CN107235969B - 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用 - Google Patents

合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用 Download PDF

Info

Publication number
CN107235969B
CN107235969B CN201710661412.3A CN201710661412A CN107235969B CN 107235969 B CN107235969 B CN 107235969B CN 201710661412 A CN201710661412 A CN 201710661412A CN 107235969 B CN107235969 B CN 107235969B
Authority
CN
China
Prior art keywords
minor
major
compound
oxindole
key intermediate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710661412.3A
Other languages
English (en)
Other versions
CN107235969A (zh
Inventor
田民义
刘雄利
姚震
刘雄伟
巩艺
王关炼
周英
彭礼军
余章彪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guizhou University
Original Assignee
Guizhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guizhou University filed Critical Guizhou University
Priority to CN201710661412.3A priority Critical patent/CN107235969B/zh
Publication of CN107235969A publication Critical patent/CN107235969A/zh
Application granted granted Critical
Publication of CN107235969B publication Critical patent/CN107235969B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种六氢吡啶‑2,3‑并吲哚‑2‑酮骨架化合物的关键中间体及其制备方法及应用，本发明以在碱性催化条件下，以相应的3‑单取代氧化吲哚1与硝基异恶唑烯烃2发生Michael加成反应，生成产物3。它是合成六氢吡啶‑2,3‑并吲哚‑2‑酮骨架化合物的关键中间体，六氢吡啶‑2,3‑并吲哚‑2‑酮骨架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。

