CN112174901B - 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 PDFInfo
- Publication number
- CN112174901B CN112174901B CN202011229687.8A CN202011229687A CN112174901B CN 112174901 B CN112174901 B CN 112174901B CN 202011229687 A CN202011229687 A CN 202011229687A CN 112174901 B CN112174901 B CN 112174901B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- cdcl
- nmr
- alkyl radical
- substituted phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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：
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
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：
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：
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
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
实施例2
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：
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：
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。
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。
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：
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 (7)
1.一种1,3-苯二氮卓类化合物，结构通式为：
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.根据权利要求1所述1,3-苯二氮卓类化合物在制备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。
3.根据权利要求2所述1,3-苯二氮卓类化合物在制备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。
4.一种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：
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；所述铑催化剂为[RhCp*Cl2]2或RhCp*(OAc)2，钌催化剂为[Ru(p-cymene)Cl2]2；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。
5.根据权利要求4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。
6.根据权利要求4或5所述1,3-苯二氮卓类化合物的合成方法，其特征在于：所述加热反应温度为70-120℃。
7.根据权利要求4或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。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011229687.8A CN112174901B (zh) | 2020-11-06 | 2020-11-06 | 1,3-苯二氮卓类化合物的合成方法及抗癌活性 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011229687.8A CN112174901B (zh) | 2020-11-06 | 2020-11-06 | 1,3-苯二氮卓类化合物的合成方法及抗癌活性 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112174901A CN112174901A (zh) | 2021-01-05 |
| CN112174901B true CN112174901B (zh) | 2022-02-08 |
Family
ID=73917094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011229687.8A Active CN112174901B (zh) | 2020-11-06 | 2020-11-06 | 1,3-苯二氮卓类化合物的合成方法及抗癌活性 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112174901B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939988B (zh) * | 2021-03-02 | 2023-01-24 | 河南师范大学 | 茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108164535A (zh) * | 2018-01-25 | 2018-06-15 | 浙江大学 | 三氟甲基化的苯氮卓并吲哚衍生物及其催化合成方法 |
| CN111471047B (zh) * | 2020-05-21 | 2021-04-13 | 河南师范大学 | 选择性合成吡唑并[1,2-a]吡唑酮或2-酰基吲哚类化合物的方法 |
| CN111675712B (zh) * | 2020-06-23 | 2021-05-25 | 河南师范大学 | 一种吡唑啉酮并苯二氮杂卓类化合物的合成方法 |
| CN111606849B (zh) * | 2020-07-07 | 2021-05-25 | 河南师范大学 | 一种2-(2-氨基苯基)喹啉类化合物的合成方法 |
-
2020
- 2020-11-06 CN CN202011229687.8A patent/CN112174901B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112174901A (zh) | 2021-01-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0570594B1 (en) | Hydroxamic acid derivative based on aromatic sulfonamide | |
| JP5362565B2 (ja) | オピオイド受容体のアンタゴニストまたはインバースアゴニストである新規化合物 | |
| BG108561A (bg) | Селективни модулатори на естрогенния рецептор | |
| WO2019113874A1 (zh) | 基于四甲基螺二氢茚骨架的膦配体化合物及其中间体和制备方法与用途 | |
| CN113336689B (zh) | 3-(α-氟乙烯基/羰基)吲哚类化合物的合成方法及抗癌活性 | |
| CN112174901B (zh) | 1,3-苯二氮卓类化合物的合成方法及抗癌活性 | |
| CN112939988B (zh) | 茚并吡唑并吡唑啉酮类化合物的合成方法及抗癌活性研究 | |
| CN101225056A (zh) | α-联苯基-N-烷基硝酮类化合物及其合成方法 | |
| CN113444107B (zh) | 琥珀酰亚胺螺稠合磺内酰胺类化合物的合成方法及抗癌活性 | |
| Qin et al. | Visible-Light-Induced C-3 Difluoroalkylation of Quinoxalin-2 (1H)-ones with Difluoroiodane (III) Reagents under Catalyst-Free Conditions | |
| CN115197228A (zh) | 吡唑啉酮[螺]二氢酞嗪和1,3-茚二酮[螺]二氢酞嗪类化合物的合成方法 | |
| CN110041274B (zh) | 一种空气氧化的多组分一锅法制备5-氟烷基化三氮唑类化合物的方法 | |
| CN113603679B (zh) | 2-羟基琥珀酰亚胺取代吲哚酮类化合物的合成方法及抗癌活性 | |
| Khera et al. | Synthesis of functionalized 3, 4-diarylbenzophenones and 2, 4-diarylbenzophenones by site-selective suzuki and sonogashira cross-coupling reactions of bis (triflates) of 3, 4-and 2, 4-dihydroxybenzophenone | |
| WO2015192774A1 (zh) | 手性氨基酚配体在依法韦仑不对称合成中的应用 | |
| CN110256451A (zh) | 一种苯并呋喃并[2,3-b]喹啉衍生物的合成方法 | |
| CN113717107B (zh) | N-酰基苯并咪唑类化合物的合成方法 | |
| CN115925606B (zh) | 一种5-（3-（磺酰胺基）苯基）-1h-吡咯-2-羧酸衍生物及其制备方法和应用 | |
| CN117886747A (zh) | 氟代甲基取代喹啉类化合物、应用、药物组合物、合成方法 | |
| Kaur et al. | Low catalyst loading enabled organocatalytic synthesis of chiral bis-heterocyclic frameworks containing pyrazole and isoxazole | |
| CN113943199B (zh) | 一种以腈和二芳基甲烷为原料合成酰胺类化合物的方法 | |
| KR102660894B1 (ko) | 피리미딘-2-아민 화합물의 제조방법 | |
| Sapre et al. | Synthesis of enantiomerically enriched benzimidazole-triazoles: Application as organocatalyst for asymmertric Diels-Alder reaction | |
| WO2001030771A1 (fr) | Derives de thiazolidinedione | |
| CN114573551A (zh) | 一种苯并环戊烯并噻吩类化合物的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |