CN105272971A - Coumarin-triazole compound, agriculturally acceptable salt thereof, preparation, and application thereof - Google Patents
Coumarin-triazole compound, agriculturally acceptable salt thereof, preparation, and application thereof Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The invention discloses a coumarin-triazole compound, agriculturally acceptable salt thereof, preparation, and application thereof. According to a method for preparing a compound 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazole) butanol)-3,4-substituent group coumarin (I) and agriculturally acceptable salt thereof with commercial value and microorganism killing properties, a derivative of a formula (I) is optionally prepared by condensing in an inert organic solvent through 3,4-substituent group-7-umbelliferone (A) and bromo3,3-dimethyl-2-carbonyl-1-(1,2,4-triazole) butane, and both the yield and the purity are good. The invention specifically defines R1, R2, R3 and R4. Optimally, R1 is methyl or halogenated methyl, and R2 is a novel composition of normal-butyl or amyl group. The method provided by the invention can be used for providing the compound of the formula (I) with high yield.
Description
Technical field
The present invention relates to organic chemistry and agriculture field, be specifically related to a kind of tonka bean camphor-triazole class compounds and agriculturally acceptable salt, preparation and application thereof thereof.
Background technology
From early 1960s, Dutch N.V.Philiph.Duphar company has synthesized triamiphos, and the correlative study of triazole bactericidal agent is subject to the extensive concern of research worker.1974, Bayer A.G develops containing l, and first commercial sterilant triazolone of 2,4-triazole, then develops bitertanol again.20th century 80, the nineties, the exploitation of triazole bactericidal agent obtains remarkable progress, successively has more than 20 kind commercialization.Along with deepening continuously of research, the compound of recent development is that activity profile is wide, and except having activity to Powdery Mildew, rust, black spot etc., also have good activity to multiple diseases such as net blotch, Di's mildew, eyeprint diseases, the lasting period is long.
The germicidal action of triazole bactericidal agent realizes by suppressing the biosynthesizing of ergosterol, is the important class belonged in ergosterol biosynthesis inhibitor (EBI).Triazole bactericidal agent mainly suppresses to the biosynthetic restraining effect of ergosterol the C-14 α-demethylation disturbing sterol.C-14-α-demethylation is considered to usually by oxidation cancellation: first it be converted into methylol, then be converted into formyl radical, is finally oxidized to carboxyl, then decarboxylation cancellation.Above-mentioned oxidation cancellation process is carried out under the katalysis of cytochrome P-450.The blocking action of triazole bactericidal agent mainly because the nitrogen heteroatom in sterilant triazole ring is combined with the positive iron atom of the protoheme of cytochrome P-450, and eliminates iron intrinsic the sexadentate-oxygen.Meanwhile, the non-nitrogen hetero moiety of sterilant is combined with the lipophilic position of cytochrome P-450, and occupies the position be generally occupied by C-14 Alpha-Methyl sterol, and the structure and function of microbial film suffers damage, and finally causes the death of somatic cells.
The structure activity relationship of the antifungal triazole compounds of generally acknowledging now is:
(1) triazole class compounds with enzyme on, because triazole ring 4 nitrogen-atoms are combined with the positive iron ion of protoheme porphyrin ring, thus the triazole ring in triazole bactericidal agent is active necessary group, if replace with other group, then anti-microbial activity is lost, in order to make in conjunction with effective, triazole ring is except 4, and other position does not have substituting group;
(2) in binding site, the non-nitrogen position of triazole bactericidal agent is combined with the lipophilic position of Cytochrome P450, thus occupy and be generally position shared by 14-methylsterol, therefore 1 bit substituent of triazole ring requires certain lipotropy, the nitrogen-atoms that azoles ring is 1 and the molecule central carbon atom methylene radical that is connected or is separated by is good, increase methylene radical spacer unit then bacteriostatic activity reduce or lose;
(3) in triazole bactericidal agent molecule.Triazole ring β-position is connected with a polar group usually, and this is in order to form hydrogen bond with the third carboxyl of porphyrin ring, strengthen substrate and enzyme in conjunction with effect;
(4) triazole class compounds is made salt, because the introducing of positive charge in molecule contributes to increasing the solvability of compound and the permeability of film, thus strengthen its antimicrobial acivity.
