CN110317157B - 一种吲哚类化合物及其合成方法和应用 - Google Patents
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Abstract
本发明了一种吲哚类化合物及其制备方法和应用,本发明提供的吲哚类化合物通过选择特定的取代基,通过实验发现,其作为抗癌药物对前列腺癌具有很好的抑制作用,且具有很好的抗耐药性,且副作用小;此外,本发明提供的的合成方法,通过将式(II)结构的化合物、醋酸钯、苯醌类化合物和有机酸溶于溶剂中反应,得到式(I)结构的吲哚类化合物;实验结果表明,本发明提供的方法不仅对底物的要求比较低,且得到的产物的收率较高。
Description
技术领域
本发明涉及有机合成领域,尤其涉及一种吲哚类化合物及其合成方法和应用。
背景技术
肿瘤是严重威胁人类健康的一种疾病,目前肿瘤的治疗手段仍是以药物治疗为主。因此,研究开发新的高效低毒的抗肿瘤药物具有重要意义。前列腺癌在欧美男性中是最普遍的肿瘤,它在男性中是第二致死性癌症,我国前列腺癌发病率虽然远低于西方国家,但近年来呈显著增高的趋势。
前列腺癌最初主要依赖于雄激素(AR)来促进生长。临床上治疗前列腺癌一般有三种方式:手术,雄激素靶向治疗,化疗。一般雄激素靶向治疗主要包括雄激素去除治疗;虽然雄激素去除治疗短时间内可以抑制前列腺癌的增殖,但慢慢地随着雄激素的缺乏会发展成为去势抵抗性前列腺癌。
目前,临床上常用的雄激素拮抗药物有恩杂鲁胺和阿比特龙,它们可以靶向抑制雄激素的合成,主要用于去势抵抗性前列腺癌。然而,最近的一些研究表明雄激素AR有两种亚型(具体见图1,图1为全长AR和突变AR-V7的结构;);一种是含有LBD结构域的AR全长;另一种是只含有DBD结构域的AR突变体(V7),缺乏LBD结构域的AR-VS对恩杂鲁胺和阿比特龙在内的抗雄激素治疗都会产生一定的耐药性。总而言之,依赖于配体全长的AR(AR-FL)和突变体AR(AR-VS)在去势抵抗性前列腺癌的不同转录组中都发挥着重要的作用。如今临床上使用的AR抑制剂均以LBD为靶点,因此无法克服AR-VS驱动的肿瘤细胞耐药性问题。
吲哚类化合物具有各种各样的生理活性,在药理作用方面,吲哚类化合物具有抗肿瘤,抗菌,抗病毒,抗炎,治疗高血压等作用。常用的降压药利血平含有吲哚基团,以及美国默克公司研发的消炎痛(吲哚美辛)具有较强的抗菌消炎的作用。以及一些天然产物吲哚生物碱具有各种生理活性,有的对其结构进行改造,发现更多对人类有用的药物。在药物发现和研发的过程中,吲哚可能是做重要的结构之一,很多药物都以吲哚环为结构基础。因此,研究开发针对于AR-FL和AR-VS共同为靶点的,并具有吲哚骨架的新型前列腺癌抑制剂不仅符合抗去势抵抗性前列腺癌的要求,而且具有良好的市场前景。
而且,吲哚类化合物是很多化合物的重要结构单元,广泛存在于药物及具有生物活性得化学分子中。因此研究该环的合成也具有至关重要的意义。
发明内容
有鉴于此,本发明所要解决的技术问题在于提供一种吲哚类化合物及其合成方法和应用,本发明提供的吲哚类化合物对前列腺癌具有很好的抑制作用,且该吲哚化合物的合成方法对底物的适用性广,得到的吲哚类化合物的收率较高。
与现有技术相比,本发明了一种吲哚类化合物及其合成方法和应用,本发明提供的吲哚类化合物通过选择特定的取代基,通过实验结果表明,其作为抗癌药物对前列腺癌具有很好的抑制作用,且具有很好的抗耐药性,且副作用小;此外,本发明提供的的合成方法,通过将式(II)结构的化合物、醋酸钯、苯醌类化合物和有机酸溶于溶剂中反应,得到式(I)结构的吲哚类化合物;实验结果表明,本发明提供的方法不仅对底物的要求比较低,且得到的产物的收率较高。
附图说明
图1为全长AR和突变AR-V7的结构;
图2为烯丙基苯胺类化合物2b的氢谱;
图3为烯丙基苯胺类化合物2b的碳谱;
图4为烯丙基苯胺类化合物3b的氢谱;
图5为烯丙基苯胺类化合物3b的碳谱;
图6为N-(烯丙基苯基)苯甲酰胺类化合物4k的氢谱;
图7为N-(烯丙基苯基)苯甲酰胺类化合物4k的碳谱;
图8为吲哚类化合物5k的氢谱;
图9为吲哚类化合物5k的碳谱;
图10为本发明提供的化合物对前列腺癌细胞平板克隆形成的影响;
图11为本发明所述的化合物对前列腺癌细胞Caspase-3活性的影响;
图12为本发明提供的化合物诱导前列腺癌细胞凋亡的影响;
图13为本发明所述的化合物对小鼠体内前列腺癌的影响。
具体实施方式
本发明提供了一种吲哚化合物,具有式(I)所示的结构,
其中,
所述R1-2、R1-4、R1-6独立的选自氢、C1~C6的烷基、C1~C6的烷氧基;
所述R1-3、R1-5独立的选自氢或卤素;
且所述R1-2、R1-3、R1-4、R1-5、R1-6不同时为氢;
所述R2-2选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-3选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-4选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-5选自氢、C1~C6的甲氧基或卤素;
所述R2-6选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-7选自氢、C1~C6的甲基或C1~C6的甲氧基。
按照本发明,所述R1-2选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R1-3选自氢、氟、氯或溴。
所述R1-5选自氢、氟、氯或溴。
所述R1-4选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R1-5选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R2-2选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R2-3选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R2-4选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R2-5选自氢、氟、氯、溴、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R2-6选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基。
所述R2-7选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基或正己基氧基;
更具体的,所述式(I)化合物为:
本发明还提供了一种吲哚类化合物的合成方法,包括:
将式(II)结构的化合物、醋酸钯、苯醌类化合物和有机酸溶于溶剂中反应,得到式(I)结构的化合物;
其中,所述R1-2、R1-4、R1-6独立的选自氢、C1~C6的烷基、C1~C6的烷氧基;
所述R1-3、R1-5独立的选自氢或卤素;
且所述R1-2、R1-3、R1-4、R1-5、R1-6不同时为氢;
所述R2-0选自氢、C1~C5的甲基或C1~C5的甲氧基;
所述R2-2选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-3选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-4选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-5选自氢、C1~C6的甲氧基或卤素;
所述R2-6选自氢、C1~C6的甲基或C1~C6的甲氧基;
所述R2-7选自氢、C1~C6的甲基或C1~C6的甲氧基。
本发明中,所述化合物上取代基的选择与前述相同;所述苯醌类化合物优选为苯醌,2.6二甲基苯醌,2,3-2氰基5,6-二氯苯醌;所述有机酸优选为磷酸二丁酯和二苯基磷酸中的一种或两种,更优选为磷酸二丁酯。所述溶剂为DMSO;本发明中,所述溶剂优选为DMSO、、THF、二氧六环、DMF和甲苯中的一种或几种,更优选为DMSO。
本发明中,所述式(II)结构的化合物与所述醋酸钯的摩尔比优选为1:(0.08~0.12),更优选为1:0.1;所述式(II)结构的化合物与所述苯醌类化合物的摩尔比优选为1:(2.5~3.5),更优选为1:2.8~3.2,最优选为1:3;所述式(II)结构的化合物与所述有机酸的摩尔比优选为1:(1~2),更优选为1:(1.5~1.8);所述式(II)结构的化合物与所述溶剂的用量比优选为1mmol:(0.8~1.5)mL,更优选为1mmol:1mL;所述反应的温度优选为55~65℃,更优选为60~62℃;所述反应的时间优选为24~48小时。
本发明中,所述式(II)结构的化合物优选按照以下方法制备得到:
将式(III)结构的化合物与式(IV)结构的化合物反应,得到式(II)结构的化合物,其中,为了反应更好的进行,反应中优选还加入反应助剂1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)与DMAP,所述反应的溶剂优选为二氯甲烷;所述反应优选为室温反应,反应的时间优选为12~24小时。
其中,所述R为氢、C1~C6的烷基、卤素或C6~C15的芳基;
所述R1为氢、C1~C6的烷基、C1~C6的烷氧基或卤素。
本发明中,所述式(III)结构的化合物优选按照以下方法制备得到:
将式(V)结构的化合物与三氟化硼乙醚反应,得到式(III)结构的化合物,其中,所述反应的溶剂优选为二甲苯;为了使反应更好的进行,本发明优选将式(V)结构的化合物溶于溶剂中,然后在-5~0℃条件下加入三氟化硼乙醚,然后在155~160℃条件下反应,得到式(III)结构的化合物。
本发明中,所述式(V)结构的化合物通过将苯胺和烯丙基溴混合反应得到;其中,所述反应的碱优选为碳酸钾,所述反应的溶剂优选为DMF;所述反应的温度优选为室温。
本发明还提供了一种本发明所述的式(I)结构的吲哚化合物在制备抗肿瘤药物中的应用。其中,所述肿瘤优选为前列腺癌
本发明了一种吲哚类化合物的合成方法,通过将式(II)结构的化合物、醋酸钯、苯醌类化合物和有机酸溶于溶剂中反应,得到式(I)结构的吲哚类化合物;通过实验发现,本发明提供的方法不仅对底物的要求比较低,且得到的产物的收率较高,此外,本发明提供的合成方法反应条件比较简单,反应原料易于得到。
本发明的一种吲哚类化合物及其制备方法和应用,本发明提供的吲哚类化合物通过选择特定的取代基,结果发现,其作为抗癌药物对前列腺癌具有很好的抑制作用,且具有很好的抗耐药性,且副作用小;此外,本发明提供的的合成方法,通过将式(II)结构的化合物、醋酸钯、苯醌类化合物和有机酸溶于溶剂中反应,得到式(I)结构的吲哚类化合物,该方法不仅对底物的要求比较低,且得到的产物的收率较高。
下面将结合本发明实施例的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
制备例
1)中间体烯丙基苯胺类化合物的制备,以N-烯丙基苯胺为例,如下式所示:
将苯胺(1mmol)与K2CO3(1.5mmol)加入无水DMF中,随后滴入烯丙基溴(1mmol),搅拌反应12h,加水淬灭反应,乙酸乙酯萃取,饱和食盐水洗,无水Na2SO4干燥,色谱柱分离(石油醚),得到N-烯丙基苯胺,收率60%,纯度99.99%。
对得到的化合物进行鉴定,其核磁结果如下:1H NMR(500MHz,CDCl3)δ7.25–7.20(m,2H),6.93(t,J=7.4Hz,1H),6.80(d,J=7.9Hz,1H),6.12(dq,J=11.6,6.2Hz,1H),5.29(t,J=13.2Hz,2H),3.78(s,2H),3.45(d,J=6.2Hz,2H).13C NMR(126MHz,CDCl3)δ143.76(s),134.89(s),129.08(s),126.46(s),122.91(s),117.76(s),115.01(s),114.74(s),35.37(s).
2)中间体2-烯丙苯胺类化合物的制备,以2-烯丙苯胺为例,如下式所示:
将步骤1)得到的N-烯丙苯胺(1mmol)加入1mL二甲苯中,0℃滴入BF3.Et2O(1mmol),随后160℃反应5h,冷却后0℃下加入2mol/L NaOH 2mL后,加入乙酸乙酯萃取,饱和食盐水洗,无水Na2SO4干燥,色谱柱分离(石油醚:乙酸乙酯3%),得到2-烯丙苯胺,收率33%,纯度99.89%。
对得到的化合物进行鉴定,其核磁结果如下:1H NMR(500MHz,CDCl3)δ7.25–7.20(m,2H),6.93(t,J=7.4Hz,1H),6.80(d,J=7.9Hz,1H),6.12(dq,J=11.6,6.2Hz,1H),5.29(t,J=13.2Hz,2H),3.78(s,2H),3.45(d,J=6.2Hz,2H).13C NMR(126MHz,CDCl3)δ143.76(s),134.89(s),129.08(s),126.46(s),122.91(s),117.76(s),115.01(s),114.74(s),35.37(s).
3)中间N-(烯丙基苯基)苯甲酰胺类化合物的制备,以N-(烯丙基苯基)苯甲酰胺为例,如下式所示
将步骤2)得到的2-烯丙苯胺(1mmol),苯甲酸(1mmol),EDCI(2mmol)与DMAP(2mmol)加入1mL干燥的二氯甲烷中,搅拌反应12h,加入NaHCO3后二氯甲烷萃取,饱和食盐水洗,无水Na2SO4干燥,色谱柱分离(石油醚:乙酸乙酯3-10%),得到N-(烯丙基苯基)苯甲酰胺,收率76%,纯度99.99%。
对得到的化合物进行鉴定,其核磁结果如下:1H NMR(500MHz,CDCl3)δ8.04(s,1H),8.03(s,1H),7.86(d,J=7.3Hz,2H),7.55(t,J=7.4Hz,1H),7.49(q,J=7.5Hz,3H),7.32(t,J=7.7Hz,1H),7.23(d,J=7.0Hz,1H),7.16(t,J=7.5Hz,1H),6.04(ddt,J=16.2,10.2,6.0Hz,1H),5.24(dd,J=10.1,1.4Hz,1H),5.11(dd,J=17.2,1.5Hz,1H),3.46(d,J=5.9Hz,2H).13C NMR(126MHz,CDCl3)δ165.56(s),136.28(s),134.92(s),131.86(s),130.38(s),130.11(s),128.80(s),128.64(s),127.62(s),127.08(s),125.39(s),123.63(s),116.90(s),37.05(s).
4)吲哚类化合物的制备,以1-苯甲酰基-2-甲基吲哚为例,如下式所示
氮气保护下将N-(烯丙基苯基)苯甲酰胺(1mmol),Pd(OAc)2(0.1mmol),苯醌(3mmol)与磷酸二丁酯(1.5mmol)加入1mLDMSO中,60℃搅拌反应24h,加入乙酸乙酯萃取,饱和食盐水洗,无水Na2SO4干燥,色谱柱分离(石油醚:乙酸乙酯1%),得到1-苯甲酰基-2-甲基吲哚,收率81%,纯度99.99%。
对得到的化合物进行鉴定,其核磁结果如下:1H NMR(500MHz,CDCl3)δ7.73(d,J=7.8Hz,2H),7.63(t,J=7.4Hz,1H),7.49(d7d,dd J=15.6,7.7Hz,3H),7.15(dd,J=7.4,6.4Hz,1H),7.05–6.98(m,2H),6.44(s,1H),2.42(s,3H).13C NMR(126MHz,CDCl3)δ169.89(s),137.98(s),137.18(s),135.58(s),132.88(s),129.74(s),129.56(s),128.77(s),122.67(s),122.60(s),119.81(s),114.32(s),108.58(s),15.78(s).
