4-[4-[4-(三氟甲氧基)苯氧基]哌啶-1-基]苯酚 | 681482-81-5

• 物质功能分类: 医药中间体 - 杂环化合物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 4-[4-[4-(三氟甲氧基)苯氧基]哌啶-1-基]苯酚
• 中文别名: 4-(4-(4-三氟甲氧基)-苯氧基)哌啶-1-基)苯酚
• 英文名称: 4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-phenol
• 英文别名: 4-{4-[4-(Trifluoromethoxy)phenoxy]piperidino}benzenol；4-[4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl]phenol
• CAS: 681482-81-5
• 化学式: C₁₈H₁₈F₃NO₃
• 分子量: 353.341
• InChiKey: KXHMPYHAQBAPJK-UHFFFAOYSA-N

物化性质

• 熔点：
  113-114°C
• 沸点：
  461.2±45.0 °C(Predicted)
• 密度：
  1.308±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)：
  5.1
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  41.9
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P501,P270,P264,P280,P302+P352,P337+P313,P305+P351+P338,P362+P364,P332+P313,P301+P312+P330
• 危险性描述：
  H302,H315,H319

反应信息

• 作为反应物：
  描述：

  4-[4-[4-(三氟甲氧基)苯氧基]哌啶-1-基]苯酚 在 lithium hydroxide 作用下， 以 水 、 异丙醇 为溶剂， 反应 2.0h， 生成 lithium 4-(4-(4-trifluoromethoxy-phenoxy)piperidin-1-yl)phenolate
  参考文献：
  名称：

  WO2008/140090

  摘要：

  公开号：
• 作为产物：
  描述：

  4-[4-(三氟甲氧基)苯氧基]哌啶 在 N-氯代丁二酰亚胺 、 高氯酸 、 tris(2,2'-bipyridyl)ruthenium dichloride 作用下， 反应 1.5h， 生成 4-[4-[4-(三氟甲氧基)苯氧基]哌啶-1-基]苯酚
  参考文献：
  名称：

  使用烷基胺的芳烃的实际和区域选择性胺化。

  摘要：

  用于制备芳香胺的碳-氮键的形成是全球范围内为生产高价值材料而进行的前五项反应之一，从原料化学品到药物和聚合物不等。由于这种普遍性和多样性，其制备方法影响了学术界和工业界的整个化学合成过程。通常，这些分子是通过逐步引入反应性手柄代替芳香族CH键（即硝基，卤素或硼酸）和随后的功能化或交叉偶联而组装而成的。在这里，我们表明，芳烃胺可以使用光催化作用，通过芳烃和烷基胺的直接反应来构建，而无需进行预功能化。该过程可以轻松准备高级构建基块，容忍的功能范围很广，并且可以通过批处理流协议来实现多克规模。通过对几种药物，农药，肽，手性催化剂，聚合物和有机金属配合物的修饰，证明了该策略作为后期功能化平台的优点。

  DOI：

  10.1038/s41557-019-0254-5
• 作为试剂：
  描述：

  (R)-2-氯-1-(2-甲基环氧乙烷-2-基甲基)-4-硝基咪唑 、 4-[4-[4-(三氟甲氧基)苯氧基]哌啶-1-基]苯酚 在 4-[4-[4-(三氟甲氧基)苯氧基]哌啶-1-基]苯酚 作用下， 以48的产率得到迪拉马尼
  参考文献：
  名称：

  [EN] 2,3-DIHYDRO-6-NITROIMIDAZO[2,1-b]OXAZOLES
  [FR] 2,3-DIHYDRO-6-NITROIMIDAZO[2,1-B]OXAZOLES

  摘要：

  2,3-二氢-6-硝基咪唑并[2,1-b]噁唑的一般式表示为（1）：（1）（H）[其中R1是氢或C1-6烷基; n是0至6的整数; R2是-OR3或类似物（其中R3是氢，C1-6烷基或类似物），或R1和-(CH2)nR2可以通过氮原子连接在一起，与相邻的碳原子形成一个螺环，其一般式表示为（H）（其中R41是氢，C1-6烷基或类似物）]。这些化合物对结核杆菌、多重耐药结核杆菌和非典型抗酸杆菌表现出优异的杀菌活性。

  公开号：

  WO2004033463A1

文献信息

• 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases
  作者：Andrew M. Thompson、Adrian Blaser、Brian D. Palmer、Robert F. Anderson、Sujata S. Shinde、Delphine Launay、Eric Chatelain、Louis Maes、Scott G. Franzblau、Baojie Wan、Yuehong Wang、Zhenkun Ma、William A. Denny

