CN115340530B - 一种制备含氮杂环衍生物的方法及其应用 - Google Patents
一种制备含氮杂环衍生物的方法及其应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
本发明提供了一种制备含氮杂环衍生物的方法及其应用，涉及有机合成技术领域。其方法为：以含萘化合物为底物与甲醛和DBU在溶剂中通过多组分级联反应，制备得到一系列被N‑取代的带有己内酰胺单元的不同的二氢恶嗪、二氢噻嗪、四氢苯并喹唑啉衍生物的新方法，简单易于操作，反应底物适用范围广，区域选择性好，收率高，方法新颖、环境友好，在生物科学、制药工业和材料科学方面具有广阔的应用前景。
Description
技术领域
本申请涉及有机合成技术领域，具体涉及一种制备含氮杂环衍生物的方法及其应用。
背景技术
当具有环状结构的有机化合物组成中含有杂原子氮时，这些化合物被统称为含氮杂环化合物。氮元素是生命组成中必不可少的元素之一，含氮杂环化合物及其衍生物在生物活性方面具有天然优势。在基础有机合成技术和分析手段发展的年代，人类不断发现含氮杂环化合物参与构成了许多天然产物，例如动物中的红血素，植物中的叶绿素，生物中的生物碱，碱基对等。含氮杂环化合物在声明组成中的重要性也激起了人们对人工合成含氮杂环化合物的兴趣。
由于含氮杂环化合物往往具有独特的生理活性和药理活性、高内吸性和低毒性，因此常被用作医药和农业的结构单元，在医药、除草剂、杀虫剂、杀菌剂等方面有了广泛的应用，在医药方面，含氮杂环噻唑、吡啶、吡唑、嘧啶、哌啶和吲哚等稠杂环类化合物都已广泛应用于医药合成中；在农业方面，随着传统农药的大量使用，使得病虫菌的抗药性增强，其杀虫灭菌效果已经不能够起到最佳的效果，同时由于传统农药有着毒性较大以及在生物体内代谢周期较长的缺点，已经逐渐被淘汰；由于含氮杂环化合物易于进行结构修饰，可方便地引入各种功能基，在有机金属催化材料、染料和敏化太阳能电池等领域也有应用。
中国专利申请201911351341.2中公开了一类含氮杂环衍生物及其制法和用途，其公开的化合物结构通式为：并公开了该类化合物对蛋白酪氨酸磷酸酶SHP-2有较好的抑制作用，可用于制备抗肿瘤药物。
再如中国专利申请202011122062.1公开了一种含氮杂环衍生物及其制备，所述的含氮杂环衍生物的结构式为：并公开了所示的含氮杂环化合物及其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药以及其药物组合物、制备方法，以及在由自分泌运动因子介导的疾病的预防和治疗中的用途。
酚类是极其重要的有机化工原料，广泛应用于化工原料、合成纤维、塑料、合成橡胶、医药、农药、香料、染料、涂料、炼油等行业[1-4]，因此，开发提高其使用效率的方法对化学品的升级有直接影响。近年来，通过Csp2-H直接官能化，尤其是酚的邻位官能化已被证明是制备酚类衍生物的最有效手段之一，化学家们为推动该领域的深入研究付出了很多努力[5-8]，此外，二氢恶嗪、二氢噻嗪和四氢苯并喹唑啉衍生物广泛存在于生物活性分子、天然产物和药物分子中，在生物学，制药，农用化学品和材料等许多领域都起着至关重要的作用[9-15]，因此，开发用于这些多种含氮杂环分子的邻位选择性合成策略具有重要意义。
[1]S.Quideau,D.Deffieux,C.Douat-Casassus and L.Pouységu,PlantPolyphenols:Chemical Properties,Biological Activities,andSynthesis.Angew.Chem.,Int.Ed.,2011,50,586-621；
[2]M.Mure,Tyrosine-Derived Quinone Cofactors.Acc.Chem.Res.,2004,37,131-139；
[3]P.S.Fier and K.M.Maloney,Synthesis of Complex Phenols Enabled by aRationally Designed Hydroxide Surrogate.Angew.Chem.,Int.Ed.,2017,56,4478-4482；
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[5]Z.Huang and J.P.Lumb,Phenol-Directed C-H Functionalization,ACSCatal.,2019,9,521-555；
[6]X.Xiong and Y.-Y.Yeung,Ammonium Salt-Catalyzed Highly PracticalOrtho-Selective Monohalogenation and Phenylselenation of Phenols:Scope andApplications.ACS Catal.,2018,8,4033–4043；
[7]Z.Yu,Y.Li,J.Shi,B.Ma,L.Liu and J.Zhang,(C6F5)3B CatalyzedChemoselective and ortho-Selective Substitution of Phenols withα-Aryl α-Diazoesters.Angew.Chem.,Int.Ed.,2016,55,14807–14811；
[8]J.-L.Dai,N.-Q.Shao,J.Zhang,R.-P.Jia and D.-H.Wang,Cu(II)-Catalyzedortho-Selective Aminomethylation of Phenols.J.Am.Chem.Soc.,2017,139,12390–12393.
