CN110452234B - Schiff base derivative containing trifluoromethyl pyridine dicarboxamide and application thereof - Google Patents
Schiff base derivative containing trifluoromethyl pyridine dicarboxamide and application thereof Download PDFInfo
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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
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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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
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses application of Schiff base derivatives containing trifluoromethyl pyridine dicarboxamide in antiviral agents and insecticides. The structure is shown in a general formula I. In the formula, to R 1 、R 2 、R 3 The definition of the groups is described in the specification. The compound shown in the general formula I has excellent antiviral activity, and can be used for preventing and treating plant virus diseases such as TMV, CMV and the like and diamondback moth pests.
Description
Technical Field
The invention relates to the field of agricultural chemicals, in particular to application of a Schiff base derivative containing trifluoromethyl pyridine phthalic diamide in preparation of antiviral agents and insecticides.
Background
The trifluoromethylpyridine substructure is of increasing importance in the current development of pesticides due to its special properties. Among the fluorine-containing pesticide varieties, about 2/3 is the one on the market after 90 s of the last century, and the introduction of fluorine atoms may double the biological activity of the compound, and in addition, the fluorine-containing compound has attracted increasing interest to the pesticide workers due to its advantages of small environmental impact, low toxicity, etc. Pyridine heterocycles open up a new direction for the creation of new pesticides, occupy an important position in the development of pesticides, are always a focus of attention in the pesticide creation process, and play an increasingly important role. Therefore, commercial drugs such as fluopicolide, fluazinam, fluopyram, fluoetheramide, chlorfluazuron, and sulfoxaflor have been developed because of the advantages of both of them being effectively exerted by the combination of fluorine and pyridine heterocycles.
Acylhydrazone compounds are Schiff base compounds formed by condensing hydrazide and aldehyde or ketone (Anhui agricultural science, 2010,38(13): 6644-. Acylhydrazone structures in Schiff base compounds are common groups in current commercial pesticides, and currently registered commercial pesticides include hydramethylnon, metaflumizone, azoxystrobin, diflufenzopyr, pymetrozine and the like, which all show good bactericidal, insecticidal or herbicidal activities.
Disclosure of Invention
The invention aims to splice the substructure of Schiff base and phthalic diamide containing trifluoromethyl pyridine, provide a Schiff base derivative of trifluoromethyl pyridine dicarboxamide with a novel structure, and prove the application of the compound in the aspect of antivirus, wherein the structural general formula of the compound provided by the invention is shown as I:
in the compounds of the formula I, R 1 Is halogen, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfonyl; r 2 Is mono-or di-substituted, selected from H, methyl, chlorine, bromine, fluorine, and when di-substituted, the two substituents are the sameOr different; r 3 Is C1-C3 alkyl, cycloalkyl, substituted furyl, substituted thienyl, substituted pyridyl, substituted benzene ring, N-dimethyl or substituted imidazole.
Further, in the compounds of the general formula I, R 1 Is Cl, F, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl or ethylsulfonyl; r 2 Is H, 3-methyl, 3, 5-dibromo, 2-chloro, 3-chloro, 5-chloro-3-methyl, 3, 5-dichloro or 3, 5-difluoro; r 3 Is 2-thienyl, 5-bromopyridyl, pyridyl, isopropyl, 2-methylphenyl, 6-bromopyridyl, 3-thienyl, prop-2-ylidene, 5-methylthiophenyl, imidazolyl, 2-chloropyridyl, 2-methylfuryl, 4-bromothienyl, 2-chlorophenyl or N, N-dimethyl.
Further, R 1 Is Cl, ethylthio or ethylsulfonyl; r 2 Is H, 3-methyl, 5-chloro-3-methyl, 3, 5-dichloro or 3, 5-difluoro.
Still further, the invention is preferably selected from the following structures, but not limited thereto.
The preparation method of the Schiff base derivatives of trifluoromethyl picolinamides specifically comprises the following steps:
(1) adding 3-substituted-5- (trifluoromethyl) picolinic acid, pyridine and acetonitrile into a reactor, cooling an ice salt bath to-5 ℃, then slowly adding methanesulfonyl chloride into the system, stirring after the adding is finished, adding 2-amino-substituted benzoic acid into the system at one time, stirring, slowly adding pyridine, continuously stirring after the adding is finished, slowly adding methanesulfonyl chloride, continuously stirring, removing the ice salt bath, continuously reacting for 12-24 hours after the reaction temperature is slowly increased to room temperature, adding water and dichloromethane for extraction, taking an organic layer, and passing through a column to obtain an intermediate 3; (2) adding hydrazine hydrate and THF (tetrahydrofuran) into a reactor, slowly dropwise adding a mixed solution of the intermediate 3 dissolved in THF, continuously stirring at room temperature, precipitating a large amount of solids in the system, removing the solution, adding absolute ethyl alcohol into residues for washing, filtering, and washing a filter cake with absolute ethyl alcohol to obtain an intermediate 4; (3) and putting the intermediate 4, ketone or aldehyde into a reactor, adding absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC, and after the reaction is finished, cooling and separating out solid, and recrystallizing by using absolute ethyl alcohol-DMF to obtain the target product I.
The compound provided by the invention can be used for preparing pesticides or pesticide additives for preventing and treating crop diseases and pests;
the synthesized compound can be further used for preparing plant virus agents for preventing and treating tobacco mosaic virus, potato virus Y, potato virus S, cucumber mosaic virus, tomato virus disease, pepper virus disease and rice virus disease, and the preferable objects are tobacco mosaic virus and cucumber mosaic virus. In addition, the synthesized compound can be used for preparing a compound for preventing and controlling diamondback moths.
Detailed Description
The synthesis methods of the compounds (I-1 to I-32) of the present invention are all the same, except that the starting materials used differ only in the presence of substituents. The preparation of the compounds of formula I according to the invention is illustrated in detail below by means of some typical examples of the preparation of the compounds, which are intended to illustrate the preparation of the invention and are not intended to limit the compounds according to the invention.
Example 1: preparation of 3-chloro-N- (2, 4-dichloro-6- (cyclopropylcarbamoyl) phenyl) -5- (trifluoromethyl) picolinamide (I-1)
The first step is as follows: adding 0.5g (2.22mmol) of 3-chloro-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling the ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise addition is finished, adding 0.5g (2.88mmol) of 2-amino-3, 5-dichlorobenzoic acid into the system at one time, stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine by using the constant-pressure dropping funnel, keeping the temperature below 0 ℃ during the dropwise addition, continuously stirring for 15min after the dropwise addition is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride slowly by using the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, continuously reacting for 12h after the reaction temperature is slowly increased to room temperature, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give intermediate 6, 8-dichloro-2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [ d ] [1,3] oxazin-4-one.
The second step is that: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly dropwise adding a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2 hours to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixture into a 50mL single-neck flask to remove a THF solvent, adding 5mL of absolute ethyl alcohol into the residue, washing, filtering, and washing a filter cake with the absolute ethyl alcohol to obtain a white solid.
The third step: putting 1mmol of intermediate, 1mmol of ketone and aldehyde into a three-neck flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC (thin layer chromatography), cooling and separating out solid, and recrystallizing the solid by absolute ethyl alcohol-DMF (dimethyl formamide) after the reaction is finished for about 30min to obtain the target product.
Example 2: (E) preparation of (E) -3-chloro-N- (2-methyl-6- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-15)
The first step is as follows: adding 0.5g (2.22mmol) of 3-chloro-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling an ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise adding is finished, adding 0.34g (2.22mmol) of 2-amino-3, 5-dichlorobenzoic acid into the system at one time and stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine into the constant-pressure dropping funnel, keeping the temperature below 0 ℃ in the dropwise adding process, continuously stirring for 15min after the dropwise adding is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride into the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, slowly reacting for 12h after the reaction temperature is raised to the room temperature, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give intermediate 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -8-methyl-4H-benzo [ d ] [1,3] oxazin-4-one.
