CN110452234A - A kind of derivative of the schiff bases of the diformamide containing trifluoromethyl pyridine and its application - Google Patents
A kind of derivative of the schiff bases of the diformamide containing trifluoromethyl pyridine and its application Download PDFInfo
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- CN110452234A CN110452234A CN201910810123.4A CN201910810123A CN110452234A CN 110452234 A CN110452234 A CN 110452234A CN 201910810123 A CN201910810123 A CN 201910810123A CN 110452234 A CN110452234 A CN 110452234A
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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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Pest Control & Pesticides (AREA)
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Abstract
The invention discloses a kind of application of the derivative of the schiff bases of diformamide containing trifluoromethyl pyridine in antivirotic and insecticide.Its structure is as shown in general formula I.In formula, to R1、R2、R3The restriction of equal groups is as noted in the discussion.General formula I compound represented has excellent antiviral activity, can be used to prevent and treat TMV, the viral diseases of plants such as CMV and diamondback moth pest.
Description
Technical field
The present invention relates to field of agrochemicals, it relates in particular to a kind of phthalic amide containing trifluoromethyl pyridine
The derivative of schiff bases preparing the application in antivirotic and insecticide.
Background technique
Trifluoromethyl pyridine substructure occupies more and more important ground due to special property in current Agrochemicals
Position.It is the kind listed after the nineties in last century there are about 2/3, and the introducing of fluorine atom may making in fluoro-containing pesticide kind
Close object bioactivity multiplication, further, since fluorochemical for environment influence it is small, it is less toxic the advantages that, increasingly cause agriculture
The interest of medicine worker.Pyridine heterocycle is that the initiative of novel pesticide opens new direction, is occupied in the development of pesticide important
Status is always the focus of attention during pesticides discovery, also plays an increasingly important role.Therefore, by fluorine and pyridine
The advantages of heterocycle combines, and can effectively play the two, is based on this, has developed fluopicolide, fluazinam, fluorine pyrrole acyl bacterium
The commercially available medicines such as amine, fluorine ether bacterium amide, chlorfluazuron, sulfoxaflor.
Acylhydrazone is schiff base class compound (the Agriculture of Anhui section as made of hydrazides and aldehydes or ketones condensation
Learn, 2010,38 (13): 6644-6645), due to containing a kind of substructure group (- CONHN active well in its molecular structure
=CH-), thus show good antiviral (J.Agric.Food.Chem., 2016,64 (34): 6508-6516), desinsection
(Molecules., 2015,20 (4): 5625-5637), antibacterial (J.Inorg.Biochem., 1998,69 (1): 101-112),
The bioactivity such as weeding (synthesis chemistry, 2013,21 (5): 513-517).Acylhydrazone structure in Schiff bases compound is also to work as
Common group in preceding commercialization pesticide, current registered commercialization pesticide have hydramethylnon, metaflumizone, ferimzone, fluorine pyrrole
Careless hydrazone, pymetrozine etc., they all show good sterilization, desinsection or activity of weeding.
Summary of the invention
It is an object of the invention to spell the substructure of schiff bases and the phthalic amide containing trifluoromethyl pyridine
It connects, a kind of derivative of the schiff bases of the trifluoromethyl pyridine diformamide of structure novel is provided, and prove that such compound exists
The application of anti-virus aspect, compound structure general formula provided by the invention is as shown in I:
In I compound represented of general formula, R1For halogen, C1-C3 alkoxy, C1-C3 alkylthio group, C1-C3 alkyl sulfonyl
Base；R2Be it is monosubstituted or disubstituted, be selected from H, methyl, chlorine, bromine, fluorine, when to be disubstituted, two substituent groups are identical or different；R3
For C1-C3 alkyl, naphthenic base, substituted furan base, substituted thiophene base, substituted pyridinyl, substituted benzene ring, N, N- dimethyl or substitution
Imidazoles.
Further, the compound described in general formula I, R1For Cl, F, methoxyl group, ethyoxyl, methyl mercapto, ethylmercapto group, first
Sulfonyl or ethylsulfonyl；R2For H, 3- methyl, 3,5- dibromos, 2- chlorine, 3- chlorine, 5- chlorine, the chloro- 3- methyl of 5-, 3,5- dichloros or
3,5- difluoro；R3For 2- thienyl, 5- bromopyridine base, pyridyl group, isopropyl, 2- aminomethyl phenyl, 6- bromopyridine base, 3- thiophene
Base, propyl- 2- subunit, 5- methylthiophene base, imidazole radicals, 2- chloropyridine base, 2- methylfuran base, 4- bromothiophene base, 2- chlorphenyl
Or N, N- dimethyl.
Further, R1For Cl, ethylmercapto group or ethylsulfonyl；R2For H, 3- methyl, 5- chlorine, the chloro- 3- methyl of 5-, 3,5-
Dichloro or 3,5- difluoro.
It is again further, of the present invention to be chosen in particular from carefully such as flowering structure, but not limited to this.
