2-hydroxy-6,7,8,9-tetrahydropyrido<1,2-a>pyrimidin-4-one | 42733-31-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2-hydroxy-6,7,8,9-tetrahydropyrido<1,2-a>pyrimidin-4-one
• 英文别名: 2-hydroxy-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one；2-Hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one；2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one
• CAS: 42733-31-3
• 化学式: C₈H₁₀N₂O₂
• 分子量: 166.18
• InChiKey: UVQWECKEYOAZNK-UHFFFAOYSA-N

物化性质

• 沸点：
  298.5±50.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,4-二氯苯甲酰氯 、 2-hydroxy-6,7,8,9-tetrahydropyrido<1,2-a>pyrimidin-4-one 在 三乙胺 作用下， 以 甲苯 为溶剂， 反应 5.0h， 以56%的产率得到(4-Oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-2-yl) 2,4-dichlorobenzoate
  参考文献：
  名称：

  合成和4-羟基-2-喹诺酮类和4-羟基香豆素-3-芳酰基衍生物的反应†

  摘要：

  3-芳酰基-4-羟基-2-喹诺酮类4和11可以开始进行合成1或9 通过Fries重排的相应的酯的3和10，通过氰化钾和18-冠-6催化。提出了一种一锅法，其中不需要分离酯。用锌粉还原芳基酮4和11导致苄基衍生物5和12。芳基酮4和11与羟胺反应，随后加热粗产物，通过贝克曼热重排和脱水生成恶唑喹诺酮7和14。通过Fries重排不能将2-芳氧基吡啶并[1,2- a ]嘧啶-4-酮17和20转化为相应的酮。

  DOI：

  10.1002/jhet.5570330324
• 作为产物：
  描述：

  2-羟基-4H-吡啶并[1,2-a]嘧啶-4-酮 在 palladium on activated charcoal 氢气 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 80.0 ℃ 、500.0 kPa 条件下， 反应 72.0h， 以60%的产率得到2-hydroxy-6,7,8,9-tetrahydropyrido<1,2-a>pyrimidin-4-one
  参考文献：
  名称：

  合成和4-羟基-2-喹诺酮类和4-羟基香豆素-3-芳酰基衍生物的反应†

  摘要：

  3-芳酰基-4-羟基-2-喹诺酮类4和11可以开始进行合成1或9 通过Fries重排的相应的酯的3和10，通过氰化钾和18-冠-6催化。提出了一种一锅法，其中不需要分离酯。用锌粉还原芳基酮4和11导致苄基衍生物5和12。芳基酮4和11与羟胺反应，随后加热粗产物，通过贝克曼热重排和脱水生成恶唑喹诺酮7和14。通过Fries重排不能将2-芳氧基吡啶并[1,2- a ]嘧啶-4-酮17和20转化为相应的酮。

  DOI：

  10.1002/jhet.5570330324

文献信息

• [EN] HETEROCYCLIC COMPOUND AND USE THEREOF<br/>[FR] COMPOSÉ HÉTÉROCYCLIQUE ET SON UTILISATION<br/>[ZH] 杂环化合物及其用途
  申请人：CSPC ZHONGQI PHARMACEUTICAL TECH SHIJIAZHUANG CO LTD

  公开号：WO2021249057A1

  公开（公告）日：2021-12-16

  式(I-1)所示的SHP2抑制剂或其可药用盐、立体异构体、药物组合物以及它们在治疗和/或预防通过SHP2活性介导的疾病、病症和病况的应用。
• Compounds and compositions for inhibiting the activity of SHP2
  申请人：Novartis AG

  公开号：US10934285B2

  公开（公告）日：2021-03-02

  The present invention relates to compounds of formula I: in which Y1, Y2, R1, R2 and R3 are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.

  本发明涉及式 I 的化合物：其中 Y1、Y2、R1、R2 和 R3 在发明概述中定义；能够抑制 SHP2 的活性。本发明进一步提供了制备本发明化合物的工艺、包含此类化合物的药物制剂以及使用此类化合物和组合物治疗与 SHP2 活性异常有关的疾病或紊乱的方法。
• Sulfenylation of Heterocyclic 1,3-Dicarbonyl Compounds
  作者：Barbara Schnell、Thomas Kappe

  DOI：10.1007/pl00010293

  日期：1999.9
• Discovery and Characterization of (<i>R</i>)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-<i>c</i>][1,4]oxazin-4(9<i>H</i>)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates
  作者：Antonia F. Stepan、Michelle M. Claffey、Matthew R. Reese、Gayatri Balan、Gabriela Barreiro、Jason Barricklow、Michael J. Bohanon、Brian P. Boscoe、Gregg D. Cappon、Lois K. Chenard、Julie Cianfrogna、Laigao Chen、Karen J. Coffman、Susan E. Drozda、Joshua R. Dunetz、Somraj Ghosh、Xinjun Hou、Christopher Houle、Kapil Karki、John T. Lazzaro、Jessica Y. Mancuso、John M. Marcek、Emily L. Miller、Mark A. Moen、Steven O’Neil、Isao Sakurada、Marc Skaddan、Vinod Parikh、Deborah L. Smith、Patrick Trapa、Jamison B. Tuttle、Patrick R. Verhoest、Daniel P. Walker、Annie Won、Ann S. Wright、Jessica Whritenour、Kenneth Zasadny、Margaret M. Zaleska、Lei Zhang、Christopher L. Shaffer

  DOI：10.1021/acs.jmedchem.7b00604

  日期：2017.9.28

  We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu(5) negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu(5) NAMs. Increasing the sp(3) character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu(5) NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c] [1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
• COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE ACTIVITY OF SHP2
  申请人：Novartis AG

  公开号：US20210300919A1

  公开（公告）日：2021-09-30

  The present invention relates to compounds of formula I: in which Y 1 , Y 2 , R 1 , R 2 and R 3 are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.