CN105254626A - 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 - Google Patents

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 Download PDF

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CN105254626A
CN105254626A CN201510611722.5A CN201510611722A CN105254626A CN 105254626 A CN105254626 A CN 105254626A CN 201510611722 A CN201510611722 A CN 201510611722A CN 105254626 A CN105254626 A CN 105254626A
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刘雄利
张文会
黄俊飞
陆毅
张敏
周英
俸婷婷
余章彪
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Guizhou University
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Abstract

本发明公开了一种六氢吡啶-2,3-并吲哚-2-酮类化合物及其制备方法及应用，本发明以相应的由相应的3-单取代氧化吲哚1与丙烯酸酯2先发生Michael加成反应，生成中间体3，然后中间体3与甲胺发生酰胺化反应，生成中间体4，最后中间体4通过与四氢化铝锂发生氢化还原环化反应生成最终产物六氢吡啶-2,3-并吲哚-2-酮类化合物。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。本发明针对这些衍生物对三种肿瘤细胞株如人肺癌细胞(A549)、人前列腺(PC-3)以及人白血病细胞(K562)所进行的肿瘤生长抑制活性筛选。这些衍生物发现具有一定的抑制肿瘤细胞生长活性，可预期作为抗肿瘤药物或抗肿瘤药物中间体用途。

Description

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
技术领域
本发明涉及化学技术领域，尤其是一种六氢吡啶-2,3-并吲哚-2-酮类化合物及其制备方法及应用。
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),theglandicolins(IV,V),和themeleagrins(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；KapakahineA(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，合成一系列具有六氢吡啶-2,3-并吲哚-2-酮骨架化合物可能会产生一系列结构和活性上有意义的新化合物分子，它们的合成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。
发明内容
本发明的目的是：提供一种新型六氢吡啶-2,3-并吲哚-2-酮类化合物及其制备方法及应用，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，且其合成方法非常经济简便。
本发明是这样实现的新型六氢吡啶-2,3-并吲哚-2-酮类化合物，该化合物具有如通式（Ⅰ）所示的结构：
式中，R2为烷基或芳基；R3为H或烷基或卤素。
六氢吡啶-2,3-并吲哚-2-酮类化合物的制备方法，其特征在于：由相应的3-单取代氧化吲哚1与丙烯酸酯2先发生Michael加成反应，生成中间体3，然后中间体3氮原子脱保护基团Boc得到了中间体3-1，然后中间体3-1氮原子上保护基甲基得到中间体3-2,中间体3-2再与甲胺发生酰胺化反应，生成中间体3-3，最后中间体3-3通过与四氢化铝锂发生氢化还原环化反应生成最终产物六氢吡啶-2,3-并吲哚-2-酮类化合物。
本发明还提供紫杉醇侧链苯基异丝氨酸衍生物在制备防治肿瘤疾病药物的应用。
本发明合成路线如下：
(1)20mol%CF3COOH,rt,2h;(2)干燥的溶剂DMF,1.2eqNaH,1.5eqCH3I,0oC,8h;(3)3.0mLMeOH,3.0mLMeNH2(30%inMeOH),rt,48h;(4)干燥的溶剂THF，10eqLiAlH4,0oC,5h.
其中，R1为烷基或Boc；R2为烷基或芳基；R3为H或烷基或卤素；R4为烷基。
通过采用上述技术方案，以相应的3-单取代氧化吲哚1与丙烯酸酯2先发生Michael加成反应，生成中间体3，然后中间体3氮原子脱保护基团Boc得到了中间体3-1，然后中间体3-1氮原子上保护基甲基得到中间体3-2,中间体3-2再与甲胺发生酰胺化反应，生成中间体3-3，最后中间体3-3通过与四氢化铝锂发生氢化还原环化反应生成最终产物六氢吡啶-2,3-并吲哚-2-酮类化合物。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1-6为本发明的实施例化合物4a-4c的核磁共振谱图；
附图7为本发明的技术背景说明图。
附图8为本发明化合物4k的X单晶衍射说明图。
具体实施方式，
（一）、代表性反应中间体3的合成制备，
化合物3aa:在反应瓶中加入134mgN-Boc-3-苯基氧化吲哚1a(0.4mmol)和97mg丙烯酸苄酯2a(0.6mmol)，溶解在5.0mL的二氯甲烷中，加入催化剂TBAB(10mol%,12.8mg)andK2CO3(20mol%,11.0mg)，在氩气保护下室温搅拌反应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3aa173mg,总产率92%。核磁共振和高分辨质谱测试结果如下：Lightorangeoil;Yield92%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),1.97-2.14(m,1H),2.21-2.36(m,1H),2.48-2.65(m,1H),2.76-2.96(m,1H),4.84-5.19(m,2H),7.21-7.25(d,J=4.0Hz,2H),7.29-7.34(m,11H),7.79-8.10(d,J=4.0Hz,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.7,32.9,56.0,66.5,84.6,115.4,124.7,127.0,127.7,128.3,128.5,128.7,128.8,129.8,135.5,139.2,139.9,149.1,172.2,176.2;HRMS(ESI-TOF)m/z:Calcd.forC29H29NNaO5[M+Na]+:494.1943;Found:494.1946.
通过实施例制备的化合物3ba～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3ba～3b’b’，反应产率见表1，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。
本实施例制备中间体化合物3ba:Lightorangeoil;Yield90%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),2.06(d,J=11.6Hz,1H),2.21-2.36(m,1H),2.29(s,3H),2.49-2.61(m,1H),2.78-2.89(m,1H),5.01(m,2H),7.10(d,J=8.1Hz,2H),7.71-7.23(m,4H),7.23-7.39(m,6H),7.93(d,J=8.2Hz,1H);13CNMR(CDCl3,100MHz)δ:20.1,28.0,29.7,32.8,55.7,66.4,84.4,115.3,124.7,126.8,128.2,128.5,128.7,129.3,130.0,135.5,136.2,137.5,139.9,149.1,172.2,176.3;HRMS(ESI-TOF)m/z:Calcd.forC30H31NNaO5[M+Na]+:508.2099;Found:508.2097.
本实施例制备中间体化合物3ca:Lightorangeoil;Yield87%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),2.05-2.10(m,1H),2.23-2.35(m,1H),2.25(s,6H),2.52-2.62(m,1H),2.79-2.91(m,1H),4.97-5.07(m,2H),6.75-7.00(s,2H),7.19-7.40(m,9H),7.90-7.96(d,J=8.0Hz,1H);13CNMR(CDCl3,100MHz)δ:21.4,27.5,28.0,29.7,32.7,55.9,66.4,84.5,115.3,124.3,124.7,128.3,128.5,128.6,129.5,130.2,131.1,138.2,139.1,139.8,149.2,172.3,176.4;HRMS(ESI-TOF)m/z:Calcd.forC31H33NNaO5[M+Na]+:522.2256;Found:522.2259.
