CN116239551B - 具有杀螺活性的呋喃脲类化合物及其制备和用途 - Google Patents
具有杀螺活性的呋喃脲类化合物及其制备和用途 Download PDFInfo
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
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- A—HUMAN NECESSITIES
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- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P9/00—Molluscicides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明公开了一种具有杀螺活性的呋喃脲类化合物及其制备和用途。本发明公开的化合物具有式I所示结构,该化合物具有显著的灭螺活性,施用浓度低、杀螺高效。
Description
技术领域
本发明属于化学医药领域,具体涉及一种具有杀螺活性的呋喃脲类化合物及其制备和用途。
背景技术
血吸虫病是主要的人、畜共患寄生虫病,对人体健康和经济发展危害极大。经半个多世纪的防治工作,我国城市血吸虫病疫情有了明显下降。但在基层湖泽地区和大山区血吸虫病依然十分流行。同时世界上其他很多地区受经济条件、社会发展的制约,血吸虫病仍然给人们的生命造成了不可忽视的威胁。血防是一场持久战,需要一直进行研究。在血防工程中,灭螺一直是工作重点,钉螺是血吸虫的寄生宿主,它在血吸虫病的传播过程中主要起到为血吸虫发育提供一个场所的作用,血吸虫只有经过这个中间宿主内的发育以后逸出,才可以侵入皮肤导致血吸虫感染。可见灭螺工作的重要。药物灭螺是常见的灭螺手段之一,具有成本低、见效快、现场适用性强的特点,是最常用的钉螺控制方法之一。
氯硝柳胺是德国拜耳公司研发的具有杀螺作用的化学药物,是当前世界卫生组织唯一推荐使用的杀螺剂,其对成螺、幼螺和螺卵均有较好的杀灭效果,且药效持久。氯硝柳胺虽对人畜毒性低,但是对水生类动物尤其是鱼类毒性极强,而螺孽生的环境处于潮湿的水体附近,在有效灭螺的浓度下,可引起水生生物毁灭性的破环。目前,我国血吸虫病流行区现场大多使用由WHO唯一推荐的灭螺药物——氯硝柳胺制剂;但该药对鱼类等水生动物毒性极强,一定程度上限制了其使用范围。因此,研制对水生生物低毒,能达到杀螺高效、环境友好、使用方便、价格低廉要求的灭螺药已成为迫切需要解决的问题。
发明内容
针对现有技术的不足,本发明的目的在于提供一种杀螺高效、环境友好的新型灭螺药。
本发明第一方面提供一种具有式I所示结构的化合物、或其药学上可接受的盐,
式中,R为选自下组的一个或多个取代基所取代:卤素、C1 6烷基、C1 6烷氧基、苯基、卤代的C1 6烷基、卤代的C1 6烷氧基。
在一些较佳的实施方式中,所述化合物具有式Ⅱ所示结构,
式中,R1为卤素,R2为选自下组的一个或多个取代基:氢基、卤素、C1 6烷基、C1 6烷氧基、苯基、卤代的C1 6烷基、卤代的C1 6烷氧基。
在一些较佳的实施方式中,所述化合物具有式Ⅲ所示结构,
式中,R3为选自下组的取代基:C1 6烷基、C1 6烷氧基、苯基。
在一些较佳的实施方式中,所述R为选自下组的一个取代基:卤代的C1 6烷基、卤代的C1 6烷氧基。
本发明第二方面提供所述化合物的制备方法,包括如下步骤:
在催化剂的存在下,将3-(氨甲基)四氢呋喃与苯异氰酸酯衍生物在溶剂中反应,得所述化合物;
所述催化剂为三乙胺;
所述溶剂为四氢呋喃或甲苯;
所述3-(氨甲基)四氢呋喃与苯异氰酸酯衍生物的摩尔比为1:0.9~1.2;
所述苯异氰酸酯衍生物具有式Ⅳ所示结构,
式中,R为选自下组的一个或多个取代基:卤素、C1 6烷基、C1 6烷氧基、苯基、卤代的C1 6烷基、卤代的C1 6烷氧基。
在一些较佳的实施方式中,所述苯异氰酸酯衍生物具有式Ⅴ所示结构,
式中,R1为卤素,R2为选自下组的一个或多个取代基:氢基、卤素、C1 6烷基、C1 6烷氧基、苯基、卤代的C1 6烷基、卤代的C1 6烷氧基。
在一些较佳的实施方式中,所述苯异氰酸酯衍生物具有式Ⅵ所示结构,
式中,R3为选自下组的取代基:C1 6烷基、C1 6烷氧基、苯基。
在一些较佳的实施方式中,式Ⅳ中R为选自下组的一个取代基:卤代的C1 6烷基、卤代的C1 6烷氧基。
本发明第三方面提供一种灭螺剂组合物,包含(a)本发明第一方面所述的化合物、或其药学上可接受的盐;以及(b)农药学上可接受的载体或赋形剂。
灭螺剂组合物可采用常规方法制成常规制剂,例如溶液剂、乳剂、混悬剂、粉剂、泡沫剂、糊剂、颗粒剂。在一些较佳的实施方式中,所述组分(a)在所述灭螺剂组合物中的含量为0.01~99.9wt%。
本发明第四方面提供本发明第一方面所述的化合物、或其药学上可接受的盐,或本发明第三方面所述的灭螺剂组合物的用途,用于制备防治寄生虫或杀灭寄生虫的传播媒介的药物,所述寄生虫的传播媒介为螺,所述寄生虫为血吸虫。
本发明第五方面提供一种预防寄生虫病的方法,将本发明第一方面所述的化合物、或其药学上可接受的盐,或本发明第三方面所述的灭螺剂组合物施加于寄生虫的传播媒介或遭受该传播媒介灾害的环境,所述寄生虫的传播媒介为螺,所述寄生虫为血吸虫。
在一些较佳的实施方式中,所述化合物,或其药学上可接受的盐的施用浓度为0.01~20mg/L,优选0.5~2mg/L。
与现有技术相比,本发明的有益效果在于:本发明提供的化合物具有显著的灭螺活性,施用浓度低、杀螺高效,环境友好、使用方便。
具体实施方式
以下结合具体实施例对本发明作进一步的详细说明,以使本领域的技术人员更加清楚地理解本发明。所举实例只用于解释本发明,并非用于限定本发明的范围。在本发明实施例中,若无特殊说明,所有原料组分均为本领域技术人员熟知的市售产品;若未具体指明,所用的技术手段均为本领域技术人员所熟知的常规手段。
术语定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
术语“卤素”指氟、氯、溴、或碘。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团,例如三氟甲基、三氟甲氧基或类似基团。
术语“C1 6烷基”指具有1 6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基或类似基团。
术语“C1 6烷氧基”指具有1 6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基或类似基团。
术语“苯基”指苯分子中去掉任何一个碳上的一个氢原子后剩下的一价基团,其化学式为C6H5。
本发明化合物合成方法中所用起始原料和试剂均可商业购买或通过文献报道的方法合成。
实施例1
称取2-氯苯基异氰酸酯(0.85g,5.53mmol)加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.50g,4.94mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体0.95g,产率为75.45%,纯度为98.1%,m.p.:103~104.℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.99-7.97(dd,1H),7.58(s,1H),7.26-7.24(dd,1H),7.15-7.11(m,1H),6.91-6.86(m,1H),6.55(s,1H),3.81-3.72(m,2H),3.70-3.64(m,1H),3.46-3.43(dd,1H),3.17-3.13(dd,2H),2.35-3.32(dd,1H),1.93-1.89(m,1H),1.54-1.48(m,1H)。13C NMR(101MHz,CDCl3)δ156.15,135.83,129.14,127.38,123.51,123.40,122.11,71.19,67.75,42.70,39.57,29.83。
实施例2
称取4-三氟甲氧基苯基异氰酸酯(2.50g,12.31mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.20g,11.86mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.97g,产率为82.27%,纯度:98.3%,m.p.:136-137℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.31-7.29(d,2H),7.13-7.11(d,2H),3.89-3.84(m,1H),3.77-3.68(m,2H),3.59-3.55(dd,1H),3.29-3.19(m,2H),2.50-2.41(m,1H),2.06-1.97(m,1H),1.64-1.56(m,1H)。13C NMR(101MHz,CDCl3)δ:156.30,144.85,137.52,122.05,121.32,119.32,71.27,67.87,43.17,39.48,29.75。
实施例3
称取3,4-二氯苯基异氰酸酯(0.85g,4.52mmol)加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.50g,4.94mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体0.89g,产率为62.24%,纯度97.2%,m.p.:147~148℃。
1H NMR(400MHz,CD3OD),δ(ppm):7.71-7.71(d,1H),7.36-7.34(d,1H),7.21-7.19(dd,1H),3.90-3.30(m,2H),3.77-3.71(dd,1H),3.56-3.52(dd,1H),3.22-3.19(dd,2H),2.53-2.43(m,1H),2.09-2.01(m,1H),1.70-1.62(m,1H)。13C NMR(101MHz,CD3OD)δ:157.70,141.23,133.25,131.41,125.69,121.12,119.30,72.13,68.71,43.31,41.03,30.72。
实施例4
