CN106478491B - 3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物及其制备方法及应用 - Google Patents

3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物及其制备方法及应用 Download PDF

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CN106478491B
CN106478491B CN201610876957.1A CN201610876957A CN106478491B CN 106478491 B CN106478491 B CN 106478491B CN 201610876957 A CN201610876957 A CN 201610876957A CN 106478491 B CN106478491 B CN 106478491B
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刘雄利
杨俊�
韩朔楠
陈智勇
周根
田民义
周英
俸婷婷
王丹丹
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Guizhou University
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Abstract

本发明公开了一种3‑氨甲基季碳氧化吲哚拼接3‑五元碳环螺环氧化吲哚类化合物及其制备方法及应用，该类骨架包含多重生物活性的3‑氨甲基季碳氧化吲哚骨架和3‑五元碳环螺环氧化吲哚骨架，可以为生物活性筛选提供化合物源，对多靶点多用途药物的筛选和制药行业具有重要的应用价值。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，适用性广且这些化合物具有开发成为抗肿瘤药物的潜力。

Description

3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合 物及其制备方法及应用
技术领域
本发明涉及药物化学技术领域，尤其是一种3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物及其制备方法及应用。
背景技术
基于药物设计中药效团和骨架迁越原理,把具有生物活性基团或骨架拼接到具有活性分子骨架中在有机化学和医药化学中是极其重要的研究领域。(1)、3-五元碳环螺环氧化吲哚骨架化合物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(如附图8所示)。(2)、许多具有重要生物活性分子3-季碳氧化吲哚化合物都含有3-胺甲基基团，例如：3-胺甲基基团存在于(S)-(-)-spirobrassinin,horsfiline,(+)-Dioxibrassinin和coerulescine分子骨架中。鉴于3-氨甲基季碳氧化吲哚骨架化合物和3-五元碳环螺环氧化吲哚骨架化合物具有多重生物活性。因此，把3-氨甲基季碳氧化吲哚骨架拼接到3-五元碳环螺环氧化吲哚骨架，合成一系列新的潜在多活性官能团的氧化吲哚衍生物，可以为生物活性筛选提供化合物源，对多靶点多用途药物的筛选和制药行业具有重要的应用价值(如附图8所示)。
发明内容
本发明的目的是：提供一种3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环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，对多靶点多用途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。
本发明是这样实现的3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物，该化合物具有如通式(Ⅰ)所示的结构：
式中，R1为甲基、乙基、苯基、苄基；R2为甲基、氢或卤素；R3为甲基、乙基、苯基或苄基；R4为甲基、氢或卤素；R5为烷基。
3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物的制备方法，其特征在于：由相应的氧化吲哚1与邻苯二甲醛2先发生knoevenagel缩合/Michael/环化反应，生成中间体4，然后中间体4再与仲胺与多聚甲醛发生胺甲基化反应，生成最终产物3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物5。
本发明还提供3-氨甲基季碳氧化吲哚拼接3-五元螺环氧化吲哚类化合物在制备防治肿瘤疾病药物的应用。
本发明合成路线如下：
其中，R1为甲基或乙基或苯基或苄基；R2为甲基或氢或卤素；R3为甲基或乙基或苯基或苄基；R4为甲基或氢或卤素；R5为烷基。
通过采用上述技术方案，以相应的氧化吲哚1与邻苯二甲醛2先发生knoevenagel缩合/Michael/环化反应，生成中间体4，然后中间体4再与仲胺与多聚甲醛发生胺甲基化反应，生成最终产物3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物5。它是一类重要的抗肿瘤活性先导化合物，对药物筛选和制药行业具有重要的应用价值，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
附图1及附图2为本发明的实施例1的化合物5a谱图数据；
附图3及附图4为本发明的实施例1的化合物5b谱图数据；
附图5及附图6为本发明的实施例1的化合物5c谱图数据。
附图7为本发明的实施例1的化合物4b和5k单晶图；
附图8为本发明的反应设计图。
具体实施方式
本发明的实施例1：在反应管中依次加入132.3毫克氧化吲哚1a(0.90mmol)，40.2毫克邻苯二甲醛2(0.3mmol)，哌啶(10mol％)和6.0毫升MeOH，搅拌回流16小时。反应完全后，柱层析(正己烷/乙酸乙酯＝4:1～2:1)分离得到100.9毫克中间体4。123毫克中间体4(0.3mmol)，51毫克哌啶3a(0.6mmol)溶于6.0毫升EtOAc，加入36毫克多聚甲醛(1.2mmol)，70℃油浴搅拌反应24小时。反应完全后，柱层析(正己烷/乙酸乙酯＝3:1～2:1)分离得到126.1毫克最终产物5a，白色固体，熔点：132.1-133.3℃，总产率68％；dr:>20/1。核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.22-1.28(m,6H),2.25-2.29(m,4H),2.53(s,3H),2.69(s,3H),2.94(d,J＝14.1Hz,1H),3.25(d,J＝14.1Hz,1H),4.72(s,1H),5.37(s,1H),6.20(d,J＝7.6Hz,1H),6.30(d,J＝8.0Hz,1H),6.44(d,J＝7.8Hz,1H),6.68-6.71(m,1H),6.90-6.92(m,1H),7.01-7.03(m,2H),7.31-7.33(m,2H),7.39-7.42(m,2H),8.16(d,J＝14.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:23.9,25.5,26.2,26.5,51.0,55.0,56.8,65.2,67.3,81.3,106.8,107.8,120.8,121.2,123.2,126.7,127.6,127.7,127.8,138.2,142.9,143.8,144.8,177.3,178.2；HRMS(ESI-TOF)m/z:Calcd.for C32H33N3NaO3[M+Na]+:530.2420；Found:530.2424.
