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1. 发明申请

WO2007131759A1 A PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULFONATE 审中-公开
标题翻译：一种制备亚麻酸苯并呋喃的方法
公开(公告)号：WO2007131759A1
公开(公告)日：2007-11-22
申请号：PCT/EP2007/004270
申请日：2007-05-14
申请人： LEK PHARMACEUTICALS D.D. , ANZIC, Borut , RZEN, Janez , MAROLT, Boris , FURLAN, Borut
发明人： ANZIC, Borut , RZEN, Janez , MAROLT, Boris , FURLAN, Borut
IPC分类号： C07D211/90 , C07C211/27
CPC分类号： C07D211/90 , C07C213/08 , C07C217/08
摘要： The present invention relates to novel alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate, wherein alkyl represents C 1 C 4 alkyl group, preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate in high overall yield and high purity, containing substantially less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4- dihydro-6-methyl-3,5-pyridinedicarboxylate as the single remaining impurity. No other impurities are contained in obtained pure crystalline amlodipine benzenesulfonate. Preferably, 2-chlorobenzaldehyde is contacted with ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate in an organic solvent, preferably ethanol, to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, which is converted without isolation from the reaction mixture, preferably with methyl (E)-3- aminocrotonate to form 3-ethyl 5-methyl (±)-2-[2-(N-tritylamino)ethoxymethyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate ("tritylamlodipine"), which is converted without isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, preferably ethanol, followed by isolation and purification of amlodipine benzenesulfonate. C 1 -C 4 alkyl alcohols, especially methanol, ethanol, isopropanol and mixtures thereof, are used as an organic solvent. Amlodipine benzenesulfonate (besylate) is useful as antiishemic and antihypertensive agent.
摘要翻译：本发明涉及新的2-（2-氯亚苄基）烷基-4-（2-三苯甲基氨基乙氧基）乙酰乙酸烷基酯，其中烷基代表C 1 -C 4烷基，优选乙基 2-（2-氯亚苄基）-4-（2-三苯甲基氨基乙氧基）乙酰乙酸酯，作为制备高产率和高纯度的苯磺酸氨氯地平的新方法中有用的中间体，其含量基本上小于0.1％（±）-2 - [（2-氨基乙氧基） - 甲基] -4-（2-氯苯基）-1,4-二氢-6-甲基-3,5-吡啶二羧酸二乙酯作为单一剩余杂质。得到的纯结晶氨氯地平苯磺酸盐中不含有其他杂质。优选地，将2-氯苯甲醛与有机溶剂（优选乙醇）中的乙基-4- [2-（N-三苯甲基氨基）乙氧基]乙酰乙酸酯接触形成乙基-2-（2-氯亚苄基）-4-（2-三苯甲基氨基乙氧基）乙酰乙酸酯，其不经分离从反应混合物中转化，优选用（A）-3-氨基巴豆酸甲酯转化成3-乙基5-甲基（±）-2- [2-（N-三苯甲基氨基）乙氧基甲基] -4-（ 2-氯苯基）-1,4-二氢-6-甲基-3,5-吡啶二羧酸酯（“tritylamlodipine”），其在有机溶剂，优选乙醇中不与苯磺酸在反应混合物中分离而转化，随后分离，氨氯地平苯磺酸盐的纯化。 C 1 -C 4烷基醇，特别是甲醇，乙醇，异丙醇及其混合物用作有机溶剂。苯磺酸氨氯地平（苯磺酸盐）可用作抗凝血和抗高血压药物。

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