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CN115261896B - 一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法 - Google Patents

一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法 Download PDF

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CN115261896B
CN115261896B CN202210978281.2A CN202210978281A CN115261896B CN 115261896 B CN115261896 B CN 115261896B CN 202210978281 A CN202210978281 A CN 202210978281A CN 115261896 B CN115261896 B CN 115261896B
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CN115261896A (zh
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汪太民
李嗣锋
程斌
李蓬
李兴宸
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Li Furong
Wang Jintao
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Abstract

本发明涉及化学合成领域，具体为一种4’‑烷胺基苯甲基‑3‑咪唑并[1,2‑a]吡啶类衍生物的合成方法；本发明使用咪唑并[1,2‑a]吡啶类衍生物和N‑甲基N‑烷基苯胺在电化学氧化下高效合成3‑芳甲基咪唑并[1,2‑a]吡啶类衍生物，该反应是通过N‑甲基提供亚甲基连接前述两者实现的。该反应操作简单简便安全，反应条件温和，方法简洁高效，原料易得，无副产物，化合物官能团容忍度高，且后处理方便，产率普遍较高，产品在制备过程中无需惰性气体保护，底物适用性广、操作简单、适合大量合成。通过Discovery Studio的分子对接技术可助力快速虚拟筛选具有潜在抗癌活性的产物，经细胞实验验证发现有几个产物具有较好的抗乳腺癌、结直肠癌活性。

Description

一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合 成方法
技术领域
本发明涉及化学合成领域，具体为一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法。
背景技术
咪唑并[1,2-a]吡啶是由五元环咪唑和六元环吡啶稠合的氮杂双环化合物(Comprehensive Heterocyclic Chemistry III)，官能化的咪唑并[1,2-a]吡啶展现出良好的生物活性，如具有抗真菌、抗病毒、抗癌、抗炎、抗惊厥、抗癫痫、抗结核、抗溃疡及退热等多种药理活性,还可用于治疗丙型肝炎与艾滋病毒，并在神经学、病毒学等领域发挥着重要作用(J.Med.Chem.2015,23,6087；J.Org.Chem.2012,77,5552；J.Med.Chem.2015,58,8529)。基于咪唑并[1,2-a]吡啶核心骨架已开发出多种上市药物，如安眠药唑吡坦(Zolpidem)和阿吡坦(Alpidem)、血管扩张药奥普力农(Olprinone)、抗溃疡药佐利米定(Zolimidine)和Soraprazan、抗焦虑药阿尔吡登(Alpidem)和沙立吡旦(Saripidem)等。因此，合成咪唑并[1,2-a]吡啶衍生物有利于进一步扩大潜在生物活性分子库。
