CN115322126B - 一种多芳烃类化合物及其制备方法和应用 - Google Patents
一种多芳烃类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于多芳烃类衍生物制备技术领域,具体涉及一种多芳烃类化合物及其制备方法和应用。本发明的多芳烃类化合物具有MDM2抑制活性,进一步激活p53,有效的抑制肿瘤细胞的增殖,能用于制备治疗与MDM2相关肿瘤的药物;本发明还提供了一种多芳烃类化合物的制备方法,该合成方法简单,反应条件温和,适合放大生产,易于为进一步研究提供原料。
Description
技术领域
本发明属于多芳烃类衍生物制备技术领域,具体涉及一种多芳烃类化合物及其制备方法和应用。
背景技术
恶性肿瘤是人类疾病死亡的主要原因之一,p53是一种关键的抑癌基因,可通过多种途径抑制肿瘤的生长,包括抑制细胞分化、促进细胞凋亡、衰老以及细胞自噬。人类50%左右的肿瘤中存在高表达的MDM2(murine double minute 2),能够直接与p53结合,使p53失活。因此抑制MDM2的高表达,从而抑制肿瘤细胞中MDM2-p53复合物的形成,使p53发挥正常的生物功能,是一种抑制肿瘤的有效途径。
目前针对MDM2-p53已有几个抑制剂进入临床研究,但是MDM2-p53抑制剂的种类有限,发展新型的MDM2-p53抑制剂用于抗肿瘤药物的研究具有重要的意义。
发明内容
针对上述现有技术的不足,本发明的目的是提供一种多芳烃类化合物及其制备方法和应用,该多芳烃类化合物具有MDM2抑制活性,进一步激活p53,有效的抑制肿瘤细胞的增殖,能用于制备治疗与MDM2相关肿瘤的药物。
为解决上述技术问题,本发明采用如下技术方案:
其中,R1和R2分别独立的选自氢、卤素、C1-C6的烷基;
R3选自氢、卤素、羟基、硝基、C1-C6的烷基、烷氧基、氰基、三氟甲基中的一种。
本发明还保护了多芳烃类化合物的制备方法,包括如下步骤:
本发明还保护了多芳烃类化合物在制备MDM2抑制剂中的应用。
与现有技术相比,本发明具有的有益效果是:
(1)本发明提供了一种多芳烃类化合物的制备方法,该合成方法简单,反应条件温和,适合放大生产,易于为进一步研究提供原料。
(2)本发明提供了一种多芳烃类化合物的应用,该类化合物能够显著抑制MDM2的活性,从而使p53的抗肿瘤功能被激活,有效的抑制肿瘤细胞增殖,对抗肿瘤药物的研发具有一定的价值。
附图说明
图1为本发明实施例2制得的多芳烃化合物2的氢谱图;
图2为本发明实施例2制得的多芳烃化合物2的碳谱图;
图3为本发明实施例2制得的多芳烃化合物2的高分辨质谱图;
图4为本发明实施例3制得的多芳烃化合物3的氢谱图;
图5为本发明实施例3制得的多芳烃化合物3的碳谱图;
图6为本发明实施例3制得的多芳烃化合物3的高分辨质谱图。
具体实施方式
下面对本发明的具体实施方式进行详细描述,但应当理解本发明的保护范围并不受具体实施方式的限制。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的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。本发明各实施例中所述实验方法,如无特殊说明,均为常规方法。
多芳烃类化合物的合成路线如下所示:
实施例1
多芳烃类化合物1的制备方法,包括如下步骤:
将苯磺酰氯(4.19g,0.0237mol)和4-氯苯胺(3.78g,0.0296mol)置于100mL茄形瓶,加入60mL二氯甲烷搅拌溶解,加入吡啶(1.91mL,0.0237mol),室温条件下搅拌2h;将反应液转移至250mL分液漏斗,分别用稀盐酸、饱和食盐水各洗涤1次,无水硫酸镁干燥有机层,除去硫酸镁,浓缩得粗品,柱层析分离纯化(PE:EA=8:1),得白色固体a15.41 g,收率为85.2%;1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.76(d,J=7.3Hz,2H),7.65–7.40(m,3H),7.29(d,J=8.7Hz,2H),7.10(d,J=8.7Hz,2H);13C NMR(101MHz,DMSO-d6)δ139.63,137.13,133.53,129.80,129.61,128.67,127.10,122.07;HRMS calcd for C12H11ClNO2S(M+H)+268.0199,found 268.0200.
将固体a1(2.09g,0.0078mol)置于50mL茄型瓶中,加入25mLN,N-二甲基甲酰胺搅拌溶解,加入溴乙酸甲酯(1.19g,0.0078mol),搅拌10min后加入碳酸钾(2.16g,0.0156mol),室温搅拌2h,将反应液缓慢倒入冰水浴中并搅拌,出现白色絮状沉淀,抽滤,得固体b1,干燥称重2.46g,收率92.7%;1H NMR(400MHz,DMSO-d6)δ7.72–7.65(m,3H),7.58(t,J=7.6Hz,2H),7.41(d,J=8.6Hz,2H),7.19(d,J=8.6Hz,2H),4.56(s,2H),3.62(s,3H);13CNMR(101MHz,DMSO-d6)δ169.46,138.80,138.50,133.93,132.88,130.29,129.84,129.56,127.69,52.58,52.41;HRMS calcd for C15H14ClNNaO4S(M+Na)+362.0230,found 362.0233.
将固体b1(2.15g,0.0063mol)置于50mL茄型瓶中,加入20mL甲醇搅拌溶解,加入氢氧化钠(0.51g,0.0126mol),室温搅拌1.5h,浓缩反应液,加水搅拌使固体溶解,滤去不溶物,滤液用浓盐酸调pH至2-3,抽滤,得白色固体c1,干燥称重1.69g,收率82.5%;1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),7.67(dd,J=18.8,7.3Hz,3H),7.58(t,J=7.6Hz,2H),7.40(d,J=8.7Hz,2H),7.19(d,J=8.7Hz,2H),4.43(s,2H);13C NMR(101MHz,DMSO-d6)δ170.22,138.96,138.65,133.82,132.64,130.19,129.80,129.45,127.65,52.43;HRMScalcd for C14H12ClNNaO4S(M+Na)+348.0073,found 348.0075.
