CN112174901A - 1,3-苯二氮卓类化合物的合成方法及抗癌活性 - Google Patents

1,3-苯二氮卓类化合物的合成方法及抗癌活性 Download PDF

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CN112174901A
CN112174901A CN202011229687.8A CN202011229687A CN112174901A CN 112174901 A CN112174901 A CN 112174901A CN 202011229687 A CN202011229687 A CN 202011229687A CN 112174901 A CN112174901 A CN 112174901A
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范学森
周倩婷
宋霞
张新迎
姜玉钦
赵杰
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Henan Normal University
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Abstract

本发明公开了一种具有抗癌活性的1,3‑苯二氮卓类化合物及其合成方法，属于药物开发技术领域。1,3‑苯二氮卓类化合物，结构通式为：
Figure DDA0002764769760000011
合成方法为：将N‑芳基脒1、炔丙醇酯类化合物2、铑或钌催化剂、添加剂和有机溶剂混合，升温反应得到1,3‑苯二氮卓类化合物3。本发明合成方法具有原料简单易得、操作简便、条件温和、底物适用范围广等优点，该类化合物具有显著的HeLa或Ramos等癌细胞抑制活性，为潜在的候选药物分子结构。

Description

1,3-苯二氮卓类化合物的合成方法及抗癌活性
技术领域
本发明属于有机合成和药物发现技术领域，具体涉及1,3-苯二氮卓类化合物的合成方法及抗癌活性。
背景技术
众所周知，多种1,3-苯二氮卓类化合物都具有显著的抗癌、镇痛和缓解抑郁等药物活性，并已在临床得到广泛应用，对保障生命健康和提高生活质量作出了重要贡献，然而现有1,3-苯二氮卓类化合物活性研究真正应用临床，并成功上市的药物并不多。
因此，研究并开发新1,3-苯二氮卓类化合物的抗癌类候选药物，找到比现有药物类具有更好活性，然后再进行结构改造，从而筛选出更具潜力的药物分子结构仍然非常值得期待。
同时，1,3-苯二氮卓类化合物的合成发展了一些可靠的方法，但这些方法往往存在原料不易得到、合成路线长、产物结构单一和原子经济性低等问题。采用从简单易得的原料出发，开发经过简便的步骤即可合成1,3-苯二氮卓类化合物的绿色高效新方法，具有十分重要的理论意义和实用前景。
发明内容
为了克服上述技术缺陷，本发明首先提供了一类新的1,3-苯二氮卓类化合物，并研究了其抗癌活性。其次还提供了1,3-苯二氮卓类化合物的合成方法，通过N-芳基脒和炔丙醇酯类化合物之间发生的串联反应，可以高效合成1,3-苯二氮卓类化合物，合成方法具有原料简单易得、操作简便、条件温和、底物适用范围广等优点，该类化合物具有显著的抗癌活性，为潜在的候选药物分子结构。
本发明所提供的具有抗癌活性的1,3-苯二氮卓类化合物，其结构通式为：
Figure BDA0002764769740000011
其中，R1为氢、卤素、C1-4烷基、C1-4烷氧基、C1-4烷硫基、取代苯基、取代苯乙炔基或取代苯氧基，取代苯基苯环上的取代基为氢、C1-4烷基、C1-4烷氧基或卤素；R2为C1-4烷基、C3-6环烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素；R3为噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、卤素、硝基或苯基；R4和R5各自独立为氢、苯基、C1-4烷基、C3-6环烷基或共同组成C5-6环烷基。
本发明还提供了上述结构3化合物在抗癌活性药物中的应用。
进一步地，在上述技术方案中，所述抗癌活性是指抗REC-1、HeLa、Ramos和A549等四种癌细胞活性。
在上述四种癌细胞活性实验中，以HeLa和Ramos癌细胞抑制效果最佳。具体而言，在HeLa癌细胞实验中，3c和3d结果最佳。在Ramos癌细胞实验中3w、3y、3bb、3cc和3ee结果最佳。根据以上结果，上述分子可以作为继续药物筛选的分子进行进一步结构细微修饰。
本发明还提供了上述1,3-苯二氮卓类化合物的合成方法，采用的技术方案为：
1,3-苯二氮卓类化合物的合成方法，包括如下操作：将N-芳基脒1、炔丙醇酯类化合物2、铑或钌催化剂、添加剂和有机溶剂混合，升温反应得到1,3-苯二氮卓类化合物3，反应方程式为：
Figure BDA0002764769740000021
其中，R1为氢、卤素、C1-4烷基、C1-4烷氧基或C1-4烷硫基；R2为C1-4烷基、C3-6环烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素；R3为噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、卤素、硝基或苯基；R4和R5各自独立为氢、苯基、C1-4烷基、C3-6环烷基或共同组成C5-6环烷基。
进一步地，在上述技术方案中，所述反应溶剂为起到溶解原料的作用，优选1,2-二氯乙烷、乙腈、丙酮、甲醇、乙醇或2,2,2-三氟乙醇。
进一步地，在上述技术方案中，所述铑或钌催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体{简称[RhCp*Cl2]2}、五甲基环戊二烯基醋酸铑(III){简称RhCp*(OAc)2}或二氯双(4-甲基异丙基苯基)钌(II){简称[Ru(p-cymene)Cl2]2}。采用其他催化剂，例如CoCp*(CO)I2、[IrCp*Cl2]2等时，反应未检测到产物生成。
进一步地，在上述技术方案中，所述添加剂为乙酸银、六氟锑酸银、碳酸银、醋酸铜或醋酸铜一水合物。
进一步地，在上述技术方案中，所述加热反应温度为70-120℃。
进一步地，在上述技术方案中，所述的N-芳基脒1、炔丙醇酯类化合物2、添加剂和铑或钌催化剂的投料摩尔比为1-2:1-2:0.1-1:0.01-0.07。
发明有益效果：
本发明与现有技术相比具有以下优点：1)合成过程简单、高效，通过N-芳基脒和炔丙醇酯类化合物的一锅串联反应，即可合成1,3-苯二氮卓类化合物；2)原料价廉易得，反应条件温和，操作简便，底物的适用范围广；3)1,3-苯二氮卓类化合物具有显著的抗癌活性，因此具有潜在的药用价值。
说明书附图
图1为实施例3中化合物3jj的X-单晶衍射图；
图2为实施例3中化合物3pp的X-单晶衍射图。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
Figure BDA0002764769740000031
向15mL反应瓶中，依次加入化合物1a、溶剂、催化剂、添加剂和化合物2a，盖上塞子密封，将其置于油浴中升温搅拌反应。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝300/1)得黄色固体产物3a。
通过改变反应的催化剂、添加剂、有机溶剂、反应物之间的当量比和反应温度等反应条件，得到一系列的结果，见表1。
表1不同条件下3a的合成a
Figure BDA0002764769740000032
Figure BDA0002764769740000041
实施例2
Figure BDA0002764769740000042
向15mL反应瓶中，依次加入1a(53mg,0.3mmol)、甲醇(1mL)、二氯(五甲基环戊二烯基)合铑(III)二聚体(5.6mg,0.009mmol)、醋酸铜一水合物(15mg,0.075mmol)和化合物2a(72.8mg,0.36mmol)，盖上塞子密封，将其置于90℃油浴中搅拌反应5h。待反应结束后，冷却至室温，抽滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝300/1)得黄色固体产物3a(68.4mg,72％)。该化合物的表征数据为：1H NMR(400MHz,CDCl3)δ1.27(s,9H),1.60(s,3H),1.68(s,3H),7.09-7.15(m,2H),7.21(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.29-7.35(m,4H),7.93-7.95(m,2H).13C NMR(100MHz,CDCl3)δ19.8,21.5,28.4,39.7,125.7,127.0,127.7,128.1,128.7,128.9,129.9,130.7,131.4,131.8,135.7,145.3,165.1,172.1.HRMS calcd forC22H25N2:317.2012[M+H]+,found:317.2012.