本实施例制备中间体化合物3da:Lightorangeoil;Yield88%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),2.02-2.04(m,1H),2.26(dd,J=4.9,11.8Hz,1H),2.30(s,3H),2.53-2.57(m,1H),2.82-2.86(m,1H),5.00-5.04(m,2H),7.07(d,J=7.7Hz,2H),7.11-7.40(m,10H),7.93(d,J=8.2Hz,1H);13CNMR(CDCl3,100MHz)δ:21.6,28.9,29.7,32.8,55.9,66.5,84.5,115.3,124.0,124.7,127.6,128.3,128.5,128.6,128.7,130.0,135.6,138.4,139.1,139.9,149.1,172.2,176.3;HRMS(ESI-TOF)m/z:Calcd.forC30H31NNaO5[M+Na]+:508.2099;Found:508.2098.
本实施例制备中间体化合物3ea:Lightorangeoil;Yield86%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),2.05-2.10(m,1H),2.23-2.35(m,1H),2.35(s,3H),2.51-2.62(m,1H),2.79-2.91(m,1H),4.97-5.07(m,2H),6.99(s,1H),7.20-7.23(m,1H),7.19-7.40(m,10H),7.90-7.96(m,1H);13CNMR(CDCl3,100MHz)δ:21.1,28.0,29.7,32.7,56.0,66.4,84.4,115.1,125.1,127.0,127.7,128.3,128.4,128.5,128.7,129.3,129.8,134.4,135.5,137.5,139.4,149.1,172.3,176.4;HRMS(ESI-TOF)m/z:Calcd.forC30H31NNaO5[M+Na]+:508.2099;Found:508.2097.
本实施例制备中间体化合物3fa: Lightorangeoil;Yield85%;1HNMR(CDCl3,400MHz)δ:1.60(s,9H),2.04-2.10(m,1H),2.22-2.28(m,1H),2.30(s,3H),2.34(s,3H),2.46-2.58(m,1H),2.78-2.88(m,1H),4.98-5.09(m,2H),6.98(s,1H),7.02-7.39(m,10H),7.74-7.85(m,1H);13CNMR(CDCl3,100MHz)δ:20.9,21.1,28.0,29.7,32.6,55.7,66.4,84.3,115.1,125.1,126.8,128.3,128.5,129.2,129.4,130.0,134.4,135.6,136.5,137.5,137.6,149.2,172.3,176.5;HRMS(ESI-TOF)m/z:Calcd.forC31H33NNaO5[M+Na]+:522.2256;Found:522.2257.
本实施例制备中间体化合物3ga:Lightorangeoil;Yield82%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),2.00-2.11(m,1H),2.23-2.35(m,1H),2.46-2.59(m,1H),2.78-2.91(m,1H),4.98-5.11(m,2H),6.90-6.95(m,1H),7.03-7.11(m,1H),7.20-7.40(m,10H),7.90-7.97(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.6,32.7,56.2,66.6,84.8,112.1(d,J CF =19.4Hz),115.4(d,J CF =18.0Hz),116.8(d,J CF =6.2Hz),126.8,128.0,128.3,128.6,128.8,135.4,135.8,138.6,149.0,160.0(d,J CF =194.6Hz),172.0,175.8;HRMS(ESI-TOF)m/z:Calcd.forC29H28FNNaO5[M+Na]+:512.1849;Found:512.1848.
本实施例制备中间体化合物3ha:Lightorangeoil;Yield81%;1HNMR(CDCl3,400MHz)δ:1.60(s,9H),1.99-2.11(m,1H),2.21-2.33(m,1H),2.30(s,3H),2.44-2.58(m,1H),2.76-2.92(m,1H),4.93-5.11(m,2H),6.89-6.94(m,1H),6.89-7.00(m,10H),7.91-7.98(m,1H);13CNMR(CDCl3,100MHz)δ:20.9,28.0,29.6,32.6,55.9,66.5,84.7,112.0(d,J CF =19.4Hz),115.3(d,J CF =18.1Hz),116.7(d,J CF =6.3Hz),126.7,128.3,128.5,129.5,135.5,135.7,135.8,137.8,149.1,160.0(d,J CF =194.5Hz),172.0,175.9;HRMS(ESI-TOF)m/z:Calcd.forC30H30FNNaO5[M+Na]+:526.2005;Found:526.2005.
本实施例制备中间体化合物3ia:Lightorangeoil;Yield82%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),2.07(dd,J=4.8,11.6Hz,1H),2.19-2.30(m,1H),2.31(s,3H),2.47-2.59(m,1H),2.82-2.87(m,1H),5.04(d,J=2.4Hz,2H),6.92(dd,J=2.7,7.7Hz,1H),7.00-7.38(m,10H),7.94(dd,J=4.6,9.0Hz,1H);13CNMR(CDCl3,100MHz)δ:21.6,28.0,29.6,32.6,56.1,66.6,84.7,112.1(d,J CF =24.1Hz),115.4(d,J CF =22.6Hz),116.7(d,J CF =7.8Hz),123.8,127.4,128.3,128.5,128.6,128.8,135.5,138.5,138.6,149.1,160.0(d,J CF =243.1Hz),172.0,175.8;HRMS(ESI-TOF)m/z:Calcd.forC30H30FNNaO5[M+Na]+:526.2005;Found:526.2007.
本实施例制备中间体化合物3ja:Lightorangeoil;Yield85%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),1.99-2.04(m,1H),2.26(s,6H),2.22-2.31(m,1H),2.46-2.57(m,1H),2.78-2.89(m,1H),4.99-5.09(m,2H),6.85-6.94(m,4H),7.02-.10(m,1H),7.21-7.39(m,5H),7.87-7.98(m,1H);13CNMR(CDCl3,100MHz)δ:21.4,28.0,29.6,32.5,56.1,66.6,84.7,112.0(d,J CF =19.4Hz),115.3(d,J CF =18.0Hz),116.7(d,J CF =6.2Hz),124.5,128.3,128.6,129.7,132.2,135.5,135.8,138.4,138.5,149.1,160.0(d,J CF =194.4Hz),172.1,176.0;HRMS(ESI-TOF)m/z:Calcd.forC31H32FNNaO5[M+Na]+:540.2162;Found:540.2165.
本实施例制备中间体化合物3ka:Lightorangeoil;Yield87%;1HNMR(CDCl3,400MHz)δ:1.56(s,9H),1.86-1.99(m,1H),2.11-2.33(m,2H),2.40-2.51(m,1H),2.97(d,J=13.1Hz,1H),3.12(d,J=13.1Hz,1H),3.68(s,3H),4.99(m,2H),6.55-6.61(m,2H),6.67-6.74(m,2H),7.07-7.36(m,8H),7.59(d,J=8.0Hz,1H);13CNMR(CDCl3,100MHz)δ:27.9,29.5,31.7,44.6,54.3,55.0,66.3,84.0,123.4,124.1,126.7,128.2,128.3,128.5,128.8,130.8,135.6,139.8,148.6,158.3,172.3,177.6;HRMS(ESI-TOF)m/z:Calcd.forC31H33NNaO6[M+Na]+:538.2205;Found:538.2210.
本实施例制备中间体化合物 3lb :Lightorangeoil;Yield93%;1HNMR(CDCl3,400MHz)δ:1.56(s,9H),1.84-1.94(m,1H),2.09-2.19(m,1H),2.23-2.35(m,1H),2.41-2.51(m,1H),2.98-3.05(m,1H),3.14-3.22(m,1H),3.55(s,3H),6.76-6.81(m,2H),6.99-7.29(m,6H),7.56-7.61(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.4,31.9,45.6,51.6,54.3,84.0,114.9,123.4,124.2,126.8,127.7,128.4,128.7,129.9,134.7,139.9,148.7,173.0,177.5;HRMS(ESI-TOF)m/z:Calcd.forC24H27NNaO5[M+Na]+:432.1786;Found:432.1789.
