CN108586437B - 色酮拼接3-羟甲基氧化吲哚衍生物及其制备方法及应用 - Google Patents

色酮拼接3-羟甲基氧化吲哚衍生物及其制备方法及应用 Download PDF

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CN108586437B
CN108586437B CN201810540031.4A CN201810540031A CN108586437B CN 108586437 B CN108586437 B CN 108586437B CN 201810540031 A CN201810540031 A CN 201810540031A CN 108586437 B CN108586437 B CN 108586437B
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刘雄利
张文会
徐圣文
左雄
周英
田民义
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Abstract

本发明公开了一种色酮拼接3‑羟甲基氧化吲哚衍生物，本发明由相应的靛红1与二氢色酮2先发生Knoevenagel缩合反应，生成中间体3，然后中间体3与福尔马林中甲醛发生1,3‑氢迁移反应和羟甲基化反应，生成最终产物色酮拼接3‑羟甲基氧化吲哚衍生物，该类骨架包含色酮骨架和3‑羟甲基氧化吲哚骨架；色酮拼接3‑羟甲基氧化吲哚衍生物的合成是潜在的药物分子中间体或和药物类似物，具有极其重要的研究意义。本发明发明操作简单易行，原料合成便宜易得，可以在水相中进行,无催化剂绿色反应，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。本发明发现该物质具有一定的抑制肿瘤细胞生长活性。

Description

色酮拼接3-羟甲基氧化吲哚衍生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，尤其是一种色酮拼接3-羟甲基氧化吲哚衍生物及其制备方法及应用。
背景技术
把具有生物活性天然产物骨架拼接到具有生物活性其他天然产物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-季碳氧化吲哚化合物是广泛存在多重药物活性分子中，具有消炎、抗肿瘤、抗氧化等生物活性(如附图1所示)。(2)、色酮架化合物来源于天然产物活性成分,具有多重药物活性。鉴于色酮架化合物和3-季碳氧化吲哚具有多重生物活性(如附图1所示)。因此，把色酮骨架拼接到3-季碳氧化吲哚类化合物中，合成一系列新的潜在多活性骨架的化合物，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1所示)。
特别强调的是，本发明所合成的色酮骨架拼接3-季碳氧化吲哚化合物，也是一种既含有色酮类骨架，也含有3-季碳氧化吲哚骨架。在自然界中，3-季碳氧化吲哚生物碱属于极其丰富的天然产物库，但是自然界化合物中，没有一例含有色酮骨架的3-季碳氧化吲哚骨架的天然拼接产物。因此，本发明合成一系列新的潜在多活性骨架的色酮拼接3-羟甲基氧化吲哚衍生物，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。
此外,在复杂分子的合成中，季碳中心的构建，一直是有机合成中的一个重大挑战。
发明内容
本发明的目的是：提供一种色酮拼接3-羟甲基氧化吲哚衍生物及其制备方法，它是一类重要的医药中间体和药物类似物，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。
本发明是这样实现的：色酮拼接3-羟甲基氧化吲哚衍生物，该化合物具有如下通式(I)的结构：
Figure GDA0002934633680000021
式中，R1为甲基、苄基、乙基或苯基；R2为氢、卤素或甲基，R3为氢或卤素。
靛红1与二氢色酮2先发生Knoevenagel缩合反应，生成中间体色酮拼接的3-烯基氧化吲哚3，然后中间体色酮拼接的3-烯基氧化吲哚3在无催化剂和高温条件下，与福尔马林在水中进行1,3-氢迁移和羟甲基化反应，获得色酮拼接3-羟甲基氧化吲哚衍生物4。
在水中进行反应时，加入福尔马林做羟甲基化试剂，福尔马林的加入量是色酮拼接的3-烯基氧化吲哚3摩尔量的2个当量至10个当量。
色酮拼接的3-烯基氧化吲哚3在无催化剂和福尔马林在水中进行1,3-氢迁移和羟甲基化反应的温度为60-100℃，反应时间10-36小时。
本发明的反应原理如下：
Figure GDA0002934633680000022
其中，R1，R2，R3如上所述。
由于采用了上述技术方案，与现有技术相比，本发明通过靛红1与二氢色酮2先发生Knoevenagel缩合反应，生成中间体色酮拼接的3-烯基氧化吲哚3，然后中间体3在无催化剂和高温条件下，与福尔马林在水中进行1,3-氢迁移和羟甲基化反应，获得色酮拼接3-羟甲基氧化吲哚衍生物4；色酮拼接3-羟甲基氧化吲哚衍生物4的合成也是潜在的药物分子中间体或和药物类似物，具有极其重要的研究意义。本发明发明操作简单易行，原料合成便宜易得，可以在水相中进行，无催化剂绿色反应,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为色酮架化合物和3-季碳氧化吲哚的多重生物活性及应用；
附图2和附图3为本发明的实施例化合物3a的核磁共振谱图；
附图4和附图5为本发明的实施例化合物4a的核磁共振谱图。
具体实施方式
(一)、代表性反应中间体3的合成制备
Figure GDA0002934633680000031
化合物3a:靛红1a(0.30mmol)和色酮2a(0.40mmol)溶解在4.0mL EtOH中，加入催化剂Et2NH(10mol％，0.03mmol)，室温搅拌24小时，旋干溶剂，柱层析得到中间体IA；中间体IA(0.3mmoL)和Et3N(0.6mmoL)溶解在15mL二氯甲烷中，缓慢加入MsCl(0.6mmoL)，室温搅拌24小时，加入水萃灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶剂，柱层析得到中间体IB；中间体IB(0.3mmoL)溶解在15mL MeOH中，缓慢加入5毫升水溶解的K2CO3(0.6mmoL)溶液，室温搅拌24小时，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶剂，柱层析分离得到黄色固体3a产率62％。核磁共振和高分辨质谱测试结果如下：1H NMR(CDCl3,400MHz)δ:3.14(s,3H),5.98(s,2H),6.67(d,J＝6.4Hz,1H),6.91-6.94(m,2H),6.97-7.00(m,1H),7.24-7.27(m,1H),7.41-7.44(m,1H),7.94(d,J＝5.2Hz,1H),8.29(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:26.0,67.0,107.9,117.8,120.3,121.7,122.3,122.6,127.7,127.9,132.3,136.4,137.4,145.0,161.3,167.8,184.2；HRMS(ESI-TOF)m/z:Calcd.for C18H13NNaO3[M+Na]+:314.0793；Found:314.0796.