实施例
按照制备例提供的制备方法,选择不同的原料,得到一系列R1和R2为不同取代基的吲哚类化合物,记为5b~5u,具体反应流程及得到的产物如下面反应流程所示;
对各步反应得到的产物检测,其中,图2为烯丙基苯胺类化合物2b的氢谱,图2为烯丙基苯胺类化合物2b的碳谱;图3为烯丙基苯胺类化合物3b的氢谱,图4为烯丙基苯胺类化合物3b的碳谱;图5为N-(烯丙基苯基)苯甲酰胺类化合物4k的氢谱;图6为N-(烯丙基苯基)苯甲酰胺类化合物4k的碳谱;图7为吲哚类化合物5k的氢谱,图8为吲哚类化合物5k的碳谱;具体的,反应各步得到的化合物的核磁数据以及产物的收率结果如下:
1b
收率62%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.23(t,J=7.7Hz,1H),7.17(d,J=7.2Hz,1H),6.78(t,J=7.4Hz,1H),6.72(d,J=8.0Hz,1H),6.10(ddd,J=22.5,10.5,5.3Hz,1H),5.40(dd,J=17.2,1.5Hz,1H),5.29(dd,J=10.3,1.4Hz,1H),3.92(d,J=5.3Hz,2H),3.71(s,1H).13C NMR(101MHz,CDCl3)δ146.05(s),135.70(s),130.17(s),127.20(s),122.04(s),117.21(s),116.26(s),110.13(s),46.59(s),17.56(s).
1c
收率29%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.02(d,J=8.2Hz,2H),6.58(d,J=8.3Hz,2H),5.98(ddd,J=22.4,10.5,5.4Hz,1H),3.77(d,J=5.3Hz,2H),3.65(s,1H),2.27(s,3H).13C NMR(126MHz,CDCl3)δ142.38(s),136.23(s),130.86(s),128.09(s),128.07(s),124.21(s),116.09(s),116.05(s),36.57(s),20.58(s).
1d
收率48%,纯度99.99%,1H NMR(500MHz,CDCl3)δ6.98–6.85(m,1H),6.70–6.57(m,1H),5.85(ddt,J=17.1,10.1,4.9Hz,1H),5.23–5.13(m,2H),3.89(dd,J=3.1,1.8Hz,2H).13C NMR(126MHz,CDCl3)δ155.28(d,J=235.6Hz),145.38(d,J=1.6Hz),134.03(s),116.17(s),115.38(d,J=22.7Hz),113.56(d,J=7.2Hz),53.41(s).
1e
收率56%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.29(d,J=7.8Hz,1H),7.16(dd,J=11.4,4.1Hz,1H),6.67(t,J=8.6Hz,2H),5.98(ddd,J=15.6,10.4,5.2Hz,1H),5.33(dd,J=17.2,1.3Hz,1H),5.23(dd,J=10.3,0.9Hz,1H),4.50(s,1H),3.86(s,2H).13C NMR(101MHz,CDCl3)δ143.85(s),134.80(s),129.13(s),127.77(s),119.18(s),117.34(s),116.43(s),111.54(s),46.12(s).
2b
收率40%,纯度99.79%,1H NMR(400MHz,CDCl3)δ7.23(t,J=7.7Hz,1H),7.17(d,J=7.2Hz,1H),6.78(t,J=7.4Hz,1H),6.72(d,J=8.0Hz,1H),6.10(ddd,J=22.5,10.5,5.3Hz,1H),5.40(dd,J=17.2,1.5Hz,1H),5.29(dd,J=10.3,1.4Hz,1H),3.92(d,J=5.3Hz,2H),3.71(s,1H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ146.05(s),135.70(s),130.17(s),127.20(s),122.04(s),116.26(s),110.13(s),46.59(s),17.56(s).
2c
收率76%,纯度99.88%,1H NMR(400MHz,CDCl3)δ6.97(d,J=8.1Hz,2H),6.67(d,J=7.6Hz,1H),6.04(tt,J=11.9,6.2Hz,1H),5.29–5.14(m,2H),3.56(s,2H),3.36(d,J=6.0Hz,2H),2.34(s,3H).13C NMR(101MHz,CDCl3)δ142.36(s),136.22(s),130.84(s),128.07(s),128.05(s),124.20(s),116.08(s),116.02(s),36.55(s),20.56(s).
2d
收率46%,纯度99.99%,1H NMR(400MHz,CDCl3)δ6.77(dd,J=13.9,5.8Hz,2H),6.61(dd,J=8.1,4.9Hz,1H),5.93(ddt,J=16.6,10.2,6.2Hz,1H),5.13(ddd,J=18.6,13.6,1.3Hz,2H),3.52(s,2H),3.27(d,J=6.1Hz,2H).13C NMR(101MHz,CDCl3)δ156.49((d,J=236.3Hz),140.72(d,J=2.1Hz),135.09(s),125.72(d,J=6.8Hz),116.67(s),116.56(d,J=3.0Hz),116.42(d,J=18.2Hz),113.69(d,J=22.2Hz),36.25(s).
2e
收率24%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.02(dd,J=6.5,2.4Hz,2H),6.64–6.51(m,1H),5.92(ddt,J=16.3,10.1,6.2Hz,1H),5.18-5.08(m,,2H),3.65(s,2H),3.26(d,J=6.1Hz,2H).13C NMR(101MHz,CDCl3)δ143.40(s),135.01(s),129.76(s),127.25(s),125.64(s),123.25(s),116.83(s),116.75(s),36.14(s).
4b
收率51%,纯度99.99%,1H NMR(500MHz,CDCl3)δ8.04(d,J=8.0Hz,1H),7.89(s,1H),7.74(d,J=7.3Hz,1H),7.48–7.30(m,4H),7.25–7.15(m,2H),5.98(dq,J=11.2,5.9Hz,1H),5.11(d,J=10.1Hz,1H),5.00(d,J=17.2Hz,1H),3.46(d,J=5.6Hz,2H).13CNMR(126MHz,CDCl3)δ164.71(s),135.95(s),135.63(s),135.40(s),131.63(s),130.58(s),130.56(s),130.41(s),130.35(s),130.30(s),127.52(s),127.28(s),125.82(s),123.87(s),116.79(s),36.57(s).
4c
收率64%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.96(d,J=7.8Hz,1H),7.89(s,1H),7.51(t,J=8.9Hz,2H),7.39(dd,J=13.6,7.8Hz,1H),7.26(t,J=7.7Hz,1H),7.17(dd,J=12.0,5.0Hz,2H),7.10(t,J=7.4Hz,1H),5.98(dq,J=11.1,5.9Hz,1H),5.19(d,J=10.1Hz,1H),5.05(d,J=17.2Hz,1H),3.39(d,J=5.8Hz,2H).13C NMR(126MHz,CDCl3)δ163.13(s),161.86(d,J=249.48Hz),136.18(d,J=6.8Hz),135.24(s),135.00(s),129.45(s),129.44(d,J=7.6Hz),128.83(s),126.69(s),124.55(s),122.44(s),121.34(d,J=2.5Hz),,117.85(d,J=21.4Hz),115.97(s),113.53(d,J=22.7Hz),36.10(s).
