2-morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate | 351002-11-4

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate
• 英文别名: trifluoromethanesulfonic acid 2-(morpholin-4-yl)-4-oxo-4H-chromen-8-yl ester；trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl ester；(2-morpholin-4-yl-4-oxochromen-8-yl) trifluoromethanesulfonate
• CAS: 351002-11-4
• 化学式: C₁₄H₁₂F₃NO₆S
• 分子量: 379.314
• InChiKey: PQTXIVHYFSFWFT-UHFFFAOYSA-N

物化性质

• 熔点：
  174-175 °C(Solv: ethyl acetate (141-78-6))
• 沸点：
  473.0±45.0 °C(Predicted)
• 密度：
  1.588±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  90.5
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate 在 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 以78%的产率得到4H-1-苯并吡喃-4-酮,8-羟基-2-(4-吗啉基)-
  参考文献：
  名称：

  阻转异构体苯醌衍生物对DNA依赖性蛋白激酶（DNA-PK）的强对映体选择性抑制作用†

  摘要：

  取代在7位的chromen-4-one药效基团上 8-（二苯并[ b，d ]噻吩-4-基）-2-吗啉代-4 H-铬烯-4-一NU7441是一种有效的，选择性的DNA依赖性蛋白激酶（DNA-PK）抑制剂，具有烯丙基，正丙基或甲基，可以通过手性HPLC拆分阻转异构体。对每一对阻转异构体的DNA-PK的生物学评估显示，其效价存在显着差异，而生物学活性仅存在于Laororotatory对映异构体中。

  DOI：

  10.1039/c2ob26035b
• 作为产物：
  描述：

  4-乙酰基吗啉 在 三氟甲磺酸酐 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 78.0h， 生成 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl trifluoromethanesulfonate
  参考文献：
  名称：

  Discovery of Potent Chromen-4-one Inhibitors of the DNA-Dependent Protein Kinase (DNA-PK) Using a Small-Molecule Library Approach

  摘要：

  Structure-activity relationships for inhibition of DNA-dependent protein kinase (DNA-PK) have been defined for substituted chromen-4-ones. For the 2-amino-substituted benzo[h]chromen-4-ones, a morpholine substituent at this position was essential for activity. Small libraries of 6- and 7-alkoxy-substituted chromen-4-ones showed that a number of 7-alkoxysubstituted chromenones displayed improved activity. Focused libraries incorporating 6-, 7-, and 8-aryl and heteroaryl substituents were prepared. In these cases, 6- and 7-substitution was disfavored, whereas 8-substitution was largely tolerated. Surprisingly, two compounds, 2-N-morpholino-8-dibenzofuranyl-chromen-4-one (NU7427, 32{38}) and the 2-N-morpholino-8-dibenzothiophenyl-chromen-4-one (NU7441, 32{26}) were excellent inhibitors (IC50 vs DNAPK = 40 and 13 nM, respectively). The ring-saturated analogue 2-N-morpholino-8-(6',7',8',9'-tetrahydrodibenzothiophene)chromen-4-one, 36, retained potent activity (IC50 vs DNA-PK = 23 nM). The dibenzothiophene 32{38} sensitized HeLa cells to ionizing radiation in vitro, with dose modification factors of 2.5 at 10% survival being observed at 0.5 mu M. The cytotoxicity of the topoisomerase II inhibitor etoposide was also potentiated.

  DOI：

  10.1021/jm050444b

文献信息

• [EN] DIBENZOTHIOPHENE DERIVATIVES AS DNA- PK INHIBITORS<br/>[FR] DÉRIVÉS DE DIBENZOTHIOPHÈNE EN TANT QU'INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2010136778A1

  公开（公告）日：2010-12-02

  Compound formula I: wherein: X1 and X2 may be either (a) C and O, (b) N and N, or (c) C and NH, where the dotted bonds represents a double bond in the appropriate location; R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, an optionally substituted C3-20 heterocyclyl group, or an optionally substituted C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; RN1 is selected from hydrogen and an optionally substituted C1-4 alkyl group; RC1 is selected from an optionally substituted C1-7 alkyl group, an optionally substituted C3-20 heterocyclyl group, or an optionally substituted C5-20 aryl group; or RN1 and RC1 may together form an optionally substituted C2-4 alkylene group.

  化合物公式I：其中：X1和X2可以是（a）C和O，（b）N和N，或（c）C和NH，其中点线代表适当位置的双键；R1和R2分别从氢，可选择的取代的C1-7烷基基团，可选择的取代的C3-20杂环基团，或可选择的取代的C5-20芳基基团中独立选择，或者可以与它们附着的氮原子一起形成具有4至8个环原子的可选择取代的杂环环；RN1从氢和可选择的取代的C1-4烷基基团中选择；RC1从可选择的取代的C1-7烷基基团，可选择的取代的C3-20杂环基团，或可选择的取代的C5-20芳基基团中选择；或RN1和RC1可以一起形成一个可选择取代的C2-4烷基烃基团。
• Synthetic Studies of the Phosphatidylinositol 3-Kinase Inhibitor LY294002 and Related Analogues
  作者：Belinda Abbott、Philip Thompson

  DOI：10.1071/ch03113

  日期：——

  Synthetic methodologies have been developed for the direct and high-yielding preparation of the phosphatidylinositol 3-kinase inhibitor LY294002. These methods are readily amenable to the efficient generation of analogues, which will facilitate a detailed investigation of this important family of enzymes.

  已经开发了用于直接和高产制备磷脂酰肌醇 3-激酶抑制剂 LY294002 的合成方法。这些方法很容易适用于有效生成类似物，这将有助于对这一重要的酶家族进行详细研究。
• Judicious Application of Allyl Protecting Groups for the Synthesis of 2-Morpholin-4-yl-4-oxo-4<i>H</i>-chromen-8-yl Triflate, a Key Precursor of DNA-Dependent Protein Kinase Inhibitors
  作者：Sonsoles Rodriguez Aristegui、Marine Desage El-Murr、Bernard T. Golding、Roger J. Griffin、Ian R. Hardcastle

  DOI：10.1021/ol062297x

  日期：2006.12.1

  [Structure: see text] 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl 2,2,2-trifluoromethanesulfonate is a key intermediate for the synthesis of the DNA-dependent protein kinase (DNA-PK) inhibitor 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441). Two improved methods for the synthesis of this triflate have been developed: (A) in 35% overall yield, through modification of the published route, and (B)

  [结构：见正文] 2-吗啉-4-基-4-氧代-4H-铬n-8-基2,2,2-三氟甲磺酸盐是合成DNA依赖性蛋白激酶（DNA-PK）的关键中间体）抑制剂8-二苯并噻吩-4-基-2-吗啉-4-基-铬基-4-酮（NU7441）。已开发出两种改进的合成三氟甲磺酸酯的方法：（A）通过修饰已公开的路线使总收率达到35％，（B）通过采用Baker-Venkataraman重排反应的新路线来提高总收率15％。能够生成色酮支架。两种合成都取决于对烯丙基保护基的明智使用。
• [EN] DNA-PK INHIBITORS<br/>[FR] INHIBITEURS D'ADN-PK
  申请人：KUDOS PHARM LTD

  公开号：WO2006032869A1

  公开（公告）日：2006-03-30

  A compound of formula I: and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, wherein: R1 and R2 are independently selected from hydrogen, an optionally substituted C1-7 alkyl group, C3-20 heterocyclyl group, or C5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; Q is -NH-C(=O)- or -O-; Y is an optionally substituted C1-5 alkylene group; X is selected from SR3 or NR4R5, wherein, R3, or R4 and R5 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R4 and R5 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; if Q is -O-, X is additionally selected from -C(=O)-NR6R7, wherein R6 and R7 are independently selected from hydrogen, optionally substituted C1-7 alkyl, C5-20 aryl, or C3-20 heterocyclyl groups, or R6 and R7 may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; and if Q is -NH-C(=O)-, -Y-X may additionally be selected from C1-7 alkyl.

  化合物I的分子式为：及其异构体、盐、溶剂和化学保护形式、以及其前药，其中：R1和R2独立选择氢、可选取代的C1-7烷基、C3-20杂环基或C5-20芳基，或者与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；Q为-NH-C（=O）-或-O-；Y为可选取代的C1-5烷基；X选自SR3或NR4R5，其中R3，或R4和R5独立选择氢、可选取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R4和R5可以与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；如果Q为-O-，X还被选自-C（=O）-NR6R7，其中R6和R7独立选择氢、可选取代的C1-7烷基、C5-20芳基或C3-20杂环基，或者R6和R7可以与它们连接的氮原子一起形成一个可选取代的杂环环，其具有4至8个环原子；如果Q为-NH-C（=O）-，-Y-X还可以被选自C1-7烷基。
• Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure
  作者：Sonsoles Rodriguez-Aristegui、Kate M. Clapham、Lauren Barrett、Céline Cano、Marine Desage-El Murr、Roger J. Griffin、Ian R. Hardcastle、Sara L. Payne、Tommy Rennison、Caroline Richardson、Bernard T. Golding

  DOI：10.1039/c1ob05282a

  日期：——

  5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity

  通过2,6-二溴苯胺与苯基硼酸（被Me，NO 2，OH，OMe或Cl取代）的Suzuki交叉偶联，获得氨基取代的联苯，优选在微波辐射的辅助下进行。氨基转化为硫醇之前，先进行碱诱导的分子内取代，然后通过微波加热促进其生成目标二苯并噻吩的第二个C–S键。将所获得的1-，2-，3-或4-取代的6-卤代二苯并噻吩与2-吗啉-4--4-基-8-（4,4,5,5-四甲基-1,3）进行钯介导的偶联，2-二氧杂硼烷-2-基）-4 H-chromen-4-one给出各自的6-，7-，8-或9-取代的二苯并噻吩-4-基色农酮。这些化合物被评估为DNA依赖性蛋白激酶（DNA-PK）的抑制剂，并与母体8-（dibenzo [ b，d ] thiophen-4-yl）-2-morpholin-4-yl-4 H -chromen进行了比较。 -4-一 值得注意的是，在C-8或C-9上带有羟基或甲氧基取代基的衍生物保留