CN102702062A - 一类3,5-二苯基-2h-吡唑衍生物的合成、制备方法及抗癌作用 - Google Patents
一类3,5-二苯基-2h-吡唑衍生物的合成、制备方法及抗癌作用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类3,5-二苯基-2H-吡唑衍生物的合成、制备方法及抗癌作用
背景技术
癌症具有较高的发病率和致死率。严重威胁着人类的健康和生命。目前,化疗仍然是肿瘤治疗的主要手段之一,因此新药的开发研究也依然是攻克肿瘤的重要途径之一。目前,抗癌新药的开发对象主要包括天然物质、化学合成物质及生物技术合成物质等,而且开发一种新型的抗癌药物也是解决临床上多药耐药(multidrug resistance MDR)的途径之一
当今世界,杂环化合物在医药、农药的研究开发中占有十分重要的地位。无论是天然的还是人工合成的杂环化合吡唑物,在医药(抗癌、杀虫、杀菌),农药中都起着举足轻重的作用。其中吡唑类化合物因其作用谱广、药效强烈等特点而受到越来越多的关注。
吡唑衍生物是一类多功能化合物,用途广泛,它及其配合物可以用作杀虫剂、杀菌剂、除草剂、催化剂、抗菌药、许多吡唑类化合物具有抗癌抗肿瘤、抗菌、抗病毒,抗惊厥等多种生物活性,一直是人们研究的热点。吡唑类化合物具有广泛的生物活性,许多含吡唑基团的化合物都具有良好的除草、杀虫、杀菌活性。
本文中,通过前期工作中已经合成的新型查尔酮衍生物与水合肼反应形成了一系列未经报道的吡唑衍生物类的新化合物,我们为新合成的吡唑衍生物选取的靶点是BRAF,这些新化合物可能体现出很好的抗癌活性,比如说能抗胃癌,直肠癌,黑素瘤,甲状腺癌。
发明内容
本发明的目的在于提供一类3,5-二苯基-2H-吡唑衍生物的合成、制备方法及抗癌作用。
本发明的技术方案如下:
1.一类3,5-二苯基-2H-吡唑衍生物,其特征是它有如下通式:
结构式中R1为:4-甲基,4-氟,4-氯,4-溴,4-甲氧基。
R2为:3-氢,3-氯,3-溴。
R3为:5-氯,5-溴。
2.一种制备上述的3,5-二苯基-2H-吡唑衍生物的方法,步骤如下:
步骤1.制备查尔酮原料:将取代基水杨醛(5.0mmol),取代基苯乙酮(5.0mmol)分别溶于有机溶剂,缓慢滴入碱溶液,磁搅拌,常温反应一段时间(TLC检测反应进行程度),滴加若干量的酸溶液,产物以固体析出。反应结束后抽滤,并以大量的蒸馏水冲洗固体物,最后用有机溶剂洗涤3次,干燥得取代基查尔酮。将产物重结晶。
步骤2.于25ml烧瓶中加入1mmol取代基查尔酮,过量水合肼,并溶解于有机溶剂中,40-100℃搅拌反应一段时间(TLC检测)。反应结束后,冷却到5℃以下,反应产物自动析出,抽滤并用有机溶剂洗涤2次,重结晶得到第二步产物。步骤3.
