4-fluoro-2-piperidin-1-ylbenzoic acid | 865471-09-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-fluoro-2-piperidin-1-ylbenzoic acid
• 英文别名: 4-fluoro-2-(1-piperidinyl)benzoic acid
• CAS: 865471-09-6
• 化学式: C₁₂H₁₄FNO₂
• 分子量: 223.247
• InChiKey: BJRXDURFJAVCBV-UHFFFAOYSA-N

物化性质

• 熔点：
  172-174 °C(Solv: ethanol (64-17-5); water (7732-18-5))
• 沸点：
  378.3±32.0 °C(Predicted)
• 密度：
  1.251±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-fluoro-2-piperidin-1-ylbenzoic acid 、 (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以32%的产率得到(S)-4-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-2-piperidin-1-yl-benzamide
  参考文献：
  名称：

  1,4-Benzodiazepines as Inhibitors of Respiratory Syncytial Virus. The Identification of a Clinical Candidate

  摘要：

  Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.

  DOI：

  10.1021/jm060747l
• 作为产物：
  描述：

  哌啶 、 2,4-二氟苯甲酸 在 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 24.0h， 生成 4-fluoro-2-piperidin-1-ylbenzoic acid
  参考文献：
  名称：

  2,4-二卤代芳族化合物在S N Ar取代中的邻位选择性。与哌啶反应

  摘要：

  与卤素的芳族化合物的一个全貌定位两者邻位和对位，以活化基团S中进行了研究Ñ用哌啶的Ar反应。区域选择性随取代基和溶剂的极性而变化。许多活化基团表现出对邻位取代的总体偏向，这导致非极性溶剂具有很高的邻位选择性。极性更大的溶剂使产物比率均匀地向对位取代转移。提出的证据表明，通过氢键作为许多邻位的驱动因素，可以进行配位。观察到的选择性。所提供的数据表明，对于该反应类型，几种常见的活化基团的邻位导向能力具有一般性和综合实用性。

  DOI：

  10.1016/j.tetlet.2009.11.087

文献信息

• [EN] PHARMACEUTICAL COMPOSITION COMPRISING A BENZODIAZEPINE DERIVATIVE AND A INHIBITOR OF THE RSV FUSION PROTEIN<br/>[FR] COMPOSITION PHARMACEUTIQUE COMPRENANT UN DERIVE DE BENZODIAZEPINE ET UN INHIBITEUR DE LA PROTEINE DE FUSION DU VIRUS RESPIRATOIRE SYNCYTIAL
  申请人：ARROW THERAPEUTICS LTD

  公开号：WO2005089771A1

  公开（公告）日：2005-09-29

  A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and: (a) an inhibitor of the RSV fusion protein; and (b) a benzodiazepine derivative capable of inhibiting RSV replication is found to be highly active against RSV.

  一种包含药用可接受载体或稀释剂以及：(a) RSV融合蛋白抑制剂；和(b) 能够抑制RSV复制的苯二氮䓬类衍生物的药物组合物被发现对RSV具有很高的活性。
• Ultrasound-Promoted Reaction of 2-Chlorobenzoic Acids and Aliphatic Amines
  作者：Maite L. Docampo、Rolando F. Pellón、Ana Estevez-Braun、Angel G. Ravelo

  DOI：10.1002/ejoc.200700281

  日期：2007.8

  An improvement to the use of DMF as a solvent for the condensation of 2-chlorobenzoic acids with aliphatic primary or secondary amines was described. A number of alkylaminobenzoic acids and dialkylaminobenzoic acids were synthesized in acceptable-to-good yield. The advantages of this procedure include readily available substrates, the use of an inexpensive copper powder without taking any precautions

  描述了使用 DMF 作为 2-氯苯甲酸与脂肪族伯胺或仲胺缩合溶剂的改进。许多烷基氨基苯甲酸和二烷基氨基苯甲酸以可接受到良好的产率合成。该程序的优点包括易于获得的基材、使用廉价的铜粉而无需采取任何预防措施在温和条件下排除水分，并且易于实验。此外，这种冷凝也可以在非经典条件下通过在室温下使用超声波照射来实现。我们证明了使用 DMF 作为溶剂，超声促进 2-氯苯甲酸与脂肪胺的缩合，特别是在仲胺的情况下，可以提供高产率的产物并将反应时间缩短到几分钟。
• Pharmaceutical composition comprising a benzodiazepine derivative and an inhibitor of the rsv fusion protein
  申请人：Powell Kenneth

  公开号：US20070185096A1

  公开（公告）日：2007-08-09

  A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and: (a) an inhibitor of the RSV fusion protein; and (b) a benzodiazepine derivative capable of inhibiting RSV replication is found to be highly active against RSV.

