diethyl 2-[4-(methoxycarbonyl)phenylamino]malonate | 221382-03-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: diethyl 2-[4-(methoxycarbonyl)phenylamino]malonate
• 英文别名: diethyl 2-(4-carboxymethylphenylamino)malonate；Diethyl (4-methoxycarbonylphenyl)aminomalonate；diethyl 2-(4-methoxycarbonylanilino)propanedioate
• CAS: 221382-03-2
• 化学式: C₁₅H₁₉NO₆
• 分子量: 309.319
• InChiKey: XRVLUIMFMFXPLL-UHFFFAOYSA-N

物化性质

• 熔点：
  66-69 °C
• 沸点：
  411.2±35.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  22
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  diethyl 2-[4-(methoxycarbonyl)phenylamino]malonate 在 甲醇 、 sodium tetrahydroborate 、 nitronium tetrafluoborate 、 sodium 、 sodium hydride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 61.0h， 生成 5-(2-hydroxyethyl)-5-hydroxymethyl-N-(4-methoxycarbonyl-2-nitrophenyl)pyrrolidin-2-one
  参考文献：
  名称：

  Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: modifications of essential pyrrolidinone ring substituents

  摘要：

  We recently reported the first benzoic acid, 1-[4-carboxy-2-(3-pentylamino)phenyl]-5,5-bis(hydroxymethyl)pyrrolidin-2-one (8), that is a potent inhibitor of avian influenza A neuraminidase (N9) and, unlike other reported potent neuraminidase inhibitors, does not contain a basic aliphatic amine or guanidine nor a simple N-acetyl grouping. However, 8 was a poor inhibitor of influenza B neuraminidase. In the present study we further evaluated 8 as an inhibitor of human influenza A NA isolates, and it was effective against N2 NA but found to be 160-fold less active against N1 NA. We also synthesized analogues of 8 involving moderate modifications of essential substituents on the pyrrolidinone ring. Specifically, the aminomethyl (9), hydroxyethyl (10), and aminoethyl (11) analogues were prepared. Only the most conservative change (compound 9) resulted in continued effective inhibition of influenza A, in addition to a noteworthy increase in the activity of 9 for N1 NA. The effectiveness of 9 against influenza B neuraminidase was furthermore improved 10-fold relative to 8, but this activity remained 50-fold poorer than for type A NA. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00271-2
• 作为产物：
  描述：

  溴代丙二酸二乙酯 、 4-氨基苯甲酸甲酯 反应 16.0h， 以85%的产率得到diethyl 2-[4-(methoxycarbonyl)phenylamino]malonate
  参考文献：
  名称：

  含有2-吡咯烷酮取代基的苯甲酸能有效抑制流感病毒唾液酸酶。

  摘要：

  基于铅化合物4-（N-乙酰氨基）-3-胍基苯甲酸（BANA 113），其以2.5 microM的Ki抑制甲型流感唾液酸酶，设计了几种新型的唾液酸唾液酸酶芳香抑制剂。在这项研究中，BANA 113的N-乙酰基被2-吡咯烷酮环取代，该环的部分设计目的是为引入空间定向的侧链提供可能，该侧链可能与4-，5-和/或-相互作用唾液酸酶的6个亚位点。虽然母体结构1-（4-羧基-2-胍基苯基）吡咯烷-2--2-（8）只是适度的唾液酸酶抑制剂，但在2的C5'位置引入了羟甲基或双（羟甲基）取代基-吡咯烷酮环产生的微摩尔活性低的抑制剂（分别为9和12）。这些抑制剂与唾液酸酶复合的晶体结构表明2-吡咯烷酮环的5'-位的取代基在酶的4-和/或5-亚位相互作用。用疏水的3-戊基氨基取代12中的胍导致结合力大大增强，从而产生针对甲型流感病毒唾液酸酶的IC50约为50 nM的抑制剂（14），尽管对乙型流感病毒唾液酸酶的抑

