CN111808001A - 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative, and preparation method and application thereof - Google Patents
2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative, and preparation method and application thereof Download PDFInfo
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Abstract
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: 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. 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.
Description
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:
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.
The preparation method of the 2- (bi (substituted sulfuryl) methylene) -N- (substituted phenyl) hydrazine-1-formamide derivative 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: and (3) proportioning 20 materials, heating to reflux and reacting 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: h2O2The ratio of the N-alkyl/substituted benzyl-N- (substituted phenylcarbamoyl) -1-substituted sulfenyl thiocarbonyl hydrazine is 1: 0.1-0.5: 5-20, 15-30 mL of absolute ethyl alcohol 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, solid residues are washed by water and then recrystallized by the absolute ethyl alcohol, and white solids are obtained.
The 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivative is applied to the preparation of medicines for preventing and treating bacterial diseases such as rice bacterial leaf blight, rice bacterial leaf streak, tobacco bacterial wilt, pepper bacterial leaf spot, citrus canker and the like.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can show that: according to the invention, 1,3, 4-oxadiazole ring is subjected to open-loop transformation, and a disulfone functional group is introduced into a hydrazide structure, so that the activity combination and the pharmaceutical property improvement of a disulfone and hydrazide medicinal groups are realized, and the 2- ((disubstituted sulfonyl) methylene) -N-arylhydrazine-1-formamide antibacterial drug with relatively stable physicochemical property and excellent pharmaceutical property is prepared. Experiments prove that the bactericidal composition has obvious effect on preventing bacterial diseases such as bacterial blight of rice, bacterial leaf streak of rice, bacterial wilt of tobacco, bacterial leaf spot of hot pepper, canker of citrus and the like, and has the advantages of simple structure, simple preparation process, low production cost and wide application prospect.
Detailed Description
Example 1:
the preparation method of the 2- (bis (methylsulfonyl) methylene) -N-phenylhydrazine-1-formamide (the compound is numbered as A) comprises the following steps:
(1) preparation of methyl anilinocarboxylate:
aniline (20g, 0.21mol), potassium carbonate (32.65g, 0.24mol) and dichloromethane (100-150 mL) were mixed in a 250mL three-necked flask, methyl chloroformate (24.35g, 0.26mol) was slowly added dropwise under ice bath conditions, and then the mixture was reacted at room temperature for 5 hours. After the reaction is finished, 28.65g of methyl anilinocarboxylate is obtained after the reaction system is washed, separated, dried, filtered and desolventized under reduced pressure, and the yield is 88.25%.
(2) Preparation of anilino-formylhydrazine:
mixing methyl anilinocarboxylate (15g, 0.1mol) and 80% hydrazine hydrate (62.09g, 1.0mol) in a 100mL three-neck round-bottom flask, heating to reflux reaction for 36h, cooling in an ice bath after the reaction is finished to separate out a white solid, performing suction filtration to obtain a crude anilinocarboxamide product, and recrystallizing absolute ethyl alcohol to obtain 7.46g of white flaky crystals with the yield of 49.73%.
