Journal of Pharmaceutical Sciences p. 968 - 971 (1985)
Update date:2022-08-11
Topics:
Shetty
Nelson
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-amino-2-propanol (desisopropylpropranolol, 2) with acetone provided this expected intermediate in an ~7:1 ratio of oxazolidine 6 to imine 5, as determined by 1H NMR. The mixture when treated with sodium cyanide gave the expected α-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 α-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.
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