The preparation method of the derivative of the schiff bases of trifluoromethyl pyridine amides of the invention, specifically includes following step
It is rapid:
(1) 3- substitution -5- (trifluoromethyl) pyridine carboxylic acid, pyridine, acetonitrile are added into reactor, ice salt bath cools to -5
DEG C, mesyl chloride slowly then is added dropwise to system, stirring is added dropwise, 2- amino-substituted benzoyl is added at one time into system
Acid simultaneously stirs, and pyridine is slowly added dropwise, is added dropwise and continues to stir, mesyl chloride is then slowly added dropwise, continues to stir, removes cryosel
Bath, the reaction was continued after reaction temperature is slowly brought up to room temperature 12-24h, addition water and methylene chloride extraction, takes organic layer mistake
Column obtains intermediate 3；(2) hydrazine hydrate and THF are added in the reactor, addition intermediate 3 is then slowly added dropwise and is dissolved in THF
Mixed liquor, continue to stir at room temperature, the precipitation after a large amount of solids are precipitated in system, residue be added dehydrated alcohol washing,
Filtering, filter cake are washed to obtain intermediate 4 with dehydrated alcohol；(3) intermediate 4, ketone or aldehyde are put into reactor, anhydrous second is added
Alcohol is heated to reflux, and TLC monitoring reaction, after completion of the reaction, the cooling solid dehydrated alcohol-DMF being precipitated recrystallizes to get arriving
Target product I.
Compound provided by the invention can be used as poisons and the pesticide of pest or pesticide addition in preparation prevention and treatment crop disease
Purposes in agent；
Further synthesized compound can be used for preparing prevention and treatment tobacco mosaic virus (TMV), marmor upsilon, potato S
Virus, cucumber mosaic virus, tomato virus disease, pepper virus disease, Virus Diseases of Rice plant virus agent, preferred controlling object are
Tobacco mosaic virus (TMV), cucumber mosaic virus.In addition, synthesized compound can be used for preparing prevention and treatment diamondback moth.
Specific embodiment
The synthetic method of the compounds of this invention (I-1~I-32) is consistent, except that used starting material is only
The difference on substituted base.Formula of the invention is specifically described below by way of the preparating example of the typical compound in part
The preparation method of Compound I, these embodiments are only illustrated preparation method of the invention, rather than to chemical combination of the invention
Object is limited.
The chloro- N- of embodiment 1:3- (2,4- bis- chloro- 6- (cyclopropylcarbamoyl) phenyl) -5- (trifluoromethyl) pyridine acyl
The preparation of amine (I-1)
Step 1: 3- chloro- 5- (trifluoromethyl) the pyridine first of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to system
0.51g (4.43mmol) mesyl chloride is added dropwise, after stirring 5min is added dropwise, 0.5g is added at one time into system
(2.88mmol) 2- amino -3,5- dichlorobenzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), intermediate 6, the chloro- 2- of 8- bis- (3- chloro- 5- (trifluoromethyl) pyridine -2- base) -4H- benzo [d] [1,3] oxazines-are obtained
4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol ketone, aldehyde investment with reflux condensing tube, thermometer there-necked flask in, be added
5mL dehydrated alcohol, is heated to reflux, and is monitored and is reacted with TLC, about 30min end of reaction, the cooling solid dehydrated alcohol-being precipitated
DMF recrystallizes to arrive target product.
Embodiment 2:(E) the chloro- N- of -3- (2- methyl -6- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (fluoroform
Base) picolinamide (I-15) preparation
Step 1: 3- chloro- 5- (trifluoromethyl) the pyridine first of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to system
0.51g (4.43mmol) mesyl chloride is added dropwise, after stirring 5min is added dropwise, 0.34g is added at one time into system
(2.22mmol) 2- amino -3,5- dichlorobenzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), intermediate 2- (3- chloro- 5- (trifluoromethyl) pyridine -2- base) -8- methyl -4H- benzo [d] [1,3] oxazines -4- is obtained
Ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol ketone, aldehyde investment with reflux condensing tube, thermometer there-necked flask in, be added
5mL dehydrated alcohol, is heated to reflux, and is monitored and is reacted with TLC, about 30min end of reaction, the cooling solid dehydrated alcohol-being precipitated
DMF recrystallizes to arrive target product.
Embodiment 3:(E)-N- (2- (2- ((4- bromothiophene -2- base) methylene) hydrazine -1- carbonyl) -4,6- difluorophenyl) -
The preparation of 3- chloro- 5- (trifluoromethyl) picolinamide (I-19)
Step 1: 3- chloro- 5- (trifluoromethyl) the pyridine first of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to system
0.51g (4.43mmol) mesyl chloride is added dropwise, after stirring 5min is added dropwise, 0.38g is added at one time into system
(2.22mmol) 2- amino -3,5- difluoro-benzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), fluoro- 4H- benzo [d] [1, the 3] oxazines-of intermediate 2- (3- chloro- 5- (trifluoromethyl) pyridine -2- base) -6,8- bis- is obtained
4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol ketone, aldehyde investment with reflux condensing tube, thermometer there-necked flask in, be added
5mL dehydrated alcohol, is heated to reflux, and is monitored and is reacted with TLC, about 30min end of reaction, the cooling solid dehydrated alcohol-being precipitated
DMF recrystallizes to arrive target product.
