CN104592332A - 一种阿维菌素酰硫脲类化合物及其制备方法和其在制备农药中的用途 - Google Patents
一种阿维菌素酰硫脲类化合物及其制备方法和其在制备农药中的用途 Download PDFInfo
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- CN104592332A CN104592332A CN201410482532.3A CN201410482532A CN104592332A CN 104592332 A CN104592332 A CN 104592332A CN 201410482532 A CN201410482532 A CN 201410482532A CN 104592332 A CN104592332 A CN 104592332A
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- avrmectin
- lsothiocyanates
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- avermectin
- acyl thiourea
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 16
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Abstract
本发明属于农药领域,涉及一种阿维菌素酰硫脲类化合物,还涉及该化合物的制备方法和其在制备农药中的用途。所述的阿维菌素酰硫脲类化合物的制备方法:将4″-氨基-阿维菌素溶于乙腈,在惰性气体保护下加入酰基异硫氰酸酯,反应结束后,用氯仿稀释,过滤、水洗、氯仿反萃,合并有机层,用无水硫酸钠干燥,过滤浓缩后用柱层析分离得4″-阿维菌素酰硫脲类化合物。本发明所述的阿维菌素酰硫脲类化合物在制备防治农业害虫的农药中应用、在治理抗性害虫方面的应用和在制备防治甘蓝蚜的农药中应用。本发明的化合物结构新颖、工艺简单、产品纯度高。因结构与阿维菌素不同,可用于防治对阿维菌素产生抗性的害虫种类。
Description
技术领域
本发明属于农药领域,涉及一种阿维菌素酰硫脲类化合物,还涉及该化合物的制备方法和其在制备农药中的用途。
背景技术
农药是与人类生存活动密切相关的一类重要的农用化学品,农药安全性的各项标准趋于严格化,并不断地淘汰、限制高毒高残留农药,因而农药工业一直处于不断更新的动态发展中。在这种背景下,谁能代表新农药开发的新潮流,谁就能主宰农药市场。
随着社会的进步,人们对绿色、有机食品的需求不断增加,给生物农药提供了足够的发展空间。阿维菌素(avermectins)又称阿佛曼菌素,是由日本北里大学大村智等和美国Merck公司首先从链霉菌(Streptomyces avermiti)中分离获得的一组大环内酯类农畜两用抗生素,阿维菌素作为生物农药的一种,自发现以来,已经日益受到人们的重视。阿维菌素对线虫、昆虫和螨虫均有驱杀作用,可用于治疗畜禽的线虫病、螨和寄生性昆虫病,具有广谱、高效、安全等特点,其机理是作用于昆虫神经元突触或神经肌肉突触的GABA受体,干扰昆虫体内神经末梢的信息传递,激发神经未梢释放出神经传递抑制剂γ-氨基丁酸(GABA),促使GABA门控的氯离子通道延长开放,对氯离子通道具有激活作用,由于大量氯离子涌入造成神经膜电位超级化,致使神经膜处于抑制状态,从而阻断神经未梢与肌肉的联系,使昆虫麻痹、拒食、死亡。近年来,除通过生物技术手段提高菌种的产素能力,以及通过生产工艺和制剂技术的改进来提高其活性外,对其母体结构的衍生化改造更具有重要意义。目前,围绕阿维菌素衍生物的研究已经取得了很大进展,近千种阿维菌素衍生物已合成出来,并且相继商品化的有甲胺基阿维菌素苯甲酸盐、伊维菌素、埃珀利诺菌素、埃玛菌素、道拉菌素、雷皮菌素和弥拜霉素等,改造后的新化合物克服了原母体阿维菌素的某些不足,在扩大防治谱、提高杀虫活性以及降低对人畜和环境毒性等方面取得了明显的改善。目前关于化学结构修饰、构效关系、农药剂型的制备及与其他杀虫剂复配成混剂等方面的研究工作,已有相关的专利和文献报道。
到目前为止,尚未见有4″-阿维菌素酰硫脲类化合物的合成及此类化合物作为农药进行农业害虫防治的文献报道。
发明内容
本发明要解决的技术问题是克服现有的缺陷,提供了一种阿维菌素酰硫脲类化合物,还提供了该化合物的制备方法和其在制备农药中的用途。
为了解决上述技术问题,本发明提供了如下的技术方案:
一种阿维菌素酰硫脲类化合物,该类化合物具有式(I)所示的化学结构:
结构式(I)中:取代基R选自苯基、对氯苯基、间氯苯基、邻氟苯基、对氟苯基、对溴苯基、间溴苯基、对甲基苯基、噻吩基、3-吡啶基、2-呋喃基、2-萘基、环己基、甲基、环戊基。
