diethyl ((3-bromophenyl)difluoromethyl)phosphonate | 221876-80-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: diethyl ((3-bromophenyl)difluoromethyl)phosphonate
• 英文别名: diethyl [(3-bromophenyl)difluoromethyl]phosphonate；1-bromo-3-[diethoxyphosphoryl(difluoro)methyl]benzene
• CAS: 221876-80-8
• 化学式: C₁₁H₁₄BrF₂O₃P
• 分子量: 343.105
• InChiKey: GCAQDTHUAFPUKF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  diethyl ((3-bromophenyl)difluoromethyl)phosphonate 在 四(三苯基膦)钯 、 三甲基溴硅烷 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 一水合肼 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 7.0h， 生成 ((4'-((aminooxy)methyl)-[1,1'-biphenyl]-3-yl)difluoromethyl)phosphonic acid
  参考文献：
  名称：

  Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase

  摘要：

  Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 mu M) was converted from a subs trate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid, and by attachment of an aminooxy handle for further structural optimization by mime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequenly employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition Of intracellular Y pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.

  DOI：

  10.1021/jm200022g
• 作为产物：
  描述：

  1-溴-3-碘苯 、 溴氟甲基膦酸二乙酯 在 锌 、 copper(I) bromide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 以96%的产率得到diethyl ((3-bromophenyl)difluoromethyl)phosphonate
  参考文献：
  名称：

  Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase

  摘要：

  Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 mu M) was converted from a subs trate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid, and by attachment of an aminooxy handle for further structural optimization by mime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequenly employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition Of intracellular Y pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.

  DOI：

  10.1021/jm200022g

文献信息

• Copper-Mediated Introduction of the CF₂ PO(OEt)₂ Motif: Scope and Limitations
  作者：Maria V. Ivanova、Alexandre Bayle、Tatiana Besset、Xavier Pannecoucke、Thomas Poisson

  DOI：10.1002/chem.201703542

  日期：2017.12.6

  can be functionalised. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated molecules at room temperature. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalised

  在本文中，报告了访问包含CF 2 PO（OEt）2的分子的一般程序。试剂CuCF 2 PO（OEt）2可以通过简单的协议访问，并且可以对多种底物进行功能化。该方法允许在室温下将芳基重氮盐以及芳基，杂芳基，乙烯基和炔基碘鎓盐转化为相应的氟化分子。进行了机理研究，以更好地了解反应途径。在相似的条件下，乙烯基和芳基碘化物，烯丙基卤化物和苄基溴化物也被官能化，并且研究了反应的范围和局限性。最后，该程序扩展到二硫化物，以提供新的SCF 2通道含PO（OEt）2的分子。
• Substrate-Based Fragment Identification for the Development of Selective, Nonpeptidic Inhibitors of Striatal-Enriched Protein Tyrosine Phosphatase
  作者：Tyler D. Baguley、Hai-Chao Xu、Manavi Chatterjee、Angus C. Nairn、Paul J. Lombroso、Jonathan A. Ellman

  DOI：10.1021/jm401037h

  日期：2013.10.10

  Alzheimer’s disease. Herein, a substrate-based approach for the discovery and optimization of fragments called substrate activity screening (SAS) has been applied to the development of low molecular weight (<450 Da) and nonpeptidic, single-digit micromolar mechanism-based STEP inhibitors with greater than 20-fold selectivity across multiple tyrosine and dual specificity phosphatases. Significant levels of