4d
收率69%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.96(d,J=8.0Hz,1H),7.89(s,1H),7.66(d,J=7.9Hz,2H),7.26–7.16(m,3H),7.13(d,J=7.4Hz,1H),7.06(t,J=7.4Hz,1H),5.95(dq,J=11.1,5.9Hz,1H),5.15(d,J=10.1Hz,1H),5.03(d,J=17.2Hz,1H),3.36(d,J=5.8Hz,2H),2.34(s,3H).13C NMR(126MHz,CDCl3)δ164.42(s),141.30(s),135.36(s),135.24(s),131.05(s),129.30(s),128.81(s),128.40(s),126.56(s),126.01(s),124.14(s),122.44(s),115.82(s),36.04(s),20.46(s).
4e
收率66%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.99(s,1H),7.79(d,J=7.8Hz,1H),7.64(d,J=8.2Hz,2H),7.29(d,J=8.3Hz,2H),7.17(t,J=7.6Hz,1H),7.10(d,J=7.4Hz,1H),7.05(t,J=7.4Hz,1H),5.97–5.84(m,1H),5.09(d,J=10.1Hz,1H),4.97(d,J=17.2Hz,1H),3.31(d,J=5.8Hz,2H).13C NMR(126MHz,CDCl3)δ163.57(s),136.99(s),135.25(s),134.93(s),132.14(s),129.55(s),129.32(s),127.91(s),127.48(s),126.50(s),124.64(s),122.86(s),115.80(s),35.91(s).
4f
收率83%,纯度99.99%,1H NMR(400MHz,CDCl3)δ8.04(d,J=8.0Hz,1H),7.87(d,J=26.7Hz,1H),7.83–7.71(m,2H),7.36–7.27(m,1H),7.22(dd,J=7.5,1.4Hz,1H),7.14(td,J=7.5,1.1Hz,1H),7.04–6.89(m,2H),6.05(ddt,J=16.1,10.2,5.9Hz,1H),5.28–5.19(m,1H),5.12(ddd,J=17.2,3.3,1.6Hz,1H),3.88(s,3H),3.46(d,J=5.9Hz,2H),1.61(s,1H).13C NMR(126MHz,CDCl3)δ165.02(s),162.48(s),136.48(s),136.36(s),130.34(s),129.74(s),128.88(s),127.61(s),127.14(s),125.09(s),123.46(s),116.84(s),113.98(s),55.47(s),37.12(s).
4g
收率66%,纯度99.98%,1H NMR(500MHz,CDCl3)δ8.04(d,J=5.0Hz,1H),7.55(s,1H),7.46(s,1H),7.32(d,J=6.8Hz,1H),7.22(d,J=7.5Hz,1H),7.16(t,J=7.4Hz,1H),7.02–6.89(m,2H),5.97(dq,J=11.1,6.0Hz,1H),5.14(d,J=10.1Hz,1H),5.00(d,J=17.2Hz,1H),3.42(d,J=5.7Hz,2H),2.52(s,3H).13C NMR(126MHz,CDCl3)δ167.14(s),163.46(d,J=250.7Hz),140.11(d,J=8.2Hz),136.07(s),136.01(s),132.47(s),130.42(s),129.91(s),128.69(d,J=8.8Hz),127.62(s),125.56(s),123.41(s),118.20(d,J=21.4Hz),116.81(s),112.76(d,J=21.4Hz),36.89(s),20.16(s).
4h
收率55%,纯度99.99%,1H NMR(400MHz,CDCl3)δ8.06(d,J=7.0Hz,1H),7.59(s,1H),7.35–7.27(m,2H),7.24–7.20(m,1H),7.15(d,J=8.3Hz,3H),5.98(ddt,J=16.3,10.2,6.0Hz,1H),5.15(dd,J=10.1,1.4Hz,1H),5.02(dd,J=17.2,1.6Hz,1H),3.42(d,J=6.0Hz,2H),2.48(s,3H),2.36(s,3H).13C NMR(101MHz,CDCl3)δ168.26(s),136.21(s),136.05(s),135.47(s),133.43(s),131.29(s),130.99(s),130.33(s),130.00(s),127.56(s),127.31(s),125.39(s),123.43(s),116.73(s),36.83(s),20.88(s),19.50(s).
4i
收率74%,纯度99.99%,1H NMR(500MHz,CDCl3)δ8.19(s,1H),7.89(d,J=8.0Hz,1H),7.41(s,1H),7.35(d,J=7.6Hz,1H),7.30(t,J=7.9Hz,1H),7.23(t,J=7.7Hz,1H),7.17(d,J=7.4Hz,1H),7.11(t,J=7.4Hz,1H),7.02(d,J=8.1Hz,1H),5.96(dq,J=11.1,6.0Hz,1H),5.16(d,J=10.1Hz,1H),5.06(d,J=17.2Hz,1H),3.77(s,3H),3.38(d,J=6.0Hz,2H).13C NMR(126MHz,CDCl3)δ165.59(s),159.95(s),136.31(s),136.27(s),136.18(s),130.89(s),130.28(s),129.74(s),127.44(s),125.55(s),124.01(s),118.90(s),118.00(s),116.82(s),112.55(s),55.40(s),36.86(s).
4j
收率78%,纯度99.97%,1H NMR(400MHz,CDCl3)δ7.98(d,J=8.2Hz,1H),7.96(s,1H),7.89–7.82(m,2H),7.35–7.28(m,1H),7.24-7.21(m,1H),7.18-7.13(m,3H),6.04(ddt,J=16.2,10.2,6.0Hz,1H),5.23(dd,J=10.1,1.6Hz,1H),5.10(dd,J=17.2,1.7Hz,1H),3.45(d,J=5.9Hz,2H).13C NMR(101MHz,CDCl3)δ164.91(d,J=253.51Hz),164.48(s),136.33(s),136.15(s),131.08(d,J=3.0Hz),130.41(s),130.10(s),129.40(d,J=9.0Hz),127.63(s),125.50(s),123.65(s),116.85(s),115.83(d,J=22.2Hz),,37.07(s).13C NMR(101MHz,CDCl3)δ163.88(d,J=253.5Hz),163.45(s),135.30(s),135.12(s),130.04(d,J=3.0Hz),129.37(s),129.06(s),128.37(d,J=9.0Hz),126.60(s),124.47(s),122.62(s),115.82(s),114.79(d,J=22.2Hz),36.03(s).
4k
收率59%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.90(d,J=7.4Hz,2H),7.68(s,1H),7.57(d,J=7.3Hz,1H),7.49(dd,J=20.6,12.9Hz,2H),7.23–7.06(m,3H),5.96(ddt,J=16.6,10.1,6.2Hz,1H),5.09(dd,J=10.1,1.1Hz,1H),4.96(dd,J=17.1,1.5Hz,1H),3.38(d,J=6.2Hz,2H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ164.68(s),135.89(s),135.30(s),133.29(s),133.07(s),130.76(s),128.11(s),127.70(s),126.66(s),126.51(s),126.20(s),114.90(s),36.06(s),17.54(s).
