2-fluoro-4-biphenylacetonitrile

• 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-fluoro-4-biphenylacetonitrile
• 英文别名: 2-Fluorobiphenyl-4-acetonitrile；2-(3-fluoro-4-phenylphenyl)acetonitrile
• 化学式: C₁₄H₁₀FN
• 分子量: 211.239
• InChiKey: FSUMNZMCADOFGQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  23.8
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-fluoro-4-biphenylacetonitrile 在 二甲胺基甲硼烷 、 sodium hydroxide 、 sodium t-butanolate 作用下， 以 乙醇 、 水 为溶剂， 反应 5.0h， 生成 氟比洛芬
  参考文献：
  名称：

  胺-硼烷/ N，N-二甲基甲酰胺系统作为甲基源的选择性α-单甲基化

  摘要：

  开发了一种新的实用的α-单甲基化策略，该方法使用胺-硼烷/ N，N-二甲基甲酰胺（R 3 N-BH 3 / DMF）系统作为甲基来源。已发现该方案对芳基乙腈和芳基乙酰胺的α-单甲基化有效。机理研究表明，DMF的甲酰基传递了碳原子和甲基的一个氢原子，而R 3 N-BH 3则贡献了其余的两个氢原子。如此独特的反应路径使得使用Me 2 NH-BH 3 / d可控制地组装CDH 2，CD 2 H和CD 3单元。7 ‐ DMF ，Me 3 N‐BD 3 / DMF和Me 3 N‐BD 3 / d 7 ‐ DMF系统。证实了该方法在抗炎药氟比洛芬及其各种氘标记衍生物的简便合成中的进一步应用。

  DOI：

  10.1002/anie.201804794
• 作为产物：
  描述：

  4-溴-3-氟甲苯 在 N-溴代丁二酰亚胺(NBS) 、 四丁基溴化铵 、 palladium diacetate 、 sodium carbonate 、 过氧化苯甲酰 作用下， 以 四氯化碳 、 乙醇 、 水 为溶剂， 反应 3.0h， 生成 2-fluoro-4-biphenylacetonitrile
  参考文献：
  名称：

  Inhibition of Amyloidogenesis by Nonsteroidal Anti-inflammatory Drugs and Their Hybrid Nitrates

  摘要：

  Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (I) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to I, however, esterification led to elevated A beta(1-42) levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated A beta(1-42) at higher concentration, SALA activity was observed at low concentrations (<= 1 mu M): both A beta(1-42) and the ratio of A beta(1-42)/A beta(1-40) were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.

  DOI：

  10.1021/jm101450p

文献信息

• 一种用新型的碳酸二甲酯甲基化催化剂在制备α-甲基苯乙酸中的应用
  申请人：江苏瑞科医药科技有限公司

  公开号：CN110872237A

  公开（公告）日：2020-03-10

  本发明涉及医药合成领域，具体涉及一种新型的碳酸二甲酯甲基化催化剂，在制备α‑甲基苯乙酸式IV中的应用。该制备方法以苯乙腈式I为起始原料，在催化剂作用下经甲基化、脱羧和水解反应，使用的催化剂为碱金属或碱土金属阳离子与弱酸根离子、卤素离子或氰根离子的任意组合的盐，或使用的催化剂为季胺盐，制备目标产物α‑甲基苯乙酸式IV。其中以醋酸钾、溴化钾等无机盐为代表的高效低廉的催化剂，98％以上的转化率实现单甲基化产物，工业化放大生产适用性强，实现催化剂的无限直接套用。
• Compositions and methods of treating cell proliferation disorders
  申请人：Hangauer G. David

  公开号：US20060160800A1

  公开（公告）日：2006-07-20

  The invention relates to compounds and methods for treating cell proliferation disorders.

  这项发明涉及化合物和治疗细胞增殖紊乱的方法。
• New Flurbiprofen Derivatives: Synthesis, Membrane Affinity and Evaluation of in Vitro Effect on β-Amyloid Levels
  作者：Piera Sozio、Lisa Marinelli、Ivana Cacciatore、Antonella Fontana、Hasan Türkez、Gianfabio Giorgioni、Dario Ambrosini、Francesco Barbato、Lucia Grumetto、Stephanie Pacella、Amelia Cataldi、Antonio Di Stefano

  DOI：10.3390/molecules180910747

  日期：——

  Alzheimer’s disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate γ-secretase, reducing β amyloid (Aβ) levels, have been considered as potential therapeutics for AD. Among these the (R)-enantiomer of flurbiprofen (FLU) seems to be very promising, but it shows low brain penetration. In this study, in order to improve the properties of FLU against Alzheimer’s pathogenesis we synthesized some novel FLU lipophilic analogues. Lipophilicity of the new molecules has been characterized in terms of clogP, log KC18/W and log K IAM/W values. Permeability has been determined in both gastrointestinal PAMPA (PAMPA-GI) at different pH values and in brain blood barrier PAMPA (PAMPA-BBB) models. They were also tested for their ability to inhibit in vitro γ-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce Aβ 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.

