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1. 发明公开

EP4192839A1 REMDESIVIR INTERMEDIATES 审中-实审
公开(公告)号：EP4192839A1
公开(公告)日：2023-06-14
申请号：EP21756058.0
申请日：2021-08-06
申请人： Richter Gedeon Nyrt.
发明人： BORZA, István , UJVÁRI, Viktor , BANA, Péter , PETRO, József Levente , ÉLES, János , BÓDI, József , VARRÓ, Gábor , KLADNI, László János , SPRÁNITZ, Péter , KRÁMOS, Balázs
IPC分类号： C07H1/00 , C07D487/04 , C07D519/00 , C07H15/18 , A61P31/12 , A61P31/14

2. 发明授权

EP1963260B1 PROCESS FOR THE PRODUCTION OF EZETIMIBE AND INTERMEDIATES USED IN THIS PROCESS 有权
标题翻译：用于生产依泽替米贝此方法中使用的中间产品
公开(公告)号：EP1963260B1
公开(公告)日：2010-11-03
申请号：EP06831516.7
申请日：2006-12-18
申请人： Richter Gedeon Nyrt.
发明人： BÓDI, József , ÉLES, János , SZÖKE, Katalin , VUKICS, Krisztina , GÁTI, Tamás , TEMESVÁRI, Krisztina , KISS-BARTOS, Dorottya
IPC分类号： C07D205/08 , C07D413/06 , C07D317/30 , C07D405/06 , C07F7/02
CPC分类号： C07D205/08 , C07D317/30 , C07D405/06 , C07D413/06 , C07F7/186 , C07F7/1892
摘要： This invention provides a novel, industrially easily realizable and economical process comprising only few steps, and built on new intermediates for the production of 1-(4-3(R)- [3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) according to the following reaction scheme: (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) wherein, the substances of the general Formulas II, IV, VI, VIII, IX, X and XI are new, Formula III is a non-isolated intermediate, Rl, R2 and R3 are represented by the compounds of Formulas Va-Vd, (Va), (Vb), (Vc), (Vd) and R4 is a silil, e.g. tert.buthyl-dimethyl-silil, tert-buthyl-diphenyl-silil group.

3. 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

4. 发明公开

EP2125772A1 A PROCESS FOR THE PREPARATION OF DULOXETIN AND NEW KEY INTERMEDIATES FOR USE THEREIN 失效
标题翻译：于制备度洛西汀新的关键中间体，有BE USED
公开(公告)号：EP2125772A1
公开(公告)日：2009-12-02
申请号：EP07858827.4
申请日：2007-12-20
申请人： Richter Gedeon Nyrt.
发明人： BÓDI, József , SZÖKE, Katalin , ÉLES, János , FOGASSY, Elemér , SCHINDLER, József , VUKICS, Krisztina , FARAGÓ, János , TEMESVÁRI, Krisztina , GÁTI, Tamás
IPC分类号： C07D333/20
CPC分类号： C07D333/20
摘要： The present invention relates to a process for the preparation of duloxetin. ((S)-(+)-N-methyl-N-(3-(l-naρhthalenyloxy)-3-(2-thienyl)propanamine) of formula (I) and pharmaceutically acceptable salts thereof, said process comprising the steps of a) resolving racemic 3-(N-methyl-N-berizylamino)-1-(2-thienyl)-1-propanol of formula (II) with a D-phenylglycine derivative to obtain a compound of formula (IV); and b) reacting (S)-3-(N-methyl-N-ben2yIamino)-1-(2-thienyl)-1-propanol of formula (IV) with 1-fluoronaphthalene to yield (S)-N-methyl-N-benzyl-3-(1-naphthalenyloxy)-3-(2- thienyl)propanamine of formula (V), reacting the compound of formula (V) obtained with 1-chloroethyl chloroformate to yield duloxetin of formula (I), and if desired converting the duloxetin of formula (I) obtained into an acid addition salt thereof.

5. 发明公开

EP1963260A1 PROCESS FOR THE PRODUCTION OF EZETIMIBE AND INTERMEDIATES USED IN THIS PROCES 有权
标题翻译：用于生产依泽替米贝此方法中使用的中间产品
公开(公告)号：EP1963260A1
公开(公告)日：2008-09-03
申请号：EP06831516.7
申请日：2006-12-18
申请人： Richter Gedeon NYRT
发明人： BÓDI, József , ÉLES, János , SZÖKE, Katalin , VUKICS, Krisztina , GÁTI, Tamás , TEMESVÁRI, Krisztina , KISS-BARTOS, Dorottya
IPC分类号： C07D205/08 , C07D413/06 , C07D317/30 , C07D405/06 , C07F7/02
CPC分类号： C07D205/08 , C07D317/30 , C07D405/06 , C07D413/06 , C07F7/186 , C07F7/1892
摘要： This invention provides a novel, industrially easily realizable and economical process comprising only few steps, and built on new intermediates for the production of 1-(4-3(R)- [3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) according to the following reaction scheme: (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) wherein, the substances of the general Formulas II, IV, VI, VIII, IX, X and XI are new, Formula III is a non-isolated intermediate, Rl, R2 and R3 are represented by the compounds of Formulas Va-Vd, (Va), (Vb), (Vc), (Vd) and R4 is a silil, e.g. tert.buthyl-dimethyl-silil, tert-buthyl-diphenyl-silil group.

6. 发明公开

EP2566850A1 INDUSTRIAL PROCESS FOR THE SYNTHESIS OF IVABRADINE SALTS 有权转让
标题翻译：工业化妆品合成Ⅳ维生素B
公开(公告)号：EP2566850A1
公开(公告)日：2013-03-13
申请号：EP11724733.8
申请日：2011-05-06
申请人： Richter Gedeon Nyrt.
发明人： UJVÁRI, Viktor , BÓDI, József , FARAGÓ, János , SZ KÉ, Katalin , FAIGL, Ferenc , NÉMET, Zoltán , TEMESVÁRI, Krisztina , KISS, Róbert , MÁTRAVÖLGYI, Béla , KASSAI, Ferencné , KISS-BARTOS, Dorottya
IPC分类号： C07D223/16
CPC分类号： C07D223/16
摘要： Process for the synthesis of Ivabradine salts of formula (I) the chemical name of which is: 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene- 7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one salts (HQ=HCl, HBr, HI, HNO3, HClO4, (COOH)2), and new intermediates thereof. Certain crystalline forms of the acid addition salts of Ivabradine (I) with nitric acid (I, HQ=HNO3), hydrobromic acid (I, HQ=HBr), hydroiodic acid (I, HQ=HI), oxalic acid (I, HQ= (COOH)2) and perchloric acid (I, HQ=HClO4)).
摘要翻译：合成式（I）的伊伐布拉定盐的方法，其化学名称为：3- {3 - [（（S）-3,4-二甲氧基 - 双环[4.2.0]八氢-1,3,5- 三烯-7-基甲基） - 甲基 - 氨基] - 丙基} -7,8-二甲氧基-1,3,4,5-四氢-2H-苯并氮杂-2-酮盐（HQ = HCl，HBr，HI， HNO 3，HClO 4，（COOH）2）及其新的中间体。 Ivabradine（I）与硝酸（I，HQ = HNO 3），氢溴酸（I，HQ = HBr），氢碘酸（I，HQ = HI），草酸（I，HQ）的酸加成盐的某些结晶形式 =（COOH）2）和高氯酸（I，HQ = HClO 4））。

7. 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).

8. 发明授权

EP2566850B1 INDUSTRIAL PROCESS FOR THE SYNTHESIS OF IVABRADINE HYDROBROMIDE SALT 有权转让
标题翻译：工业生产盐酸艾布加丁盐的方法
公开(公告)号：EP2566850B1
公开(公告)日：2018-04-11
申请号：EP11724733.8
申请日：2011-05-06
申请人： Richter Gedeon Nyrt.
发明人： UJVÁRI, Viktor , BÓDI, József , FARAGÓ, János , SZÖKE, Katalin , FAIGL, Ferenc , NÉMET, Zoltán , TEMESVÁRI, Krisztina , KISS, Róbert , MÁTRAVÖLGYI, Béla , KASSAI, Ferencné , KISS-BARTOS, Dorottya
IPC分类号： C07D223/16
CPC分类号： C07D223/16
摘要： Process for the synthesis of Ivabradine salts of formula (I) the chemical name of which is: 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene- 7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one salts (HQ=HCl, HBr, HI, HNO3, HClO4, (COOH)2), and new intermediates thereof. Certain crystalline forms of the acid addition salts of Ivabradine (I) with nitric acid (I, HQ=HNO3), hydrobromic acid (I, HQ=HBr), hydroiodic acid (I, HQ=HI), oxalic acid (I, HQ= (COOH)2) and perchloric acid (I, HQ=HClO4)).

9. 发明授权

EP2125772B1 A PROCESS FOR THE PREPARATION OF DULOXETIN AND NEW KEY INTERMEDIATES FOR USE THEREIN 失效
标题翻译：于制备度洛西汀新的关键中间体，有BE USED
公开(公告)号：EP2125772B1
公开(公告)日：2013-09-11
申请号：EP07858827.4
申请日：2007-12-20
申请人： Richter Gedeon Nyrt.
发明人： BÓDI, József , SZÖKE, Katalin , ÉLES, János , FOGASSY, Elemér , SCHINDLER, József , VUKICS, Krisztina , FARAGÓ, János , TEMESVÁRI, Krisztina , GÁTI, Tamás
IPC分类号： C07D333/20
CPC分类号： C07D333/20

10. 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).

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