CN115010715A - 3-(吲哚-2-基)琥珀酰亚胺和吲哚并苯并二氮卓类化合物的合成方法及抗癌活性 - Google Patents

3-(吲哚-2-基)琥珀酰亚胺和吲哚并苯并二氮卓类化合物的合成方法及抗癌活性 Download PDF

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CN115010715A
CN115010715A CN202210728165.5A CN202210728165A CN115010715A CN 115010715 A CN115010715 A CN 115010715A CN 202210728165 A CN202210728165 A CN 202210728165A CN 115010715 A CN115010715 A CN 115010715A
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范学森
王悦
陈�光
李静怡
张新迎
姜玉钦
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Abstract

本发明公开了3‑(吲哚‑2‑基)琥珀酰亚胺类化合物和吲哚并苯并二氮卓类化合物的合成方法及其抗癌活性，有机合成和药物发现技术领域。将2‑(1H‑吲哚‑1‑基)苯胺类化合物1、马来酰亚胺类化合物2、催化剂[Ru(p‑cymene)Cl2]2、添加剂1、添加剂2和溶剂混合，升温反应得到3‑(吲哚‑2‑基)琥珀酰亚胺类化合物3；在前述升温反应结束时加入BF3·Et2O继续升温反应，利用一锅两步串联反应直接得到五环稠合的吲哚并苯并二氮卓类化合物4。这两类化合物的合成方法均具有原料简单易得、操作简便、条件温和、底物适用范围广等优点。同时，这两类化合物具有显著的抗癌活性。

Description

3-(吲哚-2-基)琥珀酰亚胺和吲哚并苯并二氮卓类化合物的 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3-(吲哚-2-基)琥珀酰亚胺和吲哚并苯并二氮卓类化合物的合成方法及抗癌活性。
背景技术
琥珀酰亚胺/马来酰亚胺是多种天然产物以及抗惊厥、抗精神病等药物分子的重要结构单元。琥珀酰亚胺/马来酰亚胺及其衍生物还是常用的有机合成中间体，广泛应用于吡咯烷、吡唑、羧酸、酯、二酰胺、马来酰亚胺、γ-内酰胺等的制备。
官能团化吲哚不仅在自然界中普遍存在，而且往往具有良好的生物活性及物理、化学性能，目前已被广泛应用于医药、农药、香料、食品饲料添加剂、功能染料等领域。
鉴于琥珀酰亚胺/马来酰亚胺重要性，将琥珀酰亚胺/马来酰亚胺结构单元引入到吲哚环上以获得新杂化体类化合物，有望发现具有更强生物活性的先导化合物。与此同时，苯二氮卓是一类重要的含氮稠杂环，是许多抗抑郁、抗真菌、抗精神病、抗高血压和抗肿瘤药物的核心骨架。
因此，研究并开发从简单易得的原料出发，经过简便的步骤合成3-(吲哚-2- 基)琥珀酰亚胺/马来酰亚胺和吲哚并苯并二氮卓类化合物的的绿色高效新方法，具有十分重要的理论意义和实用前景。
发明内容
本发明解决的技术问题是提供了一种3-(吲哚-2-基)琥珀酰亚胺类化合物及其合成方法，该合成方法通过2-(1H-吲哚-1-基)苯胺与马来酰亚胺的反应来实现。本发明解决的另一个技术问题是提供了一种吲哚并苯并二氮卓类化合物及其合成方法，该合成方法是将BF3·Et2O直接加入到2-(1H-吲哚-1-基)苯胺与马来酰亚胺的反应体系中，利用一锅两步串联反应直接得到五环稠合的吲哚并苯并二氮卓类化合物。这两类化合物的合成方法均具有原料简单易得、操作简便、条件温和、底物适用范围广等优点。另外，这两类化合物具有显著的抗癌活性，因此具有潜在的药用价值。
本发明提供了3-(吲哚-2-基)琥珀酰亚胺类化合物，其结构通式为：
Figure RE-GDA0003777733600000021
其中：R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、 C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基。
本发明还提供了上述3-(吲哚-2-基)琥珀酰亚胺类化合物3的合成方法，包括如下操作：将2-(1H-吲哚-1-基)苯胺类化合物1、马来酰亚胺类化合物2、催化剂 [Ru(p-cymene)Cl2]2、添加剂1、添加剂2和溶剂混合，升温反应得到3-(吲哚-2- 基)琥珀酰亚胺类化合物3，反应方程式为：
Figure RE-GDA0003777733600000022
其中：R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、 C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基。所述添加剂 1为六氟锑酸银、三氟甲烷磺酸银、四氟硼酸银、双三氟甲烷磺酰亚胺银或三氟乙酸银，所述添加剂2为醋酸、特戊酸、苯甲酸、2,4,6-三甲基苯甲酸或1-金刚烷甲酸。
进一步地，在上述技术方案中，所述溶剂为乙酸乙酯、四氢呋喃、1,2-二氯乙烷、乙腈、甲苯或1,4-二氧六环。
进一步地，在上述技术方案中，所述化合物1、化合物2、催化剂、添加剂 1与添加剂2摩尔比为1:1-2:0.025-0.05:0.1-0.3:3-7。
进一步地，在上述技术方案中，所述反应温度为60-120℃。
本发明还提供了具有抗癌活性的吲哚并苯并二氮卓类化合物，其结构通式为：
Figure RE-GDA0003777733600000023
其中：R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、 C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基。
本发明提供了上述吲哚并苯并二氮卓类化合物4的合成方法，包括如下操作：将2-(1H-吲哚-1-基)苯胺类化合物1、马来酰亚胺类化合物2、催化剂 [Ru(p-cymene)Cl2]2、添加剂1、添加剂2和溶剂混合，升温至反应结束；然后加入BF3·Et2O，继续升温反应，得到吲哚并苯并二氮卓类化合物4，反应方程式为：
Figure RE-GDA0003777733600000031
其中R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、 C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基。所述添加剂 1为六氟锑酸银、三氟甲烷磺酸银、四氟硼酸银、双三氟甲烷磺酰亚胺银或三氟乙酸银，所述添加剂2为醋酸、特戊酸、苯甲酸、2,4,6-三甲基苯甲酸或1-金刚烷甲酸。
进一步地，在上述技术方案中，所述溶剂为乙酸乙酯、四氢呋喃、1,2-二氯乙烷、乙腈、甲苯或1,4-二氧六环。
进一步地，在上述技术方案中，所述化合物1、化合物2、催化剂、添加剂 1、添加剂2与BF3·Et2O摩尔比为1:1-2:0.025-0.05:0.1-0.3:3-7:2-4。
进一步地，在上述技术方案中，所述反应温度为60-120℃。
本发明还提供了上述3-(吲哚-2-基)琥珀酰亚胺类化合物4和吲哚并苯并二氮卓类化合物5在合成抗癌活性药物中的应用，所述抗癌活性为抗A-549、抗Ramos 和抗Hela。
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2-(1H- 吲哚-1-基)苯胺与马来酰亚胺的直接反应或者一锅串联反应，可以方便合成得到 3-(吲哚-2-基)琥珀酰亚胺类化合物或者五环稠合的吲哚并苯并二氮卓类化合物，反应原子经济性高；(2)原料价廉易得，反应条件温和，操作简便；(3)底物适用范围广、官能团耐受性好；(4)3-(吲哚-2-基)琥珀酰亚胺类化合物和吲哚并苯并二氮卓类化合物具有显著的抗癌活性，为药物筛选提供了新的结构单元。
附图说明
图1为实施例2中化合物3a的X-射线单晶衍射图；
图2为实施例4中化合物4a的X-射线单晶衍射图。
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 RE-GDA0003777733600000041
向15mL反应管中依次加入化合物1a、2a、二氯双(4-甲基异丙基苯基)钌(II) ([Ru(p-cymene)Cl2]2)催化剂、添加剂1、添加剂2和溶剂，在空气条件下将反应管密封，将其置于油浴中升温搅拌反应。待反应结束后，冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，过滤，用二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝4/1)得到黄色固体产物3a。
通过改变反应的溶剂、添加剂1、添加剂2和物料比等反应条件，得到一系列的结果，见表1。
表1不同条件下3a的合成a
Figure RE-GDA0003777733600000042
Figure RE-GDA0003777733600000051
a反应条件:1a(0.2mmol),2a(0.3mmol),[Ru(p-cymene)Cl2]2(5mol％),添加剂1(0.04 mmol),添加剂2(1mmol),溶剂(2mL),80℃,12h。b分离收率。c温度120℃。d温度60℃。e添加剂2(0.8mmol)。f添加剂2(1.2mmol)。g添加剂1(0.02mmol)。h添加剂1(0.06mmol)。i催化剂(2.5mol％)。j2a(0.2mmol)。k2a(0.4mmol)。
-----------------------------------------
实施例2
Figure RE-GDA0003777733600000052
向15mL耐压管中依次加入1a(41.6mg,0.2mmol)、2a(33.3mg,0.3mmol)、 [Ru(p-cymene)Cl2]2(6.12mg,0.01mmol)、六氟锑酸银(13.7mg,0.04mmol)、醋酸(57μL,1.0mmol)和乙酸乙酯(2mL)，然后将反应管密封，并置于80℃油浴中反应12h。反应结束后，将反应体系冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，过滤，用二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液浓缩，过硅胶柱分离(石油醚/乙酸乙酯＝4/1)得到黄色固体产物3a(43.4mg, 68％)。该化合物的表征数据为：1H NMR(600MHz,CDCl3):δ7.62-7.60(m,1H),7.30-7.27(m,1.4H),7.15-7.13(m,2H),7.02(d,J＝7.8Hz,0.6H),6.96-6.94(m,1H),6.88-6.80(m,2H),6.57(s,0.6H),6.56(s,0.4H),4.13-4.08(m,1H),3.54(br s,2H),2.96-2.83(m,5H).13C{1H}NMR(150MHz,CDCl3):δ176.8,176.0,175.7,175.6, 144.8,144.5,138.0,137.6,136.0,135.9,130.6,130.54,130.48,130.3,127.73,127.68, 122.7,121.81,121.79,120.82,120.80,120.74,120.68,119.0,118.7,116.7,116.3, 110.5,110.4,102.4,101.7,39.2,39.0,36.4,35.9,25.1.HRMS(ESI)m/z:[M+Na]+ Calcd forC19H17N3O2Na 342.1213；Found 342.1207.