[9]N.Li,B.Sun,S.Liu,J.Zhao and Q.Zhang,Highly EnantioselectiveConstruction of Dihydrooxazines via Pd-Catalyzed AsymmetricCarboetherification,Org.Lett.,2020,22,190-193；
[10]A.Jaganathan,A.Garzan,D.C.Whitehead,R.J.Staples and B.Borhan,ACatalytic Asymmetric Chlorocyclization of Unsaturated Amides,Angew.Chem.,Int.Ed.,2011,50,2593-2596；
[11]P.Kralova,V.Fulopova,M.Malon,T.Volna,I.Popa and M.Soural,Stereoselective Polymer-Supported Synthesis of Morpholine-and Thiomorpholine-3-carboxylic Acid Derivatives,ACS Comb.Sci.,2017,19,173-180.
[12]B.Quiclet-Sire and S.Z.Zard,An Expedient Route toDihydrothiazines,a Virtually Unknown Class of Heterocycles,Org.Lett.,2013,15,5886-5889；
[13]A.Balsamo,P.Crotti,B.Macchia,F.Macchia,G.Nannini,E.Dradi andA.Forgione,Chemistry of the dihydrothiazine ring moiety of cephalosporins.1.Regiospecificity and stereoselectivity in the bromine addition to 2-cephemderivatives.A new route to 2-methoxy cephalosporins,J.Org.Chem.,1976,41,2150-2153.
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发明内容
本发明提供了一种制备含氮杂环衍生物的方法，即在无金属和无添加剂的条件下通过由含萘化合物与甲醛和DBU在水中制备多种类型含氮杂环衍生物的新方法。
本申请所述的方法通过以及技术方案实现：
一种制备含氮杂环衍生物的方法，其步骤为：含萘化合物与甲醛和DBU在溶剂中通过多组分串联反应，分别获得一系列被N-取代的带有己内酰胺单元的不同的含氮杂环衍生物。
所述的含萘化合物为萘酚、硫萘酚或萘胺中的一种。
所述的溶剂为水，四氢呋喃，乙醇，1,2-二氯乙烷，N,N-二甲基甲酰胺，丙酮和1,4-二氧六环中的一种或几种；优选为H2O。
所述的含萘化合物、甲醛和DBU得摩尔比为1:4:1.5-1:4:2；
所述的含萘化合物与溶剂的摩尔体积比(mmol/mL)比为0.3:1-2:1；
上述反应的反应温度为80-100℃；优选为90℃。
所述的萘酚为下式1所述的化合物：
其中，基团R为氢原子，甲氧基，卤原子，羟基，芳基或烷基。
优选地，所述的萘酚选自 中的一种。
含萘化合物为萘酚时，制备含氮杂环衍生物的反应方程式为：
所述的硫萘酚为下式2所述的化合物：
其中，基团R为氢原子，甲氧基，卤原子，羟基，芳基或烷基；
优选地，所述的硫萘酚选自中的一种。
含萘化合物为硫萘酚时，制备含氮杂环衍生物的反应方程式为：
所述的萘胺为下式3所述的化合物：
其中，基团R为氢原子，甲氧基，卤原子，羟基，芳基或烷基；
所述的萘胺选自中的一种。
含萘化合物为萘胺时，制备含氮杂环衍生物的反应方程式为：
本申请还公开了上述氮杂环衍生物在制备治疗人神经母细胞瘤细胞SY5Y增殖药物中的应用。
与现有技术相比本申请的有益效果在于：
本发明技术方案制备一系列被N-取代的带有己内酰胺单元的不同的二氢恶嗪、二氢噻嗪、四氢苯并喹唑啉衍生物的新方法，简单易于操作，反应底物适用范围广，区域选择性好，收率高，方法新颖、环境友好，在生物科学、制药工业和材料科学方面具有广阔的应用前景。
具体实施方式
以下结合实施例对本发明作进一步说明。
实施例1：
将43.2mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，89％产率。
1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.2Hz,1H),7.64–7.59(m,2H),7.47(t,J＝8.3Hz,1H),7.34(t,J＝7.5Hz,1H),7.01(d,J＝8.9Hz,1H),4.91(s,2H),4.31(s,2H),3.45(t,J＝7.2Hz,2H),3.36–3.31(m,2H),2.81(t,J＝7.1Hz,2H),2.52–2.47(m,2H),1.82(p,J＝7.2Hz,2H),1.70–1.58(m,6H).
