2-fluoroethyl 4-nitrophenyl methylphosphonate | 1428268-01-2

• 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: 2-fluoroethyl 4-nitrophenyl methylphosphonate
• 英文别名: 2-Fluoroethyl 4-Nitrophenyl Methylphosphonate；1-[2-fluoroethoxy(methyl)phosphoryl]oxy-4-nitrobenzene
• CAS: 1428268-01-2
• 化学式: C₉H₁₁FNO₅P
• 分子量: 263.162
• InChiKey: BBDQLOUKNUVPFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  81.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-fluoroethyl 4-nitrophenyl methylphosphonate 在 sodium hydroxide 作用下， 以 乙腈 为溶剂， 反应 13.3h， 生成 对硝基苯酚
  参考文献：
  名称：

  新型有机磷酸酯配体O-(2-氟乙基)-O-(对硝基苯基)甲基膦酸酯：合成、水解稳定性以及胆碱酯酶抑制和再激活的分析

  摘要：

  有机磷酸酯O -(2-氟乙基) -O -(对硝基苯基)甲基膦酸酯1是同类首创的氟 18 放射性标记有机磷酸酯乙酰胆碱酯酶 (AChE) 抑制剂 ([ 18 F] 1 )。在大鼠中，[ 18 F] 1位于大脑和其他组织中富含 AChE 的区域，在那里它可能以 (CH 3 )( 18 FCH 2 CH 2 O)P(O)-AChE 加合物 (ChE- 1 ) 的形式存在。该加合物的表征将定义抑制机制以及随后的抑制后途径和再激活率。为了验证该加合物，测定了1的稳定性（水解）和 ChE- 1 的再激活率。 1的碱水解产生对硝基苯酚和 (CH 3 ) (FCH 2 CH 2 O)P(O)OH，在 pH 7.4 (PBS) 下伪一级速率常数 ( k obsd ) 为 3.25 × 10 –4 min –1 ( t 1/2 = 35.5 h) 在 25 °C 和 8.70 × 10 –4 min –1 (

  DOI：

  10.1021/acs.chemrestox.6b00160
• 作为产物：
  描述：

  在 air 作用下， 反应 0.08h， 以148 mg的产率得到2-fluoroethyl 4-nitrophenyl methylphosphonate
  参考文献：
  名称：

  新型有机磷酸酯配体O-(2-氟乙基)-O-(对硝基苯基)甲基膦酸酯：合成、水解稳定性以及胆碱酯酶抑制和再激活的分析

  摘要：

  有机磷酸酯O -(2-氟乙基) -O -(对硝基苯基)甲基膦酸酯1是同类首创的氟 18 放射性标记有机磷酸酯乙酰胆碱酯酶 (AChE) 抑制剂 ([ 18 F] 1 )。在大鼠中，[ 18 F] 1位于大脑和其他组织中富含 AChE 的区域，在那里它可能以 (CH 3 )( 18 FCH 2 CH 2 O)P(O)-AChE 加合物 (ChE- 1 ) 的形式存在。该加合物的表征将定义抑制机制以及随后的抑制后途径和再激活率。为了验证该加合物，测定了1的稳定性（水解）和 ChE- 1 的再激活率。 1的碱水解产生对硝基苯酚和 (CH 3 ) (FCH 2 CH 2 O)P(O)OH，在 pH 7.4 (PBS) 下伪一级速率常数 ( k obsd ) 为 3.25 × 10 –4 min –1 ( t 1/2 = 35.5 h) 在 25 °C 和 8.70 × 10 –4 min –1 (

  DOI：

  10.1021/acs.chemrestox.6b00160

文献信息

• Cholinesterase Inhibitors
  申请人：Thompson Charles M.

  公开号：US20130343994A1

  公开（公告）日：2013-12-26

  The invention provides compounds that inhibit cholinesterases, such as acetylcholinesterase and butyrylcholinesterase. Such compounds are useful to prevent or treat exposure of a patient (e.g., a human) to an organophosphoric nerve agent (e.g., sarin and VX) or to treat a patient suffering from a neurodegenerative disorder such as Alzheimer's Disease or Lewy Body Dementia. The compounds are further useful as diagnostic tools for use in medical or research radiography (e.g., positron emission tomography) when synthesized with a radionuclide (e.g., [18F]. Synthetic schemes to produce such compounds are also provided.

