CN113200970B - 蛇床子素异噁唑啉类衍生物、及其制备方法和应用 - Google Patents
蛇床子素异噁唑啉类衍生物、及其制备方法和应用 Download PDFInfo
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- CN113200970B CN113200970B CN202110452323.4A CN202110452323A CN113200970B CN 113200970 B CN113200970 B CN 113200970B CN 202110452323 A CN202110452323 A CN 202110452323A CN 113200970 B CN113200970 B CN 113200970B
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- osthole
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- vibration absorption
- isoxazoline
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- -1 Osthole isoxazoline derivatives Chemical class 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
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- 239000000575 pesticide Substances 0.000 claims description 10
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- 238000012360 testing method Methods 0.000 abstract description 17
- 230000000749 insecticidal effect Effects 0.000 abstract description 14
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 229930014626 natural product Natural products 0.000 abstract description 8
- 231100000053 low toxicity Toxicity 0.000 abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 4
- 239000002917 insecticide Substances 0.000 abstract description 4
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
技术领域
本发明属于蛇床子素异噁唑啉类衍生物技术领域,具体涉及一种蛇床子素异噁唑啉类衍生物、及其制备方法和应用。
背景技术
蛇床子素(Osthole,结构式如上),化学名称为7-甲氧基-8-异戊烯基香豆素,又名甲氧基欧芹酚或欧芹酚甲醚,属于线型呋喃类香豆素,含有苯环、吡喃酮环和异戊烯基结构。在蛇床子[Cnidiummonnieri(L.)Cuss]的干燥成熟果实和白花前胡[PeucedanumpraeruptorumDumn]的干燥根中含量较高。蛇床子素存在于多种植物中,最先从伞形科植物中提取分离出的天然香豆素类化合物,伞形科的当归属、独活属、欧芹属等以及芸香科的柑橘属、枳属等植物中也含有该类化合物(Yin,Q.J.,Sun,H.F.Pharmacological effects and research of osthole as abiologicalpesticide.Information on Traditional Chinese Medicine.2009,26(2),13-15.)。另外,在百部、槐花、扁蓿豆、白芷等众多药用植物中,也有关于蛇床子素的报道。
蛇床子素是从传统中药中提取出来的一种天然化合物,可以从多种植物中获得,也可以用一些廉价简洁的原料合成得到,具有多种药理活性。在医学领域中,蛇床子素可以降血糖、抗炎、抗肿瘤、保护肝脏、促进骨骼恢复,治疗哮喘病和阿尔兹海默症等。在农学领域,蛇床子素作为农药应用为我国首创,已成功开发为杀虫和杀菌剂,2003年获得国家专利作为农药上市销售(石志琦,陈浩.新型植物源创制农药蛇床子素[J].世界农药,2010,32(06):52-54.)。0.4%蛇床子素乳油获得了国家“绿色认证”和出口许可,1%蛇床子素粉剂是国内第一个通过有机认证的杀菌剂,两者可以取代有机磷和菊酯类化学农药,1%蛇床子素8000IUμL-1Bt悬浮剂可以有效防治菜青虫和小菜蛾,对夜蛾科害虫卵块有独特的杀灭作用。蛇床子素纯品毒性较小,小鼠急性口服LD50大于5g/kg,且对肝脏无不良影响,而且易降解,对环境友好,为我国的绿色农业做出了卓越的贡献。
合成蛇床子素的方法主要有克莱森重排、付-克烷基化、自由基反应和烯烃置换反应等(Daoubi M,Durán-Patrón R,Hmamouchi M,et al.Screening study for potentiallead compounds for natural product-based fungicides:I.Synthesis and in vitroevaluation of coumarins against Botrytis cinerea[J].Pest management science,2004,60(9):927-932.Dyke S F,Ollis W D,Sainsbury M,et al.The extractives ofpiscidiaerythrina L.—II:Synthetical evidence concerning the structure ofichthynone[J].Tetrahedron,1964,20(5):1331-1338.。)Daniela报道了一种微波辅助的一锅法合成肉桂酸和香豆素衍生物的方法,适用于蛇床子素的全合成。以2-羟基,4-甲氧基苯甲醛为起始原料,首先与炔烃缩合,然后用氢气催化加氢,最后与磷叶立德试剂发生克莱森重排反应,成功关环并引入异戊烯基侧链。通过三步反应,总产率高达78%。此方法产率高,选择性强,且不需要酚羟基保护,可应用于多种天然化合物及衍生物的合成(KonrádováD,KozubíkováH,K,et al.Microwave-assisted synthesis of phenylpropanoidsand coumarins:total synthesis of osthol[J].Eur.J.Org.Chem,2017,2017:5204-5213)。对蛇床子素的结构优化大部分在内酯环的修饰上,将内酯环开环后连接不同的基团或直接连接各种结构,能够增强母体化合物的活性。Saleem等人利用click化学方法,首先将蛇床子素的内酯环打开,然后炔丙基溴与酚羟基发生取代反应,最后连接三氮类芳基化合物,生成一系列蛇床子素三氮唑类衍生物,并测定了目标化合物对7种不同癌细胞的抑制活性,结果表明,所有化合物对肿瘤细胞展现了广谱的细胞毒活性,其中对位氰基取代的目标化合物通过破坏线粒体膜电位可以诱导Colo-205细胞凋亡,表现出显著的抗肿瘤活性(Farooq S,Hussain A,Hamid A,et al.Click chemistry inspired synthesis andbioevaluation of novel triazolyl derivatives of Osthol as potent cytotoxicagents[J].European journal of medicinal chemistry,2014,84:545-554.)。
