tetraethyl [(4-fluorophenylamino)methyl]-1,1-bisphosphonate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: tetraethyl [(4-fluorophenylamino)methyl]-1,1-bisphosphonate
• 英文别名: tetraethyl ((4-fluorophenylamino)methylene)bisphosphonate；tetraethyl (4-fluorophenylamino)methylenebisphosphonate；N-[bis(diethoxyphosphoryl)methyl]-4-fluoroaniline
• 化学式: C₁₅H₂₆FNO₆P₂
• 分子量: 397.32
• InChiKey: LUQWKOGFYNIFAB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  25
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  83.1
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tetraethyl [(4-fluorophenylamino)methyl]-1,1-bisphosphonate 在 三甲基溴硅烷 、 甲醇 作用下， 以 乙腈 为溶剂， 反应 24.5h， 以77%的产率得到[(4-fluorophenylamino)methyl]-1,1-bisphosphonic acid
  参考文献：
  名称：

  Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors

  摘要：

  The complexity of matrix metalloproteinase inhibitors (MMPIs) design derives from the difficulty in carefully addressing their inhibitory activity towards the MMP isoforms involved in many pathological conditions. In particular, specific metalloproteinases, such as MMP-2 and MMP-9, are key regulators of the 'vicious cycle' occurring between tumor metastases growth and bone remodeling. In an attempt to devise new approaches to selective inhibitor derivatives, we describe novel bisphosphonate bone seeking MMP inhibitors (BP-MMPIs), capable to be selectively targeted and to overcome undesired side effects of broad spectrum MMPIs.In vitro activity (IC50 values) for each inhibitor was determined against MMP-2, -8, -9 and -14, because of their relevant role in skeletal development and renewal. The results show that BP-MMPIs reached IC50 values of enzymatic inhibition in the low micromolar range. Computational studies, used to rationalize some trends in the observed inhibitory profiles, suggest a possible differential binding mode in MMP-2 that explains the selective inhibition of this isoform.In addition, survival assay was conducted on J774 cell line, a well known model system used to evaluate the structure-activity relationship of BPs for inhibiting bone resorption. The resulting data, confirming the specific activity of BP-MMPIs, and their additional proved propensity to bind hydroxyapatite powder in vitro, suggest a potential use of BP-MMPIs in skeletal malignancies. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.08.054
• 作为产物：
  描述：

  亚磷酸二乙酯 、 4-氟苯胺 在 ytterbium perfluorooctanoate 、 原甲酸三乙酯 作用下， 反应 0.3h， 以90%的产率得到tetraethyl [(4-fluorophenylamino)methyl]-1,1-bisphosphonate
  参考文献：
  名称：

  A facile synthesis of aminomethylene bisphosphonates catalyzed by ytterbium perfluorooctanoate under ionic liquid condition

  摘要：

  Three-component reactions of amines, triethylorthoformate and diethyl phosphite are efficiently catalyzed by ytterbium perfiuorooctanoate [Yb(PFO)(3)] in 1-butyl-3-methylimidazolium chloride ([bmim][Cl]) ionic liquid, giving the corresponding aminomethylene bisphosphonates in good yields. The catalyst can be recovered and reused for several times without any significant loss of activity. (C) 2011 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.jfluchem.2011.10.005

文献信息

• Synthesis of new functionalized aryl and pyridyl aminomethylenebisphosphonic acids and their derivatives via silicon-assisted methodology
  作者：Andrey A. Prishchenko、Roman S. Alekseyev、Mikhail V. Livantsov、Olga P. Novikova、Ludmila I. Livantsova、Valery S. Petrosyan

  DOI：10.1016/j.jorganchem.2020.121177

  日期：2020.4

  The new convenient synthesis of functionalized aryl and pyridyl aminomethylenebisphosphonic acids and their derivatives has been developed via silicon-assisted methodology. New functionalized aminomethylenebisphosphonic acids containing pyridines moieties were obtained using unique reaction of tris(trimethylsilyl) phosphite with N-formyl aminopyridines and trimethylsilyl triflate as a catalyst under

  通过硅辅助方法已经开发了新的方便的合成官能化的芳基和吡啶基氨基亚甲基双膦酸及其衍生物的方法。利用亚磷酸三（三甲基甲硅烷基）酯与N的独特反应，获得了含有吡啶部分的新功能化氨基亚甲基双膦酸-甲酰基氨基吡啶和三氟甲磺酸三甲基甲硅烷基酯在温和条件下作为催化剂。中间体–形成的四（三甲基甲硅烷基）氨基亚甲基双膦酸酯通过用过量甲醇进一步处理而转化为目标酸。相反，在氯化锌催化剂的存在下，在加热（130℃）下，将四种组分的混合物（亚磷酸二乙基三甲基甲硅烷基酯，原甲酸三乙基酯，芳基或吡啶基胺和亚磷酸二乙基酯）合成相应的四乙基氨基亚甲基双膦酸酯。提出并详细讨论了目标物质形成的催化方案。
• Facile Synthesis, Antioxidant and Antimicrobial Activity of Amino Methylene Bisphosphonates
  作者：Uma Maheswara Rao Kunda、Satheesh Krishna Balam、Bakthavatchala Reddy Nemallapudi、Syama Sundar Chereddy、Sandip Kumar Nayak、Suresh Reddy Cirandur

