CN103497159B - 1,2-二取代-5-磺酰基咪唑类化合物的制备方法 - Google Patents
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
Abstract
本发明属于化合物的合成方法，具体涉及一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法。所述1,2-二取代-5-磺酰基咪唑类化合物的制备方法，是以通式III化合物经5位磺酰化反应获的得通式IV化合物，反应方程式如下：其中R1为烷基或环烷基；R2为烷基或芳基；R3为烷基或芳基。本发明提供的技术方案通过三步反应合成目标产物，总产率超过50%，为前述文献方法的7倍以上，不涉及有毒或危险试剂，操作简单，适合在工业化生产中使用。
Description
技术领域
本发明属于化合物的合成方法，具体涉及一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法。
背景技术
1,2-二取代-5-磺酰基咪唑类化合物是一类潜在的抗热带病药物，如果1-N位先进行取代后磺酰基只会取代在4位上，A.Shafiee等在J.HeterocyclicChemistry,35,141-144,1998中提供了1,2-二取代-5-磺酰基咪唑类化合物的两条合成路线，具体路线如下：
上述工艺路线长，并涉及使用剧毒试剂和强氧化试剂，造成环境污染，总收率一般也非常低（少于7%），根本无法用于工业化生产。
发明内容
本发明所要解决的技术问题是1,2-二取代-5-磺酰基咪唑类化合物目前的工艺路线不适于工业化生产，为了克服以上不足，提供了一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法。
为了解决上述技术问题，本发明的技术方案是：所述1,2-二取代-5-磺酰基咪唑类化合物的制备方法，是以通式III化合物经5位磺酰化反应获的得通式IV化合物，反应方程式如下:
其中
R1为烷基或环烷基；
R2为烷基或芳基；
R3为烷基或芳基。
优选地是，所述5位磺酰化反应是通式III化合物在格氏试剂作用下与取代磺酰氯反应获得通式IV化合物。
优选地是，所述格氏试剂为乙基溴化镁。
优选地是，所述通式III化合物是以通式I化合物为起始原料，首先经5位碘代反应获通式II化合物，再经烷基取代反应获通式III化合物，反应路线如下：
优选地是，所述R1为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基、环戊烷基或环己烷基；R2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、苄基或三苯甲基；R3为甲基、乙基或苄基。
优选地是，所述5位碘代反应是通式I化合物先进行4,5-二碘代反应后，再经还原反应获得通式II化合物，所述还原反应的还原试剂为亚硫酸钠。
优选地是，所述亚硫酸钠与通式I化合物的摩尔比为2.5～3.5:1。
优选地是，所述还原反应的溶剂为乙醇水溶液。
优选地是，所述还原反应的反应温度为50～100℃。
定义
如下列出了本文所用各种术语的定义：
术语“烷基”指饱和的直链或支链，例如直链的乙基、丙基，支链的异丙基、异丁基。
术语“环烷基”指单环或多个稠和环的碳链（碳环）取代基，实例如单环的环己基、环戊基，多个稠和环的十氢萘等。
术语“芳基”指芳香环衍生出的取代基，实例如对苯甲基、苄基和三苯甲基等。
术语“卤素”指氟、氯、溴或碘。
本发明提供的技术方案仅有三步反应，总产率超过50%，为前述文献方法的7倍以上，不涉及有毒或危险试剂，操作简单，适合在工业化生产中使用。
具体实施方式
本发明通过以下实施例进一步说明，以下实施例仅用于更具体说明本发明的优选实施方式，不用于对本发明的技术方案进行限定。上述本发明的技术方案均可实现本发明目的。即以下实施例所采用温度和试剂，均可用上文所述相应温度和试剂替代以实现本发明之目的。
下述制备例中：
核磁共振由400M Bruker核磁共振仪测定，TMS为内标，化学位移单位为ppm。
质谱由安捷伦液质联用色谱仪测定。
实施例中所用试剂均为市售商品。
实施例15-碘-2-甲基-1H-咪唑的合成
将2-甲基-1H-咪唑(5g,60.9mmol)投入1,4-二氧六环水溶液(1:1,500ml)中,向体系中添加碳酸钠(25.8g,243.6mmol)和I2(46.4g,182.7mmol),室温条件下搅拌过夜。反应完全后浓缩、浓缩液用饱和硫代硫酸钠稀释，收集沉淀物并水洗、干燥得4,5-二碘代-2-甲基-1H-咪唑的粗品。将获得的粗品和亚硫酸钠(22.6g,179mmol)投入到乙醇水溶液(1:1,800ml)中，然后加热到100℃反应48小时。收集沉淀物，水洗，干燥即得5-碘-2-甲基-1H-咪唑纯品9.7g，收率77%。