Description

合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及 其制备方法及应用
技术领域
本发明涉及化学技术领域，尤其是一种合成六氢吡啶-2,3-并吲哚 -2-酮骨架化合物的关键中间体及其制备方法及应用。
背景技术
六氢吡啶-2,3-并吲哚-2-酮骨架广泛存在于许多具有重要生物活性的吲哚生物碱中，例如Neoxaline(I)1979年从一个日本曲霉培养液 fg-551中分离出来，测试显示具有抗癌活性，机制研究显示；该化合物能抑制细胞增殖，在细胞分裂G期阻滞细胞进程；至目前为止， 10种相关的天然产物9-epi-neoxaline(II),oxaline(III),the glandicolins(IV,V),和the meleagrins(VI-X)也已经在对青霉菌的培养液中分离出来，测试显示也都具有抗癌活性；Kapakahine A(XI)也包含六氢吡啶-2,3-并吲哚-2-酮骨架，具有抗肿瘤活性(如图7所示)。在这个背景下，鉴于含六氢吡啶-2,3-并吲哚-2-酮天然产物具有潜在的生物活性，因此，合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法，可以为生物活性筛选提供化合物源，对寻找新型的抗肿瘤活性先导化合物具有重要的意义(如图8和图9所示)。
发明内容
本发明的目的是：提供一种合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法，六氢吡啶-2,3-并吲哚-2-酮骨架化合物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，且其合成方法非常经济简便。
本发明是这样实现的合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体，该化合物具有如通式(Ⅰ)所示的结构：
Figure BDA0001370661700000021
式中，R1为苄基或各种取代的苄基；R2为H或卤素。
合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体的制备方法，其特征在于：在碱性条件催化下,由相应的3-单取代氧化吲哚 1与硝基异恶唑烯烃2发生Michael加成反应得到；
合成路线如下：
Figure BDA0001370661700000022
式中，R1为苄基或各种取代的苄基；R2为H或卤素。
一种如权利要求1所述的化合物作为合成六氢吡啶-2,3-并吲哚 -2-酮骨架化合物关键中间体；合成路线为：
Figure BDA0001370661700000023
式中，R1为苄基或各种取代的苄基；R2为H或卤素。
通过采用上述技术方案，在碱性催化条件下，以相应的3-单取代氧化吲哚1与硝基异恶唑烯烃2发生Michael加成反应，生成产物3。它是合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体，六氢吡啶-2,3-并吲哚-2-酮骨架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1-6为本发明的实施例化合物3aa，3ab和7cg的核磁共振谱图；
附图7-9为本发明的技术背景说明图。
具体实施方式
(一)、六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体3的制备
Figure BDA0001370661700000031
化合物3aa:在反应瓶中加入94.8mg N-甲基-3-苄基氧化吲哚1a(0.4mmol) 和138mg硝基异恶唑烯烃2a(0.6mmol)，溶解在5.0mL的二氯甲烷中，加入催化剂TBAB(10mol％,12.8mg)and K2CO3(20mol％,11.0mg)，在氩气保护下 50℃搅拌反应24h,TLC检测完全后，直接经硅胶柱层析[洗脱剂：V(乙酸乙酯): V(石油醚)＝10:1～5:1]，分离得到黄色液体3aa 171.8mg,产率92％,2:1dr。核磁共振和高分辨质谱测试结果如下：白色固体；m.p.151.6-152.1℃；Yield 92％；2:1dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.36(s,1.8H,minor),2.40(s,3H, major),2.66(s,1.8H,minor),2.85(s,3H,major),2.88-2.91(m,1H,major),3.18(d,J ＝10.4Hz,0.6H,minor),3.26(d,J＝10.4Hz,0.6H,minor),3.48(d,J＝10.4Hz,1H, major),3.51-3.52(m,1H,major),3.83-3.87(m,1H,minor),3.95-4.05(m,2H,major), 6.37(d,J＝6.4Hz,0.6H,minor),6.42(d,J＝6.4Hz,1.0H,major),6.72-6.77(m,3.2 H,major+minor),6.92-6.97(m,4.6H,major+minor),6.99-7.02(m,1H,major), 7.08-7.18(m,11H,major+minor),7.42(d,J＝6.0Hz,0.6H,minor)；13C NMR(CDCl3,100MHz)δ(major+minor):11.5,11.6,25.5,25.8,28.2,29.4,41.7,42.4, 49.2,49.9,57.7,58.0,107.8,107.9,121.9,126.4,127.3,127.4,127.8,127.9,128.3, 129.7,129.8,143.7,155.2,172.9,173.3,176.7,177.7；HRMS(ESI-TOF)m/z:Calcd. forC28H25N3NaO4[M+Na]+:490.1743；Found:490.1745.
通过实施例制备的化合物3ab～3b’b的制备方法同化合物3aa，投料比与化合物3aa相同，可得到化合物3ab～3b’b，反应产率见表1和表2，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表1与表2 所表示的内容。
表1为合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体3的化学结构
Figure BDA0001370661700000041
表2为合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体3的化学结构
Figure BDA0001370661700000051
本实施例制备中间体化合物3ab:White soild,m.p.152.1-152.6℃；Yield 85％；20:1dr；1H NMR(CDCl3,400MHz)δ:2.42(s,3H),2.85(s,3H),2.94(d,J＝12.4 Hz,1H),3.51(d,J＝12.8Hz,1H),3.57-3.61(m,1H),3.98-4.10(m,2H),6.39(d,J＝ 7.6Hz,1H),6.74-6.76(m,2H),6.80-6.84(m,2H),6.93-7.03(m,4H),7.07-7.11(m, 3H),7.17(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.6,25.8,28.1,42.1, 48.6,57.7,107.9,114.9(d,JCF＝21.3Hz),122.0,124.6,126.4,127.4,128.4,129.7, 135.0,143.5,155.3,161.8(d,JCF＝225.8Hz),173.2,177.5；HRMS(ESI-TOF)m/z: Calcd.for C28H24FN3NaO4[M+Na]+:508.1649；Found:508.1651.
本实施例制备中间体化合物3ac:White soild,m.p.147.2-147.7℃；Yield 81％；8:7dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.38(s,3.0H,major),2.43(s, 2.5H,minor),2.69(s,3.0H,major),2.86(s,2.6H,minor),2.92(d,J＝12.4Hz,0.8H, minor),3.16(d,J＝12.8Hz,1H,major),3.23(d,J＝12.8Hz,1H,major),3.49(d,J＝ 12.8Hz,0.8H,minor),3.55-3.62(m,0.8H,minor),3.78-3.81(m,2.0H,major), 3.95-4.02(m,2.6H,major+minor),6.39-6.42(m,1.8H,major+minor),6.73-6.76 (m,3.8H,major+minor),6.82-6.90(m,3.8H,major+minor),6.93-7.04(m,8.5H, major+minor),7.08-7.20(m,5.6H,major+minor),7.44(d,J＝7.2Hz,0.9H,minor)；13C NMR(CDCl3,100MHz)δ(major+minor):11.5,11.6,25.5,25.8,28.2,29.5, 41.8,42.3,48.9,49.4,57.5,57.8,107.9,108.0,114.7(d,JCF＝21.2Hz),122.2(d,JCF＝20.2Hz),123.7,124.7,126.5,127.4,128.5,128.6,129.7,129.8,134.9,155.3,160.9 (d,JCF＝244.1Hz),172.4,173.0,176.5,177.4；HRMS(ESI-TOF)m/z:Calcd.for C28H24FN3NaO4[M+Na]+:508.1649；Found:508.1648.
本实施例制备中间体化合物3ad:White soild,m.p.167.6-168.1℃；Yield 85％；13:1dr；1H NMR(CDCl3,400MHz)δ:2.44(s,3H),2.91(s,3H),3.14(d,J＝10.0Hz, 1H),3.77(d,J＝10.0Hz,1H),3.95-3.98(m,1H),4.08-4.14(m,1H),4.76-4.80(m, 1H),6.32(d,J＝6.0Hz,1H),6.78-6.80(m,2H),6.93-7.00(m,6H),7.04-7.07(m, 2H),7.29-7.31(m,1H),7.34(d,J＝5.6Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.6, 25.8,28.8,42.0,43.7,57.6,107.4,121.8,124.4,126.5,126.6,127.4,128.0,128.2, 128.6,129.4,129.9,143.0,155.3,173.3,177.6；HRMS(ESI-TOF)m/z:Calcd.for C28H24ClN3NaO4[M+Na]+:524.1353；Found:524.1357.
