CN104016985B - A kind of Pyrazolopyrimidine compound and application thereof - Google Patents
A kind of Pyrazolopyrimidine compound and application thereof Download PDFInfo
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- CN104016985B CN104016985B CN201310067016.XA CN201310067016A CN104016985B CN 104016985 B CN104016985 B CN 104016985B CN 201310067016 A CN201310067016 A CN 201310067016A CN 104016985 B CN104016985 B CN 104016985B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero 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
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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Abstract
The invention discloses compound shown in formula I and its it is used as the application in terms of Plant activator, wherein R1It is independently selected from：Hydrogen, C1 C6 alkyl, C1 C6 haloalkyls, C3 C6 cycloalkyl, halogen, nitro, hydroxyl；R2It is independently selected from：C1 C6 alkyl, C1 C6 haloalkyls, hydroxyl, C1 C6 alkoxies, C1 C6 halogenated alkoxies, substituted or unsubstituted C6 C14 aryl, halogen, nitro, amino, C1 C6 alkylaminos, carboxyl, C1 C3 alkoxyl formyls, the heterocycle of 5 yuan or 6 yuan of nitrogenous, oxygen or sulphur；N is selected from 05.The compounds of this invention suppresses pathogen, rather than direct killing or suppression pathogen by inducing plant to produce disease resistance；The advantages of the compounds of this invention possesses systematicness, persistence, broad spectrum activity and security, therefore can reduce the consumption of highly toxic pesticide, it is environment-friendly and with great industrialization, commercialization prospect and market value.
Description
Technical field
The present invention relates to technical field of agriculture science.Specifically, the present invention relates to heterocyclic compound shown in Formulas I and its
Plant is induced to produce the application in anti-insect activity.
Background technology
Agricultural chemicals (Pesticides) is primarily referred to as preventing various diseases (insect, evil mite, line in agriculture forest and husbandry production
Worm, pathogen, weeds and muroid) and coordinate plant growth chemicals.Before the eighties, being mainly used in of agricultural chemicals does harm to thing
" kill ", but since the eighties, the concept of agricultural chemicals has a very large change.Today, people do not focus on " killing ", but
It is more concerned with regulation.Therefore, the objective of modern is that insect pest germ is efficiently prevented and treated, and non-target organism and environment should be pacified
Entirely.
Agricultural chemicals has had the history of very long development in about 150 years in the world, and 70, the eighties, the scientific research of chemical pesticide, open
Send out and produce unprecedentedly active, the novel agricultural chemicals new type of efficient, low toxicity, the mechanism of action, such as pyrethroid, pyrazoles, pyrrole
Pyridine class, nicotinoids, pyroles, process for preparation of benzoylurea compounds；Carbamates, beta-methoxy acrylic ester, benzimidazole
Class, triazole bactericidal agent；Imidazolone type, sulfonylurea herbicide etc. emerge in an endless stream, and promote chemical pesticide to step into and develop rapidly
Fast traffic lane.But the negative effect that is brought to environment of the large-scale use of traditional agricultural chemicals and cause pathogenic microorganism and insect
Drug resistance makes its application power have a greatly reduced quality, and harmful organism is unable to effectively preventing if lacking with agricultural chemicals, often results in agricultural and subtracts
Production, directly influences the development of national economy, and the agricultural chemicals of 21 century progressively develops to the new ideas of biological regulation.
China is a large agricultural country, after liberation, and China's pesticide industry flourishes, and pesticide species and yield are into multiplication
Long, China's agricultural chemicals yield is had been able to the need for meeting agricultural, and has a number of outlet, but kind is still not enough.I
State is every year using pesticidal preparations up to 65~700,000 tons, and active ingredient amount is up to 22~250,000 tons.Harmful organism really can be prevented very
Few, the agricultural chemicals that there are about more than 90% is dissipated in farmland and pollutes environment, and particularly highly toxic pesticide pollution environment is more serious.
Since being delivered first on " the acquisition physiologic immunity of plant " text from Chester K. in 1933, some existing works
Person is summarized it.System resume most study wherein on tobacco, different researchers are antiviral, antimycotic to its
System research, such as tobacco resisting tobacco mosaic virus (TMV), anti-eye spot (Cercospora have been carried out with bacteria resistance
Nicotianae), anti-balck shank (Phytophthora parasitica), downy mildew resistance (Peronospora tabacina),
Antibacterium wildfire (Pseudomonas syrtngae pv.tabaci) etc., and find pathogenesis-related proteins and system is resisted
Characteristic of disease gene coded protein.Eighties of last century beginning of the sixties, Ross researchs tobacco mosaic virus (TMV) proposes botanical system and obtains disease-resistant
Property (systemic acquired resistance, SAR), i.e. when the induction bacterium of necrotic type pathogen or screening infects or certain
After a little chemicals induction processing, some plant can infect generation resistance to subsequent pathogen.And these can induce plant
The biological and chemical agents that thing produces SAR are known as plant disease resistance inductor or activator.
