CN114524761B - 五并环吲哚啉类化合物、其制备方法及其应用 - Google Patents
五并环吲哚啉类化合物、其制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一类五并环吲哚啉类化合物,属于有机化学合成技术领域,该类化合物具有如式(Ⅰ)所示的结构,本发明还公开了该类化合物的制备方法,为将3‑硝基吲哚(Ⅱ)和2‑烯基茚酮(Ⅲ)溶解在有机溶剂中,然后加入碱和相转移催化剂,在室温下搅拌反应,待反应完毕后,分离纯化得到产物(Ⅰ);本发明所提供的五并环吲哚啉类化合物同时具有环戊烷并吲哚啉和茚酮结构单元,可以为新药的研发及药物的筛选提供更多候选分子,其在抗肿瘤药物研究中具有很好的潜在价值;而且本发明的制备方法具有新颖、简捷、操作简单、反应条件温和、收率高、非立体选择性选择性高等优点;同时,该方法是第一例涉及贫电子芳杂环的高阶去芳构化反应。
Description
技术领域
本发明涉及有机合成领域,尤其涉及一种含有环戊烷并吲哚啉和茚酮结构单元的五并环吲哚啉类化合物及其制备方法。
背景技术
不对称去芳构化是有机合成领域的一个难点,目前主要的研究方向为富电子芳香化合物,例如吲哚、萘酚等,主要利用这类化合物固有的亲核性。近些年,3-硝基吲哚,作为一类贫电子的杂芳烃类化合物,已经引起了有机化学家广泛的兴趣。通过去芳构化手段,有机化学家利用3-硝基吲哚为底物,合成了各种结构新颖的含吲哚啉骨架的多环杂环类化合物(Chin.J.Chem.,2020,38,287-294)。
高阶的环加成反应是一种非常原子经济的方法,可以一步构建复杂的多环类化合物。与传统的6Π电子的环加成反应相比,高阶的环加成反应涉及到8Π、10Π、12Π和14Π电子等还处于发展幼期。因此,发展高阶的环加成反应具有非常大的挑战性,也是有机合成领域的一个重点和难点,特别是实现活性较低的芳环类化合物的去芳构化高阶环加成反应。
发明内容
本发明的目的之一,就在于提供一类新的五并环吲哚啉类化合物,以解决上述问题。
为了实现上述目的,本发明采用的技术方案是这样的:五并环吲哚啉类化合物,具有如下结构式(Ⅰ)所示的结构:
上述结构式中,R基选自叔丁氧羰基、苄氧羰基、乙氧羰基、对甲基苯磺酰基、苯磺酰基、甲烷磺酰基等吸电子取代中的一种;R1基为单取代基或多取代基,取代基选自氢,烷基,烷氧基或卤素;R2基为芳基或烷基。
通过文献调研,我们发现,目前涉及到的3-硝基吲哚的反应全部是正常的6Π电子的反应,而涉及到去芳构化高阶环加成反应还没有报道。因此,实现3-硝基吲哚的去芳构化高阶反应,不仅在合成手段是具有非常重要的理论价值,而且可以一步构建具有广泛生物活性的含吲哚啉结构片段的复杂多环类化合物,从而为生物活性化合物筛选和药物先导化合物筛选提供更多的候选分子。
本发明实现了3-硝基吲哚的去芳构化高阶[10+2]环加成反应,具有非常重要的意义:不仅是第一例涉及贫电子杂芳环的去芳构化高阶环加成反应,并且生成的五环吲哚啉类化合物广泛存在于生物活性分子中,具有多样性的生物活性,是开发新药的重要来源。
本发明的目的之二,在于提供一种上述的五并环吲哚啉类化合物的制备方法,采用的技术方案为:将3-硝基吲哚(Ⅱ)、2-烯基茚酮(Ⅲ)溶解在有机溶剂中,然后加碱和相转移催化剂,在室温下搅拌反应,待反应完毕后,分离纯化得到产物Ⅰ,其中,
所述3-硝基吲哚(Ⅱ)、2-烯基茚酮(Ⅲ)分别具有如下结构:
其反应式为:
作为优选的技术方案:所述的反应溶剂选自甲苯、均三甲苯、二氯甲烷、氯仿、四氢呋喃、乙醚、乙腈、乙醇、甲醇、1,4-二氧六环、氯苯中的一种或者多种混合。
所述反应溶剂进一步优选二氯甲烷,因为反应的收率最高。
作为优选的技术方案:所述碱为碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾、三乙胺等无机碱或有机碱。
所述反应的碱进一步优选碳酸钾和碳酸钠,因为反应的收率最高。
作为优选的技术方案:其特征在于:所述相转移催化剂为各种季铵盐、季膦盐、冠醚等,如:四丁基碘化铵、四丁基溴化铵、苄基三乙基氯化铵,18-冠-6等。
所述反应的相转移催化剂(PTC)进一步优选季铵盐,更进一步优选苄基三乙基氯化铵,因为反应的收率最高。
本发明的目的之三,在于提供上述的化合物在抗肿瘤药物中的用途。
具体而言,本发明公开的上述化合物的应用价值在于:通过初步的细胞活性实验,表明该类化合物对人前列腺癌细胞PC-3具有很好的杀害作用,细胞活性研究结果见表1。因此,通过进一步的研究,这类化合物有望成为抗肿瘤药物的先导化合物。
与现有技术相比,本发明的优点在于:本发明实现了第一例贫电子杂芳环的去芳构化高阶环加成反应,具体是3-硝基吲哚和2-烯基茚酮的去芳构化高阶[10+2]环加成反应。首次公开了一系列新的五并环吲哚啉类化合物及其合成方法。本发明所提供的五并环吲哚啉类化合物同时具有环戊烷并吲哚啉和茚酮结构单元,可以为新药的研发及药物的筛选提供更多候选分子;为临床新药筛选提供更丰富的候选分子。同时,通过初步的细胞活性研究,表明该类化合物对人前列腺癌细胞PC-3具有很好的抑制作用,有望成为抗肿瘤药物的先导化合物;而且本发明的制备方法具有新颖、简捷、操作简单、反应条件温和、收率高、非立体选择性选择性高等优点。
附图说明
图1为实施例1制得的I-a的氢谱图;
图2为实施例1制得的I-a的碳谱图;
图3为实施例1制得的I-a的单晶图。
具体实施方式
下面将结合附图对本发明作进一步说明。
本发明所用的原料、溶剂、催化剂、碱等,均为市购。
实施例1:合成化合物Ⅰ-a
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol;反应完全后,粗产品经柱色谱分离纯化(二氯甲烷:石油醚=4:1)得化合物I-a,不同的反应条件如表1所示,具体反应过程如下:
表1不同的反应条件
entry | 相转移催化剂(PTC) | 溶剂 | 碱 | 时间 | dr | 收率(%) |
1 | 四丁基溴化铵(TBAB) | CH2Cl2 | Cs2CO3 | 6 | >20:1 | 73 |
2 | 四丁基氯化铵(TBAC) | CH2Cl2 | Cs2CO3 | 6 | >20:1 | 76 |
3 | 溴化十六烷三甲基铵(CTAB) | CH2Cl2 | Cs2CO3 | 6 | >20:1 | 74 |
4 | 苄基三乙基氯化铵(TEBA) | CH2Cl2 | Cs2CO3 | 6 | >20:1 | 85 |
5 | 苄基三乙基氯化铵(TEBA) | CH2Cl2 | NaOH | 12 | >20:1 | 84 |
6 | 苄基三乙基氯化铵(TEBA) | CH2Cl2 | K2CO3 | 12 | >20:1 | 96 |
7 | 苄基三乙基氯化铵(TEBA) | CH2Cl2 | Na2CO3 | 17 | >20:1 | 98 |
