2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative, and preparation method and application thereof

文档序号：997780 发布日期：2020-10-23 浏览：13次中文

阅读说明：本技术 2-（（双取代砜基）亚甲基）-n-芳基肼-1-甲酰胺衍生物、其制备方法及应用 (2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative, and preparation method and application thereof ) 是由宋宝安张阿伟陆红霞金林红甘秀海胡德禹张建李绍远谢丹丹李洪德王于 2020-08-05 设计创作，主要内容包括：本发明公开了一种2-((双取代砜基)亚甲基)-N-芳基肼-1-甲酰胺衍生物、其制备方法及应用,其结构通式(I)如下：<Image he="119" wi="334" file="DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式中：R<Sub>1</Sub>为氢原子、4-氯苯基、4-氟苯基、3-甲基苯基、3,5-二甲苯基、2,6-二甲苯基等取代基；R<Sub>2</Sub>为甲基、乙基、丙基、异丙基、苄基以及4-甲基苄基等取代基。本发明在水稻白叶枯病、水稻细菌性条斑病、烟草青枯病、辣椒细菌性叶斑病和柑橘溃疡病等细菌性病害等细菌性病害中抗菌活性优良,结构简单且化合物性质相对稳定。(The invention discloses a 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative, a preparation method and application thereof, wherein the general structural formula (I) is as follows: in the formula: r 1 Is a substituent such as a hydrogen atom, 4-chlorophenyl group, 4-fluorophenyl group, 3-methylphenyl group, 3, 5-xylyl group, 2, 6-xylyl group, etc.; r 2 And is a substituent such as methyl, ethyl, propyl, isopropyl, benzyl, 4-methylbenzyl and the like. The invention is used for treating bacterial blight of rice, bacterial leaf streak of rice and bacterial wilt of tobaccoBacterial diseases such as pepper bacterial leaf spot and citrus canker and the like have excellent antibacterial activity, simple structure and relatively stable compound property.)

1. A2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative has a general structural formula (I) as follows:

in the formula: r₁Is a substituent such as a hydrogen atom, 4-chlorophenyl group, 4-fluorophenyl group, 3-methylphenyl group, 3, 5-xylyl group, 2, 6-xylyl group, etc.; r₂And is a substituent such as methyl, ethyl, propyl, isopropyl, benzyl, 4-methylbenzyl and the like.

2. 2- ((disubstituted sulfone) methylene) -N-arylhydrazine-1-carboxamide derivatives as claimed in claim 1, specific compounds being as follows:

a compound A: 2- (bis (methylsulfonyl) methylene) -N-phenylhydrazine-1-carboxamide;

compound B: 2- (bis (ethylsulfonyl) methylene) -N-phenylhydrazine-1-carboxamide;

compound C: 2- (bis (propylsulfonyl) methylene) -N-phenylhydrazine-1-carboxamide;

compound D: 2- (bis (methylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide;

compound E: 2- (bis (ethylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide;

compound F: 2- (bis (propylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide;

compound G: 2- (bis (isopropylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide;

compound H: 2- (bis (methylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide;

a compound I: 2- (bis (ethylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide;

compound J: 2- (bis (propylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide;

compound K: 2- (bis (benzylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide;

a compound L: 2- (bis (4-methylbenzylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide;

compound M: 2- (bis (methylsulfonyl) methylene) -N- (3-tolyl) hydrazine-1-carboxamide;

the compound N2- (bis (ethylsulfonyl) methylene) -N- (3-tolyl) hydrazine-1-carboxamide;

compound O: 2- (bis (methylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-carboxamide;

compound P: 2- (bis (ethylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-carboxamide;

compound Q: 2- (bis (4-methylbenzylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-carboxamide;

a compound R: 2- (bis (methylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-carboxamide;

a compound S: 2- (bis (ethylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-carboxamide;

a compound T: 2- (bis (4-methylbenzylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-carboxamide;

compound U: 2- (bis (methylsulfonyl) methylene) -N- (4-tolyl) hydrazine-1-carboxamide;

compound V: 2- (bis (ethylsulfonyl) methylene) -N- (4-tolyl) hydrazine-1-carboxamide;

