CN109485651B - 2,3-稠环吲哚啉衍生物及其制备方法和应用 - Google Patents

2,3-稠环吲哚啉衍生物及其制备方法和应用 Download PDF

Info

Publication number
CN109485651B
CN109485651B CN201811425104.1A CN201811425104A CN109485651B CN 109485651 B CN109485651 B CN 109485651B CN 201811425104 A CN201811425104 A CN 201811425104A CN 109485651 B CN109485651 B CN 109485651B
Authority
CN
China
Prior art keywords
cdcl
nmr
group
yield
represent hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201811425104.1A
Other languages
English (en)
Other versions
CN109485651A (zh
Inventor
莫冬亮
马小盼
吴思仪
陈威利
苏桂发
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangxi Normal University
Original Assignee
Guangxi Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangxi Normal University filed Critical Guangxi Normal University
Priority to CN201811425104.1A priority Critical patent/CN109485651B/zh
Publication of CN109485651A publication Critical patent/CN109485651A/zh
Application granted granted Critical
Publication of CN109485651B publication Critical patent/CN109485651B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Abstract

本发明公开了一系列2,3‑稠环吲哚啉衍生物及其制备方法和应用。该衍生物如式(I)所示，其制备方法包括：取式(II)所示化合物置于有机溶剂中在氧气存在下反应即得目标物粗品。式(I)和式(II)所示结构如下：
Figure DDA0001881417470000011
其中X为氧，n＝1，各取代基的选择为：R1、R3和R4均为氢，R2为苯基亚乙烯基；或R1和R4均为氢，R2为苯基亚乙烯基，R3为4‑甲氧基；或R1和R4均为氢，R2为苯基亚乙烯基，R3为4‑叔丁基；或R1和R4均为氢，R2为苯基亚乙烯基，R3为3‑甲氧基；或R1和R4均为氢，R2为苯基亚乙烯基，R3为3,5‑二甲基；或R1和R4均为氢，R2为苯基亚乙烯基，R3为2‑甲基。

