CN113444101A - 环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物及其制备方法及应用 - Google Patents

环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物及其制备方法及应用 Download PDF

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CN113444101A
CN113444101A CN202110622646.3A CN202110622646A CN113444101A CN 113444101 A CN113444101 A CN 113444101A CN 202110622646 A CN202110622646 A CN 202110622646A CN 113444101 A CN113444101 A CN 113444101A
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田民义
刘雄利
周韦
何学雯
周英
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Abstract

本发明公开了一种戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物，本发明以将各种取代的色酮‑茚二酮底物1作为3C合成子，和各种取代的3‑烯氧化吲哚底物2，在有机溶剂中，在有机小分子三级胺催化剂的催化作用下，进行反应，获得环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物3，该类化合物包含潜在生物活性环戊环并色满酮骨架和螺环茚二酮骨架以及螺环氧化吲哚骨架，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。且该骨架化合物对人白血病细胞具有抑制活性的作用。本发明操作简单易行，原料合成便宜易得，可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。

Description

环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物及其制 备方法及应用
技术领域
本发明涉及化学技术和药学技术领域，尤其是一种环戊环并色满酮拼接双螺 环茚二酮氧化吲哚类化合物及其制备方法及应用。
背景技术
根据药物设计的活性骨架拼接原理，把两个或多个具有生物活性骨架拼接成 一个潜在生物活性的多骨架分子在有机化学和医药化学中是极其重要的研究领 域。(1)环戊环并色满酮骨架广泛存在天然产物和合成药物分子中，吸引了许多 化学工作者及医药化学团队的广泛关注，例如：天然产物分子Cryptosporioptide, Preussochromones D,Diaportheone B和Cryptosporioptide B。(2)螺环茚二酮骨 架也普遍存在天然产物和药物分子中。例如:天然产物分子Fredericamycin A， tephrosin和Indacrinone(MK-196)共享一个螺环茚二酮骨架单元。(3)螺环氧化 吲哚骨架也普遍存在天然产物和药物分子中。例如:天然产物分子Citrinalin A， Cyclopiamine B和Marcfortine B。鉴于环戊环并色满酮骨架和螺环茚二酮骨架以 及螺环氧化吲哚骨架具有潜在的生物活性。因此，把环戊环并色满酮骨架和螺环 茚二酮骨架拼接到螺环氧化吲哚骨架上，合成一系列新的潜在多活性官能团的环 戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物，可以为生物活性筛选提供化 合物源，对药物的筛选和制药行业具有重要的应用价值(如图6所示)。
发明内容
本发明的目的是：提供一种环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化 合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似 物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明还发现该类化合物在制备在防治肿瘤K562(人慢性髓系白血病)细 胞的药物应用。
本发明是这样实现的：一种环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化 合物，该化合物具有如下通式(I)的结构：
Figure BDA0003100509590000021
式中，R1为甲基、甲氧基、卤素或氢；R2为甲基、甲氧基、卤素或氢。
环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的制备方法，将各种取 代的色酮-茚二酮底物1作为3C合成子，和各种取代的3-烯氧化吲哚底物2，在 有机溶剂中，在有机小分子三级胺催化剂的催化作用下，进行[3+2]环加成反应， 获得环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物3。
合成路线举例如下：
Figure BDA0003100509590000022
其中合成路线中的化合物，其取代基满足式中，R1为甲基、甲氧基、卤素 或氢；R2为甲基、甲氧基、卤素或氢。
反应机理如下：
Figure BDA0003100509590000023
所述的有机溶剂为所述的有机溶剂为氯仿、甲苯、四氢呋喃、二氯甲烷或乙 醇。
所述的有机小分子三级胺催化剂为DABCO或三乙胺或环己基二胺衍生的 碱性催化剂或1,2-二苯基二胺衍生的碱性催化剂或金鸡纳碱衍生的碱性催化剂。
环己基二胺衍生的碱性催化剂或1,2-二苯基二胺衍生的碱性催化剂或金鸡 纳碱衍生的碱性催化剂，举例如下：
Figure BDA0003100509590000031
各种取代的色酮-茚二酮底物1作为3C合成子，和各种取代的3-烯氧化吲哚 底物2，在有机溶剂中，在有机小分子三级胺催化剂的催化作用下，进行[3+2] 环加成反应，反应时间为1-48小时。
环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物在防治肿瘤K562(人 慢性髓系白血病)细胞的药物应用。
通过采用上述技术方案，以各种取代的色酮-茚二酮底物1作为3C合成子， 和各种取代的3-烯氧化吲哚底物2，在有机溶剂中，在有机小分子三级胺催化剂 的催化作用下，进行[3+2]环加成反应，获得环戊环并色满酮拼接双螺环茚二酮 氧化吲哚类化合物3，该类化合物包含潜在生物活性环戊环并色满酮骨架和螺环 茚二酮骨架以及螺环氧化吲哚骨架，可以为生物活性筛选提供化合物源，对药物 的筛选和制药行业具有重要的应用价值。且该骨架化合物对人白血病细胞 (K562)具有抑制活性的作用。本发明操作简单易行，原料合成便宜易得，可 以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代 基都有很好的兼容性。
附图说明
图1-2为本发明的实施例的化合物3a谱图数据；
图3-4为本发明的实施例的化合物3b谱图数据；
图5为本发明的实施例的化合物3j和3p单晶图；
图6为本发明所合成的化合物的设计思路及其创造性；
图7为本发明所合成的化合物3d-3zd的结构式示意图。
具体实施方式
本发明的实施例：在反应管中依次加入色酮-茚二酮底物1a(0.30mmol)，3-烯氧化吲哚 底物2a(0.20mmol)，催化剂Et3N(20mol％,0.04mmol)和1.5mL CHCl3，室温中搅拌反应15 小时，TLC检测基本反应完全，直接上样经柱层析(洗脱剂：V(石油醚)：V(乙酸乙酯) ＝8:1～5:1)纯化得化合物3a，浅黄色固体,熔点：195.7-197.2℃；产率76％,20:1dr。核磁 共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.73(s,9H),2.75(s,3H), 4.11(d,J＝14.4Hz,1H),4.41(s,1H),5.68(d,J＝14.0Hz,1H),6.83(d,J＝8.4Hz,1H), 6.88-6.92(m,1H),7.21-7.25(m,1H),7.33-7.37(m,2H),7.56-7.59(m,1H),7.82-7.89(m,3H),8.02-8.06(m,2H),8.25(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.1,54.7,54.9, 55.0,58.6,82.1,86.0,115.2,117.2,119.9,121.3,121.9,122.9,123.8,125.0,126.2,127.8,128.4, 129.9,134.5,135.1,135.4,139.8,140.0,142.8,159.9,164.9,169.7,176.3,188.5,197.3,199.9； HRMS(ESI-TOF)m/z:Calcd.for C34H27NNaO8[M+Na]+:600.1629.
化合物3b至3zi的制备方法同化合物3a，投料比与化合物3a相同，可得到化合物3b至3zi，反应产率和dr值见表1和表2，但需强调的是本发明的化合物不限于表1和表2所 表示的内容。
表1为一种环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的化学结构
Figure BDA0003100509590000041
表2为一种环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的化学结构
Figure BDA0003100509590000051
本实施例制备化合物3b:浅黄色固体,熔点：244.9-246.4℃,产率71％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.77(s,9H),2.73(s,3H),3.77 (s,3H),4.09(d,J＝14.4Hz,1H),5.65(d,J＝14.4Hz,1H),6.83-6.92(m,3H),7.34-7.38(m,1H), 7.49(d,J＝2.8Hz,1H),7.56-7.58(m,1H),7.81-7.89(m,2H),8.02-8.06(m,2H),8.17(d,J＝9.2 Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.2,25.7,54.3,54.6,54.6,54.7,58.1,81.7,85.7,108.7, 113.5,115.9,116.8,119.6,120.9,121.6,122.5,125.8,128.7,132.8,134.1,134.7,135.0,139.6, 142.5,156.6,159.5,164.5,169.0,175.9,188.1,197.0,199.4；HRMS(ESI-TOF)m/z:Calcd.for C35H29NNaO9[M+Na]+:630.1735；Found:630.1737.
本实施例制备化合物3c:浅黄色固体,熔点：276.9-278.4℃,产率69％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.75(s,9H),2.32(s,3H),2.74 (s,3H),4.11(d,J＝14.0Hz,1H),5.66(d,J＝14.0Hz,1H),6.83(d,J＝8.4Hz,1H),6.88-6.92 (m,1H),7.14(d,J＝8.4Hz,1H),7.33-7.37(m,1H),7.56-7.58(m,1H),7.60(s,1H),7.82-7.90 (m,2H),8.02-8.07(m,2H),8.12(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.3,25.7, 26.1,54.7,54.8,55.0,58.5,82.1,86.0,115.0,117.2,120.0,121.2,121.9,122.8,124.2,126.2, 127.7,128.8,134.4,134.8,135.1,135.3,137.5,139.9,142.9,160.0,165.0,169.6,176.5,188.6, 197.5,199.8；HRMS(ESI-TOF)m/z:Calcd.for C35H29NNaO8[M+Na]+:614.1785；Found: 614.1783.
本实施例制备化合物3d:浅黄色固体,熔点：259.0-260.5℃,产率75％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.78(s,9H),2.74(s,3H),4.09 (d,J＝14.0Hz,1H),4.41(s,1H),5.62(d,J＝14.4Hz,1H),6.84(d,J＝8.4Hz,1H),6.89-6.93 (m,1H),7.02-7.07(m,1H),7.35-7.38(m,1H),7.57(d,J＝6.8Hz,1H),7.63-7.66(m,1H), 7.83-7.90(m,2H),8.02-8.06(m,2H),8.24-8.27(m,1H)；13C NMR(CDCl3,100MHz)δ:25.6, 26.1,54.8,54.9,55.1,58.2,82.5,85.9,111.5(d,JC,F＝25.2Hz),114.8(d,JC,F＝23.3Hz),116.7 (d,JC,F＝8.1Hz),117.1,119.9,121.4,122.0,122.9,126.2,129.8,134.6,135.1,135.4,135.8, 140.0,142.7,159.7(d,JC,F＝244.1Hz),159.8,164.6,169.5,175.8,188.2,197.1,199.9；HRMS (ESI-TOF)m/z:Calcd.forC34H26FNNaO8[M+Na]+:618.1535；Found:618.1539.
本实施例制备化合物3e:浅黄色固体,熔点：285.5-287.0℃,产率76％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.79(s,9H),2.74(s,3H),4.08 (d,J＝14.4Hz,1H),4.40(s,1H),5.63(d,J＝14.0Hz,1H),6.84(d,J＝8.4Hz,1H),6.89-6.93 (m,1H),7.32-7.39(m,2H),7.56-7.59(m,1H),7.83-7.91(m,3H),8.03-8.08(m,2H),8.21(d,J＝ 8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.2,25.7,54.2,54.3,54.6,57.6,82.1,85.3,116.0, 116.6,119.4,120.9,121.5,122.4,123.6,125.8,127.9,129.2,130.0,134.1,134.7,135.0,137.7, 139.5,142.3,159.3,164.1,169.0,175.2,187.7,196.6,199.3；HRMS(ESI-TOF)m/z:Calcd.for C34H26ClNNaO8[M+Na]+:634.1239；Found:634.1241.
