CN105503751A - 一种喹喔啉衍生物的高效合成方法 - Google Patents

一种喹喔啉衍生物的高效合成方法 Download PDF

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CN105503751A
CN105503751A CN201510969658.8A CN201510969658A CN105503751A CN 105503751 A CN105503751 A CN 105503751A CN 201510969658 A CN201510969658 A CN 201510969658A CN 105503751 A CN105503751 A CN 105503751A
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reaction
synthetic method
enamine
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ethyl acetate
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CN105503751B (zh
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潘成学
苏桂发
焦艳晓
魏凯
莫冬亮
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Guangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

本发明公开了一种喹喔啉衍生物的合成方法，新路线以普通芳胺跟酮酸酯、3-氧代腈或1,3-二羰基合成得到的烯胺化合物为原料，经烷基亚硝酸酯亚硝基化后，在乙酸酐下经6π电子环化反应合成得到2,3-二取代喹喔啉化合物。本发明是酮酸酯、3-氧代腈或1,3-二羰基先与芳胺缩合得到烯胺化合物，然后烯胺化合物再与烷基亚硝酸酯反应得到亚硝基化烯胺，生成的烯胺无需分离纯化，直接在乙酸酐中反应得到喹喔啉化合物；本发明专利可适用的底物和芳胺的种类更加广，本专利方法可合成得到种类更多的喹喔啉化合物。

Description

一种喹喔啉衍生物的高效合成方法
技术领域
本发明涉及有机化学，具体涉及一种喹喔啉衍生物的高效合成方法。
背景技术
喹喔啉又叫苯并吡嗪,1,4-二氮杂萘,是一类非常重要的杂环化合物，在药物化学、材料科学等领域有广泛应用，仅2010年以来有关喹喔啉的合成及应用研究报道的相关文献就将近6800篇(以“quinoxalines”为研究主题在SciFinder数据库中检索得到的结果).
总的来说，现有的最主要合成方法可用以下的例子表示，以起始原料为邻苯二胺、邻位卤代或邻位硝基化的芳胺为原料与邻二羰基化合物、邻位官能团化的酮类化合物、炔烃化合物或环氧化合物等来合成。
由于氨基邻位官能团化的芳胺种类要远远少于邻位非官能团化的普通芳胺，其价格也要比邻位非官能团化的普通芳胺贵得多，所以发展处以邻位非官能团化的普通芳胺为原料来合成喹喔啉类化合物将具有重要的应用价值。在此领域中相关的报道有：
1.Ila2005年的合成报道(Venkatesh,C.；Singh,B.；Mahata,P.K.；Ila,H.；Junjappa,H.Org.Lett.,2005,7,2169.)，但这一合成方法只能合成出2-位上的取代基为甲硫基，3-位上的取代基为氯的喹喔啉化合物；
Ila的报道
2.Kaufmann's的报道(a)Synthesis2008,2575；b)J.Org.Chem.2009,74,4727；c)Eur.J.Org.Chem.,2013,2091.).这一合成方法只能合成出单N-氧化的喹喔啉化合物，要得到N-没有氧化的喹喔啉化合物，还需将其还原，并且2,3-位上的取代基也仅局限于氯等。
Kaufmann's的报道
3.Kobayashi等的报道(；Org.Lett.,2011,13,6280.)和焦宁等人的报道(Angew.Chem.Int.Ed.,2014,53,10495.)。这些合成方法只能合成出单N-氧化的喹喔啉化合物，要得到N-没有氧化的喹喔啉化合物需要进一步还原，并且2,3-位上的取代基也仅局限于腈基或芳基等。
