CN103086970A - 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 - Google Patents
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 Download PDFInfo
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Abstract
一类带有三氟甲苯基的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。R3为:3-氢,3-氯,3-溴。R2为:5-氯,5-溴。本发明公开了其制法。
Description
技术领域
本发明涉及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
背景技术
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)和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杂环化合物,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,据许多文献报道,很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,因此一直是人们研究的热点。
本文中,通过前期工作中已经合成的新型查尔酮衍生物与过量水合肼反应形成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,甲状腺癌以及抗菌活性。
发明内容
本发明的目的在于提供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。
本发明的技术方案如下:
1.一类带有三氟甲苯基的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。
R3为:3-氢,3-氯,3-溴。
R2为:5-氯,5-溴。
2.一种制备上述的带有三氟甲苯基的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.取第一步产物(1mmol)及4-氯-3,5-二硝基三氟甲苯(1mmol)分别溶于N,N-二甲基甲酰胺(DMF)(5-10ml),加入催化剂叔丁醇钾(0.75mmol),常温搅拌约4-6小时,反应完全后(TLC检测),用乙酸乙酯及饱和水溶液萃取,取有机层,70℃旋转蒸发仪旋出乙酸乙酯,呈现油状物,常温滴加少量乙醇,析出固体;再用柱层析(石油醚和醋酸乙酯(1∶1))纯化得目标化合物。
步骤3.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,重结晶得到第三步产物。
步骤4.反应生成酰胺系列:将步骤3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-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲苯基)-4,5-二氢-1H-吡唑-1-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5h(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。取第一步产物(1mmol)及4-氯-3,5-二硝基三氟甲苯(1mmol)分别溶于N,N-二甲基甲酰胺(DMF)(5-10ml),加入催化剂叔丁醇钾(0.75mmol),常温搅拌约4-6h,反应完全后(TLC检测),用乙酸乙酯及饱和水溶液萃取,取有机层,70℃旋转蒸发仪旋出乙酸乙酯,呈现油状物,常温滴加少量乙醇,析出固体;再用柱层析(石油醚和醋酸乙酯(1∶1))纯化得目标化合物。将产物纯化,干燥后,称取2mmol加入到另一个50ml单口烧瓶内,加入0.4ml水合肼,并溶解于10ml正丙醇中,90℃搅拌反应10h(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,重结晶纯化得到第三步产物。将步骤3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10h(TLC检测)。反应结束后,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50ml 8%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:65%.熔点:203-205℃.1HNMR(300MHz,DMSO)δ:1.98(s,3H),2.33(d,J=6.42Hz,3H),3.76-3.83(m,1H),3.99-4.06(m,2H),5.64-5.69(m,1H),7.00(d,J=2.19Hz,1H),7.30(t,J=8.78Hz,2H),7.65(t,J=6.30Hz,1H),7.80-7.85(m,2H),9.85(s,1H),MS(ESI):685(C25H18Br2F3N4O6,[M+H]+).Anal C25H17Br2F3N4O6.Calcd for:C,43.76;H,2.50;N,8.16.Found:C,43.68;H,2.45;N,8.21.
实施例二:1-(5-(3,5-二氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲苯基)-4,5-二氢-1H-吡唑-1-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:71%.熔点:245-247℃.1H NMR(300MHz,DMSO)δ:2.00(s,3H),2.50(t,J=1.83Hz,3H),3.40(s,1H),4.42(J=4.56Hz,2H),5.66(m,1H),7.57-7.64(m,3H),7.74-7.78(m,1H),8.28(m,1H),11.98(m,1H),12.40(s,1H),MS(ESI):597(C25H18Cl2F3N4O6,[M+H]+).Anal C25H17Cl2F3N4O6.Calcd for:C,50.27;H,2.87;N,9.38.Found:C,49.98;H,2.85;N,9.31.