本实施例制备中间体化合物3ae:White soild,m.p.170.1-170.8℃；Yield 86％；9:8dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.33(s,3H,major),2.46(s, 2.6H,minor),2.85(s,3H,major),2.90(s,2.6H,minor),2.95(d,J＝10.0Hz,1H, major),3.03(d,J＝10.0Hz,1H,major),3.13(d,J＝10.0Hz,0.9H,minor),3.47(d,J ＝6.4Hz,2H,major),3.75(d,J＝10.0Hz,0.9H,minor),3.96-4.00(m,0.9H,minor), 4.08-4.10(m,0.9H,minor),4.71-7.74(m,0.9H,minor),4.81-4.84(m,1.0H,major), 6.33(d,J＝6.0Hz,0.9H,minor),6.43(d,J＝6.0Hz,1.0H,major),6.63(d,J＝6.0Hz, 2.0H,major),6.78-6.80(m,1.8H,minor),6.89-7.06(m,9.0H,major+minor), 7.07-7.11(m,0.9H,minor),7.14-7.17(m,1.0H,major),7.25(s,1.0H,major), 7.31-7.33(m,1.8H,major+minor),7.38-7.39(m,0.9H,minor),7.43-7.44(m,1.0H, major),7.98(d,J＝6.8Hz,1.0H,major)；13C NMR(CDCl3,100MHz)δ(major+ minor):11.4,11.6,25.7,25.8,28.6,30.3,42.0,43.1,43.3,57.1,57.5,107.6,107.9, 122.7,127.2,127.4,127.5,128.4,129.2,129.6,129.8,134.6,142.9,143.5,155.3, 155.4,171.8,173.0,176.6,177.4；HRMS(ESI-TOF)m/z:Calcd.forC28H23Cl2N3NaO4[M+Na]+:558.0963；Found:558.0965.
本实施例制备中间体化合物3ag:White soild,m.p.164.3-164.9℃；Yield 91％；9:8dr；1H NMR(CDCl3,400MHz)δ:1.26(s,9H),2.41(s,3H),2.83-2.84(m,4H), 3.31-3.41(m,2H),3.78-3.84(m,1H),4.02-4.06(m,1H),6.45(d,J＝7.6Hz,1H), 6.68-6.70(m,2H),6.89-6.96(m,3H),7.02-7.06(m,1H),7.12-7.15(m,3H), 7.18-7.23(m,3H)；13C NMR(CDCl3,100MHz)δ:11.6,25.8,28.4,31.2,34.4,42.6, 48.5,57.9,107.8,121.9,124.8,125.3,126.3,127.3,128.3,129.0,129.7,133.7,135.3, 143.9,150.5,155.2,173.3,177.9；HRMS(ESI-TOF)m/z:Calcd.for C32H33N3NaO4 [M+Na]+:546.2369；Found:546.2371.
本实施例制备中间体化合物3ba:White soild,m.p.201.4-201.7℃；Yield 84％；2:1dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.36(s,1.9H,minor),2.40(s, 3.0H,major),2.69(s,1.9H,minor),2.86-2.88(m,4H,major),3.14(d,J＝12.8Hz, 0.6H,minor),3.21(d,J＝12.8Hz,0.6H,minor),3.42-3.48(m,2H),3.81-3.84(m,1H, major),3.90-4.04(m,2.6H,major+minor),6.42(d,J＝8.0Hz,0.6H,minor),6.46(d, J＝7.8Hz,1H,major),6.65(d,J＝8.4Hz,2H,major),6.67-6.71(m,1.3H,minor), 6.89-6.93(m,3H,major+minor),7.00-7.04(m,1.0H,major),7.08-7.18(m,11.4H, major+minor),7.40(d,J＝7.2Hz,0.6H,minor)；13C NMR(CDCl3,100MHz)δ (major+minor):11.5,11.6,25.5,25.8,28.2,29.3,40.9,41.6,49.2,49.9,57.6,57.8, 103.0,108.1,108.2,122.0,124.9,127.5,127.6,127.7,127.8,127.9,128.0,128.5, 129.1,131.0,131.1,133.7,155.2,172.7,173.1,176.4,177.5；HRMS(ESI-TOF)m/z: Calcd.for C28H24ClN3NaO4[M+Na]+:524.1353；Found:524.1357.
本实施例制备中间体化合物3bc:White soild,m.p.156.1-156.7vC；Yield 79％；3:2dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.38(s,2.0H,minor),2.43(s, 3.0H,major),2.72(s,2.0H,minor),2.86-2.90(m,4H,major),3.12(d,J＝12.8Hz, 0.6H,minor),3.19(d,J＝12.8Hz,0.6H,minor),3.45(d,J＝12.4Hz,1H,major), 3.53-3.56(m,1H,major),3.76-3.78(m,1.3H,minor),3.92-4.04(m,2.6H,major+ minor),6.44-6.48(m,1.6H,major+minor),6.66-6.70(m,3.3H,major+minor), 6.83-6.89(m,3.0H,major+minor),6.92(d,J＝8.4Hz,5.0H,major+minor), 7.02-7.06(m,1H,major),7.10-7.21(m,5.0H,major+minor),7.42(d,J＝6.4Hz, 0.6H,minor)；13C NMR(CDCl3,100MHz)δ(major+minor):11.4,11.5,25.6,25.8, 28.1,29.4,41.0,41.5,49.0,49.5,57.4,57.6,108.2,108.3,114.8(d,JCF＝21.3Hz), 122.3(d,JCF＝19.9Hz),123.6,124.6,127.6,128.7,128.8,131.1,131.2,132.4,133.5, 155.3,160.9,162.1(d,JCF＝240.8Hz),172.3,172.8,177.2；HRMS(ESI-TOF)m/z: Calcd.for C28H23ClFN3NaO4[M+Na]+:542.1259；Found:542.1259.
本实施例制备中间体化合物3bd:White soild,m.p.179.3-179.9℃；Yield 72％；3:1dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.32(s,1.2H,minor),2.44(s, 3.0H,major),2.89(s,1.2H,minor),2.93(s,3.4H,major+minor),3.03(d,J＝ 12.8Hz,0.3H,minor),3.09(d,J＝12.8Hz,1.0H,major),3.50(d,J＝8.0Hz,1.0H, major),3.73(d,J＝12.8Hz,1.0H,major),3.89-3.94(m,1.0H,major),4.02-4.05(m, 1.0H,minor),4.74-4.78(m,1.0H,major),4.84-4.88(m,0.3H,minor),6.37(d,J＝ 7.8Hz,1.0H,major),6.48(d,J＝7.8Hz,0.3H,minor),6.57(s,0.3H,minor),6.59(s, 0.4H,minor),6.72(s,1.0H,major),6.74(s,1.0H,major),6.86(s,0.3H,minor),6.88 (s,0.3H,minor),6.93-6.99(m,4.0H,major),7.02-7.10(m,3.4H,major+minor), 7.15-7.17(m,0.3H,minor),7.19-7.15(m,0.4H,minor),7.26-7.30(m,1.4H,major+ minor),7.32-7.37(m,1.8H,major+minor),7.41(d,J＝6.4Hz,0.4H),7.96-7.99(m, 0.4H,minor)；13C NMR(CDCl3,100MHz)δ(major+minor):11.4,11.6,25.8,28.8, 41.1,41.2,43.5,43.7,57.0,57.5,107.7,108.0,122.0,124.3,126.6,127.6,128.0, 128.4,128.7,129.5,131.2,142.9,143.4,155.3,172.0,173.1,176.4,177.4；HRMS (ESI-TOF)m/z:Calcd.for C28H23Cl2N3NaO4[M+Na]+:558.0963；Found:558.0960.
