Synthesis of 5-(3,4-dichlorophenyl)-4-[(methyloxy)methyl]-2-azabicyclo[3.2.1]octane derivatives as constrained aryl-piperidines with activity as triple re-uptake inhibitors

Stereochemical and synthetic aspects encountered during the preparation of the four possible isomers of 1 are reported. The 5-aryl 2-azabicyclo [3.2.1] octane derivatives represent a novel class of compounds which can be deemed as an example of aryl-piperidine conformationally constrained of potential interest for medicinal chemistry exploration. In particular isomers of 1 are characterised by a potent in vitro serotonine, dopamine and noradrenaline re-uptake inhibitor (TRUI) activity superior/comparable to standard compounds such as DOV 21,947 and DOV 102,677.