合成路线1

Tropinone (I) is demethylated by treatment with 1-chloroethyl chloroformate, followed by decomposition of the intermediate carbamate in refluxing MeOH. The resultant N-nortropinone (II) is then protected with Boc2O to produce (III). Treatment of N-Boc-nortropinone (III) with N-phenyl trifluoromethanesulfonimide in the presence of potassium bis(trimethylsilyl)amide gives rise to the vinyl triflate (IV), which is further converted to the stannyl derivative (V) with hexamethylditin in the presence of palladium catalyst. Stille coupling of the stannyl compound (V) with ethyl 2-bromobenzoate (VI) produces the aryl tropane derivative (VII). Catalytic hydrogenation of the double bond of (VII) gives rise to a mixture of cis (VIII) and trans (IX) saturated isomers, which are separated by either chromatography or by recrystallization. The desired isomer (VIII) is then deprotected under acidic conditions to furnish the secondary amine (X). Coupling of (X) with (R)-N-Boc-2-amino-5-phenylpentanoic acid (XI) yields amide (XII).