(2R,3R)-3-(2-bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol | 1575608-59-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R,3R)-3-(2-bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
• 英文别名: (2R,3R)-3-(2-bromo-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol
• CAS: 1575608-59-1
• 化学式: C₁₇H₁₈BrF₂N₇O
• 分子量: 454.277
• InChiKey: DJKABEDAILJPHT-PIGZYNQJSA-N

物化性质

• 沸点：
  671.1±65.0 °C(Predicted)
• 密度：
  1.72±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R)-3-(2-bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 、 3-吡啶硼酸频哪醇酯 在 四(三苯基膦)钯 、 caesium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 8.0h， 以55.5%的产率得到(2R,3R)-2-(2,4-difluorophenyl)-3-(2-(pyridin-3-yl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
  参考文献：
  名称：

  Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility

  摘要：

  Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]-triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.

  DOI：

  10.1021/jm4016284
• 作为产物：
  描述：

  1-(((2R,3S),2-(2,4-二氟苯基)-3-甲基环氧乙烷-2-基)甲基)-1H-1,2,4-三唑 在 sodium azide 、 palladium 10% on activated carbon 、 氢气 、 苄基三甲基氯化铵 、 sodium cyanoborohydride 、 碳酸氢钠 、 氯化铵 、 溶剂黄146 、 sodium iodide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 20.0~105.0 ℃ 、101.33 kPa 条件下， 反应 35.0h， 生成 (2R,3R)-3-(2-bromo-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
  参考文献：
  名称：

  改进了 YC-071 的实验室合成，这是一种有效的唑类抗真菌剂

  摘要：

  已开发出 YC-071（一种有效的唑类抗真菌剂）的改进实验室合成方法。与原路线相比，新路线操作简单，仅需对所有中间体进行有限纯化。新路线是重要的可扩展合成，满足了YC-071用于临床前研究的需要。

  DOI：

  10.3184/174751917x14902201357419

文献信息

• Design, Synthesis, and Structure–Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility
  作者：Xufeng Cao、Zhaoshuan Sun、Yongbing Cao、Ruilian Wang、Tongkai Cai、Wenjing Chu、Wenhao Hu、Yushe Yang

  DOI：10.1021/jm4016284

  日期：2014.5.8

  Triazoles with fused-heterocycle nuclei were designed and evaluated for their in vitro activity on the basis of the binding mode of albaconazole using molecular docking, along with SAR of antifungal triazoles. Tetrahydro-[1,2,4]-triazolo[1,5-a]pyrazine and tetrahydro-thiazolo[5,4-c]pyridine nuclei were preferable to the other four fused-heterocycle nuclei investigated. Potent in vitro activity, broad spectrum and better water solubility were attained when triazoles containing nitrogen aromatic heterocycles were attached to these two nuclei. The most potent compounds 27aa and 45x, with low hERG inhibition and hepatocyte toxicity, both exhibited excellent activity against Candida, Cryptococcus, and Aspergillus spp., as well as selected fluconazole-resistant strains. A high water-soluble compound 58 (the disulfate salt of 45x) displayed unsatisfactory in vivo activity because of its poor PK profiles. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with 27aa displayed significantly improved survival rates. 27aa also showed favorable pharmacokinetic (PK) profiles.
• Improved Laboratory Synthesis of YC-071, a Potent Azole Antifungal Agent
  作者：Yazhou Zheng、Anran Qian、Chenyu Ling、Xufeng Cao、YongMei Cui、Yushe Yang

  DOI：10.3184/174751917x14902201357419

  日期：2017.4

  An improved laboratory synthesis of YC-071, a potent azole antifungal agent, has been developed. Compared with the original route, the new route is operationally simple, requiring only limited purification of all the intermediates. The new route is an important scalable synthesis, which meets the need for YC-071 for use in preclinical studies.

  已开发出 YC-071（一种有效的唑类抗真菌剂）的改进实验室合成方法。与原路线相比，新路线操作简单，仅需对所有中间体进行有限纯化。新路线是重要的可扩展合成，满足了YC-071用于临床前研究的需要。