However, so far, the research and development of Plant activator are mostly based on the expansion of 1,2,3- thiadiazoles, this limitation
Cause to be difficult to produce initiative achievement in research.
Therefore, the Plant activator that development and application possesses new mother nucleus structure is badly in need of in this area.
The content of the invention
It is an object of the invention to provide the anti-disease activity rather than direct killing that can induce plant or suppression pathogenic
The heterocyclic compound of body and its application as Plant activator.
In a first aspect, the present invention provides the heterocyclic compound shown in formula I,
In formula,
R1It is independently selected from：Hydrogen, C1-C6 alkyl, C1-C6 haloalkyls, C3-C6 cycloalkyl, halogen, nitro, hydroxyl；
R2It is independently selected from：C1-C6 alkyl, C1-C6 haloalkyls, hydroxyl, C1-C6 alkoxies, C1-C6 halogenated alkoxies,
Substituted or unsubstituted C6-C14 aryl, halogen, nitro, amino, C1-C6 alkylaminos, carboxyl, C1-C3 alkoxyl formyls, 5 yuan
Or the heterocycle of 6 yuan of nitrogenous, oxygen or sulphur；
N is the integer selected from 0-5.
In a preferred embodiment, in formula I, R1It is methyl；R2It is independently selected from：C1-C3 alkyl, C1-C3 alkyl halides
Base, C1-C3 alkoxies, C1-C3 halogenated alkoxies, halogen, nitro；N is the integer selected from 0-5.
In further preferred embodiment, the compound is selected from the group：
In second aspect, the present invention provides a kind of composition of induction plant disease-resistant, includes acceptable in Pesticide Science carry
Body and be used as induction plant disease-resistant active component first aspect present invention described in compound.
In a preferred embodiment, the composition is used to prevent and treat the infringement of bacterium, fungi or virus to plant.
In a preferred embodiment, the composition is used to prevent and treat by muskmelon spherical cavity bacterium (Mycosphaerella
Melonis), the withered bacterium of stem (Corynespora cassiicola), pseudomonas syringae angular leaf spot of cucumber pathological form
(Pseudomonas syringae pv.Lachrymans), phytophthora infestans (Phytophthora infestans (Mont.)
De Bary), thanatephorus cucumeris(frank) donk (Thanatephorus cucumeris (Frank) Donk.), Botrytis cinerea (Botrytis
Cinerea Pers.ex Fr.) or pinch outs cucumber specialized form (Fusarium oxysporum (Schl.) F.sp
Cucumerinum Owen) germ plant disease.
In a preferred embodiment, the plant includes but is not limited to：Cucumber, paddy rice, tomato, wax gourd, soybean tobacco,
Corn, wheat, various flowers etc..
In a preferred embodiment, the composition is bacillary for preventing and treating cucumber blight dis-ease, Cucumber Target Leaf Spot, cucumber
Angular leaf spot, tomato late blight, rice sheath blight disease, gray mold of cucumber or cucumber fusarium axysporum.
In the third aspect, the compound that the present invention provides described in first aspect present invention is preparing the group of induction plant disease-resistant
Purposes in compound.
In a preferred embodiment, the composition is used to prevent and treat the infringement of bacterium, fungi or virus to plant.
In a preferred embodiment, the plant includes but is not limited to：Cucumber, paddy rice, tomato, wax gourd, soybean tobacco.
In a preferred embodiment, the composition is used to prevent and treat by muskmelon spherical cavity bacterium (Mycosphaerella
Melonis), the withered bacterium of stem (Corynespora cassiicola), pseudomonas syringae angular leaf spot of cucumber pathological form
(Pseudomonas syringae pv.Lachrymans), phytophthora infestans (Phytophthora infestans (Mont.)
De Bary), thanatephorus cucumeris(frank) donk (Thanatephorus cucumeris (Frank) Donk.), Botrytis cinerea (Botrytis
Cinerea Pers.ex Fr.) or pinch outs cucumber specialized form (Fusarium oxysporum (Schl.) F.sp
Cucumerinum Owen) germ plant disease.
In a preferred embodiment, the composition is bacillary for preventing and treating cucumber blight dis-ease, Cucumber Target Leaf Spot, cucumber
Angular leaf spot, tomato late blight, rice sheath blight disease, gray mold of cucumber or cucumber fusarium axysporum.
In fourth aspect, the present invention provides a kind of method for inducing plant disease-resistant, and methods described includes：By the present invention first
The composition described in compound or second aspect of the present invention described in aspect is applied to the plant.
The method for preparing compound shown in formula I in fourth aspect, offer of the present invention, methods described includes implementing following close
Into the reaction shown in route：
Using 1- alkyl -4- carboxylate -5- amino-pyrazols and formyl ammonium as initiation material, intermediate A is obtained by reaction；In
Mesosome A is by POCl3Chloro, obtains intermediate B；Intermediate B hydrazinolysis obtains compound C；Intermediate C forms corresponding with various aldehyde
Hydrazone（Methylene diazanyl）Compound P.
