title: Attempts to use cyanide ion to trap imine intermediates in the microsomal N-dealkylation of propranolol: formation of alpha-aminonitriles as artifacts when using ether for extraction.
abstract: Cyanide anion was used to attempt to trap possible imine intermediates in the oxidative N-dealkylation of propranolol (1). Reaction of 3-(1-naphthoxy)-1-amino-2-propanol (desisopropylpropranolol, 2) with acetone provided this expected intermediate in an approximately 7:1 ratio of oxazolidine 6 to imine 5, as determined by 1H NMR. The mixture when treated with sodium cyanide gave the expected alpha-aminonitrile 7. Microsomal oxidation of propranolol in the presence of sodium cyanide gave two cyanide-containing adducts as shown by GC-MS (12a and 12b). Using specifically deuterated propranolols (8, 9, 10, and 11) as substrates showed both of these cyanide-containing adducts to have lost the N-isopropyl group. Compounds 12a and 12b were shown to be diastereomeric alpha-aminonitriles arising from the reaction of 2 with propionaldehyde, a contaminant from the ether used for extraction, and cyanide anion. Authentic 7, stable to derivatization and GC-MS conditions, rapidly decomposed under the conditions of the metabolic experiments.
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002849:Chromatography, Gas; D003486:Cyanides; D003640:Dealkylation; D004355:Drug Stability; D007097:Imines / Q000302:isolation & purification*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D009570:Nitriles / Q000138:chemical synthesis*; D011433:Propranolol / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D003486:Cyanides; D007097:Imines; D009570:Nitriles; D011433:Propranolol