CN106187881B - 一类具有3-(2-羟基苯基)喹啉结构单元的化合物、其制备方法及应用 - Google Patents

一类具有3-(2-羟基苯基)喹啉结构单元的化合物、其制备方法及应用 Download PDF

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CN106187881B
CN106187881B CN201610530836.1A CN201610530836A CN106187881B CN 106187881 B CN106187881 B CN 106187881B CN 201610530836 A CN201610530836 A CN 201610530836A CN 106187881 B CN106187881 B CN 106187881B
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CN106187881A (zh
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汪游清
岑娟
朱超群
邓卓飞
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Henan University
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Abstract

一类具有3‑（2‑羟基苯基）喹啉结构单元的化合物、其制备方法及应用，所述化合物的结构式如下：，其中，X,Y均为H、卤素、甲基、甲氧基或叔丁基，R为、、、或苯乙炔基，其中，R1为H、卤素、甲基、甲氧基或

Description

一类具有3-(2-羟基苯基)喹啉结构单元的化合物、其制备方 法及应用
技术领域
本发明属于有机合成领域，具体涉及一类具有3-(2-羟基苯基)喹啉结构单元的化合物、其制备方法及应用。
背景技术
喹啉及其衍生物是一类重要的含氮杂环化合物，其广泛存在于天然产物中，许多含有喹啉环的化合物具有抗菌、抗疟疾和抗癌活性[Journal of OrganometallicChemistry 2014,768,75-114]，因此它们被发现是一类重要的药物，下面式1的三个常见的药物都含有喹啉结构单元：
喹啉类化合物除了作为药物吸引人们的注意外，它们还被用来制备农药、缓蚀剂以及染料等。此外一些含有羟基的喹啉类化合物，例如8-羟基喹啉，可以作为配体用于金属的测定和分离，也可以用于有机金属化学中。
由于喹啉类化合物在药物和合成化学领域的重要性，自从1880年Skraup首次报道了它的合成方法之后便得到了广泛的研究。传统的合成喹啉及其衍生物都是以苯胺类化合物为原料合成的，近来的研究中出现了用亚胺化合物和炔烃为原料来合成喹啉类化合物，然而所用的底物范围比较狭窄，所用到的亚胺均为碳氮双键在环外的非环状亚胺。尽管环内亚胺作为一种更为稳定且具有特定E式碳氮双键的亚胺，但是，用环内亚胺和炔烃为原料合成喹啉类化合物仍然没有报道。
发明内容
本发明的目的在于提供一类具有3-(2-羟基苯基)喹啉结构单元的化合物、其制备方法及应用。
基于上述目的，本发明采取如下技术方案：
一类具有3-(2-羟基苯基)喹啉结构单元的化合物，所述化合物的结构式如下：其中，X,Y均为H、卤素、甲基、甲氧基或叔丁基，R为 或苯乙炔基，其中，R1为H、卤素、甲基、甲氧基或
上述的具有3-(2-羟基苯基)喹啉结构单元的化合物的制备方法，反应式如下：
具体步骤为：将原料化合物1和化合物2加入到有机溶剂中，在铁盐的作用下加热到80℃-100℃反应10～40h，反应结束后经分离提纯即得目标化合物。
优选地，所述有机溶剂为1,2-二氯乙烷、二氯甲烷、甲苯、氯仿或乙腈。
所述铁盐为无水三氯化铁、六水合三氯化铁、无水氯化亚铁、四水合氯化亚铁或溴化亚铁。
所述化合物1、化合物2和铁盐摩尔比为1:2:1或1:2:2。
上述的具有3-(2-羟基苯基)喹啉结构单元的化合物在制备抗肿瘤药物中的应用，所述抗肿瘤药物为治疗人白血病和乳腺癌的药物。
本发明具有以下优点：
1.二苯并1,4-氧氮杂卓亚胺(即化合物1)比较稳定且容易制备，反应操作简单，具有原子经济性。
2.能得到官能团化的各种类型喹啉衍生物，例如芳基、烷基等取代的产物。
3.反应所用到的无水三氯化铁廉价易得，无毒，且对环境友好。
4.比较传统合成方法，此方法以二苯并1,4-氧氮杂卓亚胺(即化合物1)为原料来制备官能团化的多取代的喹啉，扩大了合成喹啉衍生物所用的原料，反应周期较短，为合成官能团化的多取代的喹啉提供了一种新的方法。
具体实施方式
下面通过具体实施例对本发明的技术方案进行详细的说明。
其中，用到的二苯并1,4-氧氮杂卓亚胺(即化合物1)按照文献((1)Wardrop,A.W.H.；Sainsbury,G.L.；Harrison,J.M.；Inch,T.D.J.Chem.Soc.,Perkin Trans.1 1976,1279；(2)Jorapur,Y.R.；Rajagopal,G.；Saikia,P.J.；Pal,R.R.Tetrahedron Lett.2008,49,1495.)的实验操作过程制备。
下述实施例中Rf值中的溶剂的比例均为体积比。
实施例1：条件的优化
在密封管中依次加入二苯并1,4-氧氮杂卓亚胺1a(0.1mmol)、苯乙炔2a(0.2mmol)、铁盐(0.01-0.1mmol)和重新蒸过的1毫升溶剂，密封后在80-100℃的条件下搅拌反应，反应结束后，冷却至室温，加入二氯甲烷(10mL)和水(10mL)稀释，分层后分液，水相继续用二氯甲烷萃取(2×10mL)，合并有机相，并用无水硫酸钠干燥，除去溶剂后直接柱层析(体积比，石油醚/乙酸乙酯＝3:1—1:1洗脱)分离得到纯的产物，反应式如下：
表1.3-(2-羟基苯基)喹啉3aa的制备：不同反应条件优化
