⁹F NMR experiments showed the presence of carbinolamine and imine species from these primary amines and fluorinated carbonyl compounds in solution. Mass spectral experiments under atmospheric pressure chemical ionization and electrospray ionization-ion trap conditions showed formation of imine metabolites (and/or oxazolidine from 7) as well as products of N-dealkylation and aromatic hydroxylation when the secondary amine substrates were incubated with rat liver microsomes or CYP1A2. In spite of mass spectral evidence for these imines as metabolites, we were unable to detect the carbinolamines under the conditions used in these studies. Their presence is inferred from the results of the ¹⁹F NMR experiments.