摘要
天然吡啶类化合物广泛存在于烟草等植物中,具有广谱生物活性和结构多样性的特点。将烟草的提取物作为杀虫剂的研究与应用具有悠久的历史。然而,合成吡啶类化合物作为农药的研究在近10多年来才获得了迅速发展。近几年来,对天然烟碱类化合物的结构进行改造后,成功地合成出许多(新烟碱类化合物结构)较高活性的农药,如吡虫啉、吡虫清、氟虫腈、噻虫啉、吡氟磷,万亩定等。这一研究表明吡啶类化合物在杀虫剂、杀菌剂、除草剂等农药合成中取得了突破性的进展,吡啶类化合物在农药生物活性方面也起着重要的作用,吡啶类化合物的合成和生物活性研究,已成为化学界和生物界的研究热点之一。
本文采用活性基团拼接法,将活性基团N-氧化和硝基取代后的吡啶环与活性基团二甲酰亚胺基进行拼接,设计合成了四类共45个吡啶类化合物。
第一类:N-甲基-N-取代吡啶甲胺类化合物的合成。2-氯-5-胺甲基吡啶是甲胺吡啶类化合物重要的中间体。合成方法是由邻苯二甲酰亚胺、碳酸钾和2-氯-5-氯甲基吡啶发生Gabriel一步法缩合反应,其缩合产物先在强碱性溶液中水解,水解产物经过水蒸汽蒸馏,重结晶得2-氯-5-胺甲基吡啶。中间体2-氯-5-胺甲基吡啶再经过5-位甲胺基的烷基化、酰基化,合成了N-甲基-N-取代吡啶甲胺类化合物11个,经IR、MS、~1H NMR、~(13)C NMR谱图解析和元素分析确证了合成化合物的结构。
第二类:N-(6-氯-3-吡啶甲基)二甲酰亚胺类化合物的合成。二甲酰亚胺钾盐是吡啶基二甲酰亚胺类化合物重要的中间体。合成方法是由起始原料尿素在熔融状态下放出氨气,再与二元酸酐制成二甲酰亚胺,该亚胺与强碱作用合成亲核试剂二甲酰亚胺钾盐,该盐与2-氯-5-氯甲基吡啶发生亲核取代反应,合成二甲酰亚胺化合物7个,经IR、MS、~1H NMR、~(13)C NMR谱图解析和元素分析确证了化合物的结构。
第三类:N-(6-氯-1-氧-3-吡啶甲基)二甲酰亚胺类化合物的合成.合成方法是以2-氯-5-氯甲基吡啶为原料,以双氧水为氧化剂,在三氯乙酸存在下将吡啶环的N原子氧化得2-氯-1-氧-5-氯甲基吡啶。2-氯-1-氧-5-氯甲基吡啶与亲核试剂二甲酰亚胺钾反应,合成目标产物N-(6-氯-1-氧-3-吡啶甲基)二甲酰亚胺类新型吡啶化合物7个,经IR、MS、~1H NMR、~(13)C NMR谱图解析和元素分析确证了化合物的结构.
第四类:N-取代基多取代吡啶胺类化合物的合成。合成方法是以2-氨基-5-溴吡啶为原料,在浓硫酸、发烟硝酸中首先合成了N-硝基-2-氨基-5-溴吡啶,然后N-硝基-2-氨基-5-溴吡啶再硝化反应合成2-氨基-3-硝基-5-溴吡啶,2-氨基-3-硝基-5-溴吡啶的胺基烷基化、酰基化,设计合成新的多取代吡啶化合物20个,经IR、MS、~1H NMR、~(13)C NMR谱图解析和元素分析确证了化合物的结构.
在上述四类化合物的合成过程中,本文对中间体和目标化合物的合成方法和试验条件进行了优化和筛选.采用常规合成和微波合成两种方法,对第二类和第三类化合物的亲核取代反应合成条件做了对比.试验结果表明,微波合成法能很好的促进亲核取代反应的进行,缩短反应时间,提高产率.目标化合物N-(6-氯-3-吡啶甲基)邻苯二甲酰亚胺的合成反应时间从常规方法的9 h缩短到20 min,产率从80%提高到97%.