实施例三:1-(5-(5-溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲苯基)-4,5-二氢-1H-吡唑-1-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:65%.熔点:245-247℃.1H NMR(300MHz,DMSO)δ:1.98(s,3H),2.32(d,J=7.14Hz,3H),3.72-3.82(m,1H),3.99-4.06(m,2H),5.54-5.59(m,1H),6.79(d,J=8.61Hz,1H),6.91(d,J=2.01Hz,1H),7.21-7.26(m,3H),7.65(d,J=7.86Hz,2H),9.99(s,1H),MS(ESI):607(C25H19BrF3N4O6,[M+H]+).Anal C25H18 BrF3N4O6.Calcd for:C,49.44;H,2.99;N,9.23.Found:C,49.38;H,2.95;N,9.21.
实施例四:1-(5-(5-氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲苯基)-4,5-二氢-1H-吡唑-1-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:79%.熔点:260-262℃.1H NMR(300MHz,DMSO)δ:1.99(s,3H),2.35(d,J=2.04Hz,3H),3.72-3.82(m,1H),3.99-4.06(m,2H),5.54-5.59(m,1H),6.87(d,J=3.69Hz,1H),6.96(d,J=2.01Hz,1H),7.24(s,3H),7.69(d,J=2.07Hz,2H),9.93(s,1H),MS(ESI):563(C25H19ClF3N4O6,[M+H]+).Anal C25H18ClF3N4O6.Calcd for:C,53.34;H,3.22;N,9.95.Found:C,53.38;H,3.19;N,9.91
实施例五1-(5-(3,5-二溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲氧苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物5)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:75%.熔点:245-247℃.1H NMR(300MHz,DMSO)δ:2.50(s,3H),2.35(d,J=2.04Hz,3H),3.42-3.48(m,3H),5.68(d,J=6.93Hz,1H),7.01(d,J=2.19Hz,1H),7.31(t,J=2.01Hz,2H),7.65(d,J=2.19Hz,1H),7.83(t,J=7.13Hz,2H),9.79(s,1H),MS(ESI):701(C25H18Br2F3N4O6,[M+H]+).AnalC25H17Br2F3N4O6.Calcd for:C,42.76;H,2.44;N,7.98.Found:C,42.58;H,2.29;N,7.91.
实施例六:1-(5-(3,5-二氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲氧苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物6)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:74%.熔点:198-200℃.1H NMR(300MHz,DMSO)δ:2.19(s,3H),3.45(d,J=2.04Hz,4H),4.33(s,2H),7.61(d,J=2.19Hz,1H),7.78(t,J=2.01Hz,2H),8.16-8.26(m,2H),10.92(s,2H),11.52(d,J=12.78Hz,1H),MS(ESI):701(C25H18Cl2F3N4O6,[M+H]+).Anal C25H17Cl2F3N4O6.Calcd for:C,48.96;H,2.79;N,9.13.Found:C,48.88;H,2.72;N,9.11.
实施例七:1-(5-(5-溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲氧苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物7)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-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:67%.熔点:245-247℃.1H NMR(300MHz,DMSO)δ:2.28(s,3H),3.75(d,J=12.06Hz,4H),3.97-4.06(m,2H),5.51-5.56(m,1H),6.77(d,J=8.61Hz,1H),6.88(s,1H),6.97(d,J=8.79Hz,2H),7.18-7.22(m,1H),7.67(d,J=8.79Hz,2H),9.96(s,1H),MS (ESI):701(C25H19BrF3N4O7,[M+H]+).Anal C25H18BrF3N4O7.Calcd for:C,48.17;H,2.91;N,8.99.Found:C,48.28;H,2.92;N,9.11.
实施例八:1-(5-(5-氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对甲氧苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物8)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:70%.熔点:255-257℃.1H NMR(300MHz,DMSO)δ:2.34(d,J=18.84Hz,3H),3.76(t,J=10.98Hz,4H),3.99(s,2H),5.56(d,J=7.68Hz,1H),6.82(t,J=11.34Hz,2H),6.99(d,J=8.79Hz,2H),7.10(d,J=8.79Hz,1H),7.70(d,J=8.61Hz,2H),9.99(s,1H),MS(ESI):579(C25H19ClF3N4O7,[M+H]+).Anal C25H18ClF3N4O7.Calcd for:C,51.87;H,3.13;N,9.68.Found:C,51.78;H,3.02;N,9.71.