  DOI：10.1248/cpb.60.104

  日期：——

  A green and efficient preparation method for the amino bisphosphonates is accomplished by simple mixing and stirring of diethylphosphite, triethylorthoformate and various amines in the presence of amberlyst-15 as catalyst at room temperature under solvent free conditions. The title compounds are characterized by IR, 1H-, 13C-, 31P-NMR and mass spectra, also studied their antimicrobial and antioxidant activity.

  在室温无溶剂条件下，以琥珀酸酯-15 为催化剂，通过简单混合和搅拌亚磷酸二乙酯、正甲酸三乙酯和各种胺，实现了一种绿色高效的氨基双膦酸盐制备方法。通过红外光谱、1H-、13C-、31P-NMR 和质谱对标题化合物进行了表征，并对其抗菌和抗氧化活性进行了研究。
• Di-n-butyl ammonium chlorosulfonate as a highly efficient and recyclable ionic liquid for the synthesis of N-containing bisphosphonates
  作者：MudumalaVeeranarayana Reddy、Reddi Mohan Naidu Kalla、Lee Sang Dong、Yeon Tae Jeong

  DOI：10.1016/j.catcom.2014.12.021

  日期：2015.2

  The preparation and description of a novel secondary amine ionic liquid, di-n-butyl ammonium chlorosulfonate, is described. The di-n-butyl ammonium ionic liquid (DBA IL) was characterized by FT-IR, elemental analysis, NMR spectroscopies, and wide-angle X-ray scattering techniques, as well as thermogravimetric analysis. The DBA IL functions as an efficient, environmentally benign, and recyclable catalyst with short reaction times and high catalytic activity for the synthesis of a variety of N-containing bisphosphonates in high yields. Another merit of this ionic liquid shown that the purification of products by non-chromatographic method with good to excellent yields of the desired products. (C) 2014 Elsevier B.V. All rights reserved.
• ——
  作者：V. I. Krutikov、A. V. Erkin、P. A. Pautov、M. M. Zolotukhina

  DOI：10.1023/a:1024775501781

  日期：——

  A series of substituted aminomethylenebisphosphonates is prepared by reaction of dialkyl hydrogen phosphites with triethyl orthoformate and corresponding heteryl- or arylamine. The determining factor in the formation of the target products is appearance of an intermediate associate between the ortho ester and amine. The rate and selectivity of the process can be increased by using a nonpolar solvent to stabilize the transition state of the reaction. Crown ether catalysis increases the selectivity of the process by 10-20%. The synthesized aminomethylenebisphosphonates whose structure was established by NMR spectroscopy exhibit a moderate antibacterial and anticholinesterase activity.
• Arylamino methylene bisphosphonate derivatives as bone seeking matrix metalloproteinase inhibitors
  作者：Marilena Tauro、Antonio Laghezza、Fulvio Loiodice、Mariangela Agamennone、Cristina Campestre、Paolo Tortorella

  DOI：10.1016/j.bmc.2013.08.054

  日期：2013.11

  The complexity of matrix metalloproteinase inhibitors (MMPIs) design derives from the difficulty in carefully addressing their inhibitory activity towards the MMP isoforms involved in many pathological conditions. In particular, specific metalloproteinases, such as MMP-2 and MMP-9, are key regulators of the 'vicious cycle' occurring between tumor metastases growth and bone remodeling. In an attempt to devise new approaches to selective inhibitor derivatives, we describe novel bisphosphonate bone seeking MMP inhibitors (BP-MMPIs), capable to be selectively targeted and to overcome undesired side effects of broad spectrum MMPIs.In vitro activity (IC50 values) for each inhibitor was determined against MMP-2, -8, -9 and -14, because of their relevant role in skeletal development and renewal. The results show that BP-MMPIs reached IC50 values of enzymatic inhibition in the low micromolar range. Computational studies, used to rationalize some trends in the observed inhibitory profiles, suggest a possible differential binding mode in MMP-2 that explains the selective inhibition of this isoform.In addition, survival assay was conducted on J774 cell line, a well known model system used to evaluate the structure-activity relationship of BPs for inhibiting bone resorption. The resulting data, confirming the specific activity of BP-MMPIs, and their additional proved propensity to bind hydroxyapatite powder in vitro, suggest a potential use of BP-MMPIs in skeletal malignancies. (C) 2013 Elsevier Ltd. All rights reserved.