(3) Preparation of potassium N- (anilinoformyl) dithiocarbamate:
mixing anilino formyl hydrazine (5g, 0.033mol), potassium hydroxide (3.71g, 0.066mol) and 100mL absolute ethyl alcohol in a 250mL three-neck round-bottom flask, stirring at room temperature until the solid is completely dissolved, slowly dropwise adding carbon disulfide (7.55g, 0.099mol), stirring at room temperature for 5 hours, filtering the system, washing a filter cake with a large amount of absolute ethyl alcohol to obtain a white solid 7.5g, wherein the yield is 85.44%;
(4) preparation of N-carboxanilido hydrazino-1-methyl dithioester:
mixing potassium N- (anilino formyl) dithiocarbamate (1g, 3.77mmol), potassium carbonate (0.52g, 3.77mmol), potassium iodide (62.55mg, 0.38mmol) and 50mL of water in a 100mL three-neck round-bottom flask, stirring at room temperature until the solid is completely dissolved, slowly dropwise adding methyl iodide (1.07g, 7.54mmol), stirring at room temperature (20 ℃) for 12h to finish the reaction, filtering the system, washing a filter cake with petroleum ether, and recrystallizing with absolute ethanol to obtain 0.64g of white solid with the yield of 66.9%;
(5) preparation of 2- (bis (methylsulfonyl) methylene) -N-phenylhydrazine-1-carboxamide:
n-carboxanilido-hydrazino-1-methyldithiolate (0.213g, 0.834mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round bottom flask, stirred at room temperature until the system was homogeneous, and then a 30% hydrogen peroxide solution (1.89g, 16.68mmol) containing ammonium molybdate (0.103g, 0.083mmol) was slowly added dropwise and stirred at room temperature (20 ℃ C.) for 24 h. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.17g of white solid with the yield of 63.82%;
example 2:
the preparation method of the 2- (bis (ethylsulfonyl) methylene) -N-phenylhydrazine-1-formamide (the compound number is B) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N-phenylhydrazine-1-carboxamide:
n-carboxanilido-hydrazino-1-ethyldithio ester (0.20g, 0.706mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.60g, 14.11mmol) containing ammonium molybdate (0.087g, 0.071mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.191g of white solid with the yield of 77.91%;
example 3:
the preparation method of the 2- (bis (propylsulfonyl) methylene) -N-phenylhydrazine-1-formamide (the compound number is C) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (propylsulfonyl) methylene) -N-phenylhydrazine-1-carboxamide:
n-carbamoylhydrazino-1- (propyl) dithioester (0.20g, 0.672mmol) and 10mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, stirred at room temperature until the system became homogeneous, and then a 30% hydrogen peroxide solution (0.46g, 13.45mmol) containing ammonium molybdate (0.083g, 0.067mmol) was slowly added dropwise and stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.21g of white solid with the yield of 86.41%;
example 4:
the preparation method of 2- (bis (methylsulfonyl) methylene) -N- (4-chlorphenyl) hydrazine-1-formamide (the compound number is D) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1-methyldithiolate (0.169g, 0.583mmol) and 8mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.32g,11.66mmol) containing ammonium molybdate (0.072g, 0.058mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.146g of white solid with the yield of 70.76%;
example 5:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (4-chlorphenyl) hydrazine-1-formamide (the compound number is E) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1-ethyldithio ester (0.34g, 1.07mmol) and 20mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.21g, 10.07mmol) containing ammonium molybdate (0.132g, 0.107mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.335g of white solid with the yield of 82.02%;
example 6:
the preparation method of 2- (bis (propylsulfonyl) methylene) -N- (4-chlorphenyl) hydrazine-1-formamide (the compound number is F) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (propylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1-propyldithio ester (0.21g, 0.706mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (0.48g, 14.12mmol) containing ammonium molybdate (0.087g, 0.071mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.207g of white solid with the yield of 81.12%;
example 7:
the preparation method of 2- (bis (isopropylsulfonyl) methylene) -N- (4-chlorphenyl) hydrazine-1-formamide (the compound number is G) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (isopropylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1- (isopropyl) dithioester (0.27g, 0.908mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (0.62g, 18.16mmol) containing ammonium molybdate (0.112g, 0.091mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.25g of white solid with the yield of 76.20%;
example 8:
the preparation method of 2- (bis (methylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-formamide (the compound number is H) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1-methyldithiolate (0.226g, 0.827mmol) and 20mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.87g, 16.54mmol) containing ammonium molybdate (0.102g, 0.083mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.228g of white solid with the yield of 81.75 percent;