步骤3.反应生成酰胺系列:将步骤2产物与乙酸以1∶1.2的摩尔比分别加入50ml烧瓶中,用有机溶剂溶解,20-60℃搅拌反应一段时间(TLC检测)。反应结束,用真空将溶剂抽干,将烧瓶中残余固体溶于有机溶剂中,用酸溶液洗涤萃取3次。真空抽干萃取液,得到残余固体用有机溶剂重结晶,得到最终产物。
具体实施方式
实施例一:1-(5-(3,5-二溴-2-羟基苯基)-3-(对甲基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物1)的制备
于50ml单口烧瓶内将3.5-二溴水杨醛(5.0mmol),N-对甲基苯乙酮(5.0mmol)分别溶于20ml乙醇,缓慢滴入40%NaOH溶液10ml,磁搅拌,常温反应5小时(TLC检测反应进行程度),产物以固体析出。反应结束后抽滤,并以大量的蒸馏水冲洗固体物,最后用乙醇洗涤3次,干燥得取代基查尔酮。将产物纯化,干燥后,称取2mmol加入到另一个50ml单口烧瓶内,0.4ml水合肼,并溶解于10ml正丙醇中,90℃搅拌反应10小时(TLC检测)。反应结束后,置于冰浴中冷却,析出白色固体,待产物重分析出后抽滤并用乙醇洗涤2次,重结晶纯化得到第二步产物。将步骤2产物与乙酸以1∶1.2的摩尔比分别加入50ml烧瓶中,用20ml氯仿溶解,50℃搅拌反应10小时(TLC检测)。应结束,用真空将溶剂抽干,将烧瓶中残余固体溶于30ml乙酸乙酯中,用50ml8%稀盐酸洗涤萃取3次。真空抽干萃取液,得到残余固体用乙醇重结晶纯化,得到白色固体最终产物。产率:63%.熔点:246-248℃.1H NMR(500MHz,DMSO)δ:2.33(d,J=13.3Hz,6H),3.77(s,1H),4.31(d,J=4.58Hz,2H),5.65-5.68(m,1H),6.98(d,J=2.15Hz,1H),7.27(d,J=8.05Hz,2H),7.63-7.67(m,3H)MS(ESI):451(C18H17Br2N2O2,[M+H]+).Anal C18H16Br2N2O2.Calcd for:C,47.82;H,3.57;N,6.20.Found:C,47.83;H,3.58;N,6.15.
实施例二:1-(5-(3,5-二氯-2-羟基苯基)-3-(对甲基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物2)的制备
制备方法同实施例一。以3,5-二氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:61%.熔点:237-239℃.1H NMR(500MHz,DMSO)δ:2.33(d,J=13.3Hz,6H),3.77(s,1H),4.32(d,J=4.58Hz,2H),5.66(s,1H),6.95(d,J=2.15Hz,1H),7.26(d,J=8.05Hz,2H),7.63-7.67(m,3H)MS(ESI):363(C18H17Cl2N2O2,[M+H]+).Anal C18H16Cl2N2O2.Calcdfor:C,59.52;H,4.44;N,7.71.Found:C,59.53;H,4.48;N,7.79
实施例三:1-(5-(5-溴-2-羟基苯基)-3-(对甲基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物3)的制备
制备方法同实施例一。以5-溴水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:69%.熔点:215-216℃.1H NMR(500MHz,DMSO)δ:2.31(s,6H),4.32(t,J=5.03Hz,3H),5.57(d,J=7.3Hz,1H),6.78(s,1H),6.84(d,J=8.55Hz,1H),6.85(s,2H),6.99-7.10(m,1H),7.71(d,J=8.7Hz,2H)MS(ESI):345(C18H18BrN2O2,[M+H]+).Anal C18H17BrN2O2.Calcdfor:C,57.92;H,4.59;N,7.51.Found:C,,57.93;H,4.58;N,7.49.
实施例四:1-(5-(5-氯-2-羟基苯基)-3-(对甲基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物4)的制备
制备方法同实施例一。以5-氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:78%.熔点:209-211℃.11H NMR(500MHz,DMSO)δ:2.32(s,6H),4.32(t,J=5.03Hz,3H),5.57(d,J=7.3Hz,1H),6.78(s,1H),6.84(d,J=8.7Hz,1H),6.85(s,2H),6.99-7.10(m,1H),7.71(d,J=8.55Hz,2H)MS(ESI):329(C18H18ClN2O2,[M+H]+).Anal C18H17ClN2O2.Calcdfor:C,65.75;H,5.21;N,8.52.Found:C,65.73;H,5.18;N,8.49.
实施例五1-(5-(3,5-二溴-2-羟基苯基)-3-(对氯基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物5)的制备
制备方法同实施例一。以对氯苯乙酮代替例一中的对甲基苯乙酮,得到白色晶体状目标化合物。产率:78%.熔点:208-210℃.1H NMR(500MHz,DMSO)δ:2.32(s,3H),3.79-3.85(m,1H),4.31(t,J=5.1Hz,2H),5.65-5.68(m,1H),6.88(d,J=8.55Hz,1H),7.41(d,J=2.4Hz,1H),7.65(s,2H),7.69(t,J=12.88Hz,2H)MS(ESI):471(C17H14Br2ClN2O2,[M+H]+).Anal C17H13Br2ClN2O2.Calcdfor:C,43.21;H,2.77;N,5.93.Found:C,43.23;H,2.78;N,5.99.
