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1.发明授权
公开(公告)号：US4585879A
公开(公告)日：1986-04-29
申请号：US700371
申请日：1985-02-11
IPC分类号： C07D209/42
CPC分类号： C07D209/42
摘要： Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivatives thereof) comprising the following steps: (a) reducing .alpha.-oxo-2-nitrobenzenepropanoic acid to .alpha.-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20.degree. C., (c) reducing the nitro group of the resulting .alpha.-chloro-2-nitrobenzenepropanoic acid to obtain .alpha.-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.
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2.发明授权Process for the asymmetric synthesis of chiral .alpha.-hydroxy-2-nitrobenzenepropanoic acid 失效手性α-羟基-2-硝基苯丙酸的不对称合成方法
公开(公告)号：US4727183A
公开(公告)日：1988-02-23
申请号：US925430
申请日：1986-10-31
IPC分类号： C07D209/42 , C07C99/00
CPC分类号： C07D209/42
摘要： Disclosed herein is a process for producing an asymmetric indoline-2-carboxylic acid of the structural Formula: ##STR1## wherein X is hydrogen, bromine, chlorine, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, which comprises:(a) assymetrically reducing an o-nitrophenylpyruvic acid III by contacting the acid III with a reducing complex formed from (R)-proline or (S)-proline, respectively, and sodium borohydride in an inert solvent to form, respectively, an (S) or (R)-.alpha.-hydroxy-2-nitrobenzenepropanoic acid IV;(b) reacting, respectively, said (S) or (R)-.alpha.-hydroxy-2-nitrobenzenepropanoic acid III with a Vilsmeier chlorinating reagent in which the chlorinating agent thereof is selected from a group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride and sulfuryl chloride and the amide thereof is selected from a group consisting of dimethylformamide, diethylformamide, dimethylacetamide and diethylacetamide, said reaction being run at temperatures of at least 20.degree. C., in order to obtain, respectively, and (R) or (S)-.alpha.-chloro-2-nitrobenzenepropanoic acid IV;(c) reducing the nitro group of said (R) or (S)-.alpha.-chloro-2-nitrobenzenepropanoic acid (V) to an amino group; and(d) cyclizing the resulting (R) or (S)-.alpha.-chloro-2-aminobenzenepropanoic acid in aqueous base.
摘要翻译： 本文公开了一种制备结构式：其中X是氢，溴，氯，C 1-4烷基或C 1-4烷氧基的结构式的不对称二氢吲哚-2-羧酸的方法，其包括： （a）通过使酸III与由（R） - 脯氨酸或（S） - 脯氨酸分别形成的还原络合物和硼氢化钠在惰性溶剂中分别形成的（III）化合物分别对（ - S）或（R）-α-羟基-2-硝基苯丙酸IV; （b）分别使所述（S）或（R）-α-羟基-2-硝基苯丙酸III与Vilsmeier氯化试剂反应，其中氯化剂选自亚硫酰氯，草酰氯，磷 三氯氧化物，五氯化磷和磺酰氯，其酰胺选自二甲基甲酰胺，二乙基甲酰胺，二甲基乙酰胺和二乙基乙酰胺，所述反应在至少20℃的温度下进行，以分别得到（R ）或（S）-α-氯-2-硝基苯丙酸IV; （c）将所述（R）或（S）-α-氯-2-硝基苯丙酸（V）的硝基还原成氨基; 和（d）使得到的（R）或（S）-α-氯-2-氨基苯丙酸在碱性水溶液中环化。
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3.发明授权Process for preparing indoline-2-carboxylic acids via .alpha.-hydroxy-2-nitrobenzenepropanoic acid 失效通过α-羟基-2-硝基苯丙酸制备二氢吲哚-2-羧酸的方法
公开(公告)号：US4645857A
公开(公告)日：1987-02-24
申请号：US829674
申请日：1986-02-14
IPC分类号： C07D209/42 , C07C101/447
CPC分类号： C07D209/42
摘要： Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivaties thereof) comprising the following step: (a) reducing .alpha.-oxo-2-nitrobenzenepropanoic acid to .alpha.-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20.degree. C., (c) reducing the nitro group of the resulting .alpha.-chloro-2-nitrobenzenepropanoic acid to obtain .alpha.-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.