(4)化合物1的合成:
取固体c1(0.26g,0.79mmol)置于25mL茄型瓶中,加入10mL干燥二氯甲烷搅拌溶解,依次加入2-氯苯酚(0.10g,0.79mmol),DMAP(0.097g,0.79mmol),EDCI(0.15g,0.79mmol),室温搅拌2.5h,将反应液转移到100mL分液漏斗中,依次用稀盐酸、饱和食盐水洗涤,有机层用无水硫酸镁干燥过夜,滤除硫酸镁,浓缩得粗品1,柱层析分离纯化(PE:EA=15:1),得白色固体10.22g,收率64.2%;1H NMR(400MHz,DMSO-d6)δ7.71(dd,J=7.2,5.5Hz,3H),7.63–7.54(m,3H),7.47–7.37(m,3H),7.29(ddd,J=17.0,13.0,8.3Hz,4H),4.96(s,2H);13C NMR(101MHz,DMSO-d6)δ167.20,146.57,138.59,138.36,134.05,133.08,130.65,130.35,129.89,129.64,129.02,128.41,127.79,126.08,124.38,52.41;HRMS calcd forC20H15Cl2NNaO4S(M+Na)+457.9997,found 458.0000。
实施例2
多芳烃类化合物2的制备方法,包括如下步骤:与实施例1的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物2,收率67.3%;1HNMR(400MHz,DMSO-d6)δ7.72(dd,J=10.2,4.1Hz,3H),7.60(dd,J=8.1,7.3Hz,2H),7.45(dd,J=9.9,7.7Hz,3H),7.37(dd,J=8.1,1.0Hz,1H),7.25(dd,J=6.6,4.9Hz,3H),7.09(ddd,J=8.1,2.1,0.9Hz,1H),4.86(s,2H);13C NMR(101MHz,DMSO-d6)δ167.83,151.15,138.78,138.29,134.07,133.85,133.02,131.55,130.26,129.91,129.67,127.80,126.81,122.37,120.99,52.73;HRMS calcd for C20H15Cl2NNaO4S(M+Na)+457.9997,found457.9999。
实施例3
多芳烃类化合物3的制备方法,包括如下步骤:与实施例1的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物3,收率63.8%;1H NMR(400MHz,DMSO-d6)δ7.72(dd,J=10.6,4.3Hz,3H),7.64–7.55(m,2H),7.53–7.39(m,4H),7.23(d,J=8.7Hz,2H),7.18–7.09(m,2H),4.85(s,2H);13C NMR(101MHz,DMSO-d6)δ167.91,149.27,138.79,138.29,134.06,133.01,130.77,130.25,130.02,129.90,129.67,127.78,123.89,52.74;HRMS calcd for C20H15Cl2NNaO4S(M+Na)+457.9997,found 457.9996。
实施例4
多芳烃类化合物4的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的2-氯苯磺酰氯,得到化合物a2,收率83.3%;1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.05(d,J=7.8Hz,1H),7.61(d,J=3.0Hz,2H),7.52–7.50(m,1H),7.27(d,J=8.7Hz,2H),7.12(d,J=8.8Hz,2H);13C NMR(101MHz,DMSO-d6)δ136.66,136.49,135.24,132.36,132.08,131.19,129.62,128.48,128.22,121.21;HRMS calcd for C12H9Cl2NO2SNa(M+Na)+323.9629,found323.9633.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a2,得到化合物b2,收率90.9%;1H NMR(400MHz,DMSO-d6)δ7.84–7.82(m,1H),7.72(d,J=7.5Hz,1H),7.66(dd,J=10.9,4.2Hz,1H),7.46(t,J=7.5Hz,1H),7.39(d,J=8.7Hz,2H),7.29(d,J=8.7Hz,2H),4.74(s,2H),3.65(s,3H);13C NMR(101MHz,DMSO-d6)δ169.72,138.04,136.41,135.50,133.07,132.63,132.48,131.36,130.40,129.71,128.31,53.33,52.65;HRMScalcd for C15H13Cl2NNaO4S(M+Na)+395.9840,found 395.9842.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b2,得到化合物c2,收率85.5%;1H NMR(400MHz,DMSO-d6)δ7.71(d,J=7.7Hz,1H),7.65(t,J=7.1Hz,1H),7.56(s,1H),7.51–7.44(m,1H),7.38(d,J=8.6Hz,2H),7.28(d,J=8.7Hz,2H),4.61(s,2H);13C NMR(101MHz,DMSO-d6)δ170.47,138.24,136.63,135.41,133.55,132.83,132.61,132.39,131.32,130.49,130.31,129.91,129.62,128.29,125.39,53.49;HRMScalcd for C14H11Cl2NNaO4S(M+Na)+381.9684,found 381.9682.
(4)化合物4的合成:
与实施例1的制备步骤相同,不同之处仅在于,将c1替换为等物质的量的c2,得化合物4,收率70.1%;1HNMR(400MHz,DMSO-d6)δ7.86(dd,J=8.0,1.5Hz,1H),7.75(dd,J=8.0,1.1Hz,1H),7.68(td,J=7.7,1.6Hz,1H),7.58(dd,J=7.9,1.5Hz,1H),7.48(td,J=7.9,1.2Hz,1H),7.44–7.39(m,3H),7.36–7.29(m,4H),5.13(s,2H);13C NMR(101MHz,DMSO-d6)δ167.50,146.56,137.79,136.19,135.66,133.24,132.69,132.60,131.44,130.67,130.43,129.82,129.07,128.47,128.38,126.07,124.43,53.22;HRMS calcd forC20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9611。
实施例5
多芳烃类化合物5的制备方法,包括如下步骤:与实施例4的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物5,收率67.3%;1H NMR(400MHz,DMSO-d6)δ7.86(dd,J=7.9,1.5Hz,1H),7.75(dd,J=8.0,1.0Hz,1H),7.68(td,J=7.7,1.4Hz,1H),7.48–7.42(m,4H),7.39–7.29(m,4H),7.12(ddd,J=8.1,2.1,0.9Hz,1H),5.04(s,2H);13C NMR(101MHz,DMSO-d6)δ168.12,151.13,137.97,136.22,135.65,133.87,133.20,132.69,132.58,131.57,131.42,130.40,129.83,128.39,126.85,122.41,121.02,53.57;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9611。
实施例6
多芳烃类化合物6的制备方法,包括如下步骤:与实施例4的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物6,收率71.9%;1H NMR(400MHz,DMSO-d6)δ7.85(dd,J=7.9,1.1Hz,1H),7.74(d,J=7.4Hz,1H),7.70–7.65(m,1H),7.49(d,J=8.7Hz,3H),7.42(d,J=8.7Hz,2H),7.32(d,J=8.8Hz,2H),7.16(d,J=8.7Hz,2H),5.04(s,2H);13C NMR(101MHz,DMSO-d6)δ168.18,149.25,137.98,136.23,135.65,133.19,132.69,132.57,131.41,130.81,130.39,130.04,129.83,129.59,128.39,123.92,117.38,53.58;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found491.9599。
实施例7
多芳烃类化合物7的制备方法,包括如下步骤:与实施例4的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的2-甲基苯酚,得化合物7,收率63.7%;1H NMR(600MHz,DMSO):δ1H NMR(400MHz,DMSO-d6)δ7.87(dd,J=7.9,1.4Hz,1H),7.75(dd,J=8.0,1.0Hz,1H),7.68(td,J=7.7,1.5Hz,1H),7.51–7.49(m,1H),7.44–7.42(m,2H),7.36–7.34(m,2H),7.29–7.27(m,1H),7.21(ddd,J=12.2,7.4,1.5Hz,2H),7.04–7.02(m,1H),5.08(s,2H),2.01(s,3H);13C NMR(101MHz,DMSO-d6)δ168.02,149.18,138.05,136.28,135.63,133.12,132.70,132.55,131.56,131.42,130.28,130.18,129.81,128.39,127.56,126.80,122.22,53.42,15.96;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found472.0156。
实施例8
