7-氯-1-(2,6-二氯苯基)-5-(2,4-二氟苯基)-1,6-二氮杂萘-2-酮 | 872973-93-8

• 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
• 中文名称: 7-氯-1-(2,6-二氯苯基)-5-(2,4-二氟苯基)-1,6-二氮杂萘-2-酮
• 英文名称: 7-chloro-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2-(1H)-one
• 英文别名: 7-chloro-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2(1H)-one；7-Chloro-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-1,6-naphthyridin-2-one
• CAS: 872973-93-8
• 化学式: C₂₀H₉Cl₃F₂N₂O
• 分子量: 437.66
• InChiKey: RMEPBOZBTRWKFQ-UHFFFAOYSA-N

物化性质

• 沸点：
  576.1±50.0 °C(Predicted)
• 密度：
  1.540±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  28
• 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：

  7-氯-1-(2,6-二氯苯基)-5-(2,4-二氟苯基)-1,6-二氮杂萘-2-酮 、 1-叔丁基-4-氯哌啶 在 铁粉 magnesium 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成
  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：

  1,3-丙酮二羧酸二甲酯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride potassium tert-butylate 、 四甲基氯化铵 、 sodium hydride 、 caesium carbonate 、 对甲苯磺酸 、 sodium t-butanolate 、 三氯氧磷 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 甲苯 为溶剂， 反应 45.0h， 生成 7-氯-1-(2,6-二氯苯基)-5-(2,4-二氟苯基)-1,6-二氮杂萘-2-酮
  参考文献：
  名称：

  从丙酮二羧酸酯高效合成三取代的1,6-萘啶酮和区域选择性的Suzuki芳基化

  摘要：

  描述了一种有效的五步合成1,3-萘啶酮3b（一种p38丝裂原活化蛋白（MAP）激酶抑制剂中间体），从丙酮二羧酸酯（ADC）开始，总产率为32％的情况。合成从ADC二甲基酯烯酸酯9的选择性单酰胺化开始。新型伴随的烯胺形成和酰亚胺环化提供了氮差异保护的烯酰胺酰亚胺12。KO t治疗12Bu和3-乙氧基丙烯酸酯定量生成内酰胺15，通过一锅对-甲氧基苄基（PMB）脱保护和双氯化反应将其转化为四氯萘啶酮19。高度区域选择性的Pd（OAc）2 / IMes催化的Suzuki偶联完成了合成。

  DOI：

  10.1021/jo0514927

文献信息

• 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.
• Efficient Synthesis of a Trisubstituted 1,6-Naphthyridone from Acetonedicarboxylate and Regioselective Suzuki Arylation
  作者：John Y. L. Chung、Chaoxian Cai、J. Christopher McWilliams、Robert A. Reamer、Peter G. Dormer、Raymond J. Cvetovich

  DOI：10.1021/jo0514927

  日期：2005.12.1

  An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide

  描述了一种有效的五步合成1,3-萘啶酮3b（一种p38丝裂原活化蛋白（MAP）激酶抑制剂中间体），从丙酮二羧酸酯（ADC）开始，总产率为32％的情况。合成从ADC二甲基酯烯酸酯9的选择性单酰胺化开始。新型伴随的烯胺形成和酰亚胺环化提供了氮差异保护的烯酰胺酰亚胺12。KO t治疗12Bu和3-乙氧基丙烯酸酯定量生成内酰胺15，通过一锅对-甲氧基苄基（PMB）脱保护和双氯化反应将其转化为四氯萘啶酮19。高度区域选择性的Pd（OAc）2 / IMes催化的Suzuki偶联完成了合成。