化合物5b-5k’的制备方法同化合物5a，投料比与化合物5a相同，可得到化合物5b-5k’，反应产率和dr值见表1、表2和表3，但需强调的是本发明的化合物不限于表1、表2和表3所表示的内容。
表1为一种姜黄酮骨架拼接3-吡咯螺环氧化吲哚类化合物的化学结构
表2为一种姜黄酮骨架拼接3-吡咯螺环氧化吲哚类化合物的化学结构
表3为一种姜黄酮骨架拼接3-吡咯螺环氧化吲哚类化合物的化学结构
本实施例制备化合物4a:白色固体，熔点：231.6-231.9℃，产率82％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.84(d,J＝11.2Hz,1H),2.50(s,3H),2.63(s,3H),4.15(d,J＝2.0Hz,1H),4.68(d,J＝6.0Hz,1H),5.51(d,J＝10.8Hz,1H),6.37(d,J＝8.0Hz,1H),6.42(d,J＝7.8Hz,1H),6.66(d,J＝7.2Hz,1H),6.77-6.81(m,1H),6.99-7.03(m,1H),7.08-7.15(m,2H),7.29(s,1H),7.39-7.47(m,3H),7.72(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.5,25.9,43.0,50.0,66.3,80.6,107.1,107.7,121.3,121.5,125.4,125.6,127.9,128.0,128.1,138.0,142.1,144.2,144.8,174.7,177.9；HRMS(ESI-TOF)m/z:Calcd.for C26H22N2NaO3[M+Na]+:433.1528；Found:433.1527.
本实施例制备化合物4b:白色固体，熔点：224.5-225.3℃，产率78％；dr:12/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(DMSO-d6,400MHz)δ:0.77-0.84(m,6H),2.68-2.73(m,1H),2.89-2.94(m,1H),3.14-3.20(m,1H),3.27-3.35(m,1H),4.34(d,J＝5.2Hz,1H),4.47(d,J＝5.2Hz,1H),5.30(d,J＝6.4Hz,1H),5.52(d,J＝10.0Hz,1H),6.44(d,J＝6.8Hz,1H),6.54-6.57(m,2H),6.62-6.65(m,1H),6.88-6.92(m,1H),7.02-7.06(m,1H),7.09-7.13(m,2H),7.27-7.34(m,3H),7.61-7.63(m,1H)；13C NMR(DMSO-d6,100MHz)δ:12.4,12.6,33.6,34.0,42.6,49.7,66.0,79.6,107.1,107.2,119.8,120.7,124.9,125.3,126.9,127.0,127.2,138.6,142.9,143.1,143.2,173.7,177.2；HRMS(ESI-TOF)m/z:Calcd.forC28H26N2NaO3[M+Na]+:461.1841；Found:461.1844.
本实施例制备化合物5b:无色油状物，总产率65％；dr:10/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.92-0.96(m,3H),0.99-1.03(m,3H),1.17-1.25(m,8H),2.15-2.19(m,2H),2.31-2.38(m,2H),2.50-2.55(m,1H),2.73-2.76(m,1H),3.10(d,J＝13.2Hz,1H),3.24(d,J＝14.0Hz,1H),3.43-3.49(m,1H),3.58-3.68(m,1H),4.57(s,1H),5.37-5.39(m,1H),6.21(d,J＝7.8Hz,1H),6.34(d,J＝8.0Hz,1H),6.41(d,J＝6.8Hz,1H),6.65-6.68(m,1H),6.85-6.89(m,1H),6.98-7.04(m,2H),7.29-7.40(m,5H),8.14(d,J＝6.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:12.5,12.9,24.0,26.4,34.4,34.9,51.4,54.8,56.8,65.7,67.3,81.4,106.8,107.9,120.5,121.0,123.1,126.7,127.5,127.6,127.7,138.0,143.0,143.3,144.0,177.0,177.5；HRMS(ESI-TOF)m/z:Calcd.forC34H37N3NaO3[M+Na]+:558.2733；Found:558.2733.
本实施例制备化合物5c:白色固体，熔点：132.1-133.3℃，总产率64％；dr:12/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.24-1.26(m,8H),2.26-2.28(m,2H),2.36-2.37(m,2H),3.23(d,J＝14.0Hz,1H),3.34(d,J＝16.0Hz,1H),3.41(d,J＝14.0Hz,1H),3.63(d,J＝16.0Hz,1H),4.68(s,1H),4.85(d,J＝16.0Hz,1H),5.09(d,J＝15.8Hz,1H),5.51(d,J＝11.8Hz,1H),6.10(d,J＝7.6Hz,1H),6.19(d,J＝8.0Hz,1H),6.50(d,J＝7.8Hz,1H),6.74-6.78(m,1H),6.95-7.02(m,3H),7.08-7.11(m,2H),7.15-7.24(m,9H),7.34-7.36(m,2H),7.41-7.44(m,2H),8.25(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:23.9,26.0,43.5,43.6,51.8,55.0,57.1,65.9,67.4,81.8,108.1,109.1,121.4,123.1,124.3,124.8,126.6,127.0,127.2,127.4,127.5,127.7,127.9,128.4,128.7,128.9,129.3,135.6,136.1,137.8,142.9,177.4,178.1；HRMS(ESI-TOF)m/z:Calcd.forC44H41N3NaO3[M+Na]+:682.3046；Found:682.3045.
本实施例制备化合物5d:白色固体，熔点：231.1-232.3℃，总产率62％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.23-1.32(m,6H),2.18(s,3H),2.24(s,3H),2.29-2.31(m,4H),2.85(s,3H),2.88(d,J＝13.2Hz,1H),3.03(s,3H),3.23(d,J＝14.0Hz,1H),4.69(s,1H),5.35(d,J＝11.2Hz,1H),6.27-6.29(m,1H),6.58-6.62(m,1H),6.80-6.85(m,3H),7.25-7.39(m,5H),8.16(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.9,19.0,24.0,26.5,28.8,29.6,52.1,54.0,56.8,65.3,66.4,81.4,118.0,119.2,120.5,121.0,122.8,123.2,124.9,125.1,127.5,127.6,127.7,130.2,131.3,132.5,138.4,141.8,142.8,143.0,178.0,179.0；HRMS(ESI-TOF)m/z:Calcd.forC34H37N3NaO3[M+Na]+:558.2733；Found:558.2731.
本实施例制备化合物5e:白色固体，熔点：191.4-192.1℃，总产率67％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.26-1.30(m,6H),2.12(s,3H),2.25-2.31(m,4H),2.34(s,3H),2.53(s,3H),2.70(s,3H),2.92(d,J＝14.0Hz,1H),3.22(d,J＝14.0Hz,1H),4.67(s,1H),5.38(d,J＝11.8Hz,1H),6.11(d,J＝8.0Hz,1H),6.21(d,J＝8.0Hz,1H),6.28(s,1H),6.82-6.86(m,2H),7.33-7.42(m,4H),8.15(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.1,21.4,24.0,25.2,25.9,26.5,29.8,50.9,55.0,56.8,65.0,67.5,81.2,106.4,107.5,125.7,127.5,127.7,127.8,127.9,129.2,130.0,138.5,141.6,142.7,142.9,177.3,178.1；HRMS(ESI-TOF)m/z:Calcd.for C34H37N3NaO3[M+Na]+:558.2733；Found:558.2734.
