CN103450091A - 一类咪唑类衍生物及其制备方法与用途 - Google Patents
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Abstract
一类咪唑类衍生物及其制备方法,其特征是它有如下通式:
Description
技术领域
本发明涉及咪唑类衍生物及其制备方法与用途。
背景技术
癌症是当前严重威胁人类健康的重要疾病之一,其治疗和预防引起广泛重视。当前临床用于治疗癌症的化学药物种类较多,如铂类、氮芥类、三唑类等,但大多数药物由于毒性大、不良反应多、生物利用度低而使其应用受到了限制。因此,寻找高效、低毒的抗癌药物已成为当前药物化学领域重点研究课题之一。
咪唑环是生物体内组胺、组氨酸产生生物活性和发挥生理作用的重要基团。咪唑环是结构中含有2个氮原子的五元芳氮杂环,易产生多种非共价键相互作用,如氢键与金属离子配位相互作用等。以这种特殊结构的咪唑环构筑的咪唑类衍生物具有较大的发展潜力,作为药物具有广泛的生物活性,如组胺受体阻滞剂,尤其作为抗癌药物显示了广阔的应用前景,近些年来其研究备受关注。
查尔酮不仅是一种重要的有机合成中间体,还具有多种药理作用。由于其分子结构具有较大的柔性,能与不同的受体结合,因此具有广泛的生物活性。由于其显著的生物药理活性及独特的可塑性结构,近年来引起了化学工作者的研究兴趣。据有关文献报道,许多查尔酮化合物具有抗蛲虫、抗肿瘤、抑制和清除氧自由基、抗菌、抗病毒、抗溃疡和解痉等生物活性。
咪唑类化合物作为抗癌药物存在药动学性质差、细胞毒性大等特点,根据其抗癌的结构特点及其构效关系,对其结构进行有效的改造,并借助计算机辅助设计和利用化学方法在一些先导化合物的结构基础上进行改造,以获得结构新颖、靶向性强的高效低毒咪唑类药物。随着研究的深入,必将有越来越多的咪唑类抗癌药物应用于临床,造福于癌症患者。
本发明的目的在于提供一类咪唑类衍生物及其制备方法与用途。
本发明的技术方案如下:
1.一类咪唑类衍生物及其制备,其特征是它有如下通式:
一类上述的咪唑类衍生物的制法,它由下列步骤组成:
步骤.在搅拌下依次将咪唑衍生物、有机溶剂、醛、无机盐溶液按一定比例加入到反应容器中,在一定的温度下反应一段时间(TLC监测反应),在反应结束后,向反应物中加适量的水或直接过滤得粗产品,粗品经柱层析或采用适当的有机溶剂重结晶提纯得目标化合物.
具体实施方案:
实施例一:
2-(2-(3-氟)-5-硝基-1-咪唑)乙醇
在搅拌下依次将甲硝唑(1.7g,10mmol)、DMSO(10mL)、间氟苯甲醛(1.3g,10mmol)、甲醇钠的甲醇溶液(0.8g,15mmol)加入到250mL圆底烧瓶中,恒温35℃搅拌反应3.5小时后(TLC跟踪反应;展开剂:V二氯甲烷∶V乙酸乙酯=2∶1),将反应液倒入蒸馏水(300mL)中,过滤得粗品,将得到的粗品溶于无水乙醇重结晶提纯得到淡黄色目标化合物1.8g。产率65.1%.m.p.75~78℃;1H NMR(DMSO-d6,300MHz)δ:8.22(s,1H,CH),7.79~7.69(m,2H,ArH),7.57(d,J=7.71Hz,1H,CH),7.51~7.42(m,2H,ArH),7.24~7.18(m,1H,CH),4.99(s,1H,OH),4.65(t,J=5.1Hz,2H,CH2),3.71(s,2H,CH2).
实施例二:
1-(5-硝基-2-苯乙烯基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以苯甲醛代替间氟苯甲醛,得到橘黄色目标化合物,产率73%。m.p.77~78℃;1H NMR(DMSO-d6,300MHz)δ:8.21(s,1H,CH),7.80~7.75(m,3H,ArH,CH),7.47~7.35(m,4H,ArH),5.02(d,J=5.4,1H,OH),4.58~4.39(m,2H,CH2),3.89~3.87(m,2H,CH),1.16(d,J=6.3,H,CH3).