a compound W: 2- (bis (methylsulfonyl) methylene) -N- (2,4, 6-trimethylphenyl) hydrazine-1-carboxamide;

compound X: 2- (bis (ethylsulfonyl) methylene) -N- (2,4, 6-trimethylphenyl) hydrazine-1-carboxamide;

compound Y: 2- (bis (methylsulfonyl) methylene) -N- (2, 6-diethylphenyl) hydrazine-1-carboxamide;

compound Z: 2- (bis (ethylsulfonyl) methylene) -N- (2, 6-diethylphenyl) hydrazine-1-carboxamide.

3. A preparation method of 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivatives comprises the following steps:

(1) preparation of N-substituted phenyl carbamate:

in a mixed system of substituted aniline, potassium carbonate and dichloromethane, slowly dropwise adding methyl chloroformate under an ice bath condition, and then reacting at room temperature for 3-5 h, wherein the molar ratio of substituted aniline: potassium carbonate: methyl chloroformate = 1: 1.1: 1.2, adding 500-750 mL of dichloromethane into each mole of aniline, and carrying out water washing, liquid separation, drying, suction filtration and decompression desolventizing on a reaction system to obtain an N-substituted phenyl methyl carbamate intermediate;

(2) preparation of N-substituted phenylamido formylhydrazine:

according to the molar ratio of N-substituted phenyl carbamate to hydrazine hydrate (the mass fraction is 80 percent) of 1: 5-1: 20, proportioning, heating to reflux reaction for 20-36h, and pointing a plate to track the reaction process; after the reaction is finished, placing the reaction system under an ice bath condition for cooling, separating out a white solid, performing suction filtration to obtain a crude product of the N-substituted phenylcarbamyl hydrazine, and recrystallizing with absolute ethyl alcohol to obtain a white flaky crystal;

(3) preparation of potassium N- (substituted phenylamidoformyl) dithiocarbamate:

mixing N-substituted phenylamido formylhydrazine, potassium hydroxide and absolute ethyl alcohol, stirring at room temperature until the solid is completely dissolved, and slowly dropwise adding carbon disulfide according to the molar ratio of the N-substituted phenylamido formylhydrazine: potassium hydroxide: carbon disulfide = 1: 2: 3, 300-450 mL of ethanol is needed for each 0.1mol of N-substituted phenylcarbamyl hydrazine, the mixture is stirred at room temperature until no solid is separated out, a pumping filtration system is adopted, and a filter cake is washed by a large amount of absolute ethanol to obtain a white solid;

(4) preparation of N-substituted carboxanilido hydrazino-1-substituted dithioesters:

putting potassium N- (substituted anilino formyl) dithiocarbamate, potassium carbonate, potassium iodide and water in a three-neck round-bottom flask, stirring at room temperature until the solid is completely dissolved, and slowly dropwise adding halogenated hydrocarbon, wherein the molar ratio of the halogenated hydrocarbon to the potassium N- (substituted anilino formyl) dithiocarbamate is as follows: halogenated hydrocarbon/benzyl halide: potassium carbonate: potassium iodide = 1: 2: 1:0.1, 10-15 mL of water is needed for every 0.001 mol of potassium N- (substituted anilino formyl) dithiocarbamate, the mixture is stirred for 5 hours at room temperature until no solid is separated out, a pumping filtration system is adopted, a filter cake is washed by a large amount of water to obtain a thioether crude product, and anhydrous ethanol is recrystallized to obtain a white solid;

(5) preparing a target compound 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide:

mixing N-substituted benzoyl hydrazine-1-substituted dithioester and absolute ethyl alcohol in a three-neck round-bottom flask, stirring at room temperature until the system is homogeneous, and slowly dropwise adding a 30% hydrogen peroxide solution dissolved with catalyst ammonium molybdate, wherein the molar ratio of the N-substituted benzoyl hydrazine-1-substituted dithioester is as follows: catalyst ammonium molybdate: h₂O₂And (3) 5-20: 5-5: 5, 15-30 mL of absolute ethanol is needed for every 0.001 mol of N-alkyl/substituted benzyl-N- (substituted phenylcarbamoyl) -1-substituted sulfenyl thiocarbonyl hydrazine, after 24h of reaction, a rotary evaporator is used for decompression and desolventization, and the solid residue is washed by water and recrystallized by the absolute ethanol to obtain a white solid.

