1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2(1H)-one | 444665-44-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2(1H)-one
• 英文别名: 1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2-one
• CAS: 444665-44-5
• 化学式: C₂₀H₁₀Cl₂F₂N₂O
• 分子量: 403.215
• InChiKey: LEQIYANLBCTNDM-UHFFFAOYSA-N

物化性质

• 沸点：
  546.1±50.0 °C(Predicted)
• 密度：
  1.481±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  33.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2(1H)-one 在 间氯过氧苯甲酸 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以88%的产率得到1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2(1H)-one 6-oxide
  参考文献：
  名称：

  Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor

  摘要：

  Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4- addition on the enelactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.

  DOI：

  10.1021/jo061618f
• 作为产物：
  描述：

  2-氯-4-溴吡啶 在 potassium chloride 、 palladium diacetate 四丁基溴化铵 、 sodium acetate 、 sodium carbonate 、 三苯基膦 、 potassium bromide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 水 、 甲苯 为溶剂， 生成 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2(1H)-one
  参考文献：
  名称：

  Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor

  摘要：

  Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4- addition on the enelactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.

  DOI：

  10.1021/jo061618f

文献信息

• [EN] (HALO-BENZO CARBONYL)HETEROCYCLO FUSED PHENYL P38 KINASE INHIBITING AGENTS<br/>[FR] AGENTS INHIBITEURS DE P38 KINASE (HALO-BENZO CARBONYL)HETEROCYCLO- FUSIONNES PHENYL
  申请人：MERCK & CO INC

  公开号：WO2002058695A1

  公开（公告）日：2002-08-01

  Compounds described by the chemical formula (I) or a pharmaceutically acceptable salt thereof, are inhibitors of p38 useful in the treatment of inflammatory diseases such as arthritis.

  化学式（I）或其药学上可接受的盐所描述的化合物是p38的抑制剂，可用于治疗炎症性疾病，如关节炎。
• p38 MAP kinase inhibitors. Part 5: Discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold
  作者：Swaminathan R. Natarajan、Luping Liu、Mark Levorse、James E. Thompson、Edward A. O’Neill、Stephen J. O’Keefe、Kalpit A. Vora、Raymond Cvetovich、John Y. Chung、Ester Carballo-Jane、Denise M. Visco

  DOI：10.1016/j.bmcl.2006.06.084

  日期：2006.10

  A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC50 doses as low as 0.2 mpk. (c) 2006 Elsevier Ltd. All rights reserved.
• EP1345603A4
  申请人：——

  公开号：EP1345603A4

  公开（公告）日：2004-09-08
• (HALO-BENZO CARBONYL)HETEROCYCLO FUSED PHENYL P38 KINASE INHIBITING AGENTS
  申请人：Merck & Co., Inc.

  公开号：EP1345603A1

  公开（公告）日：2003-09-24
• Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor
  作者：John Y. L. Chung、Raymond J. Cvetovich、Mark McLaughlin、Joseph Amato、Fuh-Rong Tsay、Mark Jensen、Steve Weissman、Daniel Zewge

  DOI：10.1021/jo061618f

  日期：2006.10.1

  Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4- addition on the enelactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.