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，可以合成出各种3-(吲哚-2-基)琥珀酰亚胺类化合物3，具体结果如下：
Figure RE-GDA0003777733600000061
a反应条件：1(0.2mmol),2(0.3mmol),[Ru(p-cymene)Cl2]2(0.01mmol),六氟锑酸银(0.04mmol),醋酸(1mmol),乙酸乙酯(2mL),80℃,12h,空气氛围；b分离收率。
-----------------------------
代表性产物表征数据如下：
3-(1-(2-Aminophenyl)-6-methyl-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione (3b)1H NMR(600MHz,CDCl3):δ7.48(d,J＝7.8Hz,1H),7.30-7.26(m,1.55H), 7.02(dd,J1＝7.8Hz,J2＝1.2Hz,0.45H),6.98(d,J＝7.8Hz,1H),6.89-6.81(m,2H), 6.74(s,0.55H),6.73(s,0.45H),6.52(s,0.45H),6.51(s,0.55H),4.11-4.06(m,1H), 3.70(s,0.9H),3.41(s,1.1H),2.95-2.83(m,5H),2.38(s,3H).13C{1H}NMR(150 MHz,CDCl3):δ176.9,176.0,175.8,175.7,144.9,144.6,138.4,138.0,135.2,135.1, 132.7,130.6,130.5,130.4,130.3,125.53,125.46,122.59,122.55,121.99,121.97, 120.4,120.3,118.9,118.6,116.6,116.2,110.3,110.2,102.2,101.6,39.2,39.0,36.4, 35.9,25.1,21.8.HRMS(ESI)m/z:[M+H]+Calcd for C20H20N3O2 334.1550；Found 334.1543.
3-(1-(2-Aminophenyl)-6-methoxy-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione (3c)1H NMR(600MHz,CDCl3):δ7.47(d,J＝9.0Hz,1H),7.31-7.27(m,1.6H), 7.03(dd,J1＝7.8Hz,J2＝1.2Hz,0.4H),6.89-6.80(m,3H),6.50(s,0.4H),6.49(s, 0.6H),6.40(d,J＝1.8Hz,0.6H),6.39(d,J＝1.8Hz,0.4H),4.10-4.05(m,1H),3.733 (s,1.8H),3.729(s,1.2H),3.71(s,0.8H),3.43(s,1.2H),2.95-2.82(m,5H).13C{1H} NMR(150MHz,CDCl3):δ176.9,176.1,175.8,175.7,157.1,144.8,144.5,138.8, 138.4,134.6,134.5,130.53,130.50,130.46,130.3,121.82,121.76,121.4,121.3, 119.0,118.7,116.7,116.3,110.8,110.7,102.3,101.7,93.81,93.77,55.7,39.3,39.0, 36.4,35.9,25.1.HRMS(ESI)m/z:[M+Na]+Calcd for C20H19N3O3Na 372.1319； Found 372.1309.
3-(1-(2-Aminophenyl)-6-fluoro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3d) 1H NMR(600MHz,CDCl3):δ7.52-7.50(m,1H),7.30-7.27(m,1.5H),7.02-7.01(m,0.5H),6.92-6.81(m,3H),6.65-6.62(m,1H),6.55(s,0.5H),6.54(s,0.5H),4.12-4.07 (m,1H),3.71(s,1H),3.41(s,1H),2.97-2.83(m,5H).13C{1H}NMR(150MHz, CDCl3):δ176.7,175.9,175.6,175.5,160.3(d,1JC-F＝237.0Hz),144.7,144.4,138.1 (d,3JC-F＝11.9Hz),137.7(d,3JC-F＝12.0Hz),136.4(d,4JC-F＝2.3Hz),136.3(d, 4JC-F＝2.7Hz),130.8,130.7,130.4,130.1,124.1,124.0,121.55(d,3JC-F＝9.9Hz), 121.51,121.48(d,3JC-F＝9.9Hz),121.4,119.1,118.8,116.8,116.4,109.61(d,2JC-F＝25.8Hz),109.58(d,2JC-F＝23.4Hz),102.4,101.8,96.99(d,2JC-F＝27.2Hz),96.95 (d,2JC-F＝26.1Hz),39.2,39.0,36.3,35.8,25.1.19F NMR(565MHz,CDCl3):δ-119.39–-119.43(m).HRMS(ESI)m/z:[M+Na]+Calcd forC19H16FN3O2Na 360.1119；Found 360.1119.
3-(1-(2-Aminophenyl)-6-chloro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3e) 1H NMR(600MHz,CDCl3):δ7.50(d,J＝8.4Hz,1H),7.31-7.27(m,1.55H),7.11-7.10(m,1H),7.00(d,J＝6.6Hz,0.45H),6.94(s,0.55H),6.93(s,0.45H),6.88-6.81 (m,2H),6.55(s,0.45H),6.54(s,0.55H),4.11-4.06(m,1H),3.70(s,0.9H),3.41(s, 1.1H),2.96-2.82(m,5H).13C{1H}NMR(150MHz,CDCl3):δ176.6,175.7,175.5, 175.4,144.7,144.4,138.4,138.0,136.8,136.7,130.9,130.8,130.4,130.2,128.7, 126.22,126.16,121.63,121.59,121.56,121.1,119.1,118.8,116.9,116.4,110.45, 110.41,102.4,101.7,39.2,38.9,36.2,35.7,25.2.HRMS(ESI)m/z:[M+Na]+Calcd for C19H16ClN3O2Na376.0823；Found 376.0814.
3-(1-(2-Aminophenyl)-6-bromo-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3f) 1H NMR(600MHz,CDCl3):δ7.56-7.53(m,1H),7.27-7.16(m,2.6H),6.93-6.89(m,1.4H),6.83-6.81(m,1H),6.72-6.63(m,2H),4.93(s,1.2H),4.77(s,0.8H),4.28(dd, J1＝9.6Hz,J2＝5.2Hz,0.6H),4.08-4.04(m,0.4H),2.95-2.84(m,2H),2.81(s,1.2H), 2.70(s,1.8H).13C{1H}NMR(100MHz,DMSO):δ177.3,176.6,176.4,176.0,146.3, 139.2,139.0,138.4,138.3,130.8,130.6,130.5,130.4,127.1,126.9,123.4,122.5, 120.0,119.9,117.0,116.9,116.6,116.4,115.0,114.8,113.1,112.9,103.8,101.2, 38.9,36.5,35.0,25.2,25.0.HRMS(ESI)m/z:[M+Na]+Calcd for C19H16BrN3O2Na 420.0318；Found 420.0295.
3-(1-(2-Aminophenyl)-6-(trifluoromethyl)-1H-indol-2-yl)-1-methylpyrrolidine-2, 5-dione(3g)1H NMR(600MHz,CDCl3):δ7.68(d,J＝8.4Hz,1H),7.38(d,J＝8.4 Hz,1H),7.32-7.28(m,1.7H),7.22(s,0.7H),7.21(s,0.3H),7.02-7.01(m,0.3H), 6.90-6.82(m,2H),6.63(s,0.3H),6.62(s,0.7H),4.14(dd,J1＝9.6Hz,J2＝5.4Hz,0.3H),4.10(dd,J1＝9.6Hz,J2＝5.4Hz,0.7H),3.72(br s,0.6H),3.42(br s,1.4H), 2.97-2.83(m,5H).13C{1H}NMR(150MHz,CDCl3):δ176.4,175.6,175.4,175.3, 144.7,144.4,139.0,138.9,136.9,136.5,131.04,131.01,130.4,130.12,130.09,130.0, 125.0(q,1JC-F＝270.3Hz),124.8(q,2JC-F＝31.8Hz),121.2,121.1,120.81,120.79, 119.2,118.9,117.5(q,3JC-F＝3.6Hz),117.0,116.5,108.0(q,3JC-F＝4.4Hz),102.5, 101.8,39.2,38.9,36.2,35.7,25.18,25.16.19F NMR(565MHz,CDCl3):δ-60.51(s), -60.52(s).HRMS(ESI)m/z:[M+Na]+Calcd for C20H16F3N3O2Na 410.1087；Found 410.1074.
3-(1-(2-Aminophenyl)-5-methyl-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione (3h)1H NMR(600MHz,CDCl3):δ7.38(s,1H),7.28-7.23(m,1.5H),7.00(dd,J1＝7.2Hz,J2＝1.2Hz,0.5H),6.96(d,J＝8.4Hz,1H),6.85-6.78(m,3H),6.47(s,0.5H), 6.46(s,0.5H),4.08-4.04(m,1H),3.69(br s,1H),3.41(br s,1H),2.93-2.81(m,5H), 2.42(s,3H).13C{1H}NMR(150MHz,CDCl3):δ176.8,176.0,175.8,175.7,144.9, 144.6,136.4,136.0,135.9,130.5,130.43,130.39,130.28,130.14,130.11,128.0, 127.9,124.3,122.00,121.96,120.4,120.3,118.9,118.6,116.6,116.2,110.14,110.12, 101.9,101.2,39.2,39.0,36.4,35.9,25.1,21.4.HRMS(ESI)m/z:[M+Na]+Calcd for C20H19N3O2Na356.1369；Found 356.1363.
3-(1-(2-Aminophenyl)-5-methoxy-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione (3i)1H NMR(600MHz,CDCl3):δ7.30-7.25(m,1.5H),7.06(d,J＝1.8Hz,1H), 7.01(dd,J1＝7.8Hz,J2＝1.2Hz,0.5H),6.87-6.79(m,4H),6.49(s,0.5H),6.48(s, 0.5H),4.10-4.05(m,1H),3.84(s,3H),3.70(s,1H),3.40(s,1H),2.96-2.83(m,5H). 13C{1H}NMR(150MHz,CDCl3):δ176.8,176.0,175.8,175.6,154.99,154.97, 144.9,144.6,136.4,136.3,133.2,132.8,130.53,130.47,130.4,130.3,128.12,128.08, 121.94,121.91,118.9,118.6,116.7,116.2,112.8,111.24,111.21,102.5,102.4,101.9, 101.4,55.94,55.93,39.3,39.0,36.4,35.9,25.1.HRMS(ESI)m/z:[M+Na]+Calcd for C20H19N3O3Na372.1319；Found 372.1306.
3-(1-(2-Aminophenyl)-5-fluoro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3j) 1H NMR(600MHz,CDCl3):δ7.30-7.24(m,2.5H),7.01(dd,J1＝7.2Hz,J2＝1.2Hz,0.5H),6.91-6.81(m,4H),6.531(s,0.5H),6.526(s,0.5H),4.11-4.07(m,1H),3.70(s,1H),3.39(s,1H),2.98-2.83(m,5H).13C{1H}NMR(150MHz,CDCl3):δ176.6, 175.8,175.6,175.5,158.56(d,1JC-F＝234.3Hz),158.55(d,1JC-F＝234.3Hz),144.8, 144.5,137.6,137.5,134.5,134.1,130.71,130.68,130.5,130.2,127.97(d,3JC-F＝7.2 Hz),127.90(d,3JC-F＝7.5Hz),121.5,119.1,118.7,116.8,116.4,111.25(d,3JC-F＝ 6.3Hz),111.18(d,3JC-F＝6.5Hz),111.16,111.0,105.6(d,2JC-F＝23.0Hz),105.5(d, 2JC-F＝22.8Hz),102.2(d,4JC-F＝4.4Hz),101.7(d,4JC-F＝4.2Hz),39.2,39.0,36.3, 35.8,25.2.19F NMR(565MHz,CDCl3):δ-123.45–-123.49(m),-123.51–-123.55(m).HRMS(ESI)m/z:[M+Na]+Calcd forC19H16FN3O2Na 360.1119；Found 360.1106.
3-(1-(2-Aminophenyl)-5-chloro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3k) 1H NMR(600MHz,CDCl3):δ7.57(d,J＝1.8Hz,1H),7.30-7.27(m,1.6H), 7.11-7.09(m,1H),7.00(dd,J1＝7.8Hz,J2＝1.2Hz,0.4H),6.88-6.81(m,3H),6.52 (s,0.4H),6.51(s,0.6H),4.11-4.07(m,1H),3.69(s,0.8H),3.39(s,1.2H),2.98-2.82 (m,5H).13C{1H}NMR(150MHz,CDCl3):δ176.5,175.7,175.5,175.4,144.7, 144.4,137.4,137.3,136.3,135.9,130.79,130.76,130.4,130.1,128.7,128.6,126.53, 126.50,123.0,121.3,120.1,120.0,119.1,118.8,116.8,116.4,111.55,111.50,101.9, 101.3,39.2,38.9,36.2,35.7,25.2.HRMS(ESI)m/z:[M+Na]+Calcd for C19H16ClN3O2Na 376.0823；Found 376.0820.
3-(1-(2-Aminophenyl)-5-bromo-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3l) 1H NMR(600MHz,CDCl3):δ7.73(d,J＝0.6Hz,1H),7.30-7.28(m,1.6H),7.23(d,J＝9.0Hz,1H),7.00(d,J＝7.2Hz,0.4H),6.88-6.81(m,3H),6.514(s,0.4H),6.510 (s,0.6H),4.12-4.07(m,1H),3.68(s,0.8H),3.38(s,1.2H),2.97-2.82(m,5H).13C{1H} NMR(150MHz,CDCl3):δ176.5,175.7,175.5,175.4,144.7,144.4,137.25,137.15, 136.6,136.2,130.82,130.78,130.4,130.1,129.32,129.26,125.6,123.2,123.1,121.3, 119.1,118.8,116.8,116.4,114.08,114.05,112.0,111.9,101.8,101.2,39.1,38.9, 36.2,35.7,25.2.HRMS(ESI)m/z:[M+Na]+Calcd for C19H16BrN3O2Na 420.0318； Found 420.0303.
3-(1-(2-Aminophenyl)-4-methyl-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione (3m)1H NMR(600MHz,CDCl3):δ7.30-7.26(m,1.4H),7.07-7.01(m,1.6H),6.94 (d,J＝7.2Hz,1H),6.87-6.77(m,3H),6.59(s,0.6H),6.58(s,0.4H),4.14-4.10(m, 1H),3.68(s,1.2H),3.40(s,0.8H),2.93-2.87(m,5H),2.55(s,3H).13C{1H}NMR (150MHz,CDCl3):δ176.9,176.1,175.8,175.7,144.8,144.5,137.7,137.3,135.4, 135.3,130.50,130.49,130.4,130.3,130.25,127.6,127.5,122.9,122.05,122.00, 121.02,120.98,118.95,118.65,116.7,116.3,108.04,108.01,100.9,100.2,39.3,39.0, 36.5,36.0,25.1,18.7.HRMS(ESI)m/z:[M+Na]+Calcd for C20H19N3O2Na 356.1369； Found 356.1354.
3-(1-(2-Aminophenyl)-4-fluoro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3n) 1H NMR(600MHz,CDCl3):δ7.30-7.26(m,1.6H),7.07-7.03(m,1H),7.01(dd,J1＝7.8Hz,J2＝1.2Hz,0.4H),6.88-6.79(m,3H),6.74-6.71(m,1H),6.66(s,0.4H),6.65 (s,0.6H),4.12-4.06(m,1H),3.71(brs,0.8H),3.42(brs,1.2H),2.97-2.84(m,5H). 13C{1H}NMR(150MHz,CDCl3):δ176.5,175.7,175.5,175.4,156.2(d,1JC-F＝ 247.7Hz),156.1(d,1JC-F＝248.1Hz),144.7,144.4,140.4(d,3JC-F＝11.7Hz),140.0 (d,3JC-F＝10.4Hz),136.1,136.0,130.80,130.76,130.4,130.1,123.25,123.20, 121.46,121.44,119.0,118.7,116.84(d,2JC-F＝21.3Hz),116.83,116.79(d,2JC-F＝ 22.2Hz),116.4,106.6(d,4JC-F＝3.0Hz),106.5(d,4JC-F＝3.3Hz),105.7(d,2JC-F＝ 18.6Hz),105.6(d,2JC-F＝18.9Hz),98.4,97.7,39.2,38.9,36.3,35.7,25.2.19F NMR (565MHz,CDCl3):δ-122.12(dd,J1＝10.2Hz,J2＝5.7Hz),-122.16((dd,J1＝9.6 Hz,J2＝5.1Hz)).HRMS(ESI)m/z:[M+Na]+Calcd forC19H16FN3O2Na 360.1119； Found 360.1100.
3-(1-(2-Aminophenyl)-7-fluoro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3o) 1H NMR(400MHz,CDCl3):δ7.35-7.30(m,1.45H),7.24-7.21(m,1H),7.06-6.99(m,1.55H),6.83-6.75(m,3H),6.57(s,1H),4.07-4.01(m,1H),3.57(br s,2H),2.90- 2.81(m,5H).13C{1H}NMR(100MHz,CDCl3):δ176.6,175.8,175.6,175.4,149.67 (d,1JC-F＝246.2Hz),149.64(d,1JC-F＝246.3Hz),144.69,144.65,137.54,137.49, 131.58(d,3JC-F＝8.7Hz),131.54(d,3JC-F＝8.6Hz),130.55,130.50,130.0,129.9, 125.6(d,2JC-F＝35.7Hz),125.5(d,2JC-F＝35.4Hz),123.4,123.3,120.98(d,4JC-F＝ 2.4Hz),120.92(d,4JC-F＝3.9Hz),118.6,118.3,116.54(d,3JC-F＝6.4Hz),116.50(d, 3JC-F＝7.3Hz),116.4,116.0,108.5(d,2JC-F＝16.9Hz),108.4(d,2JC-F＝17.0Hz), 103.2,102.5,39.0,38.7,36.3,35.9,25.18,25.17.19F NMR(376MHz,CDCl3):δ -135.64(d,J＝10.5Hz),-135.83(d,J＝11.3Hz).HRMS(ESI)m/z:[M+Na]+Calcd for C19H16FN3O2Na 360.1119；Found 360.1108.