由表1可知，最佳反应条件为：铁盐为FeCl3，二苯并1,4-氧氮杂卓亚胺1a、苯乙炔2a与铁盐的摩尔比为1:2:1，溶剂为DCE(1,2-二氯乙烷)，反应温度为100℃，反应时间10h。
实施例2：无水三氯化铁促进二苯并1,4-氧氮杂卓亚胺1a与不同炔烃2a-2n的反应合成喹啉衍生物3aa-3an
在密封管中依次加入二苯并1,4-氧氮杂卓亚胺1a(0.4mmol)、端炔烃2a-2n(0.8mmol)、无水三氯化铁(0.4mmol)和重新蒸过的1毫升1,2-二氯乙烷(DCE)，密封后在100℃搅拌10小时。反应结束后，冷却至室温，加入二氯甲烷(10mL)和水(10mL)稀释，分层后分液，水相继续用二氯甲烷萃取(2×10mL)，合并有机相，并用无水硫酸钠干燥，除去溶剂后直接柱层析(石油醚/乙酸乙酯洗脱)分离得到纯的产物。
反应式如下：
表2.二苯并1,4-氧氮杂卓亚胺1a与不同炔烃2a-2n反应制备喹啉衍生物3aa-3an
所得到的喹啉产物表征数据如下：
3aa：3-(2-羟基苯基)-4-苯基喹啉，黄色固体,86％分离收率,Rf＝0.18(石油醚/乙酸乙酯＝3:1)；熔点:243-244℃.1H NMR(300MHz,DMSO-d6):δ9.49(s,1H),8.82(s,1H),8.12(d,J＝8.4Hz,1H),7.79-7.73(m,1H),7.54(d,J＝3.9Hz,2H),7.34-7.22(m,5H),7.05(t,J＝7.6Hz,1H),6.88(d,J＝7.5Hz,1H),6.82(d,J＝8.1Hz,1H),6.62(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.9,152.4,146.8,145.5,136.1,131.7,130.7,129.7,129.1,129.0,128.9,128.8,127.9,127.6,126.9,126.8,125.8,124.8,118.5,115.3.
3ab：3-(2-羟基苯基)-4-(4-氰基苯基)喹啉，黄色固体,55％分离收率,Rf＝0.13(石油醚/乙酸乙酯＝3:1)；熔点:281-282℃.1H NMR(300MHz,DMSO-d6):δ9.51(s,1H),8.84(s,1H),8.14(d,J＝8.1Hz,1H),7.85-7.78(m,3H),7.58(t,J＝7.5Hz,1H),7.47-7.43(m,3H),7.09(t,J＝7.8Hz,1H),6.95(d,J＝6.3Hz,1H),6.80(d,J＝8.1Hz,1H),6.68(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.8,152.3,146.8,143.9,141.5,131.8,131.6,130.9,130.6,129.3,127.3,126.0,125.4,124.2,118.8,118.7,115.4,110.5.
3ac：3-(2-羟基苯基)-4-(4-乙酰基苯基)喹啉，黄色固体,53％分离收率,Rf＝0.11(石油醚/乙酸乙酯＝3:1)；熔点:258-259℃.1H NMR(300MHz,DMSO-d6):δ9.51(s,1H),8.83(s,1H),8.14(d,J＝8.4Hz,1H),7.94(d,J＝8.2Hz,2H),7.79(t,J＝7.0Hz,1H),7.56(t,J＝7.3Hz,1H),7.48-7.38(m,3H),7.07(t,J＝7.0Hz,1H),6.94(d,J＝7.5Hz,1H),6.81(d,J＝7.8Hz,1H),6.65(t,J＝7.3Hz,1H),2.57(s,3H)；13C NMR(75MHz,DMSO-d6):δ197.6,154.9,152.3,146.7,144.6,141.2,135.8,131.7,130.6,130.2,129.3,129.2,129.1,127.8,127.1,126.4,125.6,124.5,118.7,115.4,26.8.
3ad：3-(2-羟基苯基)-4-(4-氟苯基)喹啉，黄色固体,88％分离收率,Rf＝0.22(石油醚/乙酸乙酯＝3:1)；熔点:232-233℃.1H NMR(300MHz,DMSO-d6):δ9.46(s,1H),8.81(s,1H),8.12(d,J＝8.4Hz,1H),7.80-7.75(m,1H),7.59-7.52(m,2H),7.29-7.15(m,4H),7.08(t,J＝7.6Hz,1H),6.95(d,J＝6.9Hz,1H),6.82(d,J＝8.1Hz,1H),6.67(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ163.1,159.9,154.9,152.3,146.8,144.6,132.5,132.4,131.9,131.8,131.6,131.0,129.2,129.0,129.0,127.0,126.9,125.7,124.7,118.6,115.4,115.0,114.7.
3ae：3-(2-羟基苯基)-4-(4-氯苯基)喹啉，黄色固体,73％分离收率,Rf＝0.20(石油醚/乙酸乙酯＝3:1)；熔点:254-255℃.1H NMR(300MHz,DMSO-d6):δ9.51(s,1H),8.82(s,1H),8.12(d,J＝8.4Hz,1H),7.80-7.75(m,1H),7.58-7.51(m,2H),7.41(d,J＝8.4Hz,2H),7.25(d,J＝7.8Hz,2H),7.09(t,J＝7.3Hz,1H),6.92(d,J＝7.2Hz,1H),6.83(d,J＝8.1Hz,1H),6.68(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.8,152.3,146.8,144.3,135.1,132.5,131.6,130.8,129.2,129.1,129.1,128.0,127.1,126.6,125.6,124.6,118.7,115.4.
