CN109456283B - 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone), and preparation and application thereof - Google Patents
2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone), and preparation and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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- C07—ORGANIC CHEMISTRY
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone), and a preparation method and an application thereof, wherein the general formula of the derivative is as follows: r 1 Is methyl, ethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, propyl, butyl, pentyl, 4-cyanobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl,
(ii) a X is S or-S (O) 2 -. The invention can prevent and control the southern root-knot nematode, rice tripe blight, tobacco bacterial wilt and citrus canker complex infection.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to 2- (trifluoromethyl) benzamide derivatives containing 1,3,4-thiadiazole thioether (sulfone), a preparation method of the 2- (trifluoromethyl) benzamide derivatives containing 1,3,4-thiadiazole thioether (sulfone), and application of the 2- (trifluoromethyl) benzamide derivatives containing 1,3,4-thiadiazole thioether (sulfone) in the aspects of nematicidal effect and inhibition of crop bacterial diseases.
Background
Plant parasitic nematodes are widely distributed around the world and host range is wide. When the host plant is infected by the nematode, the host plant is easy to be infected by bacteria, fungi and other germs, a complex infection system is caused, and the safe production of crops is seriously threatened. Diseases caused by plant parasitic nematodes and bacteria in agricultural production in China are characterized by high frequency, heavy harm, wide occurrence range, frequent occurrence and the like, and are lack of medicaments for preventing and controlling the nematodes and the bacteria simultaneously. The crop bacterial diseases caused by plant parasitic nematodes and bacteria are often simultaneously generated and are a main compound disease in the crop safety production, so that the serious loss and even the no harvest of crops are caused, and the problem of harming the agricultural production is already solved. Therefore, the search for a high-efficiency, low-toxicity and environment-friendly nematicide and antibacterial agent becomes an urgent problem in the plant protection field in China.
In 2012, (J. Y. Cassel, M. Ai Lejia spm, T. Lu Keshen, P. Reynolds. Insecticidal compound [ P ]. CN 103534237a 2014-01-22) based on arylthioacetamide derivatives disclose a series of arylthioacetamide-containing derivatives, and biological activity determination results show that partial compounds of arylthioacetamide derivatives have good inhibitory activity against root-knot nematodes.
In 2016, yang Song, wang Peiyi, zhou Lei, wu Zhibing, hu Deyu, xue Wei (pyridine salt compound containing 1,3,4-oxa (thia) diazolyl and a preparation method and application [ P ]. CN 541822A 2016-01-05 ]). Disclosed is a pyridine salt compound containing 1,3,4-oxa (thia) diazolyl, and a biological activity determination result shows that the compound has a good inhibition effect on pathogenic bacteria and fungi and has a good inhibition effect on rice bacterial blight, tobacco pseudomonas solanacearum and citrus canker.
2016 (Song Baoan, chen Xuewen, chen Yongzhong, hu Deyu, xue Wei, chen Jixiang, wang Yanjiao, wang Zhenzhen (trifluorobutene-containing 1,3,4-oxa (thia) diazole thioether (sulfone) derivatives), and preparation method and application thereof [ P (P) 36 zxft 3236, chen Xuewen, 3763 zxft 5754, 3252 zxft 3532, wang Yanjiao, wang Zhenzhen (trifluorobutene-containing 1,3,4-oxa (thia) diazole) derivatives].CN:105646393 A 2016-03-31) A series of 1,3,4-oxa (thia) diazole thioether (sulfone) derivatives containing trifluorobutene are disclosed, and the results of biological activity measurement show that some compounds show higher biological activity to caenorhabditis elegans, especially the nematocidal activity (LC) of the compounds A1 and B2 50 Values of 21.92 and 44.94mg L, respectively -1 ) Are all obviously superior to the control medicament fosthiazate (72.52 mg L) -1 ) And fluensulfone (72.96 mg L -1 ) The nematicidal activity of (1).
