摘要 |
The present invention relates to a process for the synthesis of the known 17-acetoxy-11&bgr;-[4-(dimethylamino)phenyl]-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 5,10α-epoxy-3,3-[1,2-ethandiyl-bis(oxy)]-5α-oestr-9(11)-en-17-one of formula (III); iii) silylation of the hydroxyl group in position 17 of the formed 5,10α-epoxy-3,3-[1,2-ethandiyl-bis(oxy)]-17α-hydroxy-5α-oestr-9(11)-en-17&bgr;-carbonitrile of formula (IV) with trimethyl chlorosilane; iv) reacting the obtained 5,10α-epoxy-3,3-[1,2-ethandiyl-bis(oxy)]-17-[trimethylsilyl-oxy]-5α-oestr-9(11)-en-17&bgr;-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 11&bgr;-[4-(dimethylamino)phenyl]-3,3-[1,2-ethandiyl-bis(oxy)]-5-hydroxy-17α-[trimethylsilyl(oxy)]-5α-oestr-9-en-17&bgr;-carbonitrile of formula (VI) with trimethyl chlorosilane; vi) reacting the obtained 11&bgr;-[4-(dimethylamino)phenyl]-3,3-[1,2-ethandiyl-bis(oxy)]-5,17α-bis-[trimethylsilyl(oxy)]-5α-oestr-9-en-17&bgr;-carbonitrile of formula (VII) with diisobutyl aluminum hydride and after addition of acid to the reaction mixture; vii) methoxy-methylation of the obtained 11&bgr;-[4-(dimethylamino)phenyl]-3,3-[1,2-ethandiyl-bis(oxy)]-5,17α-bis-[trimethylsilyl(oxy)]-5α-oestr-9-en-17&bgr;-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 17,20&xgr;-dihydroxy-11&bgr;-[4-(dimemylamino)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 11&bgr;-[4-(dimethylamino)phenyl]-17-hydroxy-21-methoxy-19-norpregna-4,9-dien-3,20-dione of formula (X) with acetic anhydride in the presence of perchloric acid, and in given case the obtained 7-acetoxy-11&bgr;-[4-(dimethylamino)phenyl)]-21-methoxy-19-norpregna-4,9-dien-3,20-dione of formula (I) is purified by chromatography. The invention also relates to the new intermediates of formula (VII) and (VIII). |