In addition, triazole bactericidal agent, as systemic fungicide, must possess suitable membrane permeability, metabolic stability, the features such as cutin deposits perviousness, water-soluble, could work from the external point of application that enters into.Therefore the change of side-chain structure (as the change of conjugated system, the introducing etc. of hydrophile/lipophile group), capital affects the electric properties of molecule, lipid and sterically hindered etc., make the binding characteristic etc. of triazole class compounds and target enzyme, thus change the anti-mycotic activity of compound.It is above-mentioned constructional feature and physilogical characteristics that the structure of the triazole bactericidal agent now developed meets substantially, as triazolone, and triadimenol, uniconazole, olefin conversion etc.
But because triazole bactericidal agent is at Antifungi P450
14DMwhile also inhibited to mammiferous P450 system, the health of the mammal especially mankind is worked the mischief; In addition, along with the widespread use of triazole bactericidal agent, antifungal agent resistance sex chromosome mosaicism is on the rise.Find the large focus that new and effective low toxicity antifungal drug has become triazole bactericidal agent research field in recent years.
Tonka bean camphor is that to have benzopyrone be that a class of parent nucleus is present in natural natural product, and coumarins can dissociate or become the form of glycosides to exist, and is mainly distributed in about 150 kind of plant of more than 30 sections.Tonka bean camphor and analogue thereof have good biocompatibility in animal and plant body, and a lot of tonka bean camphor has the effects such as fungicidal activity, pesticide and miticide actility, weeding activity and allelopathic.In the tradition of plant milk extract as disinfectant use in agriculture just having use to be rich in tonka bean camphor among the people.The synthetic operation of simple tonka bean camphor is simple, yield is high, cost is low, is conducive to industrialization.Thus, the novel antimicrobial compound in conjunction with tonka bean camphor and triazole species dominance structure is one of best approach solving triazole bactericidal agent resistance problems and toxicity problem.
Summary of the invention
The invention provides novel Mutiple Targets, efficiently, low toxicity, the antimicrobial tonka bean camphor-triazole class compounds of wide spectrum and in agriculturally acceptable salt, preparation and application thereof.Specifically, the invention provides a class and there is the tonka bean camphor-triazole class compounds shown in following formula I: 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-tonka bean camphor,
R in formula
1, R
2respectively be selected from hydrogen, alkyl, aryl, halogen and polyhalohydrocarbon base;
R
3, R
4respectively be selected from hydrogen, alkyl, halogen and alkoxyl group.
Preferably, R
1for methyl or halogenated methyl, R
2for halogen or n-pentyl or normal-butyl.
Another object of the present invention is to provide tonka bean camphor-triazole class compounds (shown in I formula) at agriculturally acceptable salt, as salt such as its hydrochloride, vitriol, nitrate, acetate.
The present invention also aims to the preparation method that tonka bean camphor-triazole class compounds is provided, concrete steps are as follows: with the ethylphosphonoacetate of the phenols replaced, replacement for starting raw material, under the condition of sulphuric acid catalysis, temperature controls room temperature to 0 DEG C reaction 6 ~ 12 hours, obtain intermediate 3,4-substituting groups-umbelliferone; Under the existence of alkaline catalysts triethylamine, in optional inert solvent, add 1,2,4-triazole, at 70 DEG C, add a chlorine pinacolone participate in reaction, obtain intermediate 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane; 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane reacts with bromine in optional inert solvent, obtains bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane; 3,4-substituting group-umbelliferone again with bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane, obtain tonka bean camphor-triazole class compounds in inert organic solvents condensation reaction.
Further, the phenols of described replacement comprises Resorcinol, the chloro-Resorcinol of 4-;
The ethylphosphonoacetate replaced comprises 2-amyl group methyl aceto acetate, 4-chloroacetyl acetacetic ester, 2-methyl-acetoacetic ester.
The present invention also aims to provide tonka bean camphor-triazole class compounds in the preparation method of agriculturally acceptable salt, concrete steps are as follows: by 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3,4-substituting group tonka bean camphor and acid are under normal temperature condition, be dissolved in E-C mixed solution, slow dropping Glacial acetic acid, be stirred to till generating without white precipitate, dry that white solid reaction is prepared and obtains after filtering, described acid comprises hydrochloric acid, sulfuric acid, nitric acid, acetic acid.