The second step is that: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly dropwise adding a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2 hours to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixture into a 50mL single-neck flask to remove a THF solvent, adding 5mL of absolute ethyl alcohol into the residue, washing, filtering, and washing a filter cake with the absolute ethyl alcohol to obtain a white solid.
The third step: putting 1mmol of intermediate, 1mmol of ketone and aldehyde into a three-neck flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC (thin layer chromatography), cooling and separating out solid, and recrystallizing the solid by absolute ethyl alcohol-DMF (dimethyl formamide) after the reaction is finished for about 30min to obtain the target product.
Example 3: (E) preparation of (E) -N- (2- (2- ((4-bromothien-2-yl) methylene) hydrazine-1-carbonyl) -4, 6-difluorophenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-19)
The first step is as follows: adding 0.5g (2.22mmol) of 3-chloro-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling an ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise adding is finished, adding 0.38g (2.22mmol) of 2-amino-3, 5-difluorobenzoic acid into the system at one time and stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine into the constant-pressure dropping funnel, keeping the temperature below 0 ℃ in the dropwise adding process, continuing to stir for 15min after the dropwise adding is finished, then continuing to slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the constant-pressure dropping funnel, continuing to stir for 1h, removing an iced salt bath, slowly raising the reaction temperature to room temperature, continuing to react for 12h, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain intermediate 2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -6, 8-difluoro-4H-benzo [ d ] [1,3] oxazin-4-one.
The second step is that: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly dropwise adding a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2 hours to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixture into a 50mL single-neck flask to remove a THF solvent, adding 5mL of absolute ethyl alcohol into the residue, washing, filtering, and washing a filter cake with the absolute ethyl alcohol to obtain a white solid.
The third step: putting 1mmol of intermediate, 1mmol of ketone and aldehyde into a three-neck flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC (thin layer chromatography), cooling and separating out solid, and recrystallizing the solid by absolute ethyl alcohol-DMF (dimethyl formamide) after the reaction is finished for about 30min to obtain the target product.
Example 4: (E) preparation of (E) -3-chloro-N- (4-chloro-2- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-23)
The first step is as follows: adding 0.5g (2.22mmol) of 3-chloro-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling an ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise adding is finished, adding 0.38g (2.22mmol) of 2-amino-5-chlorobenzoic acid into the system at one time, stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine by using the constant-pressure dropping funnel, keeping the temperature below 0 ℃ during the dropwise adding process, continuously stirring for 15min after the dropwise adding is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride by using the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, slowly raising the reaction temperature to room temperature, continuing to react for 12h, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give intermediate 6-chloro-2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [ d ] [1,3] oxazin-4-one.
The second step is that: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly adding dropwise a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2h to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixed solution into a 50mL single-neck flask to remove THF solvent, adding 5mL of absolute ethyl alcohol into the residue to wash, filtering, and washing the filter cake with the absolute ethyl alcohol to obtain white solid.
The third step: putting 1mmol of intermediate, 1mmol of ketone and aldehyde into a three-neck flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC (thin layer chromatography), cooling and separating out solid, and recrystallizing the solid by absolute ethyl alcohol-DMF (dimethyl formamide) after the reaction is finished for about 30min to obtain the target product.
Example 5: (E) preparation of (E) -3-chloro-N- (2, 4-dichloro-6- (2- ((5-methylfuran-2-yl) methylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-28)
The first step is as follows: adding 0.5g (2.22mmol) of 3-chloro-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling the ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise addition is finished, adding 0.46g (2.22mmol) of 2-amino-3, 5-dichlorobenzoic acid into the system at one time, stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine by using the constant-pressure dropping funnel, keeping the temperature below 0 ℃ during the dropwise addition, continuously stirring for 15min after the dropwise addition is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride slowly by using the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, continuously reacting for 12h after the reaction temperature is slowly increased to room temperature, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give intermediate 6, 8-dichloro-2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [ d ] [1,3] oxazin-4-one.
The second step: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly dropwise adding a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2 hours to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixture into a 50mL single-neck flask to remove a THF solvent, adding 5mL of absolute ethyl alcohol into the residue, washing, filtering, and washing a filter cake with the absolute ethyl alcohol to obtain a white solid.
The third step: putting 1mmol of intermediate, 1mmol of ketone and 1mmol of aldehyde into a three-neck flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC (thin layer chromatography), cooling and separating out solid after the reaction is finished for about 30min, and recrystallizing the solid by absolute ethyl alcohol-DMF (dimethyl formamide) to obtain the target product.
Example 6: preparation of 3-ethylsulfanyl-N- (2, 4-dichloro-6- (2- (2-methylphenylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-29)
The first step is as follows: adding 0.5g (2.22mmol) of 3-ethylthio-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling an ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise adding is finished, adding 0.46g (2.22mmol) of 2-amino-3, 5-dichlorobenzoic acid into the system at one time, stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine into the constant-pressure dropping funnel, keeping the temperature below 0 ℃ during the dropwise adding process, continuously stirring for 15min after the dropwise adding is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride into the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, continuously reacting for 12h after the reaction temperature is slowly increased to room temperature, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate 10:1) to give intermediate 6, 8-dichloro-2- (3-ethylsulfanyl-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [ d ] [1,3] oxazin-4-one.
The second step is that: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly dropwise adding a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2 hours to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixture into a 50mL single-neck flask to remove a THF solvent, adding 5mL of absolute ethyl alcohol into the residue, washing, filtering, and washing a filter cake with the absolute ethyl alcohol to obtain a white solid.
The third step: putting 1mmol of intermediate and 1mmol of benzaldehyde into a three-necked bottle with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC, cooling and precipitating solids after the reaction is finished for about 30min, and recrystallizing the cooled and precipitated solids by using absolute ethyl alcohol-DMF to obtain the target product.
Example 7: preparation of 3-ethanesulfonyl-N- (2, 4-dichloro-6- (2- (2-methylphenylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-30)
The first step is as follows: adding 0.5g (2.22mmol) of 3-ethylsulfonyl-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling an ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise addition is finished, adding 0.46g (2.22mmol) of 2-amino-3, 5-dichlorobenzoic acid into the system at one time, stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine into the constant-pressure dropping funnel, keeping the temperature below 0 ℃ during the dropwise addition, continuously stirring for 15min after the dropwise addition is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride into the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, continuously reacting for 12h after the reaction temperature is slowly increased to room temperature, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate 10:1) to give intermediate 6, 8-dichloro-2- (3-ethylsulfonyl-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [ d ] [1,3] oxazin-4-one.
The second step: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly adding dropwise a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2h to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixed solution into a 50mL single-neck flask to remove THF solvent, adding 5mL of absolute ethyl alcohol into the residue to wash, filtering, and washing the filter cake with the absolute ethyl alcohol to obtain white solid.
The third step: putting 1mmol of intermediate and 1mmol of furan aldehyde into a three-necked flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC, cooling and precipitating solids after the reaction is finished for about 30min, and recrystallizing the cooled and precipitated solids by using absolute ethyl alcohol-DMF to obtain the target product.
