CN114105892B - Fak/plk1双靶标的喹唑啉衍生物及其制备方法和用途 - Google Patents
Fak/plk1双靶标的喹唑啉衍生物及其制备方法和用途 Download PDFInfo
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- CN114105892B CN114105892B CN202111474730.1A CN202111474730A CN114105892B CN 114105892 B CN114105892 B CN 114105892B CN 202111474730 A CN202111474730 A CN 202111474730A CN 114105892 B CN114105892 B CN 114105892B
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- fak
- plk1
- quinazoline derivative
- quinazoline
- dimethyl
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Abstract
本发明公开了FAK/PLK1双靶标的喹唑啉衍生物及其制备方法和用途,涉及含喹唑啉骨架的FAK/PLK1双靶标抑制剂。FAK/PLK1双靶标的喹唑啉衍生物,其结构式如式I所示。本发明的FAK/PLK1双靶标喹唑啉衍生物对癌细胞具有明显的抑制作用,所用原料便宜,简单易得,反应步骤少,适合工业化生产,是一类具有巨大潜力的药品。
Description
技术领域
本发明涉及含喹唑啉骨架的FAK/PLK1双靶标抑制剂,具体涉及FAK/PLK1双靶标的喹唑啉衍生物及其制备方法和用途。
背景技术
喹唑啉类化合物作为一个含氨杂环类小分子化合物,具有多种生物活性,特别是在抗肿瘤活性方面。
PLK1(Polo-like Kinase 1)属于Polo样激酶家族,是一类广泛存在于真核细胞中的丝氨酸/苏氨酸激酶。PLK1在多种肿瘤类型中高表达,是肿瘤的生物标志物和肿瘤治疗靶点。PLK1与一些重要的肿瘤相关蛋白相互作用并调节其功能,进而影响肿瘤的恶性行为,如肿瘤的增殖及侵袭转移等,所以与肿瘤的预后不良密切相关。目前已报道了PLK1调控网络中下游信号通路及上游调控。PLK1有望成为肿瘤免疫治疗的有效靶点。
黏着斑激酶(Focal adhesion kinase,FAK)在黑色素瘤、卵巢癌、前列腺癌、乳腺癌等多种恶性肿瘤中高表达,并且其表达水平与肿瘤的增殖、侵袭、迁移等密切相关,已被认为是能够抑制恶性肿瘤转移的潜在治疗性靶标。FAK激酶抑制剂在肿瘤治疗中已获得一定进展,但在抑制肿瘤转移方面的效果并不是太好,到目前为止,还没有FAK抑制剂被批准上市。总的来说,如果能够开发新型抑制剂,在抑制FAK活性的同时能够阻断FAK介导的相关信号通路或具有其他代偿信号通路,能够与FAK信号通路优势互补,极有可能克服针对FAK靶标的肿瘤细胞转移难题。
公开号为CN1481370A的申请专利公开了喹唑啉衍生物,含该化合物的药物组合物,其用途及其制备方法,其发明是关于通式(1)的喹唑啉衍生物,其互变异构体,立体异构体及其盐,特别是其与无机或有机的酸或碱所形成的生理上可接受的盐,其中化合物是有有价值药理性质,特别是对因酪氨酸激酶所引起的信号转导有抑制效果,其发明还关于其在治疗疾病,特别是肿瘤疾病及肺与呼吸道疾病上的用途,及其制备方法。