实施例3
依照实施例2的方法和步骤a,b，通过改变反应物1和反应物2，合成出系列1,3-苯二氮卓类化合物3a-3z和3aa-3qq，具体结果如下：
Figure BDA0002764769740000051
Figure BDA0002764769740000061
a反应条件：1(0.3mmol)，2(0.36mmol)，[RhCp*Cl2]2(3mol％)，Cu(OAc)2·H2O(25mol％)，MeOH(1mL)，90℃，5h；b分离收率；c用AgOAc(25mol％)和NaHCO3(0.3mmol)替代Cu(OAc)2·H2O(25mol％)，10h。
______________________________________________________________
代表性产物表征数据如下：
2-(tert-Butyl)-7-methyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3b)
Yellow oil(66.4mg,67％).1H NMR(400MHz,CDCl3)δ1.33(s,9H),1.66(s,3H),1.75(s,3H),2.33(s,3H),6.96(s,1H),7.09(dd,J1＝8.4Hz,J2＝1.6Hz,1H),7.29(d,J＝8.0Hz,1H),7.38-7.43(m,3H),8.02(dd,J1＝8.0Hz,J2＝2.0Hz,2H).13C NMR(150MHz,CDCl3)δ19.8,21.1,21.4,28.4,39.6,126.8,127.8,128.7,128.9,129.1,129.9,130.3,131.2,131.4,135.4,135.8,143.0,164.5,171.4.HRMS calcd for C23H27N2:331.2169[M+H]+,found:331.2151.
2-(tert-Butyl)-7-ethyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3c)
Yellow solid(70.3mg,68％).1H NMR(400MHz,CDCl3)δ1.20(t,J＝7.6Hz,3H),1.33(s,9H),1.66(s,3H),1.75(s,3H),2.63(q,J＝7.6Hz,2H),6.98(s,1H),7.13(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.40-7.41(m,3H),8.02(d,J＝6.4Hz,2H).13C NMR(150MHz,CDCl3)δ15.8,19.8,21.4,28.40,28.43,39.6,126.6,126.9,127.9,128.7,128.9,130.1,130.4,131.2,131.4,135.9,141.9,143.1,164.6,171.5.HRMS calcd for C24H29N2:345.2325[M+H]+,found:345.2327.
2-(tert-Butyl)-7-isopropyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3d)
Yellow solid(72.1mg,67％).1H NMR(600MHz,CDCl3)δ1.22(d,J＝6.6Hz,6H),1.33(s,9H),1.66(s,3H),1.75(s,3H),2.87-2.92(m,1H),7.00(s,1H),7.16(d,J＝8.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.39-7.43(m,3H),8.02(d,J＝7.2Hz,2H).13CNMR(150MHz,CDCl3)δ19.8,21.4,24.0,24.3,28.4,33.7,39.6,125.3,126.3,126.9,128.7,128.9,130.2,130.3,131.2,131.5,136.0,143.2,146.5,164.6,171.5.HRMS calcd for C25H31N2:359.2482[M+H]+,found:359.2463.
2-(tert-Butyl)-7-methoxy-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3e)
Yellow oil(72.8mg,70％).1H NMR(600MHz,CDCl3)δ1.33(s,9H),1.66(s,3H),1.76(s,3H),3.79(s,3H),6.68(d,J＝2.4Hz,1H),6.87(dd,J1＝9.0Hz,J2＝3.0Hz,1H),7.34(d,J＝9.0Hz,1H),7.38-7.44(m,3H),8.00(d,J＝6.6Hz,2H).13C NMR(150MHz,CDCl3)δ19.8,21.4,28.4,39.6,55.6,112.0,114.1,128.3,128.7,128.8,129.7,131.22,131.25,131.7,135.8,139.3,158.0,163.7,170.6.HRMS calcd for C23H27N2O:347.2118[M+H]+,found:347.2100.
2-(tert-Butyl)-7-(methylthio)-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3f)
Yellow solid(34.8mg,32％).1H NMR(600MHz,CDCl3)δ1.33(s,9H),1.67(s,3H),1.76(s,3H),2.47(s,3H),7.07(s,1H),7.21(d,J＝8.4Hz,1H),7.33(d,J＝7.8Hz,1H),7.40-7.44(m,3H),8.00(d,J＝7.2Hz,2H).13C NMR(150MHz,CDCl3)δ16.8,19.9,21.5,28.4,39.7,126.1,127.1,127.6,128.7,128.9,129.5,130.9,131.4,132.2,135.2,135.6,143.2,164.6,172.1.HRMS calcd for C23H27N2S:363.1889[M+H]+,found:363.1870.