本实施例制备化合物5f:白色固体，熔点：156.5-157.6℃，总产率66％；dr:17/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.24-1.30(m,6H),2.29-2.30(m,4H),2.94-3.01(m,4H),3.14-3.23(m,4H),4.67(s,1H),5.39(d,J＝10.4Hz,1H),6.32-6.35(m,1H),6.64-6.68(m,1H),6.86-6.91(m,1H),7.07-7.11(m,2H),7.25-7.41(m,5H),8.13(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:23.9,26.5,28.9,29.7,52.2,54.6,56.8,65.3,66.8,81.6,114.4,115.6,121.5,122.0,123.3,123.4,125.3,127.2,127.8,127.9,128.6,130.5,131.6,132.1,137.5,139.8,140.4,142.5,177.5,178.7；HRMS(ESI-TOF)m/z:Calcd.for C32H31Cl2N3NaO3[M+Na]+:598.1640；Found:598.1642.
本实施例制备化合物5g:白色固体，熔点：208.7-209.6℃，总产率67％；dr:9/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.96-0.99(m,3H),1.03-1.06(m,3H),1.21-1.26(m,6H),2.14(s,3H),2.20-2.24(m,5H),2.32-2.34(m,2H),2.87-2.92(m,1H),3.09-3.13(m,2H),3.22(d,J＝13.6Hz,1H),3.54-3.60(m,1H),3.75-3.81(m,1H),4.54(s,1H),5.36(d,J＝12.0Hz,1H),5.26(d,J＝7.8Hz,1H),6.54-6.58(m,1H),6.78-6.82(m,3H),7.18(d,J＝7.0Hz,1H),7.30-7.39(m,4H),8.18(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.6,15.0,18.8,18.9,24.0,26.4,36.1,36.7,52.8,53.7,56.8,65.9,66.2,81.6,117.2,118.5,120.3,120.9,122.9,123.1,124.9,125.2,127.4,127.5,128.7,130.5,131.4,132.7,138.1,141.4,142.0,143.2,177.8,178.6；HRMS(ESI-TOF)m/z:Calcd.for C36H41N3NaO3[M+Na]+:586.3046；Found:586.3044.
本实施例制备化合物5h:白色固体，熔点：164.4-165.7℃，总产率70％；dr:13/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.24-2.26(m,2H),2.40-2.44(m,2H),2.56(s,3H),2.70(s,3H),3.19-3.29(m,2H),3.32-3.39(m,4H),4.63(s,1H),5.38(d,J＝7.2Hz,1H),6.24(d,J＝6.4Hz,1H),6.34(d,J＝6.0Hz,1H),6.46(d,J＝6.0Hz,1H),6.71-6.74(m,1H),6.92-6.95(m,1H),7.03-7.07(m,2H),7.34-7.43(m,5H),8.14(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.5,26.1,51.2,54.8,55.3,65.1,67.3,67.4,81.1,106.9,107.7,120.8,123.2,124.8,126.3,127.5,127.9,128.7,137.6,142.9,144.1,144.6,177.0,178.1；HRMS(ESI-TOF)m/z:Calcd.for C31H31N3NaO4[M+Na]+:532.2212；Found:532.2215.
本实施例制备化合物5i:白色固体，熔点：149.3-149.9℃，总产率63％；dr:16/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.26-2.28(m,2H),2.39-2.43(m,2H),2.65(s,3H),2.80(s,3H),3.18-3.19(m,2H),3.36-3.38(m,4H),5.35(d,J＝9.6Hz,1H),6.16-6.18(m,1H),6.24-6.27(m,2H),6.74-6.76(m,2H),7.11(d,J＝6.4Hz,1H),7.25-7.34(m,4H),8.08(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.5,26.1,51.2,55.4,55.5,65.1,67.3,67.6,81.3,107.1,107.2,107.9,113.1(d,JCF＝25.1Hz),114.0,114.2,114.3,114.4,114.9,123.4,127.9,128.0,128.5,131.0(d,JCF＝9.2Hz),136.9,140.1(d,JCF＝2.0Hz),142.3,158.1(d,JCF＝239.0Hz),176.8,178.3；HRMS(ESI-TOF)m/z:Calcd.for C31H29F2N3NaO4[M+Na]+:568.2024；Found:568.2027.
本实施例制备化合物5j:白色固体，熔点：146.2-146.7℃，总产率64％；dr:10/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.24-2.27(m,2H),2.40-2.43(m,2H),2.97(s,3H),3.13-3.17(m,4H),3.27(d,J＝14.0Hz,1H),3.37-3.41(m,4H),4.57(s,1H),5.36-5.38(m,1H),6.31-6.33(m,1H),6.64-6.68(m,1H),6.86-6.90(m,1H),7.07-7.12(m,2H),7.19-7.25(m,1H),7.31-7.42(m,4H),8.09(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:29.0,29.7,52.5,54.5,55.5,65.3,66.7,67.3,81.5,114.7,115.6,121.6,122.1,123.3,123.5,124.9,127.1,127.9,128.1,128.4,130.8,131.6,131.8,137.0,104.1,140.4,142.5,177.3,178.6；HRMS(ESI-TOF)m/z:Calcd.for C31H29Cl2N3NaO4[M+Na]+:600.1433；Found:600.1433.
本实施例制备化合物5k:白色固体，熔点：212.3-213.1℃，总产率72％；dr:14/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.15-2.21(m,2H),2.25-2.29(m,2H),2.47-2.55(m,5H),2.64-2.69(m,5H),3.16(d,J＝14.0Hz,1H),3.35(d,J＝14.0Hz,1H),4.54(s,1H),5.36(d,J＝10.0Hz,1H),6.22(d,J＝7.8Hz,1H),6.31(d,J＝8.0Hz,1H),6.42-6.44(m,1H),6.69-6.73(m,1H),6.91-6.94(m,1H),7.02-7.06(m,2H),7.28-7.41(m,5H),8.11(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.6,26.2,28.4,51.3,55.2,56.9,65.7,67.3,81.2,107.0,107.9,120.8,121.3,124.8,127.6,127.7,128.0,128.9,137.6,142.9,144.3,144.7,177.2,178.2；HRMS(ESI-TOF)m/z:Calcd.forC31H31N3NaO3S[M+Na]+:548.1984；Found:548.1985.