本实施例制备化合物3f:浅黄色固体,熔点：269.4-270.9℃,产率74％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.74(s,3H),4.08 (d,J＝14.0Hz,1H),4.40(s,1H),5.63(d,J＝14.0Hz,1H),6.84(d,J＝8.0Hz,1H),6.90-6.93 (m,1H),7.35-7.39(m,1H),7.47-7.50(m,1H),7.56-7.59(m,1H),7.83-7.91(m,2H),7.97(d,J＝ 2.0Hz,1H),8.03-8.08(m,2H),8.16(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7, 26.2,54.6,54.7,55.1,58.1,82.6,85.8,116.9,117.1,118.1,119.9,121.4,122.1,122.9,126.2, 126.8,130.0,131.3,134.6,135.1,135.4,138.7,140.0,142.8,159.7,164.6,169.5,175.5,188.2, 197.1,199.8；HRMS(ESI-TOF)m/z:Calcd.for C34H26BrNNaO8[M+Na]+:678.0734；Found: 678.0731.
本实施例制备化合物3g:浅黄色固体,熔点：269.0-270.5℃,产率64％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.73(s,3H),4.08 (d,J＝14.0Hz,1H),5.62(d,J＝14.0Hz,1H),6.83(d,J＝8.4Hz,1H),6.90-6.93(m,1H), 7.35-7.39(m,1H),7.56-7.58(m,1H),7.68-7.70(m,1H),7.83-7.91(m,2H),8.03(d,J＝8.4Hz, 1H),8.08(d,J＝6.8Hz,1H),8.12(d,J＝1.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.2, 54.4,54.7,55.1,58.1,82.7,85.8,88.6,117.1,117.2,119.9,121.4,122.1,122.9,126.2,130.2, 132.5,134.5,135.1,135.4,137.4,139.4,140.0,142.8,159.7,164.6,169.5,175.4,188.2,197.2, 199.7；HRMS(ESI-TOF)m/z:Calcd.forC34H26INNaO8[M+Na]+:726.0595；Found:726.0598.
本实施例制备化合物3h:浅黄色固体,熔点：216.9-218.4℃,产率66％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.82(s,9H),2.21(s,3H),2.38 (s,3H),2.80(s,3H),4.15(d,J＝14.0Hz,1H),4.46(s,1H),5.70(d,J＝14.4Hz,1H),6.79(d,J＝ 8.8Hz,1H),7.20-7.24(m,2H),7.42(d,J＝1.6Hz,1H),7.66(s,1H),7.90-7.95(m,2H), 8.09-8.13(m,2H),8.18(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.3,20.3,25.7,26.1, 54.8,54.9,55.1,58.4,82.0,86.1,115.0,116.9,119.6,121.9,122.8,124.2,125.8,127.7,128.7, 130.7,134.4,134.8,135.0,136.3,137.5,139.9,142.9,158.1,165.0,169.6,176.5,188.8,197.5, 199.8；HRMS(ESI-TOF)m/z:Calcd.forC35H29NNaO9[M+Na]+:630.1735；Found:630.1736.
本实施例制备化合物3i:浅黄色固体,熔点：213.3-214.8℃,产率64％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.77(s,9H),2.73(s,3H),3.60 (s,3H),3.77(s,3H),4.07(d,J＝14.4Hz,1H),4.41(s,3H),5.61(d,J＝14.4Hz,1H),6.77(d,J＝ 9.2Hz,1H),6.84-6.87(m,1H),6.94-6.97(m,1H),6.99(d,J＝3.2Hz,1H),7.49(d,J＝2.8Hz, 1H),7.81-7.89(m,2H),8.02-8.05(m,2H),8.16(d,J＝8.8Hz,1H)；13CNMR(CDCl3,100MHz) δ:25.6,26.1,54.6,54.7,55.0,55.1,58.5,82.1,86.3,106.6,109.0,113.8,116.3,118.4,119.9, 121.9,122.8,124.3,129.1,133.2,134.4,135.0,140.0,142.8,153.5,154.6,156.9,164.9,169.4, 176.3,188.6,197.4,199.8；HRMS(ESI-TOF)m/z:Calcd.for C36H31NNaO10[M+Na]+:660.1840； Found:660.1844.
本实施例制备化合物3j:浅黄色固体,熔点：211.3-212.8℃,产率65％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.75(s,9H),2.31(s,3H),2.73 (s,3H),3.59(s,3H),4.09(d,J＝14.0Hz,1H),4.39(s,1H),5.62(d,J＝14.4Hz,1H),6.75(d,J＝ 8.8Hz,1H),6.93-6.96(m,1H),6.99(d,J＝2.8Hz,1H),7.12-7.15(m,1H),7.59(s,1H), 7.81-7.89(m,2H),8.02-8.07(m,2H),8.11(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ: 20.3,25.7,26.1,54.6,54.8,54.9,55.1,58.4,82.0,86.2,106.5,115.0,118.4,119.9,121.9,122.8, 124.2,124.3,128.7,134.4,134.8,135.0,153.5,154.7,165.0,169.6,188.7,197.5；HRMS (ESI-TOF)m/z:Calcd.for C36H31NNaO9[M+Na]+:644.1891；Found:644.1889.
本实施例制备化合物3k:浅黄色固体,熔点：246.4-247.9℃,产率63％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.79(s,9H),2.74(s,3H),3.60 (s,3H),4.06(d,J＝14.0Hz,1H),4.41(s,1H),5.57(d,J＝14.0Hz,1H),6.76(d,J＝8.8Hz,1H), 6.94-6.97(m,1H),6.99(d,J＝8.1Hz,1H),7.02-7.07(m,1H),7.63-7.66(m,1H),7.83-7.91(m, 2H),8.03-8.06(m,2H),8.23-8.27(m,1H)；13C NMR(CDCl3,100MHz)δ:25.6,26.1,54.6,54.8, 54.9,55.1,58.2,82.5,86.1,106.6,111.5(d,JC,F＝26.2Hz),114.8(d,JC,F＝22.4Hz),116.6,116.7, 118.3,119.8,121.9,122.8,124.4,129.8(d,JC,F＝9.1Hz),134.6,135.1,135.8,140.0,142.7,153.6, 154.5,159.7(d,JC,F＝244.3Hz),164.7,169.5,175.9,188.4,197.1,199.9；HRMS(ESI-TOF)m/z: Calcd.for C35H28FNNaO9[M+Na]+:648.1640；Found:648.1643.
