CN112624996A - 含磺酸酯结构的噁唑啉类衍生物及其制备和在防治植食性螨中的应用 - Google Patents
含磺酸酯结构的噁唑啉类衍生物及其制备和在防治植食性螨中的应用 Download PDFInfo
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Abstract
本发明涉及如通式(F)所示的含磺酸酯结构的噁唑啉类化合物及其制备和在防治植食性螨中的应用。该类化合物代表一种新颖的、简洁的杀螨剂结构类型。本发明的噁唑啉类衍生物F‑3、F‑9、F‑17显示出高于乙螨唑的杀朱砂叶螨活性。(其中R的意义见说明书)
Description
技术领域
本发明涉及含磺酸酯结构的噁唑啉类衍生物及其制备和在防治植食性螨中的应用,属于农业防护技术领域。
背景技术
螨是农业主要灾害之一,植食性螨种类繁多,习性和栖息地多样,适应能力极强。自上世纪70年代开始,螨已跃升为马铃薯、小麦、果树、蔬菜、棉花、玉米、花卉、豆类等多达800多种经济作物的重要灾害(J.Invertebr.Pathol.,2019,160,61-66.)。2012年,仅在中国,由螨所造成的农业损失就等同于400万公顷的土地颗粒无收(Plant Prot.,2013,39:117-121.)。它们毁坏植物的生理机能,引起植株的叶落、蕾落、果落,轻则造成农业减产,削弱植株的长势,重则造成整株枯萎甚至死亡,而且许多螨还能传播植物病菌与病毒,危害相当严重。而螨因为其个体小,繁殖较快的特点,同时由于农业生产中农药的大量过度使用,螨极其容易产生抗药性(Exp.Appl.Acarol.,2016,69(4):413-425.)。另外,现行农药市场仍然充斥着大量的对环境和人畜,以及生态系统有害的传统农药,这些农药的使用虽然能防治病害,但并不满足绿色无公害的需求(Anim.Cells Syst.,2004,43(1):43-48.)。因而,新型的、高选择性的、高效的、对人畜无害的绿色农药一直是研究的焦点。
乙螨唑是一类2,4-二苯基1,3-噁唑啉环类生长调节抑制类杀螨剂(结构式一),于1994年由日本八州化学株式会社开发,并于1998年成功上市,是迄今为止唯一的商品化的噁唑啉类化合物(Proc.Brighton Crop Protect Conf-Pests Dis.,1994,3:37-44.)。通过抑制只存在于真菌细胞壁和昆虫表皮的几丁质的合成,而达到杀螨杀虫的目的。因而该噁唑啉类杀螨剂是一种高选择性、高效的、对非靶标生物安全、低毒的农药,是一类符合当前绿色农药标准的有广大前景的农药(Collect.Czech.Chem.Commun.,1984,49:2103-2110.)。对于乙螨唑所属的噁唑啉类化合物的研究一直是研究热点。
磺酸酯官能团本身的极性较小,插入到分子结构中,有利于增加分子对脂质层的亲和性,这就使得分子比较容易的穿过细胞膜到达作用靶点,并发挥药效。同时,许多商品化杀螨剂品种中也存在磺酸酯结构,如Allied公司开发的格螨酯(Genite)、1952年Murphy公司开发的分螨酯(Fenson)以及由Dow公司开发的杀螨酯(Chlorfenson)(J.Econ.Entomol.,1958,51(5),713-714.;J.Econ.Entomol.,1959,52(5),871-877.;Pomacea canaliculata.Jpn.J.Appl.Entomol.Z.,1987,31(4),339-343.)(结构式二)。这三种农药对于螨的卵、幼螨都具有良好的防治效果。
1989年,Takeda公司对除虫脲(Diflubenzuron)的分子结构进行衍生(结构式三),发现苯环上的Cl原子被砜结构取代后(I),该类结构化合物对鳞翅目类表现出了非常高的杀虫活性(US.4843100[P],1989.)。随后,在2013年,我们课题组发现,磺酸酯基取代氯原子有利于增强化合物的杀螨活性(J.Agric.Food Chem.,2013,61(3):517-522.)。
2001年,Suzuki等报道了氯乙醛缩二甲醇法合成乙螨唑的方法(J.Pestic.Sci.,2001,26(2):215-223)。2,6-二氟苯甲酰胺先和氯乙醛缩二甲醇反应,然后再经过与间叔丁基苯乙醚的傅克反应,再在氢氧化钠下关环反应得到最终化合物乙螨唑。(反应式一)
基于磺酸酯官能团本身独特的结构特点,以及文献中引入磺酸酯基的研究结果,我们参照反应式一设计合成了一系列含有磺酸酯官能团的噁唑啉衍生物,研究了其杀螨活性和构效关系,以期望能够获得新型的杀螨高活性噁唑啉分子结构。
发明内容
本发明提供含磺酸酯结构的噁唑啉类衍生物及其制备方法和在防治植食性螨中的应用。本专利的含磺酸酯结构的噁唑啉类衍生物具有很好的杀朱砂叶螨螨卵和幼螨活性。
本发明的含磺酸酯结构的噁唑啉类衍生物具有如下通式所示结构的化合物F。
F-1~F-23按照反应式二所示的氯乙醛缩二甲醇法的方法制备:2,6-二氟苯甲酰胺A与氯乙醛缩二甲醇在浓H2SO4的作用下得到B,B与苯甲醚经过傅克反应得到傅克产物C,将C与BBr3反应得到脱甲基后的产物D,D再经过NaOH关环并分离得到E,E再经过与各种磺酰氯反应得到F-1~F-23。
上述通式中,R代表的链状烷基、环己基、烯基、苯基、取代基的苯、奈基,取代基具体所指内容见化合物F-1~F-23结构式。
F-24按照反应式三所示的方法制备:E与三氟甲磺酸酐在碱的作用下得到F-23。
本发明化合物F-1~F-24具体结构如结构式五所示:
本发明的含磺酸酯结构的噁唑啉类衍生物F,对朱砂叶螨螨卵和幼螨的杀螨效果显著,其中化合物F-3、F-9、F-17表现出与乙螨唑相当甚至更好的杀螨活性。
具体实施方式
下述的实施例和生测试验结果可用来进一步说明本发明,但不意味着限制本发明。
实施例1:B的合成
B:在200mL单口瓶中加入2,6-二氟苯甲酰胺A(15.7g,100mmol),氯乙醛缩二甲醇(44mL,300mmol),在冰水浴中剧烈搅拌下滴加浓硫酸6mL,室温搅拌,TLC(石油醚/乙酸乙酯=3/1)追踪反应进程,10小时后反应完毕。加入水和二氯甲烷,倒入分液漏斗中分液,水相用二氯甲烷萃取三次。合并有机相后水洗2次,饱和NaCl水溶液洗涤一次,无水硫酸钠干燥。过滤,减压浓缩除去二氯甲烷和过量的氯乙醛缩二甲醇(在隔膜泵上抽,出现固体),正己烷重结晶,得白色固体20.73g,收率87%。熔点91-92℃。
1H NMR(400MHz,CDCl3)δ7.46-7.38(m,1H),6.99(t,J=8.0Hz,2H),6.49(d,J=8.0Hz,1H),5.66-5.60(m,1H),3.78(dd,J=12.0,3.6Hz,1H),3.71(dd,J=12.0,4.0Hz,1H),3.51(s,3H).13C NMR(100MHz,CDCl3)δ160.0(dd,J=251.3,J=6.6Hz),160.8,132.3(t,J=10.2Hz),113.6(t,J=19.8Hz),112.2(dd,J=23.4,2.1Hz),79.5,56.4,46.2.
实施例2:C的合成
在100mL单口瓶中加入中间体B(2.5g,10mmol),苯甲醚(1.3mL,12mmol),加入15mL二氯甲烷搅拌溶解,冰浴搅拌下缓慢加入三氯化铝(2.67g,20mmol)。撤去冰水浴,室温搅拌。TLC(石油醚/乙酸乙酯=4/1)监测反应,5小时后反应完毕。搅拌下,将反应液缓慢倒入到冰水混合物中淬灭三氯化铝。倒入分液漏斗中分液,水相用二氯甲烷萃取三次。合并有机相后水洗1次,饱和NaCl水溶液洗涤一次,经无水硫酸钠干燥后过滤,减压浓缩除去二氯甲烷(在隔膜泵上抽,出现固体)。正己烷重结晶,得白色固体(其中含有邻位傅克副产物)2.93g,收率90%。HRMS(ESI):calcd for C16H15ClF2NO2[M+H]+326.0754.found:326.0756.
实施例3:D的合成
在100mL三口瓶中加入含有C的混合物(1.63g,5mmol),加入10mL重蒸二氯甲烷使之溶解,将反应液降温至-78℃,氩气保护,搅拌下缓慢注入三溴化硼(1.2mL,12mmol)。撤去低温浴,室温搅拌,TLC(石油醚/乙酸乙酯=3/1)监测反应,4个小时后反应完毕。在搅拌下,将反应液缓慢倒入到冰水混合物中淬灭三溴化硼,得黄色糊状固体混合液。加入乙酸乙酯30mL后室温搅拌,直到黄色固体消失。倒入分液漏斗中分液,水相用乙酸乙酯萃取三次。合并有机相后水洗1次,饱和氯化钠洗涤一次,经无水硫酸钠干燥后过滤,减压浓缩除去乙酸乙酯(在隔膜泵上抽,出现固体)。正己烷重结晶,得浅黄色固体(其中含有邻位傅克产物脱甲基后的杂质)1.42g,收率91%。HRMS(ESI):calcd for C15H13CIF2NO2[M+H]+312.0597.found:312.0599.
实施例4:E的合成
在200mL单口瓶中加入含有D和邻位傅克产物脱甲基后的副产物的混合物(12.44g,40mmol),氢氧化钠(3.2g,80mmol),水浴下加入50mL甲醇搅拌溶解,室温反应。TLC(石油醚/乙酸乙酯=3/1)监测反应,1小时后反应完毕。将反应液旋干,加入水和乙酸乙酯分液,水相用乙酸乙酯萃取三次。合并有机相后水洗1次,饱和氯化钠洗涤一次,经无水硫酸钠干燥后过滤,减压浓缩除去乙酸乙酯(在隔膜泵上抽,出现固体)。经石油醚/乙酸乙酯=3/1柱层析后得浅黄色固体E(4-对羟基苯基噁唑啉)5.61g,收率51%。熔点157-158℃。
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.74-7.58(m,1H),7.28(t,J=8.4Hz,2H),7.11(d,J=8.4Hz,2H),6.76(d,J=8.4Hz,2H),5.35(dd,J=10.0,8.0Hz,1H),4.77(dd,J=10.0,8.8Hz,1H),4.14(t,J=8.0Hz,1H).;13C NMR(100MHz,DMSO-d6)δ160.6(dd,J=252.9,6.7Hz),157.2,155.8,133.9(t,J=10.6Hz),132.8,128.2,115.8,112.8(dd,J=17.9,5.2Hz),107.3(t,J=18.6Hz),75.1,69.5.HRMS(ESI):calcd for C15H12F2NO2[M+H]+276.0831.found:276.0822.
实施例5:含磺酸酯结构的噁唑啉类衍生物F-1~F-23的合成
F-1的合成:在100mL单口瓶中加入E(0.55g,2mmol)和三乙胺(0.57mL,4mmol),加入10mL四氢呋喃溶解。搅拌下滴加入溶于5mL四氢呋喃的甲磺酰氯(0.19mL,2.4mmol)。TLC(石油醚/乙酸乙酯=3/1)监测反应,待反应完全后,加入乙酸乙酯和水分液,水相用乙酸乙酯萃取三次。合并有机相后水洗1次,饱和NaCl水溶液洗涤一次,无水硫酸钠干燥。过滤,减压浓缩除去乙酸乙酯。经石油醚/乙酸乙酯=5/1柱层析后正己烷重结晶。
无色透明油状液体,收率71%。1H NMR(400MHz,DMSO-d6)δ7.75-7.62(m,1H),7.44(d,J=8.8Hz,2H),7.39(d,J=8.8Hz,2H),7.30(t,J=8.4Hz,2H),5.55(dd,J=10.4,7.9Hz,1H),4.86(dd,J=10.3,8.7Hz,1H),4.24(t,J=8.0Hz,1H),3.39(s,3H).13C NMR(100MHz,DMSO-d6)δ160.1(dd,J=253.6,6.4Hz),156.2,148.3,141.2,133.7(t,J=10.4Hz),128.2,122.5,112.4(dd,J=20.0,4.8Hz),106.4(t,J=18.0Hz),74.3,68.6,37.3.HRMS(ESI):calcd for C16H14F2NO4S[M+H]+354.0606.found 354.0605.
F-2~F-23的合成参考F-1.
F-2:浅黄色油状液体,收率70%。1H NMR(400MHz,DMSO-d6)δ7.71-7.63(m,1H),7.43(d,J=8.4Hz,2H),7.36(d,J=8.8Hz,2H),7.29(t,J=8.4Hz,2H),5.54(dd,J=10.4,8.0Hz,1H),4.86(dd,J=10.4,8.8Hz,1H),4.23(t,J=8.0Hz,1H),3.52(q,J=7.2Hz,2H),1.38(t,J=7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.6(dd,J=253.5,6.2Hz),156.7,148.6,141.6,134.2(t,J=10.4Hz),128.7,122.9,112.9(dd,J=19.9,4.8Hz),106.9(t,J=18.5Hz),74.8,69.0,45.0,8.5.HRMS(ESI):calcd for C17H16F2NO4S[M+H]+368.0763.found:368.0759.
F-3:淡黄色油状液体,收率83%。1H NMR(400MHz,DMSO-d6)δ7.72-7.63(m,1H),7.44(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.30(t,J=8.8Hz,2H),5.56(dd,J=9.6,8.4Hz,1H),4.87(dd,J=10.0,9.2Hz,1H),4.24(t,J=8.4Hz,1H),3.51(t,J=7.2Hz,2H),1.91-1.80(m,2H),1.04(t,J=7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.2(dd,J=253.2,6.4Hz),156.2,148.1,141.1,133.6(t,J=10.4Hz),128.2,122.4,112.3(dd,J=20.0,4.4Hz),106.5(t,J=18.4Hz),74.3,68.6,51.3,16.9,12.3。HRMS(ESI):calcd forC18H18F2NO4S[M+H]+382.0919.found:382.0926.
F-4:无色透明油状液体,收率78%。1H NMR(400MHz,DMSO-d6)δ7.73-7.62(m,1H),7.45(d,J=8.8Hz,2H),7.37(d,J=8.8Hz,2H),7.31(t,J=8.4Hz,2H),5.55(dd,J=10.0,8.0Hz,1H),4.87(dd,J=10.0,8.8Hz,1H),4.25(t,J=8.4Hz,1H),3.57-3.50(m,2H),1.88-1.74(m,2H),1.51-1.40(m,2H),0.92(t,J=7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ160.2(dd,J=253.4,6.1Hz),156.2,148.2,141.1,133.6(t,J=10.5Hz),128.2,122.4,112.4(dd,J=20.2,4.3Hz),106.5(t,J=18.4Hz),74.3,68.6,49.4,25.1,20.6,13.3.HRMS(ESI):calcd for C19H20F2NO4S[M+H]+396.1076.found:396.1082.
F-5:无色油状液体,收率60%。1H NMR(400MHz,DMSO-d6)δ7.74-7.61(m,1H),7.43(d,J=8.8Hz,2H),7.34(d,J=8.8Hz,2H),7.30(t,J=8.4Hz,2H),5.54(dd,J=10.0,8.0Hz,1H),4.86(dd,J=10.0,8.8Hz,1H),4.24(t,J=8.4Hz,1H),3.59-3.49(m,1H),2.20(d,J=11.2Hz,2H),1.83(d,J=13.2Hz,2H),1.67-1.52(m,3H),1.42-1.32(m,2H),1.26-1.16(m,1H).13C NMR(100MHz,DMSO-d6)δ160.7(dd,J=253.6,6.0Hz),156.7,148.5,141.4,134.2(t,J=10.4Hz),128.7,122.8,112.9(dd,J=20.0,4.8Hz),106.9(d,J=8.0Hz),74.8,69.1,59.4,26.6,24.9,24.6.HRMS(ESI):calcd for C21H22F2NO4S[M+H]+422.1232.found:422.1240.
F-6:淡黄色油状液体,收率79%。1H NMR(400MHz,DMSO-d6)δ7.80-7.60(m,1H),7.42(d,J=8.8Hz,2H),7.37-7.26(m,4H),7.22(dd,J=10.0,6.4Hz,1H),6.39(d,J=10.0Hz,1H),6.30(d,J=16.4Hz,1H),5.53(dd,J=10.0,8.0Hz,1H),4.85(dd,J=10.0,8.8Hz,1H),4.23(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.1(dd,J=253.6,6.1Hz),156.3148.2,141.3,133.7(t,J=10.5Hz),133.4,132.1,128.2,122.5,112.4(dd,J=20.0,4.5Hz),106.5(t,J=18.3Hz),74.3,68.5.HRMS(ESI):calcd for C17H14F2NO4S[M+H]+366.0606.found:366.0607.
F-7:白色固体,收率90%,熔点74-75℃。1H NMR(400MHz,DMSO-d6)δ7.98-7.94(m,2H),7.72-7.63(m,1H),7.57-7.50(m,2H),7.35(d,J=8.4Hz,2H),7.29(t,J=8.4Hz,2H),7.08(d,J=8.8Hz,2H),5.50(dd,J=10.0,8.0Hz,1H),4.83(dd,J=10.4,8.8Hz,1H),4.18(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ167.3,164.8,160.6(dd,J=253.6,6.0Hz),156.8,145.2(d,J=672.4Hz),134.2(t,J=10.4Hz),132.1(d,J=10.0Hz),130.9(d,J=3.2Hz),128.7,122.8,117.7(d,J=23.2Hz),112.9(dd,J=20.0,4.8Hz),106.8(t,J=18.0Hz),74.7,68.9.HRMS(ESI):calcd for C21H15F3NO4S[M+H]+434.0668.found:434.0673.
F-8:浅黄色固体,收率88%,熔点66-67℃。1H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.8Hz,2H),7.76(d,J=8.8Hz,2H),7.77-7.63(m,1H),7.35(d,J=8.8Hz,2H),7.29(t,J=8.4Hz,2H),7.09(d,J=8.8Hz,2H),5.50(dd,J=10.0,8.0Hz,1H),4.83(dd,J=10.4,8.8Hz,1H),4.18(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ161.4(dd,J=253.5,6.1Hz),157.4,149.3,142.7,141.3,134.9(t,J=10.4Hz),134.3,131.3,131.2,129.5,123.5,113.6(dd,J=20.2,4.4Hz),107.6(t,J=18.3Hz),75.4,69.7.HRMS(ESI):calcdfor C21H15ClF2NO4S[M+H]+450.0373.found:450.0365.
F-9:无色油状液体,收率80%。1H NMR(400MHz,DMSO-d6)δ7.90(d,J=8.4Hz,2H),7.80(d,J=8.8Hz,2H),7.72-7.63(m,1H),7.35(d,J=8.8Hz,2H),7.29(t,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),5.50(dd,J=10.4,8.0Hz,1H),4.83(dd,J=10.0,8.8Hz,1H),4.18(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.7(dd,J=253.6,6.0Hz),156.7,148.6,142.0,134.2(t,J=10.4Hz),134.0,133.5,130.6,129.8,128.8,122.8,112.9(dd,J=20.0,4.8Hz),106.9(t,J=18.4Hz),74.7,69.0.HRMS(ESI):calcd for C21H15BrF2NO4S[M+H]+493.9868.found:493.9862.
