CN108558878B - 一种喹叨啉及其衍生物的合成工艺 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 31
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims abstract description 8
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- C—CHEMISTRY; METALLURGY
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种喹叨啉及其衍生物的合成方法,以2‑芳基‑3硝基喹啉类化合物做原料,三价磷试剂做还原剂,加热条件下得到喹叨啉及其衍生物。本发明的有益效果是:发明采用易于制备的2‑芳基3‑硝基喹啉类化合物作为起始原料,通过Cadogen反应直接得到喹叨啉及其衍生物。反应时间短,反应原料简单易得,条件温和,操作便捷,底物范围广,兼容不同取代基,是一种具有潜在应用价值的合成喹叨啉及其衍生物的新方法。
Description
技术领域
本发明涉及一种喹叨啉及其衍生物的合成方法,属于有机及药物合成技术领域。
背景技术
喹叨啉(quindoline)具有吲哚并喹啉的结构,是一种喹啉类生物碱,存在于白叶藤植物中。喹叨啉及其衍生物,具有广泛的生物活性,良好的光学性质等,自21世纪以来受到了广泛的关注。如白叶藤碱,最早被用作染料和治疗疟疾、寄生虫病和尿路感染及上呼吸道感染,后续研究发现其衍生物具有抗肿瘤细胞,抗真菌,抗脑膜炎,抗微生物,抗菌,降血糖,抗炎,抗高血压,抑制去甲肾上腺素受体和抗血栓等活性。特别是其抗肿瘤方面,在生物作用机理研究中发现,白叶藤碱作为一种典型的DNA插入剂,是潜在的拓扑异构酶II抑制剂,并且它的一些类似物能够稳定端粒G-四螺旋体,具有抑制端粒酶的活性。另外,喹叨啉还具有良好的光学性质,在有机光电材料中也有开发的潜质。
目前,喹叨啉的合成主要分为三类方式。(1)以吲哚或靛红为原料,通常需要多步反应,收率偏低,原料不易得。(2)使用卤素或氨基取代的喹啉作为起始原料,通常需要贵金属作为偶联催化剂,并且对底物有很大的限制。(3)使用一些其他的底物合成则通常需要多步反应和严苛的条件。因此发展一种更为便捷的方式合成喹叨啉及其衍生物是十分有必要的。
发明内容
为解决现有技术的不足,本发明的目的在于提供一种操作简便,收率较好的利用三价磷试剂直接合成喹叨啉及其衍生物的方法。
为达到上述目的,本发明是通过以下的技术方案来实现的:一种喹叨啉及其衍生物的合成工艺,其特征在于:以2-芳基-3硝基喹啉类化合物做原料,三价磷试剂做还原剂,加热条件下得到喹叨啉及其衍生物。
按上述方案,所述的2-芳基-3硝基喹啉类化合物的制备方法为下述反应方程式所得产物:
式Ⅰ中Ar为芳基或者取代芳基,R为卤素、甲基、甲氧基、氢或芳基。
按上述方案,所述的催化剂选自CuI,CuCl,CuBr,Cu2O或Cu(OTf)2,优选为CuI。
按上述方案,催化剂用量按物质的量计为硝基烯烃用量的0.01-0.2倍,优选为0.01倍。
按上述方案,反应在80-130℃的温度范围内进行,优选为110℃。
按上述方案,所述的还原剂选自PPh3,P(OEt)3或DPPE。
按上述方案,所述的还原剂为PPh3或DPPE。
按上述方案,还原剂用量按物质的量计为2-芳基-3硝基喹啉用量的0.2-3.5倍。
按上述方案,还含有溶剂,所述的溶剂为DMSO,DMF,甲苯,氯苯和二氯苯中的任意一种或它们的混合。
按上述方案,加热反应温度为80-200℃。
本发明利用Cadogen反应,使用三价磷试剂作为还原剂合成喹叨啉及其衍生物的方法,所涉及的反应方程式如下:
其中,起始原料2-芳基-3-硝基喹啉类化合物是通过硝基烯烃,邻位醛基取代的芳基叠氮在催化剂的条件下得到的,其具体反应式如式Ⅰ所示:
将式Ⅰ所得到2-芳基-3-硝基喹啉类化合为起始原料,经三价磷试剂还原后得到喹叨啉及其衍生物,其具体反应式如式Ⅱ所示:
其中,式Ⅰ、Ⅱ中R为卤素、甲基、甲氧基、氢或芳基,Ar为芳基或取代芳基。
本发明的有益效果是:发明采用易于制备的2-芳基3-硝基喹啉类化合物作为起始原料,通过Cadogen反应直接得到喹叨啉及其衍生物。反应时间短,反应原料简单易得,条件温和,操作便捷,底物范围广,兼容不同取代基,是一种具有潜在应用价值的合成喹叨啉及其衍生物的新方法。
附图说明
为了更清楚地说明本发明实施案例的技术方案,下面对实施例的附图作简单的介绍。
图1是本发明实施例1合成的2-苯基-3-硝基喹啉化合物的1H NMR表征图谱;