3-(1-(2-Aminophenyl)-7-chloro-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3p) 1H NMR(600MHz,CDCl3):δ7.51-7.50(m,1H),7.30(td,J1＝7.8Hz,J2＝1.2Hz,0.5H),7.27-7.25(m,1H),7.13-7.12(m,1H),7.06-7.02(m,1.5H),6.85-6.76(m,2H), 6.59(s,0.5H),6.58(s,0.5H),4.05-4.01(m,1H),3.47(br s,2H),2.97-2.86(m,5H). 13C{1H}NMR(100MHz,CDCl3):δ176.6,175.8,175.6,175.5,145.62,145.57, 138.0,137.9,133.0,132.6,131.1,131.0,130.8,130.7,130.6,130.4,124.32,124.26, 123.2,122.9,121.43,121.40,119.6,119.5,118.5,118.1,117.12,117.08,116.1,115.7, 103.3,102.5,39.2,38.9,36.4,35.9,25.20,25.17.HRMS(ESI)m/z:[M+Na]+Calcd for C19H16ClN3O2Na376.0823；Found 376.0813.
3-(1-(2-Amino-5-chlorophenyl)-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3q) 1H NMR(600MHz,CDCl3):δ7.62-7.61(m,1H),7.36(d,J＝1.8Hz,0.6H),7.27(d,J＝2.4Hz,0.6H),7.25(d,J＝1.8Hz,0.4H),7.19-7.15(m,2H),7.04(d,J＝2.4Hz, 0.4H),6.97-6.94(m,1H),6.83(d,J＝8.4Hz,0.4H),6.80(d,J＝9.0Hz,0.6H),6.59 (s,0.4H),6.57(s,0.6H),4.11(dd,J1＝9.6Hz,J2＝5.4Hz,0.4H),4.07(dd,J1＝9.6 Hz,J2＝4.8Hz,0.6H),3.76(s,0.8H),3.43(s,1.2H),3.05-2.83(m,5H).13C{1H} NMR(150MHz,CDCl3):δ176.6,175.8,175.5,175.4,143.7,143.2,137.8,137.3, 135.9,135.5,130.6,130.5,130.4,129.9,127.8,123.03,123.01,123.00,122.7,122.6, 121.14,121.11,120.9,120.8,117.6,117.1,110.4,110.3,102.9,101.8,39.1,38.7, 36.3,35.7,25.23,25.21.HRMS(ESI)m/z:[M+Na]+Calcd for C19H16ClN3O2Na 376.0823；Found 376.0816.
3-(1-(2-Amino-5-bromophenyl)-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione(3r) 1H NMR(400MHz,CDCl3):δ7.62-7.59(m,1H),7.49(d,J＝2.0Hz,0.5H),7.40-7.36(m,1H),7.19-7.14(m,2.5H),6.97-6.93(m,1H),6.79-6.73(m,1H),6.58(s, 0.5H),6.56(s,0.5H),4.12-4.05(m,1H),3.78(br s,1H),3.46(br s,1H),3.09-2.80(m, 5H).13C{1H}NMR(150MHz,CDCl3):δ176.6,175.8,175.5,175.4,144.2,143.7, 137.8,137.3,135.9,135.5,133.42,133.36,133.2,132.8,127.4,123.0,122.98,122.95, 121.2,121.1,120.9,120.8,118.0,117.5,110.4,110.3,109.6,109.2,102.9,101.8, 39.1,38.7,36.3,35.7,25.28,25.24.HRMS(ESI)m/z:[M+H]+Calcd for C19H17BrN3O2 398.0499；Found 398.0491.
3-(1-(2-Amino-4-methoxyphenyl)-1H-indol-2-yl)-1-methylpyrrolidine-2,5-dione (3s)1H NMR(600MHz,CDCl3):δ7.61-7.59(m,1H),7.21(d,J＝8.4Hz,0.45H),7.16-7.12(m,2H),6.98-6.95(m,1H),6.93(d,J＝8.4Hz,0.55H),6.55(s,0.55H), 6.54(s,0.45H),6.42(dd,J1＝8.4Hz,J2＝2.4Hz,0.45H),6.39-6.36(m,1.55H), 4.13-4.08(m,1H),3.82(s,1.35H),3.81(s,1.65H),3.68(s,1.1H),3.38(s,0.9H), 2.99-2.84(m,5H).13C{1H}NMR(150MHz,CDCl3):δ176.8,176.0,175.8,175.6, 161.2,145.9,145.6,138.3,137.9,136.32,136.26,131.4,131.1,127.7,127.6,122.6, 120.73,120.70,120.67,120.6,115.0,114.9,110.43,110.40,104.7,104.5,102.0, 101.4,101.3,101.2,55.4,39.2,38.9,36.4,36.0,25.1.HRMS(ESI)m/z:[M+Na]+ Calcd for C20H19N3O3Na 372.1319；Found372.1317.
3-(1-(2-Aminophenyl)-1H-indol-2-yl)-1-ethylpyrrolidine-2,5-dione(3t)1H NMR (400MHz,CDCl3):δ7.63-7.60(m,1H),7.33-7.26(m,1.3H),7.17-7.13(m,2H), 7.04(dd,J1＝7.6Hz,J2＝1.2Hz,0.7H),6.97-6.95(m,1H),6.89-6.80(m,2H),6.55 (s,1H),4.11-4.06(m,1H),3.57-3.48(m,2H),3.13(br s,2H),2.98-2.81(m,2H), 1.17-1.12(m,3H).13C{1H}NMR(100MHz,CDCl3):δ176.5,175.8,175.5,175.4, 144.9,144.5,137.9,137.5,136.3,136.2,130.6,130.5,130.4,130.2,127.8,127.7, 122.7,121.9,120.82,120.79,120.7,120.6,119.0,118.8,116.7,116.3,110.5,110.4, 101.8,101.4,39.0,38.8,36.4,36.2,34.14,34.10,13.00,12.97.HRMS(ESI)m/z: [M+Na]+Calcd forC20H19N3O2Na 356.1369；Found 356.1352.
3-(1-(2-Aminophenyl)-1H-indol-2-yl)-1-benzylpyrrolidine-2,5-dione(3u)1HNMR (600MHz,CDCl3):δ7.58-7.57(m,1H),7.35-7.34(m,2H),7.29-7.23(m,4.5H), 7.14-7.11(m,2H),7.00(dd,J1＝7.8Hz,J2＝1.2Hz,0.5H),6.95-6.93(m,1H), 6.86-6.83(m,1H),6.79-6.73(m,1H),6.47(s,0.5H),6.46(s,0.5H),4.62-4.56(m, 2H),4.06-4.03(m,1H),3.67(s,1H),3.36(s,1H),2.92-2.79(m,2H).13C{1H}NMR (150MHz,CDCl3):δ176.3,175.7,175.4,175.2,144.9,144.5,137.9,137.5,136.24, 136.21,135.65,135.61,130.6,130.49,130.45,130.2,128.88,128.86,128.7,128.10, 128.08,127.8,127.7,122.7,121.82,121.79,120.83,120.80,120.8,120.7,119.0, 118.7,116.7,116.3,110.6,110.4,101.8,101.3,42.8,42.7,39.0,38.8,36.4,36.3. HRMS(ESI)m/z:[M+Na]+Calcd forC25H21N3O2Na 418.1526；Found 418.1503.
实施例4
Figure RE-GDA0003777733600000131
向15mL耐压管中依次加入1a(41.6mg,0.2mmol)、2a(33.3mg,0.3mmol)、[Ru(p-cymene)Cl2]2(6.12mg,0.01mmol)、六氟锑酸银(13.7mg,0.04mmol)、醋酸(57μL,1.0mmol)和乙酸乙酯(2mL)，将反应管密封，并置于80℃油浴中反应12h。冷却至室温并加入三氟化硼乙醚溶液(49μL,0.4mmol)，继续置于100℃油浴中反应10h。反应结束后，将反应体系冷却至室温，饱和碳酸氢钠溶液淬灭反应，过滤，二氯甲烷萃取，合并有机相，干燥浓缩，硅胶柱分离(石油醚/乙酸乙酯＝6/1)得到白色固体产物4a(33.1mg,55％)。该化合物的表征数据为：1HNMR(400MHz,CDCl3):δ7.77(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.62(d,J＝8.4 Hz,2H),7.42(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.38-7.34(m,1H),7.29-7.25(m, 1H),7.23-7.15(m,2H),6.37(s,1H),4.02-4.00(m,1H),3.21-3.04(m,5H).13C{1H} NMR(100MHz,CDCl3):δ175.2,161.6,140.2,139.9,136.6,129.9,128.9,127.7, 126.8,125.0,124.8,122.7,121.2,120.9,111.1,98.0,34.8,31.9,26.3.HRMS(ESI) m/z:[M+H]+Calcd for C19H16N3O302.1288；Found 302.1278.