Embodiment 4:(E) the chloro- N- of -3- (the chloro- 2- of 4- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl)
The preparation of picolinamide (I-23)
Step 1: 3- chloro- 5- (trifluoromethyl) the pyridine first of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to system
0.51g (4.43mmol) mesyl chloride is added dropwise, after stirring 5min is added dropwise, 0.38g is added at one time into system
(2.22mmol) 2- amino -5- chlorobenzoic acid simultaneously stirs 10min, and 0.70g (8.87mmol) is slowly added dropwise with constant pressure funnel
Pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then continue to delay with constant pressure funnel
It is slow that 0.51g (4.43mmol) mesyl chloride is added dropwise, continue to stir 1h, removes ice salt bath, be slowly brought up to room temperature to reaction temperature
The reaction was continued afterwards 12h is added water and methylene chloride extraction, organic layer taken to cross column (petroleum ether: ethyl acetate=10:1), obtains
The chloro- 2- of mesosome 6- (3- chloro- 5- (trifluoromethyl) pyridine -2- base) -4H- benzo [d] [1,3] oxazines -4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol ketone, aldehyde investment with reflux condensing tube, thermometer there-necked flask in, be added
5mL dehydrated alcohol, is heated to reflux, and is monitored and is reacted with TLC, about 30min end of reaction, the cooling solid dehydrated alcohol-being precipitated
DMF recrystallizes to arrive target product.
Embodiment 5:(E) the chloro- N- of -3- (the chloro- 6- of 2,4- bis- (2- ((5- methylfuran -2- base) methylene) hydrazine -1- carbonyl)
Phenyl) -5- (trifluoromethyl) picolinamide (I-28) preparation
Step 1: 3- chloro- 5- (trifluoromethyl) the pyridine first of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to system
0.51g (4.43mmol) mesyl chloride is added dropwise, after stirring 5min is added dropwise, 0.46g is added at one time into system
(2.22mmol) 2- amino -3,5- dichlorobenzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), intermediate 6, the chloro- 2- of 8- bis- (3- chloro- 5- (trifluoromethyl) pyridine -2- base) -4H- benzo [d] [1,3] oxazines-are obtained
4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol ketone, aldehyde investment with reflux condensing tube, thermometer there-necked flask in, be added
5mL dehydrated alcohol, is heated to reflux, and is monitored and is reacted with TLC, about 30min end of reaction, the cooling solid dehydrated alcohol-being precipitated
DMF recrystallizes to arrive target product.
Embodiment 6:3- ethylmercapto group-N- (the chloro- 6- of 2,4- bis- (2- (2- aminomethyl phenyl methylene) hydrazine -1- carbonyl) phenyl) -
The preparation of 5- (trifluoromethyl) picolinamide (I-29)
Step 1: 3- ethylmercapto group -5- (trifluoromethyl) pyrrole of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Pyridine formic acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to
0.51g (4.43mmol) mesyl chloride is added dropwise in system, and after stirring 5min is added dropwise, 0.46g is added at one time into system
(2.22mmol) 2- amino -3,5- dichlorobenzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), intermediate 6 is obtained, the chloro- 2- of 8- bis- (3- ethylmercapto group -5- (trifluoromethyl) pyridine -2- base) -4H- benzo [d] [1,3] is disliked
Piperazine -4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol benzaldehyde investment with reflux condensing tube, thermometer there-necked flask in, add
Enter 5mL dehydrated alcohol, be heated to reflux, is monitored and reacted with TLC, about 30min end of reaction, the cooling anhydrous second of solid being precipitated
Alcohol-DMF recrystallizes to arrive target product.
Embodiment 7:3- ethylsulfonyl-N- (the chloro- 6- of 2,4- bis- (2- (2- aminomethyl phenyl methylene) hydrazine -1- carbonyl) benzene
Base) -5- (trifluoromethyl) picolinamide (I-30) preparation
Step 1: the 3- ethylsulfonyl -5- (fluoroform of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Base) pyridine carboxylic acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then slow with constant pressure funnel
Slowly 0.51g (4.43mmol) mesyl chloride is added dropwise to system, after stirring 5min is added dropwise, is added at one time into system
0.46g (2.22mmol) 2- amino -3,5- dichlorobenzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), intermediate 6 is obtained, the chloro- 2- of 8- bis- (3- ethylsulfonyl -5- (trifluoromethyl) pyridine -2- base) -4H- benzo [d] [1,
3] oxazines -4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol Furan Aldehydes investment with reflux condensing tube, thermometer there-necked flask in, add
Enter 5mL dehydrated alcohol, be heated to reflux, is monitored and reacted with TLC, about 30min end of reaction, the cooling anhydrous second of solid being precipitated
Alcohol-DMF recrystallizes to arrive target product.
Embodiment 8:3- ethylmercapto group-N- (the fluoro- 6- of 2,4- bis- (2- (- 2 methylene of 4- bromopyridine) hydrazine -1- carbonyl) benzene
Base) -5- (trifluoromethyl) picolinamide (I-31) preparation
Step 1: 3- ethylmercapto group -5- (trifluoromethyl) pyrrole of 0.5g (2.22mmol) is added into the three-necked flask of 25mL
Pyridine formic acid, 0.7g (8.87mmol) pyridine and 5mL acetonitrile, ice salt bath cool to -5 DEG C, then with constant pressure funnel slowly to
0.51g (4.43mmol) mesyl chloride is added dropwise in system, and after stirring 5min is added dropwise, 0.46g is added at one time into system
(2.22mmol) 2- amino -3,5- difluoro-benzoic acid simultaneously stirs 10min, and 0.70g is slowly added dropwise with constant pressure funnel
(8.87mmol) pyridine, dropwise addition process should keep temperature lower than 0 DEG C, are added dropwise and continue to stir 15min, then use constant pressure addition
Funnel continues that 0.51g (4.43mmol) mesyl chloride is slowly added dropwise, and continues to stir 1h, removes ice salt bath, slowly to reaction temperature
The 12h that is increased to after room temperature that the reaction was continued, is added water and methylene chloride extraction, take organic layer cross column (petroleum ether: ethyl acetate=
10:1), intermediate 6 is obtained, the fluoro- 2- of 8- bis- (3- ethylmercapto group -5- (trifluoromethyl) pyridine -2- base) -4H- benzo [d] [1,3] is disliked
Piperazine -4- ketone.