摘要翻译： 本文公开了一种获得二氢吲哚-2-羧酸（或其衍生物）的方法，包括以下步骤：（a）将α-氧代-2-硝基苯丙酸还原为α-羟基-2-硝基苯丙酸，（b）将 使用选定的Vilsmeier氯化试剂，后者的羟基与氯原子在至少20℃的温度下反应，（c）还原得到的α-氯-2-硝基苯丙酸的硝基，得到α-氯-2 - 氨基苯丙酸，和（d）将其在碱水溶液中环化形成所需的二氢吲哚-2-羧酸。 或者，步骤（c）和（d）可以通过使用例如阮内镍 - 肼还原介质在一锅步骤中组合。
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4.发明授权
公开(公告)号：US4614806A
公开(公告)日：1986-09-30
申请号：US700379
申请日：1985-02-11
IPC分类号： C07D209/42
CPC分类号： C07D209/42
摘要： Disclosed herein is a process for producing an asymmetric indoline-2-carboxylic acid of the structural Formula: ##STR1## wherein X is hydrogen, bromine, chlorine, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, which comprises:(a) assymetrically reducing an o-nitrophenylpyruvic acid III by contacting the acid III with a reducing complex formed from (R)-proline or (S)-proline, respectively, and sodium borohydride in an inert solvent to form, respectively, an (S) or (R)-.alpha.-hydroxy-2-nitrobenzenepropanoic acid IV;(b) reacting, respectively, said (S) or (R)-.alpha.-hydroxy-2-nitrobenzenepropanoic acid III with a Vilsmeier chlorinating reagent in which the chlorinating agent thereof is selected from a group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride and sulfuryl chloride and the amide thereof is selected from a group consisting of dimethylformamide, diethylformamide, dimethylacetamide and diethylacetamide, said reaction being run at temperatures of at least 20.degree. C., in order to obtain, respectively, and (R) or (S)-.alpha.-chloro-2-nitrobenzenepropanoic acid IV;(c) reducing the nitro group of said (R) or (S)-.alpha.-chloro-2-nitrobenzenepropanoic acid (V) to an amino group; and(d) cyclizing the resulting (R) or (S)-.alpha.-chloro-2-aminobenzenepropanoic acid in aqueous base.
摘要翻译： 本文公开了一种制备结构式：其中X是氢，溴，氯，C 1-4烷基或C 1-4烷氧基的结构式的不对称二氢吲哚-2-羧酸的方法，其包括： （a）通过使酸III与由（R） - 脯氨酸或（S） - 脯氨酸分别形成的还原络合物和硼氢化钠在惰性溶剂中分别形成的（III）化合物分别对（ - S）或（R）-α-羟基-2-硝基苯丙酸IV; （b）分别使所述（S）或（R）-α-羟基-2-硝基苯丙酸III与Vilsmeier氯化试剂反应，其中氯化剂选自亚硫酰氯，草酰氯，磷 三氯氧化物，五氯化磷和磺酰氯，其酰胺选自二甲基甲酰胺，二乙基甲酰胺，二甲基乙酰胺和二乙基乙酰胺，所述反应在至少20℃的温度下进行，以分别得到（R ）或（S）-α-氯-2-硝基苯丙酸IV; （c）将所述（R）或（S）-α-氯-2-硝基苯丙酸（V）的硝基还原成氨基; 和（d）使得到的（R）或（S）-α-氯-2-氨基苯丙酸在碱性水溶液中环化。
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5.发明授权Process for preparing indoline-2-carboxylic acids via alpha-hydroxy-2-nitrobenzenepropanoic acid 失效通过α-羟基-2-硝基苯丙酸制备二氢吲哚-2-羧酸的方法
公开(公告)号：US4785118A
公开(公告)日：1988-11-15
申请号：US925573
申请日：1986-10-31
IPC分类号： C07D209/42
CPC分类号： C07D209/42
摘要： Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivatives thereof) comprising the following steps: (a) reducing .alpha.-oxo-2-nitrobenzenepropanoic acid to .alpha.-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20.degree. C., (c) reducing the nitro group of the resulting .alpha.-chloro-2-nitrobenzenepropanoic acid to obtain .alpha.-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.
