Protection of 9-bromononan-1-ol (I) with tert-butyldimethylsilyl chloride and imidazole in THF gives the silyl ether (II), which reacts with Mg in the same solvent to yield the Grignard reagent (III). Reaction of compound (III) with CuI affords the corresponding organocuprate that condenses with 6,7-didehydro-19-nortestosterone (IV) to provide the adduct (V). Cleavage of the silyl ether group of (V) with HOAc/water in THF gives alcohol (VI), which is esterified with Ac2O and pyridine, yielding the corresponding diacetate (VII). Aromatization of enone (VII) with CuBr2 and LiBr in refluxing acetonitrile affords phenol (VIII), which is selectively hydrolyzed with NaOH in methanol to provide the primary alcohol (IX). The selective esterification of the phenolic OH group of (IX) with benzoyl chloride and NaOH in acetone/water furnishes the aryl benzoate (X).
By reaction of primary OH group of (X) with mesyl chloride and TEA in dichloromethane gives the mesylate (XI). Compound (XI) is condensed with 4,4,5,5,5-pentafluoropentanethiol (XII) by means of NaH in THF to yield the thioether (XIII), which is submitted to basic hydrolysis of the ester groups by means of NaOH in MeOH/water to afford the corresponding dihydroxy compound (XIV). Finally, this compound is oxidized with sodium metaperiodate to provide fulvestrant.