多芳烃类化合物8的制备方法,包括如下步骤:与实施例4的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-甲基苯酚为原料,得化合物8,收率74.8%;1HNMR(400MHz,DMSO-d6)δ7.86(dd,J=8.0,1.5Hz,1H),7.75(dd,J=8.0,1.1Hz,1H),7.68(td,J=7.7,1.6Hz,1H),7.50–7.42(m,3H),7.35–7.28(m,3H),7.09(d,J=7.6Hz,1H),6.91(d,J=5.4Hz,1H),6.58–6.53(m,1H),5.02(s,2H),2.30(s,3H);13C NMR(101MHz,DMSO-d6)δ168.27,150.48,139.87,138.03,136.29,135.62,133.16,132.69,132.56,131.42,130.41,129.82,129.80,129.57,128.38,127.30,122.31,120.04,118.90,116.30,112.77,53.60,21.21;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0155。
实施例9
多芳烃类化合物9的制备方法,包括如下步骤:与实施例4的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-甲基苯酚,得化合物9,收率66.5%;1H NMR(400MHz,DMSO-d6)δ7.86(dd,J=8.0,1.5Hz,1H),7.75(dd,J=8.0,1.1Hz,1H),7.68(td,J=7.7,1.5Hz,1H),7.50–7.46(m,1H),7.44–7.41(m,2H),7.33(d,J=8.8Hz,2H),7.21(d,J=8.3Hz,2H),6.98(d,J=8.4Hz,2H),5.02(s,2H),2.29(s,3H);13C NMR(101MHz,DMSO-d6)δ168.34,148.31,138.03,136.30,135.85,135.61,133.16,132.68,132.56,131.42,130.41,129.81,128.38,121.59,53.59,20.84;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found472.0157。
实施例10
多芳烃类化合物10的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的3-氯苯磺酰氯,将4-氯苯胺替换为等物质的量的2-氯苯胺,得到化合物a3,收率79.5%;1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),7.70(d,J=8.6Hz,2H),7.63(d,J=8.7Hz,2H),7.41(d,J=7.8Hz,1H),7.34–7.15(m,3H);13C NMR(101MHz,DMSO-d6)δ139.70,138.27,133.63,130.43,129.89,129.83,129.06,128.46,128.32;C12H10NO2SCl2(M+H)+301.9809,found301.9808.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a3,得到化合物b3,收率90.9%;1H NMR(400MHz,DMSO-d6)δ7.73–7.64(m,4H),7.55–7.46(m,2H),7.46–7.35(m,2H),3.61(s,3H),3.34(s,2H);13C NMR(101MHz,DMSO-d6)δ169.42,138.80,138.57,136.07,133.84,133.79,131.12,130.90,129.88,129.72,128.37,52.54,51.84;C15H13NO4NaSCl2(M+Na)+395.9840,found 395.9843.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b3,得到化合物c3,收率88.1%;1H NMR(400MHz,DMSO-d6)δ7.76–7.66(m,2H),7.64(dd,J=8.6,1.8Hz,2H),7.56–7.45(m,2H),7.43–7.30(m,2H),4.27(s,2H);13C NMR(101MHz,DMSO-d6)δ170.26,139.09,138.50,136.34,134.08,133.86,130.86,130.75,129.73,129.69,128.15,52.24;C14H11NO4NaSCl2(M+Na)+381.9684,found381.9687.
(4)化合物10的合成:
与实施例1的制备步骤相同,不同之处仅在于,将c1替换为等物质的量的c3,得化合物10,收率73.7%;1H NMR(400MHz,DMSO-d6):δ7.76(d,J=8.5Hz,2H),7.67(d,J=8.5Hz,2H),7.55(d,J=8.0Hz,1H),7.51–7.48(m,1H),7.45–7.41(m,3H),7.36(d,J=8.1Hz,1H),7.22(s,1H),7.09(d,J=8.2Hz,1H),4.85(s,2H);13C NMR(101MHz,DMSO-d6):δ165.93,141.19,139.52,137.08,134.21,133.29,131.92,131.14,129.65,129.32,129.05,128.08,127.91,126.59,124.88,120.43,119.07,117.13,115.10,112.76,50.20;HRMS calcd forC20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9611。
实施例11
多芳烃类化合物11的制备方法,包括如下步骤:与实施例10的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物11,收率76.1%;1H NMR(400MHz,DMSO-d6):δ7.77–7.74(m,2H),7.67(dd,J=6.9,1.9Hz,2H),7.54(dd,J=7.8,2.1Hz,1H),7.51–7.47(m,3H),7.44–7.40(m,2H),7.13(dd,J=6.9,2.0Hz,2H),4.85(s,2H);13C NMR(101MHz,DMSO-d6):δ168.50,136.85,136.16,135.68,135.21,131.56,129.50,129.29,128.81,128.56,128.32,127.92,127.69,127.45,127.23,126.26,121.98,121.45,49.72;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9610。
实施例12
多芳烃类化合物12的制备方法,包括如下步骤:与实施例10的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物12,收率70.7%;1H NMR(400MHz,DMSO-d6):δ7.77–7.75(m,2H),7.67(dd,J=6.8,1.9Hz,2H),7.58–7.54(m,2H),7.50(dd,J=7.3,2.3Hz,1H),7.46–7.38(m,3H),7.34–7.30(td,J=7.8,1.6Hz,1H),7.25(dd,J=8.0,1.6Hz,1H),4.86(s,2H);13C NMR(101MHz,DMSO-d6):δ165.25,144.68,137.07,134.04,131.83,130.03,129.39,129.10,128.76,128.08,127.94,127.12,126.57,122.46,120.68,49.90;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9606。
实施例13
多芳烃类化合物13的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的3-氯苯磺酰氯,将4-氯苯胺替换为等物质的量的3-氯苯胺为原料,得到化合物a4,收率88.1%;1HNMR(400MHz,DMSO-d6)δ10.70(s,1H),7.78(t,J=1.8Hz,1H),7.74–7.69(m,2H),7.60(t,J=7.9Hz,1H),7.28(t,J=7.9Hz,1H),7.13–7.06(m,3H);13C NMR(101MHz,DMSO-d6)δ141.36,139.26,134.44,133.94,133.69,131.98,131.53,126.66,125.84,124.74,120.01,118.90;HRMS calcd for C12H10NO2SCl2(M+H)+301.9809,found 301.9804.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a4,得到化合物b4,收率93.4%;1H NMR(400MHz,DMSO-d6)δ7.80(dd,J=7.3,2.0Hz,1H),7.72(t,J=1.6Hz,1H),7.66–7.56(m,2H),7.39(dd,J=9.6,5.1Hz,2H),7.30(d,J=1.9Hz,1H),7.18(dt,J=6.6,2.1Hz,1H),4.64(s,2H),3.63(s,3H);13CNMR(101MHz,DMSO-d6)δ169.47,140.94,140.28,134.51,133.98,133.54,131.81,131.19,128.69,128.55,127.29,126.49,52.65,52.46;HRMS calcd for C15H13NO4NaSCl2(M+Na)+395.9840,found 395.9839.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b4,得到化合物c4,收率84.7%;1H NMR(400MHz,DMSO-d6)δ7.82–7.77(m,1H),7.71(t,J=1.7Hz,1H),7.63–7.57(m,2H),7.40(dd,J=4.9,2.2Hz,2H),7.29(d,J=1.7Hz,1H),7.21–7.14(m,1H),4.51(s,2H);13C NMR(101MHz,DMSO-d6)δ170.27,141.12,140.45,134.44,133.88,133.44,131.78,131.12,128.48,128.44,127.27,127.14,126.46,124.63,52.50;HRMScalcd for C14H11NO4NaSCl2(M+Na)+381.9684,found 381.9680.