鉴于咪唑并[1,2-a]吡啶的C-3位因富电子而易于发生亲电取代与自由基取代反应，多种官能团已成功引入到该反应位点，然而其电化学C-3位芳甲基化反应未见报道。目前，仅有两例文献报道咪唑并[1,2-a]吡啶与N,N-二甲基苯胺的C-3位芳甲基化反应，都是通过添加外源性碳源并在过氧化合物作用下实现的。2016年印度国际大学(Visva-BharatiUniversity)Hajra课题组以N,N-二甲基甲酰胺为溶剂及额外的碳源，实现了N,N-二甲基苯胺对2-芳基咪唑并[1,2-a]吡啶C3位的芳基甲基化反应，然而反应需要当量的过硫酸钾为氧化剂并在80摄氏度的高温条件下才能实现(Adv.Synth.Catal.2016,358,3633-3641)；此外，该反应还需要10mol％的碘化亚铜作为催化剂，不利于后期金属残留的除去。2020年，印度中央海洋与盐类研究所(CSIR–Central Salt&Marine Chemicals Research Institute)Adimurthy等人以聚乙二醇400为溶剂及额外的碳源，以过量二乙酸碘苯为氧化剂获得了N,N-二甲基苯胺对2-芳基咪唑并[1,2-a]吡啶C3位的芳基甲基化产物，然而该反应需要在100摄氏度的高温下反应24小时(Eur.J.Org.Chem.2020,2020,3499-3507)。基于此，发展一种高效、绿色的电化学合成路线实现各类N,N-二甲基苯胺对咪唑并[1,2-a]吡啶类衍生物的C-3位芳甲基化反应，有利于获得具有潜在生物活性的氮杂双环化合物。
发明内容
本发明的主要目的在于提供了一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法。
本发明采用的技术方案具体如下：
一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法，4’-N-甲基-N-烷基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物结构式如Ⅰ所示
其中：R1或R2为氢、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6全氟烷基、卤素、C2-C6烷羰基、C6-C12芳基、苄基、C2-C6酯基、C2-C8含烯基取代基、C2-C8含炔基取代基、C2-C10杂环基、硅基、胺基中的任意一种；
R3或R4为C1-C6烷基、C1-C6全氟烷基、C2-C6烷羰基、C6-C12芳基、苄基、C2-C8含烯基取代基、C2-C8含炔基取代基、C2-C10杂环基中的任意一种；
合成方法如下式所示：
式中，化合物Ⅰ制备步骤为：
S1、将化合物Ⅱ、化合物Ⅲ、电解质和添加物置于有机溶剂中，装入阳极和阴极后通入恒定直流电反应；
S2、待化合物II消失完全后，将反应混合物减压条件下除去有机溶剂；
S3、使用硅胶柱层析洗脱得到化合物I。
所述化合物Ⅱ和化合物Ⅲ的摩尔比为Ⅱ:Ⅲ＝1.0:1.2-5.0。
所述阳极为石墨片、石墨棒、网状玻璃碳、玻璃碳、泡沫碳、铂片或铂丝制成的电极。
所述阴极为石墨片、石墨棒、各类碳纸、各类碳布、网状玻璃碳、玻璃碳、各种石墨毡、泡沫碳、铂片、铂丝、镍、铁、不锈钢、铝、锌、锡、钛、铅、钼、铌或钽制成的电极。
所述电解质包括四丁基四氟硼酸铵、四丁基六氟磷酸铵、四丁基高氯酸铵、四丁基碘化铵、四乙基四氟硼酸铵、四乙基六氟磷酸铵、四乙基对甲苯磺酸铵、苯甲酸钠、高氯酸锂、溴化锂、四乙基氯化铵、四丁基四氟硼酸铵、六氟磷酸铵、四甲基醋酸铵、四丁基硫酸氢铵、高氯酸四乙基铵、四丁基氯化铵水合物等，选择其中的一种或多种混合用做电解质。
所述有机溶剂包括苯、二甲苯、四氯化碳、乙酸乙酯、乙腈、氯乙烷、二氯乙烷、1,2-二氯丙烷、1,4-二氧六环、二甲基甲酰胺或二甲基乙酰胺中的任意一种或多种组合。
所述柱层析使用的洗脱液为石油醚和乙酸乙酯的混合液，且体积比V石油醚:V乙酸乙酯＝5:1～1:1。
本发明的有益效果为：(1)本发明提供了一种4’-N-甲基-N-烷基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物，通过利用Discovery Studio的分子对接模块发现与一些靶蛋白有较好结合作用的产物，进而快速筛选出具有去潜在生物活性的小分子。最终，通过细胞实验发现了有几个化合物具有良好的抗乳腺癌、结直肠癌的生物活性。
(2)本发明的制备方法选用电流为无痕迹氧化剂，反应无需催化剂及惰性气体保护、反应步骤少、原料易得、反应条件温和、操作简便安全、底物拓展范围广、化合物官能团容忍度高，产物收率可以达到80％以上。
(3)本发明的高效、绿色合成方法以N-甲基为额外的亚甲基来源，使其生成的产物都为三级胺，还可克级制备4’-N-甲基-N-烷基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物。
附图说明
图1为本发明实施例所得到的产物Ⅰ-1的核磁谱图(氢谱)；
图2为本发明实施例所得到的产物Ⅰ-1的核磁谱图(碳谱)；
图3为本发明实施例所得到的产物Ⅰ-3的核磁谱图(氢谱)；
图4为本发明实施例所得到的产物Ⅰ-3的核磁谱图(碳谱)；
图5为本发明实施例所得到的产物Ⅰ-9的核磁谱图(氢谱)；
图6为本发明实施例所得到的产物Ⅰ-9的核磁谱图(碳谱)；
图7为本发明实施例所得到的产物Ⅰ-1、I-2、I-3、I-6、I-9、I-13、I-17在20μM浓度下对乳腺癌、结直肠癌细胞生存率的影响。
具体实施方式
下面结合附图并通过具体的实施例进一步的说明本发明的技术方案：
以下是本发明制备化合物的最佳实施例。在以下所有实施例中，核磁谱检测通过Bruker400,JEOL400仪器在CDCl3中获得。δ值为内标相对值(CHCl3定标δ7.261H NMR和77.1613C NMR。高分辨质谱(HRMS)通过4G quadrupole time-of-flight(QTof)质谱仪器得到。
实施例1
实施例1的反应式，具体使用的化合物II-1、III-1以及产物Ⅰ-1结构如下，实验表明本发明优选的阳极是铂片，有选的阴极是石墨片，优选的的电解质是溴化锂，优选的的添加物是乙酸，优选的直流电流是6毫安，优选的机溶剂为乙腈，其反应产物的最高收率为80％，最好的原料摩尔比为化合物II和化合物III的摩尔比为II：III＝1:5，其中化合物II应是当量值，反应最优浓度为0.04M。
具体实验步骤是：将39mg(0.20mmol，1.0当量)的化合物II-1、121mg(1.0mmol，5.0当量)化合物III-1、9mg溴化锂(0.1mmol，0.5当量)、及0.5mL乙酸溶于4.5mL的乙腈中，装入铂片阳极和石墨阴极后于6毫安的直流电流下室温反应6小时。反应结束后，将反应混合物在水泵减压下旋转蒸发除去溶剂乙腈。残留物以200-300目硅胶，洗脱液(体积比V石油醚:V乙酸乙酯＝5:1～3:1)柱层析得到Ⅰ-1所示化合物，其产物经过核磁(氢谱、碳谱)、高分辨质谱鉴定。
N,N-Dimethyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(43mg,Yield＝66％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brown paste.1HNMR(400MHz,CDCl3)δ7.84–7.79(m,2H),7.74(dt,J＝6.9,1.2Hz,1H),7.67(dt,J＝9.1,1.1Hz,1H),7.46–7.40(m,2H),7.37–7.32(m,1H),7.16(ddd,J＝9.0,6.7,1.3Hz,1H),7.01(d,J＝8.7Hz,2H),6.72–6.65(m,3H),4.40(s,2H),2.92(s,6H)；13CNMR(100MHz,CDCl3)δ149.73,144.92,143.94,134.78,128.72,128.50,128.35,127.73,124.30,124.14,123.76,118.62,117.54,113.25,112.16,40.78,29.00；HRMS(ESI)m/z:[M+H]+Calcd forC22H22N3328.1808；Found 328.1808.
