CN116283773A - 青藤碱酰胺类衍生物及其制备方法和应用 - Google Patents
青藤碱酰胺类衍生物及其制备方法和应用 Download PDFInfo
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- CN116283773A CN116283773A CN202310055131.9A CN202310055131A CN116283773A CN 116283773 A CN116283773 A CN 116283773A CN 202310055131 A CN202310055131 A CN 202310055131A CN 116283773 A CN116283773 A CN 116283773A
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- sinomenine
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- amide derivatives
- pyridyl
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- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 title claims abstract description 60
- 229930002966 sinomenine Natural products 0.000 title claims abstract description 60
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- 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
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
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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
- A01P7/00—Arthropodicides
- A01P7/02—Acaricides
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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
- A01P7/00—Arthropodicides
- A01P7/04—Insecticides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Engineering & Computer Science (AREA)
- Pest Control & Pesticides (AREA)
- Insects & Arthropods (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明涉及青藤碱酰胺类衍生物及其制备方法和应用,该系列青藤碱酰胺类衍生物的结构通式(I)所示,R选自(取代)苯基,(取代)吡啶基,(取代)吡唑基的一种。经实验表明:该系列青藤碱酰胺类衍生物中部分化合物具有与阳性对照螺螨酯相当的杀螨活性;部分化合物对小菜蛾具有较好的杀虫活性,故有望用于制备高效、环保、低毒的植物源杀虫/螨剂。
Description
技术领域
本发明涉及系列具有杀虫活性的青藤碱酰胺类衍生物,以及该系列衍生物在制备植物源杀虫/螨剂中的应用。
背景技术
青藤碱(Sinomenine,结构如式IV)是从防已科植物青风藤及毛青藤的根茎中提取的一种生物碱。青藤碱具有显著的抗炎、镇痛、降压及抗脑缺血等生物活性,在临床上被应用于治疗风湿和类风湿关节炎,关节肿胀等疾病。结构上,青藤碱是由苯环(A)、半椅式六元环(B)、扭椅式六元环(C)和椅式含氮六元杂环(D)组成【European Journal of MedicinalChemistry,2013,62:280-288】。
为了发现和提高青藤碱的生物活性,近年来多名学者对青藤碱各位点进行结构改造。例如,金杰等在青藤碱A环1位和4位引入异噁唑(啉)或三氮唑杂环【European Journalof Medicinal Chemistry,2013,280–288;Natural Product Research,2019,2360–2364;Journal of Chemical Research,2020;699–704】;李新建等制备了新的青藤碱A环、C环和D环衍生物【CN 101265266】,包括青藤碱1位氨基化及其酰基化,1位C-C或者C-O方式连接,3、4位双羰基化及六元氮杂环化,4位羟基和1位氨基连接的两分子青藤碱加合等。在生物活性放,大多是关于消炎、镇痛等生物活性方面研究,有关农用活性方面研究未见报道。