本实施例制备中间体化合物3mb:Lightorangeoil;Yield87%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),1.80-1.90(m,1H),2.07-2.16(m,1H),2.21-2.31(m,1H),2.39-2.50(m,1H),3.06-3.12(m,1H),3.25-3.32(m,1H),3.51(s,3H),3.54(s,3H),6.57-6.61(m,1H),6.69-6.75(m,1H),6.92-6.97(m,1H),6.98-7.11(m,3H),7.11-7.20(m,1H),7.60-7.65(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.4,31.9,38.2,51.5,53.5,54.5,83.9,109.8,114.3,119.7,123.4,123.8,124.1,127.9,128.2,129.0,131.3,139.5,149.0,157.3,173.0,177.9;HRMS(ESI-TOF)m/z:Calcd.forC25H29NNaO6[M+Na]+:462.1892;Found:462.1895.
本实施例制备中间体化合物3nb:Lightorangeoil;Yield84%;1HNMR(CDCl3,400MHz)δ:1.62(s,9H),1.79-1.90(m,1H),2.07-2.17(m,1H),2.21-2.32(m,1H),2.40-2.52(m,1H),3.11-3.16(m,1H),3.24-3.29(m,1H),3.54(s,3H),3.67(s,3H),3.74(s,3H),6.48-6.53(m,1H),6.66-6.71(m,1H),6.75-6.80(m,1H),7.00-7.09(m,2H),7.13-7.29(m,1H),7.65-7.69(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.4,32.6,37.5,51.5,53.5,55.7,60.4,84.0,111.6,114.5,122.9,124.0,124.1,128.1,128.9,129.2,139.6,147.7,149.0,152.3,173.0,178.0;HRMS(ESI-TOF)m/z:Calcd.forC26H31NNaO7[M+Na]+:492.1998;Found:492.1997.
本实施例制备中间体化合物3ob:Lightorangeoil;Yield88%;1HNMR(CDCl3,400MHz)δ:1.55(s,9H),1.88-1.97(m,1H),2.10-2.20(m,1H),2.23-2.32(m,1H),2.40-2.49(m,1H),2.92-3.01(m,1H),3.10-3.17(m,1H),3.55(s,3H),3.58(s,3H),3.75(s,3H),6.15-6.21(m,1H),6.37-6.44(m,1H),6.53-6.58(m,1H),7.14-7.30(m,3H),7.57-7.61(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.4,32.0,45.2,51.5,54.5,55.5,55.7,84.0,110.5,112.8,115.0,122.1,123.3,124.0,127.3,128.4,129.1,140.1,147.8,148.0,148.6,172.8,177.4;HRMS(ESI-TOF)m/z:Calcd.forC26H31NNaO7[M+Na]+:492.1998;Found:492.1998.
本实施例制备中间体化合物3pb:Lightorangeoil;Yield84%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),1.95-1.81(m,1H),2.20-2.06(m,1H),2.34-2.21(m,1H),2.53-2.40(m,1H),3.11-3.03(m,1H),3.31-3.24(m,1H),3.48(s,3H),3.54(s,3H),3.63(s,3H),6.54-6.48(m,2H),6.62-6.58(m,1H),7.08-7.01(m,2H),7.29-7.12(m,1H),7.67-7.60(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.4,32.1,38.1,51.5,53.6,55.1,55.5,83.9,110.8,113.2,114.3,116.5,123.5,124.1,124.6,128.0,129.0,139.6,149.0,151.5,152.7,173.0,177.8;HRMS(ESI-TOF)m/z:Calcd.forC26H31NNaO7[M+Na]+:492.1998;Found:492.1995.
本实施例制备中间体化合物3qb:Yellowoil;Yield81%;1HNMR(CDCl3,400MHz)δ:1.61(s,9H),1.78-1.89(m,1H),2.06-2.16(m,1H),2.18-2.29(m,1H),2.37-2.49(m,1H),2.97-3.05(m,1H),3.16-3.24(m,1H),3.48(s,3H),3.54(s,3H),3.71(s,3H),6.18-6.20(m,1H),6.24-6.28(m,1H),6.82-6.86(m,1H),6.97-7.07(m,2H),7.13-7.20(m,1H),7.61-7.69(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.4,31.7,37.8,51.5,53.7,54.6,55.1,83.8,97.8,103.4,114.4,116.1,123.4,124.1,127.9,129.2,131.7,139.5,149.0,158.3,159.7,173.0,177.9;HRMS(ESI-TOF)m/z:Calcd.forC26H31NNaO7[M+Na]+:492.1998;Found:492.1996.
本实施例制备中间体化合物3rb:Yellowoil;Yield90%;1HNMR(CDCl3,400MHz)δ:1.57(s,9H),1.84-1.94(m,1H),2.07-2.20(m,4H),2.22-2.32(m,1H),2.39-2.52(m,1H),2.92-3.00(m,1H),3.10-3.16(m,1H),3.55(s,3H),6.52-6.65(m,2H),6.85-6.95(m,2H),7.06-7.29(m,3H),7.55-7.62(m,1H);13CNMR(CDCl3,100MHz)δ:21.1,28.0,29.4,31.8,45.4,51.5,54.2,83.9,114.7,123.4,124.0,126.8,127.4,127.4,128.3,128.8,130.5,134.6,137.1,139.9,148.7,172.9,177.4;HRMS(ESI-TOF)m/z:Calcd.forC25H29NNaO5[M+Na]+:446.1943;Found:446.1947.
本实施例制备中间体化合物3sb:Yellowoil;Yield85%;1HNMR(CDCl3,400MHz)δ:1.58(s,9H),1.79-1.88(m,1H),1.97(s,3H),2.06-2.15(m,1H),2.28-2.37(m,1H),2.45-2.54(m,1H),3.06-3.10(m,1H),3.15-3.21(m,1H),3.55(s,3H),6.78-6.82(m,1H),6.87-7.11(m,5H),7.21-7.27(m,1H),7.66-7.71(m,1H);13CNMR(CDCl3,100MHz)δ:19.7,28.0,29.4,31.4,41.4,51.5,53.6,84.0,114.8,123.7,124.0,125.2,126.9,128.5,128.7,130.3,130.5,133.3,137.2,139.8,148.8,172.9,177.7;HRMS(ESI-TOF)m/z:Calcd.forC25H29NNaO5[M+Na]+:446.1943;Found:446.1945.
本实施例制备中间体化合物3tb :Yellowoil;Yield89%;1HNMR(CDCl3,400MHz)δ:1.56(s,9H),1.83-1.93(m,1H),2.08-2.17(m,1H),2.20(s,3H),2.23-2.31(m,1H),2.34-2.49(m,1H),2.95-3.15(m,2H),3.55(s,3H),6.65-6.78(m,2H),6.82-6.89(m,2H),7.10-7.17(m,2H),7.21-7.24(m,1H),7.59-7.61(m,1H);13CNMR(CDCl3,100MHz)δ:20.9,27.9,29.4,31.8,45.1,51.5,54.2,83.9,109.6,114.8,122.1,123.4,124.1,128.0,128.3,128.8,129.7,129.8,131.6,136.2,139.8,148.7,173.0,177.6;HRMS(ESI-TOF)m/z:Calcd.forC25H29NNaO5[M+Na]+:446.1943;Found:446.1946.