公开号为CN101619043A的申请专利公开了喹唑啉衍生物及其医药用途,其提供了一种喹唑啉衍生物及其医药用途,具体地说涉及一种可以治疗肿瘤的表皮生长因子受体(Epidermal GrowthFactor Receptor,EGFR)活性抑制剂。其发明的喹唑啉衍生物或其药学上可接受的盐、水合物或前药与EGFR接触,可以有效地抑制该受体的活性,也可用于制备抑制EGFR活性的药物。因此,治疗有效量的一种或几种其发明的化合物或其药学上可接受的盐、水合物或前药可用于治疗由于EGFR的过度表达或过度增活所引起的肿瘤。
目前,开发高活性、高成药性的新型FAK/PLK1双靶点抑制剂还未见报道。
发明内容
本发明针对当前恶性肿瘤转移的难题,基于FAK抑制肿瘤转移产生机制的研究成果,提出筛选FAK/PLK1双靶点小分子抑制剂作为新的解决方案。FAK和PLK1抑制剂可以优势互补,能够协同发挥抗肿瘤作用,双靶点抑制剂的开发具有单靶点药物所不具有的治疗上的优势。
目前已经报道,FAK在卵巢癌、黑色素瘤、前列腺癌、乳腺癌、皮肤癌、肝癌、脑癌、骨肉瘤、胶质母细胞瘤、神经母细胞瘤、食管癌、结肠癌、鳞状喉细胞癌多种恶性肿瘤中高表达,并且其表达水平与肿瘤的增殖、侵袭、迁移等密切相关,并形成相关的疾病;PLK1在乳腺癌、结肠癌、直肠癌、子宫内膜癌、食道癌、头颈鳞状细胞癌、黑色素瘤、非小细胞肺癌、口咽癌、卵巢癌、胰腺癌、前列腺癌、乳头腺癌多种恶性肿瘤中高表达,并且其表达水平与肿瘤的增殖、侵袭、迁移等密切相关,并形成相关的疾病。FAK和PLK1已被认为能够抑制恶性肿瘤转移的潜在治疗性靶标。
本发明基于FAK和PLK1与各自配体的晶体复合物结构,借助各种计算软件研究各自抑制剂的结构相似性与差异性,筛选出活性骨架,进而分别与FAK和PLK1蛋白晶体复合物中的活性位点进行对接。本发明的目的是开发高活性、高成药性的新型FAK/PLK1双靶点抑制剂,为后续的相关机制研究提供质量可靠的工具化合物。
本发明采用最合理的CDOCKER程序,将每个系列小分子化合物与靶标结合的自由能作为评价对接结果的依据,选取与两个靶标蛋白均具有良好结合能力的活性小分子进行合成。筛选出一种FAK/PLK1双靶标的喹唑啉衍生物,其结构式如式I所示:
式(I)中,R是H原子或者R为H原子被单取代、双取代、三取代、四取代或五取代,且R选自卤素、硝基、甲基、甲氧基、卤素取代的甲基和卤素取代的甲氧基。其中卤素取代的甲基和卤素取代的甲氧基包括1、2、3卤素取代,其中卤素为氯、溴、氟或碘。
优选的,R为单取代或双取代。
具体的,R为2,6-二甲基、2,3-二甲基、2,4-二甲基、2,5-二甲基、3,4-二甲基、3,5-二甲基、3,6-二甲基、2-氟、3-氟、4-氟、3-甲基、2-甲基、4-甲基、2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、3,6-二甲氧基、2,6-二甲氧基、2-三氟甲氧基、3-三氟甲氧基、4-三氟甲氧基、2-三氟甲基、3-三氟甲基、4-三氟甲基、2-硝基、3-硝基或4-硝基。
优选的,所述R为2,6-二甲基、4-氟、3-甲基、2-甲基、4-三氟甲氧基或4-硝基。
本发明喹唑啉衍生物是FAK/PLK1双靶点抑制剂,如图3所示,
(1)在活性骨架与FAK晶体结构的结合模式中(图3左),喹唑啉骨架左边苯环上的N原子(图3左中实线方框圈出部分左侧的N原子)与FAK蛋白上的氨基酸残基Cys502形成氢键,称为骨干氢键;右边环上与苯环桥联的N原子(图3左中实线方框圈出部分右侧的N原子)与DFG(天冬氨酸、苯丙氨酸、甘氨酸)活化环上的Asp564形成氢键。与喹唑啉类抑制剂的结合导致FAK激酶区的激活环区域完全紊乱,从而特异性的抑制剂FAK活性。此外,哌嗪骨架可以与氨基酸残基Arg426形成氢键,苯环上的取代基(图3左中虚线圆圈圈出)可以与氨基酸残基Leu567形成相互的疏水作用。
