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1. 发明公开

EP2027140A1 INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 17 ALPHA -ACETOXY-11 BETA -[4-(N,N-DIMETHYL-AMINO)- PHENYL]-19-NORPREGNA-4,9-DIENE-3,20-DIONE AND NEW INTERMEDIATES OF THE PROCESS 有权转让
标题翻译： GROSS技术程序合成的17-α-乙酰氧基-11-β-[4-（N，N-二甲氨基）苯基] -19-去甲孕甾-4,9-二烯-3,20-二酮和有关过程的新的中间体
公开(公告)号：EP2027140A1
公开(公告)日：2009-02-25
申请号：EP07733862.2
申请日：2007-05-18
申请人： Richter Gedeon NYRT
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.

2. 发明授权

EP1817326B1 INDUSTRIAL PROCESS FOR THE PREPERATION OF 17-HYDROXY -6 BETA, 7-BETA, 15-BETA, 16-BETA-BISMETHYLENE-3-OXO 17-ALPHA PREGN-4-ENE-21-CARBOXYLIC ACID GAMMA-LACTONE AND KEY INTERMEDIATES FOR THIS PROCESS 有权转让
标题翻译：大型工业PROCESS FOR PRODUCING 17-羟基6beta，7beta，15BETA，16beta-双亚甲基-3-氧代-17-的α-孕甾-4-烯-21-羧酸GAMMA-内酯和关键中间体用于该方法
公开(公告)号：EP1817326B1
公开(公告)日：2010-05-19
申请号：EP05797354.7
申请日：2005-10-11
申请人： Richter Gedeon Nyrt.
发明人： SÖRÖS, Béla , HORVÁTH, Judit , GÁLIK, György , BÓDI, József , TUBA, Zoltán , MAHÓ, Sándor , BALOGH, Gábor , ARANYI, Antal
IPC分类号： C07J53/00
CPC分类号： C07J53/008

3. 发明授权

EP2027140B1 INDUSTRIAL PROCESS FOR THE SYNTHESIS OF 17 ALPHA -ACETOXY-11 BETA -[4-(N,N-DIMETHYL-AMINO)- PHENYL]-19-NORPREGNA-4,9-DIENE-3,20-DIONE AND NEW INTERMEDIATES OF THE PROCESS 有权转让
标题翻译： GROSS技术程序合成的17-α-乙酰氧基-11-β-[4-（N，N-二甲氨基）苯基] -19-去甲孕甾-4,9-二烯-3,20-二酮和有关过程的新的中间体
公开(公告)号：EP2027140B1
公开(公告)日：2013-03-13
申请号：EP07733862.2
申请日：2007-05-18
申请人： Richter Gedeon NYRT
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

4. 发明授权

EP1641812B1 PURE d-(17alpha)-13-ETHYL-17-HYDROXY-18,19-DINORPREGN-4-ENE-20-YNE-3-ONE-3E- AND -3Z-OXIME ISOMERS, AS WELL AS PROCESS FOR THE SYNTHESIS OF THE MIXTURE OF ISOMERS AND THE PURE ISOMERS 无效转让
标题翻译： D-（17α-乙烯）-13乙基17HYDROXY-18,19-DINORPREGN -4-烯-20-炔-3-酮在纯净和3E-3Z肟的形式，并用于生产的异构体和也混合物中的方法纯异构体
公开(公告)号：EP1641812B1
公开(公告)日：2010-06-09
申请号：EP04730317.7
申请日：2004-04-29
申请人： Richter Gedeon Nyrt.
发明人： TUBA, Zoltán , MAHO , Sándor , KESERU , György , KOZMA, József , HORVATH, János , BALOGH, Gábor
IPC分类号： C07J41/00
CPC分类号： C07J41/00

5. 发明授权

EP2160398B1 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
标题翻译：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：EP2160398B1
公开(公告)日：2011-10-12
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).

6. 发明授权

EP1831239B8 A PROCESS FOR THE PREPARATION OF 17-HYDROXY-6 BETA, 7 BETA, 15 BETA, 16 BETA -BISMETHYLENE-17 ALPHA-PREGN-4-ENE-3-ONE-21-CARBOXYLIC ACID GAMMA-LACTONE AND KEY-INTERMEDIATES FOR THIS PROCESS 有权转让
标题翻译：制备17-羟基-6β，7β，15β，16β-二乙烯基-17β-孕烯-4-烯-3-酮-21-羧酸γ-内酯的方法以及该中间体的关键中间体处理
公开(公告)号：EP1831239B8
公开(公告)日：2010-09-15
申请号：EP05797368.7
申请日：2005-10-11
申请人： Richter Gedeon Nyrt.
发明人： GÁLIK, György , HORVÁTH, Judit , SÖRÖS, Béla , MAHÓ, Sándor , TUBA, Zoltán , BALOGH, Gábor
IPC分类号： C07J53/00 , C07J1/00
CPC分类号： C07J53/008 , C07J1/0011

7. 发明授权

EP1638988B1 PROCESS FOR THE SYNTHESIS OF HIGH PURITY D-(17ALPHA)-13-ETHYL-17HYDROXY-18,19-DINORPRE:GN-4-ENE-20-YNE-3-ONE-OXIME 有权转让
标题翻译： METHOD FOR生产高纯度D-（17α-乙烯）-13-乙基-17-羟基18,19 DINOR孕-4-烯-20-炔-3-酮肟的
公开(公告)号：EP1638988B1
公开(公告)日：2010-03-31
申请号：EP04730316.9
申请日：2004-04-29
申请人： Richter Gedeon Nyrt.
发明人： TUBA, Zoltán , MAHO, Sándor , KISS, János , MAGYARI, Endréné , TERDY, László
IPC分类号： C07J41/00 , C07J1/00
CPC分类号： C07J41/0016 , C07J1/0096

8. 发明授权

EP1831239B1 A PROCESS FOR THE PREPARATION OF 17-HYDROXY-6 BETA, 7 BETA, 15 BETA, 16 BETA -BISMETHYLENE-17 ALPHA-PREGN-4-ENE-3-ONE-21-CARBOXYLIC ACID LAMBDA-LACTONE AND KEY-INTERMEDIATES FOR THIS PROCESS 有权转让
标题翻译： PROCESS FOR 17-羟基-β-6,7 BETA，BETA 15,16 BETA-双亚甲基 - 17α-乙烯孕甾-4-烯-3-酮-21-羧酸的γ-内酯和关键中间体此方法的制备
公开(公告)号：EP1831239B1
公开(公告)日：2010-03-24
申请号：EP05797368.7
申请日：2005-10-11
申请人： Richter Gedeon Nyrt.
发明人： GÁLIK, György , HORVÁTH, Judit , SÖRÖS, Béla , MAHÓ, Sándor , TUBA, Zoltán , BALOGH, Gábor
IPC分类号： C07J53/00 , C07J1/00
CPC分类号： C07J53/008 , C07J1/0011

9. 发明公开

EP2160398A2 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
标题翻译：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).

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