本发明所述的阿维菌素酰硫脲类化合物的制备方法,将4″-氨基-阿维菌素溶于无水乙腈,在惰性气体保护下加入酰基异硫氰酸酯,室温搅拌2~3h,反应结束后,用氯仿稀释,过滤、水洗、氯仿反萃,合并有机层,用无水硫酸钠干燥,过滤浓缩后用柱层析分离,所述柱层析分离采用石油醚-乙酸乙酯为洗脱剂洗脱,得目标产物即4″-阿维菌素酰硫脲类化合物,其中所述4″-氨基-阿维菌素与所述酰基异硫氰酸酯的用量摩尔比为1:1-1:3,所述4″-氨基-阿维菌素与所述无水乙腈的摩尔体积比(mmol/ml)为1:20-1:70。
在上述方案的基础上,所述酰基异硫氰酸酯为苯甲酰基异硫氰酸酯、对氯苯甲酰基异硫氰酸酯、间氯苯甲酰基异硫氰酸酯、邻氟苯甲酰基异硫氰酸酯、对氟苯甲酰基异硫氰酸酯、对溴苯甲酰基异硫氰酸酯、间溴苯甲酰基异硫氰酸酯、对甲基苯甲酰基异硫氰酸酯、2-噻吩甲酰基异硫氰酸酯、3-吡啶甲酰基异硫氰酸酯、2-呋喃甲酰基异硫氰酸酯、2-萘基甲酰基异硫氰酸酯、环己甲酰基异硫氰酸酯、乙酰基异硫氰酸酯或环戊甲酰基异硫氰酸酯。
在上述方案的基础上,所述4″-氨基-阿维菌素与所述酰基异硫氰酸酯的用量摩尔比为1:1.5,所述4″-氨基-阿维菌素与所述无水乙腈的摩尔体积比(mmol/ml)为1:50。
在上述方案的基础上,所述惰性气体为氮气。
在上述方案的基础上,石油醚-乙酸乙酯洗脱剂中石油醚与乙酸乙酯的体积比为5∶1~15∶1。
在上述方案的基础上,所述柱层析用硅胶柱采用200~300目的柱层析硅胶。
本发明所述的阿维菌素酰硫脲类化合物在制备防治农业害虫的农药中应用。
本发明所述的阿维菌素酰硫脲类化合物在治理抗性害虫方面的应用。
本发明所述的阿维菌素酰硫脲类化合物在制备防治甘蓝蚜的农药中应用。
本发明所述的阿维菌素酰硫脲类化合物经生物活性测定结果表明,本发明制备的4″-阿维菌素酰硫脲类化合物,对甘蓝蚜(Brevicoryne brassicae)均有不同程度的毒杀活性,其中部分化合物的毒杀活性与阿维菌素相当,因此本发明提供了该类化合物在防治农业重要害虫中的用途。本发明所述的阿维菌素酰硫脲类化合物结构新颖、工艺简单、产品纯度高。因结构与阿维菌素不同,可用于防治对阿维菌素产生抗性的害虫种类。
具体实施方式
此处所描述的优选实施例仅用于说明和解释本发明,并不用于限定本发明。
为进一步寻找高效低毒的阿维菌素类农药,本发明在掌握了阿维菌素构效关系的基础上,设计合成了一系列结构新颖的阿维菌素酰硫脲类化合物,可望通过这种结构优化方式扩大其农药活性谱、提高对抗性害虫的防治效果。
本发明所述的原料4″-氨基-阿维菌素的合成方法:
本发明的4″-氨基-阿维菌素的合成方法按照以下的化学反应式合成(参考文献:(1)Fu,M.K.et al.Chin.J.Chem.2005,23,901-904;(2)Cvetovich,R.J.et al.J.Org.Chem.1994,59,7704-7708.)。
5-O-TBDMS avermectin(2)的合成:取3g(3.42mmol)阿维菌素溶于15mL干燥的二氯甲烷中,加入1.4g(20.51mmol)咪唑,待原料溶解完后,随后加入1.56g(10.42mmol)TBDMSCl,在室温下搅拌约2.5h后,TLC检测反应完全。用乙醚稀释,水洗,水层用乙醚反复萃取,合并有机层,有机层接着依次用水、饱和食盐水洗,收集有机层,用无水硫酸镁干燥,过滤浓缩后用柱层析分离得到2.4g所需纯品。
4″-O-5-O-TBDMS avermectin(3)的合成:取2.4g 5-O-TBDMS-avermectin(2.43mmol)溶于20mL干燥的二氯甲烷中,加入0.6mL的DMSO与1.5mL的TEA,在-15℃下滴加0.6 mL的PhOPOCl2,保持-15℃反应1.5h,TLC检测反应完全。75mL1%的磷酸水溶液洗,用CH2Cl2反复萃取(25mL×3),合并有机层,有机层随后用饱和的NaHCO3(25mL)水溶液洗,无水硫酸镁干燥,过滤并在真空下旋干得到2.2g所需纯品。
4″-epi-NH2-5-O-TBDMS avermectin(4)的合成:取2.2g(2.23mmol)4″-O-5-O-TBDMS-avermectin溶于25mL无水甲醇中,随后依次加入1.8g(23.4mmol)醋酸铵,140mg(2.2mmol)氰基硼氢化钠在室温下搅拌约1h,TLC检测反应完全。NaHCO3的水溶液洗,用乙酸乙酯反复萃取(30mL×3),合并有机层并用水洗(30mL),无水硫酸镁干燥,过滤浓缩后用柱层析分离得到0.6g所需纯品。
4″-epi-NH2avermectin(5)的合成:取0.6g(0.61mmol)4″-epi-NH2-5-O-TBDMS avermectin在冰浴条件下溶于15mL l%(质量:体积)的对甲苯磺酸的甲醇溶液,在冰浴条件下反应约2.5h,TLC检测反应完全。NaHCO3的水溶液洗,用乙酸乙酯反复萃取(12mL×3),合并有机层并依次用水(15mL×3))、饱和食盐水洗(20mL),无水硫酸镁干燥,过滤浓缩后用柱层析分离得到0.3g所需纯品。
本发明所使用的酰基异硫氰酸酯的通用制备方法:(参考文献:Hemdan MM.Phosphorus Sulfur and Silicon 2010,185,620–627)
取1mmol不同取代的酸溶于15mL氯化亚砜中,加热回流4h后停止反应,减压蒸去氯化亚砜,将所得油状物用10mL乙腈稀释,逐滴加入硫氰化钾(2mmol)的乙腈溶液(10mL),滴加过程中有大量沉淀产生,TLC检测,待反应完全,滤除固体,母液减压蒸馏得不同R取代的酰基异硫氰酸酯。
实施例1
目标化合物4″-[苯甲酰硫脲基]-阿维菌素(6a)的合成
将1mmol 4″-氨基-阿维菌素溶于50mL乙腈,在氮气保护下加入1.5mmol的苯甲酰基异硫氰酸酯,室温反应,TLC跟踪检测,反应2h。反应结束后,用氯仿稀释,过滤、水洗、氯仿反萃,合并有机层,用无水硫酸钠干燥,过滤浓缩后用柱层析分离得到所需纯品。
反应所得产物检测数据如下:产率:42%,淡黄色固体,熔点:176~178℃;
1H NMR(400MHz,CDCl3)δ:11.12(d,1H,NHCS-H,J=10.0Hz),9.03(s,1H,NHCO-H),7.85(d,2H,R-H2,H6,J=7.6Hz),7.64-7.61(m,1H,R-H4),7.52(t,2H,R-H3,H5,J=7.2Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.57-5.54(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.19(d,1H,H5,J=6.4Hz),4.05(m,1H,7-OH),3.99-3.84(m,6H,H6,H13,H5′,H17,H5″,H3′),3.63(m,2H,H25,H3″),3.53(s,3H,3″-OCH3),3.49(s,1H,H2),3.45(s,3H,3′-OCH3),3.30-3.24(m,2H,H4′,H4″),2.53(m,1H,H12),2.38-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.87(s,3H,4-Me),1.80-1.77(m,1H,H18),1.61-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.26(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me),0.96-0.87(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1057.33[M+Na]+。
实施例2
目标化合物4″-[对氯苯甲酰硫脲基]-阿维菌素(6b)的合成
实验步骤与实施例1同,仅以对氯苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:45%,淡黄色固体,熔点:172~174℃;
1H NMR(400MHz,CDCl3)δ:11.04(d,1H,NHCS-H,J=10.0Hz),8.97(s,1H,NHCO-H),7.80(d,2H,R-H2,H6,J=8.4Hz),7.50(d,2H,R-H3,H5,J=8.4Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.56-5.52(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.99(br.d,1H,H15),4.78-4.65(m,3H,H1′,H8a),4.19(d,1H,H5,J=6.4Hz),4.05(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.88-3.81(m,4H,H5′,H17,H5″,H3′),3.63(m,2H,H25,H3″),3.52(s,3H,3″-OCH3),3.47(s,1H,H2),3.44(s,3H,3′-OCH3),3.32-3.23(m,2H,H4′,H4″),2.53(m,1H,H12),2.37-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.79-1.76(m,1H,H18),1.59-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.28-1.23(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=6.8Hz),0.96-0.85((m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1091.34[M+Na]+.