图2是本发明实施例1合成的2-苯基-3-硝基喹啉化合物的13C NMR表征图谱;
图3是本发明实施例2合成的2-苯基-3-硝基-6,7-二甲氧基喹啉化合物的1H NMR表征图谱;
图4是本发明实施例2合成的2-苯基-3-硝基-6,7-二甲氧基喹啉化合物的13C NMR表征图谱;
图5是本发明实施例3合成的2-苯基-3-硝基-7-氟喹啉化合物的1H NMR表征图谱;
图6是本发明实施例3合成的2-苯基-3-硝基-7-氟喹啉化合物的13C NMR表征图谱;
图7是本发明实施例4合成的喹叨啉化合物的1H NMR表征图谱;
图8是本发明实施例4合成的喹叨啉化合物的13C NMR表征图谱;
图9是本发明实施例5合成的2,3-二甲氧基喹叨啉化合物的1H NMR表征图谱;
图10是本发明实施例5合成的2,3-二甲氧基喹叨啉化合物的13C NMR表征图谱;
图11是本发明实施例6合成的3-氟喹叨啉化合物的1H NMR表征图谱;
图12是本发明实施例6合成的3-氟喹叨啉化合物的13C NMR表征图谱。
具体实施方式
为了更好地理解本发明,下面结合实施例进一步阐明本发明的内容,但本发明的内容不仅仅局限于下面的实施例。
实施例1 2-苯基-3-硝基喹啉的制备
具体步骤为:向圆底烧瓶(50mL)中加入硝基苯乙烯(1mmol)、2-叠氮苯甲醛(1.5mmol)、CuI(0.01mmol),在110℃下磁力搅拌反应2小时后,用乙酸乙酯溶解后,有机层经饱和食盐水洗涤,无水硫酸钠干燥后,减压蒸去萃取溶剂即得粗产品,粗产品用乙酸乙酯/石油醚=1:10(V/V)为淋洗液进行柱分离提纯即得产品2-苯基-3-硝基喹啉,为黄色固体,收率为90%。
所得产品的核磁氢谱图结果为:1H NMR(600MHz,DMSO-d6):δ8.60(s,1H),8.20(d,J=8.4Hz,1H),7.90(d,J=8.4Hz,1H),7.86(t,J=7.8Hz,1H),7.63(t,J=7.2Hz,1H),7.58(d,J=7.8Hz,2H),7.30(d,J=7.8Hz,2H),2.42(s,3H).13C NMR(100MHz,CDCl3,ppm)δ152.1,148.3,143.9,137.0,132.8,132.6,129.8,129.6,128.7,128.6,128.4,128.1,125.5.
实施例2 2-苯基-3-硝基-6,7-二甲氧基喹啉的制备
具体步骤为:向圆底烧瓶(50mL)中加入硝基苯乙烯(1mmol)、2-叠氮-4,5-二甲氧基苯甲醛(1.8mmol)、CuBr(0.01mmol),在130℃下磁力搅拌反应4小时后,用乙酸乙酯溶解后,有机层经饱和食盐水洗涤,无水硫酸钠干燥后,减压蒸去萃取溶剂即得粗产品,,粗产品用乙酸乙酯/石油醚=1:2.5(V/V)为淋洗液进行柱分离提纯即得产品2-苯基-3-硝基-6,7-二甲氧基喹啉,产品为黄色固体,收率为73%。
所得产品的核磁氢谱图结果为:1H NMR(600MHz,CDCl3,ppm)δ8.55(s,1H),7.60(d,J=4.8Hz,2H),7.52-7.44(m,4H),7.15(s,1H),4.05(s,3H),4.04(s,3H).13C NMR(100MHz,CDCl3,ppm)δ155.3,151.4,150.3,146.1,142.5,137.6,130.9,129.1,128.6,128.0,121.4,108.1,105.2,56.5,56.3.
实施例3 2-苯基-3-硝基-7-氟喹啉的制备
具体步骤为:向圆底烧瓶(50mL)中加入硝基苯乙烯(1mmol)、2-叠氮-4-氟苯甲醛(1.5mmol)、Cu2O(0.01mmol),DMSO(2mL),在100℃下磁力搅拌反应15小时后,用乙酸乙酯溶解后,有机层经饱和食盐水洗涤,无水硫酸钠干燥后,减压蒸去溶剂即得粗产品,,粗产品用乙酸乙酯/石油醚=1:15(V/V)为淋洗液进行柱分离提纯即得所需产品2-苯基-3-硝基-7-氟喹啉,产品为黄色固体,收率为72%。
所得产品的核磁氢谱图结果为:1H NMR(600MHz,CDCl3,ppm)δ8.70(s,1H),8.03-7.97(m,1H),7.86(d,J=9.6Hz,1H),7.65(s,2H),7.48-7.51(m,4H).13C NMR(150MHz,CDCl3,ppm)δ166.0,164.3,153.3,149.6(d,J=13.4Hz),143.5,136.7,132.7,130.8(d,J=10.4Hz),129.8,128.8,122.5,119.3(d,J=25.9Hz),113.8(d,J=21.0Hz).
