CN111675665A - 一类含苯乙烯基喹喔啉酮衍生物及其制备方法 - Google Patents
一类含苯乙烯基喹喔啉酮衍生物及其制备方法 Download PDFInfo
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- C07D241/40—Benzopyrazines
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Abstract
本发明属于药物化学技术领域,具体涉及一类含苯乙烯基喹喔啉酮衍生物及其制备方法,所述合成的化合物的结构如下式I所示。它是以简单易得的4,5‑二氯‑1,2苯二胺和丙酮酸为原料,同时兼具条件温和,方法简单,反应易得的优点,拓宽了现有喹喔啉酮类化合物的种类,具有重要的理论和经济价值。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一类含苯乙烯基喹喔啉酮衍生物及其制备方法。
背景技术
喹喔啉酮及其衍生物是一类重要的医药化工中间体,具有广泛的生物活性,如抗菌、抗肿瘤、抗病毒、抗氧化、抗结核、抗疟疾、镇痛和抗炎等作用。此外其应用范围涵盖除草剂、杀虫剂、染料,甚至用于发光材料和有机半导体等领域,具有广阔的开发应用前景。
喹喔啉酮及其衍生物可作为荧光报告基团,通过半胱氨酸与丙烯酸酯特异性的加成环化反应,可用来检测体内半胱氨酸含量。近年来恶性肿瘤的不断增长,严重危害着人类健康,抗肿瘤药物成为热点。很多文献报道喹喔啉酮类化合物具有体外抗肿瘤活性,主要通过抑制肿瘤细胞增殖、逆转肿瘤细胞多药耐药和传统的细胞毒三种途径来发挥抗肿瘤作用,可作为候选抗肿瘤药物。因此,以喹喔啉酮为基本骨架设计合成多个新型喹喔啉酮衍生物具有重要的理论和经济价值。
发明内容
本发明提供一种简单高效的合成一类含苯乙烯基喹喔啉酮衍生物的方法。
本发明的技术方案如下:
一类含苯乙烯基喹喔啉酮的衍生物,其化学结构式如下:
式中,R选自氢、2-甲基、3-甲基、4-甲基、2-乙基、3-乙基、4-乙基、2-羟基、3-羟基、4-羟基、2-甲氧基、3-甲氧基、4-甲氧基、2-氟、3-氟、4-氟、2-氯、3-氯、4-氯、2-溴、3-溴、4-溴、2-三氟甲基、3-三氟甲基、4-三氟甲基、2-苄氧基、3-苄氧基、4-苄氧基、2-硝基、3-硝基、4-硝基、2-氰基、3-氰基、4-氰基、2-羧基、3-羧基、4-羧基、2-酯基、3-酯基、4-酯基、2-甲硫基、3-甲硫基、4-甲硫基、2-二甲氨基、3-二甲氨基、4-二甲氨基、2-乙酰氨基、3-乙酰氨基、4-乙酰氨基、2-萘醛中的一种及以上。
本发明所述一类苯乙烯基喹喔啉酮衍生物,其制备步骤如下:
步骤a:将4,5-二氯-1,2苯二胺(II)预溶于蒸馏水中,加入丙酮酸并在50℃下搅拌反应混合物。经TLC确认反应完成后,过滤产物并用蒸馏水洗涤,干燥得到化合物(III);
步骤b:将化合物(III)溶于乙酸中,加入相应取代基的苯甲醛,在浓硫酸催化下回流反应,经TLC确认反应完成后,将反应冷却至室温,过滤产物,用饱和碳酸氢钠溶液洗涤3次,干燥得到化合物(I)。
具体实施方式
下面通过具体实施例对本发明作进一步的描述,但本发明的保护范围及实施方式不限于此。
实施例一:
6,7-二氯-3-苯乙烯基喹喔啉-2(1H)-酮(I-1)的制备
将4,5-二氯-1,2苯二胺(0.177g,1.0mmol)预溶于50mL蒸馏水中加入丙酮酸(0.088g,1.0mmol)并在50℃下搅拌反应混合物。经TLC确认反应完成后,过滤产物并用蒸馏水洗涤,干燥得到0.195g黄色固体化合物III。将化合物III(0.229g,1.0mmol)溶于30mL乙酸中,加入苯甲醛,在浓硫酸(0.2mL)催化下回流反应,经TLC确认反应完成后,将反应冷却至室温,过滤产物,用饱和碳酸氢钠溶液洗涤3次,干燥得到化合物I-1。其为黄色固体粉末,即6,7-二氯-3-苯乙烯基喹喔啉-2酮,产率79%。1H NMR(600MHz,DMSO-d6)δ12.70-12.52(m,1H),8.06(d,J=16.2Hz,1H),7.99(s,1H),7.76-7.70(m,2H),7.58(d,J=16.2Hz,1H),7.50-7.37(m,4H).