2016 (Song Baoan, chen Yongzhong, chen Jixiang, wang Yanjiao, wang Zhenzhen, zhou Dagui and Gan Xiuhai) (styrene-containing 1,3,4 oxadiazole thioether compound, preparation method and application thereof [ P ] S]106674147A 2017-05-17) discloses a styryl-containing 1,3,4 oxadiazole thioether compound synthesis and nematicidal activity, and the nematicidal activity test result shows that: LC of Compounds a, b and k against Citrus nematodes 50 Values of 8.2, 9.7 and 8.0mg L, respectively -1 Is superior to the control drug ethoprophos (32.7 mg L) -1 )。
In 2017, song Baoan, chen Jixiang, yang Song, zeng Song, he Wu, tian Pingyi, zhou Dagui, yichong powder, li Mingwei, wang Yanjiao, li Xiangyang (disulfide ether derivative containing 1,3,4 oxadiazole, preparation method and application thereof [ P ]. CN: 106639A 2017-05-10) a series of disulfide derivatives containing 1,3,4-oxadiazole. The biological activity test result shows that: most of the compounds have high nematicidal activity on citrus nematodes, and are superior to the control medicaments of fenamiphos and fosthiazate.
In 2017, song Baoan, chen Jixiang, yang Song, zeng Song, he Wu, tian Pingyi, zhou Dagui, yichong powder, li Mingwei, wang Yanjiao, li Xiangyang (disulfide derivatives containing 1,3,4 oxadiazole), a preparation method thereof and application thereof [ P ]. CN: 106639A 2017-05-10) a series of disulfide derivatives containing 1,3,4-oxadiazole. The biological activity test result shows that: most of the compounds have high nematicidal activity on citrus nematodes, and are superior to the control agents of fenamiphos and fosthiazate.
In summary, the 1,3,4-thiadiazole and the amide compounds have biological activities of resisting bacteria, killing nematodes and the like, and are very important agricultural biological activity structures; the pesticide has the characteristics of high biological activity, low toxicity, easy preparation and the like, and is very in line with the development requirement of green pesticides. However, no research report has been made so far about the simultaneous nematicidal and antibacterial effects of 2- (trifluoromethyl) benzamide compounds containing 1,3,4-thiadiazole thioether (sulfone).
Disclosure of Invention
The invention aims to overcome the defects and provide a 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone) which can prevent and control meloidogyne incognita, rice tripelenium blight, tobacco bacterial wilt and citrus canker complex infection.
The invention also aims to provide a preparation method of the 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone).
The invention also aims to provide application of the 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone) in medicaments for preventing and treating meloidogyne incognita, rice tripelenium blight, tobacco bacterial wilt and citrus canker.
The invention relates to a 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone), which has the following general formula:
wherein: r 1 Is methyl, ethyl, 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl, propyl, butyl, pentyl, 4-cyanobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl,
x is S or-S (O) 2 -。
Preferred compounds are as follows:
compound A1: n- (2- ((3-chloro-5- (trimethyl) pyridin-2-yl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A2: n- (5- (methylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A3: n- (5- (ethylsulfanyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A4: n- (5- (propylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A5: n- (5- (butylsulfanyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A6: n- (5- (pentylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A7: n- (5- ((2-fluoroethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A8: n- (5- ((2-chloroethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound A9: n- (5- ((2-bromoethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a10: n- (5- ((cyanomethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a11: n- (5- ((2-cyanoethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a12: n- (5- ((3-cyanopropyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a13: n- (5- ((2-fluorobenzyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a14: n- (5- ((4-chlorobenzyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a15: n- (5- ((4-cyanobenzyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a16: n- (5- (methylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a17: n- (5- (ethylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a18: n- (5- (propylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a19: n- (5- (butylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a20: n- (5- (pentylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a21: n- (5- ((2-fluoroethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a22: n- (5- ((2-chloroethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a23: n- (5- ((2-bromoethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a24: n- (5- ((cyanomethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a25: n- (5- ((2-cyanoethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a26: n- (5- ((3-cyanopropyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a27: n- (5- ((2-fluorobenzyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a28: n- (5- ((4-chlorobenzyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide;
compound a29: n- (5- ((4-cyanobenzyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide.