实施例六:1-(5-(5-溴-2-羟基苯基)-3-(对氯基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物6)的制备
制备方法同实施例一。以对氯苯乙酮代替例一中的对甲基苯乙酮,以5-溴水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:74%.熔点:270-272℃.1HNMR(500MHz,DMSO)δ:2.32(s,3H),3.79-3.85(m,1H),4.31(t,J=5.1Hz,2H),5.65-5.68(m,1H),6.88(d,J=8.55Hz,1H),7.41(d,J=2.4Hz,1H),7.65(s,2H),7.69(t,J=12.88Hz,2H)MS(ESI):471(C17H14Br2ClN2O2,[M+H]+).Anal C17H13Br2ClN2O2.Calcdfor:C,43.21;H,2.77;N,5.93.Found:C,43.23;H,2.78;N,5.99.
实施例七:1-(5-(5-氯-2-羟基苯基)-3-(对氯基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物7)的制备
制备方法同实施例一。以对氯苯乙酮代替例一中的对甲基苯乙酮,以5-氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:71%.熔点:263-265℃.1H NMR(500MHz,DMSO)δ:2.33(s,3H),4.29-4.34(m,3H),5.60(s,1H),6.84(d,J=8.55Hz,2H),7.11(d,J=8.55Hz,1H),7.52(d,J=8.55Hz,2H),7.79(d,J=8.55Hz,2H)MS(ESI):349(C17H15ClN2O2,[M+H]+).Anal C17H14ClN2O2.Calcdfor:C,58.47;H,4.04;N,8.02.Found:C,58.43;H,3.98;N,7.97.
实施例八:1-(5-(3,5-二溴-2-羟基苯基)-3-(对溴基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物8)的制备
制备方法同实施例一。以对溴苯乙酮代替例一中的对甲基苯乙酮,得到白色晶体状目标化合物。产率:72%.熔点:223-225℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.35(s,2H),3.76-3.86(m,1H),5.64-5.70(m,1H),7.01(d,J=2.19Hz,1H),7.64-7.78(m,5H)MS(ESI):515(C17H14Br3N2O2,[M+H]+).AnalC17H13Br3N2O2.Calcdfor:C,39.49;H,2.53;N,5.42.Found:C,39.48;H,2.48;N,5.43.
实施例九:1-(5-(3,5-二氯2-羟基苯基)-3-(对溴基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物9)的制备
制备方法同实施例一。以对溴苯乙酮代替例一中的对甲基苯乙酮,以3,5-二氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:76%.熔点:237-239℃.1H NMR(300MHz,DMSO)δ:2.32-2.50(m,3H),3.76-3.86(m,1H),4.33(s,2H),5.64-5.70(m,1H),7.01(d,J=2.19Hz,1H),7.64-7.73(m,5H)MS(ESI):427(C17H14BrCl2N2O2,[M+H]+).Anal C17H14BrCl2N2O2.Calcdfor:C,47.69;H,3.06;N,6.54.Found:C,47.68;H,3.05;N,6.53.
实施例十:1-(5-(5-溴-2-羟基苯基)-3-(对溴基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物10)的制备
制备方法同实施例一。以对溴苯乙酮代替例一中的对甲基苯乙酮,以5-溴水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:76%.熔点:297-299℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.75-3.85(m,3H),5.56-5.61(m,1H),6.83(t,J=4.38Hz,2H),7.10-7.13(m,1H),7.64-7.73(m,4H)MS(ESI):437(C17H15BrClN2O2,[M+H]+).Anal C17H14BrClN2O2.Calcd for:C,51.87;H,3.58;N,7.12.Found:C,51.78;H,3.58;N,7.13.