Step 2: 80% hydrazine hydrate and 2mLTHF are added in 50mL there-necked flask, then it is slowly added dropwise and 1.2g is added
Intermediate is dissolved in the mixed liquor of 5mLTHF, and about 10min is added dropwise to complete, and continues stirring 2 hours at room temperature, is precipitated in system a large amount of
Solid, stops that mixing being transferred in 50mL single port bottle after reacting and sloughs THF solvent, and the washing of 5mL dehydrated alcohol is added in residue,
Filtering, filter cake are washed to obtain white solid with dehydrated alcohol.
Step 3: by 1mmol intermediate, 1mmol4- bromopyridine -2- aldehyde investment is with reflux condensing tube, three mouthfuls of thermometer
In bottle, 5mL dehydrated alcohol is added, is heated to reflux, monitored and reacted with TLC, about 30min end of reaction, the cooling solid being precipitated is used
Dehydrated alcohol-DMF recrystallizes to arrive target product.
Using above-mentioned similar method, the preferred compound of other in this case can be prepared.Synthesized part
It is as follows to close the column such as nuclear magnetic spectrogram data, the physico-chemical property of object:
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- (thiophene -2- methylene) hydrazine -1- carbonyl) phenyl) -5- (fluoroform
Base) picolinamide (I-1): yield 67.5%, white solid, 243-244 DEG C of fusing point；1H 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)13C 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), 18.47.19F NMR
(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C20H13Cl2F3N4O2S[M+H]+:501.01611,
found:501.01526.
N- (2- (2- ((5- bromopyridine -2- base) methylene) hydrazine -1- carbonyl) the chloro- 6- aminomethyl phenyl of -4-) chloro- 5- (three of -3-
Methyl fluoride) picolinamide (I-2): yield 57.0%, white solid, 268-269 DEG C of fusing point；1HNMR(400MHz,DMSO)δ
12.12 (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)13C 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), 121.89,121.35,18.43.19F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):
Calculated for C21H13BrCl2F3N5O2[M+H]+:573.96545,found:573.96423.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- (pyridin-4-yl methylene) hydrazine -1- carbonyl) phenyl) -5- (fluoroform
Base) picolinamide (I-3): yield 56.3%, white solid, 296-297 DEG C of fusing point；1HNMR(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).13C 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,
18.42.19F NMR(376MHz,DMSO)δ-60.88.HR-MS(ESI):Calculated for C21H14Cl2F3N5O2[M+H
]+:496.05494,found:496.05402.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- (2- methyl propylene) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyrrole
Pyridine amide (I-4): yield 64.3%, white solid, 240-241 DEG C of fusing point；1H 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)13C 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), 31.49,20.03,18.46.19F
NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C19H17Cl2F3N4O2[M+H]+:
461.07534,found:461.07413.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl) pyridine
Amide (I-5): yield 76.8%, white solid, 247-249 DEG C of fusing point；1H 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).13C 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), 19.41,18.49.19F NMR(376MHz,DMSO)δ-60.88.HR-MS
(ESI):Calculated for C23H17Cl2F3N4O2[M+H]+:509.07534,found:509.07465.
N- (2- (2- ((6- bromopyridine -3- base) methylene) hydrazine -1- carbonyl) the chloro- 6- aminomethyl phenyl of -4-) chloro- 5- (three of -3-
Methyl fluoride) picolinamide (I-6): yield 53.8%, white solid, 261-262 DEG C of fusing point；1HNMR(400MHz,DMSO)δ
12.10 (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)13C 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), 18.44.19F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):
Calculated for C21H13BrCl2F3N5O2[M+H]+: 573.96545, found:573.96442.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- (thiene-3-yl methylene) hydrazine -1- carbonyl) phenyl) -5- (fluoroform
Base) picolinamide (I-7): yield 56.6%, white solid, 260-261 DEG C of fusing point；1H 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)13C 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,
18.48.19F NMR(376MHz,HDMSO)δ-60.87.HR-MS(ESI):Calculated for C20H13Cl2F3N4O2S[M+
H]+:501.01611,found:501.01483.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- (propyl- 2- subunit) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyridine
Amide (I-8): yield 91.1%, white solid, 245-246 DEG C of fusing point；1H 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).13C 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), 25.57,18.50,18.34.19F NMR(376MHz,DMSO)δ-60.84.HR-MS(ESI):
Calculated for C18H15Cl2F3N4O2[M+H]+:447.05969,found:447.05878.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- ((5- methylthiophene -2- base) methylene) hydrazine -1- carbonyl) phenyl) -5-
(trifluoromethyl) picolinamide (I-9): yield 56.7%, white solid, 247-248 DEG C of fusing point；1H NMR(400MHz,DMSO)
δ 11.74 (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).13C 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), 18.47,15.85.19F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated
for C21H15Cl2F3N4O2S[M+H]+:515.03176,found:515.03113.
