N-(2-hydroxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide | 1005325-42-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(2-hydroxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide
• 英文别名: desmethyl-PBR28；N-[(2-hydroxyphenyl)methyl]-N-(4-phenoxy-3-pyridinyl)acetamide；N-[(2-hydroxyphenyl)methyl]-N-(4-phenoxypyridin-3-yl)acetamide
• CAS: 1005325-42-7
• 化学式: C₂₀H₁₈N₂O₃
• 分子量: 334.375
• InChiKey: IJYHHRVIZVDACH-UHFFFAOYSA-N

物化性质

• 熔点：
  131-133 °C (decomp)
• 沸点：
  533.5±50.0 °C(Predicted)
• 密度：
  1.266±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  62.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(2-hydroxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide 在 potassium tert-butylate 、 四丁基氟化铵 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.0h， 生成 N-(2-[18F]fluoromethoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide
  参考文献：
  名称：

  药物设计中的氟：以氟苯甲醚为例的研究

  摘要：

  苯甲醚和氟苯甲醚显示出独特的构象偏好，从对其晶体结构的调查中可以明显看出。除了改变游离配体的构象外，不同程度的氟化对理化和药代动力学性质也有很大的影响。辉瑞公司数据库中苯甲醚和氟苯甲醚匹配分子对的分析显示出有趣的趋势：1）PhOCF 3比PhOCH 3化合物的log D增加约 1 log单位；2）PhOCF 3尽管具有更高的亲脂性，但其被动渗透性却较低；和3）与PhOCH 3相比，PhOCF 3不能明显改善其代谢稳定性。来自调查的二氟苯甲醚（PhOCF2 H）取得了更好的性能平衡，与PhOCF 3相比，log D和跨细胞通透性具有明显优势 。综合评估表明，获得二氟茴香醚的途径通常比三氟茴香醚的途径更为直接。尽管用PhOCF 3代替PhOCH 3是优化ADME性能的常用策略，但我们的分析表明，PhOCF 2 H可能是更具吸引力的替代方法，建议对该基序进行更多利用。

  DOI：

  10.1002/cmdc.201402555
• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 5.0h， 以203 mg的产率得到N-(2-hydroxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide
  参考文献：
  名称：

  A novel one-pot palladium-mediated synthesis of N-[(2-hydroxyphenyl)methyl]-N-(4-phenoxy-3-pyridinyl) acetamide, the precursor to [11C]PBR28, a PET biomarker for the peripheral benzodiazepine receptor

  摘要：

  Due to an urgent need to image the peripheral benzodiazepine receptor (PBR) in living human subjects using positron emission tomography imaging, we had cause to prepare N-[(2-hydroxyphenyl)methyl]-N-(4-phenoxy-3-pyridinyl) acetamide (desmethyl-PBR28 (1)), the precursor to [C-11]PBR28. Herein, we report a new synthesis of the precursor in which palladium-mediated reduction of the nitro pyridine to the corresponding amino pyridine, and subsequent reductive amination, can be achieved with decaborane in a convenient one-pot procedure. This procedure is operationally simpler than the current alternatives and provides high quality precursor suitable for use in clinical applications. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2010.04.089

文献信息

• HPLC-free <i>in situ</i>¹⁸F-fluoromethylation of bioactive molecules by azidation and MTBD scavenging
  作者：Yingqing Lu、Ji Young Choi、Sang Eun Kim、Byung Chul Lee

  DOI：10.1039/c9cc04901k

  日期：——

  Sequential usage of azide and MTBD, which generates pure [¹⁸F]fluoromethyl tosylate and scavenges unreacted desmethyl precursors, provided an efficient HPLC-free strategy for the radio-synthesis of ¹⁸F-fluoromethylated compounds.

  使用叠氮和MTBD的顺序使用，生成纯[18F]氟甲基对甲苯磺酰基，并清除未反应的去甲基前体，为18F-氟甲基化合物的无HPLC合成提供了高效策略。
• Highlighting the versatility of the Tracerlab synthesis modules. Part 2: fully automated production of [11C]-labeled radiopharmaceuticals using a Tracerlab FXC-Pro
  作者：Xia Shao、Raphaël Hoareau、Adam C. Runkle、Louis J. M. Tluczek、Brian G. Hockley、Bradford D. Henderson、Peter J. H. Scott

  DOI：10.1002/jlcr.1937

  日期：2011.12

  Herein, we continue our series of articles showcasing the versatility of the Tracerlab FX synthesis modules by presenting straightforward, fully automated methods for preparing a range of carbon‐11 labeled radiopharmaceuticals using a Tracerlab FXC‐Pro. Strategies for production of [11C]acetate, [11C]carfentanil, [11C]choline, [11C]3‐amino‐4‐[2‐[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile ([11C]DASB)

  放射化学领域正在朝着自动合成模块的专用化方向发展，以生产临床放射药物剂量。这样的举动不仅具有许多优势，而且还给放射化学工作者带来了重新配置合成模块的挑战，以生产需要非常规放射化学同时又要保持全自动的放射性药物。在此，我们将继续介绍一系列文章，展示通过使用Tracerlab FX C-Pro制备一系列碳11标记的放射性药物的直接，全自动方法，来展示Tracerlab FX合成模块的多功能性。产生[ 11 C]乙酸盐，[ 11 C]芬太尼，[ 11 C]胆碱，[ 11C] 3-氨基-4- [2-[（（（（二（甲基）氨基）甲基]苯基]硫烷基苄腈（[ 11 C] DASB），（+）-[ 11 C]二氢萜烯嗪（[ 11 C] DTBZ） ，[ 11 C]氟马西尼（[ 11 C] FMZ），间羟基麻黄碱（[ 11 C] HED），[ 11 C]蛋氨酸，[ 11 C] PBR28，[ 11 C]匹兹堡化合物B（[
• Preclinical comparison study between [18F]fluoromethyl-PBR28 and its deuterated analog in a rat model of neuroinflammation
  作者：Byung Seok Moon、Jae Ho Jung、Hyun Soo Park、Marialessandra Contino、Nunzio Denora、Byung Chul Lee、Sang Eun Kim