本实施例制备化合物5l:白色固体，熔点：173.5-174.3℃，总产率69％；dr:6/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.98-1.00(m,3H),1.03-1.03(m,3H),2.18-2.22(m,2H),2.30-2.33(m,2H),2.47-2.51(m,2H),2.57-2.59(m,1H),2.68-2.71(m,2H),2.78-2.80(m,1H),3.11(d,J＝11.6Hz,1H),3.45-3.53(m,2H),3.62-3.67(m,1H),4.50(s,1H),5.39(s,1H),6.26-6.29(m,1H),6.37-6.42(m,2H),6.68-6.71(m,1H),6.88-6.92(m,1H),7.03-7.08(m,2H),7.22-7.25(m,1H),7.32-7.42(m,3H)；13C NMR(CDCl3,100MHz)δ:12.6,12.7,28.1,34.4,34.8,51.5,54.9,56.9,65.8,67.2,81.3,106.9,107.9,120.5,121.0,123.1,126.3,127.4,127.5,127.8,137.5,142.9,143.5,143.8,176.7,177.3；HRMS(ESI-TOF)m/z:Calcd.for C33H35N3NaO3S[M+Na]+:576.2297；Found:576.2297.
本实施例制备化合物5m:白色固体，熔点：116.3-117.5℃，总产率68％；dr:10/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.13(s,3H),2.21-2.25(m,2H),2.28-2.33(m,2H),2.35(s,3H),2.49-2.53(m,2H),2.56(s,3H),2.66-2.70(m,5H),3.15(d,J＝11.2Hz,1H),3.34(d,J＝11.6Hz,1H),4.51(s,1H),5.38(s,1H),6.15(d,J＝6.0Hz,1H),6.24(d,J＝6.4Hz,1H),6.28(s,1H),6.85-6.88(m,2H),7.14(s,1H),7.35-7.44(m,4H),8.11(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.0,21.2,25.2,25.7,28.3,51.1,55.1,56.8,65.4,67.3,81.0,106.5,107.4,123.2,125.6,127.1,127.5,128.1,129.1,129.9,137.8,141.9,142.5,142.9,177.0,177.9；HRMS(ESI-TOF)m/z:Calcd.forC33H35N3NaO3S[M+Na]+:576.2297；Found:576.2294.
本实施例制备化合物5n:白色固体，熔点：218.9-219.6℃，总产率67％；dr:15/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.22(s,3H),2.26(s,3H),2.27-2.33(m,4H),2.53-2.57(m,2H),2.68-2.72(m,2H),2.88(s,3H),3.04(s,3H),3.17(d,J＝11.6Hz,1H),3.32(d,J＝11.2Hz,1H),4.53(s,1H),3.36(d,J＝8.8Hz,1H),6.29(d,J＝5.6Hz,1H),6.61-6.64(m,1H),6.83-6.87(m,3H),7.14-7.16(m,1H),7.33-7.42(m,4H),8.14(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.7,18.8,28.2,28.7,29.4,52.3,54.2,56.8,65.7,66.2,81.2,118.1,119.2,120.4,120.9,122.7,123.2,124.4,124.7,127.4,127.5,128.4,129.5,131.4,132.4,137.6,142.2,142.6,142.9,177.7,178.8；HRMS(ESI-TOF)m/z:Calcd.for C33H35N3NaO3S[M+Na]+:576.2297；Found:576.2297.
本实施例制备化合物5o:白色固体，熔点：184.0-185.1℃，总产率58％；dr:15/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.21-2.26(m,2H),2.29-2.34(m,2H),2.49-2.56(m,2H),2.66-2.71(m,5H),2.81(s,3H),3.16(d,J＝14.0Hz,1H),3.30(d,J＝14.0Hz,1H),4.51(s,1H),5.35(d,J＝6.0Hz,1H),6.15-6.18(m,1H),6.23-6.27(m,2H),6.74-6.80(m,2H),7.05-7.08(m,1H),7.31-7.42(m,3H),8.08(d,J＝8.0Hz,1H)；13CNMR(CDCl3,100MHz)δ:25.5,26.1,28.4,51.2,55.7,57.0,65.7,67.6,81.3,107.9,108.0,113.0(d,JCF＝25.1Hz),114.0,114.1,114.2,114.4,115.0(d,JCF＝23.1Hz),123.4,127.9,128.1,128.5,130.8,136.8,140.2,142.3,158.1(d,JCF＝240.0Hz),176.8,178.3；HRMS(ESI-TOF)m/z:Calcd.for C31H29F2N3NaO3S[M+Na]+:584.1795；Found:584.1798.
本实施例制备化合物5p:白色固体，熔点：138.9-139.6℃，总产率57％；dr:14/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.25-2.31(m,4H),2.48-2.53(m,2H),2.65-2.68(m,2H),2.98(s,3H),3.12-3.17(m,4H),3.36(d,J＝14.0Hz,1H),4.50(s,1H),5.36(d,J＝9.2Hz,1H),6.31-6.33(m,1H),6.65-6.67(m,1H),6.88-6.91(m,1H),7.07-7.10(m,2H),7.14-7.16(m,1H),7.33-7.42(m,4H),8.08(d,J＝7.8Hz,1H)；13CNMR(CDCl3,100MHz)δ:28.4,29.0,29.7,52.5,54.9,57.0,65.8,66.7,81.5,114.6,115.6,121.5,122.1,123.3,123.5,124.8,127.1,127.8,128.1,128.4,130.7,131.6,131.7,136.9,140.2,140.3,142.6,177.3,178.6；HRMS(ESI-TOF)m/z:Calcd.for C31H29Cl2N3NaO3S[M+Na]+:616.1204；Found:616.1207.
本实施例制备化合物5q:白色固体，熔点：116.7-118.3℃，总产率63％；dr:20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.51-1.54(m,4H),2.26-2.29(m,2H),2.41-2.45(m,2H),2.50(s,3H),2.68(s,3H),3.32-3.41(m,2H),4.72(s,1H),5.37(d,J＝11.2Hz,1H),6.19(d,J＝8.0Hz,1H),6.32(d,J＝8.0Hz,1H),6.44(d,J＝7.8Hz,1H),6.69-6.72(m,1H),6.91-6.95(m,1H),7.02-7.04(m,2H),7.31-7.36(m,4H),8.17(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.2,25.6,26.2,51.7,55.0,56.5,63.9,67.4,81.3,106.9,107.8,121.0,121.3,123.2,124.8,126.7,127.6,127.8,138.0,142.8,143.9,144.8,177.3,178.1；HRMS(ESI-TOF)m/z:Calcd.for C31H31N3NaO3[M+Na]+:516.2263；Found:516.2263.
