CN110642677B - 双芳基衍生物的制备、双芳基衍生物及应用 - Google Patents

双芳基衍生物的制备、双芳基衍生物及应用 Download PDF

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CN110642677B
CN110642677B CN201910814135.4A CN201910814135A CN110642677B CN 110642677 B CN110642677 B CN 110642677B CN 201910814135 A CN201910814135 A CN 201910814135A CN 110642677 B CN110642677 B CN 110642677B
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朱勍
窦言东
蔡春晖
章苗
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Abstract

本发明涉及一种双芳基衍生物及其制备方法与应用，所述双芳基衍生物结构如式(II)所示。本发明提供了双芳基衍生物及铜催化芳基偶联合成双芳基的方法，操作过程简单，原料都已商品化容易得到，催化剂廉价易得且环境友好，反应条件温和，位点选择性高，反应高效，只需一步便可制得双芳基类生物。此外，该反应利用表面活性剂作为辅助溶剂，使该反应可以在水溶液中进行，克服了传统双芳基偶联反应对酸和有机溶剂的需求。

Description

双芳基衍生物的制备、双芳基衍生物及应用
(一)技术领域
本发明涉及一种双芳基衍生物的制备方法、双芳基衍生物及应用。
(二)背景技术
双芳基化合物，尤其是双酚和联二萘酚，是一类非常有价值的有机分子，存在于各种生物活性分子、天然产物和功能材料中。此外，含有两个酚羟基的姜黄素等化合物具有有效的抗氧化和抗炎活性。由于双酚具有杀菌和杀菌的特性，因此除了工业用途外，双酚还被用作防腐剂和消毒剂。另一方面，对映选择性芳基-芳基交叉耦合，如联二萘酚，提供了最直接的进入阿托品双芳基，在化学科学领域具有显著的应用潜力。然而，它们在不对称合成中作为手性配体或催化剂最为重要。因此，开发一种新的、有效的双酚和联二萘酚的合成方法是非常紧迫的。
(三)发明内容
本发明的目的是提供一种水相中双芳基化合物偶联的新方法，以及利用该方法获得的一种双芳基衍生物及其应用。
本发明采用的技术方案是：
一种双芳基衍生物的制备方法，所述方法包括：将式(I)所示化合物溶于水中，加入氧化剂、铜催化剂和添加剂，常温反应完全后，反应液经分离纯化得到式(II)所示芳基偶联化合物；所述氧化剂为下列之一：过硫酸钾，二氧化锰，二醋酸碘苯，苯醌；所述铜催化剂为下列之一：醋酸铜，氯化铜，二乙酰丙酮铜；所述添加剂为下列之一：醋酸银，碳酸银，三氟甲磺酸银；
Figure BDA0002185852700000021
式(I)、(II)中，R为H、卤素、C1～C7的烷基、C1～C7的烷氧基或取代芳基，所述取代芳基的取代基为H、卤素、甲氧基或C1～C7的烷基。或者，所述R为苯基、间甲基苯基、对甲基苯基、对氯苯基、对硝基苯基、邻氟苯基、对甲氧基苯基、C6脂肪环基、C4脂肪烷基或C4烷氧基。
所述反应液中还可添加有表面活性剂，所述表面活性剂为聚乙二醇辛基苯基醚，在反应液中的添加量为1～5％(w/w)，优选为2％。
本发明方法催化剂廉价易得且环境友好、反应条件温和、位点选择性高，反应高效。表面活性剂的使用使得该反应克服对强酸、有机溶剂的要求，更加绿色环保。此外，该反应突破了非对位双酚邻位偶联的瓶颈。
所述的催化剂优选为醋酸铜；所述的氧化剂优选为过硫酸钾；进一步，所述的添加剂为乙酸银；所述氧化剂、添加剂、催化剂与苯酚类化合物(I)的物质的量之比优选为1.2:1.2:0.2:1。
所述分离纯化方法如下：反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过硫酸镁干燥、过滤、常温下旋转蒸除溶剂，即得粗品；将粗品进硅胶柱层析，以体积比为1：3～10的乙酸乙酯和石油醚的溶液为流动相，TLC跟踪收集Rf值为0.3～0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到所述芳基偶联化合物。
所述R优选为苯基、间甲基苯基、对甲基苯基、对氯苯基、对硝基苯基、邻氟苯基、对甲氧基苯基、C6脂肪环基、C4脂肪烷基或C4烷氧基。
更为优选的，所述双芳基衍生物为下列之一：
Figure BDA0002185852700000031
本发明还涉及一种按照上述方法制备的双芳基衍生物，结构为下式之一：
Figure BDA0002185852700000041
本发明还涉及上述双芳基衍生物在制备抗肿瘤药物中的应用。
本发明的有益效果主要体现在：(1)本发明提供了一种新的双芳基化合物，具有一定的抗肿瘤活性，为肿瘤药物筛选提供了基础；(2)本发明提供了一种铜催化芳基偶联合成双芳基的方法，操作过程简单，原料都已商品化容易得到，催化剂廉价易得且环境友好，反应条件温和，位点选择性高，反应高效，只需一步便可制得双芳基类生物。此外，该反应利用表面活性剂作为辅助溶剂，使该反应可以在水溶液中进行，克服了传统双芳基偶联反应对酸和有机溶剂的需求。
(四)附图说明
图1为化合物(II-1)的氢谱；
图2为化合物(II-1)的碳谱；
图3为化合物(II-1)的质谱；
图4为化合物(II-1)的抗肿瘤活性图。
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此：
实施例1：
Figure BDA0002185852700000051
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将1mmol对对乙酰氨基苯酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：9的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-1)所示的化合物纯品42mg。