摘要翻译： 本文公开了一种获得二氢吲哚-2-羧酸（或其衍生物）的方法，包括以下步骤：（a）将α-氧代-2-硝基苯丙酸还原为α-羟基-2-硝基苯丙酸，（b）将 使用选定的Vilsmeier氯化试剂，后者的羟基与氯原子在至少20℃的温度下反应，（c）还原得到的α-氯-2-硝基苯丙酸的硝基，得到α-氯-2 - 氨基苯丙酸，和（d）将其在碱水溶液中环化形成所需的二氢吲哚-2-羧酸。 或者，步骤（c）和（d）可以通过使用例如阮内镍 - 肼还原介质在一锅步骤中组合。
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6.发明授权
公开(公告)号：US4644081A
公开(公告)日：1987-02-17
申请号：US829662
申请日：1986-02-14
IPC分类号： C07D209/42 , C07C101/447
CPC分类号： C07D209/42
摘要： Disclosed herein is a process for producing an asymmetric indoline-2-carboxylic acid of the structural Formula: ##STR1## wherein X is hydrogen, bromine, chlorine, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, which comprises:(a) assymetrically reducing an o-nitrophenylpyruvic acid III by contacting the acid III with a reducing complex formed from (R)-proline or (S)-proline, respectively, and sodium borohydride in an inert solvent to form, respectively, an (S) or (R)-.alpha.-hydroxy-2-nitrobenzenepropanoic acid IV;(b) reacting, respectively, said (S) or (R)-.alpha.-hydroxy-2-nitrobenzenepropanoic acid III with a Vilsmeier chlorinating reagent in which the chlorinating agent thereof is selected from a group consisting of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride and sulfuryl chloride and the amide thereof is selected from a group consisting of dimethylformamide, diethylformamide, dimethylacetamide and diethylacetamide, said reaction being run at temperatures of at least 20.degree. C., in order to obtain, respectively, and (R) or (S)-.alpha.-chloro-2-nitrobenzenepropanoic acid IV;(c) reducing the nitro group of said (R) or (S)-.alpha.-chloro-2-nitrobenzenepropanoic acid (V) to an amino group; and(d) cyclizing the resulting (R) or (S)-.alpha.-chloro-2-aminobenzenepropanoic acid in aqueous base.
摘要翻译： 本文公开了一种制备结构式：其中X是氢，溴，氯，C 1-4烷基或C 1-4烷氧基的不对称二氢吲哚-2-羧酸的方法，其包括：（a）按比例减少 通过使酸III与由（R） - 脯氨酸或（S） - 脯氨酸分别形成的还原络合物和硼氢化钠在惰性溶剂中分别与（S）或（R（R））形成的邻硝基苯基丙酮酸III反应， ）-α-羟基-2-硝基苯丙酸IV; （b）分别使所述（S）或（R）-α-羟基-2-硝基苯丙酸III与Vilsmeier氯化试剂反应，其中氯化剂选自亚硫酰氯，草酰氯，磷 三氯氧化物，五氯化磷和磺酰氯，其酰胺选自二甲基甲酰胺，二乙基甲酰胺，二甲基乙酰胺和二乙基乙酰胺，所述反应在至少20℃的温度下进行，以分别得到（R ）或（S）-α-氯-2-硝基苯丙酸IV; （c）将所述（R）或（S）-α-氯-2-硝基苯丙酸（V）的硝基还原成氨基; 和（d）使得到的（R）或（S）-α-氯-2-氨基苯丙酸在碱性水溶液中环化。
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7.发明授权Process for the synthesis C-2, C-3 substituted N-alkylated indoles useful as cPLA2 inhibitors 有权用于合成C-2，C-3取代的N-烷基化吲哚的方法，其用作cPLA2抑制剂公开(公告)号：US08034960B2
公开(公告)日：2011-10-11
申请号：US12943958
申请日：2010-11-11
申请人： Ronald S. Michalak , Mahmut Levent , Frederick J. Vyverberg , Ara R. Boyajian , Panolil Raveendranath , Michel Cantin , Alan Stockton , Michael W. Winkley , Mousumi Ghosh , Christoph Dehnhardt , Charles Guinosso
发明人： Ronald S. Michalak , Mahmut Levent , Frederick J. Vyverberg , Ara R. Boyajian , Panolil Raveendranath , Michel Cantin , Alan Stockton , Michael W. Winkley , Mousumi Ghosh , Christoph Dehnhardt , Charles Guinosso
IPC分类号： C07D209/20
CPC分类号： C07C311/14 , C07C303/38 , C07C303/40 , C07C311/13 , C07D209/14
摘要： The present invention provides a compound of formula 1: wherein R1 is CF3, R2 is H′ R3 is H.