本实施例制备化合物5r:白色固体，熔点：191.8-192.5℃，总产率55％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.46-1.54(m,4H),2.07-2.10(m,2H),2.32-2.34(m,2H),3.12(d,J＝12.0Hz,1H),3.41(d,J＝12.4Hz,1H),4.26(s,1H),5.52(d,J＝10.4Hz,1H),5.97-5.99(m,1H),6.22-6.24(m,1H),6.60(d,J＝7.8Hz,1H),6.68-6.78(m,3H),7.05-7.12(m,2H),7.27-7.37(m,11H),7.50-7.58(m,4H)；13C NMR(CDCl3,100MHz)δ:24.3,55.1,55.8,57.0,65.0,67.4,80.7,108.8,109.5,121.8,122.6,127.4,127.7,127.8,127.9,128.0,128.4,129.3,129.4,130.3,130.8,134.6,135.3,140.6,144.1,145.5,146.3,175.0,178.7；HRMS(ESI-TOF)m/z:Calcd.for C41H35N3NaO3[M+Na]+:640.2576；Found:640.2580.
本实施例制备化合物5s:白色固体，熔点：141.5-142.3℃，总产率65％；dr:19/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87-0.91(m,3H),1.01-1.04(m,3H),1.44-1.47(m,4H),2.15-2.17(m,2H),2.38-2.41(m,2H),2.48-2.53(m,1H),2.72-2.77(m,1H),3.22(d,J＝13.6Hz,1H),3.46-3.51(m,1H),3.61-3.68(m,2H),4.59(s,1H),5.39(d,J＝11.6Hz,1H),6.20(d,J＝7.8Hz,1H),6.35(d,J＝7.8Hz,1H),6.42-6.44(m,1H),6.66-6.70(m,1H),6.87-6.91(m,1H),6.99-7.06(m,2H),7.27-7.41(m,5H),8.15(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:12.1,12.9,24.1,34.3,34.9,51.7,54.8,56.1,63.9,67.3,81.4,106.9,107.9,120.7,121.0,123.1,125.1,127.5,127.7,128.8,138.0,142.9,143.3,144.0,177.0,177.5；HRMS(ESI-TOF)m/z:Calcd.for C33H35N3NaO3[M+Na]+:544.2576；Found:544.2581.
本实施例制备化合物5t:白色固体，熔点：201.2-202.4℃，总产率67％；dr:20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.49-1.52(m,4H),2.11(s,3H),2.26-2.29(m,2H),2.33(s,3H),2.41-2.45(m,2H),2.50(s,3H),2.68(s,3H),3.30(d,J＝7.2Hz,1H),3.40(d,J＝12.8Hz,1H),4.65(s,1H),5.36(d,J＝11.2Hz,1H),6.09-6.11(m,1H),6.22-6.24(m,1H),6.28(s,1H),6.82-6.86(m,2H),7.17(s,1H),7.32-7.42(m,4H),8.15(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:21.1,21.4,24.2,25.3,25.9,51.7,55.0,56.4,63.9,67.5,81.3,106.5,107.6,123.2,125.6,127.5,127.6,127.7,128.0,130.8,138.3,141.7,142.7,142.8,177.3,178.0；HRMS(ESI-TOF)m/z:Calcd.forC33H35N3NaO3[M+Na]+:544.2576；Found:544.2577.
本实施例制备化合物5u:白色固体，熔点：201.1-202.6℃，总产率69％；dr:9/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.50-1.56(m,4H),2.18(s,3H),2.26(s,3H),2.29-2.34(m,2H),2.42-2.45(m,2H),2.83(s,3H),3.02(s,3H),3.30-3.39(m,2H),4.68(s,1H),5.34(d,J＝11.8Hz,1H),6.29(d,J＝7.8Hz,1H),6.59-6.63(m,1H),6.81-6.84(m,3H),7.19-7.21(m,1H),7.31(d,J＝4.6Hz,2H),7.36-7.41(m,1H),8.17(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.8,19.0,24.2,28.9,29.6,52.9,54.0,56.5,64.1,66.3,81.5,118.1,119.2,120.7,121.1,122.7,123.1,124.8,125.0,127.5,128.7,130.5,131.4,132.5,138.1,141.8,142.7,142.9,177.8,178.9；HRMS(ESI-TOF)m/z:Calcd.for C33H35N3NaO3[M+Na]+:544.2576；Found:544.2573.
本实施例制备化合物5v:白色固体，熔点：218.5-219.3℃，总产率56％；dr:15/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.55-1.61(m,4H),1.84(s,3H),1.95(s,3H),2.03(s,3H),2.18-2.21(m,2H),2.46-2.53(m,2H),3.16-3.20(m,1H),3.84-3.88(m,1H),4.08-4.13(m,2H),4.18(s,1H),4.55(s,1H),5.01(d,J＝16.2Hz,1H),5.22(d,J＝16.6Hz,1H),5.49(d,J＝12.4Hz,1H),6.41(d,J＝7.8Hz,1H),6.70-6.75(m,1H),6.82-6.84(m,2H),6.91-6.95(m,1H),7.03-7.25(m,13H),7.36-7.43(m,4H),8.27(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:18.5,18.7,24.0,44.7,45.0,53.8,54.4,56.6,64.9,66.4,82.0,118.3,119.5,120.7,121.4,122.8,123.2,125.0,125.1,125.5,125.8,126.7,127.0,127.6,127.8,128.4,128.9,129.0,130.2,131.9,132.9,137.5,138.2,142.1,142.2,143.0,178.3,179.2；HRMS(ESI-TOF)m/z:Calcd.for C45H43N3NaO3[M+Na]+:696.3202；Found:696.3207.
本实施例制备化合物5w:白色固体，熔点：202.3-203.7℃，总产率68％；dr:6/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87-0.89(m,3H),1.00-1.02(m,3H),1.42-1.44(m,4H),2.07-2.13(m,5H),2.29-2.37(m,5H),2.51(s,1H),2.74(s,1H),3.12-3.14(m,1H),3.48-3.53(m,1H),3.63-3.68(m,2H),4.51(d,J＝5.2Hz,1H),5.34-5.38(m,1H),6.10-6.12(m,1H),6.24(s,2H),6.79-6.84(m,2H),7.03(s,1H),7.30-7.36(m,4H),8.09(br s,1H)；13C NMR(CDCl3,100MHz)δ:12.1,12.9,21.1,21.2,24.1,33.9,34.5,51.8,54.9,56.0,63.8,67.3,81.3,106.5,107.7,123.1,125.9,127.4,127.6,128.0,129.2,129.8,138.2,141.1,141.7,141.8,143.0,177.0,177.5；HRMS(ESI-TOF)m/z:Calcd.for C35H39N3NaO3[M+Na]+:572.2889；Found:572.2888.