Description

2,3-稠环吲哚啉衍生物及其制备方法和应用
本申请是“2,3-稠环吲哚啉衍生物及其合成方法和应用”的分案申请，原申请的申请日为：2017年6月29日，申请号为：201710518658.5，发明名称为：2,3-稠环吲哚啉衍生物及其合成方法和应用。
技术领域
本发明涉及医药技术领域，具体涉及2,3-稠环吲哚啉衍生物及其合成方法和应用。
背景技术
吲哚生物碱是一类重要的天然产物，由于其数目众多，结构复杂，往往具有显著的生理活性，因此一直备受合成化学家以及药物化学家的青睐。
稠环吲哚啉骨架，特别是2，3-稠环吲哚啉是吲哚啉生物碱中广泛存在的核心结构，在化合物的生理活性及药理活性中起到了决定性作用，2，3-稠环吲哚啉核心骨架的成功构建是这类生物碱全合成的重点和难点，因此2，3-稠环吲哚啉骨架的高效构建一直是有机合成中的热点和难点之一。构建这类骨架的策略可以通过钯催化的串联反应(Zhang,G.Z.；Catalano,V.J.；Zhang,L.M.J.Am.Chem.Soc.2007,129,11358-11359.)，氧化偶联、分子内环化反应(Zuo,Z.W.；Xie,W.Q.；Ma,D.W.J.Am.Chem.Soc.2010,132,13226-13228)等，但这些方法都存在底物受限，官能团兼容性差，步骤繁琐以及使用原料较复杂等不足。
发明内容
本发明要解决的技术问题是提供一系列结构新颖的2,3-稠环吲哚啉衍生物，以及它们的合成方法和应用。
本发明涉及下述式(I)所示化合物或其药学上可接受的盐：
Figure BDA0001881417460000011
其中：
R1表示氢、C1～4的烷基、C1～4的烷氧基、C1～4的全氟烷基或卤原子，或者是未取代、单取代、二取代、三取代、四取代或五取代的苯基，或者是未取代的呋喃基，或者是未取代的噻吩基，或者是未取代的萘基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～4的烷基、氰基或卤原子；
R2表示氢、C1～4的烷基、C1～4的烷氧基、C1～4的全氟烷基或卤原子，或者是未取代、单取代、二取代、三取代、四取代或五取代的苯基，或者是未取代的呋喃基，或者是未取代的噻吩基，或者是未取代的萘基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～4的烷基、氰基或卤原子；
R3表示氢、C1～8的烷基、C1～6的烷氧基或C1～4的全氟烷基，或者是未取代、单取代或二取代的苯基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～6的烷基或卤原子；
R4表示氢、C1～8的烷基、C1～6的烷氧基或C1～4的全氟烷基，或者是未取代、单取代或二取代的苯基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～6的烷基或卤原子；
X表示氧或氮原子；
n＝1、2或3。
上述化合物中：
R1进一步优选为氢或C1～4烷基，或者是未取代、单取代或二取代的苯基；
R2进一步优选为氢或C1～4烷基，或者是未取代、单取代或二取代的苯基；
R3进一步优选为氢或C1～4烷基，或者是未取代、单取代或二取代的苯基；
R4进一步优选为氢或C1～4烷基，或者是未取代、单取代或二取代的苯基。
上述式(I)所示化合物的合成方法，主要包括以下步骤：取如下式(II)所示化合物置于有机溶剂中，在氧气存在的条件下反应，制得目标物粗品；
Figure BDA0001881417460000021
其中：
R1表示氢、C1～4的烷基、C1～4的烷氧基、C1～4的全氟烷基或卤原子，或者是未取代、单取代、二取代、三取代、四取代或五取代的苯基，或者是未取代的呋喃基，或者是未取代的噻吩基，或者是未取代的萘基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～4的烷基、氰基或卤原子；
R2表示氢、C1～4的烷基、C1～4的烷氧基、C1～4的全氟烷基或卤原子，或者是未取代、单取代、二取代、三取代、四取代或五取代的苯基，或者是未取代的呋喃基，或者是未取代的噻吩基，或者是未取代的萘基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～4的烷基、氰基或卤原子；
R3表示氢、C1～8的烷基、C1～6的烷氧基或C1～4的全氟烷基，或者是未取代、单取代或二取代的苯基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～6的烷基或卤原子；
R4表示氢、C1～8的烷基、C1～6的烷氧基或C1～4的全氟烷基，或者是未取代、单取代或二取代的苯基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～6的烷基或卤原子；
X表示氧或氮原子；
n＝1、2或3。
上述合成方法中，R1、R2、R3和R4的优先选择如前所述。
上述合成方法中，式(II)所示化合物为N-芳基α,β-不饱和硝酮衍生物，其可参考现有文献(Xiao-Pan Ma,Wei-Min Shi,Xue-Ling Mo,Xiao-Hua Li,Liang-Gui Li,Cheng-Xue Pan,Bo Chen*,Gui-Fa Su*and Dong-Liang Mo*,J.Org.Chem.2015,80,10098-10107.)进行合成，也可自选设计合成路线进行合成，在此不再详述。
上述合成方法中，所述的有机溶剂可以是选自苯、甲苯、环己烷、石油醚、四氯化碳、四氢呋喃、乙酸乙酯、乙腈、乙醚、二氯甲烷、丙酮、三氯甲烷、正己烷和二氧六环中一种或两种以上的组合。当有机溶剂的选择为上述两种以上物质的组合时，它们的配比可以为任意配比。
上述合成方法中，反应一般选择在空气条件下进行，同时反应优选是在低于100℃的条件下进行，进一步优选是在常温至80℃的条件下进行。反应是否完全可采用TLC跟踪检测。根据申请人的经验，当反应在80℃条件下进行时，反应时间控制在5～20h较为适宜。
本发明所述的合成方法中，所述有机溶剂的用量以能够溶解参加反应的原料为宜，通常情况下，1mmol的式(II)所示化合物通常用1～10mL的有机溶剂来溶解。
由上述方法制得的是式(I)化合物的粗品，可采用现有常规的纯化方法对其进行纯化以提高式(I)化合物的纯度。通常采用硅胶薄层色谱或硅胶柱层析，或者是重结晶的方式进行纯化，在层析时用的洗脱剂和重结晶时用的溶剂相同，可以是由石油醚和乙酸乙酯组成的混合溶剂，也可以是由正己烷和乙酸乙酯组成的混合溶剂。在前述混合溶剂中，石油醚和乙酸乙酯的体积比优选为50：1～10：1，正己烷和乙酸乙酯的体积比优选为50:1～10:1。
本发明还提供上述式(I)所示化合物或其药学上可接受的盐在制备抗肿瘤药物中的应用。
与现有技术相比，本发明提供了一系列结构新颖的2,3-稠环吲哚啉衍生物以及它们的合成方法和它们应用，申请人发现部分2,3-稠环吲哚啉衍生物具有一定的抗肿瘤活性。另一方面，本发明提供的合成方法简单易控，周期短，产率较高，不需无水无氧条件。
具体实施方式
下面结合具体实施例对本发明作进一步的详述,以更好地理解本发明的内容,但本发明并不限于以下实施例。
以下各实施例中涉及的N-芳基α,β-不饱和硝酮衍生物(即式(II)所示化合物)参照下述合成路线进行合成：
Figure BDA0001881417460000041
其中：
R1表示氢、C1～4的烷基、C1～4的烷氧基、C1～4的全氟烷基或卤原子，或者是未取代、单取代、二取代、三取代、四取代或五取代的苯基，或者是未取代的呋喃基，或者是未取代的噻吩基，或者是未取代的萘基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～4的烷基、氰基或卤原子；
R2表示氢、C1～4的烷基、C1～4的烷氧基、C1～4的全氟烷基或卤原子，或者是未取代、单取代、二取代、三取代、四取代或五取代的苯基，或者是未取代的呋喃基，或者是未取代的噻吩基，或者是未取代的萘基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～4的烷基、氰基或卤原子；
R3表示氢、C1～8的烷基、C1～6的烷氧基或C1～4的全氟烷基，或者是未取代、单取代或二取代的苯基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～6的烷基或卤原子；
R4表示氢、C1～8的烷基、C1～6的烷氧基或C1～4的全氟烷基，或者是未取代、单取代或二取代的苯基；其中，取代基为C1～4的烷氧基、C1～4的全氟烷基、C1～6的烷基或卤原子；
X表示氧或氮原子；
n＝1、2或3。
具体的合成方法为：将α,β-不饱和肟底物S1(0.5mmol)和氢氧化钾(0.75mmol)置于反应管中，加入5mL四氯化碳，室温下搅拌5min，加入高价碘试剂S2(0.75mmol)，室温反应1-24h后，所得反应物减压除去溶剂，残渣上硅胶柱层析分离(石油醚/乙酸乙酯＝4：1～1：1，体积比)，得到目标产物1(即式(II)所示化合物N-芳基α,β-不饱和硝酮)。
实施例1
按下述合成路线合成本发明所述的2,3-稠环吲哚啉衍生物。
Figure BDA0001881417460000042
2a:R1＝H,R2＝PhCH＝CH,R3＝H,R4＝H,n＝1；
2b:R1＝H,R2＝PhCH＝CH,R3＝4-OMe,R4＝H,n＝1；
2c:R1＝H,R2＝PhCH＝CH,R3＝4-Me,R4＝H,n＝1；
2d:R1＝H,R2＝PhCH＝CH,R3＝4-tBu,R4＝H,n＝1；
2e:R1＝H,R2＝PhCH＝CH,R3＝4-Cl,R4＝H,n＝1；
2f:R1＝H,R2＝PhCH＝CH,R3＝4-F,R4＝H,n＝1；
2g:R1＝H,R2＝PhCH＝CH,R3＝4-CF3,R4＝H,n＝1；
2h:R1＝H,R2＝PhCH＝CH,R3＝4-CO2Me,R4＝H,n＝1；
2i:R1＝H,R2＝PhCH＝CH,R3＝3-OMe,R4＝H,n＝1；
2j:R1＝H,R2＝PhCH＝CH,R3＝3-NO2,R4＝H,n＝1；
2k:R1＝H,R2＝PhCH＝CH,R3＝3,5-Me,R4＝H,n＝1；
2l:R1＝H,R2＝PhCH＝CH,R3＝2-Me,R4＝H,n＝1；
2ab:R1＝H,R2＝(4-OMe)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ac:R1＝H,R2＝(4-Me)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ad:R1＝H,R2＝(4-F)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ae:R1＝H,R2＝(4-CF3)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2af:R1＝H,R2＝(3-OMe)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ag:R1＝H,R2＝(3-Br)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ah:R1＝H,R2＝(2-Br)C6H4CH＝CH,R3＝H,R4＝H,n＝1；
2ai:R1＝H,R2＝(2-furyl)CH＝CH,R3＝H,R4＝H,n＝1；
2aj:R1＝H,R2＝Me,R3＝H,R4＝H,n＝1；
2ak:R1＝H,R2＝Me,R3＝H,R4＝Me,n＝1；
2al:R1＝H,R2＝PhCH＝CH,R3＝H,R4＝Ph,n＝1；
2am:R1＝4-F,R2＝PhCH＝CH,R3＝H,R4＝H,n＝1；
2an:R1＝3-Br,R2＝Me,R3＝H,R4＝H,n＝1；
2ao:R1＝3,5-Me,R2＝Me,R3＝H,R4＝H,n＝1；
2ap:R1＝H,R2＝H,R3＝H,R4＝H,n＝1；
2aq:R1＝H,R2＝H,R3＝H,R4＝H,n＝1,X＝NH；
2ar:R1＝H,R2＝H,R3＝H,R4＝H,n＝2；
2as:R1＝H,R2＝H,R3＝H,R4＝H,n＝3。
取N-芳基α,β-不饱和硝酮底物1(0.2mmol)置于反应管中，加入2mL有机溶剂(其中目标物2a-2l采用的有机溶剂为四氯化碳，目标物2af-2am采用的有机溶剂分别为苯、甲苯、环己烷、石油醚、四氢呋喃、乙酸乙酯、乙腈和乙醚，目标物2an-2as采用的有机溶剂均为苯和四氢呋喃按1：1的体积比组成的混合溶剂)在80℃下搅拌反应5-20h，所得反应物减压除去溶剂，残渣上硅胶柱层析分离(石油醚/乙酸乙酯＝50：1～10：1，体积比)，得到目标产物2。不同的目标产物及其表征如下：
Figure BDA0001881417460000051
2a：固体,50mg,70％yield；mp 161–162℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.29(d,J＝7.6Hz,2H),7.24(t,J＝7.2Hz,2H),7.19–7.15(m,1H),7.11(d,J＝7.6Hz,1H),7.07–7.03(m,J＝6.8Hz,3H),6.90–6.86(m,2H),6.76(t,J＝6.8Hz,2H),6.63(d,J＝8.0Hz,1H),6.40(d,J＝15.6Hz,1H),4.66(d,J＝12.8Hz,1H),4.30(brs,1H),4.27(d,J＝12.4Hz,1H)；13C NMR(100MHz,CDCl3):δ197.0,154.2,149.9,135.7,132.7,130.1,129.1,129.0,128.6,128.2,127.4,126.9,126.8,124.6,122.7,122.1,120.3,117.6,110.8,69.9,63.0,61.6.IR(thin film)3367,2925,2848,1709,1602,1482,1214,1059,755cm-1；HRMS(ESI)m/zcalcd for C24H20NO2[M+H]+:354.1494,found:354.1495.
Figure BDA0001881417460000061
2b：固体,52mg,67％yield；mp 51–52℃.1H NMR(400MHz,CDCl3):δ9.51(s,1H),7.29(d,J＝7.2Hz,2H),7.24–7.21(m,2H),7.19–7.15(m,1H),7.12(d,J＝7.6Hz,1H),7.08–7.04(m,1H),6.90–6.86(m,2H),6.77(d,J＝8.4Hz,1H),6.64(d,J＝6.4Hz,3H),6.40(d,J＝16.0Hz,1H),4.65(d,J＝16.4Hz,1H),4.28(d,J＝12.4Hz,1H),4.10(brs,1H),3.64(s,3H).13C NMR(100MHz,CDCl3):δ202.2,154.6,144.3,139.6,136.2,131.5,129.8,128.6,128.5,128.4,127.9,127.7,127.5,126.6,122.1,117.5,115.4,111.9,110.4,71.0,66.5,64.9,55.3.IR(thin film)3433,3025,2924,1709,1638,1459,1272,752cm-1；HRMS(ESI)m/zcalcd for C25H22NO3[M+H]+:384.1600,found:384.1594.
Figure BDA0001881417460000062
2c：固体,46mg,63％yield；mp 186–188℃.1H NMR(400MHz,CDCl3):δ9.49(s,1H),7.30(d,J＝7.6Hz,2H),7.25–7.15(m,3H),7.11–7.04(m,2H),6.90–6.86(m,4H),6.77(d,J＝8.4Hz,1H),6.55(d,J＝9.2Hz,1H),6.40(d,J＝15.6Hz,1H),4.66(d,J＝12.4Hz,1H),4.29(d,J＝12.8Hz,1H),4.20(brs,1H),2.17(s,3H).13C NMR(100MHz,CDCl3):δ197.1,154.2,147.6,135.8,132.6,130.7,129.9,129.3,128.9,128.6,128.1,127.5,127.1,126.8,125.1,122.8,122.1,117.6,110.7,70.0,62.7,61.4,20.6.IR(thin film)3360,3028,2923,1709,1614,1493,1263,821,748cm-1；HRMS(ESI)m/z calcd for C25H22NO2[M+H]+:368.1651,found:368.1664.
Figure BDA0001881417460000063
2d：固体,49mg,60％yield；mp 163–164℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.30(d,J＝7.2Hz,2H),7.25–7.21(m,2H),7.19–7.16(m,1H),7.11–7.03(m,4H),6.89–6.85(m,2H),6.77(d,J＝8.0Hz,1H),6.59(d,J＝8.4Hz,1H),6.41(d,J＝16.0Hz,1H),4.67(d,J＝12.4Hz,1H),4.31(d,J＝12.4Hz,1H),4.19(brs,1H),1.18(s,9H).13C NMR(100MHz,CDCl3):δ197.3,154.3,147.5,143.6,135.8,132.5,129.5,128.9,128.6,128.1,127.5,127.2,127.1,126.8,122.4,122.0,121.3,117.7,110.4,70.0,63.1,61.9,34.3,31.5.IR(thin film)3376,3033,2960,1716,1613,1490,1270,824,749cm-1；HRMS(ESI)m/z calcdforC28H28NO2[M+H]+:410.2120,found:410.2115.
Figure BDA0001881417460000071
2e：固体,41mg,53％yield；mp 167–168℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.29–7.17(m,5H),7.10(t,J＝7.2Hz,2H),7.02(d,J＝8.4Hz,2H),6.90–6.84(m,2H),6.79(d,J＝8.0Hz,1H),6.55(d,J＝8.0Hz,1H),6.38(d,J＝15.6Hz,1H),4.62(d,J＝12.4Hz,1H),4.32(brs,1H),4.28(d,J＝15.6Hz,1H).13C NMR(100MHz,CDCl3):δ196.4,154.2,148.4,135.5,133.0,130.1,129.2,128.7,128.6,128.3,127.4,126.8,126.5,125.0,124.9,124.6,122.3,117.7,111.7,70.4,62.8,61.6.IR(thin film)3360,2923,2854,1713,1602,1482,756,690cm-1；HRMS(ESI)m/z calcd for C24H19ClNO2[M+H]+:388.1104,found:388.1087.
Figure BDA0001881417460000072
2f：固体,45mg,60％yield；mp 169–170℃.1H NMR(400MHz,CDCl3):δ9.52(s,1H),7.30(d,J＝7.2Hz,2H),7.26(t,J＝7.2Hz,2H),7.20–7.18(m,1H),7.12–7.06(m,2H),6.91–6.86(m,2H),6.80–6.74(m,3H),6.57(dd,J＝8.4Hz,4.0Hz,1H),6.39(d,J＝16.0Hz,1H),4.63(d,J＝12.4Hz,1H),4.28(d,J＝12.4Hz,1H),4.20(brs,1H).13C NMR(100MHz,CDCl3):δ196.7,158.8(d,J＝237Hz),154.2,145.9,135.6,132.9,129.1,128.8,128.6,128.3,127.4,126.8,126.7,124.4(d,J＝8Hz),122.3,117.7,116.8(d,J＝23.3Hz),112.1(d,J＝24.1Hz),111.4(d,J＝8.1Hz),70.6,62.8,61.8.IR(thin film)3359,2925,2853,1708,1608,1487,1221,757cm-1；HRMS(ESI)m/z calcd for C24H19FNO2[M+H]+:372.1400,found:372.1385.
Figure BDA0001881417460000073
2g：固体,34mg,40％yield；mp 122–123℃.1H NMR(400MHz,CDCl3):δ9.53(s,1H),7.33–7.18(m,7H),7.12–7.08(m,2H),6.93–6.89(m,1H),6.87–6.79(m,2H),6.68(d,J＝8.0Hz,1H),6.40(d,J＝16.0Hz,1H),4.64(d,J＝12.4Hz,1H),4.59(brs,1H),4.33(d,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3):δ196.2,154.2,152.5,135.4,133.1,129.3,128.7,128.5,128.3,128.1,128.0,127.4,126.8,126.1,123.2,122.4,122.2,122.1,117.9,110.0,70.2,62.7,61.2.IR(thinfilm)3339,2923,2853,1710,1623,1274,1104,758cm-1；HRMS(ESI)m/z calcdfor C25H19F3NO2[M+H]+:422.1368,found:422.1368.
Figure BDA0001881417460000081
2h：固体,40mg,49％yield；mp 73–74℃.1H NMR(400MHz,CDCl3):δ9.51(s,1H),7.82(d,J＝8.0Hz,1H),7.75(s,1H),7.30–7.18(m,5H),7.11–7.07(m,2H),6.91–6.83(m,2H),6.79(d,J＝8.4Hz,1H),6.63(d,J＝8.0Hz,1H),6.39(d,J＝16.0Hz,1H),4.71(brs,1H),4.67(d,J＝12.4Hz,1H),4.33(d,J＝12.8Hz,1H),3.77(s,3H).13C NMR(100MHz,CDCl3):δ196.2,166.5,154.2,153.7,135.4,133.0,132.9,129.3,128.7,128.4,128.0,127.4,126.8,126.6,126.2,122.8,122.3,122.0,117.9,109.6,70.4,63.1,61.2,51.7.IR(thin film)3345,3025,2924,1708,1518,1285,753cm-1；HRMS(ESI)m/z calcd forC26H22NO4[M+H]+:412.1549,found:412.1552.
Figure BDA0001881417460000082
2i：固体,48mg,63％yield；mp 43–44℃.1H NMR(400MHz,CDCl3):δ9.48(s,1H),9.46(s,1H),7.30(d,J＝7.2Hz,4H),7.24(t,J＝7.2Hz,4H),7.19–7.16(m,2H),7.11–7.03(m,4H),6.95–6.83(m,6H),6.77(d,J＝8.0Hz,2H),6.58(d,J＝7.6Hz,1H),6.51(d,J＝7.6Hz,1H),6.47–6.36(m,4H),4.97(d,J＝12.4Hz,1H),4.65(d,J＝12.0Hz,1H),4.28–4.19(m,4H),2.20(s,3H),2.16(s,3H).13C NMR(100MHz,CDCl3):δ197.0,196.3,155.0,154.2,150.2,150.0,140.4,137.0,135.8,133.0,132.6,130.1,129.2,129.0,128.9,128.8,128.6,128.5,128.2,128.1,127.4,127.3,127.2,127.0,126.9,126.8,126.7,124.3,122.8,122.1,122.0,121.2,119.8,119.5,117.7,117.5,111.6,108.6,70.4,70.0,63.0,62.9,62.6,61.4,21.3,18.5.IR(thin film)3368,3025,2924,1708,1614,1459,1272,752cm-1；HRMS(ESI)m/z calcd for C25H22NO3[M+H]+:384.1600,found:384.1583.
Figure BDA0001881417460000091
2j：固体,38mg,48％yield；mp 187–188℃.1H NMR(400MHz,CDCl3):δ9.60(s,1H),7.43(d,J＝8.0Hz,1H),7.28–7.18(m,6H),7.11(d,J＝7.6Hz,2H),6.92–6.89(m,2H),6.83(d,J＝8.0Hz,1H),6.72(d,J＝16.0Hz,1H),6.72(d,J＝16.0Hz,1H),4.61(brs,1H),4.60(d,J＝12.6Hz,1H),4.54(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ195.7,154.1,150.5,150.0,135.3,133.5,130.0,129.5,128.7,128.6,127.8,127.4,126.8,125.9,125.1,122.6,117.8,115.7,105.1,70.8,62.9,61.5.IR(thin film)3349,2923,2852,1716,1529,1351,802,759cm-1；HRMS(ESI)m/z calcd for C24H19N2O2[M+H]+:399.1345,found:399.1339.
Figure BDA0001881417460000092