example 9:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-formamide (the compound number is I) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1-ethyldithio ester (0.368g, 1.22mmol) and 25mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (2.77g, 24.42mmol) containing ammonium molybdate (0.151g, 0.122mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.354g of white solid with the yield of 79.35 percent;
example 10:
the preparation method of 2- (bis (propylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-formamide (the compound number is J) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (propylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide:
n- (4-Fluorophenylcarbamoyl) hydrazine-1-propyldithio ester (0.21g, 0.637mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.45g, 12.75mmol) containing ammonium molybdate (0.079g, 0.064mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.19g of white solid with the yield of 75.76%;
example 11:
the preparation method of 2- (bis (benzylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-formamide (the compound number is K) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (benzylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1-benzyldithioester (0.356g, 0.837mmol) and 20mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.90g, 16.73mmol) containing ammonium molybdate (0.103g, 0.084mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.361g of white solid with the yield of 85.28%;
example 12:
the preparation method of 2- (bis (4-methylbenzyl sulfuryl) methylene) -N- (4-fluorophenyl) hydrazine-1-formamide (the compound number is L) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (4-methylbenzylsulfonyl) methylene) -N- (4-fluorophenyl) hydrazine-1-carboxamide:
n- (4-Chloroanilinoyl) hydrazine-1- (4-methylbenzyl) dithioester (0.169g, 0.373mmol) and 10mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (0.422g, 3.73mmol) containing ammonium molybdate (0.046g, 0.037mmol) was slowly added dropwise thereto, followed by stirring at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.146g of white solid with the yield of 73.38%;
example 13:
a method for preparing 2- (bis (methylsulfonyl) methylene) -N- (3-tolyl) hydrazine-1-formamide (compound number is M) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (3-tolyl) hydrazine-1-carboxamide:
n- (3-toluidinoyl) hydrazine-1-methyldithiolate (0.20g, 0.742mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.68g, 14.85mmol) containing ammonium molybdate (0.92g, 0.074mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.204g of white solid with the yield of 82.42%;
example 14:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (3-tolyl) hydrazine-1-formamide (the compound number is N) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (3-tolyl) hydrazine-1-carboxamide:
n- (3-toluidinoyl) hydrazine-1-ethyldithio ester (0.20g, 0.672mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.52g, 13.45mmol) containing ammonium molybdate (0.92g, 0.067mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.22g of white solid with the yield of 90.52 percent;
example 15:
the preparation method of 2- (bis (methylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-formamide (the compound number is O) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-carboxamide:
n- (3, 5-Dimethylanilinoyl) hydrazine-1-methyldithiolate (0.2g, 0.706mmol) and 20mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.6g, 14.11mmol) containing ammonium molybdate (0.087g, 0.071mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.207g of white solid with the yield of 84.43%;
example 16:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-formamide (the compound number is P) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-carboxamide:
n- (3, 5-Dimethylanilinoyl) hydrazine-1-ethyldithio ester (0.227g, 0.729mmol) and 20mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.65g, 14.58mmol) containing ammonium molybdate (0.091g, 0.073mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.231g of white solid with the yield of 84.42%;
example 17:
the preparation method of 2- (bis (4-methylbenzyl sulfuryl) methylene) -N- (3, 5-xylyl) hydrazine-1-formamide (the compound number is Q) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (4-methylbenzylsulfonyl) methylene) -N- (3, 5-xylyl) hydrazine-1-carboxamide:
n- (3, 5-Dimethylanilinoyl) hydrazine-1- (4-methylbenzyl) dithioester (0.2g, 0.431mmol) and 10mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (0.978g, 8.63mmol) containing ammonium molybdate (0.053g, 0.043mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.168g of white solid with the yield of 73.81 percent;
example 18:
the preparation method of 2- (bis (methylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-formamide (the compound number is R) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-carboxamide:
n- (2, 6-Dimethylanilinoyl) hydrazine-1-methyldithiolate (0.23g, 0.812mmol) and 20mL of absolute ethanol were mixed in a 50mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.84g, 16.23mmol) containing ammonium molybdate (0.1g, 0.081mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.221g of white solid with the yield of 78.39%;
example 19:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-formamide (the compound number is S) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-carboxamide:
n- (2, 6-Dimethylanilinoyl) hydrazine-1-ethyldithio ester (0.062g, 0.199mmol) and 5mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (0.451g, 3.98mmol) containing ammonium molybdate (0.025g, 0.02mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.066g of white solid with the yield of 88.31%;
example 20:
the preparation method of 2- (bis (4-methylbenzyl sulfuryl) methylene) -N- (2, 6-xylyl) hydrazine-1-formamide (the compound number is T) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (4-methylbenzylsulfonyl) methylene) -N- (2, 6-xylyl) hydrazine-1-carboxamide:
n- (2, 6-Dimethylanilinoyl) hydrazine-1- (4-methylbenzyl) dithioester (0.2g, 0.431mmol) and 10mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (0.978g, 8.63mmol) containing ammonium molybdate (0.053g, 0.043mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.165g of white solid with the yield of 72.49%;
example 21:
a method for preparing 2- (bis (methylsulfonyl) methylene) -N- (4-tolyl) hydrazine-1-formamide (compound number is U), which comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (4-tolyl) hydrazine-1-carboxamide:
n- (4-toluidinoyl) hydrazine-1-methyldithiolate (0.32g, 1.19mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (2.69g, 23.76mmol) containing ammonium molybdate (0.147g, 0.119mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.34g of white solid with the yield of 85.85%;
example 22:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (4-tolyl) hydrazine-1-formamide (the compound number is V) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (4-tolyl) hydrazine-1-carboxamide:
n- (4-toluidinoyl) hydrazine-1-ethyldithio ester (0.20g, 0.672mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.52g, 13.45mmol) containing ammonium molybdate (0.83g, 0.067mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.21g of white solid with the yield of 86.41%;
example 23:
the preparation method of 2- (bis (methylsulfonyl) methylene) -N- (2,4, 6-trimethylphenyl) hydrazine-1-formamide (the compound number is W) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (2,4, 6-trimethylphenyl) hydrazine-1-carboxamide:
n- (2,4, 6-trimethylbenzoyl) hydrazine-1-methyldithiolate (0.27g, 0.908mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (2.06g, 18.16mmol) containing ammonium molybdate (0.112g, 0.091mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.26g of white solid with the yield of 79.86%;
example 24:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (2,4, 6-trimethylphenyl) hydrazine-1-formamide (the compound number is X) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (2,4, 6-trimethylphenyl) hydrazine-1-carboxamide:
n- (2,4, 6-trimethylbenzoyl) hydrazine-1-ethyldithio ester (0.23g, 0.701mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.60g, 14.13mmol) containing ammonium molybdate (0.087g, 0.071mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.235g of white solid with the yield of 85.39%;
example 25:
the preparation method of 2- (bis (methylsulfonyl) methylene) -N- (2, 6-diethylphenyl) hydrazine-1-formamide (the compound number is Y) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (methylsulfonyl) methylene) -N- (2, 6-diethylphenyl) hydrazine-1-carboxamide:
n- (2, 6-Diethylaminoformyl) hydrazine-1-methyldithiolate (0.17g, 0.546mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.24g, 10.92mmol) containing ammonium molybdate (0.067g, 0.055mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.153g of white solid with the yield of 74.66%;
example 26:
the preparation method of 2- (bis (ethylsulfonyl) methylene) -N- (2, 6-diethylphenyl) hydrazine-1-formamide (the compound number is Z) comprises the following steps:
steps (1) to (4) were carried out in the same manner as in example 1
(5) Preparation of 2- (bis (ethylsulfonyl) methylene) -N- (2, 6-diethylphenyl) hydrazine-1-carboxamide:
n- (2, 6-Diethylaminoformyl) hydrazine-1-ethyldithio ester (0.22g, 0.648mmol) and 15mL of absolute ethanol were mixed in a 25mL three-necked round-bottomed flask, and after stirring at room temperature until the system became homogeneous, a 30% hydrogen peroxide solution (1.47g, 12.96mmol) containing ammonium molybdate (0.08g, 0.065mmol) was slowly added dropwise thereto, and the mixture was stirred at room temperature (20 ℃ C.) for 24 hours. After the reaction is finished, decompressing and desolventizing by a rotary evaporator, washing solid residues by a large amount of water, and recrystallizing by absolute ethyl alcohol to obtain 0.229g of white solid with the yield of 87.58%;
the structural formula and the molecular formula of the target compound prepared in the above example are shown in table 1, and the physicochemical properties and the spectrum information thereof are shown in table 2.
TABLE 1 structural formulas and molecular formulas of target compounds obtained in examples 1 to 26
TABLE 2 physicochemical Properties and spectral data of the target Compounds obtained in examples 1 to 26
Test example 1: the activity tests of the target compounds for indoor inhibition of bacterial blight of rice, bacterial streak of rice and canker citrus in table 3, table 4 and table 5 are shown.
The synthesized target compounds A-U and commercial reference drug were prepared into NB liquid medium containing drugs at concentrations of 50 and 5. mu.g/mL, respectively, and 40. mu.L of the above prepared waterSubjecting NB liquid culture medium of rice bacterial blight bacteria (Xoo), rice bacterial leaf streak bacteria (Xoc) and citrus canker bacteria (Xac) to shake culture in constant temperature shaking table at 28 deg.C and 180rpm for 24-48 h to logarithmic phase of growth, and measuring OD value (OD) of bacterial liquid of each concentration on enzyme labeling instrument595). Then, OD values (OD) of sterile NB liquid medium containing the objective compound and the control drug at concentrations of 200 and 100. mu.g/mL were measured595) The OD value due to the medium itself was corrected. The calculation formula for correcting the OD value and the inhibition rate is as follows:
corrected OD value-bacteria-containing medium OD value-sterile medium OD value
Setting 5 corresponding concentration gradients for part of target compounds, and determining EC for rice bacterial blight disease (Xoo), rice bacterial streak disease (Xoc) and citrus canker disease (Xac)50The value is obtained.
The antibacterial activity and EC of the target compounds obtained in examples 1 to 26 were determined in the manner described above50The values and results are shown in tables 3 to 5.
TABLE 3 examples 1-26 test for bacteriostatic Activity of target Compounds against Paddy rice bacterial blight disease (Xoo)
As can be seen from Table 3, the sulfonyl-containing thiohydrazide compounds have excellent bacteriostatic activity on rice bacterial blight (Xoo), especially the bacteriostatic activity EC of the compounds A, D, H, M, O, R, U, W and Y50Values of 0.6, 0.36, 0.43, 0.69, 0.53, 0.44, 0.48, 0.38 and 0.42. mu.g/mL, respectively, are much lower than the control drug bismerthiazol (EC)5076.59 μ g/mL) and thiediazole copper (EC)50＝91.72μg/mL)。
Table 4 partial implementationExamples 1-26 inhibition of bacterial leaf streak disease in Rice EC (Xoc)50Value of
As shown in Table 4, the sulfonyl-containing thiohydrazide compound also has excellent bacteriostatic activity on rice bacterial leaf streak pathogens, wherein the compounds A, D, H, M, O, R, U, W and Y have bacteriostatic activity EC on rice bacterial leaf streak pathogens (Xoc)50The values are respectively 3.11, 4.37, 3.64, 5.05, 3.75, 4.29, 2.09, 4.83 and 4.51 mu g/mL, which are far better than the control medicament bismerthiazol (EC)5083.35 μ g/mL) and thiediazole copper (EC)50＝114.0μg/mL)。
TABLE 5 partial examples 1-26 inhibition of Citrus canker pathogen (Xac) by target Compounds EC50Value of
As shown in Table 5, the sulfonyl-containing thiohydrazide compound also has excellent bacteriostatic activity on citrus canker pathogen, wherein the compounds A, D, H, M, O, R, U, W and Y have bacteriostatic activity EC on citrus canker pathogen (Xac)50The values are respectively 2.92, 4.04, 3.43, 5.22, 9.5, 4,97, 3.90, 4.64 and 6.28 mu g/mL, which are far better than the control medicament bismerthiazol (EC)50107.23 μ g/mL) and thiediazole copper (EC)50＝66.81μg/mL)。
From tables 3,4 and 5, it can be seen that the derivatives have more significant antibacterial activity against rice bacterial blight, especially the compound 2- (bis (methylsulfonyl) methylene) -N- (4-chlorophenyl) hydrazine-1-carboxamide (compound D), which will be subjected to in vivo pot experiments.
Test example 2: living pot experiment of high-activity compound D on rice bacterial blight
(1) Protection effect of rice bacterial leaf blight living pot experiment
The compound D with better activity to pathogenic bacteria of bacterial leaf blight of rice, the contrast agents of bismerthiazol and thiediazole copper are respectively prepared into medicine-containing solutions with the concentration of 200 mu g/mL by using 0.1% Tween solutions, and the medicine-containing solutions are sprayed on the surfaces of leaves of rice until liquid drops drop. After one week, cutting off the leaf tips by using scissors stained with bacterial liquid of rice bacterial blight at the position 1-2 cm away from the leaf tips of the rice leaves, soaking the wounds in the bacterial liquid for about 10s, and simultaneously setting clear water control and bacterial liquid control without adding a medicament. Each 30 rice seedlings are treated, the disease incidence condition is checked after the application of the pesticide for 14 days, the length of disease spots of the rice leaves is recorded, the disease index and the prevention effect are calculated, and the results are shown in table 6.
(2) Treatment effect of rice bacterial leaf blight living pot experiment
And (3) cutting off the leaf tips at the positions, 1-2 cm away from the leaf tips, of the rice leaves by using scissors stained with pathogenic bacteria of bacterial leaf blight of rice, and soaking the wounds in bacterial liquid for about 10 s. After one week, the compound D with better activity to pathogenic bacteria of bacterial leaf blight of rice, the control drugs of bismerthiazol and copper thielavide are respectively prepared into medicine-containing solutions with the concentration of 200 mu g/mL by using 0.1% Tween solutions, and the medicine-containing solutions are sprayed on the surfaces of leaves of rice until liquid drops drop. Meanwhile, a clear water contrast and a bacteria liquid contrast without adding medicaments are arranged. Each 30 rice seedlings are treated, the disease incidence condition is checked after the application of the pesticide for 14 days, the length of disease spots of the rice leaves is recorded, the disease index and the prevention effect are calculated, and the results are shown in table 6.
Control effect (%) - (control group lesion length-treatment group lesion length)/control group lesion length x 100
TABLE 6 results of in vivo pot culture experiment of target compound D on rice bacterial blight (Xoo)
As can be seen from table 6: under the condition that the concentration of the compound D is 200 mug/mL, the compound D has certain treatment and protection effects on rice bacterial leaf blight 14 days after application, the prevention effects respectively reach 41.7 percent and 38.99 percent, and the prevention effects are superior to those of control medicaments of bismerthiazol and thiabendazole.
Test example 3: living pot experiment of high-activity compound D on ralstonia solanacearum
The high-activity compound D and the reference medicaments of ethylicin, quinolinone and thiediazole copper are respectively prepared into compound D medicine-containing liquid medicines with the concentrations of 200 mu g/mL, 100 mu g/mL and 50 mu g/mL by using 0.1 percent Tween solution, and ethylicin, quinolinone and thiediazole copper liquid medicines with the concentrations of 100 mu g/mL, 200 mu g/mL and 400 mu g/mL. The ralstonia solanacearum is inoculated on tobacco leaves with growth inhibition, and after one day, 200 mu g/mL, 100 mu g/mL and 50 mu g/mL compound D drug-containing liquid, 100 mu g/mL ethylicin, 200 mu g/mL quinolinone, 400 mu g/mL thiediazole copper and clean water are prepared and sprayed on the leaf surfaces of the tobacco until liquid drops drop. Meanwhile, a clear water contrast and a bacteria liquid contrast without adding medicaments are arranged. The number of inoculated germs of each tobacco plant is 120, the disease incidence condition is checked 7 days after the application of the tobacco plant, the number of the dead spots is recorded, the disease incidence rate and the prevention effect are calculated, and the results are shown in a table 7.
Control (%) control/control x 100
TABLE 7 in vivo pot culture test results of target Compound D on tobacco bacterial wilt
According to the data in table 7 show: the control effects of the compound D, the ethylicin, the quinolinone and the thiabendazole on tobacco bacterial wilt after concentration sequential treatment are 38.54%, 46.88%, 50%, 25%, 41.67% and 21.88% respectively. The in-vivo control effect of the compound D on the tobacco ralstonia solanacearum at the concentration of 200 mug/mL is obviously better than that of 100 mug/mL ethylicin, 200 mug/mLd quinolinone and 400 mug/mL thiediazole copper of a contrast medicament, which indicates that the compound D has the most excellent control activity on the tobacco ralstonia solanacearum at the same concentration.
Test example 4: in vivo potting test for bacterial leaf spot of capsicum annuum by using high-activity compound D
The high active compound D and the control agent copper abietate are respectively prepared into liquid medicines with the concentrations of 200 mug/mL and 100 mug/mL by using 0.1 percent Tween solution. The liquid medicine is respectively sprayed on the pepper leaves which are just infected with pepper bacterial leaf spot germs, and disease indexes of disease onset before and 14 days after spraying are investigated. Randomly investigating 100 pepper plants, recording the disease indexes before and after the drug, and calculating the control effect, wherein the results are shown in table 8.
TABLE 8 field control experiment results of target compound D on bacterial leaf spot of capsicum annuum
According to the data in table 8 show: the in-vivo field control effect of the compound D on the pepper bacterial leaf spot at the concentrations of 200 mu g/mL and 100 mu g/mL is 77.85% and 62.34% respectively, and the in-vivo field control effect of the control medicament copper rosinate on the pepper bacterial leaf spot at the concentration of 200 mu g/mL is 64.31%. Experimental results show that the compound D has good field control effect on pepper bacterial leaf spot.
In conclusion, the series of 2- ((disubstituted sulfuryl) methylene) -N-aryl hydrazine-1-formamide derivatives have excellent bacteriostatic activity, and particularly, the compounds A, D, H, L, P and T have the most excellent indoor bacteriostatic activity on rice bacterial blight bacteria, rice bacterial streak bacteria, citrus canker bacteria and the like. When the concentration of the compound D is 200 mug/mL, the compound D has excellent in-vivo prevention and treatment effects on rice bacterial blight, tobacco bacterial wilt, pepper bacterial leaf spot and the like. The treatment and protection activities of the compound D with the concentration of 200 mu g/mL on the indoor living bodies of the rice bacterial blight fungus are 41.70 percent and 38.99 percent respectively, the treatment and protection activities are respectively better than 37.36 percent and 40.88 percent of bismerthiazol, and 27.01 percent and 32.0 percent of thiediazole copper; the indoor therapeutic activity to the tobacco ralstonia solanacearum is 50 percent, which is superior to that of a control medicament 100 mug/mL ethylicin (25 percent), 200 mug/mL quinolinone (41.67 percent) and 400 mug/mL thiabendazole copper (21.88 percent); the field control effect on pepper bacterial leaf spot pathogen is 77.85%, which is obviously superior to that of control medicament copper abietate 62.34%.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.
Claims (4)
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.
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