3af：3-(2-羟基苯基)-4-(4-溴苯基)喹啉，黄色固体,53％分离收率,Rf＝0.23(石油醚/乙酸乙酯＝3:1)；熔点:264-265℃.1H NMR(300MHz,DMSO-d6):δ9.49(s,1H),8.81(s,1H),8.12(d,J＝8.4Hz,1H),7.81-7.76(m,1H),7.59-7.51(m,4H),7.19(d,J＝7.8Hz,2H),7.12-7.06(m,1H),6.94-6.92(m,1H),6.82(d,J＝8.1Hz,1H),6.68(t,J＝7.4Hz,1H)；13CNMR(75MHz,DMSO-d6):δ154.8,152.3,146.8,144.4,135.5,132.0,131.7,130.9,130.8,129.2,129.1,127.1,126.5,125.6,124.5,121.2,118.7,115.4.
3ag：3-(2-羟基苯基)-4-(4-甲氧基苯基)喹啉，黄色固体,63％分离收率,Rf＝0.20(石油醚/乙酸乙酯＝3:1)；熔点:248-249℃.1H NMR(300MHz,DMSO-d6):δ9.46(s,1H),8.78(s,1H),8.10(d,J＝8.1Hz,1H),7.78-7.73(m,1H),7.61-7.51(m,2H),7.15(d,J＝8.1Hz,1H),7.09-7.40(m,1H),6.92-6.87(m,3H),6.83(d,J＝7.8Hz,1H),6.65(t,J＝7.3Hz,1H),3.74(s,3H)；13C NMR(75MHz,DMSO-d6):δ158.5,154.9,152.4,146.9,145.4,131.7,131.0,130.9,129.2,128.9,128.8,128.2,126.7,126.0,125.1,118.6,115.4,113.4,55.0.
3ah：3-(2-羟基苯基)-4-(4-甲基苯基)喹啉，黄色固体,73％分离收率,Rf＝0.22(石油醚/乙酸乙酯＝3:1)；熔点:243-245℃.1H NMR(300MHz,DMSO-d6):δ9.47(s,1H),8.79(s,1H),8.10(d,J＝8.4Hz,1H),7.78-7.72(m,1H),7.57-7.49(m,2H),7.16-7.09(m,3H),7.08-7.03(m,1H),6.89-6.87(m,1H),6.83(d,J＝8.1Hz,1H),6.64(t,J＝7.3Hz,1H)；13CNMR(75MHz,DMSO-d6):δ154.9,152.4,146.8,145.6,136.7,133.2,131.7,130.8,129.6,129.1,128.9,128.8,128.5,127.1,126.7,125.9,125.0,118.6,115.4,20.8.
3ai：3-(2-羟基苯基)-4-(3-氯苯基)喹啉，黄色固体,72％分离收率,Rf＝0.23(石油醚/乙酸乙酯＝3:1)；熔点:206-207℃.1H NMR(300MHz,DMSO-d6):δ9.50(s,1H),8.82(s,1H),8.13(d,J＝8.4Hz,1H),7.79(t,J＝7.2Hz,1H),7.60-7.50(m,2H),7.39-7.30(m,3H),7.20(d,J＝3.3Hz,1H),7.09(t,J＝7.2Hz,1H),6.95(d,J＝7.2Hz,1H),6.83(d,J＝8.1Hz,1H),6.68(t,J＝7.5Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.8,152.2,146.8,144.0,138.3,132.5,131.6,130.8,129.8,129.4,129.2,129.2,129.1,128.5,127.7,127.2,126.5,125.6,124.4,118.7,115.4.
3aj：3-(2-羟基苯基)-4-(3-甲氧基苯基)喹啉，黄色固体,71％分离收率,Rf＝0.20(石油醚/乙酸乙酯＝3:1)；熔点:221-222℃.1H NMR(300MHz,DMSO-d6):δ9.49(s,1H),8.79(s,1H),8.11(d,J＝8.4Hz,1H),7.77(t,J＝7.0Hz,1H),7.61-7.52(m,2H),7.27(t,J＝7.8Hz,1H),7.07(t,J＝7.5Hz,1H),6.92-6.80(m,5H),6.65(t,J＝7.3Hz,1H),3.65(s,3H)；13C NMR(75MHz,DMSO-d6):δ158.6,155.0,152.3,146.8,145.4,137.4,131.6,130.7,129.1,129.0,126.8,126.8,125.9,124.9,122.1,118.6,115.4,115.3,113.2,54.9.
3ak：3-(2-羟基苯基)-4-(2-甲氧基苯基)喹啉，黄色固体,82％分离收率,Rf＝0.16(石油醚/乙酸乙酯＝3:1)；熔点:220-221℃.1H NMR(300MHz,DMSO-d6):δ9.48(s,1H),8.85(s,1H),8.09(d,J＝8.4Hz,1H),7.75-7.70(m,1H),7.50(t,J＝7.5Hz,1H),7.40(d,J＝8.1Hz,1H),7.34-7.29(m,1H),7.07-7.00(m,3H),6.92-6.83(m,3H),6.59(t,J＝7.3Hz,1H),3.57(s,3H)；13C NMR(75MHz,DMSO-d6):δ156.8,154.8,152.5,146.5,143.0,131.4,130.9,130.6,129.6,129.0,128.8,127.3,126.6,126.0,125.0,124.9,120.2,118.4,115.4,111.2,55.2.
3al：3-(2-羟基苯基)-4-(2-噻吩基)喹啉，黄色固体,71％分离收率,Rf＝0.22(石油醚/乙酸乙酯＝3:1)；熔点:244-245℃.1H NMR(300MHz,DMSO-d6):δ9.50(s,1H),8.80(s,1H),8.10(d,J＝8.1Hz,1H),7.79-7.71(m,2H),7.60-7.52(m,2H),7.42(d,J＝1.8Hz,1H),7.13-7.07(m,1H),6.99(d,J＝4.8Hz,1H),6.92(d,J＝7.5Hz,1H),6.86(d,J＝7.8Hz,1H),6.68(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.9,152.3,146.8,141.1,135.8,131.5,131.2,129.4,129.2,129.1,129.0,127.1,126.9,125.9,125.7,125.5,125.0,118.7,115.4.