本实施例制备化合物5x:白色固体，熔点：199.5-200.6℃，总产率72％；dr:7/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.87-0.91(m,3H),1.02-1.06(m,3H),1.44-1.46(m,4H),2.12(s,3H),2.13-2.18(m,2H),2.21(s,3H),2.36-2.40(m,2H),2.85-2.90(m,1H),3.07-3.12(m,1H),3.16(d,J＝13.6Hz,1H),3.58-3.63(m,1H),3.72(d,J＝13.2Hz,1H),3.76-3.80(m,1H),4.52(s,1H),5.35(d,J＝12.0Hz,1H),6.27-6.29(m,1H),6.54-6.58(m,1H),6.77-6.83(m,4H),7.11-7.14(m,1H),7.30-7.40(m,4H),8.18(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.1,15.1,18.8,18.9,24.1,35.9,36.7,53.2,53.7,56.1,64.2,66.2,81.6,117.3,118.5,120.5,120.9,123.0,123.1,124.8,125.2,127.4,127.5,128.7,131.0,131.5,132.7,137.9,141.5,142.0,143.1,177.9,178.6；HRMS(ESI-TOF)m/z:Calcd.for C35H39N3NaO3[M+Na]+:572.2889；Found:572.2891.
本实施例制备化合物5y:白色固体，熔点：173.2-174.1℃，总产率66％；dr:18/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.57(s,4H),2.34-2.35(m,2H),2.45-2.47(m,2H),2.96(s,3H),3.13(s,3H),3.34(d,J＝10.8Hz,1H),3.44(d,J＝10.8Hz,1H),4.67(s,1H),5.38(s,1H),6.33-6.35(m,1H),6.65-6.67(m,1H),6.89-6.91(m,1H),7.08-7.11(m,2H),7.23-7.35(m,5H),8.15(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.1,28.8,29.5,52.7,54.5,56.3,64.0,66.7,81.4,114.2,115.3,121.5,121.9,123.1,123.2,125.1,127.2,127.6,127.7,128.3,130.4,131.3,132.3,137.1,139.6,140.1,142.3,177.3,178.5；HRMS(ESI-TOF)m/z:Calcd.for C31H29Cl2N3NaO3[M+Na]+:584.1484；Found:584.1487.
本实施例制备化合物5z:白色固体，熔点：121.1-122.4℃，总产率56％；dr:20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.54-1.57(m,4H),2.32-2.34(m,2H),2.45-2.47(m,2H),2.67(s,3H),2.86(s,3H),3.36(s,2H),4.69(s,1H),5.38(s,1H),6.16(d,J＝8.0Hz,1H),6.28(d,J＝8.4Hz,1H),6.48(d,J＝5.0Hz,1H),7.03-7.04(m,2H),7.24-7.444(m,5H),8.12(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.3,25.7,26.3,51.6,55.3,56.6,64.0,67.4,81.6,107.8,108.6,123.3,125.1,126.4,126.5,126.8,126.9,127.8,127.9,128.0,128.6,128.9,131.7,137.2,142.1,142.6,143.4,176.8,178.1；HRMS(ESI-TOF)m/z:Calcd.for C31H29Cl2N3NaO3[M+Na]+:584.1484；Found:584.1484.
本实施例制备化合物5a’:白色固体，熔点：126.3-127.5℃，总产率62％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:1.56-1.59(m,4H),2.35-2.37(m,2H),2.47-2.49(m,2H),2.65(s,3H),2.82(s,3H),3.34-3.41(m,2H),4.71(s,1H),5.39(s,1H),6.16-6.17(m,1H),6.28-6.30(m,2H),6.78-6.79(m,2H),7.13-7.15(m,1H),7.28-7.42(m,3H),8.15(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:24.1,25.4,25.9,51.4,55.4,56.4,63.9,67.5,81.3,106.7,106.8,107.7,107.8,112.9(d,JCF＝20.5Hz),113.9(d,JCF＝19.4Hz),114.3,114.7,123.1,126.3,127.7,128.5,131.6,137.1,139.7,140.6,142.1,158.0(d,JCF＝205.4Hz),176.8,178.1；HRMS(ESI-TOF)m/z:Calcd.forC31H29F2N3NaO3[M+Na]+:552.2075；Found:552.2078.
本实施例制备化合物5b’:白色固体，熔点：172.5-173.4℃，总产率64％；dr:7/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.95-0.98(m,3H),1.08-1.11(m,3H),1.48-1.50(m,4H),2.20-2.22(m,2H),2.42-2.44(m,2H),3.20(d,J＝14.8Hz,1H),3.32-3.37(m,1H),3.53-3.58(m,2H),3.74-3.78(m,2H),4.51(s,1H),5.41(s,1H),6.32-6.33(m,1H),6.61-6.64(m,1H),6.84-6.88(m,1H),7.08-7.10(m,2H),7.17(d,J＝6.0Hz,1H),7.32-7.35(m,3H),7.39-7.41(m,1H),8.16(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.1,15.0,24.0,35.9,36.7,52.9,54.2,56.0,64.1,66.5,81.4,113.6,114.8,121.4,121.7,123.1,123.3,124.8,127.4,127.5,127.6,128.4,130.5,131.5,132.8,137.0,139.3,139.6,142.5,177.2,178.1；HRMS(ESI-TOF)m/z:Calcd.for C33H33Cl2N3NaO3[M+Na]+:612.1797；Found:612.1795.
本实施例制备化合物5c’:白色固体，熔点：192.1-193.0℃，总产率73％；dr:10/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.52(s,3H),2.70(s,3H),3.18-3.22(m,2H),3.41-3.45(m,2H),3.51(d,J＝13.6Hz,1H),3.76(d,J＝14.0Hz,1H),4.65(s,1H),5.38(d,J＝10.4Hz,1H),5.51(s,2H),6.20(d,J＝7.6Hz,1H),6.34(d,J＝7.8Hz,1H),6.45-6.47(m,1H),6.70-6.73(m,1H),6.94-6.96(m,1H),7.04-7.05(m,2H),7.32-7.34(m,4H),8.20(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.7,26.2,51.8,55.7,63.4,66.0,67.4,81.4,106.9,107.9,121.0,121.4,123.2,127.2,127.6,127.7,127.9,137.8,142.8,144.2,144.8,177.2,178.1；HRMS(ESI-TOF)m/z:Calcd.forC31H29N3NaO3[M+Na]+:514.2107；Found:514.2109.