实施例3
目标化合物4″-[间氯苯甲酰硫脲基]-阿维菌素(6c)的合成
实验步骤与实施例1同,仅以间氯苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:38%,白色固体,熔点:177~179℃;
1H NMR(400MHz,CDCl3)δ:10.99(d,1H,NHCS-H,J=9.2Hz),8.97(s,1H,NHCO-H),7.86(s,1H,R-H2),7.71(d,1H,R-H6,J=8.4Hz),7.60(d,1H,R-H4,J=8.0Hz),7.46(t,1H,R-H5,J=8.0Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.56-5.52(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.99(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.19(d,1H,H5,J=6.0Hz),4.04(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.88-3.84(m,4H,H5′,H17,H5″,H3′),3.63(m,2H,H25,H3″),3.52(s,3H,3″-OCH3),3.47(s,1H,H2),3.45(s,3H,3′-OCH3),3.30-3.24(m,2H,H4′,H4″),2.53(m,1H,H12),2.37-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.79-1.76(m,1H,H18),1.58-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.27-1.23(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=7.2Hz),0.96-0.85(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1091.38[M+Na]+.
实施例4
目标化合物4″-[邻氟苯甲酰硫脲基]-阿维菌素(6d)的合成
实验步骤与实施例1同,仅以邻氟苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:48%,白色固体,熔点:189~191℃;
1H NMR(400MHz,CDCl3)δ:11.06(d,1H,NHCS-H,J=9.6Hz),9.61(d,1H,NHCO-H,J=15.2Hz),8.08(t,1H,R-H6,J=7.2Hz),7.61(dd,1H,R-H4),7.33(t,1H,R-H5,J=7.6Hz),7.24-7.21(m,1H,R-H3),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.56-5.52(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.19(d,1H,H5,J=6.8Hz),4.04(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.86-3.81(m,4H,H5′,H17,H5″,H3′),3.63(m,2H,H25,H3″),3.52(s,3H,3″-OCH3),3.49(d,1H,H2,J=9.2Hz),3.45(s,3H,3′-OCH3),3.30-3.24(m,2H,H4′,H4″),2.53(m,1H,H12),2.36-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.79-1.76(m,1H,H18),1.60-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.27-1.24(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=6.8Hz),0.96-0.85(m, 10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1075.42[M+Na]+.
实施例5
目标化合物4″-[对氟苯甲酰硫脲基]-阿维菌素(6e)的合成
实验步骤与实施例1同,仅以对氟苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:52%,黄色固体,熔点:182~183℃;
1H NMR(400MHz,CDCl3)δ:11.06(d,1H,NHCS-H,J=9.6Hz),8.95(s,1H,NHCO-H),7.88(dd,2H,R-H2,H6,J=5.2Hz,8.4Hz),7.20(t,2H,R-H3,H5,J=8.4Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.56-5.52(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.97(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.19(d,1H,H5,J=6.4Hz),4.05(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.84(m,4H,H5′,H17,H5″,H3′),3.63(m,2H,H25,H3″),3.52(s,3H,3″-OCH3),3.47(s,1H,H2),3.44(s,3H,3′-OCH3),3.30-3.23(m,2H,H4′,H4″),2.53(m,1H,H12),2.36-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.79-1.76(m,1H,H18),1.58-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.25-1.23(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=7.2Hz),0.96-0.87(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1075.29[M+Na]+.
实施例6
目标化合物4″-[对溴苯甲酰硫脲基]-阿维菌素(6f)的合成
实验步骤与实施例1同,仅以对溴苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:54%,黄色固体,熔点:157~159℃;
1H NMR(400MHz,CDCl3)δ:11.02(d,1H,NHCS-H,J=10.0Hz),8.95(s,1H,NHCO-H),7.72(d,2H,R-H2,H6,J=8.4Hz),7.66(d,2H,R-H3,H5,J=8.0Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.56-5.51(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.98(m,1H,H15),4.78(s,1H,H1′),4.69(m,2H,H8a),4.29(d,1H,H5,J=6.8Hz),4.04(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.86(m,4H,H5′,H17,H5″,H3′),3.63(m,2H,H25,H3″),3.52(s,3H,3″-OCH3),3.48(s,1H,H2),3.44(s,3H,3′-OCH3),3.30-3.23(m,2H,H4′,H4″),2.53(m,1H,H12),2.36-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.74(m,1H,H18),1.57-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.25-1.23(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=7.2Hz),0.95-0.85(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1135.29[M+Na]+.
实施例7
目标化合物4″-[间溴苯甲酰硫脲基]-阿维菌素(6g)的合成
实验步骤与实施例1同,仅以间溴苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:40%,淡黄色固体,熔点:177~179℃;
1H NMR(400MHz,CDCl3)δ:10.99(d,1H,NHCS-H,J=10.4Hz),8.96(s,1H,NHCO-H),8.02(s,1H,R-H2),7.75(d,2H,R-H4,H6,J=7.6Hz),7.39(t,1H,R-H5,J=8.0Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.57-5.52(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.78-4.69(m,3H,H1′,H8a),4.19(d,1H,H5,J=6.4Hz),4.05(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.86-3.82(m,4H,H5′,H17,H5″,H3′),3.63-3.60(m,2H,H25,H3″),3.53(s,3H,3″-OCH3),3.48(s,1H,H2),3.46(s,3H,3′-OCH3),3.30-3.24(m,2H,H4′,H4″),2.53(m,1H,H12),2.37-2.13(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.79(m,1H,H18),1.59-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.26-1.23(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=7.2Hz),0.96-0.86(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1135.43[M+Na]+。
实施例8
目标化合物4″-[对甲苯甲酰硫脲基]-阿维菌素B1a(6h)的合成
实验步骤与实施例1同,仅以对甲基苯甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:41%,淡黄色固体,熔点:166~168℃;
1H NMR(400MHz,CDCl3)δ:9.08(d,1H,NHCS-H,J=10.0Hz),8.61(s,1H,NHCO-H),7.77(d,2H,R-H2,H6,J=8.0Hz),7.29(d,2H,R-H3,H5,J=8.0Hz),5.86(m,1H,H9),5.78-5.74(m,3H,H23,H10,H11),5.55(d,1H,H22,J=10.0Hz),5.48(br.s,1H,H3),5.42(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.30(d,1H,H5,J=6.0Hz),3.99-3.94(m,2H,H6,H13),3.86-3.73(m,4H,H5′,H17,H5″,H3′),3.62-3.52(m,2H,H25,H3″),3.49(s,3H,3″-OCH3),3.45(s,3H,3′-OCH3),3.27-3.14(m,2H,H4′,H4″),2.52(m,1H,H12),2.42(s,3H,R-Me),2.38-2.03(m,7H,5-OH,H16,H24,H2′,H18),1.87(s,3H,4-Me),1.77(m,1H,H18),1.59-1.46(m,9H,H20,H26,H27,14-Me,H2″),1.28-1.16(m,9H,6′-Me,6″-Me,12-Me), 0.98-0.79(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1071.46[M+Na]+。
实施例9
目标化合物4″-[2-噻吩甲酰硫脲基]-阿维菌素(6i)的合成
实验步骤与实施例1同,仅以2-噻吩甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:46%,淡黄色固体,熔点:184~186℃;
1H NMR(400MHz,CDCl3)δ:10.91(d,1H,NHCS-H,J=9.6Hz),8.87(s,1H,NHCO-H),7.70-7.66(m,2H,R-H3,H5),7.17(t,1H,R-H4,J=4.4Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.57-5.50(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.30(d,1H,H5,J=5.2Hz),3.99-3.94(m,2H,H6,H13),3.87-3.80(m,4H,H5′,H17,H5″,H3′),3.62(m,2H,H25,H3″),3.51(s,3H,3″-OCH3),3.47(s,1H,H2),3.44(s,3H,3′-OCH3),3.30-3.23(m,2H,H4′,H4″),2.52(m,1H,H12),2.29-2.11(m,6H,5-OH,H16,H24,H2′),2.05(s,1H,H20),1.88(s,3H,4-Me),1.79-1.75(m,1H,H18),1.61-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.33-1.22(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=6.8Hz),0.96-0.85(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1063.47[M+Na]+。
实施例10
目标化合物4″-[3-吡啶甲酰硫脲基]-阿维菌素(6j)的合成
实验步骤与实施例1同,仅以3-吡啶甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:30%,白固体,熔点:179~180℃;
1H NMR(400MHz,CDCl3)δ:10.96(d,1H,NHCS-H,J=9.6Hz),9.10(s,1H,NHCO-H),9.04(s,1H,R-H2),8.85(d,1H,R-H6,J=4.4Hz),8.16(d,1H,R-H4,J=8.0Hz),7.48(dd,1H,R-H5,J=4.8Hz,8.4Hz),5.86(m,1H,H9),5.78-5.73(m,3H,H23,H10,H11),5.56-5.43(m,2H,H22,H3),5.38(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.20(d,1H,H5,J=6.8Hz),4.05(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.88-3.82(m,2H,H5′,H17,H5″,H3′),3.65-3.60(m,2H,H25,H3″),3.52(s,3H,3″-OCH3),3.47(s,1H,H2),3.45(s,3H,3′-OCH3),3.30-3.24(m,2H,H4′,H4″),2.53(m,1H,H12),2.36-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.87(s,3H,4-Me),1.78(d,1H,H18,J=13.6Hz),1.60-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.26-1.19(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=6.8Hz),0.96-0.87(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1058.44[M+Na]+。
实施例11
目标化合物4″-[2-呋喃甲酰硫脲基]-阿维菌素(6k)的合成
实验步骤与实施例1同,仅以2-呋喃甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:45%,黄色固体,熔点:168~170℃;
1H NMR(400MHz,CDCl3)δ:10.85(d,1H,NHCO-H,J=9.6Hz),9.14(s,1H,NHCS-H),7.58(s,1H,R-H5),7.33(d,1H,R-H3,J=3.2Hz),6.60(s,1H,R-H4),5.86(m,1H,H9),5.78-5.72(m,3H,H23,H10,H11),5.56-5.50(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.97(br.d,1H,H15),4.76(s,1H,H1′),4.69(m,2H,H8a),4.17(d,1H,H5,J=6.4Hz),4.04(s,1H,7-OH),3.99-3.94(m,2H,H6,H13),3.87-3.79(m,4H,H5′,H17,H5″,H3′),3.62(m,2H,H25,H3″),3.51(s,3H,3″-OCH3),3.47(s,1H,H2),3.44(s,3H,3′-OCH3),3.30-3.23(m,2H,H4′,H4″),2.52(m,1H,H12),2.36-2.12(m,6H,5-OH,H16,H24,H2′),2.05(s,1H,H20),1.88(s,3H,4-Me),1.76-1.74(m,1H,H18),1.58-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.25-1.22(m,6H,6′-Me,6″-Me),1.17(d,3H,12-Me,J=6.8Hz),0.95-0.87(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1047.29[M+Na]+。
实施例12
目标化合物4″-[2-萘甲酰硫脲基]-阿维菌素(6l)的合成
实验步骤与实施例1同,仅以2-萘甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:50%,淡黄色固体,熔点:176~178℃;
1H NMR(400MHz,CDCl3)δ:11.19(d,1H,NHCS-H,J=10.0Hz),9.19(s,1H,NHCO-H),8.40(s,1H,R-H1),7.98-7.86(m,4H,R-H3,H4,H5,H8),7.67-7.59(m,2H,R-H6,H7),5.86(m,1H,H9),5.79-5.73(m,3H,H23,H10,H11),5.57-5.55(m,2H,H22,H3),5.43(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.78(s,1H,H1′),4.69(m,2H,H8a),4.30(d,1H,H5,J=6.0Hz),4.05(m,1H,7-OH),3.99-3.95(m,2H,H6,H13),3.87-3.83(m,4H,H5′,H17,H5″,H3′),3.64-3.61(m,2H,H25,H3″),3.54(s,3H,3″-OCH3),3.50(s,1H,H2),3.45(s,3H,3′-OCH3),3.27(t,2H,H4′,H4″,J=8.8Hz), 2.53(m,1H,H12),2.36-2.14(m,6H,5-OH,H16,H24,H2′),2.03(s,1H,H20),1.88(s,3H,4-Me),1.80-1.77(m,1H,H18),1.62-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.28-1.25(m,6H,6′-Me,6″-Me),1.18(d,3H,12-Me,J=6.8Hz),0.96-0.87(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1107.42[M+Na]+。
实施例13
目标化合物4″-[环己甲酰硫脲基]-阿维菌素(6m)的合成
实验步骤与实施例1同,仅以环己甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:30%,淡黄色固体,熔点:175~177℃;
1H NMR(400MHz,CDCl3)δ:10.92(d,1H,NHCS-H,J=10.0Hz),8.45(s,1H,NHCO-H),5.85(m,1H,H9),5.78-5.72(m,3H,H23,H10,H11),5.55(d,1H,H22,J=10.0Hz),5.48(br.d,1H,H3),5.42(br.s,2H,H19,H1″),4.97(m,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.29(m,1H,H5),4.05(m,1H,7-OH),3.98-3.94(m,2H,H6,H13),3.88-3.76(m,4H,H5′,H17,H5″,H3′),3.61-3.58(m,2H,H25,H3″),3.50(s,3H,3″-OCH3),3.47(s,1H,H2),3.42(s,3H,3′-OCH3),3.29(s,1H,H4″),3.23(t,1H,H4′,J=8.8Hz),2.53(m,1H,H12),2.36-2.14(m,7H,5-OH,H16,H24,H2′,R-H1),2.03(s,1H,H20),1.93-1.77(m,3H,H18,R-H2,H6),1.67-1.42(m,17H,H20,H26,H27,14-Me,H2″,R-H2,H6,R-H3,R-H4,R-H5),1.28-1.26(m,6H,6′-Me,6″-Me),1.18-0.83(m,13H,12-Me,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1063.47[M+Na]+。
实施例14
目标化合物4″-[乙酰硫脲基]-阿维菌素(6n)的合成
实验步骤与实施例1同,仅以乙酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:35%,白色固体,熔点:183~185℃;
1H NMR(400MHz,CDCl3)δ:10.91(d,1H,NHCS-H,J=10.0Hz),8.53(s,1H,NHCO-H),5.85(m,1H,H9),5.78-5.72(m,3H,H23,H10,H11),5.57(d,1H,H22,J=2.0Hz),5.54-5.48(m,3H,H3,H19,H1″),4.97(m,1H,H15),4.77(s,1H,H1′),4.69(m,2H,H8a),4.31(m,1H,H5),4.05(s,1H,7-OH),3.98-3.93(m,2H,H6,H13),3.88-3.76(m,4H,H5′,H17,H5″,H3′),3.64-3.58(m,2H,H25,H3″),3.49(s,3H,3″-OCH3),3.47(s,1H,H2),3.43(s,3H,3′-OCH3),3.29(s,1H,H4″),3.23(t,1H,H4′,J=8.8Hz),2.52(m,1H,H12),2.36-2.14(m,6H,5-OH,H16,H24,H2′),2.14(s,3H,R-Me),2.05(s,1H,H20),1.87(s,3H,4-Me),1.77(d,1H,H18,J=12.8Hz),1.58-1.42(m,9H,H20,H26,H27,14-Me,H2″),1.28-1.15(m,9H,6′-Me,6″-Me,12-Me),0.95-0.83(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:995.60[M+Na]+。
实施例15
目标化合物4″-[环戊甲酰硫脲基]-阿维菌素(6o)的合成
实验步骤与实施例1同,仅以环戊甲酰基异硫氰酸酯代替苯甲酰基异硫氰酸酯。
反应所得产物检测数据如下:产率:32%,白色固体,熔点:185~187℃;
1H NMR(400MHz,CDCl3)δ:10.91(d,1H,NHCS-H,J=10.0Hz),8.51(s,1H,NHCO-H),5.86(m,1H,H9),5.78-5.72(m,3H,H23,H10,H11),5.55(d,1H,H22,J=10.0Hz),5.49(br.s,1H,H3),5.43(br.s,2H,H19,H1″),4.98(br.d,1H,H15),4.76(s,1H,H1′),4.69-4.65(m,2H,H8a),4.14(d,1H,H5,J=7.2Hz),4.05(s,1H,7-OH),3.98-3.93(m,2H,H6,H13),3.86-3.77(m,4H,H5′,H17,H5″,H3′),3.61-3.58(m,2H,H25,H3″),3.50(s,3H,3″-OCH3),3.47(s,1H,H2),3.42(s,3H,3′-OCH3),3.29(s,1H,H4″),3.23(t,1H,H4′,J=9.2Hz),2.60(t,1H,R-H1,J=7.6Hz),2.52(m,1H,H12),2.37-2.11(m,6H,5-OH,H16,H24,H2′),1.91-1.70(m,6H,4-Me,H18,R-H2,H5),1.66-1.42(m,15H,H20,H26,H27,14-Me,H2″,R-H2,H5,H3,H4),1.28-1.24(m,9H,6′-Me,6″-Me,12-Me),0.99-0.86(m,10H,27-Me,24-Me,26-Me,H18ax);
ESI-MS m/z:1049.43[M+Na]+。
实施例16
化合物6a-6o的生物活性
(1)供试昆虫:甘蓝蚜(Brevicoryne brassicae)成蚜,采自甘肃省农业科学院温室的油菜上,为未接触任何农药的敏感品系。
(2)供试药剂:化合物阿维菌素类似物6a-6o(按照实施例1-15制备),以阿维菌素为对照药剂。
(3)生物活性测定方法:参照已报道权威经典测试方法—点滴法(Zhao Q.Q.,Li Y.Q.,Xiong L.X.,et al.J.Agric.Food Chem.2010,58,4992-4998.)。将化合物溶解在适量丙酮-水(9∶1)溶液中,配成250mg/L的浓度,取其1mL再用含T-20的蒸馏水分别稀释成100、50、10、1mg/L的供试药液。用微量点样器(体积0.042uL)滴在30头甘蓝蚜成蚜胸部背部,将其放置在预先放有新鲜甘蓝叶片的培养皿中,并用医疗胶带封好以防蚜虫逃匿。培养皿统一放置在温度(25±1)℃、RH为85%左右的生化培养箱中,24h后检测死亡率。以含有同样丙酮的蒸馏水点滴作为溶剂对照。对照组死亡率在10%以下为有效测定,用Abbott公式对处理组死亡率进行校正。化合物各个浓度测试平行进行三次,取平均值。分析试验结果采用SPSS统计软件(版本13.0)进行分析,计算致死中浓度LC50值。测定结果见表1。
表1 阿维菌素酰硫脲衍生物6a-6o对甘蓝蚜的生物活性
(注:相对毒力=阿维菌素LC50/化合物6a-6o的LC50)
生物测定结果表明(表1),本发明制备的15个阿维菌素酰硫脲衍生物对甘蓝蚜具有不同程度的触杀活性,其中6h和6o的触杀活性与阿维菌素相当,可用于制备防治农业害虫特别是抗性害虫的杀虫剂。
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。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 (10)
1.阿维菌素酰硫脲类化合物,其特征在于,该类化合物具有式(I)所示的化学结构:
结构式(I)中:取代基R选自苯基、对氯苯基、间氯苯基、邻氟苯基、对氟苯基、对溴苯基、间溴苯基、对甲基苯基、噻吩基、3-吡啶基、2-呋喃基、2-萘基、环己基、甲基、环戊基。
2.根据权利要求1所述的阿维菌素酰硫脲类化合物的制备方法,其特征在于:
将4″-氨基-阿维菌素溶于无水乙腈,在惰性气体保护下加入酰基异硫氰酸酯,室温搅拌2~3h,反应结束后,用氯仿稀释,过滤、水洗、氯仿反萃,合并有机层,用无水硫酸钠干燥,过滤浓缩后用柱层析分离,所述柱层析分离采用石油醚-乙酸乙酯为洗脱剂洗脱,得目标产物即4″-阿维菌素酰硫脲类化合物,其中所述4″-氨基-阿维菌素与所述酰基异硫氰酸酯的用量摩尔比为1:1-1:3,所述4″-氨基-阿维菌素与所述无水乙腈的摩尔体积比(mmol/ml)为1:20-1:70。
3.根据权利要求2所述阿维菌素酰硫脲类化合物的制备方法,其特征在于:所述酰基异硫氰酸酯为苯甲酰基异硫氰酸酯、对氯苯甲酰基异硫氰酸酯、间氯苯甲酰基异硫氰酸酯、邻氟苯甲酰基异硫氰酸酯、对氟苯甲酰基异硫氰酸酯、对溴苯甲酰基异硫氰酸酯、间溴苯甲酰基异硫氰酸酯、对甲基苯甲酰基异硫氰酸酯、2-噻吩甲酰基异硫氰酸酯、3-吡啶甲酰基异硫氰酸酯、2-呋喃甲酰基异硫氰酸酯、2-萘基甲酰基异硫氰酸酯、环己甲酰基异硫氰酸酯、乙酰基异硫氰酸酯或环戊甲酰基异硫氰酸酯。
4.根据权利要求2或3所述阿维菌素酰硫脲类化合物的制备方法,其特征在于:所述4″-氨基-阿维菌素与所述酰基异硫氰酸酯的用量摩尔比为1:1.5,所述4″-氨基-阿维菌素与所述无水乙腈的摩尔体积比(mmol/ml)为1:50。
5.根据权利要求4所述阿维菌素酰硫脲类化合物的制备方法,其特征在于:所述惰性气体为氮气。
6.根据权利要求5所述阿维菌素酰硫脲类化合物的制备方法,其特征在于:石油醚-乙酸乙酯洗脱剂中石油醚与乙酸乙酯的体积比为5:1~15:1。
7.根据权利要求6所述阿维菌素酰硫脲类化合物的制备方法,其特征在于:所述柱层析分离用硅胶柱采用200~300目的柱层析硅胶。
8.本发明所述的阿维菌素酰硫脲类化合物在制备防治农业害虫的农药中应用。
9.本发明所述的阿维菌素酰硫脲类化合物在治理抗性害虫方面的应用。
10.本发明所述的阿维菌素酰硫脲类化合物在制备防治甘蓝蚜的农药中应用。
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