2k：固体,46mg,60％yield；mp 96–97℃.1H NMR(400MHz,CDCl3):δ9.58(s,1H),7.42(d,J＝8.0Hz,1H),7.26–7.17(m,4H),7.10(d,J＝7.6Hz,3H),6.92–6.85(m,2H),6.80(d,J＝8.0Hz,1H),6.72(d,J＝16.0Hz,1H),6.70(d,J＝16.0Hz,1H),4.65(brs,1H),4.60(d,J＝12.6Hz,1H),4.52(d,J＝12.4Hz,1H),2.06(s,3H),2.03(s,3H).13C NMR(100MHz,CDCl3):δ195.7,154.1,150.5,150.0,135.3,133.5,130.0,129.5,128.7,128.6,127.8,127.4,126.8,125.9,125.1,122.6,117.8,115.7,105.1,70.8,62.9,61.5,16.8,16.1.IR(thin film)3451,3032,2924,2850,1733,1606,1510,968,635cm-1；HRMS(ESI)m/z calcdforC26H24NO2[M+H]+:382.1807,found:382.1829.
Figure BDA0001881417460000093
2l：固体,50mg,68％yield；mp 220–221℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.30(d,J＝7.6Hz,2H),7.25–7.21(m,2H),7.19–7.13(m,2H),7.08–7.04(m,1H),6.89–6.86(m,4H),6.77(d,J＝8.0Hz,1H),6.72(t,J＝7.6Hz,1H),6.43(d,J＝16.0Hz,1H),4.64(d,J＝12.4Hz,1H),4.31(d,J＝12.4Hz,1H),4.09(brs,1H),2.07(s,3H).13C NMR(100MHz,CDCl3):δ197.1,154.3,148.5,135.8,132.6,131.1,129.4,128.9,128.6,128.5,128.2,127.4,127.2,126.8,122.2,122.0,120.5,120.2,117.7,69.7,63.2,62.0,16.7.IR(thinfilm)3352,3023,2926,1705,1582,1485,1058,762,688cm-1；HRMS(ESI)m/z calcdforC25H22NO2[M+H]+:368.1651,found:368.1640.
Figure BDA0001881417460000101
2ab：固体,58mg,75％yield；mp 59–60℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.23(d,J＝8.4Hz,2H),7.12(d,J＝7.6Hz,1H),7.07–7.03(m,3H),6.89(d,J＝7.6Hz,1H),6.82–6.73(m,5H),6.63(d,J＝8.0Hz,1H),6.27(d,J＝15.6Hz,1H),4.66(d,J＝12.4Hz,1H),4.29(brs,1H),4.26(d,J＝12.8Hz,1H),3.72(s,3H).13C NMR(100MHz,CDCl3):δ197.0,159.7,154.3,149.9,132.2,130.1,128.9,128.5,128.0,127.5,127.1,126.9,124.6,122.7,122.1,120.3,117.6,114.0,110.7,70.0,63.0,61.6,55.3.IR(thin film)3360,3032,2924,1709,1606,1257,809,753cm-1；HRMS(ESI)m/z calcd for C25H22NO3[M+H]+:384.1600,found:384.1586.
Figure BDA0001881417460000102
2ac：固体,32mg,43％yield；mp 38–39℃.1H NMR(400MHz,CDCl3):δ9.51(s,1H),7.20(d,J＝7.2Hz,2H),7.12–7.04(m,6H),6.90(t,J＝7.2Hz,2H),6.77–6.75(m,2H),6.65(d,J＝8.0Hz,1H),6.36(d,J＝16.0Hz,1H),4.74(brs,1H),4.67(d,J＝12.0Hz,1H),4.30(d,J＝12.4Hz,1H),2.26(s,3H).13C NMR(100MHz,CDCl3):δ197.0,154.2,149.7,138.2,133.0,132.6,130.1,129.3,128.9,128.1,127.5,127.0,126.7,124.7,122.7,122.1,120.3,117.6,110.8,70.0,63.0,61.6,21.1.IR(thin film)3371,3001,2924,1708,1607,1483,1261,1100,803cm-1；HRMS(ESI)m/z calcd for C25H22NO2[M+H]+:368.1651,found:368.1636.
Figure BDA0001881417460000103
2ad：固体,35mg,47％yield；mp 132–133℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.23(d,J＝7.2Hz,2H),7.12–7.04(m,6H),6.90(t,J＝7.2Hz,2H),6.75–6.70(m,2H),6.65(d,J＝8.0Hz,1H),6.36(d,J＝16.0Hz,1H),4.73(brs,1H),4.65(d,J＝12.0Hz,1H),4.33(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.1,153.2,149.1,138.2,133.0,132.4,130.1,129.1,128.8,128.0,127.4,127.0,125.7,124.5,122.4,122.0,120.3,117.3,110.8,70.3,63.1,61.6.IR(thin film)3369,3004,2925,1706,1605,1481,1260,1106,801cm-1；HRMS(ESI)m/z calcd for C24H19NO2[M+H]+:372.1400,found:372.1387.
Figure BDA0001881417460000111
2ae：固体,48mg,57％yield；mp 128–129℃.1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.25(d,J＝7.6Hz,2H),7.12–7.07(m,2H),7.00(t,J＝8.0Hz,3H),6.85–6.80(m,3H),6.71–6.66(m,2H),6.53(d,J＝8.0Hz,1H),6.46(d,J＝15.8Hz,1H),4.59(d,J＝12.0Hz,1H),4.49(d,J＝12.0Hz,1H),4.45(brs,1H).13C NMR(100MHz,CDCl3):δ196.1,155.2,153.5,134.4,133.2,128.9,128.7,128.4,128.2,128.1,128.0,127.9,126.7,126.0,123.1,122.3,122.1,122.0,117.8,110.0,70.1,62.5,61.1.IR(thin film)3365,2924,2846,1705,1603,1480,1262,1105,794cm-1；HRMS(ESI)m/z calcd for C25H19F3NO2[M+H]+:422.1368,found:422.1347.
Figure BDA0001881417460000112
2af：固体,48mg,62％yield；mp 67–68℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.17(d,J＝9.2Hz,1H),7.10–7.04(m,3H),6.90–6.81(m,3H),6.84(d,J＝9.2Hz,2H),6.77–6.75(m,3H),6.64(d,J＝8.0Hz,1H),6.40(d,J＝15.6Hz,1H),4.67(d,J＝12.4Hz,1H),4.30(brs,1H),4.27(d,J＝12.4Hz,1H),3.71(s,1H).13C NMR(100MHz,CDCl3):δ196.9,159.8,154.2,149.8,143.3,137.1,132.6,130.1,129.6,129.4,129.0,127.4,124.6,122.6,122.2,120.4,119.4,117.7,113.9,112.0,110.8,69.9,63.0,61.6,55.2.IR(thin film)3364,3002,2931,1705,1600,1481,1263,1105,796cm-1；HRMS(ESI)m/z calcd forC25H22NO3[M+H]+:384.1600,found:384.1605.
Figure BDA0001881417460000121
2ag：固体,56mg,65％yield；mp 56–57℃.1H NMR(400MHz,CDCl3):δ9.49(s,1H),7.44(s,1H),7.31(d,J＝7.6Hz,1H),7.21–7.18(m,2H),7.12–7.05(m,4H),6.91(t,J＝7.2Hz,1H),6.85(d,J＝16.0Hz,1H),6.79–6.75(m,2H),6.65(d,J＝7.6Hz,1H),6.41(d,J＝15.6Hz,1H),4.67(d,J＝12.4Hz,1H),4.35(brs,1H),4.30(d,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3):δ196.9,154.2,149.7,137.9,131.2,131.0,130.8,130.2,130.1,129.6,129.1,127.3,126.5,125.4,124.7 122.8,122.6,122.2,120.5,117.8,110.9,69.8,63.0,61.7.IR(thin film)3368,2925,2854,1709,1606,1483,1261,1022,752cm-1；HRMS(ESI)m/zcalcd for C24H19BrNO2[M+H]+:432.0599,found:432.0583.
Figure BDA0001881417460000122
2ah：固体,52mg,60％yield；mp 54–55℃.1H NMR(400MHz,CDCl3):δ9.46(s,1H),7.49(d,J＝7.6Hz,1H),7.34(d,J＝7.6Hz,1H),7.28(d,J＝15.6Hz,1H),7.18–7.13(m,2H),7.09–7.02(m,4H),6.92–6.89(m,1H),6.79(t,J＝7.6Hz,2H),6.67(d,J＝8.0Hz,1H),6.29(d,J＝16.0Hz,1H),4.69(d,J＝12.4Hz,1H),4.35(brs,1H),4.31(d,J＝12.4Hz,1H).13CNMR(100MHz,CDCl3):δ197.1,154.2,149.9,136.2,132.8,132.2,131.8,130.2,129.4,129.1,127.5,127.4,127.3,126.6,124.6,123.9,122.6,122.2,120.4,117.7,110.9,69.9,63.0,61.5.IR(thin film)3360,2923,2852,1703,1609,1465,1259,741cm-1；HRMS(ESI)m/zcalcd for C24H19BrNO2[M+H]+:432.0599,found:432.0583.
Figure BDA0001881417460000123
2ai：固体,38mg,55％yield；mp 59–60℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.27–7.24(m,1H),7.11–7.04(m,4H),6.90–6.86(m,1H),6.78–6.74(m,2H),6.69–6.61(m,2H),6.37(d,J＝15.6Hz,1H),6.31–6.28(m,1H),6.21(m,1H),4.65(d,J＝12.4Hz,1H),4.28(brs,1H),4.25(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ196.8,154.3,151.5,149.8,142.5,130.1,129.0,127.6,127.4,126.7,124.7,122.7,122.1,121.0,120.4,117.6,111.4,110.8,109.5,69.8,63.0,61.7.IR(thin film)3364,2924,2853,1714,1604,1261,1016,752cm-1；HRMS(ESI)m/z calcd for C22H18NO3[M+H]+:344.1287,found:344.1275.
Figure BDA0001881417460000131