化合物I-2
N,N,3-Trimethyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(42mg,Yield＝59％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brown paste.1HNMR(400MHz,CDCl3)δ7.78–7.74(m,2H),7.70(dt,J＝9.0,1.1Hz,1H),7.66(dt,J＝6.9,1.2Hz,1H),7.44–7.39(m,2H),7.35–7.31(m,1H),7.18(ddd,J＝9.1,6.7,1.3Hz,1H),6.72–6.68(m,2H),6.54(d,J＝8.5Hz,1H),6.41(dd,J＝8.5,2.8Hz,1H),4.28(s,2H),2.91(s,6H),2.41(s,3H)；13C NMR(100MHz,CDCl3)δ149.73,144.94,144.16,137.03,134.73,128.68,128.24,127.65,127.57,124.08,123.67,122.40,118.30,117.52,115.06,112.17,110.66,40.73,26.83,20.40；HRMS(ESI)m/z:[M+H]+Calcd for C23H24N3342.1965；Found342.1963.
化合物I-3
N-Methyl-N-pentyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(45mg,Yield＝59％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brownpaste.1H NMR(400MHz,CDCl3)δ7.84–7.80(m,2H),7.76(dt,J＝6.9,1.2Hz,1H),7.68(dt,J＝9.0,1.1Hz,1H),7.46–7.40(m,2H),7.37–7.32(m,1H),7.17(ddd,J＝9.1,6.7,1.2Hz,1H),6.99(d,J＝8.7Hz,2H),6.70(td,J＝6.8,1.2Hz,1H),6.65–6.59(m,2H),4.39(s,2H),3.26(t,J＝7.5Hz,2H),2.89(s,3H),1.61–1.51(m,2H),1.37–1.24(m,4H),0.89(t,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)δ148.46,144.86,143.83,134.75,128.71,128.57,128.35,127.72,124.16,123.82,123.36,118.72,117.50,112.62,112.16,52.97,38.41,29.45,28.96,26.47,22.72,14.22；HRMS(ESI)m/z:[M+H]+Calcd for C26H30N3384.2434；Found 384.2437.
化合物I-4
4-((2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(49mg,Yield＝69％,Rf＝0.2(PE/EA＝5:1))was isolated as a lightbrown paste.1H NMR(400MHz,CDCl3)δ7.80–7.68(m,3H),7.65(dt,J＝9.1,1.2Hz,1H),7.17–7.09(m,1H),7.03–6.92(m,4H),6.70–6.62(m,3H),4.36(s,2H),3.82(s,3H),2.90(s,6H)；13C NMR(100MHz,CDCl3)δ159.34,149.66,144.75,143.72,129.45,128.43,127.35,124.35,123.91,123.57,117.87,117.25,114.13,113.20,111.97,55.35,40.72,28.93；HRMS(ESI)m/z:[M+H]+Calcd for C23H24N3O 358.1914；Found 358.1916.
化合物I-5
4-((2-(3-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(42mg,Yield＝59％,Rf＝0.2(PE/EA＝5:1))was isolated as a lightbrown paste.1H NMR(400MHz,CDCl3)δ7.75(dt,J＝6.9,1.2Hz,1H),7.67(dt,J＝9.1,1.2Hz,1H),7.40(dd,J＝2.7,1.5Hz,1H),7.37–7.32(m,2H),7.17(ddd,J＝9.1,6.7,1.3Hz,1H),7.03–6.98(m,2H),6.90(ddd,J＝7.9,2.6,1.4Hz,1H),6.72–6.65(m,3H),4.41(s,2H),3.82(s,3H),2.91(s,6H)；13C NMR(100MHz,CDCl3)δ159.98,149.74,144.86,143.83,136.19,129.68,128.51,124.36,124.16,123.75,120.73,118.84,117.59,114.16,113.28,112.20,55.44,40.80,29.04(1C is merged with other peaks)；HRMS(ESI)m/z:[M+H]+Calcd for C23H24N3O 358.1914；Found 358.1915.
化合物I-6
N,N-Dimethyl-4-((2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(42mg,Yield＝61％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brown paste.1HNMR(400MHz,CDCl3)δ7.75–7.63(m,4H),7.27–7.22(m,2H),7.18–7.11(m,1H),7.01(d,J＝12.2Hz,2H),6.72–6.62(m,3H),4.38(s,2H),2.91(s,6H),2.39(s,3H)；13C NMR(100MHz,CDCl3)δ149.68,144.81,143.93,137.45,131.85,129.41,128.48,128.18,124.38,123.98,123.65,118.31,117.39,113.21,112.03,40.74,28.99,21.37；HRMS(ESI)m/z:[M+H]+Calcdfor C23H24N3342.1965；Found 342.1962.