13C NMR(100MHz,CDCl3)δ175.83,151.84,131.86,128.94,128.64,128.00,126.52,123.45,121.05,118.53,111.78,82.23,49.84,49.34,47.83,46.36,37.30,29.99,28.73,26.77,23.43.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26N2O2 339.1994,found:339.1995.
实施例2：
将52.2mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，74％产率。
1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.9Hz,1H),7.52(d,J＝8.8Hz,1H),6.99(dd,J＝8.9,2.3Hz,1H),6.85(d,J＝8.6Hz,1H),6.82(d,J＝2.6Hz,1H),4.88(s,2H),4.21(s,2H),3.90(s,3H),3.44(t,J＝7.3Hz,2H),3.31(dd,J＝6.8,3.3Hz,2H),2.79(t,J＝7.1Hz,2H),2.50–2.44(m,2H),1.80(p,J＝7.2Hz,2H),1.62(ddd,J＝23.0,10.6,5.7Hz,6H).
13C NMR(100MHz,CDCl3)δ175.78,158.33,152.49,133.09,130.15,127.69,124.15,115.96,115.25,110.86,100.40,82.12,55.36,49.81,49.40,48.05,46.35,37.31,29.98,28.72,26.80,23.43.
HRMS(ESI)m/z:[M+H]+Calcd for C22H28N2O3 369.2100,found:369.2104.
实施例3：
将66.6mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，83％产率。
1H NMR(400MHz,CDCl3)δ7.70(d,J＝3.2Hz,1H),7.54(td,J＝10.5,10.1,5.4Hz,2H),7.36(dd,J＝8.2,5.5Hz,1H),6.97(d,J＝8.6Hz,1H),4.88(s,2H),4.20(s,2H),3.42(q,J＝5.6,3.6Hz,2H),3.31(q,J＝4.1Hz,2H),2.80–2.71(m,2H),2.49–2.43(m,2H),1.78(t,J＝7.6Hz,2H),1.68–1.58(m,4H).
13C NMR(100MHz,CDCl3)δ175.80,152.70,133.17,130.21,127.90,127.29,126.64,123.49,120.99,119.02,111.06,82.34,49.79,49.35,47.59,46.24,37.29,29.97,28.73,26.75,23.42.
HRMS(ESI)m/z:[M+H]+Calcd for C21H25BrN2O2 417.1099,found:417.1089.
实施例4：
将66.0mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，64％产率。
1H NMR(400MHz,CDCl3)δ7.83–7.78(m,2H),7.71(d,J＝7.6Hz,2H),7.64(d,J＝8.9Hz,1H),7.59(d,J＝8.4Hz,1H),7.49(t,J＝7.6Hz,2H),7.38(t,J＝7.4Hz,1H),7.03(d,J＝8.8Hz,1H),4.93(s,2H),4.37(s,2H),3.46(t,J＝7.2Hz,2H),3.34–3.27(m,2H),2.83(t,J＝7.1Hz,2H),2.52–2.46(m,2H),1.83(p,J＝7.2Hz,2H),1.68–1.56(m,6H).
13C NMR(100MHz,CDCl3)δ175.76,152.35,141.49,139.36,132.20,129.20,128.91,128.13,127.78,127.61,127.48,123.23,119.21,118.67,112.06,82.31,49.79,49.44,47.94,46.33,37.33,29.99,28.76,26.85,23.46.
HRMS(ESI)m/z:[M+H]+Calcd for C27H31N2O2 415.2380,found:415.2371.
