CN114230551A - 一种环丙基取代的噻吩类化合物的制备方法 - Google Patents
一种环丙基取代的噻吩类化合物的制备方法 Download PDFInfo
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- -1 cyclopropyl-substituted thiophene compound Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
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Abstract
本发明属于药物化学技术领域,公开一种环丙基取代的噻吩类化合物的制备方法,其以烯酰基环丙酰胺化合物和巯基羧酸酯为原料,碱为催化剂,溶于有机溶剂中,在低温条件下反应,通过分子间的迈克尔加成/分子内环化反应的串联,能高效、便捷、快速的获得结构多样性的环丙基取代的噻吩类化合物,为高效抗菌剂的创制提供了新思路,同时拓展了噻吩类抗菌剂的化合物筛选库;同时,提供上述方法制备得到的环丙基取代的噻吩类化合物在制备抗菌药物中的应用。
Description
技术领域
本发明属于药物化学技术领域,尤其是涉及一种环丙基取代的噻吩类化合物的制备方法。
背景技术
随着抗生素在临床上的广泛使用,滥用现象和细菌的耐药性问题日益突出,从而导致抗生素的疗效下降。目前,世界卫生组织已将细菌耐药性作为21世纪最大的公共卫生安全问题之一。因此,开发针对耐药菌株以及具有全新抗菌作用的新型抗菌药物具有重要的现实意义。
噻吩衍生物因其独特的分子结构及其高效、低毒的药理活性(如抗菌、抗病毒、杀螨虫、抗炎和杀灭微生物等),引起了很多药物学家与合成化学家广泛的重视(CatalysisCommunication,41(2013),119-122.)。此外,该类化合物也是一类重要的有机合成中间体,广泛应用于多种重要复杂分子的合成,为新农药的研究开发提供了极其广阔的发展空间。
在多样化的噻吩衍生物中,研究已表明组合了噻吩和环丙烷两种活性基团的环丙基取代噻吩类化合物对金黄色葡萄球菌、溶血性链球菌、福氏痢疾杆菌、白喉杆菌等抑制效果明显优于含单一活性基团噻吩或环丙基的化合物,而且该类化合物不仅能够有效降低单一活性物质的使用剂量,而且有助于降低其潜在的毒性(Inf.Chim.,No.187,147(1979)),因而被视为药物化学和合成化学研究中非常具有吸引力的结构框架。现阶段虽然对于环丙基取代噻吩类化合物的合成有一定的报道(Bioorganic&Medicinal Chemistry Letters11(2001)2011–2015;Inf.Chim.,No.187,147(1979)),但是现有的方法仍存在底物结构复杂难得、反应条件苛刻、反应路线较长、产率偏低、普适性较差等不足,从而导致该类抗菌类候选药物的制备受到了限制。
发明内容
为解决上述问题,本发明的目的是提供一种环丙基取代的噻吩类化合物的制备方法,其在碱性物质条件下,通过迈克尔加成反应(Michael addition reaction),能高效、便捷、快速的获得结构多样性的环丙基取代的噻吩类化合物,为高效抗菌剂的创制提供了新思路,同时拓展了噻吩类抗菌剂的化合物筛选库。
为实现上述发明目的,本发明采用如下技术方案:
一种环丙基取代的噻吩类化合物的制备方法,其以烯酰基环丙酰胺化合物A和巯基羧酸酯B为原料,碱为催化剂,溶于有机溶剂中,在低温条件下反应20~30min,通过分子间的迈克尔加成/分子内环化反应的串联,快速制备得到环丙基取代噻吩类化合物C;
反应路线如下:
其中,Ar1选自苯基、4-甲氧基苯基、4-氯苯基、2-甲基苯基、吡啶基、呋喃基或噻吩中的一种;Ar2选自苯基、4-甲氧基苯基、4-氯苯基、2-甲基苯基、苄基、萘基中的一种;R’选自乙基、甲基、异丙基、苯基或苄基中的一种。
进一步地,上述的烯酰基环丙酰胺化合物A和巯基羧酸酯B的摩尔比为1:1~1.3mmol,烯酰基环丙酰胺化合物A、有机溶剂和碱的用量之比为1mmol:5~8mL:1~2mmol。
进一步地,上述的碱为碳酸钾、碳酸铯、氢氧化钠、氢氧化钾或1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)中的一种。