虽然蛇床子素母体具有一定的杀虫活性,但是其杀虫作用谱窄,活性一般,难以满足市场需求,因此对其进行结构优化,以期开发出杀虫更好的蛇床子素衍异噁唑啉类衍生物,制备具有更优效果、毒性更小的天然产物杀虫剂。
发明内容
发明目的:针对上述技术问题,本发明提供了一种高效、低毒具有杀虫活性的蛇床子素异噁唑啉类衍生物、及其制备方法和应用。
技术方案:为了达到上述发明目的,本发明所采用的技术方案如下:
一种蛇床子素异噁唑啉类衍生物,其化学结构如通式(I)所示:
R选自取代的苯基;
所述取代的苯基是被卤素或氰基取代的苯基。
优选,所述取代的苯基是被取代基单取代或双取代的苯基,取代基选自卤素、氰基的一种或几种。
进一步优选,所述R选自以下:
本发明还公开了所述的蛇床子素异噁唑啉类衍生物的制备方法,包括如下步骤:
(1)在碱性条件下,不同取代的苯甲醛(a)与盐酸羟胺反应,生成苯甲醛肟(b);
(2)苯甲醛肟(b)进一步被NCS取代,生成苯甲醛氯肟(c);
(3)最后,蛇床子素与苯甲醛氯肟(c)异戊烯基上的双键发生加成反应,即得通式(I)化合物;
其中,R同上所述。
优选,步骤(1)反应在超纯水中进行,反应温度90-110℃。
优选,步骤(2)反应在无水乙腈中进行,反应温度70-90℃。
优选,步骤(3)反应在无水二氯甲烷中进行,同时加入Et3N,反应温度0-45℃。
进一步优选的反应过程如下:
R-PhCHO进一步优选自:2-氟苯甲醛、3-氟苯甲醛、4-氟苯甲醛、2-氯苯甲醛、3-氯苯甲醛、4-氯苯甲醛、2-溴苯甲醛、3-溴苯甲醛、4-溴苯甲醛、4-氰基苯甲醛、3-溴-4-氯苯甲醛、2-氯-4-氟苯甲醛、2,3-二氯苯甲醛、3-氯-4-氟苯甲醛、3-溴-4-氟苯甲醛、2-氟-4-氯苯甲醛,3,5-二氟苯甲醛、2-氟-4-溴苯甲醛、2-溴-4-氯苯甲醛,2-氟-5-溴苯甲醛、2,4-二氯苯甲醛。
有益效果:相对于现有技术,本发明提供了一种新的蛇床子素异噁唑啉类衍生物,其异噁唑啉环含有氮、氧杂原子和双键结构,是理想的分子骨架,又有潜在的杀虫活性基团,其具有良好的杀虫活性,并且该衍生物高效低毒,有望用于制备新型的天然产物杀虫剂;同时蛇床子素异噁唑啉类衍生物对试虫体内乙酰胆碱酯酶也具有抑制活性。该类化合物制备工艺简单,成本低,且对人体健康无害。
附图说明
图1为本发明化合物6红外谱图;
图2为本发明化合物6核磁1H谱图;
具体实施方式
以下通过实例对本发明做进一步详细阐述。
实施例1蛇床子素异噁唑啉类衍生物的合成
(1)苯甲醛肟(b)的合成
不同取代的苯甲醛和盐酸羟胺溶于超纯水中,加入碳酸钾,加热至100℃回流,用TLC检测,1-2h后反应结束。反应完成后在反应液中加入少量超纯水稀释,将反应液减压浓缩,柱层析分离,得到苯甲醛肟(b)。
(2)苯甲醛氯肟(c)的合成
将苯甲醛肟(b)用适量无水乙腈溶解,加入NCS,室温下搅拌6-12h,TLC检测。待反应完成后直接蒸干反应溶剂,柱层析法分离,得到苯甲醛氯肟(c)。
(3)蛇床子素异噁唑啉类衍生物的合成(化合物1)
称取蛇床子素50mg加2mL无水二氯甲烷溶解,在冰浴条件下加入苯甲醛氯肟c和三乙胺,冰浴中搅拌,缓慢升至室温。用TLC检测反应,12-24h反应基本结束,薄层色谱法(PTLC)分离,产物旋干,加少量二氯溶解,然后加入石油醚使其缓慢析出结晶得到目标化合物1的纯品。结构如下:
化合物1的理化性质:
1)、棕色固体,熔点:141-142℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2974,2931cm-1为饱和碳氢伸缩振动吸收,1728cm-1为酯羰基伸缩振动吸收,1610cm-1为芳环C-C骨架振动吸收,1279,1258,1123,1095cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.50-7.54(m,1H,-Ph),7.41(d,J=9.6Hz,1H,-Ph),7.06(d,J=8.4Hz,1H,-Ph),6.98-7.02(m,1H,-Ph),6.88-6.91(m,1H,-Ph),6.47(d,J=8.4Hz,1H,-Ph),6.11(d,J=9.6Hz,1H,-Ph),3.83-3.88(m,1H,-CH2-),3.75(s,3H,-OCH3),3.10(t,J=12.4Hz,1H,-CH-),2.88-2.93(m,1H,-CH2-),1.60(s,3H,-CH3),1.42(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:161.0,160.7,160.2,158.5,158.1(d,J=1.0Hz),153.0,143.3,130.6,130.5,129.6(d,J=3.0Hz),127.0,123.5(d,J=3.0Hz),119.1,119.0,115.0,114.7,114.0,112.8,112.3,106.4,87.3,55.7,53.5,53.4,29.7,27.8,22.0,20.7.MS(ESI)m/z calcd for C22H20FNO4([M+H]+)381.14,found 382.16.
实施例2蛇床子素异噁唑啉类衍生物的合成(化合物2)
采用实施例1所述方法,蛇床子素与3-氟苯甲醛氯肟(c)反应,合成化合物2,化合物2的结构和理化性质如下:
1)、黄色固体,熔点:77-80℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2926cm-1为饱和碳氢伸缩振动吸收,1731cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1282,1252,1118,1092.cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:8.33(s,1H,-Ph),8.11(d,J=8.0Hz,1H,-Ph),7.70-7.73(m,1H,-Ph),7.34(d,J=8.0Hz,1H,-Ph),7.14(d,J=9.2Hz,2H,-Ph),6.73(d,J=8.4Hz,1H,-Ph),6.44(d,J=9.6Hz,1H,-Ph),5.32-5.36(m,1H,H-2'),3.89(s,3H,-OCH3),3.56(d,J=6.8Hz,2H,H-1'),1.72(s,3H,-CH3),1.63(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:162.7,159.5,156.6,150.4,136.0,134.7,132.77,132.75,131.1,129.9,128.3,125.8,122.5,121.0,117.9,113.2,111.6,107.0,56.0,25.7,22.0,17.9.MS(ESI)m/z calcd for C22H22FNO4([M+H]+)382.14,found 382.16.