8 | 苄基三乙基氯化铵(TEBA) | THF | Na2CO3 | 17 | >20:1 | 85 |
9 | 苄基三乙基氯化铵(TEBA) | CH3CN | Na2CO3 | 17 | >20:1 | 43 |
10 | 苄基三乙基氯化铵(TEBA) | EtOH | Na2CO3 | 17 | >20:1 | 17 |
11 | 苄基三乙基氯化铵(TEBA) | EtOAc | Na2CO3 | 17 | >20:1 | 90 |
从表1中可见,采用催化剂苄基三乙基氯化铵(TEBA)(20mol%,碳酸钠或者碳酸钾(1.0equiv)作碱、二氯甲烷作溶剂、反应温度为室温,是较为优选的技术方案。
所得化合物I-a为淡黄色固体,经HPLC检测纯度为>99%;>20:1dr;m.p.222.6-223.2℃。
结构鉴定:1H NMR(300MHz,CDCl3)δ8.70(dd,J=8.4,2.2Hz,1H),8.58(d,J=2.2Hz,1H),8.48(d,J=8.5Hz,1H),7.82(d,J=8.2Hz,1H),7.54–7.43(m,3H),7.40–7.30(m,3H),7.14(d,J=8.0Hz,2H),6.93(t,J=7.7Hz,1H),6.10(d,J=7.9Hz,1H),5.50(d,J=2.9Hz,1H),4.37(dd,J=8.0,2.9Hz,1H),4.21(d,J=11.7Hz,1H),3.71(dd,J=11.6,7.9Hz,1H),2.33(s,3H);13C NMR(75MHz,CDCl3)δ200.0,158.4,149.1,145.5,143.1,135.7,133.1,132.5,132.2,130.4,130.0,129.9,129.2,129.0,128.7,128.3,126.9,124.7,122.8,120.2,116.6,105.9,75.5,55.9,54.7,52.8,21.6;HRMS(ESI)calcd.for C31H23N3O7S[M+Na]+604.1149,found:604.1152;
单晶衍衍射实验:
单晶培养:将实施例1中得到的主要组分化合物I-a(40mg)溶于20mL二氯甲烷和乙醇的混合液中(V二氯甲烷:V二氯甲烷=1:10)中,于室温下静置7天,有单晶析出,收集单晶进行单晶衍射测试。测试参数如表3所示:
表3单晶测试参数
具体的结构鉴定的氢谱、碳谱和单晶图,如图1、图2和图3所示。
实施例2:合成化合物Ⅰ-b
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-b0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-b。
淡黄色固体;收率为91%;>20:1dr,m.p.224.3-224.9℃。
结构鉴定:1H NMR(400MHz,CDCl3)δ8.64(dd,J=8.5,2.2Hz,1H),8.52(d,J=2.1Hz,1H),8.44(d,J=8.4Hz,1H),7.74(d,J=8.3Hz,1H),7.44(d,J=8.2Hz,2H),7.41–7.36(m,1H),7.34–7.26(m,1H),7.15–7.04(m,4H),7.00–6.91(m,1H),6.91–6.82(m,1H),6.33(d,J=7.8Hz,1H),5.50(s,1H),4.41(s,2H),3.66(s,1H),2.25(s,3H);13C NMR(101MHz,CDCl3)δ200.4,161.4(d,J=249.1Hz),158.5,149.2,145.6,142.9,135.7,132.9,132.5,131.0(d J=8.8Hz),130.5,130.1,128.5,127.1,124.7,124.3,123.0,120.3,116.4,116.0(d,J=22.4Hz),105.3,75.6,55.7,53.0,21.6;HRMS(ESI)calcd.forC31H22FN3O7S[M+Na]+622.1055,found:622.1075。
实施例3:合成化合物Ⅰ-c
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-c0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-c。
淡黄色固体;收率为97%;>20:1dr,m.p.224.1-224.7℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.45(d,J=8.5Hz,1H),8.35(d,J=2.3Hz,1H),7.73(dd,J=8.5,2.1Hz,3H),7.56–7.52(m,1H),7.42–7.37(m,1H),7.34(d,J=8.2Hz,2H),7.26–7.21(m,1H),7.08–7.04(m,1H),7.01(d,J=7.9Hz,1H),7.00–6.96(m,1H),6.08(dd,J=7.9,1.3Hz,1H),5.64(d,J=2.7Hz,1H),4.51(dd,J=7.9,2.7Hz,1H),4.43(d,J=11.2Hz,1H),3.95(dd,J=11.2,7.8Hz,1H),2.32(s,3H);13C NMR(151MHz,DMSO-d6)δ201.4,162.1(d,J=243.7Hz),159.2,149.0,145.8,143.1,137.4(d,J=7.4Hz),136.4,133.4,133.2,130.7,130.6,130.5,130.4,128.9(d,J=22.4Hz),127.7,124.6,123.5,119.4,115.9(d,J=20.5Hz),115.7,106.0,75.1,56.2,53.9,53.0,21.5;HRMS(ESI)calcd.for C31H22FN3O7S[M+Na]+622.1055,found:622.1056。
实施例4:合成化合物Ⅰ-d
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-d0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-d。
淡黄色固体;收率为92%;>20:1dr,m.p.224.0-224.9℃。