4.2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivatives are applied to the preparation of medicines for preventing and treating bacterial blight of rice, bacterial leaf streak of rice, bacterial wilt of tobacco, bacterial leaf spot of pepper and canker of citrus.

Technical Field

The invention relates to the field of chemical industry and pesticides, in particular to a 2- ((disubstituted sulfonyl) methylene) -N-aryl hydrazine-1-formamide derivative, a preparation method of the 2- ((disubstituted sulfonyl) methylene) -N-aryl hydrazine-1-formamide derivative, and application of the 2- ((disubstituted sulfonyl) methylene) -N-aryl hydrazine-1-formamide derivative in medicines for preventing and treating bacterial diseases such as bacterial blight of rice, bacterial streak of rice, bacterial wilt of tobacco, bacterial leaf spot of capsicum, canker of citrus and the like.

Background

The plant bacterial diseases are a third main plant disease which is caused by bacterial infection of plants and is only next to fungal diseases and virus diseases, and bacterial diseases such as rice bacterial blight, rice bacterial streak, tobacco bacterial wilt, citrus canker and the like are all important diseases in the world. In recent years, with the change of crop cultivation systems and environmental climates in China, crop bacterial diseases such as rice bacterial blight, rice bacterial streak pathogen, citrus canker pathogen, tobacco bacterial wilt and the like are in a trend of being more serious in China. The diseases have the characteristics of quick onset, large harm, wide distribution and the like, no effective chemical agent or other prevention and control methods exist so far, great loss is caused to agricultural production, and effective agents are urgently developed for prevention and control. Therefore, the search for a high-efficiency, low-toxicity and environment-friendly chemical agent for resisting plant bacterial diseases is an urgent problem to be solved in the field of plant protection.

The sulfone derivative has the biological activities of resisting tumor, killing bacteria, resisting virus, weeding, killing pests and the like, and has great application prospect and research value in the creation of novel efficient pesticides. In recent years, intensive research on the compounds has been carried out, and bactericides such as oxycarboxin, dichlofluanid, tolylfluanid, cyazofamid and amisulbrom are developed successively.

The inventor Xuvering, Korean phenanthrene, congratulation, Chen scholarly, Pan Zhaoxi, Wang Jian, 20319and the Chinese publication No. CN102499247A discloses oxadiazole sulfone compounds for preventing and treating crop bacterial diseases in 2012, 06 and 20 months. The methylsulfonylconazole has good indoor antibacterial and field control activity on bacterial diseases such as tobacco bacterial wilt, rice bacterial leaf blight and cabbage soft rot, and the indoor antibacterial activity and the field control effect are superior to 3000 compared with those of a control medicament.

The inventor discloses the application of oxadiazole sulfones in preventing and treating crop bacterial diseases in 2014 12-24 days by using Songbean, Lipejian, Populus, Hudiyu, Xuehavia, Jinlinhong, Xuwinoming, Heming, Gaomanni, Shili, Yangxia, Chen schwaring and Yangbei and China publication No. CN 104222106A. Finding out the bacteriostatic activity EC of the fluorobenzyloxyethyl sulfone on rice bacterial blight bacteria and rice bacterial streak pathogens₅₀The values are respectively 1.07 mu g/mL and 7.14 mu g/mL, which are both superior to the control medicaments of bismerthiazol and thiabendazole.

The inventor of poplar, royal peiye, peri-epi, Wu Shi Bingbing, Hudayu, Xue Wei, Chinese publication No. CN105541822A discloses a pyridine salt compound containing 1,3, 4-oxa (thia) diazolyl sulfuryl and a preparation method and application thereof in 2016, 5.4.s.

The inventor discloses application of a 2, 5-substituent-1, 3, 4-oxadiazole disulfone derivative in prevention and treatment of rice bacterial blight and citrus canker pathogen in 2018, 6 months and 22 days of China publication No. CN108191786A, wherein the derivative is Songbean, plum culture, hudeyu, Jinlinhong, Zhang-Awei, Xidan, Yilimin, Ningning, and the series of compounds show good bacteriostatic activity on rice bacterial blight and citrus canker pathogen.

The amide and hydrazide derivatives have good medical activities of resisting cancers, resisting bacteria and the like. In 2018, the inventor Zhao Zhilong, Zhang Hui Zhen, House Peng jin, Liu Qinglong, China publication No. CN108078969A in 2018 5, 29 discloses an application of naphthohydrazide compounds in preparing microbial drugs, the compounds have strong in vitro antimicrobial activity, and especially show high inhibitory activity on gram-positive bacteria such as staphylococcus aureus, methicillin-resistant staphylococcus aureus, bacillus subtilis, micrococcus luteus and the like, gram-negative bacteria such as escherichia coli, proteus, pseudomonas aeruginosa, salmonella typhi and the like, and fungi such as candida utilis, aspergillus flavus, saccharomyces cerevisiae, candida albicans and the like.

The inventor of the invention is Lingyun, Lenpeng, Yanxinling, Xuyan, Zhang Xiaohe, Xugaofei, Chinese publication No. CN105037263A discloses an N' -substituted benzylidene-1, 2,3, 4-tetrahydroquinolyl-1- (thio) hydrazide compound in 11.11.2015, a preparation method and application thereof, and the series of compounds have broad-spectrum bactericidal activity and especially have obvious inhibition effects on apple rot pathogen, rice sheath blight pathogen and wheat take-all pathogen.

The inventor of Zhao Fenqin, Zhang Wei Rui, Wang Zhi, Yang Tong, Wanna, Shenrui and Hu Qiang, Chinese publication No. CN106749325A discloses a synthesis, a preparation method and an application of an ofloxacin aldehyde thiosemicarbazone derivative, and discovers that the series of compounds have excellent anticancer activity.

The inventor discloses an imidazole hydrazide alcohol derivative, a preparation method and application thereof in 2015, 05 and 13 days, namely Chenconghui, Xufeng, Chenjiajun, Yanzhen, Von Xilai, Yangxian and China publication No. CN 104610159A.

In summary, the small drug molecules containing sulfone groups and amide/hydrazide structures have broad-spectrum biological activities, wherein the derivatives containing 1,3, 4-oxadiazole sulfone groups are widely applied to the creation of pesticide antibacterial agents, and in recent decades, the inventors have also developed a plurality of sulfone bactericides containing 1,3, 4-oxadiazole structures, such as methanesulfonylazole and fluorobenzyloxazole sulfone. However, in industrial development, the 1,3, 4-oxadiazole sulfone compound is found to lack of drug-forming property due to unstable physicochemical property, and the unstable reason is that the 1,3, 4-oxadiazole group is directly connected with a methylsulfonyl group, so that the methylsulfonyl group is easy to undergo an affinity substitution reaction and decompose. On the other hand, the amide/hydrazide derivatives have good biological activity in the aspects of killing insects and resisting fungi, but have not been reported in the aspect of resisting plant bacterial diseases.

Disclosure of Invention

The invention aims to overcome the defects and provide the 2- ((disubstituted sulfone) methylene) -N-arylhydrazine-1-formamide drug which has excellent antibacterial activity in bacterial diseases such as bacterial blight of rice, bacterial streak of rice, bacterial wilt of tobacco, bacterial leaf spot of pepper, canker of citrus and the like, simple structure and relatively stable compound property.

The invention also aims to provide a preparation method of the 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative.

The invention also aims to provide application of the 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative in preventing and treating bacterial diseases such as bacterial blight of rice, bacterial streak of rice, bacterial wilt of tobacco, bacterial leaf spot of pepper, canker of citrus and the like.

The 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative has the following structural general formula (I):

in the formula: r₁Is hydrogen atom, 4-chlorophenyl, 4-fluorophenyl, 3-methylA substituent such as an phenylphenyl group, a 3, 5-xylyl group, a 2, 6-xylyl group or the like; r₂And is a substituent such as methyl, ethyl, propyl, isopropyl, benzyl, 4-methylbenzyl and the like.

Preferred compounds are as follows: