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).

A different strategy for preparing the target 6-methylated steroid nucleus was based on the conjugate addition of an organocuprate reagent to a dienone. The intermediate hydroxy enone (IV) was acylated with isopropenyl acetate to produce the bis-acetate (XII). Bromination of (XII) with N-bromosuccinimide, followed by dehydrohalogenation with Li2CO3 and LiBr in refluxing DMF, gave rise to dienone (XIII). Conjugate addition of methyllithium to (XIII) in the presence of CuI afforded the methylated compound (XIV). Aromatization of the cyclohexenone system was achieved by oxidation with CuCl2. Subsequent acetate ester hydrolysis under basic conditions generated diol (XV), which was converted to the bis-mesylate (XVI) upon treatment with methanesulfonyl chloride and Et3N. Displacement of the aliphatic mesylate with vanillic acid diethylamide (VII) yielded ether (XVII). Then, simultaneous amide reduction and reductive cleavage of the aryl mesylate with LiAlH4 provided the title compound.

The intermediate diol (XV) was also obtained by an alternative procedure. Aromatization of enone (IV) in the presence of isopropanol, I2 and O2 gave rise to the isopropoxy ketone (XVIII). The free hydroxyl group was then protected as the tetrahydropyranyl ether (V). Alkylation at the alpha position of the keto group of (V) , followed by acidic hydrolysis of the tetrahydropyranyl group, furnished the alpha-methyl ketone (VI). The keto group of (VI) was subsequently reduced by hydrogenation over Pd/C to afford (XIX). Further isopropyl ether cleavage with AlCl3 afforded diol (XV).