The invention relates to a preparation method of 2- (trifluoromethyl) benzamide derivatives containing 1,3,4-thiadiazole thioether (sulfone), which comprises the following steps:
(1) Taking thiosemicarbazide, potassium hydroxide and carbon disulfide as raw materials, taking absolute ethyl alcohol as a solvent, and mixing the raw materials in a molar ratio of thiosemicarbazide: potassium hydroxide: anhydrous ethanol = 1-2:2-3:1-3: feeding materials 50-500, heating and refluxing for 8-10h, after the reaction is finished, decompressing and removing the solvent, adding ice water, adjusting the pH to 3-4 by using 5% hydrochloric acid, filtering and collecting solids, and recrystallizing by using absolute ethyl alcohol to obtain an intermediate 2-amino-5-mercapto-1,3,4-thiadiazole;
(2) Taking 2-amino-5-mercapto-1,3,4-oxadiazole, potassium carbonate and halohydrocarbon or substituted benzyl chloride as raw materials, DMF as a solvent, and performing reaction according to a molar ratio of 2-amino-5-mercapto-1,3,4-oxadiazole: potassium carbonate: halogenated hydrocarbon or substituted benzyl chloride: DMF =1 to 2:2 to 3:1 to 3: 2-50, stirring at room temperature for 2-6h, adding ice water after the reaction is finished, filtering and collecting solids, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5-substituent mercapto-1,3,4-thiadiazole;
(3) Taking 2-amino-5-substituted mercapto-1,3,4-oxadiazole, potassium carbonate and 2- (trifluoromethyl) benzoyl chloride as raw materials, toluene as a solvent (50-200 mL), and performing reaction on the raw materials according to a molar ratio of 2-amino-5-substituted mercapto-1,3,4-oxadiazole: potassium carbonate: 2- (trifluoromethyl) benzoyl chloride: toluene =1 to 3:2 to 3:1 to 3: 20-200, stirring at room temperature for 1-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering, collecting the solid, and purifying by a chromatographic column to obtain a target compound N- (5- (substituent thio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide;
(4) Taking N- (5- (substituent thio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, hydrogen peroxide and ammonium molybdate as raw materials, taking absolute ethyl alcohol as a solvent, and performing reaction according to the molar ratio of N- (5- (substituent thio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide: ammonium molybdate: hydrogen peroxide: absolute ethyl alcohol =1 to 2, 0.1 to 2:1 to 3: 20-200, stirring at room temperature for 2-8h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering, collecting the solid, and purifying by a chromatographic column to obtain the target compound N- (5- (substituent sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide.
The 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone) is applied to medicaments for preventing and treating meloidogyne incognita, rice tripelenium blight, tobacco bacterial wilt and citrus canker.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can show that: the invention takes thiosemicarbazide as a starting material to prepare the 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole thioether (sulfone) through ring closure, etherification, amidation or oxidation reaction, so that one medicament can prevent and treat the complex infection caused by meloidogyne incognita, rice tripelenium wilt, tobacco bacterial wilt and citrus canker pathogen.
Detailed Description
Example 1: synthesis of N- (2- ((3-chloro-5- (trimethyl) pyridin-2-yl) thio) -1,3,4-thiadiazol-2-yl) -5- (trifluoromethyl) benzamide (compound No. A1) comprising the following steps:
(1) Putting thiosemicarbazide (10.0 mmol), potassium hydroxide (15.0 mmol) and absolute ethyl alcohol (60 mL) as solvents into a 100mL three-necked bottle, continuously stirring at room temperature until the solid is dissolved, slowly dropwise adding carbon disulfide (15.0 mmol), heating and refluxing for 8-10h, after the reaction is finished, adding ethanol removed under reduced pressure, adding ice water, adjusting the pH to 3-4 by using 5% hydrochloric acid, filtering and collecting the solid, and recrystallizing by using absolute ethyl alcohol to obtain an intermediate 2-amino-5-mercapto-1,3,4-thiadiazole;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding 2,3-dichloro-5- (trifluoromethyl) pyridine (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering, collecting the solid, and recrystallizing with absolute ethanol to obtain an intermediate 2- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) sulfur) -5-amino-1,3,4-thiadiazole;
(3) Adding 2- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) sulfur) -5-amino-1,3,4-thiadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) into a 50mL three-necked flask, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracing the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (2- ((3-chloro-5- (trimethyl) pyridin-2-yl) sulfur) -1,3,4-thiadiazole-2-yl) -5- (trifluoromethyl) benzamide, wherein the yield is 88.7%, and the melting point: 215-217 ℃.
Example 2: synthesis of N- (5- (methylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound number A2) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until the solid is dissolved, slowly dropwise adding methyl iodide (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5-methylthio-1,3,4-oxadiazole;
(3) Putting 2-amino-5-methylmercapto-1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, purifying by a chromatographic column to obtain a compound N- (5- (methylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 84.6%, and the melting point: 215-217 ℃.