实施例5：
将43.5mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，81％产率。
1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.43(d,J＝5.8Hz,1H),7.71(d,J＝9.0Hz,1H),7.38(d,J＝6.0Hz,1H),7.06(d,J＝8.9Hz,1H),4.94(s,2H),4.24(s,2H),3.43(t,J＝7.2Hz,2H),3.32(d,J＝7.9Hz,2H),2.77(t,J＝7.1Hz,2H),2.49–2.44(m,2H),1.78(p,J＝7.2Hz,2H),1.61(ddd,J＝16.7,10.4,5.3Hz,6H).
13C NMR(100MHz,CDCl3)δ175.80,155.38,152.28,143.63,135.08,127.84,124.25,119.99,114.62,110.82,82.73,49.80,49.30,47.07,46.21,37.28,29.96,28.74,26.71,23.41.
HRMS(ESI)m/z:[M+H]+Calcd for C21H20N3 340.1947,found:340.1948.
实施例6：
将43.5mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，80％产率。
1H NMR(400MHz,CDCl3)δ8.75–8.66(m,1H),7.90(d,J＝8.6Hz,1H),7.82(d,J＝9.2Hz,1H),7.30(td,J＝6.3,5.2,3.1Hz,1H),7.17(d,J＝9.1Hz,1H),4.87(s,2H),4.24(s,2H),3.40(t,J＝7.3Hz,2H),3.28(d,J＝7.2Hz,2H),2.74(t,J＝7.1Hz,2H),2.43(d,J＝8.8Hz,2H),1.75(p,J＝7.2Hz,2H),1.64–1.51(m,6H).
13C NMR(100MHz,CDCl3)δ175.78,152.00,147.49,144.20,129.41,129.29,126.86,122.14,121.10,111.50,82.36,49.79,49.23,47.25,46.25,37.25,29.91,28.68,26.67,23.37.
HRMS(ESI)m/z:[M+H]+Calcd for C21H20N3 340.1947,found:340.1948.
实施例7：
将43.5mg(0.3mmol)如下所示的2-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，68％产率。
1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.01(dd,J＝7.9,1.7Hz,1H),7.60(dd,J＝7.6,1.9Hz,1H),7.56–7.47(m,2H),4.95(s,2H),4.30(s,2H),3.45(t,J＝7.2Hz,2H),3.36–3.30(m,2H),2.79(t,J＝7.0Hz,2H),2.51–2.45(m,2H),1.79(p,J＝7.1Hz,2H),1.64(dq,J＝26.4,5.4,4.9Hz,6H).
13C NMR(100MHz,CDCl3)δ175.88,143.42,143.14,130.02,127.11,126.61,126.54,121.19,120.50,82.59,49.85,49.48,46.86,46.24,37.27,29.95,28.72,26.66,23.41.
HRMS(ESI)m/z:[M+H]+Calcd for C21H20N3 340.1947,found:340.1950.
实施例8：
将48.0mg(0.3mmol)如下所示的2-萘酚、72.0mg(2.4mmol)甲醛、136.8mg(0.90mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(4ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，62％产率。
1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.8Hz,2H),6.81(d,J＝8.8Hz,2H),4.90(s,4H),4.41(s,4H),3.42(t,J＝7.2Hz,4H),3.35–3.30(m,4H),2.66(t,J＝7.1Hz,4H),2.50–2.45(m,4H),1.76(q,J＝7.2Hz,4H),1.63(ddd,J＝25.3,9.8,4.9Hz,12H).
13C NMR(100MHz,CDCl3)δ175.76,153.11,133.80,129.35,125.48,115.96,112.17,80.97,51.94,49.78,48.23,46.24,37.27,29.96,28.71,26.68,23.39.
HRMS(ESI)m/z:[M+H]+Calcd for C32H44N4O4 549.3363,found:549.3362.
实施例9：
将48.0mg(0.3mmol)如下所示的2-萘酚、72.0mg(2.4mmol)甲醛、136.8mg(0.90mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(4ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，71％产率。
1H NMR(400MHz,CDCl3)δ7.53(d,J＝9.3Hz,2H),7.34(d,J＝8.8Hz,2H),4.97(s,4H),4.28(s,4H),3.42(t,J＝7.3Hz,4H),3.31(d,J＝7.2Hz,4H),2.80(t,J＝7.1Hz,4H),2.46(d,J＝8.5Hz,4H),1.78(p,J＝7.2Hz,4H),1.67–1.55(m,12H).