摘要翻译： 本发明提供式1化合物：其中R1是CF3，R2是H'R3是H.
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公开(公告)号：US4935515A
公开(公告)日：1990-06-19
申请号：US432245
申请日：1989-11-06
IPC分类号： C07D487/04
CPC分类号： C07D487/04
摘要： Disclosed herein are novel 1,2,3,4,5,6-hexahydro[1,3,6]triazocino[1,2-a]benzimidazole of Formulas I and II: ##STR1## wherein R.sup.1 may be phenyl, m- or p-nitrophenyl, m- or p-methylsulfonylaminophenyl, napthtyl, naphthyl mono-substituted by nitro or methylsulfonylamino, benzofurazanyl, 2-pyrimidinyl, 2- or 4-pyridinyl, 2- or 4-naphthyridinyl, pyrazinyl, isoquinolinyl, or quinolinyl;R.sup.2 may be hydrogen; C.sub.1 -C.sub.8 alkyl; phenyl(C.sub.1 -C.sub.4)alkyl or substituted-phenyl(C.sub.1 -C.sub.4)alkyl, in which phenyl may have one to three substituents selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, fluorine, chlorine or bromine; phenyl or substituted-phenyl in which the phenyl substituents are the same as for substituted-phenyl (C.sub.1 -C.sub.4)alkyl; 2- or 4-pyrimidinyl; pyrazinyl; imidazolyl; C.sub.1 -C.sub.4 alkanoyl; halo or dihalo-(C.sub.1 -C.sub.4)alkanoyl, in which halo is fluoro or chloro; benzoyl or benzoyl substituted on the phenyl ring by one or two C.sub.1 -C.sub.4 alkyl groups; C.sub.1 -C.sub.4 alkanoyloxy; C.sub.1 -C.sub.4 alkylamino(C.sub.1 -C.sub.4 alkanoyl; C.sub.1 -C.sub.4 alkyloxycarbonyl; C.sub.1 -C.sub.4 alkylaminocarbonyl; phenylaminocarbonyl in which phenyl may have one to three C.sub.1 -C.sub.4 alkyl groups; phenyloxy or naphthyloxy-(C.sub.1 -C.sub.4)alkyl in which the phenyl or naphthyl ring may be substituted by one to three C.sub.1 -C.sub.4 alkyl groups; C.sub.1 -C.sub.4 alkylsulfonyl; (C.sub.1 -C.sub.4)alkyl- or N-di-(C.sub.1 -C.sub.4 alkyl)carboxamido(C.sub.1 -C.sub.4)alkyl; N-phenyl or substituted phenyl-carboxamido-(C.sub.1 -C.sub.4)alkyl in which phenyl may be substituted as above for C.sub.1 -C.sub.4 alkyl-substituted phenyl; cyano; amidino in which each N atom is substituted by a C.sub.1 -C.sub.4 alkyl group; and C.sub.1 -C.sub.4 alkylguanidino; andR.sup.3 and R.sup.4 are, independently, selected from hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, fluorine and chlorine, or acid addition salts thereof. Compounds of formulas I and II having certain values of R.sup.2 are antiarrhythmic or antiischaemic agents. The remaining values of R.sup.2 provide intermediate compounds of formulas I and II.Also disclosed herein a novel tetrahydro-3-substituted-7-substituted-1H[1,2,5]triazepino[1,2-a][1,2,4]benzotriazines, wherein the 7 substituent may be --SMe, --Cl or Br and the 3 substituent is the same as R.sup.2 in formulas I and II above. These compounds also serve as intermediates for the production of the antiarrhythmic agents for formula II above.