称取4-氟苯基异氰酸酯(2.08g,15.71mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.50g,14.83mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.22g,产率为62.89%,纯度为98.2%,m.p.:m.p.:110-111℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.25-7.20(m,2H),6.99-6.95(m,2H),3.88-3.82(m,1H),3.77-3.67(m,2H),3.56-3.52(dd,1H),3.26-3.16(m,2H),2.48-2.38(m,1H),2.04-1.95(m,1H),1.62-1.55(m,1H)。13C NMR(101MHz,CDCl3)δ:160.64,156.63,134.52,123.08,123.00,116.11,115.89,71.30,67.89,43.17,39.52,29.79。
实施例5
称取3,4-二氟苯基异氰酸酯(2.55g,16.44mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.50g,14.83mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体3.04g,产率为80.00%,纯度:99.1%,m.p.:102-103℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.83-7.80(d,1H),7.28-7.22(m,1H),7.01-6.94(dd,1H),6.81-6.78(m,1H),5.92-5.86(m,1H),3.86-3.81(m,1H),3.74-3.66(m,2H),3.55-3.51(dd,1H),3.20-3.17(t,2H),2.41-2.34(m,1H),2.00-1.93(m,1H),1.59-1.51(m,1H)。13C NMR(101MHz,CDCl3)δ:151.58,149.13,145.42,135.49,117.49,115.85,109.94,71.37,67.97,43.18,39.59,29.82。
实施例6
称取对甲苯基异氰酸酯(2.00g,15.02mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.52g,15.03mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体1.67g,产率为47.44%,纯度98.7%,m.p.103-104℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.14(s,4H),3.88-3.83(m,1H),3.79-3.68(m,2H),3.55-3.51(dd,1H),3.30-3.19(m,2H),2.51-2.44(m,1H),2.05-1.97(m,1H),1.64-1.56(m,1H)。
实施例7
称取间甲苯基异氰酸酯(1.07g,8.04mmol)加加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.89g,8.80mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体1.18g,产率为62.77%,纯度98.6%,m.p.106-107℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.90(s,1H),7.11-7.03(m,3H),6.80-6.78(dd,1H),6.21-6.15(m,1H),3.80-3.74(m,1H),3.72-3.65(m,2H),3.45-3.42(dd,1H),3.13-3.10(t,2H),2.32-2.25(m,1H),2.22(s,3H),1.93-1.85(m,1H),1.53-1.45(m,1H)。13C NMR(101MHz,CDCl3)δ:157.04,138.89,138.78,128.77,123.81,120.76,117.17,71.13,67.66,42.66,39.68,29.78,21.38。
实施例8
称取3-氯苯基异氰酸酯(0.84g,5.47mmol)加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.50g,4.94mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体1.10g,产率为87.30%,纯度为98.5%,m.p.:116-117℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.82(s,1H),7.33-7.32(t,1H),7.15-7.07(m,2H),6.97-6.94(m,1H),5.94(s,1H),3.85-3.80(m,1H),3.75-3.65(m,2H),3.52-3.49(dd,1H),3.19-3.17(d,2H),2.39-2.28(m,1H),2.00-1.92(m,1H),1.58-1.50(m,1H)。13C NMR(101MHz,CDCl3)δ156.60,140.22,134.67,130.11,123.13,119.95,117.96,71.21,67.82,42.93,39.64,29.80。
实施例9