通过实施例制备的化合物3c,3d,3h,3m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3c,3d,3h,3m，反应产率见如下，但需强调的是实施例旨在阐述而不是限制本发明的范围。本发明的化合物不限于如下所表示的内容。
制备色酮拼接的3-烯基氧化吲哚3的化学结构
Figure GDA0002934633680000041
本实施例制备中间体化合物3c:黄色固体；Yield 81％；1H NMR(CDCl3,400MHz)δ:1.26-1.29(m,3H),3.77-3.81(m,2H),6.08(s,2H),6.79(d,J＝6.0Hz,1H),6.99-7.02(m,2H),7.06-7.09(m,1H),7.32-7.35(m,1H),7.49-7.53(m,1H),8.02-8.04(m,1H),8.38(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:12.6,34.5,67.0,108.0,117.8,120.5,121.7,122.4,122.5,127.9,132.3,136.4,137.3,144.1,161.4,167.4,184.3；HRMS(ESI-TOF)m/z:Calcd.for C19H15NNaO3[M+Na]+:328.0950；Found:328.0953.
本实施例制备中间体化合物3d:黄色固体；Yield 75％；1H NMR(CDCl3,400MHz)δ:6.13(s,2H),6.77(d,J＝6.4Hz,1H),7.06-7.15(m,3H),7.30-7.33(m,1H),7.44-7.51(m,3H),7.55-7.62(m,3H),8.10-8.13(m,1H),8.50(d,J＝6.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:67.2,109.4,117.9,121.9,123.2,127.0,127.9,128.0,128.6,129.8,132.4,136.5,145.2,161.4,167.4,184.2；HRMS(ESI-TOF)m/z:Calcd.for C23H15NNaO3[M+Na]+:376.0950；Found:376.0951.
本实施例制备中间体化合物3h:黄色固体；Yield 76％；1H NMR(CDCl3,400MHz)δ:2.37(s,3H),3.24(s,3H),6.10(s,2H),6.69(d,J＝6.4Hz,1H),7.04(d,J＝6.8Hz,1H),7.10-7.13(m,1H),7.18(d,J＝6.0Hz,1H),7.53-7.57(m,1H),8.08-8.10(m,1H),8.23(s,1H)；13C NMR(CDCl3,100MHz)δ:21.3,26.0,67.0,107.6,117.7,120.3,121.7,122.4,127.9,128.2,131.6,132.0,132.8,136.3,137.0,142.8,161.4,167.8,184.2；HRMS(ESI-TOF)m/z:Calcd.for C19H15NNaO3[M+Na]+:328.0950；Found:328.0950.
本实施例制备中间体化合物3m:黄色固体；Yield 78％；2.54(s,3H),3.51(s,3H),6.06(s,2H),6.86-6.90(m,1H),6.96(d,J＝7.2Hz,1H),7.08(d,J＝6.0Hz,1H),7.42-7.44(m,1H),7.97(d,J＝2.0Hz,1H),8.19(d,J＝6.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:19.4,29.7,67.4,119.5,121.0,122.6,123.2,125.5,127.2,127.3,132.0,135.8,136.2,136.7,143.0,159.8,168.5,183.4；HRMS(ESI-TOF)m/z:Calcd.for C19H14ClNNaO3[M+Na]+:362.0560；Found:362.0563.
(二)、代表性反应中间体3的合成制备
Figure GDA0002934633680000051
化合物4a:色酮拼接的3-烯基氧化吲哚3a(0.3mmol)溶解在5毫升的水中，加入6eq的37％福尔马林，90℃加温搅拌24小时，乙酸乙酯萃取，硫酸钠干燥，旋干溶剂，柱层析分离得到白色固体4a,产率92％。熔点：182.8-185.3℃；核磁共振和高分辨质谱测试结果如下：1H NMR(CDCl3,400MHz)δ:3.11-3.13(m,1H),3.31(s,3H),3.81-3.84(m,1H),4.08-4.12(m,1H),6.88-6.94(m,2H),7.04(d,J＝5.6Hz,1H),7.23-7.27(m,2H),7.40(d,J＝6.8Hz,1H),7.56-7.59(m,1H),7.96-7.98(m,1H),8.35(br s,1H)；13C NMR(CDCl3,100MHz)δ:26.7,52.9,64.4,108.6,117.9,122.0,122.7,123.1,123.7,125.2,125.9,128.7,128.9,133.8,144.3,155.4,156.0,176.5,177.8；HRMS(ESI-TOF)m/z:Calcd.for C19H15NNaO4[M+Na]+:344.0899；Found:344.0897。
化合物4b～4w的制备方法同化合物4a，投料比与化合物4a相同，可得到化合物4b～4w，反应产率如下，但需强调的是本发明的化合物不限于如下所表示的内容。
色酮拼接3-羟甲基氧化吲哚衍生物的化学结构
Figure GDA0002934633680000061
色酮拼接3-羟甲基氧化吲哚衍生物的化学结构
Figure GDA0002934633680000071
本发明的实施例化合物4b:白色固体，熔点：212.8-214.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.92-3.95(m,1H),4.19-4.22(m,1H),4.89(d,J＝13.2Hz,1H),5.09(d,J＝12.8Hz,1H),5.33-5.35(m,1H),6.74(d,J＝6.4Hz,1H),6.87-6.91(m,1H),7.11-7.14(m,2H),7.25-7.28(m,1H),7.32-7.35(m,2H),7.42-7.45(m,1H),7.53(d,J＝5.6Hz,2H),7.66-7.67(m,1H),7.76-7.80(m,1H),7.89-7.91(m,1H),8.63(brs,1H)；13C NMR(DMSO-d6,100MHz)δ:43.2,53.4,64.3,108.5,118.3,121.6,123.0,125.1,127.1,127.2,128.4,130.4,136.7,144.3,155.3,155.4,174.7,176.5；HRMS(ESI-TOF)m/z:Calcd.for C25H19NNaO4[M+Na]+:420.1212；Found:420.1215。
本实施例制备化合物4c:白色固体，熔点：81.1-82.3℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:1.20-1.24(m,3H),2.18(s,3H),3.71-3.79(m,3H),4.07(d,J＝10.0Hz,1H),5.18(s,1H),6.90-6.92(m,2H),7.02-7.04(m,1H),7.39-7.43(m,1H),7.65(d,J＝8.8Hz,1H),7.75-7.79(m,1H),7.84-7.87(m,1H),8.56(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:12.3,20.7,34.2,53.3,64.1,107.6,118.3,123.3,124.0,125.0,125.5,127.9,130.0,130.5,134.3,141.8,155.0,155.4,174.7,175.7；HRMS(ESI-TOF)m/z:Calcd.for C21H19NNaO4[M+Na]+:372.1212；Found:372.1215。