3am：3-(2-羟基苯基)-4-(3-噻吩基)喹啉，黄色固体,68％分离收率,Rf＝0.26(石油醚/乙酸乙酯＝3:1)；熔点:239-240℃.1H NMR(300MHz,DMSO-d6):δ9.54(s,1H),8.81(s,1H),8.12(d,J＝8.1Hz,1H),7.84-7.77(m,2H),7.63-7.58(m,2H),7.14-7.08(m,3H),6.97-6.94(m,1H),6.87(d,J＝8.1Hz,1H),6.69(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ155.1,152.3,146.8,138.5,135.7,132.1,131.4,129.6,129.3,129.2,127.8,127.3,127.2,127.0,125.7,124.6,118.6,115.4.
3an：3-(2-羟基苯基)-4-异丙烯基喹啉，黄色固体,63％分离收率,Rf＝0.24(石油醚/乙酸乙酯＝3:1)；熔点:209-220℃.1H NMR(300MHz,DMSO-d6):δ9.52(s,1H),8.69(s,1H),8.06(d,J＝8.1Hz,1H),7.99(d,J＝8.4Hz,1H),7.76(t,J＝7.5Hz,1H),7.62(t,J＝7.5Hz,1H),7.22(t,J＝7.6Hz,1H),7.16(d,J＝6.9Hz,1H),6.96(d,J＝8.1Hz,1H),6.85(t,J＝7.3Hz,1H),5.36(s,1H),4.97(s,1H),1.84(s,3H)；13C NMR(75MHz,DMSO-d6):δ154.9,152.3,147.5,146.8,140.2,131.4,129.3,129.2,129.0,126.8,125.6,125.5,124.8,118.7,117.9,115.5,23.7.
实施例3：无水三氯化铁促进不同二苯并1,4-氧氮杂卓亚胺1b-1m与苯乙炔2a的反应合成喹啉衍生物3ba-3ma
在密封管中依次加入不同取代的二苯并1,4-氧氮杂卓亚胺1b-1m(0.4mmol)、苯乙炔2a(0.8mmol)、无水三氯化铁(0.4mmol)和重新蒸过的1毫升1,2-二氯乙烷(DCE)，密封后在100℃搅拌10小时。反应结束后，冷却至室温，加入二氯甲烷(10mL)和水(10mL)稀释，分层后分液，水相继续用二氯甲烷萃取(2×10mL)，合并有机相，并用无水硫酸钠干燥，除去溶剂后直接柱层析(石油醚/乙酸乙酯洗脱)分离得到纯的产物，反应式如下：
所得到的喹啉产物表征数据如下：
3ba：3-(2-羟基苯基)-4-苯基-5-甲基喹啉，黄色固体,68％分离收率,Rf＝0.18(石油醚/乙酸乙酯＝3:1)；熔点:250-251℃.1H NMR(300MHz,DMSO-d6):δ9.34(s,1H),8.66(s,1H),7.98(d,J＝8.0Hz,1H),7.63(t,J＝7.7Hz,1H),7.33(d,J＝7.1Hz,1H),7.22(s,5H)7.01-6.95(m,1H),6.81(d,J＝6.2Hz,1H),6.74(d,J＝8.0Hz),6.57(t,J＝7.4Hz,1H),1.83(s,3H)；13C NMR(75MHz,DMSO-d6):δ154.8,151.0,148.2,146.0,139.8,135.4,132.3,131.6,130.2,128.6,128.5,127.3,125.9,125.1,118.1,115.0,23.9.
3ca：3-(2-羟基苯基)-4-苯基-6-甲基喹啉，棕色固体,49％分离收率,Rf＝0.11(石油醚/乙酸乙酯＝3:1)；熔点:259-260℃.1H NMR(300MHz,DMSO-d6):δ9.46(s,1H),8.72(s,1H),8.01(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1H),7.34-7.19(m,6H),7.04(t,J＝7.9Hz,1H),6.85(d,J＝7.5Hz,1H),6.80(d,J＝8.1Hz,1H),6.61(t,J＝7.5Hz,1H),2.38(s,3H)；13C NMR(75MHz,DMSO-d6):δ154.9,151.4,145.4,144.9,136.3,136.2,131.7,131.1,130.8,129.7,129.0,128.8,127.9,127.6,126.8,124.9,124.5,118.5,115.3,21.5.
3da：3-(2-羟基苯基)-4-苯基-7-甲基喹啉，黄色固体,64％分离收率,Rf＝0.14(石油醚/乙酸乙酯＝3:1)；mp:254-255℃.1H NMR(300MHz,DMSO-d6):δ9.45(s,1H),8.75(s,1H),7.90(s,1H),7.44-7.19(m,7H),7.04(t,J＝7.8Hz,1H),6.86-6.79(m,1H),6.61(t,J＝7.3Hz,1H),2.52(s,3H)；13C NMR(75MHz,DMSO-d6):δ154.9,152.3,147.0,145.3,138.8,136.3,131.8,130.0,129.7,128.9,128.7,128.0,127.9,127.5,125.6,124.9,124.8,118.5,115.3,21.2；HRMS(ESI):m/z calculated for C22H18NO[M+H]+312.1383,found:312.1372.
3ea：3-(2-羟基苯基)-4-苯基-7-叔丁基喹啉，黄色固体,65％分离收率,Rf＝0.30(石油醚/乙酸乙酯＝3:1)；熔点:270-271℃.1H NMR(300MHz,DMSO-d6):δ9.42(s,1H),8.76(s,1H),8.00(d,J＝1.8Hz,1H),7.68-7.64(dd,J＝8.9,1.9Hz,1H),7.47(d,J＝8.9Hz,1H),7.34-7.30(m,3H),7.23-7.21(m,2H),7.07-7.02(m,1H),6.87-6.84(m,1H),6.80(d,J＝7.7Hz,1H),6.62(t,J＝7.3Hz,1H),1.39(s,9H)；13C NMR(75MHz,DMSO-d6):δ155.0,152.2,151.7,146.9,145.2,136.3,131.8,130.2,129.7,128.8,127.8,127.6,125.6,125.5,125.0,124.9,124.1,118.5,115.4,34.7,30.9.