称取4-氯苯基异氰酸酯(2.00g,13.02mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.19g,11.76mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.58g,产率为86.00%,纯度为96.8%,m.p.:151-152℃。
1H NMR(400MHz,CD3OD)δ(ppm):7.35-7.33(d,2H),7.23-7.21(d,2H),4.86(s,1H),3.89-3.82(m,2H),3.76-3.71(dd,1H),3.56-3.52(dd,1H),3.25-3.16(dd,2H),2.52-2.42(m,1H),2.09-2.00(m,1H),1.70-1.62(m,1H)。13C NMR(101MHz,CD3OD)δ:158.08,139.89,129.69,128.11,121.34,72.14,68.71,43.31,41.08,30.73。
实施例10
称取4-溴苯基异氰酸酯(2.12g,10.71mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-氨甲基呋喃(1.00g,9.89mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.43g,产率为82.09%,纯度为98.2%,m.p.:157-159℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.40-7.38(d,2H),7.21-7.18(d,2H),3.91-3.86(m,1H),3.80-3.69(m,2H),3.59-3.56(dd,1H),3.30-3.20(m,2H),2.51-2.45(m,1H),2.08-1.99(m,1H),1.66-1.58(m,1H)。13C NMR(101MHz,CDCl3)δ:156.18,137.89,132.28,122.07,116.27,71.36,67.95,43.29,39.43,29.81。
实施例11
称取3-氟苯基异氰酸酯(2.02g,10.80mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.00g,9.89mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.11g,产率为74.04%,纯度为98.3%,m.p.:132-133℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.56(s,1H),7.49-7.48(d,1H),7.38-7.33(m,2H),7.26-7.24(d,1H),5.5(s,1H),3.90-3.85(m,1H),3.78-3.68(m,2H),3.59-3.56(dd,1H),3.29-3.21(m,2H),2.47-2.44(m,1H),2.05-1.98(m,1H),1.64-1.57(m,1H)。13C NMR(101MHz,CDCl3)δ156.08,139.40,131.71,129.76,125.34,123.04,119.97,116.60,71.30,67.90,43.25,39.39,29.75。
实施例12
称取4-氟苯基异氰酸酯(2.00g,10.69mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.00g,9.89mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.10g,产率为73.68%,纯度:98.9%,m.p.:161-162℃。
1H NMR(400MHz,CDCl3)δ(ppm):7.54-7.52(d,2H),7.45-7.43(d,2H),6.72(s,1H),5.01(s,1H),3.94-3.89(m,1H),3.82-3.71(m,2H),3.63-3.60(dd,1H),3.35-3.26(m,2H),2.57-2.47(m,1H),2.11-2.03(m,1H),1.70-1.61(m,1H)。
实施例13
称取2,6-二氯苯基异氰酸酯(0.52g,2.77mmol)加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.25g,2.47mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体0.55g,产率为77.46%,纯度98.6%,m.p.164~166℃。
1H NMR(400MHz,DMSO-d),δ(ppm):7.94(s,1H),7.48-7.46(d,2H),7.27-7.23(t,1H),6.49-6.46(t,1H),3.74-3.66(m,2H),3.64-3.58(m,1H),3.43-3.39(dd,1H),3.08-3.05(dd,2H),2.41-2.30(m,1H),1.95-1.86(m,1H),1.60-1.52(m,1H)。13C NMR(101MHz,CDCl3)δ:155.78,134.44,132.87,128.73,128.25,71.36,67.91,43.31,39.62,29.80。
实施例14