2-(tert-Butyl)-7-fluoro-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3g)
Yellow solid(46.2mg,46％).1H NMR(400MHz,CDCl3)δ1.33(s,9H),1.67(s,3H),1.77(s,3H),6.87(dd,J1＝8.8Hz,J2＝3.2Hz,1H),7.00(td,J1＝8.8Hz,J2＝3.2Hz,1H),7.34-7.41(m 1H),7.43-7.45(m,3H),7.97-7.99(m,2H).13C NMR(150MHz,CDCl3)δ19.8,21.4,28.3,39.7,113.6(d,2JC-F＝20.7Hz),115.4(d,2JC-F＝23.0Hz),128.6(d,3JC-F＝8.7Hz),128.8,129.0,131.6(d,3JC-F＝7.7Hz),132.8,135.5,141.8(d,4JC-F＝2.1Hz),161.1(d,1JC-F＝243.9Hz),164.4,171.8.19F NMR(565MHz,CDCl3)δ-117.81(dd,J1＝14.1Hz,J2＝7.9Hz).HRMS calcd for C22H24FN2:335.1918[M+H]+,found:335.1903.
2-(tert-Butyl)-7-chloro-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3h)
Yellow oil(61.1mg,58％).1H NMR(400MHz,CDCl3)δ1.23(s,9H),1.67(s,3H),1.77(s,3H),7.15(d,J＝2.4Hz,1H),7.23-7.25(m,1H),7.32(d,J＝8.4Hz,1H),7.41-7.46(m,3H),7.99(dd,J1＝8.4Hz,J2＝1.6Hz,2H).13C NMR(150MHz,CDCl3)δ19.8,21.5,28.3,39.8,127.2,128.3,128.4,128.8,128.9,131.1,131.6,131.7,133.0,135.3,144.0,164.9,172.7.HRMS calcd for C22H24ClN2:351.1623[M+H]+,found:351.1623.
7-Bromo-2-(tert-butyl)-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3i)
Yellow solid(78.3mg,66％).1H NMR(400MHz,CDCl3)δ1.25(s,9H),1.59(s,3H),1.69(s,3H),7.19(d,J＝8.4Hz,1H),7.23(d,J＝2.0Hz,1H),7.30-7.38(m,4H),7.90-7.92(m,2H).13C NMR(150MHz,CDCl3)δ19.9,21.5,28.3,39.8,119.0,128.70,128.75,128.8,128.9,130.1,131.2,131.7,132.1,133.0,135.3,144.4,165.0,172.8.HRMS calcd forC22H24BrN2:395.1117[M+H]+,found:395.1102.
2-(tert-Butyl)-7-iodo-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3j)
Yellow solid(83.6mg,63％).1H NMR(600MHz,CDCl3)δ1.32(s,9H),1.66(s,3H),1.76(s,3H),7.13(d,J＝8.4Hz,1H),7.40-7.46(m,3H),7.50(d,J＝1.8Hz,1H),7.57(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.98(d,J＝7.2Hz,2H).13C NMR(150MHz,CDCl3)δ19.9,21.5,28.3,39.8,90.0,128.7 128.8,128.9,129.0,131.7,132.6,133.0,135.3,136.1,137.0,145.0,165.1,172.9.HRMS calcd for C22H24IN2:443.0979[M+H]+,found:443.0981.
2-(tert-Butyl)-8-methyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3k)
Yellow oil(60.5mg,61％).1H NMR(400MHz,CDCl3)δ1.33(s,9H),1.66(s,3H),1.74(s,3H),2.32(s,3H),7.03-7.07(m,2H),7.23(s,1H),7.36-7.42(m,3H),7.99-8.01(m,2H).13C NMR(150MHz,CDCl3)δ19.7,21.1,21.4,28.4,39.6,126.7,127.3,127.5,128.0,128.7,128.9,129.8,131.3,131.4,135.8,138.0,145.1,165.0,172.1.HRMS calcd forC23H27N2:331.2169[M+H]+,found:331.2167.
2-(tert-Butyl)-8-chloro-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3l)
Yellow solid(61.1mg,58％).1H NMR(400MHz,CDCl3)δ1.32(s,9H),1.67(s,3H),1.74(s,3H),7.09(d,J＝8.4Hz,1H),7.18(dd,J1＝8.4Hz,J2＝2.4Hz,1H),7.37-7.44(m,4H),7.97-7.99(m,2H).13C NMR(150MHz,CDCl3)δ19.8,21.5,28.3,39.8,125.7,126.8,128.80,128.84,128.9,129.0,129.1,131.6,132.7,133.6,135.3,146.4,165.3,173.4.HRMS calcd for C22H24ClN2:351.1623[M+H]+,found:351.1623.
2-(tert-Butyl)-9-chloro-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3m)
Yellow solid(37.9mg,36％).1H NMR(600MHz,CDCl3)δ1.29(s,9H),1.60(s,3H),1.68(s,3H),7.00(d,J＝7.2Hz,1H),7.04(t,J＝7.8Hz,1H),7.28-7.37(m,4H),7.92(d,J＝7.8Hz,2H).13C NMR(150MHz,CDCl3)δ19.9,21.5,28.3,40.1,126.1,126.4,128.8,128.9,129.0,129.2,131.6,131.7,132.80.132.82,135.4,142.1,165.7,172.9.HRMS calcd forC22H24ClN2:351.1623[M+H]+,found:351.1622.
2-Cyclohexyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3n)
Yellow oil(49.3mg,48％).1H NMR(400MHz,CDCl3)δ1.28-1.51(m,5H),1.61-1.65(m,1H),1.68(s,3H),1.74(s,3H),1.80-1.86(m,3H),2.14-2.17(m,1H),2.56-2.63(m,1H),7.17(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.22(td,J1＝7.6Hz,J2＝1.2Hz,1H),7.30(td,J1＝8.0Hz,J2＝2.0Hz,1H),7.37-7.46(m,4H),8.01-8.03(m,2H).13C NMR(150MHz,CDCl3)δ19.8,21.5,25.9,26.1,26.2,29.7,31.3,48.0,125.9,126.8,127.8,128.2,128.7,129.0,130.0,130.9,131.5,132.0,135.5,145.0,165.8,170.0.HRMS calcd for C24H27N2:343.2169[M+H]+,found:343.2159.