实施例二:
6,7-二氯-3-(4-甲基苯乙烯基)喹喔啉-2(1H)-酮(I-2)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-甲基苯乙烯基)喹喔啉-2(1H)-酮,产率:85%。1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),8.03(d,J=16.2Hz,1H),7.98(s,1H),7.61(d,J=7.8Hz,2H),7.53(d,J=16.2Hz,1H),7.42(s,1H),7.26(d,J=7.8Hz,2H),2.35(s,3H).
实施例三:
6,7-二氯-3-(2-甲氧基苯乙烯基)喹喔啉-2(1H)-酮(I-3)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(2-甲氧基苯乙烯基)喹喔啉-2(1H)-酮,产率:87%。1H NMR(600MHz,DMSO-d6)δ12.58(s,1H),8.34(d,J=16.3Hz,1H),8.02(s,1H),7.74(dd,J=7.8,1.7Hz,1H),7.61(d,J=16.3Hz,1H),7.45-7.36(m,2H),7.11(d,J=8.3Hz,1H),7.02(t,J=7.5Hz,1H),3.90(s,3H).
实施例四:
6,7-二氯-3-(3-甲氧基苯乙烯基)喹喔啉-2(1H)-酮(I-4)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(3-甲氧基苯乙烯基)喹喔啉-2(1H)-酮,产率:77%。1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),8.05(d,J=16.2Hz,1H),7.99(s,1H),7.58(d,J=16.2Hz,1H),7.44(s,1H),7.36(t,J=7.9Hz,1H),7.30(d,J=7.9Hz,1H),7.27(t,J=2.0Hz,1H),7.01-6.96(m,1H),3.83(s,3H).
实施例五:
6,7-二氯-3-(4-甲氧基苯乙烯基)喹喔啉-2(1H)-酮(I-5)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-甲氧基苯乙烯基)喹喔啉-2(1H)-酮,产率:67%。1H NMR(600MHz,DMSO-d6)δ12.56(s,1H),8.02(d,J=16.1Hz,1H),7.95(s,1H),7.68(d,J=8.7Hz,2H),7.44(d,J=16.1Hz,1H),7.41(s,1H),7.04-6.96(m,2H),3.82(s,3H).
实施例六:
6,7-二氯-3-(3,4-二甲氧基苯乙烯基)喹喔啉-2(1H)-酮(I-6)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(3,4-二甲氧基苯乙烯基)喹喔啉-2(1H)-酮,产率:65%。1H NMR(600MHz,DMSO-d6)δ12.58(s,1H),8.03(d,J=16.1Hz,1H),7.94(s,1H),7.46(d,J=16.1Hz,1H),7.41(s,1H),7.31(d,J=2.1Hz,1H),7.25(dd,J=8.4,2.0Hz,1H),7.01(d,J=8.3Hz,1H),3.83(d,J=23.7Hz,6H).
