SYNTHESIS OF SIBUTRAMINE, A NOVEL CYCLOBUTYLALKYLAMINE USEFUL IN THE TREATMENT OF OBESITY, AND ITS MAJOR HUMAN METABOLITES

Synthetic routes to 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N, N-dimethylamine(sibutramine) I and its demethylated and hydroxylated human metabolites orophenyl)cyclobutyl]-3-methylbutyl}-N-methylamine 2 , -[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine 3, -[1-(4-chlorop henyl)cyclobutyl]-2-methylbutan-1-ol 4 and 3-methylbutyl)-3-(4-chlorop henyl)cyclobutan-r-1-ol 5a are described, Key steps are tandem Grignar d-reduction reactions on 1-(4-chlorophenyl)cyclobutanecarbonitrile 7 a nd its 3-(tetrahydropyran-2-yloxy)substituted analogue 14 and a conven ient one-pot conversion of 4-chlorophenylacetonitrile 6 into the 3-hyd roxycyclobutanecarbonitrile 13.