本实施例制备中间体化合物3be:White soild,m.p.188.5-188.9℃；Yield 76％；5:1dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.33(s,0.8H,minor),2.46(s, 3.0H,major),2.89(s,0.8H,minor),2.93(s,3.0H,major),2.99(d,J＝0.2H,minor), 3.08(d,J＝12.8Hz,1.0H,major),3.45(d,J＝8.0Hz,0.5H,minor),3.71(d,J＝ 12.4Hz,1.3H,major+minor),3.91-3.96(m,1.0H,major),4.04(d,J＝11.6Hz,1.0H, major),4.69-4.73(m,1.0H,major),4.79-4.83(m,0.3H,minor),6.38(d,J＝7.6Hz, 1H,major),6.48(d,J＝8.0Hz,0.2H,minor),6.57(d,J＝8.4Hz,0.5H,minor),6.71(s, 1H),6.73(s,1H),6.88(d,J＝8.4Hz,0.5H,minor),6.93-6.98(m,3.0H,major), 7.04-7.07(m,3.0H,major),7.11(d,J＝7.6Hz,0.2H,minor),7.18(d,J＝7.2Hz,0.2H, minor),7.22-7.25(m,1.0H,major),7.30-7.33(m,1.3H,major+minor),7.38-7.39(m, 0.2H,minor),7.43(d,J＝7.2Hz,0.3H,major+minor),7.95(d,J＝8.4Hz,0.2H, minor)；13C NMR(CDCl3,100MHz)δ(major+minor):11.6,25.9,28.6,41.1,43.3, 57.4,107.9,108.2,122.1,124.2,127.0,127.6,128.7,128.9,129.3,131.1,133.3, 142.8,155.4,172.8,177.2；HRMS(ESI-TOF)m/z:Calcd.forC28H22Cl3N3NaO4 [M+Na]+:592.0574；Found:592.0575.
本实施例制备中间体化合物3bh:White soild,m.p.186.7-187.2℃；Yield 79％；>20:1dr；1H NMR(CDCl3,400MHz)δ:2.38(s,3H),2.73(s,3H),3.08-3.19(m,2H), 3.69-3.79(m,2H),3.89-3.93(m,1H),6.45(d,J＝7.6Hz,1H),6.68(d,J＝8.0Hz, 2H),6.92(d,J＝8.4Hz,2H),7.03-7.32(m,6H),7.41(d,J＝7.2Hz,1H)；13C NMR (CDCl3,100MHz)δ:11.5,25.6,29.3,41.0,49.4,57.6,108.3,121.8,122.4,123.5, 127.6,128.4,128.8,129.5,130.9,131.1,132.4,133.4,139.5,143.7,155.3,172.2, 176.2；HRMS(ESI-TOF)m/z:Calcd.for C28H23BrClN3NaO4[M+Na]+:602.0458； Found:602.0459.
本实施例制备中间体化合物3bj:White soild,m.p.199.2-199.9℃；Yield 85％；20:1dr；1H NMR(CDCl3,400MHz)δ:2.18(s,3H),2.23(s,3H),2.35(s,3H),2.79 (s,3H),3.08(d,J＝12.8Hz,1H),3.26(d,J＝12.4Hz,1H),3.69-3.75(m,1H), 3.82-3.88(m,1H),4.23-4.27(m,1H),6.47(d,J＝7.6Hz,1H),6.66(d,J＝8.4Hz, 2H),6.86-6.91(m,4H),6.99-7.04(m,1H),7.10(d,J＝7.2Hz,1H),7.15-7.20(m, 2H)；13C NMR(CDCl3,100MHz)δ:11.5,20.1,20.9,25.7,29.7,40.2,42.6,57.4, 108.1,122.2,123.8,126.7,127.5,127.8,128.5,131.2,131.3,133.3,133.7,143.7, 155.3,173.1,176.9；HRMS(ESI-TOF)m/z:Calcd.forC30H28ClN3NaO4[M+Na]+: 552.1666；Found:552.1667.
本实施例制备中间体化合物3cc:White soild,m.p.149.9-150.3℃；Yield 84％；3:2dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.38(s,2.2H,minor),2.43(s, 3.0H,major),2.72(s,2.2H,minor),2.89(s,3.6H,major+minor),3.10(d,J＝12.8Hz,0.7H,minor),3.18(d,J＝12.4Hz,0.7H,minor),3.45(d,J＝12.4Hz,1.0H, major),3.52-3.56(m,1.0H,major),3.75-3.78(m,1.6H,major+minor),3.92-4.01(m, 2.8H,major+minor),6.44-6.48(m,1.7H,major+minor),6.60-6.64(m,3.6H,major +minor),6.83-6.93(m,5.4H,major+minor),7.02-7.23(m,9.9H,major+minor), 7.42(d,J＝7.2Hz,0.8H)；13C NMR(CDCl3,100MHz)δ(major+minor):11.5,11.6, 25.6,25.9,28.1,29.7,41.1,41.5,49.0,49.5,57.3,57.6,108.2,108.3,114.8(d,JCF＝ 21.4Hz),120.6,122.3(d,JCF＝20.1Hz),123.6,124.6,128.7,128.9,129.5,130.6, 131.4,131.5,155.3,162.2(d,JCF＝233.1Hz),172.3,172.8,176.2,177.2；HRMS (ESI-TOF)m/z:Calcd.for C28H23BrFN3NaO4[M+Na]+:586.0754；Found:586.0755.
本实施例制备中间体化合物3cd:White soild,m.p.159.4-159.8℃；Yield 74％；20:1dr；1H NMR(CDCl3,400MHz)δ:2.37(s,3H),2.86(s,3H),3.01(d,J＝12.8Hz, 1H),3.65(d,J＝12.8Hz,1H),3.81-3.86(m,1H),3.94-4.01(m,1H),4.67-4.71(m, 1H),6.30(d,J＝7.6Hz,1H),6.60(d,J＝8.4Hz,2H),6.86-6.92(m,2H),6.97-7.03 (m,5H),7.19-7.22(m,1H),7.26(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ: 11.6,25.8,28.8,41.2,43.7,57.4,107.7,122.0,124.3,126.6,128.0,128.5,128.7, 129.5,130.5,131.6,134.0,142.9,155.3,173.1,177.3；HRMS(ESI-TOF)m/z:Calcd. for C28H23BrClN3NaO4[M+Na]+:602.0458；Found:602.0461.
本实施例制备中间体化合物3cg:White soild,m.p.161.7-162.2℃；Yield 90％；>20:1dr；1H NMR(CDCl3,400MHz)δ:1.24(s,9H),2.35(s,3H),2.71(s,3H),3.06 (d,J＝13.2Hz,1H),3.16(d,J＝12.8Hz,1H),3.75-3.77(m,2H),3.89-3.93(m,1H), 6.41(d,J＝7.6Hz,1H),6.62(d,J＝8.4Hz,2H),7.04-7.08(m,5H),7.15-7.19(m, 3H),7.36(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.5,25.5,29.5,31.2, 34.4,41.1,49.5,57.7,108.1,120.4,122.2,123.6,124.7,128.5,128.8,130.5,131.5, 134.0,134.4,143.8,150.5,155.2,172.9,176.5；HRMS(ESI-TOF)m/z:Calcd.for C32H32BrN3NaO4[M+Na]+:624.1474；Found:624.1477.
本实施例制备中间体化合物3ch:White soild,m.p.174.1-174.5℃；Yield 89％；>20:1dr；1H NMR(CDCl3,400MHz)δ:2.38(s,3H),2.73(s,3H),3.08(d,J＝ 12.8Hz,1H),3.15(d,J＝12.8Hz,1H),3.73-3.76(m,2H),3.89-3.92(m,1H),6.46(d, J＝7.6Hz,1H),6.63(d,J＝8.4Hz,2H),7.03-7.09(m,3H),7.11-7.15(m,2H), 7.19-7.23(m,1H),7.25(s,1H),7.29-7.32(m,1H),7.40(d,J＝7.6Hz,1H)；13C NMR (CDCl3,100MHz)δ:11.5,25.6,29.3,41.0,49.5,57.6,108.3,120.6,121.8,122.4, 123.5,128.3,128.9,129.5,130.5,130.9,131.5,134.0,139.4,143.7,155.3,172.2, 176.2；HRMS(ESI-TOF)m/z:Calcd.forC28H23Br2N3NaO4[M+Na]+:645.9953； Found:645.9957.
本实施例制备中间体化合物3ci:White soild,m.p.157.4-157.9℃；Yield 75％；20:1dr；1H NMR(CDCl3,400MHz)δ:2.18(s,3H),2.33(s,3H),2.69(s,3H),3.06 (d,J＝12.8Hz,1H),3.16(d,J＝12.8Hz,1H),3.75-3.77(m,2H),3.84-3.86(m,1H), 6.40(d,J＝7.6Hz,1H),6.61(d,J＝8.0Hz,2H),6.88-6.95(m,3H),6.99-7.07(m, 4H),7.13-7.17(m,1H),7.35(d,J＝6.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.6, 21.4,25.7,29.5,41.0,49.9,57.8,108.2,120.6,122.3,123.8,127.8,128.5,128.7, 130.6,131.6,134.5,137.5,144.0,155.4,172.9,176.6；HRMS(ESI-TOF)m/z:Calcd. for C29H26BrN3NaO4[M+Na]+:582.1004；Found:582.1001.