R in formula1And R2It is as defined above.
In a preferred embodiment, methods described includes implementing the reaction shown in following synthetic route：
R1It is as defined above.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Embodiment
Inventor is by in-depth study extensively, it was unexpectedly found that using pyrazolopyrimidine shown in the Formulas I of parent nucleus
There is compound outstanding induction plant to produce the activity of disease resistance, can not only mitigate pathogen, such as fungi, bacterium or disease
Threat of the poison to plant, moreover it is possible to the consumption of reduction traditional agricultural chemicals, particularly highly toxic pesticide, it is environmentally friendly.Such compound pole
Have industrialization, commercialization prospect, there is huge market value in international and national, have a extensive future, remarkable in economical benefits.
The present invention is completed on this basis.
Group definition
Term " alkyl " used herein includes side chain and straight chained alkyl, and it generally comprises 1-6 carbon atom, preferably 1-4
Individual carbon atom, more preferably 1-3 carbon atom.The example of alkyl includes but is not limited to：Methyl, ethyl, propyl group, butyl, the tert-butyl group,
Isobutyl group etc..
Term " alkoxy " used herein refers to " alkyl-O- " group, wherein, alkyl can be C1-C6 straight chain or
Branched alkyl, preferably C1-C4 or C1-C3 straight or branched alkyls.Alkoxy available for the present invention includes but is not limited to：Methoxy
Base, ethyoxyl, propoxyl group etc..
Term " aryl " used herein refers to the monocyclic, bicyclic or tricyclic aromatic group containing 6-14 carbon atom.This
Invention aryl used includes but is not limited to：Phenyl, naphthyl, phenanthryl, anthryl, indenyl, Fluorene bases, tetrahydro naphthyl, dihydroindene
Base etc..Aryl optionally by 1-5 (for example, 1,2,3,4 or 5) replace selected from following substituent：Halogen (for example, F,
Cl or Br), C1-4Aldehyde radical, C1-6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, the alkyl of halogen substitution
(include but is not limited to：Trifluoromethyl), the alkoxy (include but is not limited to trifluoromethoxy, bromine propoxyl group etc.) of halogen substitution,
Carboxyl, C1-4Alkoxy, ethoxycarbonyl, N (CH3) and C1-4Acyl group.In a particular embodiment, aryl can be by 1-5
Selected from following substituent group：Halogen ,-OH, C1-4Alkoxy, C1-4Alkyl ,-NO2、-NH2、-N(CH3)2, carboxyl and methylamino ethoxy
Acyl group etc..
" heterocycle " used herein is that, containing 5-10 atom in finger ring, and have 6,10 or 14 electronics in member ring systems
It is upper to share.And institute's ontaining annular atoms are carbon atom and the 1-3 hetero atom selected from oxygen, nitrogen or sulphur.
Useful heteroaryl includes thienyl, furyl, pyranose, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, including
But it is not limited to：2- pyridine radicals, 3- pyridine radicals and 4- pyridine radicals, pyrazinyl, pyrimidine radicals etc..
Heteroaryl optionally can be replaced by 1-5 selected from following substituent：Halogen, C1-4Aldehyde radical, C1-6Straight or branched alkane
Base, cyano group, nitro, amino, hydroxyl, methylol, the alkyl of halogen substitution（Such as trifluoromethyl）, halogen substitution alkoxy
（Such as trifluoromethoxy）, carboxyl, C1-4Alkoxy, ethoxycarbonyl, N (CH3) and C1-4Acyl group.Optionally, except being taken containing fluorine
Outside Dai Ji, others discussed above substituent, such as Cl, Br ,-OH, C can also be contained on aryl1-4Alkoxy, C1-4Alkyl
Chain ,-NO2,-NH2,-N (CH3)2, carboxyl, and ethoxycarbonyl etc..
Term " halogen " used herein refers to fluorine, chlorine, bromine or iodine.Term " halo " refers to by identical or different one
Or the group of multiple above-mentioned halogen atom substitutions, such as trifluoromethyl, pentafluoroethyl group or similar group.
In addition, unless stated otherwise, group of the present invention is " substituted or unsubstituted ", otherwise base of the invention
The substituent that group can be selected from the following group is replaced：Halogen, itrile group, nitro, hydroxyl, amino, C1-6 alkyl-aminos, C1-6 alkane
Base, C2-6 alkenyls, C2-6 alkynyls, C1-6 alkoxies, halo C1-6 alkyl, halo C2-6 alkenyls, halo C2-6 alkynyls, halo
C1-6 alkoxies, pi-allyl, benzyl, C6-12 aryl, C1-6 alkoxy -C 1-6 alkyl, C1-6 alkoxy-carbonyls, carbonyl phenoxy
Base, C2-6 alkynyls-carbonyl, C2-6 alkenyls-carbonyl, C3-6 cycloalkyl-carbonyls, C1-6 alkyl-sulfonyls base, benzoyl, furans
Carbonyl or N, N- Dimethylaminocarbonyl or by it is one or more be selected from halogen, C1-6 haloalkyls, C1-6 alkyl, C1-6
Benzoyl, furanylcarbonyl or N, N- Dimethylaminocarbonyl that the substituent of alkoxy and C1-6 alkyl-carbonyl is replaced etc..