实施例3蛇床子素异噁唑啉类衍生物的合成(化合物3)
采用实施例1所述方法,蛇床子素与4-氟苯甲醛氯肟(c)反应,合成化合物3,化合物3的结构和理化性质如下:
1)、棕色固体,熔点:82-84℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2925cm-1为饱和碳氢伸缩振动吸收,1723cm-1为酯羰基伸缩振动吸收,1610cm-1为芳环C-C骨架振动吸收,1282,1250,1116cm-1为C-O-C伸缩振动吸收,836cm-1为C-F伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.52(d,J=9.2Hz,1H,-Ph),7.30-7.33(m,2H,-Ph),7.17(d,J=8.4Hz,1H,-Ph),6.71(t,J=8.4Hz,2H,-Ph),6.55(d,J=8.4Hz,1H,-Ph),6.18(d,J=9.6Hz,1H,-Ph),3.74(s,3H,-OCH3),3.58(t,J=8.0Hz,1H,-CH-),3.04(d,J=7.2Hz,2H,-CH2-),1.57(s,3H,-CH3),1.33(s,3H,-CH3).13CNMR(100MHz,CDCl3)δ:167.7,160.9,160.6,160.1,153.1,143.5,130.9,128.7,128.6,127.1,114.8,114.6,112.9,112.6,106.8,87.2,55.8,52.6,27.7,22.0,20.4.MS(ESI)m/zcalcd for C22H20FNO4([M+H]+)381.14,found 382.15.
实施例4蛇床子素异噁唑啉类衍生物的合成(化合物4)
采用实施例1所述方法,蛇床子素与2-氯苯甲醛氯肟(c)反应,合成化合物4,化合物4的结构和理化性质如下:
1)、黄色固体,熔点:123-124℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2968cm-1为饱和碳氢伸缩振动吸收,1716cm-1为酯羰基伸缩振动吸收,1610cm-1为芳环C-C骨架振动吸收,1279,1252,1121,1095.cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.39-7.42(m,2H,-Ph),7.06(d,J=8.4Hz,1H,-Ph),7.00-7.04(m,1H,-Ph),6.95-6.99(m,1H,-Ph),6.87-6.89(m,1H,-Ph),6.52(d,J=8.8Hz,1H,-Ph),6.11(d,J=9.6Hz,1H,-Ph),4.29-4.32(m,1H,-CH2-),3.81(s,3H,-OCH3),3.09-3.15(m,1H,-CH-),2.81(dd,J=4.8,13.6Hz,1H,-CH2-),1.56(s,3H,-CH3),1.50(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.9,160.7,160.1,152.7,143.4,132.5,131.2,129.9,129.8,129.0,127.0,125.9,113.8,112.8,112.3,106.6,87.6,55.7,55.3,27.6,21.5,21.0.MS(ESI)m/z calcd for C22H20ClNO4([M+H]+)397.11,found398.14,400.12.
实施例5蛇床子素异噁唑啉类衍生物的合成(化合物5)
采用实施例1所述方法,蛇床子素与3-氯苯甲醛氯肟(c)反应,合成化合物5,化合物5的结构与理化性质如下:
1)、黄色固体,熔点:95-96℃
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2924cm-1为饱和碳氢伸缩振动吸收,1731cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1280,1252,1117,1092cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.51(d,J=9.6Hz,1H,-Ph),7.30(d,J=7.6Hz,1H,-Ph),7.26(s,1H,-Ph),7.16(d,J=8.4Hz,1H,-Ph),7.06(d,J=1.6Hz,1H,-Ph),6.98-7.02(m,1H,-Ph),6.52(d,J=8.8Hz,1H,-Ph),6.18(d,J=9.6Hz,1H,-Ph),3.73(s,3H,-OCH3),3.55-3.59(m,1H,-CH-),3.01-3.12(m,2H,-CH2-),1.60(s,3H,-CH3),1.34(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.7,160.0,153.0,143.5,133.6,132.5,128.9,128.8,127.3,126.9,124.8,114.6,112.9,112.6,106.8,87.6,55.8,52.3,29.7,27.7,22.0,20.5.MS(ESI)m/z calcd for C22H20ClNO4([M+H]+)397.11,found398.14,400.12.
实施例6蛇床子素异噁唑啉类衍生物的合成(化合物6)
采用实施例1所述方法,蛇床子素与4-氯苯甲醛氯肟(c)反应,合成化合物6,化合物6的结构理化性质如下:
1)、白色固体,熔点:153-155℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2982cm-1为饱和碳氢伸缩振动吸收,1732cm-1为酯羰基伸缩振动吸收,1610cm-1为芳环C-C骨架振动吸收,1281、1254、1124、1091cm-1为C-O-C伸缩振动吸收。824cm-1为C-Cl伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.52(d,J=9.6Hz,1H,-Ph),7.24(d,J=6.0Hz,2H,-Ph),7.19(d,J=8.4Hz,1H,-Ph),7.00(d,J=8.4Hz,2H,-Ph),6.55(d,J=8.4Hz,1H,-Ph),6.18(d,J=9.6Hz,1H,-Ph),3.74(s,3H,-OCH3),3.57-3.61(m,1H,-CH-),3.03(d,J=7.6Hz,2H,-CH2-),1.58(s,3H,-CH3),1.33(s,3H,-CH3).13CNMR(100MHz,CDCl3)δ:160.9,160.6,160.1,153.1,143.4,134.8,129.1,128.0,127.8,127.1,114.8,113.0,112.6,106.8,87.4,55.8,52.5,27.8,22.0,20.5.MS(ESI)m/zcalcdfor C22H20ClNO4([M+H]+)397.11,found 398.14,400.12.