本实施例制备中间体化合物3cj:White soild,m.p.137.1-137.6℃；Yield 88％；>20:1dr；1H NMR(CDCl3,400MHz)δ:2.10(s,3H),2.15(s,3H),2.27(s,3H),3.00 (d,J＝12.8Hz,1H),3.18(d,J＝12.8Hz,1H),3.71-3.84(m,2H),4.15-4.19(m,1H), 6.40(d,J＝7.2Hz,1H),6.53(d,J＝8.4Hz,2H),6.78(d,J＝7.2Hz,2H),6.92-7.04 (m,4H),7.08-7.11(m,2H)；13C NMR(CDCl3,100MHz)δ:11.5,20.0,20.9,25.6, 30.0,40.1,42.6,57.3,108.1,122.2,123.8,126.6,127.7,128.4,130.4,131.2,131.5, 133.2,134.2,143.7,155.2,173.1,176.8；HRMS(ESI-TOF)m/z:Calcd.for C30H28BrN3NaO4[M+Na]+:596.1161；Found:596.1165.
本实施例制备中间体化合物3da:White soild,m.p.132.1-132.6℃；Yield 90％；18:1 dr；1H NMR(CDCl3,400MHz)δ:2.34(s,3H),2.66(s,3H),3.10-3.14(m,1H),3.19 (d,J＝12.8Hz,1H),3.77-3.83(m,2H),3.91-3.95(m,1H),6.39(d,J＝7.6Hz,1H), 6.59-6.64(m,2H),6.68-6.72(m,2H),7.06-7.18(m,7H),7.39-7.41(m,1H)；13C NMR(CDCl3,100MHz)δ:11.5,11.6,25.5,25.8,28.2,29.4,40.8,41.6,49.1,49.8, 58.0,58.5,108.0,108.1,114.1,114.2(d,JCF＝17.7Hz),122.2(d,JCF＝19.6Hz), 123.7,127.7,127.9,128.0,131.2,131.3,143.7,143.9,155.3,161.4(d,JCF＝216.7 Hz),172.8,173.2,176.6；HRMS(ESI-TOF)m/z:Calcd.for C28H24FN3NaO4 [M+Na]+:508.1649；Found:508.1647.
本实施例制备中间体化合物3dc:White soild,m.p.134.2-134.7℃；Yield 83％；5:1dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.38(s,3.0H,major),2.43(s, 0.8H,minor),2.71(s,3.0H,major),2.88(s,0.8H,minor),3.12(d,J＝10.4Hz,1.0H, major),3.20(d,J＝10.4Hz,1.0H,major),3.47(d,J＝10.0Hz,0.3H,minor), 3.53-3.57(m,0.3H,minor),3.70-3.74(m,1.0H,major),3.77-3.79(m,1.7H,major+ minor),3.94-3.99(m,1.4H,major+minor),6.42-6.46(m,1.3H,major+minor), 6.62-6.65(m,2.6H,major+minor),6.68-6.73(m,2.6H,major+minor),6.83-6.91 (m,2.3H,major+minor),6.92-6.94(m,1.6H,major+minor),7.02-7.06(m,0.3H, minor),7.10-7.16(m,2.6H,major+minor),7.18-7.21(m,1.3H,major+minor),7.43 (d,J＝5.6Hz,1.0H,major)；13C NMR(CDCl3,100MHz)δ(major+minor):11.5, 11.6,25.5,25.8,28.2,29.4,41.0,41.4,48.8,49.4,57.8,58.4,108.2,114.3(d,JCF＝ 17.9Hz),114.8(d,JCF＝17.6Hz),122.4,123.6,125.1,128.6,128.8,129.3,129.4, 130.6,131.2,131.3,139.7,139.8,143.6,143.8,155.3,161.5(d,JCF＝194.3Hz), 162.1(d,JCF＝196.2Hz),172.3,172.9,175.1,176.4；HRMS(ESI-TOF)m/z:Calcd. for C28H23F2N3NaO4[M+Na]+:526.1554；Found:526.1554.
本实施例制备中间体化合物3dd:White soild,m.p.172.4-173.1℃；Yield 80％；>20:1dr；1H NMR(CDCl3,400MHz)δ:2.32(s,3H),2.88(s,3H),2.93(d,J＝12.8Hz,1H),3.03(d,J＝12.8Hz,1H),3.51(d,J＝8.0Hz,2H),4.85-4.89(m,1H), 6.46(d,J＝7.6Hz,1H),6.58-6.60(m,4H),7.07-7.11(m,1H),7.15-7.27(m,2H), 7.32-7.38(m,2H),7.42(d,J＝6.8Hz,1H),7.98-8.01(m,1H)；13C NMR(CDCl3,100 MHz)δ:11.4,25.7,30.3,41.0,43.4,57.2,108.0,114.0(d,JCF＝16.9Hz),122.7, 123.3,127.2,128.5,129.0,129.5,131.1,131.2,143.4,155.2,161.5(d,JCF＝195.8 Hz),172.1,176.6；HRMS(ESI-TOF)m/z:Calcd.for C28H23ClFN3NaO4[M+Na]+: 542.1259；Found:542.1257.
本实施例制备中间体化合物3de:White soild,m.p.164.1-164.8℃；Yield 89％；15:1dr；1H NMR(CDCl3,400MHz)δ:2.33(s,3H),2.88(s,3H),2.90-2.93(m,1H), 2.99(d,J＝12.8Hz,1H),3.46(d,J＝8.0Hz,2H),4.79-4.83(m,1H),6.47(d,J＝7.6 Hz,1H),6.59(d,J＝7.6Hz,4H),7.07-7.12(m,1H),7.16-7.20(m,1H),7.27-7.34(m, 1H),7.39-7.44(m,2H),7.96(d,J＝8.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:11.4, 25.7,30.2,41.1,43.0,57.1,108.1,114.0(d,JCF＝21.3Hz),122.8,123.2,127.5, 128.6,129.2,131.1,131.2,132.0,143.4,155.3,161.5(d,JCF＝250.1Hz),171.7, 176.4；HRMS(ESI-TOF)m/z:Calcd.forC28H22Cl2FN3NaO4[M+Na]+:576.0869； Found:576.0871.
本实施例制备中间体化合物3dg:White soild,m.p.142.3-142.9℃；Yield 90％；>20:1dr；1H NMR(CDCl3,400MHz)δ:1.27(s,9H),2.41(s,3H),2.87(s,3H), 3.28-3.32(m,1H),3.35(d,J＝10.4Hz,1H),3.70-3.80(m,2H),4.02-4.05(m,1H), 6.50(d,J＝6.0Hz,1H),6.59-6.66(m,4H),7.04-7.07(m,1H),7.13-7.20(m,4H), 7.23(d,J＝6.4Hz,2H)；13CNMR(CDCl3,100MHz)δ:11.6,25.8,28.4,31.2,34.4, 41.8,48.4,57.9,108.0,114.1(d,JCF＝17.4Hz),122.0,124.9,125.2,128.0,128.5, 131.1,131.2,133.7,143.9,150.7,155.2,161.5(d,JCF＝195.4Hz),173.2,177.8； HRMS(ESI-TOF)m/z:Calcd.for C32H32FN3NaO4[M+Na]+:564.2275；Found: 564.2278.
本实施例制备中间体化合物3di:White soild,m.p.161.7-161.9℃；Yield 81％；5:1dr；1H NMR(CDCl3,500MHz)δ(major+minor):2.14(s,0.8H,minor),2.18(s, 3.0H,major),2.28(s,0.8H,minor),2.34(s,3.0H,major),2.63(s,0.8H,minor),2.80 (s,3.0H,major),3.02-3.06(m,0.5H,minor),3.11-3.14(m,0.2H,minor),3.11-3.34 (m,2.0H,major),3.71-3.73(m,0.5H,minor),3.77-3.82(m,1.0H,major),3.90-3.93 (m,1.0H,major),4.22-4.25(m,1.0H,major),6.34(d,J＝6.4Hz,0.2H,minor),6.41 (d,J＝6.0Hz,1.0H,major),6.53-6.65(m,5.0H,major+minor),6.83-7.02(m,6.6H, major+minor),7.06-7.10(m,2.3H,major+minor),7.31(d,0.2H,J＝6.0H,minor), 7.45-7.46(m,0.5H,minor),7.63-7.65(m,0.5H,minor)；13C NMR(CDCl3,125MHz) δ(major+minor):11.6,13.7,19.2,21.3,25.8,28.3,29.7,30.5,41.7,49.0,49.7,57.8, 65.6,108.0,114.1(d,JCF＝22.3Hz),122.0,125.1,127.8,128.1,128.5,128.8,130.9, 131.2,136.7,137.6,143.8,155.2,161.5(d,JCF＝248.3Hz),173.2,177.7；HRMS (ESI-TOF)m/z:Calcd.forC29H26FN3NaO4[M+Na]+:522.1805；Found:522.1807.