The compounds of this invention
Herein, term " compound of the invention ", " Plant activator of the invention " or " induction of the invention
Active ingredient in the composition of plant disease-resistant " has identical implication, can be each meant following logical with used interchangeably herein
Compound shown in Formulas I,
In formula,
R1It is independently selected from：Hydrogen, C1-C6 alkyl, C1-C6 haloalkyls, C3-C6 cycloalkyl, halogen, nitro, hydroxyl；
R2It is independently selected from：C1-C6 alkyl, C1-C6 haloalkyls, hydroxyl, C1-C6 alkoxies, C1-C6 halogenated alkoxies,
Substituted or unsubstituted C6-C14 aryl, halogen, nitro, amino, C1-C6 alkylaminos, carboxyl, C1-C3 alkoxyl formyls, 5 yuan
Or the heterocycle of 6 yuan of nitrogenous, oxygen or sulphur；
N is the integer selected from 0-5.
In a preferred embodiment, R1It is methyl；R2It is independently selected from：C1-C3 alkyl, C1-C3 haloalkyls, C1-C3 alkane
Epoxide, C1-C3 halogenated alkoxies, halogen, nitro；N is the integer selected from 0-5.
In further preferred embodiment, the compound is selected from the group：
Compound shown in the formula I of the present invention can be prepared by implementing the reaction shown in following synthetic route：
Using 1- alkyl -4- carboxylate -5- amino-pyrazols and formyl ammonium as initiation material, intermediate A is obtained by reaction；In
Mesosome A is by POCl3Chloro, obtains intermediate B；Intermediate B hydrazinolysis obtains compound C；Intermediate C and various aldehyde, for example, replace
Benzaldehyde form corresponding hydrazone（Methylene diazanyl）Compound P.
R in formula1And R2It is as defined above.
In a preference, methods described includes implementing the reaction shown in following synthetic route：
R1And R2It is as defined above.
Induce plant disease-resistant activity
Term " induction plant disease-resistant " used herein has identical meaning with " induction plant disease-resistant activity ", herein
In be used interchangeably.The two represents certain compound in itself and its metabolin has no directly killing or suppresses the work of pathogen
Property, but the immune system of plant can be stimulated and cause plant generation system to obtain the material of disease-resistant performance.Such disease resistance has
Following characteristics：Systematicness, SAR shows the non-induced factor treatment position of plant；Persistence, sustainable several weeks after SAR is produced
Or even some months；Broad spectrum activity, SAR produces inhibitory action to disease caused by some fungies, bacterium, germ simultaneously；Security, these
Derivant does not produce toxic action to germ in itself, but induction plant produces resistance, therefore does not produce side effect to environment.
In a particular embodiment, described " induction plant disease-resistant " represents to prevent and treat pathogen, such as bacterium, fungi or disease
Infringement of the poison to plant.
In a preferred embodiment, described " induction plant disease-resistant " represents to be used to prevent and treat by muskmelon spherical cavity bacterium
(Mycosphaerella melonis), the withered bacterium of stem (Corynespora cassiicola), pseudomonas syringae cucumber angle
Pinta pathological form (Pseudomonas syringae pv.Lachrymans), phytophthora infestans (Phytophthora
Infestans (Mont.) De Bary), thanatephorus cucumeris(frank) donk (Thanatephorus cucumeris (Frank) Donk.), grey grape
Spore (Botrytis cinerea Pers.ex Fr.) or pinch outs cucumber specialized form (Fusarium oxysporum
(Schl.) F.sp cucumerinum Owen) germ plant disease.
In a preferred embodiment, the plant includes but is not limited to：Cucumber, paddy rice, tomato, wax gourd, soybean, cigarette
Grass, corn, wheat, various flowers etc..
In a preferred embodiment, described " induction plant disease-resistant " composition is brown for preventing and treating cucumber blight dis-ease, cucumber
Pinta, cucumber bacterial angular leaf spot, bacterial spot of tomato, tomato late blight, rice sheath blight disease, gray mold of cucumber or cucumber
Droop.
Induce the composition of plant disease-resistant
The present invention also includes the composition of the induction plant disease-resistant containing the compounds of this invention.In specific embodiment
In, 0.01 (weight) %~95 (weight) % the compounds of this invention can be contained in composition of the invention as active component.
In specific embodiment, the composition of induction plant disease-resistant of the invention includes acceptable carrier in Pesticide Science.The agriculture
Pharmaceutically acceptable carrier includes various solid carriers known in the art, liquid-carrier, carrier gas etc..
