合成路线1

The Grignard reaction of the protected epoxide (I) with 4-(dimethylamino)phenylmagnesium bromide (II) gives the 11-substituted compound (III), which is submitted to an Oppenhauer oxidation with cyclohexanone and aluminum isopropoxide yielding the 17-keto derivative (IV). The photochemical epimerization of the 13beta-methyl of (IV) with a high pressure mercury lamp in dioxane affords the epimer (V), which is condensed with 1-tetrahydropyranyloxy-2-propyne (VI) by means of butyllithium in THF to give the acetylenic alcohol (VII). Finally, this compound is reduced with hydrogen over Pd/C in ethanol and deprotected and dehydrated by treatment with hot aqueous acetic acid.

合成路线2

The reaction of 3,3-(ethylenedioxy)estra-5(10),9(11)-diene-17(beta)-one (I) with propynylmagnesium bromine (II) in THF gives 3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)estra-5(10),9(11)-diene-17(beta)-ol (III), which is epoxidized with H2O2 in hexafluoroacetone-methylene chloride yielding 3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)-5(alpha),10(alpha)-epoxyestra-9(11)-en-17(beta)-ol (IV). The reaction of (IV) with 4-dimethylaminophenylmagnesium bromide (V) in THF affords 11(beta)-(4-dimethylaminophenyl)-3,3-(ethylenedioxy)-17(beta)-(propyn-1-yl)estra-9-en-17(beta)-ol (VI), which is finally deprotected by a treatment with HCl in metnanol.

合成路线3

The reaction of cyanohydrineketal (I) with dimethyl(chloromethyl)silyl chloride (A), TEA and DMAP in THF gives the silylated cyanohydrine (II), which is treated with Li and 4,4'-di-tert-butylbiphenyl (DBB) in THF followed by acidification with HCl yields 17alpha-hydroxy-19-norpregna-4,9-diene-3,20-dione (III). The reaction of (III) with ethylene-glycol and TsOH afford the bis ethylenedioxy derivative (IV), which is epoxidized with H2O2 and trifluoroacetone in dichloromethane affording the monoepoxide (V). The Grignard condensation of (V) with 4-(dimethylamino)phenylmagnesium bromide in THF provides the 11-beta-(dimethylamino) derivative (VII), which is dehydrated and deprotected with sulfuric acid in refluxing ethanol to furnish 11-beta-[4-(dimethylamino)phenyl]-17alpha-hydroxy-19-norpregna-4,9-diene-3,20-dione (VIII). Finally, this compound is acetylated with AcOH and trifluoroacetic anhydride in dichloromethane.

合成路线4

Protection of cyanohydrin ketal (I) with bromomethyldimethylsilyl chloride (A) in presence of DMAP and Et3N affords derivative (II), which is converted into (III) by means of LDA in cyclohexane and aqueous HBr. Treatment of (III) with KOAc in acetone yields acetoxy derivative (IV), which is then hydrolyzed to provide (V) by means of KHCO3 in refluxing MeOH. Protection of (V) as its acetal form by treatment with ethylene glycol in p-TsOH affords (VI), which is converted into methyl ether (VII) by treatment with Me3O+BF4- in presence of 1,8-bis(dimethylamino)-naphthalene. Oxidation of (VII) by means of H2O2, Na2HPO4 and (CF3)2CO in CH2Cl2 yields epoxide (VIII), which is converted into (X) by a Grignard reaction with (IX) in THF followed by treatment with CuCl. Diketal (X) is then deprotected by means of TFA in THF to provide derivative (XI), which is finally acetylated with (CF3CO)2O in a mixture of HOAc, p-TsOH and CH2Cl2.

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合成路线7