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1. 发明申请

WO2007144674A1 INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 17α-ACETOXY-11β-[4-(N,N-DIMETHYL-AMINO)- PHENYL]-19-NORPREGNA-4,9-DIENE-3,20-DIONE AND NEW INTERMEDIATES OF THE PROCESS 审中-公开
标题翻译：合成17a-乙酰基-11β-[4-（N，N-二甲基氨基） - 苯基] -19-壬基-4,9-二烯-3,20-二酮的工业方法和该方法的新中间体
公开(公告)号：WO2007144674A1
公开(公告)日：2007-12-21
申请号：PCT/HU2007/000045
申请日：2007-05-18
申请人： RICHTER GEDEON NYRT , DANCSI, Lajosné , VISKY, György , TUBA, Zoltán , CSÖRGEI, János , MOLNÁR, Csaba , MAGYARI, Endréné
发明人： DANCSI, Lajosné , VISKY, György , TUBA, Zoltán , CSÖRGEI, János , MOLNÁR, Csaba , MAGYARI, Endréné
IPC分类号： C07J21/00 , C07J31/00 , C07J41/00 , C07J71/00
CPC分类号： C07J21/006 , C07J31/006 , C07J41/0083 , C07J71/001
摘要： The present invention relates to a new industrial process for the synthesis of solvate- free 17α-acetoxy-11β-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione [CDB -2914] of formula (I) which is a strong antiprogestogene and antiglucocorticoid agent. The invention also relates to compounds of formula (VII) and (VIII) used as intermediates in the process. The process according to the invention is the following: i) 3-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one of formula (X) is reacted with potassium acetilyde formed in situ in dry tetrahydrofuran by known method, ii) the obtained 3-(ethylene-dioxy)-17α-ethynyl-17β-hydroxy-estra-5(10),9(11)-diene of formula (IX) is reacted with phenylsulfenyl chloride in dichloromethane in the presence of triethylamine and acetic acid, iii) the obtained isomeric mixture of 3-(ethylene-dioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraene of formula (VIII) is reacted first with sodium methoxide in methanol, then with trimethyl phosphite, iv) the obtained 3-(ethylene-dioxy)-17α-hydroxy-20-methoxy-19-norpregna-5(10),9(11),20-triene of formula (VII) is reacted with hydrogen chloride in methanol, then v) the obtained 3-(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11l)-diene-20- one of formula (VI) is reacted with ethylene glycol hi dichloromethane in the presence of trimethyl orthoformate and p-toluenesulfonic acid by known method, vi) the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-19-norpregna- 5(10),9(11)-diene of formula (V) is reacted with hydrogen peroxide in a mixture of pyridine and dichloromethane in the presence of hexachloroacetone by known method, vii) the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-5,10-epoxy-19-norpregn-9(11)-ene of formula (IV), containing approximately a 1:1 mixture of 5α,10α- and 5β,10β-epoxides, is isolated from the solution and reacted with a Grignard reagent obtained from 4-bromo-N,N-dimethyl-aniline in tetrahydrofuran in the presence of copper(I) chloride catalyst without separation of the isomers by known method, viii) the obtained 3,3,20,20-bis(ethylene-dioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)-phenyl]-19-norpregn-9(11)-ene of formula (III) is reacted with potassium hydrogensulfate in water by known method, ix) the obtained 11β-[4-(N,N-dimethylamino)-phenyl]-17α-hydroxy-19-norpregn-4,9-diene-3,20-dione of formula (II) is acetylated with acetic anhydride in the presence of perchloric acid by known method, finally x) the solvate-free compound of formula (I) is liberated from the obtained solvate containing compound of formula (I) in a 1 : 1 mixture of ethanol and water at 70° C.
摘要翻译：本发明涉及合成无溶剂合物的17-乙酰氧基-11β-[4-（N，N-二甲基 - 氨基） - 苯基] -19-去甲基-4,9-二烯-3的新工业方法，（I）的20-二酮[CDB -2914]，其是强抗对虾和抗糖皮质激素剂。本发明还涉及在该方法中用作中间体的式（Ⅶ）和（Ⅷ）化合物。根据本发明的方法如下：i）式（X）的3-（亚乙基 - 二氧基） - 雌-5（10），9（11） - 二烯-17-与原位形成的乙酸乙酯反应在干燥的四氢呋喃中通过已知的方法，ii）将得到的式（IX）的3-（亚乙基 - 二氧基）-17a-乙炔基-17β-羟基 - 雌-5（10），9（11） - 二烯与苯基亚硫酰氯在三乙胺和乙酸的存在下在二氯甲烷中反应，iii）得到的3-（亚乙基 - 二氧基）-2-（苯基 - 亚磺酰基）-19-去甲基-5（10），9（11），17（ 20），式（VIII）的20-四烯首先与甲醇钠在甲醇中反应，然后与亚磷酸三甲酯反应，iv）得到的3-（亚乙基 - 二氧基）-17a-羟基-20-甲氧基-19-去甲基-5 （10），9（11），式（VII）的20-三烯与氯化氢在甲醇中反应，然后v）得到的3-（亚乙基 - 二氧基）-17a-羟基-19-去甲基-5（10），9（11l） - 二烯-20-酮（VI）与乙二醇二氯甲烷在三甲基邻位甲酸和对甲苯磺酸的方法，vi）得到的式（I）的3,3,20,20-双（亚乙基 - 二氧基）-17α-羟基-19-去甲酚-5（10），9（11） - 二烯（V）在六氯丙酮存在下，通过已知方法与吡啶和二氯甲烷的混合物中的过氧化氢反应，vii）获得的3,3,20,20-双（亚乙基 - 二氧基）-17a-羟基-5,10 从溶液中分离含有大约1：1的5a，10a-和5β，10β-环氧化物的1:1的式（IV）的1-环氧-19-降孕-9（11） - 烯，并与获得的格氏试剂反应在氯化铜（I）催化剂存在下，由4-溴-N，N-二甲基 - 苯胺在四氢呋喃中的溶液，而不用已知方法分离异构体，viii）得到的3,3,20,20-双（亚乙基 - 二氧基）-5α，17α-二羟基-11β-[4-（N，N-二甲基氨基） - 苯基] -19-去甲-9（11） - 烯与硫酸氢钾在水中的反应通过已知方法， ix）得到的11β-[4-（N，N-二甲基氨基） - 苯基] -17a-羟基-19-去甲基-4,9-二烯-3,20 （II）的二酮通过已知方法在高氯酸存在下用乙酸酐乙酰化，最后x）将无溶剂化物的式（I）化合物从所得到的含式（I）化合物的式 1：1乙醇和水的混合物在70℃