The solid carrier can be, for example, clay material such as kaolin, diatomite, synthetic hydrated silicon oxide, swelling
The fine powder or particle of soil, Fubasami clays and acid clay；All kinds of talcums, ceramic and other inorganic material such as sericite, stone
English, sulphur, activated carbon, the fine powder or particle of calcium carbonate and hydrated SiO 2；And chemical fertilizer such as ammonium sulfate, ammonium phosphate, nitric acid
The fine powder or particle of ammonium, urea and ammonium chloride.
The liquid-carrier can include for example, water；Alcohols such as methanol and ethanol；Ketone such as acetone and methyl ethyl ketone；
Hydro carbons such as hexane, hexamethylene, kerosene and light oil；Esters such as ethyl acetate and butyl acetate；Nitrile such as acetonitrile and isobutyronitrile；Ethers
If Di Iso Propyl Ether is He dioxane；Amide-type such as DMF and DMA；Halogenated hydrocarbons such as dichloro
Methane, trichloroethanes and carbon tetrachloride；Dimethyl sulfoxide (DMSO)；And vegetable oil such as soya-bean oil and cottonseed oil.
The carrier gas or propellant can include but is not limited to, freon, butane, LPG (liquefied petroleum gas), two
Methyl ether and carbon dioxide.
It can also contain surfactant, such as alkyl sulfate, alkylsulfonate, alkylaryl sulphur in the composition of the present invention
Hydrochlorate, alkyl aryl ether and their polyethylene oxide derivant, polyglycol ether, polyol ester and sugar alcohol derivant.
The composition of the present invention can also contain adjuvant, such as fixative or dispersant, for example, casein, gelatin, many
Sugared (such as starch, gum arabic, cellulose derivative and alginic acid), lignin derivative, bentonite, sugar and such as polyethylene
The synthetic polymers such as alcohol, polyvinylpyrrolidone and polyacrylic acid.
The present invention composition can also contain stabilizer, for example, PAP (isopropyl acid phosphoric acid ester), BHT (2,6- bis--
Tert-butyl -4- methylphenols), the BHA (mixing of 2- tert-butyl -4- metoxyphenols and 3- tert-butyl -4- metoxyphenols
Thing), vegetable oil, mineral oil, surfactant, fitter acids and its ester.
Composition of the invention can be made by the way that various components are mixed with each other.
The composition of the present invention can directly using or use after being diluted with water.In addition, it can with other insecticides,
Nematicide, acaricide, bactericide, mould inhibitor, herbicide, plant growth regulator, synergist, fertilizer, soil conditioner and/
Or animal feed blending uses or does not blend but while use.
On the basis of the composition of induction plant disease-resistant, the present invention also provides a kind of method of controlling plant diseases, side
Method includes by, for example, sprinkling crop, imposes on means such as crop root in soil by the composition of the present invention and be applied to plant.Should
During with the composition of the present invention, those skilled in the art can be according to including preparation type, the number of times of required dispenser, place and applying
With the appropriate amount of application of method, the specific species of pathogen and extent of damage etc. decision and concentration.
Advantages of the present invention：
1. the compounds of this invention provides a kind of brand-new thinking for controlling plant diseases；
2. the compounds of this invention can induce plant to produce the disease resistance for resisting fungi, bacterium or virus；
3. the consumption of traditional agricultural chemicals, particularly highly toxic pesticide can be reduced using the compounds of this invention, it is environmentally friendly；With
4. the compounds of this invention has great industrialization, commercialization prospect and market value, remarkable in economical benefits.
Technical scheme is further described below in conjunction with specific implementation case, but following case study on implementation is not constituted
Limitation of the present invention, the various application processes that all principles and technological means according to the present invention are used, belongs to the present invention
Scope.The experimental method of unreceipted actual conditions in the following example, generally according to normal condition, or is built according to manufacturer
The condition of view.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Embodiment
The synthesis of embodiment 1.4- benzylidene diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-1)
(1) synthesis of 1- methyl pyrazoles [3,4-d] and pyrimidin-4-one
5- amino -1- methylpyrazole -4- carboxylic acid, ethyl esters (2g, 11.8mmol) are weighed in 25mL single-necked flasks, are measured
15mL formamides are added, and are heated to 180 °C of stirring reaction 5h, are subsequently cooled to room temperature, are filtered, ethanol (2 × 8mL) washing, nothing
Need purifying.
(2) synthesis of the chloro- 1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] of 4- and pyrimidine
Weigh 1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidin-4-one (500mg, 3.3mmol) is in 25mL three-necked flasks
In, measure the steamed POCl3 of 5mL weights and add, heating reflux reaction 5h is cooled to room temperature, decompression boils off solvent, by residue
Solid is added in frozen water, and saturated sodium bicarbonate is neutralized, ethyl acetate (25mL) extraction, through saturated sodium bicarbonate solution and water after elder generation
Organic phase is washed, anhydrous sodium sulfate drying rotates solvent evaporated, obtains faint yellow solid 450mg, yield 80%, GC/MS：168.
(3) synthesis of 4- diazanyls -1- methyl pyrazoles [3,4-d] and pyrimidine
Weigh the chloro- 1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] of 4- and pyrimidine (200mg, 1.1mmol) is in 25mL single-necked flasks
In, 5mL absolute ethyl alcohols are added, stirring to substrate is all dissolved, 5mL hydrazine hydrates are slowly added dropwise, 70oC back flow reaction 3h are heated to,
Room temperature is subsequently cooled to, white solid is separated out, filtering, filter cake is washed with cold absolute ethyl alcohol, is dried, is obtained white solid 150mg,
Yield 77%, ESI：164.1.
(4) synthesis of 4- benzylidenes diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-1)
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, measure 10mL absolute ethyl alcohol, 50mg acetic acid be added dropwise, heating stirring to raw material is completely dissolved, weigh benzaldehyde (129mg,
Above-mentioned reaction system 1.2mmol) is added, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, is filtered, filter cake is with anhydrous
Ethanol is washed, and absolute ethyl alcohol is recrystallized to give white solid 130mg, yield 84%, 238.0-240.3 °C of fusing point.1H NMR
(400MHz,DMSO-d6)δ12.09(s,1H),8.38(d,J=2.4Hz,2H),8.28(s,1H),7.80(d,J=7.2Hz,
2H),7.53-7.43(m,3H),3.97(s,3H)。13C NMR(100MHz,DMSO-d6)δ156.5,155.4,154.0,
145.9,134.6,130.3,129.5,127.3,99.7,33.9。HRMS(EI/[M+]):C13H12N6Calculated value:252.1123;
Experiment value:252.1127.
The synthesis of embodiment 2.4- (3- nitros benzylidene)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-2)
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs 3- nitrobenzaldehydes
(184mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, filters, filter cake
Washed with absolute ethyl alcohol, absolute ethyl alcohol is recrystallized to give white solid 153mg, yield 84%, 306.3-308.7 °C of fusing point.1H
NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.51(s,1H),8.40-8.36(m,3H),8.26(dd,J1=8.0Hz,J2
=8.4Hz,2H),7.77(dd,J1=8.0Hz,J2=7.6Hz,1H),3.97(s,3H)。HRMS(EI/[M+]):C13H11N7O2Calculate
Value:297.0974;Experiment value:297.0978.
Embodiment 3.4- (the fluoro- 4- trifluoromethyls benzylidenes of 2-)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-
3) synthesis
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs the fluoro- 4- trifluoromethyls of 2-
Benzaldehyde (234mg, 1.22mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, mistake
Filter, filter cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 181mg, yield 87%, fusing point 247.2-
249.0°C。1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.45-8.37(m,3H),8.24(dd,J1=7.6Hz,J2
=7.6Hz,1H),7.79(d,J=10.8Hz,1H),7.69(d,J=8.4Hz,1H),3.97(s,3H)。13C NMR(100MHz,
DMSO-d6)δ161.4,158.9,156.3,155.2,154.0,137.3,134.4,128.3,126.4,125.0,122.3,
114.299.7,33.9。19F NMR(376MHz,DMSO-d6)δ-61.28,-117.94。HRMS(EI/[M+]):C14H10F4N6Meter
Calculation value:338.0903;Experiment value:338.0907.
The synthesis of embodiment 4.4- (2,3- difluoros benzylidene)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-4)
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs 2,3- difluorobenzaldehydes
(173mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, filters, filter cake
Washed with absolute ethyl alcohol, absolute ethyl alcohol is recrystallized to give white solid 150mg, yield 85%, 290.2-292.5 °C of fusing point.1H
NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.39(s,1H),8.37(s,1H),8.30(s,1H),7.77(dd,J1=
6.4Hz,J2=6.4Hz,1H),7.46(d,J=8.8Hz,1H),7.31(d,J=5.6Hz,1H),3.95(s,3H)。13CNMR
(100MHz,DMSO-d6)δ156.3,155.3,154.0,138.0,134.4,125.8,125.7,124.5,122.5,118.6,
118.4,99.7,33.9。19F NMR(376MHz,DMSO-d6)δ-138.82,-145.96。HRMS(EI/[M+]):C13H10F2N6
Calculated value:288.0935;Experiment value:288.0934.
The conjunction of embodiment 5.4- (2,3,6- trifluoros benzylidene)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-5)
Into
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs 2,3,6- trifluoromethyl benzonitriles
Aldehyde (195mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, filters, filter
Cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 160mg, yield 85%, 284.6-286.0 °C of fusing point.1H
NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.40(s,1H),8.35(s,1H),8.29(s,1H),7.56(d,J=
4.8Hz,1H),7.26(s,1H),3.95(s,3H)。19F NMR(376MHz,DMSO-d6)δ-118.29,-137.70,-
142.13。HRMS(EI/[M+]):C13H9F3N6Calculated value:306.0841;Experiment value:306.0844.