实施例5
Figure RE-GDA0003777733600000141
向15mL耐压管中依次加入1a(41.6mg,0.2mmol)、2a(22.2mg,0.2mmol)、 [Ru(p-cymene)Cl2]2(3.06mg,0.005mmol)、六氟锑酸银(6.9mg,0.02mmol)、醋酸(34μL,0.6mmol)和乙酸乙酯(2mL)，将反应管密封，并置于60℃油浴中反应12h。冷却至室温并加入三氟化硼乙醚溶液(49μL,0.4mmol)，继续置于80℃油浴中反应10h。反应结束后，将反应体系冷却至室温，加入饱和碳酸氢钠溶液淬灭反应，过滤，二氯甲烷萃取，合并有机相，干燥浓缩，硅胶柱分离(石油醚 /乙酸乙酯＝6/1)得到白色固体产物4a(5.6mg,9％)。
实施例6
Figure RE-GDA0003777733600000142
向15mL耐压管中依次加入1a(41.6mg,0.2mmol)、2a(44.4mg,0.4mmol)、 [Ru(p-cymene)Cl2]2(6.12mg,0.05mmol)、六氟锑酸银(20.6mg,0.06mmol)、醋酸(80μL,1.4mmol)和乙酸乙酯(2mL)，将反应管密封，并置于100℃油浴中反应12h。冷却至室温并加入三氟化硼乙醚溶液(99μL,0.8mmol)，继续置于 120℃油浴中反应10h。反应结束后，将反应体系冷却至室温，饱和碳酸氢钠溶液淬灭反应，过滤，二氯甲烷萃取，合并有机相，干燥浓缩，硅胶柱分离(石油醚/乙酸乙酯＝6/1)得到白色固体产物4a(34.3mg,57％)。
实施例7
依照实施例4的方法和步骤a,b，通过改变反应物1和反应物2，可以合成出各种吲哚并苯并二氮卓类化合物4，具体结果如下：
Figure RE-GDA0003777733600000151
a反应条件：1(0.2mmol),2(0.3mmol),[Ru(p-cymene)Cl2]2(0.01mmol),六氟锑酸银(0.04mmol),醋酸(1mmol),乙酸乙酯(2mL),80℃,12h；三氟化硼乙醚 (0.4mmol),100℃,10h，空气氛围；b分离收率。
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代表性产物表征数据如下：
3,11-Dimethyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7-a]in dol-12(11H)-one(4b)1H NMR(600MHz,CDCl3):δ7.77(d,J＝7.8Hz,1H),7.50 (d,J＝7.8Hz,1H),7.43-7.40(m,2H),7.35(t,J＝7.8Hz,1H),7.28(t,J＝7.8Hz,1H),7.01(d,J＝7.8Hz,1H),6.31(s,1H),3.99(d,J＝8.4Hz,1H),3.18-3.04(m, 5H),2.45(s,3H).13C{1H}NMR(150MHz,CDCl3):δ175.3,161.7,140.2.139.4, 137.0,132.6,130.0,127.7,126.7,125.1,124.7,122.9,120.5,111.0,97.8,34.8,31.9, 26.3,22.0.HRMS(ESI)m/z:[M+H]+Calcd for C20H18N3O 316.1444；Found 316.1438.
3-Methoxy-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1 ,7-a]indol-12(11H)-one(4c)1H NMR(600MHz,CDCl3):δ7.76(d,J＝7.8Hz,1H), 7.49(d,J＝8.4Hz,1H),7.41(d,J＝7.8Hz,1H),7.36(t,J＝7.8Hz,1H),7.27(t,J＝7.8Hz,1H),7.12(s,1H),6.84(dd,J1＝8.4Hz,J1＝1.8Hz,1H),6.29(s,1H),3.99(d, J＝8.4Hz,1H),3.81(s,3H),3.16-3.04(m,5H).13C{1H}NMR(150MHz,CDCl3):δ175.3,161.9,156.8,140.3,139.1,137.4,129.9,127.7,126.8,124.8,124.7,123.0, 121.4,110.8,97.8,95.1,55.8,34.7,31.9,26.3.HRMS(ESI)m/z:[M+H]+Calcd for C20H18N3O2 332.1394；Found 332.1382.
3-Fluoro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4d)1H NMR(600MHz,CDCl3):δ7.71(d,J＝7.8Hz,1H), 7.53(dd,J1＝8.4Hz,J2＝5.4Hz,1H),7.42(dd,J1＝7.8Hz,J2＝1.2Hz,1H),7.37(t, J＝7.8Hz,1H),7.32-7.27(m,2H),6.94(td,J1＝9.0Hz,J2＝1.8Hz,1H),6.35(s, 1H),4.02(d,J＝8.4Hz,1H),3.18-3.06(m,5H).13C{1H}NMR(150MHz,CDCl3): δ175.1,161.7,160.1(d,1JC-F＝237.5Hz),140.4(d,4JC-F＝4.2Hz),140.2,136.6(d, 3JC-F＝12.0Hz),129.6,127.8,127.1,125.3,125.0,124.5,121.6(d,3JC-F＝9.8Hz), 109.8(d,2JC-F＝24.9Hz),97.9,97.8(d,2JC-F＝27.2Hz),34.8,31.8,26.4.19F NMR (376MHz,CDCl3):δ-119.18(td,J1＝9.8Hz,J2＝6.0Hz,).HRMS(ESI)m/z: [M+H]+Calcd for C19H15FN3O 320.1194；Found320.1187.
3-Chloro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4e)1H NMR(400MHz,CDCl3):δ7.70(d,J＝7.6Hz,1H), 7.60(s,1H),7.50(d,J＝8.4Hz,1H),7.43-7.35(m,2H),7.31-7.27(m,1H),7.12(dd,J1＝8.4Hz,J2＝1.2Hz,1H),6.34(s,1H),3.98(d,J＝7.2Hz,1H),3.17-3.03(m, 5H).13C{1H}NMR(100MHz,CDCl3):δ175.0,161.6,140.7,140.2,136.9,129.4, 128.6,127.8,127.4,127.2,125.0,124.8,121.8,121.7,111.1,98.0,34.8,31.8,26.4. HRMS(ESI)m/z:[M+H]+Calcd for C19H15ClN3O 336.0898；Found 336.0879.
3-Bromo-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4f)1H NMR(600MHz,CDCl3):δ7.76(s,1H),7.72(dd,J1＝ 7.8Hz,J2＝1.2Hz,1H),7.47(d,J＝8.4Hz,1H),7.42(dd,J1＝7.8Hz,J2＝1.2Hz,1H),7.40-7.37(m,1H),7.32-7.29(m,1H),7.27(dd,J1＝8.4Hz,J2＝1.2Hz,1H), 6.35(s,1H),4.00-3.98(m,1H),3.16(dd,J1＝18.0Hz,J2＝2.4Hz,1H),3.12(s,3H), 3.08(dd,J1＝18.6Hz,J2＝9.0Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ175.0, 161.5,140.5,140.2,137.3,129.3,127.8,127.7,127.3,125.0,124.8,124.4,122.1, 116.2,114.0,98.0,34.7,31.8,26.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H15BrN3O 380.0393；Found 380.0373.
11-Methyl-3-(trifluoromethyl)-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]dia zepino[1,7-a]indol-12(11H)-one(4g)1H NMR(600MHz,CDCl3):δ7.89(s,1H), 7.74(d,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.45-7.41(m,3H),7.35-7.33(m,1H),6.45(s,1H),4.05(d,J＝7.8Hz,1H),3.22-3.10(m,5H).13C{1H}NMR(100 MHz,CDCl3):δ.174.9,161.4,142.4,140.3,135.6,131.3,129.2,127.9,127.5,125.2, 125.0(q,1JC-F＝269.8Hz),124.79,124.77(q,2JC-F＝31.8Hz),121.3,117.8(q,3JC-F＝3.9Hz),108.6(q,3JC-F＝3.9Hz),98.1,34.9,31.8,26.4.19F NMR(565MHz, CDCl3):δ-60.60(s).HRMS(ESI)m/z:[M+H]+Calcd for C20H15F3N3O 370.1162； Found 370.1151.
2,11-Dimethyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7-a]in dol-12(11H)-one(4h)1H NMR(400MHz,CDCl3):δ7.74(d,J＝8.0Hz,1H),7.49 (d,J＝8.4Hz,1H),7.41-7.39(m,2H),7.33(t,J＝7.6Hz,1H),7.25(t,J＝7.2Hz,1H),7.02(d,J＝8.4Hz,1H),6.27(s,1H),3.95(d,J＝8.0Hz,1H),3.15(dd,J1＝ 18.4Hz,J2＝2.4Hz,1H),3.10(s,3H),3.03(dd,J1＝18.0Hz,J2＝8.8Hz,1H),2.43 (s,3H).13C{1H}NMR(100MHz,CDCl3):δ175.3,161.6,140.1,139.9,134.9,130.6, 130.0,129.2,127.7,126.6,124.9,124.8,124.2,120.6,110.8,97.6,34.8,31.9,26.3, 21.4.HRMS(ESI)m/z:[M+H]+Calcd for C20H18N3O 316.1444；Found 316.1434.
