[(E)-(R)-1-(3,4-dichlorobenzyl)-3-((R)-2-oxoazepan-3-ylcarbamoyl)allyl]methylcarbamic acid tert-butyl ester | 583028-46-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [(E)-(R)-1-(3,4-dichlorobenzyl)-3-((R)-2-oxoazepan-3-ylcarbamoyl)allyl]methylcarbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(E,2R)-1-(3,4-dichlorophenyl)-5-oxo-5-[[(3R)-2-oxoazepan-3-yl]amino]pent-3-en-2-yl]-N-methylcarbamate
• CAS: 583028-46-0
• 化学式: C₂₃H₃₁Cl₂N₃O₄
• 分子量: 484.423
• InChiKey: BDSMZGUYZWWNQJ-XABOCNADSA-N

物化性质

• 熔点：
  153-154 °C(Solvent: Diethyl ether)
• 沸点：
  702.4±60.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  87.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [(E)-(R)-1-(3,4-dichlorobenzyl)-3-((R)-2-oxoazepan-3-ylcarbamoyl)allyl]methylcarbamic acid tert-butyl ester 在 4-二甲氨基吡啶 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 6.5h， 生成 DNK 333
  参考文献：
  名称：

  Stereoselective Preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist

  摘要：

  In a program aimed at the development of neurokinin antagonists, N- [(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-D-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK1 (pK(i) = 8.38) and NK2 (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.

  DOI：

  10.1021/jm030786m
• 作为产物：
  描述：

  (R)-2-(tert-butoxycarbonylmethylamino)-3-(3,4-dichlorophenyl)propionic acid methyl ester 在 4-二甲氨基吡啶 、 正丁基锂 、 二异丁基氢化铝 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 甲苯 为溶剂， 反应 23.0h， 生成 [(E)-(R)-1-(3,4-dichlorobenzyl)-3-((R)-2-oxoazepan-3-ylcarbamoyl)allyl]methylcarbamic acid tert-butyl ester
  参考文献：
  名称：

  Stereoselective Preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist

  摘要：

  In a program aimed at the development of neurokinin antagonists, N- [(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-D-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK1 (pK(i) = 8.38) and NK2 (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.

  DOI：

  10.1021/jm030786m

文献信息

• Stereoselective Preparation of <i>N</i>-[(<i>R,R</i>)-(<i>E</i>)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-<i>N</i>-methyl-3,5-bis(trifluoromethyl)benzamide, a Potent and Orally Active Dual Neurokinin NK₁/NK₂ Receptor Antagonist
  作者：Marc Gerspacher、Christine Lewis、Howard A. Ball、Colin Howes、Natarajan Subramanian、Karin Ryffel、John R. Fozard

  DOI：10.1021/jm030786m

  日期：2003.7.1

  In a program aimed at the development of neurokinin antagonists, N- [(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK1/NK2 receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-D-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK1 (pK(i) = 8.38) and NK2 (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK1 and NK2 receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.