CN103450177A - 一类甲硝唑接枝噻唑腙类衍生物的合成及制备方法 - Google Patents
一类甲硝唑接枝噻唑腙类衍生物的合成及制备方法 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类甲硝唑接枝噻唑腙类衍生物的合成及制备方法。
背景技术
甲硝唑,又名灭滴灵,为硝基咪唑类抗生素,对革兰氏阳性和阴性的厌氧菌,对脆弱类杆菌均有强力的杀菌作用。是临床上常用的抗感染基本药物。临床上用于治疗滴虫病、阿米巴病及防冶厌氧菌感染等。随着甲硝唑在临床上的广泛应用和对其药理机制的不断深入研究,各种文献报道甲硝唑的不良反应屡见不鲜。甲硝唑的常见不良反应有恶心、呕吐、头痛、腹痛、皮炎及变态反应等,其中最常见的不良反应有消化道反应、周围神经感觉异常和变态反应。所以对甲硝唑进行修饰,增强其抗菌作用,减少不良反应,是药物化学领域一个热门课题。
在杂环化合物中,以噻唑环最为令人关注,继1962年Merck公司成功开发噻菌灵以来,国内外相继成功开发出多个噻唑类杀菌剂,如三环唑、灭瘟唑、烯丙异噻唑、克菌强、噻氟酰胺、噻唑菌等。近年来含O、N、S的席夫碱,以其良好的抑菌抗病毒生物活性受到人们的重视,其中由于噻唑类席夫碱具有较强药理活性,将噻唑环引进到席夫碱分子中可能有加合作用,产生更强的活性而为人们所青睐,而且由于噻唑环具有对人体低毒及较好的生物活性,从而这类药物成为绿色药物研究的一个热点。
所以我们设计了一类甲硝唑接枝噻唑腙类衍生物,并对其药理活性进行深层次的研究。
发明内容
本发明的目的在于提供一类甲硝唑接枝噻唑腙类衍生物的合成及制备方法。
本发明的技术方案如下:
1.一类甲硝唑接枝噻唑腙类衍生物,其特征是它们有如下通式:
其中间体为
式中,R1、R2、R3选自H、C1-5烷基、C1-5烷氧基、卤素、卤素取代的C1-5烷基。
一种制备权利要求1所述的一类甲硝唑接枝噻唑腙类衍生物的合成及制备方法,它们由下列步骤成:
步骤1.将上面得到的化合物1和氨基硫脲混合,加入一定量的有机溶剂溶解,滴加适量的酸做催化剂,在室温下搅拌反应,TLC跟踪反应,反应完全后,减压蒸去有机溶剂得粗品,粗品经柱层析提纯得白色粉末2。
步骤2.将上面得到的化合物2,含各种取代基的α-溴代苯乙酮溶解于适量有机溶剂中,经TLC跟踪反应,反应完全后减压除去溶剂,经纯化得到本发明的目标物甲硝唑接枝噻唑腙类衍生物。
具体实施方式:
实施例一:(E)-2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)氨基硫脲的制备
取4-(2-(2-甲基-5-硝基-1-咪唑)乙氧基)-苯甲醛(0.1g,0.36mmoL)加入到50mL单口圆底烧瓶中,加25mL异丙醇溶解,再加入0.03g的氨基硫脲,滴加0.25mL的冰乙酸做催化剂,室温下搅拌反应,TLC跟踪反应,约24h后结束反应,减压蒸干,得到白色粉末。产率89.3%.m.p 216~219℃.1H NMR(DMSO-d6,300MHz)δ:1.05(t,J=7.0Hz,3H),2.08(s,1H),3.32(s,1H),3.48~3.40(m,2H),4.39~4.31(m,2H),4.72(t,J=4.9Hz,1H),6.91(d,8.7).7.71(d,J=8.7Hz,1H).
实施例二:(E)-2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基苯并噻唑的制备
取上述白色粉末(0.12g,0.35mmoL)置于50mL的单口圆底烧瓶中,加25mL异丙醇溶解,再加入等物质量(67.5mg,0.35mmoL)的α-溴代苯乙酮,室温下搅拌反应,TLC跟踪,约48h后反应完全,将得到的固体溶于无水乙醇重结晶提纯得到淡黄色粉末状目标化合物。产率85.3%.m.p 197~199℃.1HNMR(DMSO-d6,300MHz)δ:3.52(s,3H),4.38(t,J=5.0Hz,2H),4.73(t,J=4.1Hz,2H),6.95(d,J=8.7Hz,2H),7.30(t,J=7.2Hz,2H),7.40(t,J=7.6Hz,2H),7.57(d,J=8.7Hz,2H),7.85(d,7.44,2H),7.96(s,1H),8.04(s,1H).
实施例三:(E)-2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-4甲氧基苯并噻唑的制备
制备方法同实施例二,以4-甲氧基-α-溴代苯乙酮代替α-溴代苯乙酮,得到淡黄色粉末状目标化合物。产率83.2%.m.p 233~235℃.1H NMR(DMSO-d6,300MHz)δ:2.53(s,3H),3.79(s,3H),4.38(t,J=4.8Hz,2H),4.72(t,J=4.8Hz,2H),6.95(d,J=7.3Hz,2H),7.10(s,1H),7.36(s,1H),7.58(t,J=7.3Hz,3H),7.79(t,J=7.8Hz,2H),7.96(d,J=3.6Hz,2H),8.03(s,1H).
实施例四:(E)-2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-4溴苯并噻唑的制备
制备方法同实施例二,以4-溴-α-溴代苯乙酮代替α-溴代苯乙酮,得到淡黄色粉末状目标化合物。产率73.4%.m.p 249~250℃.1H NMR(DMSO-d6,300MHz)δ:2.53(s,3H),3.79(s,3H),4.38(t,J=4.8Hz,2H),4.72(t,J=4.8Hz,2H),6.95(d,J=8.7Hz,2H),7.60~7.55(m,4H),7.79(d,J=8.9Hz,2H),7.97(s,1H),8.04(s,1H).
实施例五:(E)-2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-4-三氟甲基苯并噻唑的制备
制备方法同实施例二,以4-三氟甲基-α-溴代苯乙酮代替α-溴代苯乙酮,得到黄色粉末状目标化合物。产率69.6%.m.p 234~236℃.1H NMR(DMSO-d6,300MHz)δ:2.54(s,3H),4.38(t,J=4.8Hz,2H),4.73(t,J=5.4Hz,2H),6.96(d,J=8.6Hz,2H),7.57(t,J=8.7Hz,3H),7.75(d,J=8.3Hz,2H),7.98(s,1H),8.06(d,J=7.6Hz,3H).
实施例六:(E)-2-(4-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-2溴苯并噻唑的制备
制备方法同实施例二,以2-溴-α-溴代苯乙酮代替α-溴代苯乙酮,得到黄色粉末状目标化合物。产率59.9%.m.p 249~250℃.1H NMR(DMSO-d6,300MHz)δ:2.53(s,3H),4.38(t,J=4.9Hz,2H),4.73(t,J=4.9Hz,2H),6.96(d,J=8.6Hz,2H),7.36(t,J=7.3Hz,2H),7.48(t,J=7.6Hz,2H),7.72(d,J=8.3Hz,4H),7.96(d,7.6,2H),8.04(s,1H)。
实施例七:(E)-2-(3-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)氨基硫脲的制备
取3-(2-(2-甲基-5-硝基-1-咪唑)乙氧基)-苯甲醛(0.1g,0.36mmoL)加入到50 mL单口圆底烧瓶中,加25mL异丙醇溶解,再加入0.03g的氨基硫脲,滴加0.25mL的冰乙酸做催化剂,室温下搅拌反应,TLC跟踪反应,约48h后结束反应,减压蒸干,得到白色粉末。产率89.3%.m.p 207~208℃.1H NMR(DMSO-d6,300MHz)δ:3.52(s,3H),4.38(t,J=5.0Hz,2H),4.73(t,J=4.1Hz,2H),6.88~6.92(m,2H),7.29(d,J=6.0Hz,2H),7.38(s,1H),8.01,(d,J=14.6Hz,3H),8.23(s,1H).
实施例八:(E)-2-(3-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基苯并噻唑的制备
取上述白色固体(0.12g,0.35mmoL)置于50mL的单口圆底烧瓶中,加25mL异丙醇溶解,再加入等物质量(67.5mg,0.35mmoL)的α-溴代苯乙酮,室温下搅拌反应,TLC跟踪,约24h后反应完全,将得到的固体溶于无水乙醇重结晶提纯得到淡色晶体状目标化合物。产率90.8%.m.p 225~227℃.1H NMR(DMSO-d6,300MHz)δ:2.47(s,3H),4.30(t,J=4.9Hz,2H),4.65(t,J=4.9Hz,2H),6.82(d,J=9.2Hz,2H),7.05(s,1H),7.16~7.26(m,4H),7.32(t,J=7.6Hz,2H),7.77(d,J=7.5Hz,2H),7.89(s,1H),7.95(s,1H).
实施例九:(E)-2-(3-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-4-甲氧基苯并噻唑的制备
制备方法同实施例八,以4-甲氧基-α-溴代苯乙酮代替α-溴代苯乙酮,得到黄色晶体状目标化合物,产率78.9%.m.p 222~224℃.1H NMR(DMSO-d6,300 MHz)δ:2.56(s,3H),3.89(s,3H),4.38(t,J=5.1Hz,2H),4.75(t,J=4.9Hz,2H),6.88~6.98(m,3H),7.14(d,J=7.2Hz,2H),7.24~7.35(m,2H),7.78(d,J=8.6Hz,2H),7.97(s,1H),8.08(s,1H).
实施例十:(E)-2-(3-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-4溴苯并噻唑的制备
制备方法同实施例八,以4-溴-α-溴代苯乙酮代替α-溴代苯乙酮,得到黄色粉末状目标化合物,产率68.9%.m.p 210~213℃.1H NMR(DMSO-d6,300MHz)δ:2.55(s,3H),4.38(t,J=4.8Hz,2H),4.73(t,J=4.9Hz,2H),6.90(d,J=7.9Hz,2H),7.14(s,1H),7.24~7.34(m,2H),7.40(s,1H),7.59(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.98(s,1H),8.03(s,1H)
实施例十一:(E)-2-(3-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-2-溴苯并噻唑的制备
制备方法同实施例八,以2-溴-α-溴代苯乙酮代替α-溴代苯乙酮,得到淡黄色粉末状目标化合物,产率87.8%.m.p 216~218℃.1H NMR(DMSO-d6,300MHz)δ:2.55(s,3H),4.39(t,J=4.9Hz,2H),4.74(t,J=4.9Hz,2H),6.92(d,J=6.9Hz,2H),7.15(s,1H),7.25~7.36(m,2H),7.59(s,1H),7.77(d,J=8.5Hz,2H),7.99(s,1H),8.06(t,J=6.1Hz,3H).
实施例十二:(E)-2-(3-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙氧基)苯亚甲基)亚联氨基-4-三氟甲基苯并噻唑的制备
制备方法同实施例八,以4-三氟甲基-α-溴代苯乙酮代替α-溴代苯乙酮,得到淡黄色粉末状目标化合物。产率83.4%.m.p 233~235℃.1H NMR(DMSO-d6,300MHz)δ:2.47(s,3H),4.30(t,J=5.0Hz,2H),4.66(t,J=4.9Hz,2H),6.82(d,J=7.8Hz,2H),7.06(s,1H),7.17~7.25(m,2H),7.28(t,J=6.5Hz,2H),7.39(t,J=7.6Hz,2H),7.64(d,J=8.3Hz,2H),8.87(t,J=7.8Hz,3H),7.96(s,1H) 。
Claims (1)
1.一类甲硝唑接枝噻唑腙类衍生物,其特征是它们有如下通式:
其中间体为
式中,R1、R2、R3选自H、C1-5烷基、C1-5烷氧基、卤素、卤素取代的C1-5烷基。
一种制备权利要求1所述的一类甲硝唑接枝噻唑腙类衍生物的合成及制备方法,它们由下列步骤成:
步骤1.将上面得到的化合物1和氨基硫脲混合,加入一定量的有机溶剂溶解,滴加适量的酸做催化剂,在室温下搅拌反应,TLC跟踪反应,反应完全后,减压蒸去有机溶剂得粗品,粗品经柱层析提纯得白色粉末2。
步骤2.将上面得到的化合物2,含各种取代基的α-溴代苯乙酮溶解于适量有机溶剂中,经TLC跟踪反应,反应完全后减压除去溶剂,经纯化得到本发明的目标物甲硝唑接枝噻唑腙类衍生物。
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