本实施例制备化合物4d:白色固体，熔点：142.6-143.5℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:4.00-4.04(m,1H),4.22-4.25(m,1H),5.35-5.37(m,1H),6.73(d,J＝6.0Hz,1H),6.95-6.98(m,1H),7.17-7.21(m,2H),7.42-7.47(m,2H),7.52-7.54(m,2H),7.59-7.62(m,2H),7.67-7.69(m,1H),7.78-7.81(m,1H),7.91-7.93(m,1H),8.65(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:53.8,64.7,108.7,118.8,123.4,123.8,125.6,127.3,128.2,128.3,130.0,130.6,135.7,145.6,155.6,155.9,175.3,176.6；HRMS(ESI-TOF)m/z:Calcd.for C24H17NNaO4[M+Na]+:406.1055；Found:406.1057。
本实施例制备化合物4e:白色固体，熔点：208.9-210.2℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.18(s,3H),3.83-3.86(m,1H),4.13-4.16(m,1H),5.25-5.27(m,1H),6.98(d,J＝6.4Hz,1H),7.29(d,J＝1.6Hz,1H),7.42-7.44(m,2H),7.66(d,J＝6.8Hz,1H),7.77-7.80(m,1H),7.84-7.86(m,1H),8.53(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:26.5,53.5,63.7,109.7,113.4,118.3,122.4,122.9,125.0,125.6,125.9,130.4,132.9,134.5,144.8,155.4,155.5,174.7,176.0；HRMS(ESI-TOF)m/z:Calcd.for C19H14BrNNaO4[M+Na]+:422.0004；Found:422.0005。
本实施例制备化合物4f:白色固体，熔点：184.9-186.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.19(s,3H),3.82-3.86(m,1H),4.13-4.17(m,1H),5.25-5.27(m,1H),7.03(d,J＝8.4Hz,1H),7.19(d,J＝2.0Hz,1H),7.29-7.31(m,1H),7.42-7.46(m,1H),7.67(d,J＝8.4Hz,1H),7.77-7.82(m,1H),7.85-7.87(m,1H),8.54(brs,1H)；13C NMR(DMSO-d6,100MHz)δ:26.5,53.5,54.9,63.7,109.1,118.3,122.4,122.9,123.2,125.0,125.6,127.6,132.5,134.5,144.3,155.4,155.5,174.7,176.1；HRMS(ESI-TOF)m/z:Calcd.for C19H14ClNNaO4[M+Na]+:378.0509；Found:378.0513。
本实施例制备化合物4g:白色固体，熔点：201.3-202.5℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.19(s,3H),3.81-3.84(m,3H),4.12-4.20(m,1H),5.23-5.25(m,1H),6.98-7.09(m,3H),7.41-7.44(m,1H),7.66-7.68(m,1H),7.77-7.80(m,1H),7.85-7.87(m,1H),8.54(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:26.0,53.3,63.3,107.8,107.9,110.8(d,JCF＝20.1Hz),113.2(d,JCF＝18.8Hz),117.8,122.0,122.4,124.5,125.1,131.8,131.9,134.0,141.1,154.9,157.7(d,JCF＝235.1Hz),174.2,175.7；HRMS(ESI-TOF)m/z:Calcd.for C19H14FNNaO4[M+Na]+:362.0805；Found:362.0803。
本实施例制备化合物4h:白色固体，熔点：203.2-204.5℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.18(s,3H),3.17(s,3H),3.79-3.82(m,1H),4.07-4.10(m,1H),5.17(d,J＝3.2Hz,1H),6.87-6.92(m,2H),7.03-7.05(m,1H),7.40-7.43(m,1H),7.65(d,J＝6.8Hz,1H),7.76-7.79(m,1H),7.84-7.86(m,1H),8.56(br s,1H)；13CNMR(DMSO-d6,100MHz)δ:20.7,26.4,53.3,64.0,107.6,118.3,123.0,123.3,123.9,125.0,125.6,128.0,130.3,130.4,143.0,155.1,155.4,174.7,176.4；HRMS(ESI-TOF)m/z:Calcd.for C20H17NNaO4[M+Na]+:358.1055；Found:358.1055。
本实施例制备化合物4i:白色固体，熔点：207.8-209.5℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.34(s,3H),3.86-3.90(m,1H),4.08-4.11(m,1H),5.22-5.24(m,1H),6.88-6.92(m,1H),7.05-7.07(m,1H),7.22-7.24(m,1H),7.42-7.46(m,1H),7.68(d,J＝6.4Hz,1H),7.78-7.82(m,1H),7.85-7.87(m,1H),8.56(br s,1H)；13CNMR(DMSO-d6,100MHz)δ:29.5,53.1,64.0,113.5,118.3,122.0,122.7,122.8,122.9,125.0,125.7,130.0,133.6,134.5,141.0,155.2,155.4,174.6,177.0；HRMS(ESI-TOF)m/z:Calcd.for C19H14ClNNaO4[M+Na]+:378.0509；Found:378.0509。
本实施例制备化合物4j:白色固体，熔点：182.7-185.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.57(s,3H),3.47(s,3H),3.81-3.84(m,1H),4.04-4.07(m,1H),5.14-5.16(m,1H),6.77-6.80(m,1H),6.92(d,J＝5.6Hz,1H),6.97(d,J＝6.0Hz,1H),7.39-7.43(m,1H),7.63-7.66(m,1H),7.75-7.78(m,1H),7.85-7.87(m,1H),8.56(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:18.6,29.5,52.7,64.2,118.3,118.8,121.0,121.4,123.0,123.5,125.0,125.5,130.8,131.5,134.3,142.9,155.0,155.4,174.6,177.1；HRMS(ESI-TOF)m/z:Calcd.for C20H17NNaO4[M+Na]+:358.1055；Found:358.1058。
本实施例制备化合物4k:白色固体，熔点：195.0-196.4℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.19(s,3H),3.78-3.83(m,1H),4.08-4.11(m,1H),5.18-5.21(m,1H),6.89-6.92(m,1H),6.99(d,J＝6.4Hz,1H),7.08-7.10(m,1H),7.22-7.26(m,1H),7.74(d,J＝7.2Hz,1H),7.79-7.84(m,2H),8.60(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:26.3,53.2,63.9,107.8,120.9,121.5,123.1,123.2,124.0,124.1,127.9,130.0,130.1,134.4,145.2,154.0,155.5,173.7,176.2；HRMS(ESI-TOF)m/z:Calcd.forC19H14ClNNaO4[M+Na]+:378.0509；Found:378.0512。
