3,3-diethyl-4-(phenylsulfonyl)azetidin-2-one | 741280-49-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: 3,3-diethyl-4-(phenylsulfonyl)azetidin-2-one
• 英文别名: 4-(Benzenesulfonyl)-3,3-diethylazetidin-2-one
• CAS: 741280-49-9
• 化学式: C₁₃H₁₇NO₃S
• 分子量: 267.349
• InChiKey: XXVXXRUDPUADCQ-UHFFFAOYSA-N

物化性质

• 熔点：
  156-158 °C
• 沸点：
  503.6±50.0 °C(Predicted)
• 密度：
  1.191±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  71.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3,3-diethyl-4-(phenylsulfonyl)azetidin-2-one 在 四丁基溴化铵 、 potassium carbonate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 2-[(2-Benzenesulfonyl-3,3-diethyl-4-oxo-azetidin-1-yl)-ethoxycarbonyl-methoxycarbonylamino]-benzoic acid methyl ester
  参考文献：
  名称：

  Design, Synthesis, and Enzymatic Evaluation of N-Acyloxyalkyl- and N¹-Oxazolidin-2,4-dion-5-yl-Substituted β-lactams as Novel Inhibitors of Human Leukocyte Elastase

  摘要：

  Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5 ' S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.

  DOI：

  10.1021/jm0501331
• 作为产物：
  描述：

  2-吖丁啶酮,4-(乙酰氧基)-3,3-二乙基- 在 sodium hydroxide 、 间氯过氧苯甲酸 作用下， 以 丙酮 为溶剂， 生成 3,3-diethyl-4-(phenylsulfonyl)azetidin-2-one
  参考文献：
  名称：

  N-酰氧基甲基-和N-氨基羰氧基甲基-2-氮杂环丁烷酮作为人白细胞弹性蛋白酶抑制剂的设计，合成和稳定性。

  摘要：

  设计了一系列一系列2-氮杂环丁烷酮的N-酰氧基甲基-和N-氨基羰基氧基甲基衍生物3，它们在β-内酰胺C-3和C-4位置具有不同的取代基图案，被认为是潜在的基于机制的人白细胞弹性蛋白酶抑制剂。被发现对酶具有抑制力和选择性。

  DOI：

  10.1016/s0960-894x(01)00131-7

文献信息

• Design, Synthesis and Stability of N-Acyloxymethyl- and N-Aminocarbonyloxymethyl-2-azetidinones as Human Leukocyte Elastase Inhibitors
  作者：A Clemente、A Domingos、A.P Grancho、J Iley、R Moreira、J Neres、N Palma、A.B Santana、E Valente

  DOI：10.1016/s0960-894x(01)00131-7

  日期：2001.4

  N-acyloxymethyl- and N-aminocarbonyloxymethyl derivatives of 2-azetidinones, 3, with different substituent patterns at the beta-lactam C-3 and C-4 positions, were designed as potential mechanism-based inhibitors for human leukocyte elastase and found to exhibit inhibitory potency and selectivity for the enzyme.

  设计了一系列一系列2-氮杂环丁烷酮的N-酰氧基甲基-和N-氨基羰基氧基甲基衍生物3，它们在β-内酰胺C-3和C-4位置具有不同的取代基图案，被认为是潜在的基于机制的人白细胞弹性蛋白酶抑制剂。被发现对酶具有抑制力和选择性。
• Kinetics and Mechanism of Hydrolysis of <i>N</i>-Acyloxymethyl Derivatives of Azetidin-2-one
  作者：Emília Valente、José R. B. Gomes、Rui Moreira、Jim Iley

  DOI：10.1021/jo0358123

  日期：2004.5.1

  The pH-independent, acid-catalyzed and base-catalyzed hydrolyses of N-acyloxymethylazetidin-2-ones all occur at the ester function. The pH-independent hydrolysis involves rate-limiting alkyl C−O fission and formation of an exocyclic β-lactam iminum ion. This iminium ion is then trapped by water at the exocyclic iminium carbon atom, rather than at the β-lactam carbonyl carbon atom, to form the corresponding