(2)在活性骨架与PLK1晶体结构的结合模式中(图3右),此类化合物能够结合在PLK1的ATP结合位点,其中喹唑啉骨架上左边苯环上的N原子(图3右中实线方框圈出部分左侧苯环上的N原子)通过氢键结合到PLK1蛋白上的氨基酸残基Cys133,和右边苯环上的N原子(图3右中实线方框圈出部分右侧苯环上的N原子)通过氢键结合到PLK1蛋白上的氨基酸残基Asp194,这是化合物具有PLK1抑制活性的关键。此外,哌嗪骨架可以与氨基酸残基Arg57形成氢键,苯环上的取代基(图3右中虚线圆圈圈出)可以与氨基酸残基Leu130形成相互的疏水作用。
由此可见,此类结构对FAK和PLK1均具有较好的亲和性。
本发明还提供了一种药物,含有上述的喹唑啉衍生物。
本发明含有苯胺结构的喹唑啉衍生物对癌细胞具有明显的抑制作用,因此本发明的含有苯胺结构的喹唑啉衍生物可以用于制备抗癌(如乳腺癌、宫颈癌)药物。药物还含有药学上可添加的辅料,制成相适应的剂型。
本发明还提供了上述喹唑啉衍生物在制备用于治疗FAK/PLK1蛋白过表达或活性增强引起的疾病的药物中的应用。
具体的,所述疾病为黑色素瘤、骨肉瘤、胶质母细胞瘤或神经母细胞瘤,或者乳腺、结肠、肺、前列腺、直肠、卵巢、皮肤、肝、脑、食管、食道、喉、子宫内膜、头颈、咽或胰腺部位的癌。
本发明又提供了上述喹唑啉衍生物的制备方法,包括如下步骤:
(1)将喹唑啉类化合物溶于溶剂中,加入哌嗪类化合物和碱进行反应,制得产物a;
(2)碱存在下,将产物a、钯催化剂以及配体溶于有机溶剂中,加入不同取代基的苯胺进行反应,制得所述的喹唑啉衍生物;
其中,步骤(1)中溶剂为醇类溶剂;步骤(2)中有机溶剂为芳香烃类有机溶剂,不同取代基的苯胺中,取代基为所述R基团。
优选的,所述喹唑啉类化合物为4,7-二氯喹唑啉,哌嗪类化合物为1-甲基哌嗪,其中喹唑啉类化合物与哌嗪类化合物的摩尔比为1:1-1.5。
优选的,所述碱为碳酸钾、三乙胺、叔丁醇钠、碳酸铯、叔丁醇钾或氢化钠。
优选的,所述钯催化剂为三(二亚苄基丙酮)二钯、四(三苯基膦)钯或双(三苯基膦)二氯化钯;配体为1,1'-双(二苯基膦)二茂铁。
优选的,产物a与不同取代基苯胺的摩尔比为1:1-10。
有益效果:
本发明的FAK/PLK1双靶标喹唑啉衍生物对癌细胞具有明显的抑制作用,所用原料便宜,简单易得,反应步骤少,适合工业化生产,是一类具有巨大潜力的药品。
附图说明
图1为喹唑啉衍生物的结构式。
图2为虚拟筛选及筛选所得FAK/PLK1双靶点抑制剂过程图。
图3为活性骨架分别与FAK和PLK1晶体结构活性中心的可能作用模式图;左图为活性骨架与FAK晶体结构活性中心的作用模式图;右图为活性骨架与PLK1晶体结构活性中心的作用模式图。
图4为化合物1的结构式;a为产物a的结构式;b为化合物1的结构式。
图5为化合物2的结构式。
图6为化合物3的结构式。
图7为化合物4的结构式。
图8为化合物5的结构式。
图9为化合物6的结构式。
具体实施方式
本发明含有苯胺结构的喹唑啉衍生物,其设计思路为:
从Protein Data Bank(RSCB PDB)网站获得FAK和PLK1晶体结构,选取代表性晶体复合物,利用计算机辅助药物设计软件总结出FAK/PLK1双靶点抑制剂的基本药效团模型,进而将这些活性骨架分别与FAK和PLK1蛋白晶体复合物中的活性位点进行模拟对接。根据前期研究基础,我们采用最合理的CDOCKER程序,将每个系列小分子化合物与靶标结合的自由能作为评价对接结果的依据,选取与两个靶标蛋白均具有良好结合能力的活性小分子进行合成。筛选出的小分子化学结构式如图1所示,虚拟筛选及筛选所得FAK/PLK1双靶点抑制剂过程图如图2所示。
合理药物设计及计算机辅助药物设计思路:
计算机模拟对接分析结果显示:
(1)在活性骨架与FAK晶体结构的结合模式中(图3左),喹唑啉骨架左边苯环上的N原子(图3左中实线方框圈出部分左侧的N原子)与FAK蛋白上的氨基酸残基Cys502形成氢键,称为骨干氢键;右边环上与苯环桥联的N原子(图3左中实线方框圈出部分右侧的N原子)与DFG(天冬氨酸、苯丙氨酸、甘氨酸)活化环中的Asp564残基形成氢键。与喹唑啉类抑制剂的结合导致FAK激酶区的激活环区域完全紊乱,从而特异性的抑制剂FAK活性。此外,哌嗪骨架可以与氨基酸残基Arg426形成氢键,苯环上的取代基(图3左中虚线圆圈圈出)可以与氨基酸残基Leu567形成相互的疏水作用。
(2)在活性骨架与PLK1晶体结构的结合模式中(图3右),此类化合物能够结合在PLK1的ATP结合位点,其中喹唑啉骨架上左边苯环上的N原子(图3右中实线方框圈出部分左侧苯环上的N原子)通过氢键结合到PLK1蛋白上的氨基酸残基Cys133,和右边苯环上的N原子(图3右中实线方框圈出部分右侧苯环上的N原子)通过氢键结合到PLK1蛋白上的氨基酸残基Asp194,这是化合物具有PLK1抑制活性的关键。此外,哌嗪骨架可以与氨基酸残基Arg57形成氢键,苯环上的取代基(图3右中虚线圆圈圈出)可以与氨基酸残基Leu130形成相互的疏水作用。
由此可见,此类结构对FAK和PLK1均具有较好的亲和性。
实施例1
化合物1的制备。
(1)将1.2g 4,7-二氯喹唑啉溶解在100mL异丙醇中,加入1-甲基哌嗪816μL,再加入1.5mL三乙胺,85℃回流搅拌12h,反应结束后将反应液减压旋蒸,通过柱层析纯化粗产物(甲醇:二氯甲烷的体积比为1:5),得到纯的产物a,其结构式如图4-a所示。
其中产物a为白色粉末,核磁共振氢谱结果为:1H NMR(400MHz,CDCl3)δ(ppm):2.75(s,3H),3.14(s,4H),4.22-4.25(t,J=5.1Hz,4H),7.48-7.51(m,J=8.9,2.1Hz,1H),7.79-7.82(d,J=8.9Hz,1H),7.96(d,J=2.1Hz,1H),8.77(s,1H)。
(2)称取1mmol产物a,0.05mmol Pd2(dba)3(三(二亚苄基丙酮)二钯),0.1mmoldppf(1,1'-双(二苯基膦)二茂铁),然后加入25mL甲苯,最后加入2mmol叔丁醇钠,使用双排管置换N2,先常温搅拌30min,升温至100℃时注射4mmol 2,6-二甲基苯胺,继续升温至120℃回流搅拌6h。反应结束后反应溶液抽滤浓缩,残渣通过柱层析纯化(甲醇:二氯甲烷体积比为1:10),得到化合物1,其结构式如图4-b所示。核磁共振氢谱结果为:1H NMR(400MHz,CDCl3)δ(ppm):2.24(s,6H),2.39(s,3H),2.61-2.63(t,J=4.8Hz,4H),3.74-3.76(t,J=4.8Hz,4H),5.72(s,1H),6.63-6.64(d,J=2.4Hz,1H),6.81-6.83(m,J=9.0,2.3Hz,1H),7.16(s,3H),7.71-7.73(d,J=9.0Hz,1H),8.56(s,1H)。
实施例2
化合物2的制备。
制备方法同实施例1,在步骤(2)中,以4-氟苯胺代替2,6-二甲基苯胺,得化合物2,其结构式如图5所示。核磁共振氢谱结果为:1H NMR(400MHz,CDCl3)δ(ppm):2.40(s,3H),2.61-2.64(t,J=4.8Hz,4H),3.76-3.79(t,J=4.8Hz,4H),6.27(s,1H),7.00-7.08(m,3H),7.21-7.24(m,3H),7.73-7.75(d,J=9.0Hz,1H),8.60(s,1H)。
实施例3
化合物3的制备。
