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首页> 外国专利> NOVEL PROCESS FOR THE PREPARATION OF FUNCTIONALIZED BENZOCYCLOBUTENES, AND APPLICATION TO THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID

NOVEL PROCESS FOR THE PREPARATION OF FUNCTIONALIZED BENZOCYCLOBUTENES, AND APPLICATION TO THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID

机译：新型功能性苯环戊二烯的制备新工艺及其在合成IVABRADINE及其盐类中的应用（加入药学可接受的酸中）

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Preparing a bicyclo[4.2.0]octa-1(6),2,4-triene compound (IV) comprises: cyclization reaction of an ethyl-benzene compound (V) in the presence of a catalyst/ligand comprising a palladium catalyst and an organic phosphine (including tri-tert-butyl phosphine, 2-biphenyl-di-tert-butylphosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene and tris(4-methoxy-2-methylphenyl)phosphine, or phosphonium salt such phosphine, a base in an organic solvent), base and organic solvent. Preparing a bicyclo[4.2.0]octa-1(6),2,4-triene compound of formula (IV) comprises: cyclization reaction of an ethyl-benzene compound of formula (V) in the presence of a catalyst/ligand comprising a palladium catalyst and an organic phosphine (including tri-tert-butyl phosphine, 2-biphenyl-di-tert-butylphosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene and tris(4-methoxy-2-methylphenyl)phosphine, or phosphonium salt such phosphine, a base in an organic solvent), base and organic solvent. Either R 1-R 4 : H, 1-6C alkyl, 1-6C alkoxy, F, Cl, protected amine group, protected hydroxyl group, 1-6C alkoxycarbonyl group, or CF 3; or R 1, R 4 : H; or CR 2R 3 : 1,3-dioxolane; R 5 : 1-6C alkyl, optionally saturated, 1-6C hydroxyalkyl (which hydroxyl function is protected), or CO 2R 7; R 7 : 1-6C alkyl; R 6 : CN or CO 2R 8; R 8 : 1-6C alkyl; and X : halo (preferably Br) or triflate group. Independent claims are included for: (1) a process for preparing bicyclo[4.2.0]octa-triene-7-carboxylic acid methyl ester compounds of formula (VIIa) comprising converting an ethyl-benzene compound (V) (where R 5 is CO 2R 7 and R 6 is CO 2R 8) into bicyclo[4.2.0]octa-1(6),2,4-triene compound (IV) (where R 5 is CO 2R 7 and R 6 is CO 2R 8); and converting (IV) by a reaction of hydrolysis or saponification of ester into a bicyclo[4.2.0]octa-1(6),2,4-triene-7,7-dicarboxylic acid methyl ester compound of formula (VIa); and decarboxylating (VIa) to give (VIIa); (2) bicyclo[4.2.0]octa-1(6),2,4-triene compound (IV) (where R 5 is CO 2R 7 and R 6 is CO 2R 8); (3) 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7,7-dicarboxylic acid methyl ester compound of formula (VIb); (4) 