本实施例制备化合物4l:白色固体，熔点：260.0-261.4℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.18(s,3H),3.16(s,3H),3.77-3.81(m,1H),4.06-4.10(m,1H),5.18-5.21(m,1H),6.87-6.94(m,2H),7.04(d,J＝7.6Hz,1H),7.74-7.77(m,1H),7.80-7.85(m,2H),8.60(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:20.7,26.3,53.3,63.9,107.5,120.9,123.2,123.9,124.0,128.0,130.0,130.3,134.3,142.9,154.0,155.4,173.6,176.0；HRMS(ESI-TOF)m/z:Calcd.for C20H16ClNNaO4[M+Na]+:392.0666；Found:392.0661。
本实施例制备化合物4m:白色固体，熔点：207.1-209.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.58(s,3H),3.46(s,3H),3.78-3.82(m,1H),4.01-4.05(m,1H),5.15-5.18(m,1H),6.77-6.80(m,1H),6.90-6.94(m,1H),6.98(d,J＝7.6Hz,1H),7.73-7.76(m,1H),7.80-7.85(m,2H),8.59(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:18.6,29.4,52.6,64.1,118.8,120.9,121.0,121.4,123.4,124.0,130.0,130.5,131.5,134.3,142.9,154.0,155.4,173.6,176.8；HRMS(ESI-TOF)m/z:Calcd.forC20H16ClNNaO4[M+Na]+:392.0666；Found:392.0668。
本实施例制备化合物4n:白色固体，熔点：206.4-207.8℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.18(s,3H),3.81-3.84(m,1H),4.11-4.14(m,1H),5.25-5.27(m,1H),6.98-7.09(m,3H),7.73-7.76(m,1H),7.79-7.83(m,2H),8.57(brs,1H)；13C NMR(DMSO-d6,100MHz)δ:26.5,53.7,63.7,108.3,108.4,111.3,111.5,113.7,113.9,120.9,122.5,124.0,124.1,130.1,134.4,141.6,154.0,155.8,157.3,159.2,173.8,176.0；HRMS(ESI-TOF)m/z:Calcd.for C19H13ClFNNaO4[M+Na]+:396.0415；Found:396.0416。
本实施例制备化合物4o:白色固体，熔点：187.2-188.6℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.19(s,3H),3.78-3.83(m,1H),4.08-4.11(m,1H),5.18-5.20(m,1H),6.89-6.92(m,1H),6.99-7.01(m,1H),7.08-7.12(m,1H),7.22-7.25(m,1H),7.53-7.55(m,1H),7.66-7.71(m,1H),7.77-7.80(m,1H),8.61(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:26.3,53.2,63.9,107.8,109.6(d,JCF＝23.7Hz),121.2,121.3,121.5,122.5,122.6,122.8,123.1,127.9,130.2,145.3,151.9,155.5,158.9(d,JCF＝242.5Hz),174.1,176.3；HRMS(ESI-TOF)m/z:Calcd.for C19H14FNNaO4[M+Na]+:362.0805；Found:362.0804。
本实施例制备化合物4p:白色固体，熔点：172.4-174.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.57(s,3H),3.46(s,3H),3.76-3.82(m,1H),4.02-4.05(m,1H),5.14-5.16(m,1H),6.76-6.79(m,1H),6.89-6.93(m,1H),6.98(d,J＝6.0Hz,1H),7.53-7.57(m,1H),7.67-7.71(m,1H),7.77-7.81(m,1H),8.59(br s,1H)；13CNMR(DMSO-d6,100MHz)δ:18.1,28.9,52.1,63.7,109.1(d,JCF＝22.5Hz),118.3,120.5,120.9,122.3,130.1,131.0,142.4,151.4,154.8,154.9,158.5(d,JCF＝242.5Hz),173.5,176.5；HRMS(ESI-TOF)m/z:Calcd.for C20H16FNNaO4[M+Na]+:376.0961；Found:376.0960。
本实施例制备化合物4q:白色固体，熔点：184.2-186.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.91-3.94(m,1H),4.19-4.23(m,1H),4.86(d,J＝16.0Hz,1H),5.06(d,J＝16.0Hz,1H),5.36-5.38(m,1H),6.72(d,J＝8.4Hz,1H),7.17-7.21(m,2H),7.24-7.28(m,1H),7.32-7.35(m,2H),7.44-7.51(m,3H),7.70(d,J＝8.4Hz,1H),7.80-7.84(m,1H),7.89-7.91(m,1H),8.57(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:43.2,53.6,64.0,109.7,118.4,123.3,125.0,125.6,125.8,127.1,127.5,128.4,136.3,143.3,155.4,155.6,174.7,176.2；HRMS(ESI-TOF)m/z:Calcd.for C25H18ClNNaO4[M+Na]+:454.0822；Found:454.0825。
本实施例制备化合物4r:白色固体，熔点：254.8-256.5℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.91-3.95(m,1H),4.20-4.23(m,1H),4.87(d,J＝12.8Hz,1H),5.06(d,J＝13.2Hz,1H),5.36-5.39(m,1H),6.68(d,J＝6.8Hz,1H),7.24-7.28(m,1H),7.30-7.35(m,4H),7.45-7.51(m,3H),7.70(d,J＝6.8Hz,1H),7.79-7.83(m,1H),7.89-7.91(m,1H),8.56(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:43.2,53.6,64.0,110.3,113.6,118.4,122.2,122.9,125.1,125.7,126.0,127.2,128.5,130.3,133.1,134.6,136.3,143.8,155.5,155.7,174.7,176.2；HRMS(ESI-TOF)m/z:Calcd.forC25H18BrNNaO4[M+Na]+:498.0317；Found:498.0314。