13C NMR(100MHz,CDCl3)δ175.70,142.66,126.43,124.19,121.50,111.39,82.75,49.81,49.34,47.58,46.27,37.27,29.95,28.71,26.74,23.41.
HRMS(ESI)m/z:[M+H]+Calcd for C32H44N4O4 549.3363,found:549.3462.
实施例10：
将43.5mg(0.3mmol)如下所示的1-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，83％产率。
1H NMR(400MHz,CDCl3)δ8.17–8.08(m,1H),7.75–7.70(m,1H),7.43(td,J＝6.4,5.7,3.5Hz,2H),7.34(d,J＝8.3Hz,1H),7.03(d,J＝8.3Hz,1H),5.02(s,2H),4.08(s,2H),3.43(t,J＝7.3Hz,2H),3.34–3.26(m,2H),2.80(t,J＝7.1Hz,2H),2.51–2.44(m,2H),1.79(p,J＝7.2Hz,2H),1.61(td,J＝12.5,11.9,5.8Hz,6H).
13C NMR(100Hz,CDCl3)δ175.76,149.23,133.24,127.54,125.86,125.36,125.28,124.72,121.23,119.79,113.76,82.73,50.44,49.82,49.07,46.36,37.33,29.98,28.72,26.74,23.43.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26N2O2 339.1994,found:339.1997.
实施例11：
将53.4mg(0.3mmol)如下所示的1-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，70％产率。
1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.2Hz,2H),7.51(dt,J＝19.7,7.1Hz,2H),7.12(s,1H),5.00(s,2H),4.03(s,2H),3.42(t,J＝7.2Hz,2H),3.30(d,J＝7.6Hz,2H),2.77(t,J＝7.1Hz,2H),2.50–2.44(m,2H),1.77(p,J＝7.2Hz,2H),1.69–1.56(m,6H).
13C NMR(100Hz,CDCl3)δ175.77,148.46,130.17,126.92,126.00,125.85,125.15,124.20,122.69,121.60,114.07,82.89,50.01,49.82,49.01,46.29,37.31,29.97,28.73,26.67,23.42.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26ClN2O2 373.1677,found:373.1677.
实施例12：
将52.2mg(0.3mmol)如下所示的1-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，80％产率。
1H NMR(400MHz,CDCl3)δ8.15(d,J＝7.7Hz,1H),8.06(d,J＝7.8Hz,1H),7.49–7.41(m,2H),6.35(s,1H),4.97(s,2H),4.06(s,2H),3.92(s,3H),3.44(t,J＝7.3Hz,2H),3.35–3.30(m,2H),2.81(t,J＝7.1Hz,2H),2.51–2.46(m,2H),1.81(p,J＝7.2Hz,2H),1.64(dt,J＝17.7,5.0Hz,6H).
13C NMR(100MHz,CDCl3)δ175.76,149.19,142.93,126.00,125.58,125.29,125.15,121.77,120.88,113.04,102.84,82.40,55.69,50.77,49.85,49.13,46.42,37.34,29.99,28.73,26.77,23.43.
HRMS(ESI)m/z:[M+H]+Calcd for C22H29N2O3 369.2172,found:369.2174.
实施例13：
将65.4mg(0.3mmol)如下所示的1-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，51％产率。
1H NMR(400MHz,CDCl3)δ8.32(d,J＝9.1Hz,1H),8.07(t,J＝7.9Hz,2H),8.02(d,J＝9.2Hz,1H),7.94(d,J＝7.6Hz,1H),7.86(s,2H),7.72(s,1H),5.19(s,2H),4.42(s,2H),3.48(t,J＝7.3Hz,2H),3.35–3.32(m,2H),2.87(t,J＝7.1Hz,2H),2.52–2.48(m,2H),1.85(t,J＝7.2Hz,2H),1.67–1.60(m,6H).
13C NMR(100MHz,CDCl3)δ175.92,148.41,131.49,131.41,126.87,126.45,125.87,125.04,124.91,124.71,124.68,124.30,124.17,123.67,120.63,119.08,117.48,83.18,50.91,49.91,48.89,46.45,37.30,29.98,28.71,26.69,23.40.
HRMS(ESI)m/z:[M+H]+Calcd for C29H30N2O2 413.2151,found:413.2143.