4l
收率71%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.66–7.57(m,2H),7.42(td,J=7.9,5.7Hz,1H),7.25–7.06(m,4H),5.94(ddt,J=16.5,10.2,6.2Hz,1H),5.08(dd,J=10.1,1.0Hz,1H),4.95(dd,J=17.1,1.4Hz,1H),3.35(d,J=6.2Hz,2H),2.24(s,3H).13C NMR(101MHz,CDCl3)δ164.60(s),162.82(d,J=249.5Hz),136.82(s),136.59(s),136.53(s),136.38(d,J=4.0Hz),136.26(s),133.80(s),130.37(d,J=7.9Hz),129.14(s),127.70(s),122.66(d,J=3.0Hz),118.77(d,J=21.2Hz),115.99(s),114.70(d,J=22.2Hz),37.02(s),18.47(s).
4m
收率55%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.87(t,J=7.9Hz,3H),7.58(t,J=7.3Hz,1H),7.49(t,J=7.6Hz,2H),7.03-6.59(m,2H),6.02(tt,J=16.6,6.0Hz,1H),5.26(d,J=10.1Hz,1H),5.12(d,J=17.2Hz,1H),3.43(d,J=5.9Hz,2H).13CNMR(101MHz,CDCl3)δ164.69(s),159.12(d,J=245.4Hz),134.39(s),133.53(s),132.46(d,J=7.0Hz),130.95(s),130.91(s),127.77(s),126.01(s),124.94(d,J=8.3Hz),116.30(s),115.77(d,J=22.2Hz),113.00(d,J=22.2Hz),35.68(s).
4n
收率85%,纯度99.96%,1H NMR(500MHz,CDCl3)δ7.93–7.82(m,1H),7.46(d,J=11.8Hz,2H),7.06–6.82(m,4H),5.94(ddt,J=16.5,10.4,6.0Hz,1H),5.17(d,J=10.1Hz,1H),5.01(d,J=17.2Hz,1H),3.38(d,J=5.9Hz,2H),2.51(s,3H).13C NMR(126MHz,CDCl3)δ166.23(s),162.48(d,J=250.7Hz),159.17(d,J=245.7Hz),139.12(d,J=8.8Hz),134.13(s),132.15(d,J=6.3Hz),131.10(s),130.71(d,J=2.5Hz),127.63(d,J=9.1Hz),124.66(d,J=7.5Hz),117.23(d,J=21.4Hz),116.30(s),115.88(d,J=22.7Hz),113.07(d,J=22.7Hz),111.78(d,J=21.4Hz),35.58(s),19.13(s).
4o
收率83%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.82–7.72(m,3H),7.43(dd,J=8.7,2.4Hz,2H),7.02–6.88(m,2H),6.05–5.90(m,1H),5.23(dd,J=10.1,1.4Hz,1H),5.08(dd,J=17.2,1.6Hz,1H),3.39(d,J=5.9Hz,2H).13C NMR(101MHz,CDCl3)δ163.70(s),159.22(d,J=246.44Hz),137.21(s),134.42(s),132.55(s),131.86(s),130.70(d,J=2.1Hz),128.02(s),127.44(s),124.98(d,J=8.3Hz),116.34(s),115.86(d,J=8.3Hz),113.07(d,J=22.22Hz),35.72(s).
4p
收率70%,纯度99.98%,1H NMR(400MHz,CDCl3)δ7.85–7.76(m,2H),7.65(d,J=8.2Hz,2H),7.19(d,J=8.1Hz,2H),6.95–6.83(m,2H),5.91(ddt,J=16.2,10.2,6.0Hz,1H),5.15(dd,J=10.1,1.5Hz,1H),5.02(dd,J=17.2,1.6Hz,1H),3.32(d,J=6.0Hz,2H),2.34(s,3H).13C NMR(126MHz,CDCl3)δ165.65(s),160.05(d,J=244.4Hz),142.49(s),135.46(s),133.29(d,J=7.4Hz),132.09(d,J=2.6Hz),131.71(s),129.46(s),127.04(s),125.87(d,J=8.1Hz),117.31(s),116.77(d,J=22.7Hz),114.02(d,J=22.7Hz),36.78(s),21.51(s).
4q
收率91%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.89–7.77(m,4H),7.04–6.86(m,4H),6.00(ddt,J=16.4,10.2,6.0Hz,1H),5.24(dd,J=10.1,1.2Hz,1H),5.10(dd,J=17.2,1.4Hz,1H),3.87(s,3H),3.40(d,J=6.0Hz,2H).13C NMR(126MHz,CDCl3)δ164.19(s),161.52(s),158.98(d,J=244.4Hz),134.50(s),132.22(d,J=7.5Hz),131.14(d,J=2.8Hz),127.87(s),125.71(s),124.87(d,J=8.3Hz),116.25(s),115.73(d,J=22.7Hz),112.98(d,J=22.7Hz),112.96(s),54.44(s),35.75(s).
4r
收率45%,纯度99.99%,1H NMR(400MHz,CDCl3)δ8.00(d,J=8.7Hz,1H),7.84(s,1H),7.80(d,J=8.8Hz,2H),7.30–7.26(m,1H),7.20(d,J=2.4Hz,1H),6.98(t,J=5.8Hz,2H),6.02(ddt,J=16.2,10.3,5.9Hz,1H),5.28(dd,J=10.1,1.4Hz,1H),5.14(dd,J=17.2,1.5Hz,1H),3.87(s,3H),3.41(d,J=5.9Hz,2H).13C NMR(101MHz,CDCl3)δ164.96(s),162.63(s),135.44(s),135.07(s),131.53(s),130.08(s),130.01(s),128.87(s),127.54(s),126.78(s),124.66(s),117.48(s),114.04(s),55.49(s),36.77(s).
4s
收率59%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.86(dd,J=16.9,8.1Hz,4H),7.55(t,J=7.3Hz,1H),7.48(t,J=7.5Hz,2H),7.13(d,J=8.1Hz,1H),7.04(s,1H),6.03(dq,J=10.9,6.0Hz,1H),5.22(d,J=10.1Hz,1H),5.11(d,J=17.2Hz,1H),3.42(d,J=5.8Hz,2H),2.34(s,3H).13C NMR(126MHz,CDCl3)δ164.46(s),135.40(s),134.08(s),133.97(s),132.57(s),130.71(s),129.94(s),129.10(s),127.72(s),127.12(s),125.98(s),122.68(s),115.66(s),36.00(s),19.91(s).
4t
收率82%,纯度99.96%,1H NMR(500MHz,CDCl3)δ7.98(s,1H),7.79(d,J=7.5Hz,1H),7.57(t,J=9.8Hz,2H),7.43(dd,J=13.6,7.8Hz,1H),7.23(td,J=8.3,2.0Hz,1H),7.10(d,J=8.1Hz,1H),7.03(s,1H),6.01(dq,J=10.7,6.0Hz,1H),5.22(d,J=10.1Hz,1H),5.10(d,J=17.2Hz,1H),3.40(d,J=5.9Hz,2H),2.34(s,3H).13C NMR(126MHz,CDCl3)δ164.31(s),162.85(d,J=248.2Hz),137.23(d,J=6.8Hz),136.45(s),135.50(s),133.28(s),131.01(s),130.60(s),130.39(d,J=7.9Hz),128.14(s),123.95(s),122.42(d,J=2.6Hz),118.73(d,J=21.4Hz),116.74(s),114.57(d,J=22.7Hz),36.99(s),20.97(s).