Example 8: preparation of 3-ethylsulfanyl-N- (2, 4-difluoro-6- (2- (4-bromopyridin-2 ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-31)
The first step is as follows: adding 0.5g (2.22mmol) of 3-ethylthio-5- (trifluoromethyl) picolinic acid, 0.7g (8.87mmol) of pyridine and 5mL of acetonitrile into a 25mL three-neck flask, cooling an ice salt bath to-5 ℃, then slowly adding 0.51g (4.43mmol) of methanesulfonyl chloride into the system by using a constant-pressure dropping funnel, stirring for 5min after the dropwise adding is finished, adding 0.46g (2.22mmol) of 2-amino-3, 5-difluorobenzoic acid into the system at one time, stirring for 10min, slowly adding 0.70g (8.87mmol) of pyridine into the constant-pressure dropping funnel, keeping the temperature below 0 ℃ during the dropwise adding process, continuously stirring for 15min after the dropwise adding is finished, then continuously adding 0.51g (4.43mmol) of methanesulfonyl chloride into the constant-pressure dropping funnel, continuously stirring for 1h, removing the ice salt bath, continuously reacting for 12h after the reaction temperature is slowly increased to the room temperature, adding water and dichloromethane for extraction, the organic layer was subjected to column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give intermediate 6, 8-difluoro-2- (3-ethylsulfanyl-5- (trifluoromethyl) pyridin-2-yl) -4H-benzo [ d ] [1,3] oxazin-4-one.
The second step is that: adding 80% hydrazine hydrate and 2mL HF into a 50mL three-neck flask, then slowly dropwise adding a mixed solution of 1.2g of an intermediate dissolved in 5mL HF, completing dropwise addition for about 10min, continuously stirring at room temperature for 2 hours to precipitate a large amount of solid in the system, after the reaction is stopped, transferring the mixture into a 50mL single-neck flask to remove a THF solvent, adding 5mL of absolute ethyl alcohol into the residue, washing, filtering, and washing a filter cake with the absolute ethyl alcohol to obtain a white solid.
The third step: putting 1mmol of intermediate and 1mmol of 4-bromopyridine-2-aldehyde into a three-neck flask with a reflux condenser tube and a thermometer, adding 5mL of absolute ethyl alcohol, heating and refluxing, monitoring the reaction by TLC, after the reaction is finished for about 30min, cooling and separating out solid, and recrystallizing with absolute ethyl alcohol-DMF to obtain the target product.
Other preferred compounds of the present invention can be prepared by similar methods as described above. The nuclear magnetic spectrum data, physicochemical properties and the like of the synthesized partial compounds are as follows:
3-chloro-N- (4-chloro-2-methyl-6- (2- (thiophen-2-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-1): yield 67.5%, white solid, melting point 243-; 1 H NMR(400MHz,DMSO)δ11.81(s,1H),10.53(s,1H),9.06(d,J＝1.0Hz,1H),8.64(d,J＝1.3Hz,1H),8.49(s,1H),7.68(d,J＝5.1Hz,1H),7.62–7.56(m,1H),7.52(d,J＝2.4Hz,1H),7.47(dd,J＝3.6,0.9Hz,1H),7.14(dd,J＝5.0,3.6Hz,1H),2.33(s,3H). 13 C NMR(101MHz,DMSO)δ162.84,162.25,154.43,144.47,143.18,139.44,139.27,136.84,135.24,132.51,132.23,131.56,131.39,129.76,129.55,128.39,127.72(q,J＝33.3Hz),126.10,122.97(d,J＝273.4Hz),18.47. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 20 H 13 Cl 2 F 3 N 4 O 2 S[M+H] + :501.01611,found:501.01526.
n- (2- (2- ((5-bromopyridin-2-yl) methylene) hydrazine-1-carbonyl) -4-chloro-6-methylphenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-2) in 57.0% yield as a white solid at melting point 268. sup. nd 269 ℃; 1 HNMR(400MHz,DMSO)δ12.12(s,1H),10.56(s,1H),9.04(d,J＝0.9Hz,1H),8.75(t,J＝5.3Hz,1H),8.63(d,J＝1.2Hz,1H),8.30(s,1H),8.14(dd,J＝8.5,2.3Hz,1H),7.90(d,J＝8.5Hz,1H),7.63(d,J＝2.0Hz,1H),7.57(d,J＝2.3Hz,1H),2.34(s,3H). 13 C NMR(101MHz,DMSO)δ162.91,162.67,154.51,152.43,150.79,147.22,144.49(q,J＝4.0Hz),140.13,139.30,136.79(q,J＝3.5Hz),135.03,132.55,132.45,131.45,129.69,127.71(q,J＝33.3Hz),126.13,122.97(q,J＝273.3Hz),121.89,121.35,18.43. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 21 H 13 BrCl 2 F 3 N 5 O 2 [M+H] + :573.96545,found:573.96423.
3-chloro-N- (4-chloro-2-methyl-6- (2- (pyridin-4-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-3) in 56.3% yield as a white solid at 296 ℃ and 297 ℃; 1 HNMR(400MHz,DMSO)δ12.13(s,1H),10.55(s,1H),9.05(d,J＝1.0Hz,1H),8.66(dd,J＝4.5,1.5Hz,2H),8.63(d,J＝1.3Hz,1H),8.29(s,1H),7.66(dd,J＝4.5,1.5Hz,2H),7.56(d,J＝2.3Hz,1H),7.39(dd,J＝8.3,4.2Hz,1H),2.34(s,3H). 13 C NMR(101MHz,DMSO)δ162.93,162.73,150.78,150.47,145.62,144.50(d,J＝3.9Hz),141.86,139.27,136.78(d,J＝3.5Hz),135.04,132.53,132.43,131.42,129.69,127.71(q,J＝33.4Hz),126.16,122.96(q,J＝273.5Hz),121.44,18.42. 19 F NMR(376MHz,DMSO)δ-60.88.HR-MS(ESI):Calculated for C 21 H 14 Cl 2 F 3 N 5 O 2 [M+H] + :496.05494,found:496.05402.
3-chloro-N- (4-chloro-2-methyl-6- (2- (2-methylpropylidene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-4) in a yield of 64.3% as a white solid, mp 240 ℃ and 241 ℃; 1 H NMR(400MHz,DMSO)δ11.36(s,1H),10.49(s,1H),9.06(dd,J＝1.8,0.7Hz,1H),8.65(d,J＝1.3Hz,1H),7.57(dd,J＝2.4,0.6Hz,1H),7.52(d,J＝5.2Hz,1H),7.45(d,J＝2.1Hz,1H),2.31(s,3H),1.05(d,J＝6.9Hz,6H),0.89(d,J＝6.8Hz,1H). 13 C NMR(101MHz,DMSO)δ162.80,162.10,157.08,154.40,144.46(q,J＝4.0Hz),139.29,136.83(q,J＝3.5Hz),135.51,132.42,132.02,131.39,129.78,127.73(q,J＝33.3Hz),126.05,122.98(q,J＝273.4Hz),31.49,20.03,18.46. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 19 H 17 Cl 2 F 3 N 4 O 2 [M+H] + :461.07534,found:461.07413.
3-chloro-N- (4-chloro-2-methyl-6- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-5) in 76.8% yield as a white solid, m.p. 247-; 1 H NMR(400MHz,DMSO)δ11.81(s,1H),10.56(s,1H),9.05(d,J＝1.0Hz,1H),8.63(d,J＝1.3Hz,1H),8.60(s,1H),7.81(d,J＝7.7Hz,1H),7.61(d,J＝1.9Hz,1H),7.55(d,J＝2.2Hz,1H),7.35–7.29(m,1H),7.27(t,J＝7.2Hz,2H),7.22–7.13(m,1H),2.41(s,3H),2.33(s,3H). 13 C NMR(101MHz,DMSO)δ162.84,162.31,154.47,146.84,144.48(q,J＝5.0Hz),139.31,137.34,136.82(q,J＝3.5Hz),135.25,132.59,132.25,131.38,130.34,129.75,127.71(q,J＝33.2Hz),126.69,126.28,126.07,122.97(q,J＝273.1Hz),19.41,18.49. 19 F NMR(376MHz,DMSO)δ-60.88.HR-MS(ESI):Calculated for C 23 H 17 Cl 2 F 3 N 4 O 2 [M+H] + :509.07534,found:509.07465.
n- (2- (2- ((6-bromopyridin-3-yl) methylene) hydrazine-1-carbonyl) -4-chloro-6-methylphenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-6) in 53.8% yield as a white solid, mp 261-; 1 HNMR(400MHz,DMSO)δ12.10(s,1H),10.54(s,1H),9.05(d,J＝1.0Hz,1H),8.67(d,J＝2.3Hz,1H),8.63(d,J＝1.3Hz,1H),8.32(s,1H),8.08(dd,J＝8.4,2.4Hz,1H),7.75(d,J＝8.3Hz,1H),7.62(d,J＝2.5Hz,1H),7.54(d,J＝2.4Hz,1H),2.33(s,3H). 13 C NMR(101MHz,DMSO)δ162.88,162.60,154.47,149.83,144.51(q,J＝3.9Hz),144.03,142.84,139.26,136.92,136.80(q,J＝3.4Hz),135.06,132.54,132.38,131.38,130.49,129.71,128.93,127.71(q,J＝33.2Hz),126.16,122.97(q,J＝273.3Hz),18.44. 19 F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C 21 H 13 BrCl 2 F 3 N 5 O 2 [M+H] + :573.96545，found:573.96442.
3-chloro-N- (4-chloro-2-methyl-6- (2- (thien-3-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-7) in 56.6% yield as a white solid with a melting point of 260 ℃ at 261 ℃; 1 H NMR(400MHz,DMSO)δ11.73(s,1H),10.53(s,1H),9.05(d,J＝1.0Hz,1H),8.63(d,J＝1.3Hz,1H),8.32(s,1H),7.94(dd,J＝2.8,1.1Hz,1H),7.64(dd,J＝5.0,2.9Hz,1H),7.60(d,J＝1.9Hz,1H),7.52(d,J＝2.4Hz,1H),7.46(dd,J＝5.1,0.9Hz,1H),2.33(s,3H). 13 C NMR(101MHz,DMSO)δ162.85,162.35,154.45,144.48,143.77,139.26,137.87,136.80,135.39,132.47,132.16,131.38,129.73,128.99,128.24,127.70(q,J＝33.1Hz).,126.11,122.97(q,J＝273.6Hz),123.18,18.48. 19 F NMR(376MHz,HDMSO)δ-60.87.HR-MS(ESI):Calculated for C 20 H 13 Cl 2 F 3 N 4 O 2 S[M+H] + :501.01611,found:501.01483.
3-chloro-N- (4-chloro-2-methyl-6- (2- (prop-2-ylidene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-8) in 91.1% yield as a white solid at 245 ℃ and 246 ℃; 1 H NMR(400MHz,DMSO)δ10.48(s,1H),10.39(s,1H),9.07(s,1H),8.66(s,1H),7.57(s,1H),7.43(s,1H),2.30(s,3H),1.96(s,3H),1.89(s,3H). 13 C NMR(101MHz,DMSO)δ162.95,162.34,158.91,154.20,144.50,139.11,136.94,136.01,132.17,131.83,131.43,129.79,127.78(q,J＝33.5Hz),126.48,122.97(q,J＝273.3Hz),25.57,18.50,18.34. 19 F NMR(376MHz,DMSO)δ-60.84.HR-MS(ESI):Calculated for C 18 H 15 Cl 2 F 3 N 4 O 2 [M+H] + :447.05969,found:447.05878.
3-chloro-N- (4-chloro-2-methyl-6- (2- ((5-methylthiophen-2-yl) methylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-9) in 56.7% yield as a white solid, m.p. 247-; 1 H NMR(400MHz,DMSO)δ11.74(s,1H),10.53(s,1H),9.06(d,J＝0.9Hz,1H),8.64(d,J＝1.2Hz,1H),8.38(s,1H),7.60(d,J＝2.0Hz,1H),7.51(d,J＝2.3Hz,1H),7.26(d,J＝3.5Hz,1H),6.84(dd,J＝3.5,1.0Hz,1H),2.47(s,3H),2.32(s,3H). 13 C NMR(101MHz,DMSO)δ162.85,162.15,154.46,144.48(q,J＝3.8Hz),143.51,143.41,139.26,137.16,36.81(q,J＝3.2Hz),135.30,132.48,132.17,131.99,131.38,129.75,127.71(q,J＝33.4Hz),126.87,126.07,122.97(q,J＝273.3Hz).,18.47,15.85. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 21 H 15 Cl 2 F 3 N 4 O 2 S[M+H] + :515.03176,found:515.03113.
n- (2- (2- ((1H-imidazol-4-yl) methylene) hydrazine-1-carbonyl) -4-chloro-6-methylphenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-10) in 67.2% yield as a white solid, mp 199-; 1H NMR (400MHz, DMSO) δ 12.56(s,1H),11.64(s,1H),10.56(s,1H),9.05(s,1H),8.64(d, J ═ 0.9Hz,1H),8.22(s,1H),7.78(s,1H),7.60(d, J ═ 2.1Hz,1H),7.52(d, J ═ 2.3Hz,2H),2.33(s,3H), 13C NMR (101MHz, DMSO) δ 162.81,162.09,154.41,144.48(q, J ═ 3.8 Hz.), 139.27,136.84(q, J ═ 4.2Hz),135.47,132.49,132.11,131.40,129.75,127.70(q, J ═ 33.3Hz),126.10,122.97(d, J ═ 273.3Hz),18.50.19F (MHz, 376, DMSO) δ ms-esi (HR-esi) (C for cu: 33.3Hz),126.10,122.97(d, J ═ 273.3Hz),18.50.19F (MHz, 376, DMSO), HR-ms-60.86 HR-esi) (C) 19 H 13 Cl 2 F 3 N 6 O 2 [M+H] + :485.05019,found:485.04910.
3-chloro-N- (4-chloro-2- (2- ((2-chloropyridin-3-yl) methylene) hydrazine-1-carbonyl) -6-methylphenyl) -5- (trifluoromethyl) picolinamide (I-11) in 73.1% yield as a white solid, m.p. 269-; 1 H NMR(400MHz,DMSO)δ12.22(s,1H),10.58(s,1H),9.05(d,J＝0.9Hz,1H),8.66–8.63(m,2H),8.48(dd,J＝4.7,1.9Hz,1H),8.36–8.33(m,1H),7.64(d,J＝2.0Hz,1H),7.59(d,J＝2.3Hz,1H),7.57–7.54(m,1H),2.34(s,3H). 13 C NMR(101MHz,DMSO)δ162.89,162.58,154.49,151.37,149.82,144.52,142.84,139.25,136.81,136.39,136.16,134.88,132.49,131.40,129.70,128.91,127.87,126.13,124.35,124.03,18.43. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 21 H 13 Cl 3 F 3 N 5 O 2 [M+H] + :530.01597,found:530.01508.