实施例7蛇床子素异噁唑啉类衍生物的合成(化合物7)
采用实施例1所述方法,蛇床子素与2-溴苯甲醛氯肟反应,合成化合物7,化合物7的结构和理化性质如下:
1)、白色固体,熔点:158-160℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2966cm-1为饱和碳氢伸缩振动吸收,1716,cm-1为酯羰基伸缩振动吸收,1610cm-1为芳环C-C骨架振动吸收,1276,1254,1122,1094cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.40(d,J=9.6Hz,1H,-Ph),7.36(d,J=6.8Hz,1H,-Ph),7.07(d,J=5.2Hz,1H,-Ph),7.09(d,J=9.2Hz,2H,-Ph),6.88-6.92(m,1H,-Ph),6.52(d,J=8.4Hz,1H,-Ph),6.12(d,J=9.6Hz,1H,-Ph),4.39(dd,J=4.8,11.2Hz,1H,-CH2-),3.81(s,3H,-OCH3),3.09-3.15(m,1H,-CH-),2.80(dd,J=4.8,13.2Hz,1H,-CH2-),1.56(s,3H,-CH3),1.52(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:161.9,160.6,160.1,143.4,132.3,131.7,129.9,127.0,126.4,121.8,113.8,112.9,112.4,106.6,87.7,55.7,53.1,27.5,21.4,21.1.MS(ESI)m/z calcd for C22H20BrNO4([M+H]+)441.06,found 442.06,444.04.
实施例8蛇床子素异噁唑啉类衍生物的合成(化合物8)
采用实施例1所述方法,蛇床子素与3-溴苯甲醛氯肟(c)反应,合成化合物8,化合物8的结构和理化性质如下:
1)、棕色固体,熔点:88-90℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2925cm-1为饱和碳氢伸缩振动吸收,1731cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1280,1252,1117,1092cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.52(d,J=9.2Hz,1H,-Ph),7.36(d,J=8.0Hz,1H,-Ph),7.16(d,J=8.8Hz,1H,-Ph),7.19-7.22(m,2H,-Ph),6.92-6.96(m,1H,-Ph),6.52(d,J=8.8Hz,1H,-Ph),6.18(d,J=9.6Hz,1H,-Ph),3.73(s,3H,-OCH3),3.54-3.58(m,1H,-CH-),2.99-3.09(m,2H,-CH2-),1.60(s,3H,-CH3),1.34(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.7,160.6,160.0,152.9,143.6,132.7,131.7,129.7,129.2,127.4,125.2,121.7,114.5,112.9,112.6,106.8,87.6,55.8,52.2,27.7,22.0.20.5.MS(ESI)m/z calcd for C22H20BrNO4([M+H]+)441.06,found 442.04,444.04.
实施例9蛇床子素异噁唑啉类衍生物的合成(化合物9)
采用实施例1所述方法,蛇床子素与4-溴苯甲醛氯肟反应,合成化合物9,化合物9的结构和理化性质如下:
1)、棕色固体,熔点:169-171℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:3434cm-1为不饱和碳氢伸缩振动吸收,2981cm-1为饱和碳氢伸缩振动吸收,1730cm-1为酯羰基伸缩振动吸收,1609cm-1为芳环C-C骨架振动吸收,1281,1254,1124,1094cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.52(d,J=9.2Hz,1H,-Ph),7.17-7.21(m,5H,-Ph),6.56(d,J=8.4Hz,1H,-Ph),6.19(d,J=9.2Hz,1H,-Ph),3.74(s,3H,-OCH3),3.57-3.60(m,1H,-CH-),3.03-3.05(m,2H,-CH2-),1.58(s,3H,-CH3),1.33(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:161.0,160.5,160.1,153.1,143.4,130.8,129.5,128.3,127.1,123.1,114.8,113.0,112.6,106.9,87.4,55.8,52.5,27.8,22.0,20.5.MS(ESI)m/z calcd for C22H20BrNO4([M+H]+)441.06,found 442.04,444.07.
实施例10蛇床子素异噁唑啉类衍生物的合成(化合物10)
采用实施例1所述方法,蛇床子素与4-氰基苯甲醛氯肟(c)反应,合成化合物10,化合物10的结构和理化性质如下:
1)、棕色固体,熔点:88-91℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2925cm-1为饱和碳氢伸缩振动吸收,1728cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1251,1117cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.44(d,J=9.2Hz,1H,-Ph),7.31(dd,J=2.0,7.6Hz,1H,-Ph),7.26(s,1H,-Ph),7.11-7.15(m,2H,-Ph),6.96-7.00(m,1H,-Ph),6.57(d,J=8.4Hz,1H,-Ph),6.11(d,J=9.6Hz,1H,-Ph),4.29(dd,J=4.8,11.6Hz,1H,-CH2-),3.83(s,3H,-OCH3),3.08-3.15(m,1H,-CH-),2.78-2.82(m,1H,-CH2-),1.55(s,3H,-CH3),1.53(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.5,160.1,152.6,143.4,132.7,132.2,130.8,130.5,129.7,127.3,126.5,113.5,112.8,112.4,106.7,88.0,55.7,53.2,29.7,27.6,21.3,21.1.MS(ESI)m/z calcd for C23H20NO4([M+H]+)388.14,found 389.22.
实施例11蛇床子素异噁唑啉类衍生物的合成(化合物11)
采用实施例1所述方法,蛇床子素与3-溴-4-氯苯甲醛氯肟(c)反应,合成化合物11,化合物11的结构和理化性质如下:
1)、棕色固体,熔点:90-92℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2926cm-1为饱和碳氢伸缩振动吸收,1731cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1281,1252,1118,1092cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.53(d,J=9.2Hz,1H,-Ph),7.33-7.36(m,1H,-Ph),7.27(d,J=2.0Hz,1H,-Ph),7.20(d,J=8.8Hz,1H,-Ph),7.13(d,J=8.4Hz,1H,-Ph),6.56(d,J=8.8Hz,1H,-Ph),6.19(d,J=9.6Hz,1H,-Ph),3.76(s,3H,-OCH3),3.51-3.55(m,1H,-CH-),2.98-3.08(m,2H,-CH2-),1.60(s,3H,-CH3),1.34(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.5,160.0,159.8,152.9,143.5,134.7,131.8,130.9,130.8,129.4,128.8,127.5,126.6,121.6,114.5,113.0,112.7,106.8,87.8,55.9,52.3,30.5,27.7,22.0,20.4.MS(ESI)m/z calcd forC22H19BrClNO4([M+H]+)475.02,found476.00,478.00.
