CN106074541B - 一类2-芳基乙烯基苯并噁唑衍生物的制备方法和在抗肿瘤方面的应用 - Google Patents
一类2-芳基乙烯基苯并噁唑衍生物的制备方法和在抗肿瘤方面的应用 Download PDFInfo
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Abstract
本发明公开了一类2‑芳基乙烯基苯并噁唑类衍生物的结构及其制备方法。以2‑甲基苯并噁唑及不同取代基芳醛为原料，在无水无氧条件，并在叔丁醇钾的作用下一步反应生成2‑芳基乙烯基苯并噁唑类杂环化合物。该制备方法具有反应步骤简单、反应时间短、选择性较好等优点。另外还提供了抗肿瘤作用的应用研究，化合物1、2、3、4体外抑制HepG2细胞增殖均显示出一定生物活性。其中，化合物1化合物在100μM浓度下对HepG2细胞体外增殖的抑制率达到了85.4％，化合物4在100μM浓度下对HepG2细胞体外增殖的抑制率高达93.4％。
Description
技术领域
本发明属于有机合成技术领域，涉及一类2-芳基乙烯基苯并噁唑衍生物的制备方法和在抗肿瘤方面的应用。
背景技术
噁唑类化合物是一类重要的化学中间体，当噁唑环上含有一些特殊取代基时，光物理性质、生物活性会发生明显改变。苯并噁唑是噁唑的衍生化合物，引入苯环后，通过调节苯环上的取代基种类改变化合物性质从而被应用到不同领域，成为如今该类化合物的主要研究方向。一方面，该类化合物具有良好的抗肿瘤、抗炎、抗HIV、抗菌杀菌以及褪黑色素受体拮抗剂等多种生物活性，在生物、医学领域中有着广泛的应用前景。例如，以2-(2-吡啶)苯并噁唑为配体的钯配合物以及2-甲酸甲酯基苯并噁唑均具有较好的抗癌活性，是合成许多抗癌药物的化学中间体；2-硫代苯并噁唑具有良好的抗菌、止痛、消炎等功效；4-甲基-5-(2′-氯乙基)噁唑因具有催眠和抗惊厥作用而被运用到催眠药物中。在设计合成药物时，苯并噁唑类化合物作为中间体，可以进一步制备成安眠药、止痛药、退热剂、镇静剂、抗炎药、除草剂、杀虫剂、抗菌剂、抗癌、治疗糖尿病肌肉松弛等药物。例如，目前已用于临床的抗炎药苯噁洛芬(Benoxaprofe)和氯唑沙宗(Chlorzoxazone)具有安眠和止痛作用，且该类药物药效快，毒副作用小；还有抗菌抗癌药物多卡米星以及以多氟苯基苯并噁唑为母体合成的杀虫剂威霸等等。另一方面，苯并噁唑类化合物大多具有较好的荧光性能，荧光量子产率高，已经被广泛运用到荧光增白剂和感光乳剂中的增感染料中。例如目前普遍使用的聚酯型(DT)增白剂即为苯并噁唑型结构，即苯并噁唑噻吩型荧光增白剂(EBF)和双苯并噁唑二苯乙烯型荧光增白剂。还有很多研究者利用苯并噁唑化合物的强荧光性质，对其进行结构拓展以运用到荧光传感器中，以及做为荧光探针检测金属离子。苯并噁唑类化合物还可以作为聚合物改性剂，嵌入PPV聚合物中后能够改善PPV聚合物的发光性能。因此开展这类化合物的合成研究具有重要的意义。
发明内容
发明目的：针对现有技术中存在的不足，本发明的目的是提供一类2-芳基乙烯基苯并噁唑衍生物。本发明的另一目的是提供一类上述芳基乙烯基苯并噁唑衍生物制备方法和在抗肿瘤方面的应用。化合物1、2、3、4体外抑制HepG2细胞增殖均显示出一定的生物活性。其中，化合物1化合物在100μM浓度下对HepG2细胞体外增殖的抑制率达到了85.4％，化合物4在100μM浓度下对HepG2细胞体外增殖的抑制率高达93.4％。
技术方案：为了实现上述发明目的，本发明采用的技术方案为：
对位取代苯甲醛修饰的苯并噁唑衍生物，其结构通式如下：
式中，R为等。
一种制备上述苯并噁唑衍生物的方法，步骤如下：
(1)在氩气保护下及在0℃条件下，在反应容器中加入叔丁醇钾、新干燥的四氢呋喃、2-甲基苯并噁唑，搅拌均匀后，滴加苯甲醛的四氢呋喃溶液，滴加完毕后，继续搅拌反应2小时。
(2)停止反应，倒入水中，用二氯甲烷萃取分离，有机层经水洗、干燥，除去有机溶剂，残留物经硅胶层析柱分离提纯，洗脱剂为二氯甲烷，再经n-Hexane-CH2Cl2重结晶得到纯产物。具体化学反应式如下：