3-chloro-N- (4-chloro-2-methyl-6- (2- ((5-methylfuran-2-yl) methylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl)Pyridine amide (I-12) yield 86.0%, white solid, melting point 230-; 1 HNMR(400MHz,DMSO)δ11.73(s,1H),10.56(s,1H),9.06(s,1H),8.65(s,1H),8.07(s,1H),7.61(d,J＝2.0Hz,1H),7.51(d,J＝2.2Hz,1H),6.81(d,J＝3.2Hz,1H),6.26(d,J＝2.4Hz,1H),2.34(s,3H),2.32(s,3H). 13 C NMR(101MHz,DMSO)δ162.80,162.23,155.14,154.39,148.24,144.49(q,J＝3.5Hz),139.29,137.71,136.84(q,J＝3.0Hz),135.28,132.53,132.20,131.38,129.75,127.71(q,J＝33.2Hz),126.04,122.98(q,J＝273.5Hz),116.07,109.09,18.49,13.96. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 21 H 15 Cl 2 F 3 N 4 O 3 [M+H] + :499.05451,found:499.05328.
n- (2- (2- ((4-bromothiophen-2-yl) methylene) hydrazine-1-carbonyl) -4-chloro-6-methylphenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-13): yield 53.4%, white solid, melting point 251-; 1 H NMR(400MHz,DMSO)δ11.96(s,1H),10.54(s,1H),9.06(d,J＝0.9Hz,1H),8.64(d,J＝1.3Hz,1H),8.45(s,1H),7.79(s,1H),7.61(d,J＝2.2Hz,1H),7.56(d,J＝1.4Hz,1H),7.52(d,J＝2.3Hz,1H),2.32(s,3H). 13 C NMR(101MHz,DMSO)δ162.87,162.38,154.48,144.52(q,J＝4.0Hz).,141.65,140.93,139.24,136.81(q,J＝3.5Hz),135.08,133.01,132.49,132.31,131.37,129.72,127.71(q,J＝33.4Hz),126.77,126.12,122.98(q,J＝273.4Hz),109.77,18.44. 19 F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C 20 H 12 BrCl 2 F 3 N 4 O 2 S[M+H] + :578.92663,found:578.92383.
3-chloro-N- (4-chloro-2- (2- (2-chlorobenzylidene) hydrazine-1-carbonyl) -6-methylphenyl) -5- (trifluoromethyl) picolinamide (I-14) in 71.4% yield as whiteSolid, melting point 251-; 1 H NMR(400MHz,DMSO)δ12.08(s,1H),10.58(s,1H),9.05(s,1H),8.71(s,1H),8.65(d,J＝1.0Hz,1H),8.00(dd,J＝7.2,2.2Hz,1H),7.63(d,J＝2.0Hz,1H),7.58(d,J＝2.2Hz,1H),7.55(d,J＝1.8Hz,1H),7.48–7.43(m,2H),2.34(s,3H). 13 C NMR(101MHz,DMSO)δ162.90,162.52,154.54,144.49(q,J＝3.2Hz),144.06,139.24,136.81(q,J＝3.4Hz),135.07,133.67,132.37,132.09,131.87,131.52,131.39,130.46,129.70,128.15,127.69(q,J＝33.6Hz).,127.27,126.13,122.97(q,J＝273.3Hz),18.45. 19 F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C 22 H 14 Cl 3 F 3 N 4 O 2 [M+H] + :529.02072,found:529.02002.
3-chloro-N- (2-methyl-6- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-15) in 57.3% yield as a white solid at melting point 242 and 243 ℃; 1 H NMR(400MHz,DMSO)δ11.75(s,1H),10.54(s,1H),9.05(d,J＝0.9Hz,1H),8.67–8.58(m,2H),7.82(d,J＝7.8Hz,1H),7.48(t,J＝7.5Hz,2H),7.39(d,J＝7.6Hz,1H),7.32(d,J＝2.3Hz,1H),7.30–7.28(m,1H),7.27(s,1H),2.41(s,3H),2.34(s,3H). 13 C NMR(101MHz,DMSO)δ163.79,162.79,154.74,146.37,144.48(q,J＝3.9Hz),137.25,136.77(q,J＝3.5Hz).,136.72,133.68,133.35,132.89,132.70,131.36,130.23,129.68,127.62(d,J＝33.2Hz),127.28,126.68,126.39,126.20,122.99(q,J＝273.4Hz),19.41,18.72. 19 F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C 23 H 18 ClF 3 N 4 O 2 [M+H] + :326.03025,found:326.02969.
3-chloro-N- (4-chloro-2- (2- ((dimethylamino) methylene) hydrazine-1-carbonyl) -6-methylphenyl) -5- (trifluoromethyl) picolinamide (I-16)The rate is 90.3 percent, the light yellow solid has the melting point of 124-126 ℃; 1 H NMR(400MHz,DMSO)δ10.59(s,1H),10.55(s,1H),9.07(s,1H),8.66(s,1H),7.81(s,1H),7.52(d,J＝2.1Hz,1H),7.39(d,J＝2.2Hz,1H),2.81(s,6H),2.29(s,3H). 13 C NMR(101MHz,DMSO)δ162.24,161.21,155.48,153.68,144.47,138.91,137.15,135.46,132.58,131.60,131.04,130.09,128.02,125.82,124.32,18.77. 19 F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C 18 H 16 Cl 2 F 3 N 5 O 2 [M+H] + :462.07059,found:462.06979.
3-chloro-N- (2-methyl-6- (2- (thien-2-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-17) in 62.7% yield as a white solid, mp 244-; 1 H NMR(400MHz,DMSO)δ11.75(s,1H),10.50(s,1H),9.06(d,J＝1.0Hz,1H),8.64(d,J＝1.3Hz,1H),8.50(s,1H),7.67(d,J＝5.1Hz,1H),7.50–7.42(m,3H),7.38(d,J＝7.5Hz,1H),7.14(dd,J＝5.0,3.6Hz,1H),2.34(s,3H). 13 C NMR(101MHz,DMSO)δ163.74,162.78,154.71,144.49(q,J＝3.5Hz),142.76,139.60,136.78(q,J＝3.5Hz),136.68,133.63,133.32,132.87,131.35,129.71,129.39,128.36,127.64(q,J＝33.1Hz),127.28,126.42,122.99(q,J＝273.5Hz),18.71. 19 F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C 20 H 14 ClF 3 N 4 O 2 S[M+H] + :467.05509,found:467.05392.
n- (2- (2- ((5-bromopyridin-2-yl) methylene) hydrazine-1-carbonyl) -6-methylphenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-18) in 77.9% yield as a white solid at 245 ℃ C; 1 H NMR(400MHz,DMSO)δ12.06(s,1H),10.52(s,1H),9.04(s,1H),8.75(d,J＝2.2Hz,1H),8.63(d,J＝0.7Hz,1H),8.31(d,J＝1.6Hz,1H),8.31(d,J＝1.6Hz,1H),8.14(dd,J＝8.5,2.2Hz,1H),7.90(d,J＝8.5Hz,1H),7.49(dd,J＝11.8,7.6Hz,2H),7.40(d,J＝7.6Hz,1H),2.35(s,3H). 13 C NMR(101MHz,DMSO)δ164.14,162.86,154.80,152.57,150.75,146.78,144.48(q,J＝3.6Hz),140.10,136.73(q,J＝3.7Hz),136.71,133.47,133.34,133.08,129.63,127.62(q,J＝32.4Hz),127.35,126.46,122.99(q,J＝273.3Hz),121.82,121.23,18.65. 19 F NMR(376MHz,DMSO)δ-60.85.HR-MS(ESI):Calculated for C 21 H 14 BrClF 3 N 5 O 2 [M+H] + :540.00443,found:540.00354.
n- (2- (2- ((4-bromothien-2-yl) methylene) hydrazine-1-carbonyl) -4, 6-difluorophenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-19) in 50.6% yield as a white solid, mp 231-; 1 H NMR(400MHz,DMSO)δ12.07(s,1H),10.63(s,1H),9.06(d,J＝1.0Hz,1H),8.66(d,J＝1.3Hz,1H),8.46(s,1H),7.80(d,J＝0.5Hz,1H),7.66–7.61(m,1H),7.59(d,J＝1.4Hz,1H),7.47–7.42(m,1H). 13 C NMR(101MHz,DMSO)δ162.84,160.31(dd,J＝247.3,11.9Hz),161.26(t,J＝2.7Hz),157.84(dd,J＝251.2,12.3Hz),153.76,144.48,142.13,140.75,136.98(q,J＝3.2Hz),135.34(dd,J＝8.6,1.7Hz),133.30,132.10,129.96,127.88(q,J＝33.2Hz),126.98,122.95(d,J＝273.3Hz),119.87(dd,J＝14.4,3.8Hz),111.81,109.81,107.10(t,J＝25.9Hz). 19 F NMR(376MHz,DMSO)δ-60.88,-110.83(d,J＝7.6Hz),-112.10(d,J＝7.7Hz).HR-MS(ESI):Calculated for C 19 H 9 BrClF 5 N 4 O 2 S[M+H] + :566.93110,found:566.93024.