The present invention also aims to provide tonka bean camphor-triazole class compounds (I) and at agriculturally acceptable salt or their solvate or their mixture for the preparation of the purposes of the agricultural chemicals such as antibacterium, fungi and the application prepared in plant protection product.
These and other features of the present invention, aspect and advantage better can be understood with reference to the following description and appended claim.
" about " herein refers to certain preferred operations scope, as the scope of reagent mol ratio, amount and temperature, does not definitely determine.This is obvious to those skilled in the art.Such as, 120 DEG C to 135 DEG C are about to the temperature range that organic chemical reactions is enumerated, other temperature expecting to have and benefit speed of response should be understood to include, such as 105 DEG C or 150 DEG C.Instruct in the experience lacking those of ordinary skill, when lacking from the instructing of article, and do not enumerate more specifically rule time, the scope of " about " should be no more than 10% of an end points absolute value or enumerate 15% of scope, gets less.
Unless otherwise indicated, the present invention's substituting group term " alkyl " used, " alkoxyl group " and " haloalkyl ", be used alone or use as a more macromolecular part, comprise the straight or branched containing at least 1 or 2 carbon atom, as suitable to this substituting group, and be preferably at most 12 carbon atoms, being more preferably 10 carbon atoms at the most, is particularly preferably 5 carbon atoms at the most.Term " aryl " refers to phenyl or naphthyl, is optionally replaced by one or more halogen, alkyl, alkoxyl group or haloalkyl." halogen " or " halo " refers to fluorine, bromine, iodine or chlorine.Term " room temperature " refers to that temperature range is the temperature of about 20 DEG C to 30 DEG C.Some solvent, catalyzer etc. show with their known abbreviations.They comprise abbreviation " DMAC " and refer to N, N N,N-DIMETHYLACETAMIDE, " DMF " refer to N, dinethylformamide, " THF " refer to tetrahydrofuran (THF), " DMAP " refer to 4 dimethyl aminopyridines, " DBN " refer to 1,5 one diazabicylos [4.3.0]-5-in ninth of the ten Heavenly Stems alkene and " DBU " refer to 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.Term " glyme " refers to a kind solvent, comprises a glyme, diglyme, triglyme, tetraethylene glycol dimethyl ether and poly-glyme.
The invention has the advantages that:
1, synthesized 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-tonka bean camphor is structurally distinguished and triazole bactericidal agent in the past, can solve the resistance problems of part triazole bactericidal agent.
2, synthesized 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-tonka bean camphor productive rate in preparation method is higher, and method is environmental protection more.
3, synthesized 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-tonka bean camphor agriculturally the solvability of acceptable salt in water is more superior, environmental protection more compared with organic solvent.
4, synthesized 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-tonka bean camphor finds in antibacterial activity test, to gibberella saubinetii cause of disease bacterium, wheat grey mold pathogenic bacteria, rice banded sclerotial blight cause of disease bacterium has good fungistatic effect.
Accompanying drawing explanation
Fig. 1 is embodiment 1 compound 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-4-methylcoumarin (I-1)
1hNMR collection of illustrative plates.
Embodiment
The synthesis of umbelliferone (A):
Phenols and acyl acetic acid ester, under acid catalysis, temperature controls, room temperature to 0 DEG C reaction 6 ~ 12 hours, to obtain intermediate umbelliferone;
The synthesis of bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane:
Under the existence of alkaline catalysts, in optional inert solvent, add 1,2,4-triazole, at 70 DEG C, add a chlorine pinacolone participate in reaction, obtain intermediate 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane; 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane reacts with bromine in optional inert solvent, obtains bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane;
The synthesis of tonka bean camphor-triazole class compounds:
Under the existence of alkaline catalysts, in optional inert solvent, add formula (A) umbelliferone, at 0 DEG C, add the reaction of bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane.
The inert solvent that preferred at least one is suitable in above-mentioned reaction.
Preferred organic solvent comprises polarity or non-polar solvent, solvent used in the present invention comprises the solvent of halogenation, such as (but being not restricted to) chlorobenzene, tetracol phenixin, Australia's methylene dichloride, two Australia's methyl chloride, three smell methane, chloroform, Australia's methyl chloride, Butyryl Chloride, methylene dichloride, zellon, trieline, 1,1,1 one three chloro-ethane, 1,1,2 one trichloroethane, 1,1 one ethylene dichloride, 2 cbloropropane isopropyl chloride, phenyl-hexafluoride, 2,4 one trichlorobenzene, 1,2-dichlorobenzene, fluorobenzene and other halogenated solvent known in the art.