3fa：3-(2-羟基苯基)-4-苯基-7-氯喹啉，黄色固体,80％分离收率,Rf＝0.34(石油醚/乙酸乙酯＝3:1)；熔点:241-242℃.1H NMR(300MHz,DMSO-d6):δ9.51(s,1H),8.85(s,1H),8.17-8.16(d,J＝1.7Hz,1H),7.61-7.52(m,2H),7.35-7.33(m,3H),7.23-7.21(m,2H),7.08-7.03(m,1H),6.87(d,J＝7.4Hz,1H),6.83-6.80(d,J＝8.0Hz,1H),6.64-6.59(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.9,153.7,147.2,145.7,135.6,133.6,131.6,131.2,129.7,129.0,128.0,127.8,127.7,127.4,125.6,124.4,118.6,115.4.
3ga：3-(2-羟基苯基)-4-苯基-7-氟喹啉，黄色固体,74％分离收率,Rf＝0.32(石油醚/乙酸乙酯＝3:1)；熔点:228-229℃.1H NMR(300MHz,DMSO-d6):δ9.50(s,1H),8.83(s,1H),7.87-7.83(m,1H),7.60-7.55(m,1H),7.52-7.45(m,1H),7.38-7.33(m,3H),7.24-7.21(m,2H),7.08-7.02(m,1H),6.88-6.85(m,1H),6.82(d,J＝8.1Hz,1H),6.62(t,J＝7.2Hz,1H)；13C NMR(75MHz,DMSO-d6):δ163.7,160.4,154.9,153.7,147.8,147.7,145.9,135.9,131.7,130.4,130.4,129.7,129.0,128.8,128.7,128.0,127.8,124.5,124.2,118.6,117.1,116.8,115.4,112.7,112.4.
3ha：3-(2-羟基苯基)-4-苯基-6-氯喹啉，黄色固体,76％分离收率,Rf＝0.20(石油醚/乙酸乙酯＝3:1)；熔点:249-250℃.1H NMR(300MHz,DMSO-d6):δ9.53(s,1H),8.84(s,1H),8.15(d,J＝9Hz,1H),7.81-7.78(m,1H),7.45(d,J＝2.4Hz),7.39-7.35(m,3H),7.25-7.22(m,2H),7.09-7.03(m,1H),6.89-6.86(m,1H),6.82(d,J＝7.8HZ,1H),6.63(t,J＝6.9Hz,1H)；13C NMR(75MHz,DMSO-d6):δ154.9,153.0,145.2,144.9,135.5,131.8,131.6,131.5,131.4,129.7,129.6,129.1,128.1,128.0,127.8,124.4,124.3,118.6,115.4.
3ia：3-(2-羟基苯基)-4-苯基-6-氟喹啉，黄色固体,67％分离收率,Rf＝0.16(石油醚/乙酸乙酯＝3:1)；熔点:236-237℃.1H NMR(300MHz,DMSO-d6):δ9.52(s,1H),8.81(s,1H),8.22-8.17(m,1H),7.73-7.66(m,1H),7.39-7.30(m,3H),7.25-7.22(m,2H),7.15-7.10(m,1H),7.09-7.03(m,1H),6.89-6.86(m,1H),6.83(d,J＝7.5Hz,1H),6.64(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ161.6,158.3,154.9,152.0,145.1,145.1,144.0,135.7,132.2,132.1,131.6,131.5,129.6,129.0,128.1,127.9,127.7,124.5,119.2,118.8,118.6,115.4,109.1,108.8.
3ja：3-(2-羟基-3-甲基苯基)-4-苯基喹啉，黄色固体,79％分离收率,Rf＝0.38(石油醚/乙酸乙酯＝3:1)；熔点:203-204℃.1H NMR(300MHz,DMSO-d6):δ8.80(s,1H),8.43(s,1H),8.14(d,J＝8.1Hz,1H),7.79(t,J＝6.0Hz,1H),7.58-7.53(m,2H),7.33-7.28(m,5H),6.97(d,J＝6.9Hz,1H),6.71(d,J＝7.2Hz,1H),6.57(t,J＝7.3Hz,1H)；13C NMR(75MHz,DMSO-d6):δ152.7,152.4,146.9,145.9,136.2,130.8,130.2,129.7,129.4,129.2,129.0,127.9,127.6,127.1,126.8,126.0,125.4,124.8,118.8,16.6.
3ka：3-(2-羟基-5-甲基苯基)-4-苯基喹啉，黄色固体,79％分离收率,Rf＝0.18(石油醚/乙酸乙酯＝3:1)；熔点:204-205℃.1H NMR(300MHz,DMSO-d6):δ9.21(s,1H),8.79(s,1H),8.10(s,1H),7.75(s,1H),7.53(s,2H),7.34-7.23(m,5H),6.84-6.69(m,3H),2.03(s,3H)；13C NMR(75MHz,DMSO-d6):δ152.7,152.4,146.8,145.5,136.2,132.0,130.9,129.7,129.3,129.2,129.0,127.9,127.6,126.9,126.8,125.9,124.6,115.2,20.0.
3la：3-(2-羟基-5-氟苯基)-4-苯基喹啉，黄色固体,86％分离收率,Rf＝0.16(石油醚/乙酸乙酯＝3:1)；熔点:222-223℃.1H NMR(300MHz,DMSO-d6):δ9.49(s,1H),8.82(s,1H),8.12(d,J＝7.5Hz,1H),7.78(s,1H),7.54(m,2H),7.36-7.26(m,5H),6.89-6.76(m,3H)；13C NMR(75MHz,DMSO-d6):δ156.3,153.2,151.9,151.3,146.9,145.8,135.9,129.7,129.2,129.2,128.0,127.8,127.0,126.8,126.0,125.9,125.8,117.9,117.6,116.2,116.1,115.3,115.0.