进一步地,上述的有机溶剂为乙醇、异丙醇、甲醇、1,4-二氧六环、氮氮二甲基甲酰胺、二甲亚砜或四氢呋喃中的一种。
进一步地,上述的低温条件为-10~0℃。
进一步地,上述的环丙基取代的噻吩类化合物的制备方法,其用薄层色谱TLC监测反应进程,待反应物A完全消失后,向反应体系中加水停止反应,再用萃取剂萃取,合并有机相;有机相用干燥剂干燥,过滤、浓缩、柱层层析,获得目标环丙基取代噻吩类化合物C。
更进一步地,上述的萃取剂为二氯甲烷、乙酸乙酯、***或氯仿。
更进一步地,上述的有机相干燥剂为无水硫酸钠、无水氯化钙或无水硫酸镁。
本发明的另一目的是提供一种环丙基取代的噻吩类化合物,根据前面所述的方法制备而成,结构式为:
其中,Ar1选自苯基、4-甲氧基苯基、4-氯苯基、2-甲基苯基、吡啶基、呋喃基或噻吩中的一种;Ar2选自苯基、4-甲氧基苯基、4-氯苯基、2-甲基苯基、苄基、萘基中的一种;R’选自乙基、甲基、异丙基、苯基或苄基中的一种。
本发明的另一目的是提供由上述制备方法得到的环丙基取代的噻吩类化合物在制备抗菌药物中的应用。
进一步地,上述的抗菌药物是抗金黄色葡萄球菌、溶血性链球菌、福氏痢疾杆菌、白喉杆菌的药物。
由于采用如上所述的技术方案,本发明具有如下优越性:
本发明环丙基取代的噻吩类化合物的制备方法,其通过分子间C-S亲核加成以及随后分子内C-C亲核加成,构建环丙基取代噻吩类化合物;原料来源广,结构多样化,易操作,反应时间短,成本低,路线短,原子经济性好,收率高,具有良好的应用前景。
附图说明
图1是实施例1中的目标产物C1的氢谱图;
图2是实施例3中的目标产物C3的氢谱图。
具体实施方式
参照以下实施例可以对本发明作进一步详细说明;但是,以下实施例仅仅是例证,本发明并不局限于这些实施例。
实施例1
向50mL圆底烧瓶中加入α-烯酰基环丙酰胺A1(0.29g,1mmol)、巯基乙酸乙酯B1(0.1mL,1mmol)、乙醇6mL,然后缓慢加入碳酸钾(0.14g,1mmol),0℃搅拌20min;TLC监测反应完毕,将反应液倾入冰水中,剧烈搅拌后,用二氯甲烷萃取三次(3×10mL),合并有机相,然后用无水硫酸钠干燥,旋蒸除去溶剂,柱层析分离纯化,得白色产物C1 0.4g,产率为98%。
具体反应式为:
化合物C1的1HNMR(CDCl3,400MHz):δ:0.96-1.08(m,3H),1.28(t,J=8.0Hz,3H),1.55-1.61(m,1H),2.04-2.09(m,1H),2.41-2.47(m,1H),4.17-4.26(m,2H),4.42(s,1H),4.73-4.78(m,1H),7.13(t,J=8.0Hz,1H),7.24-7.28(m,5H),7.32-7.36(m,2H),7.50-7.63(m,2H),8.79(s,1H)。
实施例2
向50mL圆底烧瓶中加入α-烯酰基环丙酰胺A2(0.32g,1mmol)、巯基乙酸乙酯B1(0.12mL,1.2mmol)、四氢呋喃8mL,然后缓慢加入碳酸铯(0.49g,1.5mmol),-5℃搅拌25min;TLC监测反应完毕,将反应液倾入冰水中,剧烈搅拌后,用氯仿萃取三次(3×10mL),合并有机相,然后用无水硫酸镁干燥,旋蒸除去溶剂,柱层析分离纯化,得白色产物C2 0.41g,产率为93%。
具体反应式为:
化合物C2的1HNMR(CDCl3,400MHz):δ:0.94-1.08(m,3H),1.28(t,J=6.0Hz,3H),1.49-1.55(m,1H),2.03-2.07(m,1H),2.38-2.44(m,1H),3.80(s,3H),4.16-4.26(m,2H),4.41(s,1H),4.74-4.79(m,1H),6.87(d,J=8.0Hz,2H),7.24-7.39(m,5H),7.60(d,J=8.0Hz,2H),8.54(s,1H)。
实施例3
向50mL圆底烧瓶中加入α-烯酰基环丙酰胺A3(0.32g,1mmol)、巯基乙酸乙酯B1(0.1mL,1.0mmol)、氮氮二甲基甲酰胺5mL,然后缓慢加入碳酸铯(0.49g,1.5mmol),0℃搅拌30min;TLC监测反应完毕,将反应液倾入冰水中,剧烈搅拌后,用氯仿萃取五次(5×10mL),合并有机相,然后用无水硫酸镁干燥,旋蒸除去溶剂,柱层析分离纯化,得白色产物C20.40g,产率为89%。
具体反应式为:
化合物C3的1HNMR(CDCl3,400MHz):δ:0.95-1.05(m,3H),1.28(t,J=8.0Hz,3H),1.55-1.58(m,1H),2.01-2.06(m,1H),2.33-2.39(m,1H),4.17-4.22(m,2H),4.41(s,1H),4.70-4.74(m,1H),7.10-7.14(m,1H),7.28-7.35(m,4H),7.46-7.56(m,4H),8.76(s,1H)。
实施例4
向50mL圆底烧瓶中加入α-烯酰基环丙酰胺A4(0.29g,1mmol)、巯基乙酸甲酯B1(0.12mL,1.3mmol)、乙醇7mL,然后缓慢加入氢氧化钠(0.04g,1.0mmol),-10℃搅拌25min;TLC监测反应完毕,将反应液倾入冰水中,剧烈搅拌后,用乙酸乙酯萃取四次(4×10mL),合并有机相,然后用无水氯化钙干燥,旋蒸除去溶剂,柱层析分离纯化,得白色产物C2 0.36g,产率为91%。
具体反应式为:
化合物C4的1HNMR(CDCl3,400MHz):δ:1.17-1.23(m,3H),1.57-1.59(m,1H),2.11-2.14(m,1H),2.35-2.39(m,1H),3.96(s,3H),4.46(s,1H),4.77-4.79(m,1H),7.23-7.36(m,3H),7.44-7.51(m,2H),7.68-7.77(m,4H),8.91(s,1H)。
实施例5
向50mL圆底烧瓶中加入α-烯酰基环丙酰胺A5(0.29g,1mmol)、巯基乙酸苄酯B3(0.18mL,1.1mmol)、乙醇8mL,然后缓慢加入DBU(0.15mL,1.0mmol),0℃搅拌30min;TLC监测反应完毕,将反应液倾入冰水中,剧烈搅拌后,用***萃取三次(3×10mL),合并有机相,然后用无水硫酸钠干燥,旋蒸除去溶剂,柱层析分离纯化,得白色产物C5 0.38g,产率为81%。
具体反应式为:
化合物C5的1HNMR(CDCl3,400MHz):δ:0.92-0.96(m,3H),1.44-1.47(m,1H),2.01-2.06(m,1H),2.27-2.31(m,1H),4.24(s,2H),4.43(s,1H),4.64-4.68(m,1H),6.91-6.97(m,4H),7.11-7.35(m,6H),7.43-7.58(m,3H),7.62-7.89(m,2H),8.71(s,1H)。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其烯酰基环丙酰胺化合物A和巯基羧酸酯B的摩尔比为1:1~1.3mmol,烯酰基环丙酰胺化合物A、有机溶剂和碱的用量之比为1mmol:5~8mL:1~2mmol。
3.根据权利要求1所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其碱为碳酸钾、碳酸铯、氢氧化钠、氢氧化钾或1,8-二氮杂双环[5.4.0]十一碳-7-烯中的一种。
4.根据权利要求1所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其有机溶剂为乙醇、异丙醇、甲醇、1,4-二氧六环、氮氮二甲基甲酰胺、二甲亚砜或四氢呋喃中的一种。
5.根据权利要求1所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其低温条件为-10~0℃。
6.根据权利要求1所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其用薄层色谱TLC监测反应进程,待反应物A完全消失后,向反应体系中加水停止反应,再用萃取剂萃取,合并有机相;有机相用干燥剂干燥,过滤、浓缩、柱层层析,获得目标环丙基取代噻吩类化合物C。
7.根据权利要求6所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其萃取剂为二氯甲烷、乙酸乙酯、***或氯仿。
8.根据权利要求6所述的环丙基取代的噻吩类化合物的制备方法,其特征是:其有机相干燥剂为无水硫酸钠、无水氯化钙或无水硫酸镁。
10.一种权利要求9所述的环丙基取代的噻吩类化合物在制备抗菌药物中的应用。
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