近年来,有多项研究表明青藤碱的镇痛作用是通过GABA受体介导的【Biomolecules&Therapeutics,2017,586–592;British Journal of Pharmacology,2016,173:1693–1702;Scientific Reports,2021,11:9300】。昆虫GABA受体作为一类重要的杀虫剂作用靶标【Pesticide Biochemistry and Physiology,2017,34–40】,具有高效、对哺乳动物安全的特点;昆虫GABA受体已被证实具有多个作用位点,并且这些位点之间没有交互抗性。与此同时,哺乳动物GABA受体与昆虫GABA受体具有高度同源性(跨膜区为保守区域,高度同源),据此作者预测青藤碱或青藤碱类化合物可作用于昆虫GABA受体,且具有优秀的杀虫活性。在分子结构上,青藤碱与现有商品化农药有着巨大区别,因此其可能作用于受体上其它作用位点,与现有农药没有交互抗性,可治理害虫抗性发展。
综上所述,本发明提供了一种结构新颖的青藤碱酰胺类衍生物的制备方法和其在杀虫/螨活性方面的应用。
发明内容
基于发明人的新研究发现,本发明目的是提供系列新的青藤碱酰胺类衍生物,并给出了衍生物的制备方法。根据青藤碱酰胺类衍生物具有高效、低毒的杀虫活性,能够用于制备植物源杀虫/螨剂。
为实现上述任务,本发明是通过下列技术措施得以实现:
青藤碱酰胺类衍生物,该衍生物的化学结构式如结构通式(I)所示:
式(I)中:取代基R选自4-苯基苯基、4-苯氧基苯基、2,4,5-三氟苯基、4-三氟甲基苯基、2-氟-4-三氟甲基苯基、3,5-二氯苯基、3,5-二甲基苯基,4-三氟甲基-3-吡啶基、5-溴-2-氯-3-吡啶基、3-甲氧羰基-2-吡啶基、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基、N-叔丁氧羰基-甘氨基。
在结构通式(I)中按表1对应取代基R,得到青藤碱酰胺类衍生物1~12。
表1.本发明制备的青藤碱酰胺类衍生物1~12对应取代基R及化合物结构式
上述青藤碱酰胺类衍生物的制备路线如下:
步骤(1),以青藤碱母体与亚硝酸钠反应制得中间体1。
步骤(2),中间体1与氯化亚锡反应得到胺类化合物中间体2。
步骤(3),中间体与RCOOH反应,得到式(I)所示化合物1~12,其中取代基R选自4-苯基苯基、4-苯氧基苯基、2,4,5-三氟苯基、4-三氟甲基苯基、2-氟-4-三氟甲基苯基、3,5-二氯苯基、3,5-二甲基苯基,4-三氟甲基-3-吡啶基、5-溴-2-氯-3-吡啶基、3-甲氧羰基-2-吡啶基、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基、N-叔丁氧羰基-甘氨基。
可选的,步骤(1)反应在亚硝酸钠、浓盐酸的乙醇溶液中进行,反应温度为0℃。
可选的,步骤(2)反应在氯化亚锡的乙醇溶液中进行,反应温度80℃。
可选的,步骤(3)所述RCOOH选自4-苯基苯甲酸、4-苯氧基苯甲酸、2,4,5-三氟苯甲酸、4-三氟甲基苯甲酸、2-氟-4-三氟甲基苯甲酸、3,5-二氯苯甲酸、3,5-二甲基苯甲酸,4-三氟甲基-3-吡啶甲酸、5-溴-2-氯-3-吡啶甲酸、3-甲氧羰基-吡啶-2-甲酸、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-甲酸、N-叔丁氧羰基-甘氨酸的一种。
可选的,步骤(3)反应在DMF溶液中进行,同时加入HATU和Et3N,反应温度为20-30℃。
本发明的青藤碱酰胺类衍生物用于制备杀虫剂的应用。并且本发明的青藤碱酰胺类衍生物用于制备杀螨剂的应用。所述的螨指农业常见的螨,例如的朱砂叶螨、二斑叶螨等;所述害虫包括农业上常见的鳞翅目类害虫,比如常见的小菜蛾等。
附图说明
图1为化合物3的核磁共振氢谱谱图;
图2为化合物7的核磁共振氢谱谱图;
具体实施方式
以下通过附图和发明人给出的实施例对本发明做进一步详细阐述。
除非有特殊说明,本文中的术语根据相关领域普通技术人员认识理解。
本发明所述青藤碱酰胺类衍生物的合成路线如下:
依据上述合成路线:
首先,将青藤碱溶于适当的溶剂中(如乙醇),在适当条件下与亚硝酸钠反应,得到中间体1;
其次,中间体1与适量氯化亚锡在合适溶剂(如乙醇)条件(如反应温度为80℃)下反应,得到中间体2;
适量中间体2与有机酸RCOOH在合适反应体系(如存在O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、三乙胺(Et3N)和N,N-二甲基甲酰胺(DMF)的反应体系)和反应条件(如反应温度为20-30℃)下反应制得本发明的化合物。