本实施例制备中间体化合物3ub:Yellowoil;Yield83%;1HNMR(CDCl3,400MHz)δ:1.12-1.16(m,6H),1.56(s,9H),1.83-1.92(m,1H),2.08-2.17(m,1H),2.22-2.31(m,1H),2.41-2.50(m,1H),2.72-2.78(m,1H),2.97-3.15(m,2H),3.55(s,3H),6.66-6.74(m,2H),6.86-6.93(m,2H),7.09-7.29(m,3H),7.57-7.61(m,1H);13CNMR(CDCl3,100MHz)δ:23.8,23.9,28.0,29.4,31.7,33.5,45.2,51.6,54.2,83.9,114.8,123.4,124.1,125.6,128.3,128.9,129.8,131.9,139.8,147.3,148.6,173.0,177.5;HRMS(ESI-TOF)m/z:Calcd.forC27H33NNaO5[M+Na]+:474.2256;Found:474.2261.
本实施例制备中间体化合物3vb:Lightyellowoil;Yield88%;1HNMR(CDCl3,400MHz)δ:1.21(s,9H),1.56(s,9H),1.83-1.92(m,1H),2.09-2.19(m,1H),2.22-2.32(m,1H),2.39-2.50(m,1H),2.97-3.03(m,1H),3.08-3.14(m,1H),3.55(s,3H),6.67-6.74(m,2H),7.04-7.29(m,5H),7.57-7.63(m,1H);13CNMR(CDCl3,100MHz)δ:28.0,29.5,31.2,31.7,34.3,45.1,51.6,54.2,83.9,114.8,123.5,124.1,124.5,128.3,129.0,129.6,131.6,139.9,148.7,149.6,173.0,177.5;HRMS(ESI-TOF)m/z:Calcd.forC28H35NNaO5[M+Na]+:488.2412;Found:488.2416.
本实施例制备中间体化合物3wb:Lightyellowoil;Yield80%;1HNMR(CDCl3,400MHz)δ:1.53(s,9H),1.85-1.95(m,1H),2.10-2.20(m,1H),2.25-2.36(m,1H),2.43-2.53(m,1H),3.04-3.12(m,1H),3.28-3.19(m,1H),3.56(s,3H),6.85-6.93(m,2H),7.16-7.33(m,5H),7.52-7.60(m,1H);13CNMR(CDCl3,100MHz)δ:27.90,29.33,32.00,45.17,51.63,54.16,84.33,115.01,122.95,123.20,124.40,124.52,125.12,128.20,128.79,128.97,129.23,130.09,138.87,139.84,148.34,172.77,177.00;HRMS(ESI-TOF)m/z:Calcd.forC25H26F3NNaO5[M+Na]+:500.1660;Found:500.1663.
本实施例制备中间体化合物3xb:Lightyellowoil;Yield80%;1HNMR(CDCl3,400MHz)δ:1.78(dd,J=11.0,5.2Hz,1H),1.96(s,3H),1.97-2.09(m,1H),2.20(s,3H),2.32(dd,J=11.1,5.3Hz,1H),2.40(dd,J=11.0,5.4Hz,1H),3.00-3.13(m,5H),3.53(s,3H),6.71-6.78(m,4H),6.90-6.95(m,2H),7.18-7.24(m,1H);13CNMR(CDCl3,100MHz)δ:19.8,20.8,25.9,29.3,31.3,39.4,51.5,53.3,107.8,122.0,124.0,125.8,128.1,130.0,130.3,131.0,136.0,136.8,143.7,173.1,179.0;HRMS(ESI-TOF)m/z:Calcd.forC22H25NNaO3[M+Na]+:374.1732;Found:374.1733.
本实施例制备中间体化合物3yb:Yellowoil;Yield86%;1HNMR(CDCl3,400MHz)δ:1.74-1.87(m,1H),1.99-2.11(m,1H),2.21-2.26(m,1H),2.36-2.42(m,1H),2.93(d,J=13.3Hz,1H),3.08(s,3H),3.33(d,J=13.3Hz,1H),3.53(s,3H),3.57(s,3H),3.67(s,3H),3.78(s,3H),6.25(s,1H),6.44(s,1H),6.63(d,J=7.7Hz,1H),6.92-6.99(m,1H),7.07-7.18(m,2H);13CNMR(CDCl3,100MHz)δ:25.9,29.4,31.5,35.8,51.5,53.7,55.7,55.8,56.1,96.5,107.4,114.2,115.6,121.5,124.3,127.8,130.1,141.8,143.6,147.9,151.4,173.2,179.1;HRMS(ESI-TOF)m/z:Calcd.forC23H27NNaO6[M+Na]+:436.1736;Found:436.1738.
本实施例制备中间体化合物3zb:Yellowoil;Yield81%;1HNMR(CDCl3,400MHz)δ:1.74-1.86(m,1H),2.00-2.10(m,1H),2.20-2.30(m,1H),2.34-2.43(m,1H),2.96-3.01(m,1H),3.11(s,3H),3.19-3.25(m,1H),3.53(s,3H),3.62(s,3H),3.68(s,3H),3.76(s,3H),6.38-6.43(m,1H),6.59-6.67(m,2H),6.91-6.98(m,1H),7.02-7.08(m,1H),7.10-7.17(m,1H);13CNMR(CDCl3,100MHz)δ:26.0,29.3,31.7,36.1,51.5,53.5,55.8,60.5,60.6,106.1,107.4,122.0,124.5,124.9,127.8,130.0,141.6,143.6,152.1,152.3,173.3,179.1;HRMS(ESI-TOF)m/z:Calcd.forC23H27NNaO6[M+Na]+:436.1736;Found:436.1739.
本实施例制备中间体化合物3a'b:Yellowoil;Yield78%;1HNMR(CDCl3,400MHz)δ:1.81-1.85(m,1H),2.05-2.08(m,1H),2.25-2.29(m,1H),2.37-2.45(m,1H),2.98(s,3H),3.01(d,J=13.0Hz,1H),3.16(d,J=12.9Hz,1H),3.55(s,3H),6.46-6.53(m,1H),6.62(d,J=7.7Hz,2H),6.71-6.76(m,1H),7.10-7.10(m,2H),7.13-7.28(m,2H);13CNMR(CDCl3,100MHz)δ:25.8,29.3,31.7,43.7,43.8,51.6,53.8,108.0,113.4(d,J CF =20.8Hz),116.5(d,J CF =21.3Hz),122.4,123.5,125.5(d,J CF =2.8Hz),128.4,128.8(d,J CF =8.3Hz),129.5,138.0,138.1,143.7,162.0(d,J CF =243.6Hz),173.0,178.0;HRMS(ESI-TOF)m/z:Calcd.forC20H20FNNaO3[M+Na]+:364.1324;Found:364.1325.