2-Isopropyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3o)
Yellow oil(56.2mg,62％).1H NMR(400MHz,CDCl3)δ1.19(d,J＝6.4Hz,3H),1.38(d,J＝6.8Hz,3H),1.68(s,3H),1.75(s,3H),2.86-2.93(m,1H),7.18(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.23(td,J1＝7.6Hz,J2＝1.6Hz,1H),7.30(td,J1＝8.0Hz,J2＝1.6Hz,1H),7.38-7.44(m,4H),8.01-8.04(m,2H).13C NMR(100MHz,CDCl3)δ19.6,19.8,21.2,21.5,38.1,126.0,126.8,127.8,128.2,128.7,129.0,129.9,130.9,131.6,132.1,135.5,145.0,166.1,170.7.HRMS calcd for C21H23N2:303.1856[M+H]+,found:303.1856.
2-Isopropyl-7-methyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3p)
Yellow oil(55.0mg,58％).1H NMR(600MHz,CDCl3)δ1.10(d,J＝6.6Hz,3H),1.31(d,J＝7.2Hz,3H),1.60(s,3H),1.67(s,3H),2.27(s,3H),2.78-2.83(m,1H),6.89(s,1H),7.03(d,J＝8.4Hz,1H),7.23(d,J＝7.8Hz,1H),7.32-7.38(m,3H),7.95(d,J＝7.8Hz,2H).13C NMR(100MHz,CDCl3)δ19.6,19.8,21.1,21.3,21.4,38.1,126.7,127.8,128.7,129.0,129.2,129.9,130.5,131.4,131.7,135.6,135.8,142.7,165.5,170.0.HRMS calcd forC22H25N2:317.2012[M+H]+,found:317.2009.
7-Chloro-2-isopropyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3q)
Yellow solid(52.6mg,52％).1H NMR(600MHz,CDCl3)δ1.11(d,J＝7.2Hz,3H),1.29(d,J＝6.6Hz,3H),1.61(s,3H),1.69(s,3H),2.78-2.83(m,1H),7.08(s,1H),7.18-7.19(m,1H),7.26(d,J,＝8.4Hz,1H),7.34-7.41(m,3H),7.93(d,J＝7.8Hz,2H).13C NMR(100MHz,CDCl3)δ19.5,19.9,21.1,21.5,38.1,127.3,128.2,128.4,128.8,128.9,129.0,131.4,131.8,131.9,133.3,135.1,143.7,165.9,171.2.HRMScalcd for C21H22ClN2:337.1466[M+H]+,found:337.1467.
2-Cyclopropyl-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3r)
Yellow solid(40.6mg,45％).1H NMR(400MHz,CDCl3)δ0.83-0.93(m,2H),0.97-1.02(m,1H),1.34-1.39(m,1H),1.68(s,3H),1.76(s,3H),1.92-1.97(m,1H),7.16(d,J＝7.6Hz,1H),7.22(t,J＝7.6Hz,1H),7.28-7.32(m,1H),7.37-7.46(m,4H),7.96(d,J＝7.2Hz,2H).13C NMR(100MHz,CDCl3)δ7.02,8.49,19.2,19.8,21.5,125.8,126.7,127.9,128.3,128.7,129.0,129.8,130.4,131.7,132.5,135.4,145.2,166.86,166.89.HRMScalcd for C21H21N2:301.1699[M+H]+,found:301.1687.
2,4-Diphenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3s)
Yellow solid(33.3mg,33％).1H NMR(400MHz,CDCl3)δ1.66(s,3H),1.75(s,3H),7.24(s,1H),7.30(t,J＝7.2Hz,1H),7.37(t,J＝7.6Hz,1H),7.42-7.48(m,6H),7.58(d,J＝8.0Hz,1H),8.15(d,J＝7.2Hz,2H),8.26-8.27(m,2H).13C NMR(100MHz,CDCl3)δ19.9,21.6,126.7,127.8,128.0,128.1,128.3,128.4,128.8,129.2,130.0,130.1,130.4,131.8,132.8,135.6,138.0,145.6,159.4,166.1.HRMS calcd for C24H21N2:337.1699[M+H]+,found:337.1698.
7-Chloro-2,4-diphenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3t)
Yellow solid(35.6mg,32％).1H NMR(400MHz,CDCl3)δ1.66(s,3H),1.77(s,3H),7.22(d,J＝2.4Hz,1H),7.32(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.44-7.51(m,7H),8.13(dd,J1＝8.4Hz,J2＝1.6Hz,2H),8.22-8.25(m,2H).13C NMR(150MHz,CDCl3)δ19.9,21.6,127.5,128.0,128.3,128.7,129.0,129.20,129.23,130.6,130.9,132.0,132.1,134.0,135.3,137.7,144.3,159.7,165.9.HRMS calcd for C24H20ClN2:371.1310[M+H]+,found:371.1298.
7-Bromo-2,4-diphenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3u)
Yellow solid(37.4mg,30％).1H NMR(400MHz,CDCl3)δ1.66(s,3H),1.77(s,3H),7.38(s,1H),7.42-7.51(m,8H),8.13(d,J＝7.6Hz,2H),8.22-8.25(m,2H).13CNMR(100MHz,CDCl3)δ20.0,21.6,120.0,128.0,128.3,128.9,129.0,129.2,129.5,130.5,130.6,131.3,131.5,132.1,134.0,135.2,137.7,144.7,159.8,166.0.HRMScalcd for C24H20BrN2:415.0804[M+H]+,found:415.0803.
7-Chloro-2-(4-chlorophenyl)-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3v)
Yellow solid(37.7mg,31％).1H NMR(400MHz,CDCl3)δ1.65(s,3H),1.77(s,3H),7.22(s,1H),7.32(dd,J1＝8.8Hz,J2＝1.2Hz,1H),7.42-7.51(m,6H),8.11(d,J＝7.6Hz,2H),8.18(d,J＝8.0Hz,2H).13C NMR(150MHz,CDCl3)δ19.9,21.6,127.6,128.5,128.8,128.9,129.0,129.2,129.3,129.4,130.8,132.2,132.4,134.1,135.1,136.2,136.7,144.1,158.6,166.2.HRMS calcd for C24H19Cl2N2:405.0920[M+H]+,found:405.0910.
7-Bromo-2-(4-bromophenyl)-4-phenyl-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3w)
Yellow solid(51.9mg,35％).1H NMR(400MHz,CDCl3)δ1.65(s,3H),1.77(s,3H),7.37-7.43(m,2H),7.47-7.52(m,4H),7.59(d,J＝8.4Hz,2H),8.11(d,J＝7.6Hz,4H).13CNMR(150MHz,CDCl3)δ20.0,21.6,120.4,125.3,128.8,129.0,129.3,129.5,129.6,130.5,131.2,131.5,131.6,132.2,134.2,135.0,136.7,144.5,158.8,166.4.HRMS calcd forC24H19Br2N2:492.9910[M+H]+,found:492.9894.
