(R)-benzyl 1-methoxy-2-oxo-2,4,5,6-tetrahydro-1H-imidazo[4,5,1-ij]quinolin-5-yl(methyl)carbamate | 222415-94-3

• 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: (R)-benzyl 1-methoxy-2-oxo-2,4,5,6-tetrahydro-1H-imidazo[4,5,1-ij]quinolin-5-yl(methyl)carbamate
• 英文别名: benzyl N-[(10R)-3-methoxy-2-oxo-1,3-diazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-10-yl]-N-methylcarbamate
• CAS: 222415-94-3
• 化学式: C₂₀H₂₁N₃O₄
• 分子量: 367.404
• InChiKey: YFSQOFDUNMLNFJ-MRXNPFEDSA-N

物化性质

• 沸点：
  518.1±60.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  62.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-benzyl 1-methoxy-2-oxo-2,4,5,6-tetrahydro-1H-imidazo[4,5,1-ij]quinolin-5-yl(methyl)carbamate 在 palladium dihydroxide 氢气 作用下， 以 乙醇 为溶剂， 反应 19.0h， 以2.2 g的产率得到(R)-5-(甲基氨基)-5,6-二氢-1H-咪唑并[4,5,1-ij]喹啉-2(4h)-酮
  参考文献：
  名称：

  Synthesis of the Selective D₂ Receptor Agonist PNU-95666E from d-Phenylalanine Using a Sequential Oxidative Cyclization Strategy

  摘要：

  Compound 1 (PNU-95666E) is a selective and high-affinity agonist at the dopamine D-2 receptor subtype and is of interest as a potential agent for the treatment of Parkinson's disease. Requiring a synthetic route amenable to scale-up, a synthesis of this enantiomerically pure tricyclic compound was developed, starting from D-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulations to provide the tricyclic ring system. A highly efficient reduction with borane-methyl sulfide was used to reduce three different functional groups, a total of six hydrides transferred, with no concomitant racemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been demonstrated by the completion this synthesis on multikilogram scale.

  DOI：

  10.1021/jo970526a
• 作为产物：
  描述：

  (R)-苄基(1,2,3,4-四氢喹啉-3-基)氨基甲酸甲酯 在 [双(三氟乙酰氧基)碘]苯 作用下， 以 四氢呋喃 、 氯仿 、 三乙胺 、 甲苯 为溶剂， 反应 78.0h， 生成 (R)-benzyl 1-methoxy-2-oxo-2,4,5,6-tetrahydro-1H-imidazo[4,5,1-ij]quinolin-5-yl(methyl)carbamate
  参考文献：
  名称：

  Synthesis of the Selective D₂ Receptor Agonist PNU-95666E from d-Phenylalanine Using a Sequential Oxidative Cyclization Strategy

  摘要：

  Compound 1 (PNU-95666E) is a selective and high-affinity agonist at the dopamine D-2 receptor subtype and is of interest as a potential agent for the treatment of Parkinson's disease. Requiring a synthetic route amenable to scale-up, a synthesis of this enantiomerically pure tricyclic compound was developed, starting from D-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulations to provide the tricyclic ring system. A highly efficient reduction with borane-methyl sulfide was used to reduce three different functional groups, a total of six hydrides transferred, with no concomitant racemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been demonstrated by the completion this synthesis on multikilogram scale.

  DOI：

  10.1021/jo970526a

文献信息

• Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism
  作者：Alessandro Bonifazi、Hideaki Yano、Michael P. Ellenberger、Ludovic Muller、Vivek Kumar、Mu-Fa Zou、Ning Sheng Cai、Adrian M. Guerrero、Amina S. Woods、Lei Shi、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.6b01875

  日期：2017.4.13

  The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or beta-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-S-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G(i/o)-proteins, while reducing or suppressing potency and efficacy toward beta-arrestin recruitment. Compound 19 was identified as a new lead for its selective D-2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus beta-arrestin recruitment in D2R-BRET functional assays.
• J. Org. Chem. 1997, 62, 6582-6587
  作者：

  DOI：——

  日期：——
• Synthesis of the Selective D₂ Receptor Agonist PNU-95666E from <scp>d</scp>-Phenylalanine Using a Sequential Oxidative Cyclization Strategy
  作者：Arthur G. Romero、William H. Darlington、Moses W. McMillan

  DOI：10.1021/jo970526a

  日期：1997.9.1

  Compound 1 (PNU-95666E) is a selective and high-affinity agonist at the dopamine D-2 receptor subtype and is of interest as a potential agent for the treatment of Parkinson's disease. Requiring a synthetic route amenable to scale-up, a synthesis of this enantiomerically pure tricyclic compound was developed, starting from D-phenylalanine. Critical to the success of this synthesis were two oxidative nitrogen annulations to provide the tricyclic ring system. A highly efficient reduction with borane-methyl sulfide was used to reduce three different functional groups, a total of six hydrides transferred, with no concomitant racemization, contributing to the synthesis of 1 in eight steps with an overall yield of 26%. The utility of this synthetic route has been demonstrated by the completion this synthesis on multikilogram scale.