3ma：3-(2-羟基-3-氯苯基)-4-苯基喹啉，黄色固体,78％分离收率,Rf＝0.38(石油醚/乙酸乙酯＝3:1)；熔点:214-215℃.1H NMR(300MHz,DMSO-d6):δ9.35(s,1H),8.81(s,1H),8.15(d,J＝8.1Hz,1H),7.81(t,J＝607Hz,1H),7.60-7.55(m,2H),7.35-7.23(m,6H),6.89(d,J＝7.5Hz,1H),6.69(t,J＝7.8Hz,1H)；13C NMR(75MHz,DMSO-d6):δ151.8,150.6,147.1,146.2,135.8,130.7,129.8,129.3,129.2,128.0,127.8,127.7,127.0,126.9,126.0,121.0,119.9.
实施例4：无水三氯化铁促进不同二苯并1,4-氧氮杂卓亚胺1a-1l与苯乙炔基乙炔反应制备含炔烃的喹啉4a-4l
在密封管中依次加入不同取代的二苯并1,4-氧氮杂卓亚胺1a-1l(0.4mmol)、苯乙炔基乙炔(0.8mmol)、无水三氯化铁(0.8mmol)和重新蒸过的1毫升1,2-二氯乙烷(DCE)，密封后在80℃搅拌40小时。反应结束后，冷却至室温，加入二氯甲烷(10mL)和水(10mL)稀释，分层后分液，水相继续用二氯甲烷萃取(2×10mL)，合并有机相，并用无水硫酸钠干燥，除去溶剂后直接柱层析(石油醚/乙酸乙酯洗脱)分离得到纯的产物。
反应式如下：
所得到的喹啉产物表征数据如下：
4a：3-(2-羟基苯基)-4-苯乙炔基喹啉，黄色固体,64％分离收率,Rf＝0.17(石油醚/乙酸乙酯＝3:1)；mp:238-239℃.1H NMR(300MHz,DMSO-d6):δ9.82(s,1H),8.95(s,1H),8.45-8.42(m,1H),8.10(d,J＝7.8Hz,1H),7.87-7.82(m,1H),7.79-7.73(m,1H),7.52-7.49(m,1H),7.47-7.44(m,5H),7.36-7.31(m,1H),7.06(d,J＝7.5Hz,1H),7.00(t,J＝7.5Hz,1H)；13C NMR(75MHz,DMSO-d6):δ155.0,151.0,144.7,137.5,134.1,131.8,131.6,129.9,129.6,129.1,128.8,126.7,125.7,124.6,124.0,121.8,118.8,115.8,100.5,85.0,21.4.
4b：3-(2-羟基苯基)-4-苯乙炔基-5-甲基喹啉，黄色固体,97.1mg,48％分离收率,Rf＝0.18(石油醚/乙酸乙酯＝3:1)；熔点:224-225℃.1H NMR(300MHz,DMSO-d6):δ9.69(s,1H),8.82(s,1H),7.94(d,J＝7.8Hz,1H),7.64(t,J＝7.2Hz,1H),7.47-7.37(m,6H),7.18(s,2H),7.07(d,J＝7.5Hz,1H),6.97(t,J＝6.6Hz,1H),3.15(s,3H)；13C NMR(75MHz,DMSO-d6):δ155.2,150.9,147.9,136.4,135.7,131.7,130.7,130.1,129.6,129.4,129.1,128.8,128.5,126.2,125.7,124.9,122.1,118.7,115.7,101.7,89.3.23.7.
4c：3-(2-羟基苯基)-4-苯乙炔基-6-甲基喹啉，黄色固体,37％分离收率,Rf＝0.16(石油醚/乙酸乙酯＝3:1)；熔点:209-210℃.1H NMR(300MHz,DMSO-d6):δ9.78(s,1H),8.87(s,1H),8.17(s,1H),8.00(d,J＝8.4Hz,1H),7.67(d,J＝8.4Hz,1H),7.50-7.45(m,6H),7.33(t,J＝7.8Hz,1H),7.07-6.97(m,2H),2.61(s,3H)；13C NMR(75MHz,DMSO-d6):δ155.0,151.0,144.7,137.5,134.1,131.8,131.6,129.9,129.6,129.1,128.8,126.7,125.7,124.6,124.0,121.8,118.8,115.8,100.5,85.0,21.4.
4d：3-(2-羟基苯基)-4-苯乙炔基-7-甲基喹啉，黄色固体,49％分离收率,Rf＝0.18(石油醚/乙酸乙酯＝3:1)；熔点:235-236℃.1H NMR(300MHz,DMSO-d6):δ9.78(s,1H),8.90(s,1H),8.31(d,J＝8.4Hz,1H),7.89(s,1H),7.59(d,J＝8.4Hz,1H),7.50-7.44(m,5H),7.33(t,J＝7.4Hz,1H),7.06(d,J＝7.8Hz,1H),6.99(t,J＝7.2Hz,1H),2.56(s,3H)；13CNMR(75MHz,DMSO-d6):δ155.0,152.0,146.3,139.6,133.2,131.8,131.5,129.9,129.8,129.6,128.8,128.3,126.1,125.6,124.8,124.0,121.7,118.8,115.8,100.4,85.0,21.3.
4e：3-(2-羟基苯基)-4-苯乙炔基-7-叔丁基喹啉，黄色固体,60％分离收率,Rf＝0.33(石油醚/乙酸乙酯＝3:1)；熔点:235-236℃.1H NMR(300MHz,DMSO-d6):δ9.79(s,1H),8.93(s,1H),8.35(d,J＝8.4Hz,1H),7.99(s,1H),7.84(d,J＝8.7Hz,1H),7.50-7.43(m,6H),7.33(t,J＝7.5Hz,1H),7.07(d,J＝8.1Hz,1H),6.99(t,J＝7.4Hz,1H),1.41(s,9H)；13CNMR(75MHz,DMSO-d6):δ155.0,152.4,151.9,146.2,133.4,131.2,131.5,129.9,129.6,128.9,126.4,125.9,125.5,124.8,124.3,124.0,121.8,118.8,115.9,100.4,85.0,34.8,30.8.
4f：3-(2-羟基苯基)-4-苯乙炔基-7-氟喹啉，黄色固体,46％分离收率,Rf＝0.28(石油醚/乙酸乙酯＝3:1)；熔点:227-228℃.1H NMR(300MHz,DMSO-d6):δ9.84(s,1H),8.91(s,1H),8.48(t,J＝7.7Hz,1H),7.85(d,J＝9.9Hz,1H),7.67(t,J＝8.4Hz,1H),7.51-7.44(m,6H),7.34(t,J＝7.7Hz,1H),7.07(d,J＝8.1Hz,1H),6.99(t,J＝7.5Hz,1H)；13C NMR(75MHz,DMSO-d6):δ164.1,160.8,155.0,147.1,147.0,133.5,131.8,131.6,130.1,129.8,128.9,128.8,128.6,126.7,123.9,123.6,121.5,118.8,117.9,117.6,115.9,113.0,112.8,101.0,84.6.
4g：3-(2-羟基苯基)-4-苯乙炔基-6-氯喹啉，黄色固体,34％分离收率,Rf＝0.20(石油醚/乙酸乙酯＝3:1)；熔点:217-218℃.1H NMR(300MHz,DMSO-d6):δ9.87(s,1H),8.97(s,1H),8.33(s,1H),8.11(d,J＝9.0Hz,1H),7.84(d,J＝8.7Hz,1H),7.51-7.44(m,6H),7.34(t,J＝7.4Hz,1H),7.06(d,J＝8.1Hz,1H),6.99(t,J＝7.4Hz,1H)；13C NMR(75MHz,DMSO-d6):δ151.5,150.6,146.4,133.1,131.6,130.6,130.1,129.8,129.4,128.9,127.9,127.1,127.0,126.6,126.0,121.5,121.4,120.3,101.3,84.5.
4h：3-(2-羟基苯基)-4-苯乙炔基-6-氟喹啉，黄色固体,57％分离收率,Rf＝0.22(石油醚/乙酸乙酯＝3:1)；熔点:237-238℃.1H NMR(300MHz,DMSO-d6):δ9.86(s,1H),8.94(s,1H),8.16(t,J＝6.8Hz,1H),8.04(d,J＝9.0Hz,1H),7.74(t,J＝7.5Hz,1H),7.51-7.32(m,7H),7.08(d,J＝7.8Hz,1H),1H),6.99(t,J＝6.9Hz,1H)；13C NMR(75MHz,DMSO-d6):δ162.4,159.1,155.0,151.6,143.3,134.7,132.4,132.3,131.7,131.6,130.2,129.7,128.8,127.8,127.7,126.1,126.0,123.6,121.5,119.8,119.5,118.8,115.9,109.4,109.1,101.1,84.4.
4i：3-(2-羟基-3-甲基苯基)-4-苯乙炔基喹啉，黄色固体,38％分离收率,Rf＝0.29(石油醚/乙酸乙酯＝3:1)；熔点:188-189℃.1H NMR(300MHz,DMSO-d6):δ8.92(s,1H),8.66(s,1H),8.44(d,J＝8.1Hz,1H),8.12(d,J＝8.4Hz,1H),7.85(t,J＝7.5Hz,1H),7.77(t,J＝7.2Hz,1H),7.44(s,5H),7.30(d,J＝7.5Hz,1H),7.25(d,J＝7.2Hz,1H),6.95(t,J＝7.4Hz,1H),2.30(s,3H)；13C NMR(75MHz,DMSO-d6):δ152.6,152.1,146.2,134.4,131.5,131.2,129.7,129.6,129.4,128.9,127.8,126.8,126.7,125.9,125.5,124.8,121.7,119.2,100.8,85.0,16.8.
4j：3-(2-羟基-5-甲基苯基)-4-苯乙炔基喹啉，黄色固体,35％分离收率,Rf＝0.20(石油醚/乙酸乙酯＝3:1)；熔点:220-221℃.1H NMR(300MHz,DMSO-d6):δ9.56(s,1H),8.95(s,1H),8.44(d,J＝8.1Hz,1H),8.10(d,J＝8.1Hz,1H),7.84(t,J＝7.2Hz,1H),7.76(t,J＝7.2Hz,1H),7.46(s,5H),7.32(s,1H),7.14(d,J＝8.1Hz,1H),6.96(d,J＝8.4Hz,1H),2.30(s,3H)；13C NMR(75MHz,DMSO-d6):δ152.7,152.1,146.0,134.1,132.0,131.5,130.4,129.7,129.6,129.3,128.9,127.8,127.2,126.7,126.2,125.9,123.5,121.7,115.8,100.7,85.0,20.2.
4k：3-(2-羟基-5-甲氧基苯基)-4-苯乙炔基喹啉，黄色固体,35％分离收率,Rf＝0.11(石油醚/乙酸乙酯＝3:1)；熔点:220-221℃.1H NMR(300MHz,DMSO-d6):δ9.35(s,1H),8.97(s,1H),8.45(d,J＝7.8Hz,1H),8.11(d,J＝7.8Hz,1H),7.85-7.77(m,2H),7.46(m,5H),7.11(s,1H),6.97(m,2H),3.72(s,3H)；13C NMR(75MHz,DMSO-d6):δ152.1,151.8,148.8,146.8,133.9,131.6,129.8,129.7,129.4,128.9,127.8,126.7,126.4,125.9,124.2,121.7,116.6,116.5,115.8,100.9,84.9,55.5.