称取2,3-二氯苯基异氰酸酯(1.03g,5.48mmol)加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.50g,4.94mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体1.02g,产率为71.33%,纯度98.1%,m.p.156~158℃。
1H NMR(400MHz,CDCl3),δ(ppm):8.10(s,1H),8.02-8.00(d,1H),7.16-7.08(m,1H),5.86(s,1H),3.90-3.85(dd,1H),3.82-3.79(t,1H),3.75-3.71(dd,1H),3.58-3.55(dd,1H),3.31-3.20(m,2H),2.49-2.44(m,1H),2.05-2.00(m,1H),1.65-1.58(m,1H)。13CNMR(101MHz,CDCl3)δ154.92,137.46,132.85,127.84,124.20,121.27,119.32,71.42,67.96,43.44,39.47,29.93。
实施例15
称取2,4,6-三氯苯基异氰酸酯(0.61g,2.74mmol)加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.25g,2.47mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体0.47g,产率为58.75%,纯度98.8%,m.p.185~187℃。
1H NMR(400MHz,DMSO-d),δ(ppm):7.98(s,1H),7.68(s,2H),6.54-6.51(t,1H),3.74-3.65(m,2H),3.63-3.58(dd,1H),3.42-3.38(dd,1H),3.07-3.04(dd,2H),2.40-2.30(m,1H),1.94-1.86(m,1H),1.59-1.51(m,1H)。
实施例16
称取3-氯-4-甲基苯基异氰酸酯(2.00g,11.93mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.21g,11.96mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体2.58g,产率为80.37%,纯度98.6%,m.p.131~133℃。
1H NMR(400MHz,CDCl3),δ(ppm):7.98-7.93(m,1H),7.24-7.23(d,1H),7.01-6.92(m,2H),6.13(s,1H),3.82-3.76(m,1H),3.73-3.64(m,2H),3.48-3.44(dd,1H),3.15-3.12(dd,2H),2.34-2.27(m,1H),2.22(s,3H),1.96-1.88(m,1H),1.54-1.46(m,1H)。13C NMR(101MHz,CDCl3)δ:156.89,137.71,134.44,131.06,130.71,120.88,118.74,71.23,67.80,42.91,39.71,,29.84,19.35。
实施例17
称取4-氯-3-三氟甲基异氰酸苯酯(1.11g,5.01mmol)加加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.56g,5.54mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体0.53g,产率为32.72%,纯度99.5%,m.p.132-133℃。
1H NMR(400MHz,CDCl3),δ(ppm):7.64(s,1H),7.53-7.51(d,1H),7.39-7.37(d,1H),7.00(s,1H),3.94-3.88(dd,1H),3.80-3.70(m,2H),3.63-3.57(dd,1H),3.29-3.27(m,2H),2.52-2.47(m,1H),2.11-2.02(m,1H),1.62-1.59(m,1H)。
实施例18
称取4-甲氧基苯基异氰酸酯(2.09g,14.01mmol)加入到圆底烧瓶中,加入20mL无水四氢呋喃,2mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(1.56g,15.42mmol)的无水四氢呋喃(10mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(20mL)淬灭反应,用乙酸乙酯萃取(30mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体1.96g,产率为55.84%,纯度98.4%,m.p.97-99℃。
1H NMR(400MHz,CDCl3),δ(ppm):7.44(s,1H),7.13-7.10(d,2H),6.77-6.75(d,2H),5.74(s,1H),3.81-3.75(m,1H),3.72(s,3H),3.70-3.62(m,2H),3.47-3.43(dd,1H),3.17-3.07(m,2H),2.36-2.29(m,1H),1.95-1.86(m,1H),1.54-1.46(m,1H)。13C NMR(101MHz,CDCl3)δ:157.39,156.24,131.63,123.25,114.36,71.22,67.76,55.52,42.86,39.70,29.80。