Embodiment 6.4- [(2,3,4,5- tetrafluoros benzylidene)-diazanyl] -1- methyl pyrazoles [3,4-d] and pyrimidine (P-6)
Synthesis
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs 2,3,4,5- phenyl tetrafluorides
Formaldehyde (216mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, filters,
Filter cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 175mg, yield 88%, 313.2-314.1 °C of fusing point
。1H NMR(400MHz,DMSO-d6)δ12.31(s,1H),8.41(s,1H),8.39(s,1H),8.34(s,1H),7.89-7.87
(m,1H),3.95(s,3H)。19F NMR(376MHz,DMSO-d6)δ-138.59,-145.40,-154.61,-156.13。HRMS
(EI/[M+]):C13H8F4N6Calculated value:324.0747;Experiment value:324.0745.
Embodiment 7.4- (the chloro- 4- trifluoromethoxies benzylidenes of 3-)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine
(P-7) synthesis
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs the chloro- 4- trifluoros methoxies of 3-
Benzaldehyde (273mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature,
Filtering, filter cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 192mg, yield 85%, fusing point 219.8-
221.6°C。1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.36(s,1H),8.30(s,1H),8.21(s,1H),
7.96-7.89(m,2H),7.62(d,J=7.6Hz,1H),3.95(s,3H)。13C NMR(100MHz,DMSO-d6)δ155.8,
154.7,153.4,144.3,142.4,135.0,134.0,128.9,126.6,123.3,121.2,118.6,99.1,33.4。19F NMR(376MHz,DMSO-d6)δ-56.95。HRMS(EI/[M+]):C14H10ClF3N6O calculated values:370.0557;Experiment
Value:370.0558.
Embodiment 8.4- (the chloro- 4- trifluoromethyls benzylidenes of 3-)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-
8) synthesis
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs the chloro- 4- trifluoromethyls of 3-
Benzaldehyde (254mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, mistake
Filter, filter cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 200mg, yield 92%, fusing point 282.8-
282.9 °C too accurate.1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.38(s,1H),8.27(s,1H),8.22
(s,1H),7.92-7.86(m,3H),3.95(s,3H)。13C NMR(100MHz,DMSO-d6)δ156.3,155.1,153.9,
142.5,140.3,134.3,131.7,129.7,128.9,127.0,125.5,124.6,121.8,99.7,33.9。19F NMR
(376MHz,DMSO-d6)δ-61.11。HRMS(EI/[M+]):C14H10ClF3N6Calculated value:354.0608;Experiment value:
354.0600。
Embodiment 9.4- (the bromo- 5- trifluoromethyls benzylidenes of 2-)-diazanyl -1- methyl pyrazoles [3,4-d] and pyrimidine (P-
9) synthesis
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs the bromo- 5- trifluoromethyls of 2-
Benzaldehyde (308mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature, mistake
Filter, filter cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 212mg, yield 87%, fusing point 293.0-
295.4°C。1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.60(s,1H),8.40(s,1H),8.20(s,1H),
8.16(s,1H),7.94(d,J=8.8Hz,1H),7.70-7.68(m,1H),3.95(s,3H)。19F NMR(376MHz,DMSO-
d6)δ-61.79。HRMS(EI/[M+]):C14H10BrF3N6Calculated value:398.0102;Experiment value:398.0106.
Embodiment 10.4- [(3- methyl -6- trifluoromethyls benzylidene)-diazanyl] -1- methyl pyrazoles [3,4-d] are simultaneously phonetic
The synthesis of pyridine (P-10)
Weigh 4- diazanyls -1- methyl isophthalic acids-hydrogen-pyrazoles [3,4-d] and pyrimidine (100mg, 609 μm of ol) is in 25mL single-necked flasks
In, 10mL absolute ethyl alcohol is measured, 50mg acetic acid is added dropwise, heating stirring to raw material is completely dissolved, and weighs 3- methyl -6- fluoroforms
Benzaldehyde (229mg, 1.2mmol) adds above-mentioned reaction system, continues heating reflux reaction 2.5h, is subsequently cooled to room temperature,
Filtering, filter cake is washed with absolute ethyl alcohol, and absolute ethyl alcohol is recrystallized to give white solid 190mg, yield 93%, fusing point 270.5-
272.3°C。1H NMR(400MHz,Acetone-d6)δ11.19-11.17(m,1H),8.68(s,1H),8.40(d,J=8.0Hz,
2H),8.24(s,1H),7.72(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),4.02(s,3H),2.57(s,3H)。19F
NMR(376MHz,DMSO-d6)δ-56.39。HRMS(EI/[M+]):C15H13F3N6Calculated value:334.1154;Experiment value:
334.1157。
The plant disease-resistant Activation Activity of embodiment 11. is tested
The present embodiment examines the compounds of this invention as prevention effect of the Plant activator to phytopathogen：
1. experimental subjects：Anti-yellowing melon blight dis-ease, anti-Cucumber Target Leaf Spot, anti-cucumber bacterial angular leaf spot, anti-tomato late blight,
Rice sheath blight disease, gray mold of cucumber, cucumber fusarium axysporum.