本实施例制备化合物5d’:白色固体，熔点：104.6-105.3℃，总产率69％；dr:8/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.84-0.89(m,3H),1.00-1.04(m,3H),2.48-2.57(m,1H),2.73-2.79(m,1H),3.13(d,J＝9.6Hz,2H),3.39-3.49(m,4H),3.59-3.69(m,1H),3.86(d,J＝13.6Hz,1H),4.58(s,1H),5.39(d,J＝11.2Hz,1H),5.48(s,2H),6.21(d,J＝7.8Hz,1H),6.36(d,J＝8.0Hz,1H),6.43(d,J＝7.2Hz,1H),6.66-6.70(m,1H),6.88-6.92(m,1H),7.00-7.06(m,2H),7.26-7.42(m,5H),8.16(d,J＝7.2Hz,1H)；13CNMR(CDCl3,100MHz)δ:12.2,12.9,34.3,34.9,51.7,55.5,63.1,65.9,67.3,81.4,106.9,108.0,109.4,120.7,121.1,123.2,127.1,127.6,127.8,137.9,143.0,143.4,144.0,177.1,177.5；HRMS(ESI-TOF)m/z:Calcd.for C33H33N3NaO3[M+Na]+:542.2420；Found:542.2424.
本实施例制备化合物5e’:白色固体，熔点：187.9-188.6℃，总产率63％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.68(s,3H),2.86(s,3H),3.25-3.27(m,2H),3.45-3.52(m,3H),3.72(d,J＝13.6Hz,1H),4.61(s,1H),6.16(d,J＝8.4Hz,1H),6.28(d,J＝8.4Hz,1H),6.47(d,J＝2.0Hz,1H),7.02-7.07(m,2H),7.29-7.45(m,5H),8.15(d,J＝7.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.8,26.3,51.7,56.0,63.6,66.3,67.4,81.6,107.8,108.7,123.4,125.1,126.4,126.5,126.7,126.8,127.1,127.9,128.0,128.6,128.9,131.4,136.9,142.1,142.8,143.4,176.7,178.1；HRMS(ESI-TOF)m/z:Calcd.for C31H27Cl2N3NaO3[M+Na]+:582.1327；Found:582.1331.
本实施例制备化合物5f’:白色固体，熔点：176.1-176.6℃，总产率66％；dr:20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:2.63(s,3H),2.80(s,3H),3.23-3.26(m,2H),3.43-3.52(m,3H),3.67-3.69(m,1H),4.61(s,1H),5.37(s,1H),5.52(s,2H),6.12-6.15(m,1H),6.25-6.28(m,2H),6.73-6.79(m,2H),7.08-7.10(m,1H),7.31-7.43(m,3H),8.15(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:25.6,26.1,51.7,56.2,63.6,66.2,67.6,81.5,100.0,107.0,112.9,114.1(d,JCF＝24.1Hz),114.3,123.3,127.1,127.9,128.0,128.7,137.0,140.2,142.2,142.3,158.3(d,JCF＝224.4Hz),159.3,176.9,178.3；HRMS(ESI-TOF)m/z:Calcd.for C31H27F2N3NaO3[M+Na]+:550.1918；Found:550.1918.
本实施例制备化合物5g’:白色固体，熔点：205.6-206.3℃，总产率59％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:3.08-3.12(m,2H),3.40-3.47(m,3H),3.59(d,J＝15.8Hz,1H),3.78(d,J＝16.0Hz,1H),4.26(d,J＝13.6Hz,1H),4.55(s,1H),5.20-5.28(m,1H),5.40(d,J＝15.6Hz,1H),5.51(d,J＝11.2Hz,1H),5.56(s,2H),5.91(d,J＝8.4Hz,1H),6.10(d,J＝7.8Hz,1H),6.68(s,1H),7.10-7.25(m,13H),7.35-7.48(m,4H),8.20(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:43.5,43.8,51.8,56.3,63.1,65.8,67.4,82.0,109.6,110.4,113.6,114.2,126.6,126.7,126.8,127.1,127.2,127.6,127.9,128.2,128.6,128.9,131.0,131.7,135.1,135.3,136.6,142.2,143.1,177.0,178.1；HRMS(ESI-TOF)m/z:Calcd.for C43H35Br2N3NaO3[M+Na]+:822.0943；Found:822.0944.
本实施例制备化合物5h’:白色固体，熔点：229.8-230.4℃，总产率69％；dr:18/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.68-0.71(m,6H),2.34-2.39(m,4H),2.53(s,3H),2.70(s,3H),3.27-3.35(m,2H),4.64(s,1H),5.37(d,J＝11.2Hz,1H),6.19(d,J＝7.8Hz,1H),6.31(d,J＝7.6Hz,1H),6.43-6.45(m,1H),6.69-6.72(m,1H),6.90-6.94(m,1H),7.00-7.05(m,2H),7.31-7.42(m,5H),8.17(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.3,25.5,26.2,47.8,51.6,55.4,62.5,67.4,81.4,106.8,107.8,120.7,121.3,126.9,127.6,127.7,127.8,128.8,138.0,142.9,144.1,144.8,177.4,178.2；HRMS(ESI-TOF)m/z:Calcd.for C31H33N3NaO3[M+Na]+:518.2420；Found:518.2416.
本实施例制备化合物5i’:白色固体，熔点：172.8-173.1℃，总产率56％；dr:7/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.65-0.68(m,6H),2.33-2.46(m,4H),3.27(d,J＝14.0Hz,1H),3.35(d,J＝16.0Hz,1H),3.63(d,J＝16.0Hz,1H),3.83(d,J＝14.0Hz,1H),4.62(s,1H),4.88(d,J＝16.0Hz,1H),5.11(d,J＝16.4Hz,1H),5.51(d,J＝12.0Hz,1H),6.07-6.09(m,1H),6.19(d,J＝8.0Hz,1H),6.50-6.52(m,1H),6.75-6.79(m,1H),6.98-7.03(m,3H),7.15-7.22(m,11H),7.34-7.45(m,4H),8.24(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:10.7,43.3,43.6,47.7,52.1,55.7,62.6,67.5,81.8,108.1,109.1,126.6,127.1,127.2,128.4,128.7,129.1,135.6,136.0,137.7,143.0,143.8,143.9,177.6,178.2；HRMS(ESI-TOF)m/z:Calcd.for C43H41N3NaO3[M+Na]+:670.3046；Found:670.3047.