4u
收率65%,纯度99.96%,1H NMR(500MHz,CDCl3)δ8.08(s,1H),7.95(d,J=7.9Hz,1H),7.85-7.84(m,1H),7.70(d,J=7.7Hz,1H),7.51-7.49(m,1H),7.39(t,J=7.9Hz,1H),7.32–7.28(m,1H),7.23-7.21(m,1H),7.18-7.15(m,1H),6.02(dd,J=17.2,10.2Hz,1H),5.24(ddd,J=10.1,3.0,1.5Hz,1H),5.12(ddd,J=17.2,3.4,1.7Hz,1H),3.44(d,J=6.0Hz,2H).
13C NMR(126MHz,CDCl3)δ164.1,136.5,136.2,135.8,134.8,131.7,130.3,130.3,129.9,127.5,127.5,125.6,124.9,123.6,116.9,37.0.
HRMS(ESI+,m/z)calculated for C16H14ClNO[M+H]+:272.0837;found:272.0833;
5b
收率73%,纯度99.98%,1H NMR(400MHz,CDCl3)δ7.52–7.47(m,3H),7.46–7.39(m,2H),7.35(d,J=8.3Hz,1H),7.20(t,J=7.3Hz,1H),7.10(t,J=7.8Hz,1H),6.41(s,1H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ166.92(s),137.24(s),136.80(s),136.41(s),131.97(s),131.74(s),130.35(s),129.93(s),129.26(s),127.36(s),123.69(s),123.59(s),119.78(s),114.81(s),110.34(s),16.17(s).
5c
收率91%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.51–7.41(m,4H),7.35-7.31(m,1H),7.16(t,J=7.2Hz,1H),7.10–6.97(m,2H),6.44(s,1H),2.41(s,3H).13C NMR(126MHz,CDCl3)δ168.46(s),162.65(d,J=249.5Hz),137.78(s),137.63(d,J=7.6Hz),137.01(s),130.53(d,J=7.8Hz),129.62(s),125.43(s),125.41(s),122.91(d,J=3.6Hz),119.94(s),119.88(d,J=21.4Hz),116.58(d,J=22.7Hz),114.26(s),109.08(s),15.80(s).
5d
收率81%,纯度99.98%,1H NMR(500MHz,CDCl3)δ7.64(d,J=7.8Hz,2H),7.48(d,J=7.7Hz,1H),7.30(d,J=7.8Hz,2H),7.17–7.11(m,1H),7.03(d,J=3.8Hz,2H),6.43(s,1H),2.47(s,3H),2.44(s,3H).13C NMR(126MHz,CDCl3)δ169.84(s),143.88(s),138.02(s),137.23(s),132.64(s),130.04(s),129.49(s),129.45(s),122.52(s),122.42(s),119.77(s),114.24(s),108.22(s),21.79(s),15.67(s).
5c
收率62%,纯度99.96%,1H NMR(400MHz,CDCl3)δ7.67(d,J=8.5Hz,2H),7.48(dd,J=8.6,2.0Hz,3H),7.15(t,J=7.4Hz,1H),7.08–6.95(m,2H),6.44(s,1H),2.42(s,3H).13CNMR(126MHz,CDCl3)δ168.69(s),139.38(s),137.86(s),137.00(s),133.82(s),131.23(s),129.58(s),129.16(s),122.80(s),122.79(s),119.95(s),114.18(s),108.82(s),15.76(s).
5f
收率93%,纯度99.98%,1H NMR(500MHz,CDCl3)δ7.73(d,J=8.4Hz,2H),7.48(d,J=7.8Hz,1H),7.14(dt,J=7.8,4.0Hz,1H),7.03(d,J=4.0Hz,2H),6.97(d,J=8.4Hz,2H),6.43(s,1H),3.90(s,3H),2.45(s,3H).13C NMR(126MHz,CDCl3)δ169.21(s),163.65(s),138.03(s),137.26(s),132.45(s),129.41(s),127.43(s),122.39(s),122.23(s),119.78(s),114.03(s),107.83(s),55.58(s),15.45(s).
5g
收率76%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.45(d,J=7.7Hz,1H),7.39(dd,J=8.4,5.8Hz,1H),7.19–7.13(m,1H),7.13–6.94(m,5H),6.41(s,1H),2.32(s,3H),2.31(s,3H).13C NMR(126MHz,CDCl3)δ169.13(s),165.60(d,J=255.78Hz),140.09(d,J=8.6Hz),137.51(s),136.76(s),132.50(d,J=3.2Hz),130.83(d,J=9.1Hz),129.76(s),123.36(s),123.20(s),119.85(s),118.17(d,J=21.4Hz),114.35(s),113.43(d,J=21.4Hz),109.66(s),19.47(d,J=1.2Hz),16.19(s).
5h
收率73%,纯度99.97%,1H NMR(500MHz,CDCl3)δ7.33(d,J=7.7Hz,1H),7.14(d,J=7.5Hz,1H),7.10–7.02(m,4H),6.94(t,J=7.8Hz,1H),6.29(s,1H),2.22(s,3H),2.19(s,3H),2.11(s,3H).13C NMR(126MHz,CDCl3)δ170.37(s),137.65(s),136.84(s),136.34(s),135.99(s),133.21(s),131.91(s),131.09(s),129.76(s),128.60(s),123.32(s),123.09(s),119.69(s),114.57(s),109.49(s),20.85(s),18.73(s),16.25(s).
5i
收率84%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.42(d,J=7.7Hz,1H),7.33(t,J=7.9Hz,1H),7.23-7.202m,2H),7.13-7.09(m,2H),7.06–6.96(m,2H),6.38(s,1H),3.79(s,3H),2.37(s,3H).13C NMR(126MHz,CDCl3)δ169.71(s),159.87(s),137.94(s),137.19(s),136.86(s),129.80(s),129.54(s),122.73(s),122.65(s),122.16(s),119.77(s),119.24(s),114.37(s),114.09(s),108.66(s),55.56(s),15.76(s).
5j
收率79%,纯度99.98%,1H NMR(500MHz,CDCl3)δ7.76(dd,J=8.5,5.5Hz,2H),7.48(d,J=7.8Hz,1H),7.21–7.12(m,3H),7.04(t,J=7.7Hz,1H),6.97(d,J=8.3Hz,1H),6.44(s,1H),2.44(s,3H).13C NMR(126MHz,CDCl3)δ168.61(s),165.60(d,J=255.78Hz),137.92(s),137.08(s),132.48(d,J=9.2Hz),131.60(d,J=3.2Hz),129.56(s),122.71(s),122.66(s),119.94(s),116.06(d,J=22.7Hz),114.11(s),108.63(s),15.66(s).
5k
收率68%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.74(d,J=7.8Hz,2H),7.62(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),7.40(d,J=7.8Hz,1H),7.13(t,J=7.5Hz,1H),6.95(d,J=7.3Hz,1H),6.39(s,1H),2.23(s,3H),2.07(s,3H).13C NMR(126MHz,CDCl3)δ171.11(s),137.01(s),136.97(s),135.71(s),133.84(s),130.38(s),129.93(s),128.93(s),125.58(s),123.02(s),122.49(s),117.71(s),106.17(s),20.41(s),15.10(s).