实施例12蛇床子素异噁唑啉类衍生物的合成(化合物12)
采用实施例1所述方法,蛇床子素与2-氯-4-氟苯甲醛氯肟反应,合成化合物12,化合物12的结构和理化性质如下:
1)、黄色固体,熔点:147-150℃
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2925cm-1为饱和碳氢伸缩振动吸收,1713cm-1为酯羰基伸缩振动吸收,1611cm-1为芳环C-C骨架振动吸收,1273,1256,1121,1092cm-1为C-O-C伸缩振动吸收。835cm-1为C-F或C-Cl伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.44(d,J=9.6Hz,1H,-Ph),7.38-7.41(m,1H,-Ph),7.12(d,J=8.4Hz,1H,-Ph),6.72-6.76(m,1H,-Ph),6.61-6.64(m,1H,-Ph),6.56(d,J=8.4Hz,1H,-Ph),6.14(d,J=9.2Hz,1H,-Ph),4.22-4.27(m,1H,-CH2-),3.82(s,3H,-OCH3),3.08-3.14(m,1H,-CH-),2.80-2.84(m,1H,-CH2-),1.56(s,3H,-CH3),1.49(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.1,160.0,152.7,143.3,132.6,132.5,127.0,126.3,116.5,116.2,113.8,113.3,113.1,112.9,112.4,106.6,87.7,55.7,53.2,27.6,21.6,21.0.MS(ESI)m/z calcd forC22H19ClFNO4([M+H]+)415.10,found416.13,418.12.
实施例13蛇床子素异噁唑啉类衍生物的合成(化合物13)
采用实施例1所述方法,蛇床子素与2,3-二氯苯甲醛氯肟(c)反应,合成化合物13,化合物13的结构和理化性质如下:
1)、棕色固体,熔点:78-80℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2926cm-1为饱和碳氢伸缩振动吸收,1731cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1407cm-1为C-O伸缩振动吸收,1251,1117,1093cm-1为C-O-C伸缩振动吸收,832cm-1为C-Cl伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.44(d,J=9.2Hz,1H,-Ph),7.31(dd,J=1.6,7.6Hz,1H,-Ph),7.11-7.15(m,2H,-Ph),6.97(t,J=8.0Hz,1H,-Ph),6.57(d,J=8.4Hz,1H,-Ph),6.11(d,J=9.6Hz,1H,-Ph),4.29(dd,J=4.8,11.6Hz,1H,-CH2-),3.83(s,3H,-OCH3),3.09-3.15(m,1H,-CH-),2.78-2.83(m,1H,-CH2-),1.55(s,3H,-CH3),1.53(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.4,160.1,152.6,143.4,132.7,132.2,130.8,130.5,129.7,127.3,126.5,113.5,112.8,112.4,106.7,88.0,55.7,53.2,29.2,27.6,21.3,21.1.MS(ESI)m/z calcd forC22H19Cl2NO4([M+H]+)431.07,found432.06,434.12.
实施例14蛇床子素酯类衍生物的合成(化合物14)
采用实施例1所述方法,蛇床子素与3-Cl-4-氟苯甲醛氯肟(c),合成化合物14,化合物14的结构和理化性质如下:
1)、棕色固体,熔点:86-90℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2925cm-1为饱和碳氢伸缩振动吸收,1733cm-1为酯羰基伸缩振动吸收,1608,cm-1为芳环C-C骨架振动吸收,1499cm-1为-CH3弯曲振动吸收,1252,1117,1092cm-1为C-O-C伸缩振动吸收,831cm-1为C-Cl、C-F伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.54(d,J=9.6Hz,1H,-Ph),7.31-7.35(m,1H,-Ph),7.20(d,J=8.8Hz,1H,-Ph),7.13(dd,J=2.0,7.2Hz,1H,-Ph),6.83-6.87(m,1H,-Ph),6.57(d,J=8.4Hz,1H,-Ph),6.19(d,J=9.6Hz,1H,-Ph),3.76(s,3H,-OCH3),3.53-3.57(m,1H,-CH-),3.02-3.07(m,2H,-CH2-),1.59(s,3H,-CH3),1.34(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.0,159.9,153.0,143.5,130.9,129.1,128.8,128.0(d,J=4.0Hz),127.4,126.7(d,J=1.0Hz),120.2,116.0,115.8,114.6,113.0,112.6,106.8,87.7,55.8,52.4,27.7,22.0,20.4.MS(ESI)m/z calcdforC22H19ClFNO4([M+H]+)415.10,found 416.12,418.16.
实施例15蛇床子素异噁唑啉类衍生物的合成(化合物15)
采用实施例1所述方法,蛇床子素与3-溴-4-氟苯甲醛氯肟反应,合成化合物15,化合物15的结构和理化性质如下:
1)、白色固体,熔点:124-125℃
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:3074cm-1为不饱和碳氢伸缩振动吸收,2930cm-1为饱和碳氢伸缩振动吸收,1715cm-1为酯羰基伸缩振动吸收1608cm-1为芳环C-C骨架振动吸收,1495cm-1为-CH3弯曲振动吸收,1277,1255,1118,1092cm-1为C-O-C伸缩振动吸收,825cm-1为C-Br、C-F伸缩振动吸收.。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.53(d,J=9.6Hz,1H,-Ph),7.37-7.41(m,1H,-Ph),7.24(d,J=2.0Hz,1H,-Ph),7.19(d,J=8.8Hz,1H,-Ph),6.81(t,J=8.4Hz,1H,-Ph),6.56(d,J=8.4Hz,1H,-Ph),6.19(d,J=9.6Hz,1H,-Ph),3.76(s,3H,-OCH3),3.52-3.56(m,1H,-CH-),2.98-3.07(m,2H,-CH2-),1.60(s,3H,-CH3),1.34(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.5,160.0,159.8,157.8,153.0,143.5,132.0,128.4,127.4,115.8,115.6,114.5,113.0,112.7,108.1,106.8,87.7,55.8,52.4,27.7,22.0,20.4.MS(ESI)m/z calcd forC22H19BrFNO4([M+H]+)459.05,found 460.02,462.02.