Kobayashi等的报道
焦宁等人的报道
4.温州大学的ZhangXing-Guo等报道(Chem.Commun.,2014,50,14554)，他们以带三氟甲基的烯胺为原料，以硝基甲烷为氮源，在过氧叔丁基的氧化下得到喹喔啉化合物。
ZhangXing-Guo等报道的方法
最近，发明人申请了2,3-二取代喹喔啉衍生物的制备方法的发明专利，专利公开号为CN104086491A，其主要工艺是以羰基化合物1及普通芳胺为原料，1先与亚硝酸反应得2，2再与芳胺缩合成3，3在三氯氧磷存在下于乙腈中发生关环反应得到目标化合物4。
潘成学等的发明专利CN104086491A的制备方法
发明内容
本发明的主要内容是发展了一种合成喹喔啉类化合物的新路线，新路线以普通芳胺跟酮酸酯、3-氧代腈或1,3-二羰基合成得到的烯胺化合物为原料，经烷基亚硝酸酯亚硝基化后，在乙酸酐下经6π电子环化反应合成得到2,3-二取代喹喔啉化合物。其技术路线可用下式表示：以羰基化合物1(EWG为吸电子基团，包括酯基、腈基和酮羰基等)及邻位非官能团化的普通芳胺为原料，缩合得到烯胺5后，与烷基亚硝酸酯反应得到烯胺5的亚硝基化产物6，6直接在乙酸酐中经6π电子环化反应得到目标化合物2。
其中,1)R’可为芳基、杂环、烷基、酯基等；R可为一个或多个处于苯环不同位置上的氢,烷基，烷氧基,卤素,三氟甲基,酯基，腈基等；EWG为酯基、腈基和酮羰基等。
本的喹喔啉衍生物的制备方法包括如下步骤：
(1)向25mL圆底烧瓶中加入烯胺(1mmol)、乙腈(5～10mL),室温下搅拌溶解后,一次性加入异丁基亚硝酸酯(1.2mmol),室温搅拌反应5～20min后,TLC监测(V乙酸乙酯:V石油醚＝1:2～1:10),原料点基本消失.停止反应,直接旋蒸蒸去溶剂得到粗产物,粗产物不经提纯可直接进行接下来的反应.
(2)反应瓶中加入重蒸的乙酸酐(5mL),加热回流反应8～24h.TLC监测(V乙酸乙酯:V石油醚＝1:2～1:10),原料点基本消失后,停止反应.冷却至室温,向反应液中加入饱和NaHCO3至不再有气泡产生,用乙酸乙酯萃取(10mL×3),无水Na2SO4干燥,过滤,减压蒸去溶剂,残留物快速柱层析(洗脱剂为V乙酸乙酯:V石油醚＝1:4～1:20)得到相应的喹喔啉衍生物.
本发明跟专利CN104086491A的方法比较主要有以下差别及优势：1是工艺上有差别：专利CN104086491A的方法是先用亚硝酸将酮酸酯氧化成肟，然后与芳胺缩合，最后再用三氯氧磷在溶剂乙腈中进行关环得到目标化合物，而本发明是酮酸酯、3-氧代腈或1,3-二羰基先与芳胺缩合得到烯胺化合物，然后烯胺化合物再与烷基亚硝酸酯反应得到亚硝基化烯胺，生成的烯胺无需分离纯化，直接在乙酸酐中反应得到喹喔啉化合物；2是本发明专利可适用的底物和芳胺的种类更加广，1的底物可以拓展到3-氧代腈，或拓展到更多的1,3-二酮化合物及酮酸酯化合物，而芳胺可以拓展到可以制备得到苯环上有强吸电子的基团，因此本专利方法可合成得到种类更多的喹喔啉化合物。
本发明跟温州大学的ZhangXing-Guo等报道(Chem.Commun.,2014,50,14554)方法比较有以下差别及优势：1是工艺上有差别：他们的方法是以带三氟甲基的烯胺为原料，以硝基甲烷为氮源，在过氧叔丁基的氧化下得到喹喔啉化合物，而本发明是烯胺化合物与烷基亚硝酸酯反应得到亚硝基化烯胺，然后直接在乙酸酐中反应得到喹喔啉化合物。2是因此本专利方法可合成得到种类更多的喹喔啉化合物，ZhangXing-Guo等报道(Chem.Commun.,2014,50,14554)方法可合成得到的目标化合物的2-位上只有三氟甲基，3-位上只能是芳环和杂环。而我们可合成得到的目标化合物，其2-位上可以为酯基、腈基和酮羰基等，3-位可为芳基、杂环、烷基、酯基等。
具体实施方式
实施例1
化合物的合成方法为：
1、向25mL圆底烧瓶中加入烯胺(1mmol)、乙腈(5～10mL),室温下搅拌溶解后,一次性加入异丁基亚硝酸酯(1.2mmol),室温搅拌反应5～20min后,TLC监测(V乙酸乙酯:V石油醚＝1:2～1:10),原料点基本消失.停止反应,直接旋蒸蒸去溶剂得到粗产物,粗产物不经提纯可直接进行接下来的反应.
2、向反应瓶中加入重蒸的乙酸酐(5mL),加热回流反应8～24h.TLC监测(V乙酸乙酯:V石油醚＝1:2～1:10),原料点基本消失后,停止反应.冷却至室温,向反应液中加入饱和NaHCO3至不再有气泡产生,用乙酸乙酯萃取(10mL×3),无水Na2SO4干燥,过滤,减压蒸去溶剂,残留物快速柱层析(洗脱剂为V乙酸乙酯:V石油醚＝1:4～1:20)得到相应的喹喔啉衍生物.
产物为黄色油状物，产率为83％，化合物的结构数据表征：1HNMR(500MHz,CDCl3)δ1.20(t,J＝7.1Hz,3H,CH3CH2-),4.02(s,3H,CH3O-),4.35(q,J＝7.1Hz,2H,CH3CH2-),7.52～7.55(m,5H,Ar-H),7.73～7.74(m,2H,Ar-H),8.08(d,J＝8.9Hz,1H,Ar-H)；13CNMR(125MHz,CDC13)δ13.76,55.96,62.33,106.53,125.43,128.53,128.59,129.24,130.27,138.01,138.67,141.67,145.46,149.90,161.29,166.82.
实施例2
化合物为黄色固体,产率77％,m.p.68℃，其合成方法同实施例1，化合物的结构数据表征为：1HNMR(500MHz,CDCl3)δ1.19(t,J＝7.2Hz,3H,CH3CH2-),2.64(s,3H,CH3-),4.35(q,J＝7.1Hz,2H,CH3CH2-),7.51～7.53(m,3H,Ar-H),7.70(d,J＝8.5Hz,1H,Ar-H),7.74～7.75(m,2H,Ar-H),8.00(s,1H,Ar-H),8.09(d,J＝8.6Hz,1H,Ar-H)；13CNMR(125MHz,CDC13)δ13.75,21.93,62.32,128.28,128.56,128.61,128.84,129.42,134.12,137.97,140.04,140.82,141.28,145.61,151.42,166.77.
实施例3
化合物为黄色油状物,产率68％.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ1.20(t,J＝7.2Hz,3H,CH3CH2-),4.36(q,J＝7.2Hz,2H,CH3CH2-),7.53～7.554(m,3H,Ar-H),7.65～7.69(m,1H,Ar-H),7.75～7.76(m,2H,Ar-H),7.85～7.87(m,1H,Ar-H),8.20～8.23(m,1H,Ar-H)；13CNMR(125MHz,CDC13)δ13.74,62.54,112.88,113.05,122.17,122.38,128.54,128.74,129.70,131.46,131.54,137.47,139.55,140.66,140.77,146.52,151.60,151.62,162.03,164.05,166.42.
实施例4
化合物为黄色固体,产率67％,m.p.90～92℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ1.21(t,J＝7.2Hz,3H,CH3CH2-),4.36(q,J＝7.2Hz,2H,CH3CH2-),7.54～7.55(m,3H,Ar-H),7.75～7.77(m,2H,Ar-H),7.95(dd,J＝8.9Hz,2.2Hz,1H,Ar-H),8.07(d,J＝8.9Hz,1H,Ar-H),8.41(d,J＝2.1Hz,1H,Ar-H)；13CNMR(125MHz,CDC13)δ13.75,62.27,124.58,128.55,128.73,128.85,129.86,130.63,130.92,131.75,137.38,140.43,141.03,146.53,152.45,166.29.
实施例5
化合物为黄色固体,产率72％,m.p.65～66℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ1.20(t,J＝7.1Hz,3H,CH3CH2-),4.36(q,J＝7.1Hz,2H,CH3CH2-),7.53～7.54(m,1H,Ar-H),7.76～7.77(m,1H,Ar-H),7.84～7.91(m,1H,Ar-H),8.21～8.26(m,1H,Ar-H)；13CNMR(125MHz,CDC13)δ13.75,62.41,128.58,128.65,129.37,129.59,130.54,131.70,137.82,139.94,142.28,145.76,152.28,166.62.
实施例6
化合物为黄色油状物,产率75％.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ1.22(t,J＝7.2Hz,3H,CH3CH2-),2.87(s,3H,CH3-),4.37(q,J＝7.2Hz,2H,CH3CH2-),7.53～7.56(m,3H,Ar-H),7.72～7.73(m,2H,Ar-H),7.82～7.84(m,2H,Ar-H),8.07～8.08(m,1H,Ar-H)；13CNMR(126MHz,CDCl3)δ167.02,150.70,145.14,141.45,139.97,138.14,137.88,131.48,130.27,129.50,128.81,128.56,127.30,62.35,17.10,13.78.
