2-amino-4-benzyloxy-6-methylaminopyrimidine | 1159107-85-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-amino-4-benzyloxy-6-methylaminopyrimidine
• 英文别名: 6-(benzyloxy)-N⁴-methylpyrimidine-2,4-diamine；4-(benzyloxy)-6-(methylamino)pyrimidine-2,4-diamine；4-N-methyl-6-phenylmethoxypyrimidine-2,4-diamine
• CAS: 1159107-85-3
• 化学式: C₁₂H₁₄N₄O
• 分子量: 230.269
• InChiKey: MXMWBKBTYCTDIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  73.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-amino-4-benzyloxy-6-methylaminopyrimidine 在 溶剂黄146 、 sodium nitrite 作用下， 以 水 为溶剂， 以90%的产率得到2-amino-6-benzyloxy-4-(N-methylamino)-5-nitrosopyrimidine
  参考文献：
  名称：

  6-（甲基氨基）-5-亚硝基嘧啶的酰化和8-甲基异黄th呤N（5）-氧化物的1，3-偶极环加成。的合成C（6） ，N（8）二取代Isoxanthopterins

  摘要：

  Abstractmagnified imageAcylation of 2‐amino‐4‐(benzyloxy)‐6‐(methylamino)‐5‐nitrosopyrimidine (5) with acetic anhydride or chloroacetic anhydride in the presence of 4‐(dimethylamino)pyridine (DMAP) led to the C(2)‐acylamino derivatives 6 and 7, respectively. In the absence of a base, acetylation did not lead to a product, while chloroacetylation led to the 6‐chloropteridine 11. Chloroacetylation in the presence of Hünig's base provided the pteridinone N(5)‐oxide 10, suggesting that acylation of 5 is readily reversible, and that the unfavourable equilibrium must be displaced by a follow‐up reaction to trap the acylation product. Acylation of 5 with hexadienoyl chloride, followed by intramolecular Diels–Alder reaction, provided the pteridinone 12. A high yielding 1,3‐dipolar cycloaddition of the acylnitrone 10 to electron‐poor and electron‐rich dipolarophiles, followed by spontaneous N,O‐bond cleavage, gave the C(6)‐substituted pteridinones 19a–19e that were deprotected to the pteridine‐4,7(3H,8H)‐diones 20a–20e. Substitution of the 6‐chloropterin 11 provided the 6‐morpholinopteridine 25. Sonogashira coupling yielded the fluorescent [(pteridin‐6‐yl)ethynyl]‐glucopyranoside 26, 6‐ethynylpteridine 28, and 6,6′‐(ethynediyl)bispteridine 29. The alkyne 28 reacted with Me3SiCl and LiBr in MeCN to produce the bromoalkene 31.

  DOI：

  10.1002/hlca.200900009
• 作为产物：
  描述：

  6-氯-N~4~-甲基嘧啶-2,4-二胺 、 苯甲醇 在 sodium hydride 作用下， 以 二甲基亚砜 、 mineral oil 为溶剂， 反应 5.33h， 以29%的产率得到2-amino-4-benzyloxy-6-methylaminopyrimidine
  参考文献：
  名称：

  发现有效的和选择性的肿瘤MTH1抑制剂：启用快速靶标（In）验证

  摘要：

  我们描述了三种结构上有区别的有效和选择性MTH1抑制剂的发现，以及它们随后用于研究MTH1作为肿瘤靶标，最终达到靶标（无效）的目的。四氢萘啶5被迅速鉴定为高效MTH1抑制剂（IC 50 = 0.043 nM）。的共结晶5与MTH1揭示在Φ-配体顺式- ñ - （吡啶-2-基）乙酰胺构象使得关键分子内氢键和极性相互作用的残基Gly34和Asp120。用O-和N修饰文献化合物TH287-连接的芳基和烷基芳基取代基导致发现有效的嘧啶-2,4,6-三胺25（IC 50 = 0.49 nM）。三唑并吡啶32以具有高选择性的铅化合物出现，在大鼠中具有合适的体外特性和所需的药代动力学特性。研究了根据MTH1敲低和/或小分子抑制作用来研究DNA损伤反应，细胞活力和氧代-NTPs（氧化的核苷三磷酸）的细胞内浓度。根据我们的发现，我们无法提供证据进一步将MTH1用作肿瘤靶标。