本实施例制备化合物4s:白色固体，熔点：197.5-199.0℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.91-3.95(m,1H),4.21-4.24(m,1H),4.87(d,J＝16.0Hz,1H),5.06(d,J＝16.0Hz,1H),5.36-5.39(m,1H),6.68-6.72(m,1H),6.94-6.99(m,1H),7.05-7.08(m,1H),7.24-7.28(m,1H),7.32-7.36(m,2H),7.43-7.48(m,1H),7.52(d,J＝7.2Hz,2H),7.67-7.70(m,1H),7.78-7.82(m,1H),7.90-7.92(m,1H),8.59(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:43.2,53.9,64.1,108.9,111.3(d,JCF＝25.1Hz),113.6(d,JCF＝23.3Hz),118.3,122.3,122.9,125.0,125.6,127.2,128.4,128.5,132.4,132.5,134.5,136.4,140.5,155.4,155.6,158.2(d,JCF＝236.2Hz),174.7,176.3；HRMS(ESI-TOF)m/z:Calcd.for C25H18FNNaO4[M+Na]+:438.1118；Found:438.1119。
本实施例制备化合物4t:白色固体，熔点：195.4-197.8℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.10(s,3H),3.59-3.62(m,1H),4.88(s,2H),4.96(d,J＝8.0Hz,1H),6.58(s,1H),6.60(d,J＝8.0Hz,1H),6.91-6.99(m,2H),7.05-7.08(m,1H),7.20(s,1H),7.25-7.28(m,1H),7.33-7.36(m,2H),7.45(d,J＝7.2Hz,2H),7.52(d,J＝7.2Hz,2H)；13C NMR(DMSO-d6,100MHz)δ:20.5,43.0,52.1,66.9,108.8,117.8,120.5,121.4,125.6,126.4,127.2,127.3,128.3,128.4,129.4,130.9,136.3,141.2,161.3,176.4,190.1；HRMS(ESI-TOF)m/z:Calcd.for C26H21NNaO4[M+Na]+:434.1368；Found:434.1371。
本实施例制备化合物4u:白色固体，熔点：184.0-185.6℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:3.88-3.91(m,1H),4.15-4.21(m,1H),4.86(d,J＝12.8Hz,1H),5.06(d,J＝12.8Hz,1H),5.31-5.34(m,1H),6.72(d,J＝6.4Hz,1H),6.87-6.90(m,1H),7.10-7.13(m,2H),7.24-7.27(m,1H),7.32-7.35(m,2H),7.51(d,J＝6.0Hz,2H),7.76-7.78(m,1H),7.83-7.86(m,2H),8.64(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:43.1,53.4,64.2,108.5,121.0,121.7,123.0,124.0,124.1,127.2,128.5,130.1,130.2,136.6,144.3,154.1,155.7,173.7,176.3；HRMS(ESI-TOF)m/z:Calcd.for C25H18ClNNaO4[M+Na]+:454.0822；Found:454.0822。
本实施例制备化合物4v:白色固体，熔点：214.8-216.6℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:2.15(s,3H),3.86-3.89(m,1H),4.13-4.16(m,1H),4.83(d,J＝12.8Hz,1H),5.03(d,J＝13.2Hz,1H),5.30-5.32(m,1H),6.60(d,J＝6.4Hz,1H),6.91-6.93(m,2H),7.24-7.26(m,1H),7.32-7.34(m,2H),7.49(d,J＝6.0Hz,2H),7.76-7.78(m,1H),7.84-7.87(m,2H),8.63(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:20.7,43.1,53.4,64.2,108.2,121.0,123.1,124.0,124.1,127.1,127.2,128.4,130.0,130.2,130.5,136.7,141.9,154.1,155.6,173.7,176.2；HRMS(ESI-TOF)m/z:Calcd.forC26H20ClNNaO4[M+Na]+:468.0979；Found:468.0982。
本实施例制备化合物4w:白色固体，熔点：178.2-179.1℃；核磁共振和高分辨质谱测试结果如下：1H NMR(DMSO-d6,400MHz)δ:1.21-1.24(m,1H),3.73-3.80(m,3H),4.06-4.09(m,1H),5.18-5.20(m,1H),6.87-6.91(m,1H),7.03(d,J＝6.0Hz,1H),7.07-7.09(m,1H),7.21-7.25(m,1H),7.75(d,J＝7.2Hz,1H),7.79-7.84(m,2H),8.60(br s,1H)；13C NMR(DMSO-d6,100MHz)δ:12.3,34.3,53.2,64.0,107.9,120.9,121.3,123.2,123.3,124.0,124.1,127.9,130.0,130.3,134.3,144.2,154.0,155.5,173.7,175.7；HRMS(ESI-TOF)m/z:Calcd.for C20H16ClNNaO4[M+Na]+:392.0666；Found:392.0664。
化合物4d,4f,4g,4h,4k,4l,4o,4s,4u和4w的单晶数据如下：
Figure GDA0002934633680000131
化合物4d的晶体数据和细化的结构
Identification code 4d
Empirical formula C24H19NO5
Formula weight 401.40
Temperature/K 99.99(10)
Crystal system monoclinic
Space group C2/c
Figure GDA0002934633680000141
28.3770(19),7.1579(5),19.4046(16)
α/°,β/°,γ/° 90,103.671(7),90.
Figure GDA0002934633680000142
3829.8(5)
Z 8
ρcalcg/cm3 1.392
μ/mm-1 0.098
F(000) 1680.0
Crystal size/mm3 0.18×0.15×0.13
Radiation 1MoKα(λ＝0.71073)
2Θrange for data collection/° 4.32 to 59.128
Index ranges -38≤h≤37,-9≤k≤9,-16≤l≤25
Reflections collected 10036
Independent reflections 4532[Rint＝0.0319,Rsigma＝0.0523]
Data/restraints/parameters 4532/0/275
Goodness-of-fit on F2 1.065
Final R indexes[I>＝2σ(I)] R1＝0.0515,wR2＝0.1031
Final R indexes[all data] R1＝0.0734,wR2＝0.1135
Largest diff.peak/hole/
Figure GDA0002934633680000143
0.28/-0.25
4d晶体结构的测定
Crystal data for C24H19NO5(M＝401.40g/mol):monoclinic,space group C2/c(no.15),
Figure GDA0002934633680000144
Figure GDA0002934633680000145
β＝103.671(7)°,
Figure GDA0002934633680000146
Z＝8,T＝99.99(10)K,μ(MoKα)＝0.098mm-1,Dcalc＝1.392g/cm3,10036reflectionsmeasured(4.32°≤2Θ≤59.128°),4532unique(Rint＝0.0319,Rsigma＝0.0523)which wereused in all calculations.The final R1 was 0.0515(I>2σ(I))and wR2 was 0.1135(all data).