3-chloro-N- (2, 4-difluoro-6- (2- (thien-2-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-20) in 59.1% yield as a white solid, mp 234-; 1 H NMR(400MHz,DMSO)δ11.93(s,1H),10.63(s,1H),9.06(s,1H),8.66(s,1H),8.49(s,1H),7.69(d,J＝5.0Hz,1H),7.67–7.61(m,1H),7.50(d,J＝2.9Hz,1H),7.45(d,J＝8.2Hz,1H),7.15(dd,J＝4.9,3.7Hz,1H). 13 C NMR(101MHz,DMSO)δ162.81,160.34(dd,J＝245.4,13.0Hz),161.13,157.86(dd,J＝250.5,12.2Hz),153.76,144.48(q,J＝3.2Hz).,143.63,139.26,136.99(q,J＝3.2Hz),135.52(dd,J＝8.3,1.3Hz),131.87,129.99,129.78,129.14,128.43,127.88(q,J＝33.3Hz),122.95(q,J＝273.7Hz),119.86(dd,J＝14.7,3.9Hz),111.88(dd,J＝23.3,2.8Hz),107.01(t,J＝25.9Hz). 19 F NMR(376MHz,DMSO)δ-60.88,-110.87(d,J＝8.1Hz),-111.95(d,J＝8.5Hz).HR-MS(ESI):Calculated for C 19 H 10 ClF 5 N 4 O 2 S[M+H] + :489.02059,found:489.01941.
3-chloro-N- (2, 4-difluoro-6- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-21) at 75.5% yield as a white solid, melting point 250 ℃ and 251 ℃; 1 H NMR(400MHz,DMSO)δ11.94(s,1H),10.66(s,1H),9.06(d,J＝0.9Hz,1H),8.66(d,J＝1.2Hz,1H),8.61(s,1H),7.82(d,J＝7.5Hz,1H),7.65(td,J＝10.1,2.8Hz,1H),7.50–7.47(m,1H),7.32(dd,J＝6.8,2.0Hz,1H),7.27(d,J＝7.2Hz,2H),2.42(s,3H). 13 C NMR(101MHz,DMSO)δ162.82,160.40(dd,J＝251.1,7.3Hz),161.20(t,J＝2.6Hz),157.89(dd,J＝249.3,12.2Hz),153.79,147.35,144.47(d,J＝3.9Hz),137.45,137.03,137.00,132.43,131.42,130.49,129.97,127.87(q,J＝33.4Hz),126.74,126.34,122.95(q,J＝273.4Hz),111.86(dd,J＝23.6,2.1Hz),107.05(t,J＝26.0Hz),19.92,19.44. 19 F NMR(376MHz,DMSO)δ-60.89(s),-110.88(d,J＝7.2Hz),-111.88(d,J＝7.7Hz).HR-MS(ESI):Calculated for C 22 H 14 ClF 5 N 4 O 2 [M+H] + :497.07982,found:497.07895.
3-chloro-N- (4-chloro-2- (2- (thien-2-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-22) in 45.2% yield as a white solid, mp 247-; 1 H NMR(400MHz,DMSO)δ12.12(s,2H),9.16(s,1H),8.69(d,J＝1.0Hz,1H),8.59(d,J＝8.2Hz,2H),7.93(d,J＝2.4Hz,1H),7.76–7.68(m,2H),7.53(d,J＝2.9Hz,1H),7.17(dd,J＝4.9,3.7Hz,1H). 13 C NMR(101MHz,DMSO)δ163.10,161.49,150.96,144.69,144.49(q,J＝3.9Hz),139.07,138.37(q,J＝3.2Hz),137.16,132.50,132.27,131.28,130.09,128.78,128.47,128.48(d,J＝33.3Hz),128.06,123.87,123.11,122.85(q,J＝273.3Hz). 19 F NMR(376MHz,DMSO)δ-60.92.HR-MS(ESI):Calculated for C 19 H 11 Cl 2 F 3 N 4 O 2 S[M+H] + :487.00046,found:486.99829.
3-chloro-N- (4-chloro-2- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-23) in 52.9% yield as a white solid at 284 ℃ C. -; 1 H NMR(400MHz,DMSO)δ12.22(s,1H),12.14(s,1H),9.14(d,J＝1.0Hz,1H),8.73(s,1H),8.69(d,J＝1.2Hz,1H),8.62(d,J＝9.0Hz,1H),7.98(d,J＝2.5Hz,1H),7.86(d,J＝7.7Hz,1H),7.74(dd,J＝9.0,2.5Hz,1H),7.34(dd,J＝6.8,1.9Hz,2H),7.28(t,J＝7.3Hz,3H). 13 C NMR(101MHz,DMSO)δ163.25,161.47,150.93,148.37,144.45(q,J＝3.6Hz),138.40(q,J＝3.2Hz),137.67,137.30,132.56,132.36,131.41,131.31,130.66,128.73,128.49(q,J＝33.1Hz),128.04,126.73,126.25,123.70,123.07,122.84(q,J＝273.5Hz),19.40. 19 F NMR(376MHz,DMSO)δ-60.94.HR-MS(ESI):Calculated for C 22 H 15 Cl 2 F 3 N 4 O 2 [M+H] + :495.05969,found:495.05844.
n- (2- (2- ((4-bromothien-2-yl) methylene) hydrazine-1-carbonyl) -4-chlorophenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-24) in 52.9% yield as a white solid, mp 254-; 1 H NMR(400MHz,DMSO)δ12.25(s,1H),12.07(s,1H),9.15(d,J＝0.8Hz,1H),8.69(d,J＝1.2Hz,1H),8.59–8.53(m,2H),7.93(d,J＝2.5Hz,1H),7.83(s,1H),7.73(dd,J＝9.0,2.4Hz,1H),7.61(d,J＝1.3Hz,1H). 13 C NMR(101MHz,DMSO)δ163.23,161.51,150.98,144.48(q,J＝3.7Hz),143.14,140.53,138.34(q,J＝3.3Hz),137.13,133.64,132.59,131.26,128.84,128.47(q,J＝33.6Hz),128.09,127.24,123.81,123.20,122.84(d,J＝273.5Hz),109.87. 19 F NMR(376MHz,DMSO)δ-60.93.HR-MS(ESI):Calculated for C 19 H 10 BrCl 2 F 3 N 4 O 2 S[M+H] + :564.91098,found:564.91071.
n- (2- (2- ((4-bromothien-2-yl) methylene) hydrazine-1-carbonyl) -4, 6-dichlorophenyl) -3-chloro-5- (trifluoromethyl) picolinamide (I-25) in 51.8% yield as a white solid, melting point 252 ℃ at 253 ℃; 1 H NMR(400MHz,DMSO)δ12.24(s,1H),12.06(s,1H),9.15(d,J＝0.9Hz,1H),8.69(d,J＝1.2Hz,1H),8.59–8.53(m,2H),7.93(d,J＝2.5Hz,1H),7.83(s,1H),7.73(dd,J＝9.0,2.5Hz,1H),7.61(d,J＝1.3Hz,1H). 13 C NMR(101MHz,DMSO)δ163.23,161.52,151.01,144.49(q,J＝3.8Hz),143.14,140.54,138.34(q,J＝3.6Hz),137.13,133.65,132.59,131.25,128.84,128.47(q,J＝33.5Hz),128.09,127.24,122.85(d,J＝273.5Hz),123.84,123.21,109.87. 19 F NMR(376MHz,DMSO)δ-60.92.