N- (2- (2- ((1H- imidazol-4 yl) methylene) hydrazine -1- carbonyl) the chloro- 6- aminomethyl phenyl of -4-) chloro- 5- (three of -3-
Methyl fluoride) picolinamide (I-10): yield 67.2%, white solid, 199-201 DEG C of fusing point；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=3.8Hz), 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 NMR (376MHz, DMSO) δ -60.86.HR-MS (ESI): Calculated for
C19H13Cl2F3N6O2[M+H]+:485.05019,found:485.04910.
The chloro- N- of 3- (the chloro- 2- of 4- (2- ((2- chloropyridine -3- base) methylene) hydrazine -1- carbonyl) -6- aminomethyl phenyl) -5- (three
Methyl fluoride) picolinamide (I-11): yield 73.1%, white solid, 269-270 DEG C of fusing point；1H NMR(400MHz,DMSO)δ
12.22 (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).13C 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,
127.87,126.13,124.35,124.03,18.43.19F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):
Calculated for C21H13Cl3F3N5O2[M+H]+:530.01597,found:530.01508.
The chloro- N- of 3- (4- chloro-2-methyl -6- (2- ((5- methylfuran -2- base) methylene) hydrazine -1- carbonyl) phenyl) -5-
(trifluoromethyl) picolinamide (I-12): yield 86.0%, white solid, 230-231 DEG C of fusing point；1HNMR(400MHz,DMSO)
δ 11.73 (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).13C 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), 116.07,109.09,18.49,13.96.19F
NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for C21H15Cl2F3N4O3[M+H]+:
499.05451,found:499.05328.
N- (2- (2- ((4- bromothiophene -2- base) methylene) hydrazine -1- carbonyl) the chloro- 6- aminomethyl phenyl of -4-) chloro- 5- (three of -3-
Methyl fluoride) picolinamide (I-13): yield 53.4%, white solid, 251-252 DEG C of fusing point；1H NMR(400MHz,DMSO)δ
11.96 (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).13C NMR (101MHz, DMSO) δ 162.87,162.38,154.48,144.52 (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), 109.77,18.44.19F NMR
(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C20H12BrCl2F3N4O2S[M+H]+:
578.92663,found:578.92383.
The chloro- N- of 3- (the chloro- 2- of 4- (2- (2- chlorobenzene methylene) hydrazine -1- carbonyl) -6- aminomethyl phenyl) -5- (trifluoromethyl) pyrrole
Pyridine amide (I-14): yield 71.4%, white solid, 251-252 DEG C of fusing point；1H 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).13C NMR (101MHz, DMSO) δ 162.90,162.52,154.54,144.49 (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), 18.45.19F NMR(376MHz,DMSO)δ-60.87.HR-MS(ESI):Calculated for
C22H14Cl3F3N4O2[M+H]+:529.02072,found:529.02002.
The chloro- N- of 3- (2- methyl -6- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl) picolinamide
(I-15): yield 57.3%, white solid, 242-243 DEG C of fusing point；1H 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).13C 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), 19.41,18.72.19F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):
Calculated for C23H18ClF3N4O2[M+H]+:326.03025,found:326.02969.
The chloro- N- of 3- (the chloro- 2- of 4- (2- ((dimethylamino) methylene) hydrazine -1- carbonyl) -6- aminomethyl phenyl) -5- (trifluoro
Methyl) picolinamide (I-16): yield 90.3%, light yellow solid, 124-126 DEG C of fusing point；1H NMR(400MHz,DMSO)δ
10.59 (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)13C 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,
125.82,124.32,18.77.19F NMR(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for
C18H16Cl2F3N5O2[M+H]+:462.07059,found:462.06979.
The chloro- N- of 3- (2- methyl -6- (2- (thiophene -2- methylene) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyridine
Amide (I-17): yield 62.7%, white solid, 244-245 DEG C of fusing point；1H 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).13C NMR (101MHz, DMSO) δ 163.74,162.78,154.71,144.49 (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), 18.71.19F NMR
(376MHz,DMSO)δ-60.86.HR-MS(ESI):Calculated for C20H14ClF3N4O2S[M+H]+:467.05509,
found:467.05392.
N- (2- (2- ((5- bromopyridine -2- base) methylene) hydrazine -1- carbonyl) -6- aminomethyl phenyl) chloro- 5- (fluoroform of -3-
Base) picolinamide (I-18): yield 77.9%, white solid, 245-246 DEG C of fusing point；1H 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)13C NMR(101MHz,
DMSO) δ 164.14,162.86,154.80,152.57,150.75,146.78,144.48 (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), 121.82,121.23,18.65.19F NMR(376MHz,DMSO)δ-
60.85.HR-MS(ESI):Calculated for C21H14BrClF3N5O2[M+H]+:540.00443,found:
540.00354.