Example 3: synthesis of N- (5- (ethylsulfanyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. A3) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding bromoethane (4.0 mmol), then stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5-ethylmercapto-1,3,4-oxadiazole;
(3) Putting 2-amino-5-ethylmercapto-1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, purifying by a chromatographic column to obtain a compound N- (5- (ethylthio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 70.5%, and the melting point: 155-157 ℃.
Example 4: synthesis of N- (5- (propylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound number A4) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until the solid is dissolved, slowly dropwise adding bromopropane (4.0 mmol), then stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5-propylmercapto-1,3,4-oxadiazole;
(3) Putting 2-amino-5-propylmercapto-1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, purifying by a chromatographic column to obtain a compound N- (5- (propylthio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 86.2%, and the melting point: 119-121 ℃.
Example 5: synthesis of N- (5- (butylsulfanyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. A5) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding bromobutane (4.0 mmol), then stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5-butylmercapto-1,3,4-oxadiazole;
(3) Putting 2-amino-5-butylmercapto-1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC (thin layer chromatography), stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, purifying by using a chromatographic column to obtain a compound N- (5- (butylthio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 80.5%, and the melting point: 245-247 ℃.
Example 6: synthesis of N- (5- (pentylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound number A6) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until the solid is dissolved, slowly dropwise adding bromopentane (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5-pentylmercapto-1,3,4-oxadiazole;
(3) Putting 2-amino-5-pentylmercapto-1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, purifying by a chromatographic column to obtain a compound N- (5- (pentylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 86.0%, and the melting point: 124-126 ℃.
Example 7: synthesis of N- (5- ((2-fluoroethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. A7) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until the solid is dissolved, slowly dropwise adding 1-bromo-2-fluoroethane (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethanol to obtain an intermediate 2-amino-5- ((2-fluoroethyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((2-fluoroethyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((2-fluoroethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 52.6%, and the melting point: 153-155 ℃.
Example 8: synthesis of N- (5- ((2-chloroethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. A8) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding 1,2-dichloroethane (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethanol to obtain an intermediate 2-amino-5- ((2-chloroethyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((2-chloroethyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((2-chloroethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 75.6%, and the melting point: 142-144 ℃.
Example 9: synthesis of N- (5- ((2-bromoethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. A9) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding 1,2-dibromoethane (4.0 mmol), then stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethanol to obtain an intermediate 2-amino-5- ((2-bromoethyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((2-bromoethyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((2-bromoethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 55.9%, and the melting point: 157-159 deg.C
Example 10: n- (5- ((cyanomethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 10) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding bromoacetonitrile (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5- ((cyanomethyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((cyanomethyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((cyanomethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 76.8%, and the melting point: 159-161 deg.C
Example 11: synthesis of N- (5- ((2-cyanoethyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 11) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding bromopropionitrile (4.0 mmol), then stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5- ((2-cyanoethyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((2-cyanoethyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((2-cyanoethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 53.5%, and the melting point: 168-170 ℃.
Example 12: synthesis of N- (5- ((3-cyanopropyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 12) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding bromobutyronitrile (4.0 mmol), then stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5- ((3-cyanopropyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((3-cyanopropyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((3-cyanopropyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 62.8%, and the melting point: 154-156 ℃.
Example 13: synthesis of N- (5- ((2-fluorobenzyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 13) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until the solid is dissolved, slowly dropwise adding 2-fluorobenzyl chloride (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering to collect the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5- ((2-fluorobenzyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((2-fluorobenzyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent by decompression, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((2-fluorobenzyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 82.8%, and the melting point: 145-147 ℃.
Example 14: synthesis of N- (5- ((4-chlorobenzyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 14) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding 4-chlorobenzyl chloride (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering and collecting the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5- ((4-chlorobenzyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((4-chlorobenzyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((4-chlorobenzyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 86.5%, and the melting point: 182 to 184 ℃.
