CN105503751B - 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

Info

Publication number
CN105503751B
CN105503751B CN201510969658.8A CN201510969658A CN105503751B CN 105503751 B CN105503751 B CN 105503751B CN 201510969658 A CN201510969658 A CN 201510969658A CN 105503751 B CN105503751 B CN 105503751B
Authority
CN
China
Prior art keywords
compound
nmr
enamine
cdcl
reaction
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
CN201510969658.8A
Other languages
English (en)
Other versions
CN105503751A (zh
Inventor
潘成学
苏桂发
焦艳晓
魏凯
莫冬亮
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 CN201510969658.8A priority Critical patent/CN105503751B/zh
Publication of CN105503751A publication Critical patent/CN105503751A/zh
Application granted granted Critical
Publication of CN105503751B publication Critical patent/CN105503751B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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.Ila 2005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)Synthesis 2008,2575；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Zhang Xing-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。
Zhang Xing-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Zhang Xing-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，Zhang Xing-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：1H NMR(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)；13C NMR(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：1H NMR(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： 1H NMR(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)；13C NMR(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：1H NMR(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)；13C NMR(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：1H NMR(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)；13C NMR(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： 1H NMR(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)；13C NMR(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：1H NMR(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-)；13C NMR(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：1H NMR(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-)；13C NMR(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：1H NMR(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-)；13C NMR(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：1H NMR(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)；13C NMR(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：1H NMR(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-)；13C NMR(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：1H NMR(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)；13C NMR(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]+calcd for C13H15N2O3:247.1083；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：1H NMR(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).13C NMR(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]+calcd for C14H17N2O3:261.1239；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：1H NMR(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).13C NMR(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]+calcd for C15H19N2O3:275.1396；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：1H NMR(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)；13C NMR(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：1H NMR(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-)； 13C NMR(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：1H NMR(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]+calcd for C19H19N2O3:323.1396；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：1H NMR(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). 13C NMR(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]+calcd for C18H16N2O3Br,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：1H NMR(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).13C NMR(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]+calcd for C17H16N3O3:310.1192；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：1H NMR(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]+calcd forC16H12N3O: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：1H NMR(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-)；13C NMR(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：1H NMR(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-)；13C NMR(126MHz,CDCl3)δ165.14,143.83,141.39,132.69,129.87,53.58.

Claims (1)

1.一种喹喔啉衍生物的合成方法，其特征是，化学合成路线为：
其中，Ar为R为一个或多个烷基、烷氧基、卤素、三氟甲基；R’为芳基、烷基、酯基；EWG为酯基、氰基或苯甲酰基；
其合成方法为：以式1所示的化合物与ArNH2为原料，缩合得到烯胺5后，与亚硝酸异丁酯反应得到烯胺5的亚硝化产物6，化合物6无需分离纯化，即可直接在乙酸酐中经6π电子环化反应得到喹喔啉衍生物2。
CN201510969658.8A 2015-12-22 2015-12-22 一种喹喔啉衍生物的高效合成方法 Expired - Fee Related CN105503751B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510969658.8A CN105503751B (zh) 2015-12-22 2015-12-22 一种喹喔啉衍生物的高效合成方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510969658.8A CN105503751B (zh) 2015-12-22 2015-12-22 一种喹喔啉衍生物的高效合成方法

Publications (2)

Publication Number Publication Date
CN105503751A CN105503751A (zh) 2016-04-20
CN105503751B true CN105503751B (zh) 2018-06-05

Family

ID=55712120

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510969658.8A Expired - Fee Related CN105503751B (zh) 2015-12-22 2015-12-22 一种喹喔啉衍生物的高效合成方法

Country Status (1)

Country Link
CN (1) CN105503751B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484514B (zh) * 2018-03-29 2021-04-20 广西师范大学 血小板衍生生长因子受体抑制剂ag1296的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104086491A (zh) * 2014-07-09 2014-10-08 广西师范大学 2,3-二取代喹喔啉衍生物的制备方法
CN105073758A (zh) * 2013-03-15 2015-11-18 吉里德科学公司 丙型肝炎病毒抑制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105073758A (zh) * 2013-03-15 2015-11-18 吉里德科学公司 丙型肝炎病毒抑制剂
CN104086491A (zh) * 2014-07-09 2014-10-08 广西师范大学 2,3-二取代喹喔啉衍生物的制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Dehydrogenative N-Incorporation: A Direct Approach to Quinoxaline N-Oxides under Mild Conditions;Feng Chen等;《Angewandte Chemie International Edition》;20140805;第53卷(第39期);第10498页方案4 *
Heteroannulation of Nitroketene N,S-Arylaminoacetals with POCl3: A Novel Highly Regioselective Synthesis of Unsymmetrical 2,3-Substituted Quinoxalines;C. Venkatesh等;《ORGANIC LETTERS》;20050430;第7卷(第11期);第2169-2172页 *
Synthesis of Novel Functionalized Hydroxyiminoimines by Direct Nitrosation of β-Thio-β-amino-α,β-unsaturated Ketones and Their Further Transformations: New General Syntheses for Imidazole, Quinoxaline, and Thiazole Derivatives;Azizur-Rahman等;《Journal of the Chemical Society, Chemical》;19840101;第7卷;第430-431页 *
Synthesis of quinoxalines by cyclization of α-arylimino oximes of a-dicarbonyl compounds;N. P. Xekoukoulotakis等;《Tetrahedron Letters》;20001223;第41卷;第10299-10302页，尤其是第10300页方案1、表1 *

Also Published As

Publication number Publication date
CN105503751A (zh) 2016-04-20

Similar Documents

Publication Publication Date Title
CN106488909A (zh) 制备3‑(3‑氯‑1h‑吡唑‑1‑基)吡啶的方法
Lee et al. Chemical transformation of Baylis–Hillman adducts: the reaction of methyl 3-arylamino-2-methylene-3-phenylpropanoates in polyphosphoric acid
Keyume et al. Convenient DABCO-catalyzed one-pot synthesis of multi-substituted pyrano [2, 3-c] pyrazole dicarboxylates
Hingane et al. An efficient new route towards biologically active isocryptolepine and γ-carboline derivatives using an intramolecular thermal electrocyclization strategy
Majo et al. Dimerization of substituted 2-aminobenzoic acids under Vilsmeier conditions: A novel route to the synthesis of 4-(3H)-quinazolinones
Łukasik et al. Simple Synthesis of 2-Aminoaryliminophosphoranes from N-Aryl-2-nitrosoanilines and Their Application in 2-Aminobenzimidazole Synthesis
Thirupathaiah et al. Solvent-free sonochemical multi-component synthesis of benzopyranopyrimidines catalyzed by polystyrene supported p-toluenesulfonic acid
CN105503751B (zh) 一种喹喔啉衍生物的高效合成方法
Zhang et al. One‐pot Sequential Reaction for the Synthesis of Polysubstituted 3‐(3‐Nitro‐2‐phenylchroman‐4‐yl)‐3‐arylaminoacrylates
Kim et al. Synthesis of 3, 4-disubstituted 2 (1H)-quinolinones via intramolecular Friedel–Crafts reaction of N-arylamides of Baylis–Hillman adducts
Zhang et al. Copper (I)‐Catalyzed Intramolecular N‐N Coupling of Cyclopropyl O‐Acyl Ketoximes: Synthesis of Spiro‐fused Pyrazolin‐5‐ones
CN104045643B (zh) 一种铜催化水相制备吡唑并[1,5-c]喹唑啉骨架化合物的方法
CN104892485B (zh) 2‑全氟烷基吲哚衍生物及其合成方法
CN109897033A (zh) 一种合成含碘咪唑并[1，2a]吡啶类化合物的方法
CN103965203B (zh) 一类咪唑[1,2-c]-喹唑啉-3（2H）-酮稠杂环化合物及其制备方法
CN104761558B (zh) 一种一锅法合成喹唑啉酮并吲唑衍生物的方法
Gao et al. Efficient and divergent synthesis of polyfunctionalized 2-pyridones from β-keto amides
Wang et al. The Synthesis of 3, 4-Disubstituted Dihydroquinolin-2 (1 H)-One Under Metal-Free Conditions in Aqueous Solution
CN109836383B (zh) 一种制备3,4-二氢喹啉-2(1h)-酮类化合物的方法
CN110117258B (zh) 一种2,4,6-三芳基取代嘧啶类化合物的制备方法
Sheikhhosseini et al. Efficient synthesis of novel 3-substituted coumarin-3-carboxamide
Chen et al. A Novel Method for One‐pot Synthesis of Furo [3, 2‐c] coumarin Derivatives from 4‐Hydroxycoumarin and Arylglyoxal under Microwave Irradiation
CN107056808B (zh) 3-芳基取代异噁唑并琥珀酰亚胺类化合物及其合成方法
Zhuravel' et al. Synthesis of substituted 3‐(5‐amino‐[1, 3, 4] thiadiazol‐2‐yl)‐2H‐pyrano [2, 3‐c] pyridin‐2‐ones
CN114230526B (zh) 一种4-3(h）喹唑啉酮及其衍生物的合成方法

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into 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
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20180605

Termination date: 20201222