  阿尔茨海默病（AD）的特征是不可逆的、渐进性的记忆和认知丧失以及显著的神经细胞损失。目前针对阿尔茨海默病的治疗策略主要针对多种靶点，旨在逆转或预防疾病，但不幸的是，现有的治疗往往没有显著的临床益处。在过去的几十年里，抑制或调节γ-分泌酶、减少β淀粉样蛋白（Aβ）水平的化合物被认为是阿尔茨海默病的潜在治疗方案。在这些化合物中，氟比洛芬（FLU）的(R)-对映体似乎非常有前途，但其脑部渗透性较低。在本研究中，为了改善FLU在阿尔茨海默病发病机制中的作用，我们合成了一些新型的FLU脂溶性类似物。新分子的脂溶性通过clogP、log KC18/W和log K IAM/W值进行了表征。其通透性在不同pH值的胃肠道PAMPA（PAMPA-GI）和脑血屏障PAMPA（PAMPA-BBB）模型中进行了测定。它们还被测试了抑制大鼠CTXTNA2星形胶质细胞体外γ-分泌酶活性的能力。有趣的是，研究的分子显示出能够在明确的浓度依赖性方式下降低Aβ 42水平，而不影响淀粉样前体蛋白APP的水平。
• Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy
  作者：Yuan Lei、Sheng Han、Yang Yang、Christophe Pannecouque、Erik De Clercq、Chunlin Zhuang、Fen-Er Chen

  DOI：10.3390/molecules25051050

  日期：——

  The key problems of human immunodeficiency virus (HIV) therapy are the rapid emergence of drug-resistant mutant strains and significant cumulative drug toxicities. Therefore, there is an urgent demand for new anti-HIV agents with low toxicity and broad-spectrum antiviral potency. A series of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker were designed using a molecular hybridization strategy. The cell-based anti-HIV assay showed that most of the compounds exhibited moderate to good activities against wild-type HIV-1 and clinically relevant mutant strains with a more favorable toxicity, and the enzymatic assay showed they had nanomolar activity against reverse transcriptase (RT). Compound 10p exhibited the best activity against wild-type HIV-1 with an EC50 (50% HIV-1 replication inhibitory concentration) value of 0.027 µM, an acceptable CC50 (50% cytotoxic concentration) value of 36.4 µM, and selectivity index of 1361, with moderate activities against the single mutants (EC50: E138K, 0.17 µM; Y181C, 0.87 µM; K103N, 0.9 µM; L100I, 1.21 µM, respectively), and an IC50 value of 0.059 µM against the RT enzyme, which was six-fold higher than nevirapine (NVP). The preliminary structure–activity relationship (SAR) of these new compounds was concluded. The molecular modeling predicted the binding modes of the new compounds with RT, providing molecular insight for further drug design.

  人类免疫缺陷病毒（HIV）治疗的关键问题是药物耐药突变株的快速出现和显著的累积药物毒性。因此，迫切需要具有低毒性和广谱抗病毒效力的新型抗HIV药物。采用分子杂交策略设计了一系列含有氰甲基连接剂的联苯取代二芳基嘧啶化合物。细胞基抗HIV实验显示，大多数化合物对野生型HIV-1和临床相关突变株表现出中等至良好的活性，毒性更为有利，酶活性实验显示它们对逆转录酶（RT）具有纳摩尔级活性。化合物10p对野生型HIV-1表现出最佳活性，EC50（50% HIV-1复制抑制浓度）值为0.027 µM，CC50（50%细胞毒性浓度）值为36.4 µM，选择性指数为1361，对单突变株（EC50：E138K，0.17 µM；Y181C，0.87 µM；K103N，0.9 µM；L100I，1.21 µM）表现出中等活性，对RT酶的IC50值为0.059 µM，比奈韦拉平（NVP）高出六倍。总结了这些新化合物的初步结构活性关系（SAR）。分子建模预测了新化合物与RT的结合方式，为进一步药物设计提供了分子洞察。
• 一种芳基丙酸类非甾体抗炎药的合成方法
  申请人：中国科学技术大学

  公开号：CN107137387B

  公开（公告）日：2020-05-12

  本发明公开了一种芳基丙酸类非甾体抗炎药的合成方法，特征是以芳基乙腈类化合物作为底物，使用胺硼烷络合物，N,N‑二甲基甲酰胺作为溶剂，在碱性条件下，经甲基化反应，得到芳基丙腈类化合物；再在强碱性条件下水解，即得到芳基丙酸类非甾体抗炎药。本发明首次使用胺硼烷络合物和N,N‑二甲基甲酰胺共同作为作为甲基化试剂，从而完全避免了使用碘甲烷、硫酸二甲酯等传统甲基化试剂所造成的双甲基化和毒性大等问题；合成方法简便、易操作，所得芳基丙酸类非甾体抗炎药产率高、纯度高。不同于以往金属催化体系，本发明方法采用的是非金属体系，从而避免了过渡金属的使用，对于避免合成药物中的金属残留提供了一种新的方法。