The title compound was synthesized starting from the known drug CP-99,994 (I), which was subjected to catalytic hydrogenolysis of the N-(2-methoxybenzyl) group to yield (S,S)-3-amino-2-phenylpiperidine (II). Subsequent reductive alkylation of amine (II) with 2-methoxy-5-trifluoromethoxybenzaldehyde (III) in the presence of either NaBH3CN or NaBH(OAc)3 furnished the title compound.
The precursor 2-methoxy-5-trifluoromethoxybenzaldehyde (III) was prepared as follows. Alkylation of 4-(trifluoromethoxy)phenol (VIII) by means of iodomethane and K2CO3 or dimethyl carbonate and DMAP furnished 4-(trifluoromethoxy)anisole (IX). Formylation of (IX) to the target aldehyde (III) was achieved by treatment with dichloromethyl methyl ether and TiCl4 or with hexamethylenetetraamine and trifluoroacetic acid.
In an alternative procedure, the reductive alkylation of 3-amino-2-chloropyridine (IV) with 2-methoxy-5-trifluoromethoxybenzaldehyde (III) in the presence of NaBH(OAc)3 produced the 3-(benzylamino)pyridine (V). The 2-phenyl pyridine derivative (VII) was then prepared by chloride displacement with phenylmagnesium bromide (VI) in the presence of bis(triphenylphosphino)nickel(II) chloride. Catalytic hydrogenation of pyridine (VII) produced the racemic cis-piperidine, which was finally resolved into the enantiomers by using (S)-mandelic acid.