本实施例制备中间体化合物3ed:White soild,m.p.158.7-159.3℃；Yield 82％；3:2dr；1H NMR(CDCl3,400MHz)δ(major+minor):2.28(s,2.2H,minor),2.38(s, 3.0H,major),2.82(s,1.9H,minor),2.83(s,3.0H,major),2.87(d,J＝10.4Hz,0.8H, minor),2.95(d,J＝10.4Hz,0.8H,minor),3.02(d,J＝10.0Hz,1.0H,major), 3.43-3.50(m,1.0H,major),3.67(d,J＝10.4Hz,1.0H,major),3.85-3.89(m,1.0H, major),3.99-4.04(m,1.0H,major),4.22-4.25(m,0.6H,minor),4.63-4.66(m,0.9H, minor),4.70-4.73(m,0.8H,minor),6.15(d,J＝6.8Hz,1.0H,major),6.30(d,J＝6.8 Hz,0.8H,minor),6.47(d,J＝6.8Hz,1.6H,major+minor),6.63(d,J＝6.8Hz,1.9H, major+minor),6.90-6.93(m,1.0H,major),6.99-7.02(m,3.4H,major+minor), 7.06-7.08(m,2.8H,major+minor),7.16-7.19(m,2.0H,major),7.22-7.24(m,0.8H, minor),7.27-7.33(m,2.4H,major+minor),7.43(d,J＝12.0Hz,1.0H,major),7.84 (d,J＝5.6Hz,0.7H,minor)；13C NMR(CDCl3,100MHz)δ(major+minor):11.4, 11.6,25.9,28.6,29.7,40.8,41.0,43.4,43.7,57.2,57.7,65.6,109.1,109.5,126.4, 126.7,127.5,127.8,129.0,129.2,129.6,129.7,130.6,130.8,130.9,131.3,131.4, 131.5,133.6,141.9,142.5,155.3,155.4,171.7,172.9,175.9,176.8；HRMS (ESI-TOF)m/z:Calcd.for C28H22Br2ClN3NaO4[M+Na]+:679.9563；Found: 679.9565.
(二)、六氢吡啶-2,3-并吲哚-2-酮类化合物7cg的合成制备
Figure BDA0001370661700000141
中间体化合物4cg:在反应瓶中加入化合物3cg(601mg,1.0mmol)和SnCl2·2H2O(677mg,3.0mmol)，溶解在20.0mL四氢呋喃中，加入20毫升水和36％HCl(1.0mL)，加热回流15小时,冷却至室温，减压除去溶剂，加入水，乙酸乙酯萃取，硫酸钠干燥，除去溶剂后直接经硅胶柱层析[洗脱剂：V(乙酸乙酯):V(石油醚)＝ 5:1～2:1]，分离得到浅黄色固体4cg(81％产率)。
中间体化合物5cg:在反应瓶中加入4cg(519mg,1.0mmol)，溶解在MeOH(30mL) 中，在冰浴下加入SOCl2(350μL)后，在室温下搅拌反应5h,旋干溶剂，直接经硅胶柱层析[洗脱剂：V(乙酸乙酯):V(石油醚)＝5:1]，分离得到黄色液体5cg(88％产率)。
中间体化合物6cg:在反应瓶中加入中间体化合物5cg(0.40mmol)，溶解在3.0 mL的MeOH中，加入MeNH2(3mL,30％in MeOH)，在室温下搅拌反应48h后， TLC检测完全后，减压蒸干溶剂，溶解在二氯甲烷中经硅胶柱层析[洗脱剂：V(乙酸乙酯):V(石油醚)＝5:1]，分离得到黄色液体6cg(84％产率)。
终产物7cg:在反应瓶中加入中间体化合物6cg(0.4mmol)，溶解在Na干燥过的6.0mL的THF中，在0℃下加入LiAlH4(6.0eq,2.4mmol,91.2mg)，在0℃下搅拌反应5h后，TLC检测完全后，用饱和的氯化铵萃灭反应，乙酸乙酯萃取多次后，硫酸钠干燥后，减压蒸干溶剂，二氯甲烷溶解经硅胶柱层析[洗脱剂：V(乙酸乙酯):V(石油醚)＝3:1]，分离得到淡黄色固体7cg(71％产率)。
本实施例制备终产物5cg:Light yellow soild；m.p.158.7-159.4℃；Yield88％； >20:1dr；1H NMR(CDCl3,400MHz)δ:1.15(s,9H),2.54(s,3H),2.79-2.92(m,2H),2.99(d,J＝13.2Hz,1H),3.09(d,J＝12.8Hz,1H),3.41(s,3H),3.64-3.71(m,1H), 6.33(d,J＝8.0Hz,1H),6.58(d,J＝8.4Hz,2H),6.81(d,J＝8.0Hz,2H),6.98-7.05 (m,5H),7.09-7.13(m,1H),7.28(d,J＝7.2Hz,1H)；13C NMR(CDCl3,100MHz)δ: 25.4,31.2,34.3,35.6,40.3,48.2,51.7,58.0,107.9,120.3,121.9,124.0,124.3,128.4, 128.6,130.5,131.6,134.9,144.1,149.9,172.2,177.0；HRMS(ESI-TOF)m/z:Calcd. for C30H32BrNNaO3[M+Na]+:556.1463；Found:556.1467.
本实施例制备终产物7cg:Light yellow soild；m.p.86.7-87.1℃；Yield 71％；>20:1dr；；1H NMR(CDCl3,400MHz)δ:1.26(s,9H),2.44(s,3H),2.69-2.75(m, 3H),2.78-2.82(m,1H),3.04(s,3H),3.53-3.56(m,1H),4.28(s,1H),6.25(d,J＝ 8.0Hz,1H),6.54-6.55(m,2H),6.65-6.72(m,2H),6.90(d,J＝8.4Hz,2H),6.99-7.00 (m,3H),7.04-7.08(m,1H),7.25(d,J＝8.4Hz,2H)；13C NMR(CDCl3,100MHz)δ: 31.3,34.4,34.5,35.3,35.7,39.9,44.4,52.1,86.5,107.6,118.0,123.6,125.2,126.4, 127.7,128.6,128.9,130.0,131.4,136.4,136.9,149.7,150.0,170.7；HRMS (ESI-TOF)m/z:Calcd.for C30H34N2NaO[M+Na]+:461.2569；Found:461.2573.
本发明由式(1)所述的其中化合物3cg，继续进一步合成的六氢吡啶-2,3- 并吲哚-2-酮类化合物7cg具有重要的生物活性，体外对人肺癌细胞(A549),人白血病细胞(K562),以及体外对人前列腺(PC-3)共三株肿瘤细胞的细胞毒性试验表明：六氢吡啶-2,3-并吲哚-2-酮类化合物7cg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或防治肿瘤药物中间体。必须说明，本发明的药理实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护否认范围。
药理实施例1：化合物7cg对A549细胞的细胞毒性
A549(人非小细胞肺癌肺癌)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7cg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6.25μmol/L,12.5μmol/L,25μmol/L,50μmol/L和100μmol/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7cg对A549细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物7cg对A549肿瘤细胞的IC50为27.4μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为27.5μmol/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)所示的六氢吡啶-2,3-并吲哚-2-酮类化合物7cg 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7cg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。具体方法如药理实施例1。化合物7cg对K562肿瘤细胞的IC50为31.0μmol/L；而阳性对照顺铂对K562肿瘤细胞的IC50为24.7μmol/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)所示的六氢吡啶-2,3-并吲哚-2-酮类化合物7cg 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，有可能发展成新的具有抗肿瘤作用的药物或中间体。
药理实施例3：化合物7cg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。具体方法如药理实施例1。化合物7cg 对PC-3肿瘤细胞的IC50为27.1μmol/L而阳性对照顺铂对PC-3肿瘤细胞的IC50为25.2μmol/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)所示的六氢吡啶-2,3-并吲哚-2-酮类化合物7cg 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六氢吡啶-2,3-并吲哚-2-酮类化合物7cg对这三株肿瘤细胞都显示有一定的细胞毒性。可见六氢吡啶-2,3-并吲哚-2- 酮类化合物具有开发成为抗肿瘤药物或中间体的潜力，值得继续深入研究下去。