实施例七:
6,7-二氯-3-(4-(三氟甲基)苯乙烯基)喹喔啉-2(1H)-酮(I-7)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-(三氟甲基)苯乙烯基)喹喔啉-2(1H)-酮,产率:54%。1H NMR(600MHz,DMSO-d6)δ12.69(s,1H),8.11(d,J=16.3Hz,1H),8.01(s,1H),7.95(d,J=8.1Hz,2H),7.77(d,J=8.1Hz,2H),7.69(d,J=16.3Hz,1H),7.44(s,1H).
实施例八:
3-(4-(苄氧基)苯乙烯基)-6,7-二氯喹喔啉-2(1H)-酮(I-8)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即3-(4-(苄氧基)苯乙烯基)-6,7-二氯喹喔啉-2(1H)-酮,产率:52%。1H NMR(600MHz,DMSO-d6)δ12.55(s,1H),8.02(d,J=16.2Hz,1H),7.96(s,1H),7.69(d,J=8.4Hz,2H),7.51-7.43(m,3H),7.43-7.38(m,3H),7.35(t,J=7.3Hz,1H),7.08(d,J=8.5Hz,2H),5.18(s,2H).
实施例九:
6,7-二氯-3-(2-氟苯乙烯基)喹喔啉-2(1H)-酮(I-9)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(2-氟苯乙烯基)喹喔啉-2(1H)-酮,产率:57%。1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),8.17(d,J=16.4Hz,1H),8.03(s,1H),7.87(td,J=7.8,1.7Hz,1H),7.63(d,J=16.4Hz,1H),7.51-7.39(m,2H),7.34-7.26(m,2H).
实施例十:
6,7-二氯-3-(3-氟苯乙烯基)喹喔啉-2(1H)-酮(I-10)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(3-氟苯乙烯基)喹喔啉-2(1H)-酮,产率:49%。1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),8.04(d,J=16.2Hz,1H),7.97(s,1H),7.63-7.53(m,3H),7.48(td,J=7.9,6.1Hz,1H),7.42(s,1H),7.26-7.20(m,1H).
实施例十一:
6,7-二氯-3-(4-氟苯乙烯基)喹喔啉-2(1H)-酮(I-11)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-氟苯乙烯基)喹喔啉-2(1H)-酮,产率:51%。1H NMR(600MHz,DMSO-d6)δ8.05(d,J=16.2Hz,1H),7.97(s,1H),7.80(dd,J=8.4,5.4Hz,2H),7.52(d,J=16.2Hz,1H),7.42(s,1H),7.27(t,J=8.6Hz,2H).
实施例十二:
6,7-二氯-3-(4-氯苯乙烯基)喹喔啉-2(1H)-酮(I-12)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-氯苯乙烯基)喹喔啉-2(1H)-酮,产率:79%。1H NMR(600MHz,DMSO-d6)δ12.62(s,1H),8.02(d,J=16.2Hz,1H),7.96(s,1H),7.77-7.68(m,2H),7.56(d,J=16.2Hz,1H),7.51-7.45(m,2H),7.41(s,1H).
实施例十三:
6,7-二氯-3-(4-溴苯乙烯基)喹喔啉-2(1H)-酮(I-13)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-溴苯乙烯基)喹喔啉-2(1H)-酮,产率:58%。1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),8.00(d,J=16.2Hz,1H),7.97(s,1H),7.68(d,J=8.2Hz,2H),7.62(d,J=8.2Hz,2H),7.58(d,J=16.2Hz,1H),7.42(s,1H).
实施例十四:
6,7-二氯-3-(4-硝基苯乙烯基)喹喔啉-2(1H)-酮(I-14)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-硝基苯乙烯基)喹喔啉-2(1H)-酮,产率:34%。1H NMR(600MHz,DMSO-d6)δ8.25(d,J=8.5Hz,2H),8.14(d,J=16.2Hz,1H),7.98(d,J=8.6Hz,2H),7.88(s,1H),7.79(d,J=16.3Hz,1H),7.39(s,1H).
