合成路线1

The ketalization of 11alpha-hydroxy-18-methyl-DELTA4-estrene-3,17-dione (I) with ethylene glycol (A) by means of ethyl orthoformate and p-toluene sulfonic acid gives the diketal (II), which is oxidized with CrO3 in acetone yielding the ketone (III). The Wittig reaction of (III) with triphenylmethyl-phosphonium bromide (B) by means of NaH in benzene-DMSO affords 11-methylene-18-methyl-DELTA4-estren-3,17-dione diethyleneketal (IV), which is hydrolyzed with HCl in acetone to the diketone (V). The reaction of (V) with pyrrolidine (C) in methanol gives the N-pyrrolidinyl derivative (VI), which is condensed with potassium acetylide (D) in THF yielding 17alpha-ethynyl derivative (VII). Finally, this compound is hydrolyzed with acetic acid in methanol - water.

合成路线2

The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer predominantly with the desired stereochemistry (VIII).The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is eliminated by hydrogenation with hydrogen over Pd/C in ethyl acetate.

合成路线3

The alkylation of 2-iodo-5-(trifluoromethyl)phenol (I) with ethyl 2-bromoacetate (II) and K2CO3 in acetone gives the phenyl ether (III), which is condensed with the phosphonate (IV) by means of BuLi in THF to yield the ketophosphonate (V). The condensation of the Corey aldehyde (VI) with phosphonate (V) by means of ClLi and TEA in THF affords the ketonic intermediate (VII), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-DIPCl] in THF to produce C-15 hydroxy epimer (VIII) predominantly with the desired stereochemistry. The hydrolysis of the benzoate group of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with DHP and Ts-OH in dichloromethane to yield the bis-tetrahydropyranyl ether (X). The lactone group of (X) is reduced with DIBAL in THF to yield the lactol (XI), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XII) by means of tBu-OK in THF to afford the carboxylic acid (XIII). The esterification of (XIII) with isopropyl iodide and DBU in acetone affords the isopropyl ester (XIV), which is deprotected (elimination of the THP protecting groups) with HCl in methanol/water and purified by chromatography (elimination of the unwanted C15-epimer) to afford the precursor (XV). Finally the iodine atom of (XV) is substituted with tritium by hydrogenation with tritium gas over Pd/C in ethyl acetate.

合成路线4