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    INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11ß-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS
    8.
    发明公开
    INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11ß-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS 有权
    工业过程[4-（二甲基氨基）苯基] 17乙酰氧基11ß--21甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮的合成和该过程的关键中间体

    公开(公告)号：EP2160398A2

    公开(公告)日：2010-03-10

    申请号：EP08762676.8

    申请日：2008-06-19

    申请人： Richter Gedeon Nyrt.

    发明人： BÓDI, József ,  VISKY, György ,  SZÉLES, János ,  MAHÓ, Sándor ,  SÁNTA, Csaba ,  CSÖRGEI, János ,  TUBA, Zoltán ,  TERDY, László ,  MOLNÁR, Csaba ,  ARANYI, Antal ,  HORVÁTH, Zoltán ,  BALOGH, Gábor

    IPC分类号： C07J21/00 ,  C07J41/00 ,  C07J51/00

    CPC分类号： C07J41/0083 ,  C07J21/006 ,  C07J41/0094 ,  C07J51/00 ,  Y02P20/55

    摘要： The present invention relates to a process for the synthesis of the known 17-acetoxy-11-β-[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(l l)-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-[l,2-ethandiyl- bis(oxy)]-oestr-5(10),9(l l)-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-[l,2-ethandiyl-bis(oxy)]-5α-oestr-9(l l)-en-17-one of formula (III); iii) silylation of the hydroxyl group in position 17 of the formed 5,10α-epoxy-3,3-[l,2- ethandiyl-bis(oxy)]-17α-hydroxy-5α-oestr-9(l l)-en-17β-carbonitrile of formula (IV) with trimethyl chlorosilane; iv) reacting the obtained 5,10α-epoxy-3,3-[l,2-ethandiyl-bis(oxy)]-17-[trimethyl-silyl-oxy]-5α-oestr-9(l l)-en-17β-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 l lβ-[4-(dimethyl-amino)-phenyl] -3,3 - [1,2-ethandiyl-bis(oxy)] -5 -hydroxy- 17α- [trimethylsilyl-(oxy)] -5 α-oestr-9-en-17β-carbonitrile of formula (VI) with trimethyl chlorosilane; vi) reacting the obtained llβ-[4-(dimethylamino)-phenyl]-3,3-[l,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 l lβ-[4-(dimethylamino)-phenyl]-3,3-[1,2-ethandiyl-bis(oxy)]-5, 17α-bis-[trimethyl-silyl-(oxy)]-5α-oestr-9-en-17β-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 17,20ξ-dihydroxy-11β-[4-(dimemylarnino)-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 11β-[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-11β-[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).

    16-HYDROXY-11-(SUBSTITUTED PHENYL)-ESTRA-4,9-DIENE DERIVATIVES
    9.
    发明授权
    16-HYDROXY-11-(SUBSTITUTED PHENYL)-ESTRA-4,9-DIENE DERIVATIVES 失效
    16-羟基-11-（取代的苯基）雌甾-4,9-二烯衍生物

    公开(公告)号：EP0973792B1

    公开(公告)日：2003-09-03

    申请号：EP98906887.9

    申请日：1998-01-13

    申请人： Akzo Nobel N.V.

    发明人： GROEN, Marinus, Bernard ,  GEBHARD, Ronald

    IPC分类号： C07J41/00 ,  C07J1/00 ,  C07J31/00

    CPC分类号： C07J1/0096 ,  C07J21/006 ,  C07J31/006 ,  C07J41/0083 ,  C07J51/00 ,  C07J71/001

    摘要： The present invention relates to 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene derivatives according to formula (I), wherein R1 is C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, triflate, pyridyl or phenyl where the phenyl moiety is optionally substituted by one or more substituents selected from cyano, halogen and C1-4alkyl; R2 is hydrogen, C1-6alkyl, 1-oxo-C1-6alkyl or carboxy-1-oxo-C1-6alkyl; R3 is hydrogen, halogen or C1-6alkyl optionally substituted by one or more substituents selected from C1-6alkoxy and halogen; R4 is hydrogen, C1-6alkyl, 1-oxo-C1-6alkyl or carboxy-1-oxo-C1-6alkyl; and X is (H, OH), O or NOH; or a pharmaceutically acceptable salt or solvate thereof; to processes for their preparation, to pharmaceutical formulations containing them and to their use in medical therapy, particularly in the treatment or prophylaxis of glucocorticoid dependent diseases or symptoms.