  DOI：10.1016/j.bmcl.2017.03.069

  日期：2017.6

  its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, "thio-delamanid"

  为了寻求抗结核药物类前驱体（PA-824）的备份，我们研究了未开发的6-硝基-2,3-二氢咪唑并[2,1-b] [1,3]-噻唑和相关的-恶唑。硝基咪唑并噻唑是由2-溴-4-硝基咪唑通过与取代的噻喃和二异丙基乙胺加热而高产率制备的。这两个结构类别的等效实例提供了可广泛比较的MIC，其中2-甲基取代和优选的芳氧基甲基侧链扩展；尽管，S-氧化的噻唑类药物对结核病无效。联苯噻唑的有利的微粒体稳定性数据（45）与相应的恶唑（48）一起在急性结核分枝杆菌小鼠模型中进行了评估，但事实证明后者更为有效。体外对动素体疾病的筛选显示，硝基咪唑并噻唑对利什曼病无活性，但对查加斯病表现出有趣的活性，优于硝基咪唑并恶唑。总体而言，“硫磺-德拉曼尼德”（49）被认为是最佳的铅。
• [EN] SYNTHETIC INTERMEDIATE OF OXAZOLE COMPOUND AND METHOD FOR PRODUCING THE SAME<br/>[FR] INTERMÉDIAIRE SYNTHÉTIQUE D'UN COMPOSÉ OXAZOLE ET PROCÉDÉ DE PRODUCTION ASSOCIÉ
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2011093529A1

  公开（公告）日：2011-08-04

  An object of the present invention is to provide a method for producing an oxazole compound in a high yield. The object can be achieved by a compound represented by Formula (11): wherein R1 is a hydrogen atom or lower-alkyl group; R2 is a 1-piperidyl group substituted at the 4-position with a substituent selected from (A1a) a phenoxy group substituted on the phenyl moiety with one or more halogen-substituted lower-alkoxy groups, (A1b) a phenoxy-substituted lower-alkyl group substituted on the phenyl moiety with one or more halogen-substituted lower-alkyl groups, (A1c) a phenyl-substituted lower-alkoxy lower-alkyl group substituted on the phenyl moiety with halogen, (A1d) a phenyl-substituted lower-alkyl group substituted on the phenyl moiety with one or more halogen-substituted lower-alkoxy groups, (A1e) an amino group substituted with a phenyl group substituted with one or more halogen-substituted lower-alkoxy groups, and a lower-alkyl group, and (A1f) a phenyl-substituted lower-alkoxy group substituted on the phenyl moiety with one or more halogen-substituted lower-alkoxy groups; n is an integer from 1 to 6; and X3 is an organic sulfonyloxy group.

  本发明的目的是提供一种高产率生产噁唑化合物的方法。该目的可以通过由式（11）表示的化合物实现：其中R1是氢原子或较低的烷基基团；R2是在4-位被取代的1-哌啶基团，所述取代基选自（A1a）苯氧基在苯基上取代一个或多个卤素取代的较低烷氧基团，（A1b）苯氧基取代的较低烷基基团在苯基上取代一个或多个卤素取代的较低烷基基团，（A1c）苯基取代的较低烷氧基较低烷基基团在苯基上取代卤素，（A1d）苯基取代的较低烷基基团在苯基上取代一个或多个卤素取代的较低烷氧基团，（A1e）氨基取代的苯基取代一个或多个卤素取代的较低烷氧基团和较低烷基基团，以及（A1f）苯基取代的较低烷氧基团在苯基上取代一个或多个卤素取代的较低烷氧基团；n是1到6之间的整数；X3是有机磺酰氧基团。
• Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo
  作者：Katsunori Sasahara、Yoshihiko Shimokawa、Yukihiro Hirao、Noriyuki Koyama、Kazuyoshi Kitano、Masakazu Shibata、Ken Umehara

  DOI：10.1124/dmd.115.064527

  日期：2015.8

  Delamanid, a new anti-tuberculosis drug, is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-dihydroimidazo[2,1- b ] oxazole moiety, in plasma albumin in vitro. The metabolic activities in dogs and humans are higher than those in rodents. In this study, we characterized the pharmacokinetics and metabolism of delamanid in animals and humans. Eight metabolites (M1–M8) produced by cleavage of the imidazooxazole moiety of delamanid were identified in the plasma after repeated oral administration by liquid chromatography–mass spectrometry analysis. Delamanid was initially catalyzed to M1 and subsequently metabolized by three separate pathways, which suggested that M1 is a crucial starting point. The major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure among the eight metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. The overall metabolism of delamanid was qualitatively similar across nonclinical species and humans but was quantitatively different among the species. After repeated administration, the metabolites had much higher concentrations in dogs and humans than in rodents. The in vitro metabolic activity of albumin on delamanid probably caused the species differences observed. We determined that albumin metabolism is a key component of the pharmacokinetics and metabolism of delamanid. Nonhepatic formation of M1 and multiple separate pathways for metabolism of M1 suggest that clinically significant drug–drug interactions with delamanid and M1 are limited.