  DOI：

  10.1021/jm980707k

文献信息

• Potent Inhibition of Influenza Sialidase by a Benzoic Acid Containing a 2-Pyrrolidinone Substituent
  作者：Venkatram R. Atigadda、Wayne J. Brouillette、Franco Duarte、Shoukath M. Ali、Yarlagadda S. Babu、Shanta Bantia、Pooran Chand、Naiming Chu、John A. Montgomery、David A. Walsh、Elise A. Sudbeck、James Finley、Ming Luo、Gillian M. Air、Graeme W. Laver

  DOI：10.1021/jm980707k

  日期：1999.7.1

  1-(4-carboxy-2-guanidinophenyl)pyrrolidin-2-one (8) was only a modest inhibitor of sialidase, the introduction of a hydroxymethyl or bis(hydroxymethyl) substituent at the C5' position of the 2-pyrrolidinone ring resulted in inhibitors (9 and 12, respectively) with low micromolar activity. Crystal structures of these inhibitors in complex with sialidase demonstrated that the substituents at the 5'-position of the 2-pyrrolidinone

  基于铅化合物4-（N-乙酰氨基）-3-胍基苯甲酸（BANA 113），其以2.5 microM的Ki抑制甲型流感唾液酸酶，设计了几种新型的唾液酸唾液酸酶芳香抑制剂。在这项研究中，BANA 113的N-乙酰基被2-吡咯烷酮环取代，该环的部分设计目的是为引入空间定向的侧链提供可能，该侧链可能与4-，5-和/或-相互作用唾液酸酶的6个亚位点。虽然母体结构1-（4-羧基-2-胍基苯基）吡咯烷-2--2-（8）只是适度的唾液酸酶抑制剂，但在2的C5'位置引入了羟甲基或双（羟甲基）取代基-吡咯烷酮环产生的微摩尔活性低的抑制剂（分别为9和12）。这些抑制剂与唾液酸酶复合的晶体结构表明2-吡咯烷酮环的5'-位的取代基在酶的4-和/或5-亚位相互作用。用疏水的3-戊基氨基取代12中的胍导致结合力大大增强，从而产生针对甲型流感病毒唾液酸酶的IC50约为50 nM的抑制剂（14），尽管对乙型流感病毒唾液酸酶的抑
• Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors
  申请人：——

  公开号：US06509359B1

  公开（公告）日：2003-01-21

  A compound having the formula: wherein all variables are as defined in the specification, for use as a neuramninidase inhibitor.

  一种具有以下式子的化合物：其中所有变量均如规范中定义，用作神经氨酸酶抑制剂。
• Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: modifications of essential pyrrolidinone ring substituents
  作者：Wayne J Brouillette、Saroj N Bajpai、Shoukath M Ali、Sadanandan E Velu、Venkatram R Atigadda、Barbara S Lommer、James B Finley、Ming Luo、Gillian M Air

  DOI：10.1016/s0968-0896(03)00271-2

  日期：2003.7

  We recently reported the first benzoic acid, 1-[4-carboxy-2-(3-pentylamino)phenyl]-5,5-bis(hydroxymethyl)pyrrolidin-2-one (8), that is a potent inhibitor of avian influenza A neuraminidase (N9) and, unlike other reported potent neuraminidase inhibitors, does not contain a basic aliphatic amine or guanidine nor a simple N-acetyl grouping. However, 8 was a poor inhibitor of influenza B neuraminidase. In the present study we further evaluated 8 as an inhibitor of human influenza A NA isolates, and it was effective against N2 NA but found to be 160-fold less active against N1 NA. We also synthesized analogues of 8 involving moderate modifications of essential substituents on the pyrrolidinone ring. Specifically, the aminomethyl (9), hydroxyethyl (10), and aminoethyl (11) analogues were prepared. Only the most conservative change (compound 9) resulted in continued effective inhibition of influenza A, in addition to a noteworthy increase in the activity of 9 for N1 NA. The effectiveness of 9 against influenza B neuraminidase was furthermore improved 10-fold relative to 8, but this activity remained 50-fold poorer than for type A NA. (C) 2003 Elsevier Science Ltd. All rights reserved.