本实施例制备化合物3l:浅黄色固体,熔点：198.3-199.5℃,产率66％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.76(s,9H),2.16(s,3H),2.77 (s,3H),4.11(d,J＝14.4Hz,1H),4.42(s,1H),5.65(d,J＝14.0Hz,1H),6.75(d,J＝7.6Hz,1H), 7.17-7.20(m,1H),7.23-7.27(m,1H),7.35-7.39(m,2H),7.84-7.92(m,3H),8.04-8.08(m,2H), 8.27(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.3,25.7,26.1,54.7,55.0,55.1,58.6, 82.1,86.1,115.2,116.9,119.6,121.9,122.8,123.8,125.0,125.8,127.9,128.4,130.8,134.4, 135.1,136.4,139.8,140.0,142.9,158.1,164.9,169.7,176.3,188.7,197.4,200.0；HRMS (ESI-TOF)m/z:Calcd.for C35H29NNaO8[M+Na]+:614.1785；Found:614.1789.
本实施例制备化合物3m:浅黄色固体,熔点：179.1-180.6℃,产率66％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.84(s,9H),2.21(s,3H),2.80 (s,3H),3.84(s,3H),4.13(d,J＝14.0Hz,1H),4.48(s,1H),5.68(d,J＝14.0Hz,1H),6.80(d,J＝ 8.4Hz,1H),6.91-6.94(m,1H),7.22-7.25(m,1H),7.42(d,J＝1.6Hz,1H),7.56(d,J＝2.4Hz, 1H),7.88-7.96(m,2H),8.09-8.12(m,2H),8.24(d,J＝9.2Hz,1H)；13CNMR(CDCl3,100MHz) δ:20.3,26.6,27.1,55.7,56.0,56.1,56.2,59.5,83.1,87.2,110.1,114.8,117.3,118.0,120.6,123.0, 123.8,126.8,130.2,131.8,134.2,135.4,136.1,137.4,141.0,143.9,158.0,159.1,166.0,170.4, 177.3,189.7,198.5,200.8；HRMS(ESI-TOF)m/z:Calcd.for C36H31NNaO9[M+Na]+:644.1891； Found:644.1895.
本实施例制备化合物3n:浅黄色固体,熔点：158.0-159.5℃,产率67％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.82(s,9H),2.21(s,3H),2.38 (s,3H),2.80(s,3H),4.15(d,J＝14.0Hz,1H),4.46(s,1H),5.70(d,J＝14.4Hz,1H),6.79(d,J＝ 8.8Hz,1H),7.20-7.24(m,2H),7.41(d,J＝1.6Hz,1H),7.66(s,1H),7.88-7.96(m,2H), 8.09-8.13(m,2H),8.19(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.3,20.3,25.7,26.1, 54.8,54.9,55.1,58.4,82.0,86.1,115.0,116.9,119.6,121.9,122.8,124.2,125.8,127.7,128.7, 130.7,134.4,134.8,135.0,136.3,137.5,139.9,142.9,158.1,165.0,169.6,176.5,188.8,197.5, 199.8；HRMS(ESI-TOF)m/z:Calcd.forC36H31NNaO8[M+Na]+:628.1942；Found:628.1947.
本实施例制备化合物3o:浅黄色固体,熔点：189.1-180.6℃,产率71％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.78(s,9H),2.14(s,3H),2.73 (s,3H),4.06(d,J＝14.0Hz,1H),4.40(s,1H),5.58(d,J＝14.0Hz,1H),6.73(d,J＝8.8Hz,1H), 7.01-7.07(m,1H),7.15-7.18(m,1H),7.35(d,J＝1.6Hz,1H),7.63-7.65(m,1H),7.83-7.90(m, 2H),8.02-8.05(m,2H),8.23-8.26(m,1H)；13C NMR(CDCl3,100MHz)δ:19.3,25.6,26.1,55.0, 55.1,58.2,82.4,86.0,111.5(d,JC,F＝26.2Hz),114.8(d,JC,F＝22.5Hz),116.6(d,JC,F＝8.3Hz), 116.9,119.5,121.9,122.8,125.8,129.9,131.0,134.6,135.1,136.4,140.1,142.8,157.9,159.7(d, JC,F＝245.2Hz),164.7,169.5,175.9,188.4,197.2,199.9；HRMS(ESI-TOF)m/z:Calcd.for C35H28FNNaO8[M+Na]+:632.1691；Found:632.1695.
本实施例制备化合物3p:浅黄色固体,熔点：213.6-215.1℃,产率69％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.79(s,9H),2.14(s,3H),2.74 (s,3H),4.05(d,J＝14.0Hz,1H),4.40(s,1H),5.59(d,J＝14.4Hz,1H),6.72(d,J＝8.8Hz,1H), 7.15-7.18(m,1H),7.31-7.35(m,2H),7.83-7.90(m,3H),8.02-8.07(m,2H),8.21(d,J＝8.8Hz, 1H)；13C NMR(CDCl3,100MHz)δ:19.3,25.7,26.1,54.7,54.9,55.1,58.1,82.6,85.9,116.5, 116.8,119.5,122.0,122.8,124.0,125.8,128.3,129.8,130.5,131.0,134.5,135.1,136.4,138.2, 140.0,142.8,157.9,164.7,169.5,175.7,188.4,197.2,199.8；HRMS(ESI-TOF)m/z:Calcd.for C35H28ClNNaO8[M+Na]+:648.1396；Found:648.1397.