(4)化合物13的合成:
与实施例1的制备步骤相同,不同之处仅在于,将c1替换为等物质的量的c4,得化合物13,收率64.2%;1H NMR(400MHz,DMSO-d6):δ7.83–7.78(m,2H),7.63(d,J=5.0Hz,2H),7.48–7.40(m,3H),7.38–7.34(m,2H),7.26–7.21(m,2H),7.10–7.08(m,1H),4.94(s,2H);13CNMR(101MHz,DMSO-d6):δ165.94,149.21,132.69,132.23,131.97,129.99,129.68,129.42,126.93,126.62,125.48,124.95,124.67,120.47,119.07,50.88;HRMS calcd forC20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9598。
实施例14
多芳烃类化合物14的制备方法,包括如下步骤:与实施例13的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物14,收率70.6%;1H NMR(400MHz,DMSO-d6):δ7.83–7.80(m,1H),7.77(s,1H),7.64-7.62(m,2H),7.48(d,J=8.8Hz,2H),7.44–7.42(m,2H),7.33(s,1H),7.23-7.21(m,1H),7.13(d,J=8.8Hz,2H),4.93(s,2H);13C NMR(101MHz,DMSO-d6):δ169.15,156.66,156.16,150.96,143.99,143.37,141.48,135.66,134.14,133.23,131.76,128.17,125.74,123.74,122.39,121.99,118.16,113.96,113.55,112.56,104.85,51.05;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found491.9608。
实施例15
多芳烃类化合物15的制备方法,包括如下步骤:与实施例13的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物15,收率68.2%;1H NMR(400MHz,DMSO-d6):δ7.83–7.79(m,2H),7.63(d,J=5.0Hz,2H),7.58–7.55(m,1H),7.44-7.39(m,3H),7.34–7.30(m,2H),7.29–7.27(m,1H),7.25–7.23(m,1H),5.04(s,2H);13C NMR(101MHz,DMSO-d6):δ167.92,149.23,140.93,140.10,134.59,134.11,133.65,131.86,131.29,130.81,130.03,128.81,128.50,127.37,127.30,126.56,123.86,52.78;HRMScalcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9602。
实施例16
多芳烃类化合物16的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的3-氯苯磺酰氯,得到化合物a5,收率89.4%;1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),7.75–7.67(m,3H),7.59(t,J=7.9Hz,1H),7.32(d,J=8.7Hz,2H),7.10(d,J=8.8Hz,2H);13C NMR(101MHz,DMSO-d6)δ141.44,136.65,134.38,133.58,131.92,129.75,129.18,126.65,125.85,122.53;HRMS calcd for C12H10Cl2NO2S(M+H)+301.9809,found 301.9802.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a5,得到化合物b5,收率91.9%;1H NMR(400MHz,DMSO-d6)δ7.78–7.73(m,2H),7.60(d,J=7.5Hz,2H),7.43(d,J=8.7Hz,2H),7.23(d,J=8.7Hz,2H),4.62(s,2H),3.62(s,3H);13C NMR(101MHz,DMSO-d6)δ169.43,140.41,138.47,134.50,133.87,133.24,131.77,130.49,129.68,127.25,126.49,52.60;HRMS calcd for C15H13Cl2NNaO4S(M+Na)+395.9840,found 395.9842.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b5,得到化合物c5,收率90.3%;1H NMR(400MHz,DMSO-d6)δ7.78(d,J=7.8Hz,1H),7.70(s,1H),7.62–7.55(m,2H),7.43(d,J=8.7Hz,2H),7.22(d,J=8.7Hz,2H),4.47(s,2H);13C NMR(101MHz,DMSO-d6)δ170.18,140.56,138.64,134.40,133.81,132.98,131.79,130.40,129.60,127.20,126.46,52.66;HRMS calcd for C14H11Cl2NNaO4S(M+Na)+381.9684,found381.9682.