Example 15: synthesis of N- (5- ((4-cyanobenzyl) thio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 15) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Putting 2-amino-5-mercapto-1,3,4-oxadiazole (4.0 mmol), potassium carbonate (6.0 mmol) and DMF (2 mL) as a solvent into a 100mL three-necked bottle, continuously stirring until a solid is dissolved, slowly dropwise adding 4-chlorobenzyl chloride (4.0 mmol), stirring at room temperature for 2-6h, removing the solvent under reduced pressure after the reaction is finished, adding ice water, filtering and collecting the solid, and recrystallizing with absolute ethyl alcohol to obtain an intermediate 2-amino-5- ((4-cyanobenzyl) sulfur) -1,3,4-oxadiazole;
(3) Putting 2-amino-5- ((4-cyanobenzyl) sulfur) -1,3,4-oxadiazole (2.6 mmol), potassium carbonate (3.9 mmol) and toluene (20 mL) as solvents into a 100mL three-necked bottle, dropwise adding 2- (trifluoromethyl) benzoyl chloride (2.6 mmol) after the solid is completely dissolved, reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the reaction is finished, removing the solvent under reduced pressure, adding 30mL of water for washing, performing suction filtration and water washing to obtain a crude product, and purifying by using a chromatographic column to obtain a compound N- (5- ((4-cyanobenzyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 81.2%, and the melting point: 194 to 196 ℃ is adopted.
Example 16: synthesis of N- (5- (methylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 16) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 2;
(3) The same procedure as in step (3) of example 2;
(4) N- (5- (methylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) is put into a 50mL three-necked round bottom flask, absolute ethyl alcohol is used as a solvent, after stirring for 5min, a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol) is added dropwise, then the reaction is carried out at room temperature, TLC tracks the reaction progress, after the raw material point disappears, the reaction is stopped, the solvent is removed under reduced pressure to obtain a solid, water is added for washing, the solid is filtered, and the solid is purified by a chromatographic column to obtain the N- (5- (methylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, the yield is 91.3%, and the melting point: 168-170 ℃.
Example 17: synthesis of N- (5- (ethylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 17) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 3;
(3) The same procedure as in step (3) of example 3;
(4) Putting N- (5- (ethylthio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, then dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after the raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, purifying by a chromatographic column to obtain the N- (5- (ethylsulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 86.8 percent, the melting point: 160-162 ℃.
Example 18: synthesis of N- (5- (propylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 18) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 4;
(3) The same procedure as in step (3) of example 4;
(4) Putting N- (5- (propylthio) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, then dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, purifying by using a chromatographic column to obtain the N- (5- (propylsulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 85.5%, and the melting point: 144-146 ℃.
Example 19: synthesis of N- (5- (butylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 19) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 5;
(3) The same procedure as in step (3) of example 5;
(4) N- (5- (butylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) was put in a 50mL three-necked round bottom flask, stirred for 5min with absolute ethanol as a solvent, and then added dropwise with a solution of ammonium molybdate (0.18 mmol) in hydrogen peroxide (8.0 mmol), followed by reaction at room temperature, TLC followed the progress of the reaction, after disappearance of the starting material spot, the reaction was stopped, the solvent was removed under reduced pressure to give a solid, which was washed with water and then filtered, and purified with a chromatography column to give N- (5- (butylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, yield 75.2%, melting point: 120-122 ℃.
Example 20: synthesis of N- (5- (pentylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 20) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 6;
(3) The same procedure as in step (3) of example 6;
(4) N- (5- (pentylthio) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) was put in a 50mL three-necked round-bottomed flask, stirred for 5min with absolute ethanol as a solvent, and then a solution of ammonium molybdate (0.18 mmol) in hydrogen peroxide (8.0 mmol) was added dropwise, followed by reaction at room temperature, TLC followed the progress of the reaction, the reaction was stopped after the starting material point disappeared, the solvent was removed under reduced pressure to give a solid, which was washed with water and then filtered, and purified with a chromatography column to give N- (5- (pentylsulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, yield 61.4%, melting point: 121-123 ℃.
Example 21: synthesis of N- (5- ((2-fluoroethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 21) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 7;
(3) The same procedure as in step (3) of example 7;
(4) Putting N- (5- ((2-fluoroethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((2-fluoroethyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 82.6%, and the melting point: 181-183 ℃.
Example 22: synthesis of N- (5- ((2-chloroethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 22) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Same as in step (2) of example 8;
(3) Same as in step (3) of example 8;
(4) Putting N- (5- ((2-chloroethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((2-chloroethyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 90.7%, and the melting point: 158-160 ℃.