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid methyl ester compound of formula (VIIc); and (5) a process for preparing ivabradine (I) and its salts or hydrates comprising: converting ethyl-benzene compound (V) (where R 1 and R 4 is H, R 2 and R 3 is OCH 3, R 5 is CO 2R 7 and R 6 is CO 2R 8) in to 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid methyl ester compound (VIIc); reacting (VIIc) with methylamine to obtain 3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid methylamide (VIII); reducing (VIII) to give (3,4-dimethoxy-bicyclo[4.2.0]octa-1(6),2,4-trien-7-ylmethyl)-methyl-amine (III); resolution of (III) in the presence of camphosulfonic acid to give 1-[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0]octa-1(6),2,4-trienyl]-N-methyl-methanamine (II); and converting (II) into (I), which can be converted into its addition salts with acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid and camphoric acid, or their hydrates. R 9, R 10 : 1-6C alkyl. [Image] [Image] [Image] ACTIVITY : Cardiant; Vasotropic; Antianginal; Antiarrhythmic. MECHANISM OF ACTION : None given.
机译：制备双环[4.2.0]八-1（6），2,4-三烯化合物（IV）包括：在包含钯催化剂的催化剂/配体存在下，乙苯化合物（V）的环化反应。有机膦（包括三叔丁基膦，2-联苯基-二叔丁基膦，1,2,3,4,5-五苯基-1'-（二叔丁基膦基）二茂铁和三（4-甲氧基-2-甲基苯基）膦或phospho盐（例如膦，有机溶剂中的碱），碱和有机溶剂。式（IV）的双环[4.2.0] octa-1（6），2,4-三烯化合物的制备包括：在催化剂/配体的存在下，式（V）的乙基苯化合物的环化反应包括：钯催化剂和有机膦（包括三叔丁基膦，2-联苯基-二叔丁基膦，1,2,3,4,5-五苯基-1'-（二叔丁基膦基）二茂铁和三（4-甲氧基-2-甲基苯基）膦，或phospho盐如膦，有机溶剂中的碱），碱和有机溶剂。 R 1-R 4：H，1-6C烷基，1-6C烷氧基，F，Cl，被保护的胺基，被保护的羟基，1-6C烷氧羰基或CF 3;或R 1，R 4：H;或或CR 2R 3：1，3-二氧戊环;或R 5：1-6C烷基，可选地为饱和的1-6C羟烷基（其羟基官能团被保护）或CO 2R 7; R 7：1-6C烷基; R 6：CN或CO 2 R 8; R 8：1-6C烷基; X：卤素（优选Br）或三氟甲磺酸酯基。包括以下独立权利要求：（1）一种制备式（VIIa）的双环[4.2.0]八-三烯-7-羧酸甲酯化合物的方法，该方法包括转化乙基苯化合物（V）（其中R 5是将CO 2R 7和R 6为CO 2R 8转化为双环[4.2.0] octa-1（6），2,4-三烯化合物（IV）（其中R 5为CO 2R 7和R 6为CO 2R 8） ;通过酯的水解或皂化反应将（IV）转化为式（VIa）的双环[4.2.0] octa-1（6），2,4-三烯-7,7-二羧酸甲酯化合物;使（VIa）脱羧得到（VIIa）; （2）双环[4.2.0]八-1（6），2,4-三烯化合物（IV）（其中R 5为CO 2R 7和R 6为CO 2R 8）; （3）式（VIb）的3,4-二甲氧基-双环[4.2.0] octa-1（6），2,4-三烯-7,7-二羧酸甲酯化合物; （4）式（VIIc）的3,4-二甲氧基-双环[4.2.0] octa-1（6），2,4-三烯-7-羧酸甲酯化合物; （5）制备伊伐布雷定（I）及其盐或水合物的方法，该方法包括：转化乙苯化合物（V）（其中R 1和R 4为H，R 2和R 3为OCH 3，R 5为CO 2R 7和R 6是CO 2R 8）形成3,4-二甲氧基-双环[4.2.0] octa-1（6），2,4-三烯-7-羧酸甲酯化合物（VIIc）;使（VIIc）与甲胺反应，得到3,4-二甲氧基-双环[4.2.0] octa-1（6），2,4-三烯-7-羧酸甲酰胺（VIII）;还原（VIII），得到（3,4-二甲氧基-双环[4.2.0] octa-1（6），2,4-三烯-7-基甲基）-甲基胺（III）;樟脑磺酸存在下拆分（III），得到1-[（（8S）-3,4-二甲氧基-8-双环[4.2.0] octa-1（6），2,4-三烯基] -N-甲基甲胺（II）;并将（II）转化为（I），其可以用酸如盐酸，氢溴酸，硫酸，磷酸，乙酸，三氟乙酸，乳酸，丙酮酸，丙二酸，琥珀酸转化为其加成盐。酸，戊二酸，富马酸，酒石酸，马来酸，柠檬酸，抗坏血酸，草酸，甲磺酸，苯磺酸和樟脑酸或它们的水合物。 R 9，R 10：1-6C烷基。 [图片] [图片] [图片]活动：Cardiant;变压性抗心绞痛抗心律不整。作用机理：未给出。

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