化合物I-7
4-((2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(46mg,Yield＝67％,Rf＝0.3(PE/EA＝2:1))was isolated as a lightbrown solid；mp94–95℃.1H NMR(400MHz,CDCl3)δ7.78–7.72(m,3H),7.66(dt,J＝9.1,1.2Hz,1H),7.17(ddd,J＝9.1,6.7,1.3Hz,1H),7.14–7.08(m,2H),7.02–6.96(m,2H),6.73–6.65(m,3H),4.36(s,2H),2.91(s,6H).；13C NMR(100MHz,CDCl3)δ162.64(d,J＝245.4Hz),149.76,144.87,143.03,130.89(d,J＝3.3Hz),129.97(d,J＝8.1Hz),128.42,124.30,124.04,123.75,118.41,117.47,115.66(d,J＝21.4Hz),113.24,112.27,40.75,28.90；19FNMR(376MHz,CDCl3)δ–114.50.HRMS(ESI)m/z:[M+H]+Calcd for C22H21N3F 346.1714；Found346.1712.
化合物I-8
4-((2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(37mg,Yield＝51％,Rf＝0.3(PE/EA＝2:1))was isolated as a lightbrown solid；mp 124–126℃.1H NMR(400MHz,CDCl3)δ7.76–7.71(m,3H),7.66(dt,J＝9.1,1.1Hz,1H),7.41–7.36(m,2H),7.18(ddd,J＝9.1,6.7,1.3Hz,1H),7.00–6.96(m,2H),6.71(td,J＝6.7,1.1Hz,1H),6.69–6.65(m,2H),4.37(s,2H),2.91(s,6H)；13C NMR(100MHz,CDCl3)δ149.79,144.97,142.77,133.66,133.33,129.53,128.91,128.43,124.40,123.94,123.76,118.80,117.56,113.26,112.34,40.74,28.94；HRMS(ESI)m/z:[M+H]+Calcd forC22H21N3Cl 362.1419；Found 362.1415.
化合物I-9
4-((2-(3-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(37mg,Yield＝51％,Rf＝0.25(PE/EA＝5:1))was isolated as a lightbrown paste.1H NMR(400MHz,CDCl3)δ7.89–7.85(m,1H),7.75(dt,J＝6.8,1.2Hz,1H),7.68–7.62(m,2H),7.36–7.29(m,2H),7.18(ddd,J＝9.0,6.7,1.3Hz,1H),7.02–6.96(m,2H),6.75–6.65(m,3H),4.39(s,2H),2.91(s,6H)；13C NMR(100MHz,CDCl3)δ149.78,144.96,142.49,136.71,134.73,129.91,128.47,128.40,127.76,126.30,124.46,123.93,123.83,119.18,117.66,113.27,112.38,40.75,28.96.；HRMS(ESI)m/z:[M+H]+Calcd forC22H21N3Cl 362.1419；Found 362.1417.
化合物I-10
4-((2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(55mg,Yield＝68％,Rf＝0.25(PE/EA＝5:1))was isolated as a lightbrown solid；mp108–110℃.1H NMR(400MHz,CDCl3)δ7.73(dt,J＝6.9,1.2Hz,1H),7.70–7.63(m,3H),7.56–7.50(m,2H),7.17(ddd,J＝9.1,6.7,1.3Hz,1H),7.01–6.94(m,2H),6.73–6.62(m,3H),4.35(s,2H),2.91(s,6H)；13C NMR(100MHz,CDCl3)δ149.74,144.92,142.68,133.73,131.81,129.79,128.38,124.40,123.84,123.71,121.85,118.81,117.51,113.21,112.32,40.69,28.89；HRMS(ESI)m/z:[M+H]+Calcd for C22H21N3Br 406.0913；Found 406.0914.