化合物1：化合物2：化合物3：化合物4：
上述步骤(1)中，2-甲基苯并噁唑与苯甲醛的摩尔比为1.1∶1；
上述步骤(1)中，叔丁醇钾与苯甲醛摩尔比为2∶1；
上述步骤(1)中，所述催化剂为叔丁醇钾；
上述步骤(1)中，反应条件为：无水无氧及在0℃条件下反应；
上述步骤(2)中，洗脱剂为二氯甲烷；
上述步骤(2)中，采用扩散法重结晶；
本发明的有益效果
与现有技术相比，本发明中包含不同芳基乙烯修饰苯并噁唑衍生物的制备方法所具有的优点有：(1)本方法通过在苯并噁唑甲基位置引入共轭的芳环，扩大了分子的共轭体系，吸收光谱和发射光谱吸收发生红移并使得分子刚性增强，提高荧光性能；(2)通过在芳环上引入不同取代基，增强了苯并噁唑化合物的生物活性；(3)反应选择性好、产率较高；还具有操作简便经济、能耗少等优点；(4)制备的不同取代基芳基乙烯修饰的苯并噁唑衍生物在抗肿瘤方面有着潜在的应用前景。
附图说明
图1为本发明实施例1化合物1的核磁共振氢谱；
图2为本发明实施例2化合物2的核磁共振氢谱；
图3为本发明实施例3化合物3的核磁共振氢谱；
图4为本发明实施例3化合物3的核磁共振氢谱；
图5为体外抑制HepG2细胞增殖活性的抑制率。
具体实施方式
下面结合具体实例对本发明做进一步地解释，具体实施事例并不对本发明做任何限定。
用1H-NMR表征并证实不同取代苯共轭苯并噁唑的结构。检测所用仪器为：BrukerARX600型核磁共振仪(TMS为内标，氘代氯仿为溶剂)，美国Thermo ELECTRONCORPORATION质谱工作站。
实施例1
化合物1的合成：在氩气保护下，在反应容器中加入叔丁醇钾2.20g(19.6mmol)和新干燥的四氢呋喃，在0℃搅拌10分钟，然后逐滴加入2-甲基苯并噁唑1.44g(10.8mmol)，在0℃搅拌10分钟反应10分钟，接着在0℃慢慢滴加1.59g对叔丁基苯甲醛(9.8mmol)的四氢呋喃溶液，继续在0℃条件下搅拌反应2小时。停止反应，将反应混合物倒入200mL水中，用二氯甲烷萃取3次(50mL x3)，合并有机层，水洗，无水Na2SO4干燥，减压旋蒸，除去有机溶剂，残留物经硅胶层析柱分离提纯，洗脱剂为二氯甲烷，再经n-Hexane-CH2Cl2重结晶得到纯的浅黄色产物。产率：38％。1H NMR(CDCl3)δ7.79-7.83(d，1H)，7.73-7.75(d，J＝4.8，1H)，7.57-7.59(d，2H)，7.47-7.49(d，1H)，7.54-7.56(m，1H)，7.35-7.37(m，2H)，7.06-7.10(d，1H)，1.37(s，9H)(图1)；ESI-MS cacd for[C19H19NO+H]+278.1466，found：278.1558[M+H+]。
实施例2
化合物2的合成：氩气保护条件下，将2.2g(19.6mmol)叔丁醇钾加入20mL无水四氢呋喃中，然后在0℃下搅拌10分钟，向上述悬浮液逐滴加入1.3mL(10.8mmol)2-甲基苯并噁唑，搅拌10min，再向上述溶液中缓慢加入1.81g(9.8mmol)溶于5mL无水四氢呋喃的对溴苯甲醛，搅拌反应2小时后，将混合液倒入200mL水中，有黄色固体析出，滤得固体后，使用乙醇重结晶得纯的产物，产率为25％。1H NMR(CDCl3)δ7.73-7.77(m，2H)，7.58-7.59(d，1H)，7.57(s，1H)，7.54-7.57(m，1H)，7.49(s，1H)，7.47(s，1H)，7.36-7.38(m，2H)，7.07-7.11(d，1H)(图2)；ESI-HRMScacd for[C15H10BrNO+H]+299.99，found：300.0023[M+H+]。
实施例3
化合物3的合成：在氩气保护下，在反应容器中加入叔丁醇钾2.20g(19.6mmol)和新干燥的四氢呋喃，在0℃搅拌10分钟，然后逐滴加入2-甲基苯并噁唑1.1mL(10.8mmol)，在0℃搅拌反应10分钟，接着在0℃慢慢滴加1.1mL对氟苯甲醛(9.8mmol)的四氢呋喃溶液，继续在0℃条件下搅拌反应2小时。反应结束后，将反应混合物倒入200毫升水中，用二氯甲烷萃取3次(50mL×3)，合并有机层，水洗，无水Na2SO4干燥，减压旋蒸，除去有机溶剂，残留物经硅胶层析柱分离提纯，洗脱剂为二氯甲烷，再经n-Hexane-CH2Cl2重结晶得到纯产物。产率：23.6％。1H NMR(CDCl3)δ7.74-7.78(d，J＝16.2，1H)，7.71-7.73(m，1H)，7.57-7.60(m，2H)，7.51-7.56(m，2H)，7.33-7.35(m，2H)，7.10-713(m，2H)，6.98-7.01(d，J＝16.2，1H)(图3)；ESI-MS cacd for[C15H10FNO+H]+240.07，found：240.0821[M+H+]。
实施例4
化合物4的合成：在氩气保护下，在反应容器中加入叔丁醇钾2.20g(19.6mmol)和新干燥的四氢呋喃，在0℃搅拌10分钟，然后逐滴加入2-甲基苯并噁唑1.1mL(10.8mmol)，在0℃搅拌反应10分钟，接着在0℃慢慢滴加1.75g 2，6-二氯苯甲醛(9.8mmol)的四氢呋喃溶液，继续在0℃条件下搅拌反应2小时。反应结束后，将反应混合物倒入200mL水中，用二氯甲烷萃取3次(50mL×3)，合并有机层，水洗，无水Na2SO4干燥，减压旋蒸，除去有机溶剂，残留物经硅胶层析柱分离提纯，洗脱剂为二氯甲烷，再经n-Hexane-CH2Cl2重结晶得到纯产物。产率：12.7％。1H NMR(CDCl3)δ7.88-7.92(d，J＝16.8，1H)，7.74-7.76(d，1H)，7.56-7.58(d，1H)，7.38-7.40(d，2H)，7.32-7.38(m，2H)，7.29-733(d，1H)，7.18-7.22(m，1H)(图4)；ESI-MS cacd for[C15H9Cl2NO+H]+290.01，found：290.0412[M+H+]。
实施例4在抗肿瘤方面的应用
使用MTT法研究化合物1-4的抗肿瘤活性，在96孔板中每孔接种2×103个细胞，待细胞贴壁6h后，每孔加不同剂量的各化合物培养72h，于加药后68h每孔加入20μl MTT(4mg/mL)，37℃培养4h，离心并吸除上清，每孔加入200μL DMSO，测量570nm处吸光值。将化合物分别作用于乳腺癌MDA-MB-231细胞、结肠癌HCT116细胞、和肝癌HepG2细胞。MTT结果显示(图4)，该系列化合物具有显著的抗肝癌活性，化合物1、2、3、4体外抑制HepG2细胞增殖的均显示出一定的生物活性。其中，化合物1化合物在100μM浓度下对HepG2细胞体外增殖的抑制率达到了85.4％，化合物4在100μM浓度下对HepG2细胞体外增殖的抑制率高达93.4％。
Claims (3)
1.一类2-芳基乙烯基苯并噁唑衍生物，其特征在于，结构式如下：
式中，R为
2.权利要求1所述一类2-芳基乙烯基苯并噁唑衍生物的制备方法，其特征在于，步骤如下：
1)在氩气保护下，在反应容器中将叔丁醇钾溶于新干燥的四氢呋喃，0℃搅拌10分钟后，逐滴滴加2-甲基苯并噁唑，继续在0℃条件下搅拌10分钟，接着在0℃慢慢滴加芳基甲醛的四氢呋喃溶液，继续搅拌反应2小时；其中，叔丁醇钾与苯甲醛的摩尔比为2∶1；2-甲基苯并噁唑与芳基甲醛的摩尔比为1.1∶1；
2)反应停止后，倒入200毫升水中，用二氯甲烷萃取3次，合并有机层，水洗，干燥，除去有机溶剂，残留物经硅胶层析柱分离提纯，洗脱剂为二氯甲烷，再经n-Hexane-CH2Cl2重结晶得到纯产物。
3.权利要求1所述的2-芳基乙烯基苯并噁唑衍生物，其特征在于，所述的衍生物在100μM浓度下对HepG2细胞体外增殖的抑制率高达93.4％。
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