(R)-(-)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline | 1159997-92-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (R)-(-)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
• 英文别名: (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline；(1R)-1-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline
• CAS: 1159997-92-8
• 化学式: C₁₆H₁₄F₃N
• 分子量: 277.289
• InChiKey: YPHQWGSEPCKQEG-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-(-)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline 在 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 48.0h， 生成 (R)-4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid
  参考文献：
  名称：

  Optimization of Potency and Pharmacokinetic Properties of Tetrahydroisoquinoline Transient Receptor Potential Melastatin 8 (TRPM8) Antagonists

  摘要：

  Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values < 3 mg/kg.

  DOI：

  10.1021/jm401955h
• 作为产物：
  描述：

  4-三氟甲基苯基溴化镁 在 titanium(IV) isopropylate 、 氢气 、 碘 、 对甲苯磺酸 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 30.0 ℃ 、6.08 MPa 条件下， 反应 20.25h， 生成 (R)-(-)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  一锅N-脱保护和催化分子内不对称还原胺化反应合成四氢异喹啉

  摘要：

  描述了用于制备对映体纯的四氢异喹啉生物碱的一锅法N-Boc脱保护和催化分子内还原胺化协议。碘桥联的二聚铱络合物显示出极好的立体选择性，可在温和的反应条件下以优异的收率得到四氢异喹啉，包括几种关键的药物中间体。三种添加剂在该反应中起重要作用：异丙氧基钛（IV）和分子碘促进了中间体亚胺向四氢异喹啉产物的转化；对甲苯磺酸有助于立体控制。

  DOI：

  10.1002/anie.201611181

文献信息

• [EN] TRP-M8 RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS<br/>[FR] LIGANDS DU RÉCEPTEUR TRP-M8 ET LEUR UTILISATION DANS DES TRAITEMENTS
  申请人：AMGEN INC

  公开号：WO2009073203A1

  公开（公告）日：2009-06-11

  Tetrahydroisoquinoline compounds of formula (I), and compositions containing them, for the treatment of acute, inflammatory and neurophatic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neurophatic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintened pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

  公式（I）的四氢异喹啉化合物及含有它们的组合物，用于治疗急性、炎症性和神经性疼痛、牙痛、普通头痛、偏头痛、集群头痛、混合血管和非血管综合征、紧张性头痛、一般炎症、关节炎、风湿性疾病、骨关节炎、炎症性肠道疾病、炎症性眼部疾病、炎症性或不稳定的膀胱疾病、牛皮癣、带有炎症成分的皮肤疾病、慢性炎症症状、炎症性疼痛及相关的过敏性疼痛和触痛、神经性疼痛及相关的过敏性疼痛和触痛、糖尿病性神经病痛、烧灼性疼痛、交感神经维持性疼痛、感觉缺失综合征、哮喘、上皮组织损伤或功能障碍、单纯疱疹、呼吸、泌尿、消化或血管区域内脏运动障碍、伤口、烧伤、过敏性皮肤反应、瘙痒、白癜风、一般胃肠道疾病、胃溃疡、十二指肠溃疡、腹泻、坏死性剂引起的胃病变、毛发生长、血管运动性或过敏性鼻炎、支气管疾病或膀胱疾病。
• Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ as Activator
  作者：Mu-Wang Chen、Yue Ji、Jie Wang、Qing-An Chen、Lei Shi、Yong-Gui Zhou

  DOI：10.1021/acs.orglett.7b02502

  日期：2017.9.15

  traceless activation reagent, a general iridium-catalyzed asymmetric hydrogenation of isoquinolines and pyridines is developed with up to 99% ee. This method avoids tedious steps of installation and removal of the activating groups. The mechanism studies indicated that hydrogen halide generated in situ acted as an activator of isoquinolines and pyridines.

  通过使用卤化物三氯异氰尿酸作为无痕活化剂，可以开发出具有高达99％ee的一般铱催化的异喹啉和吡啶的不对称氢化反应。该方法避免了安装和拆卸活化基团的繁琐步骤。机理研究表明，原位产生的卤化氢起异喹啉和吡啶的活化剂作用。
• Enantioselective hydrogenation of cyclic imines catalysed by Noyori–Ikariya half-sandwich complexes and their analogues
  作者：B. Vilhanová、J. Václavík、P. Šot、J. Pecháček、J. Zápal、R. Pažout、J. Maixner、M. Kuzma、P. Kačer

  DOI：10.1039/c5cc06712j

  日期：——

  A method for enantioselective hydrogenation of cyclic imines with gaseous hydrogen has been developed. Easily accessible Noyori-Ikariya Ru(II) and Rh(III) complexes can be used directly without inert atmosphere. Substrate activation...

  已经开发了用气态氢对环亚胺进行对映选择性氢化的方法。易于获得的Noyori-Ikariya Ru（II）和Rh（III）配合物可在没有惰性气氛的情况下直接使用。基板活化...
• A Highly Efficient and Enantioselective Access to Tetrahydroisoquinoline Alkaloids: Asymmetric Hydrogenation with an Iridium Catalyst
  作者：Mingxin Chang、Wei Li、Xumu Zhang

  DOI：10.1002/anie.201104476

  日期：2011.11.4

  Efficient and enantioselective: Using the iodine‐bridged dimeric iridium complex [Ir(H)[(S,S)‐(f)‐binaphane]}2(μ‐I)3]+I− (1) a wide range of tetrahydroisoquinoline alkaloids, including the substructure of the pharmaceutical drug solifenacin, were obtained with excellent enantioselectivities and high turnover numbers (see scheme).

  高效和对映选择性：使用碘桥接的二聚体铱络合物[的Ir（H）[（小号，小号） - （F）-binaphane]} 2（μ-I）3 ] +我- （1）广泛的获得了四氢异喹啉碱生物碱，包括药物索非那新的亚结构，具有出色的对映选择性和高周转率（参见方案）。
• Josiphos-Type Binaphane Ligands for Iridium-Catalyzed Enantioselective Hydrogenation of 1-Aryl-Substituted Dihydroisoquinolines
  作者：Huifang Nie、Yupu Zhu、Xiaomu Hu、Zhao Wei、Lin Yao、Gang Zhou、Pingan Wang、Ru Jiang、Shengyong Zhang

  DOI：10.1021/acs.orglett.9b03251

  日期：2019.11.1

  displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral

  描述了一系列Josiphos型双苯甲醚配体的简便合成方法和有用的应用。这些手性二膦的铱络合物在具有挑战性的1-芳基取代的二氢异喹啉底物的不对称氢化中显示出出色的对映选择性和良好的反应性（完全转化，高达> 99％ee，4000 TON）。使用40％HBr（水溶液）作为添加剂可显着改善这些催化剂的不对称诱导。该转化提供了对手性1-芳基取代的四氢异喹啉的高效和对映选择性的途径，这在天然产物和生物活性分子中非常重要且常见。