2,4-二氟-3-碘吡啶 | 837364-88-2

• 物质功能分类: 医药中间体 - 杂环化合物 - 吡啶类化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2,4-二氟-3-碘吡啶
• 中文别名: 2,4-二氟-3-碘-吡啶
• 英文名称: 2,4-difluoro-3-iodopyridine
• CAS: 837364-88-2
• 化学式: C₅H₂F₂IN
• 分子量: 240.979
• InChiKey: AYKASHJPLZSRDC-UHFFFAOYSA-N

物化性质

• 熔点：
  76-78 °C(Solv: hexane (110-54-3))
• 沸点：
  225.4±35.0 °C(Predicted)
• 密度：
  2.129

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  9
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  12.9
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R22
• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

反应信息

• 作为反应物：
  描述：

  2,4-二氟-3-碘吡啶 在 lithium diisopropyl amide 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 以67%的产率得到2,4-二氟-5-碘吡啶
  参考文献：
  名称：

  Regiochemically Flexible Substitutions of Di-, Tri-, and Tetrahalopyridines:  The Trialkylsilyl Trick

  摘要：

  2,4-Difluoropyridine, 2,4-dichloropyridine, 2,4,6-trifluoropyridine, 2,4,6-trichloropyridine and 2,3,4,6-tetrafluoropyridine react with standard nucleophiles exclusively at the 4-position under halogen displacement. However, the regioselectivity can be completely reversed if a trialkylsilyl group is introduced in the 5-position of the 2,4-dihalopyridines or in the 3-position of the 2,4,6-trihalopyridines or 2,3,4,6-tetrahalopyridine. Then only the halogen most remote from the bulky silyl unit (at the 2-position in the case of the 2,4-halopyridines, at the 6-position with the other substrates) gets involved in the exchange process. After removal of the silyl protective group the nucleophile is invariably found to occupy the nitrogen-neighboring position.

  DOI：

  10.1021/jo047962z
• 作为产物：
  描述：

  2,4,6-三氟吡啶 在 正丁基锂 、 四丁基氟化铵 、 一水合肼 、 copper(II) sulfate 、 二异丙胺 作用下， 以 四氢呋喃 、 正己烷 、 水 为溶剂， 反应 11.17h， 生成 2,4-二氟-3-碘吡啶
  参考文献：
  名称：

  Regiochemically Flexible Substitutions of Di-, Tri-, and Tetrahalopyridines:  The Trialkylsilyl Trick

  摘要：

  2,4-Difluoropyridine, 2,4-dichloropyridine, 2,4,6-trifluoropyridine, 2,4,6-trichloropyridine and 2,3,4,6-tetrafluoropyridine react with standard nucleophiles exclusively at the 4-position under halogen displacement. However, the regioselectivity can be completely reversed if a trialkylsilyl group is introduced in the 5-position of the 2,4-dihalopyridines or in the 3-position of the 2,4,6-trihalopyridines or 2,3,4,6-tetrahalopyridine. Then only the halogen most remote from the bulky silyl unit (at the 2-position in the case of the 2,4-halopyridines, at the 6-position with the other substrates) gets involved in the exchange process. After removal of the silyl protective group the nucleophile is invariably found to occupy the nitrogen-neighboring position.

  DOI：

  10.1021/jo047962z

文献信息

• SPIRO-TETRACYCLIC RING COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE
  申请人：CHENG Yuan

  公开号：US20110251190A1

  公开（公告）日：2011-10-13

  The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and other related conditions. In one embodiment, the compounds have a general Formula I wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 2 , R 7 , X and Y of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I.