实施例19
称取4-联苯异氰酸苯酯(0.99g,5.07mmol)加加入到圆底烧瓶中,加入15mL无水四氢呋喃,1mL三乙胺,搅拌并加热升温到40℃后,向烧瓶中缓慢滴加3-(氨甲基)四氢呋喃(0.56g,5.54mmol)的无水四氢呋喃(5mL)溶液,滴加完毕,继续搅拌反应4h,TLC监测反应结束,自然冷却。向反应液中加入水(15mL)淬灭反应,用乙酸乙酯萃取(20mL×3),有机相依次用5%盐酸,饱和氯化钠盐水洗涤一次,无水硫酸钠干燥24h,减压抽滤,旋蒸除去溶剂,柱层析分离。得到白色固体0.51g,产率为34.00%,纯度98.9%,m.p.163-165℃。
1H NMR(400MHz,CDCl3),δ(ppm):7.64(s,1H),7.43-7.38(dd,4H),7.33-7.19(m,5H),5.85(s,1H),3.78-3.73(m,1H),3.70-3.66(dd,1H),3.64-3.58(dd,1H),3.48-3.45(dd,1H),3.19-3.10(m,2H),2.38-2.28(m,1H),1.93-1.84(m,1H),1.53-1.45(m,1H)。
将实施例1-19制备获得的化合物进行灭螺活性测试。
测试例1
选取在湖北省潜江市采集的高7~10mm、宽3~4mm的钉螺为测试对象,用脱氯自来水适应性饲养24h后选取活力较强的钉螺用于实验。取实施例1-19制备获得的化合物用脱氯自来水分别配制成药物浓度为1mg/L的药液,设置脱氯自来水对照组。每组药物及对照组均设3个培养皿,每个培养皿投放10只钉螺,分别注入药液浸没钉螺,置于温度25℃、湿度60%、光照充足的实验室内。每组3个培养皿分别浸杀24h、48h、72h后倒去药液,用脱氯自来水清洗3次,置于脱氯自来水中复苏24h,采用敲击法鉴定钉螺死活,计算各组钉螺死亡率。每组实验重复3次,计算平均死亡率,结果如表1所示。
表1
可以看出,本发明的化合物均表现出有灭螺活性,其中,实施例2、3、4、5、8、11、12、13、14、15、16、18、19的化合物表现出较好的灭螺活性,药物浓度为1mg/L在72h内的灭杀效果均能达到50%以上,实施例3、4、13、14、18的化合物在48h内的灭杀效果即可达到50%以上。实施例3和18的化合物灭螺活性尤其突出,在药物浓度为1mg/L在48h内的灭杀效果能达到80%以上,特别是实施例3的化合物在48h内的灭杀效果能达到100%。
测试例2
选取实施例3、实施例4、实施例13、实施例14和实施例18制备获得的化合物用脱氯自来水分别配制成不同药物浓度的药液,按照测试例1的方法进行灭螺活性测试,计算48h钉螺平均死亡率,结果如表2所示。
表2
溶液浓度 | 实施例3 | 实施例4 | 实施例13 | 实施例14 | 实施例18 |
2mg/L | 100% | 63.3% | 60% | 76.7% | 93.3% |
1mg/L | 100% | 50% | 50% | 60% | 80% |
0.5mg/L | 80% | 26.7% | 26.7% | 33.3% | 80% |
0.25mg/L | 33.3% | 20% | 20% | 23.3% | 36.7% |
0.125mg/L | 20% | 13.3% | 16.7% | 20% | 20% |
0.06mg/L | 13.3% | 10% | 10% | 13.3% | 10% |
0.03mg/L | 10% | 10% | 13.3% | 10% | 13.3% |
0.015mg/L | 13.3% | 10% | 10% | 10% | 10% |
0.008mg/L | 10% | 10% | 10% | 10% | 10% |
可以看出,本发明的化合物在药物浓度低于0.01mg/L时即表现出灭螺活性,药物浓度在0.5mg/L以上时,实施例3和18的化合物均具有良好的灭螺活性。
以上所述仅为本发明的较佳实施例,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、改进等,均应包含在本发明的保护范围之内。
Claims (5)
1.一种化合物、或其药学上可接受的盐,其特征在于,所述化合物具有式Ⅱ所示结构,
式Ⅱ,
式中,R1为卤素,R2为C1~6烷基或卤代的C1~6烷基;
或所述化合物具有式Ⅲ所示结构,
式Ⅲ,
式中,R3为选自下组的取代基:C1~6烷氧基、苯基;
或所述化合物为
或或或或或或或或或或。
2.一种灭螺剂组合物,其特征在于,包含(a)权利要求1所述的化合物、或其药学上可接受的盐;以及(b)农药学上可接受的赋形剂。
3.根据权利要求2所述的灭螺剂组合物,其特征在于,所述组分(a)在所述灭螺剂组合物中的含量为0.01~99.9wt%。
4. 权利要求1所述的化合物、或其药学上可接受的盐,或权利要求2所述的灭螺剂组合物的用途,其特征在于,用于制备杀灭寄生虫的传播媒介的药物,所述寄生虫的传播媒介为钉螺,所述寄生虫为血吸虫。
5.一种化合物、或其药学上可接受的盐的用途,其特征在于,用于制备杀灭寄生虫的传播媒介的药物,所述寄生虫的传播媒介为钉螺,所述寄生虫为血吸虫,所述化合物为
或或。
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