5l
收率71%,纯度99.99%,1H NMR(400MHz,CDCl3)δ7.51–7.36(m,4H),7.32(t,J=7.9Hz,1H),7.13(t,J=7.5Hz,1H),6.96(d,J=7.2Hz,1H),6.39(s,1H),2.22(s,3H),2.06(s,3H).13C NMR(126MHz,CDCl3)δ169.71(s),162.73(d,J=249.5Hz),137.82(d,J=6.8Hz),136.91(s),136.80(s),130.58(d,J=7.8Hz),130.01(s),126.13(d,J=3.1Hz),125.83(s),123.01(s),122.78(s),120.90(d,J=21.4Hz),117.81(s),116.99(d,J=22.7Hz),106.70(s),20.46(s),15.13(s).
5m
收率69%,纯度99.98%,1H NMR(400MHz,CDCl3)δ7.70(d,J=7.5Hz,2H),7.64(t,J=7.4Hz,1H),7.50(t,J=7.6Hz,2H),7.12(dd,J=8.8,2.2Hz,1H),7.00(dd,J=8.9,4.4Hz,1H),6.76(td,J=9.1,2.3Hz,1H),6.38(s,1H),2.37(s,3H).13C NMR(101MHz,CDCl3)δ168.61(s),158.19(d,J=240.4Hz),138.57(s),134.32(s),132.50(s),131.94(s),129.35(s),128.62(s),127.79(s),114.12(d,J=9.1Hz),109.4(d,J=25.2Hz),107.34(d,J=3.8Hz),104.22(d,J=24.2Hz),14.86(s).
5n
收率72%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.37(dd,J=8.4,5.7Hz,1H),7.15(dd,J=9.1,4.5Hz,1H),7.10(dd,J=8.7,2.6Hz,1H),7.06–6.95(m,2H),6.80(td,J=9.1,2.6Hz,1H),6.36(s,1H),2.30(s,3H),2.25(d,J=0.5Hz,3H).13C NMR(126MHz,CDCl3)δ168.85(s),163.63(d,J=253.3Hz),169.49(d,J=240.7Hz),140.06(d,J=8.6Hz),139.06(s),133.15(s),132.27(d,J=3.2Hz),130.75(d,J=9.4Hz),118.20(d,J=21.4Hz),115.43(d,J=9.1Hz),113.46(d,J=21.4Hz),110.92(d,J=25.2Hz),109.41(d,J=3.7Hz),105.42(d,J=23.9Hz),19.34(d,J=1.1Hz),16.19(s).
5o
收率67%,纯度99.97%,1H NMR(500MHz,CDCl3)δ7.71–7.60(m,2H),7.57–7.41(m,2H),7.12(dd,J=8.8,2.6Hz,1H),6.99(dd,J=9.0,4.4Hz,1H),6.78(td,J=9.1,2.6Hz,1H),6.39(s,1H),2.38(d,J=0.9Hz,3H).13C NMR(126MHz,CDCl3)δ168.47(s),159.27(d,J=239.4Hz),139.52(s),139.46(s),133.58(s),133.37(s),131.15(s),130.49(d,J=10.0Hz),129.22(s),115.05(d,J=9.2Hz),110.54(d,J=25.2Hz),108.63(d,J=3.7Hz),105.43(d,J=23.9Hz),15.92(s).
5p
收率65%,纯度99.98%,1H NMR(400MHz,CDCl3)δ7.61(d,J=7.8Hz,2H),7.29(d,J=7.8Hz,2H),7.12(d,J=8.9Hz,1H),7.00(dd,J=9.0,4.4Hz,1H),6.76(t,J=9.1Hz,1H),6.37(s,1H),2.47(s,3H),2.39(s,3H).13C NMR(101MHz,CDCl3)δ169.58(s),159.11(d,J=239.4Hz),144.00(s),139.64(s),133.58(s),132.39(s),130.32(d,J=10.1Hz),129.94(s),129.48(s),115.03(d,J=9.2Hz),110.21(d,J=25.2Hz),107.99(d,J=3.8Hz),105.15(d,J=23.2Hz),21.76(s),15.77(s).
5q
收率77%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.70(d,J=8.5Hz,2H),7.12(dd,J=8.9,2.5Hz,1H),6.97(dd,J=9.1,3.1Hz,3H),6.75(td,J=9.1,2.4Hz,1H),6.37(s,1H),3.90(s,3H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ167.90(s),162.69(s),157.98(d,J=239.4Hz),138.63(s),132.58(s),131.34(s),129.16(d,J=10.0Hz),126.11(s),113.73(d,J=9.1Hz),113.04(s),109.07(d,J=25.2Hz),106.57(d,J=3.9Hz),104.08(d,J=23.2Hz),54.53(s),14.51(s).
5r
收率75%,纯度99.98%,1H NMR(500MHz,CDCl3)δ7.77–7.62(m,2H),7.44(d,J=2.0Hz,1H),7.02–6.87(m,4H),6.36(s,1H),3.90(s,3H),2.43(d,J=0.9Hz,3H).13C NMR(126MHz,CDCl3)δ167.82(s),162.81(s),138.44(s),134.54(s),131.44(s),129.50(s),126.75(s),125.89(s),121.43(s),118.25(s),113.86(s),113.08(s),106.01(s),54.56(s),14.40(s).
5s
收率78%,纯度99.99%,1H NMR(500MHz,CDCl3)δ7.63(d,J=7.8Hz,2H),7.54(t,J=7.4Hz,1H),7.41(t,J=7.5Hz,2H),7.18(s,1H),6.76(q,J=8.5Hz,2H),6.28(s,1H),2.32(s,3H),2.30(s,3H).13C NMR(126MHz,CDCl3)δ169.81(s),138.10(s),135.71(s),135.40(s),132.71(s),132.11(s),129.82(s),129.65(s),128.72(s),123.95(s),119.76(s),114.05(s),108.47(s),21.23(s),15.86(s).
5t
收率75%,纯度99.97%,1H NMR(400MHz,CDCl3)δ7.42-7.37(m,3H),7.30–7.22(m,1H),7.21(s,1H),6.85-6.79(m,2H),6.31(s,1H),2.35(s,3H),2.34(s,3H).13C NMR(101MHz,CDCl3)δ168.34(s),162.65(d,J=250.5Hz),137.90(s),137.80(d,J=7.8Hz),135.27(s),132.44(s),130.48(d,J=7.8Hz),129.91(s),125.34(d,J=3.1Hz),124.21(s),119.92(s),119.69(d,J=21.2Hz),116.51(d,J=23.2Hz),114.01(s),108.99(s),21.23(s),15.87(s).
5u
收率65%,纯度99.97%,1H NMR(500MHz,CDCl3)δ7.73(t,J=1.8Hz,1H),7.64–7.56(m,2H),7.48(d,J=7.7Hz,1H),7.43(t,J=7.9Hz,1H),7.18-7.16(m,1H),7.08–7.00(m,2H),6.45(d,J=0.5Hz,1H),2.41(d,J=1.1Hz,3H).
13C NMR(126MHz,CDCl3)δ168.3,137.6,137.2,134.9,134.9,132.7,130.0,129.5,129.5,127.7,122.9,122.9,120.0,114.2,109.1,15.8.