2-Methoxy-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1 ,7-a]indol-12(11H)-one(4i)1H NMR(400MHz,CDCl3):δ7.72(d,J＝7.6Hz,1H), 7.50(d,J＝8.8Hz,1H),7.40(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.35-7.31(m,1H),7.27-7.23(m,1H),7.06(d,J＝2.0Hz,1H),6.85(dd,J1＝8.8Hz,J2＝2.0Hz,1H), 6.27(s,1H),3.93(d,J＝7.6Hz,1H),3.83(s,3H),3.14(dd,J1＝18.4Hz,J2＝2.8Hz, 1H),3.10(s,3H),3.04(dd,J1＝18.4Hz,J2＝9.2Hz,1H).13C{1H}NMR(100MHz, CDCl3):δ175.2,161.5,155.0,140.2,140.0,131.7,130.0,129.6,127.7,126.6,124.81, 124.77,112.5,112.0,102.6,97.7,55.9,34.8,31.9,26.3.HRMS(ESI)m/z:[M+H]+ Calcd for C20H18N3O2332.1394；Found 332.1391.
2-Fluoro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4j)1H NMR(600MHz,CDCl3):δ7.72-7.71(m,1H),7.53 (dd,J1＝9.0Hz,J2＝4.2Hz,1H),7.42(dd,J1＝7.8Hz,J2＝0.6Hz,1H),7.38-7.35 (m,1H),7.29-7.24(m,2H),6.94(td,J1＝9.0Hz,J2＝2.4Hz,1H),6.33(s,1H),3.98 (d,J＝7.8Hz,1H),3.16(dd,J1＝18.0Hz,J2＝2.4Hz,1H),3.12(s,3H),3.07(dd,J1＝18.6Hz,J2＝9.0Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ175.1,161.5,158.4 (d,1JC-F＝235.8Hz),141.3,140.1,133.1,129.7,129.4(d,3JC-F＝9.0Hz),127.8, 127.0,124.9,124.7,112.0(d,3JC-F＝9.0Hz),110.8(d,2JC-F＝25.2Hz),105.8(d, 2JC-F＝23.1Hz),97.9(d,4JC-F＝4.1Hz),34.8,31.8,26.4.19F NMR(376MHz, CDCl3):δ-122.65(td,J1＝9.0Hz,J2＝4.1Hz).HRMS(ESI)m/z:[M+H]+Calcd for C19H15FN3O 320.1194；Found 320.1178.
2-Chloro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4k)1H NMR(600MHz,CDCl3):δ7.69(d,J＝8.4Hz,1H), 7.56(d,J＝1.8Hz,1H),7.51(d,J＝9.0Hz,1H),7.42(dd,J1＝8.4Hz,J2＝1.2Hz, 1H),7.38-7.36(m,1H),7.29-7.26(m,1H),7.14(dd,J1＝9.0Hz,J2＝1.8Hz,1H), 6.30(s,1H),3.98(d,J＝7.8Hz,1H),3.15(dd,J1＝18.0Hz,J2＝2.4Hz,1H),3.11(s, 3H),3.07(dd,J1＝18.0Hz,J2＝9.0Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ 175.0,161.5,141.1,140.2,134.9,130.0,129.5,127.8,127.1,126.7,124.9,124.8, 122.9,120.3,112.2,97.5,34.8,31.8,26.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H15ClN3O 336.0898；Found 336.0883.
2-Bromo-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4l)1H NMR(600MHz,CDCl3):δ7.73(d,J＝1.8Hz,1H), 7.69(dd,J1＝7.8Hz,J2＝0.6Hz,1H),7.47(d,J＝9.0Hz,1H),7.42(dd,J1＝7.8Hz, J2＝1.8Hz,1H),7.39-7.36(m,1H),7.29-7.26(m,2H),6.31(s,1H),3.99(d,J＝7.8 Hz,1H),3.16(dd,J1＝18.6Hz,J2＝3.0Hz,1H),3.12(s,3H),3.08(dd,J1＝18.0Hz, J2＝9.0Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ175.0,161.5,141.0,140.2, 135.2,130.6,129.5,127.8,127.2,125.5,124.9,124.8,123.4,114.2,112.6,97.4,34.8, 31.8,26.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H15BrN3O 380.0393；Found 380.0381.
1,11-Dimethyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7-a]in dol-12(11H)-one(4m)1H NMR(400MHz,CDCl3):δ7.77(d,J＝8.0Hz,1H),7.47 (d,J＝8.4Hz,1H),7.41(d,J＝7.6Hz,1H),7.35(t,J＝7.2Hz,1H),7.29-7.25(m,1H),7.13(t,J＝7.6Hz,1H),6.98(d,J＝6.8Hz,1H),6.39(s,1H),4.03(d,J＝8.8 Hz,1H)3.25-3.06(m,5H),2.55(s,3H),.13C{1H}NMR(150MHz,CDCl3):δ175.3, 161.7,140.2,139.3,136.4,130.4,130.0,128.7,127.6,126.8,125.1,124.8,122.8, 121.4,108.7,96.4,34.8,31.9,26.3,18.7.HRMS(ESI)m/z:[M+H]+Calcd for C20H18N3O 316.1444；Found316.1444.
1-Fluoro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4n)1H NMR(600MHz,CDCl3):δ7.74(d,J＝7.8Hz,1H), 7.43-7.37(m,3H),7.28(t,J＝7.8Hz,1H),7.14-7.11(m,1H),6.86-6.83(m,1H),6.48(s,1H),4.01(d,J＝8.4Hz,1H),3.20(dd,J1＝18.6Hz,J2＝2.4Hz,1H), 3.13-3.08(m,4H).13C{1H}NMR(150MHz,CDCl3):δ175.0,161.7,156.1(d,1JC-F＝246.0Hz),140.2,139.9,138.9(d,3JC-F＝10.5Hz),129.6,127.8,127.2,125.0, 124.9,123.2(d,3JC-F＝7.5Hz),118.0(d,2JC-F＝21.9Hz),107.2(d,4JC-F＝3.9Hz), 106.0(d,2JC-F＝17.4Hz),93.9,34.7,31.8,26.4.19F NMR(376MHz,CDCl3):δ -121.94–-121.98(m).HRMS(ESI)m/z:[M+H]+Calcdfor C19H15FN3O 320.1194； Found 320.1194.
1-Chloro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4o)1H NMR(600MHz,CDCl3):δ7.72(d,J＝7.2Hz,1H), 7.52(d,J＝8.4Hz,1H),7.43(d,J＝7.8Hz,1H),7.38(t,J＝7.2Hz,1H),7.28(t,J＝7.2Hz,1H),7.18(d,J＝7.2Hz,1H),7.13(t,J＝7.2Hz,1H),6.51(s,1H),4.03(d,J ＝8.4Hz,1H)3.23(d,J＝18.0Hz,1H),3.13-3.09(m,4H).13C{1H}NMR(150MHz, CDCl3):δ175.0,161.6,140.5,140.3,137.2,129.5,127.8,127.7,127.3,126.1,125.0, 124.9,123.2,120.9,109.8,96.6,34.8,31.8,26.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H15ClN3O336.0898；Found 336.0890.
4-Fluoro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4p)1H NMR(600MHz,CDCl3):δ7.47(t,J＝7.8Hz,1H), 7.39(d,J＝7.8Hz,1H),7.35-7.33(m,2H),7.24-7.21(m,1H),7.11-7.08(m,1H),6.95-6.92(m,1H),6.45(s,1H),3.95(d,J＝7.8Hz,1H),3.17-3.14(m,4H),3.08(dd, J1＝18.0Hz,J2＝9.0Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ175.0,161.9, 149.3(d,1JC-F＝247.3Hz),142.4,140.2,132.7(d,3JC-F＝3.8Hz),130.1(d,4JC-F＝ 2.1Hz),127.0,126.8(d,5JC-F＝7.1Hz),126.2,124.3(d,2JC-F＝8.4Hz),124.2,121.5 (d,3JC-F＝7.2Hz),116.6(d,4JC-F＝3.3Hz),109.1(d,2JC-F＝19.2Hz),99.5(d,4JC-F＝ 2.1Hz),34.6,32.0,26.4.19F NMR(565MHz,CDCl3):δ-121.97–-122.01(m). HRMS(ESI)m/z:[M+H]+Calcd for C19H15FN3O320.1194；Found 320.1189.
4-Chloro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4q)1H NMR(400MHz,CDCl3):δ7.54(dd,J1＝8.0Hz,J2＝ 0.8Hz,1H),7.36-7.33(m,2H),7.30-7.16(m,3H),7.11(t,J＝8.0Hz,1H),6.48(d,J＝1.2Hz,1H),3.96-3.93(m,1H),3.18-3.12(m,4H),3.07(dd,J1＝18.4Hz,J2＝8.8 Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ175.0,162.5,144.1,141.0,132.8, 131.9,129.5,129.0,127.1,125.6,125.0,123.3,121.9,119.4,117.7,99.9,34.7,32.0, 26.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H15ClN3O 336.0898；Found 336.0890.
8-Methoxy-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1 ,7-a]indol-12(11H)-one(4r)1H NMR(400MHz,CDCl3):δ7.66(d,J＝9.2Hz,1H), 7.61(d,J＝7.6Hz,1H),7.58(d,J＝8.0Hz,1H),7.22-7.13(m,2H),6.93(d,J＝2.8Hz,1H),6.84(dd,J1＝8.8Hz,J2＝2.8Hz,1H),6.35(s,1H),4.00(d,J＝8.4Hz,1H), 3.88(s,3H),3.18(dd,J1＝18.4Hz,J2＝2.4Hz,1H),3.10-3.03(m,4H).13C{1H} NMR(100MHz,CDCl3):δ175.6,162.3,158.5,141.7,139.9,137.0,129.1,126.2, 123.5,122.9,121.32,121.26,112.2,111.5,111.3,97.8,56.1,35.3,32.2,26.7.HRMS (ESI)m/z:[M+H]+Calcd forC20H18N3O2 332.1394；Found 332.1385.