2. test concentrations：This test uses 100mg/L test concentrations.
3. method of testing：The good various crops of sowing in advance, and sample is quantitatively weighed, dissolved with DMF and add appropriate surface to live
Property agent, is diluted with water to setting concentration.Using roll-back method 7 days before inoculation, 5 days, 3 days, 1 day, drug-treated is carried out in four times,
Then it is disposable to be inoculated with pathogen simultaneously.Experiment is carried out using pot-culture method, is repeated 3 times.The calculating of disease index and protection effect
Mode is as follows：Disease index=[∑ (the sick numbers of sheets at different levels × relative value of series) × 100]/(investigation total number of sheets × morbidity is at the highest level
Representative numerical value), prevention effect (%)=[(check plot disease index-treatment region disease index) × 100]/check plot state of an illness refers to
Number.
4. experimental result
The present invention employs the disease-resistant work of induction of the method as described above to five kinds of diseases to 10 imidazo thiazine derivatives
Property be tested, early stage compound test activity data as shown in following table 1：
The disease-resistant Activation Activity test result of the compounds of this invention of table 1.
N/A：Do not measure
The compounds of this invention of embodiment 12. suppresses the active testing of phytopathogen
In in vitro bacteriostatic experiment, inventor further tests the compounds of this invention to the suppression of the pathogen or killed
Hinder action activity.
As a result find：Phytopathogen equal unrestraint of the compounds of this invention to test is acted on.So as to further prove this
Invention compound does not possess directly killing or inhibitory action to phytopathogen, but is supported by the disease resistance of activated plant
The infringement of imperial pathogen.
Discuss：
From embodiment 12 as can be seen that the compounds of this invention possesses the activity of controlling plant diseases, in conjunction with the embodiments 12
As a result the compound for further proving the present invention is not direct killing or suppression phytopathogen, but by inducing plant to produce
The disease resistance of each row pathogen is resisted to realize the effect of controlling plant diseases, this with traditional agricultural chemicals, such as jinggangmeisu extremely
It is different.In addition, from embodiment 11 it can also be seen that the compounds of this invention has preventive and therapeutic effect for plurality of plant diseases, therefore
The broad spectrum activity often not possessed with traditional agricultural chemicals.Those skilled in the art also it should be appreciated that, although Traditional Agricultural medicine, such as Jing Gang
Mycin also has good preventive and therapeutic effect to plant disease, but they often have residual, pollution environment etc. in the presence of the single, agricultural chemicals of effect
Open defect.With Traditional Agricultural medicine phases ratio, the compounds of this invention possesses that broad spectrum activity, toxicity is low, advantages of environment protection, and then possesses
High economic value and application prospect.
All documents referred in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (7)
1. the heterocyclic compound shown in formula I,
In formula,
R1It is methyl；
R2It is independently selected from：C1-C3 alkyl, C1-C3 haloalkyls, C1-C3 alkoxies, C1-C3 halogenated alkoxies, halogen, nitro；
N is the integer selected from 0-5.
2. compound as claimed in claim 1, it is characterised in that the compound is selected from the group：
3. a kind of composition of induction plant disease-resistant, comprising acceptable carrier in Pesticide Science and active as induction plant disease-resistant
Compound described in the claim 1 or 2 of composition.
4. composition as claimed in claim 3, it is characterised in that the composition is used to prevent and treat bacterium, fungi or viral right
The infringement of plant.
5. the composition as described in claim 3 or 4, it is characterised in that the composition is used to prevent and treat cucumber blight dis-ease, cucumber
Brown spot, cucumber bacterial angular leaf spot, tomato late blight, rice sheath blight disease, gray mold of cucumber or cucumber fusarium axysporum.
6. purposes of the compound in the composition for preparing induction plant disease-resistant described in claim 1 or 2.
7. a kind of method for inducing plant disease-resistant, it is characterised in that methods described includes：By the chemical combination described in claim 1 or 2
Composition described in thing or claim 3 or 4 is applied to the plant.
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| WO2004009596A2 (en) * | 2002-07-23 | 2004-01-29 | Smithkline Beecham Corporation | Pyrazolopyrimidines as kinase inhibitors |
| WO2004009602A1 (en) * | 2002-07-23 | 2004-01-29 | Smithkline Beecham Corporation | Pyrazolopyrimidines as kinase inhibitors |
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| WO2003037898A1 (en) * | 2001-10-31 | 2003-05-08 | Bayer Healthcare Ag | Pyrimido [4,5-b] indole derivatives |
| WO2004009596A2 (en) * | 2002-07-23 | 2004-01-29 | Smithkline Beecham Corporation | Pyrazolopyrimidines as kinase inhibitors |
| WO2004009602A1 (en) * | 2002-07-23 | 2004-01-29 | Smithkline Beecham Corporation | Pyrazolopyrimidines as kinase inhibitors |
| WO2005117909A2 (en) * | 2004-04-23 | 2005-12-15 | Exelixis, Inc. | Kinase modulators and methods of use |
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