实施例4喹叨啉的制备
具体步骤为:向实施例1所得2-苯基-3-硝基喹啉中加入DPPE(1.1mmol),在150℃下磁力搅拌反应4小时后,得到粗产品,粗产品用乙酸乙酯/石油醚=1:1.5(V/V)为淋洗液进行柱分离提纯即得所需产品喹叨啉,产品为黄色固体,收率45%。
所得产品的核磁氢谱图结果为:1H NMR(600MHz,DMSO-d6,ppm)δ11.46(s,1H),8.37(d,J=7.2Hz,1H),8.30(s,1H),8.21(d,J=8.4Hz,1H),8.11(d,J=8.4Hz,1H),7.67-7.53(m,4H),7.29(t,J=7.2Hz,1H).13C NMR(150MHz,DMSO-d6,ppm)δ145.7,144.1,143.4,132.5,129.7,128.7,127.5,126.7,126.1,124.9,121.4,121.0,119.4,113.1,111.5.
实施例5 2,3-二甲氧基喹叨啉的制备
具体步骤为:向实施例2所得2-苯基-3-硝基-6,7-二甲氧基喹啉中加入三苯基磷(2.2mmol),邻二氯苯(5mL),在130℃下磁力搅拌反应5小时后,旋干溶剂后乙醇溶解,加入无水氯化锌除去三苯氧磷,过滤后减压蒸馏除去溶剂得到粗产品,粗产品用乙酸乙酯/石油醚=1:2(V/V)为淋洗液进行柱分离提纯即得所需产品2,3-二甲氧基喹叨啉,产品为黄色固体,收率54%。
所得产品的核磁氢谱图结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.26(s,1H),8.26(d,J=7.6Hz,1H),8.14(s,1H),7.59-7.50(m,3H),7.45(s,1H),7.22-7.26(m,1H),3.95(s,3H),3.93(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ150.1,148.9,143.1,142.9,140.3,131.7,128.6,122.5,121.3,120.7,119.1,112.3,111.4,107.3,105.1,55.6,55.6.
实施例6 3-氟喹叨啉的制备
具体步骤为:向实施例3所得2-苯基-3-硝基-7-氟喹啉中加入DPPE(2mmol),在130℃下磁力搅拌反应8小时后得到粗产品,粗产品用乙酸乙酯/石油醚=1:1.5(V/V)为淋洗液进行柱分离提纯即得所需产品3-氟喹叨啉,产品为黄色固体,收率35%。
所得产品的核磁氢谱图结果为:1H NMR(400MHz,DMSO-d6,ppm)δ11.26(s,1H),8.26(d,J=7.6Hz,1H),8.14(s,1H),7.59-7.50(m,3H),7.45(s,1H),7.22-7.26(m,1H),3.95(s,3H),3.93(s,3H).13C NMR(100MHz,DMSO-d6,ppm)δ150.1,148.9,143.1,142.9,140.3,131.7,128.6,122.5,121.3,120.7,119.1,112.3,111.4,107.3,105.1,55.6,55.6.
本发明采用易于制备的2-芳基-3-硝基喹啉作为起始原料,通过candogen反应直接得到喹叨啉及其衍生物。反应时间短,操作便捷,是一种具有潜在应用价值的方法。
上述施例不以任何形式限制本发明,凡采用等同替换或等小变换的方式所获得的技术方案,均落在本发明的保护范围内。
Claims (8)
2.根据权利要求1所述合成工艺,其特征在于:所述的催化剂选自CuI,CuCl,CuBr,Cu2O。
3.根据权利要求1或2所述合成工艺,其特征在于:催化剂用量按物质的量计为硝基烯烃用量的0.01-0.2倍。
4.根据权利要求1所述合成工艺,其特征在于:反应在80-130℃的温度范围内进行。
5.根据权利要求1所述合成工艺,其特征在于:所述的还原剂选自PPh3或DPPE。
6.根据权利要求5所述合成工艺,其特征在于:还原剂用量按物质的量计为2-芳基-3硝基喹啉用量的0.2-3.5倍。
7.根据权利要求1所述合成工艺,其特征在于还含有溶剂,所述的溶剂为DMSO,DMF,甲苯,氯苯和二氯苯中的任意一种或它们的混合。
8.根据权利要求1所述合成工艺,其特征在于:加热反应温度为80-200℃。
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