7-Fluoro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4s)1H NMR(600MHz,CDCl3):δ7.64-7.62(m,2H),7.51 (dd,J1＝9.0Hz,J2＝1.8Hz,1H),7.38(dd,J1＝8.4Hz,J2＝6.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.19(t,J＝7.2Hz,1H),7.10-7.07(m,1H),6.38(s,1H),4.01(d,J＝8.4 Hz,1H),3.18(d,J＝18.6Hz,1H),3.10-3.07(m,4H).13C{1H}NMR(150MHz, CDCl3):δ175.0,161.5,159.1(d,1JC-F＝243.0Hz),139.6,136.6(d,4JC-F＝2.7Hz), 136.4,130.5(d,3JC-F＝10.5Hz),129.1(d,3JC-F＝8.1Hz),129.0,123.0,121.6,121.1, 114.0(d,2JC-F＝21.6Hz),111.6(d,2JC-F＝24.9Hz),110.9,98.6,34.7,31.9,26.3.19F NMR(565MHz,CDCl3):δ-116.62–-116.66(m).HRMS(ESI)m/z:[M+H]+Calcd for C19H15FN3O 320.1194；Found320.1186.
7-Chloro-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4t)1H NMR(400MHz,CDCl3):δ7.78(d,J＝2.0Hz,1H), 7.63(d,J＝8.4Hz,2H),7.36-7.30(m,2H),7.28-7.24(m,1H),7.20(t,J＝7.6Hz,1H),6.39(s,1H),4.01(dd,J1＝8.8Hz,J2＝1.6Hz,1H),3.19(dd,J1＝18.4Hz,J2＝ 2.8Hz,1H),3.13-3.06(m,4H).13C{1H}NMR(100MHz,CDCl3):δ175.0,161.9, 139.6,138.8,136.4,130.7,129.7,129.0,128.9,126.9,124.7,123.1,121.6,121.1, 110.9,98.7,34.8,31.9,26.4.HRMS(ESI)m/z:[M+H]+Calcd for C19H15ClN3O 336.0898；Found 336.0891.
7-Bromo-11-methyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7 -a]indol-12(11H)-one(4u)1H NMR(600MHz,CDCl3):δ7.91(s,1H),7.61(d,J＝ 7.8Hz,2H),7.45(d,J＝7.2Hz,1H),7.28-7.24(m,2H),7.19(t,J＝7.2Hz,1H), 6.38(s,1H),3.98(d,J＝8.4Hz,1H),3.17(d,J＝18.0Hz,1H),3.10-3.06(m,4H). 13C{1H}NMR(150MHz,CDCl3):δ175.0,161.9,139.6,139.3,136.4,131.0,129.8, 129.2,129.0,127.6,123.1,121.6,121.1,117.1,110.8,98.7,34.8,31.9,26.4.HRMS (ESI)m/z:[M+H]+Calcdfor C19H15BrN3O 380.0393；Found 380.0390.
11-Ethyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7-a]indol-12 (11H)-one(4v)1H NMR(600MHz,CDCl3):δ7.78(d,J＝7.8Hz,1H),7.65-7.63(m, 2H),7.41(d,J＝7.2Hz,1H),7.36(t,J＝7.8Hz,1H),7.27(t,J＝7.8Hz,1H),7.22(t, J＝7.8Hz,1H),7.18(t,J＝7.2Hz,1H),6.38(s,1H),4.00(d,J＝8.4Hz,1H), 3.78-3.73(m,1H),3.69-3.64(m,1H),3.17(dd,J1＝18.0Hz,J2＝2.4Hz,1H),3.07 (dd,J1＝18.6Hz,J2＝8.4Hz,1H),1.19(t,J＝7.2Hz,3H).13C{1H}NMR(150MHz, CDCl3):δ175.0,161.0,140.2,140.0,136.6,129.9,129.0,127.7,126.7,124.9,124.7, 122.6,121.1,120.9,111.1,97.9,35.0,34.7,31.9,12.6.HRMS(ESI)m/z:[M+H]+ Calcd for C20H18N3O 316.1444；Found316.1433.
11-Benzyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7-a]indol-1 2(11H)-one(4w)1H NMR(600MHz,CDCl3):δ7.77(d,J＝7.8Hz,1H),7.63(d,J＝8.4Hz,2H),7.42-7.39(m,3H),7.35-7.33(m,1H),7.27-7.20(m,5H),7.17(t,J＝7.8 Hz,1H),6.38(s,1H),4.86(d,J＝13.8Hz,1H),4.74(d,J＝14.4Hz,1H),4.01(d,J ＝8.4Hz,1H),3.19(dd,J1＝18.6Hz,J2＝2.4Hz,1H),3.08(dd,J1＝18.0Hz,J2＝ 9.0Hz,1H).13C{1H}NMR(150MHz,CDCl3):δ175.0,160.8,140.1,139.9,136.6, 136.0,129.9,129.0,128.8,128.5,127.8,127.7,126.7,124.9,124.8,122.6,121.1, 120.9,111.1,98.1,43.5,34.8,31.9.HRMS(ESI)m/z:[M+H]+Calcd for C25H20N3O 378.1601；Found 378.1599.
11-Isobutyl-13,13a-dihydrobenzo[2,3]pyrrolo[2',3':5,6][1,4]diazepino[1,7-a]indol -12(11H)-one(4x)1H NMR(400MHz,CDCl3):δ7.78(d,J＝7.6Hz,1H),7.65-7.62(m,2H),7.39(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.37-7.33(m,1H),7.29-7.27(m, 1H),7.22-7.16(m,2H),6.38(s,1H),4.00(d,J＝7.6Hz,1H),3.53(dd,J1＝13.2Hz, J2＝7.6Hz,1H),3.44(dd,J1＝13.2Hz,J2＝7.6Hz,1H),3.19(dd,J1＝18.4Hz,J2＝ 2.4Hz,1H),3.08(dd,J1＝18.4Hz,J2＝9.2Hz,1H),2.19-2.09(m,1H),0.84-0.80(m, 6H).13C{1H}NMR(100MHz,CDCl3):δ175.5,161.6,140.3,140.1,136.5,129.8, 129.0,127.7,126.7,124.9,124.6,122.5,121.1,120.9,111.1,97.7,47.1,34.6,31.7, 26.5,20.05,20.01.HRMS(ESI)m/z:[M+H]+Calcd for C22H22N3O 344.1757；Found 344.1757.
实施例8
利用本发明所合成的产物3-(吲哚-2-基)琥珀酰亚胺类化合物3，可以合成进一步的衍生物3-(吲哚-2-基)马来酰亚胺类化合物5a,b。例如：在15mL圆底烧瓶中依次加入3a(63.8mg,0.2mmol)、偶氮二甲酸二乙酯(31.5μL,0.2mmol)和碳酸钾(138.2mg,1mmol)，再加入N,N-二甲基甲酰胺(1mL)将其溶解，之后将反应体系在室温反应2小时，待反应结束后加入20mL水淬灭反应。用乙酸乙酯萃取，合并有机相，水洗、干燥、过滤、浓缩，过硅胶柱分离(石油醚/ 乙酸乙酯＝6/1)得黄色固体产物5a(39.9mg,63％)。该化合物的表征数据如下：1H NMR(400MHz,CDCl3):δ7.93(s,1H),7.74(d,J＝7.6Hz,1H),7.34(t,J＝7.2 Hz,1H),7.26-7.25(m,1H),7.18(t,J＝7.6Hz,1H),7.08(d,J＝7.2Hz,1H),6.99(d, J＝8.0Hz,1H),6.90-6.85(m,2H),5.54(s,1H),3.50(br s,2H),2.98(s,3H).13C{1H} NMR(100MHz,CDCl3):δ171.3,170.5,144.2,140.5,134.4,131.0,129.7,128.2, 127.9,126.0,122.7,122.5,121.6,119.3,118.7,116.6,112.7,110.7,23.8.HRMS (ESI)m/z:[M+H]+Calcd forC19H16N3O2 318.1237；Found 318.1228.
依照合成5a的方法和步骤a,b，利用3-(吲哚-2-基)琥珀酰亚胺类化合物3可以合成各种3-(吲哚-2-基)马来酰亚胺类化合物5，具体结果如下：
Figure RE-GDA0003777733600000231
a反应条件：3(0.2mmol),碳酸钾(1mmol),偶氮二甲酸二乙酯(0.2mmol),N,N- 二甲基甲酰胺(2mL),室温,2h.b分离收率。
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代表性产物表征数据如下：
3-(1-(2-Aminophenyl)-6-methyl-1H-indol-2-yl)-1-methyl-1H-pyrrole-2,5-dione (5b)1H NMR(600MHz,CDCl3):δ7.89(s,1H),7.61(d,J＝8.4Hz,1H),7.35-7.32 (m,1H),7.07(dd,J1＝7.2Hz,J2＝1.2Hz,1H),7.01(d,J＝7.8Hz,1H),6.90-6.86 (m,2H),6.76(s,1H),5.47(s,1H),3.52(s,2H),2.96(s,3H),2.39(s,3H).13C{1H} NMR(150MHz,CDCl3):δ171.4,170.6,144.3,141.0,136.7,134.5,130.9,129.7, 127.8,125.9,123.7,122.7,122.3,119.3,117.7,116.6,112.8,110.4,23.8,22.1. HRMS(ESI)m/z:[M+H]+Calcd forC20H18N3O2 332.1394；Found 332.1381.
