trans-methyl 2-(4-fluorophenyl)cyclopropanecarboxylate

• 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: trans-methyl 2-(4-fluorophenyl)cyclopropanecarboxylate
• 英文别名: methyl trans-2-(4-fluorophenyl)cyclopropanecarboxylate；methyl 2-(4-fluorophenyl)cyclopropane-1-carboxylate；Methyl (1S,2S)-2-(4-fluorophenyl)cyclopropane-1-carboxylate
• 化学式: C₁₁H₁₁FO₂
• 分子量: 194.206
• InChiKey: DCDIKIXTVDWWPH-ZJUUUORDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  3

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	trans-2-(4-fluorophenyl)cyclopropanecarboxylic acid	——	C10H9FO2	180.179

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	trans-2-(4-fluorophenyl)cyclopropanecarboxylic acid	——	C10H9FO2	180.179

反应信息

• 作为反应物：
  描述：

  trans-methyl 2-(4-fluorophenyl)cyclopropanecarboxylate 在 lithium aluminium tetrahydride 、 sodium hydride 、 一水合肼 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 38.5h， 生成
  参考文献：
  名称：

  Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia

  摘要：

  Triazolopyridine ethers with mGlu(2) positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10 mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10 mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mG1u(2) PAMs for the treatment of schizophrenia and merit further preclinical investigation. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.11.018
• 作为产物：
  描述：

  对氟碘苯 在 palladium diacetate 、 四丁基氯化铵 、 potassium carbonate 作用下， 以 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.5h， 生成 trans-methyl 2-(4-fluorophenyl)cyclopropanecarboxylate
  参考文献：
  名称：

  trans-2-Aryl-N,N-dipropylcyclopropylamines:  Synthesis and Interactions with 5-HT_1A Receptors

  摘要：

  Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been prepared and assayed for their ability to displace [H-3]-8-OH-DPAT from rat brain 5-HT1A receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-fluorophenyl (7h), and 2-hydroxy-5-fluorophenyl (7I) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT1A receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT1A receptor affinity. The racemic mixtures of the interesting 7j and 7I were resolved into the enantiomers; 7j and 7I exhibited a high enantiomeric 5-HT1A receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7I were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (LR,2R)-7j behaved as a partial agonist whereas (1R,2S)-7I appeared as an efficacious 5-HT1A receptor agonist, stimulating both autoreceptors and postsynaptic receptors.

  DOI：

  10.1021/jm9507136

文献信息

• Donor–Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes
  作者：Konstantin V. Potapov、Dmitry A. Denisov、Valeriia V. Glushkova、Roman A. Novikov、Yury V. Tomilov

  DOI：10.1021/acs.joc.0c02293

  日期：2020.12.4

  the presence of Lewis acids was used as a synthetic equivalent of 1,6-zwitterions. Opening of both cyclopropane rings in 2′-aryl-1,1′-bicyclopropyl-2,2-dicarboxylates (D–A bicyclopropyl, ABCDs) in the presence of GaI3 + Bu4N+GaI4– results in 5-iodo-5-arylpent-2-enylmalonates as products of HI formal 1,6-addition to the bicyclopropyl system. The use of GaCl3 or GaBr3 as a Lewis acid and terminal aryl

  通过在路易斯酸存在下结合供体基团和受体基团而活化的双环丙基体系被用作1,6-两性离子的合成等价物。在存在GaI 3 + Bu 4 N + GaI 4的情况下，在2'-芳基-1,1'-双环丙基-2,2-二羧酸酯（DA双环丙基，ABCD）中打开两个环丙烷环–产生5-碘-5-芳基戊二烯基丙二酸酯作为双环丙基系统中HI正式1，6-加成的产物。使用GaCl 3或GaBr 3作为路易斯酸，如末端的芳基或烷基乙炔作为1，6-两性离子拦截剂，可使烷基取代基生长，得到相应的无环7-氯（溴）-庚-2,6-二烯基丙二酸酯。Yb（OTf）3催化ABCD与4-苯基-1,2,4-三唑啉-3,5-二酮（PTAD）的反应也导致两个环丙烷环的打开。反应产物是四氢哒嗪衍生物-（7,9-二氧代-1,6,8-三氮杂双环[4.3.0]非-3-烯-2-基甲基）丙二酸酯-在丙二酸基团中包含一个以上的PTAD部分。
• Arylcyclopropanecarboxyl Guanidines as Novel, Potent, and Selective Inhibitors of the Sodium Hydrogen Exchanger Isoform-1
  作者：Saleem Ahmad、Lidia M. Doweyko、Sundeep Dugar、Nyeemah Grazier、Khehyong Ngu、Shung C. Wu、Kenneth J. Yost、Bang-Chi Chen、Jack Z. Gougoutas、John D. DiMarco、Shih-Jung Lan、Brian J. Gavin、Alice Y. Chen、Charles R. Dorso、Randy Serafino、Mark Kirby、Karnail S. Atwal