Preferred polar organic solvent comprises ether, as (but being not restricted to) Methylal(dimethoxymethane), THF, furans, diethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, TRIGLYME, t-butyl methyl ether and other ether known in the art.Other polar organic solvent used in the present invention comprises as (but being not restricted to) third cyanogen, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, Nitromethane 99Min., glyme and other polar solvent known in the art.
Other organic solvent used in the present invention comprises polar aprotic solvent, such as (but being not restricted to) DMF, DMAC, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (pyrimidinone), 1,3-dimethyl-2-imidazolidone, N-methyl adjoins pyrrolidone, methane amide, N-methylacetamide, N-METHYLFORMAMIDE, acetonitrile, dimethyl sulfoxide (DMSO), tetramethylene sulfone, N, N-dimethyl propylene county amine, tetramethyl-urea, hempa county amine and other polar aprotic solvent known in the art.
Protic solvent is comprised for carrying out other organic solvent of the present invention, as (but being not restricted to) water, methyl alcohol, ethanol, 2-nitroethyl alcohol, 2-fluoroethanol, 2,2, oneself other protic solvent of knowing of 2-trifluoroethanol, ethylene glycol, 1-propyl alcohol, 2-propyl alcohol, 2-methyl cellosolve, n-butyl alcohol, 2-butanols, isopropylcarbinol, the trimethyl carbinol, cellosolvo, Diethylene Glycol, 1-.2-or 3-amylalcohol, 2,2-dimethyl-1-propyl alcohol, uncle-amylalcohol, hexalin, methyl-phenoxide, phenylcarbinol, glycerine and this area.Other organic solvent used in the present invention comprises: basic solvent is as (but being not restricted to) 2-, 3-or 4-picoline. pyrroles, tetramethyleneimine, beautiful jade, pyridine, piperidines, triethylamine and other basic solvent known in the art; With varsol as (but being not restricted to) benzene, hexanaphthene, pentane, hexane, toluene, suberane, methylcyclohexane, heptane, ethylbenzene, former, or p-dimethylbenzene, octane, 1,2-indane, nonane, Cai and varsol known in the art.
Wherein, the organic solvent being best suited for synthesis is those low price, can improve initiator solubleness to promote speed of reaction and the minimum compound of solvolysis.If the particularly preferred organic solvent of alkylation carrying out tonka bean camphor (A) is toluene.
When carrying out chemical reaction, during the extensive organic chemical reactions of product needed for especially production commercial quantities, must process multi-solvent and provide enough maintain optimum reaction condition solvent between keep balance.There is provided the available ratio of the solvent of optimum reaction condition and reactant to be about the scope of 2.5/1 to 20/1 (wt/wt), be preferably about the scope of 3/1 to 15/1.
Preferred acid comprises (but being not restricted to): mineral acid, organic acid, acidic oxide and mineral acid acid salt etc.Mineral acid used in the present invention comprises (but being not restricted to) sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid.Organic acid used in the present invention comprises (but being not restricted to) formic acid, acetic acid, tosic acid, phenylformic acid.Acidic oxide used in the present invention comprises (but being not restricted to) five phosphorus oxide, phosphorus pentachloride, sulfurous gas.Mineral acid acid salt used in the present invention comprises (but being not restricted to) sal enixum, sodium pyrosulfate, SODIUM PHOSPHATE, MONOBASIC.
Preferred alkaline catalysts comprises (but being not restricted to): basic metal, alkaline-earth metal and transition metal halide, hydride, oxyhydroxide, supercarbonate, carbonate etc.Metal halide used in the present invention comprises (but being not restricted to) lithium chloride, lithium fluoride, lithiumbromide, lithium iodide, sodium-chlor, Sodium Fluoride, Sodium Bromide, sodium iodide, Repone K, Potassium monofluoride, Potassium Bromide, potassiumiodide, magnesium chloride, magnesium fluoride, magnesium bromide, magnesium iodide, calcium chloride, Calcium Fluoride (Fluorspan), Calcium Bromide, calcium iodide, Silver monobromide and Silver iodide.Metal hydride used in the present invention comprises (but being not restricted to) lithium hydride, sodium hydride, potassium hydride KH, magnesium hydride, hydrolith and barium hydride.Metal hydroxides used in the present invention comprises (but being not restricted to) lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and hydrated barta.Alkali metal bicarbonate salt used in the present invention comprises (but being not restricted to) sodium bicarbonate and saleratus.Metal carbonate used in the present invention comprises (but being not restricted to) sodium carbonate and salt of wormwood.Those skilled in the art according to existing technology can select known in the art can be used as catalyzer other basic metal, alkaline-earth metal and transition metal halide, hydride, oxyhydroxide, supercarbonate and carbonate.