  一种制药组合物，包括一种药用可接受载体或稀释剂和：(a)一种RSV融合蛋白的抑制剂；以及(b)一种苯二氮平衍生物，能够抑制RSV复制，发现对RSV具有高度活性。
• Benzodiazepines for Treating or Preventing Rsv Infection
  申请人：Dowdell Verity

  公开号：US20080139536A1

  公开（公告）日：2008-06-12

  Use of a compound which is (a) a benzodiazepine derivative of the formula (I) or an N-oxide thereof or (b) a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing an RSV infection wherein: —R 1 represents C 1-6 alkyl, aryl or heteroaryl; —R 2 represents hydrogen or C 1-6 alkyl; each R 3 is the same or different and represents halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, vitro, cyano, —CO 2 R′, —CONR′R″, —NH—CO—R′, —S(O)R′, —S(O) 2 R′, —NH—S(O) 2 R′, —S(O)NR′R″ or —S(O) 2 NR′R″, wherein each R′ and R″ is the same or different and represents hydrogen or C 1-6 alkyl; n is from O to 3; R 4 represents hydrogen or C 1-6 alkyl; X represents —CO—, —CO—NR′—, —S(O)— or —S(O) 2 —, wherein R′ is hydrogen or a C 1 -C 6 alkyl group; and R 5 represents a heteroaryl or heterocyclyl group which is substituted by a C1C6 hydroxyalkyl group or a —(C 1 -C 4 alkyl)-X 1 —(C 1 -C 4 alkyl)-X 2 —(C 1 -C 4 alkyl} group, wherein X 1 represents -0-, —S— or —NR′—, wherein R′ represents H or a C 1 -C 4 alkyl group and X 2 represents —CO—, —SO— or —SO 2 —, or R 5 represents -A 1 -Y-A 2 , wherein: -A 1 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group; 25 —Y represents a direct bond or a C 1 -C 4 alkylene, —SO 2 —, —CO—, -0-, —S— or —NR′-moiety, wherein R′ is a C 1 -C 6 alkyl group; and -A 2 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group.

  使用化合物（a）式（I）的苯二氮平衍生物或其N-氧化物，或（b）其药学上可接受的盐，制备用于治疗或预防RSV感染的药物，其中：-R1代表C1-6烷基，芳基或杂环芳基；-R2代表氢或C1-6烷基；每个R3相同或不同，代表卤素，羟基，C1-6烷基，C1-6烷氧基，C1-6烷基硫基，C1-6卤代烷基，C1-6卤代烷氧基，氨基，单（C1-6烷基）氨基，二（C1-6烷基）氨基，体外，氰基，-CO2R'，-CONR'R"，-NH-CO-R'，-S（O）R'，-S（O）2R'，-NH-S（O）2R'，-S（O）NR'R"或-S（O）2NR'R"，其中每个R'和R"相同或不同，代表氢或C1-6烷基；n为0至3；R4代表氢或C1-6烷基；X代表-CO-，-CO-NR'-，-S（O）-或-S（O）2-，其中R'代表氢或C1-C6烷基；R5代表被C1C6羟基烷基或-(C1-C4烷基)-X1-(C1-C4烷基)-X2-(C1-C4烷基)基取代的杂环芳基或杂环烷基基团，其中X1代表-0-，-S-或-NR'-，其中R'代表H或C1-C4烷基，X2代表-CO-，-SO-或-SO2-，或R5代表-A1-Y-A2，其中：-A1是芳基，杂环芳基，碳环芳基或杂环烷基基团；-Y代表直接键或C1-C4烷基，-SO2-，-CO-，-0-，-S-或-NR'-基，其中R'是C1-C6烷基基团；-A2是芳基，杂环芳基，碳环芳基或杂环烷基基团。
• PHARMACEUTICAL COMPOSITION COMPRISING A BENZODIAZEPINE DERIVATIVE AND A INHIBITOR OF THE RSV FUSION PROTEIN
  申请人：Arrow Therapeutics Limited

  公开号：EP1727551A1

  公开（公告）日：2006-12-06