N- (2- (2- ((4- bromothiophene -2- base) methylene) hydrazine -1- carbonyl) -4,6- difluorophenyl) chloro- 5- (trifluoro of -3-
Methyl) picolinamide (I-19): yield 50.6%, white solid, 231-232 DEG C of fusing point；1H NMR(400MHz,DMSO)δ
12.07 (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)13C
NMR (101MHz, DMSO) δ 162.84,160.31 (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)19F NMR
(376MHz, DMSO) δ -60.88, -110.83 (d, J=7.6Hz), -112.10 (d, J=7.7Hz) .HR-MS (ESI):
Calculated for C19H9BrClF5N4O2S[M+H]+:566.93110,found:566.93024.
The chloro- N- of 3- (the fluoro- 6- of 2,4- bis- (2- (thiophene -2- methylene) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyrrole
Pyridine amide (I-20): yield 59.1%, white solid, 234-235 DEG C of fusing point；1H 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)
.13C NMR (101MHz, DMSO) δ 162.81,160.34 (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)19F NMR (376MHz, DMSO) δ -60.88, -110.87 (d, J=8.1Hz), -
111.95 (d, J=8.5Hz) .HR-MS (ESI): Calculated for C19H10ClF5N4O2S[M+H]+:489.02059,
found:489.01941.
The chloro- N- of 3- (the fluoro- 6- of 2,4- bis- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl) picolinamide
(I-21): yield 75.5%, white solid, 250-251 DEG C of fusing point；1H 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)13C NMR (101MHz, DMSO) δ 162.82,160.40 (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 19.92,19.44.19F NMR (376MHz, DMSO) δ -60.89 (s), -110.88 (d, J=7.2Hz), -
111.88 (d, J=7.7Hz) .HR-MS (ESI): Calculated for C22H14ClF5N4O2[M+H]+:497.07982,
found:497.07895.
The chloro- N- of 3- (the chloro- 2- of 4- (2- (thiophene -2- methylene) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyridine acyl
Amine (I-22): yield 45.2%, white solid, 247-248 DEG C of fusing point；1H 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)13C NMR(101MHz,DMSO)δ
(163.10,161.49,150.96,144.69,144.49 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)19F NMR(376MHz,DMSO)δ-60.92.HR-MS(ESI):
Calculated for C19H11Cl2F3N4O2S[M+H]+:487.00046,found:486.99829.
The chloro- N- of 3- (the chloro- 2- of 4- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl) picolinamide (I-
23): yield 52.9%, white solid, 284-285 DEG C of fusing point；1H 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)13C 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), 19.40.19F NMR(376MHz,DMSO)δ-60.94.HR-MS
(ESI):Calculated for C22H15Cl2F3N4O2[M+H]+:495.05969,found:495.05844.
N- (2- (2- ((4- bromothiophene -2- base) methylene) hydrazine -1- carbonyl) -4- chlorphenyl) chloro- 5- of -3- (trifluoromethyl)
Picolinamide (I-24): yield 52.9%, white solid, 254-255 DEG C of fusing point；1H 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)13C
NMR (101MHz, DMSO) δ 163.23,161.51,150.98,144.48 (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), 109.87.19F NMR(376MHz,DMSO)δ-
60.93.HR-MS(ESI):Calculated for C19H10BrCl2F3N4O2S[M+H]+:564.91098,found:
564.91071.
N- (2- (2- ((4- bromothiophene -2- base) methylene) hydrazine -1- carbonyl) -4,6- dichlorophenyl) chloro- 5- (trifluoro of -3-
Methyl) picolinamide (I-25): yield 51.8%, white solid, 252-253 DEG C of fusing point；1H NMR(400MHz,DMSO)δ
12.24 (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).13C NMR (101MHz, DMSO) δ 163.23,161.52,151.01,144.49 (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), 123.84,123.21,109.87.19F NMR
(376MHz,DMSO)δ-60.92.
The chloro- N- of 3- (the chloro- 6- of 2,4- bis- (2- (thiophene -2- methylene) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyrrole
Pyridine amide (I-26): yield 49.2%, white solid, 256-257 DEG C of fusing point；1H 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)
.13C NMR (101MHz, DMSO) δ 163.10,161.50,150.98,144.68,144.50 (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)19F NMR(376MHz,DMSO)
δ-60.92.
The chloro- N- of 3- (the chloro- 6- of 2,4- bis- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl) picolinamide
(I-27): yield 58.2%, light yellow solid, 289-290 DEG C of fusing point；1H 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).13C 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), 19.40.19F NMR(376MHz,DMSO)δ-60.94.HR-MS
(ESI):Calculated for C22H14Cl3F3N4O2[M+H]+:529.02072,found:529.02014.
The chloro- N- of 3- (the chloro- 6- of 2,4- bis- (2- ((5- methylfuran -2- base) methylene) hydrazine -1- carbonyl) phenyl) -5- (three
Methyl fluoride) picolinamide (I-28): yield 45.3%, white solid, 226-228 DEG C of fusing point；1H NMR(400MHz,DMSO)δ
12.23 (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)13C 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),
116.90,109.24,13.98.19F NMR(376MHz,DMSO)δ-60.94.
3- ethylmercapto group-N- (the chloro- 6- of 2,4- bis- (2- (2- methylbenzilidene) hydrazine carbonyl) phenyl) -5- (trifluoromethyl) pyridine
Amide (I-27):1H NMR (400MHz, DMSO) δ 12.22 (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, 3H13C 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), 19.60,14.84,7.68.19F NMR(376MHz,DMSO)δ-60.56.