结构鉴定:1H NMR(300MHz,DMSO-d6)δ8.77(dd,J=8.5,2.3Hz,1H),8.45(d,J=8.4Hz,1H),8.35(d,J=2.3Hz,1H),7.72(dd,J=8.3,2.4Hz,3H),7.60–7.48(m,1H),7.33(d,J=8.0Hz,2H),7.24–7.15(m,4H),6.99(t,J=7.6Hz,1H),6.06(d,J=7.8Hz,1H),5.65(d,J=2.7Hz,1H),4.55–4.44(m,1H),4.38(d,J=11.5Hz,1H),3.89(dd,J=11.5,7.8Hz,1H),2.31(s,3H);13C NMR(75MHz,DMSO-d6)δ200.9,162.1(d,J=244.0Hz),158.8,148.5,145.3,142.6,135.9,132.8(d,J=20.3Hz),132.3,132.2,130.2,130.1,128.8,128.4,127.2,124.2,123.1,119.0,115.2(d,J=9.0Hz),114.9,105.6,74.5,55.8,53.2,52.6,21.0;HRMS(ESI)calcd.for C31H22FN3O7S[M+Na]+622.1055,found:622.1064。
实施例5:合成化合物Ⅰ-e
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-e0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-e。
淡黄色固体;收率为91%;>20:1dr,m.p.229.1-229.8℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.77(dd,J=8.4,2.3Hz,1H),8.46(d,J=8.4Hz,1H),8.35(d,J=2.3Hz,1H),7.74(dd,J=8.4,2.0Hz,3H),7.57–7.52(m,1H),7.49–7.45(m,1H),7.38(t,J=7.9Hz,1H),7.34(d,J=8.1Hz,2H),7.25–7.22(m,1H),7.16(dt,J=7.9,1.3Hz,1H),7.03–6.94(m,1H),5.66(d,J=2.7Hz,1H),4.50(dd,J=8.0,2.7Hz,1H),4.42(d,J=11.3Hz,1H),3.94(dd,J=11.4,7.9Hz,1H),2.32(s,3H);13C NMR(151MHz,DMSO-d6)δ201.4,159.2,148.9,145.8,143.1,137.2,136.4,133.4,133.2,133.1,130.7,130.6,130.3,129.4,129.0,128.9,128.8,127.7,124.5,123.5,119.4,115.7,105.9,75.0,56.3,53.7,53.0,21.5;HRMS(ESI)calcd.for C31H22ClN3O7S[M+Na]+638.0759,found:638.0761。
实施例6:合成化合物Ⅰ-f
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-f0.12 mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-f。
淡黄色固体;收率为98%;>20:1dr,m.p.218.3-219.2℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.77(dd,J=8.4,2.3Hz,1H),8.46(d,J=8.5Hz,1H),8.35(d,J=2.3Hz,1H),7.74(dd,J=8.5,2.2Hz,3H),7.58–7.51(m,1H),7.46–7.40(m,2H),7.34(d,J=8.2Hz,2H),7.21(d,J=8.1Hz,2H),7.05–6.96(m,1H),6.12(dd,J=7.8,1.6Hz,1H),5.66(t,J=1.9Hz,1H),4.52–4.47(m,1H),4.40(d,J=11.5Hz,1H),3.94–3.82(m,1H),2.31(s,3H);13C NMR(151MHz,DMSO-d6)δ201.3,159.3,148.9,145.8,143.1,136.4,133.8,133.5,133.4,133.2,132.5,130.7,130.6,129.1,128.8,128.6,127.6,124.7,123.5,119.4,115.7,105.9,74.9,56.2,53.6,53.0,21.5;HRMS(ESI)calcd.for C31H22ClN3O7S[M+Na]+638.0759,found:638.0749。
实施例7:合成化合物Ⅰ-g
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-g0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-g。
淡黄色固体;收率为91%;>20:1dr,m.p.229.2-229.9℃。
结构鉴定:1H NMR(300MHz,CDCl3)δ8.70(dd,J=8.4,2.2Hz,1H),8.57(d,J=2.2Hz,1H),8.47(d,J=8.4Hz,1H),7.82(d,J=8.2Hz,1H),7.58–7.43(m,5H),7.15(d,J=8.1Hz,2H),7.03–6.88(m,3H),6.21(dd,J=7.9,1.3Hz,1H),5.51(d,J=2.8Hz,1H),4.42–4.31(m,1H),4.13(d,J=11.7Hz,1H),3.64(dd,J=11.7,7.9Hz,1H),2.34(s,3H);13C NMR(75MHz,CDCl3)δ199.8,158.2,149.1,145.6,143.1,135.5,133.0,132.7,131.9,131.4,130.8,130.5,130.0,129.6,128.3,126.9,124.8,123.5,122.5,120.3,116.5,105.6,75.4,55.3,54.9,52.7,21.6;HRMS(ESI)calcd.for C31H22BrN3O7S[M+Na]+684.0238,found:684.0243。
实施例8:合成化合物Ⅰ-h
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-h0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-h。