本实施例制备化合物5j’:白色固体，熔点：218.3-219.4℃，总产率70％；dr:>20/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.69-0.73(m,6H),2.18(s,3H),2.24(s,3H),2.36-2.41(m,4H),2.84(s,3H),3.03(s,3H),3.26-3.32(m,2H),4.59(s,1H),5.34(d,J＝11.2Hz,1H),6.28(d,J＝7.6Hz,1H),6.57-6.60(m,1H),6.62-6.83(m,3H),7.17-7.19(m,1H),7.25-7.33(m,4H),8.16(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.2,18.9,19.0,28.8,29.6,47.7,52.8,54.5,62.6,66.4,81.5,118.0,119.3,120.4,121.0,122.8,123.2,124.9,125.2,127.5,127.6,128.7,130.0,131.3,132.5,138.2,142.1,142.7,143.0,178.0,179.0；HRMS(ESI-TOF)m/z:Calcd.for C33H37N3NaO3[M+Na]+:546.2733；Found:546.2735.
本实施例制备化合物5k’:白色固体，熔点：106.7-107.3℃，总产率71％；dr:18/1；核磁共振和高分辨质谱测试等结果如下：1H NMR(CDCl3,400MHz)δ:0.67-0.71(m,6H),2.11(s,3H),2.33-2.37(m,7H),2.52(s,3H),2.69(s,3H),3.28-3.30(m,2H),4.57(s,1H),5.36(d,J＝11.2Hz,1H),6.10(d,J＝8.0Hz,1H),6.22(d,J＝8.0Hz,1H),6.27(s,1H),6.81-6.86(m,2H),7.19-7.21(m,1H),7.30-7.35(m,4H),8.15(d,J＝7.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.4,21.1,21.3,25.2,25.9,47.9,51.6,55.4,62.4,67.6,81.2,106.4,107.5,127.5,127.8,127.9,129.2,129.3,129.9,130.7,138.3,141.9,142.6,142.9,177.4,178.1；HRMS(ESI-TOF)m/z:Calcd.for C33H37N3NaO3[M+Na]+:546.2733；Found:546.2733.
本发明的式(1)化合物具有重要的生物活性，体外对人肺癌细胞(A549)、PC-3(人前列腺癌)以及人白血病细胞(K562)共三株肿瘤细胞的细胞毒性试验表明：此类式(1)所示的结构的3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。
药理实施例1：化合物5c,5f,5p,5x,5y,5b’,5j’,5i’和5k’对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用DMEM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4000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5c,5f,5p,5x,5y,5b’,5j’,5i’和5k’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5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/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5c,5f,5p,5x,5y,5b’,5j’,5i’和5k’对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物5c对K562肿瘤细胞的IC50为9.7μmol/L；化合物5f对K562肿瘤细胞的IC50为32.8μmol/L；化合物5p对K562肿瘤细胞的IC50为21.9μmol/L；化合物5x对K562肿瘤细胞的IC50为21.4μmol/L；化合物5y对K562肿瘤细胞的IC50为21.0μmol/L；化合物5b’对K562肿瘤细胞的IC50为8.8μmol/L；化合物5j’对K562肿瘤细胞的IC50为26.7μmol/L；化合物5i’对K562肿瘤细胞的IC50为7.4μmol/L；化合物5k’对K562肿瘤细胞的IC50为27.8μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为25.4μmol/L。
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3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物对K562细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级或活性比顺铂更好，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例2：化合物5y，5b’，5j’和5i’对A549细胞的细胞毒性
A549(人非小细胞肺癌肺癌)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。具体方法如药理实施例1。化合物5y对K562肿瘤细胞的IC50为37.2μmol/L；化合物5b’对A549肿瘤细胞的IC50为24.4μmol/L；化合物5j’对A549肿瘤细胞的IC50为54.8μmol/L；化合物5i’对A549肿瘤细胞的IC50为18.1μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为24.7μmol/L。
实验结论：A549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3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物对A549细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。
药理实施例2：化合物5y，5b’，5j’和5i’对PC-3细胞的细胞毒性
PC-3(人前列腺癌)细胞用RPMI-1640培养基培养，培养基中含10％的胎牛血清，100U/mL青霉素及100U/mL的链霉素。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5y，5b’，5j’和5i’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5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/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5y，5b’，5j’和5i’对PC-3细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物5y对PC-3肿瘤细胞的IC50为39.7μmol/L；化合物5b’对PC-3肿瘤细胞的IC50为27.9μmol/L；化合物5j’对PC-3肿瘤细胞的IC50为21.4μmol/L；化合物5i’对PC-3肿瘤细胞的IC50为17.7μmol/L；而阳性对照顺铂对PC-3肿瘤细胞的IC50为23.1μmol/L。
实验结论：PC-3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3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物对PC-3细胞具有较强的细胞毒性，和肿瘤治疗一线用药顺铂同一数量级，有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些化合物对这三株肿瘤细胞都显示有一定的细胞毒性。可见这些化合物具有开发成为抗肿瘤药物的潜力，值得继续深入研究下去。

Claims (1)

1.一种3-氨甲基季碳氧化吲哚拼接3-五元碳环螺环氧化吲哚类化合物，其特征在于：该化合物具有如通式(Ⅰ)所示的结构：
具体为如下结构式之一:
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WO2008036168A2 (en) * 2006-08-30 2008-03-27 The Regents Of The University Of Michigan New small molecule inhibitors of mdm2 and the uses thereof
CN102443005A (zh) * 2011-08-12 2012-05-09 温州医学院 查尔酮的螺杂环类化合物及其用途
WO2012099454A1 (en) * 2011-01-21 2012-07-26 Universiti Sains Malaysia Curcumin compounds and their preparations thereof
CN104276994A (zh) * 2014-07-23 2015-01-14 贵州大学 3,3′-双取代氧化吲哚与3-烯键氧化吲哚拼接衍生物及其制备方法及应用

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WO2008036168A2 (en) * 2006-08-30 2008-03-27 The Regents Of The University Of Michigan New small molecule inhibitors of mdm2 and the uses thereof
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