本实施例制备中间体化合物3b'b:Lightyellowoil;Yield76%;1HNMR(CDCl3,400MHz)δ:1.84-1.90(m,1H),2.04-2.13(m,1H),2.24-2.30(m,1H),2.35-2.41(m,1H),3.03(s,3H),3.25(d,J=11.6Hz,1H),3.41(d,J=11.6Hz,1H),3.54(m,3H),6.54(s,1H),6.68-6.72(m,2H),6.92(d,J=3.6Hz,1H),7.07-7.10(m,1H),7.18(d,J=5.6Hz,1H),7.23-7.27(m,1H);13CNMR(CDCl3,100MHz)δ:26.0,29.3,31.7,37.9,51.6,53.7,108.0,122.5,123.5,124.1,126.1,126.8,128.5,129.8,137.2,144.2,173.0,178.1;HRMS(ESI-TOF)m/z:Calcd.forC18H19NNaO3S[M+Na]+:352.0983;Found:352.0984.
（二）、产物六氢吡啶-2,3-并吲哚-2-酮类化合物4的合成制备，
中间体化合物3-1:在反应瓶中加入化合物3(0.5mmol)，溶解在5.0mLCaH2刚干燥过的二氯甲烷中，加入CF3COOH(20mol%,11.4mg)，在室温搅拌反应2h,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3-1。
中间体化合物3-2:在反应瓶中加入中间体化合物3-1(0.45mmol)，溶解在NaOH干燥过的5.0mL的DMF中，加入NaH(60%dispersioninmineraloil,1.2eq,21.6mg)，在0oC下搅拌反应10分钟后，再加入CH3I(1.5eq,95.9mg)，在0oC下搅拌反应8h,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)=5:1]，分离得到黄色液体3-2。
中间体化合物3-3:在反应瓶中加入中间体化合物3-2(0.40mmol)，溶解在3.0mL的MeOH中，加入MeNH2(3mL,30%inMeOH)，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3-3。
终产物4a-4z:在反应瓶中加入中间体化合物3-3(0.4mmol)，溶解在Na干燥过的6.0mL的THF中，在0oC下加入LiAlH4(10.0eq,4.0mmol,152mg)，在0oC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]，分离得到黄色液体或固体4a-4z。
通过实施例制备的化合物4a-4z,反应产率见表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2和表3所表示的内容。
本实施例制备终产物4a:Whitepowder,m.p.143.2-143.9oC;Overallyield62%;1HNMR(CDCl3,400MHz)δ:2.21-2.41(m,3H),2.50-2.65(m,1H),2.91(s,3H),3.15(s,3H),4.87(s,1H),6.42-6.55(m,1H),6.71-6.82(m,1H),6.91-7.01(m,1H),7.12-7.42(m,6H);13CNMR(CDCl3,100MHz)δ:30.4,33.9,34.1,36.1,53.6,91.5,106.4,118.5,124.9,126.4,126.9,128.8,131.4,146.7,150.8,174.3;HRMS(ESI-TOF)m/z:Calcd.forC19H20N2NaO[M+Na]+:315.1473;Found:315.1475.
本实施例制备终产物4b:Whitepowder,m.p.128.9-129.8oC;Overallyield57%;1HNMR(CDCl3,400MHz)δ:2.19-2.41(m,6H),2.49-2.61(m,1H),2.90(s,3H),3.15(s,3H),4.87(s,1H),6.45-6.51(m,1H),6.72-6.80(m,1H),6.93-6.99(m,1H),7.03-7.13(m,3H),7.13-7.27(m,2H);13CNMR(CDCl3,100MHz)δ:21.6,30.4,34.0,34.1,36.1,53.5,91.5,106.4,118.4,123.5,124.9,126.9,127.6,128.6,128.7,131.5,138.3,146.7,150.8,174.4;HRMS(ESI-TOF)m/z:Calcd.forC20H22N2NaO[M+Na]+:329.1629;Found:329.1632.
本实施例制备终产物4c:Whitepowder,m.p.166.2-166.9oC;Overallyield59%;1HNMR(CDCl3,400MHz)δ:2.20-2.39(m,6H),2.48-2.59(m,1H),2.90(s,3H),3.14(s,3H),4.84(s,1H),6.45-6.50(m,1H),6.72-6.79(m,1H),6.89-6.98(m,1H),7.10-7.20(m,5H);13CNMR(CDCl3,100MHz)δ:20.9,30.4,33.9,34.2,36.1,53.2,91.7,106.4,118.5,124.8,126.3,128.7,129.4,130.9,131.7,136.6,143.8,150.8,174.4;HRMS(ESI-TOF)m/z:Calcd.forC20H22N2NaO[M+Na]+:329.1629;Found:329.1633.
本实施例制备终产物4d:Whitepowder,m.p.147.2-148.6oC;Overallyield61%;1HNMR(CDCl3,400MHz)δ:2.28(s,9H),2.31-2.43(m,1H),2.49-2.58(m,3H),2.90(s,3H),4.86(s,1H),6.45-6.50(m,1H),6.74-6.79(m,1H),6.88(s,3H),6.93-7.00(m,1H),7.14-7.21(m,1H);13CNMR(CDCl3,100MHz)δ:21.5,30.4,34.1,34.3,36.1,53.4,60.4,91.6,106.3,118.4,124.2,125.0,128.6,131.7,138.2,146.7,150.8,174.5;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO[M+Na]+:343.1786;Found:343.1784.
本实施例制备终产物4e:Paleyellowoil;Overallyield60%;1HNMR(CDCl3,400MHz)δ:2.21-2.42(m,6H),2.49-2.60(m,1H),2.88(s,3H),3.12(s,3H),4.84(s,1H),6.30-6.43(m,1H),6.63-6.70(m,1H),6.82-6.90(m,1H),7.15(s,4H);13CNMR(CDCl3,100MHz)δ:20.8,30.2,33.4,35.0,36.0,53.1,92.1,107.0(d,JCF=6.4Hz),112.1(d,JCF=19.3Hz),114.8(d,JCF=18.5Hz),126.1,129.5,133.5(d,JCF=5.6Hz),136.9,143.0,147.0,157.1(d,JCF=187.9Hz),174.0;HRMS(ESI-TOF)m/z:Calcd.forC20H21FN2NaO[M+Na]+:347.1535;Found:347.1536.
本实施例制备终产物4f:Paleyellowoil;Overallyield60%;1HNMR(CDCl3,400MHz)δ:2.20-2.43(m,6H),2.48-2.62(m,1H),2.89(d,J=9.2Hz,3H),3.14(d,J=7.9Hz,3H),4.86(d,J=4.1Hz,1H),6.39(dd,J=4.1,8.6Hz,1H),6.69(dd,J=2.6,8.3Hz,1H),6.82-6.99(m,1H),7.01-7.13(m,3H),7.15-7.28(m,1H);13CNMR(CDCl3,100MHz)δ:21.6,30.2,33.5,34.9,36.0,53.4,92.0,106.9(d,JCF=7.9Hz),112.2(d,JCF=24.2Hz),114.9(d,JCF=23.1Hz),123.3,126.8,127.8,128.7,133.2(d,JCF=7.3Hz),138.5,145.9,156.8(d,JCF=233.4Hz),174.1;HRMS(ESI-TOF)m/z:Calcd.forC20H21FN2NaO[M+Na]+:347.1535;Found:347.1536.
