An improved synthesis of 6, 7endo-dimethyl-1-(3-hydroxyphenyl)-6-azabicyclo [3, 2, 1]-octane (10c), a new analgetic agent with a low addiction liability, is described. Grignard reaction of 3-ethoxy-2-cyclohexen-1-one (1) with m-methoxyphenylmagnesium bromide gave the α, β-unsaturated ketone (2b). Hydrocyanation of the latter followed by methanolysis yielded the keto ester (5b). The bicyclic lactam (8b), a key intermediate in the original synthesis was obtained by reductive amination of 5b with methylamine. As a result of this sequence of reactions, 10c could be obtained in 7 steps from 1 in 42% overall yield. By an application of this new method, a number of 1-phenyl-6-azabicyclo [3, 2, 1] octane derivatives with various substituents on benzene ring (10d-k), nitrogen (31), and C8 (39-46) have been prepared for pharmacological evaluation.