(4)化合物16的合成:
与实施例1的制备步骤相同,不同之处仅在于,将c1替换为等物质的量的c5,得化合物16,收率78.4%;1H NMR(400MHz,DMSO-d6)δ7.81–7.78(m,2H),7.62(dd,J=3.7,1.5Hz,2H),7.56(dd,J=7.9,1.5Hz,1H),7.49–7.45(m,2H),7.40(td,J=7.7,1.5Hz,1H),7.30(tdd,J=7.8,6.6,1.6Hz,4H),5.02(s,2H);13C NMR(101MHz,DMSO-d6)δ167.21,146.54,140.23,138.27,134.59,134.03,133.40,131.84,130.66,130.56,129.77,129.04,128.44,127.34,126.59,126.07,124.37,52.55;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9611。
实施例17
多芳烃类化合物17的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚为原料,得化合物17,收率66.2%;1HNMR(400MHz,DMSO-d6):δ7.74–7.67(m,4H),7.48–7.42(m,3H),7.40–7.35(m,2H),7.25–7.20(m,2H),7.10–7.08(m,1H),4.89(s,2H);13C NMR(101MHz,DMSO-d6):δ167.21,150.52,140.45,138.51,136.50,133.27,133.04,130.97,130.70,129.47,129.22,128.13,127.89,126.61,126.24,121.76,120.38,52.12;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9610。
实施例18
多芳烃类化合物18的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物18,收率75.5%;1HNMR(400MHz,DMSO-d6):δ7.73–7.67(m,4H),7.50–7.47(m,2H),7.44–7.41(m,2H),7.34–7.33(m,1H),7.22–7.19(m,1H),7.15–7.12(m,2H),4.88(s,2H);13C NMR(101MHz,DMSO-d6):δ166.00,147.36,145.04,139.17,137.21,135.21,133.22,129.41,128.91,128.16,127.91,126.82,126.56,125.28,121.98,110.75,107.92,50.83;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9609。
实施例19
多芳烃类化合物19的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的2-甲基苯酚,得化合物19,收率71.0%;1HNMR(400MHz,DMSO-d6)δ7.81–7.79(m,2H),7.62(dd,J=4.0,2.2Hz,2H),7.48–7.46(m,2H),7.30–7.26(m,3H),7.19(ddd,J=12.4,7.4,1.6Hz,2H),7.00(dd,J=7.8,1.3Hz,1H),4.97(s,2H),1.98(s,3H);13C NMR(101MHz,DMSO-d6)δ167.73,149.15,140.23,138.50,134.58,134.02,133.28,131.88,131.55,130.41,130.17,129.77,127.54,127.30,126.77,126.56,122.19,52.71,15.91;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found472.0154。
实施例20
多芳烃类化合物20的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-甲基苯酚,得化合物20,收率66.7%;1HNMR(400MHz,DMSO-d6)δ7.81–7.78(m,2H),7.62(dd,J=4.1,2.3Hz,2H),7.48–7.46(m,2H),7.28(dd,J=9.5,7.4Hz,3H),7.08(d,J=7.6Hz,1H),6.87(d,J=11.4Hz,2H),4.90(s,2H),2.30(s,3H);13C NMR(101MHz,DMSO-d6)δ167.99,150.46,140.29,139.85,138.50,134.57,134.01,133.31,131.87,130.50,129.79,127.32,127.28,126.57,122.28,118.87,52.87,21.20;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found472.0154。
实施例21
多芳烃类化合物21的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-甲基苯酚,得化合物21,收率72.9%;1HNMR(400MHz,DMSO-d6)δ7.80–7.79(m,2H),7.62(dd,J=4.2,2.4Hz,2H),7.48–7.46(m,2H),7.28–7.26(m,2H),7.20(d,J=8.3Hz,2H),6.94(d,J=8.4Hz,2H),4.89(s,2H),2.28(s,3H);13C NMR(101MHz,DMSO-d6)δ168.07,148.29,140.27,138.49,135.84,134.56,134.01,133.30,131.86,130.47,130.40,129.78,127.31,126.56,121.56,52.85,20.83;HRMScalcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0153。
实施例22
多芳烃类化合物22的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-乙基苯酚,得化合物22,收率73.5%;1HNMR(400MHz,DMSO-d6)δ7.80(s,2H),7.62(d,J=3.3Hz,2H),7.47(d,J=7.7Hz,2H),7.30(dd,J=16.3,7.8Hz,3H),7.11(d,J=7.5Hz,1H),6.88(d,J=10.9Hz,2H),4.90(s,2H),2.60(dd,J=14.9,7.4Hz,2H),1.15(t,J=7.6Hz,3H);13C NMR(101MHz,DMSO-d6)δ167.97,150.55,146.15,140.31,138.50,134.56,134.01,133.31,131.86,130.50,129.86,129.79,127.32,126.56,126.08,121.04,119.12,52.88,28.27,15.75;HRMS calcd forC22H20Cl2NO4S(M+H)+464.0490,found 464.0489。
实施例23
多芳烃类化合物23的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-溴苯酚,得化合物23,收率67.5%;1H NMR(400MHz,DMSO-d6)δ7.80(s,2H),7.62(d,J=5.0Hz,2H),7.47(d,J=8.8Hz,2H),7.39(d,J=1.9Hz,2H),7.28(d,J=8.7Hz,2H),7.13(d,J=8.1Hz,1H),6.94(s,1H),4.92(s,2H);13CNMR(101MHz,DMSO-d6)δ167.83,159.07,151.13,140.23,138.45,134.57,134.02,133.33,131.85,131.62,130.48,129.79,129.69,127.33,126.56,125.15,122.28,122.11,121.95,121.33,118.57,115.03,52.86;HRMS calcd for C20H14Cl2BrNNaO4S(M+Na)+535.9102,found 535.9099。
实施例24
多芳烃类化合物24的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氟苯酚,得化合物24,收率71.8%;1H NMR(400MHz,DMSO-d6)δ7.79(s,2H),7.62(d,J=4.6Hz,2H),7.48(d,J=8.6Hz,3H),7.27(d,J=8.7Hz,2H),7.16(td,J=8.5,1.9Hz,1H),7.06(d,J=9.7Hz,1H),6.96(d,J=8.2Hz,1H),4.92(s,2H);13C NMR(101MHz,DMSO-d6)δ167.76,151.39,140.24,138.44,134.57,134.04,133.35,131.87,131.47,131.38,130.51,129.81,127.33,126.58,118.31,113.79,113.58,110.08,109.84,52.86;HRMS calcd for C20H14Cl2FNNaO4S(M+Na)+475.9902,found475.9907。
实施例25
多芳烃类化合物25的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-甲氧基苯酚,得化合物25,收率60.7%;1HNMR(400MHz,DMSO-d6)δ7.81–7.79(m,2H),7.62(d,J=4.6Hz,2H),7.48(d,J=8.7Hz,2H),7.30(dd,J=19.4,8.5Hz,3H),6.86–6.84(m,1H),6.64(d,J=6.4Hz,2H),4.90(s,2H),3.74(s,3H);13C NMR(101MHz,DMSO-d6)δ167.83,160.60,151.46,140.26,138.48,134.56,134.02,133.31,131.87,130.55,130.49,129.79,127.32,126.57,113.98,112.42,107.84,55.86,52.86;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+488.0102,found488.0103。
实施例26
多芳烃类化合物26的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-硝基苯酚,得化合物26,收率63.5%;1HNMR(400MHz,DMSO-d6)δ8.17(dd,J=8.2,1.2Hz,1H),8.05(d,J=2.0Hz,1H),7.81(t,J=3.6Hz,2H),7.74(t,J=8.2Hz,1H),7.64–7.60(m,3H),7.48(d,J=8.7Hz,2H),7.29(d,J=8.7Hz,2H),4.97(s,2H);13C NMR(101MHz,DMSO-d6)δ167.89,150.71,148.75,140.20,138.47,134.58,134.07,133.36,131.88,131.51,130.52,129.81,129.06,127.34,126.59,121.71,117.55,52.93;HRMS calcd for C20H15Cl2N2O6S(M+H)+481.0028,found 481.0029。
实施例27
多芳烃类化合物27的制备方法,包括如下步骤:与实施例16的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-三氟甲基苯酚,得化合物27,收率67.3%;1H NMR(400MHz,DMSO-d6)δ7.80(d,J=5.3Hz,2H),7.68–7.62(m,4H),7.53(s,1H),7.47(d,J=8.7Hz,3H),7.29(d,J=8.7Hz,2H),4.95(s,2H);13C NMR(101MHz,DMSO-d6)δ167.91,150.70,140.23,138.47,134.56,134.01,133.35,131.83,131.50,130.51,129.78,127.34,126.56,126.44,52.90;HRMS calcd for C21H14Cl2F3NNaO4S(M+Na)+525.9870,found525.9872.