Available alkaline catalysts also comprises alkali metal alcoholates as (but being not restricted to) sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, potassium tert.-butoxide and other alkali metal alcoholates known in the art.Other available alkaline catalysts comprises organic alkylamine and cyclammonium, as (but being not restricted to) methylamine, ethamine, dimethylamine, diethylamine, Trimethylamine 99, triethylamine, ethyl diisopropylamine, butylamine, pyridine, DMAP, 2,6-lutidine, piperidines, piperazine, beautiful jade, quinoline, DBN, DBU and other alkylamine known in the art and cyclammonium.
Preferred bases catalyzer comprises sodium carbonate, salt of wormwood, sodium hydride, triethylamine, pyridine, DMAP, DBN, DBU, sodium methylate, potassium methylate and potassium tert.-butoxide.Particularly preferred alkaline catalysts comprise sodium carbonate, salt of wormwood, DMAP, DBN and DBU.
For the amount existing for alkaline catalysts of the present invention be: the molar ratio range of alkaline catalysts and tonka bean camphor (A) is about 0.0001/1 to about 3/1, preferably this scope is about 0.5/1 to about 2/1.The alkaline catalysts of additional content can also be added, if when such as needing to make reaction accelerate.
Temperature when carrying out the alkylation of chemical reaction as tonka bean camphor (A) depends on that following condition changes: carry out the solvent, reaction pattern (as intermittent type, semibatch or continous way), the alkylating agent that react and/or whether use catalyzer.The alkylation of tonka bean camphor (A) as above herein carries out about 20 hours usually in about 10 DEG C to the temperature of 200 DEG C of scopes, preferably in about envrionment temperature to about carrying out about 10 hours between room temperature-120 DEG C, more than more preferably proceeding to 6 hours.
The present invention can be undertaken by the flow process described in following examples.These embodiments only play explanation, without any restrictions to the present invention, because be obvious to those skilled in the art to disclosed further improvement of the present invention.All these improvement are all considered as within right of the present invention.
Initial substance required for the present invention and reaction component can be prepared by simple method and also can provide in a large number.Another advantage is that reaction method can carry out easily with being separated of reaction product.
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
The preparation of 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-4-methylcoumarin (I-1)
analyse and obtain about 1.43g (84% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-4-methylcoumarin (I1).Fusing point: 138-139 DEG C,
1hNMR (600MHz, CDCl
3) δ: 8.49 (s, 1H), 8.00 (s, 1H), 7.55 ~ 7.51 (d, 1H), 6.99 ~ 7.05 (m, 3H), 6.21 (s, 1H), 2.39 (s, 3H), 1.30 (s, 9H) ppm.
Embodiment 2
7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, the preparation of 4-methylcoumarin (I-2)
ethyl ester solution.This mixture reflux about 6 hours.Filter this mixture, concentrating under reduced pressure removes organic solvent, petrol ether/ethyl acetate (3:1) column chromatography obtains about 1.73g (84% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, 4-methylcoumarin (I2).
Embodiment 3
7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, the preparation of 4-methylcoumarin (I-2)
mL ethyl acetate extracts 3 times.United extraction thing, uses dried over mgso.Filter this mixture, concentrating under reduced pressure removes organic solvent, petrol ether/ethyl acetate (3:1) column chromatography obtains 1.68g (82% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, 4-methylcoumarin (I2).
1HNMR(600MHz，CDCl
3)δ：8.41(s,1H),7.91(s,1H),7.44～7.45(d,1H),6.92～6.95(m,3H),2.54(t,2H),2.28(s,3H),1.41(d,2H),1.27(m,4H),1.22(s,9H),0.81(t,3H)ppm.