3-chloro-N- (2, 4-dichloro-6- (2- (thien-2-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-26) in 49.2% yield as a white solid, mp 256-; 1 H NMR(400MHz,DMSO)δ12.12(d,J＝3.0Hz,2H),9.16(d,J＝1.0Hz,1H),8.69(d,J＝1.3Hz,1H),8.60(s,1H),7.93(d,J＝2.5Hz,1H),7.75–7.70(m,2H),7.53(dd,J＝3.6,0.9Hz,1H),7.17(dd,J＝5.0,3.6Hz,1H). 13 C NMR(101MHz,DMSO)δ163.10,161.50,150.98,144.68,144.50(q,J＝3.4Hz),139.07,138.37(q,J＝3.4Hz),137.15,132.50,132.28,131.27,130.09,128.79,128.48(q,J＝33.4Hz),128.48,128.06,123.88,123.12,122.85(q,J＝273.3Hz). 19 F NMR(376MHz,DMSO)δ-60.92.
3-chloro-N- (2, 4-dichloro-6- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-27) in 58.2% yield as a pale yellow solid, mp 289-; 1 H NMR(400MHz,DMSO)δ12.21(s,1H),12.13(s,1H),9.14(d,J＝1.0Hz,1H),8.73(s,1H),8.69(d,J＝1.2Hz,1H),8.62(d,J＝9.0Hz,1H),7.97(d,J＝2.5Hz,1H),7.86(d,J＝7.7Hz,1H),7.74(dd,J＝9.0,2.4Hz,1H),7.37–7.32(m,1H),7.28(s,1H),2.45(s,3H). 13 C NMR(101MHz,DMSO)δ163.25,161.47,150.92,148.38,144.44(q,J＝3.0Hz),138.40(q,J＝3.1Hz),137.67,137.30,132.56,132.36,131.41,131.32,130.66,128.73,128.50(q,J＝33.4Hz),128.04,126.72,126.26,123.70,123.07,122.84(q,J＝273.5Hz),19.40. 19 F NMR(376MHz,DMSO)δ-60.94.HR-MS(ESI):Calculated for C 22 H 14 Cl 3 F 3 N 4 O 2 [M+H] + :529.02072,found:529.02014.
3-chloro-N- (2, 4-dichloro-6- (2- ((5-methylfuran-2-yl) methylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-28) in 45.3% yield as a white solid, mp 226-; 1 H NMR(400MHz,DMSO)δ12.23(s,1H),12.04(s,1H),9.15(d,J＝1.0Hz,1H),8.69(d,J＝1.2Hz,1H),8.60(d,J＝9.0Hz,1H),7.92(d,J＝2.5Hz,1H),7.72(dd,J＝9.0,2.5Hz,1H),6.88(d,J＝3.3Hz,1H),6.29(dd,J＝3.3,0.9Hz,1H),2.36(s,3H). 13 C NMR(101MHz,DMSO)δ163.16,161.37,155.56,150.69,148.04,144.43(q,J＝3.8Hz),139.06,138.49(q,J＝3.6Hz),137.19,132.48,131.38,128.66,128.52(q,J＝33.4Hz),128.01,124.20,123.79,122.84(q,J＝273.3Hz),116.90,109.24,13.98. 19 F NMR(376MHz,DMSO)δ-60.94.
3-ethylsulfanyl-N- (2, 4-dichloro-6- (2- (2-methylbenzylidene) hydrazinecarbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-27): 1 H NMR(400MHz,DMSO)δ12.22(s,1H),12.15(s,1H),9.16(d,J＝1.0Hz,1H),8.56(s,1H),8.45(d,J＝1.2Hz,1H),8.12(d,J＝9.0Hz,1H),7.87(d,J＝2.5Hz,1H),7.84(d,J＝7.7Hz,1H),7.56(dd,J＝9.0,2.4Hz,1H),7.35–7.23(m,1H),3.53(q,J＝13.6Hz,2H),2.44(s,3H)，1.39(t,J＝13.6Hz,3H 13 C NMR(101MHz,DMSO)δ163.43,161.43,150.62,148.58,144.34(q,J＝3.0Hz),138.41(q,J＝3.1Hz),137.45,137.33,132.54,132.31,131.34,131.35,130.64,128.71,128.43(q,J＝33.4Hz),128.23,126.71,126.24,123.71,123.23,122.81(q,J＝274.5Hz),19.60，14.84,7.68. 19 F NMR(376MHz,DMSO)δ-60.56.
3-ethanesulfonyl-N- (2, 4-dichloro-6- (2- ((5-methylfuran-2-yl) methylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-30): 1 H NMR(500MHz,Chloroform)δ9.04(d,J＝3.1Hz,1H),8.61(s,1H),8.47(d,J＝2.9Hz,1H),7.94(dd,J＝20.2,3.0Hz,2H),6.85(d,J＝14.8Hz,1H),6.28(d,J＝15.0Hz,1H),3.51(q,J＝13.6Hz,2H),2.36(s,3H),1.19(t,J＝13.6Hz,3H). 13 C NMR(101MHz,DMSO)δ164.36,160.34,156.67,150.63,148.14,144.42(q,J＝3.8Hz),139.23,138.43(q,J＝3.6Hz),137.32,132.45,131.34,128.65,126.51(q,J＝33.4Hz),128.11,124.23,123.78,121.86(q,J＝273.3Hz),116.90,109.24,52.6,14.79,7.67. 19 F NMR(376MHz,DMSO)δ-61.94.
3-ethylsulfanyl-N- (2, 4-difluoro-6- (2- ((5-methylpyridin-2-yl) methylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-31):
1 H NMR(500MHz,Chloroform)δ8.67(d,J＝2.9Hz,1H),8.41(d,J＝3.1Hz,1H),8.35(d,J＝15.0Hz,1H),8.26(d,J＝2.9Hz,1H),8.07(dd,J＝15.0,3.1Hz,1H),7.48(dd,J＝16.0,3.0Hz,1H),7.29(s,1H),7.15(td,J＝16.0,3.0Hz,1H),3.00(q,J＝13.2Hz,2H),1.31(t,J＝13.2Hz,3H). 13 C NMR(125MHz,Chloroform)δ167.60,163.41,162.94,156.44,155.81,152.13,150.09,148.44,143.93,142.48,137.74,137.25,135.19,129.49,128.76,124.92,121.85,121.27,112.78,104.81,24.92,13.02. 19 F NMR(472MHz,Chloroform)δ-62.10,-113.10,-125.90.
3-ethylsulfanyl-N- (4-chloro-2- (2- (thiophen-2-ylmethylene) hydrazine-1-carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-22): 1 H NMR(400MHz,DMSO)δ12.24(s,2H),9.26(s,1H),8.76(d,J＝1.0Hz,1H),8.59(d,J＝8.2Hz,2H),7.98(d,J＝2.4Hz,1H),7.72–7.61(m,2H),7.54(d,J＝2.9Hz,1H),7.21(dd,J＝4.9,3.7Hz,1H),3.10(q,J＝13.2Hz,2H),1.35(t,J＝13.2Hz,3H). 13 C NMR(101MHz,DMSO)δ163.21,161.43,150.92,144.74,144.22(q,J＝4.0Hz),139.07,138.34(q,J＝3.2Hz),137.13,132.54,132.22,131.24,130.13,128.71,128.42,128.44(d,J＝33.3Hz),128.16,123.23,123.15,122.54(q,J＝273.3Hz). 19 F NMR(376MHz,DMSO)δ-60.65.
the activity against Tobacco Mosaic Virus (TMV) and Cucumber Mosaic Virus (CMV) is exemplified, but the use of the compounds of the present invention against other viruses is not limited.