2aj：固体,24mg,46％yield；mp 123–124℃.1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.26(d,J＝7.2Hz,1H),7.08–7.02(m,3H),6.93(d,J＝7.2Hz,1H),6.76(dd,J＝13.6Hz,7.6Hz,2H),6.58(d,J＝7.6Hz,1H),4.49(d,J＝12.4Hz,1H),4.30(brs,1H),4.26(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ198.7,153.5,149.8,129.9,129.4,128.7,125.6,124.8,123.4,121.9,120.0,117.5,110.7,65.5,62.7,60.9,24.5.IR(thin film)3365,3072,2952,1707,1606,1251,1094,804cm-1；HRMS(ESI)m/z calcd for C17H16NO2[M+H]+:266.1181,found:266.1208.
Figure BDA0001881417460000132
2ak：固体,25mg,44％yield；mp 138–139℃.1H NMR(400MHz,CDCl3):δ7.25(d,J＝7.6Hz,1H),7.05–6.98(m,3H),6.89(t,J＝7.2Hz,1H),6.76–6.72(m,1H),6.65(d,J＝8.0Hz,1H),6.53(d,J＝7.6Hz,1H),4.53(d,J＝12.4Hz,1H),4.26(d,J＝12.8Hz,1H),4.23(brs,1H),2.00(s,3H),1.60(s,3H).13C NMR(100MHz,CDCl3):δ209.1,153.7,150.1,130.0,129.3,128.3,127.2,125.7,123.9,121.7,120.1,117.3,110.9,66.1,64.1,62.7,28.7,24.3.IR(thin film)3434,3013,2925,1697,1607,1464,1093,755,630cm-1；HRMS(ESI)m/zcalcd forC18H18NO2[M+H]+:280.1338,found:280.1325.
Figure BDA0001881417460000133
2al：固体,57mg,66％yield；mp 208–209℃.1H NMR(400MHz,CDCl3):δ7.24–7.08(m,9H),7.06(dd,J＝17.6Hz,8.0Hz,5H),6.87–6.83(m,1H),6.77–6.72(m,2H),6.60–6.56(m,2H),6.31(d,J＝16.0Hz,1H),4.72(d,J＝12.0Hz,1H),4.60(d,J＝12.0Hz,1H),4.07(brs,1H).13C NMR(100MHz,CDCl3):δ201.9,154.7,150.5,139.7,136.1,131.5,131.4,129.7,129.0,128.6,128.5,128.4,127.9,127.8,127.5,127.4,126.8,126.6,124.6,122.1,120.4,117.7,111.1,70.9,67.1,64.6.IR(thin film)3329,2924,2852,1651,1484,1238,744cm-1；HRMS(ESI)m/z calcd for C30H24NO2[M+H]+:430.1807,found:430.1803.
Figure BDA0001881417460000141
2am：固体,39mg,52％yield；mp 110–111℃.1H NMR(400MHz,CDCl3):δ9.50(s,1H),7.31–7.18(m,5H),7.10(dd,J＝18.4Hz,7.6Hz,2H),6.91(d,J＝16.0Hz,1H),6.81–6.71(m,4H),6.67(d,J＝7.6Hz,1H),6.37(d,J＝15.6Hz,1H),4.66(d,J＝12.4Hz,1H),4.28(brs,1H),4.25(d,J＝12.0Hz,1H).13C NMR(100MHz,CDCl3):δ196.7,158.9(d,J＝239.1Hz),150.4,149.6,135.5,133.1,130.2,128.8,128.7,128.4,128.1(d,J＝5.8Hz),126.8,124.6,122.4,120.5,119.1(d,J＝8Hz),116.4(d,J＝23.3Hz),113.2(d,J＝23.3Hz),110.8,70.0,63.3,61.4.IR(thin film)3363,2936,2867,1704,1602,1481,1267,1083,797cm-1；HRMS(ESI)m/z calcd for C24H19FNO2[M+H]+:372.1400,found:372.1395.
Figure BDA0001881417460000142
2an：固体,26mg,38％yield；mp 59–60℃.1H NMR(400MHz,CDCl3):δ9.61(s,1H),7.11–7.01(m,4H),6.77–6.73(m,1H),6.58(d,J＝8.0Hz,1H),4.50(d,J＝12.4Hz,1H),4.25(brs,1H),4.21(d,J＝12.4,1H),1.67(s,3H).13C NMR(100MHz,CDCl3):δ198.2,154.4,149.6,130.1,127.9,127.0,125.1,124.8,123.1,121.6,120.6,120.3,110.7,65.4,62.8,60.7,24.3.IR(thin film)3350,2925,1709,1597,1261,1034,832cm-1；HRMS(ESI)m/zcalcd for C17H15BrNO2[M+H]+:344.0286,found:344.0274.
Figure BDA0001881417460000143
2ao：固体,28mg,48％yield；mp 187–188℃.1H NMR(400MHz,CDCl3):δ9.64(s,1H),7.08–7.01(m,2H),6.96(s,1H),6.75–6.71(m,1H),6.58(d,J＝8.0Hz,1H),6.50(s,1H),4.46(d,J＝12.4Hz,1H),4.26(brs,1H),4.21(d,J＝12.0,1H),2.12(s,3H),2.07(s,3H),1.67(s,3H).13C NMR(100MHz,CDCl3):δ198.9,151.4,149.9,137.5,130.1,129.8,126.1,125.7,124.8,123.7,120.0,118.1,110.7,65.4,62.8,61.1,24.6,19.4,19.1.IR(thinfilm)3368,3021,2924,1717,1604,1463,1261,1094,803cm-1；HRMS(ESI)m/z calcd forC19H20NO2[M+H]+:294.1494,found:294.1475.
Figure BDA0001881417460000144
2ap：固体,26mg,51％yield；mp 100–101℃.1H NMR(400MHz,CDCl3):δ9.62(s,1H),7.25(d,J＝7.2Hz,1H),7.09–7.03(m,3H),6.95(d,J＝7.2Hz,1H),6.78(dd,J＝13.2Hz,7.2Hz,2H),6.50(d,J＝7.6Hz,1H),4.49(d,J＝12.4Hz,1H),4.30(brs,1H),4.26(d,J＝12.4Hz,1H),4.01(s,1H).13C NMR(100MHz,CDCl3):δ198.5,152.3,148.8,129.3,129.4,128.5,125.4,124.7,123.1,121.2,120.1,117.5,110.4,65.2,62.7,60.5.IR(thin film)3363,2951,2829,1708,1605,1250,1084,802cm-1；HRMS(ESI)m/z calcd for C16H14NO2[M+H]+:252.1025,found:252.1006.
Figure BDA0001881417460000151
2aq：固体,25mg,50％yield；mp 103–104℃.1H NMR(400MHz,CDCl3):δ9.62(s,1H),7.24(d,J＝7.2Hz,1H),7.08–7.02(m,2H),6.92(d,J＝7.2Hz,2H),6.75(dd,J＝13.6Hz,7.6Hz,2H),6.53(d,J＝7.6Hz,1H),4.45(d,J＝12.4Hz,1H),4.33(brs,2H),4.26(d,J＝12.4Hz,1H),4.10(s,1H).13C NMR(100MHz,CDCl3):δ198.3,153.4,149.8,129.3,129.2,128.5,125.6,124.6,123.1,121.7,121.0,117.0,110.7,65.4,62.7,60.6.IR(thin film)3360,2959,2826,1706,1604,1240,1054,801cm-1；HRMS(ESI)m/z calcd for C16H15NO2[M+H]+:251.1184,found:251.1172.
Figure BDA0001881417460000152
2ar：固体,23mg,43％yield；mp 123–124℃.1H NMR(400MHz,CDCl3):δ9.61(s,1H),7.27(d,J＝7.4Hz,1H),7.07–7.03(m,3H),6.92(d,J＝7.2Hz,1H),6.74(dd,J＝13.6Hz,7.6Hz,2H),6.50(d,J＝7.6Hz,1H),4.32(brs,1H),4.17(s,1H),3.91–3.84(m,2H),2.46–2.37(m,2H).13C NMR(100MHz,CDCl3):δ197.9,153.2,149.7,129.7,129.4,128.0,125.8,124.7,123.4,121.9,120.6,117.1,110.0,65.4,62.7,60.8,30.6.IR(thin film)3360,3014,2950,2822,1705,1603,1254,1074,793cm-1；HRMS(ESI)m/z calcd for C17H16NO2[M+H]+:266.1181,found:266.1172.
Figure BDA0001881417460000153
2as：固体,22mg,39％yield；mp 133–134℃.1H NMR(400MHz,CDCl3):δ9.65(s,1H),7.27(d,J＝7.2Hz,1H),7.04–7.01(m,2H),6.91(d,J＝7.2Hz,2H),6.73(dd,J＝13.6Hz,7.6Hz,2H),6.54(d,J＝7.6Hz,1H),4.31(brs,1H),4.16(s,1H),3.90–3.81(m,2H),2.43–2.35(m,2H),2.00–1.89(m,2H).13C NMR(100MHz,CDCl3):δ197.8,153.2,149.2,129.8,129.4,128.7,125.7,124.0,123.4,121.8,120.6,117.0,110.2,65.6,62.4,60.1,30.6,28.5.IR(thin film)3361,3021,2941,2824,1706,1602,1250,1074,797 cm-1；HRMS(ESI)m/z calcd forC18H18NO2[M+H]+:280.1338,found:280.1324.
实施例2
按下述合成路线合成本发明所述的2,3-稠环吲哚啉衍生物。
Figure BDA0001881417460000161
2ba:R1＝4-Br,R2＝PhCH＝CH,R3＝4-Br,R4＝H,n＝1；
2bb:R1＝4-Br,R2＝PhCH＝CH,R3＝3-Br,R4＝H,n＝1；
2bc:R1＝4-Br,R2＝(3-Br)C6H4CH＝CH,R3＝4-Cl,R4＝H,n＝1；
2bd:R1＝4-Br,R2＝(4-Me)C6H4CH＝CH,R3＝4-Cl,R4＝Me,n＝1；
2be:R1＝3-Cl,R2＝Me,R3＝4-Me,R4＝H,n＝1；
2bf:R1＝4-Br,R2＝Me,R3＝4-Me,R4＝4-ClC6H4,n＝1；
2bg:R1＝3-Cl,R2＝Me,R3＝4-Me,R4＝Me,n＝1；
2bh:R1＝4-Br,R2＝H,R3＝4-Br,R4＝H,n＝1；
2bi:R1＝4-Br,R2＝H,R3＝3-Cl,R4＝Me,n＝2；
2bj:R1＝4-Br,R2＝Me,R3＝4-Br,R4＝Me,n＝1,X＝N。
取N-芳基α,β-不饱和硝酮底物1(0.2 mmol)置于反应管中，加入2 mL有机溶剂(其中目标物2ba-2bd采用的有机溶剂分别为丙酮、三氯甲烷、正己烷和二氧六环，目标物2be-2bj采用的有机溶剂均为四氯化碳)，在25℃下搅拌反应10-36 h，所得反应物减压除去溶剂，残渣上硅胶柱层析分离(石油醚/乙酸乙酯＝50：1～10：1，体积比)，得到目标产物2。不同的目标产物及其表征如下：
Figure BDA0001881417460000162