实施例2：
Figure BDA0002185852700000052
将1mmol对乙基苯酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得2A-2化合物粗品。化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：8的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-2)所示的化合物纯品48mg。1H NMR(500MHz,CDCl3)δ7.16(dd,J＝8.2,2.2Hz,2H),7.11(d,J＝2.1Hz,2H),6.97(d,J＝8.2Hz,2H),5.66(s,2H),2.65(q,J＝7.6Hz,4H),1.26(t,J＝7.6Hz,9H).13C NMR(126MHz,CDCl3)δ150.89(s),137.34(s),130.42(s),129.21(s),123.71(s),116.53(s),28.02(s),15.79(s).
实施例3：
Figure BDA0002185852700000061
将1mmol对2，4-二甲基苯酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：10的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-3)所示的化合物纯品39mg。1H NMR(500MHz,CDCl3)δ7.03–7.00(m,1H),6.89(d,J＝0.9Hz,1H),5.31(s,3H).13C NMR(126MHz,CDCl3)δ149.18(s),131.92(s),129.99(s),128.62(s),125.23(s),122.54(s),53.41(s),50.77(s),20.40(s),16.15(s).
实施例4：
Figure BDA0002185852700000071
将1mmol2-溴4甲基苯酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：8的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-4)所示的化合物纯品62mg。1H NMR(500MHz,CDCl3)d＝7.28(d,J＝1.7Hz,2H),6.93(d,J＝1.7Hz,2H),5.72(s,2H),2.23(s,6H)；13C NMR(126MHz,CDCl3)d＝147.11(s),132.58(s),131.60(s),131.45(s),125.33(s),110.94(s),20.24(s)；
实施例5：
Figure BDA0002185852700000072
将1mmol乙基苯酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：10的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-5)所示的化合物纯品57mg。1H NMR(500MHz,CDCl3,):δ7.21(J＝7.4Hz,2H),7.07(J＝7.3Hz,2H),6.94(t,J＝7.3Hz,2H),5.18(s,2H),2.32(s,6H)ppm.13CNMR(126MHz,CDCl3,):δ151.7，131.6,128.5,125.7,122.2,121.0,16.4ppm.
实施例6：
Figure BDA0002185852700000081
将1mmol2-溴苯酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：10的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-6)所示的化合物纯品47mg。1H NMR(500MHz,CDCl3),δ(ppm):7.58(dd,2H,J)8.1,1.5Hz),7.26(dd,2H,J)7.6Hz,1.5Hz),6.96(t,2H,J＝8.1Hz),5.94(s,2H).13C NMR(126MHz,CDCl3),δ(ppm):149.5,132.4,131.1,125.6,122.0,111.4.
实施例7：
Figure BDA0002185852700000091
将1mmol2萘酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：15的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-7)所示的化合物纯品55mg。1H NMR(500MHz,DMSO)δ9.22(s,1H),7.86(dd,J＝8.3,5.5Hz,2H),7.34(d,J＝8.9Hz,1H),7.26–7.22(m,1H),7.17(td,J＝8.1,6.8,1.2Hz,1H),6.96(d,J＝8.4Hz,1H).13C NMR(126MHz,DMSO)δ153.00(s),134.13(s),128.64(s),128.13(s),127.85(s),125.82(s),124.40(s),122.27(s),118.54(s),115.41(s).
实施例8：
Figure BDA0002185852700000092
将1mmol2，7-二羟基萘酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：5的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-8)所示的化合物纯品29mg。1H NMR(500MHz,DMSO)δ9.21(s,1H),8.95(s,1H),7.69(dd,J＝8.7,6.7Hz,2H),7.08(d,J＝8.8Hz,1H),6.80(dd,J＝8.8,2.4Hz,1H),6.30(d,J＝2.3Hz,1H).13C NMR(126MHz,DMSO)δ155.42(s),153.23(s),136.01(s),129.40(s),128.25(s),123.06(s),115.30(s),114.83(s),114.34(s),106.23(s).