2-(tert-Butyl)-5-(propan-2-ylidene)-4-(p-tolyl)-5H-benzo[d][1,3]diazepine(3x)
Yellow oil(63.4mg,64％).1H NMR(400MHz,CDCl3)δ1.33(s,9H),1.67(s,3H),1.74(s,3H),2.36(s,3H),7.14-7.21(m,4H),7.25-7.29(m,1H),7.39(dd,J1＝8.0Hz,J2＝0.8Hz,1H),7.90(d,J＝8.0Hz,2H).13C NMR(150MHz,CDCl3)δ19.7,21.4,21.5,28.4,39.7,125.6,126.9,127.7,128.0,128.9,129.5,130.0,130.8,131.4,133.0,141.9,145.3,165.0,172.2.HRMS calcd for C23H27N2:331.2169[M+H]+,found:331.2169.
2-(tert-Butyl)-4-(4-methoxyphenyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3y)
Yellow solid(67.6mg,65％).1H NMR(400MHz,CDCl3)δ1.25(s,9H),1.60(s,3H),1.66(s,3H),3.74(s,3H),6.80-6.83(m,2H),7.06(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.11(td,J1＝7.6Hz,J2＝1.6Hz,1H),7.17-7.21(m,1H),7.31(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.87-7.90(m,2H).13C NMR(150MHz,CDCl3)δ19.7,21.4,28.4,39.7,55.4,114.1,125.5,126.9,172.7,128.0,128.3,130.1,130.75,130.79,131.3,145.4,162.3,164.5,172.3.HRMScalcd for C23H27N2O:347.2118[M+H]+,found:347.2115.
2-(tert-Butyl)-4-(4-fluorophenyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3z)
Yellow solid(50.2mg,50％).1H NMR(600MHz,CDCl3)δ1.33(s,9H),1.67(s,3H),1.75(s,3H),7.07(t,J＝9.0Hz,2H),7.15(d,J＝7.2Hz,1H),7.21(t,J＝7.2Hz,1H),7.29(t,J＝7.2Hz,1H),7.40(d,J＝7.8Hz,1H),8.00-8.02(m,2H).13C NMR(150MHz,CDCl3)δ19.7,21.4,28.4,39.7,115.8(d,2JC-F＝21.9Hz),125.8,127.0,127.6.128.2,129.8,130.5,131.1(d,3JC-F＝8.9Hz),131.9(d,4JC-F＝2.1Hz),132.0,145.2,163.8,164.9(d,1JC-F＝250.5Hz),171.9.19F NMR(565MHz,CDCl3)δ-108.35–-108.40(m).HRMS calcd forC22H24FN2:335.1918[M+H]+,found:335.1914.
2-(tert-Butyl)-4-(4-chlorophenyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3aa)
Yellow solid(66.3mg,63％).1H NMR(400MHz,CDCl3)δ1.33(s,9H),1.66(s,3H),1.75(s,3H),7.13-7.15(m,1H),7.21(t,J＝7.2Hz,1H),7.28-7.32(m,1H),7.35-7.41(m,3H),7.94(d,J＝8.8Hz,2H).13C NMR(150MHz,CDCl3)δ19.7,21.4,28.3,39.7,125.8,127.0,127.6,128.2,129.0,129.6,130.1,130.4,132.1,134.2,137.6,145.2,163.8,171.9.HRMScalcd for C22H24ClN2:351.1623[M+H]+,found:351.1617.
2-(tert-butyl)-4-(4-nitrophenyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3bb)
Yellow solid(59.6mg,55％).1H NMR(400MHz,CDCl3)δ1.35(s,9H),1.67(s,3H),1.78(s,3H),7.19(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.24-7.28(m,1H),7.33(td,J1＝8.0Hz,J2＝1.6Hz,1H),7.44(dd,J1＝8.0Hz,J2＝1.2Hz,1H),8.14-8.17(m,2H),8.23-8.26(m,2H).13C NMR(150MHz,CDCl3)δ19.7,21.5,28.3,39.8,123.9,126.3,127.3,127.6,128.5,129.2,129.6,130.0,133.1,141.5,145.1,149.4,162.6,171.4.HRMS calcd forC22H24N3O2:362.1863[M+H]+,found:362.1846.
4-([1,1'-Biphenyl]-4-yl)-2-(tert-butyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3cc)
Yellow solid(77.7mg,66％).1H NMR(400MHz,CDCl3)δ1.27-1.28(m,9H),1.63(s,3H),1.68(s,3H),7.11-7.14(m,2H),7.18-7.22(m,1H),7.27-7.28(m,1H),7.32-7.37(m,3H),7.49-7.54(m,4H),7.98-8.00(m,2H).13C NMR(150MHz,CDCl3)δ19.8,21.6,28.4,39.8,125.7,127.0,127.2,127.4,127.8,127.9,128.2,128.9,129.4,130.0,130.7,131.8,134.6,140.3,144.1,145.3,164.6,172.1.HRMS calcd for C28H29N2:393.2325[M+H]+,found:393.2334.
2-(tert-Butyl)-5-(propan-2-ylidene)-4-(m-tolyl)-5H-benzo[d][1,3]diazepine(3dd)
Yellow solid(65.4mg,66％).1H NMR(400MHz,CDCl3)δ1.34(s,9H),1.67(s,3H),1.74(s,3H),2.38(s,3H),7.16-7.23(m,3H),7.25-7.30(m,2H),7.39(d,J＝7.6Hz,1H),7.78(d,J＝7.2Hz,1H),7.82(s,1H).13C NMR(150MHz,CDCl3)δ19.7,21.47,21.5,28.4,39.7,125.6,126.3,126.9,127.7,128.1,128.6,129.1,130.1,130.8,131.6,132.2,135.7,138.4,145.3,165.3,172.1.HRMS calcd for C23H27N2:331.2169[M+H]+,found:331.2160.