实施例16蛇床子素异噁唑啉类衍生物的合成(化合物16)
采用实施例1所述方法,蛇床子素与2-氟-4-氯苯甲醛氯肟(c)反应,合成化合物16,化合物16的结构和理化性质如下:
1)、白色固体,熔点:149-151℃
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2969cm-1为饱和碳氢伸缩振动吸收,1737cm-1为酯羰基伸缩振动吸收,1609cm-1为芳环C-C骨架振动吸收,1279,1255,1121,1092cm-1为C-O-C伸缩振动吸收,836cm-1为C-C或C-F伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.45(d,J=8.8Hz,2H,-Ph),7.13(d,J=8.8Hz,1H,-Ph),6.86(d,J=8.4Hz,1H,-Ph),6.54(d,J=8.8Hz,1H,-Ph),6.48(d,J=10.4Hz,1H,-Ph),6.13(d,J=9.6Hz,1H,-Ph),4.28-4.31(m,1H,-CH2-),3.78(s,3H,-OCH3),3.07(t,J=12.4Hz,1H,-CH-),2.86(dd,J=4.0,12.8Hz,1H,-CH2-),1.59(s,3H,-CH3),1.41(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.2,157.1,152.9,143.2,130.4,128.8,127.0,123.9,117.8,115.6,115.4,113.9,112.9,112.3,106.5,87.6,55.8,53.4,29.7,27.8,22.1,20.7.MS(ESI)m/z calcd forC22H19ClFNO4([M+H]+)415.10,found 416.14,418.15.
实施例17蛇床子素异噁唑啉类衍生物的合成(化合物17)
采用实施例1所述方法,蛇床子素与3,5-二氟苯甲醛氯肟(c)反应,合成化合物17,化合物17的结构和理化性质如下:
1)、白色固体,熔点:78-80℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2925cm-1为饱和碳氢伸缩振动吸收,1736cm-1为酯羰基伸缩振动吸收,1606cm-1为芳环C-C骨架振动吸收,1250,1121,1092cm-1为C-O-C伸缩振动吸收。831cm-1为C-F伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.55(d,J=9.6Hz,1H,-Ph),7.21(d,J=8.8Hz,1H,-Ph),6.82(dd,J=2.0,8.4Hz,2H,-Ph),6.58(d,J=8.4Hz,2H,-Ph),6.21(d,J=9.6Hz,1H,-Ph),3.77(s,3H,-OCH3),3.52-3.56(m,1H,-CH-),3.05-3.08(m,2H,-CH2-),1.59(s,3H,-CH3),1.33(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.5,160.1,153.0,143.5,133.9,130.9,128.8,127.4,114.5,113.0,112.6,109.7,109.5,106.8,104.1,88.1,55.8,52.2,27.7,22.0,20.4.MS(ESI)m/z calcd forC22H19F2NO4([M+H]+)399.13,found 400.14.
实施例18蛇床子素异噁唑啉类衍生物的合成(化合物18)
采用实施例1所述方法,蛇床子素与2-氟-4-溴苯甲醛氯肟反应,合成化合物18,化合物18的结构和理化性质如下:
1)、白色固体,熔点:154-156℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2967cm-1为饱和碳氢伸缩振动吸收,1733cm-1为酯羰基伸缩振动吸收,1608cm-1为芳环C-C骨架振动吸收,1279,1254,1120,1091cm-1为C-O-C伸缩振动吸收。837cm-1为C-Br或C-F伸缩振动吸收
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.46(d,J=9.2Hz,1H,-Ph),7.37-7.41(m,1H,-Ph),7.14(d,J=8.4Hz,1H,-Ph),7.01(d,J=8.0Hz,1H,-Ph),6.63(d,J=10.4Hz,1H,-Ph),6.54(d,J=8.8Hz,1H,-Ph),6.13(d,J=9.6Hz,1H,-Ph),3.79(s,3H,-OCH3),3.07-3.13(m,2H,-CH2-),2.85-2.90(m,1H,-CH-),1.59(s,3H,-CH3),1.41(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.2,158.0,157.2,153.0,143.2,130.6(d,J=4.0Hz),127.0,126.9,126.8,123.2,118.5,118.2,113.9,112.9,112.3,106.5,87.6,55.8,53.3,45.9,29.7,27.8,22.1,20.7,8.6.MS(ESI)m/z calcd forC22H19BrFNO4([M+H]+)459.05,found 460.05,462.03.
实施例19蛇床子素异噁唑啉类衍生物的合成(化合物19)
采用实施例1所述方法,蛇床子素与2-溴-4-氯苯甲醛氯肟反应,合成化合物19,化合物19的结构和理化性质如下:
1)、棕色固体,熔点:127-129℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2971cm-1为饱和碳氢伸缩振动吸收,1725cm-1为酯羰基伸缩振动吸收,1605cm-1为芳环C-C骨架振动吸收,1247,1115cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.45(d,J=9.6Hz,1H,-Ph),7.28(d,J=8.0Hz,1H,-Ph),7.13(d,J=8.8Hz,1H,-Ph),7.01-7.07(m,2H,-Ph),6.57(d,J=8.8Hz,1H,-Ph),6.14(d,J=9.6Hz,1H,-Ph),4.32-4.36(m,1H,-CH2-),3.83(s,3H,-OCH3),3.07-3.13(m,1H,-CH-),2.77(dd,J=4.4,13.2Hz,1H,-CH2-),1.55(s,3H,-CH3),1.51(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.9,160.6,160.1,152.6,143.3,135.0,132.4,131.8,130.5,127.1,126.6,122.0,113.7,112.9,112.4,106.7,87.9,55.8,53.0,27.6,21.4,21.1.MS(ESI)m/z calcd forC22H19BrClNO4([M+H]+)475.02,found476.01,477.98.