2ba:固体,64 mg,63％yield；mp 89–90℃.1H NMR(400 MHz,CDCl3):δ9.45(s,1H),7.49(d,J＝7.6 Hz,1H),7.34(d,J＝7.6 Hz,1H),7.28(d,J＝15.6Hz,1H),7.18–7.13(m,2H),7.09–7.02(m,3H),6.92(s,1H),6.79(t,J＝7.6 Hz,2H),6.67(d,J＝8.0 Hz,1H),6.29(d,J＝16.0 Hz,1H),4.69(d,J＝12.4 Hz,1H),4.35(brs,1H),4.31(d,J＝12.4 Hz,1H).13CNMR(100MHz,CDCl3):δ197.0,153.2,149.8,136.1,132.7,132.1,131.7,130.0,129.2,129.1,127.6,127.3,126.4,124.5,122.4,122.2,120.3,117.6,110.8,69.8,63.1,61.4.IR(thin film)3361,2920,2851,1703,1600,1461,1259,740 cm-1；HRMS(ESI)m/z calcdforC24H18Br2NO2[M+H]+:509.9704,found:509.9702.
Figure BDA0001881417460000171
2bb:固体,63mg,61％yield；mp 93–94℃.1H NMR(400MHz,CDCl3):δ9.46(s,1H),7.48(d,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.29(d,J＝15.6Hz,1H),7.18–7.15(m,2H),7.08–7.01(m,3H),6.90(s,1H),6.80(t,J＝7.6Hz,2H),6.65(d,J＝8.0Hz,1H),6.30(d,J＝16.0Hz,1H),4.68(d,J＝12.4Hz,1H),4.34(brs,1H),4.30(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.1,154.2,149.7,136.3,132.6,132.2,131.7,129.4,129.0,127.5,127.4,126.3,124.4,123.3,122.5,122.3,120.3,117.6,110.7,69.6,63.0,61.3.IR(thinfilm)3359,2922,2854,1702,1604,1460,1258,741cm-1；HRMS(ESI)m/z calcdforC24H18Br2NO2[M+H]+:509.9704,found:509.9711.
Figure BDA0001881417460000172
2bc:固体,50mg,46％yield；mp 95–96℃.1H NMR(400MHz,CDCl3):δ9.46(s,1H),7.49(d,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),7.29(d,J＝15.6Hz,1H),7.18–7.16(m,2H),7.08–7.03(m,2H),6.93(s,1H),6.82(t,J＝7.6Hz,2H),6.64(d,J＝8.0Hz,1H),6.31(d,J＝16.0Hz,1H),4.67(d,J＝12.4Hz,1H),4.33(brs,1H),4.31(d,J＝12.4Hz,1H).13C NMR(100MHz,CDCl3):δ197.2,154.2,149.4,136.3,132.5,132.4,131.6,130.0,129.4,129.1,127.3,127.2,127.0,126.3,125.4,122.9,122.6,122.2,120.1,117.5,110.7,69.5,63.1,61.3.IR(thinfilm)3359,2923,2853,1700,1603,1462,1257,742cm-1；HRMS(ESI)m/zcalcdfor C24H17Br2ClNO2[M+H]+:543.9315,found:543.9327.
Figure BDA0001881417460000173
2bd:固体,45mg,45％yield；mp 80–81℃.1H NMR(400MHz,CDCl3):δ7.49(d,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.28(d,J＝15.6Hz,1H),7.19–7.16(m,2H),7.07–7.03(m,2H),6.95(s,1H),6.84(t,J＝7.6Hz,2H),6.67(d,J＝8.0Hz,1H),6.30(d,J＝16.0Hz,1H),4.66(d,J＝12.4Hz,1H),4.35(brs,1H),4.30(d,J＝12.4Hz,1H),2.32(s,3H),2.14(s,3H).13C NMR(100MHz,CDCl3):δ197.1,153.2,148.4,137.3,132.6,132.3,131.5,130.1,129.2,129.0,128.1,127.5,127.0,126.2,125.4,123.1,122.8,122.5,121.4,117.4,110.3,69.4,63.0,61.2,27.5,21.3.IR(thin film)3362,2922,2851,1705,1601,1460,1256,743cm-1；HRMS(ESI)m/z calcd for C26H22BrClNO2[M+H]+:494.0522,found:494.0534.
Figure BDA0001881417460000181
2be:固体,40mg,56％yield；mp 85–86℃.1H NMR(400MHz,CDCl3):δ9.64(s,1H),7.08–7.01(m,2H),6.96(s,1H),6.75–6.71(m,1H),6.58(d,J＝8.0Hz,1H),6.50(s,1H),4.46(d,J＝12.4Hz,1H),4.26(brs,1H),4.21(d,J＝12.0,1H),2.07(s,3H),1.67(s,3H).13CNMR(100MHz,CDCl3):δ198.9,151.4,149.9,137.5,130.1,129.8,126.1,125.7,124.8,123.7,120.0,118.1,110.7,65.4,62.8,61.1,24.6,19.1.IR(thin film)3368,3021,2924,1717,1604,1463,1261,1094,803cm-1；HRMS(ESI)m/z calcd for C18H17NO2[M+H]+:358.0443,found:358.0421.
Figure BDA0001881417460000182
2bf:固体,47mg,51％yield；mp 110–111℃.1H NMR(400MHz,CDCl3):δ7.07–7.02(m,3H),6.95(s,1H),6.74–6.71(m,3H),6.78(d,J＝8.0Hz,1H),6.57(d,J＝8.0Hz,1H),6.51(s,1H),4.44(d,J＝12.4Hz,1H),4.25(brs,1H),4.20(d,J＝12.0,1H),2.02(s,3H),1.65(s,3H).13C NMR(100MHz,CDCl3):δ200.1,151.4,149.9,137.5,136.2,134.2,132.6,130.1,129.8,126.1,125.7,124.8,123.7,122.6,120.0,118.1,110.7,65.4,62.8,61.1,24.6,19.1.IR(thin film)3363,3020,2922,1715,1600,1461,1262,1093,801cm-1；HRMS(ESI)m/z calcd forC24H20BrClNO2[M+H]+:468.0366,found:468.0352.
Figure BDA0001881417460000183
2bg:固体,39mg,60％yield；mp 117–118℃.1H NMR(400MHz,CDCl3):δ7.09–7.00(m,2H),6.97(s,1H),6.75–6.71(m,1H),6.59(d,J＝8.0Hz,1H),6.52(s,1H),4.45(d,J＝12.4Hz,1H),4.27(brs,1H),4.20(d,J＝12.0,1H),2.13(s,3H),2.07(s,3H),1.66(s,3H).13C NMR(100MHz,CDCl3):δ206.1,151.3,149.8,137.4,132.1,129.7,128.1,125.3,124.2,123.5,120.1,118.0,110.2,65.1,62.6,61.0,24.6,24.4,19.1.IR(thin film)3366,3020,2923,1714,1600,1461,1260,1092,802cm-1；HRMS(ESI)m/z calcd for C19H19ClNO2[M+H]+:328.1104,found:328.1123.
Figure BDA0001881417460000191
2bh:固体,50mg,62％yield；mp 120–121℃.1H NMR(400MHz,CDCl3):δ9.62(s,1H),7.23(d,J＝7.2Hz,1H),7.07–7.02(m,2H),6.96(d,J＝7.2Hz,1H),6.76(d,J＝7.2Hz,1H),6.52(d,J＝7.6Hz,1H),4.49(d,J＝12.4Hz,1H),4.31(brs,1H),4.25(d,J＝12.4Hz,1H),4.00(s,1H).13C NMR(100MHz,CDCl3):δ198.9,152.1,148.7,129.7,129.2,128.7,125.5,124.6,123.0,121.3,120.0,117.4,110.3,65.1,62.8,60.4.IR(thin film)3360,2952,2828,1706,1604,1251,1083,800cm-1；HRMS(ESI)m/z calcd for C16H12BrNO2[M+H]+:407.9235,found:407.9221.
Figure BDA0001881417460000192
2bi:固体,40mg,51％yield；mp 120–121℃.1H NMR(400MHz,CDCl3):δ7.25(d,J＝7.4Hz,1H),7.07–7.02(m,1H),6.91(d,J＝7.2Hz,1H),6.72(d,J＝7.6Hz,2H),6.53(d,J＝7.6Hz,1H),4.33(brs,1H),4.15(s,1H),3.92–3.81(m,2H),2.45–2.39(m,2H).13C NMR(100MHz,CDCl3):δ197.8,153.0,149.5,129.6,129.3,128.1,125.3,124.8,123.2,121.0,120.7,117.3,110.1,65.3,63.7,60.2,30.5.IR(thin film)3359,3015,2952,2821,1704,1602,1250,1071,792cm-1；HRMS(ESI)m/z calcd for C18H16BrClNO2[M+H]+:392.0053,found:392.0042.
Figure BDA0001881417460000193
2bj:固体,51mg,57％yield；mp 121–122℃.1H NMR(400MHz,CDCl3):δ7.09–7.03(m,2H),6.95(s,1H),6.74–6.71(m,1H),6.57(d,J＝8.0Hz,1H),6.52(s,1H),4.43(d,J＝12.4Hz,1H),4.26(brs,1H),4.21(d,J＝12.0,1H),2.12(s,3H),2.04(s,3H),1.65(s,3H).13C NMR(100MHz,CDCl3):δ206.2,151.1,149.5,137.3,132.0,129.4,128.9,125.2,124.1,123.2,120.0,118.2,110.1,65.0,62.7,61.9,24.3,24.1,19.9.IR(thin film)3368,3021,2920,1716,1605,1462,1263,1094,801cm-1；HRMS(ESI)m/z calcd for C19H19Br2N2O[M+H]+:448.9864,found:448.9862.
实验例1：本发明所述2,3-稠环吲哚啉衍生物对多种人肿瘤株进行体外抑制活性实验：
(1)细胞培养：将MGC-803、HepG-2、NCI-H460、SKOV3、T24、7702细胞培养于含10％(体积比)胎牛血清和1％(体积比)双抗(含青霉素和链霉素)的DMEM培养基，在温度37℃、5％CO2及95％空气的培养箱中培养，隔天换液。待细胞长满后进行传代，冻存。
(2)种板：取处于对数生长期的细胞，去掉旧培养基，用PBS洗涤两次，胰蛋白酶消化细胞，待细胞变圆后加入新的培养基终止细胞消化并吹打悬浮细胞，制成单个细胞悬液。取适量的细胞悬液，加入一定量的培养基稀释，接种到96孔板中，每孔180μL，每孔细胞数为20000-40000。
(3)加药：于种有肿瘤细胞的96孔板中加入待测样品，每孔20μL，使样品的最终浓度为10μM，进行初筛。根据初筛的结果，对化合物设置不同的浓度梯度进行筛选，每组设置5个复孔。加化合物后放CO2培养箱培养48h，每孔加入10μL配好的MTT溶液，放CO2培养箱继续培养4～6h。
(4)测试：吸弃96孔板内的培养基，加入100μL的DMSO，放摇床上震荡5～10min，使结晶的甲瓒完全溶解。用酶标仪以570nm的吸收波长，630nm的参比波长双波长测定吸光度(OD)值，计算抑制率。抑制率＝(1-样品组OD值/空白组OD值)×100％，用SPSS软件分别计算各化合物对不同肿瘤细胞株的IC50值。其测试结果如下表1所示：
表1：
Figure BDA0001881417460000201

Claims (6)

1.下述式(I)所示化合物的制备方法，其特征在于：主要包括以下步骤：取如下式(II)所示化合物置于有机溶剂中，在氧气存在的条件下反应，制得目标物粗品；
Figure FDA0002709139130000011
其中，X表示氧原子，n＝1，R1、R2、R3和R4的定义为下述选择之一：
R1、R3和R4均表示氢，R2表示苯基亚乙烯基；或者是
R1和R4均表示氢，R2表示苯基亚乙烯基，R3表示4-甲氧基；或者是
R1和R4均表示氢，R2表示苯基亚乙烯基，R3表示4-叔丁基；或者是
R1和R4均表示氢，R2表示苯基亚乙烯基，R3表示3-甲氧基；或者是
R1和R4均表示氢，R2表示苯基亚乙烯基，R3表示3,5-二甲基；或者是
R1和R4均表示氢，R2表示苯基亚乙烯基，R3表示2-甲基。
2.根据权利要求1所述的制备方法，其特征在于：所述的有机溶剂为选自苯、甲苯、环己烷、石油醚、四氯化碳、四氢呋喃、乙酸乙酯、乙腈、乙醚、二氯甲烷、丙酮、三氯甲烷、正己烷和二氧六环中一种或两种以上的组合。
3.根据权利要求1所述的制备方法，其特征在于：反应在低于100℃的条件下进行。
4.根据权利要求1所述的制备方法，其特征在于：反应在低于80℃的条件下进行。
5.根据权利要求1～4中任一项所述的制备方法，其特征在于：还包括纯化步骤：具体是将制得的目标物粗品进行硅胶薄层色谱、硅胶柱层析或者是重结晶，得到纯化后的目标物。
6.根据权利要求5所述的制备方法，其特征在于：在硅胶薄层色谱或硅胶柱层析时用的洗脱剂和重结晶时用的溶剂相同，具体为由石油醚或正己烷和乙酸乙酯组成的混合溶剂。
CN201811425104.1A 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其制备方法和应用 Expired - Fee Related CN109485651B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811425104.1A CN109485651B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其制备方法和应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710518658.5A CN107266458B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其合成方法和应用
CN201811425104.1A CN109485651B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其制备方法和应用