实施例九:1-(5-(3,5-二溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氟苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物9)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:72%.熔点:199-201℃.1H NMR(300MHz,DMSO)δ:2.41 (d,J=18.84Hz,3H),3.77(s,2H),3.83(d,J=7.68Hz,1H),5.65-5.70(m,1H),7.01(s,1H),7.30(t,J=8.87Hz,2H),7.64(d,J=2.19Hz,1H),7.83(t,J=8.61Hz,2H),9.79(s,1H),MS(ESI):689(C25H15Br2F4N4O6,[M+H]+).Anal C25H14Br2F4N4O6.Calcd for:C,41.76;H,2.04;N,8.12.Found:C,41.78;H,2.02;N,8.11.
实施例十:1-(5-(3,5-二氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氟苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物10)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:71%.熔点:213-215℃.1H NMR(300MHz,DMSO)δ:2.43(d,J=2.19Hz,3H),3.79(d,J=2.19Hz,2H),3.85(d,J=8.87Hz,1H),5.70(s,1H),7.04(s,1H),7.32(d,J=8.87Hz,2H),7.67(t,J=2.19Hz,1H),7.85(d,J=8.87Hz,2H),9.92(s,1H),MS(ESI):601(C25H15Cl2F4N4O6,[M+H]+).Anal C25H14Cl2F4N4O6.Calcd for:C,47.94;H,2.35;N,9.32.Found:C,47.78;H,2.32;N,9.21.
实施例十一:1-(5-(5-溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氟苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物11)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:67%.熔点:215-217℃.1H NMR(300MHz,DMSO)δ:2.30(s,3H),3.89(d,J=8.4Hz,2H),3.95(s,1H),5.75(s,1H),6.79(t,J=7.13Hz,1H),7.06(d,J=2.13Hz,1H),7.24(d,J=2.13Hz,2H),7.75(d,J=8.4Hz,2H),9.92(s,1H),MS(ESI):567(C24H15BrF4N4O6,[M+H]+).Anal C24H14BrF4N4O6.Calcd for:C,47.15;H,2.47;N,9.17.Found:C,47.09;H,2.52;N,9.11.
实施例十二:1-(5-(5-氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氟苯基)-4,5-二氢-1H-吡唑-1-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,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:195-197℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),4.03(t,J=7.13Hz,3H),5.80(s,1H),6.83(d,J=9.15Hz,1H),7.10(d,J=8.4Hz,1H),7.28(t,J=8.78Hz,2H),7.81(t,J=7.13Hz,2H),10.00(s,1H),MS(ESI):567(C24H15ClF4N4O6,[M+H]+).Anal C24H14ClF4N4O6.Calcd for:C,50.85;H,2.67;N,9.88.Found:C,50.78;H,2.62;N,9.81.
实施例十三:1-(5-(3,5-二溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氯苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物13)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:63%.熔点:205-207℃.1H NMR(300MHz,DMSO)δ:2.27(s,3H),3.58(s,3H),6.47(d,J=8.4Hz,2H),6.87(t,J=2.19Hz,1H),7.17(d,J=2.17Hz,2H),7.45(t,J=8.61.Hz,2H),9.95(s,1H),MS(ESI):705(C24H15Br2ClF3N4O6,[M+H]+).Anal C24H14Br2ClF3N4O6.Calcd for:C,40.79;H,2.00;N,7.93.Found:C,40.78;H,2.02;N,8.01.
实施例十四:1-(5-(3,5-二氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氯苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物14)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:66%.熔点:213-215℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.74-3.84(m,3H),6.78(d,J=8.58Hz,2H),6.94(d,J=2.19Hz,1H),7.21-7.25(m,2H),7.51(d,J=8.61Hz,2H),10.00(s,1H),MS(ESI):617(C24H15Cl3F3N4O6,[M+H]+).Anal C24H14Cl3F3N4O6.Calcd for:C,46.66;H,2.28;N,9.07.Found:C,46.78;H,2.22;N,9.01.
实施例十五:1-(5-(5-溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氯苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物15)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:65%.熔点:271-273℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.76(s,1H),4.02(d,J=8.58Hz,2H),6.87(d,J=2.37Hz,1H),7.40(d,J=2.37Hz,1H),7.51(d,J=8.58Hz,2H),7.60-7.65(m,1H),7.78(d,J=8.58Hz,2H),7.94(s,1H),9.91(s,1H),MS(ESI):627(C24H16BrClF3N4O6,[M+H]+).Anal C24H15BrClF3N4O6.Calcd for:C,45.92;H,2.41;N,8.92.Found:C,45.88;H,2.42;N,8.97.
实施例十六:1-(5-(5-氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对氯苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物16)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: 275-277℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.79(s,1H),4.05(t,J=2.37Hz,2H),6.93(d,J=2.37Hz,1H),7.45(t,J=8.4Hz,1H),7.51(d,J=8.58Hz,2H),7.68(s,1H),7.81(t,J=2.13Hz,2H),7.93(d,J=8.58Hz,1H),9.95(s,1H),MS(ESI):627(C24H16Cl2F3N4O6,[M+H]+).Anal C24H15Cl2F3N4O6.Calcd for:C,49.42;H,2.59;N,9.61.Found:C,49.38;H,2.52;N,9.57.
实施例十七:1-(5-(3,5-二溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对溴苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物17)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:65%.熔点:247-249℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.76(d,J=8.58Hz,2H),4.32(s,1H),5.64-5.69(m,1H),7.01(s,1H),7.64-7.73(m,5H),9.76(s,1H),MS(ESI):749(C24H15Br3F3N4O6,[M+H]+).AnalC24H14Br3F3N4O6.Calcd for:C,38.38;H,1.88;N,7.46.Found:C,38.41;H,1.82;N,7.47.
实施例十八:1-(5-(3,5-二氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对溴苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物18)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:69%.熔点:245-247℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.82(s,1H),4.33(s,2H),5.64-5.69(m,1H),7.01(d,J=2.19Hz,1H),7.64-7.73(m,5H),9.76(s,1H),MS(ESI):749(C24H15BrCl2F3N4O6,[M+H]+).Anal C24H14BrCl2F3N4O6.Calcd for:C,43.53;H,2.13;N,8.46.Found:C,43.46;H,2.12;N,8.47.
实施例十九:1-(5-(5-溴-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对溴苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物19)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:68%.熔点:255-257℃.1H NMR(300MHz,DMSO)δ:2.32(s,3H),3.47(s,1H),4.33(s,2H),5.64-5.70(m,1H),6.75(d,J=8.79Hz,2H),7.01(d,J=2.19Hz,1H),7.64-7.73(m,4H),9.77(s,1H),MS(ESI):671(C24H16Br2F3N4O6,[M+H]+).Anal C24H15Br2F3N4O6.Calcd for:C,42.88;H,2.25;N,8.33.Found:C,42.86;H,2.22;N,8.37.
实施例二十:1-(5-(5-氯-2-(2,6-二硝基-4-(三氟甲基)苯氧基)苯基)-3-(对溴苯基)-4,5-二氢-1H-吡唑-1-基)乙酮
(化合物18)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:2.33(s,3H),3.80(s,1H),4.34(s,2H),5.61(s,1H),6.84(d,J=8.79Hz,2H),7.11(t,J=4.29Hz,1H),7.64-7.73(m,4H),10.01(s,1H),MS(ESI):627(C24H16BrClF3N4O6,[M+H]+).Anal C24H15BrClF3N4O6.Calcd for:C,45.92;H,2.41;N,8.92.Found:C,45.86;H,2.32;N,8.87。
Claims (5)
2.根据权利要求1所述的带有三氟苯甲基的3,5-二苯基-2H-吡唑衍生物,其特征是所述衍生物由以下步骤制备:
步骤1.制备查尔酮原料:将取代基水杨醛,取代基苯乙酮分别溶于有机溶剂,缓慢滴入碱溶液,磁力搅拌,在一定的温度下冰浴一段时间后常温反应一段时间(TLC检测反应进行程度),滴加若干量的酸溶液,调制到适度的PH值,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.取第一步产物及4-氯-3,5-二硝基三氟甲苯分别溶于N,N-二甲基甲酰胺(DMF),加入催化剂叔丁醇钾,常温搅拌,反应完全后(TLC检测),用乙酸乙酯及饱和水溶液萃取,取有机层,旋转蒸发仪旋出乙酸乙酯,呈现油状物,常温滴加少量乙醇,析出固体;再用柱层析纯化得目标化合物。
步骤3.于25ml烧瓶中加入取代基查尔酮,过量水合肼,并溶解于有机溶剂中,搅拌反应一段时间(TLC检测)。反应结束后,冷却反应产物自动析出,抽滤并用有机溶剂洗涤2次,重结晶得到第三步产物。
步骤4.反应生成酰胺系列:将步骤3产物与乙酸分别加入50ml烧瓶中,用有机溶剂溶解,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。
3.根据权利要求1或2所述的带有三氟苯甲基的3,5-二苯基-2H-吡唑衍生物,其特征是步骤1中所述的取代苯乙酮与取代基水杨醛的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为乙醇,所述的磁力搅拌时间为10min,所述的冰浴温度为零下5℃至0℃,最优温度为0℃,所述调至酸性的pH值为5.0-6.5,最优pH值为6.0,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。步骤2中所述的第一步产物,4-氯-3,5-二硝基三氟甲苯,叔丁醇钾的投料摩尔比为(4∶4-5∶3-4),最优投料摩尔比为(4∶4∶3),常温搅拌约4-6h,80℃旋转蒸发仪旋出乙酸乙酯,柱层析为(石油醚和醋酸乙酯(1∶1))进行纯化目标化合物。步骤3中所述的搅拌温度为40-100℃(最适80℃),冷却的温度为5℃以下,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。步骤4中所述的步骤3产物与乙酸的投料摩尔比为1∶1.2,溶解所用的有机溶剂是二氯甲烷,搅拌温度为20-60℃,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。
4.一类带有三氟苯甲基的3,5-二苯基-2H-吡唑衍生物的制备方法,其特征是所述方法包括以下步骤:
步骤1.制备查尔酮原料:将取代基水杨醛,取代基苯乙酮分别溶于有机溶剂,缓慢滴入碱溶液,磁力搅拌,在一定的温度下冰浴一段时间后常温反应一段时间(TLC检测反应进行程度),滴加若干量的酸溶液,调制到适度的PH值,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.取第一步产物及4-氯-3,5-二硝基三氟甲苯分别溶于N,N-二甲基甲酰胺(DMF),加入催化剂叔丁醇钾,常温搅拌,反应完全后(TLC检测),用乙酸乙酯及饱和水溶液萃取,取有机层,旋转蒸发仪旋出乙酸乙酯,呈现油状物,常温滴加少量乙醇,析出固体;再用柱层析纯化得目标化合物。
步骤3.于25ml烧瓶中加入取代基查尔酮,过量水合肼,并溶解于有机溶剂中,搅拌反应一段时间(TLC检测)。反应结束后,冷却反应产物自动析出,抽滤并用有机溶剂洗涤2次,重结晶得到第三步产物。
步骤4.反应生成酰胺系列:将步骤3产物与乙酸分别加入50ml烧瓶中, 用有机溶剂溶解,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。
5.根据权利要求4所述的带有三氟苯甲基的3,5-二苯基-2H-吡唑衍生物的制备方法,其特征是步骤1中所述的取代苯乙酮与取代基水杨醛的投料摩尔比为1∶(1-1.1),最优投料摩尔比为1∶1.05,所述的有机溶剂为乙醇,所述的磁力搅拌时间为10min,所述的冰浴温度为零下5℃至0℃,最优温度为0℃,所述调至酸性的pH值为5.0-6.5,最优pH值为6.0,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。步骤2中所述的第一步产物,4-氯-3,5-二硝基三氟甲苯,叔丁醇钾的投料摩尔比为(4∶4-5∶3-4),最优投料摩尔比为(4∶4∶3),常温搅拌约4-6h,80℃旋转蒸发仪旋出乙酸乙酯,柱层析为(石油醚和醋酸乙酯(1∶1))进行纯化目标化合物。步骤3中所述的搅拌温度为40-100℃(最适80℃),冷却的温度为5℃以下,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。步骤4中所述的步骤3产物与乙酸的投料摩尔比为1∶1.2,溶解所用的有机溶剂是二氯甲烷,搅拌温度为20-60℃,所述的重结晶条件为采用体积比为10∶1的乙醇与丙酮混合液重结晶。
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