实施例14：
将48.0mg(0.3mmol)如下所示的1-萘酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，69％产率。
1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.5Hz,2H),7.01(d,J＝8.5Hz,2H),5.00(s,4H),4.07(s,4H),3.44(t,J＝7.3Hz,4H),3.37–3.32(m,4H),2.79(t,J＝7.1Hz,4H),2.52–2.47(m,4H),1.80(p,J＝7.2Hz,4H),1.65(ddd,J＝20.9,10.5,5.4Hz,12H).
13C NMR(100MHz,CDCl3)δ175.78,149.13,124.74,124.39,113.93,113.14,82.73,50.39,49.86,49.06,46.40,37.32,30.00,28.73,26.74,23.43.
HRMS(ESI)m/z:[M+H]+Calcd for C32H45N4O4 549.3435,found:549.3431.
实施例15：
将48.0mg(0.3mmol)如下所示的1-萘硫酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，82％产率。
1H NMR(400MHz,CDCl3)δ8.06(d,J＝8.3Hz,1H),7.74(d,J＝7.6Hz,1H),7.48(d,J＝8.3Hz,2H),7.44(t,J＝7.2Hz,1H),7.03(d,J＝8.3Hz,1H),4.67(s,2H),4.14(s,2H),3.44(t,J＝7.2Hz,2H),3.35–3.29(m,2H),2.72(t,J＝7.0Hz,2H),2.51–2.45(m,2H),1.76(q,J＝7.2Hz,2H),1.63(ddd,J＝20.5,9.9,4.9Hz,6H).
13C NMR(100MHz,CDCl3)δ175.80,132.54,130.74,129.32,128.37,126.61,125.95,125.78,124.78,123.89,122.80,55.15,54.84,49.92,48.79,46.50,37.32,29.98,28.72,26.14,23.41.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26N2OS 355.1766,found:355.1773.
实施例16：
将48.0mg(0.3mmol)如下所示的2-萘硫酚、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，85％产率。
1H NMR(400MHz,CDCl3)δ7.74(dd,J＝7.6,4.0Hz,2H),7.56(d,J＝8.6Hz,1H),7.47(ddd,J＝8.5,6.8,1.4Hz,1H),7.39(t,J＝7.5Hz,1H),7.09(d,J＝8.6Hz,1H),4.59(s,2H),4.41(s,2H),3.49–3.43(m,2H),3.36–3.30(m,2H),2.75(t,J＝7.0Hz,2H),2.52–2.45(m,2H),1.78(t,J＝7.2Hz,2H),1.64(dtt,J＝20.3,9.7,4.8Hz,6H).
13C NMR(100MHz,CDCl3)δ175.79,131.87,131.62,130.56,128.95,126.65,126.62,124.65,122.24,120.51,54.72,50.69,49.91,49.15,46.49,37.35,30.02,28.77,26.31,23.47.
HRMS(ESI)m/z:[M+H]+Calcd for C21H26N2OS 355.1766,found:355.1773.
实施例17：
将42.9mg(0.3mmol)如下所示的1-萘胺、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，53％产率。
1H NMR(400MHz,CDCl3)δ7.79(d,J＝9.2Hz,1H),7.77–7.71(m,1H),7.43(dq,J＝6.1,3.8,2.4Hz,2H),7.28(d,J＝8.2Hz,1H),7.04(d,J＝8.3Hz,1H),4.21(s,2H),3.98(s,2H),3.45(t,J＝7.2Hz,2H),3.37–3.33(m,2H),2.62(t,J＝7.3Hz,2H),2.52–2.46(m,2H),1.85(p,J＝7.3Hz,2H),1.71–1.59(m,6H).
13C NMR(100MHz,CDCl3)δ175.88,137.04,133.07,128.37,125.85,125.47,125.22,124.35,120.10,119.11,115.08,63.87,53.79,50.36,49.81,46.52,37.32,29.98,28.73,26.26,23.42.
HRMS(ESI)m/z:[M+H]+Calcd for C21H27N3O 338.2154,found:338.2150.
