CN103304559A - 一类含吡唑啉与噻吩(或呋喃)结构的噻唑类衍生物及其制法与用途 - Google Patents
一类含吡唑啉与噻吩(或呋喃)结构的噻唑类衍生物及其制法与用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类含吡唑啉与噻吩(或呋喃)结构的噻唑类衍生物及其制备方法与用途。
背景技术
含有吡唑啉结构的化合物拥有广泛的药理特性:解热镇痛,抗风湿等。这类衍生物在被报道具有较好抗炎活性的同时,也被认为是一个有效的抗糖尿病靶向基团。大量报道中具有抗癌活性的化合物也都含有吡唑啉基团。近期,此类杂环氮衍生物已被证实具有二价阳离子载体的潜能,可作用于硫氰酸盐选择性细胞膜传感器。
作为其中一组化合物,噻吩类衍生物广泛应用于合成医药、农药、染料、化学试剂、高分子助剂等。带有噻吩环的抗生素比苯基同系物具有更好的疗效。许多新型的消炎镇痛、解痉挛、心血管、抗病毒、抗组胺、抗糖尿病、抗肿瘤药物均含有噻吩结构。
作为其中一组化合物。呋喃类衍生物能作用于细菌的酶系统,干扰细菌的糖代谢而有抑菌作用。目前使用的呋喃类药物有10余种。
噻唑类衍生物在医药工业中可作为多种新型中间体,也可作为抗血吸虫病药的中间体,并可作为第三代青霉素的基础原料。
基于以上研究我们合成了一系列含吡唑啉与噻吩(或呋喃)结构的噻唑类衍生物,此类化合物可能成为潜在的抗菌与抗肿瘤药物,对此类化合物的深入研究具有一定的理论和实际价值,对于寻找具有更高或更广谱的生物活性、更高的选择性、更低的毒性的药物前体,有着重要的意义。
发明内容
本发明的目的在于提供一类新型的含吡唑啉与噻吩(或呋喃)结构的噻唑类衍生物及其制备方法与用途。
本发明的技术方案如下:
一类含吡唑啉与噻吩(或呋喃)结构的噻唑类衍生物,它具有如下通式:
结构式中R1为:
R2为:H,-OCH3;
X为:S,O;
特别的,当R1为:
R2为--OCH3;X为O.
一种制备上述噻唑类衍生物的方法,它包括如下步骤:
步骤一:将取代基苯乙酮(5.0mmol),噻吩-2-甲醛(或糠醛)(5.1mmol)溶于20ml乙醇中,磁搅拌10min使混合均匀,缓慢滴入40%NaOH溶液10ml,磁搅拌,常温反应2h(TLC检测反应进行程度),产物以固体析出。反应结束后抽滤,并以大量的蒸馏水洗涤固体物,最后用冷乙醇洗涤3次(每次约3ml),干燥,产物用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶。
步骤二:在50ml烧瓶中加入2.0mmol步骤一中所得产物,2.0mmol硫代氨基脲,以20ml异丙醇(或20ml乙醇)加热至80℃溶解,80℃搅拌反应10h(TLC检测)。反应结束后,冷却至5℃以下,产物以固体形态析出,抽滤并以冷乙醇洗涤3次(每次约3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶得到第二步产物。
步骤三:取1.0mmol 步骤二中所得产物,1.0mmol含取代基的溴代苯乙酮,以20ml异丙醇(或20ml乙醇)加热至80℃溶解,加入0.05mmolNaOH固体,80℃搅拌反应10h(TLC检测)。反应过程中有部分产物析出,反应结束后,冷却至5℃以下,产物全部以固体形态析出,抽滤并以冷乙醇洗涤3次(每次约3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶得到目标化合物。
此类化合物可能成为潜在的抗菌与抗肿瘤药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但应注意本发明的范围并不受这些实施例的任何限制。
实施例一:2-(3-(4-溴苯基)-5-(噻吩-2-基)-4,5-二氢-1H-吡唑-1-基)-4-苯基噻唑(化合物1a)的制备
取5.0mmol对溴苯乙酮和5.1mmol噻吩-2-甲醛加入到50ml的圆底烧中,加入20ml无水乙醇,磁搅拌10min使混合均匀,缓慢滴入40%NaOH溶液10ml,磁搅拌,常温反应2h(TLC检测反应进行程度),产物以固体析出,抽滤,并以大量的蒸馏水洗涤固体物,用冷乙醇洗涤3次(每次3ml),干燥,产物用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶;在50ml烧瓶中加入2.0mmol上述产物,2.0mmol硫代氨基脲,以20ml异丙醇加热至80℃溶解,80℃回流反应10h(TLC检测)。反应结束后,冷却至5℃以下,产物以固体形态析出,抽滤并以冷乙醇洗涤3次(每次3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶;取1.0mmol上述产物,1.0mmol含取代基的溴代苯乙酮,以20ml异丙醇加热至80℃溶解,加入0.05mmolNaOH固体,80℃回流反应10h(TLC检测)。反应过程中有部分产物析出,反应结束后,冷却至5℃以下,产物全部以固体形态析出,抽滤并以冷乙醇洗涤3次(每次3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶得到纯净的化合物1a(淡黄色晶体)。Yellow crystal,Yield 79%;mp:183-186℃.1H NMR(CDCl3,300MHz)δ:3.50-3.54(d,2H,J=12.1Hz),6.50(m,1H),6.82(s,1H),6.94-6.97(m,1H),7.20-7.23(d,1H,J=6.3H z),7.30-7.32(m,1H),7.36-7.41(m,3H),7.57-7.60(d,2H, J=8.7Hz),7.65-7.68(d,2H,J=8.7Hz),7.80-7.82(d,2H,J=8.4Hz).MS(ESI):466.00(C22H16BrN3S2,[M+H]+).Anal.Calcd for C22H16BrN3S2:C,56.65;H,3.46;Br,17.13;N,9.01;S,13.75.Found:C,56.67;H,3.43;N,9.03.
实施例二:2-(3-(4-溴苯基)-5-(噻吩-2-基)-4,5-二氢-1H-吡唑-1-基)-4-(4-甲氧苯基)噻唑(化合物2a)的制备
制备方法同实施例一。以对甲氧基溴代苯乙酮代替实例一中的溴代苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,Yield 76%.mp:194-196℃.1H NMR(CDCl3,300MHz)δ:3.49-3.58(m,2H ),3.90-3.93(s,3H),6.57(s,1H),6.86(m,1H),6.96-6.97(m,3H),7.59-7.70(m,6H),7.77(m,1H),7.84(m,1H),MS(ESI):496.01(C23H18BrN3OS2,[M+H]+).Anal.Calcd for C23H18BrN3OS2:C,55.65;H,3.65;Br,16.10;N,8.46;O,3.22;S,12.92.Found:C,55.68;H ,3.64;N,8.46.
实施例三:2-(3-(3,4-二氯苯基)-5-(噻吩-2-基)-4,5-二氢-1H-吡唑-1-基)-4-苯基噻唑(化合物3a)的制备
制备方法同实施例一。以3,4-二氯苯乙酮代替实例一中的对溴苯乙酮,得到浅黄色晶体状目标化合物。Yellow crystal,Yield 73%;mp:192-193℃.1H NMR(CDCl3,300MHz)δ:3.45-3.50(m,1H),3.83-3.89(m,1H),6.07-6.10(m,1H),6.89(s,1H),6.97-6.98(m,1H),7.22-7.23(m,2H),7.28-7.29(m,1H),736-7.39(m,2H),7.50-7.52(d,1H,J=4.8Hz),7.60-7.62(d,1H ,J=5.1Hz),7.78-7.80(d,2H,J=4.5Hz),7.85(m,1H).MS(ESI):456.01(C22H15Cl2N3S2,[M+H]+).Anal.Calcd forC22H15Cl2N3S2:C,57.89;H ,3.31;Cl,15.54;N,9.21;S,14.05.Found:C,57.93;H,3.29;N,9.22.
实施例四:2-(3-(3,4-二氯苯基)-5-(噻吩-2-基)-4,5-二氢-1H-吡唑-1-基)-4-(4-甲氧苯基)噻唑(化合物4a)的制备
制备方法同实施例一。以3,4-二氯苯乙酮代替实例一中的对溴苯乙酮并以对甲氧基溴代苯乙酮代替实例一中的溴代苯乙酮,得到淡黄色晶体状目标化合物。
Yellow crystal,Yield 73%,mp:186-187℃.1H NMR(CDCl3,300MHz)δ:3.47-3.50(m,1H),3.85-3.86(s,3H),3.90(m,1H),6.70(s,1H),6.90-6.92(d,2H,J=5.1Hz),6.95-6.96(m,1H),7.21-7.22(d,1H,J=3.0Hz).7.29(m,1H),7.32(m,1H),7.50-7.52(d,1H,J=5.1Hz),7.60-7.62(d,1H,J=5.1Hz),7.72-7.74(d,2H,J=5.1Hz),7.85(s,1H).MS(ESI):486.02(C23H17Cl2N3OS2,[M+H]+).Anal.Calcd for C23H17Cl2N3OS2:C,56.79;H,3.52;Cl,14.58;N,8.64;O,3.29;S,13.18.Found:C,56.83;H,3.51;N,8.63.
实施例五:2-(3-(4-溴苯基)-5-(呋喃-2-基)-4,5-二氢-1H-吡唑-1-基)-4-苯基噻唑(化合物1b)的制备
制备方法同实施例一。以糠醛代替实例一中的噻吩-2-甲醛,得到淡黄色晶体状目标化合物。YelloW crystal,yield 78%,mp:203-205℃.1H NMR (CDCl3,300MHz)δ:3.74-3.78(d,2H ,J=12.1H z),6.35(m,1H),6.80(s,1H ),6.90(m,1H),7.32-7.35(m,2H),7.40-7.43(m,2H),7.58-7.60(d,3H,J=5.1H z),7.66-7.67(d,2H,J=5.1Hz),7.83-7.85(d,2H,J=4.8Hz).MS(ESI):450.02(C22H16BrN3OS,[M+H]+).Anal.Calcd for C22H16BrN3OS:C,58.67;H ,3.58;Br,17.74;N,9.33;O,3.55;S,7.12.Found:C,58.70;H,3.55;N,9.34.
实施例六:2-(3-(4-溴苯基)-5-(呋喃-2-基)-4,5-二氢-1H-吡唑-1-基)-4-(4-甲氧苯基)噻唑(化合物2b)的制备
制备方法同实施例一。以糠醛代替实例一中的噻吩-2-甲醛并以对甲氧基溴代苯乙酮代替实施例一中的溴代苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,yield 76%,mp:206-208℃.1H NMR(CDCl3,300MHz)δ:3.83-3.84(m,2H),3.97-3.99(s,3H),6.52(m,1H),6.93-7.01(m,6H ),7.19-7.20(d,1H,J=3.0Hz),7.78-7.80(d,2H,J=5.1Hz),7.84-7.86(d,2H ,J=5.1H z),7.92-7.94(m,1H).MS(ESI):480.03(C23H18BrN3O2S,[M+H]+).Anal.Calcd for C23H18BrN3O2S:C,57.51;H,3.78;Br,16.63;N,8.75;O,6.66;S,6.67.Found:C,57.52;H,3.77;N,8.76.
实施例七:2-(3-(3,4-二氯苯基)-5-(呋喃-2-基)-4,5-二氢-1H-吡唑-1-基)-4-苯基噻唑(化合物3b)的制备
制备方法同实施例一。以3,4二氯苯乙酮代替实例一中的对溴苯乙酮并以糠醛代 替实施例一中的噻吩-2-甲醛,得到淡黄色晶体状目标化合物。Yellow crystal,yield 73%,mp:217-219℃.1H NMR(CDCl3, 300MHz)δ:3.59-3.61(m,1H),3.70-3.76(m,1H),6.21(m,1H),6.36(m,1H),6.73(s,1H),6.85(m,1H ),7.23-7.34(m,2H),7.38-7.42(m,2H),7.51-7.53(d,1H,J=4.8Hz),7.62-7.63(d,1H,J=4.8Hz),7.81-7.83(d,2H,J=4.5Hz),7.86-7.87(m,1H).MS(ESI):440.03(C22H15Cl2N3OS,[M+H]+).Anal.Calcd for C22H15Cl2N3OS:C,60.01;H,3.43;Cl,16.10;N,9.54;O,3.63;S,7.28.Found:C,63.11;H,4.43;N,5.57.
实施例八:2-(3-(3,4-二氯苯基)-5-(呋喃-2-基)-4,5-二氢-1H-吡唑-1-基)-4-(4-甲氧苯基)噻唑(化合物4b)的制备
制备方法同实施例一。以3,4二氯苯乙酮、糠醛、对甲氧基溴代苯乙酮分别代替实例一中的对溴苯乙酮、噻吩-2-甲醛、溴代苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,yield 71%,mp:198-199℃.1H NMR(CDCl3,300MHz)δ:3.60-3.64(m,1H),3.70-3.75(m,1H),3.84-3.87(s,3H),6.35(m,1H),6.68(s,1H),6.83(m,1H),6.93-6.95(d,2H,J=5.1Hz),7.26(m,1H),7.33(m,1H ),7.52-7.54(d,1H,J=5.1Hz),7.62-7.64(d,1H,J=5.1Hz),7.76-7.78(d,2H,J=5.1Hz),7.87(s,1H).MS(ESI):470.04(C23H17Cl2N3O2S,[M+H]+).Anal.Calcd for C23H17Cl2N3O2S:C,58.73;H,3.64;Cl,15.07;N,8.93;O,6.80,S,6.82.Found:C,58.75;H,3.63;N,8.95.
实施例九:2-(3-(4-氟苯基)-5-(呋喃-2-基)-4,5-二氢-1H-吡唑-1-基)-4-(4- 甲氧苯基)噻唑(化合物5b)的制备
制备方法同实施例一。以对氟苯乙酮、糠醛、对甲氧基溴代苯乙酮分别代替实例一中的对溴苯乙酮、噻吩-2-甲醛、溴代苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,yield 75%,mp:205℃.1H NMR(CDCl3,300MHz)δ:3.86-3.91(m,5H),6.34(m,1H),6.56(s,1H),6.98-6.99(d,2H,J=5.1Hz),7.39(d,1H,J=1.8Hz),7.44-7.49(m,3H),7.61(m,1H),7.77-7.79(d,2H,J=5.1Hz),7.85-7.87(d,2H,J=5.1Hz).MS(ESI):420.11(C23H18FN3O2S,[M+H]+).Anal.Calcd for C23H18FN3O2S:C,65.86;H,4.33;F,4.53;N,10.02;O,7.63;S,7.64.Found:C,65.90;H,4.32;N,10.02.
实施例十:2-(5-(呋喃-2-基)-3-(对甲苯基)-4,5-二氢-1H-吡唑-1-基)-4-(4-甲氧苯基)噻唑(化合物6b)的制备
制备方法同实施例一。以对甲基苯乙酮、糠醛、对甲氧基溴代苯乙酮分别代替 实例一中的对溴苯乙酮、噻吩-2-甲醛、溴代苯乙酮,得到淡黄色晶体状目标化合物。Yellow crystal,yield 71%,mp:182-183℃.1H NMR(CDCl3,300MHz)δ:2.41(s,3H),3.61-3.66(m,1H),3.70-3.79(m,1H),3.84-3.87(s,3H),6.34(m,1H),6.67(s,1H),6.92-6.94(d,2H,J=5.1Hz),7.24(m,1H ),7.33(m,1H),7.38-7.40(m,3H),7.68-7.70(d,2H,J=4.8Hz),7.75-7.77(d,2H ,J=5.1Hz).MS(ESI):416.14(C24H21N3O2S,[M+H]+).Anal.Calcd for C24H21N3O2S:C,6937;H,5.09;N,10.11;O,7.70;S,7.72.Found:C,69.38;H,5.05;N,10.12。
Claims (4)
2.一种制备上述的噻唑类衍生物的方法,它由下列步骤组成:
步骤1.将取代基苯乙酮(5.0mmol),噻吩-2-甲醛(或糠醛)(5.1mmol)溶于20ml乙醇中,磁搅拌10min使混合均匀,缓慢滴入40%NaOH溶液10ml,磁搅拌,常温反应2h(TLC检测反应进行程度),产物以固体析出。反应结束后抽滤,并以大量的蒸馏水洗涤固体物,最后用冷乙醇洗涤3次(每次约3ml), 干燥,产物用乙醇与丙酮混合液(体积比乙醇∶丙酮=10)∶1)重结晶。
步骤2.在50ml烧瓶中加入2.0mmol步骤1中所得产物,20mmol硫代氨基脲,以20ml异丙醇(或20ml乙醇)加热至80℃溶解,80℃搅拌反应10h(TLC检测)。反应应结束后,冷却至5℃以下,产物以固体形态析出,抽滤并以冷乙醇洗涤3次(每次约3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶得到第二步产物。
步骤3.取1.0mmol步骤2中所得产物,1.0mmol含取代基的溴代苯乙酮,以20ml异丙醇(或20ml乙醇)加热下80℃溶解,加入0.05mmolNaOH固体,80℃搅拌反应10h(TLC检测)。反应过程中有部分产物析出,反应结束后,冷却至5℃以下,产物全部以固体形态析出,抽滤并以冷乙醇洗涤3次(每次约3ml),用乙醇与丙酮混合液(体积比乙醇∶丙酮=10∶1)重结晶得到目标化合物。
3.根据权利要求2所述的噻唑类衍生物的制备方法。
4.权利要求1所述的噻唑类衍生物在制备抗菌和抗肿瘤药物中的应用。
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