所述RCOOH选自选自4-苯基苯甲酸、4-苯氧基苯甲酸、2,4,5-三氟苯甲酸、4-三氟甲基苯甲酸、2-氟-4-三氟甲基苯甲酸、3,5-二氯苯甲酸、3,5-二甲基苯甲酸,4-三氟甲基-3-吡啶甲酸、5-溴-2-氯-3-吡啶甲酸、3-甲氧羰基-吡啶-2-甲酸、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-甲酸、N-叔丁氧羰基-甘氨酸的一种。
实施例1:
制备青藤碱酰胺类衍生物1~12化合物
中间体1的制备方法:
将青藤碱(10.0mmol)溶于适当的溶剂中(如DMF)中,然后置于冰浴中搅拌的条件下,加入浓盐酸(20mL)和亚硝酸钠水溶液(15.0mmol in 5mL H2O),继续搅拌至TLC检测反应完全,缓慢加入饱和碳酸钠水溶液至pH为碱性,二氯甲烷(30mL×3)萃取,合并有机相,无水Na2SO4干燥,浓缩,乙醇重结晶得到2.6g黄色固体。
中间体2的制备方法:
称取中间体1(2.7mmol)和氯化亚锡二水合物(SnCl2·H2O,16.2mmol)于50mL乙醇中,80℃回流5h,反应完全后加入1M盐酸(20mL)搅拌均匀,用氨水调pH至碱性,DCM(30mL×3)萃取,合并有机相,无水Na2SO4干燥,浓缩得棕色固体745mg,直接用于下步反应。
目标化合物1~化合物12的制备方法:
中间体2(0.3mmol),RCOOH(0.45mmol),HATU(0.36mmol)和Et3N(1.5mmol)溶于DMF(5mL)中,继续室温搅拌,TLC跟踪检测,反应完全后加入乙酸乙酯(30mL)稀释,再依次加入0.1M盐酸水溶液(15mL),5%碳酸氢钠水溶液(15mL)和饱和食盐水洗涤(15mL),有机相干燥浓缩,薄层层析分离得化合物1~化合物12。
上述制备方法制备得到的化合物1~化合物12具有以下通式,
化合物1的理化性质如下:
1)淡黄色固体,熔点:166-168℃;收率:40%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:7.99(d,J=7.8Hz,2H),7.89(s,1H),7.68(d,J=7.8Hz,2H),7.61(d,J=7.8Hz,2H),7.46(t,J=7.8Hz,2H),7.39–7.41(m,1H),7.10(s,1H),6.11–6.25(m,1H),5.46(s,1H),4.35(d,J=15.6Hz,1H),3.81(s,3H),3.50(s,3H),3.25(s,1H),3.02–3.07(m,2H),2.76–2.80(m,2H),2.54(s,3H),2.46(d,J=15.6Hz,1H),2.32–2.37(m,2H),2.02–2.08(m,2H).
化合物2的理化性质如下:
1)淡黄色固体,熔点:138-140℃;收率:41%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:7.87(d,J=7.8Hz,2H),7.69(s,1H),7.37(t,J=7.8Hz,2H),7.17(d,J=7.8Hz,1H),7.12(s,1H),7.03–7.07(m,4H),6.10–6.33(m,1H),5.45(s,1H),4.35(d,J=15.6Hz,1H),3.79(s,3H),3.47(s,3H),3.36(s,1H),3.12(s,1H),2.93(d,J=18.0Hz,1H),2.64(d,J=12.6Hz,2H),2.44–2.46(m,4H),2.20(t,J=10.2Hz,1H),1.94–2.01(m,2H).
化合物3的理化性质如下:
1)淡黄色固体,熔点:154-156℃;收率:48%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,DMSO-d6)δ:9.65(s,1H),8.57(s,1H),7.81–7.86(m,1H),7.71–7.75(m,1H),6.86(s,1H),5.68(s,1H),4.15(d,J=15.6Hz,1H),3.72(s,3H),3.36(s,3H),3.16–3.22(m,1H),2.83–2.92(m,2H),2.56–2.61(m,1H),2.44(d,J=15.0Hz,2H),2.30(s,3H),1.90–1.94(m,1H),1.76–1.82(m,2H).
化合物4的理化性质如下:
1)淡黄色固体,熔点:173-175℃;收率:37%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:8.00(d,J=7.8Hz,2H),7.69–7.75(m,3H),7.15(s,1H),6.04–6.31(m,1H),5.47(s,1H),4.35(d,J=15.6Hz,1H),3.82(s,3H),3.49(s,3H),3.35(s,1H),3.07(s,1H),2.91(d,J=18.0Hz,1H),2.63(s,1H),2.39–2.48(m,4H),2.19–2.25(m,1H),1.90–2.04(m,2H).