本实施例制备终产物4g:Whitepowder,m.p.157.6-158.2oC;Overallyield60%;1HNMR(CDCl3,400MHz)δ:2.20-2.42(m,9H),2.48-2.60(m,1H),2.89(d,J=8.8Hz,3H),3.14(d,J=8.3Hz,3H),4.86(d,J=4.3Hz,1H),6.39(dd,J=4.1,8.6Hz,1H),6.69(dd,J=2.6,8.3Hz,1H),6.82-7.27(m,4H);13CNMR(CDCl3,100MHz)δ:21.5,30.3,33.7,34.9,36.0,53.3,53.4,92.0,106.8(d,JCF=8.0Hz),112.3(d,JCF=24.1Hz),114.8(d,JCF=23.1Hz),124.0,128.7,133.4(d,JCF=7.3Hz),138.3,145.9,147.0,156.8(d,JCF=234.3Hz),174.2;HRMS(ESI-TOF)m/z:Calcd.forC21H23FN2NaO[M+Na]+:361.1692;Found:361.1694.
本实施例制备终产物4h:Whitepowder,m.p.132.5-133.9oC;Overallyield52%;1HNMR(CDCl3,400MHz)δ:2.25(s,3H),2.27-2.40(m,3H),2.49-2.60(m,1H),2.88(s,3H),3.13(s,3H),4.82(s,1H),6.38-6.44(m,1H),6.76(s,1H),6.93-7.02(m,1H),7.20-7.39(m,5H);13CNMR(CDCl3,100MHz)δ:20.8,30.4,33.7,34.8,34.0,53.5,92.0,106.6,125.5,126.4,136.8,128.0,128.7,129.1,131.9,146.7,148.7,174.3;HRMS(ESI-TOF)m/z:Calcd.forC20H22N2NaO[M+Na]+:329.1629;Found:329.1631.
本实施例制备终产物4i:Whitepowder,m.p.164.1-164.9oC;Overallyield61%;1HNMR(CDCl3,400MHz)δ:2.19-2.41(m,9H),2.47-2.59(m,1H),2.87(s,3H),3.12(s,3H),4.79(s,1H),6.40(d,J=8.0Hz,1H),6.74(d,J=1.1Hz,1H),6.91-7.01(m,1H),7.10-7.26(m,4H);13CNMR(CDCl3,100MHz)δ:20.7,20.8,30.3,33.6,34.8,36.0,53.1,92.1,106.5,125.3,126.3,127.9,129.0,129.3,132.1,136.4,143.8,148.7,174.3;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO[M+Na]+:343.1786;Found:343.1789.
本实施例制备终产物4j:Paleyellowoil,Overallyield65%;1HNMR(CDCl3,400MHz)δ:2.01-2.29(m,4H),2.63(s,3H),2.86-2.91(m,1H),2.95(s,3H),2.99-3.04(m,1H),4.62(s,1H),6.28-6.34(m,1H),6.70-6.77(m,1H),6.86-6.94(m,3H),7.08-7.15(m,1H),7.16-7.27(m,3H);13CNMR(CDCl3,100MHz)δ:29.9,31.9,34.6,34.8,47.5,50.0,87.0,106.7,118.2,123.0,126.8,128.0,128.7,130.3,131.9,136.6,150.9,173.5;HRMS(ESI-TOF)m/z:Calcd.forC20H22N2NaO[M+Na]+:329.1629;Found:329.1628.
本实施例制备终产物4k:Whitecrystal,m.p.150.5-151.4oC;Overallyield67%;1HNMR(CDCl3,400MHz)δ:1.97-2.24(m,4H),2.28(s,3H),2.65(s,3H),2.85(d,J=13.5Hz,1H),2.97(d,J=15.4Hz,4H),4.63(s,1H),6.32(d,J=7.8Hz,1H),6.73(t,J=7.4Hz,1H),6.80(d,J=7.9Hz,2H),6.91(d,J=7.0Hz,1H),7.01(d,J=7.8Hz,2H),7.10-7.14(m,1H);13CNMR(CDCl3,100MHz)δ:20.9,29.8,31.7,34.5,34.8,46.8,49.8,86.9,106.5,118.1,123.0,128.5,130.1,131.9,133.3,136.2,150.7,173.6;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO[M+Na]+:343.1786;Found:343.1786.
本实施例制备终产物4l:Whitepowder,m.p.139.7-140.3oC;Overallyield64%;1HNMR(CDCl3,400MHz)δ:1HNMR(CDCl3,400MHz)δ(ppm):1.99(s,3H),2.03-2.27(m,4H),2.80(s,3H),2.92(d,J=13.8Hz,1H),3.00(s,3H),3.08(d,J=13.7Hz,1H),4.60(s,1H),6.36(d,J=7.8Hz,1H),6.61-6.69(m,2H),6.83-7.15(m,5H);13CNMR(CDCl3,100MHz)δ:19.8,29.7,31.1,34.8,43.0,50.2,87.6,106.5,118.1,123.1,125.4,126.7,128.6,130.4,131.4,134.9,137.2,150.5,173.4;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO[M+Na]+:343.1786;Found:343.1789.
本实施例制备终产物4m:Paleyellowoil;Overallyield65%;1HNMR(CDCl3,400MHz)δ:2.06-2.28(m,7H),2.64(s,3H),2.84-2.88(m,1H),2.93-3.00(m,4H),4.63(s,1H),6.30-6.34(m,1H),6.67(s,1H),6.70-6.78(m,2H),6.90-6.94(m,1H),6.98-7.03(m,1H),7.07-7.15(m,2H);13CNMR(CDCl3,100MHz)δ:21.3,29.9,31.6,34.6,34.8,47.4,49.9,86.9,106.6,118.2,123.0,127.4,127.8,128.6,131.1,132.0,136.4,137.5,150.9,173.6;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO[M+Na]+:343.1786;Found:343.1786.
本实施例制备终产物4n:Whitepowder,m.p.124.6-125.5oC;Overallyield60%;1HNMR(CDCl3,400MHz)δ:2.01-2.25(m,4H),2.70(s,3H),2.87-2.95(m,4H),3.10-3.19(m,1H),3.78(s,3H),4.77(s,1H),6.30-6.35(m,1H),6.69-6.79(m,3H),6.83-6.88(m,1H),6.95-7.00(m,1H),7.07-7.13(m,1H),7.14-7.27(m,1H);13CNMR(CDCl3,100MHz)δ:30.0,31.7,34.7,34.9,39.8,50.3,55.1,87.0,106.5,110.4,118.1,120.2,123.2,128.0,128.4,132.1,132.6,150.8,157.5,173.8;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO2[M+Na]+:359.1735;Found:359.1739.
本实施例制备终产物4o:Paleyellowoil;Overallyield61%;1HNMR(CDCl3,400MHz)δ:1.97-2.31(m,4H),2.66(s,3H),2.80-2.88(m,1H),2.91-3.00(m,4H),3.76(s,3H),4.61(s,1H),6.32(d,J=7.8Hz,1H),6.69-6.77(m,3H),6.78-6.85(m,2H),6.90(dd,J=0.9,7.4Hz,1H),7.08-7.28(m,1H);13CNMR(CDCl3,100MHz)δ:29.9,31.8,34.7,34.9,46.5,50.0,55.1,87.0,106.6,113.3,118.1,123.0,128.6,131.2,131.9,150.9,158.4,173.6;HRMS(ESI-TOF)m/z:Calcd.forC21H24N2NaO2[M+Na]+:359.1735;Found:359.1736.