化合物I-11
N,N-Dimethyl-4-((2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(40mg,Yield＝50％,Rf＝0.25(PE/EA＝5:1))was isolated as alight brown paste.1H NMR(400MHz,CDCl3)δ7.92(d,J＝7.9Hz,2H),7.78(dt,J＝6.8,1.2Hz,1H),7.71–7.65(m,3H),7.21(ddd,J＝9.1,6.7,1.2Hz,1H),7.03–6.96(m,2H),6.74(td,J＝6.8,1.2Hz,1H),6.70–6.65(m,2H),4.41(s,2H),2.92(s,6H)；13C NMR(100MHz,CDCl3)δ149.84,145.09,142.37,138.39,129.38(q,J＝21.7Hz),128.42,125.65(q,J＝3.8Hz),124.69,124.45(q,J＝271.0Hz),123.84,123.71,119.57,117.75,115.02,113.28,112.56,40.72,28.95；19F NMR(376MHz,CDCl3)δ–62.30.HRMS(ESI)m/z:[M+H]+Calcd forC23H21N3F3396.1682；Found396.1683.
化合物I-12
N,N-Dimethyl-4-((2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(46mg,Yield＝61％,Rf＝0.2(PE/EA＝5:1))was isolated as a lightbrown paste.1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.97(dd,J＝8.5,1.8Hz,1H),7.93–7.83(m,3H),7.79(dt,J＝6.9,1.2Hz,1H),7.73(dt,J＝9.0,1.1Hz,1H),7.51–7.45(m,2H),7.20(ddd,J＝9.0,6.7,1.3Hz,1H),7.01(d,J＝8.6Hz,2H),6.76–6.67(m,3H),4.48(s,2H),2.93(s,6H)；13C NMR(100MHz,CDCl3)δ149.71,144.96,143.70,133.65,132.92,132.20,128.52,128.45,128.29,127.74,127.15,126.41,126.17,126.04,124.27,123.73,119.09,117.48,113.25,112.23,40.73,29.09(1C is merged with other peaks)；HRMS(ESI)m/z:[M+H]+Calcd for C26H24N3378.1965；Found 378.1962.
化合物I-13
N,N-Dimethyl-4-((2-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)methyl)aniline(47mg,Yield＝70％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brownpaste.1H NMR(400MHz,CDCl3)δ7.75(dt,J＝7.0,1.2Hz,1H),7.63(dt,J＝9.1,1.1Hz,1H),7.42(dd,J＝3.6,1.1Hz,1H),7.34(dd,J＝5.1,1.1Hz,1H),7.14(ddd,J＝9.2,6.7,1.3Hz,1H),7.08(dd,J＝5.1,3.6Hz,1H),7.05–6.99(m,2H),6.70–6.62(m,3H),4.44(s,2H),2.89(s,6H)；13C NMR(100MHz,CDCl3)δ149.71,144.77,138.31,137.85,128.53,127.79,125.47,124.55,124.37,123.83,123.45,118.32,117.31,113.16,112.29,40.70,28.95；HRMS(ESI)m/z:[M+H]+Calcd for C20H20N3S 334.1372；Found 334.1375.