  该发明提供了抑制胆碱酯酶的化合物，例如乙酰胆碱酯酶和丁酰胆碱酯酶。这些化合物可用于预防或治疗患者（例如人类）暴露于有机磷神经毒剂（例如沙林和VX）或治疗患有神经退行性疾病（如阿尔茨海默病或路易体痴呆症）的患者。这些化合物还可作为诊断工具用于医学或研究放射学（例如正电子发射断层扫描）时，当与放射性核素（例如[18F]）合成时。还提供了用于合成这些化合物的合成方案。
• An improved radiosynthesis of O-(2-[¹⁸ F]fluoroethyl)-O-(<i>p</i> -nitrophenyl)methylphosphonate: A first-in-class cholinesterase PET tracer
  作者：Kiel D. Neumann、Charles M. Thompson、Joseph E. Blecha、John M. Gerdes、Henry F. VanBrocklin

  DOI：10.1002/jlcr.3511

  日期：2017.6.15

  cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [18 F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [18 F]1 tracer synthesis was slow even with microwave acceleration

  O-(2-氟乙基)-O-(对硝基苯基)甲基膦酸酯 1 是一种有机磷酸酯胆碱酯酶抑制剂，可在酶活性位点产生膦酰丝氨酸共价加合物，阻断体内胆碱酯酶活性。相应的放射性标记的 O-(2-[18 F] 氟乙基)-O-(对硝基苯基) 甲基膦酸酯，[18 F]1，先前已制备，并被发现是一种极好的正电子发射断层扫描成像示踪剂，用于评估胆碱酯酶活的大脑、外周组织和血液。然而，之前报道的 [18 F]1 示踪剂合成即使在微波加速下也很慢，需要高效液相色谱法将示踪剂与杂质分离，并且放射化学产率不太理想。在本文中，我们报告了一种新的合成方法来规避这些缺点，该方法依赖于双-(O,Op-硝基苯基) 甲基膦酸酯，2，在 DBU 存在下与 2-氟乙醇的简易反应性。冷合成被成功地转化为提供更稳健的放射合成。使用这种新策略，所需示踪剂 [18 F]1 以 8 ± 2% (n = 7) 的非衰变校正放射化学产率获得，> 99%
• Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates
  作者：S. Kaleem Ahmed、Yamina Belabassi、Lakshmi Sankaranarayanan、Chih-Kai Chao、John M. Gerdes、Charles M. Thompson

  DOI：10.1016/j.bmcl.2013.02.010

  日期：2013.4

  Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of beta-substituted ethoxy and gamma-substituted propoxy phosphonoesters of the type p-NO2PhO-P(X)(R)[(O(CH2)(n)Z] (R = Me, Et; X = O, S; n = 2, 3; Z = halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The beta-fluoroethoxy methylphosphonate analog (R = Me, Z = F, n = 2) was the most potent anti-AChE compound comparable (k(i); similar to 6 x 10(6) M-1 min(-1)) to paraoxon against EEAChE. Analogs with Z = Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R = Me) were more potent than the corresponding ethyl phosphonates (R = Et). As expected, analogs with a thionate linkage (P=S) were poor inhibitors of the AChEs. (C) 2013 Elsevier Ltd. All rights reserved.
• The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE
  作者：Chih-Kai Chao、Narayanaganesh Balasubramanian、John M. Gerdes、Charles M. Thompson

  DOI：10.1016/j.cbi.2018.06.019

  日期：2018.8

  In this study, the mechanisms of HuAChE and HuBChE inhibition by Me-P(0) (OPNP) (OR) [PNP = p-ni-trophenyl; R = CH2CH3, CH2CH2F, OCH(CH3)(2), OCH(CH3) (CH2F)] representing surrogates and fluoro-surrogates of VX and sarin were studied by in vitro kinetics and mass spectrometry. The in vitro measures showed that the VX- and fluoro-VX surrogates were relatively strong inhibitors of HuAChE and HuBChE (k(i) similar to 10(5)- 10(6) M-1 min(-1)) and underwent spontaneous and 2-PAM-mediated reactivation within 30 min. The sarin surrogates were weaker inhibitors of HuAChE and HuBChE (k(i) similar to 10(4) -10(5) M-1 min(-1)), and in general did not undergo spontaneous reactivation, although HuAChE adducts were partially reactivatable at 18 h using 2-PAM. The mechanism of HuAChE and HuBChE inhibition by the surrogates was determined by Q-TOF and MALDI-TOF mass spectral analyses. The surrogate-adducted proteins were trypsin digested and the active site-containing peptide bearing the OP-modified serine identified by Q-TOF as triply- and quadruply-charged ions representing the respective increase in mass of the attached OP moiety. Correspondingly, monoisotopic ions of the Cryptic peptides representing the mass increase of the OP-adducted peptide was identified by MALDI-TOF. The mass spectrometry analyses validated the identity of the OP moiety attached to HuAChE or HuBChE as MeP(O) (OR)O-serine peptides (loss of the PNP leaving group) via mechanisms consistent with those found with chemical warfare agents. MALDI-TOF MS analyses of the VX-modified peptides versus time showed a steady reduction in adduct versus parent peptide (reactivation), whereas the sarin-surrogate-modified peptides remained largely intact over the course of the experiment (24 h). Overall, the presence of a fluorine atom on the surrogate modestly altered the rate constants of inhibition and reactivation, however, the mechanism of inhibition (ejection of PNP group) did not change.