实施例28
多芳烃类化合物28的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的3-氯苯磺酰氯,将4-氯苯胺替换为等物质的量的4-甲基苯胺,得到化合物a6,收率84.7%;1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),7.66(dd,J=39.0,8.6Hz,4H),7.00(dd,J=30.1,8.2Hz,4H),2.18(s,3H);13C NMR(101MHz,DMSO-d6)δ138.78,138.13,135.10,134.25,130.12,129.82,129.06,121.43,20.76;HRMS calcd for C13H13ClNO2S(M+H)+282.0356,found282.0358.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a6,得到化合物b6,收率95.7%;1H NMR(400MHz,DMSO-d6)δ7.64(s,4H),7.14(d,J=8.1Hz,2H),7.04(d,J=8.2Hz,2H),4.51(s,2H),3.61(s,3H),2.27(s,3H);13C NMR(101MHz,DMSO-d6)δ169.52,138.60,138.21,137.75,137.05,130.13,129.83,129.68,128.62,52.84,52.54,21.04;HRMS calcd for C16H16ClNNaO4S(M+Na)+376.0386,found 376.0386.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b6,得到化合物c6,收率82.1%;1H NMR(400MHz,DMSO-d6)δ7.64(s,4H),7.14(d,J=8.1Hz,2H),7.05(d,J=8.2Hz,2H),4.38(s,2H),2.26(s,3H);13C NMR(101MHz,DMSO-d6)δ170.29,138.48,137.99,137.93,137.23,130.04,129.79,129.65,128.59,52.86,21.04;HRMS calcd forC15H14ClNNaO4S(M+Na)+362.0230,found 362.0229.
(4)化合物28的合成:
与实施例1的步骤相同,不同之处仅在于,将c1替换为等物质的量的c6,得化合物28,收率63.8%;1H NMR(400MHz,DMSO-d6)δ7.70–7.65(m,4H),7.57(dd,J=7.9,1.6Hz,1H),7.40(td,J=7.7,1.6Hz,1H),7.32(td,J=7.7,1.6Hz,1H),7.26(dd,J=8.0,1.6Hz,1H),7.17(d,J=8.2Hz,2H),7.11–7.09(m,2H),4.90(s,2H),2.28(s,3H);13C NMR(101MHz,DMSO-d6)δ167.30,146.58,138.75,138.37,137.56,136.88,130.66,130.20,129.91,129.78,129.05,128.65,128.41,126.09,124.38,52.79,21.06;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0154。
实施例29
多芳烃类化合物29的制备方法,包括如下步骤:与实施例28的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物29,收率64.3%;1HNMR(400MHz,DMSO-d6)δ7.70–7.65(m,4H),7.45(t,J=8.1Hz,1H),7.36(ddd,J=8.1,1.9,0.9Hz,1H),7.22(t,J=2.1Hz,1H),7.18(d,J=8.2Hz,2H),7.10–7.06(m,3H),4.81(s,2H),2.28(s,3H);13C NMR(101MHz,DMSO-d6)δ167.89,151.16,138.77,138.35,137.48,137.06,133.85,131.56,130.24,129.92,129.78,128.59,126.79,122.36,120.99,53.12,21.06;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0154。
实施例30
多芳烃类化合物30的制备方法,包括如下步骤:与实施例28的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物30,收率61.8%;1H NMR(400MHz,DMSO-d6)δ7.67(d,J=2.4Hz,4H),7.48(d,J=8.9Hz,2H),7.20–7.16(m,2H),7.13–7.08(m,4H),4.81(s,2H),2.28(s,3H);13C NMR(101MHz,DMSO-d6)δ167.97,149.28,138.76,138.35,137.48,137.06,130.75,130.23,130.02,129.91,129.76,129.59,128.58,123.88,117.38,53.14,21.06;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found472.0153。
实施例31
多芳烃类化合物31的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的3-甲基苯磺酰氯,得到化合物a7,收率75.7%;1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),7.64(d,J=8.1Hz,2H),7.30(dd,J=20.2,8.4Hz,4H),7.10(d,J=8.8Hz,2H),2.31(s,3H);13C NMR(101MHz,DMSO)δ143.90,137.28,136.82,130.21,129.57,128.52,127.16,121.92,21.40;HRMS calcd for C13H13ClNO2S(M+H)+282.0356,found 282.0355.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a7,得到化合物b7,收率90.3%;1HNMR(400MHz,DMSO-d6)δ7.53(d,J=8.1Hz,2H),7.40(t,J=9.2Hz,4H),7.19(d,J=8.7Hz,2H),4.53(s,2H),3.62(s,3H),2.38(s,3H);13C NMR(101MHz,DMSO)δ169.47,144.35,138.93,135.66,132.75,130.26,130.16,129.52,127.76,52.56,52.33,21.49;HRMS calcd for C16H16ClNNaO4S(M+Na)+376.0386,found 376.0388.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b7,得到化合物c7,收率88.5%;1H NMR(400MHz,DMSO-d6)δ7.52(d,J=8.1Hz,2H),7.38(t,J=8.6Hz,4H),7.18(d,J=8.7Hz,2H),4.40(s,2H),2.38(s,3H);13C NMR(101MHz,DMSO)δ170.15,144.23,139.07,135.80,132.51,130.24,130.07,129.42,127.71,52.33,21.49;HRMS calcd for C15H14ClNNaO4S(M+Na)+362.0230,found 362.0230.