  本发明涉及一类新的化合物，可用于调节β-分泌酶酶活性和治疗β-分泌酶介导的疾病，包括阿尔茨海默病（AD）和其他相关疾病。在一种实施例中，所述化合物具有一般的I式，其中I式中的A1，A2，A3，A4，A5，A6，R2，R7，X和Y已在此定义。本发明还包括使用这些化合物于制备药物组合物，用于治疗与β-分泌酶蛋白活性相关的疾病和症状，包括例如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他与大脑斑块形成和/或沉积相关和/或由此引起的中枢神经系统疾病。本发明还包括I式的进一步实施例、中间体和制备I式化合物的有用工艺。
• Spiro-tetracyclic ring compounds as beta-secretase modulators and methods of use
  申请人：Cheng Yuan

  公开号：US08883782B2

  公开（公告）日：2014-11-11

  The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and other related conditions. In one embodiment, the compounds have a general Formula I wherein A1, A2, A3, A4, A5, A6, R2, R7, X and Y of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I.

  本发明涉及一类新的化合物，可用于调节β-分泌酶酶活性和治疗β-分泌酶介导的疾病，包括阿尔茨海默病（AD）和其他相关疾病。 在一种实施例中，化合物具有一般式I，其中式I中的A1，A2，A3，A4，A5，A6，R2，R7，X和Y的定义如本文所述。 本发明还包括将这些化合物用于制备药物组合物，用于治疗与β-分泌酶蛋白活性相关的疾病和症状，包括例如阿尔茨海默病、认知缺陷、认知障碍、精神分裂症和其他与大脑斑块的形成和/或沉积相关和/或由此引起的中枢神经系统疾病。本发明还包括式I的进一步实施例、中间体和制备式I化合物的有用工艺。
• Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
  作者：Oleg Epstein、Marian C. Bryan、Alan C. Cheng、Katayoun Derakhchan、Thomas A. Dineen、Dean Hickman、Zihao Hua、Jason B. Human、Charles Kreiman、Isaac E. Marx、Matthew M. Weiss、Robert C. Wahl、Paul H. Wen、Douglas A. Whittington、Stephen Wood、Xiao Mei Zheng、Robert T. Fremeau、Ryan D. White、Vinod F. Patel

  DOI：10.1021/jm501266w

  日期：2014.12.11

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.
• Rerouting Nucleophilic Substitution from the 4-Position to the 2- or 6-Position of 2,4-Dihalopyridines and 2,4,6-Trihalopyridines: The Solution to a Long-Standing Problem
  作者：Manfred Schlosser、Thierry Rausis、Carla Bobbio

  DOI：10.1021/ol047826g

  日期：2005.1.1

  2,4-Difluoro-, 2,4,6-trifluoro-, and 2,3,4,6-tetrafluoropyridine undergo nucleophilic substitution preferentially if not exclusively at the 4-position. However, after the introduction of a trialkylsilyl group at C-3 or C-5, the halogen at the 6-(2-)position is displaced selectively. This synthetically valuable regiocontrol can also be realized with other halopyridines such as 2,4-dichloro- and 2,4,6-trichloropyridine.
• Regiochemically Flexible Substitutions of Di-, Tri-, and Tetrahalopyridines:  The Trialkylsilyl Trick
  作者：Manfred Schlosser、Carla Bobbio、Thierry Rausis

  DOI：10.1021/jo047962z

  日期：2005.4.1

  2,4-Difluoropyridine, 2,4-dichloropyridine, 2,4,6-trifluoropyridine, 2,4,6-trichloropyridine and 2,3,4,6-tetrafluoropyridine react with standard nucleophiles exclusively at the 4-position under halogen displacement. However, the regioselectivity can be completely reversed if a trialkylsilyl group is introduced in the 5-position of the 2,4-dihalopyridines or in the 3-position of the 2,4,6-trihalopyridines or 2,3,4,6-tetrahalopyridine. Then only the halogen most remote from the bulky silyl unit (at the 2-position in the case of the 2,4-halopyridines, at the 6-position with the other substrates) gets involved in the exchange process. After removal of the silyl protective group the nucleophile is invariably found to occupy the nitrogen-neighboring position.