合成路线1

Several improved synthetic procedures have been described for the synthesis of the title compound, using estrone-3-methyl ether (I) as the starting compound. Horner-Emmons condensation of ketone (I) with triethyl phosphonoacetate (II) provided the unsaturated ester (III). Birch reduction of aromatic ring and ester functions of (III) afforded, after acidic hydrolysis of the intermediate enol ether, enone (IV). Protection of the hydroxyl group of (IV) with dihydropyran, followed by air oxidation and treatment with isopropyl bromide, furnished the isopropoxy ketone (V). Methylation of the lithium enolate of ketone (V) and subsequent acidic cleavage of the tetrahydropyranyl protecting group gave the alpha-methyl ketone (VI). The free hydroxyl group of (VI) was then converted to the corresponding mesylate, which was further condensed with vanillic acid diethylamide (VII) in the presence of Cs2CO3, yielding ether (VIII). Cleavage of the isopropyl ether in the presence of AlCl3, followed by simultaneous reduction of the amide and ketone functions with LiAlH4-AlCl3, afforded the title compound, which was isolated after formation of the corresponding citrate salt. The intermediate alpha-methyl ketone (VIII) was also obtained through a related reaction sequence. Alcohol (IV) was initially condensed with vanillic acid diethylamide (VII), via activation as the mesylate (IX), to afford the corresponding ether, which was further oxidized in the presence of isopropyl bromide, producing the isopropoxy ketone (XI). This was then methylated at the alpha position employing iodomethane and LDA to furnish intermediate (VIII).