  德拉马尼是一种新型抗结核药物，在体外血浆白蛋白中被代谢为M1，这是一种通过切割6-硝基-2,3-二氢咪唑并[2,1-b]恶唑部分形成的独特代谢物。狗和人类的代谢活性高于啮齿动物。本研究对动物和人体内德拉马尼的药代动力学和代谢进行了特征分析。通过液相色谱-质谱分析，在反复口服给药后，在血浆中鉴定出由德拉马尼的咪唑并恶唑部分切割产生的八种代谢物（M1-M8）。德拉马尼最初被催化成M1，然后通过三条单独的途径进行代谢，这表明M1是一个关键的起始点。人类主要的代谢途径是对M1的恶唑部分进行羟化形成M2，然后主要由CYP3A4连续氧化成酮形式（M3）。在反复口服给药后，M1在八种代谢物中的暴露量最高，这表明M1是主要的代谢产物。德拉马尼的整体代谢在非临床物种和人类中在定性上相似，但在物种之间在定量上有所不同。反复给药后，狗和人体内的代谢物浓度远高于啮齿动物。白蛋白对德拉马尼的体外代谢活性可能是观察到的物种差异的原因。我们确定白蛋白代谢是德拉马尼药代动力学和代谢的关键组成部分。非肝脏形成M1和多条单独的代谢途径表明，德拉马尼和M1的临床显著药物-药物相互作用有限。
• [EN] METHOD OF PRODUCING AMINOPHENOL COMPOUNDS<br/>[FR] PROCEDE DE FABRICATION DE COMPOSES AMINOPHENOLS
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2005092832A1

  公开（公告）日：2005-10-06

  The present invention provides an industrially advantageous method of producing aminophenol compounds represented by the formula (1) by a simple and easy procedure at a high yield and a high purity. The present invention provides a method of producing an aminophenol compound represented by the formula (1): (wherein each of R1 and R2, which may be the same or different, is a hydrogen atom, a substituted or unsubstituted lower alkyl group or the like; R1 and R2, taken together with the adjacent nitrogen atom, may form a 5- or 6-membered heterocycle with or without other intervening heteroatoms; the heterocycle may be substituted by 1 to 3 substituents selected from the group consisting of a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryloxy group and the like; and the hydroxyl group in the formula (1) is substituted on the 2- or 4-position to the amino group on the phenyl ring), which comprises allowing a cyclohexanedione compound represented by the formula (2) to react with an amine compound represented by the formula (3) (wherein R1 and R2 are as defined above), under a neutral or basic condition.

  本发明提供一种在高产率和高纯度下通过简单易行的程序生产由式（1）表示的氨基酚化合物的工业上有利的方法。本发明提供了一种生产由式（1）表示的氨基酚化合物的方法：（其中R1和R2中的每一个，可能相同也可能不同，是氢原子，取代或未取代的较低烷基基团或类似物；R1和R2与相邻氮原子一起可以形成5或6成员的杂环，有或无其他插入的杂原子；该杂环可以被1至3个取代基取代，所述取代基选自羟基团、取代或未取代的较低烷基基团、取代或未取代的芳基基团、取代或未取代的芳氧基团等；并且在式（1）中的羟基团被取代在苯环上的氨基团的2-或4-位置），其包括使由式（2）表示的环己二酮化合物与由式（3）表示的胺化合物（其中R1和R2如上定义）在中性或碱性条件下反应。
• [EN] TREATMENT OF PARASITIC DISEASE<br/>[FR] TRAITEMENT D'UNE MALADIE PARASITAIRE
  申请人：UNIV DUNDEE

  公开号：WO2017072523A1

  公开（公告）日：2017-05-04

  The present invention provides compounds such as delamanid for use in the treatment of a parasitic disease caused by or associated with parasites selected from -the Order Kinetoplastida consisting of species belonging to the genera Leishmania and Trypanosoma.

  本发明提供了类似德拉曼胺的化合物，用于治疗由或与属于原肠纲的寄生虫引起的寄生虫病，这些寄生虫包括属于利什曼原虫和锥虫属的物种。