Example 23: synthesis of N- (5- ((2-bromoethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 23) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 9;
(3) Same as in step (3) of example 9;
(4) Putting N- (5- ((2-bromoethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((2-bromoethyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 85.4%, and the melting point: 164-166 ℃.
Example 24: synthesis of N- (5- ((cyanomethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 24) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Same as example 10 in step (2);
(3) The same procedure as in step (3) of example 10;
(4) Putting N- (5- ((cyanomethyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction process by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((cyanomethyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 70.5%, and the melting point: 190-192 ℃.
Example 25: synthesis of N- (5- ((2-cyanoethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 25) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Same as in step (2) of example 11;
(3) The same procedure as in step (3) of example 11;
(4) Putting N- (5- ((2-cyanoethyl) sulfur) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((2-cyanoethyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 82.6%, and the melting point: 153-155 ℃.
Example 26: synthesis of N- (5- ((3-cyanopropyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 26) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 12;
(3) The same procedure as in step (3) of example 12;
(4) Putting N- (5- ((3-cyanopropyl) sulfur) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-necked round bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after the starting material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((3-cyanopropyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 89.0%, and the melting point: 158-160 ℃.
Example 27: synthesis of N- (5- ((2-fluorobenzyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 27) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Same as in step (2) of example 13;
(3) The same procedure as in step (3) of example 13;
(4) Putting N- (5- ((2-fluorobenzyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((2-fluorobenzyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 80.9%, and the melting point: 170-172 ℃.
Example 28: synthesis of N- (5- ((4-chlorobenzyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 28) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) The same procedure as in step (2) of example 14;
(3) The same procedure as in step (3) of example 14;
(4) Putting N- (5- ((4-chlorobenzyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round bottom flask, stirring for 5min by using absolute ethyl alcohol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((4-chlorobenzyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 73.6%, and the melting point: 160-162 ℃.
Example 29: synthesis of N- (5- ((4-cyanobenzyl) sulfonyl) -1,3,4-thiadiazol-2-yl) -2- (trifluoromethyl) benzamide (compound No. a 29) comprising the following steps:
(1) The same procedure as in step (1) of example 1;
(2) Same as in step (2) of example 15;
(3) Same as in step (3) of example 15;
(4) Putting N- (5- ((4-cyanobenzyl) sulfur) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide (1.0 mmol) into a 50mL three-neck round-bottom flask, stirring for 5min by using absolute ethanol as a solvent, dropwise adding a hydrogen peroxide (8.0 mmol) solution dissolved with ammonium molybdate (0.18 mmol), reacting at room temperature, tracking the reaction progress by TLC, stopping the reaction after a raw material point disappears, removing the solvent under reduced pressure to obtain a solid, adding water for washing, filtering, and purifying by using a chromatographic column to obtain the N- (5- ((4-cyanobenzyl) sulfonyl) -1,3,4-thiadiazole-2-yl) -2- (trifluoromethyl) benzamide, wherein the yield is 69.1%, and the melting point: 202-204 ℃.
NMR spectra of 2- (trifluoromethyl) benzamide derivatives containing 1,3,4-thiadiazole thioether (sulfone) (prepared in example: (R) (R)) 1 H NMR), carbon spectrum ( 13 C NMR) and High Resolution Mass Spectrometry (HRMS) data are shown in table 1.
TABLE 1 Popp data for the compounds of examples 1-29
Test example 1: test for inhibitory Activity of target Compound against Meloidogyne incognita
1. Test of indoor biological activity of meloidogyne incognita
1.1, testing the biological activity of the compound on meloidogyne incognita by adopting a contact killing method;
1.2, 0.0010g of the compound to be tested is weighed, dissolved in 50. Mu.L of DMF and diluted to 50mg L with 1% Tween 80 -1 The final MDF content does not exceed 1% (v/v);
1.3, picking eggs, hatching to obtain second-instar larvae, and then centrifugally concentrating to prepare 10 mu L of the second-instar larvae containing 200-300 nematodes;
1.4, adding 200 mu L of prepared solution to be detected into a biochemical culture plate with 48 holes, and then adding 10 mu L of nematode suspension;
1.5, taking Loifuda (41.7%), abamectin (96%) and fosthiazate (98%) as control medicaments;
1.6, placing the 48-hole biochemical culture plate in a thermostat at 27 ℃ for counting the death conditions of 24h and 48h respectively, and calculating the death rate.