2-(tert-Butyl)-4-(3-chlorophenyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3ee)
Yellow solid(75.8mg,72％).1H NMR(400MHz,CDCl3)δ1.34(s,9H),1.67(s,3H),1.75(s,3H),7.16(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.23(td,J1＝7.6Hz,J2＝1.2Hz,1H),7.28-7.34(m,2H),7.38-7.42(m,2H),7.86(td,J1＝6.4Hz,J2＝1.2Hz,1H),7.97-7.98(m,1H).13C NMR(100MHz,CDCl3)δ19.7,21.5,28.3,39.7,125.9,127.1,127.7,128.3,128.6,129.5,130.0,130.3,131.3,132.4,134.9,137.6,145.1,163.6,171.7.HRMS calcd forC22H24ClN2:351.1623[M+H]+,found:351.1624.
2-(tert-Butyl)-5-(propan-2-ylidene)-4-(o-tolyl)-5H-benzo[d][1,3]diazepine(3ff)
Yellow solid(35.7mg,36％).1H NMR(400MHz,CDCl3)δ1.27(s,9H),1.56(s,3H),1.64(s,3H),2.64(s,3H),7.12-7.18(m,4H),7.19-7.23(m,2H),7.33-7.35(m,1H),7.70-7.72(m,1H).13C NMR(150MHz,CDCl3)δ19.8,20.9,23.8,28.4,39.6,125.7,125.9,127.1,127.8,128.0,130.1,131.0,131.4,131.8,132.3,135.3,139.4,145.0,167.3,171.6.HRMScalcd for C23H27N2:331.2169[M+H]+,found:331.2160.
2-(tert-Butyl)-5-(propan-2-ylidene)-4-(thiophen-2-yl)-5H-benzo[d][1,3]diazepine(3gg)
Yellow solid(69.7mg,72％).1H NMR(400MHz,CDCl3)δ1.31(s,9H),1.75(s,3H),1.78(s,3H),7.02-7.04(m,1H),7.09-7.11(m,1H),7.19(td,J1＝7.6Hz,J2＝1.2Hz,1H),7.28(td,J1＝8.0Hz,J2＝1.6Hz,1H),7.38(d,J＝8.0Hz,1H),7.43(dd,J1＝4.8Hz,J2＝1.2Hz,1H),7.53(dd,J1＝4.0Hz,J2＝1.2Hz,1H).13C NMR(150MHz,CDCl3)δ19.8,21.7,28.3,39.7,125.7,127.0,127.8,128.0,128.2,130.1,130.4,131.6,131.7,132.5,142.4,145.2,159.9,171.7.HRMS calcd for C20H23N2S:323.1576[M+H]+,found:323.1574.
2-(tert-Butyl)-5-(pentan-3-ylidene)-4-phenyl-5H-benzo[d][1,3]diazepine(3hh)
Yellow solid(78.5mg,76％).1H NMR(400MHz,CDCl3)δ0.81-0.87(m,6H),1.28(s,9H),1.96-2.06(m,3H),2.10-2.17(m,1H),7.13-7.14(m,2H),7.20-7.24(m,1H),7.30-7.36(m,4H),7.95-7.97(m,2H).13C NMR(100MHz,CDCl3)δ11.9,13.1,22.0,24.7,28.6,39.6,125.8,126.9,127.4,128.0,128.6,128.9,129.2,130.2,131.4,136.0,142.3,145.3,164.4,171.9.HRMS calcd for C24H29N2:345.2325[M+H]+,found:345.2321.
2-(tert-Butyl)-5-cyclopentylidene-4-phenyl-5H-benzo[d][1,3]diazepine(3ii)
Yellow solid(69.9mg,68％).1H NMR(400MHz,CDCl3)δ1.34(s,9H),1.50-1.61(m,2H),1.62-1.75(m,2H),2.00-2.19(m,3H),2.55-2.63(m,1H),7.17-7.30(m,3H),7.37-7.45(m,4H),8.03(dd,J1＝8.8Hz,J2＝1.6Hz,2H).13C NMR(100MHz,CDCl3)δ26.1,26.2,28.4,30.2,31.4,39.8,125.8,126.6,127.1,127.3,128.1,128.7,129.0,131.4,131.7,135.6,144.4,144.8,166.0,172.1.HRMS calcd for C24H27N2:343.2169[M+H]+,found:343.2166.
2-(tert-Butyl)-5-cyclohexylidene-4-phenyl-5H-benzo[d][1,3]diazepine(3jj)
Yellow solid(80.2mg,75％).1H NMR(400MHz,CDCl3)δ1.28-1.34(m,11H),1.38-1.59(m,4H),1.96-2.05(m,2H),2.08-2.19(m,2H),7.05-7.07(m 1H),7.12(td,J1＝7.6Hz,J2＝1.2Hz,1H),7.20(td,J1＝8.0Hz,J2＝1.6Hz,1H),7.29-7.35(m,4H),7.94-7.97(m,2H).13C NMR(100MHz,CDCl3)δ26.4,27.6,28.2,28.6,29.9,32.1,39.6,125.6,126.8,127.0,127.8,128.1,128.6,128.8,130.2,131.4,136.1,139.2,145.5,164.7,172.1.HRMS calcdfor C25H29N2:357.2325[M+H]+,found:357.2315.
2-(tert-Butyl)-5-cyclohexylidene-4-(p-tolyl)-5H-benzo[d][1,3]diazepine(3kk)
Yellow solid(62.2mg,56％).1H NMR(400MHz,CDCl3)δ1.35-1.40(m,11H),1.47-1.65(m,4H),2.07-2.14(m,2H),2.17-2.26(m,2H),2.36(s,3H),7.11(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.16-7.19(m,3H),7.24-7.29(m,1H),7.39(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.92(d,J＝8.4Hz,2H).13C NMR(100MHz,CDCl3)δ21.5,26.4,27.6,28.2,28.6,29.8,32.0,39.6,125.5,126.91,126.93,127.8,128.0,128.9,129.4,130.2,133.3,138.9,141.9,145.5,164.6,172.2.HRMS calcd for C26H31N2:371.2482[M+H]+,found:371.2486.
(Z)-5-Benzylidene-2-(tert-butyl)-4-phenyl-5H-benzo[d][1,3]diazepine(3ll)
Yellow solid(64.5mg,59％).1H NMR(400MHz,CDCl3)δ1.30(s,9H),6.44(s,1H),7.05-7.10(m,7H),7.25-7.29(m,1H),7.34-7.43(m,4H),8.07-8.09(m,2H).13CNMR(100MHz,CDCl3)δ28.6,39.9,126.4,126.9,127.6,128.1,128.3,128.68,128.7,128.9,129.0,129.3,129.6,131.8,134.7,135.0,135.5,145.3,164.6,172.6.HRMS calcd for C26H25N2:365.2012[M+H]+,found:365.2003.