本实施例制备化合物3q:浅黄色固体,熔点：231.7-233.2℃,产率67％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.14(s,3H),2.73 (s,3H),4.05(d,J＝14.0Hz,1H),4.39(s,1H),5.58(d,J＝14.0Hz,1H),6.72(d,J＝8.4Hz,1H), 7.15-7.18(m,1H),7.34(d,J＝2.4Hz,1H),7.47-7.49(m,1H),7.82-7.90(m,2H),7.97(d,J＝2.0 Hz,1H),8.02-8.07(m,2H),8.15(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.3,25.7, 26.2,54.6,54.8,55.1,58.1,82.6,85.9,116.8,118.0,119.5,122.0,122.8,125.8,126.8,130.1, 131.0,131.2,134.5,135.1,136.4,138.7,140.0,142.8,157.9,164.7,169.5,175.6,188.4,197.2, 199.8；HRMS(ESI-TOF)m/z:Calcd.forC35H28BrNNaO8[M+Na]+:692.0891；Found:692.0896.
本实施例制备化合物3r:浅黄色固体,熔点：152.5-154.0℃,产率61％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.14(s,3H),2.73 (s,3H),4.05(d,J＝14.0Hz,1H),4.39(s,1H),5.57(d,J＝14.4Hz,1H),6.72(d,J＝8.4Hz,1H), 7.15-7.18(m,1H),7.34(s,1H),7.67-7.69(m,1H),7.85-7.89(m,2H),8.02-8.08(m,3H),8.12(d, J＝1.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.3,26.7,27.2,55.4,55.9,56.2,59.1,83.6,86.9, 89.7,117.9,118.2,120.6,123.1,123.9,126.9,131.4,132.0,133.5,135.5,136.1,137.5,138.3, 140.4,141.1,143.8,158.9,165.7,170.6,176.5,189.4,198.3,200.7；HRMS(ESI-TOF)m/z: Calcd.for C35H28INNaO8[M+Na]+:740.0752；Found:740.0752.
本实施例制备化合物3s:浅黄色固体,熔点：246.1-247.6℃,产率64％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.82(s,3H),4.16 (d,J＝14.0Hz,1H),4.47(s,1H),5.74(d,J＝14.0Hz,1H),6.88-6.92(m,1H),7.13-7.18(m,1H), 7.26-7.32(m,2H),7.41-7.45(m,1H),7.89-7.96(m,3H),8.09-8.13(m,2H),8.32(d,J＝8.0Hz, 1H)；13C NMR(CDCl3,100MHz)δ:25.0,25.3,53.8,54.2,58.0,81.5,85.5,110.5(d,JC,F＝24.2 Hz),114.5,118.1,118.2,119.8(d,JC,F＝6.3Hz),121.2,122.0(d,JC,F＝21.4Hz),122.2,123.0, 124.3,126.9,127.7,133.8,134.4,139.1,139.2,142.0,155.4,155.7(d,JC,F＝242.3Hz),164.0, 168.9,175.4,186.9,196.4,199.1；HRMS(ESI-TOF)m/z:Calcd.for C34H26FNNaO8[M+Na]+: 618.1535；Found:618.1536.
本实施例制备化合物3t:浅黄色固体,熔点：232.2-233.7℃,产率74％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.84(s,9H),2.80(s,3H),3.85 (s,3H),4.14(d,J＝14.4Hz,1H),4.47(s,1H),5.71(d,J＝14.4Hz,1H),6.89-6.95(m,2H), 7.13-7.18(m,1H),7.26-7.31(m,1H),7.54(s,1H),7.90-7.98(m,2H),8.09-8.13(m,2H),8.24(d, J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.6,25.1,53.7,53.9,54.0,57.5,81.2,85.3, 108.1,110.3(d,JC,F＝23.2Hz),112.9,115.4,117.8(d,JC,F＝7.2Hz),119.6,121.0,121.8(d,JC,F＝24.3Hz),121.9,127.9,132.2,133.6,134.2,138.9,141.8,155.1,155.5(d,JC,F＝242.2Hz), 156.0,163.8,168.3,175.1,186.6,196.2,198.7；HRMS(ESI-TOF)m/z:Calcd.for C35H28FNNaO9 [M+Na]+:648.1640；Found:648.1640.
本实施例制备化合物3u:浅黄色固体,熔点：268.2-269.7℃,产率64％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.82(s,9H),2.39(s,3H),2.80 (s,3H),4.16(d,J＝14.0Hz,1H),4.45(s,1H),5.73(d,J＝14.4Hz,1H),6.88-6.91(m,1H), 7.12-7.17(m,1H),7.21-7.23(m,1H),7.23-7.30(m,1H),7.65(s,1H),7.90-7.98(m,2H), 8.09-8.14(m,2H),8.19(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.3,25.7,26.0,54.5, 54.6,54.9,58.5,82.2,86.2,111.3(d,JC,F＝24.4Hz),115.1,118.8,118.9,120.6(d,JC,F＝7.5Hz), 122.0,122.7(d,JC,F＝24.2Hz),122.9,124.1,127.5,128.8,134.5,134.9,135.2,137.5,139.9, 142.8,156.2,156.7(d,JC,F＝243.3Hz),164.9,169.5,176.4,187.7,197.3,199.7；HRMS (ESI-TOF)m/z:Calcd.for C35H28FNNaO8[M+Na]+:632.1691；Found:632.1694.
本实施例制备化合物3v:浅黄色固体,熔点：187.3-188.8℃,产率75％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.85(s,9H),2.81(s,3H),4.14 (d,J＝14.0Hz,1H),4.47(s,1H),5.68(d,J＝14.0Hz,1H),6.89-6.92(m,1H),7.10-7.19(m,2H), 7.28-7.31(m,1H),7.68-7.71(m,1H),7.92-7.99(m,2H),8.10-8.13(m,2H),8.31-8.34(m,1H)； 13C NMR(CDCl3,100MHz)δ:25.6,26.1,54.6,54.9,58.3,82.6,86.1,111.3(d,JC,F＝23.2Hz), 111.5(d,JC,F＝25.1Hz),114.9(d,JC,F＝22.4Hz),116.7(d,JC,F＝7.7Hz),118.8(d,JC,F＝8.2 Hz),122.0,122.9(d,JC,F＝24.1Hz),123.0,134.7,135.2,140.0,142.7,156.0,156.4(d,JC,F＝ 243.1Hz),159.5(d,JC,F＝244.1Hz),164.5,169.4,175.7,187.4,196.9,199.8；HRMS(ESI-TOF) m/z:Calcd.for C34H25F2NNaO8[M+Na]+:636.1440；Found:636.1443.
本实施例制备化合物3w:浅黄色固体,熔点：271.5-273.0℃,产率65％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87(s,9H),2.81(s,3H),4.13 (d,J＝14.0Hz,1H),4.46(s,1H),5.68(d,J＝14.0Hz,1H),6.89-6.92(m,1H),7.14-7.19(m,1H), 7.28-7.31(m,1H),7.55-7.58(m,1H),7.91-7.99(m,2H),8.02(d,J＝2.0Hz,1H),8.10-8.15(m, 2H),8.23(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:26.7,27.2,55.5,56.0,59.2,83.8, 87.1,112.3(d,JC,F＝23.4Hz),117.9,119.1,119.8(d,JC,F＝8.1Hz),123.1,123.9,124.0(d,JC,F＝ 24.3Hz),127.9,130.9,132.4,135.7,136.2,139.7,141.0,143.7,157.0,157.6(d,JC,F＝240.1Hz), 165.5,170.5,176.5,188.4,198.0,200.7；HRMS(ESI-TOF)m/z:Calcd.for C34H25BrFNNaO8 [M+Na]+:696.0640；Found:696.0645.
本实施例制备化合物3x:浅黄色固体,熔点：284.3-285.8℃,产率66％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87(s,9H),2.80(s,3H),4.13 (d,J＝13.6Hz,1H),4.45(s,1H),5.68(d,J＝14.4Hz,1H),6.88-6.92(m,1H),7.14-7.19(m,1H), 7.28-7.30(m,1H),7.75-7.78(m,1H),7.91-7.99(m,2H),8.09-8.18(m,4H)；13C NMR(CDCl3, 100MHz)δ:25.7,26.2,54.2,54.4,54.9,58.1,82.8,86.0,88.7,111.3(d,JC,F＝24.3Hz),117.2, 118.8(d,JC,F＝7.5Hz),122.1,122.9,123.0(d,JC,F＝25.2Hz),130.1,132.5,134.7,135.2,137.4, 139.4,140.0,142.7,156.0,157.0(d,JC,F＝243.0Hz),164.5,169.5,175.3,187.3,197.0,199.6； HRMS(ESI-TOF)m/z:Calcd.for C34H25FINNaO8[M+Na]+:744.0501；Found:744.0504.
本实施例制备化合物3y:浅黄色固体,熔点：234.2-235.7℃,产率65％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.82(s,3H),4.15 (d,J＝14.0Hz,1H),4.46(s,1H),5.73(d,J＝14.4Hz,1H),6.88(d,J＝8.8Hz,1H),7.29-7.33 (m,1H),7.36-7.38(m,1H),7.41-7.45(m,1H),7.59(d,J＝2.8Hz,1H),7.89-7.98(m,3H), 8.09-8.13(m,2H),8.32(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.1,54.5,54.6, 54.9,58.7,82.3,86.1,115.3,118.8,120.9,121.9,122.9,123.8,125.1,125.5,126.9,127.5,128.5, 134.6,135.1,135.2,139.8,139.9,142.8,158.4,164.7,169.6,176.1,187.3,197.1,199.8；HRMS (ESI-TOF)m/z:Calcd.for C34H26ClNNaO8[M+Na]+:634.1239；Found:634.1241.
本实施例制备化合物3z:浅黄色固体,熔点：212.2-213.7℃,产率78％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.84(s,9H),2.79(s,3H),3.84 (s,3H),4.13(d,J＝14.0Hz,1H),4.46(s,1H),5.71(d,J＝14.0Hz,1H),6.88(d,J＝8.8Hz,1H), 6.92-6.95(m,1H),7.36-7.39(m,1H),7.53-7.59(m,2H),7.89-7.96(m,2H),8.09-8.13(m,2H), 8.23(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.8,25.3,53.8,53.9,54.0,54.1,57.8, 81.5,85.4,108.3,113.1,115.6,118.1,120.1,121.2,122.1,124.8,126.1,128.0,132.4,133.8, 134.3,134.4,139.1,142.0,156.2,157.6,164.0,168.5,175.3,186.5,196.3,198.9；HRMS (ESI-TOF)m/z:Calcd.for C35H28ClNNaO9[M+Na]+:664.1345；Found:664.1346.
本实施例制备化合物3za:浅黄色固体,熔点：245.5-247.0℃,产率73％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.82(s,9H),2.39(s,3H),2.80 (s,3H),4.16(d,J＝14.0Hz,1H),4.45(s,1H),5.72(d,J＝14.0Hz,1H),6.87(d,J＝8.8Hz,1H), 7.21-7.23(m,1H),7.35-7.38(m,1H),7.59-7.65(m,2H),7.89-7.98(m,2H),8.09-8.14(m,2H), 8.19(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.9,25.3,25.7,54.1,54.2,54.5,58.2, 81.8,85.7,114.7,118.5,120.5,121.6,122.5,123.7,125.2,126.5,127.1,128.5,134.2,134.5, 134.7,134.8,137.0,139.5,142.5,158.1,164.5,169.1,176.0,187.0,196.9,199.3；HRMS (ESI-TOF)m/z:Calcd.for C35H28ClNNaO8[M+Na]+:648.1396；Found:648.1392.
本实施例制备化合物3zb:浅黄色固体,熔点：241.0-242.5℃,产率74％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.85(s,9H),2.80(s,3H),4.13 (d,J＝14.0Hz,1H),4.47(s,1H),5.68(d,J＝14.0Hz,1H),6.88(d,J＝8.8Hz,1H),7.10-7.15 (m,1H),7.37-7.40(m,1H),7.59(d,J＝2.8Hz,1H),7.68-7.71(m,1H),7.91-7.99(m,2H), 8.10-8.13(m,2H),8.31-8.34(m,1H)；13C NMR(CDCl3,100MHz)δ:25.1,25.6,53.9,54.1,54.4, 57.7,82.1,85.4,110.8(d,JC,F＝26.1Hz),114.4(d,JC,F＝23.3Hz),116.1(d,JC,F＝8.2Hz),118.2, 120.3,121.5,122.4,125.0,126.5,134.2,134.7,135.2,139.5,142.1,157.7,159.2(d,JC,F＝244.2 Hz),163.9,168.8,169.6,175.2,186.5,196.3,199.2；HRMS(ESI-TOF)m/z:Calcd.for C34H25ClFNNaO8[M+Na]+:652.1145；Found:652.1145.
本实施例制备化合物3zc:浅黄色固体,熔点：231.5-233.0℃,产率67％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.86(s,9H),2.80(s,3H),4.14 (d,J＝14.0Hz,1H),4.46(s,1H),5.68(d,J＝14.0Hz,1H),6.88(d,J＝8.8Hz,1H),7.37-7.41 (m,2H),7.59(d,J＝2.8Hz,1H),7.88(d,J＝2.4Hz,1H),7.91-7.99(m,2H),8.10-8.14(m,2H), 8.28(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.2,25.7,53.9,54.0,54.5,57.7,82.3, 85.5,116.1,118.3,120.4,121.6,122.5,123.6,125.2,126.7,128.1,129.0,130.2,134.3,134.8, 137.8,139.6,142.3,157.8,164.1,169.0,175.1,186.6,196.4,199.2；HRMS(ESI-TOF)m/z: Calcd.for C34H25Cl2NNaO8[M+Na]+:668.0849；Found:668.0852.
本实施例制备化合物3zd:浅黄色固体,熔点：211.4-212.9℃,产率65％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87(s,9H),2.80(s,3H),4.16 (d,J＝14.0Hz,1H),4.45(s,1H),5.68(d,J＝14.0Hz,1H),6.88(d,J＝9.2Hz,1H),7.37-7.40 (m,1H),7.55-7.59(m,2H),7.91-7.99(m,2H),8.02(s,1H),8.10-8.15(m,2H),8.22(d,J＝8.8 Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.1,54.4,54.5,54.9,58.1,82.8,85.9,116.9, 118.1,118.8,120.8,122.1,122.9,125.6,126.8,127.1,129.8,131.4,134.7,135.2,138.7,140.0, 142.7,158.2,164.5,169.4,175.4,187.0,196.9,199.6；HRMS(ESI-TOF)m/z:Calcd.for C34H25BrClNNaO8[M+Na]+:712.0344；Found:712.0342.
本实施例制备化合物3ze:浅黄色固体,熔点：233.3-234.8℃,产率65％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.80(s,9H),2.82(s,3H),4.15 (d,J＝14.0Hz,1H),4.46(s,1H),5.73(d,J＝14.0Hz,1H),6.82(d,J＝8.8Hz,1H),7.29-7.33 (m,1H),7.41-7.45(m,1H),7.49-7.52(m,1H),7.74(d,J＝2.4Hz,1H),7.89-7.98(m,3H), 8.09-8.12(m,2H),8.32(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.1,54.4,54.5, 54.9,58.7,82.3,86.1,114.0,115.3,119.2,121.3,121.9,122.9,123.8,125.1,127.5,128.5,128.7, 134.6,135.2,137.9,139.8,139.9,142.8,158.9,164.7,169.6,176.1,187.2,197.1,199.8；HRMS (ESI-TOF)m/z:Calcd.for C34H26BrNNaO8[M+Na]+:678.0734；Found:678.0732.
本实施例制备化合物3zf:浅黄色固体,熔点：239.9-241.4℃,产率68％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.84(s,9H),2.79(s,3H),3.84 (s,3H),4.12(d,J＝14.4Hz,1H),4.46(s,1H),5.70(d,J＝14.4Hz,1H),6.82(d,J＝9.2Hz,1H), 6.92-6.95(m,1H),7.49-7.54(m,2H),7.74(d,J＝2.4Hz,1H),7.89-7.97(m,2H),8.09-8.12(m, 1H),8.23(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.6,26.1,54.5,54.7,54.8,54.9, 58.5,82.2,86.1,109.0,113.9,114.0,116.4,119.2,121.3,122.0,122.9,128.7,128.8,133.2,134.6, 135.2,137.9,139.9,142.8,157.0,158.9,164.8,169.3,176.1,187.2,197.1,199.6；HRMS (ESI-TOF)m/z:Calcd.for C35H28BrNNaO9[M+Na]+:708.0840；Found:708.0842.
本实施例制备化合物3zg:浅黄色固体,熔点：263.0-264.5℃,产率67％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.81(s,9H),2.39(s,3H),2.80 (s,3H),4.15(d,J＝14.0Hz,1H),4.45(s,1H),5.73(d,J＝14.0Hz,1H),6.81(d,J＝8.8Hz,1H), 7.21-7.23(m,1H),7.48-7.51(m,1H),7.65(s,1H),7.74(d,J＝2.8Hz,1H),7.90-7.98(m,2H), 8.09-8.14(m,2H),8.19(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:20.3,25.7,26.0,54.3, 54.6,54.9,58.5,82.2,86.1,114.0,115.1,119.2,121.3,122.0,122.9,124.1,127.4,128.6,128.9, 134.5,134.9,135.2,137.5,137.9,139.9,142.8,158.9,164.8,169.5,176.3,187.3,197.2,199.6； HRMS(ESI-TOF)m/z:Calcd.forC35H28BrNNaO8[M+Na]+:692.0891；Found:692.0895.