本实施例制备终产物4p:Paleyellowoil;Overallyield63%;1HNMR(CDCl3,400MHz)δ:2.07-2.24(m,4H),2.70(s,3H),2.89-2.97(m,4H),3.01-3.07(m,1H),3.77(s,3H),3.86(s,3H),4.87(s,1H),6.28-6.37(m,2H),6.73-6.79(m,2H),6.81-6.86(m,1H),6.99-7.04(m,1H),7.08-7.14(m,1H);13CNMR(CDCl3,100MHz)δ:29.9,31.5,34.7,34.8,39.9,50.4,55.6,64.1,86.4,106.6,110.9,118.1,122.8,123.3,123.8,128.5,130.4,132.5,147.4,150.8,152.7,173.8;HRMS(ESI-TOF)m/z:Calcd.forC22H26N2NaO3[M+Na]+:389.1841;Found:389.1846.
本实施例制备终产物4q:Paleyellowoil;Overallyield62%;1HNMR(CDCl3,400MHz)δ:2.00-2.03(m,1H),2.12-2.30(m,3H),2.56(s,3H),2.75-2.80(m,1H),3.98-3.03(m,4H),3.56(s,3H),3.83(s,3H),4.57(s,1H),6.04-6.09(m,1H),6.26-6.31(m,1H),6.56-6.60(m,1H),6.72-6.79(m,2H),6.95-6.99(m,1H),7.09-7.14(m,1H);13CNMR(CDCl3,100MHz)δ:29.9,32.1,34.8,34.9,47.2,50.2,55.4,55.8,86.7,106.9,110.4,113.0,118.1,122.2,123.1,128.7,129.2,131.6,147.8,148.2,151.4,173.5;HRMS(ESI-TOF)m/z:Calcd.forC22H26N2NaO3[M+Na]+:389.1841;Found:389.1842.
本实施例制备终产物4r:Paleyellowoil;Overallyield61%;1HNMR(CDCl3,400MHz)δ:1.99-2.21(m,4H),2.72(s,3H),2.86(d,J=13.6Hz,1H),2.96(s,3H),3.04(d,J=13.6Hz,1H),3.76(s,6H),4.74(s,1H),6.23-6.36(m,2H),6.44(d,J=2.4Hz,1H),6.67(d,J=8.3Hz,1H),6.74(dd,J=0.8,7.4Hz,1H),6.96(dd,J=0.8,7.3Hz,1H),7.05-7.14(m,1H);13CNMR(CDCl3,100MHz)δ:30.0,31.7,34.8,35.0,39.2,50.3,55.0,55.2,87.0,98.3,103.8,106.5,117.5,118.0,123.0,132.5,150.8,158.4,159.6,173.9;HRMS(ESI-TOF)m/z:Calcd.forC22H26N2NaO3[M+Na]+:389.1841;Found:389.1843.
本实施例制备终产物4s:Whitepowder,m.p.155.5-156.1oC;Overallyield64%;1HNMR(CDCl3,400MHz)δ:2.02-2.29(m,4H),2.57(s,3H),2.73-2.77(m,1H),3.00(s,3H),3.10-3.16(m,1H),3.47(s,3H),3.80(s,3H),3.85(s,3H),4.66(s,1H),6.00(s,1H),6.24-6.30(m,1H),6.50(s,1H),6.73-6.78(m,1H),6.99-7.12(m,2H);13CNMR(CDCl3,100MHz)δ:29.9,32.1,34.8,35.0,39.4,50.5,55.9,56,0,56.1,86.5,96.9,106.8,115.1,116.5,118.0,122.9,128.5,132.0,142.1,147.9,151.4,151.5,173.5;HRMS(ESI-TOF)m/z:Calcd.forC23H28N2NaO4[M+Na]+:419.1946;Found:419.1948.
本实施例制备终产物4t:Whitepowder,m.p.150.4-151.4oC;Overallyield63%;1HNMR(CDCl3,400MHz)δ:2.08-2.28(m,4H),2.76(s,3H),2.89-2.94(m,1H),2.98-3.03(m,4H),3.83-3.86(m,6H),3.89(s,3H),4.88(s,1H),6.35-6.38(m,1H),6.46-6.53(m,2H),6.75-6.81(m,1H),7.01-7.05(m,1H),7.12-7.17(m,1H);13CNMR(CDCl3,100MHz)δ:24.1,30.0,31.8,34.9,40.0,50.4,55.9,60.8,64.3,86.7,106.8,118.2,122.5,122.9,126.2,128.6,132.6,142.1,150.9,152.2,152.5,174.1;HRMS(ESI-TOF)m/z:Calcd.forC23H28N2NaO4[M+Na]+:419.1946;Found:419.1950.
本实施例制备终产物4u:Paleyellowoil;Overallyield57%;1HNMR(CDCl3,400MHz)δ:2.06-2.27(m,4H),2.63(s,3H),2.81-2.86(m,1H),2.97(s,3H),3.13-3.18(m,1H),3.53(s,3H),3.77(s,3H),4.74(s,1H),6.18-6.20(m,1H),6.28-6.32(m,1H),6.66-6.70(m,1H),6.73-6.80(m,2H),7.00-7.04(m,1H),7.08-7.12(m,1H);13CNMR(CDCl3,100MHz)δ:30.0,31.9,34.8,34.9,40.0,50.4,55.4,55.7,86.7,106.7,111.4,113.1,117.2,118.1,122.9,126.2,128.5,132.3,151.1,151.7,152.8,173.7.HRMS(ESI-TOF)m/z:Calcd.forC22H26N2NaO3[M+Na]+:389.1841;Found:389.1843.
本实施例制备终产物4v:Paleyellowoil;Overallyield56%;1HNMR(CDCl3,400MHz)δ:1.28(s,9H),2.02-2.28(m,4H),2.63(s,3H),2.84-2.98(m,5H),4.62(s,1H),6.30-6.34(m,1H),6.71-6.77(m,1H),6.82-6.87(m,2H),6.91-6.96(m,1H),7.09-7.15(m,1H),7.20-7.27(m,2H);13CNMR(CDCl3,100MHz)δ:29.9,31.3,31.8,34.3,34.5,34.7,46.8,49.9,86.9,106.6,118.2,123.0,124.8,128.6,129.9,132.2,133.4,149.7,150.8,173.6;HRMS(ESI-TOF)m/z:Calcd.forC24H30N2NaO[M+Na]+:385.2255;Found:385.2257.