实施例9：
Figure BDA0002185852700000101
将1mmol 2，6-二羟基萘酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：3的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-9)所示的化合物纯品33mg。1H NMR(500MHz,MeOD)δ7.68(d,J＝8.9Hz,1H),7.23(d,J＝8.9Hz,1H),7.15(d,J＝2.4Hz,1H),6.93(d,J＝9.1Hz,1H),6.82(dd,J＝9.1,2.5Hz,1H).13C NMR(126MHz,MeOD)δ154.07(s),151.87(s),131.67(s),130.41(s),128.80(s),127.44(s),119.63(s),119.26(s),116.49(s),110.53(s).
实施例10：
Figure BDA0002185852700000111
将1mmol6-溴2-萘酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：3的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式所示的化合物纯品33mg。1H NMR(500MHz,CDCl3)δ7.93(d,J＝8.9Hz,1H),7.75(d,J＝8.7Hz,1H),7.47(dd,J＝8.7,1.9Hz,1H),7.37(d,J＝8.9Hz,1H),7.24(d,J＝1.8Hz,1H),5.36(s,1H).13C NMR(126MHz,CDCl3)δ153.62(s),134.74(s),131.53(s),130.11(s),127.88(s),127.64(s),126.01(s),122.34(s),118.34(s),109.89(s).
实施例11：
Figure BDA0002185852700000112
将1mmol7-溴-2萘酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：3的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-11)所示的化合物纯品31mg。1H NMR(500MHz,DMSO)δ9.54(s,1H),8.13(d,J＝2.1Hz,1H),7.88(d,J＝8.9Hz,1H),7.38(d,J＝8.9Hz,1H),7.33(dd,J＝9.0,2.1Hz,1H),6.88(d,J＝9.0Hz,1H).13C NMR(126MHz,DMSO)δ153.61(s),132.63(s),129.65(s),129.36(s),128.91(s),128.25(s),126.60(s),119.75(s),115.28(s),115.10(s).
实施例12：
Figure BDA0002185852700000121
将1mmol 6-甲氧基-2萘酚加入4ml的水溶中(含有2％Triton-X-100表面活性剂)，向其中加入0.2mmol醋酸铜，1.0mmol过硫酸钾，1.0mmol乙酸银，常温下反应12小时，反应结束后，反应液中加入饱和NaCl水溶液，用二氯甲烷萃取，取有机层经过无水硫酸钠干燥、过滤、减压蒸干，即得化合物粗品。将化合物粗品进硅胶柱层析，以乙酸乙酯和石油醚的体积比为1：3的溶液为流动相，TLC跟踪收集Rf值为0.3-0.5的洗脱液，收集得到的洗脱液经减压除去溶剂，干燥，得到式(II-12)所示的化合物纯品30mg。1H NMR(500MHz,CDCl3)δ7.89(d,J＝8.8Hz,1H),7.80(d,J＝8.9Hz,1H),7.24(d,J＝8.9Hz,1H),7.05(dd,J＝8.9,2.5Hz,1H),6.50(d,J＝2.5Hz,1H),5.12(s,1H),3.59(s,3H).13C NMR(126MHz,CDCl3)δ159.14(s),153.36(s),134.75(s),131.12(s),130.01(s),124.81(s),116.04(s),115.14(s),110.13(s),103.21(s),55.16(s).
实施例12：抗肿瘤活性检测
将肿瘤细胞HeLa接种4000个细胞/瓶至含有10％胎牛血清的DMEM高汤培养液的细胞培养瓶中，置于5％CO2、37℃的培养箱中培养3天、取出细胞培养瓶在无菌操作台中收集细胞。将细胞以4000个/孔的浓度接种至含有10％胎牛血清的DMEM高汤培养液的96孔板中，并在板盖上加上注释，于5％CO2、37℃培养12小时，待细胞在96孔板上贴壁，在无菌操作台中用移液枪加待测药物(实施例1制备的化合物(II-1))，使每孔药物浓度分别为0.01、0.1、1、10.0、100.0μM五个浓度梯度，每个浓度设置有五个平行组，以雌激素酮作为对照)，并再次将96孔板置于5％CO2、37℃培养24小时。取出96孔板，向每个孔中加入20μL的MTS试剂盒试剂(购自Promega公司)，避光孵化40分钟，利用酶标仪测其吸光度。从而计算出细胞抑制率和细胞毒性，用ICEstimator software软件处理，计算IC50以及IC50 95％可信区间，结果见图4所示(图中1Z为雌激素酮，2Z-1为化合物(II-1))。由图可见，偶联化合物(II-1)对HeLa的抑制毒性相对于雌激素酮提高了约3.5倍。

Claims (1)

1.结构如（II-1）所示双芳基衍生物在制备抗肿瘤药物中的应用：
Figure QLYQS_1
（II-1）
所述抗肿瘤药物为抑制肿瘤细胞HeLa细胞毒性的药物。
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