实施例三:
1-(2-(4-溴苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以对溴苯甲醛代替间氟苯甲醛,得到黄色目标化合物,产率80%。M.p.65~66℃;1H NMR(DMSO-d6,300MHz)δ:8.21(s,1H,CH),7.77~7.72(m,3H,ArH),7.63(d,J=8.5,2H,CH),7.44~7.39(m,1H,ArH),5.00(d,J=5.4,1H,OH),4.58~4.40(m,2H,CH2),3.90~3.84(m,1H,CH),1.16(d,J=6.2,3H,CH3).
实施例四:
1-(2-(4-氟苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以对氟苯甲醛代替间氟苯甲醛,得到褐色标化合物,产率80%。m.p.77~78℃;1H NMR(DMSO-d6,300MHz)δ:8.20(s,1H,CH),7.86~7.74(m,3H,ArH),7.36~7.25(m,3H,ArH,CH),5.00(d,J=5.46,1H,OH),4.53~4.44(m,2H,CH2),3.93~3.8(m,1H,CH),1.16(d,J=2.4,3H,CH3).
实施例五:
1-(2-(4-氯苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以对氯苯甲醛代替间氟苯甲醛,得到黄色目标化合物,产率80%。m.p.78~79℃;1H NMR(DMSO-d6,300MHz)δ:8.21(s,1H,CH),7.82~7.73(m,3H,ArH),7.51~7.37(m,3H,ArH,CH),5.01(s,1H,OH),4.57~4.45(m,2H,CH2),3.93~3.80(m,1H,CH),1.17(d,J=6.3,3H,CH3).
实施例六:
2-(2-(4-氟)-5-硝基-1-咪唑)乙醇
制备方法同实施例一,以对氟苯甲醛代替间氟苯甲醛,得到橘黄色目标化合物,产率73%。M.p.65~66℃;1H NMR(DMSO-d6,300MHz)δ:8.22(d,J=4.74,1H,CH),7.86~7.75(m,3H,ArH),7.39~7.25(m,3H,ArH,CH),5.04~4.97(m,1H,OH),4.64~4.49(m,2H,CH2),3.73~3.68(m,2H,CH2).
实施例七:
1-(2-(3-氟苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,得到淡黄色标化合物,产率80%。M.p.82~83℃;1H NMR(DMSO-d6,300MHz)δ:8.21(s,1H,CH),7.79~7.68(m,2H,CH),7.58~7.40(m,3H,ArH),7.23~7.17(m,1H,A rH),5.01(d,J=5.4,1H,OH),4.59~4.41(m,2H,CH2),3.88~3.86(m,1H,CH).,1.17(d,J=6.60,3H,CH3).
实施例八:
1-(2-(3-氯苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以间氯苯甲醛代替间氟苯甲醛,得到淡绿色目标化合物,产率80%。M.p.62~63℃;1H NMR(DMSO-d6,300MHz)δ:8.22(d,J=3.0,1H,CH),7.93(s,1H,ArH),7.78~7.68(m,2H,CH),7.48~7.41(m,3H,ArH),5.00(s,1H,OH),4.60~4.43(m,2H,CH2),3.86(s,1H,CH),1.16(d,J=6.3,3H,CH3).
实施例九:
1-(2-(4-甲氧基苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以对甲氧基苯甲醛代替间氟苯甲醛,得到黄色目标化合物,产率80%。M.p.64~65℃;1H NMR(DMSO-d6,300MHz)δ:8.19(s,1H,CH),7.76~7.70(m,2H,ArH),7.24~7.19(m,2H,ArH),6.99(d,J=8.6,2H,CH),5.00(d,J=5.4,1H,OH),4.56~4.37(m,2H,CH2),3.87~3.81(m,4H,CH,CH3),1.15(d,J=6.2,3H,CH3).