Figure GDA0002934633680000147
化合物4f的晶体数据和细化的结构
Identification code 4f
Empirical formula C19H14ClNO4
Formula weight 355.76
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/n
Figure GDA0002934633680000151
8.95357(19),11.3492(2),15.4615(3)
α/°,β/°,γ/° 90,100.458(2),90.
Figure GDA0002934633680000152
1545.04(6)
Z 4
ρcalcg/cm3 1.529
μ/mm-1 2.420
F(000) 736.0
Crystal size/mm3 0.18×0.14×0.12
Radiation CuKα(λ＝1.54184)
2Θrange for data collection/° 9.724to 147.72
Index ranges -10≤h≤11,-11≤k≤13,-19≤l≤18
Reflections collected 5451
Independent reflections 3018[Rint＝0.0261,Rsigma＝0.0267]
Data/restraints/parameters 3018/0/229
Goodness-of-fit on F2 1.048
Final R indexes[I>＝2σ(I)] R1＝0.0428,wR2＝0.1154
Final R indexes[all data] R1＝0.0440,wR2＝0.1165
Largest diff.peak/hole/
Figure GDA0002934633680000153
0.63/-0.34
4f晶体结构的测定
Crystal data for C19H14ClNO4(M＝355.76g/mol):monoclinic,space groupP21/n(no.14),
Figure GDA0002934633680000154
Figure GDA0002934633680000155
β＝100.458(2)°,
Figure GDA0002934633680000156
Z＝4,T＝100.00(10)K,μ(CuKα)＝2.420mm-1,Dcalc＝1.529g/cm3,5451reflections measured(9.724°≤2Θ≤147.72°),3018unique(Rint＝0.0261,Rsigma＝0.0267)which were used in all calculations.The final R1 was 0.0428(I>2σ(I))and wR2 was 0.1165(all data).
Figure GDA0002934633680000157
化合物4g的晶体数据和细化的结构
Identification code 4g
Empirical formula C19H14FNO4
Formula weight 339.31
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/n
Figure GDA0002934633680000161
8.8536(3),11.0840(4),15.3754(6)
α/°,β/°,γ/° 90,101.430(4),90.
Figure GDA0002934633680000162
1478.91(10)
Z 4
ρcalcg/cm3 1.524
μ/mm-1 0.116
F(000) 704.0
Crystal size/mm3 0.14×0.12×0.11
Radiation MoKα(λ＝0.71073)
2Θrange for data collection/° 6.922 to 59.072
Index ranges -11≤h≤12,-15≤k≤13,-20≤l≤21
Reflections collected 12618
Independent reflections 3609[Rint＝0.0285,Rsigma＝0.0314]
Data/restraints/parameters 3609/0/229
Goodness-of-fit on F2 1.027
Final R indexes[I>＝2σ(I)] R1＝0.0433,wR2＝0.1097
Final R indexes[all data] R1＝0.0526,wR2＝0.1165
Largest diff.peak/hole/
Figure GDA0002934633680000163
0.40/-0.28
4g晶体结构的测定
Crystal data for C19H14FNO4(M＝339.31g/mol):monoclinic,space group P21/n(no.14),
Figure GDA0002934633680000164
Figure GDA0002934633680000165
β＝101.430(4)°,
Figure GDA0002934633680000166
Z＝4,T＝100.00(10)K,μ(MoKα)＝0.116mm-1,Dcalc＝1.524g/cm3,12618reflectionsmeasured(6.922°≤2Θ≤59.072°),3609unique(Rint＝0.0285,Rsigma＝0.0314)which wereused in all calculations.The final R1 was 0.0433(I>2σ(I))and wR2 was 0.1165(all data).
Figure GDA0002934633680000167
化合物4h的晶体数据和细化的结构
Identification code 4h
Empirical formula C20H17NO4
Formula weight 335.35
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/n
Figure GDA0002934633680000168
9.0065(5),11.3472(6),15.15.5009(9)
α/°,β/°,γ/° 90,100.690(5),90.
Figure GDA0002934633680000171
1556.68(15)
Z 4
ρcalcg/cm3 1.431
μ/mm-1 0.100
F(000) 704.0
Crystal size/mm3 0.16×0.14×0.12
Radiation MoKα(λ＝0.71073)
2Θrange for data collection/° 6.768 to 59.022
Index ranges -11≤h≤12,-14≤k≤15,-20≤l≤20
Reflections collected 11973
Independent reflections 3851[Rint＝0.0434,Rsigma＝0.0508]
Data/restraints/parameters 3851/0/229
Goodness-of-fit on F2 1.039
Final R indexes[I>＝2σ(I)] R1＝0.0484,wR2＝0.1097
Final R indexes[all data] R1＝0.0647,wR2＝0.1208
Largest diff.peak/hole/
Figure GDA0002934633680000172
0.34/-0.30
4h晶体结构的测定
Crystal data for C20H17NO4(M＝335.35g/mol):monoclinic,space group P21/n(no.14),
Figure GDA0002934633680000173
Figure GDA0002934633680000174
β＝100.690(5)°,
Figure GDA0002934633680000175
Z＝4,T＝100.00(10)K,μ(MoKα)＝0.100mm-1,Dcalc＝1.431g/cm3,11973reflectionsmeasured(6.768°≤2Θ≤59.022°),3851unique(Rint＝0.0434,Rsigma＝0.0508)which wereused in all calculations.The final R1 was 0.0484(I>2σ(I))and wR2 was 0.1208(all data).
Figure GDA0002934633680000176
化合物4k的晶体数据和细化的结构
Identification code 4k
Empirical formula C19H14ClNO4
Formula weight 355.76
Temperature/K 99.99(10)
Crystal system monoclinic
Space group P21/c
Figure GDA0002934633680000177
14.9389(9),6.8341(3),15.4499(10)
α/°,β/°,γ/° 90,97.164(6),90.
