tert-butyl (1R,4r)-4-[(R)-1-(2-nitrophenylsulfonyl)aziridin-2-yl]cyclohexylcarbamate | 1373311-88-6

• 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: tert-butyl (1R,4r)-4-[(R)-1-(2-nitrophenylsulfonyl)aziridin-2-yl]cyclohexylcarbamate
• 英文别名: (R)-trans-tert-butyl 4-(1-(2-nitrophenylsulfonyl)aziridin-2-yl)-cyclohexylcarbamate
• CAS: 1373311-88-6
• 化学式: C₁₉H₂₇N₃O₆S
• 分子量: 425.506
• InChiKey: LHEJOMYYWAQPRN-QZCDYUCJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.05
• 重原子数：
  29.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  118.62
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  tert-butyl (1R,4r)-4-[(R)-1-(2-nitrophenylsulfonyl)aziridin-2-yl]cyclohexylcarbamate 在 sodium hydride 、 potassium carbonate 、 苯硫酚 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.75h， 生成 (R)-2-(trans-[4-(1-amino-2-(7-fluoro-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)cyclohexylamino]-methyl)-6Hpyrimido[5,4-b][1,4]oxazin-7(8H)-one
  参考文献：
  名称：

  Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa

  摘要：

  Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.

  DOI：

  10.1016/j.bmc.2014.07.040
• 作为产物：
  描述：

  [N-(2-nitrophenylsulfonyl)imino]phenyliodinane 在 Cu(OTf)₂ 作用下， 以 正己烷 、 异丙醇 、 乙腈 为溶剂， 反应 3.0h， 生成 tert-butyl (1R,4r)-4-[(R)-1-(2-nitrophenylsulfonyl)aziridin-2-yl]cyclohexylcarbamate
  参考文献：
  名称：

  Optimization of physicochemical properties and safety profile of novel bacterial topoisomerase type II inhibitors (NBTIs) with activity against Pseudomonas aeruginosa

  摘要：

  Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. Compound 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.

  DOI：

  10.1016/j.bmc.2014.07.040

文献信息

• A Multikilogram-Scale Synthesis of (R)-Methyl 2-[(1r,4R)-4-(tert-Butoxy­carbonylamino)cyclohexyl]-2-(2-nitrophenylsulfonamido)acetate - A Doubly Protected Building Block with Three Points of Variation
  作者：Gregory Carr、Sam Butterworth、Phil Walker、Folkert Reck、Bolin Geng、Lakshmipathi Pandarinathan

  DOI：10.1055/s-0031-1289724

  日期：2012.3

  A robust and scalable synthesis of (R)-methyl 2-[(1r,4R)-4-(tert-butoxycarbonylamino)cyclohexyl]-2-(2-nitrophenylsulfon­amido)acetate is reported. This serves as a scaffold for the preparation of trans-substituted aminocyclohexanes. The key synthetic step is the reduction of d-4-hydroxyphenylglycine, or a protected equivalent, to achieve the required regiochemistry across the cyclohexyl ring.

  报告了 2-[(1r,4R)-4-(叔丁氧羰基氨基)环己基]-2-(2-硝基苯磺酰胺基)乙酸(R)-甲基酯的可靠且可扩展的合成方法。它是制备反式取代氨基环己烷的支架。关键的合成步骤是还原 d-4- 羟基苯甘氨酸或受保护的等价物，以实现环己基环上所需的区域化学反应。