4l：3-(2-羟基-3-氯苯基)-4-苯乙炔基喹啉，黄色固体,35％分离收率,Rf＝0.22(石油醚/乙酸乙酯＝3:1)；熔点:219-220℃.1H NMR(300MHz,DMSO-d6):δ9.60(s,1H),8.93(s,1H),8.45(d,J＝7.5Hz,1H),8.13(d,J＝7.8Hz,1H),7.87(t,J＝7.2Hz,1H),7.79(t,J＝7.5Hz,1H),7.55-7.45(m,7H),7.06(t,J＝7.4Hz,1H)；13C NMR(75MHz,DMSO-d6):δ151.5,150.6,146.4,133.1,131.6,130.6,130.1,129.8,129.4,128.9,127.9,127.1,127.0,126.6,126.0,121.5,121.4,120.3,101.3,84.5.
实施例5：无水三氯化铁促进含有取代基的二苯并1,4-氧氮杂卓亚胺1f与4-甲氧基苯乙炔2c反应制备喹啉衍生物3fc
在密封管中依次加入取代的二苯并1,4-氧氮杂卓亚胺1f(0.4mmol)、4-甲氧基苯乙炔(0.8mmol)2c、无水三氯化铁(0.4mmol)和重新蒸过的1毫升1,2-二氯乙烷(DCE)，密封后在100℃搅拌10小时。反应结束后，冷却至室温，加入二氯甲烷(10mL)和水(10mL)稀释，分层后分液，水相继续用二氯甲烷萃取(2×10mL)，合并有机相，并用无水硫酸钠干燥，除去溶剂后直接柱层析(石油醚/乙酸乙酯洗脱)分离得到纯的产物。反应式如下：
所得到的喹啉产物表征数据如下：
3fc：3-(2-羟基苯基)-4-(4-甲氧基苯基)-7-氯喹啉，黄色固体,63％分离收率,Rf＝0.18(石油醚/乙酸乙酯＝3:1)；熔点:251-252℃.1H NMR(300MHz,DMSO-d6):δ9.47(s,1H),8.82(s,1H),8.15(s,1H),7.63-7.56(m,2H),7.14(d,J＝8.1Hz,2H),7.10-7.04(m,1H),6.92-6.82(m,4H),6.68-6.63(m,1H),3.75(s,3H)；13C NMR(75MHz,DMSO-d6):δ158.7,154.9,153.7,147.3,145.6,133.5,131.6,131.4,131.0,129.0,128.1,127.6,127.3,126.0,124.6,118.7,115.4,113.4,55.0.
实施例6：获得的部分喹啉化合物应用在体外抗肿瘤活性的测试
人类白血病细胞株K562,人类白血病多药耐药(MDR)细胞株K562/A02和人乳腺癌细胞株MCF-7均购自中国科学院上海细胞库。敏感细胞K562和MCF-7分别用含10％小牛血清的RPMI1640和DMEM培养基在37℃、5％CO2饱和湿度的条件下培养；而耐药细胞K562/A02则用含10％小牛血清并加入终浓度为1mg/L阿霉素的RPMI1640培养基在37℃、5％CO2饱和湿度的条件下培养，并且实验前MCF-7/ADM细胞株在无阿霉素的条件下培养14天。取对数生长期的细胞，以5×104个/ml密度接种于96孔培养板中，每孔180μl，在37℃5％CO2条件下培养。过夜后分组，分别为空白对照组、阳性对照组和受试化合物组。阳性对照组和受试化合物组中分别加入终浓度均为1，3，10，30，100μM的5-氟脲嘧啶、阿霉素及各化合物；空白对照组给予等体积的PBS。给药体积均为20μl。再培养48h后，然后每孔加入20μl MTT(5mg/ml)，再培养4小时，离心，洗板机吸去培养液，每孔加入150μl DMSO溶解，摇床振摇10min，然后在酶标仪上于波长570nm处读取光密度(OD)，计算化合物对细胞的抑制率。细胞抑制率＝(1-试验组OD平均值/对照组OD平均值)×100％，基于各组抑制率、通过Bliss法计算各化合物的半数抑制浓度IC50。结果用平均值±S.D.表示，组间比较用SPSS软件进行t检验，P＜0.01为极显著性差异。
表3.喹啉化合物在人类白血病细胞株K562,人类白血病多药耐药(MDR)细胞株K562/A02和人乳腺癌细胞株MCF-7中的IC50值，其中，**表示和5-氟脲嘧啶比较最优的结果；##表示和阿霉素比较最优的结果。
从表中可以看出，化合物对血液病K562细胞杀伤作用普遍优于实体瘤MCF-7细胞，其中化合物3ad作用较强。化合物3ad对K562细胞的杀伤作用优于5-氟脲嘧啶，化合物3ad对MCF-7细胞的杀伤作用也优于5-氟脲嘧啶。化合物3aa和3ad对耐药细胞K562/A02杀伤作用不仅优于5-氟脲嘧啶，而且也优于阿霉素，其中化合物3ad对耐药细胞K562/A02杀伤效果远胜阿霉素，提示本发明中的此类喹啉化合物具有较强的抗肿瘤活性，具备作为抗癌药物的潜在开发价值。

Claims (1)

1.一类具有3-（2-羟基苯基）喹啉结构单元的化合物的制备方法，其特征在于，合成路线如下：
具体合成过程如下：
在密封管中依次加入不同取代的二苯并1,4-氧氮杂卓亚胺1a-1l 0.4mmol 、苯乙炔基乙炔0.8 mmol、无水三氯化铁0.8 mmol和重新蒸过的1毫升1,2-二氯乙烷，密封后在80℃搅拌40小时；反应结束后，冷却至室温，加入二氯甲烷10 mL和水10 mL稀释，分层后分液，水相继续用二氯甲烷2×10 mL萃取，合并有机相，并用无水硫酸钠干燥，除去溶剂后直接柱层析石油醚/乙酸乙酯洗脱=3:1分离得到纯的产物。
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