(2Z)-2-氰基-3-(3,4-二羟基-5-硝基苯基)-N,N-二乙基-2-丙烯酰胺 | 145195-63-7

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 中文名称: (2Z)-2-氰基-3-(3,4-二羟基-5-硝基苯基)-N,N-二乙基-2-丙烯酰胺
• 中文别名: 顺式-恩他卡朋；顺式-安托卡朋；顺式恩他卡朋
• 英文名称: (2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide
• 英文别名: [E]-2-cyano-N,N-diethyl-3-[3,4-dihydroxy-5-nitrophenyl]propenamide；(Z)-entacapone；entacapone；entacapone impurity A；ASH-276；(Z)-N,N-diethyl-2-cyαno-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide；(Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide
• CAS: 145195-63-7
• 化学式: C₁₄H₁₅N₃O₅
• 分子量: 305.29
• InChiKey: JRURYQJSLYLRLN-YHYXMXQVSA-N

物化性质

• 熔点：
  142-144°C
• 沸点：
  526.6±50.0 °C(Predicted)
• 密度：
  1.392±0.06 g/cm3(Predicted)
• 溶解度：
  二氯甲烷（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• WGK Germany：
  3
• 储存条件：
  Hygroscopic, stored at -20°C in a freezer under an inert atmosphere.

制备方法与用途

Entacapone is a metabolite of the catechol-O-methyltransferase (COMT) inhibitor, entacapone. It can also be a potential impurity in commercial entacapone preparations and is formed as a degradant when exposed to UV light.

反应信息

• 作为反应物：
  描述：

  (2Z)-2-氰基-3-(3,4-二羟基-5-硝基苯基)-N,N-二乙基-2-丙烯酰胺 在 盐酸 作用下， 以 水 、 甲苯 为溶剂， 反应 4.0h， 以14%的产率得到恩他卡朋
  参考文献：
  名称：

  WO2008/7093

  摘要：

  公开号：
• 作为产物：
  描述：

  entacapone 以 甲苯 为溶剂， 反应 4.0h， 生成 (2Z)-2-氰基-3-(3,4-二羟基-5-硝基苯基)-N,N-二乙基-2-丙烯酰胺
  参考文献：
  名称：

  WO2007/94007

  摘要：

  公开号：

文献信息

• Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches
  作者：Baojian Wu、Xiaoqiang Wang、Shuxing Zhang、Ming Hu

  DOI：10.1007/s11095-012-0666-z

  日期：2012.6

  Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods. Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate. 3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q2 = 0.548, r2 = 0.949, r pred 2  = 0.775; CoMSIA: q2 = 0.579, r2 = 0.876, r pred 2  = 0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence. CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.

  通过实验使用145种酚类化合物，并通过3D-QSAR方法分析，确定了人UGT1A9的催化选择性。UGT1A9是一种重要的膜结合酶，催化外源性物质的葡糖醛酸化反应。通过动力学分析确定了UGT1A9的催化效率。使用CoMFA和CoMSIA技术分析了定量结构活性关系。通过将葡糖醛酸化位点及其相邻的芳香环重叠，实现了底物结构的最大立体重叠。对于具有多个活性葡糖醛酸化位点的底物，每个位点被视为单独的底物。3D-QSAR分析产生了统计上可靠的模型，具有良好的预测能力（CoMFA：q2=0.548，r2=0.949，r pred 2=0.775；CoMSIA：q2=0.579，r2=0.876，r pred 2=0.700）。通过轮廓系数图阐明了底物中负责选择性差异的结构特征。将轮廓系数图叠加在UGT1A9的同源模型的催化口袋中，能够高度自信地识别UGT1A9的催化口袋。CoMFA/CoMSIA模型可以预测底物的选择性和UGT1A9的体外清除率。我们的发现还提供了理解UGT1A9功能和底物选择性的可能分子基础。
• ENTACAPONE-DERIVATIVES
  申请人：Hansen Klaus

  公开号：US20080103191A1

  公开（公告）日：2008-05-01

  Pharmaceutical composition comprising one or more entacapone derivatives and one or more pharmaceutically acceptable carriers, a process for producing the pharmaceutical composition, specific entacapone derivatives, a process for the preparation of entacapone derivatives, and the use of the entacapone derivatives for the preparation of a medicament.

