4-碘-2-甲基嘧啶 | 84586-49-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 4-碘-2-甲基嘧啶
• 英文名称: 4-iodo-2-methylpyrimidine
• CAS: 84586-49-2
• 化学式: C₅H₅IN₂
• mdl: MFCD13193601
• 分子量: 220.013
• InChiKey: MTSMVADXHUTRBK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  8
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  25.8
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-碘-2-甲基嘧啶 、 1-(tert-butyl) 2-(1,3-dioxoisoindolin-2-yl) azetidine-1,2-dicarboxylate 在 乙二醇二甲醚溴化镍 、 二氢吡啶 、 碳酸氢钠 、 4,4'-二叔丁基-2,2'-二吡啶 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 以40 %的产率得到tert-butyl 2-(2-methylpyrimidin-4-yl)azetidine-1-carboxylate
  参考文献：
  名称：

  用于获取 2-杂芳基氮杂环丁烷的脱羧交叉偶联平台：在药物化学中的应用构建块

  摘要：

  光氧化还原-过渡金属双催化为构建富含sp 3的化学物质提供了独特的平台。在这里，我们报告了镍催化的市售或易于制备的氧化还原活性 NHP 氮杂环丁烷-2-羧酸盐与市售杂芳基碘化物的交叉偶联，得到 2-杂芳基氮杂环丁烷。这种“现成”的方法产生了适合多样化的产品，从而获得了对药物化学项目有用的新型饱和杂环支架。还介绍了 Hantzsch 酯在杂芳基卤化物和 α-氨基自由基的镍催化交叉偶联中的另一种机制。

  DOI：

  10.1021/acs.orglett.2c03852

文献信息

• 1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia
  作者：Petr Vachal、Shouwu Miao、Joan M. Pierce、Deodial Guiadeen、Vincent J. Colandrea、Matthew J. Wyvratt、Scott P. Salowe、Lisa M. Sonatore、James A. Milligan、Richard Hajdu、Anantha Gollapudi、Carol A. Keohane、Russell B. Lingham、Suzanne M. Mandala、Julie A. DeMartino、Xinchun Tong、Michael Wolff、Dietrich Steinhuebel、Gerard R. Kieczykowski、Fred J. Fleitz、Kevin Chapman、John Athanasopoulos、Gregory Adam、Can D. Akyuz、Dhirendra K. Jena、Jeffrey W. Lusen、Juncai Meng、Benjamin D. Stein、Lei Xia、Edward C. Sherer、Jeffrey J. Hale

  DOI：10.1021/jm201542d

  日期：2012.4.12

  The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.