  N-酰氧基甲基氮杂环丁烷-2-酮的不依赖pH值，酸催化和碱催化的水解都发生在酯官能团上。非pH依赖性水解涉及限速烷基CO裂变和环外β-内酰胺亚胺酸离子的形成。然后，该亚胺离子被水捕获在环亚氨基碳原子上，而不是β-内酰胺羰基碳原子上，从而形成相应的N-羟甲基氮杂环丁烷-2-酮。在理论上以B3LYP / 6-31 + G（d）进行的计算也支持水的亲核攻击发生在亚环离子上的环外碳而不是β-内酰胺羰基碳上。酸催化途径的机制涉及可能在β-内酰胺氮处的预平衡质子化，然后通过速率限制的烷基C-O裂变形成环外亚胺酸离子。碱催化的水解涉及在酯羰基碳上的限速氢氧化物攻击。这些结果暗示了含有带正电荷的酰胺氮原子的β-内酰胺系统的形成，该酰胺基氮原子通过保留产物中β-内酰胺结构的途径进行水解，并提供了进一步的证据表明β-内酰胺C-N键的裂解并非如此。轻而易举，就像人们通常想象的那样。
• The efficiency of C-4 substituents in activating the β-lactam scaffold towards serine proteases and hydroxide ion
  作者：Jalmira Mulchande、Luísa Martins、Rui Moreira、Margarida Archer、Tania F. Oliveira、Jim Iley

  DOI：10.1039/b706622h

  日期：——

  that second-order rate constants for the alkaline hydrolysis and elastase inactivation by N-carbamoyl monobactams are independent of the pKa of the leaving group at C-4. Indeed, the effect exerted by these substituents is purely inductive: electron-withdrawing substituents at C-4 of N-carbamoyl-3,3-diethylmonobactams increase the rate of alkaline hydrolysis and elastase inactivation, with Hammett pI

  通常认为在单bactams C-4处有一个离去基团是这些酰化剂基于机制抑制人白细胞弹性蛋白酶的必要条件。我们报告说，N-氨基甲酰基单bactams的碱性水解和弹性蛋白酶失活的二级速率常数与C-4上离去基团的pKa无关。实际上，这些取代基发挥的作用纯粹是感应性的：N-氨基甲酰基-3,3-二乙基单bactams C-4处的吸电子取代基可提高碱性水解和弹性蛋白酶的失活速率，哈米特pI值分别为3.4和2.5。 ，表明在过渡态中产生负电荷。当与化学过程相比时，这些pI值之间的大小差异与酶促反应的较早过渡状态一致。这些结果表明，弹性蛋白酶失活的限速步骤是四面体中间体的形成，并且β-内酰胺开环与离去基团离开C-4不协调。即使不存在与主要识别位点相互作用所需的C-3乙基，单bactamulfones仍然是有效的弹性蛋白酶抑制剂。对于一种这样的化合物，已经通过X射线晶体学检查了涉及猪胰弹性蛋白酶的1：1酶抑
• Design, Synthesis, and Enzymatic Evaluation of <i>N</i>-Acyloxyalkyl- and <i>N</i>¹-Oxazolidin-2,4-dion-5-yl-Substituted β-lactams as Novel Inhibitors of Human Leukocyte Elastase
  作者：Rui Moreira、Ana Bela Santana、Jim Iley、João Neres、Kenneth T. Douglas、Peter N. Horton、Michael B. Hursthouse

  DOI：10.1021/jm0501331

  日期：2005.7.1

  Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be responsible for the onset of chronic obstructive pulmonary disease (COPD). A novel series of C-3-, C-4-, and N-1-substituted azetidin-2-ones were prepared as potential mechanism-based inhibitors of HLE to restore the protease/antiprotease imbalance. N-Acyloxyalkylazetidin-2-ones, 4, and their carbamate counterparts, 5, are weak HLE inhibitors, being 5 times less active than their bicyclic oxazolidin-2,4-dione-substituted analogues, 6, containing an electron-withdrawing substituent at C-4. Compounds 6 containing a C-4 substituent exist as two diastereomeric pairs of enantiomers, each pair presenting similar inhibitory activity against HLE. Comparative docking experiments with the C-4-substituted oxazolidin-2,4-dione inhibitors 6 suggest that only the 4R,5 ' S and 4S,5'S diastereomers consistently interact with the beta-lactam carbonyl carbon atom accessible to the serine hydroxyl oxygen.