制备方法同实施例1,在步骤(2)中,以3-甲基苯胺代替2,6-二甲基苯胺,得化合物3,其结构式如图6所示。核磁共振氢谱结果为:1H NMR(400MHz,CDCl3)δ(ppm):2.37-2.40(d,J=13.9Hz,6H),2.62-2.64(t,J=4.8Hz,4H),3.77-3.79(t,J=4.7Hz,4H),6.24(s,1H),6.91-6.93(d,J=7.5Hz,1H),7.05-7.09(m,J=8.0,4.1Hz,3H),7.23-7.26(t,J=7.7Hz,1H),7.37-7.38(d,J=2.4Hz,1H),7.74-7.76(d,J=9.0Hz,1H),8.62(s,1H)。
实施例4
化合物4的制备。
制备方法同实施例1,在步骤(2)中,以2-甲基苯胺代替2,6-二甲基苯胺,得化合物4,其结构式如图7所示。核磁共振氢谱结果为:1H NMR(400MHz,CDCl3)δ(ppm):2.29(s,3H),2.41(s,3H),2.63-2.65(t,J=4.9Hz,4H),3.77-3.80(t,J=4.9Hz,4H),5.94(s,1H),6.99-7.01(m,J=9.0,2.3Hz,1H),7.07(d,J=2.3Hz,1H),7.11-7.13(t,J=7.4Hz,1H),7.21-7.30(m,2H),7.35-7.37(d,J=7.8Hz,1H),7.72-7.75(d,J=9.0Hz,1H),8.59(s,1H)。
实施例5
化合物5的制备。
制备方法同实施例1,在步骤(2)中,以4-三氟甲氧基苯胺代替2,6-二甲基苯胺,得化合物5,其结构式如图8所示。核磁共振氢谱结果为:1H NMR(400MHz,CDCl3)δ(ppm):2.40(s,3H),2.62-2.65(t,J=4.8Hz,4H),3.78-3.81(t,J=4.9Hz,4H),6.34(s,1H),7.07-7.10(m,J=9.1,2.3Hz,1H),7.20-7.22(d,J=8.6Hz,2H),7.25-7.28(d,J=9.1Hz,2H),7.36-7.37(d,J=2.2Hz,1H),7.77-7.79(d,J=8.9Hz,1H),8.63(s,1H)。
实施例6
化合物6的制备。
制备方法同实施例1,在步骤(2)中,以4-硝基苯胺代替2,6-二甲基苯胺,得化合物6,其结构式如图9所示。核磁共振氢谱结果为:1H NMR(400MHz,d-DMSO)δ(ppm):2.27(s,3H),2.52(s,4H),3.71(s,4H),7.36-7.52(d,J=62.6Hz,4H),7.95-8.54(t,J=117.6Hz,4H),9.80(s,1H)。
实施例7
下面是实施例1-6的FAK/PLK1双靶标喹唑啉衍生物抗癌活性的检测研究。
(1)实验材料
1)细胞株
人宫颈癌细胞Hela;人乳腺癌细胞株MCF-7。
2)试剂
DMEM培养基(GIBCO),新生牛血清(杭州四季青生物工程材料),胰蛋白酶(Sigma),10000单位的双抗(Gibco USA),PBS缓冲液(上海源培生物科技股份有限公司)。其它常用化学试剂均为国产分析纯。
(2)实验方法
1)培养基的配制
90mL DMEM培养基(Gibcio USA)培养基加灭活新生牛血清(杭州四季青生物工程材料)10mL以及1mL10000单位的双抗(Gibco USA)即为完全培养液,做好标记,于4℃保存备用。胰蛋白酶用PBS缓冲液配成0.25%溶液,过滤除菌后4℃保存备用。
2)药液的配制
准确称取被测样品1.0mg。加到灭菌的1.5mL离心管中,加入DMSO 1mL,配成1mg/mL原液,-40℃冷冻保存。临用前融化后用适量PBS冲液稀释成相应浓度应用。
3)细胞培养及传代