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公开(公告)号：US4801706A
公开(公告)日：1989-01-31
申请号：US187187
申请日：1988-04-28
IPC分类号： C07D255/02 , A61K31/55
CPC分类号： C07D255/02 , Y02P20/55
摘要： Disclosed herein are N-substituted-hexahydro-1,2,5-triazepines of formula I, which is ##STR1## or a pharmaceutically acceptable acid addition salt thereof, wherein R.sup.4 and R.sup.5 are independently hydrogen or C.sub.1 -C.sub.4 alkyl;R.sup.1 is (R.sup.6).sub.2 --CH--(CH.sub.2).sub.n -- in which n is 0, 1, 2 or 3 and R.sup.6 is p-fluoro, chloro or methoxyphenyl; andR.sup.3 is hydrogen and R.sup.2 is benzoyl, 2,6-dimethyl or diethylbenzoyl, 2,6-dichlorobenzoyl, N-methyl, ethyl or propylcarboxamido, N-phenylcarboxamido, N-2,6-dimethyl or diethylphenylcarboxamido, N-2,6-dichlorophenylcarboxamido, N-methyl, ethyl or propylacetamido, N-phenylacetamido, N-2,6-dimethyl or diethylphenylacetamido, or N-2,6-dichlorophenylacetamido orR.sup.2 and R.sup.3 are the same and are N-methyl, ethyl or propylcarboxamido, benzoyl, 2,6-dimethyl or diethlbenzoyl, 2,6-dichlorobenzoyl, benzyl, 2,6-dimethyl or diethlbenzoyl, 2,6-dichlorobenzoyl, or a removable amino protective group. Also disclosed are N-substituted-hexahydro-1,2,5-triazepines of formula II in which R.sup.1 of formula I is replaced by R.sup.7 which is C.sub.1 -C.sub.4 alkyl, and R.sup.2 and R.sup.3 of formula I are replaced by R.sup.8 and R.sup.9 which are, respectively, N-2,6-dimethyl, diethyl or dichlorophenylcarboxamido or N-2,6-dimethyl, diethyl or dichlorophenylacetamido and hydrogen. The compounds of the invention have antiarrhythmic properties or are intermediates for the preparation thereof.
摘要翻译： 本文公开了式I的N-取代 - 六氢-1,2,5-三氮杂，其为I或其药学上可接受的酸加成盐，其中R 4和R 5独立地为氢或C 1 -C 4烷基; R1是（R6）2-CH-（CH2）n-，其中n是0,1,2或3，R6是对氟，氯或甲氧基苯基; 并且R 3是氢，R 2是苯甲酰基，2,6-二甲基或二乙基苯甲酰基，2,6-二氯苯甲酰基，N-甲基，乙基或丙基甲酰胺基，N-苯基甲酰胺基，N-2,6-二甲基或二乙基苯基甲酰胺基，N-2,6 乙基或丙基乙酰氨基，N-苯基乙酰胺基，N-2,6-二甲基或二乙基苯基乙酰胺基，或N-2,6-二氯苯乙酰氨基或R2和R3相同，为N-甲基，乙基或丙基甲酰胺基， 苯甲酰基，2,6-二甲基或二乙基苯甲酰基，2,6-二氯苯甲酰基，苄基，2,6-二甲基或二乙基苯甲酰基，2,6-二氯苯甲酰或可除去的氨基保护基。 还公开了式II的N-取代 - 六氢-1,2,5-三氮杂，其中式I的R 1被作为C 1 -C 4烷基的R 7代替，式I的R 2和R 3被R 8和R 9取代， 分别为N-2,6-二甲基，二乙基或二氯苯基甲酰胺基或N-2,6-二甲基，二乙基或二氯苯乙酰氨基和氢。 本发明的化合物具有抗心律失常性质或者是其制备的中间体。
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公开(公告)号：US4001214A
公开(公告)日：1977-01-04
申请号：US627486
申请日：1975-10-30
IPC分类号： C07D295/092 , C07D295/08
CPC分类号： C07D295/088 , Y10S514/821
摘要： Octamethyleneiminoalkyl and heptamethyleneiminoalkyl ethers of 2,2'- and 3,3'-dihydroxybenzil are prepared by reacting the dithallium salt of 2,2'- or 3,3'-dihydroxybenzil with an N-chloroalkyl octamethyleneimine or heptamethyleneimine. The products have antiarrhythmic activity.
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