合成路线1

The title compound was synthesized by two related procedures. 3-Fluoro-N-methylaniline (XIV) was obtained from 3-fluoroaniline (XI) by condensation with 1-(hydroxymethyl)benzotriazole (XII), followed by reduction of the anilinomethylbenzotriazole (XIII) with NaBH4. Subsequent condensation with 3-formylbenzoyl chloride (XV) (prepared from the corresponding acid and SOCl2) provided amide (XVI). Then, condensation of (XVI) with piperazine (V) and benzotriazole in the presence of a catalytic amount of Et3N in refluxing toluene furnished (XVII) as a mixture of epimers. 3-Bromophenol (XVIII) was protected as the silyl ether (XIX) with tert-butyldimethylsilyl chloride and imidazole. This compound was converted to the organolithium derivative with n-butyllithium in THF at -78 C, and further transformed to the arylmagnesium reagent (XX) by treatment with magnesium bromide etherate in THF. Condensation of (XVII) with organometallic compound (XX) afforded the benzhydrylpiperazine (XXI) as a 10:1 mixture of epimers. Desilylation of (XXI) by treatment with HCl in aqueous THF, followed by recrystallization of the major isomer from EtOAc/hexane yielded the title compound.