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201710518658.5A Division CN107266458B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其合成方法和应用

Publications (2)

Publication Number Publication Date
CN109485651A CN109485651A (zh) 2019-03-19
CN109485651B true CN109485651B (zh) 2021-02-02

Family

ID=60070958

Family Applications (3)

Application Number Title Priority Date Filing Date
CN201811425104.1A Expired - Fee Related CN109485651B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其制备方法和应用
CN201710518658.5A Expired - Fee Related CN107266458B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其合成方法和应用
CN201811425106.0A Expired - Fee Related CN109232591B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉生物碱及其合成方法和应用

Family Applications After (2)

Application Number Title Priority Date Filing Date
CN201710518658.5A Expired - Fee Related CN107266458B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉衍生物及其合成方法和应用
CN201811425106.0A Expired - Fee Related CN109232591B (zh) 2017-06-29 2017-06-29 2,3-稠环吲哚啉生物碱及其合成方法和应用

Country Status (1)

Country Link
CN (3) CN109485651B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109879873B (zh) * 2019-01-31 2021-05-11 广西师范大学 四氢二苯并萘啶化合物及其合成方法和应用
CN109761993B (zh) * 2019-01-31 2021-03-23 广西师范大学 螺苯并呋喃-3,3′-喹啉衍生物及其合成方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014777A1 (en) * 1992-12-28 1994-07-07 Eisai Co., Ltd. Heterocyclic carbonic acid derivatives which bind to retinoid receptors (rar)
CN106432043A (zh) * 2016-09-26 2017-02-22 广西师范大学 2，3‑吲哚二酮‑3‑n‑烯基硝酮衍生物及其合成方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014777A1 (en) * 1992-12-28 1994-07-07 Eisai Co., Ltd. Heterocyclic carbonic acid derivatives which bind to retinoid receptors (rar)
CN106432043A (zh) * 2016-09-26 2017-02-22 广西师范大学 2，3‑吲哚二酮‑3‑n‑烯基硝酮衍生物及其合成方法和应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Catalytic Enantioselective Synthesis of β-Lactams: Intramolecular Kinugasa Reactions and Interception of an Intermediate in the Reaction Cascade";Ryo Shintani et al.;《Angew. Chem. Int. Ed.》;20031231;第42卷;第4082-4085页 *
"Complex Bioactive Alkaloid-Type Polycycles through Efficient Catalytic Asymmetric Multicomponent Aza-Diels–Alder Reaction of Indoles with Oxetane as Directing Group";Zhilong Chen et al.;《Angew. Chem. Int. Ed.》;20130109;第52卷;第2027-2031页 *
"Construction of 2,3-quaternary fused indolines from alkynyl tethered oximes and diaryliodonium salts through a cascade strategy of N-arylation/cycloaddition/[3,3]-rearrangement";Xiao-Pan Ma et al.;《Green Chemistry》;20171031;第19卷(第24期);第5761-5766页 *
"Synthesis of chromenoindole derivatives from Robinia pseudoacacia";Lisa Dejon et al.;《MedChemComm》;20131008;第4卷(第12期);第1580-1583页 *

Also Published As

Publication number Publication date
CN107266458A (zh) 2017-10-20
CN109232591B (zh) 2021-02-02
CN109232591A (zh) 2019-01-18
CN107266458B (zh) 2019-05-10
CN109485651A (zh) 2019-03-19

Similar Documents

Publication Publication Date Title
CN109485651B (zh) 2,3-稠环吲哚啉衍生物及其制备方法和应用
Lin et al. 3-Methyl-4-nitro-5-isatylidenyl-isoxazoles as 1, 3-dipolarophiles for synthesis of polycyclic 3, 3′-pyrrolidinyl-dispirooxindoles and their biological evaluation for anticancer activities
Zhang et al. Facile synthesis of highly functionalized six-membered heterocycles via PPh3-catalyzed [4+ 2] annulations of activated terminal alkynes and hetero-dienes: scope, mechanism, and application
Xu et al. Synthesis and biological evaluation of 20-hydroxytriptonide and its analogues
CN111303058A (zh) 续随子醇衍生物及其制备方法和用途
CN108623530B (zh) 1，2，8-氧代二氮杂环壬-9-硫酮衍生物及其合成方法和应用
CN111892608A (zh) 一种具有光学活性的螺杂环2,3-二氢苯并呋喃类化合物及其应用
CN109761993B (zh) 螺苯并呋喃-3,3′-喹啉衍生物及其合成方法和应用
CN110684033B (zh) 四氢呋喃二喹啉化合物及其合成方法和应用
CN114805182A (zh) 一种可见光催化合成吲哚螺环丙烷类化合物的方法
CN110642866B (zh) 二氢呋喃喹啉衍生物及其合成方法和应用
Fang et al. Synthesis of biologically relevant steroidal spiro β-lactams from dienamides through the cascade 4-endo N-cyclization/aerobic oxidation sequence
CN108276420B (zh) 一种8,13-二氢苯并[5,6]色烯并[2,3-b]吲哚类化合物及其合成方法
CN111039844A (zh) 多取代芳基吡咯化合物
CN109879873B (zh) 四氢二苯并萘啶化合物及其合成方法和应用
Wei et al. Asymmetric Total Syntheses of Macroline-Type Alkaloids Alstomicine and Alstofolinine A
CN117024437A (zh) 色烯[4,3-b]吲哚啉衍生物及其合成方法和应用
CN110105361B (zh) 一种Evodiakine及其衍生物的制备方法
CN114805168B (zh) 吡咯啉酮类化合物及其合成方法
CN109467558B (zh) 1-氢吡咯嗪衍生物及其合成方法和应用
CN114181182B (zh) 一种多取代的4h-吡喃类化合物的合成方法
Shi et al. Rapid construction of the tricyclic core of annotinine hydrate
Prasad et al. Total synthesis of the indole alkaloids henrycinol A and B
Ma et al. Synthesis of novel matrine derivatives containing furanone skeleton and preliminary evaluation of their anticancer activity in vitro
CN108129479B (zh) 一种5,6-二氢苯并[f]吲哚并[2,3-b]喹啉类化合物及其合成方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20210202

Termination date: 20210629

CF01 Termination of patent right due to non-payment of annual fee