(4)化合物31的合成:
与实施例1的制备步骤相同,不同之处仅在于,将c1替换为等物质的量的c7,得化合物31,收率67.9%;1H NMR(400MHz,DMSO-d6)δ7.59(d,J=8.4Hz,1H),7.45–7.36(m,4H),7.26–7.23(m,2H),7.18(t,J=8.3Hz,2H),6.81(d,J=1.5Hz,2H),6.74(d,J=7.2Hz,1H),4.83(s,2H),2.38(s,3H);13C NMR(101MHz,DMSO-d6)δ167.82,159.01,151.16,144.51,138.92,135.45,133.91,133.87,132.93,131.50,131.24,130.32,130.15,129.63,127.86,126.77,122.36,120.95,119.23,115.72,114.66,52.67,21.49;HRMS calcd forC21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0153。
实施例32
多芳烃类化合物32的制备方法,包括如下步骤:与实施例31的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物32,收率67.8%;1H NMR(400MHz,DMSO-d6)δ7.58(dd,J=11.5,8.8Hz,3H),7.42(dd,J=17.3,8.4Hz,5H),7.31(d,J=6.8Hz,1H),7.26(t,J=8.2Hz,3H),4.92(s,2H),2.39(s,3H);13C NMR(101MHz,DMSO-d6)δ167.20,146.56,144.49,138.70,135.49,132.93,130.64,130.32,130.22,129.60,129.02,128.40,127.84,126.07,124.37,52.32,21.50;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0152。
实施例33
多芳烃类化合物33的制备方法,包括如下步骤:与实施例31的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物33,收率73.0%;1H NMR(400MHz,DMSO-d6)δ7.56(d,J=8.3Hz,1H),7.48(d,J=8.9Hz,1H),7.43(d,J=8.8Hz,1H),7.39(d,J=8.1Hz,1H),7.24–7.22(m,1H),7.20–7.18(m,4H),7.12(d,J=8.9Hz,1H),6.77–6.75(s,2H),4.82(s,2H),2.39(s,3H);13C NMR(101MHz,DMSO-d6)δ167.92,156.77,149.27,144.52,138.91,135.40,132.87,130.76,130.34,130.13,130.02,129.63,129.59,127.85,123.90,122.77,117.38,52.66,21.51;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0154。
实施例34
多芳烃类化合物34的制备方法,包括如下步骤:
与a1的制备方法相同,不同之处仅在于,将苯磺酰氯替换为等物质的量的4-氯苯磺酰氯,得到化合物a8,收率88.1%;1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),7.74(d,J=8.5Hz,2H),7.63(d,J=8.5Hz,2H),7.30(d,J=8.7Hz,2H),7.10(d,J=8.7Hz,2H);13C NMR(101MHz,DMSO-d6)δ138.46,138.43,136.79,129.98,129.71,129.05,122.43;HRMS calcdfor C12H10Cl2NO2S(M+H)+301.9809,found 301.9800.
与b1的制备步骤相同,不同之处仅在于,将a1替换为等物质的量的a8,得到化合物b8,收率96.1%;1H NMR(400MHz,DMSO-d6)δ7.66(s,4H),7.43(d,J=8.6Hz,2H),7.22(d,J=8.7Hz,2H),4.57(s,2H);13C NMR(101MHz,DMSO-d6)δ169.40,138.87,138.57,137.34,133.15,130.48,129.96,129.69,129.67,52.60,52.50;HRMS calcd for C15H13Cl2NNaO4S(M+Na)+395.9840,found 395.9837.
与化合物c1的制备方法相同,不同之处仅在于,将b1替换为等物质的量的b8,得到化合物c8,收率93.6%;1H NMR(400MHz,DMSO-d6)δ7.65(s,4H),7.41(d,J=8.7Hz,2H),7.22(d,J=8.7Hz,2H),4.41(s,2H);13C NMR(101MHz,DMSO-d6)δ170.23,138.83,138.69,137.57,132.84,130.36,129.90,129.67,129.54,52.67;HRMS calcd for C14H11Cl2NNaO4S(M+Na)+381.9684,found 381.9683.
(4)化合物34的合成:
与实施例1的制备步骤相同,不同之处仅在于,将c1替换为等物质的量的c8,得化合物34,收率79.3%;1H NMR(400MHz,DMSO-d6)δ7.72–7.67(m,4H),7.57(dd,J=7.9,1.5Hz,1H),7.48–7.46(m,2H),7.39(dd,J=7.7,1.5Hz,1H),7.32(td,J=7.7,1.6Hz,1H),7.30–7.26(m,3H),4.95(s,2H);13C NMR(101MHz,DMSO-d6)δ165.94,149.21,132.69,132.23,131.97,129.99,129.68,129.42,126.93,126.62,125.48,124.95,124.67,120.47,119.07,50.88;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9608。
实施例35
多芳烃类化合物35的制备方法,包括如下步骤:与实施例34的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-氯苯酚,得化合物35,收率71.8%;1H NMR(400MHz,DMSO-d6)δ7.72–7.67(m,4H),7.48–7.44(m,3H),7.37(ddd,J=8.1,1.9,0.9Hz,1H),7.27–7.25(m,3H),7.09(ddd,J=8.1,2.2,0.9Hz,1H),4.86(s,2H);13C NMR(101MHz,DMSO-d6)δ167.80,151.11,139.02,138.55,137.09,133.85,133.26,131.57,130.48,130.06,129.79,126.84,122.38,121.00,52.79;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9606。
实施例36
多芳烃类化合物36的制备方法,包括如下步骤:与实施例34的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-氯苯酚,得化合物36,收率74.7%。1HNMR(400MHz,DMSO-d6)δ7.69(d,J=2.2Hz,4H),7.49–7.45(m,4H),7.26(d,J=8.8Hz,2H),7.13(d,J=8.9Hz,2H),4.86(s,2H);13C NMR(101MHz,DMSO-d6)δ167.87,156.77,149.24,139.01,138.55,137.09,133.26,130.79,130.46,130.05,130.03,129.78,129.58,123.89,117.38,52.80;HRMS calcd for C20H14Cl3NNaO4S(M+Na)+491.9607,found 491.9599。
实施例37
多芳烃类化合物37的制备方法,包括如下步骤:与实施例34的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的2-甲基苯酚,得化合物37,收率67.5%;1HNMR(400MHz,DMSO-d6)δ7.72–7.67(m,4H),7.48–7.46(m,2H),7.27(dd,J=12.3,5.6Hz,3H),7.19–7.17(m,2H),7.01–6.99(m,1H),4.90(s,2H),1.98(s,3H);13C NMR(101MHz,DMSO-d6)δ167.69,149.15,138.99,138.60,137.10,133.20,131.54,130.39,130.17,130.06,129.76,127.53,126.77,122.20,52.64,15.90;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0155。