实施例7
化合物为白色固体,产率80％,m.p.79～80℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.40(d,J＝8.4Hz,1H,Ar-H),8.21(d,J＝7.3Hz,1H,Ar-H),7.87(dt,J＝11.2,4.7Hz,3H,Ar-H),7.57～7.53(m,3H,Ar-H),4.40(q,J＝7.1Hz,2H,CH3CH2-),1.23(t,J＝7.1Hz,3H,CH3CH2-)；13CNMR(126MHz,CDCl3)δ166.44(s),152.07(s),146.39(s),139.64(s),139.12(s),136.95(s),133.74(s),130.20(s),129.68(t,J＝5.3Hz),128.95(d,J＝4.7Hz),128.70(s),128.30(s),128.06(s),124.44(s),122.26(s),62.66(s),13.74(s).
实施例8
化合物为黄色固体,产率71％,m.p.131～133℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.00(dd,J＝8.0,2.7Hz,1H,Ar-H),7.87～7.82(m,3H,Ar-H),7.56～7.53(m,3H,Ar-H),4.38(q,J＝7.1Hz,2H,CH3CH2-),1.22(t,J＝7.1Hz,3H,CH3CH2-)；13CNMR(126MHz,CDCl3)δ166.19,163.16,161.12,151.77,151.75,147.05,140.84,140.73,137.37,137.36,136.83,130.09,128.87,128.75,125.86,125.77,125.71,125.48,112.91,112.74,62.70,13.74.
实施例9
化合物为白色固体,产率81％,m.p.115～116℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ7.79(s,1H,Ar-H),7.77～7.72(m,2H,Ar-H),7.54～7.48(m,4H,Ar-H),4.32(q,J＝7.1Hz,2H,CH3CH2-),2.82(s,3H,CH3-),2.58(s,3H,CH3-),1.15(t,J＝7.1Hz,3H,CH3CH2-)；13CNMR(126MHz,CDCl3)δ167.16,151.63,143.72,142.61,142.15,138.20,137.84,137.57,132.82,129.31,128.57,128.56,128.55,125.96,62.03,22.04,17.04,13.71.
实施例10
化合物为黄色固体,产率87％,m.p.154～155℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ1.19(t,J＝7.2Hz,3H,CH3CH2-),4.09(s,3H,CH3O-),4.10(s,3H,CH3O-),4.33(q,J＝7.2Hz,2H,CH3CH2-),7.46(s,1H,Ar-H),7.50～7.52(m,4H,Ar-H),7.69～7.71(m,2H,Ar-H)；13CNMR(125MHz,CDC13)δ13.78,55.51,56.55,62.15,106.57,106.76,128.50,128.53,129.08,137.40,138.42,140.04,142.69,150.55,153.48,154.50,166.92.
实施例11
化合物为白色固体,产率83％,m.p.105～106℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ9.32(dd,J＝6.6,2.9Hz,1H,Ar-H),8.07(q,J＝9.1Hz,2H,Ar-H),7.96(dd,J＝6.0,3.1Hz,1H,Ar-H),7.89(dd,J＝7.6,1.7Hz,2H,Ar-H),7.81～7.76(m,2H,Ar-H),7.59～7.53(m,3H,Ar-H),4.40(q,J＝7.1Hz,2H,CH3CH2-),1.24(t,J＝7.1Hz,3H,CH3CH2-)；13CNMR(126MHz,CDCl3)δ167.06,150.69,144.61,141.19,139.66,138.11,134.02,132.33,130.52,129.66,129.48,128.97,128.55,128.07,127.74,126.36,125.18,62.32,13.79.
实施例12
化合物为黄色固体，产率82％,m.p.59～60℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ1.51(t,J＝7.1Hz,3H,CH3CH2-),2.94(s,3H,CH3-),3.97(s,3H,CH3O-),4.57(q,J＝7.1Hz,2H,CH3CH2-),7.47(dd,J＝5.7Hz,2.7Hz,1H,Ar-H),7.50(d,J＝2.8Hz,1H,Ar-H),7.93(d,J＝9.4Hz,1H,Ar-H)；13CNMR(125MHz,CDCl3)δ14.30,22.43,55.90,62.41,106.74,125.50,129.31,138.92,141.49,144.00,150.27,160.61,165.83.HRMS(APCI):m/z[M+H]+calcdforC13H15N2O3:247.1083；found:247.1079.
实施例13
13)化合物为白色固体,产率85％,m.p.50-51℃.其合成方法同实施例1，结构数据表征为：1HNMR(600MHz,CDCl3)δ7.92(d,J＝9.1Hz,Ar-H,1H),7.44(dd,J＝9.1,2.8Hz,Ar-H,1H),7.42(d,J＝2.7Hz,Ar-H,1H),4.53(q,J＝7.1Hz,CH3CH2,2H),3.93(s,CH3O,3H),3.20(q,J＝7.5Hz,CH3CH2,2H),1.47(t,J＝7.1Hz,CH3CH2,3H),1.38(t,J＝7.5Hz,CH3CH2,3H).13CNMR(151MHz,CDCl3)δ166.17,160.70,154.62,144.47,141.48,139.13,129.64,125.30,106.77,62.51,55.98,29.19,14.38,13.59.HRMS(APCI):m/z[M+H]+calcdforC14H17N2O3:261.1239；found:261.1226.
实施例14
化合物为白色固体,产率84％,m.p.113-115℃.其合成方法同实施例1，结构数据表征为：1HNMR(600MHz,CDCl3)δ7.89(d,J＝9.1Hz,Ar-H,1H),7.43–7.37(m,Ar-H,2H),4.50(q,J＝7.1Hz,CH3CH2,2H),3.90(s,CH3O,3H),3.14–3.10(m,CH3CH2CH2,2H),1.84–1.75(m,CH3CH2CH2,2H),1.43(d,J＝7.1Hz,CH3CH2,3H),0.99(t,J＝7.4Hz,CH3CH2CH2,3H).13CNMR(151MHz,CDCl3)δ166.11,160.68,153.52,144.59,141.43,139.00,129.55,125.27,106.69,62.42,55.92,37.75,23.01,14.32,14.18.HRMS(APCI):m/z[M+H]+calcdforC15H19N2O3:275.1396；found:275.1378.
实施例15
化合物为黄色固体,产率90％,m.p.93-94℃,其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ2.83(s,3H,CH3-),2.92(s,3H,CH3-),3.99(s,3H,CH3O-),7.35(d,J＝2.8Hz,1H,Ar-H),7.47(dd,J＝9.2Hz,2.8Hz,1H,Ar-H),7.90(d,J＝9.2Hz,1H,Ar-H)；13CNMR(125MHz,CDC13)δ24.02,27.85,55.83,106.63,125.49,129.26,138.93,141.32,146.97,150.33,160.42,201.53.
实施例16
16)化合物为黄色油状物,产率54％,其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.16–8.12(m,1H,Ar-H),7.58(dd,J＝9.3,2.8Hz,1H,Ar-H),7.51(d,J＝2.8Hz,1H,Ar-H),4.10(s,3H,CH3-),4.09(s,3H,CH3-),4.01(s,3H,CH3-)；13CNMR(126MHz,CDCl3)δ165.58,163.11,143.61,137.79,130.90,126.52,121.43,114.39,106.65,56.15,53.48,53.44.
实施例17
化合物为黄色油状物,产率84％,其合成方法同实施例1，结构数据表征为：1HNMR(600MHz,CDCl3)δ8.04(d,J＝9.0Hz,Ar-H,1H),7.55–7.50(m,Ar-H,2H),7.37–7.33(m,Ar-H,1H),7.30(d,J＝7.5Hz,Ar-H,1H),7.28–7.25(m,Ar-H,2H),4.21(q,J＝7.1Hz,CH3CH2,2H),3.99(s,CH3O,3H),2.22(s,CH3,3H),1.05(t,J＝7.1Hz,CH3CH2,3H).13CNMR(151MHz,CDCl3)δ165.89,161.48,151.45,145.45,142.03,138.65,138.06,136.31,130.42,130.28,129.01,128.88,125.81,125.76,106.78,62.21,56.11,19.87,13.74.HRMS(APCI):m/z[M+H]+calcdforC19H19N2O3:323.1396；found:323.1384.
实施例18
化合物为白色固体,产率88％,m.p.97-98℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.04(d,J＝9.2Hz,Ar-H,1H),7.65–7.62(m,Ar-H,2H),7.61–7.58(m,Ar-H,2H),7.52(dd,J＝9.2,2.8Hz,Ar-H,1H),7.49(d,J＝2.7Hz,Ar-H,1H),4.37(q,J＝7.2Hz,CH3CH2,2H),3.99(s,CH3,3H),1.25(t,J＝7.1Hz,CH3CH2,3H).13CNMR(126MHz,CDCl3)δ166.55,161.50,148.67,144.98,141.77,138.62,136.91,131.73,130.21,130.18,125.68,123.86,122.07,114.41,106.49,62.49,55.97,13.85.HRMS(APCI):m/z[M+H]+calcdforC18H16N2O3Br,C18H18N2O3Br:387.0344,389.0324；found:387.0324,389.0299.