  DOI：10.1021/jm010100v

  日期：2001.9.1

  A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are

  合成了一系列新的芳基环丙烷羧基胍，并评估了其对钠氢交换异构体-1（NHE-1）的活性。在表达人NHE-1亚型的AP1细胞系中进行的生物学分析中，起始环丙烷3a（IC（50）= 3.5 microM）表现出与甲立哌啶相当的抑制活性（IC（50）= 3.4 microM）。通过筛选芳基和环丙基环上的取代基的作用，使用结构活性关系优化各种酰基胍对NHE-1的亲和力。已证明在苯环上引入适当的疏水基团和在环丙烷环上引入宝石二甲基基团最多可将NHE-1抑制活性提高3个数量级（化合物7f，IC（50）= 0.003 microM）。此外，宝石二甲基系列类似物似乎在大鼠中显示出改善的口服生物利用度和更长的血浆半衰期。此外，与卡立哌利德相比，苯并二氢呋喃基铅类似物1（BMS-284640）表现出的NHE-1抑制活性提高了380倍以上，并且对NHE-1的选择性提高了。
• Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors
  作者：Ting-Yueh Tsai、Tsu Hsu、Chiung-Tong Chen、Jai-Hong Cheng、Teng-Kuang Yeh、Xin Chen、Chung-Yu Huang、Chung-Nien Chang、Kai-Chia Yeh、Su-Huei Hsieh、Chia-Hui Chien、Yi-Wei Chang、Chih-Hsiang Huang、Yu-Wen Huang、Chen-Lung Huang、Ssu-Hui Wu、Min-Hsien Wang、Cheng-Tai Lu、Yu-Sheng Chao、Weir-Torn Jiaang

  DOI：10.1016/j.bmc.2009.02.020

  日期：2009.3

  DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC50 values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance

  合成了一系列反式-2-芳基-环丙胺衍生的化合物，并评估了其对DPP-IV的生物学活性。构效关系（SAR）导致发现了一系列新的DPP-IV抑制剂，其IC 50值<100 nM，对密切相关的酶DPP8，DPP-II和FAP具有优异的选择性。研究确定了一种有效的选择性DPP-IV抑制剂24b，该抑制剂具有显着抑制大鼠血浆DPP-IV活性并改善瘦小鼠和饮食诱发的肥胖小鼠对葡萄糖的耐受性的能力。
• Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia
  作者：Mendi A. Higgins、Lawrence R. Marcin、F. Christopher Zusi、Robert Gentles、Min Ding、Bradley C. Pearce、Amy Easton、Walter A. Kostich、Matthew A. Seager、Clotilde Bourin、Linda J. Bristow、Kim A. Johnson、Regina Miller、John Hogan、Valerie Whiterock、Michael Gulianello、Meredith Ferrante、Yanling Huang、Adam Hendricson、Andrew Alt、John E. Macor、Joanne J. Bronson

  DOI：10.1016/j.bmc.2016.11.018

  日期：2017.1

  Triazolopyridine ethers with mGlu(2) positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10 mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10 mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mG1u(2) PAMs for the treatment of schizophrenia and merit further preclinical investigation. (C) 2016 Elsevier Ltd. All rights reserved.
• <i>trans</i>-2-Aryl-<i>N</i>,<i>N</i>-dipropylcyclopropylamines:  Synthesis and Interactions with 5-HT_1A Receptors
  作者：Jerk Vallgårda、Ulf Appelberg、Lars-Erik Arvidsson、Stephan Hjorth、Björn E. Svensson、Uli Hacksell

  DOI：10.1021/jm9507136

  日期：1996.1.1

  Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been prepared and assayed for their ability to displace [H-3]-8-OH-DPAT from rat brain 5-HT1A receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-fluorophenyl (7h), and 2-hydroxy-5-fluorophenyl (7I) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT1A receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT1A receptor affinity. The racemic mixtures of the interesting 7j and 7I were resolved into the enantiomers; 7j and 7I exhibited a high enantiomeric 5-HT1A receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7I were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (LR,2R)-7j behaved as a partial agonist whereas (1R,2S)-7I appeared as an efficacious 5-HT1A receptor agonist, stimulating both autoreceptors and postsynaptic receptors.