5-chloro-6-methyl-2-(methylthio)pyrimidin-4(3H)-one | 6328-59-2

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 5-chloro-6-methyl-2-(methylthio)pyrimidin-4(3H)-one
• 英文别名: 5-chloro-6-methyl-2-methylsulfanyl-3H-pyrimidin-4-one；5-Chlor-6-methyl-2-methylmercapto-3H-pyrimidin-4-on；5-Chloro-6-methyl-2-(methylsulfanyl)pyrimidin-4(1h)-one；5-chloro-4-methyl-2-methylsulfanyl-1H-pyrimidin-6-one
• CAS: 6328-59-2
• 化学式: C₆H₇ClN₂OS
• 分子量: 190.653
• InChiKey: VJVKERKTPVPFEJ-UHFFFAOYSA-N

物化性质

• 熔点：
  260-261 °C(Solv: isopropanol (67-63-0))
• 沸点：
  271.9±50.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 海关编码：
  2933599090

反应信息

• 作为反应物：
  描述：

  5-chloro-6-methyl-2-(methylthio)pyrimidin-4(3H)-one 在 palladium on activated charcoal 、 氢气 、 sodium hexamethyldisilazane 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基苯胺 为溶剂， 115.0 ℃ 、206.85 kPa 条件下， 反应 57.0h， 生成 2-(5-chloro-2-(methylthio)pyrimidin-4-yl)-1-(1-(trifluoromethyl)-cyclopropyl)ethenol
  参考文献：
  名称：

  Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1H-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors

  摘要：

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

  DOI：

  10.1021/jm5013598
• 作为产物：
  描述：

  6-甲基-4-羟基-2-甲硫基嘧啶 在 iron(III) chloride 、 磺酰氯 、 乙酸酐 、 溶剂黄146 作用下， 反应 36.0h， 以69%的产率得到5-chloro-6-methyl-2-(methylthio)pyrimidin-4(3H)-one
  参考文献：
  名称：

  Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1H-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors

  摘要：

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.

  DOI：

  10.1021/jm5013598

文献信息

• Synthesis of Chloropyrimidines by Reaction with N-Chlorosuccinimide, and by Condensation Methods¹
  作者：Robert A. West、Harold W. Barrett

  DOI：10.1021/ja01641a009

  日期：1954.6
• GERSHON, H.;GREFIG, A. T., J. HETEROCYCL. CHEM., 1984, 21, N 4, 1161-1167
  作者：GERSHON, H.、GREFIG, A. T.

  DOI：——

  日期：——
• Lead Optimization toward Proof-of-Concept Tools for Huntington’s Disease within a 4-(1<i>H</i>-Pyrazol-4-yl)pyrimidine Class of Pan-JNK Inhibitors
  作者：John Wityak、Kevin F. McGee、Michael P. Conlon、Ren Hua Song、Bryan C. Duffy、Brent Clayton、Michael Lynch、Gwen Wang、Emily Freeman、James Haber、Douglas B. Kitchen、David D. Manning、Jiffry Ismail、Yuri Khmelnitsky、Peter Michels、Jeff Webster、Macarena Irigoyen、Michele Luche、Monica Hultman、Mei Bai、IokTeng D. Kuok、Ryan Newell、Marieke Lamers、Philip Leonard、Dawn Yates、Kim Matthews、Lynette Ongeri、Steve Clifton、Tania Mead、Susan Deupree、Pat Wheelan、Kathy Lyons、Claire Wilson、Alex Kiselyov、Leticia Toledo-Sherman、Maria Beconi、Ignacio Muñoz-Sanjuan、Jonathan Bard、Celia Dominguez

  DOI：10.1021/jm5013598

  日期：2015.4.9

  Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.