CN106432131A - 一种三亚胺噻唑衍生物的制备方法 - Google Patents

一种三亚胺噻唑衍生物的制备方法 Download PDF

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CN106432131A
CN106432131A CN201610841332.1A CN201610841332A CN106432131A CN 106432131 A CN106432131 A CN 106432131A CN 201610841332 A CN201610841332 A CN 201610841332A CN 106432131 A CN106432131 A CN 106432131A
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thiazoles
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CN106432131B (zh
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李明
王鹏飞
袁文揆
文丽荣
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Tancheng Medical Chemical Industry Development Group Co ltd
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Qingdao University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

本发明公开了属于有机合成技术领域的一种三亚胺噻唑衍生物的制备方法。所述方法为：向反应器中，加入硫脲和异腈，在乙酰丙酮镍(Ni(acac)2)的作用下，室温搅拌至反应完毕，有大量固体析出，过滤，并用甲醇洗涤，干燥得到目标化合物。本发明所提供的三亚胺噻唑衍生物的制备方法科学合理，具有溶剂绿色，合成方法简单，反应时间短，产率较高，后处理简单，产品易于纯化等特点。其反应方程式如下。

Description

一种三亚胺噻唑衍生物的制备方法
技术领域
本发明属于有机合成技术领域，具体涉及一种三亚胺噻唑衍生物的制备方法。
背景技术
在农药领域，三亚胺噻唑衍生物表现出良好的杀螨作用，三亚胺噻唑类农药如德国拜耳公司生产的氟螨噻(Flubenzimine)(Bayer AG.DE2210882A1,1972.)，对仁果类、李树上的螨属害虫防治效果显著，对辣根猿叶甲幼虫100％有效。因此合成三亚胺噻唑衍生物具有重要意义。
三亚胺噻唑衍生物的制备方法有：
1)Bayer合成法：以硫脲和全氟代二甲基乙二胺为起始原料，在氟化钠作用下合成三亚胺噻唑衍生物。
利用上述方法在实验室中制备三亚胺噻唑衍生物，具有明显的缺点：1)全氟化合物具有持久性和生物积累性，污染严重，不符合绿色化学的要求。2)全氟化合物具有多种毒性，如抑制免疫系统，影响线粒体代谢，导致肝细胞损伤、生殖细胞受损等，对人体健康极为不利。
发明内容
为了克服上述现有技术的不足，本发明提供了一种三亚胺噻唑衍生物的制备方法。
一种三亚胺噻唑衍生物的制备方法，所述三亚胺噻唑衍生物具有式Ⅰ所示的结构：
式Ⅰ中，其中R1、R2选自苯基、取代苯基、苄基、萘基、环己基、甲基、吡啶、噻吩、炔基、羟基和酯基，取代苯基取代原子是三氟甲基、氟原子、氯原子、溴原子、甲基、甲氧基；R3选自取代苯基、环己基、叔丁基、正丁基，取代苯基取代原子是甲基；其特征在于，由硫脲和异腈，在乙酰丙酮镍(Ni(acac)2)的作用下，50℃搅拌至反应完毕，有大量固体析出，过滤，并用甲醇洗涤，干燥得到目标化合物；其化学过程见反应式Ⅱ：
所述的硫脲、异腈和Ni(acac)2的摩尔比值为1:2.5:0.03，溶剂选自丙酮(分析纯)，且在使用前无需进一步处理；反应时间为1h，反应温度为50℃。
本发明的有益效果为：本发明提供的三亚胺噻唑衍生物的合成方法科学合理，并且具有溶剂绿色，合成方法简单，反应时间短，产率较高，后处理简单，产品易于纯化等特点。
附图说明
图1为实施例1制备的化合物3a的1H NMR图谱；
图2为实施例1制备的化合物3a的13C NMR图谱；
图3为实施例4制备的化合物3d的1H NMR图谱；
图4为实施例4制备的化合物3d的13C NMR图谱；
图5为实施例10制备的化合物3j的1H NMR图谱；
图6为实施例10制备的化合物3j的13C NMR图谱。
具体实施方式
下面结合附图和具体的实施例对本发明进一步详细的说明：
下述实施例中所述试验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。
实施例1
1)三亚胺噻唑衍生物3a的制备
将二苯基硫脲(0.6mmol,137mg)，环己基异腈(1.50mmol,164mg)加入到25mL单口瓶中，加入催化剂Ni(acac)2(0.018mmol,5mg)作催化剂，2mL丙酮作溶剂，50℃搅拌1h。体系析出固体，抽滤得到白色粉末状固体，用甲醇溶液进行洗涤即可得到纯净的目标产物。经NMR,HRMS证实为三亚胺噻唑衍生物3a，其收率为93％。
谱图解析数据3a:
1H NMR(CDCl3,500MHz):δ7.48–7.45(m,2H),7.40–7.39(m,2H),7.36–7.33(m,1H),7.29–7.26(m,2H),7.08(t,J＝7.35Hz,1H),6.87(d,J＝7.80Hz,2H),4.71(br s,1H),3.06(br s,1H),1.77–1.72(m,4H),1.66–1.64(m,4H),1.58–1.52(m,4H),1.41–1.35(m,3H),1.29–1.18(m,5H)；13C NMR(CDCl3,125MHz):δ150.8,149.5,144.6,144.2,137.4,129.1,128.9,128.6,127.7,124.0,121.6,67.9,56.1,33.9,32.4,25.9,25.6,24.5,23.7；HRMS(ESI)m/z calcd for C18H13ClN3OS+[M+H]+445.2426,found 445.2419.
实施例2
用1b代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3b:
1H NMR(CDCl3,500MHz):δ7.40–7.37(m,2H),7.30–7.28(m,3H),4.69(br s,1H),3.18(br s,1H),3.08(br s,1H),1.81–1.79(m,4H),1.68–1.61(m,8H),1.57–1.55(m,2H),1.44–1.43(m,3H),1.28–1.22(m,11H),0.89–0.87(m,2H)；13C NMR(CDCl3,125MHz):δ145.5,145.0,144.4,138.1,129.3,128.1,126.9,67.7, 62.6,55.8,34.0,33.8,32.4,29.7,25.9,25.7,25.5,24.6,23.8；HRMS(ESI)m/z calcd for C27H39N4S+[M+H]+451.28899,found451.28915.
实施例3
用1c代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3c:
1H NMR(CDCl3,500MHz):δ7.45–7.42(m,2H),7.34–7.31(m,1H),7.27–7.25(m,2H),4.68(br s,1H),3.22–3.19(m,1H),3.12(s,3H),1.83–1.82(m,4H),1.63–1.58(m,7H),1.53–1.45(m,4H),1.27–1.15(m,5H)；13C NMR(CDCl3,125MHz):δ150.3,144.4,144.3,137.9,129.2,128.6,127.5,67.9,55.9,39.6,34.0,33.2,32.4,25.9,25.7,25.1,24.6,23.7；HRMS(ESI)m/z calcd for C22H31N4S+[M+H]+383.22639,found 383.22647.
实施例4
用1d代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3d:
1H NMR(CDCl3,500MHz):δ7.46–7.43(m,2H),7.34–7.28(m,5H),7.23–7.19(m,3H),4.71(br s,1H),4.58(s,2H),3.20–3.17(m,1H),1.82–1.81(m,4H),1.66–1.60(m,7H),1.53(br s,1H),1.45(br s,3H),1.28–1.21(m,5H)；13C NMR(CDCl3,125MHz):δ150.2,144.3,144.1,139.7,137.9,129.2,128.5,128.2,127.3,127.1,126.5,68.0,56.4,56.0,33.9,32.3,25.9,25.7,24.6,23.7；HRMS(ESI)m/z calcd for C28H35N4S+[M+H]+459.25769,found459.25763.
实施例5
用1e代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3e:
1H NMR(CDCl3,500MHz):δ7.87–7.83(m,2H),7.59–7.57(m,1H),7.52(t,J＝7.72Hz,1H),7.45–7.37(m,3H),4.68–4.64(m,1H),3.26(br s,1H),3.08–3.05(m,1H),1.85–1.76(m,5H),1.64–1.61(m,7H),1.51–1.45(m,8H),1.25–0.98(m,10H)； 13C NMR(CDCl3,125MHz):δ145.1,144.9,144.6,135.6,134.3,130.4,128.2,128.1,127.7,125.7,125.5,123.6,67.7,62.7,55.8,33.9,33.7,32.5,32.3,25.8,25.4,24.6,23.8；HRMS(ESI)m/z calcd for C31H41N4S+[M+H]+501.30464,found 501.30463.
实施例6
用1f代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3f:
1H NMR(CDCl3,500MHz):δ8.39(d,J＝3.57Hz,1H),7.58–7.55(m,1H),7.48–7.45(m,2H),7.38–7.34(m,3H),6.97–6.94(m,1H),6.91(d,J＝8.10Hz,1H),4.76(br s,1H),3.34–3.31(m,1H),1.81–1.80(m,4H),1.67–1.59(m,7H),1.54–1.52(m,1H),1.47–1.42(m,3H),1.31–1.16(m,5H)；13C NMR(CDCl3,125MHz):δ159.1,152.4,147.2,143.5,137.8,137.6,129.2,128.4,127.5,120.3,119.1,67.0,56.0,33.8,32.6,25.9,25.7,24.5,23.7；HRMS(ESI)m/z calcd for C26H32N5S+[M+H]+446.23729,found 446.23663.
实施例7
用1g代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3g:
1H NMR(CDCl3,500MHz):δ7.45–7.42(m,2H),7.34–7.31(m,1H),7.28–7.26(m,2H),4.68(br s,1H),4.11(d,J＝2.46Hz,2H),3.22–3.19(m,1H),2.23(t,J＝2.35Hz,1H),1.83–1.81(m,4H),1.64–1.59(m,7H),1.53–1.44(m,4H),1.26–1.15(m,5H)；13C NMR(CDCl3,125MHz):δ153.4,144.0,143.4,137.5,129.1,128.6,127.6,80.5,71.4,68.2,56.0,41.1,33.8,32.4,25.8,25.7,24.5,23.7；HRMS(ESI)m/z calcd for C24H31N4S+[M+H]+407.22639,found 407.22638.
实施例8
用2b代替实例1中的2a,其他条件同实例1,实验结果见表1。
谱图解析数据3h:
1H NMR(CDCl3,500MHz):δ7.45–7.42(m,2H),7.35–7.30(m,3H),7.27–7.24(m,2H),7.05(t,J＝7.38Hz,1H),6.87(d,J＝7.70Hz,2H),1.36(s,9H),1.27(s,9H)；13C NMR(CDCl3,125MHz):δ150.8,149.3,143.0,140.8,138.3,129.3,128.8,128.4,127.3,123.8,121.8,58.6,54.8,29.8,27.9；HRMS(ESI)m/z calcd for C23H29N4S+(M+H)+393.21074,found393.21078.
实施例9
用2c代替实例1中的2a,其他条件同实例1,实验结果见表1。
谱图解析数据3i:
1H NMR(CDCl3,500MHz):δ7.51–7.48(m,2H),7.40–7.36(m,3H),7.30–7.27(m,2H),7.10–7.07(m,1H),6.88(d,J＝7.70Hz,2H),3.99(t,J＝7.05Hz,2H),3.37(t,J＝6.68Hz,2H),1.76–1.70(m,2H),1.52–1.40(m,4H),1.33–1.26(m,2H),0.95(t,J＝7.35Hz,3H),0.86(t,J＝7.32Hz,3H)；13C NMR(CDCl3,125MHz)δ150.4,149.4,148.1,145.6,137.2,129.0,128.9,128.0,124.1,121.5,59.1,49.7,33.3,32.1,20.6,13.8；HRMS(ESI)m/z calcd forC23H29N4S+[M+H]+393.21074,found 393.21094.
实施例10
用2d代替实例1中的2a,其他条件同实例1,实验结果见表1。
谱图解析数据3j:
1H NMR(CDCl3,500MHz):δ7.58(br s,4H),7.44(br s,1H),7.24–7.21(m,2H),7.05–7.03(m,1H),6.92–6.83(m,7H),6.74–6.72(m,1H),2.12(s,6H),1.91(s,6H)；13C NMR(CDCl3,125MHz):δ149.7,149.2,148.6,148.4,146.4,145.1,136.5,129.4,129.0,128.8,128.3,127.3,125.0,124.6,122.2,121.1,18.4,17.6；HRMS(ESI)m/z calcd for C31H29N4S+[M+H]+489.21074,found 489.21063.
表1
。

Claims (3)

1.一种三亚胺噻唑衍生物的制备方法，所述三亚胺噻唑衍生物具有式Ⅰ所示的结构：
式Ⅰ中，其中R1、R2选自苯基、取代苯基、苄基、萘基、环己基、甲基、吡啶、噻吩、炔基、羟基和酯基，取代苯基取代原子是三氟甲基、氟原子、氯原子、溴原子、甲基、甲氧基；R3选自取代苯基、环己基、叔丁基、正丁基，取代苯基取代原子是甲基；其特征在于，由硫脲和异腈，在乙酰丙酮镍(Ni(acac)2)的作用下，溶剂中搅拌至反应完毕，有大量固体析出，过滤，并用甲醇洗涤，干燥得到目标化合物；其化学过程见反应式Ⅱ：
。
2.根据权利要求1所述的制备方法，其特征在于，硫脲、异腈和Ni(acac)2的摩尔比值为1:2.5:0.03，溶剂选自丙酮(分析纯)，且在使用前无需进一步处理。
3.根据权利要求1所述的制备方法，其特征在于反应时间为1h,反应温度为50℃。
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