实施例十一:1-(5-(5-氯-2-羟基苯基)-3-(对溴基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物11)的制备
制备方法同实施例一。以对溴苯乙酮代替例一中的对甲基苯乙酮,以5-氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:65%.熔点:270-272℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.75-3.85(m,3H),5.56-5.61(m,1H),6.63(t,J=4.47Hz,2H),7.10-7.13(m,1H),7.64-7.63(m,4H)MS(ESI):393(C17H15BrClN2O2,[M+H]+).Anal C17H14BrClN2O2.Calcd for:C,51.87;H,3.58;N,7.12.Found:C,51.78;H,3.58;N,7.13.
实施例十二:1-(5-(3,5-二溴-2-羟基苯基)-3-(对氟基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物12)的制备
制备方法同实施例一。以对氟苯乙酮代替例一中的对甲基苯乙酮,得到白色晶体状目标化合物。产率:68%.熔点:215-216℃.1H NMR(300MHz,DMSO)δ:2.33(s,3H),3.61-3.68(m,3H),5.81-5.83(m,1H),6.94(d,J=2.1Hz,1H),7.08(t,J=8.55Hz,2H),7.51(d,J=2.1Hz,1H),7.69-7.74(m,2H)MS(ESI):455(C17H14Br2FN2O2,[M+H]+).Anal C17H13Br2FN2O2.Calcd for:C,44.77;H,2.87;N,6.14.Found:C,44.73;H,2.88;N,6.19.
实施例十三:1-(5-(3,5-二氯-2-羟基苯基)-3-(对氟基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物13)的制备
制备方法同实施例一。以对氟苯乙酮代替例一中的对甲基苯乙酮,以3,5-二氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:61%.熔点:209-211℃.1H NMR(300MHz,DMSO)δ:2.33(s,3H),3.61-3.66(m,3H),5.81-5.85(m,1H),6.88(d,J=2.1Hz,1H),6.99(t,J=8.55Hz,2H),7.47(d,J=2.1Hz,1H),7.65-7.70(m,2H)MS(ESI):367(C17H14Cl2FN2O2,[M+H]+).AnalC17H13Cl2FN2O2.Calcd for:C,55.60;H,3.57;N,7.63.Found:C,55.53;H,3.58;N,7.69.
实施例十四:1-(5-(5-溴-2-羟基苯基)-3-(对氟基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物14)的制备
制备方法同实施例一。以对氟苯乙酮代替例一中的对甲基苯乙酮,以5-溴水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:71%.熔点:233-235℃.1H NMR(300MHz,DMSO)δ:2.33(s,3H),3.61-3.65(m,3H),5.79-5.81(m,1H),6.77(d,J=1.8Hz,2H),7.07-7.18(m,3H),7.68-7.76(m,2H),MS(ESI):377(C17H15BrFN2O2,[M+H]+).Anal C17H14BrFN2O2.Calcdfor:C,54.13;H,3.74;N,7.43.Found:C,54.15;H,3.78;N,7.39.
实施例十五:1-(5-(5-氯-2-羟基苯基)-3-(对氟基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物15)的制备
制备方法同实施例一。以对氟苯乙酮代替例一中的对甲基苯乙酮,以5-氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:68%.熔点:212-214℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.61-3.68(m,3H),5.79-5.81(m,1H),6.80(d,J=1.8Hz,2H),7.07-7.18(m,3H),7.72-7.76(m,2H)MS(ESI):333(C17H15ClFN2O2,[M+H]+).Anal C17H14ClFN2O2.Calcdfor:C,61.37;H,4.24;N,8.42.Found:C,61.33;H,4.28;N,8.39.
实施例十六:1-(5-(3,5-二溴-2-羟基苯基)-3-(对甲氧基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物16)的制备
制备方法同实施例一。以对甲氧基苯乙酮代替例一中的对甲基苯乙酮,得到白色晶体状目标化合物。产率:65%.熔点:214-215℃.1H NMR(500MHz,DMSO)δ:2.41(d,J=13.5Hz,3H),4.33(s,6H),5.68(d,J=7Hz,1H),7.01(s,1H),7.30(t,J=8.85Hz,2H),7.64(d,J=2.15Hz,1H),7.83(t,J=7.18Hz,2H)MS(ESI):467(C18H17Br2N2O3,[M+H]+).Anal C18H16Br2N2O3.Calcd for:C,46.18;H,3.44;N,5.98.Found:C,46.13;H,3.48;N,5.99.
实施例十七:1-(5-(3,5-二氯-2-羟基苯基)-3-(对甲氧基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物17)的制备
制备方法同实施例一。以对甲氧基苯乙酮代替例一中的对甲基苯乙酮,以3,5-二氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:64%.熔点:206-208℃.1H NMR(300MHz,DMSO)δ:2.41(d,J=13.5Hz,3H),3.79-4.32(m,6H),5.66-5.69(m,1H),7.01(s,1H),7.29(t,J=5.22Hz,2H),7.63(s,1H),7.83(t,J=4.17Hz,2H)MS(ESI):379(C18H17Cl2FN2O3,[M+H]+).Anal C18H16Cl2FN2O3.Calcdfor:C,57.01;H,4.25;N,7.39.Found:C,56.93;H,4.28;N,7.43.
实施例十八:1-(5-(5-氯-2-羟基苯基)-3-(对甲氧基苯基)-4,5-二氢-1氢-1-吡唑基)乙酮
(化合物18)的制备
制备方法同实施例一。以对甲氧基苯乙酮代替例一中的对甲基苯乙酮,以5-氯水杨醛代替例一中的3,5-二溴水杨醛,得到白色晶体状目标化合物。产率:65%.熔点:262-264℃.1H NMR(500MHz,DMSO)δ:2.31(s,3H),3.76(t,J=13.88Hz,3H),4.32(t,J=5.03Hz,3H),5.57(d,J=7.3Hz,1H),6.78(s,1H),6.84(d,J=8.55Hz,1H),6.85(s,2H),6.99-7.10(m,1H),7.71(d,J=8.7Hz,2H)MS(ESI):345(C18H18ClN2O3,[M+H]+).Anal C18H17ClN2O3.Calcdfor:C,62.70;H,4.97;N,8.12.Found:C,62.73;H,4.98;N,8.19.
Claims (2)
- 2.一种制备上述的3,5-二苯基-2H-吡唑衍生物的方法,步骤如下:步骤1.制备查尔酮原料:将取代基水杨醛(5.0mmol),取代基苯乙酮(5.0mmol)分别溶于有机溶剂,缓慢滴入碱溶液,磁搅拌,常温反应一段时间(TLC检测反应进行程度),滴加若干量的酸溶液,产物以固体析出。反应结束后抽滤,并以大量的蒸馏水冲洗固体物,最后用有机溶剂洗涤3次,干燥得取代基查尔酮。将产物重结晶。步骤2.于25ml烧瓶中加入1mmol取代基查尔酮,过量水合肼,并溶解于有机溶剂中,40-100℃搅拌反应一段时间(TLC检测)。反应结束后,冷却到5℃以下,反应产物自动析出,抽滤并用有机溶剂洗涤2次,重结晶得到第二步产物。步骤3.步骤3.反应生成酰胺系列:将步骤2产物与乙酸以1∶1.2的摩尔比分别加入50ml烧瓶中,用有机溶剂溶解,20-60℃搅拌反应一段时间(TLC检测)。反应结束,用真空将溶剂抽干,将烧瓶中残余固体溶于有机溶剂中,用酸溶液洗涤萃取3次。真空抽干萃取液,得到残余固体用有机溶剂重结晶,得到最终产物。
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CN103664786A (zh) * | 2013-11-04 | 2014-03-26 | 南京大学 | 一类水杨醛的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用 |
CN103724267A (zh) * | 2012-10-15 | 2014-04-16 | 南京大学 | 一类由水杨醛制备的吡唑啉类衍生物及其制法 |
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CN103724267A (zh) * | 2012-10-15 | 2014-04-16 | 南京大学 | 一类由水杨醛制备的吡唑啉类衍生物及其制法 |
CN103724267B (zh) * | 2012-10-15 | 2016-01-20 | 南京大学 | 一类由水杨醛制备的吡唑啉类衍生物及其制法 |
CN103086970A (zh) * | 2013-01-09 | 2013-05-08 | 南京大学 | 一类带有三氟甲苯基的3,5-二苯基-2h-吡唑衍生物的合成、制备方法及抗菌、抗癌作用 |
CN103664786A (zh) * | 2013-11-04 | 2014-03-26 | 南京大学 | 一类水杨醛的二氢吡唑磺胺衍生物的合成及在抗癌药物中的应用 |
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