3- ethylsulfonyl-N- (the chloro- 6- of 2,4- bis- (2- ((5- methylfuran -2- base) methylene) hydrazine -1- carbonyl) phenyl) -
5- (trifluoromethyl) picolinamide (I-30):1H NMR (500MHz, Chloroform) δ 9.04 (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)13C
NMR (101MHz, DMSO) δ 164.36,160.34,156.67,150.63,148.14,144.42 (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), 116.90,109.24,52.6,14.79,7.67.19F
NMR(376MHz,DMSO)δ-61.94.
3- ethylmercapto group-N- (the fluoro- 6- of 2,4- bis- (2- ((5- picoline -2- base) methylene) hydrazine -1- carbonyl) phenyl) -5-
(trifluoromethyl) picolinamide (I-31):
1H NMR (500MHz, Chloroform) δ 8.67 (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)13C 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,
124.92,121.85,121.27,112.78,104.81,24.92,13.02.19F NMR(472MHz,Chloroform)δ-
62.10,-113.10,-125.90.
3- ethylmercapto group-N- (the chloro- 2- of 4- (2- (thiophene -2- methylene) hydrazine -1- carbonyl) phenyl) -5- (trifluoromethyl) pyrrole
Pyridine amide (I-22):1H NMR (400MHz, DMSO) δ 12.24 (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)13C NMR
(101MHz, DMSO) δ 163.21,161.43,150.92,144.74,144.22 (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)19F NMR(376MHz,DMSO)δ-60.65.
It is with resisting tobacco mosaic virus (Tobacco Mosaic Virus, TMV) and the activity of cucumber mosaic virus (CMV)
Example, but do not limit the application that the compounds of this invention resists other viruses.
Embodiment 9:
Resisting tobacco mosaic virus (TMV) biological activity test
Using half leaf withered spot method, using tobacco mosaic virus (TMV) as research object, commercially available Ningnanmycin is comparison medicament, to target
Compound carries out antiviral activity test.
The purifying of TMV virus
Reference literature report method[71], tobacco leaf of the selection inoculation TMV viral time at three weeks or more, ice bath item
Under part, it is ground in 0.2M phosphate buffer, extracting solution is then filtered to obtain by double gauze.Fourth is added to it
15min is stirred after alcohol, 4 DEG C, 10000rpm, centrifugation 20min obtains supernatant, and polyethylene glycol (PEG) and sodium chloride, stirring is added
1h, at 4 DEG C, 10000rpm, centrifugation 20min takes precipitating, and 0.01M PBS is added, and stirs 1h, 4 DEG C, 10000rpm, is centrifuged
15min takes supernatant, and PEG and sodium chloride is added, and stirs 1h, 4 DEG C, 10000rpm, centrifugation 20min takes precipitating that 0.01M is added
PBS stirs 1h, and 4 DEG C, 10000rpm, centrifugation 5min takes supernatant to get TMV viral extract.It is estimated with ultraviolet specrophotometer
Absorbance value at 260nm.
Virus concentration=(A260× dilution ratio)/E1cm 0.1%, 260nm
Living body therapeutic activity of the target compound for TMV virus
Left and right leaf blade size and age identical Nicotiana tabacum leaves are selected, after entire blade is sprinkled with the uniform diamond dust of thin and thick
TMV virus is inoculated on entire blade.After 30min, with water by the diamond dust washes clean on leaf and naturally dry.Later will
Certain density compound solution is applied to left side, and solvent is applied to right side as control.Go out within 3 to 4 days after counting inoculation
The quantity of existing local patholoic change.Each compound is repeated three times.
Living body protection activity of the target compound for TMV virus
Left and right leaf blade size and age identical Nicotiana tabacum leaves are selected, certain density compound solution is applied to a left side
Side, solvent are applied to the right side of Nicotiana tabacum leaves as control.After 20-22 hours, entire blade is sprinkled with the uniform Buddha's warrior attendant of thin and thick
Sand is simultaneously inoculated with TMV virus on entire blade.After 30min, with water by the diamond dust washes clean on leaf.It counts 3 after being inoculated with
The quantity of the local patholoic change occurred to 4 days.Each compound is repeated three times.
Target compound is passivated activity for the living body of TMV virus
By inhibiting virus with compound solution mixing 30min with same volume virus.Select left and right leaf blade size and
Age identical Nicotiana tabacum leaves, entire blade is sprinkled with after uniform diamond dust will spread virus with isometric solvent (DMSO and
Buffer) mixed liquor be seeded in the left sides of Nicotiana tabacum leaves, the right side of the mixture inoculation leaf of solvent and virus is as control.
Count 3 to 4 days local disease parameters occurred after being inoculated with.Each compound is repeated three times.
As a result investigation and analysis
After 3 to 4 days, the local scab number that counter-blade or so occurs, calculating inhibiting rate according to following formula, (" av " is indicated
Average value).
Compound is determined to the guarantor of TMV under 500 μ g/mL concentration according to activity test method described in embodiment 6
Shield, treatment, passivation activity, test result are shown in Table I-1.