(Z)-2-(tert-Butyl)-5-ethylidene-4-phenyl-5H-benzo[d][1,3]diazepine(3mm)
Yellow solid(27.2mg,30％).1H NMR(400MHz,CDCl3)δ1.35(s,9H),1.79(d,J＝6.8Hz,3H),5.74(q,J＝7.2Hz,1H),7.18(dd,J1＝7.6Hz,J2＝1.6Hz,1H),7.21-7.23(m,1H),7.30-7.34(m,1H),7.38-7.47(m,4H),8.05-8.07(m,2H).13CNMR(100MHz,CDCl3)δ13.7,28.5,39.8,125.7,125.9,127.4,127.6,128.5,128.6,129.0,129.5,131.5,135.7,136.1,145.1,165.8,172.3.HRMS calcd for C21H23N2:303.1856[M+H]+,found:303.1848.
2-(tert-Butyl)-5-(propan-2-ylidene)-4-(p-tolyl)-5H-benzo[d][1,3]diazepine(3nn)Yellow solid(35.7mg,34％).1H NMR(400MHz,CDCl3)δ1.65(s,3H),1.74(s,3H),2.42(s,3H),7.23-7.31(m,4H),7.36(t,J＝7.6Hz,1H),7.42-7.48(m,3H),7.56(d,J＝8.0Hz,1H),8.13-8.16(m,4H).13C NMR(100MHz,CDCl3)δ19.9,21.5,21.6,126.4,127.7,127.9,128.1,128.4,128.8,129.0,129.2,130.0,130.1,131.7,132.7,135.3,135.7,140.6,145.6,159.5,166.0.HRMS calcd for C25H23N2:351.1856[M+H]+,found:351.1856.
2-(tert-Butyl)-4-(4-chlorophenyl)-5-(propan-2-ylidene)-5H-benzo[d][1,3]diazepine(3oo)
Yellow oil(25.6mg,23％).1H NMR(400MHz,CDCl3)δ1.65(s,3H),1.75(s,3H),7.22(dd,J1＝7.6Hz,J2＝1.2Hz,1H),7.31(td,J1＝7.6Hz,J2＝1.2Hz,1H),7.37-7.39(m,1H),7.41-7.43(m,2H),7.46-7.49(m,3H),7.58(dd,J1＝8.0Hz,J2＝1.2Hz,1H),8.06-8.09(m,2H),8.22-8.25(m,2H).13C NMR(150MHz,CDCl3)δ19.9,21.6,126.8,127.90,127.93,127.96,128.3,128.5,129.1,129.67,129.69,130.5,133.2,134.1,137.8,138.1,145.5,159.1,164.8.HRMS calcd for C24H20ClN2:371.1310[M+H]+,found:371.1297.
(Z)-5-Benzylidene-2,4-diphenyl-5H-benzo[d][1,3]diazepine(3pp)
Yellow solid(31.1mg,27％).1H NMR(400MHz,CDCl3)δ6.48(s,1H),7.05-7.10(m,5H),7.16-7.18(m,2H),7.38-7.48(m,7H),7.60(d,J＝8.0Hz,1H),8.22-8.24(m,4H).13CNMR(100MHz,CDCl3)δ126.2,126.3,127.1,127.22,127.24,127.27,127.5,127.8,128.21,128.25,128.7,128.9,129.5,131.1,133.4,133.7,134.4,137.0,141.3,144.6,158.8,164.5.HRMS calcd for C28H21N2:385.1699[M+H]+,found:385.1699.
(Z)-5-Benzylidene-4-(4-chlorophenyl)-2-phenyl-5H-benzo[d][1,3]diazepine(3qq)
Yellow solid(37.7mg,30％).1H NMR(400MHz,CDCl3)δ6.53(s,1H),7.10-7.17(m,5H),7.18-7.23(m,2H),7.42-7.47(m,6H),7.68(d,J＝8.0Hz,1H),8.22-8.25(m,2H),8.26-8.30(m,2H).13C NMR(100MHz,CDCl3)δ127.2,127.5,128.0,128.1,128.36,128.4,128.6,129.1,129.3,129.4,130.0,131.2,133.9,134.25,134.3,137.8,138.6,145.6,159.6,164.3.HRMS calcd for C28H20ClN2:419.1310[M+H]+,found:419.1291.
