Syntheses of 4‐(benzo[<i>b</i>]furan‐2 or 3‐yl)‐ and 4‐(benzo[<i>b</i>]‐thiophen‐3‐yl)piperidines with 5‐HT₂ antagonist activity

Abstract

Abstract The syntheses of 4‐(benzo[ b ]furan‐3‐yl)piperidines, 4‐(benzo[ b ]furan‐2‐yl)piperidines and 4‐(benzo[ b ]thiophen‐3‐yl)piperidines with 5‐HT 2 antagonist activity are described. Reaction of 1‐acetyl‐4‐(2,4‐difluorobenzo‐yl)piperidine 2 with methyl glycolate gave methyl 6‐fluoro‐3‐(1‐acetylpiperidin‐4‐yl)benzo[ b ]furan‐2‐carboxylate 3 , which was converted to 2‐[2‐[4‐(benzo[ b ]furan‐3‐yi)piperidin‐1‐yl]ethyl‐5,6,7,8‐tetrahydro‐1,2,4‐triazolo‐[4,3‐ a ]pyridin‐3(2 H )‐one hydrochloride 9 . Analogous benzo[ b ]furans 17a‐d and benzo[ b ]thiophenes 10a,b and 18a were prepared by a similar method. Cyclization of 4‐fluoro‐2‐(4‐pyridinylmethoxy)acetophenones 20a,b afforded 4‐(benzo[ b ]furan‐2‐yl)pyridines 21a,b , which were converted to 2‐[2‐[4‐(benzo[ b ]furan‐2‐yl)‐piperidin‐1‐yl]ethyl‐5,6,7,8‐tetrahydro‐1,2,4‐triazolo[4,3‐ a ]pyridin‐3(2 H )‐one hydrochlorides 24a,b. Among them, benzo[ b ]furans 9 and 17a,d and benzo[ b ]thiophenes 10 and 18a showed potent 5‐HT 2 antagonist activity in vitro.