  在许多神经精神疾病如阿尔茨海默病中观察到高水平的纹状体富集蛋白酪氨酸磷酸酶 (STEP) 活性。STEP 的过度表达导致许多关键神经元信号分子的去磷酸化和失活，包括离子型谷氨酸受体。此外，降低 AD 小鼠模型中 STEP 水平的基因显着逆转了认知缺陷并降低了谷氨酸受体内化。这些结果支持 STEP 作为治疗阿尔茨海默病药物发现的潜在靶点。在此，一种用于发现和优化称为底物活性筛选 (SAS) 的基于底物的方法已应用于低分子量 (<450 Da) 和非肽类的开发，基于单位数微摩尔机制的 STEP 抑制剂，对多种酪氨酸和双特异性磷酸酶的选择性超过 20 倍。还观察到大鼠皮层神经元中显着水平的 STEP 抑制。
• Copper‐Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate Mimics
  作者：Maria V. Ivanova、Alexandre Bayle、Tatiana Besset、Thomas Poisson、Xavier Pannecoucke

  DOI：10.1002/anie.201507130

  日期：2015.11.2

  A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodology using TMSCF2PO(OEt)2, iodonium salts and a copper salt provided a straightforward manifold to reach these highly relevant products. The reaction proved to be highly functional group tolerant and proceeded under mild conditions, giving the corresponding products in

  描述了一般和有效地获得芳基，杂芳基，乙烯基和炔基二氟甲基膦酸酯的方法。使用TMSCF 2 PO（OEt）2，碘鎓盐和铜盐开发的方法为获得这些高度相关的产品提供了直接途径。该反应被证明是高度官能团耐受的，并且在温和的条件下进行，从而给出相应的产物，收率良好至优异。该方法代表了这一重要类别的氟化支架的第一个通用合成路线，众所周知，该支架为体内稳定的磷酸盐替代物。
• Synthesis and biological evaluation of α,α-difluorobenzylphosphonic acid derivatives as small molecular inhibitors of protein-tyrosine phosphatase 1B
  作者：Tsutomu Yokomatsu、Tetsuo Murano、Ikuko Umesue、Shinji Soeda、Hiroshi Shimeno、Shiroshi Shibuya

  DOI：10.1016/s0960-894x(99)00027-x

  日期：1999.2

  series of alpha,alpha-difluorobenzylphosphonic acids having a hydrophobic functional group were prepared via the Stille coupling reaction from halogenated alpha,alpha-difluorobenzylphosphonates. Evaluation of inhibitory activity toward protein tyrosine phosphatase (PTP 1B) revealed that the ethynyl, phenylethynyl and (E)-styryl groups on the benzene nuclei increased the inhibitory activity of alpha,alph

  通过Stille偶联反应，由卤化的α，α-二氟苄基膦酸酯制备了一系列具有疏水性官能团的α，α-二氟苄基膦酸。对蛋白酪氨酸磷酸酶（PTP 1B）的抑制活性的评估表明，苯核上的乙炔基，苯基乙炔基和（E）-苯乙烯基增加了α，α-二氟苄基膦酸的抑制活性。将（E）-苯乙烯基和双甲基磺酰胺官能团同时引入到α，α-二氟苄基膦酸的苯核上时，抑制活性显着提高。
• Copper-Mediated Synthesis of Aryldifluoromethylphosphonates: A Sandmeyer Approach
  作者：Alexandre Bayle、Chloé Cocaud、Cyril Nicolas、Olivier R. Martin、Thomas Poisson、Xavier Pannecoucke

  DOI：10.1002/ejoc.201500373

  日期：2015.6

  Difluoromethylated arenes are scaffolds of great interest. We report herein a mild and general method for the introduction of the CF2PO(OEt)2 moiety into arenes. The CuCF2PO(OEt)2 species, which is generated in situ from the corresponding silylated derivatives, in combination with aryl diazonium salts furnished the highly valuable aryl difluoromethylphosphonates in moderate to good yields. This represents

  二氟甲基化芳烃是非常受关注的支架。我们在此报告了一种将 CF2PO(OEt)2 部分引入芳烃的温和且通用的方法。CuCF2PO(OEt)2 物质是由相应的甲硅烷基化衍生物原位生成的，与芳基重氮盐相结合，以中等至良好的产率提供了非常有价值的二氟甲基膦酸芳基酯。这是在温和条件下引入二氟甲基膦酸酯的第一种通用方法。