实施例4
本发明所合成的产物1,3-苯二氮卓类化合物可以进行一系列反应，从而合成进一步的衍生物。例如：
Figure BDA0002764769740000171
向15mL反应管中依次加入3i(39.5mg，0.1mmol)、苯乙炔(16.5μL，0.15mmol)、PPh3(5.2mg,0.02mmol)、K3PO4(25.5mg,0.12mmol)、Pd(OAc)2(1.1mg,0.005mmol)和DMSO(1mL)。将得到的混合物置于80℃油浴中，于氩气气氛下搅拌24h。反应结束后，冷却至室温，加入乙酸乙酯稀释，依次用水和盐水洗涤。分离的有机层用无水硫酸钠干燥，过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝300/1)得到黄色固体4(27.9mg,67％)。该化合物的表征数据如下：1H NMR(600MHz,CDCl3)δ1.34(s,9H),1.68(s,3H),1.80(s,3H),7.32-7.38(m,5H),7.41-7.43(m,2H),7.44-7.46(m,2H),7.52-7.53(m,2H),8.01-8.03(m,2H).13C NMR(150MHz,CDCl3)δ19.9,21.5,28.3,39.8,89.6,90.0,120.4,123.4,127.2,128.2,128.4,128.8,129.0,129.2,130.8,130.9,131.50,131.54,131.58,132.7,135.4,145.5,165.2,173.0.HRMS calcd for C30H29N2:417.2325[M+H]+,found:417.2312。
Figure BDA0002764769740000181
向15mL反应管中依次加入3i(79.1mg,0.2mmol)、苯酚(28.2mg,0.3mmol)、N,N-二甲基甘氨酸盐酸盐(8.4mg,0.06mmol)、Cs2CO3(130.3mg,0.4mmol)、CuI(3.8mg,0.02mmol)和二氧六环(1mL)。将得到的混合物置于90℃油浴中，于氩气气氛下搅拌24h。反应结束后，冷却至室温，加入乙酸乙酯稀释，依次用水和盐水洗涤。分离的有机层用无水硫酸钠干燥，过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝300/1)得到黄色固体5(58.0mg,71％)。该化合物的表征数据如下：1H NMR(600MHz,CDCl3)δ1.34(s,9H),1.65(s,3H),1.76(s,3H),6.88(d,J＝2.4Hz,1H),6.95-6.98(m,3H),7.06(t,J＝7.2Hz,1H),7.28-7.31(m,2H),7.37-7.40(m,3H),7.43-7.44(m,3H),7.97-7.98(m,2H).13C NMR(150MHz,CDCl3)δ19.8,21.4,28.4,39.7,118.0,118.1,119.5,122.9,128.5,128.7,128.8,129.4,129.7,131.4,131.7,132.3,135.7,141.5,154.8,157.9,164.5,171.6.HRMS calcd for C28H29N2O:409.2274[M+H]+,found:409.2278。
Figure BDA0002764769740000182
向15mL反应管中依次加入3i(39.5mg,0.1mmol)、苯硼酸(18.3mg,0.15mmol)、PPh3(15.7mg,0.06mmol)、K2CO3(55.3mg,0.4mmol)、Pd(OAc)2(2.2mg,0.01mmol)和二氧六环(1mL)。将得到的混合物置于80℃油浴中搅拌24h。反应结束后，冷却至室温，加入乙酸乙酯稀释，依次用水和盐水洗涤。分离的有机层用无水硫酸钠干燥，过滤，旋干，过硅胶柱分离(石油醚/乙酸乙酯＝300/1)得到黄色固体6(25.9mg,66％)。该化合物的表征数据如下：1HNMR(600MHz,CDCl3)δ1.28(s,9H),1.62(s,3H),1.75(s,3H),7.24-7.27(m,1H),7.31-7.37(m,6H),7.39(d,J＝7.8Hz,1H),7.47(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.49-7.51(m,2H),7.96-7.97(m,2H).13C NMR(150MHz,CDCl3)δ18.8,20.5,27.3,38.7,125.1,126.0,126.1,126.4,127.70,127.73,127.9,128.8,129.9,130.4,131.0,134.7,137.5,139.8,143.6,163.8,171.3.HRMS calcd for C28H29N2:393.2325[M+H]+,found:393.2312。
实施例5
化合物的抗癌活性是利用CCK8分析方法，通过检测化合物抗癌细胞增殖活性研究来评估的。首先，将细胞以每孔5000个细胞的密度接种到每孔装有100μL培养基的96孔板中，并在37℃和5％CO2环境下孵育过夜。第二天，在每孔中加入100μL用培养基稀释的待测化合物(浓度为0.03nM-30μM)，接着，细胞在37℃和5％CO2环境下孵育72小时。然后，向每个孔中加入10μL的CCK8，并将96孔板置于37℃孵育2小时。使用多功能酶标仪(PerkinermerEnVision multilatelbel)在450nm处测量吸光度(用630nm作为参考波长)，用GraphPadPrism 6.0软件计算出IC50值。所有实验均布施三个平行样品，并重复三次。选择REC-1、HeLa、Ramos和A549等四种癌细胞作为研究对象，5-氟尿嘧啶(5-FU)被用作药物的阳性对照品。
部分化合物的抗癌活性结果如下：
Figure BDA0002764769740000191
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。

Claims (10)

1.一种1,3-苯二氮卓类化合物，结构通式为：
Figure FDA0002764769730000011
其中，R1为氢、卤素、C1-4烷基、C1-4烷氧基、C1-4烷硫基、取代苯基、取代苯乙炔基或取代苯氧基，取代苯基苯环上的取代基为氢、C1-4烷基、C1-4烷氧基或卤素；R2为C1-4烷基、C3-6环烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素；R3为噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、卤素、硝基或苯基；R4和R5各自独立为氢、苯基、C1-4烷基、C3-6环烷基或共同组成C5-6环烷基。
2.如权利要求1所述1,3-苯二氮卓类化合物在抗癌活性药物中的应用。
3.根据权利要求2所述1,3-苯二氮卓类化合物在抗癌活性药物中的应用，其特征在于：所述抗癌活性为抗REC-1、HeLa、Ramos或A549癌细胞活性。
4.根据权利要求3所述1,3-苯二氮卓类化合物在抗癌活性药物中的应用，其特征在于：所述抗癌活性为抗HeLa或Ramos癌细胞活性。
5.一种1,3-苯二氮卓类化合物的合成方法，其特征在于，包括如下操作：将N-芳基脒1、炔丙醇酯类化合物2、铑或钌催化剂、添加剂和有机溶剂混合，升温反应得到1,3-苯二氮卓类化合物3，反应方程式为：
Figure FDA0002764769730000012
其中R1为氢、卤素、C1-4烷基、C1-4烷氧基或C1-4烷硫基，R2为C1-4烷基、C3-6环烷基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基或卤素，R3为噻吩基、苯基或取代苯基，取代苯基苯环上的取代基为C1-4烷基、C1-4烷氧基、卤素、硝基或苯基，R4和R5各自独立为氢、苯基、C1-4烷基、C3-6环烷基或共同组成C5-6环烷基。
6.根据权利要求5所述1,3-苯二氮卓类化合物的合成方法，其特征在于：有机溶剂选自1,2-二氯乙烷、乙腈、丙酮、甲醇、乙醇或2,2,2-三氟乙醇。
7.根据权利要求5所述1,3-苯二氮卓类化合物的合成方法，其特征在于：所述铑催化剂为[RhCp*Cl2]2或RhCp*(OAc)2，钌催化剂为[Ru(p-cymene)Cl2]2。
8.根据权利要求5所述1,3-苯二氮卓类化合物的合成方法，其特征在于：所述添加剂为乙酸银、六氟锑酸银、碳酸银、醋酸铜或醋酸铜一水合物。
9.根据权利要求5-8任意一项所述1,3-苯二氮卓类化合物的合成方法，其特征在于：所述加热反应温度为70-120℃。
10.根据权利要求5-8任意一项所述1,3-苯二氮卓类化合物的合成方法，其特征在于：所述N-芳基脒1、炔丙醇酯类化合物2、添加剂和铑或钌催化剂的投料摩尔比为1-2:1-2:0.1-1:0.01-0.07。
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