本实施例制备终产物4w:Whitepowder,m.p.95.2-95.9oC;Overallyield64%;1HNMR(CDCl3,400MHz)δ:1.19-1.22(m,6H),2.06-2.28(m,4H),2.64(s,3H),2.81-2.90(m,2H),2.92(s,3H),2.94-2.99(m,1H),4.62(s,1H),6.30-6.35(m,1H),6.72-6.77(m,1H),6.81-6.85(m,2H),6.90-6.95(m,1H),7.04-7.09(m,2H),7.10-7.15(m,1H);13CNMR(CDCl3,100MHz)δ:23.9,24.0,29.9,31.7,33.6,34.6,34.8,46.9,49.9,86.9,106.6,118.2,123.0,126.0,128.6,130.2,132.2,133.7,147.4,150.8,173.6;HRMS(ESI-TOF)m/z:Calcd.forC23H28N2NaO[M+Na]+:371.2099;Found:371.2097.
本实施例制备终产物4x:Whitepowder,m.p.140.0-140.7oC;Overallyield62%;1HNMR(CDCl3,400MHz)δ:2.05-2.30(m,4H),2.64(s,3H),2.87(d,J=13.4Hz,1H),2.97(s,3H),3.01(d,J=13.4Hz,1H),4.59(s,1H),6.32(d,J=7.9Hz,1H),6.51-6.55(m,1H),6.68(d,J=7.7Hz,1H),6.73-6.79(m,1H),6.86-6.94(m,2H),7.10-7.22(m,2H);13CNMR(CDCl3,100MHz)δ:29.7,31.5,34.6,34.8,47.1,49.9,86.8,106.7,113.5,116.8(d,JCF=21.1Hz),118.3,122.9,125.8(d,JCF=2.8Hz),128.9,129.2,138.9(d,JCF=7.2Hz),150.7,162.3(d,JCF=244.5Hz),173.5;HRMS(ESI-TOF)m/z:Calcd.forC20H21FN2NaO[M+Na]+:347.1535;Found:347.1539.
本实施例制备终产物4y:Paleyellowoil;Overallyield63%;1HNMR(CDCl3,400MHz)δ:2.04-2.30(m,4H),2.61(s,3H),2.93(d,J=13.2Hz,1H),2.98(s,3H),3.08(d,J=13.3Hz,1H),4.58(d,J=7.5Hz,1H),6.31(d,J=7.8Hz,1H),6.76(t,J=7.4Hz,1H),6.85-7.00(m,3H),7.11-7.15(m,1H),7.42-7.56(m,2H);13CNMR(CDCl3,100MHz)δ:29.7,31.6,34.5,34.9,47.2,50.0,86.8,106.8,118.3,122.9,124.7,124.8,128.8,129.0,130.5,130.9,130.7,130.4,132.2,140.7,150.8,167.7,173.3;HRMS(ESI-TOF)m/z:Calcd.forC21H21F3N2NaO[M+Na]+:397.1503;Found:397.1506.
本实施例制备终产物4z:Whitepowder,m.p.126.8-127.7oC;Overallyield64%;1HNMR(CDCl3,400MHz)δ:2.00-2.31(m,4H),2.69(s,3H),3.00(s,3H),3.17(d,J=14.8Hz,1H),3.24(d,J=14.7Hz,1H),4.62(s,1H),6.36(d,J=7.9Hz,1H),6.65(d,J=3.1Hz,1H),6.74-6.79(m,1H),6.86-6.89(m,1H),7.00-7.05(m,1H),7.06-7.12(m,1H),7.14-7.17(m,1H);13CNMR(CDCl3,100MHz)δ:30.0,33.0,34.6,35.4,41.3,49.7,86.9,106.6,118.4,122.9,124.6,126.4,127.2,128.9,131.5,138.4,151.2,174.0;HRMS(ESI-TOF)m/z:Calcd.forC18H20N2NaOS[M+Na]+:335.1194;Found:335.1190.
本发明的式（1）六氢吡啶-2,3-并吲哚-2-酮类化合物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：此类式（1）所示的结构的六氢吡啶-2,3-并吲哚-2-酮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4i、4k、4o、4r、4u、4v或4w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4i、4k、4o、4r、4u、4v或4w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10μLMTT（5mg/mL)的磷酸盐缓冲液，再继续在37oC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4i、4k、4o、4r、4u、4v或4w对A549细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物4i对A549肿瘤细胞的IC50为7.23μmol/L；化合物4k对A549肿瘤细胞的IC50为17.34μmol/L；化合物4o对A549肿瘤细胞的IC50为7.41μmol/L；化合物4r对A549肿瘤细胞的IC50为9.36μmol/L；化合物4u对A549肿瘤细胞的IC50为5.65μmol/L；化合物4v对A549肿瘤细胞的IC50为18.17μmol/L；化合物4w对A549肿瘤细胞的IC50为12.65μmol/L；而阳性对照顺铂对A549肿瘤细胞的IC50为28.4μmol/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4i、4q、4r、4u、4v、4w或4k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4i对K562肿瘤细胞的IC50为32.86μmol/L；化合物4q对K562肿瘤细胞的IC50为52.97μmol/L；化合物4r对K562肿瘤细胞的IC50为54.56μmol/L；化合物4v对K562肿瘤细胞的IC50为27.99μmol/L；化合物4w对K562肿瘤细胞的IC50为35.54μmol/L；化合物4k对K562肿瘤细胞的IC50为45.81μmol/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）所示的六氢吡啶-2,3-并吲哚-2-酮类化合物对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或中间体。
药理实施例3：化合物4i、4o、4q、4r、4u、4v、4w或4k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37oC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4i对PC-3肿瘤细胞的IC50为9.10μmol/L；化合物4o对PC-3肿瘤细胞的IC50为17.56μmol/L；化合物4q对PC-3肿瘤细胞的IC50为23.27μmol/L；化合物4r对PC-3肿瘤细胞的IC50为15.90μmol/L；化合物4u对PC-3肿瘤细胞的IC50为27.05μmol/L；化合物4v对PC-3肿瘤细胞的IC50为29.20μmol/L；化合物4w对PC-3肿瘤细胞的IC50为17.19μmol/L；化合物4k对PC-3肿瘤细胞的IC50为46.12μmol/L；而阳性对照顺铂对PC-3肿瘤细胞的IC50为26.2μmol/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。
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或中间体的潜力，值得继续深入研究下去。

Claims (3)

1.一种具有抑制肿瘤生长活性的六氢吡啶-2,3-并吲哚-2-酮类化合物，其特征在于：该化合物具有如通式（Ⅰ）所示的结构：
式中，R2为烷基或芳基；R3为H或烷基或卤素。
2.一种如权利要求1所述的六氢吡啶-2,3-并吲哚-2-酮类化合物的制备方法，其特征在于：由相应的3-单取代氧化吲哚1与丙烯酸酯2先发生Michael加成反应，生成中间体3，然后中间体3氮原子脱保护基团Boc得到了中间体3-1，然后中间体3-1氮原子上保护基甲基得到中间体3-2,中间体3-2再与甲胺发生酰胺化反应，生成中间体3-3，最后中间体3-3通过与四氢化铝锂发生氢化还原环化反应生成最终产物六氢吡啶-2,3-并吲哚-2-酮类化合物，
合成路线如下：
。
3.一种如权利要求1所述的六氢吡啶-2,3-并吲哚-2-酮类化合物在制备防治肿瘤疾病药物的应用。
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CN108299491A (zh) * 2018-03-26 2018-07-20 广东工业大学 3-双烷基化-2-吲哚酮衍生物及其制备方法
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