3-(1-(2-Aminophenyl)-5-methyl-1H-indol-2-yl)-1-methyl-1H-pyrrole-2,5-dione (5c)1H NMR(600MHz,CDCl3):δ7.85(s,1H),7.51(s,1H),7.34-7.31(m,1H), 7.09(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.06(dd,J1＝7.2Hz,J2＝1.2Hz,1H), 6.89-6.85(m,3H),5.51(s,1H),3.50(s,2H),2.98(s,3H),2.44(s,3H).13C{1H} NMR(150MHz,CDCl3):δ171.4,170.5,144.2,139.1,134.5,131.0,130.9,129.6, 128.2,128.1,127.9,122.7,122.0,119.3,118.3,116.6,112.2,110.4,23.8,21.4. HRMS(ESI)m/z:[M+H]+Calcd forC20H18N3O2 332.1394；Found 332.1385.
3-(1-(2-Aminophenyl)-4-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrrole-2,5-dione(5d) 1H NMR(600MHz,CDCl3):δ8.00(s,1H),7.37-7.34(m,1H),7.20-7.17(m,1H),7.09(dd,J1＝7.2Hz,J2＝1.2Hz,1H),6.92-6.88(m,2H),6.86-6.83(m,1H),6.78(d, J＝8.4Hz,1H),5.57(s,1H),3.51(s,2H),3.01(s,3H).13C{1H}NMR(150MHz, CDCl3):δ171.1,170.2,157.2(d,1JC-F＝250.8Hz),144.0,142.5(d,3JC-F＝10.4Hz), 134.0,131.2,129.5,128.1,126.5(d,3JC-F＝7.7Hz),122.2,119.6,119.4,117.6(d, 2JC-F＝23.0Hz),116.7,108.3,106.8(d,4JC-F＝2.6Hz),106.1(d,2JC-F＝18.5Hz), 23.9.19F NMR(565MHz,CDCl3):δ-119.46–-119.48(m).HRMS(ESI)m/z: [M+Na]+Calcd for C19H14FN3O2Na 358.0962；Found358.0954.
3-(1-(2-Aminophenyl)-7-chloro-1H-indol-2-yl)-1-methyl-1H-pyrrole-2,5-dione(5e) 1H NMR(600MHz,CDCl3):δ7.97(s,1H),7.67(d,J＝8.4Hz,1H),7.34(t,J＝7.8Hz,1H),7.25(d,J＝7.2Hz,1H),7.10(t,J＝7.8Hz,1H),7.07(d,J＝7.8Hz,1H), 6.85-6.82(m,2H),5.48(s,1H),3.56(s,2H),3.02(s,3H).13C{1H}NMR(150MHz, CDCl3):δ171.1,170.4,145.2,135.2,133.8,131.3,130.6,130.4,129.8,127.3,123.9, 122.0,121.5,120.3,118.8,117.5,116.0,113.0,23.9.HRMS(ESI)m/z:[M+H]+ Calcd for C19H15ClN3O2352.0847；Found 352.0844.
3-(1-(2-Amino-5-chlorophenyl)-1H-indol-2-yl)-1-methyl-1H-pyrrole-2,5-dione(5f) 1H NMR(600MHz,CDCl3):δ7.93(s,1H),7.74(d,J＝8.4Hz,1H),7.33-7.28(m,2H),7.20(t,J＝1.2Hz,1H),7.10(d,J＝2.4Hz,1H),6.99(d,J＝8.4Hz,1H),6.85 (d,J＝9.0Hz,1H),5.63(s,1H),3.57(s,2H),3.00(s,3H).13C{1H}NMR(150MHz, CDCl3):δ171.1,170.3,143.0,140.4,134.2,131.0,129.4,128.0,127.9,126.3,123.3, 123.2,122.8,121.9,118.8,117.4,113.2,110.6,23.9.HRMS(ESI)m/z:[M+Na]+ Calcd forC19H14ClN3O2Na 374.0667；Found 374.0657.
实施例9
通过CellTiter-Glo(Promega,USA)测定评估细胞抗增殖活性。首先在二甲基亚砜中配制1000×化合物溶液，将1μL 1000×化合物加入49μL细胞培养基中制成20×化合物。将细胞培养基中的细胞悬液稀释至所需浓度，取95μL至 96孔板中，再向96孔板中加入5μL20×化合物，使每个孔中最终的二甲基亚砜浓度为0.1％。然后将细胞在37℃和5％CO2环境下培养72h，孵育后将测定板平衡至室温，在每个孔中加入20μL
Figure RE-GDA0003777733600000252
试剂并在轨道振荡器上混合内容物2分钟以诱导细胞裂解，最后在室温下孵育10分钟稳定发光信号后使用 EnVision Multilabel Reader(PerkinElmer)记录荧光发光。使用以下公式计算相对于载体(二甲基亚砜)处理的对照孔的细胞活力(CV％)：细胞活力(％)＝(RLU化合物-RLU空白)/(RLU对照-RLU空白)*100％，并使用GraphPad Prism 6.0软件计算IC50值，拟合4参数方程以生成浓度响应曲线。所有测定均使用两个平行样品并重复两次，选择A-549、Ramos和Hela三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。
代表性化合物的抗癌活性结果如下：
Figure RE-GDA0003777733600000251
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)

1.3-(吲哚-2-基)琥珀酰亚胺类化合物和吲哚并苯并二氮卓类化合物，其特征在于，结构通式为：
Figure FDA0003711551130000011
其中：R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基。
2.如权利要求1所述3-(吲哚-2-基)琥珀酰亚胺类化合物和吲哚并苯并二氮卓类化合物在合成抗癌活性药物中的应用，其特征在于：所述抗癌活性为抗A-549、抗Ramos和抗Hela。
3.3-(吲哚-2-基)琥珀酰亚胺类化合物3的合成方法，其特征在于，包括如下操作：将2-(1H-吲哚-1-基)苯胺类化合物1、马来酰亚胺类化合物2、催化剂[Ru(p-cymene)Cl2]2、添加剂1、添加剂2和溶剂混合，升温反应得到3-(吲哚-2-基)琥珀酰亚胺类化合物3；反应方程式为：
Figure FDA0003711551130000012
其中：R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基；所述添加剂1为六氟锑酸银、三氟甲烷磺酸银、四氟硼酸银、双三氟甲烷磺酰亚胺银或三氟乙酸银；所述添加剂2为醋酸、特戊酸、苯甲酸、2,4,6-三甲基苯甲酸或1-金刚烷甲酸。
4.根据权利要求3所述3-(吲哚-2-基)琥珀酰亚胺类化合物3的合成方法，其特征在于：所述溶剂为乙酸乙酯、四氢呋喃、1,2-二氯乙烷、乙腈、甲苯或1,4-二氧六环。
5.根据权利要求3所述3-(吲哚-2-基)琥珀酰亚胺类化合物3的合成方法，其特征在于：所述化合物1、化合物2、催化剂、添加剂1与添加剂2摩尔比为1:1-2:0.025-0.05:0.1-0.3:3-7。
6.根据权利要求3所述3-(吲哚-2-基)琥珀酰亚胺类化合物3的合成方法，其特征在于：所述反应温度为60-120℃。
7.吲哚并苯并二氮卓类化合物4的合成方法，其特征在于，包括如下操作：将2-(1H-吲哚-1-基)苯胺类化合物1、马来酰亚胺类化合物2、[Ru(p-cymene)Cl2]2催化剂、添加剂1、添加剂2和溶剂混合，升温至反应结束，然后加入BF3·Et2O，继续升温反应，制得吲哚并苯并二氮卓类化合物4；反应方程式为：
Figure FDA0003711551130000021
其中：R1为氢、C1-4链状烷基、C1-4链状烷氧基、卤素或三氟甲基，R2为氢、C1-4链状烷基、C1-4链状烷氧基或卤素，R3为C1-4链状烷基或苄基；所述添加剂1为六氟锑酸银、三氟甲烷磺酸银、四氟硼酸银、双三氟甲烷磺酰亚胺银或三氟乙酸银；所述添加剂2为醋酸、特戊酸、苯甲酸、2,4,6-三甲基苯甲酸或1-金刚烷甲酸。
8.根据权利要求7所述吲哚并苯并二氮卓类化合物4的合成方法，其特征在于：所述溶剂为乙酸乙酯、四氢呋喃、1,2-二氯乙烷、乙腈、甲苯或1,4-二氧六环。
9.根据权利要求7所述吲哚并苯并二氮卓类化合物4的合成方法，其特征在于：所述化合物1、化合物2、催化剂、添加剂1、添加剂2与BF3·Et2O摩尔比为1:1-2:0.025-0.05:0.1-0.3:3-7:2-4。
10.根据权利要求7所述吲哚并苯并二氮卓类化合物4的合成方法，其特征在于：所述反应温度为60-120℃。
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