实施例十:
1-(2-(3-甲氧基苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以间甲氧基苯甲醛代替间氟苯甲醛,得到褐色目标化合物,产率80%。M.p.72~73℃;1HNMR(DMSO-d6,300MHz)δ:8.21(s,1H,CH),7.77~7.72(m,1H,CH),7.39~7.32(m,4H,ArH),6.99~6.95 (m,1H,CH),5.01(s,1H,OH),4.59~4.41(m,2H,CH2),3.87~3.75(m,4H,CH,CH3),1.16(d,J=6.3,4H,CH3,CH).
实施例十一:
2-(5-硝基-2-(4-硝基苯乙烯)-1-咪唑)乙醇
制备方法同实施例一,以对硝基苯甲醛代替间氟苯甲醛,得到橘黄色目标化合物,产率73%。m.p.81~82℃;1H NMR(DMSO-d6,300MHz)δ:8.29~8.20(m,4H,ArH,CH),8.05~8.00(m,2H,ArH),7.87(d,J=15.8,1H,CH),7.61(d,J=15.8,1H,CH),5.01(t,J=5.6,1H,OH),4.8(t,J=5.0,2H,CH2),3.75~3.70(m,2H,CH2).
实施例十二:
1-(5-硝基-2-(4-硝基苯乙烯)-1-咪唑)丙基-2-醇
制备方法同实施例一.,以塞克硝唑代替甲硝唑,以对硝基苯甲醛代替间氟苯甲醛,,得到橘黄色目标化合物。产率73%.m.p.80~83℃;1H NMR(DMSO-d6,300MHz)δ:8.29~8.20(m,4H,ArH,CH),8.05~8.00(m,2H,ArH),7.87(d,J=15.8,1H,CH),7.61(d,J=15.8,1H,CH),5.01(t,J=5.6,1H,OH),4.8(t,J=5.0,2H,CH2),3.75~3.70(m,2H,CH2).1.15(d,J=6.2,3H,CH3).
实施例十三:
1-(2-(2-甲氧基苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以邻甲氧基苯甲醛代替间氟苯甲醛,,得到橘黄色目标化合物.,产率73%。M.p.64~66℃;1H NMR(DMSO-d6,300MHz)δ:8.19(s,1H,CH),8.08(d,J=15.8,1H,CH),7.85~7.82(m,1H,CH),7.41~7.30(m,2H,ArH),7.10~7.00(m,2H,ArH),5.02(d,J=5.4,1H,OH),4.55~4.36(m,2H,CH2),3.92~3.84(m,4H,CH,CH3),1.16(d,J=6.3,3H,CH3).
实施例十四:
2-(2-(3-溴)-5-硝基-1-咪唑)乙醇
制备方法同实施例一,以间溴苯甲醛代替间氟苯甲醛,得到褐色目标化合物。73%.m.p.81~83℃;1HNMR(DMSO-d6,300MHz)δ:8.22(s,1H,CH),8.08(s,1H,ArH),7.76~7.71(m,2H,ArH),7.57~7.36(m,3H,ArH,CH),4.99(t,J=4.0,1H,OH),4.65(t,J=5.7,2H,CH2),3.73~3.68(m,2H,CH2).
实施例十五:
1-(2-(3-溴苯乙烯)-5-硝基-1-咪唑)丙基-2-醇
制备方法同实施例一,以塞克硝唑代替甲硝唑,以间溴苯甲醛代替间氟苯甲醛,得到褐色目标化合物.。产率73%.m.p.71~72℃;1H NMR(DMSO-d6,300MHz)δ:8.21(s,1H,CH),8.06(s,1H,ArH),7.76~7.71(m,2H,ArH),7.57~7.36(m,3H,ArH,CH),5.01(d,J=5.5,1H,OH),4.60~4.43(m,2H,CH2),3.73~3.68(m,2H,CH2).3.90~3.83(m,1H,CH).1.14(d,J=9.1,3H,CH3)。
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CN104447705A (zh) * | 2014-10-21 | 2015-03-25 | 南京大学 | 一类含1-吲哚乙酸-5-硝基咪唑衍生物的合成及其生物活性评价 |
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