Example 9:
tobacco Mosaic Virus (TMV) resistance bioactivity test
The antiviral activity of the target compound is tested by adopting a half-leaf spot method and taking tobacco mosaic virus as a research object and commercially available ningnanmycin as a contrast agent.
Purification of TMV Virus
Reference literature reports [71] Selecting tobacco leaves inoculated with TMV virus for more than three weeks, grinding the tobacco leaves in 0.2M phosphate buffer solution under ice bath condition, and filtering the ground tobacco leaves through double-layer gauze to obtain an extracting solution. Adding butanol, stirring for 15min, 4 deg.C, 10000rpm, centrifuging for 20min to obtain supernatant, adding polyethylene glycol (PEG) and sodium chloride, stirring for 1h, centrifuging at 4 deg.C, 10000rpm, centrifuging for 20min to obtain precipitate, adding 0.01M PBS, stirring for 1h, 4 deg.C, 10000rpm, centrifuging for 15min to obtain supernatant, adding PEG and sodium chloride, stirring for 1h, 4 deg.C, 10000rpm, centrifuging for 20min to obtain precipitate, adding 0.01M PBS, stirring for 1h, 4 deg.C, 10000rpm, centrifuging for 5min, and collecting supernatant to obtain TMV virus extractive solution. The absorbance value at 260nm was estimated with an ultraviolet spectrophotometer.
Concentration of virus ═ A 260 X dilution ratio)/E 1cm 0.1％,260nm
In vivo therapeutic Activity of target Compounds against TMV Virus
Selecting tobacco leaves with the same size and age of left and right leaves, spraying carborundum with uniform thickness on the whole leaves, and inoculating TMV virus on the whole leaves. After 30min, the carborundum on the leaves is washed clean by water and naturally dried. A concentration of compound solution was then smeared on the left and solvent on the right as a control. The number of local lesions that appeared 3 to 4 days after inoculation was counted. Three replicates of each compound were performed.
Activity of target Compounds for in vivo protection of TMV Virus
Selecting tobacco leaves with the same leaf size and age, smearing a solution of the compound at a certain concentration on the left side, and smearing a solvent on the right side of the tobacco leaves as a control. After 20-22 hours, the whole leaf was sprinkled with uniform thickness of carborundum and inoculated with TMV virus. After 30min, the leaf was washed clean with water. The number of local lesions that appeared 3 to 4 days after inoculation was counted. Three replicates of each compound were performed.
In vivo inactivation Activity of target Compounds against TMV Virus
The virus was inhibited by mixing the compound solution with the same volume of virus for 30 min. Tobacco leaves with the same leaf size and age are selected, the whole leaf is sprinkled with uniform carborundum, the left side of the tobacco leaf is inoculated with a mixed solution of the applied virus and an equal volume of solvent (DMSO and buffer), and the right side of the leaf inoculated with the mixture of the solvent and the virus is used as a control. The number of local lesions appearing 3 to 4 days after inoculation was counted. Three replicates of each compound were performed.
Results investigation and analysis
After 3 to 4 days, the number of local lesions appearing on the left and right sides of the leaf was counted, and the inhibition ratio ("av" means an average value) was calculated according to the following formula.
The protective, therapeutic, and inactivating activity of the compounds against TMV was determined at a concentration of 500 μ g/mL according to the activity test method described in example 6, and the test results are shown in table I-1.
TABLE I-1 test results for anti-TMV Activity of target Compounds (500. mu.g/mL)
The test results show that most compounds show good to excellent therapeutic, protective and inactivating activity at a concentration of 500. mu.g/mL, wherein substantially all target products except I-1, I-8, I-14 and I-17 have good therapeutic activity and are significantly superior to the commercial drug ribavirin, particularly the compounds I-9, I-11, I-19, I-23, I-24, I-26 and I-27. In addition, the target compounds I-2, I-8, I-10 and I-16 have significant protection effect on TMV at the concentration of 500 mu g/mL, and are significantly better than ribavirin (50.4%), and especially the protection activity of the compounds I-2 and I-8 is slightly better than that of the commercial drug Ningnanmycin. Meanwhile, the compounds I-1, I-2, I-5, I-6, I-9 and I-11 show better inactivation activity than ribavirin (73.2%) at 500. mu.g/mL. In particular, compounds I-5 and I-6 have a similar and slightly better inactivation activity than ningnanmycin.
Example 10:
biological Activity test against Cucumber Mosaic Virus (CMV)
The antiviral activity of the target compound is tested by adopting a half-leaf spot method and taking tobacco mosaic virus as a research object and commercially available ningnanmycin as a contrast agent.
Purification of CMV
Selecting tobacco leaves inoculated with CMV virus for more than three weeks by adopting a literature report method, removing veins, adding liquid nitrogen, grinding into powder, adding 0.5M PBS, chloroform and n-butanol, homogenizing, filtering with double-layer gauze to obtain a filtrate, centrifuging at 4 ℃, 8000rpm, and centrifuging for 20min to obtain a CMV virus extracting solution.
In vivo inactivation of CMV by target Compounds
The virus was inhibited by mixing the compound solution with the same volume of virus for 30 min. Selecting amaranth leaves with the same size and age of left and right leaves, spraying uniform carborundum on the whole leaves, inoculating a mixed solution of virus and an equal volume of solvent (DMSO and buffer) on the left side of tobacco leaves, inoculating the mixture of the solvent and the virus on the right side of the leaves as a control, washing off the carborundum on the leaves after 30min, and naturally drying. The number of local lesions appearing 6 to 7 days after inoculation was counted. Three replicates of each compound were performed.
Results investigation and analysis
After 6 to 7 days, the number of local lesions appearing on the left and right sides of the leaf was counted, and the inhibition ratio ("av" means average value) was calculated according to the following formula.
The CMV-inactivating activity of the compounds was determined at a concentration of 500. mu.g/mL according to the activity test method described in example 7, and the results are shown in Table I-2.
TABLE I-2 inactivation of target Compounds against CMV (500. mu.g/mL)
| Compound (I) | Passivation (%) | Compound (I) | Passivation (%) |
| I-1 | 57.1±4.6 | I-11 | 88.7±1.1 |
| I-2 | 77.3±4.4 | I-12 | 78.5±3.5 |
| I-5 | 78.8±2.1 | I-13 | 81.5±3.1 |
| I-6 | 85.1±1.5 | Ningnanmycin | 89.4±1.4 |
Example 11: insecticidal Activity test
A part of the target compounds were tested for insecticidal activity against diamondback moth using the leaf-dipping feeding method (Pest Manag Sci, 2012,68, 801-810). The test result shows that the insecticidal activity of the synthesized compounds I-1, I-2, I-3, I-4, I-5, I-7, I-9, I-11, I-13, I-12, I-25, I-27, I-28, I-29 and I-30 on diamondback moth is more than 80 percent at the concentration of 500 mg/L.
Claims (3)
1. A Schiff base derivative containing trifluoromethyl pyridine dicarboxamide has a structural general formula shown as I:
in the compounds of the formula I, R 1 Is Cl, ethylthio or ethylsulfonyl; r 2 Is 3-methyl, 5-chloro-3-methyl or 3, 5-difluoro; r is 3 Is 2-thienyl, 5-bromopyridyl, pyridyl, isopropyl, 2-methylphenyl, 6-bromopyridyl, 3-thienyl, prop-2-ylidene, 5-methylthiophenyl, imidazolyl, 2-chloropyridyl, 2-methylfuryl, 4-bromothienyl, 2-chlorophenyl or N, N-dimethyl.
2. Use of the compound according to claim 1 for the preparation of pesticides or pesticide additives for controlling plant virus agents against tobacco mosaic virus and cucumber mosaic virus.
3. Use of a compound according to claim 1 for the preparation of a pesticide or pesticide additive for the control of diamondback moth.
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