对合成目标化合物进行了杀虫和杀菌活性的生物活性测定。试验以小菜蛾、蚕豆蚜、朱砂叶螨、淡色库蚊和褐飞虱5种靶标生物,对目标化合物进行了杀虫活性筛选.结果如下:在药剂浓度为10μg/mL时,化合物Ⅲ_1、Ⅲ_7、Ⅳ_2、Ⅳ_3对淡色库蚊校正死亡率分别为92.6%、90.5%、94.6%、97.3%,化合物Ⅰ_1、Ⅱ_3、Ⅱ_7、Ⅲ_6、Ⅳ_6、Ⅳ_8、Ⅳ_(10)、Ⅳ_(11)、Ⅳ_(14)、Ⅳ_(15)、Ⅳ_(16)、Ⅳ_(19)、Ⅳ_(20)对淡色库蚊校正死亡率都为100%,与对照药剂吡虫啉的校正死亡率相当;在药剂浓度为1μg/mL下时,目标化合物Ⅱ_3、Ⅲ_7对淡色库蚊校正死亡率分别为97.5%、96.5%,目标化合物Ⅰ_1、Ⅱ_7、Ⅲ_1、Ⅲ_6、Ⅳ_(19)、Ⅳ_(20)对淡色库蚊校正死亡率都为100%,与对照药剂吡虫啉的校正死亡率相当.在药剂浓度为200μg/mL时,目标化合物Ⅰ_2、Ⅲ_1、Ⅲ_2对蚕豆蚜校正死亡率分别为93.8%、96.3%、90.5%,目标化合物Ⅰ_1、Ⅱ_7、Ⅲ_6、Ⅲ_7、Ⅳ_(20)对蚕豆蚜校正死亡率都为100%;在药剂浓度为20μg/mL时,Ⅰ_1、Ⅱ_7、Ⅳ_(20)对蚕豆蚜校正死亡率都为100%.在45个合成化合物中,有17个化合物的杀虫生物活性达到了A级,具有很好的杀虫活性。
采用生长速率法,以小麦赤霉病菌、稻瘟病、番茄灰霉病、为测试对象,对目标化合物进行了抗植物病菌活性测定.结果表明,大部分目标化合物的抑菌活性不明显.
Natural pyridine compounds and their structurally related compounds,with broad spectrum of biological activities and variety of structure,are naturally included in nicotianaspp plants,and its abstractions from nicotianaspp as pesticides have been investigated and used for long time.However,synthetic pyridines compounds as pesticides have flourished only for the recent decades.In recent years,some more effective pesticides, such as imidacloprid,hcetamiprid,thiadoprid,pyroxidechlor,pyridinthion and denment, have been synthesized through chemical modification of natural compounds of nicotianaspp.This discovery showed that synthesized pyridine compounds have been successfully developed in insecticide,fungicide and herbicide,and will play an important part in synthesis and biological activity of pesticide aspect.The synthesis and bioactivity study of pyridine compounds have became one of active studied fields to the chemicals and biological scholars.
By adopting the connection method of active structure base in this dissertation,for example,connection of pyridine N-oxide pyridine,Nitro substituted pyridine and dicarborimide,four classes pyridine compounds(total 45) have been synthesized.The main result is followed.
Series N-methyl-N-substituted methylpyridineamine compounds are synthesized firstly (labeled classⅠ).The 2-Chloro-5-aminemethylpyridine is important intermediate in the synthesis process of N-methyl-N-substituted methylpyridineamine.Its synthesis steps starts from Gabriel condensation reaction by 2-Chloro-5-Chloro methylpyridine and K_2CO_3,and reacted production was hydrolyzed in basicity solution in the same time,then hydrolytic production was distilled by vapor.By crystallizing the distilled production,we finally got intermediate 2-Chloro-5-aminomethylpyridine.Then,the reaction of N-methyl and N-substituted of 2-Chloro-5-aminomethylpyridine gave series N-methyl-N-substituted methylpyridine compounds,i.e.,the 11 target compounds.The Elemental analysis was carried on and spectra of IR,GC-MS,~1H NMR,~(13)C NMR were presented.The structures of N-methyl-N-substituted methylpyridineamine agree with the IR,GC-MS,~1H NMR,~(13)C NMR spectroscopic data.
Then series N-(6-Chloro-3-Pyridinemethy)-diearborimide compounds have been synthesised(labeled classⅡ).The dicarborimide salt of potassium is important intermediate in the synthesis process of N-(6-Chloro-3-Pyridinemethy)-dicarborimide.As the starting intermediate for the synthesis,diearborimide salt of potassium was generated through two step reactions.Firstly,reaction of raw diearboracid anhydride with carbamide produced intermediate diearborimide,then reactions of dicarborimide with KOH in methanol solution generated intermediate diearborimide salt of potassium in good yield.We researched a convenient synthesis method of target product of N-(6-Chloro-3-Pyridinemethy) -diearborimide be using the reaction of Nucleophilic substitution of diearborimide salt of potassium with 6-chloro-3-chloromethypyridine.The 7 compounds are synthesized.The Elemental analysis was carried out and spectra of IR, GC-MS,~1H NMR,~(13)C NMR were presented.The structures of N-(6-chloro-3-pyridinemethy)-diearbonylimides(Ⅱ_1-Ⅱ_7) agree with the IR,GC-MS,~1H NMR,~(13)C NMR spectroscopic data.
Series N-(6-Chloro-1-oxide-3-methylpyridine) dicarborimide compounds are also synthesised(labeled classⅢ).The N-oxidepyridine is important intermediate in the synthesis process of N-(6-Chloro-1-oxide-3-methylpyridine ) dicarborimide.Its synthesis method starts with N atom was oxidegenated by raw hydrogen peroxide in trifluoro acetic acid.Then series N-(6-Chloro-1-oxide-3-methylpyridine ) dicarborimide compounds were obtained by Gabriel condensation reaction of 6-Chloro-1-oxide-3-methylpyridine with diearborimide salt of potassium,i.e.,the 7 compounds are synthesized.The Elemental analysis was carried on and spectra of IR,~1H NMR,~(13)C NMR,GC-MS were presented.The structures of series N-(6-Chloro-1-oxide-3-Pyridinemethy)-dicarborimide compounds agree with the IR,~1H NMR,~(13)C NMR and GC-MS spectroscopic data.
Series N-substituted-base-multi-substituted pyridine compounds are finally synthesised(labeled classⅣ).The 2-amino-3-nitro-5-bromide-pyridine is important intermediate in the synthesis process of N-substituted-base-multi-substituted pyridine compounds.Raw material 2-amino-5-bromide-pyridine was added carefully into a mixture of concentrate sulfuric acid and fuming nitric acid,and N-nitro-2-amino-5-bromide-pyridine was crystallized in hot water.Then, N-nitro-2-amino-5-bromide-pyridine was added carefully into a mixture of concentrate sulfuric acid and fuming nitric acid,and 2-amino-3-nitro-5-bromide-pyridine was crystallized also in hot water.Finally,the reaction of N-methyl and N-substitution of 2-amino-3-nitro-5-bromide-pyridine gave series N-substituted-base-multi-substituted pyridine compounds,i.e.,the 20 compounds are synthesized.The Elemental analysis was carded on and spectra of IR,~1H NMR,~(13)C NMR,GC-MS were presented.The structures of N-methyl-N-formylamino-3-nitro-5-bromide- pyridine agree with the IR,GC-MS,~1H NMR, ~(13)C NMR spectroscopic data.
The experimental circumstance and the synthetic methods of the intermediate and target compounds have been investigated and optimized in the synthesis progress.The synthesis condition of reaction of nucleophilie substitution between classⅡcompounds and classⅢcompounds are analyzed under normal synthesis method and microwave-assisted synthesis method.The contrast result shows that the microwave-assisted synthesis method can be carded on with better reaction conditions and gives higher yield than the normal synthesis procedure.The microwave-assisted synthesis method possesses several advantages,i.e,faster reaction rates and higher yields rate.The reaction time of target compound N-(6-chloro-3-pyridinemethyl) phthalimide reduces from 9 h to 20 min and yields rate rises from 80%to 97%when we takepIace the normal synthesis procedure with the microwave-assisted synthesis method.
The pesticide activity and bactericidal activity of all the target compounds have been evaluated.The pesticide activity is evaluated under 5 target insects,i.e.,diamondback moth, xylostella,bean aphid,crαccivura,spider mite,nilaparvata lugens.The experimental result is followed that with the medicament concentration 10 ug/mL,the mortality ratio to C.pipiens of compoundsⅢ_1、Ⅲ_7、Ⅳ_2、Ⅳ_3 are respectively 92.6%、90.5%、94.6%、97.3 %and the mortality ratio to pipiens ofcompoundsⅠ_1、Ⅱ3、Ⅱ7、Ⅲ_6、Ⅳ_6、Ⅳ_8、Ⅳ_(10)、Ⅳ_(11)、Ⅳ_(14)、Ⅳ_(15)、Ⅳ_(16)、Ⅳ_(19)、Ⅳ_(20) are all 100%,i.e.,nearly equal mortality rate to the contrasted drug imidacloprid;with the medicament concentration 1 ug/mL,mortality rate to C.pipiens of the compoundⅡ_3 andⅢ_7 are 97.5%and 96.5%,and the mortality rate to C.pipiens of compoundsⅠ_1、Ⅱ_7、Ⅲ_1、Ⅲ_6、Ⅳ_(19)、Ⅳ_(20) are also 100%,i.e,nearly equal mortality rate to the contrasted drug imidacloprid.With the medicament concentration 200 ug/mL,the mortality ratio to A.craccivura of compoundsⅠ_2、Ⅲ_1、Ⅲ_2 are 93.8%、96.3% and 90.5%,and the mortality rate to A.craccivura of compoundsⅠ_1、Ⅱ_7、Ⅲ_6、Ⅲ_7、Ⅳ_(20) are also 100%,With the medicament concentration 20 ug/mL,the mortality ratio to A.craccivura of compounds ofⅠ_1、Ⅱ_7、Ⅳ_(20) are also 100%.Mortality ratio shows that 17 compounds of total 45 compounds are A grade activation of suppressing insecticide activities.
By using growing speed method,the bactericidal activity of all synthesized compounds have been evaluated under tested objection of botryris cinerea pers,fusarium qraminearum and pyricularia oryzae.The experimented result indicates that all the compounds don't present distinct activity of restraining bactericide.
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