实施例25-碘-2-环己烷-1H-咪唑的合成
将2-环已烷-1H-咪唑(10g,66.1mmol)投入1,4-二氧六环水溶液(1:1,500ml)中,向体系中添加碳酸钠(30g,283.3mmol)和I2(50g,190mmol),室温条件下搅拌过夜。反应完全后浓缩、浓缩液用饱和硫代硫酸钠稀释，收集沉淀物并水洗、干燥得4,5-二碘代-2-环已烷-1H-咪唑的粗品。将获得的粗品和亚硫酸钠(23.3g,185mmol)投入到乙醇水溶液(1:1,800ml)中，然后加热到100℃反应40小时。收集沉淀物，水洗，干燥即得5-碘-2-环己烷-1H-咪唑纯品13.7g，收率75%。
实施例35-碘-2-甲基-1-三苯甲基-咪唑的合成
向5-碘-2-甲基-1H-咪唑(9.7g,48.1mmol)的二氯甲烷(90ml)溶液中加入三乙胺(13.4ml,96.2mmol)和三苯基氯甲烷(20.1g,72.1mmol)，室温搅拌2小时，体系加入二氯甲烷稀释，并水洗，饱和食盐水洗，静置分层，收集有机层干燥，脱溶得粗品，甲醇纯化得白色固体16.7g，产率80%。H1NMR(400MHz,CD3OD)ppm:7.39(6H,dd),7.26-7.15(4H,m),7.13-7.11(6H,m),6.76(1H,s),1.59(3H,s);LCMS[M+H]+:m/z=451.0。
实施例42-甲基-5-甲磺酰基-1-三苯甲基-咪唑的合成
控温在0℃左右，向5-碘-2-甲基-1-三苯甲基-咪唑(2g,4.4mmol)和四氢呋喃(15ml)的混合物中滴加乙基溴化镁的乙醚溶液(2.3ml,2.5M,5.77mmol)。控制反应体系在8℃-10℃搅拌1小时。甲磺酰氯(0.76g,6.67mmol)滴加入反应体系，滴加完毕后，反应体系在8℃-10℃继续搅拌2小时。反应完成加水淬灭，乙酸乙酯提取。收集有机层干燥并脱溶纯化，得白色固体产物1.2g，收率70%。H NMR(400MHz,CDCl3)ppm:7.44(1H,s,),7.38-7.40(9H,m),7.137-7.132(6H,m),3.19(3H,s),1.705(3H,s);LCMS[M+H]+:m/z=403.0。
实施例52-甲基-5-苯甲磺酰基-1-三苯甲基-咪唑的合成
控温在0℃左右，向5-碘-2-甲基-1-三苯甲基-咪唑(5g,11mmol)和四氢呋喃(50ml)的混合物中滴加乙基溴化镁的乙醚溶液(5.3ml,2.5M,13.2mmol)。控制反应体系在8℃-10℃搅拌1小时。苯甲磺酰氯(1.38g,12.1mmol)加入反应体系，滴加完毕后，反应体系在8℃-10℃继续搅拌2小时。反应完成加水淬灭，乙酸乙酯提取。收集有机层干燥并脱溶纯化，得白色固体产物4g，收率75%。
Claims (5)
1.一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法，其特征在于，所述1,2-二取代-5-磺酰基咪唑类化合物的制备方法，是以通式III化合物经5位磺酰化反应获的得通式IV化合物，反应方程式如下:
其中
R1为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环丙基、环戊
烷基或环己烷基；R2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁
基、苄基或三苯甲基；R3为甲基、乙基或苄基；
所述5位磺酰化反应是通式III化合物在格氏试剂作用下与取代磺酰氯反应获得通式IV化合物，所述格氏试剂为乙基溴化镁；
所述通式III化合物是以通式I化合物为起始原料，首先经5位碘代反应获通式II化合物，再经烷基取代反应获通式III化合物，反应路线如下：
2.根据权利要求1所述一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法，其特征在于，所述5位碘代反应是通式I化合物先进行4,5-二碘代反应后，再经还原反应获得通式II化合物，所述还原反应的还原试剂为亚硫酸钠。
3.根据权利要求2所述一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法，其特征在于，所述亚硫酸钠与通式I化合物的摩尔比为2.5～3.5:1。
4.根据权利要求2所述一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法，其特征在于，所述还原反应的溶剂为乙醇水溶液。
5.根据权利要求2所述一种1,2-二取代-5-磺酰基咪唑类化合物的制备方法，其特征在于，所述还原反应的反应温度为50～100℃。
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