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    Process for the preparation of valsartan
    5.
    发明授权
    Process for the preparation of valsartan 有权
    制备缬沙坦的方法

    公开(公告)号：US08981109B2

    公开(公告)日：2015-03-17

    申请号：US13261552

    申请日：2011-06-24

    申请人： Raveendra Reddy Chinta ,  Gangadhara Bhima Shankar Nangi ,  Mahendar Reddy Nayini ,  Somappa Somannavar Yallapa ,  Shankar Reddy Budidet ,  Islam Aminul ,  Sivakumaran Meenakshisunderam

    发明人： Raveendra Reddy Chinta ,  Gangadhara Bhima Shankar Nangi ,  Mahendar Reddy Nayini ,  Somappa Somannavar Yallapa ,  Shankar Reddy Budidet ,  Islam Aminul ,  Sivakumaran Meenakshisunderam

    IPC分类号： C07D257/04

    CPC分类号： C07D257/04

    摘要： The present invention relates to a process for the preparation of pure Valsartan (I) substantially free from impurities of formulae (Ia), (Ib), and (Ic), which comprises: (i) condensing 2-(4′-bromomethylphenyl)benzonitrile of formula (II) with L-valine methyl ester hydrochloride of formula (V) in the presence of a base in a solvent to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (VI); (ii) treating the compound VI of step (i) with acid followed by treating with base to produce pure compound VI substantially free from dimeric impurity of formula (Via); (iii) reacting the pure compound of formula (VI) with n-valeryl chloride in the presence of a base to produce pure N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII) substantially free from alkene impurity of formula (Vila); (iv) reacting the compound of formula (VII) with trialkyltin chloride and a metal azide in a solvent at a reflux temperature to produce N-(1-oxopentyl)-N-[[2′-(2-tributyltintetrazol-5-yl)-(1,1′-biphenyl)-4-yl]methyl]-(L)-valine methyl ester of formula (VHIb) free from thermal degradation impurity (Villa); (v) hydrolyzing the compound of formula (VHIb) in the presence of alkaline conditions to produce Valsartan (I).

    摘要翻译： 本发明涉及制备基本上不含式（Ia），（Ib）和（Ic）杂质的纯缬沙坦（I）的方法，其包括：（i）将2-（4'-溴甲基苯基） （II）的苄腈与式（V）的L-缬氨酸甲酯盐酸盐在碱的存在下在溶剂中反应，得到N - [（2'-氰基联苯-4-基）甲基] - （L） - 缬氨酸 （VI）的甲酯; （ii）用酸处理步骤（i）的化合物VI，然后用碱处理以产生基本上不含式（VIa）的二聚杂质的纯化合物VI; （ⅲ）在碱的存在下使式（Ⅵ）的纯的化合物与正戊酰氯反应，得到纯的N-戊酰基-N - [（2'-氰基联苯-4-基）甲基] - （L） - 缬氨酸甲酯（VII）基本上不含式（VIIa）的烯烃杂质; （ⅳ）使式（Ⅶ）化合物与三烷基氯化锡和金属叠氮化物在溶剂中在回流温度下反应，得到N-（1-氧代戊基）-N - [[2' - （2-三丁基四唑-5-基 ） - （1,1'-联苯基）-4-基]甲基] - （L））不含热降解杂质的式（VHIb）的缬氨酸甲酯（Villa）; （v）在碱性条件存在下水解式（VHIb）化合物以制备缬沙坦（I）。