化合物I-14
4-((7-Methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(57mg,Yield＝80％,Rf＝0.25(PE/EA＝5:1))was isolated as a lightbrown paste.1H NMR(400MHz,CDCl3)δ7.81–7.77(m,2H),7.54(dd,J＝7.5,0.7Hz,1H),7.44–7.38(m,2H),7.35–7.29(m,1H),7.04–6.98(m,2H),6.95(d,J＝2.6Hz,1H),6.69–6.63(m,2H),6.40(dd,J＝7.4,2.5Hz,1H),4.34(s,2H),3.85(s,3H),2.91(s,6H)；13C NMR(100MHz,CDCl3)δ157.73,149.66,146.19,143.10,134.89,128.64,128.45,128.02,127.46,124.55,124.22,117.35,113.20,107.08,94.72,55.54,40.75,28.89；HRMS(ESI)m/z:[M+H]+Calcd for C23H24N3O 358.1914；Found 358.1912.化合物I-15
N,N-Dimethyl-4-((8-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(40mg,Yield＝59％,Rf＝0.4(PE/EA＝5:1))was isolated as a light brownsolid；mp91–92℃.1H NMR(400MHz,CDCl3)δ7.82–7.78(m,2H),7.62(d,J＝6.9Hz,1H),7.45–7.40(m,2H),7.35–7.31(m,1H),7.03–6.98(m,2H),6.96(d,J＝6.9Hz,1H),6.70–6.65(m,2H),6.62(t,J＝6.8Hz,1H),4.37(s,2H),2.91(s,6H),2.69(s,3H)；13C NMR(100MHz,CDCl3)δ149.65,145.34,143.54,135.09,128.68,128.53,127.55,127.45,124.66,122.91,121.63,118.94,113.22,112.13,40.79,29.08,17.32(1C is merged with other peaks)；HRMS(ESI)m/z:[M+H]+Calcd for C23H24N3 342.1965；Found 342.1966.
化合物I-16
N,N-Dimethyl-4-((7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(40mg,Yield＝59％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brownpaste.1H NMR(400MHz,CDCl3)δ7.83–7.78(m,2H),7.60(d,J＝7.0Hz,1H),7.44–7.39(m,3H),7.35–7.30(m,1H),7.02–6.98(m,2H),6.69–6.65(m,2H),6.51(dd,J＝6.9,1.7Hz,1H),4.36(s,2H),2.91(s,6H),2.37(s,3H)；13C NMR(100MHz,CDCl3)δ149.65,145.28,143.44,134.99,134.90,128.62,128.44,128.22,127.52,124.52,122.94,117.94,115.86,114.72,113.19,40.72,28.90,21.38；HRMS(ESI)m/z:[M+H]+Calcd for C23H24N3342.1965；Found342.1962.
化合物I-17
N,N-Dimethyl-4-((6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(31mg,Yield＝46％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brownsolid；mp 148–150℃.1H NMR(400MHz,CDCl3)δ7.82–7.77(m,2H),7.58(dd,J＝9.2,1.0Hz,1H),7.54–7.51(m,1H),7.44–7.39(m,2H),7.35–7.29(m,1H),7.04–6.99(m,3H),6.72–6.65(m,2H),4.37(s,2H),2.92(s,6H),2.24(d,J＝1.1Hz,3H)；13CNMR(100MHz,CDCl3)δ149.63,143.96,143.65,134.89,128.65,128.45,128.16,127.53,127.30,124.51,121.72,121.23,118.28,116.84,113.21,40.75,28.90,18.52；HRMS(ESI)m/z:[M+H]+Calcd forC23H24N3342.1965；Found 342.1966.
化合物I-18
N,N-Dimethyl-4-((5-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)aniline(23mg,Yield＝34％,Rf＝0.25(PE/EA＝5:1))was isolated as a light brownpaste.1H NMR(400MHz,CDCl3)δ7.70–7.66(m,2H),7.54(dt,J＝8.9,1.0Hz,1H),7.40–7.35(m,2H),7.34–7.30(m,1H),7.03(dd,J＝9.0,6.8Hz,1H),6.91–6.87(m,2H),6.72–6.65(m,2H),6.40(dt,J＝6.8,1.1Hz,1H),4.56(s,2H),2.92(s,6H),2.64(s,3H)；13C NMR(100MHz,CDCl3)δ149.29,146.86,145.60,136.59,135.04,128.91,128.75,128.50,128.31,127.63,124.45,119.89,115.88,113.50,113.29,40.76,30.76,20.18；HRMS(ESI)m/z:[M+H]+Calcdfor C23H24N3342.1965；Found342.1966.