化合物5的理化性质如下:
1)淡黄色固体,熔点:144-146℃;收率:53%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,DMSO-d6)δ:9.81(s,1H),8.67(s,1H),7.91(t,J=7.8Hz,1H),7.87(d,J=9.6Hz,1H),7.73(d,J=4.2Hz,1H),6.89(s,1H),5.69(s,1H),4.17(d,J=15.6Hz,1H),3.74(s,3H),3.35–3.39(m,4H),3.00(s,1H),2.90–2.93(m,1H),2.61–2.66(m,2H),2.36–2.43(m,4H),1.98–2.07(m,1H),1.81–1.88(m,2H).
化合物6的理化性质如下:
1)淡黄固体,熔点:176-178℃;收率:37%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:7.88(s,1H),7.79(s,2H),7.53(s,1H),6.99(s,1H),5.98–6.27(m,1H),5.45(s,1H),4.33(d,J=15.6Hz,1H),3.79(s,3H),3.46(s,3H),3.33(s,1H),3.11(s,1H),2.91(d,J=18.0Hz,1H),2.64–2.69(m,2H),2.43–2.48(m,4H),2.17(t,J=9.6Hz,1H),1.93–2.00(m,2H).
化合物7的理化性质如下:
1)黄色固体,熔点:179-181℃;收率:43%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:7.64(s,1H),7.50(s,2H),7.19(s,1H),7.08(s,1H),6.08–6.28(m,1H),5.45(s,1H),4.35(d,J=15.6Hz,1H),3.80(s,3H),3.49(s,3H),3.34–3.35(m,1H),3.14(s,1H),2.93(d,J=18.6Hz,1H),2.62–2.66(m,2H),2.45–2.48(m,4H),2.19(t,J=8.4Hz,1H),1.93–2.01(m,2H).
化合物8的理化性质如下:
1)淡黄色固体,熔点:183-181℃;收率:41%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,DMSO-d6)δ:9.99(s,1H),9.07(s,1H),8.97(d,J=4.8Hz,1H),8.70(s,1H),7.89(d,J=4.8Hz,1H),6.90(s,1H),5.68(s,1H),4.17(d,J=15.0Hz,1H),3.74(s,3H),3.32–3.38(m,4H),3.05(s,1H),2.93–2.96(m,1H),2.62–2.73(m,2H),2.37–2.48(m,4H),2.00–2.05(m,1H),1.81–1.90(m,2H).
化合物9的理化性质如下:
1)淡黄色固体,熔点:196-198℃;收率:53%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,DMSO-d6)δ:9.92(s,1H),8.66–8.73(m,2H),8.43(s,1H),6.92(s,1H),5.68(s,1H),4.16(d,J=15.0Hz,1H),3.74(s,3H),3.37–3.46(m,4H),2.96–3.04(m,2H),2.69–2.80(m,2H),2.31–2.55(m,4H),2.02–2.10(m,1H),1.81–1.86(m,2H).
化合物10的理化性质如下:
1)黄色固体,熔点:135-137℃;收率:42%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,DMSO-d6)δ:10.03(s,1H),8.63(s,1H),8.33(d,J=7.2Hz,1H),8.25–8.29(m,2H),7.27(s,1H),5.72(s,1H),4.19(d,J=15.0Hz,1H),3.96(s,3H),3.75(s,3H),3.39–3.44(m,4H),3.01(s,1H),2.87–2.90(m,1H),2.61–2.73(m,2H),2.39–2.49(m,4H),2.04–2.13(m,1H),1.79–1.89(m,2H).
化合物11的理化性质如下:
1)淡黄色固体,熔点:211-213℃;收率:19%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:8.40(d,J=4.8Hz,1H),7.86–7.89(m,2H),7.38–7.40(m,1H),6.81(s,1H),6.86(s,1H),6.12–6.26(m,1H),5.40(s,1H),4.30(d,J=16.2Hz,1H),3.70(s,3H),3.44(s,3H),3.29(s,1H),3.06(s,1H),2.82(d,J=18.0Hz,1H),2.56–2.58(m,1H),2.46–2.50(m,2H),2.38(s,3H),2.06–2.10(m,1H),1.87–1.95(m,2H).