淡黄色固体;收率为93%;>20:1dr,m.p.218.8-219.5℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.47(d,J=8.4Hz,1H),8.35(d,J=2.3Hz,1H),7.80–7.71(m,5H),7.59–7.51(m,1H),7.44(d,J=8.1Hz,2H),7.35(d,J=8.2Hz,2H),7.02–6.94(m,1H),6.06(dd,J=7.8,1.3Hz,1H),5.69(d,J=2.6Hz,1H),4.58–4.48(m,2H),4.00–3.92(m,1H),2.32(s,3H);13C NMR(151MHz,DMSO-d6)δ201.4,159.3,148.9,145.8,143.1,139.5,136.4,133.5,133.3,131.8,130.7,130.6,128.9,128.7,127.7,127.4(q,J=272.5Hz),125.4,125.3,124.6,123.5,119.4,115.6,105.8,75.0,56.4,53.6,53.0,21.5;HRMS(ESI)calcd.for C32H22F3N3O7S[M+Na]+672.1023,found:672.1034。
实施例9:合成化合物Ⅰ-i
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-i0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-i。
淡黄色固体;收率为85%;>20:1dr,m.p.208.5-209.2℃。
结构鉴定:1H NMR(300MHz,DMSO-d6)δ8.77(dd,J=8.4,2.3Hz,1H),8.43(d,J=8.4Hz,1H),8.34(d,J=2.3Hz,1H),7.71(dd,J=9.9,8.1Hz,3H),7.60–7.48(m,1H),7.32(d,J=8.0Hz,2H),7.12–6.96(m,3H),6.90(d,J=8.4Hz,2H),6.12–6.01(m,1H),5.61(d,J=2.7Hz,1H),4.44(d,J=7.8Hz,1H),4.24(d,J=11.9Hz,1H),3.87–3.79(m,1H),3.77(s,3H),2.30(s,3H);13C NMR(75MHz,DMSO-d6)δ200.8,159.4,158.8,148.5,145.3,142.6,135.9,133.0,132.6,131.1,130.2,130.1,129.2,128.3,127.1,125.2,124.2,123.1,119.0,115.3,113.5,105.7,74.5,55.3,55.2,53.7,52.5,21.0;HRMS(ESI)calcd.forC32H25N3O8S[M+Na]+634.1255,found:634.1264。
实施例10:合成化合物Ⅰ-j
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-j0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-j。
淡黄色固体;收率为99%;>20:1dr,m.p.214.6-215.3℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.69(dd,J=8.4,2.3Hz,1H),8.36(d,J=8.5Hz,1H),8.26(d,J=2.3Hz,1H),7.64(d,J=8.3Hz,1H),7.62–7.57(m,2H),7.47–7.43(m,1H),7.22(d,J=8.2Hz,2H),7.18–7.10(m,2H),6.90–6.81(m,3H),5.92(dd,J=7.9,1.3Hz,1H),5.53(d,J=2.8Hz,1H),4.39(dd,J=7.9,2.8Hz,1H),4.19(d,J=11.6Hz,1H),3.80(dd,J=11.6,7.8Hz,1H),2.22(s,3H),2.16(s,3H);13C NMR(151MHz,DMSO-d6)δ201.3,159.2,149.0,145.7,143.1,137.7,136.3,134.0,133.4,133.1,132.0,130.7,130.6,129.7,129.6,129.1,128.8,128.5,127.5,124.5,123.5,119.5,115.8,106.2,75.2,65.5,55.8,54.7,53.1,30.5,21.5,21.4;HRMS(ESI)calcd.for C32H25N3O7S[M+Na]+618.1305,found:618.1305。
实施例11:合成化合物Ⅰ-k
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-k0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-k。
淡黄色固体;收率为99%;>20:1dr,m.p.220.6-221.3℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.70(dd,J=8.4,2.3Hz,1H),8.37(d,J=8.4Hz,1H),8.27(d,J=2.3Hz,1H),7.65(d,J=8.2Hz,1H),7.64–7.59(m,2H),7.49–7.43(m,1H),7.24(d,J=8.3Hz,2H),7.12(d,J=7.9Hz,2H),6.97(d,J=7.9Hz,2H),6.92–6.86(m,1H),5.94(dd,J=7.9,1.3Hz,1H),5.54(d,J=2.8Hz,1H),4.39(dd,J=8.0,2.7Hz,1H),4.21(d,J=11.8Hz,1H),3.80(dd,J=11.8,7.8Hz,1H),2.56(q,J=7.6Hz,2H),2.23(s,3H),1.13(t,J=7.6Hz,3H);13C NMR(151MHz,DMSO-d6)δ201.2,159.2,149.0,145.7,144.7,143.1,136.3,133.4,133.1,131.2,130.7,130.6,130.3,129.5,128.7,128.0,127.5,124.6,123.5,119.5,115.8,106.2,75.0,55.6,54.4,53.0,28.3,21.5,15.9;HRMS(ESI)calcd.for C33H27N3O7S[M+Na]+632.1462,found:632.1443。
实施例12:合成化合物Ⅰ-l
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-l0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-l。
淡黄色固体;收率为96%;>20:1dr,m.p.233.9-324.5℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.44(d,J=8.4Hz,1H),8.35(d,J=2.3Hz,1H),7.72(d,J=8.2Hz,1H),7.71–7.67(m,2H),7.55–7.50(m,1H),7.31(d,J=8.2Hz,2H),7.22(d,J=8.0Hz,2H),7.05(d,J=7.9Hz,2H),6.97–6.91(m,1H),5.97(dd,J=7.9,1.3Hz,1H),5.62(d,J=2.8Hz,1H),4.47(dd,J=8.0,2.7Hz,1H),4.29(d,J=11.7Hz,1H),3.88(dd,J=11.7,7.8Hz,1H),2.92(p,J=6.9Hz,1H),2.31(s,3H),1.22(d,J=6.9Hz,6H);13C NMR(151MHz,DMSO-d6)δ201.3,159.2,149.4,149.0,145.7,143.1,136.3,133.4,133.1,131.4,130.7,130.6,130.2,129.5,128.8,127.5,126.5,124.6,123.5,119.5,115.8,106.2,75.1,55.7,54.5,53.1,33.6,24.3,24.2,21.5;HRMS(ESI)calcd.for C34H29N3O7S[M+Na]+646.1618,found:646.1629。
实施例13:合成化合物Ⅰ-m
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-m0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-m。
淡黄色固体;收率为95%;>20:1dr,m.p.219.4-220.1℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.44(dd,J=8.4,1.1Hz,1H),8.34(d,J=2.3Hz,1H),7.73(dd,J=8.3,0.9Hz,1H),7.70–7.66(m,2H),7.57–7.51(m,1H),7.32(d,J=8.1Hz,2H),7.12(d,J=8.0Hz,1H),7.00–6.97(m,1H),6.85(d,J=6.8Hz,2H),6.06(dd,J=7.8,1.3Hz,1H),5.61(d,J=2.8Hz,1H),4.44(dd,J=8.1,2.7Hz,1H),4.20(d,J=11.9Hz,1H),3.84(dd,J=11.9,7.8Hz,1H),2.31(s,3H),2.24(s,3H),2.16(s,3H);13C NMR(151MHz,DMSO-d6)δ201.2,159.2,149.0,145.7,143.1,137.2,136.4,136.3,133.5,133.1,131.4,131.1,130.7,130.6,129.7,129.6,128.7,127.5,124.5,123.5,119.5,115.8,106.1,75.0,55.6,54.5,53.0,21.5,19.8,19.6;HRMS(ESI)calcd.for C33H27N3O7S[M+Na]+632.1462,found:632.1459。
实施例14:合成化合物Ⅰ-n
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-n0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-n。
淡黄色固体;收率为97%;>20:1dr,m.p.216.4-217.1℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.79(dd,J=8.4,2.3Hz,1H),8.49(d,J=8.5Hz,1H),8.39(d,J=2.3Hz,1H),7.75–7.66(m,4H),7.58–7.52(m,1H),7.40(dd,J=8.5,2.3Hz,1H),7.31(dd,J=14.3,8.4Hz,3H),7.09–7.03(m,1H),6.48(dd,J=7.9,1.3Hz,1H),5.62(d,J=3.0Hz,1H),4.75(d,J=9.9Hz,1H),4.66(dd,J=8.2,2.9Hz,1H),3.92(dd,J=9.9,8.1Hz,1H),2.30(s,3H);13C NMR(151MHz,DMSO-d6)δ201.6,159.3,149.1,145.9,142.9,136.1,136.0,134.4,133.6,133.3,132.9,132.3,131.0,130.6,129.4,129.2,129.0,127.7,127.5,124.8,123.1,119.4,115.8,105.7,75.5,58.5,53.1,51.0,21.5;HRMS(ESI)calcd.for C31H21Cl2N3O7S[M+Na]+72.0369,found:672.0364。
实施例15:合成化合物Ⅰ-o
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-o0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-o。
淡黄色固体;收率为88%;>20:1dr,m.p.221.0-221.7℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.82(dd,J=8.4,2.3Hz,1H),8.54(d,J=8.4Hz,1H),8.35(d,J=2.3Hz,1H),7.98–7.94(m,2H),7.83(d,J=8.8Hz,1H),7.74(d,J=8.2Hz,1H),7.72–7.68(m,2H),7.53–7.46(m,3H),7.45–7.41(m,1H),7.40(d,J=7.3Hz,1H),7.31(d,J=8.2Hz,2H),6.93–6.87(m,1H),6.06(dd,J=7.9,1.3Hz,1H),5.72(d,J=3.0Hz,1H),5.30(d,J=10.6Hz,1H),4.64(dd,J=8.1,2.9Hz,1H),4.06(dd,J=10.6,8.0Hz,1H),2.28(s,3H);13C NMR(151MHz,DMSO-d6)δ201.7,159.6,149.0,145.8,142.9,136.6,133.7,133.3,133.1,133.0,131.2,130.8,130.6,129.7,129.5,129.2,129.1,128.8,127.6,127.0,126.3,125.0,124.3,123.6,123.1,119.5,115.7,106.2,75.4,58.4,52.9,49.0,21.5;HRMS(ESI)calcd.for C35H25N3O7S[M+Na]+654.1305,found:654.1310。
实施例16:合成化合物Ⅰ-p
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-p0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-p。
淡黄色固体;收率为94%;>20:1dr,m.p.219.9-220.5℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.80(dd,J=8.4,2.3Hz,1H),8.49(d,J=8.4Hz,1H),8.36(d,J=2.3Hz,1H),7.98–7.92(m,1H),7.87(dd,J=12.1,7.8Hz,2H),7.79–7.71(m,4H),7.59–7.49(m,3H),7.33(d,J=8.1Hz,2H),7.28–7.22(m,1H),6.86(t,J=7.6Hz,1H),5.99(d,J=7.8Hz,1H),5.70(d,J=2.8Hz,1H),4.61–4.48(m,2H),4.05(dd,J=11.5,7.8Hz,1H),2.31(s,3H);13C NMR(151MHz,DMSO-d6)δ201.4,159.3,149.0,145.8,143.1,136.4,133.4,133.2,133.1,132.8,131.9,130.7,130.6,129.3,128.8,128.4,128.0,127.9,127.6,127.1,127.0,124.6,123.6,119.5,115.8,106.2,75.2,56.2,54.7,53.1,21.5;HRMS(ESI)calcd.for C35H25N3O7S[M+Na]+654.1305,found:654.1300。
实施例17:合成化合物Ⅰ-q
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-a 0.1mmol,2-烯基茚酮Ⅲ-q0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-q。
淡黄色固体;收率为92%;>20:1dr,m.p.234.0-234.8℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.76(dd,J=8.4,2.3Hz,1H),8.41(d,J=8.4Hz,1H),8.35(d,J=2.3Hz,1H),7.73(t,J=8.4Hz,3H),7.64–7.58(m,1H),7.56–7.49(m,1H),7.34(d,J=8.2Hz,2H),7.10(dd,J=5.1,3.6Hz,1H),7.06(d,J=2.9Hz,1H),7.01–6.95(m,1H),6.02–5.94(m,1H),5.63(d,J=2.7Hz,1H),4.71(d,J=11.9Hz,1H),4.43(dd,J=7.9,2.7Hz,1H),3.74(dd,J=11.9,7.9Hz,1H),2.33(s,3H);13C NMR(151MHz,DMSO-d6)δ200.6,159.0,148.9,145.7,143.4,136.9,136.2,133.7,133.3,130.8,130.6,130.6,129.2,128.8,128.2,127.6,127.3,124.8,123.8,119.4,115.6,105.6,74.8,56.7,53.0,49.1,21.5;HRMS(ESI)calcd.for C29H21N3O2S2[M+Na]+610.0713,found:610.0721。
实施例18:合成化合物Ⅰ-r
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-b 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-r。
淡黄色固体;收率为89%;>20:1dr,m.p.243.8-244.7℃。
结构鉴定:1H NMR(400MHz,DMSO-d6)δ8.78(dd,J=8.5,2.3Hz,1H),8.44–8.39(m,1H),8.36(d,J=2.3Hz,1H),7.74(dd,J=9.1,4.5Hz,1H),7.69–7.63(m,2H),7.48–7.30(m,6H),7.20–7.16(m,2H),5.66–5.55(m,2H),4.52(dd,J=8.0,2.8Hz,1H),4.36(d,J=11.2Hz,1H),3.97(dd,J=11.2,7.9Hz,1H),2.32(s,3H);13C NMR(101MHz,DMSO-d6)δ201.3,159.1,158.6(d,J=242.5Hz),149.0,145.9,139.5(d,J=1.9Hz),136.4,134.0,133.0,130.8,130.7,130.2,129.3,128.8,128.7,127.6,125.3(d,J=9.2Hz),120.3(d,J=24.0Hz),119.5,117.6(d,J=9.0Hz),115.9(d,J=26.1Hz),105.7(d,J=2.0Hz),75.8,55.6,54.9,53.1,21.5;HRMS(ESI)calcd.for C31H22FN3O7S[M+Na]+622.1055,found:622.1069。
实施例19:合成化合物Ⅰ-s
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-c 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-s。
淡黄色固体;收率为82%;>20:1dr,m.p.213.5-214.3℃。
结构鉴定:1H NMR(400MHz,DMSO-d6)δ8.87(dd,J=8.5,2.3Hz,1H),8.58–8.51(m,1H),8.45(d,J=2.3Hz,1H),7.94–7.81(m,2H),7.55(dd,J=9.7,2.5Hz,1H),7.53–7.42(m,5H),7.30–7.24(m,2H),6.99–6.90(m,1H),6.07(dd,J=8.7,5.6Hz,1H),5.75(d,J=2.7Hz,1H),4.66–4.55(m,1H),4.43(d,J=11.5Hz,1H),4.06(dd,J=11.5,7.9Hz,1H),2.43(s,3H);13C NMR(101MHz,DMSO-d6)δ201.2,165.0(d,J=250.4Hz),159.0,149.0,146.1,144.8(d,J=11.9Hz),136.4,134.1,133.2,131.2(d,J=10.5Hz),130.8,130.7,130.4,129.2,128.8,128.7,127.7,119.7,119.5,112.0(d,J=23.1Hz),105.6,103.2(d,J=28.6Hz),75.8,55.9,54.5,53.0,21.5;HRMS(ESI)calcd.for C31H22FN3O7S[M+Na]+622.1055,found:622.1059.
实施例20:合成化合物Ⅰ-t
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-d 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-t。
淡黄色固体;收率为89%;>20:1dr,m.p.222.8-223.3℃。
结构鉴定:1H NMR(400MHz,DMSO-d6)δ8.75(dd,J=8.5,2.3Hz,1H),8.34(d,J=2.3Hz,1H),8.19–8.12(m,1H),7.72–7.63(m,2H),7.46–7.42(m,1H),7.41–7.35(m,4H),7.18(dd,J=4.4,1.1Hz,1H),7.15–7.12(m,2H),7.10–7.04(m,1H),5.85(dd,J=7.9,1.1Hz,1H),5.80(d,J=3.2Hz,1H),4.47(dd,J=8.2,3.2Hz,1H),4.39(d,J=11.8Hz,1H),3.90(dd,J=11.7,8.0Hz,1H),2.36(s,3H);13C NMR(101MHz,DMSO-d6)δ201.1,159.1,151.8(d,J=253.5Hz),149.0,145.9,136.3,134.1,133.6,130.8,130.7,130.1,129.3,129.1,128.8,128.4,128.2(d,J=2.0Hz),127.8,127.0(d,J=6.7Hz),125.6(d,J=3.8Hz),120.6(d,J=19.4Hz),119.6,105.6(d,J=1.8Hz),76.6,55.4,54.7,52.5,21.5;HRMS(ESI)calcd.for C31H22FN3O7S[M+Na]+622.1055,found:622.1069。
实施例21:合成化合物Ⅰ-u
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-e 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-u。
淡黄色固体;收率为86%;>20:1dr,m.p.256.0-256.7℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.42(dd,J=8.3,1.1Hz,1H),8.36(d,J=2.3Hz,1H),7.72(t,J=8.3Hz,3H),7.60(dd,J=8.8,2.3Hz,1H),7.45–7.41(m,1H),7.40–7.32(m,4H),7.18(d,J=7.5Hz,2H),5.81(d,J=2.3Hz,1H),5.61(d,J=2.7Hz,1H),4.56–4.47(m,1H),4.37(d,J=11.2Hz,1H),3.99(dd,J=11.2,7.9Hz,1H),2.33(s,3H);13C NMR(151MHz,DMSO-d6)δ201.3,159.0,149.0,146.0,142.0,136.4,134.1,133.1,133.0,130.8,130.7,130.3,129.3,129.1,128.8,128.7,128.4,127.6,125.3,119.5,117.4,105.7,75.6,55.8,54.8,53.1,21.5;HRMS(ESI)calcd.forC31H22ClN3O7S[M+Na]+638.0759,found:638.0758。
实施例22:合成化合物Ⅰ-v
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-f0.1 mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-v。
淡黄色固体;收率为75%;>20:1dr,m.p.277.9-278.7℃。
结构鉴定:1H NMR(400MHz,DMSO-d6)δ8.87(dd,J=8.4,2.3Hz,1H),8.56(d,J=8.5Hz,1H),8.47(d,J=2.3Hz,1H),8.07(dd,J=8.6,1.8Hz,1H),7.99–7.86(m,3H),7.57–7.45(m,5H),7.37–7.27(m,2H),6.28(d,J=1.7Hz,1H),5.84(d,J=2.5Hz,1H),4.74–4.67(m,1H),4.55(d,J=10.8Hz,1H),4.12(dd,J=10.8,7.9Hz,1H),2.45(s,3H);13C NMR(101MHz,DMSO-d6)δ201.3,158.8,149.0,146.5,146.4,137.1,136.5,134.5,133.3,133.2,130.9,130.6,130.5,129.3,128.9,128.7,127.8,124.4,119.4,118.2,116.0,106.4,105.4,75.7,56.4,54.8,53.3,21.5;HRMS(ESI)calcd.for C32H22N4O7S[M+Na]+629.1101,found:629.1077。
实施例23:合成化合物Ⅰ-w
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-g 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钠(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-w。
淡黄色固体;收率为76%;>20:1dr,m.p.230.4-231.2℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.77(dd,J=8.4,2.3Hz,1H),8.43(d,J=8.4Hz,1H),8.35(d,J=2.2Hz,1H),7.69–7.64(m,2H),7.61(d,J=8.3Hz,1H),7.43–7.39(m,1H),7.38–7.33(m,3H),7.32(d,J=8.2Hz,2H),7.15–7.11(m,2H),5.70–5.64(m,1H),5.58(d,J=2.8Hz,1H),4.46(dd,J=8.1,2.7Hz,1H),4.32(d,J=11.5Hz,1H),3.88(dd,J=11.5,7.9Hz,1H),2.31(s,3H),2.00(s,3H);13C NMR(151MHz,DMSO-d6)δ201.4,159.3,149.0,145.6,140.8,136.3,134.3,133.7,133.6,133.4,130.7,130.6,130.4,129.7,129.1,128.7,128.5,127.6,123.7,119.5,115.6,106.2,75.3,55.7,54.6,53.1,21.5,20.8;HRMS(ESI)calcd.for C32H24N3O7S[M+Na]+618.1305,found:618.1315。