化合物I-19
4-((7-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-N,N-dimethylaniline(39mg,Yield＝54％,Rf＝0.3(PE/EA＝5:1))was isolated as a lightbrown paste.1H NMR(400MHz,CDCl3)δ7.81–7.75(m,2H),7.68–7.61(m,2H),7.46–7.41(m,2H),7.38–7.34(m,1H),7.01–6.96(m,2H),6.71–6.64(m,3H),4.38(s,2H),2.92(s,6H)；13CNMR(100MHz,CDCl3)δ149.81,144.81,144.61,134.35,130.67,128.79,128.45,128.32,127.99,124.09,123.73,118.97,116.36,113.74,113.26,40.73,28.94；HRMS(ESI)m/z:[M+H]+Calcd for C22H21N3Cl 362.1419；Found 362.1416.
生物活性测定
利用生命科学预测工具Discovery Studio(DS)的药物发现和设计模块，将产物与含有靶蛋白的单晶结构的靶蛋白活性位点进行虚拟对接，以CDOCKER相互作用能排序筛选出产物Ⅰ-1、I-2、I-3、I-6、I-9、I-13、I-17具有潜在的抗乳腺癌、结直肠癌活性。其后，细胞实验发现有几个产物具有较好的抗癌活性，实验方法如下：
于96孔板中接种乳腺癌和肠癌细胞系，5000个细胞/孔，24小时后去除培养液，加入含有20μM化合物(或等量溶剂，DMSO)的细胞培养液200μL，细胞培养72小时候去除含药培养液，每孔加入10μL CCK-8试剂与100μL细胞培养液混合物，培养1小时后利用酶标仪测定培养液的吸光度(OD450)，细胞生存率％＝OD450加药组/OD450溶剂对照组×100％。
测试结果如图7所示，图7中显示化合物I-3、I-3、I-6有较好的抗乳腺癌活性，而化合物I-1能够较显著地抑制乳腺癌、结直肠癌细胞的生长，说明该类C3位芳甲基咪唑并[1,2-a]吡啶类衍生物在生物活性的应用有一定的前景。
对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。

Claims (2)

1.一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法，4’-N-甲基-N-烷基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物结构式如Ⅰ所示
其中：R1或R2为氢、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6全氟烷基、卤素、C2-C6烷羰基、C6-C12芳基、苄基、C2-C6酯基、C2-C8含烯基取代基、C2-C8含炔基取代基、C2-C10杂环基、硅基、胺基中的任意一种；
R3或R4为C1-C6烷基、C1-C6全氟烷基、C2-C6烷羰基、C6-C12芳基、苄基、C2-C8含烯基取代基、C2-C8含炔基取代基、C2-C10杂环基中的任意一种；
其特征在于，合成方法如下式所示：
式中，化合物Ⅰ制备步骤为：
S1、将化合物Ⅱ、化合物Ⅲ、电解质和添加物置于有机溶剂中，装入阳极和阴极后通入恒定直流电反应；
S2、待化合物II消失完全后，将反应混合物减压条件下除去有机溶剂；
S3、使用硅胶柱层析洗脱得到化合物I；
所述化合物Ⅱ和化合物Ⅲ的摩尔比为Ⅱ:Ⅲ＝1.0:1.2-5.0；
其中，阳极为铂片，阴极为石墨片，电解质为溴化锂，有机溶剂为乙腈，添加物为乙酸。
2.根据权利要求1所述的一种4’-烷胺基苯甲基-3-咪唑并[1,2-a]吡啶类衍生物的合成方法，其特征在于：所述柱层析使用的洗脱液为石油醚和乙酸乙酯的混合液，且体积比V石油醚:V乙酸乙酯＝5:1～1:1。
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