实施例19
化合物为白色固体,产率86％,m.p.175-176℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.65–8.62(m,Ar-H,1H),8.40–8.34(m,Ar-H,1H),8.06–8.01(m,Ar-H,1H),7.90–7.85(m,Ar-H,1H),7.51–7.45(m,Ar-H,2H),7.38–7.33(m,Ar-H,1H),4.49(q,J＝7.1Hz,CH3CH2,2H),3.97(s,CH3O,3H),1.36(t,J＝7.2Hz,CH3CH2,3H).13CNMR(126MHz,CDCl3)δ167.32,161.59,154.57,148.43,146.70,146.54,142.27,137.88,136.92,130.32,124.87,124.01,122.43,106.68,62.05,55.92,13.99.HRMS(APCI):m/z[M+H]+calcdforC17H16N3O3:310.1192；found:310.1177.
实施例20
化合物为黄色固体,产率89％,m.p.184-185℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.09(d,J＝9.3Hz,Ar-H,1H),8.07–8.02(m,Ar-H,2H),7.63–7.58(m,Ar-H,4H),7.43(d,J＝2.8Hz,Ar-H,1H),4.04(s,CH3O,3H).13CNMR(126MHz,CDCl3)δ161.90,152.11,142.48,139.06,135.34,130.49,130.41,129.13,128.94,128.05,127.58,116.87,105.88,56.13.HRMS(APCI):m/z[M+H]+calcdforC16H12N3O:262.0980；found:262.1259.
实施例21
化合物为黄色固体,产率59％,m.p.82-83℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,DMSO-d6)δ8.09(dd,J＝16.7,8.3Hz,2H,Ar-H),7.93(t,J＝8.1Hz,3H,Ar-H),7.85(t,J＝7.5Hz,1H,Ar-H),7.74(dd,J＝10.9,3.9Hz,1H,Ar-H),7.57(t,J＝7.7Hz,2H,Ar-H),2.71(s,3H,CH3-)；13CNMR(126MHz,DMSO-d6)δ194.43,152.34,151.05,142.02,139.16,135.70,134.85,130.88,130.57,129.57,129.32,128.80.
实施例22
化合物为黄色固体,产率51％,m.p.132-133℃.其合成方法同实施例1，结构数据表征为：1HNMR(500MHz,CDCl3)δ8.26(dd,J＝6.4,3.4Hz,2H,Ar-H),7.94(dd,J＝6.5,3.4Hz,2H,Ar-H),4.09(s,6H,CH3-)；13CNMR(126MHz,CDCl3)δ165.14,143.83,141.39,132.69,129.87,53.58.

Claims (4)

1.一种喹喔啉衍生物的合成方法，其特征是，包括如下步骤：
(1)向25mL圆底烧瓶中加入1mmol烯胺、5～10mL乙腈,室温下搅拌溶解后,一次性加入1.2mmol异丁基亚硝酸酯,室温搅拌反应5～20min后,TLC监测，原料点基本消失.停止反应,直接旋蒸蒸去溶剂得到粗产物,粗产物不经提纯可直接进行接下来的反应；
(2)向反应瓶中加入重蒸的5mL乙酸酐,加热回流反应8～24h.TLC监测,原料点基本消失后,停止反应.减压出去乙酸酐，冷却至室温,然后向反应液中加入饱和NaHCO3至不再有气泡产生,用乙酸乙酯萃取3次，每次用10毫升,无水Na2SO4干燥,过滤,减压蒸去溶剂,残留物快速柱层析，用洗脱剂洗脱，得到相应的喹喔啉衍生物。
2.根据权利要求1所述的合成方法，其特征是，所述步骤(1)的TLC监测中V乙酸乙酯:V石油醚＝1:2～1:10。
3.根据权利要求1所述的合成方法，其特征是，所述步骤(2)的TLC监测中V乙酸乙酯:V石油醚＝1:2～1:10。
4.根据权利要求1所述的合成方法，其特征是，所述步骤(2)中洗脱剂为V乙酸乙酯:V石油醚＝1:4～1:20。
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