实施例24:合成化合物Ⅰ-x
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在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-h 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-x。
淡黄色固体;收率为76%;>20:1dr,m.p.213.9-214.8℃。
结构鉴定:1H NMR(600MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.43(d,J=8.4Hz,1H),8.34(d,J=2.2Hz,1H),7.70(d,J=8.4Hz,2H),7.55(s,1H),7.42–7.38(m,1H),7.38–7.30(m,4H),7.17–7.10(m,2H),6.81–6.75(m,1H),5.84(d,J=8.0Hz,1H),5.59(d,J=2.8Hz,1H),4.43(dd,J=7.9,2.8Hz,1H),4.28(d,J=11.8Hz,1H),3.89(dd,J=11.8,7.8Hz,1H),2.37(s,3H),2.31(s,3H);13C NMR(151MHz,DMSO-d6)δ201.3,159.3,149.0,145.7,143.5,143.3,136.3,134.0,133.5,130.7,130.6,130.3,129.1,129.0,128.7,128.6,127.5,125.6,120.7,119.5,116.1,106.0,75.3,55.5,54.4,53.0,21.9,21.5;HRMS(ESI)calcd.for C32H24N3O7S[M+Na]+618.1305,found:618.1308。
实施例25:合成化合物Ⅰ-y
在一根干燥的反应试管中依次加入3-硝基吲哚Ⅱ-i 0.1mmol,2-烯基茚酮Ⅲ-a0.12mmol,碳酸钾(1.0equiv),相转移催化剂TEBA和二氯甲烷(1.0mL),室温搅拌反应,待反应完全后,粗产品经柱色谱分离纯化得化合物I-y。
淡黄色固体;收率为92%;>20:1dr,m.p.227.9-228.5℃。
结构鉴定:1H NMR(400MHz,DMSO-d6)δ8.78(dd,J=8.4,2.3Hz,1H),8.50–8.42(m,1H),8.35(d,J=2.3Hz,1H),7.84–7.79(m,2H),7.78–7.74(m,1H),7.71–7.65(m,1H),7.58–7.49(m,3H),7.41–7.32(m,3H),7.15(dt,J=6.8,1.5Hz,2H),7.01–6.90(m,1H),6.03–5.92(m,1H),5.62(d,J=2.8Hz,1H),4.54–4.45(m,1H),4.34(d,J=11.6Hz,1H),3.91(dd,J=11.6,7.9Hz,1H);13C NMR(101MHz,DMSO-d6)δ201.3,159.2,149.0,143.0,136.3,136.3,135.0,134.1,133.2,130.7,130.4,130.2,129.4,129.1,128.8,128.6,127.5,124.7,123.6,119.5,115.9,106.2,75.1,55.7,54.5,53.0;HRMS(ESI)calcd.for C30H21N3O7S[M+Na]+590.0992,found:590.1002。
生物活性试验:
试验方法:将5000个人前列腺癌细胞PC-3接种到96孔细胞培养板中,并让其生长24小时。然后分别加入一定浓度的上述合成的化合物,以抗肿瘤药物顺铂作为对照,作用48h。然后测定所有化合物的平均50%的抑制浓度(IC50)。每个浓度至少重复3次,所有实验重复3次,得到的平均结果见表1。
表1:前列腺癌细胞PC-3活性测定结果(顺铂:IC50=20.33)
化合物 | I-a | I-b | I-h | I-i | I-n | I-r | I-q | I-r | I-t | I-w |
IC50(uM) | 28.35 | 20.40 | 19.23 | 8.53 | 14.78 | 21.74 | 9.32 | 20.56 | 24.56 | 10.01 |
从表1可以看出,本发明的化合物,具有与顺铂相当甚至更好的抗PC-3活性。
Claims (8)
1.五并环吲哚啉类化合物,其特征在于,具有如下结构式所示的结构:
2.一种权利要求1所述的五并环吲哚啉类化合物的制备方法,其特征在于:将3-硝基吲哚(Ⅱ)、2-烯基茚酮(Ⅲ)溶解在有机溶剂中,然后加碱和相转移催化剂,在室温下搅拌反应,待反应完毕后,分离纯化得到五并环吲哚啉类化合物,其中,
所述3-硝基吲哚(Ⅱ)具有如下结构:
所述2-烯基茚酮(Ⅲ)具有如下结构:
其中,上述结构式中的R、R1和R2为权利要求1所述化合物的相应取代基。
3.根据权利要求2所述的制备方法,其特征在于:所述的反应溶剂选自甲苯、均三甲苯、二氯甲烷、氯仿、四氢呋喃、乙醚、乙腈、乙醇、甲醇、1,4-二氧六环、氯苯中的一种或者多种混合。
4.根据权利要求2所述的制备方法,其特征在于:所述碱为碳酸铯、碳酸钾、碳酸钠、氢氧化钠、氢氧化钾或三乙胺。
5.根据权利要求2所述的制备方法,其特征在于:所述相转移催化剂为季铵盐、季膦盐或冠醚。
6.根据权利要求5所述的制备方法,其特征在于:所述相转移催化剂为四丁基碘化铵、四丁基溴化铵、苄基三乙基氯化铵或18-冠-6。
7.根据权利要求5所述的制备方法,其特征在于:所述相转移催化剂为苄基三乙基氯化铵。
8.权利要求1所述的五并环吲哚啉类化合物在制备用于抗肿瘤的药物中的应用,其特征在于,所述肿瘤为人前列腺癌细胞PC-3。
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