化合物12的理化性质如下:
1)白色固体,熔点:165-167℃;收率:39%;
2)该化合物的核磁共振氢谱数据:1H NMR(600MHz,Chloroform-d)δ:7.95(s,1H),7.00(s,1H),6.09–6.22(m,1H),5.38(s,1H),5.33(s,1H),4.35(d,J=15.6Hz,1H),3.92(d,J=5.4Hz,1H),3.81(s,3H),3.56(s,1H),3.49(s,3H),3.39(s,1H),2.95(d,J=18.6Hz,1H),2.86–2.90(m,1H),2.67–2.71(m,1H),2.60(s,3H),2.50(d,J=16.2Hz,1H),2.33–2.38(m,1H),2.11–2.16(m,1H),1.99–2.04(m,1H),1.48(s,9H).
实施例2:
朱砂叶螨生测实验
1、供试昆虫:
朱砂叶螨(Tetranychus cinnabarinus Bois.),属于蛛形纲、蜱螨亚纲、真螨目、叶螨科、叶螨属,是一种世界性害螨,可危害棉花、豆类、柑橘、花卉等多种经济作物和观赏植物。朱砂叶螨具有繁殖力强、世代周期短、发育快等特点,极易产生抗性【InsectBiochemistry and Molecular Biology,2020,120:103347】,该实施例以朱砂叶螨为代表,叶螨是农业害螨中最大的类群;而朱砂叶螨是一种代表性害螨,主要在叶背吸食汁液,使寄主组织造成机械损伤造成为害,在我国多地均有发生【Plant Protection,2005,2:90-91】。
2、样品及试剂:
样品为:98.32%螺螨酯原药(阳性对照),98%青藤碱,及实施例1制备的化合物1~12,丙酮(溶剂,成都市科龙化工试剂厂,分析纯)、吐温-80和蒸馏水。
3、生测方法:
采用FAO推荐的玻片浸渍法:
①1‰吐温80母液配制:称取250mg吐温80溶于5mL丙酮溶液中,用蒸馏水定溶至250mL待用。
②初筛药液配制:分别称取10mg供试化合物,用200μL丙酮溶解,再用配好的1‰吐温80 定容至10mL,即配置成1mg/mL药液,供初筛使用。
③供试螨的准备:将1cm宽的双面胶的贴在载玻片的一端,用0号毛笔挑选健康活泼、螨龄一致的朱砂叶螨雌成螨,小心整齐地将其背部粘在双面胶上,每块玻片粘30头左右,排成2行,将粘有供试螨的玻片放在垫有湿润海绵的铁盘中,并将铁盘置于26±1℃、相对湿度60%~80%、光照L:D=14h:10h条件下的光照培养箱中,放置4小时后,用体视显微镜检查,剔除死亡和不活泼的个体,记录每块玻片上的活螨数量。
④浸药:将载玻片粘有螨的一端在供试药液中振荡浸渍5s后取出,用滤纸条小心吸去多余药液(注意不能触碰到螨体)后放回铁盘,置于相同饲养条件下光照培养箱中,一块玻片为一个处理,每处理重复3次,以1‰吐温80溶液为空白对照。
⑤结果统计:浸药处理24h后将玻片取出在体视显微镜下检查结果,检查时用毛笔尖轻触螨体,以其螯肢不动者为死亡,记录死亡个体数;连续观察记录72h。根据下列公式计算供试螨48h和72h的死亡率(%)及校正死亡率(%)。
表1.本发明青藤碱及衍生物1~12杀螨活性
结论:
结果说明,青藤碱在72h表现出较好的杀螨活性,上述部分青藤碱酰胺类衍生物72h杀螨活性较母体青藤碱有显著提高,其中化合物6和12杀螨活性(72h)大于70%,尤其化合物12的杀螨活性(72h)与阳性对照螺螨酯相当,故有望用于制备高效、作用靶标新颖的植物源杀螨剂。
实施例3:
小菜蛾生测实验
1、供试昆虫:
小菜蛾(Plutella xylostella)是世界性分布的蔬菜害虫,对各种蔬菜,尤其是十字花科蔬菜,如白菜、萝卜、甘蓝、花椰菜等危害严重,是影响蔬菜产量和品质的重要因素之一。
2、样品及试剂:
样品为:青藤碱,及实施例1制备的化合物1~12,DMSO(二甲基亚砜,成都市科龙化工试剂厂,分析纯)、吐温-80和蒸馏水。
3、生测方法:
采用FAO推荐的浸叶法:
①称取10mg待测化合物用DMSO(0.5mL)溶解,用0.1%的吐温溶液定容至10mL,即将供试化合物配制成浓度为1mg/mL的溶液备用,以只加DMSO(0.5mL)的药液为空白对照。
②将生长一致的甘蓝叶剪成6×6cm的叶碟(避开主叶脉部分),将叶碟浸于待测药液中,20s后取出晾干置于含有保湿滤纸的培养皿中,每个培养皿接入10头健康,长势一致的3龄前期小菜蛾。将处理的试虫置于温度为25±1℃、湿度为60%~80%、光照为L:D=16:8h条件下饲养和观察。
③48h后观察并记录试虫的死亡情况。根据下列公式计算试虫48h的死亡率(%)及校正死亡率(%)。
表2.本发明青藤碱及衍生物1~12对小菜蛾的48h的杀虫活性
结果表明,青藤碱在1mg/mL浓度下对小菜蛾的杀虫活性为32.0%(48h)。大部分青藤碱酰胺类衍生物(1,2,5,7,8,11,12)与母体青藤碱相比活性显著得到提高,其中化合物(1,2,12)的杀虫活性均高于60%。有望用于制备环保、低毒的植物源杀虫剂。
Claims (9)
2.如权利要求1所述的青藤碱酰胺类衍生物,其特征是取代基R选自4-苯基苯基、4-苯氧基苯基、2,4,5-三氟苯基、4-三氟甲基苯基、2-氟-4-三氟甲基苯基、3,5-二氯苯基、3,5-二甲基苯基,4-三氟甲基-3-吡啶基、5-溴-2-氯-3-吡啶基、3-甲氧羰基-2-吡啶基、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基、N-叔丁氧羰基-甘氨基时,所对应的青藤碱酰胺类衍生物依次分别为化合物1~12。
3.如权利要求1所述的青藤碱酰胺类衍生物的制备方法,其特征在于步骤包括:
步骤1,以青藤碱为原料,与亚硝酸钠反应制得中间体,所述中间体结构式如式(II)所示:
步骤2,中间体II与氯化亚锡反应,得到1-胺基青藤碱,所述胺类中间体结构式如式(III)所示:
步骤3,1-胺基青藤碱与RCOOH反应,得到式(I)所示化合物,取代基R选自4-苯基苯基、4-苯氧基苯基、2,4,5-三氟苯基、4-三氟甲基苯基、2-氟-4-三氟甲基苯基、3,5-二氯苯基、3,5-二甲基苯基,4-三氟甲基-3-吡啶基、5-溴-2-氯-3-吡啶基、3-甲氧羰基-2-吡啶基、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基、N-叔丁氧羰基-甘氨基。
4.如权利要求书3所述的青藤碱酰胺类衍生物制备方法,其特征在于,步骤1反应在乙醇溶液中进行,同时加入亚硝酸钠,反应温度为0-30℃。
5.如权利要求书3所述的青藤碱酰胺类衍生物制备方法,其特征在于,步骤2反应在乙醇溶液中进行,同时加入氯化亚锡,反应温度60-80℃。
6.如权利要求书3所述的青藤碱酰胺类衍生物制备方法,其特征在于,所述RCOOH选自4-苯基苯甲酸、4-苯氧基苯甲酸、2,4,5-三氟苯甲酸、4-三氟甲基苯甲酸、2-氟-4-三氟甲基苯甲酸、3,5-二氯苯甲酸、3,5-二甲基苯甲酸,4-三氟甲基-3-吡啶甲酸、5-溴-2-氯-3-吡啶甲酸、3-甲氧羰基-吡啶-2-甲酸、3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-甲酸、N-叔丁氧羰基-甘氨酸。
7.如权利要求书3所述的青藤碱酰胺类衍生物制备方法,其特征在于,步骤3反应在DMF中进行,同时加入HATU和Et3N,反应温度为0-25℃。
8.如权利要求1-7所述的青藤碱酰胺类衍生物用于制备杀虫剂的应用。
9.如权利要求1-7所述的青藤碱酰胺类衍生物用于制备杀螨剂的应用。
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