2-(tert-butoxycarbonylmethylamino)-3-(3,4-dichlorophenyl)propionic acid methyl ester | 372988-89-1

• 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: 2-(tert-butoxycarbonylmethylamino)-3-(3,4-dichlorophenyl)propionic acid methyl ester
• 英文别名: methyl 3-(3,4-dichlorophenyl)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoate
• CAS: 372988-89-1
• 化学式: C₁₆H₂₁Cl₂NO₄
• 分子量: 362.253
• InChiKey: GMLGHZDAMCPDGI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.94
• 重原子数：
  23.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  55.84
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-(tert-butoxycarbonylmethylamino)-3-(3,4-dichlorophenyl)propionic acid methyl ester 在 盐酸 、 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 23.33h， 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
• 作为产物：
  描述：

  BOC-肌氨酸甲酯 、 3,4-二氯苄溴 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 生成 2-(tert-butoxycarbonylmethylamino)-3-(3,4-dichlorophenyl)propionic acid methyl ester
  参考文献：
  名称：

  Dual neurokinin NK1/NK2 antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N′-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N′-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamides

  摘要：

  Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)- 3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1), attempts to improve the NK2 affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3- yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK2 receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK1/NK2 antagonist. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00631-x