CN103333113B - The preparation and application study of fluxapyroxad like derivatives - Google Patents
The preparation and application study of fluxapyroxad like derivatives Download PDFInfo
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- CN103333113B CN103333113B CN201310234180.5A CN201310234180A CN103333113B CN 103333113 B CN103333113 B CN 103333113B CN 201310234180 A CN201310234180 A CN 201310234180A CN 103333113 B CN103333113 B CN 103333113B
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- AXSWVQGDZNGZNT-UHFFFAOYSA-N Cc(c(-c(cc1F)cc(F)c1F)c1)ccc1F Chemical compound Cc(c(-c(cc1F)cc(F)c1F)c1)ccc1F AXSWVQGDZNGZNT-UHFFFAOYSA-N 0.000 description 1
- PAMVJPSIVIBZPC-UHFFFAOYSA-N Cc(cccc1)c1-c(cc1F)cc(F)c1F Chemical compound Cc(cccc1)c1-c(cc1F)cc(F)c1F PAMVJPSIVIBZPC-UHFFFAOYSA-N 0.000 description 1
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Abstract
The preparation method and application research of a kind of new type water oil and molten fluxapyroxad like derivatives and its salt, as shown in general formula (I, II)：Wherein：N=0,1,2,3,4,5... or (CH2)nRepresent the alkyl with branch；Y represents Cl‑, Br‑, F‑, I‑, AcO‑, acetylsalicylate, citrate, salicylate, p-methyl benzenesulfonic acid root, bisulfate ion or other anions.R1Represent the alkenyl or aryl of the alkyl of 16 carbon atoms, the alkoxy of 16 carbon atoms, 16 carbon atoms；R2Represent the alkenyl or aryl of the alkyl of 16 carbon atoms, the alkoxy of 16 carbon atoms, 16 carbon atoms；Or R1、R2Selected from such as lower structure：Ar is selected from one of following group：
Description
Technical field
The present invention relates to the preparations of fluxapyroxad like derivatives and bactericidal activity to study.
Background technology
Amides compound is a kind of important compound with bactericidal activity.It withers rust from first acid amide fungicides
Spirit (carboxin) is since 1966 are successfully developed and listed by advantageous incoming road company (existing Chemtura Corporation), amides chemical combination
The hot spot that the synthesis of object is studied with bactericidal activity becomes always pesticide or even the world of medicine is studied, there is the amides of a large amount of structure novels
Compound and kind report.Since Knott in 1883 has found that the antipyrine containing pyrazole ring has easing pain and diminishing inflammation and antipyretic effect
And nineteen forty-six Thampson has been reported since 2- pyrazoles -5- ketone can inhibit plant growth, pyrazole compound just because of it efficiently
Bioactivity cause the concern of pesticide circle personage.Pyrazolecarboxamide compounds are because containing two kinds of high activity knots of pyrazoles and amide
Structure group, and there is extensive bioactivity, successfully develop many pesticide new varieties.Pyrazole carboxamides pesticide has uniqueness
The mechanism of action, it is safe and efficient, without mutual resistance, and the multi-faceted variation of substituent group can be carried out on pyrazole ring.And pyrazoles -4-
Benzamide type fungicide is one kind that type is more in this kind again.Furametpyr is this series bactericidal agent reported at first, by
SUMITOMO CHEMICAL chemical company develops and develops.The fungicide is excellent to rice sheath blight disease preventive effect, is taken first in Japan in 1996
It must register, and be listed in 1997.Then, as a series of pyrazol acid amide compounds of templated synthesis.
Fluxapyroxad (Fluxapyroxad) is as follows：
The new pyrazole amide series bactericidal agent that the compound BASF AG announces, is succinate dehydrogenase inhibitors.
It gets the Green Light in France, Germany and Britain, the entitled Xemium of registration goods.Field trial shows that the kind is a kind of
Efficient selective fungicide has excellent preventive effect to the disease on cereal crops, soybean, corn and rape, has excellent interior
Conductive activity is inhaled, the lasting period is longer, even if the still bactericidal properties with the active constituent after being transferred on blade；To pathogen
High target, and a variety of germs that resistant strain is generated to triazole type and methoxy acrylic are efficient；It is sterilized with triazole type
Agent combination will produce production-increasing function.Currently, BASF also to U.S. EPA submit registration application, and for the product in the whole world
Range has carried out registration activity.BASF indicates, since Xemium has many-sided selection activity to a variety of important crops, because
This foreground is considerable.
The mode of action of fungicide is mainly protectiveness, therapeutic, eradicant and absorbability etc., no matter which kind of mode will
Ask fungicide active ingredient that good contact occurs with phage surface.The surface of thalline has hydrophily, therefore fungicide must be able to
It is enough affine with the hydrophily after birth superficies of pathogen, can have the ability for penetrating into pathogen cell.Traditional Agricultural
Pharmaceutically dosage form is based on missible oil, wettable powder, powders and granules, along with the development and exploitation of pesticides new formulation, the following meeting
Develop towards directions such as aqua, aqueous emulsion and microemulsions, from this development trend, this is just new to what will be succeeded in developing
More stringent requirements are proposed for pesticide molecule, not only will efficiently, low toxicity, safety and with it is environmental-friendly, while also want to drug molecule
With certain water solubility, directly uses if there is drug molecule good water solubility can be made into aqua, both may be used in this way
To reduce production cost again and can reduce when drug molecule is made into certain preparation need that a large amount of solvents, surfactant, auxiliary agent is added
And environmental pollution caused by bleeding agent etc..
Nitrogen heterocyclic ring and the compound of fluorine atom become the main body of acid amide fungicides research at present.According to statistics, ultra high efficiency
There are about 70% it is nitrogen heterocyclic ring in pesticide, and wherein has about 70% for fluorochemical.Fluoro-containing pesticide has selectivity good, living
Property the high, characteristics such as dosage is few, toxicity is low.
The purpose of the present invention is from the structure of drug molecule itself, with biphenyl pyrrole bacterium amine (Bixafen) for guideization
Object is closed, the phenyl ring containing fluorine atom is introduced, hydrophilic diamine groups is introduced in non-active target position, so as to improve the hydrophilic of them
Property, its bioactivity is improved, keeps its water-soluble --- oil is molten to reach a new better balance, to improve target organisms to it
Absorption efficiency, reduce the loss of in vitro.The new compound obtained after transformation all has a structure in which feature：It
Molecule in a part have lipophile (the strong original molecule main part of hydrophobicity), another part have hydrophily (one
Level-one, two level or tertiary amine group existing for protonated form under the conditions of physiology PH).Such water-soluble-molten balance of oil is
Drug effectively passes through necessary to biomembrane【Susan Milosovich, et al.J.Pharm.Sci., 82,227 (1993)】.
Therefore, hydrophilic parts can bond together to form the high concentration region of drug with the phosphoric acid base on the outside of cell membrane in their molecules, with
The concentration difference formed inside cell membrane can push these drug molecules to enter cell membrane；And when these drug molecules enter cell membrane
After, hydrophilic parts will propel the drug through cell film inner layer and enter cytoplasm, eventually arrive at action target spot.
Invention content
The object of the present invention is to provide fluxapyroxad like derivatives and its synthetic method of salt, such compound has
Excellent bactericidal activity.
Shown in the chemical structure of general formula of fluxapyroxad like derivatives and its salt following (I and II series), part is specific
Chemical structural formula expression see Tables 1 and 2：
Wherein：
N=0,1,2,3,4,5... or (CH2)nRepresent the alkyl with branch；Y represents Cl-, Br-, F-, I-, AcO-, second
Acyl salicylate, citrate, salicylate, p-methyl benzenesulfonic acid root, bisulfate ion or other anions.R1Represent 1-6 carbon
The alkenyl or aryl of the alkyl of atom, the alkoxy of 1-6 carbon atom, 1-6 carbon atom；R2Represent 1-6 carbon atom
The alkenyl or aryl of alkyl, the alkoxy of 1-6 carbon atom, 1-6 carbon atom；Or R1、R2Selected from such as lower structure：
Ar is selected from one of following group：
The more preferred compound of the present invention is：
N=1~4；Y represents Cl-, Br-, F-, I-, AcO-, acetylsalicylate, citrate, salicylate, to toluene sulphur
Acid group, bisulfate ion or other anions；R1, R2Selected from H, C1-C4Alkyl or R1=R2Selected from such as lower structure：
It is prepared by the following method of the general formula compound (I, II) of the present invention：
Reaction path is as follows：
Fluxapyroxad obtained is similar with (n+1)-(dialkyl group) amino -1- chloro things (being prepared), suitable
Solvent in, temperature is 0 DEG C to reacting 1-24 hours obtained products (I) under boiling point.Solvent can be dioxane, benzene, toluene, second
Acetoacetic ester, THF, acetone, n-hexane, carbon tetrachloride, chloroform or dichloromethane etc..Alkaline matter, such as sodium hydride, hydrogen-oxygen is added
Change sodium, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or saleratus etc. are to reacting advantageous.
Product (I), can be dissolved in suitable solvent by product (I) and diluted acid YH, and diluted acid YH is added, and temperature is 0 DEG C and arrives
1-24 hours obtained products (II) are reacted under boiling point.Solvent can be dioxane, benzene, toluene, ethyl acetate, THF, acetone, just
Hexane, carbon tetrachloride, chloroform or dichloromethane etc..
The present invention can also be illustrated with the compound listed in table 1, table 2, but not limit the present invention.
Table 1：Part chemical combination of the present invention as shown in general formula I
Table 2：Part the compounds of this invention as shown in general formula II
General formula (I, II) compound of the present invention has good bactericidal activity, can prevent the infringement of phytopathogen very well.
It is compared compared with similar compound, such compound shows preferably water-soluble and anti-disease activity.
The invention also includes the microbicide compositions with general formula (I, II) compound for active component.In the germicide constituent
The weight percentage of active component is 1-99%.It further include agriculturally acceptable carrier in the microbicide compositions.
The present invention general formula (I, II) compound and its a variety of systems can be made as the microbicide compositions of active component
Agent uses, and especially logical formula (II) can directly be made into aqua use, both reduce the pollution to environment using organic solvent,
The more conducively absorption and conduction of plant again.In these compositions, liquid or solid carrier can also be added, and be added suitable
Surfactant carrys out compounding application.
The present invention general formula (I, II) compound both can be used alone as microbiocidal agent can also coordinate it is other known
Fungicide, insecticide, plant growth regulator or fertilizer mix together.
It should be appreciated that within the scope of the invention as claimed, various changes and transformation can be carried out as needed.
Specific implementation mode
The following example and raw test result can be further utilized to illustrate that the activating plants of the compound of the present invention are disease-resistant
Activity, but it is not intended to limit the present invention.
Synthetic example
The preparation of target compound
1, the synthesis --- -- of general formula I shown in the present invention is by taking TM-2 as an example
Four of the sodium hydride and 20mL of 0.13g (3.2mmol) 60% Jing Guo dehydration are added into 50mL round-bottomed flasks
Hydrogen furans, stirs 10min at room temperature, and system is white turbid.It is added dropwise dissolved with 0.8g (2.1mmol) fluxapyroxad analog N-
The 5mL tetrahydrofuran solutions of [2- (3,4,5- trifluorophenyl)-phenyl] -1- methyl -3- difluoromethyl -4- pyrazolecarboxamides are stood
A large amount of bubbles are generated, 20min is stirred at room temperature after being added dropwise.Then it is added dropwise dissolved with 0.34g (2.5mmol) N, N- diethyl
The 5mL tetrahydrofuran solutions of base -2-chloroethyl amine, and the potassium iodide of catalytic amount is added.65 DEG C or so are slowly ramped to after adding to return
Stream reaction.It is light yellow turbid to have white solid generation, reaction solution in reaction process.TLC monitors reaction process, about reacts for 24 hours
Completely.Revolving removes solvents tetrahydrofurane, and 20mL ethyl acetate and 15mL saturated nacl aqueous solutions, liquid separation extraction is added.Washing
Organic layer (2 × 15mL) rotates precipitation after organic layer anhydrous sodium sulfate, obtains 1.15g yellow viscous liquids.Crude product is through column layer
Analyse [VPetroleum ether/VEthyl acetate=8/1, add a few drop triethylamines] isolated 0.55g yellow solids TM-2, yield 54.5%.
The synthesis of general formula II --- -- is by taking TM-23 as an example shown in the present invention
The middle dichloro that 0.20g (0.41mmol) TM-11 and 10mL are added Jing Guo dehydration into the round-bottomed flask of 25mL
Methane after electromagnetic agitation 5min, is slowly added dropwise under condition of ice bath and passes through aforesaid operations with the diluted 0.13g of 5mL anhydrous ethers
The hydrogen chloride of preparation is saturated diethyl ether solution.Recession is added dropwise and removes ice bath, the reaction was continued at room temperature.Stop reaction after 20min,
Reaction solution is transferred in 50mL round-bottomed flasks, and revolving precipitation obtains 0.21g white bulk solids TM-23, yield 100%.
Other compounds can be obtained by similar approach in table 1, table 2.
The nuclear magnetic data of part of compounds according to the present invention
It is raw to survey example：
In vitro bactericidal activity test has been carried out for newly synthesized list of target compound and has used in vitro Plating.For examination disease
Opportunistic pathogen：Tomato early epidemic germ (A.solani), fusarium graminearum (G.zeae), potato late blight (P.infestans), rice
Line withered (R.sasakii), Phytophthora capsici (P.capsici), cucumber be withered, peanut foxiness, apple wheel line, rape sclerotium
(S.sclerotiorum), cucumber grey mold (B.cinerea).
PDA culture medium is used for examination bacterium, it is spare after activated.Using biomass growth rate measuring method (mycelium
growth rate test).Detailed process is：It aseptically respectively draws in 1mL liquids injection culture dish, 9mL is added
10mg/L drug containing tablets are made in PDA culture medium after shaking up, the tablet to add 1mL aqua sterilisas does blank control.With diameter 4mm
Card punch cut bacterium disk along mycelia outer rim, move in drug containing tablet, it is per treatment in triplicate.Culture dish is placed on 24 ± 1
Culture in DEG C constant incubator.Each processing bacterium disk extension diameter is investigated after 72h, is averaged, the calculating phase compared with blank control
To bacteriostasis rate.
The isolated activity test result of 3 compound TM-1-TM-12 of table
Note：TM-7-TM-12 is hydrochloride, is directly used with aqua；Z is comparison medicine fluxapyroxad.
Claims (5)
1. fluorine azoles bacterium amine derivant, as shown in logical formula (I) and logical formula (II)：
In formulaRepresent alkylidene, n=0,1,2,3,4；Y represents Cl-, Br-, F-, I-, AcO-, acetylsalicylate, lemon
Lemon acid group, salicylate, p-methyl benzenesulfonic acid root, bisulfate ion；R1Represent the alkyl of 1~6 carbon atom；R2Represent 1~6 carbon
N, R in the alkyl of atom or logical formula (I) and logical formula (II)1、R2It can collectively form such as lower structure：
Ar is selected from such as lower structure：
2. compound described in claim 1, which is characterized in that in logical formula (I) and logical formula (II)：N=1~4；Y represents Cl-, Br-,
F-, I-, AcO-, acetylsalicylate, citrate, salicylate, p-methyl benzenesulfonic acid root, bisulfate ion；R1And R2Selected from 1~6
N, R in the alkyl of a carbon atom or logical formula (I) and logical formula (II)1、R2It collectively constitutes such as lower structure：
3. compound described in claim 1 or combinations thereof object is for activated plant itself disease-resistant performance and prevention and control plant
The purposes of disease.
4. a kind of fungicide mixture, containing compound described in claim 1 and agriculturally acceptable carrier, in mixture
The weight percentage of active component is 1~99%.
5. a kind of method of control plant disease, it is characterised in that：To vegetable seeds and a effective amount of claim 4 of foliage applying
The fungicide mixture.
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| CN105418504B (en) * | 2016-01-12 | 2017-12-08 | 四川大学 | The pyrazolecarboxamide compounds of the base containing diaryl-amine and its application in agricultural chemicals |
| CN110669007A (en) * | 2019-10-25 | 2020-01-10 | 浙江工业大学 | 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic ester compound and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731434A (en) * | 2012-07-10 | 2012-10-17 | 南开大学 | Preparation and plant activate antipathogen activity of benzo carboxylate derivatives of 1,2,3-thiadiazole |
| CN102838566A (en) * | 2012-07-10 | 2012-12-26 | 南开大学 | Preparation of 4-methyl-1,2,3-thiadiazolyl-5-formate derivatives with plant activated anti-disease activity |
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| JPH08176112A (en) * | 1994-12-22 | 1996-07-09 | Mitsui Toatsu Chem Inc | N,n'-disubstituted aniline derivative and microbicidal agent for agriculture and horticulture using the derivative as active component |
| US6376548B1 (en) * | 2000-01-28 | 2002-04-23 | Rohm And Haas Company | Enhanced propertied pesticides |
| DE102005007160A1 (en) * | 2005-02-16 | 2006-08-24 | Basf Ag | Pyrazolecarboxylic acid anilides, process for their preparation and compositions containing them for controlling harmful fungi |
| DE102005025989A1 (en) * | 2005-06-07 | 2007-01-11 | Bayer Cropscience Ag | carboxamides |
| US8987307B2 (en) * | 2011-03-03 | 2015-03-24 | Hoffmann-La Roche Inc. | 3-amino-pyridines as GPBAR1 agonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731434A (en) * | 2012-07-10 | 2012-10-17 | 南开大学 | Preparation and plant activate antipathogen activity of benzo carboxylate derivatives of 1,2,3-thiadiazole |
| CN102838566A (en) * | 2012-07-10 | 2012-12-26 | 南开大学 | Preparation of 4-methyl-1,2,3-thiadiazolyl-5-formate derivatives with plant activated anti-disease activity |
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