摘要
杂环化合物尤其是含氮杂环化合物由于具有生物活性高、环境相容性好、作用靶标新颖等特性,已成为农药和医药创制中的研究热点。基于活性含氮杂环化合物的结构特征,本文采用分子设计和药效团合理拼接等手段,合成了五类67个新型含吡啶母环的杂环化合物,经1H NMR、IR、MS和元素分析进行结构表征,所有化合物均未见文献报道。采用X-ray单晶衍射,解析了化合物ⅠA-d、ⅡA-b、ⅡB-b和Ⅴ-i的晶体结构。探索了一种反应条件温和的合成酰胺类化合物的新方法。生物活性测试表明,部分化合物对粘虫显示出较好的生长调节活性。全文内容概括如下:
以乙酰丙酮为起始原料,先合成中间体2,6-二甲基-3,5-二乙酰基吡啶,再经亲核加成-消除、肼关环和氮酰化等一系列反应,设计合成10个未见报道的吡啶联吡唑类化合物。通过对目标化合物ⅠA-d进行X-ray衍射单晶测定和结构解析,对氮酰化的反应机理进行了探讨。
以中间体2,6-二甲基-3,5-二乙酰基吡啶为原料,先与芳香醛发生缩合反应,然后与肼关环得到16个未见报道的吡啶联吡唑啉类化合物,通过对同分异构体化合物ⅡA-b和ⅡB-b进行X-ray衍射单晶测定和结构解析,对目标化合物的外消旋体ⅡA系列和内消旋体ⅡB系列成功进行了区分。7个化合物经除草、杀虫和杀菌活性测试,表现出较弱的生物活性。
以乙酰乙酸乙酯为起始原料,先合成中间体2,6-二甲基-3,5-二乙氧羰基吡啶,通过选择性肼解得到双边和单边吡啶酰肼,分别经关环,同时利用吡唑环具有良好的离去性能,在酸催化下胺解反应合成15个未见报道的双边和8个单边吡啶酰胺类化合物,并对酸催化条件下酰基吡唑的胺解机理进行了探讨。该合成过程反应条件温和,且未见文献报道。其中,8个化合物对2龄粘虫具有较好的生长抑制活性,但对豆蚜表现出较弱的致死活性。
以中间体双边和单边吡啶酰肼为原料,改进了1,3,4-噁二唑衍生物的合成方法。分别与芳醛进行缩合反应生成双边酰腙和单边酰腙,然后用NBS作卤代试剂进行成环反应合成12个未见报道的吡啶联噁二唑类化合物ⅣA和ⅣB,并对分子内成环的反应机理进行了探讨。其中,10个化合物对2龄粘虫具有生长抑制活性,7个化合物对黄瓜炭疽病和瓜白粉病显示出一定的防治效果,但化合物的除草活性较弱。增加分子柔性有利于提高吡啶联噁二唑化合物的昆虫生长抑制活性。
以单边吡啶酰肼为原料,经加成、环合反应,合成9个未见文献报道的吡啶联三唑并噻二唑稠杂化合物(Ⅴ)。化合物Ⅴ-i经X-ray单晶衍射呈平面刚性结构。7个化合物对2龄粘虫表现出一定的生长抑制活性。
N-atom heterocyclic compounds have drawn much attention in the research and development of medical and agricultural fields due to they always show high biological activities, good environmental compatibilities and novel interacting-target properties. According to the principle of molecule designing and combination of active groups, sixty-seven novel heterocyclic compounds bearing pyridine moieties were synthesized from a versatile precursor 3,5-di-functional groups pyridine, derived from the oxidation Hantzsch pyridine. All of them were characterized by 1H NMR, IR, MS spectroscopies and elemental analysis. In addition, the representative compoundsⅠA-d,ⅡA-b,ⅡB-b and V-i were further confirmed by X-ray diffraction crystallographic analysis. A feasible route for formation of amide bond under mild reaction conditions was developed. Meanwhile, the bioactivities of the typical products were also investigated, some of them showed good activity to adjust the growth of Mythimna separata.
Ten novel 3,5-bis(pyrazol-3-yl)pyridine derivatives (IA and IB) were designed and synthesized from 3,5-diacetyl-pyridines via addition-elimination, cyclization and N-acylation reactions. The structure of compound IA-d was further confirmed by XRD analysis. The mechanism of acylation was discussed.
Sixteen novel 3,5-bis(pyrazol-3-yl)pyridine derivatives (ⅡA andⅡB) were prepared from readily available Hantzsch pyridine via oxidation, condensation and cyclization reactions. The diastereomers (ⅡA,ⅡB) could be separated by column chromatography. The structures of enantiomerⅡA and mesomerⅡB were further confirmed by XRD analysis, respectively. Selected seven compounds showed lower herbicidal activity, insecticidal activity and antifungi activity.
Fifteen novel 3,5-bis and eight 3-mono amide bond pyridine derivatives (ⅢA andⅢB) were selectively synthesized from 3,5-diethoxylcarbonyl-pyridines via hydrazinolysis, cyclization and aminolysis reactions, in which the pyrazole groups served as excellent leaving groups. The mechanism for the formation of amide bond in the presence of a catalytic amount of acid was presented. Thus, a feasible route for formation of amide bond under mild reaction conditions was developed and it has not been reported yet. Selected eight products exhibited good activity to inhibit the growth of 2 instar larvae of Mythimna separata and weak insecticidal activity against Aphis craccivora Koch.
A series of 3,5-bis or 3-mono-(1,3,4-oxadiazol-2-yl) pyridines (ⅣA andⅣB) was obtained by condensation of 3,5-bisacylhydrazide-pyridine and 3-acylhydrazide- pyridine with aryldehydes, followed by intra-molecular cyclization reactions. The mechanism of intra-molecular cyclization in the presence of N.B.S. as halogenation reagent was also discussed. Bioactivity test showed that ten target compounds exhibited preferable inhibit activity to the growth of 2 instar larvae of Mythimna separata. Meanwhile, selected seven products showed a bit antifungi activity against Colletotrichum orbiculare and Sphaerotheca fuligine, but exhibited weak herbicidal activity. The results of primary structure-activity relationship showed properly increasing flexibility of compounds benefited to bioactivity.
Nine novel 5-[(1,2,4)-triazol[3,4-b][1,3,4]-thiadiazol-3-yl]-nicotinic acid ethyl ester derivatives were designed and synthesized from 3-acylhydrazide-pyridine via addition, cyclization reactions, and so on. The structure of compoundⅤ-i was further confirmed by XRD analysis. Selected seven compounds were found to inhibit to the growth of 2 instar larvae of Mythimna separata.
引文
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