2. 发明申请

WO2004101594A1 NEW MONO-AND BISMETHYLENE-STEROID DERIVATIVES AND PROCESS FOR THEIR SYNTHESIS 审中-公开
标题翻译：新的单 - 和双甲硅烷基甾体衍生物及其合成方法
公开(公告)号：WO2004101594A1
公开(公告)日：2004-11-25
申请号：PCT/HU2004/000027
申请日：2004-03-25
申请人： RICHTER GEDEON VEGYÉSZETI GYÁR RT. , TUBA, Zoltán , DANCSI, Lajosné , FRANCSICSNÉ CZINEGE, Erzsébet , FALKAY, György , ZUPKÓ, István , MÁRKI, Árpád , MOLNÁR, Csaba , CSÖRGEI, János , DUKÁTNÉ ABRÓK, Vilma , BALOGH, Gábor , MÁK, Marianna
发明人： TUBA, Zoltán , DANCSI, Lajosné , FRANCSICSNÉ CZINEGE, Erzsébet , FALKAY, György , ZUPKÓ, István , MÁRKI, Árpád , MOLNÁR, Csaba , CSÖRGEI, János , DUKÁTNÉ ABRÓK, Vilma , BALOGH, Gábor , MÁK, Marianna
IPC分类号： C07J7/00
CPC分类号： C07J7/00 , C07J11/00
摘要： The invention relates to new mono- and bismethylene-steroid derivatives of general formula (I) - wherein Z represents two hydrogen atoms or an oxo group; X and Y independently of each other represent either two hydrogen atoms of a CH 2 = group, with the restriction that at least one of them is CH 2 = group and if the meaning of Z is oxo group Y represents two hydrogen atoms, R represents a C 1 -C 4 alkyl group, as well as the pharmaceutical compositions containing the above compounds as active ingredients, and the processes for the synthesis of active ingredients and pharmaceutical compositions. The invention also relates to the methods of treatments with these compounds, which means administering to a mammal to be treated with progestogen - including human - effective amount/amounts of the active ingredients of the present invention as such or as medicament. The mono- and bismethylene-steroid derivatives of the general formula (I) have progestogen effect. They can be used as active ingredients of contraceptive medicaments as such or in combination with an estrogen component. Furthermore, they can be used in the treatment of endometriosis and in the substitution therapy of estrogen as gestagen agent beside the estrogen component. The mono- and bismethylene-steroid derivatives of the general formula (I) of the present invention can be synthesized by reacting a compound of the general formula (II), - wherein the meaning of Z, X and Y is as described for the compounds of formula (I) - with an acid anhydride of the general formula (R-CO) 2 O or with an acid chloride of the general formula R-CO-Cl - wherein R represents a C 1 -C 4 alkyl group - in the presence of a strong acid.
摘要翻译：本发明涉及通式（I）的新型单 - 和二亚甲基 - 类固醇衍生物 - 其中Z代表两个氢原子或氧代基; X和Y彼此独立地表示CH 2 =基团的两个氢原子，限制为它们中的至少一个是CH 2 =基团，如果Z的含义是氧代基团Y，则表示两个氢原子，R表示C1 -C4烷基，以及含有上述化合物作为活性成分的药物组合物，以及合成活性成分和药物组合物的方法。本发明还涉及用这些化合物治疗的方法，这意味着给哺乳动物施用孕激素 - 包括人有效量/本发明的活性成分本身或作为药物。通式（I）的单和二亚甲基类固醇衍生物具有孕激素作用。它们可以作为避孕药物的有效成分本身或与雌激素成分组合使用。此外，它们可用于治疗子宫内膜异位症和雌激素组分除外作为孕激素替代治疗。本发明的通式（I）的单和二亚甲基类固醇衍生物可以通过使通式（II）的化合物与其中Z，X和Y的含义如化合物式（I）的化合物与通式为（R-CO）2 O的酸酐或通式为R-CO-Cl的酰氯（其中R表示C1-C4烷基）在式强酸。