细胞菌贴壁培养于含10mL完全培养液细胞培养瓶中,于37℃、5%CO2、饱和湿度下培养。细胞长满瓶底后用灭菌的PBS缓冲液洗两次,加入0.25%胰蛋白酶消化细胞1min,倒掉胰蛋白酶,待轻摇细胞能完全脱落后,加完全培养液30mL后,用移液管吹散细胞,分装于3个新的细胞培养瓶中,继续培养。
4)抗癌活性测试
取刚刚长成完整单层的细胞一瓶,胰蛋白酶消化后收集细胞,用移液管吹打均匀,取两滴细胞悬液锥虫蓝(Trypan Blue)染色,与显微镜下计数活细胞数目至1×104个细胞/mL。向96孔培养板中每孔加入90μL细胞悬液,将培养板置于CO2培养箱中培养24h,取出培养板后于每孔中加10μL含不同浓度被测样品的溶液,使得药物终浓度分别为50,25,12.5,6.25,3.125μM,每个浓度设3个平行孔,另设6孔细胞作正常对照孔和阳性对照孔。加完药后培养板于微孔板振荡器上振荡混匀,置于CO2培养箱中继续培养24h。取出培养板,每孔加入10μL 5mg/mL的MTT液,振荡混匀,继续培养4h。加入每孔150μL DMSO后震荡15min。酶标仪测定各孔光吸收(OD值),测定波长570nm。根据各孔OD值通过SPSS软件计算药物对两种细胞增殖的抑制率,即IC50值,实验结果见表1。
表1
由表1可以看出,实施例1-6所制的喹唑啉衍生物对两株细胞增殖均有抑制效果。
Claims (9)
1.一种FAK/PLK1双靶标的喹唑啉衍生物,其结构式如式Ι所示:
式(I)中,R是H原子或者R为H原子被单取代、双取代、三取代、四取代或五取代,且R选自卤素、硝基、甲基、甲氧基、卤素取代的甲基和卤素取代的甲氧基。
2.如权利要求1所述的喹唑啉衍生物,其特征在于,R为单取代或双取代。
3.如权利要求2所述的喹唑啉衍生物,其特征在于,R为2,6-二甲基、2,3-二甲基、2,4-二甲基、2,5-二甲基、3,4-二甲基、3,5-二甲基、3,6-二甲基、2-氟、3-氟、4-氟、3-甲基、2-甲基、4-甲基、2-甲氧基、3-甲氧基、4-甲氧基、2,3-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、3,4-二甲氧基、3,5-二甲氧基、3,6-二甲氧基、2,6-二甲氧基、2-三氟甲氧基、3-三氟甲氧基、4-三氟甲氧基、2-三氟甲基、3-三氟甲基、4-三氟甲基、2-硝基、3-硝基或4-硝基。
4.如权利要求3所述的喹唑啉衍生物,其特征在于,R为2,6-二甲基、4-氟、3-甲基、2-甲基、4-三氟甲氧基或4-硝基。
5.一种药物,含有权利要求1-4任一项所述的喹唑啉衍生物。
6.权利要求1-4任一项所述喹唑啉衍生物在制备用于治疗FAK/PLK1蛋白过表达或活性增强引起的疾病的药物中的应用,所述疾病为人宫颈癌或人乳腺癌。
7.权利要求1-4任一项所述喹唑啉衍生物的制备方法,其特征在于,包括如下步骤:
(1)将喹唑啉类化合物溶于溶剂中,加入哌嗪类化合物和碱进行反应,制得产物a;
(2)碱存在下,将产物a、钯催化剂以及配体溶于有机溶剂中,加入不同取代基的苯胺进行反应,制得所述的喹唑啉衍生物;
其中,步骤(1)中溶剂为醇类溶剂;步骤(2)中有机溶剂为芳香烃类有机溶剂,不同取代基的苯胺中,取代基为所述R基团。
8.如权利要求7所述的制备方法,其特征在于,所述喹唑啉类化合物为4,7-二氯喹唑啉,哌嗪类化合物为1-甲基哌嗪,其中喹唑啉类化合物与哌嗪类化合物的摩尔比为1:1-1.5;产物a与不同取代基苯胺的摩尔比为1:1-10。
9.如权利要求7所述的制备方法,其特征在于,步骤(1)中所述碱为碳酸钾、三乙胺、叔丁醇钠、碳酸铯、叔丁醇钾或氢化钠;步骤(2)中所述钯催化剂为三(二亚苄基丙酮)二钯、四(三苯基膦)钯或双(三苯基膦)二氯化钯;配体为1,1'-双(二苯基膦)二茂铁。
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