Synthesis of 4'-hydroxypropranolol sulfate, a major non-beta-blocking propranolol metabolite in man

4'-Hydroxypropranolol sulfate was recently identified as a major metabolite of propranolol (Inderal). In order to confirm the structure and to further study disposition and biological activity, we have synthesized 8 with use of 1,4-naphthoquinone as the starting material. Reduction and alkylation with benzyl iodide gave 4-(benzyloxy)naphthol. Sulfation and chlorosulfuric acid in N,N-dimethylaniline gave potassium 1-(benzyloxy)-4-naphthol sulfate. Catalytic hydrogenation, alkylation with [[[(trifluoromethyl)sulfonyl]oxy]methyl]oxirane, and amination in isopropylamine gave 8. Racemic 8 was found to be 100-1000 times less potent than racemic propranolol as a beta-adrenergic receptor blocking agent in the dog.