实施例20蛇床子素异噁唑啉类衍生物的合成(化合物20)
采用实施例1所述方法,蛇床子素与2-氟-5-溴苯甲醛氯肟,合成化合物20,化合物20的结构和理化性质如下:
1)、白色固体,熔点:156-158℃;
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2977cm-1为饱和碳氢伸缩振动吸收,1715cm-1为酯羰基伸缩振动吸收,1609cm-1为芳环C-C骨架振动吸收,1478cm-1为-CH3弯曲振动吸收,1273,1253,1115cm-1为C-O-C伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.56-7.58(m,1H,-Ph),7.45(d,J=9.6Hz,1H,-Ph),7.07-7.12(m,2H,-Ph),6.46(d,J=8.8Hz,1H,-Ph),6.37-6.42(m,1H,-Ph),6.19(d,J=9.6Hz,1H,-Ph),3.79-3.80(m,1H,-CH2-),3.77(s,3H,-OCH3),3.09(t,J=12.4Hz,1H,-CH-),2.87(dd,J=4.8,13.2Hz,1H,-CH2-),1.61(s,3H,-CH3),1.41(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.6,160.0,157.4,156.9,153.0,143.2,133.1,133.0,132.1(d,J=3.0Hz),127.1,121.3,121.1,116.7,116.4,116.16,116.12,113.7,113.0,112.3,106.3,87.8,55.8,53.1,27.7,22.0,20.6.MS(ESI)m/z calcdforC22H19BrFNO4([M+H]+)459.05,found 460.03,462.02.
实施例21蛇床子素异噁唑啉类衍生物的合成(化合物21)
采用实施例1所述,蛇床子素与2,4-二氯苯甲醛氯肟(c)反应,方法合成化合物21,化合物21的结构理化性质如下:
1)、棕色固体,熔点:158-160℃
2)、该化合物的红外光谱图特征(IR)特征:
采用溴化钾压片法:2960cm-1为饱和碳氢伸缩振动吸收,1733cm-1为酯羰基伸缩振动吸收,1610cm-1为芳环C-C骨架振动吸收,1269,1118,1102,为C-O-C伸缩振动吸收。826cm-1为C-Cl伸缩振动吸收。
3)、该化合物的核磁共振图谱特征:1H NMR(400MHz,CDCl3)δ:7.45(d,J=9.2Hz,1H,-Ph),7.33(d,J=8.4Hz,1H,-Ph),7.13(d,J=8.8Hz,1H,-Ph),6.97(d,J=2.0,8.4Hz,1H,-Ph),6.85(d,J=2.0Hz,1H,-Ph),6.57(d,J=8.8Hz,1H,-Ph),6.14(d,J=9.6Hz,1H,-Ph),4.21-4.25(m,1H,-CH2-),3.83(s,3H,-OCH3),3.07-3.14(m,1H,-CH-),2.79(dd,J=4.8,13.2Hz,1H,-CH2-),1.56(s,3H,-CH3),1.49(s,3H,-CH3).13C NMR(100MHz,CDCl3)δ:160.5,160.7,159.9,152.7,143.3,135.0,133.2,132.1,128.7,128.6,127.0,126.2,113.7,112.9,112.4,106.7,87.8,55.7,53.2,27.6,21.6,21.0.MS(ESI)m/z calcdforC22H19Cl2NO4([M+H]+)431.07,found 432.08,434.08.
应用例1:粘虫的杀虫活性实验:
1、供试昆虫:3龄前期粘虫幼虫,虫卵购于河南省济源白云实业有限公司。
2、样品及试剂:
样品为:蛇床子素、阳性对照川楝素、实施例制备的化合物1,2,3-21、溶剂为丙酮,市售分析纯。
3、生测方法:
采用小叶蝶添加法:在直径为9厘米的培养皿底部铺一层滤纸,并加水保湿。每皿挑取10头大小一致、较健壮的3龄前期粘虫幼虫。分别称取5mg蛇床子素、川楝素、实施例制备的化合物1,2,3-21加入5ml丙酮,配成浓度为1mg/mL的药液。将玉米叶剪成1×1cm2的小叶碟,于待测药液中浸3秒,晾干后喂试虫。以丙酮液为空白对照组。每处理10头,重复3次。于室温(25℃左右)下、湿度65%~80%、光照时间为12小时光照/12小时黑暗的条件下饲养。48小时后喂以正常的叶蝶直至羽化。定期记录虫子的取食量、活口数、表现症状等,根据下列公式计算试虫的最终死亡率。测定结果见表1。
最终死亡率(%)=(试虫死亡个数)/(试虫总个数)×100
矫正死亡率(%)=(处理死亡率-对照死亡率)/(1-对照死亡率)×100
表1.蛇床子素异噁唑啉类衍生物对3龄前期粘虫的杀虫活性
从表1中可以看出,喂食该系列化合物的试虫校正死亡率呈均匀上升的趋势,说明作用于试虫生长的各个阶段,在第10、20、30天,每个阶段校正死亡率都优于阳性对照川楝素及底物蛇床子素,第20天时,18个化合物的校正死亡率超过了60%,第30天时,13个化合物的校正死亡率超过了80%,化合物2、9和12甚至超过了90%,分别为96.4%、92.9%和92.9%,在试虫产卵之前,喂食这两种化合物的虫子几乎全部死亡,而上市农药川楝素的校正死亡率仅为53.6%,目标化合物的杀虫效果远高于川楝素。蛇床子素的校正死亡率为53.6%,也远远不及所合成的目标化合物,说明通过异噁唑啉环修饰的蛇床子素,具有比底物更有优势。故本发明制备的蛇床子素异噁唑啉类衍生物有望用于制备高效,环保,低毒的天然产物杀虫剂。
应用例2:小菜蛾杀虫活性实验:
1、供试昆虫:2龄小菜蛾幼虫,虫卵购于河南省济源白云实业有限公司。
2、样品及试剂:
样品为:蛇床子素、阳性对照药乙螨唑、实施例制备的化合物1,2,3-21、溶剂为丙酮,市售分析纯。
2、生测方法:
采用浸叶法测定杀虫活性:将小菜蛾虫卵放入大托盘中,封上保鲜膜并扎孔透气,置于培养箱中在25℃条件下培养,待幼虫孵化出来后进行投食,直至长成2龄小菜蛾幼虫,选取大小一致、较健壮的2龄小菜蛾幼虫进行实验。在直径为9厘米的培养皿底部铺滤纸,每皿放置10头小菜蛾为一组,每个化合物重复三组。选取平整新鲜的包菜叶剪成1×1cm2的小叶碟,于待测药液中浸泡30秒晾干,每皿投喂3片叶碟,空白组投喂浸泡丙酮的叶碟,分别于0h、12h、24h、36h各投喂一次,控制培养箱温度为25℃、湿度65%~80%、光照时间为12小时光照/12小时黑暗的条件下饲养。48h后将浸泡过药液的叶碟取出,投喂健康的叶片,72h后计数。每次投喂时记录虫子的活口数、取食量、生命状态和表现症状等,死亡率的计算公式如下。
最终死亡率(%)=(试虫死亡个数)/(试虫总个数)×100
校正死亡率(%)=(处理死亡率-对照死亡率)/(1-对照死亡率)×100
表2.蛇床子素异噁唑啉类衍生物对2龄小菜蛾杀虫活性
采用浸叶法,测定了目标化合物1-21以及底物蛇床子素和阳性对照药乙螨唑浓度为1mg/mL时对小菜蛾幼虫的毒杀活性。从表2中我们发现,化合物1-21对小菜蛾的毒杀活性没有对粘虫明显。其中致死率最高的为3位溴原子取代的化合物8,校正死亡率为80.0%,大于阳性对照药物乙螨唑(校正死亡率为76.7%),化合物4、20、21次之,校正死亡率分别为75.0%、70.0%、70.0%,说明氯和溴这些卤素原子都可以增强底物的活性。另外还有7个化合物7、9、10、13、14、15、19活性优于底物蛇床子素,校正死亡率分别是55.0%、65.0%、55.0%、55.0%、60.0%、60.0%、65.0%。我们进一步对活性较好的化合物4、8、20、21进行了IC50的测定,发现IC50值最小的是氟原子和溴原子双取代的化合物20,仅为0.48μmol mL-1,小于阳性药乙螨唑(LC50=0.60μmol mL-1),具有开发价值。
表3.蛇床子素异噁唑啉类衍生物4、8、20和21的LC50值
应用例3:对乙酰胆碱酯酶抑制活性实验:
1、供试昆虫:5龄期粘虫幼虫,虫卵购于河南省济源白云实业有限公司。
2、样品及试剂:
样品为:磷酸氢二钠、磷酸二氢钠、乙酰胆碱酯酶(AChE)、硫代乙酰胆碱(ACTI)、5,5-二巯基-双硝基苯甲酸(DTNB)、实施例制备的化合物1,2,3-21,溶剂为甲醇,市售分析纯。
3、生测方法:
用96孔板进行吸光度的测定,每个药物设三个复孔,另设药物对照孔和空白反应孔、空白对照孔。将DTNB溶液和5%吐温-80水溶液按体积比2:1混合均匀,首先在每孔加入35μL pH为7.5的PBS缓冲液,15μL的DTNB溶液和5%吐温-80水溶液混合液,再加入如下试剂。
药物反应孔:20μL药液+20μL酶液
药物对照孔:20μL药液+20μL pH=7.5的PBS缓冲液
空白反应孔:20μL甲醇+20μL酶液
空白对照孔:20μL甲醇+20μL pH=7.5的PBS缓冲液
上述反应体系在摇床上震荡30s,37℃下恒温孵育30min后加入10μL ACTI溶液,继续孵育30min后用酶标仪在405nm处测定吸光度OD值,抑制率计算公式如下:
抑制率(%)=1-(药物反应孔OD值-药物对照孔OD值)/(空白反应孔OD值-空白反应孔OD值)×100%。
表4蛇床子素异噁唑啉类衍生物对五龄期试虫的乙酰胆碱酯酶的抑制活性
表5蛇床子素异噁唑啉类衍生物4、6、13、16和19的IC50值
采用Ellamen比色法,用虫子头部提取的乙酰胆碱酯酶作为酶源,以加兰他敏为阳性对照,测定了化合物1-21在体系浓度为200μg/mL时对酶的抑制活性。从表4中可以看出,化合物4、6、13、16、19对虫体内乙酰胆碱酯酶抑制活性较好,抑制率分别为58.9%、85.5%、57.4%、55.0%和66.7%,优于底物蛇床子素,t测验显示与底物相比有极显著差异(P<0.01)。构效关系分析发现,这些目标化合物均带有氯原子,初步确定氯原子为增强底物抑制乙酰胆碱酯酶活性的活性基团。我们进一步测定了化合物4、6、13、16、19的IC50值,综合判断,化合物6(4-Cl)是本系列对体内乙酰胆碱酯酶抑制活性最好的化合物,IC50值为109.96μg/mL。
应用例4:对鱼虾的毒性实验研究:
1、供试昆虫:草鱼苗、黑壳虾苗购于广州增辉鱼苗厂。
2、样品及试剂:
样品为:实施例制备的化合物1,2,3-21;
试剂为:饮用水经过2d除氯曝气作为养鱼/虾用水;
3、生测方法:
采用静态试验法:将饮用水经过2d除氯曝气作为养鱼/虾用水,购买的鱼苗和虾苗在3L烧杯中以(10只/烧杯)饲养一周,每天换一次水,饲养室温26℃,水温22±1℃,溶氧量8-9mg/mL,pH 7.0-7.6,光照周期为12h光照/12h黑暗,适量饲喂饲料,记录下自然死亡率,选取发育状况良好的鱼苗进行实验。将每个烧杯中的水配置成浓度为500μg/L的溶液,每个平行组放入10尾鱼苗或虾苗,每个化合物设置3个平行,记录下24h、48h的死亡情况(死亡标准:用玻璃棒轻触幼苗无任何反应视为死亡)。
死亡率(%)=(试虫死亡个数)/(试虫总个数)×100
我们测定了化合物8、19、20、21对鱼虾的毒性。用化合物配制浓度为500μg/L的水溶液作为养殖用水,连续观测72h,鱼虾的生命状态良好,未出现死亡情况,与空白组并无肉眼可见的差异。
综上,合成21个目标化合物中,在对粘虫的毒杀活性测定中,化合物2、9和12活性尤其突出;在对小菜蛾毒杀活性的测定中,化合物8优于阳性对照药物乙螨唑,化合物20的LC50值最小;对乙酰胆碱酯酶的抑制活性测定中,化合物6是本系列抑制乙酰胆碱酯酶活性最好的化合物;根据对鱼虾毒性的测定结果可知,鱼虾的存活率达到了100%,合成的噁唑啉类衍生物对鱼虾的毒性很小,具有对非靶标生物很好的选择性。故本发明制备蛇床子素异噁唑啉类衍生物具有比底物蛇床子素更强的杀虫活性,有望用于制备高效、环保、低毒的天然产物杀虫剂。
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