实验例
一、人前列腺癌细胞毒性抑制实验
实验方法:取对数生长期的前列腺癌细胞C42B,C42B/ENZ,22Rv1,VCaP-CRPC,PC3和DU145消化后接种到96孔板,每个孔100μL,约2000个细胞,置于37℃,5%二氧化碳及饱和湿度条件下培养。24h后,实验组每孔加入含不同浓度梯度的受试化合物的培养基,使其最终的浓度为0.078125μM,0.15625μM,0.3125μM,0.625μM,1.25μM,2.5μM,5μM,10μM和20μM。同时设置不含受试化合物的阴性对照组和阳性对照组,每组设3个复孔,在37℃,5%CO2及饱和湿度条件下继续培养96h。96h后,每个孔加入10μL的cck8。在5%CO2培养箱中继续培养4h。培养结束后,酶标仪450nm波长测定各孔OD值,每次实验平行两次,重复至少三次。按公式计算细胞增殖抑制率。其增殖抑制率=1-(实验组OD值-空白对照组OD值)/(对照组OD值-空白对照组OD值)×100%,并计算IC50值。表1为本发明制备得到的吲哚类衍生物的IC50值,实验结果表明,本发明提供的吲哚类衍生物具有良好的抗肿瘤活性,尤其是化合物CZ-137-1,CZ-199-1,CZ-212-2和CZ-212-3的IC50值接近于1μM,说明所公开的化合物尤其是对前列腺癌具有良好的抑制作用。
表1本发明化合物对肿瘤细胞抑制的IC50值
二、化合物对人前列腺癌的克隆形成的抑制实验
取对数生长期的细胞C42B,22Rv1,VCaP-CRPC,PC3和DU145,配成500个/mL单细胞悬液,于六孔板中每孔加入2mL细胞液。培养24h后更换新鲜的含不同浓度化合物的培养基,同时设置新鲜培养基为实验对照组。化合物的浓度为0,1μM,2μM,4μM,每组设置三个复孔。细胞置于37℃,5%CO2培养箱中继续培养10天。每隔三天换一次含有不同浓度化合物的培养基,培养10天后,取出六孔板,去除上清液,用预冷的PBS洗两遍,每孔加入1mL 4%的多聚甲醛(PA),固定15min后,去除固定液,每孔加入0.1%的结晶紫染色30min,风干后拍照。结果见图10,图10为本发明提供的化合物对前列腺癌细胞平板克隆形成的影响;从图10可以看出,本发明的化合物表现出了良好地抑制前列腺癌细胞克隆的形成。前列腺癌细胞的克隆个数及大小随着化合物浓度的升高而减少,即化合物可以明显地减少前列腺癌细胞的存活率。
三、化合物对Caspase-3活性的检测
取对数生长期的C42B,VCaP-CRPC细胞,配置成单细胞悬液,并稀释到细胞密度为5×104cells/mL,在六孔板中每孔加入2mL单细胞悬液,即1×105cells/孔,在37℃,5%CO2细胞培养箱中培养过夜。24h后加入不同浓度的化合物(0,1μM,2μM,4μM)继续培养24h,然后收集细胞,在收集的沉淀细胞中加入100μL Lysis Buffer,吹打均匀;冰上裂解30min,涡旋振荡6次,每次10秒。4℃,10000rpm,离心15min。吸取上清25μL蛋白质裂解液(保证加药组和对照组蛋白含量相同),加入25μL Caspase-3Substrate Reaction Buffer反应液,摇床震荡10min,然后测其Caspase-3的荧光值,剩余的蛋白裂解液于37℃孵育30min,酶标仪测量562nm下的OD值(蛋白浓度通过Bradford法测得),Caspase-3的荧光值与蛋白浓度的OD值的比值代表Caspase-3的活化程度。结果如图11,图11为本发明所述的化合物对前列腺癌细胞Caspase-3活性的影响,从图中可以看出,本申请的化合物化合物5q和化合物5r可以活化凋亡中的关键酶Caspase-3的活性。在经过化合物2μM,4μM浓度处理后,细胞Caspase-3活性比对照组增加了大约2-4倍。与对照组相比,有显著性差异(P<0.05,P<0.001)。
四、化合物诱导肿瘤细胞凋亡的研究取对数生长期的C42B,VCaP-CRPC细胞,制成细胞浓度为1.0×105/mL的细胞悬液,接种于6孔板中,每孔加入2mL的细胞悬液,使每孔的细胞数为2.0×105个,置于5%二氧化碳,37℃和饱和湿度的条件下培养,让其贴壁。然后加入不同浓度的化合物(0,1μM,2μM和4μM),继续培养24小时。用细胞刮将贴壁的细胞刮下来,收集到相对应的EP管中。于4℃,5000rpm离心5min,除去上清液,每孔加入120μL的细胞裂解液(配制细胞裂解液按RIPA∶PMSF∶磷酸酶抑制剂A∶磷酸酶抑制剂B=100∶1∶1∶1混合),冰上裂解15min。裂解完后的细胞,于4℃,15000rpm离心15min,收集好的蛋白裂解液用Bradford法测定蛋白的浓度,并由此计算出相同质量下的不同浓度蛋白的上样体积。根据Tris-甘氨酸SDS聚丙烯酰胺凝胶电泳获得实验结果,如图12所示,图12为本发明提供的化合物诱导前列腺癌细胞凋亡的影响;从图12Western blot检测结果显示,不同浓度的化合物作用于人前列腺癌细胞24小时后,PARP被分割出现89kDa的碎片;与图11中Caspase-3被激活相对应,活化后的Caspase-3将PARP剪切,从而使PARP失去其酶活力,导致肿瘤细胞确实发生了凋亡。
五、化合物抑制小鼠体内肿瘤生长的研究
将人源细胞22Rv1接种于scid小鼠皮下,约2周后,以每组7只小鼠,将小鼠随机二分组,分别为对照组、50mg/kg CZ化合物抑制剂组每天给药,给药方式为腹腔注射。使用游标卡尺三天称量一次体重,并用食指轻摸小鼠腹部,观察肿瘤大小。药物处理3周后,将小鼠处死,取出瘤子称重、拍照,结果如图13所示所示,图13为本发明所述的化合物对小鼠体内前列腺癌的影响,从图13可以看出,化合物CZ-212-3在体内可以抑制小鼠肿瘤的生长,而且对小鼠的体重没有影响。与对照组相比,**P<0.05
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (2)
1.一种吲哚类化合物的合成方法,包括:
将式(II)结构的化合物、醋酸钯、苯醌类化合物和有机酸溶于溶剂中反应,得到式(I)结构的化合物;
其中,所述R1-2、R1-4、R1-6独立的选自氢、C1~C6的烷基、C1~C6的烷氧基;
所述R1-3、R1-5独立的选自氢或卤素;
且所述R1-2、R1-3、R1-4、R1-5、R1-6不同时为氢;
所述R2-0选自CH2;
所述R2-2选自甲基;
所述R2-3选自氢、C1~C6的烷基或C1~C6的烷氧基;
所述R2-4选自氢、C1~C6的烷基或C1~C6的烷氧基;
所述R2-5选自氢、C1~C6的烷氧基或卤素;
所述R2-6选自氢、C1~C6的烷基或C1~C6的烷氧基;
所述R2-7选自氢、C1~C6的烷基或C1~C6的烷氧基;
所述苯醌类化合物为苯醌,2, 6- 二甲基苯醌或2,3-二氰基-5,6-二氯苯醌;
所述有机酸为磷酸二丁酯和二苯基磷酸中的一种或两种。
2.根据权利要求1所述的合成方法,其特征在于,所述溶剂为DMSO、THF、二氧六环、DMF和甲苯中的一种或几种。
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