  DOI：10.1016/j.bmcl.2018.07.011

  日期：2018.9

  translocator protein 18 kDa (TSPO)-targeted radioligand with enhanced in vivo stability. The comparison studies between [18F]fluoromethyl-PBR28 ([18F]1) and its deuterate analog ([18F]1-d2) were investigated in terms of in vitro binding affinity, lipophilicity and in vivo stability. In addition, the accuracies of both radioligands were determined by comparing the PET imaging data in the same LPS-induced neuroinflammation

  我们设计并合成了氘取代的[ 18 F]氟甲基-PBR28（[ 18 F] 1 - d 2）作为一种新型的转运蛋白18 kDa（TSPO）靶向放射性配体，具有增强的体内稳定性。从体外结合亲和力，亲脂性和体内活性方面研究了[ 18 F]氟甲基-PBR28（[ 18 F] 1）与它的氘代类似物（[ 18 F] 1 - d 2）的比较研究。稳定。此外，通过在相同的LPS诱发的神经炎症大鼠模型中比较PET成像数据，确定了两种放射性配体的准确性。两种芳氧基苯胺类似物均表现出相似的亲脂性和对TSPO的体外亲和力。然而，在离体生物分布研究中，[ 18 F] 1 - d 2提供的股骨摄取明显低于[ 18 F] 1（注射后2 h为1.5±1.2 vs. 4.1±1.7％ID / g）。[ 18楼] 1 - d 2 在LPS诱发的急性神经炎症大鼠模型中，脂蛋白也选择性地聚集在炎性病变中，具有特异性结合的放射性配
• Radiotracer introduced [18F]fluoromethyl group targeting neuroinflammation for PET imaging and Synthesis of Radiotracer and its biological evaluation Method for Radiotracer
  申请人：Bio Imaging Korea Co., Ltd.

  公开号：US20160263258A1

  公开（公告）日：2016-09-15

  Disclosed are an [ 18 F]fluoromethyl group-introduced radiotracer for brain neuroinflammation-targeting positron emission tomography (PET), the synthesis thereof, and a method for evaluating biological results using the same. In the method for the synthesis of an [ 18 F]fluoromethyl group-introduced radiotracer for brain neuroinflammation-targeting positron emission tomography, a compound obtained by introducing triazolium triflate into normethyl-PBR28 is used as a precursor and a fluoromethyl group is labeled with fluorine-18 in a single step. The [ 18 F]fluoromethyl group-introduced radiotracer for brain neuroinflammation-targeting positron emission tomography is synthesized by using a compound, obtained by introducing triazolium triflate into normethyl-PBR28, as a precursor and performing substitution with fluorine-18 in a single step.

  本发明涉及一种用于大脑神经炎症靶向正电子发射断层扫描（PET）的[18F]氟甲基引入放射性示踪剂，其合成方法以及使用该示踪剂评估生物结果的方法。在合成[18F]氟甲基引入大脑神经炎症靶向PET的放射性示踪剂的方法中，使用将三唑铵三氟甲磺酸引入正甲基-PBR28得到的化合物作为前体，并在单步反应中用氟-18标记氟甲基。使用将三唑铵三氟甲磺酸引入正甲基-PBR28得到的化合物作为前体，并在单步反应中用氟-18进行取代，合成[18F]氟甲基引入大脑神经炎症靶向PET的放射性示踪剂。
• Synthesis and Evaluation in Monkey of Two Sensitive ¹¹C-Labeled Aryloxyanilide Ligands for Imaging Brain Peripheral Benzodiazepine Receptors In Vivo
  作者：Emmanuelle Briard、Sami S. Zoghbi、Masao Imaizumi、Jonathan P. Gourley、H. Umesha Shetty、Jinsoo Hong、Vanessa Cropley、Masahiro Fujita、Robert B. Innis、Victor W. Pike

  DOI：10.1021/jm0707370

  日期：2008.1.1

  We sought to develop C-11-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline (3, PBR01) and N-(2-methoxybenzyI)-N-(4-phenoxypyridin-3-yl)acetamide (10, PBR28). 3 was hydrolyzed to 4, which was esterified with [C-11]iodomethane to provide [C-11]3. The O-desmethyl analogue of 10 was converted into [C-11]10 with [C-11]iodomethane. [C-11]3 and [C-11]10 were each injected into monkey to assess their brain kinetics with positron emission tomography (PET). After administration of either radioligand there was moderately high brain uptake of radioactivity. Receptor blocking and displacement experiments showed that a high proportion of this radioactivity was bound specifically to PBR. In monkey and rat, 3 and 10 were rapidly metabolized by ester hydrolysis and N-debenzylation, respectively, each to a single polar radiometabolite. [C-11]3 and [C-11]10 are effective for imaging PBR in monkey brain. [C-11]10 especially warrants further evaluation in human subjects.