Mortality (%) = [ (treatment mortality-blank)/(1-blank mortality) ] × 100%
TABLE 2 Example 1-29 Compounds for Activity testing of Meloidogyne incognita ex vivo(50mg L -1 )
Note: a 41.7% of suspending agent
As is clear from Table 2, the concentration of L is 50mg -1 In the process, after the application of the compound A21, the compound A22 and the compound A23 for 24 hours, the compound A22 and the compound A23 show better inhibitory activity to meloidogyne incognita, and the mortality rates are respectively 100.0%, 94.2% and 82.7%; after 48 hours of drug application, the compounds A21, A22 and A23 show better inhibitory activity to Meloidogyne incognita, the mortality rates are 100.0%, 94.2% and 82.7%, respectively, and LC thereof 50 Values of 6.5, 7.6 and 9.2mg L, respectively -1 。
2. Test of indoor biological activity of meloidogyne incognita
2.1, transplanting a week of tomato seedlings into a small flowerpot, and rooting the seedlings for a week;
2.2 picking up eggs, incubating to obtain second-instar larvae, centrifuging and concentrating to prepare nematode suspension, and inoculating about 2000 nematodes to the roots of plants;
2.3 weighing 0.0010g of the test compound, dissolving in 50. Mu.L of DMF, diluting with 1% Tween 80 to 50mg L -1 The final MDF content does not exceed 1% (v/v);
2.4, spraying 10mL of liquid medicine to be detected to the roots of the plants, culturing in a greenhouse for 30 days, and counting data;
2.5, taking Loifuda (41.7%), abamectin (96%) and fosthiazate (98%) as control medicaments;
TABLE 3 treatment concentration 50mg L -1 In-vivo control effect of temporal target compound on meloidogyne incognita
As can be seen from Table 3, the concentration was 50mg L -1 When the compound A21, the compound A22 and the compound A23 are used, the better control effect on the meloidogyne incognita is shown, and the control effect is 83.3%, 79.2% and 75.0% respectively.
Test example 2: activity test for indoor inhibition of rice bacterial blight, citrus canker pathogen and tobacco ralstonia solanacearum by target compound
Test compounds were formulated to a concentration of 50mg L -1 Then 40 μ L of the prepared NB liquid medium containing rice bacterial blight (Xoo), citrus canker bacterial (Xac) and tobacco bacterial wilt (Rs) is added, shaking culture is carried out for 24-48h at 30 ℃ and 180rpm in a constant temperature shaking table, and the OD value (OD 595) of bacterial liquid of each concentration is measured on a microplate reader. And measured at a concentration of 50mg mL -1 The OD values of NB broth for the drug and the control drug were corrected for the OD values due to the drug itself. 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;
inhibition rate (%) = (control culture solution OD value after correction-correction toxic culture solution OD value)/control culture solution OD value after correction x 100;
TABLE 4 Ex vivo antibacterial Activity of the Compounds of examples 1-29 on Xoo, xac and Rs
As can be seen from Table 4, the concentration tested was 50mg L -1 The target compound has better inhibition activity on both the rice bacterial blight bacterium citrus canker germ and the tobacco bacterial wilt bacterium. EC of Compounds A21, A22, A23 and A24 against Paddy rice bacterial blight 50 Values of 0.4, 1.3, 9.4 and 7.7mg L, respectively -1 Is superior to the commercial control medicament bismerthiazol (118.6 mg L) -1 ) Thiodiazole copper (94.9 mg L) -1 ) Heluofuda (130.2 mg L) -1 ) (ii) a EC against citrus canker pathogen 50 Values were 6.7, 7.3, 11.9 and 16.6mg L, respectively -1 (ii) a Are all superior to the prior commercial reference drugBismerthiazol (81.2 mg L) -1 ) Thiodiazole copper (61.5 mg L) -1 ) Heluofuda (68.1 mg L) -1 ) (ii) a EC against ralstonia solanacearum 50 Values of 5.1, 5.3, 6.7 and 10.7mg L, respectively -1 Are superior to the prior commercial control medicament bismerthiazol (58.1 mg L) -1 ) Thiodiazole copper (73.1 mg L) -1 ) He Luo Fu Da (81.4 mg L) -1 )。
Test example 3: high-activity compound rice bacterial leaf blight live potting test
1. Protection effect of rice bacterial leaf blight living pot experiment
Preparing compounds A21, A22, A23 and A24 with good activity on pathogenic bacteria of bacterial leaf blight of rice and control agents of bismerthiazol and copper thiediazole into 200mg L with 0.1% Tween solution -1 The medicated solution of (2) is sprayed on the surface of rice leaves until the drops drop. After one week, the leaf tips are cut off by scissors stained with bacterial liquid of bacterial blight of rice at the position 1-2 cm away from the leaf tips of the rice leaves, the wounds are soaked in the bacterial liquid for about 10s, and meanwhile, a clear water control and a bacterial liquid control without a medicament are arranged. After 20 rice seedlings are treated, the disease condition is checked after the application of the pesticide for 14 days, the length of disease spots of the rice leaves is recorded, and the disease index and the prevention effect are calculated, and the results are shown in table 5.