实施例18：
将42.9mg(0.3mmol)如下所示的2-萘胺、36.0mg(1.2mmol)甲醛、68.4mg(0.45mmol)DBU底物加入带有搅拌子的反应管中，再加入H2O(2ml)溶剂使其溶解后，在90℃条件下搅拌12小时，萃取旋干后用硅胶层析分离得到目标产物，54％产率。
1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.1Hz,1H),7.58(d,J＝8.4Hz,1H),7.54(d,J＝8.8Hz,1H),7.42(t,J＝7.7Hz,1H),7.23(d,J＝7.4Hz,1H),6.82(d,J＝8.7Hz,1H),4.17(s,2H),4.10(s,2H),3.46(t,J＝7.2Hz,2H),3.36–3.32(m,2H),2.68–2.63(m,2H),2.51–2.47(m,2H),1.86(q,J＝7.4Hz,2H),1.62(dp,J＝14.9,4.9Hz,6H).
13C NMR(100MHz,CDCl3)δ175.81,140.06,132.10,128.61,128.23,127.60,126.44,122.26,120.52,118.49,110.83,63.02,50.76,50.67,49.81,46.56,37.34,29.99,28.75,26.59,23.44.
HRMS(ESI)m/z:[M+H]+Calcd for C21H27N3O 338.2154,found:338.2150.
效果实验：
针对上述实施例制备的化合物进行了抗神经瘤活性初筛，观察其对人神经母细胞瘤细胞SY5Y增殖的抑制作用。
实验方法：
(1)将细胞配制成1*105浓度的悬液,接种100μL于96孔板,培养24h；
(2)将待测样品配制浓度梯度,每个梯度6个重复,分别取100μL至实验组每孔,另设空白组和对照组；作用48h；
(3)离心，吸出旧培养基，加100μL配置好的MTT，放入培养箱培养4h4 h；
(4)离心，弃上清，加100μLDMSO，摇床震荡10min，用酶标仪490nm处检测吸光。
检测结果见下表1。
表1
根据上表1的检测结果发现本申请实施例制备的化合物对人神经母细胞瘤细胞SY5Y具有一定的抑制活性。
最后应当说明的是，以上内容仅用以说明本发明的技术方案，而非对本发明保护范围的限制，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。
Claims (9)
1.一种制备含氮杂环衍生物的方法，其特征在于：包括以下步骤：含萘化合物与甲醛和DBU在溶剂中通过多组分级联反应，分别获得一系列被N-取代的带有己内酰胺单元的不同的含氮杂环衍生物；所述的含萘化合物为萘酚、硫萘酚或萘胺中的一种；所述的萘酚为下式1或式2所述的化合物：
其中，基团R为氢原子，甲氧基，卤原子，羟基，芳基或烷基；
当所述含萘化合物为式1所述的萘酚时，所述方法的反应方程式为：
当所述含萘化合物为式2所述的萘酚时，所述方法的反应方程式为：
所述的硫萘酚为下式3或式4所述的化合物：
其中，基团R为氢原子，甲氧基，卤原子，羟基，芳基或烷基；
当所述含萘化合物为式3所述的硫萘酚时，所述方法的反应方程式为：
所述含萘化合物为式4所述的硫萘酚时，所述方法的反应方程式为：
所述的萘胺为下式5或式6所述的化合物：
其中，基团R为氢原子，甲氧基，卤原子，羟基，芳基或烷基；
当所述含萘化合物为式5所述的萘胺时，制备含氮杂环衍生物的反应方程式为：
当所述含萘化合物为式6所述的萘胺时，制备含氮杂环衍生物的反应方程式为：
2.根据权利要求1所述的方法，其特征在于：所述的溶剂为水，四氢呋喃，乙醇，1,2-二氯乙烷，N,N-二甲基甲酰胺，丙酮和1,4-二氧六环中的一种或几种。
3.根据权利要求1所述的方法，其特征在于：所述的含萘化合物、甲醛和DBU的摩尔比为1:4:1.5-1:4:2。
4.根据权利要求1所述的方法，其特征在于：所述的含萘化合物与溶剂的摩尔体积比(mmol/mL)为0.3:1-2:1。
5.根据权利要求1所述的方法，其特征在于：所述方法的反应温度为80-100℃。
6.根据权利要求1所述的方法，其特征在于：所述的萘酚还可以选自
中的一种。
7.根据权利要求1所述的方法，其特征在于：所述的硫萘酚还可以选自中的一种。
8.根据权利要求1所述的方法，其特征在于：所述的萘胺还可以选自中的一种。
9.根据权利要求1-8任一项所述的方法制备的氮杂环衍生物在制备治疗人神经母细胞瘤细胞SY5Y增殖药物中的应用。
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