实施例十五:
6,7-二氯-3-(4-(甲硫基)苯乙烯基)喹喔啉-2(1H)-酮(I-15)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-(甲硫基)苯乙烯基)喹喔啉-2(1H)-酮,产率:47%。1H NMR(600MHz,DMSO-d6)δ12.58(s,1H),8.01(d,J=16.2Hz,1H),7.95(s,1H),7.68-7.63(m,2H),7.52(d,J=16.2Hz,1H),7.41(s,1H),7.31-7.27(m,2H),2.52(s,3H).
实施例十六:
6,7-二氯-3-(4-(二甲基氨基)苯乙烯基)喹喔啉-2(1H)-酮(I-16)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即6,7-二氯-3-(4-(二甲基氨基)苯乙烯基)喹喔啉-2(1H)-酮,产率:48%。1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),7.99(d,J=16.0Hz,1H),7.92(s,1H),7.56(d,J=8.6Hz,2H),7.39(s,1H),7.34(d,J=16.0Hz,1H),6.75(d,J=8.6Hz,2H),3.00(s,6H).
实施例十七:
N-(4-(2-(6,7-二氯-3-氧代-3,4-二氢喹喔啉-2-基)乙烯基)苯基)乙酰胺(I-17)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即N-(4-(2-(6,7-二氯-3-氧代-3,4-二氢喹喔啉-2-基)乙烯基)苯基)乙酰胺,产率:67%。1H NMR(600MHz,DMSO-d6)δ12.54(s,1H),10.15(s,1H),8.01(d,J=16.2Hz,1H),7.97(s,1H),7.67(s,4H),7.49(d,J=16.2Hz,1H),7.42(s,1H),2.08(s,3H).
实施例十八:
1-(2-(6,7-二氯-3-氧代-3,4-二氢喹喔啉-2-基)乙烯基)-2-萘醛(I-18)的制备
制备方法参考实施例一。按照上述方法制得黄色粉末,即1-(2-(6,7-二氯-3-氧代-3,4-二氢喹喔啉-2-基)乙烯基)-2-萘醛,产率:43%。1H NMR(600MHz,DMSO-d6)δ8.25-8.17(m,2H),8.00-7.90(m,4H),7.75(d,J=16.2Hz,1H),7.58-7.52(m,2H),7.42(s,1H).
上述实施例为本发明的部分实施方式,本发明的具体实施方式并不受上面实施例的影响,其它的任何未背离本发明的精神实质与原理下所作的结构修饰、条件简化均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (4)
1.一类含苯乙烯基喹喔啉酮衍生物,其特征在于具有通式I所示的结构:
其中,R选自氢、2-甲基、3-甲基、4-甲基、2-乙基、3-乙基、4-乙基、2-羟基、3-羟基、4-羟基、2-甲氧基、3-甲氧基、4-甲氧基、2-氟、3-氟、4-氟、2-氯、3-氯、4-氯、2-溴、3-溴、4-溴、2-三氟甲基、3-三氟甲基、4-三氟甲基、2-苄氧基、3-苄氧基、4-苄氧基、2-硝基、3-硝基、4-硝基、2-氰基、3-氰基、4-氰基、2-羧基、3-羧基、4-羧基、2-酯基、3-酯基、4-酯基、2-甲硫基、3-甲硫基、4-甲硫基、2-二甲氨基、3-二甲氨基、4-二甲氨基、2-乙酰氨基、3-乙酰氨基、4-乙酰氨基、2-萘醛中的一种及以上。
3.根据权利要求2所述的合成含苯乙烯基喹喔啉酮衍生物的方法,其特征在于,所述的化合物(III)6,7-二氯-3-甲基喹喔啉-2(1H)-酮与取代苯甲醛的摩尔比为1∶1~2。
4.根据权利要求2所述的制备方法,其特征在于,步骤b中,所用的催化剂为浓硫酸、磷酸、硼酸、有机磺酸中的一种或多种。
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