F-10:黄色油状液体,收率85%。1H NMR(400MHz,DMSO-d6)δ8.06(d,J=7.2Hz,2H),7.71-7.65(m,1H),7.61(d,J=8.0Hz,2H),7.35(d,J=7.2Hz,2H),7.29(t,J=8.8Hz,2H),7.09(d,J=7.6Hz,2H),5.52-5.46(m,1H),4.85-4.80(m,1H),4.18(t,J=8.4Hz,1H).13CNMR(100MHz,DMSO-d6)δ160.1(dd,J=253.6,6.4Hz),156.3,148.0,141.4,138.8,133.7(t,J=10.4Hz),129.6,128.2,122.3,115.3,112.4(dd,J=20.0,4.4Hz),106.3(t,J=18.4Hz),104.0,74.2,68.4.HRMS(ESI):calcd for C21H15F2INO4S[M+H]+541.9729.found:541.9728.
F-11:浅白色固体,收率83%,熔点50-51℃。1H NMR(400MHz,DMSO)δ7.94-7.88(m,1H),7.82-7.77(m,1H),7.71-7.61(m,2H),7.46-7.41(m,1H),7.36(d,J=8.8Hz,2H),7.28(t,J=8.4Hz,2H),7.14(d,J=8.4Hz,2H),5.49(dd,J=10.0,8.0Hz,1H),4.82(dd,J=10.4,8.8Hz,1H),4.27-4.04(m,1H).13C NMR(100MHz,DMSO-d6)δ160.1(dd,J=253.6,6.4Hz),158.5(d,J=257.6Hz),156.3,148.0,141.6,138.2(d,J=8.8Hz),133.7(t,J=10.4Hz),131.1,128.3,125.5(d,J=3.6Hz),122.2(d,J=13.6Hz),121.9,117.9(d,J=20.4Hz),112.4(dd,J=20.0,4.8Hz),106.4(t,J=18.4Hz),74.2,68.5.HRMS(ESI):calcdfor C21H15F3NO4S[M+H]+434.0668.found:434.0674.
F-12:无色油状液体,收率96%。1H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.0Hz,1H),7.76-7.70(m,3H),7.70-7.61(m,1H),7.35(d,J=8.8Hz,2H),7.28(t,J=8.4Hz,2H),7.12(d,J=8.8Hz,2H),5.50(dd,J=10.0,8.0Hz,1H),4.83(dd,J=10.0,8.8Hz,1H),4.17(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ162.2(d,J=250.0Hz),160.7(dd,J=253.6,6.2Hz),156.7,148.6,142.0,136.6(d,J=7.5Hz),134.2(t,J=10.4Hz),132.7(d,J=8.2Hz),128.7,125.1(d,J=2.8Hz),122.9(d,J=21.5Hz),122.7,115.8(d,J=25.2Hz),112.9(dd,J=19.9,4.8Hz),106.9(t,J=18.4Hz),74.7,69.0.HRMS(ESI):calcd forC21H15F3NO4S[M+H]+434.0668.found:434.0669.
F-13:无色油状液体,收率90%。1H NMR(400MHz,DMSO-d6)δ8.12(d,J=8.4Hz,2H),8.07(d,J=8.4Hz,2H),7.72-7.63(m,1H),7.36(d,J=8.8Hz,2H),7.29(t,J=8.4Hz,2H),7.12(d,J=8.8Hz,2H),5.50(dd,J=10.0,8.4Hz,1H),4.83(dd,J=10.0,8.8Hz,1H),4.18(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.2(dd,J=253.7,6.1Hz),156.2,148.0,141.7,138.2,134.3(q,J=32.3Hz),133.7(t,J=10.4Hz),129.3,128.3,127.0(q,J=3.6Hz),125.9(q,J=278Hz),122.3,112.4(dd,J=20.0,4.5Hz),106.4(t,J=18.4Hz),74.2,68.5.HRMS(ESI):calcd for C22H15F5NO4S[M+H]+484.0636.found:484.0641.
F-14:浅黄色固体,收率87%,熔点80-81℃。1H NMR(400MHz,DMSO-d6)δ7.91-7.84(m,1H),7.82-7.75(m,1H),7.72-7.63(m,1H),7.39-7.26(m,5H),7.16(d,J=8.0Hz,2H),5.50(dd,J=10.0,8.0Hz,1H),4.83(dd,J=10.4,8.8Hz,1H),4.18(t,J=8.4Hz,1H).13CNMR(100MHz,DMSO-d6)δ166.6(dd,J=257.4,12.0Hz),160.2(dd,J=253.5,6.2Hz),159.6(dd,J=259.7,14.1Hz),156.2,147.9,141.7,133.7(t,J=10.5Hz),133.4(d,J=11.5Hz),128.4,122.0,119.0(dd,J=13.9,3.7Hz),113.2(dd,J=22.7,3.6Hz),112.4(dd,J=20.0,4.5Hz),107.0(dd,J=27.2,24.9Hz),106.4(t,J=18.2Hz),74.2,68.5.HRMS(ESI):calcdfor C21H14F4NO4S[M+H]+452.0574.found:452.0579.
F-15:浅黄色固体,收率83%,熔点72-73℃。1H NMR(400MHz,DMSO-d6)δ7.72-7.62(m,2H),7.59-7.51(m,1H),7.36(d,J=8.8Hz,2H),7.29(t,J=8.8Hz,2H),7.22(d,J=8.4Hz,2H),5.51(dd,J=10.0,8.0Hz,1H),4.83(dd,J=10.0,9.2Hz,1H),4.18(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.6(dd,J=253.5,6.2Hz),156.7,155.3(ddd,J=258.8,10.0,3.3Hz),148.9(ddd,J=260.8,11.7,4.3Hz),148.4,142.4,140.7(dt,J=252.3Hz,14.9Hz),134.2(t,J=10.5Hz),128.9,126.6(dd,J=9.8,4.1Hz),122.8,120.5(dd,J=11.1,3.5Hz),114.4(dd,J=18.6,3.5Hz),112.9(dd,J=19.8,4.8Hz),106.9(t,J=18.3Hz),74.7,69.0.HRMS(ESI):calcd for C21H13F5NO4S[M+H]+470.0480.found:470.0479.
F-16:浅黄色固体,收率80%,熔点69-70℃。1H NMR(400MHz,DMSO-d6)δ7.76(d,J=8.0Hz,2H),7.72-7.62(m,1H),7.48(d,J=8.0Hz,2H),7.35-7.26(m,4H),7.06(d,J=8.4Hz,2H),5.52-5.46(m,1H),4.86-4.79(m,1H),4.20-4.15(m,1H),2.42(s,3H).13C NMR(100MHz,DMSO-d6)δ160.6(dd,J=253.6,6.0Hz),156.7,148.7,146.3,141.7,134.2(t,J=10.4Hz),131.9,130.7,128.7,128.6,122.7,112.9(dd,J=20.0,4.4Hz),106.9(t,J=18.4Hz),74.7,69.0,21.62.HRMS(ESI):calcd for C22H18F2NO4S[M+H]+430.0919.found:430.0925.
F-17:无色油状液体,收率94%。1H NMR(400MHz,DMSO-d6)δ7.82(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),7.72-7.63(m,1H),7.34(d,J=8.4Hz,2H),7.29(t,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),5.50(dd,J=10.0,8.0Hz,1H),4.83(dd,J=10.0,8.8Hz,1H),4.19(t,J=8.4Hz,1H),1.32(s,9H).13C NMR(100MHz,DMSO-d6)δ160.6(dd,J=253.6,6.4Hz),158.8,156.7,148.7,141.7,134.2(t,J=10.4Hz),132.0,128.6,128.5,127.2122.7,112.9(dd,J=20.0,4.4Hz),106.9(t,J=17.6Hz),74.7,69.0,35.6,31.1.HRMS(ESI):calcd forC25H24F2NO4S[M+H]+472.1389.found:472.1394.
F-18:白色固体,收率22%,熔点52-53℃。1H NMR(400MHz,DMSO-d6)δ7.72-7.63(m,1H),7.39-7.25(m,6H),7.13-7.08(m,3H),5.51(dd,J=10.0,8.0Hz,1H),4.84(dd,J=10.0,8.8Hz,1H),4.40-4.36(m,2H),4.35-4.30(m,2H),4.19(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO)δ160.6(dd,J=253.6,6.1Hz),156.7,149.4,148.8,144.1,141.7,134.2(t,J=10.5Hz),128.6,126.6,122.8,122.5,118.6,117.5,112.9(dd,J=19.8,4.8Hz),106.9(t,J=18.4Hz),74.7,69.0,65.0,64.5.HRMS(ESI):calcd for C23H18F2NO6S[M+H]+474.0817.found:474.0821.
F-19:浅白色固体,收率44%,熔点52-53℃。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),7.89(d,J=9.2Hz,2H),7.83(d,J=9.2Hz,2H),7.71-7.63(m,1H),7.36(d,J=8.4Hz,2H),7.31-7.25(m,2H),7.09(d,J=8.4Hz,2H),5.52(dd,J=10.0,8.0Hz,1H),4.85(dd,J=10.4,8.8Hz,1H),4.23-4.17(m,1H),2.14(s,3H).13C NMR(100MHz,DMSO-d6)δ170.0,160.6(dd,J=253.6,6.0Hz),156.8,148.8,145.3,141.6,134.1(t,J=10.4Hz),130.1,128.5,127.8,122.8,119.3,112.8(dd,J=20.0,4.4Hz),106.8(t,J=18.4Hz),74.7,69.0,24.6.HRMS(ESI):calcd for C23H19F2N2O5S[M+H]+473.0977.found:473.0978.
F-20:无色油状液体,收率75%。1H NMR(400MHz,DMSO-d6)δ8.66(d,J=8.4Hz,1H),8.42(d,J=8.4Hz,1H),8.22(d,J=8.4Hz,1H),8.12(d,J=7.2Hz,1H),7.95-7.89(m,1H),7.83-7.77(m,1H),7.68-7.63(m,2H),7.32-7.21(m,4H),6.91(d,J=6.8Hz,2H),5.45-5.39(m,1H),4.81-4.75(m,1H),4.14-4.10(m,1H).13C NMR(100MHz,DMSO-d6)δ160.6(dd,J=253.7,6.1Hz),156.7,148.7,141.8,136.9,134.2,134.1(t,J=10.4Hz),131.8,130.1,130.0,129.9,128.7,128.11,128.05,125.1,124.5,122.3,112.8(dd,J=20.3,4.3Hz),106.9(t,J=18.4Hz),74.6,69.0.HRMS(ESI):calcd for C25H18F2NO4S[M+H]+466.0919.found:466.0925.
F-21:无色油状液体,收率76%。1H NMR(400MHz,DMSO-d6)δ8.58(d,J=1.2Hz,1H),8.23(t,J=7.2Hz,2H),8.12(d,J=8.4Hz,1H),7.90(dd,J=8.8,2.0Hz,1H),7.84-7.77(m,1H),7.71(t,J=7.2Hz,1H),7.70-7.61(m,1H),7.35-7.22(m,4H),7.08(d,J=8.8Hz,2H),5.45(dd,J=10.0,8.0Hz,1H),4.80(dd,J=10.0,8.8Hz,1H),4.14(t,J=8.4Hz,1H).13CNMR(100MHz,DMSO-d6)δ160.1(dd,J=253.6,6.2Hz),156.2,148.3,141.3,135.0,133.7(t,J=10.6Hz),131.4,131.3,130.2,130.0,130.0,129.6,128.2,128.1,128.0,122.4,122.3,112.4(dd,J=20.3,4.3Hz),106.4(t,J=18.6Hz),74.2,68.5.HRMS(ESI):calcd forC25H18F2NO4S[M+H]+466.0919.found:466.0924.
F-22:黄色固体,收率85%,熔点107-108℃。1H NMR(400MHz,CDCl3)δ7.95(d,J=8.4Hz,2H),7.83(d,J=8.4Hz,2H),7.53-7.38(m,1H),7.30(d,J=8.8Hz,2H),7.06-6.94(m,4H),5.45(dd,J=10.0,8.4Hz,1H),4.82(dd,J=10.0,8.8Hz,1H),4.23(t,J=8.4Hz,1H).13C NMR(100MHz,CDCl3)δ156.4(dd,J=256.4,5.9Hz),153.4,143.9,136.7,134.6,128.2,128.0(t,J=10.4Hz),124.4,123.6,117.8,113.3,112.1,107.3(dd,J=20.3,5.2Hz),102.1(t,J=17.5Hz),69.8,64.7.HRMS(ESI):calcd for C22H15F2N2O4S[M+H]+441.0715.found:441.0717.
F-23:浅黄色固体,收率77%,熔点131-132℃。1H NMR(400MHz,DMSO-d6)δ8.47(d,J=8.8Hz,2H),8.18(d,J=8.8Hz,2H),7.73-7.62(m,1H),7.36(d,J=8.4Hz,2H),7.29(t,J=8.8Hz,2H),7.13(d,J=8.8Hz,2H),5.51(dd,J=10.0,8.0Hz,1H),4.84(dd,J=10.4,8.8Hz,1H),4.19(t,J=8.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ160.2(dd,J=253.6,6.1Hz),156.3,151.1,148.0,141.7,139.5,133.7(t,J=10.2Hz),130.0,128.4,125.0,122.3,112.4(dd,J=20.2,4.1Hz),106.3(d,J=18.3Hz),74.2,68.5.HRMS(ESI):calcdfor C21H15F2N2O6S[M+H]+461.0613.found:461.0618.
实施例6:F-24的合成
F-24的合成:在100mL单口瓶中加入E(0.55g,2mmol),NaOH(0.096g,2.4mmol)四氯化碳和水各5mL,水浴搅拌下滴加溶于5mL四氯化碳的三氟甲磺酸酐(1.13g,4mmol)。TLC(石油醚/乙酸乙酯=3/1)监测反应,3小时后反应完毕。加入二氯甲烷分液,水相用二氯甲烷萃取三次。合并有机相后水洗2次,饱和氯化钠洗涤一次,无水硫酸钠干燥。过滤,减压浓缩除去二氯甲烷和四氯化碳。经石油醚/乙酸乙酯=5/1柱层析后得0.58g白色固体F-24,收率71%。熔点167-168℃。1H NMR(400MHz,DMSO-d6)δ7.73-7.64(m,1H),7.58-7.50(m,4H),7.30(t,J=8.4Hz,2H),5.59(dd,J=10.0,8.0Hz,1H),4.88(dd,J=10.4,8.8Hz,1H),4.29-4.22(m,1H).13C NMR(100MHz,DMSO-d6)δ160.7(dd,J=253.6,6.1Hz),157.0,148.9,143.5,134.2(t,J=10.5Hz),129.3,122.2,118.7(q,J=319Hz),112.9(dd,J=20.3,4.3Hz),106.9(t,J=18.3Hz),74.7,68.9.HRMS(ESI):calcd for C16H11F5NO4S[M+H]+408.0323.found:408.0328.
实施例7:杀朱砂叶螨活性的测定,测定程序如下:
杀幼螨活性测试:
采用浸渍法以室内在豆苗上饲养的朱砂叶螨作为受试对象。将成螨接种到新长出的完整的具有两片叶子的豆苗叶片上面,剪下豆苗置于25℃有光照的温室内,并在温室中产卵24h,然后剔除成螨,保留螨卵。继续在温室中培育5天,待其螨卵孵化成幼螨后(保证每个被测叶片的虫量不少于60个)。用镊子将含有幼螨的豆苗叶片全部浸入到用吐温水配好浓度的待测样品中5-6秒,轻轻甩掉余液,放回培养杯,继续培养4天后查看结果。其中一株用不加任何待测样且其余添加物完全相同的样液进行浸渍作为空白对照。每个化合物重复三次。
杀螨卵活性测试:
采用浸渍法以室内在豆苗上饲养的朱砂叶螨作为受试对象。将成螨接种到新长出的完整的具有两片叶子的豆苗叶片上面,剪下豆苗置于25℃有光照的温室内,并在温室中产卵24h,然后剔除成螨,保留螨卵。继续在温室中培育一天后,用镊子将含有螨卵的豆苗叶片全部浸入到配好浓度的待测样品中5-6秒,轻轻甩掉余液,放回培养杯,继续培养4天后查看结果。其中一株用不加任何待测样且其余添加物完全相同的样液进行浸渍作为空白对照。每个化合物重复三次。
表1含磺酸酯结构的噁唑啉类衍生物F-1~F-24的杀螨活性测试结果:
表2高活性化合物的杀幼螨LC50
a表示0.01mg/L
表3高活性化合物的杀螨卵LC50
a表示0.05mg/L
从表1、2、3中可见含磺酸酯结构的噁唑啉类衍生物F-1~F-24表现出很好的杀朱砂叶螨活性,其中化合物F-3、F-9、F-17的杀螨活性显著,表现出与乙螨唑相当甚至更好的杀螨活性。
Claims (4)
4.权利要求1所述的含磺酸酯结构的噁唑啉类衍生物F在防治植食性螨中的应用,其特征在于对朱砂叶螨螨卵和幼螨的杀螨效果显著,其中化合物F-3、F-9、F-17表现出乙螨唑相当甚至更高的杀螨活性。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1054422A (zh) * | 1989-12-09 | 1991-09-11 | 八洲化学工业株式会社 | 2-取代苯基-2-噻唑啉或2-取代苯-2-噻唑啉的衍生物、其制备方法及含该类化合物的杀虫剂和杀螨剂 |
CN1199401A (zh) * | 1995-10-12 | 1998-11-18 | 纳幕尔杜邦公司 | 杀节肢动物的噁唑啉和噻唑啉 |
JPWO2005051932A1 (ja) * | 2003-11-28 | 2007-06-21 | 日本曹達株式会社 | アリール複素環誘導体および農園芸用殺菌剤および殺虫剤 |
CN102675237A (zh) * | 2012-05-24 | 2012-09-19 | 南京工业大学 | 2,4-二苯基噁唑啉类新化合物、合成方法及其杀螨活性 |
CN105348211A (zh) * | 2015-09-25 | 2016-02-24 | 南开大学 | 4-苯基对位含有硫醚及其衍生结构的噁唑啉类化合物、制备和作为杀虫杀螨剂的应用 |
-
2019
- 2019-09-24 CN CN201910903359.2A patent/CN112624996B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1054422A (zh) * | 1989-12-09 | 1991-09-11 | 八洲化学工业株式会社 | 2-取代苯基-2-噻唑啉或2-取代苯-2-噻唑啉的衍生物、其制备方法及含该类化合物的杀虫剂和杀螨剂 |
CN1199401A (zh) * | 1995-10-12 | 1998-11-18 | 纳幕尔杜邦公司 | 杀节肢动物的噁唑啉和噻唑啉 |
JPWO2005051932A1 (ja) * | 2003-11-28 | 2007-06-21 | 日本曹達株式会社 | アリール複素環誘導体および農園芸用殺菌剤および殺虫剤 |
CN102675237A (zh) * | 2012-05-24 | 2012-09-19 | 南京工业大学 | 2,4-二苯基噁唑啉类新化合物、合成方法及其杀螨活性 |
CN105348211A (zh) * | 2015-09-25 | 2016-02-24 | 南开大学 | 4-苯基对位含有硫醚及其衍生结构的噁唑啉类化合物、制备和作为杀虫杀螨剂的应用 |
Non-Patent Citations (1)
Title |
---|
李永强 等: "2,4-二苯基-1,3-唑啉类杀螨剂的研究进展", 《农药学学报》 * |
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