摘要
为了寻找符合21世纪药物发展要求的新型农药先导化合物,本文采用活性基团叠加原理设计并合成了通式分别为(Ⅰ)、(Ⅱ)、(Ⅲ)的目标化合物。(1)从5-氟代苯基糠酸出发,经酰化、异硫氰酸酯化,再与取代芳酰肼发生亲核加成反应合成了20种未见文献报道的N-取代芳酰氨基-5-氟代苯基糠酰硫脲(Ⅰ);(2)在系列Ⅰ的基础上经酸环化合成了20种未见文献报道的N-(5-取代芳基-1,3,4-噻二唑-2-基)-5-氟代苯基糠酰胺(Ⅱ);(3)以甘氨酸为骨架引入5-邻氯苯基糠酰基,4,6-二取代嘧啶等活性结构,采用固相合成法,经酰化、酰胺化等反应设计合成了6种未见文献报道的N-(4,6-二取代基-2-嘧啶基)-2-(5-邻氯苯基糠酰氨基)乙酰胺(Ⅲ)。
采用元素分析、红外光谱、核磁共振氢谱、质谱等对上述三个系列目标化合物进行了结构表征,并对其物理性质、波谱性质、反应条件、合成方法进行了较为系统的分析和讨论。目标化合物(Ⅰ)、(Ⅱ)、(Ⅲ)的结构通式如下:
为了进一步了解化合物的空间结构,初步探索化合物的结构与性质的关系,对具有生物活性的N-取代芳酰氨基-5-氟代苯基糠酰硫脲(Ⅰc和Ⅰd)两种化合物进行了单晶培养及X-射线衍射晶体结构测定等研究。
委托国家南方农药创制中心(上海)药效部对化合物(Ⅰ)～(Ⅲ)进行除草活性的初步普筛测定;对化合物(Ⅰ)还进行杀菌活性的初步普筛测定。结果表明:系列(Ⅰ)的部分目标化合物具有一定的除草活性;同时具有一定的选择性杀菌活性;例如化合物Ⅰr对棉花炭疽(Colletotrichum gossypii)的抑制活性达到了95.24,具有较高的选择性杀菌活性;化合物Ⅰt对苹果轮纹病(Dothiorellagregaria)的抑制活性达到了92.00,也具有较高的选择性杀菌活性。系列(Ⅱ)、(Ⅲ)的部分目标化合物具有较好的除草活性;例如化合物Ⅲe在10mg/L浓度下对双子叶植物—油菜(根/茎)的抑制率达91.9/64.3。
In order to search the introduction compounds for new pesticide, obeying theprinciple of active-factor-addition, three series of compounds shown in the formula(I)、(Ⅱ)、(Ⅲ) were designed and synthesized. Twenty new (Ⅰ) N-(substitutedarylamino)-5-(fluorophenyl)-2-furoyl thioureas were synthesized from5-(fluorophenyl)-2-furoic acid, through four steps using PEG-400 as solid-liquidtransfer catalyst. In addition, based on this earlier research work, twenty new (Ⅱ)N-(5-aryl-1,3,4-thiadiazol-2-yl)-5-(fluorophenyl)-2-furamides were synthesized underthe reflux condition using glacial acetic acid as solvent. Six new (Ⅲ)N-(4,6-disubstituted-2-pyrimidinyl)-2-(5-(2-chlorophenyl)-2-furoylamino)acetylamines were designed and synthesized by solid-state reaction under room temperature,using the primary source materials of glycine, 5-(2-chlorophenyl)-2-furoic acid,4,6-disubstituted 2-aminopyrimidine. All these target compounds are new compoundsand their structures were confirmed by IR, ~1H NMR, MS, and elementary analysis.Their physic-chemical properties, spectrum properties, reaction conditions andsyntheticmethodswerediscussedaswell.Thestructuralformulaeofcompounds(I)、(Ⅱ)、(Ⅲ)areasfollowsrespectively:
Furthermore, in order to investigate the relationship between the structure of thetarget compounds and its property, we nurtured and obtained two related crystalstructures bysingle crystal X-raydiffractionanalysis, and have somebasicdiscussionontheirstructuresandactivities.
The preliminary biological activities tests of target compounds (I)、(Ⅱ)、(Ⅲ)were finished in Shanghai Branch of National Pesticide R&D South Center. Theresults indicated that some of the target compounds of (I) have some herbicidalactivities and some of the target compounds of (Ⅰ) have good selective fungicidalactivities. For example, compoundⅠr has good selective inhibition activity againstColletotrichum gossypii, compoundⅠt also has good selective inhibition activityagainst Dothiorella gregaria. Some of the target compounds of (Ⅱ)、(Ⅲ) have someherbicidal activities, compoundⅢe have good inhibition activities againstdicotyledonousplant-Colza(root/stem)at10mg/L.
引文
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