3. 发明申请

WO2009001148A2 INDUSTRIAL METHOD FOR THE SYNTHESIS OF 17-ACETOXY-11β-[4-(DIMETHYLAMINO)-PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIEN-3,20-DIONE AND THE KEY INTERMEDIATES OF THE PROCESS 审中-公开
标题翻译：合成17-乙酰基-11β-[4-（二甲基氨基）苯基] -2-甲氧基-19-壬基-4,9-二烯-3,20-二酮的工业方法及其工艺的主要中间体
公开(公告)号：WO2009001148A2
公开(公告)日：2008-12-31
申请号：PCT/HU2008/000073
申请日：2008-06-19
申请人： RICHTER GEDEON NYRT. , BÓDI, József , VISKY, György , SZÉLES, János , MAHÓ, Sándor , SÁNTA, Csaba , CSÖRGEI, János , TUBA, Zoltán , TERDY, László , MOLNÁR, Csaba , ARANYI, Antal , HORVÁTH, Zoltán , BALOGH, Gábor
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
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).
摘要翻译：本发明涉及合成已知的17-乙酰氧基-11-β-[4-（二甲基氨基） - 苯基] -2-甲氧基-19-去甲基-4,9-二烯-3,20-二酮（10），9（11） - 二酮-17-（式（I）的化合物（CDB-4124） II）。化合物CDB-4124属于抗激素类。根据本发明的方法如下：i）在3,3- [1,2-乙二基 - 双（氧基）] - 甲酯-5（10）的5（10）位的双键上形成环氧化物，，（II）的9（II） - 二烯-17-酮与过氧化氢反应; ii）在获得的5,10a-环氧-3,3- [1,2-乙二基 - 双（氧基）]-5α-异（9）-en-17的位置17上原位形成的氰化氢的加入 - 一个式（III）的化合物; iii）形成的5,10a-环氧-3,3- [1,2-乙二基 - 双（氧基）]-17α-羟基-5a-甲酯-9（11）-en的17位羟基的甲硅烷基化（IV）的-17β-腈与三甲基氯硅烷反应; iv）使得到的5,10a-环氧-3,3- [1,2-乙二基 - 双（氧基）] - 17- [三甲基 - 甲硅烷氧基] -5a-甲酯-9（II）-en-17β （V）与4-（二甲基氨基） - 苯基溴化镁Grignard试剂在CuCl存在下的反应（Teutsch反应）; v）形成的11β-[4-（二甲基 - 氨基） - 苯基] -3,3 - [1,2-乙二基 - 双（氧基）] -5-羟基-17α的位置5的羟基的甲硅烷基化 - （三甲基甲硅烷基 - （氧基）]-5α-甲基-9-烯-17β-甲腈与三氯甲硅烷; vi）使所得的11β-[4-（二甲基氨基） - 苯基] -3,3- [1,2-乙二基 - 双（氧基）] -5,17a-双 - [三甲基 - 甲硅烷基 - （氧基）（Ⅶ）的5-甲基-9-烯-17β-腈与二异丁基氢化铝反应，并向反应混合物中加入酸; vii）所得的11β-[4-（二甲基氨基） - 苯基] -3,3- [1,2-乙二基 - 双（氧基）] -5,17a-双 - [三甲基甲硅烷基 - （氧基）]-5α-甲基-9-烯-17β-al底物与甲氧基甲基格氏试剂原位形成，同时水解三甲基甲硅烷基保护基; viii）所获得的17,20β-二羟基-11β-[4-（二甲基氨基）苯基] -21-甲氧基-19-去甲基-4,9-二烯-3-酮的20位羟基氧化式（Ⅸ）与二环己基碳二亚胺在二甲基亚砜和强有机酸（Swern氧化）存在下反应，在给定的情况下通过色谱纯化; ix）得到的17β-[4-（二甲基氨基） - 苯基] -17-羟基-21-甲氧基-19-去甲基-4,9-二烯-3,20-二酮的17位羟基乙酰化为式（X）与高氯酸存在下的乙酸酐反应，在给定情况下得到的7-乙酰氧基-11β-[4-（二甲基氨基） - 苯基）] - 21-甲氧基-19-去甲基-4,9-二烯 - （I）的3,20-二酮通过色谱法纯化。本发明还涉及式（VII）和（VIII）的新中间体。

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