The anti-TMV active testing result (500 μ g/mL) of -1 target compound of Table I
Test result shows that under 500 μ g/mL concentration, majority of compounds shows good to excellent treatment, protection
Good therapeutic activity is all had wherein essentially all target product removes outside I-1, I-8, I-14 and I-17 with passivation activity,
And it is significantly better than commercially available medicine virazole, the especially treatment of compound I-9, I-11, I-19, I-23, I-24, I-26 and I-27
Activity is significantly better than commercially available medicine Ningnanmycin.In addition, target compound I-2, I-8, I-10 and I-16 are under 500 μ g/mL concentration
There is significant protective effect to TMV, and be significantly better than virazole (50.4%), the especially protection of compound I-2 and I-8
Activity is slightly better than commercially available medicine Ningnanmycin.Compound I-1, I-2, I-5, I-6, I-9 and I-11 are in 500 μ g/mL simultaneously, display
Preferably than virazole (73.2%) passivation is active out.In particular, the passivation activity of compound I-5 and I-6 are close and are slightly better than
Ningnanmycin.
Embodiment 10:
Anti cucumber mosaic virus (CMV) biological activity test
Using half leaf withered spot method, using tobacco mosaic virus (TMV) as research object, commercially available Ningnanmycin is comparison medicament, to target
Compound carries out antiviral activity test.
CMV purification
Using literature procedure, tobacco leaf of the selection inoculation CMV viral time at three weeks or more adds after removing vein
Enter liquid nitrogen grinding into powder, 0.5M PBS, chloroform and n-butanol is then added, is filtered to get filtrate after homogenate with double gauze, 4 DEG C,
8000rpm, centrifugation 20min take supernatant to get CMV viral extract.
Living body passivation of the target compound to CMV
By inhibiting virus with compound solution mixing 30min with same volume virus.Select left and right leaf blade size and
Age identical amranth multitude leaf, is sprinkled with after uniform diamond dust that (DMSO is gentle with isometric solvent by virus to entire blade
Fliud flushing) mixed liquor be seeded in the left sides of Nicotiana tabacum leaves, the right side of the mixture inoculation leaf of solvent and virus as control,
After 30min, the diamond dust on blade, naturally dry are washed away.Count 6 to 7 days local disease parameters occurred after being inoculated with.Each chemical combination
Object is repeated three times.
As a result investigation and analysis
After 6 to 7 days, the local scab number that counter-blade or so occurs, calculating inhibiting rate according to following formula, (" av " is indicated
Average value).
Compound is determined to the blunt of CMV under 500 μ g/mL concentration according to activity test method described in embodiment 7
Change activity, test result is shown in Table I-2.
The anti-CMV of -2 target compound of Table I is passivated active (500 μ g/mL)
| Compound | It is passivated (%) | Compound | It is passivated (%) |
| 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 |
Embodiment 11: insecticidal activity test
Using leaching leaf feeding method (Pest Manag Sci, 2012,68,801-810), partial target compound pair is tested
The insecticidal activity of diamondback moth.Test result show synthesized compound 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, I-30 are greater than the insecticidal activity of diamondback moth under the concentration of 500mg/L
80%.
Claims (7)
1. a kind of derivative of the schiff bases of diformamide containing trifluoromethyl pyridine, general structure is as shown in I:
In I compound represented of general formula, R1For halogen, C1-C3 alkoxy, C1-C3 alkylthio group or C1-C3 alkyl sulphonyl；R2
Be it is monosubstituted or disubstituted, be selected from H, methyl, chlorine, bromine, fluorine, when to be disubstituted, two substituent groups are identical or different；R3For
C1-C3 alkyl, naphthenic base, substituted furan base, substituted thiophene base, substituted pyridinyl, substituted benzene ring, N, N- dimethyl or substitution miaow
Azoles.
2. compound according to claim 1, it is characterised in that: the R1For Cl, F, methoxyl group, ethyoxyl, first sulphur
Base, ethylmercapto group, mesyl or ethylsulfonyl；R2For H, 3- methyl, 3,5- dibromos, 2- chlorine, 3- chlorine, 5- chlorine, the chloro- 3- first of 5-
Base, 3,5- dichloro or 3,5- difluoro；R3For 2- thienyl, 5- bromopyridine base, pyridyl group, isopropyl, 2- aminomethyl phenyl, 6- bromine pyrrole
Piperidinyl, 3- thienyl, propyl- 2- subunit, 5- methylthiophene base, imidazole radicals, 2- chloropyridine base, 2- methylfuran base, 4- bromothiophene
Base, 2- chlorphenyl or N, N- dimethyl.
3. compound according to claim 2, it is characterised in that: the R1For Cl, ethylmercapto group or ethylsulfonyl；R2For
H, the chloro- 3- methyl of 3- methyl, 5- chlorine, 5-, 3,5- dichloro or 3,5- difluoro.
4. compound according to claim 1-3 is in pesticide or the agriculture of preparation prevention and treatment crop disease viral disease and pest
Purposes in medicine additive.
5. compound according to claim 1-3 preparation prevention and treatment resisting tobacco mosaic virus, marmor upsilon,
Potato virus S, cucumber mosaic virus, tomato virus disease, pepper virus disease, the pesticide of Virus Diseases of Rice plant virus agent or agriculture
Purposes in medicine additive.
6. compound according to claim 1-3 prevents and treats resisting tobacco mosaic virus, cucumber mosaic virus in preparation
The pesticide of plant virus agent or the purposes in pesticides additive agent.
7. compound according to claim 1-3 is in the pesticide or pesticides additive agent of preparation prevention and treatment diamondback moth
Purposes.
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