CN103333164B - The preparation and application study of pyrrole metsulfovax like derivatives - Google Patents
The preparation and application study of pyrrole metsulfovax like derivatives Download PDFInfo
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- CN103333164B CN103333164B CN201310234178.8A CN201310234178A CN103333164B CN 103333164 B CN103333164 B CN 103333164B CN 201310234178 A CN201310234178 A CN 201310234178A CN 103333164 B CN103333164 B CN 103333164B
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Abstract
The preparation method and application research of a kind of new type water oil and molten pyrrole metsulfovax 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：
Description
Technical field
Preparation and bactericidal activity research the present invention relates to pyrrole metsulfovax like derivatives.
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 pesticide always or even the world of medicine is studied has 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 with 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.
Pyrrole metsulfovax is second pyrazole amide series bactericidal agent, as follows
The compound is developed by Mitsui chemistry, is contained simultaneously there are one pyrazole ring and one with branch in structure
Chain thiphene ring.Pyrrole metsulfovax compared with compared with this of early development series bactericidal agent advantageously, with existing carboxyl acylamide fungicide
There is different fungicidal spectrums[26].Indoor and field test results show it not only to rust, the superior activity of sclerotiniose, to ash
Mildew, powdery mildew and scab of apple also show that preferable bactericidal activity, and with other fungicide no interactions resistances, therefore pole has
There may be the new mechanism of action, at present still under study for action.
The dosage form construct of China's pesticide processing is also very unreasonable at present, and missible oil, wettable powder, powders and granules etc. are old
Dosage form is still occupied an leading position, and accounts for about the 75% of total dosage form number, wherein missible oil accounts for about 50%.Contain a large amount of toluene, diformazan in missible oil
The volatile organic solvents such as benzene and methanol cause to seriously endanger, also the mankind are given birth to during production, packaging and use to human body
The environment deposited forms serious pollution.Simultaneously as worldwide crude oil price is constantly soaring, the organic solvents such as dimethylbenzene price is all the way
It raises up and (about reaches 8000 yuan/ton during highest), missible oil product cost is substantially increased.Therefore all or almost without using organic molten
The Water-borne modifications dosage form such as agent, aqueous emulsion and the microemulsion for making disperse matrix with water is valued by people.Water-borne modification dosage form significantly carries
The high safety of pesticide reduces pollution to environment and functional, and is conducive to economize on resources, reduces cost.Because by
To the limitation of solubility in water and chemical stability, the pesticide active ingredient that can be processed into aqua is few.This is just needed
From drug molecule this body structure, water oil and molten pharmacophoric group are introduced, to reach water-soluble and fat-soluble balance.
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.
The purpose of the present invention is the structure from drug molecule in itself, based on pyrrole metsulfovax (Penthiopyrad)
Using derivative synthesis and the Pesticide design synthetic method of active substructure splicing, parent is introduced in non-active target position for compound
The diamine groups of water so as to improve their hydrophily, make its water-soluble --- and oil is molten to reach a new better balance, so as to
Target organisms are improved to their absorption efficiency, reduce the loss of in vitro.The new compound obtained after transformation all has
Such design feature：A part has lipophile (the strong original molecule main part of hydrophobicity), another portion in their molecule
Dividing has hydrophily (level-one, two level or a tertiary amine group existing for protonated form under the conditions of physiology PH).It is such
Water-soluble-molten balance of oil is necessary to drug effectively passes through biomembrane【Susan Milosovich, et
Al.J.Pharm.Sci., 82,227 (1993)】.Therefore, hydrophilic parts can be with the phosphoric acid alkali on the outside of cell membrane in their molecules
Base bonds together to form the high concentration region of drug, and the concentration difference with being formed inside cell membrane can push these drug molecules to enter cell
Film；And when these drug molecules enter after cell membrane, hydrophilic parts will propel the drug through the entrance of cell film inner layer
Cytoplasm eventually arrives at action target spot.
Invention content
The object of the present invention is to provide pyrrole metsulfovax like derivatives and its synthetic method of salt, such compound has excellent
Different bactericidal activity.
Shown in the chemical structure of general formula of pyrrole metsulfovax like derivatives and its salt following (I and II series), part is specific
Tables 1 and 2 is shown in chemical structural formula expression：
Wherein：
N=0,1,2,3,4,5... or (CH2)nRepresent the alkyl with branch；Y represents Cl-, Br-, F-, I-, AcO-, acetyl
Salicylate, citrate, salicylate, p-methyl benzenesulfonic acid root, bisulfate ion or other anions.R1It is former to represent 1-6 carbon
The alkyl of son, the alkoxy of 1-6 carbon atom, 1-6 carbon atom alkenyl or aryl；R2Represent the alkane of 1-6 carbon atom
Base, the alkoxy of 1-6 carbon atom, 1-6 carbon atom alkenyl or aryl；Or R1、R2Selected from such as lower structure：
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：
By pyrrole metsulfovax analog obtained and (n+1)-(dialkyl group) amino -1- chloro things (being prepared), suitable
Solvent in, temperature is for 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..Add in alkaline matter, such as sodium hydride, hydroxide
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, add in diluted acid YH, and temperature is arrived for 0 DEG C
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：Of the present invention chemical combination of the part as shown in general formula I
Table 2：The compounds of this invention of the part 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%.Agriculturally acceptable carrier is further included 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 in, and is added in 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 embodiment
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
1st, the synthesis --- -- of the general formula I shown in the present invention is by taking TM-6 as an example
Four of the sodium hydride and 20mL of 0.13g (3.3mmol) 60% Jing Guo dehydration are added in into 50mL round-bottomed flasks
Hydrogen furans, is stirred at room temperature 10min, and system is white turbid.The 5mL dissolved with 0.6g (1.74mmol) pyrrole metsulfovax analog is added dropwise
Tetrahydrofuran solution has a large amount of bubbles to generate immediately.It is added dropwise again dissolved with 0.28g (2.1mmol) N- after stirring 20min at room temperature
The 5mL tetrahydrofuran solutions of (2- chloroethyls) nafoxidine.Then 65 DEG C of back flow reactions are slowly ramped to, are generated in reaction process
A large amount of yellow solids, reaction solution are yellow turbid.TLC monitors reaction process, and the reaction was complete by about 30h.Revolving removes solvent, adds in
20mL ethyl acetate and 15mL saturated nacl aqueous solutions, liquid separation extraction.Wash organic layer (2 × 15mL), the anhydrous sulphur of organic layer
Precipitation is rotated after sour sodium drying, obtains 0.66g yellow viscous liquids.Crude product is through column chromatography [VPetroleum ether/VEthyl acetate=6/1, add several drops
Triethylamine] isolated 0.47g yellow viscous liquids TM-6, yield 61.0%.
The synthesis --- -- of general formula II shown in the present invention is by taking TM-12 as an example
The middle dichloromethane for adding in 0.17g (0.38mmol) TM-40 and 10mL Jing Guo dehydration into 25mL round-bottomed flasks
Alkane after electromagnetic agitation 5min, is slowly added dropwise under condition of ice bath and passes through aforesaid operations system with the diluted 0.24g of 5mL anhydrous ethers
Standby hydrogen chloride saturation diethyl ether solution.Recession is added dropwise and removes ice bath, the reaction was continued at room temperature, and reaction solution is brown solution.
Stop reaction after 20min, reaction solution is transferred in 50mL round-bottomed flasks, revolving precipitation obtains 0.18g yellowish-brown bulk solids TM-
44, 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 wither, peanut foxiness, apple wheel line, rape sclerotium
(S.sclerotiorum), cucumber grey mold (B.cinerea).
It is spare after activated for examination bacterium using PDA culture medium.Using biomass growth rate measuring method (mycelium
growth rate test).Detailed process is：It aseptically respectively draws in 1mL liquids injection culture dish, adds in 9mL
PDA culture medium, is made 10mg/L drug containing tablets after shaking up, blank control is done with the tablet for adding 1mL aqua sterilisas.With diameter 4mm
Card punch cut bacterium disk along mycelia outer rim, move on drug containing tablet, it is per treatment in triplicate.Culture dish is placed on 24 ± 1
It is cultivated 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；Comparison medicine is pyrrole metsulfovax.
Claims (5)
1. pyrrole metsulfovax like derivatives, such as logical formula (I) or (II) are shown：
N=0,1,2,3,4；Y represents Cl-, Br-, F-, I-, AcO-, acetylsalicylate, citrate, salicylate, to toluene
Sulfonate radical, hydrogen sulfate ion；R1Represent the alkyl of 1~6 carbon atom；R2Represent the alkyl or general formula of 1~6 carbon atom
(I), lead to N, R in formula (II)1、R2It collectively forms such as lower structure：
2. compound as described in claim 1, which is characterized in that lead in formula (I) or (II)：N=1~4；Y represents Cl-, Br-,
F-, I-, AcO-, acetylsalicylate, citrate, salicylate, p-methyl benzenesulfonic acid root, hydrogen sulfate ion；R1And R2It is selected from
N, R in alkyl or logical formula (I), logical formula (II)1、R2It collectively forms such as lower structure：
3. compound described in claim 1 is for activated plant itself disease-resistant performance and prevention and the use of control plant disease
On the way.
4. a kind of fungicide mixture, containing compound described in claim 1 or agriculturally acceptable carrier, living in combination
Property component weight percentage be 1~99%.
A kind of 5. method for controlling plant disease, it is characterised in that：It is a effective amount of as right will to vegetable seeds and foliage applying
Seek the Fungicidai mixtures described in 4.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1146993A (en) * | 1995-04-11 | 1997-04-09 | 三井东压化学株式会社 | Substituted thiophene derivative and agricultural and horticultural fungicide containing the same as active ingredient |
| WO2001056358A2 (en) * | 2000-01-28 | 2001-08-09 | Rohm And Haas Company | Enhanced propertied pesticides |
| CN101115723A (en) * | 2005-02-16 | 2008-01-30 | 巴斯福股份公司 | Pyrazole carboxylic acid anilides, method for the production thereof and agents containing them for controlling pathogenic fungi |
| CN101212899A (en) * | 2005-06-07 | 2008-07-02 | 拜尔农作物科学股份公司 | Carboxamides |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09301974A (en) * | 1996-05-16 | 1997-11-25 | Mitsui Toatsu Chem Inc | Substituted thiophene derivative and germicide for agriculture and horticulture containing the same as active ingredient |
-
2013
- 2013-06-14 CN CN201310234178.8A patent/CN103333164B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1146993A (en) * | 1995-04-11 | 1997-04-09 | 三井东压化学株式会社 | Substituted thiophene derivative and agricultural and horticultural fungicide containing the same as active ingredient |
| WO2001056358A2 (en) * | 2000-01-28 | 2001-08-09 | Rohm And Haas Company | Enhanced propertied pesticides |
| CN101115723A (en) * | 2005-02-16 | 2008-01-30 | 巴斯福股份公司 | Pyrazole carboxylic acid anilides, method for the production thereof and agents containing them for controlling pathogenic fungi |
| CN101212899A (en) * | 2005-06-07 | 2008-07-02 | 拜尔农作物科学股份公司 | Carboxamides |
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Granted publication date: 20180615 |