Figure GDA0002934633680000178
1565.03(16)
Z 4
ρcalcg/cm3 1.510
μ/mm-1 2.389
F(000) 736.0
Crystal size/mm3 0.15×0.12×0.11
Radiation CuKα(λ＝1.54184)
2Θrange for data collection/° 11.546 to 147.286
Index ranges -18≤h≤16,-7≤k≤8,-17≤l≤19
Reflections collected 8148
Independent reflections 3069[Rint＝0.0983,Rsigma＝0.1131]
Data/restraints/parameters 3069/0/228
Goodness-of-fit on F2 1.103
Final R indexes[I>＝2σ(I)] R1＝0.1081,wR2＝0.2838
Final R indexes[all data] R1＝0.1291,wR2＝0.2927
Largest diff.peak/hole/
Figure GDA0002934633680000181
1.10/-0.66
4k晶体结构的测定
Crystal data for C19H14ClNO4(M＝355.76g/mol):monoclinic,space groupP21/c(no.14),
Figure GDA0002934633680000182
Figure GDA0002934633680000183
β＝97.164(6)°,
Figure GDA0002934633680000184
Z＝4,T＝99.99(10)K,μ(CuKα)＝2.389mm-1,Dcalc＝1.510g/cm3,8148reflections measured(11.546°≤2Θ≤147.286°),3069unique(Rint＝0.0983,Rsigma＝0.1131)which were used in all calculations.The final R1 was 0.1081(I>2σ(I))and wR2 was 0.2927(all data).
Figure GDA0002934633680000185
化合物4l的晶体数据和细化的结构
Identification code 4l
Empirical formula C20H16ClNO4
Formula weight 369.79
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/c
Figure GDA0002934633680000186
6.7526(6),29.898(2),8.2734(8)
α/°,β/°,γ/° 90,90.545(8),90.
Figure GDA0002934633680000187
1670.2(3)
Z 4
ρcalcg/cm3 1.471
μ/mm-1 0.256
F(000) 768.0
Crystal size/mm3 0.16×0.14×0.12
Radiation MoKα(λ＝0.71073)
2Θrange for data collection/° 6.4to 59.396
Index ranges -6≤h≤9,-41≤k≤34,-11≤l≤11
Reflections collected 17255
Independent reflections 4195[Rint＝0.0554,Rsigma＝0.0528]
Data/restraints/parameters 4195/0/238
Goodness-of-fit on F2 1.094
Final R indexes[I>＝2σ(I)] R1＝0.0588,wR2＝0.1468
Final R indexes[all data] R1＝0.0831,wR2＝0.1718
Largest diff.peak/hole/
Figure GDA0002934633680000191
0.58/-0.66
4l晶体结构的测定
Crystal data for C20H16ClNO4(M＝369.79g/mol):monoclinic,space groupP21/c(no.14),
Figure GDA0002934633680000192
Figure GDA0002934633680000193
β＝90.545(8)°,
Figure GDA0002934633680000194
Z＝4,T＝100.00(10)K,μ(MoKα)＝0.256mm-1,Dcalc＝1.471g/cm3,17255reflections measured(6.4°≤2Θ≤59.396°),4195unique(Rint＝0.0554,Rsigma＝0.0528)which were used in all calculations.The final R1 was 0.0588(I>2σ(I))and wR2 was 0.1718(all data).
Figure GDA0002934633680000195
化合物4o的晶体数据和细化的结构
Identification code 4o
Empirical formula C19H14FNO4
Formula weight 339.31
Temperature/K 100.01(10)
Crystal system monoclinic
Space group P21/c
Figure GDA0002934633680000196
6.3770(3),23.8555(13),9.8072(5)
α/°,β/°,γ/° 90,95.362(5),90.
Figure GDA0002934633680000197
1485.41(13)
Z 4
ρcalcg/cm3 1.517
μ/mm-1 0.115
F(000) 704.0
Crystal size/mm3 0.16×0.14×0.12
Radiation MoKα(λ＝0.71073)
2Θrange for data collection/° 4.508 to 58.916
Index ranges -8≤h≤8,-24≤k≤32,-12≤l≤12
Reflections collected 10770
Independent reflections 3639[Rint＝0.0287,Rsigma＝0.0366]
Data/restraints/parameters 3639/0/229
Goodness-of-fit on F2 1.047
Final R indexes[I>＝2σ(I)] R1＝0.0439,wR2＝0.1026
Final R indexes[all data] R1＝0.0547,wR2＝0.1098
Largest diff.peak/hole/
Figure GDA0002934633680000201
0.37/-0.23
4o晶体结构的测定
Crystal data for C19H14FNO4(M＝339.31g/mol):monoclinic,space group P21/c(no.14),
Figure GDA0002934633680000202
Figure GDA0002934633680000203
β＝95.362(5)°,
Figure GDA0002934633680000204
Z＝4,T＝100.01(10)K,μ(MoKα)＝0.115mm-1,Dcalc＝1.517g/cm3,10770reflectionsmeasured(4.508°≤2Θ≤58.916°),3639unique(Rint＝0.0287,Rsigma＝0.0366)which wereused in all calculations.The final R1 was 0.0439(I>2σ(I))and wR2 was 0.1098(all data).
Figure GDA0002934633680000205
化合物4s的晶体数据和细化的结构
Identification code 4s
Empirical formula C25H18FNO4
Formula weight 415.40
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/c
Figure GDA0002934633680000206
10.5670(8),21.4436(16),9.5202(9)
α/°,β/°,γ/° 90,114.050(10),90.
Figure GDA0002934633680000207
1970.0(3)
Z 4
ρcalcg/cm3 1.401
μ/mm-1 0.101
F(000) 864.0
Crystal size/mm3 0.16×0.12×0.11
Radiation MoKα(λ＝0.71073)
2Θrange for data collection/° 7.094 to 59.048
Index ranges -14≤h≤10,-29≤k≤20,-9≤l≤12
Reflections collected 10494
Independent reflections 4629[Rint＝0.0401,Rsigma＝0.0699]
Data/restraints/parameters 4629/0/281
Goodness-of-fit on F2 1.032
Final R indexes[I>＝2σ(I)] R1＝0.0557,wR2＝0.1080
Final R indexes[all data] R1＝0.0850,wR2＝0.1241
Largest diff.peak/hole/
Figure GDA0002934633680000211
0.30/-0.24
4s晶体结构的测定
Crystal data for C25H18FNO4(M＝415.40g/mol):monoclinic,space group P21/c(no.14),
Figure GDA0002934633680000212
Figure GDA0002934633680000213
β＝114.050(10)°,
Figure GDA0002934633680000214
Z＝4,T＝100.00(10)K,μ(MoKα)＝0.101mm-1,Dcalc＝1.401g/cm3,10494reflectionsmeasured(7.094°≤2Θ≤59.048°),4629unique(Rint＝0.0401,Rsigma＝0.0699)which wereused in all calculations.The final R1 was 0.0557(I>2σ(I))and wR2 was 0.1241(all data).