Claims (5)

1.一种合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体，其特征在于：该化合物具有如通式（Ⅰ）所示的结构：
Figure DEST_PATH_IMAGE001
（I）
式中，R1为苄基或各种取代的苄基；R2为H或卤素；
具体为如下结构之一：
Figure DEST_PATH_IMAGE003
Figure DEST_PATH_IMAGE005
。
2.一种如权利要求1所述的合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体的制备方法，其特征在于：在相转移催化下, 在有机溶剂中，由相应的3-单取代氧化吲哚1与硝基异恶唑烯烃2发生Michael加成反应得到；
合成路线如下：
Figure DEST_PATH_IMAGE007
式中，R1为苄基或各种取代的苄基；R2为H或卤素；所述的相转移催化剂为四丁基溴化胺、十六烷基三甲基溴化胺或四丁基硫酸氢胺，相转移催化剂的加入量为氧化吲哚摩尔量的1-50%。
3.根据权利要求2所述的合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
4.根据权利要求2所述的合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体的制备方法，其特征在于：由相应的3-单取代氧化吲哚1与硝基异恶唑烯烃2发生Michael加成反应, 反应温度为25-100℃，反应时间为1-48小时。
5.一种如权利要求1所述的化合物作为合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体的用途，其特征在于：合成路线如下图所示:
Figure DEST_PATH_IMAGE009
式中，R1为苄基或各种取代的苄基；R2为H或卤素。
CN201710661412.3A 2017-08-04 2017-08-04 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用 Active CN107235969B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710661412.3A CN107235969B (zh) 2017-08-04 2017-08-04 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710661412.3A CN107235969B (zh) 2017-08-04 2017-08-04 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用

Publications (2)

Publication Number Publication Date
CN107235969A CN107235969A (zh) 2017-10-10
CN107235969B true CN107235969B (zh) 2021-07-06

Family

ID=59988680

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710661412.3A Active CN107235969B (zh) 2017-08-04 2017-08-04 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用

Country Status (1)

Country Link
CN (1) CN107235969B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR202002324A2 (tr) * 2020-02-17 2021-08-23 Bahcesehir Ueniversitesi Yeni̇ mouse double minute 2 (mdm2) i̇nhi̇bi̇törü olarak kullanmak i̇çi̇n drg-mdm2-3

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254626A (zh) * 2015-09-24 2016-01-20 贵州大学 一种六氢吡啶-2,3-并吲哚-2-酮类化合物及其制备方法及应用
CN105585570A (zh) * 2015-12-15 2016-05-18 贵州大学 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用
CN106866686A (zh) * 2017-03-30 2017-06-20 贵州大学 异恶唑拼接3,3′‑吡咯双螺环氧化吲哚化合物及其制备方法及应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254626A (zh) * 2015-09-24 2016-01-20 贵州大学 一种六氢吡啶-2,3-并吲哚-2-酮类化合物及其制备方法及应用
CN105585570A (zh) * 2015-12-15 2016-05-18 贵州大学 异恶唑拼接吡咯螺环氧化吲哚化合物及其制备方法及应用
CN106866686A (zh) * 2017-03-30 2017-06-20 贵州大学 异恶唑拼接3,3′‑吡咯双螺环氧化吲哚化合物及其制备方法及应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Hydrazonyl Radical-Participated Tandem Reaction: A Strategy for the Synthesis of Pyrazoline-Functionalized Oxindoles;Duan, Xiao-Yong等;《Organic Letters》;20151207;第17卷(第24期);第6023页表3 *
Synthesis of isoxazoline-featured oxindoles by iminoxyl radical-promoted cascade oxyalkylation/alkylarylation of alkenes;Yang, Xiu-Long等;《 Organic Chemistry Frontiers》;20151211;第3卷(第2期);第185页表2 *

Also Published As

Publication number Publication date
CN107235969A (zh) 2017-10-10

Similar Documents

Publication Publication Date Title
CN110156787B (zh) 一种三氮唑并嘧啶衍生化合物、包含其的药物组合物及其用途
FR3037958A1 (zh)
CN105367576A (zh) 作为tlr7激动剂的吡咯并嘧啶化合物
CN108350006B (zh) 氘修饰的Brigatinib衍生物、含有该化合物的药物组合物及其用途
EP3741758A1 (en) Bromodomain inhibitor compound and use thereof
CN113185452A (zh) 脲衍生物或其药用盐
CN111217741B (zh) 氟取代单咔唑类衍生物、其制备方法及应用
CN112390804B (zh) 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
CN107235969B (zh) 合成六氢吡啶-2,3-并吲哚-2-酮骨架化合物的关键中间体及其制备方法及应用
CN109651333B (zh) 一种具有抗肿瘤活性的2-吲哚-3-基-喹啉类化合物及其制备方法和应用
WO2022121317A1 (zh) 1,1'-联苯-2，6-二酚类化合物及其应用
Charbonnier et al. Studies on the synthesis and structure of new urea‐linked sugar podando‐coronand derivatives
CN110511214B (zh) 二胺基取代芳杂环类化合物及其制备方法和应用
CN110105356B (zh) 一种氮杂吲哚类化合物及其制备方法和用途
CN108558808B (zh) 一种酰胺类衍生物或其药学上可接受的盐及其制备方法和应用
Erenler et al. Synthesis of hydroxy, epoxy, nitrato and methoxy derivatives of tetralins and naphthalenes
CN112745288B (zh) β-烷氧基醇二苯并呫吨类化合物及其应用
EP0390181B1 (en) Perylenequinone (UCN-1028D) derivatives
CN112645937B (zh) 氮杂螺环、多环穿心莲内酯类化合物及其制备方法、药物组合物及其应用
WO2018113277A1 (zh) 一种雷迪帕韦的制备方法及制备雷迪帕韦的中间体
CN110272417B (zh) 2-甲基-1,8-萘啶类化合物及其制备方法与应用
CN110156816B (zh) 一种四氢吡唑并哌嗪类化合物及其制备方法及应用
CN111792999B (zh) 一种二元萘胺类化合物及其制备方法与应用
CN102070645A (zh) 一种脱氧鬼臼毒素类化合物及其制备与应用
CN110105260B (zh) 芳环脲基吲哚衍生物及其制备方法和应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB03 Change of inventor or designer information
CB03 Change of inventor or designer information

Inventor after: Tian Minyi

Inventor after: Liu Xiongli

Inventor after: Yao Zhen

Inventor after: Liu Xiongwei

Inventor after: Gong Yi

Inventor after: Wang Guanlian

Inventor after: Zhou Ying

Inventor after: Peng Lijun

Inventor after: Yu Zhangbiao

Inventor before: Liu Xiongli

Inventor before: Yao Zhen

Inventor before: Liu Xiongwei

Inventor before: Gong Yi

Inventor before: Wang Guanlian

Inventor before: Zhou Ying

Inventor before: Peng Lijun

Inventor before: Yu Zhangbiao

GR01 Patent grant
GR01 Patent grant