  DOI：

  10.1021/acsmedchemlett.9b00420

文献信息

• Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation
  作者：Julie Farand、Jeffrey E. Kropf、Peter Blomgren、Jianjun Xu、Aaron C. Schmitt、Zachary E. Newby、Ting Wang、Eisuke Murakami、Ona Barauskas、Jawahar Sudhamsu、Joy Y. Feng、Anita Niedziela-Majka、Brian E. Schultz、Karen Schwartz、Serge Viatchenko-Karpinski、Dmytro Kornyeyev、Adam Kashishian、Peidong Fan、Xiaowu Chen、Eric B. Lansdon、Michael O. Ports、Kevin S. Currie、William J. Watkins、Gregory T. Notte

  DOI：10.1021/acsmedchemlett.9b00420

  日期：2020.3.12

  We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystallization of 5 with MTH1 revealed the ligand in a Φ-cis-N-(pyridin-2-yl)acetamide conformation

  我们描述了三种结构上有区别的有效和选择性MTH1抑制剂的发现，以及它们随后用于研究MTH1作为肿瘤靶标，最终达到靶标（无效）的目的。四氢萘啶5被迅速鉴定为高效MTH1抑制剂（IC 50 = 0.043 nM）。的共结晶5与MTH1揭示在Φ-配体顺式- ñ - （吡啶-2-基）乙酰胺构象使得关键分子内氢键和极性相互作用的残基Gly34和Asp120。用O-和N修饰文献化合物TH287-连接的芳基和烷基芳基取代基导致发现有效的嘧啶-2,4,6-三胺25（IC 50 = 0.49 nM）。三唑并吡啶32以具有高选择性的铅化合物出现，在大鼠中具有合适的体外特性和所需的药代动力学特性。研究了根据MTH1敲低和/或小分子抑制作用来研究DNA损伤反应，细胞活力和氧代-NTPs（氧化的核苷三磷酸）的细胞内浓度。根据我们的发现，我们无法提供证据进一步将MTH1用作肿瘤靶标。
• Acylation of a 6-(Methylamino)-5-nitrosopyrimidine and 1,3-Dipolar Cycloaddition of an 8-Methylisoxanthopterin<i>N(5)</i>-Oxide. Synthesis of<i>C(6)</i>,<i>N(8)</i>-Disubstituted Isoxanthopterins
  作者：Thomas Steinlin、Andrea Vasella

  DOI：10.1002/hlca.200900009

  日期：2009.3

  Abstractmagnified imageAcylation of 2‐amino‐4‐(benzyloxy)‐6‐(methylamino)‐5‐nitrosopyrimidine (5) with acetic anhydride or chloroacetic anhydride in the presence of 4‐(dimethylamino)pyridine (DMAP) led to the C(2)‐acylamino derivatives 6 and 7, respectively. In the absence of a base, acetylation did not lead to a product, while chloroacetylation led to the 6‐chloropteridine 11. Chloroacetylation in the presence of Hünig's base provided the pteridinone N(5)‐oxide 10, suggesting that acylation of 5 is readily reversible, and that the unfavourable equilibrium must be displaced by a follow‐up reaction to trap the acylation product. Acylation of 5 with hexadienoyl chloride, followed by intramolecular Diels–Alder reaction, provided the pteridinone 12. A high yielding 1,3‐dipolar cycloaddition of the acylnitrone 10 to electron‐poor and electron‐rich dipolarophiles, followed by spontaneous N,O‐bond cleavage, gave the C(6)‐substituted pteridinones 19a–19e that were deprotected to the pteridine‐4,7(3H,8H)‐diones 20a–20e. Substitution of the 6‐chloropterin 11 provided the 6‐morpholinopteridine 25. Sonogashira coupling yielded the fluorescent [(pteridin‐6‐yl)ethynyl]‐glucopyranoside 26, 6‐ethynylpteridine 28, and 6,6′‐(ethynediyl)bispteridine 29. The alkyne 28 reacted with Me3SiCl and LiBr in MeCN to produce the bromoalkene 31.