Figure GDA0002934633680000215
化合物4u的晶体数据和细化的结构
Identification code 4u
Empirical formula C26H21ClNO5
Formula weight 462.89
Temperature/K 100.00(10)
Crystal system triclinic
Space group P-1
Figure GDA0002934633680000216
9.1764(6),10.3922(5),11.8331(7)
α/°,β/°,γ/° 92.396(4),100.320(5),101.272(5).
Figure GDA0002934633680000217
1085.31(11)
Z 2
ρcalcg/cm3 1.416
μ/mm-1 1.895
F(000) 482.0
Crystal size/mm3 0.15×0.14×0.12
Radiation CuKα(λ＝1.54184)
2Θrange for data collection/° 7.618 to 146.836
Index ranges -10≤h≤11,-12≤k≤12,-14≤l≤10
Reflections collected 7160
Independent reflections 4207[Rint＝0.0408,Rsigma＝0.0484]
Data/restraints/parameters 4207/0/301
Goodness-of-fit on F2 1.076
Final R indexes[I>＝2σ(I)] R1＝0.0599,wR2＝0.1653
Final R indexes[all data] R1＝0.0666,wR2＝0.1747
Largest diff.peak/hole/
Figure GDA0002934633680000221
0.92/-0.64
4u晶体结构的测定
Crystal data for C26H21ClNO5(M＝462.89g/mol):triclinic,space group P-1(no.2),
Figure GDA0002934633680000222
Figure GDA0002934633680000223
α＝92.396(4)°,β＝100.320(5)°,γ＝101.272(5)°,
Figure GDA0002934633680000224
Z＝2,T＝100.00(10)K,μ(CuKα)＝1.895mm-1,Dcalc＝1.416g/cm3,7160reflections measured(7.618°≤2Θ≤146.836°),4207unique(Rint＝0.0408,Rsigma＝0.0484)which were used in all calculations.The final R1was 0.0599(I>2σ(I))and wR2 was 0.1747(all data).
Figure GDA0002934633680000225
化合物4w的晶体数据和细化的结构
Identification code 4w
Empirical formula C20H16ClNO4
Formula weight 369.79
Temperature/K 100.00(10)
Crystal system monoclinic
Space group I2/a
Figure GDA0002934633680000226
29.1728(6),6.80590(10),33.0098(7)
α/°,β/°,γ/° 90,100.459(2),90.
Figure GDA0002934633680000227
6445.1(2)
Z 16
ρcalcg/cm3 1.524
μ/mm-1 2.343
F(000) 3072.0
Crystal size/mm3 0.14×0.12×0.1
Radiation CuKα(λ＝1.54184)
2Θrange for data collection/° 5.444 to 147.526
Index ranges -25≤h≤35,-4≤k≤8,-40≤l≤37
Reflections collected 11731
Independent reflections 6319[Rint＝0.0311,Rsigma＝0.0385]
Data/restraints/parameters 6319/0/484
Goodness-of-fit on F2 1.028
Final R indexes[I>＝2σ(I)] R1＝0.0408,wR2＝0.1067
Final R indexes[all data] R1＝0.0438,wR2＝0.1096
Largest diff.peak/hole/
Figure GDA0002934633680000231
0.26/-0.27
4w晶体结构的测定
Crystal data for C20H16ClNO4(M＝369.79g/mol):monoclinic,space group I2/a(no.15),
Figure GDA0002934633680000232
Figure GDA0002934633680000233
β＝100.459(2)°,
Figure GDA0002934633680000234
Z＝16,T＝100.00(10)K,μ(CuKα)＝2.343mm-1,Dcalc＝1.524g/cm3,11731reflections measured(5.444°≤2Θ≤147.526°),6319unique(Rint＝0.0311,Rsigma＝0.0385)which were used in all calculations.The final R1 was 0.0408(I>2σ(I))and wR2 was 0.1096(all data).
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)的细胞毒性试验表明：此类式(1)所示的结构的色酮拼接3-羟甲基氧化吲哚衍生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：化合物4g、4n、4o、4w或4l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4g、4n、4o、4w或4l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12.5μmol/L,25.0μmol/L,50.0μmol/L,100.0μmol/L和100μmol/L。48小时后，每孔加入10μLMTT(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4g、4n、4o、4w或4l对K562细胞(人慢性髓系白血病细胞)半抑制浓度IC50由spss软件(19版本)分析得到。化合物4g对K562肿瘤细胞的IC50为39.7μmol/L；化合物4n对K562肿瘤细胞的IC50为41.9μmol/L；化合物4o对K562肿瘤细胞的IC50为40.4μmol/L；化合物4l对K562肿瘤细胞的IC50为54.4μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为27.4μmol/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)所示的色酮拼接3-羟甲基氧化吲哚衍生物对K562细胞具有较强的细胞毒性，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人白血病细胞(K562)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 (5)

1.一种色酮拼接3-羟甲基氧化吲哚衍生物，其特征在于：该化合物具有如下通式(Ⅰ)的结构：
Figure FDA0001678580210000011
式中，R1为甲基、苄基、乙基或苯基；R2为氢、卤素或甲基，R3为氢或卤素。
2.一种如权利要求1所述的色酮拼接3-羟甲基氧化吲哚衍生物的制备方法，其特征在于：使靛红1与二氢色酮2先发生Knoevenagel缩合反应，生成中间体色酮拼接的3-烯基氧化吲哚3，然后将中间体色酮拼接的3-烯基氧化吲哚3在无催化剂和福尔马林在水中进行1,3-氢迁移和羟甲基化反应，获得色酮拼接3-羟甲基氧化吲哚衍生物4；合成路线如下：
Figure FDA0001678580210000012
其中，R1为甲基、苄基、乙基或苯基；R2为氢、卤素或甲基，R3为氢或卤素。
3.根据权利要求2所述的色酮拼接3-羟甲基氧化吲哚衍生物的制备方法，其特征在于：在水中进行反应时，加入福尔马林作为基化试剂，福尔马林的加入量是色酮拼接的3-烯基氧化吲哚3摩尔量的2个当量至10个当量。
4.根据权利要求2所述的色酮拼接3-羟甲基氧化吲哚衍生物的制备方法，其特征在于：色酮拼接的3-烯基氧化吲哚3在无催化剂和福尔马林在水中进行1,3-氢迁移和羟甲基化反应的温度为60-100℃，反应时间10-36小时。
5.一种如权利要求1所述的色酮拼接3-羟甲基氧化吲哚衍生物在制备防治肿瘤疾病药物的应用。
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