实施例38
多芳烃类化合物38的制备方法,包括如下步骤:与实施例34的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的3-甲基苯酚,得化合物38,收率62.8%;1HNMR(400MHz,DMSO-d6)δ7.72–7.67(m,4H),7.46(dd,J=6.9,4.9Hz,2H),7.28–7.26(m,3H),7.08(d,J=7.7Hz,1H),6.86(d,J=8.1Hz,2H),4.84(s,2H);13C NMR(101MHz,DMSO-d6)δ167.93,150.44,139.83,138.96,138.58,137.17,133.22,130.47,130.03,129.76,127.26,122.27,118.86,52.80,21.20;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found472.0154。
实施例39
多芳烃类化合物39的制备方法,包括如下步骤:与实施例34的制备步骤相同,不同之处仅在于,将2-氯苯酚替换为等物质的量的4-甲基苯酚,得化合物39,收率76.1%;1HNMR(400MHz,DMSO-d6)δ7.69(d,J=2.9Hz,4H),7.46(d,J=8.8Hz,2H),7.27–7.19(m,2H),7.20(d,J=8.4Hz,2H),6.94(d,J=8.4Hz,2H),4.83(s,2H),2.29(s,3H);13C NMR(101MHz,DMSO-d6)δ168.01,148.27,138.95,138.57,137.14,135.82,133.21,130.44,130.38,130.14,130.03,129.76,121.56,115.45,52.78,20.83;HRMS calcd for C21H17Cl2NNaO4S(M+Na)+472.0153,found 472.0150。
(1)下面应用实施例1-39制得的多芳烃类化合物以对MDM2的抑制活性进行测试,具体测试方法和结果如下所示:
将实施例1-39制得的多芳烃类化合物加入到盛有50μL的MDM2(50nM)的96孔板中,蛋白缓冲液为含500mM NaCl的100mM PBS(pH=7.5),随后加入50μL荧光标记肽(10nM),检测终体积为125μL,测量缓冲液为含0.2%NaN3和0.1%BSA的100mM PBS(pH=7.5);孵育30min后,测定荧光偏振值,激发波长为530nM,发射波长为580nM,依据浓度-偏振值曲线计算化合物的Ki值,结果如表1所示:
表1化合物对MDM2的抑制活性
化合物编号 | <![CDATA[MDM2K<sub>i</sub>[μM]]]> | 化合物编号 | <![CDATA[MDM2K<sub>i</sub>[μM]]]> |
1 | 6.83±0.83 | 21 | 2.35±0.28 |
2 | 5.57±0.62 | 22 | 9.46±1.57 |
3 | 5.64±0.76 | 23 | 0.012±0.002 |
4 | 3.46±0.48 | 24 | 0.022±0.005 |
5 | 1.15±0.18 | 25 | 3.46±0.52 |
6 | 5.24±0.97 | 26 | 0.075±0.027 |
7 | 1.79±0.43 | 27 | 0.58±0.16 |
8 | 6.63±1.03 | 28 | 1.14±0.24 |
9 | 10.27±1.95 | 29 | 0.55±0.12 |
10 | 4.37±1.34 | 30 | 2.28±0.36 |
11 | 3.85±0.55 | 31 | 1.47±0.31 |
12 | 4.04±0.81 | 32 | 1.73±0.53 |
13 | 0.71±0.09 | 33 | 2.34±0.50 |
14 | 0.55±0.11 | 34 | 0.43±0.15 |
15 | 0.96±0.17 | 35 | 0.087±0.026 |
16 | 0.089±0.020 | 36 | 0.096±0.035 |
17 | 0.017±0.003 | 37 | 3.56±0.89 |
18 | 0.064±0.012 | 38 | 3.02±1.03 |
19 | 4.13±0.89 | 39 | 4.45±1.58 |
20 | 1.81±0.47 | Nutlin-3a | 0.15±0.02 |
由表1可得,39个化合物均表现出MDM2抑制活性,其中化合物16、17、18、23、24、26、35和36抑制活性优于阳性药Nutlin-3a。
(2)下面应用部分多芳烃类化合物进行抗肿瘤活性的测试,具体测试方法和结果如下所示:
将肿瘤细胞培养至对数期,0.25%Trypsin-EDTA消化收集细胞并计数,以细胞数4×103个/孔,体积200μL接种于96孔细胞培养板,贴壁过夜后,依次用培养基稀释化合物进行上样,对所有样品进行梯度筛选,起始终浓度为50μM,3倍梯度稀释,共检测8个浓度梯度,每个浓度设3个平行孔。CO2培养箱孵育48h,加入终浓度为0.5mg/mL的MTT,再孵4h后,轻轻吸去上清,加入150μL/孔DMSO,振荡至充分溶解,酶标仪540nm检测并记录各孔吸光值。抑制率按照以下计算公式计算:抑制率%=(化合物组平均OD值-对照组平均OD值)/对照组平均OD值×100%,计算IC50值,结果如表2所示:
表2部分化合物抗肿瘤活性
化合物编号 | <![CDATA[MCF7IC<sub>50</sub>[μM]]]> | <![CDATA[HCT116IC<sub>50</sub>[μM]]]> | <![CDATA[A549IC<sub>50</sub>[μM]]]> |
13 | 28.23±3.67 | 16.15±2.39 | 14.48±3.55 |
14 | 22.57±4.16 | 15.42±2.26 | 10.35±3.02 |
15 | 25.52±3.77 | 20.46±4.57 | 15.92±2.48 |
16 | 14.91±1.79 | 19.57±1.85 | 24.36±3.12 |
17 | 8.27±1.27 | 14.36±2.13 | 16.78±2.45 |
18 | 12.35±2.25 | 18.79±3.16 | 14.15±1.74 |
23 | 4.12±0.83 | 10.47±2.05 | 8.28±1.46 |
24 | 6.36±1.25 | 9.42±1.77 | 10.37±2.38 |
26 | 9.57±2.52 | 14.16±2.74 | 16.61±1.78 |
27 | 16.26±2.15 | 20.77±2.45 | 18.32±2.51 |
29 | 14.41±1.93 | 17.53±2.16 | 16.62±2.34 |
34 | 17.58±3.26 | 18.72±1.49 | 15.37±1.83 |
35 | 14.21±2.39 | 18.35±3.12 | 10.46±2.07 |
36 | 17.55±2.61 | 21.36±3.34 | 22.82±2.29 |
Nutlin-3a | 31.47±1.22 | 18.53±1.89 | 20.54±1.95 |
表中,HCT116:人结肠癌细胞株;MCF7:人乳腺癌细胞株;A549:人肺癌细胞株
由表2可得,所测试化合物均表现出抗HCT116、MCF7、A549活性的作用,且多数化合物活性优于阳性药Nutlin-3a,可以进行进一步研究,从而为研发效果更好的抗肿瘤MDM2抑制剂奠定基础。
本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
2.根据权利要求1所述的一种多芳烃类化合物,其特征在于,所述R1的卤素选自氟、氯、溴,所述R1的C1-C6的烷基选自甲基;所述R2的卤素选自氟、氯、溴,所述R2的C1-C6的烷基选自甲基;所述R3的卤素选自氟、氯、溴,所述R3的C1-C6的烷基选自甲基或乙基。
6.根据权利要求4所述的多芳烃类化合物的制备方法,其特征在于,所述步骤(2)中,化合物1和溴乙酸甲酯的摩尔比为1:0.9~1.3,所述缩合反应在碳酸钾碱性条件下进行,且所述化合物1和碳酸钾的摩尔比为1:1.0~3.0。
7.根据权利要求4所述的多芳烃类化合物的制备方法,其特征在于,所述步骤(3)中,水解反应于氢氧化钠碱性条件下进行,且所述化合物2和氢氧化钠的摩尔比为1:1.0~3.0。
9.一种权利要求1-3任一项所述的多芳烃类化合物在制备MDM2抑制剂中的应用。
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