Synthesis and SAR studies of 3-substituted 1′-benzylspiro[[2]benzoxepine1,4′-piperidines]

Article abstract of DOI:10.1002/ejoc.200390111

The preparation of the hitherto unknown spiro[[2]benzoxepine-1,4′-piperidine] ring system is described. The synthesis consists of a Wittig reaction of 2-bromobenzaldehyde (4) and (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (5) to yield an α,β-unsaturated acetal. The double bond of 6 was subsequently hydrogenated. The resulting brominated acetal 7 was treated with n-butyllithium and then with 1-benzylpiperidin-4-one (9) to yield the hydroxy acetal 10. Acid-catalyzed cyclization of 10 with p-toluenesulfonic acid or aqueous HCl resulted in the formation of the 1′-benzylspiro[[2]benzoxepine-1,4′-piperidines] 11 and 12, respectively. The substituents in the 3-position of the spiro compounds 11 and 12 were further modified by reaction with trimethylsilyl cyanide or (cyanomethylene)triphenylphosphorane in order to introduce residues with one or two carbon atoms, respectively. The synthesized compounds were evaluated for σ₁- and σ₂-receptor affinity in vitro. The most potent σ₁-ligand was the methoxy derivative 11 (K_i = 2.56 nM), whereas the cyanomethyl derivative 20 turned out to be the most σ₁-selective compound (σ₁/σ₂ selectivity 768). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.