INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11b-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS

The present invention relates to a process for the synthesis of the known 17-acetoxy-11---[4-(dimethylamino)-pheny]]-21-methoxy-19-norpregna-4,9-dien-3,20-dione (further on CDB 4124) of formula (I) from 3,3-[1,2-etandiyl-bis(oxy)]-oestr-5(10),9(11)-dien-17-one of formula (II). Compound CDB-4124 belongs to the group of anti-hormones. The process according to the invention is the following: i) formation of an epoxide on the double bond in position 5(10) of 3,3-[1,2-ethandiyl-bis(oxy)]-oestr-5(10),9(11)-dien-17-one of formula (II) with hydrogen peroxide; ii) addition of hydrogen cyanide formed in situ on position 17 of the obtained 5,10o- epoxy-3,3-[1,2-ethandiyl-bis(oxy)]-5a-oestr-9(11)-en-17-one of formula (111); iii) silylation of the hydroxyl group in position 17 of the formed 5,10o-epoxy-3,3-[1,2- ethandiyl-bis(oxy)]-17x-hydroxy-5--oes(r-9(11)-en-17)-carbonitrile of formula (IV) with trimethyl chlorosilane; iv) reacting the obtained 5,10--epoxy-3,3-[1,2-ethandiyl-bis(oxy)]-17-[trimethyl-silyl-oxy]-5,-oestr-9(11)-en-179-carbonitrile of formula (V) with 4-(dimethylamino)-phenyl magnesium bromide Grignard reagent in the presence of CuCl (Teutsch reaction); v) silylation of the hydroxyl group in position 5 of the formed 1 11-[4-(dimethyl-amino)-phenyl] -3,3 - [1,2-ethandiyl-bis(oxy)]-5-hydroxy-17-- [trimethylsilyl-(oxy)]-5--oestr-9-en-17--carbonitrile of formula (VI) with trimethyl chlorosilane; vi) reacting the obtained 11t-[4-(dimethylamino)-phenyl]-3,3-[1,2-ethandiyl-bis(oxy)]-5,17α-bis-[trimethyl-silyl-(oxy)]-5α-oestr-9-en-17β-carbonitrile of formula (VII) with diisobutyl aluminum hydride and after addition of acid to the reaction mixture; vii) methoxy-methylation of the obtained 111-[4-(dimethylamino)-phenyl]-3,3-[1,2-ethandiy1-bis(oxy)]-5,17--bis-[trimethyl-sily1-(oxy)]-5--oestr-9-en-17--carbaldehide of formula (VIII) with methoxy-methyl Grignard reagent formed in situ, while hydrolyzing the trimethylsilyl protective groups; viii) oxidation of the hydroxyl group in position 20 of the obtained 17,20o-dihydroxy-11--[4-(dimethylamino)-phenyl]-21-methoxy-19-norpregna-4,9-dien-3-one of formula (IX) with dicyclohexyl carbodiimide in the presence of dimethyl sulfoxide and a strong organic acid (Swern oxidation), and in given case after purification by chromatography; ix) acetylation of the hydroxyl group in position 17 of the obtained 11o-[4-(dimethylamino)-phenyl]-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione of formula (X) with acetic anhydride in