本实施例制备化合物3zh:L浅黄色固体,熔点：176.9-178.4℃,产率66％,>20:1dr；核磁 共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.85(s,9H),2.80(s,3H), 4.13(d,J＝14.0Hz,1H),4.46(s,1H),5.67(d,J＝14.4Hz,1H),6.83(d,J＝9.2Hz,1H), 7.10-7.15(m,1H),7.50-7.53(m,1H),7.68-7.71(m,1H),7.74(d,J＝2.4Hz,1H),7.92-7.99(m, 2H),8.10-8.13(m,2H),8.30-8.34(m,1H)；13C NMR(CDCl3,100MHz)δ:25.6,26.1,54.4,54.6, 54.9,58.3,82.6,85.9,111.5(d,JC,F＝25.3Hz),114.2,115.0(d,JC,F＝23.4Hz),116.7(d,JC,F＝ 8.3Hz),119.1,121.3,122.0,122.9,128.7,129.5(d,JC,F＝8.4Hz),134.7,135.2,135.8,138.0, 140.0,142.7,158.7,159.7(d,JC,F＝245.2Hz),164.5,169.4,175.7,187.0,196.8,199.7；HRMS (ESI-TOF)m/z:Calcd.for C34H25BrFNNaO8[M+Na]+:696.0640；Found:696.0645.
本实施例制备化合物3zi:浅黄色固体,熔点：213.3-214.8℃,产率65％,>20:1dr；核磁共 振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.86(s,9H),2.80(s,3H),4.13 (d,J＝14.0Hz,1H),4.45(s,1H),5.69(d,J＝14.0Hz,1H),6.82(d,J＝8.8Hz,1H),7.39-7.42 (m,1H),7.50-7.53(m,1H),7.74(d,J＝2.4Hz,1H),7.89(d,J＝2.4Hz,1H),7.91-7.99(m,2H), 8.10-8.14(m,2H),8.28(d,J＝8.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.1,54.3,54.5, 54.9,58.1,82.7,85.9,114.2,116.5,119.1,121.3,122.1,122.9,124.0,128.5,128.7,129.4,130.6, 134.7,135.2,138.0,138.2,140.0,142.7,158.7,164.5,169.4,175.5,186.9,196.8,199.6；HRMS (ESI-TOF)m/z:Calcd.for C34H25BrClNNaO8[M+Na]+:712.0344；Found:712.0343.
本发明的式(1)化合物具有重要的生物活性，体外对人白血病细胞(K562) 肿瘤细胞的细胞毒性试验表明：此类式(1)所示结构的环戊环并色满酮拼接双 螺环茚二酮氧化吲哚类化合物，对人白血病细胞(K562)生长具有抑制作用， 有可能发展成为新的防治人慢性髓系白血病K562的药物。
药理实施例：化合物3对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养，培养基中含10％ 的胎牛血清，100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞 的浓度加入到96孔中，在37℃含5％CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后，分别将新配 的化合物3的二甲基亚砜溶液以浓度梯度加入到各孔中，使孔中化合物最终浓度 分别为3μmol/L,7μmol/L,15μmol/L,30μmol/L和60μmol/L。48小时后，每孔 加入10μL MTT(5mg/mL)的磷酸盐缓冲液，再继续在37℃培养4小时后， 离心5分钟除去未转化的MTT，每孔中加入150μL二甲基亚砜。以溶解还原的 MTT晶体甲臜(formazan)，用酶标仪在490nm波长测定OD值。其中化合物3 对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。阳性对照顺铂对 K562肿瘤细胞的IC50为19.97μmol/L。化合物3对K562肿瘤细胞的IC50见附图 7。
实验结论：K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评 价指标。本实验表明此类式(1)所示的环戊环并色满酮拼接双螺环茚二酮氧化 吲哚类化合物对K562细胞具有较强的细胞毒性，有可能发展成新的防治人慢性 髓系白血病K562的药物，值得继续深入研究下去。

Claims (6)

1.一种环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
Figure FDA0003100509580000011
式中，R1为甲基、甲氧基、卤素或氢；R2为甲基、甲氧基、卤素或氢。
2.一种如权利要求1所述的环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的制备方法，其特征在于：将各种取代的色酮-茚二酮底物1作为3C合成子，和各种取代的3-烯氧化吲哚底物2，在有机溶剂中，在有机小分子三级胺催化剂的催化作用下，进行[3+2]环加成反应，获得环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物3。
3.根据权利要求2所述的环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的制备方法，其特征在于：所述的有机溶剂为氯仿、甲苯、四氢呋喃、二氯甲烷或乙醇。
4.根据权利要求2所述的环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的制备方法，其特征在于：所述的有机小分子三级胺催化剂为DABCO或三乙胺或环己基二胺衍生的碱性催化剂或1,2-二苯基二胺衍生的碱性催化剂或金鸡纳碱衍生的碱性催化剂。
5.根据权利要求2所述的环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物的制备方法，其特征在于：将各种取代的色酮-茚二酮底物1作为3C合成子，和各种取代的3-烯氧化吲哚底物2，在有机溶剂中，在有机小分子三级胺催化剂的催化作用下，进行[3+2]环加成反应，反应时间为1-48小时。
6.一种如权利要求1所述的环戊环并色满酮拼接双螺环茚二酮氧化吲哚类化合物在防治肿瘤K562(人慢性髓系白血病)细胞的药物应用。
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CN110028519A (zh) * 2019-02-28 2019-07-19 贵州大学 山酮素骨架拼接双螺环氧化吲哚化合物及其制备方法及应用
CN112390804A (zh) * 2019-08-14 2021-02-23 贵州大学 环戊烷并色满酮拼接螺环氧化吲哚类化合物及其制备方法及应用

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