2. Treatment effect of live pot culture test of rice bacterial leaf blight
And (3) cutting off the leaf tips at the positions of the rice leaves, which are 1-2 cm away from the leaf tips, 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 compounds A21, A22, A23 and A24 with better activity to pathogenic bacteria of bacterial blight of rice and the control drugs of bismerthiazol and copper thiediazole are respectively prepared into 200mg L by using 0.1 percent Tween solution -1 The medicinal solution is sprayed on the surface of the rice leaves until liquid drops drop. Meanwhile, a clear water control and a bacteria liquid control without adding medicaments are arranged. After 20 rice seedlings are treated, the disease condition is checked after the application of the pesticide for 14 days, the length of disease spots of the rice leaves is recorded, and the disease index and the prevention effect are calculated, and the results are shown in table 5.
Control effect (%) = (control group lesion length-treatment group lesion length)/control group lesion length x 100
TABLE 5. At a concentration of 200mg L -1 Control effect of compound on bacterial blight of rice
As can be seen from Table 5, the in vivo therapeutic effects of Compounds A21, A22, A23 and A24 against rice blight fungus were 47.9%, 48.7%, 46.6% and 47.6%, respectively; the in vivo protection effect is 55.8 percent, 51.4 percent, 48.6 percent and 50.7 percent respectively, which are better than that of the commercial control medicament of bismerthiazol (the therapeutic activity is 41.9 percent, the protective activity is 45.3 percent), the thiediazole copper (the therapeutic activity is 38.3 percent, the protective activity is 43.8 percent) and the Lofuda (the therapeutic activity is 27.4 percent, the protective activity is 36.7 percent).
In conclusion, the EC of Compounds A21, A22, A23 and A24 against Padina pavonica 50 Values of 0.4, 1.3, 9.4 and 7.7mg L, respectively -1 The in vivo treatment effect is 47.9%, 48.7%, 46.6% and 47.6% respectively; the in vivo protection effect is respectively 55.8%, 51.4%, 48.6% and 50.7%, which is superior to that of the commercial control medicament bismerthiazol (118.6 mg L) -1 And (3) the therapeutic activity: 41.9%, protective activity: 45.3%), thiodiazole copper (94.9 mg L) -1 And (3) therapeutic activity: 38.3%, protective activity: 43.8%) and Lufuda (130.2 mg L) -1 And (3) therapeutic activity: 27.4%, protective activity: 36.7%); EC against citrus canker pathogen 50 Values were 6.7, 7.3, 11.9 and 16.6mg L, respectively -1 (ii) a Are all superior to the prior commercial contrast medicament bismerthiazol (81.2 mg L) -1 ) Thiodiazole copper (61.5 mg L) -1 ) Heifuda (68.1 mg L) -1 ) (ii) a EC against ralstonia solanacearum 50 Values of 5.1, 5.3, 6.7 and 10.7mg L, respectively -1 Are superior to the prior commercial control medicament bismerthiazol (58.1 mg L) -1 ) Thiodiazole copper (73.1 mg L) -1 ) He Luo Fu Da (81.4 mg L) -1 )。
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 (2)
1. A2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole sulfone has a structural formula shown as formula A21, A22 and A23:
(A21)
(A22)/>
(A23)/>
2. the use of the 2- (trifluoromethyl) benzamide derivative containing 1,3,4-thiadiazole sulfone of claim 1 in the preparation of a medicament for controlling meloidogyne incognita, bacterial blight of rice, tobacco bacterial wilt and citrus canker.
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