  包括一种或多种恩他卡朋衍生物和一种或多种药用可接受载体的药物组合物，生产该药物组合物的方法，特定的恩他卡朋衍生物，制备恩他卡朋衍生物的方法，以及利用恩他卡朋衍生物制备药物的用途。
• [EN] AN EFFICIENT PROCESS FOR THE MANUFACTURE OF (E)-ENTACAPONE POLYMORPHIC FORM A<br/>[FR] PROCEDE EFFICACE DE PRODUCTION DE FORME A POLYMORPHE DE (E)-ENTACAPONE
  申请人：WOCKHARDT LTD

  公开号：WO2005070881A1

  公开（公告）日：2005-08-04

  The present invention describes an improved process for the manufacture of (E)-N, N-Diethyl-2-cyano-3-(3, 4-dihydroxy-5-nitrophenyl) acrylamide (Entacapone) polymorphic Form A, which is an excellent inhibitor of Catechol-O-methyltransferase (COMT) enzyme. 3, 4-Dihydroxy-5-nitrobenzaldehyde is condensed with N, N-Diethylcyanoacetamide in presence of a base in alcoholic solution to get the Entacapone. After the disappearance of reactants the crude reaction mixture is poured into aqueous ethyl acetate solution followed by adjusting pH between 3.5 to 4.0 with acetic acid. Simple extraction process provides 99.7% HPLC pure (E)- isomer of Entacapone Form A.

  该发明描述了一种改进的制备(E)-N, N-二乙基-2-氰基-3-(3,4-二羟基-5-硝基苯基)丙烯酰胺（恩他卡朋）多形式A的工艺，该工艺是一种优秀的儿茶酚-O-甲基转移酶（COMT）酶抑制剂。3,4-二羟基-5-硝基苯甲醛与N, N-二乙基氰基乙酰胺在醇溶液中在碱的存在下缩合，得到恩他卡朋。在反应物消失后，粗反应混合物倒入乙酸乙酯溶液中，随后用乙酸调节pH值在3.5至4.0之间。简单的萃取过程提供了99.7%的高效液相色谱纯(E)-异构体恩他卡朋A形式。
• [EN] IMPROVED PROCESS FOR THE PREPARATION OF ENTACAPONE<br/>[FR] PROCEDE AMELIORE DE PREPARATION DE L'ENTACAPONE
  申请人：SUVEN LIFE SCIENCES LTD

  公开号：WO2005063693A1

  公开（公告）日：2005-07-14

  The invention disclosed in this application relates to an improved process for the preparation of the Entacapone which comprises. (i)reacting 3-alkoxy- 4-hydroxy-5-nitrobenzadehyde with N,N-diethylaminocyanoactamide in the presence of mild acid catalyst and a solvent at a temperature in the range of 50-115 °C, to get the 3-O-alkylated (methyl or ethyl) Entacapone and treating with acid catalysts in the presence of organic base and solvents at temperature in the range of 20-60 °C to get Entacapone.

  这份申请中披露的发明涉及一种改进的恩他卡朋的制备过程，包括：(i)在温度范围为50-115°C的条件下，在温和酸性催化剂和溶剂的存在下，将3-烷氧基-4-羟基-5-硝基苯甲醛与N,N-二乙基氨基氰基乙酰胺反应，得到3-O-烷基化（甲基或乙基）恩他卡朋，并在有机碱和溶剂存在的条件下，在20-60°C的温度范围内用酸性催化剂处理，得到恩他卡朋。
• [EN] STABLE POLYMORPHS OF (E)-N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE<br/>[FR] POLYMORPHES STABLES DE (E)-N,N-DIETHYL-2-CYANO-3-(3,4-DIHYDROXY-5-NITROPHENYL)ACRYLAMIDE
  申请人：WOCKHARDT LTD

  公开号：WO2005066117A1

  公开（公告）日：2005-07-21

  The present invention relates to stable crystalline polymorphic forms C and D of (E)-N,N-diethyl-2-cyan-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (Entacapone) and their preparation processes. (E)-Entacapone Form C is obtained by condensing 3,4-Dihydroxy-5-nitrobenzaldehyde and N,N-Diethylcyanoacetamide in presence of a base followed by addition of acetic acid after the reaction is over and crystallization step. (E)-Entacapone Form D is prepared from Entacapone Form C, Crystallographically pure (E)-Entacapone Form A or Crystallographically essentially pure From A. Polymorphic forms C and D of (E)-Entacapone are characterized by specific Infra Red (IR) and X-ray powder diffraction peak values.

  该发明涉及(E)-N,N-二乙基-2-氰-3-(3,4-二羟基-5-硝基苯基)丙烯酰胺（恩他卡朋）的稳定结晶多形态C和D，以及它们的制备过程。通过在碱的存在下，将3,4-二羟基-5-硝基苯甲醛和N,N-二乙基氰乙酰胺缩合，反应结束后加入乙酸和结晶步骤，可以获得(E)-恩他卡朋C型。从恩他卡朋C型、晶体学纯(E)-恩他卡朋A型或晶体学基本纯A型制备(E)-恩他卡朋D型。 (E)-恩他卡朋的多形态C和D具有特定的红外（IR）和X射线粉末衍射峰值特征。