Embodiment 4
The preparation of 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3,4-dimethyl tonka bean camphors (I-3)
the 5mL toluene solution of-(1,2,4-triazol radical) butane.This mixture reflux about 4 hours.Filter this mixture, concentrating under reduced pressure removes organic solvent, petrol ether/ethyl acetate (3:1) column chromatography obtains about 1.38g (78.0% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3,4-dimethyl tonka bean camphors (I-3).Fusing point: 146-147 DEG C,
1hNMR (600MHz, CDCl
3) δ: 8.14 (s, 1H), 8.02 (s, 1H), 7.51 ~ 7.55 (d, 1H), 6.99 ~ 7.05 (m, 2H), 6.21 (s, 1H), 2.52 (s, 3H), 2.39 (s, 3H), 1.30 (s, 9H) ppm.
Embodiment 5
The preparation of 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-4-chloromethyl tonka bean camphor (I-4)
chromatography obtains about 1.51g (80.0% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-4-chloromethyl tonka bean camphor (I-4).Fusing point: 155-156 DEG C,
1hNMR (600MHz, CDCl
3) δ: 8.42 (s, 1H), 7.99 (s, 1H), 7.56 ~ 7.58 (d, 1H), 6.99 ~ 7.09 (m, 3H), 6.47 (s, 1H), 4.05 (s, 2H), 1.33 (s, 9H) ppm.
Embodiment 6
The preparation of 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base) tonka bean camphor (I-5)
organic solvent, petrol ether/ethyl acetate (4:1) column chromatography obtains about 1.24g (76.0% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base) tonka bean camphor (I-5).Fusing point: 134-136 DEG C.
1HNMR(600MHz，CDCl
3)δ：8.52(s,1H),8.04(s,1H),7.64(t,J＝7.8Hz,1H),7.45(s,1H),7.09～7.04(m,2H),7.00(d,J＝8.4Hz,1H),6.19(d,J＝8.4Hz,1H),1.29(s,9H)ppm.
Embodiment 7
7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-6-chlorine, the preparation of 4-chloromethyl tonka bean camphor (I-6)
add the 5mL toluene solution of 1.35g (0.0055mol) bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane.This mixture reflux about 6 hours.Filter this mixture, concentrating under reduced pressure removes organic solvent, petrol ether/ethyl acetate (4:1) column chromatography obtains about 1.64g (80.0% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-6-chlorine, 4-chloromethyl tonka bean camphor (I-6).Fusing point: 143-144 DEG C.
1HNMR(600MHz，CDCl
3)δ：8.46(s,1H),7.91(s,1H),7.66(s,1H),7.18(s,1H),7.01(s,1H),6.43(s,1H),4.5(d,2H),1.96(s,9H)ppm..
Embodiment 8
The preparation of 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-6-chlorine 4-methylcoumarin (I-7)
column chromatography obtains about 1.64g (87.0% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-6-chlorine 4-methylcoumarin (I-7).Fusing point: 136-137 DEG C.
1HNMR(600MHz，CDCl
3)δ：8.44(s,1H),7.94(s,1H),7.55(s,1H),7.09(s,1H),6.94(s,1H),6.18(s,1H),2.32(s,3H),1.25(s,9H).ppm.
Embodiment 9
The preparation of chloro-3, the 4-dimethyl tonka bean camphors (I-8) of 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-6-
chloro-3, the 4-dimethyl tonka bean camphors (I-8) of 1.32g (68% yield) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-6-.Fusing point: 125-126 DEG C.
1HNMR(600MHz，CDCl
3)δ：8.44(s,1H),7.922(s,1H),7.53(s,1H),7.04(s,1H),6.97(s,1H),2.27(s,3H),2.10(s,3H),1.25(s,9H)ppm.
Embodiment 10
7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, the preparation of 4-methylcoumarin nitrate (I-9)
By 0.410g (0.01mmol) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, 4-methylcoumarin (I2), be dissolved in 5mL toluene, slowly drip salpeter solution, stir, to generating without white precipitate, filtration is dry afterwards obtains white solid 0.3920g, productive rate: 83%, fusing point: 160 ~ 162 DEG C.
Embodiment 11
7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, the preparation of 4-methylcoumarin acetate (I-10)
By 0.410g (0.01mmol) 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3-n-pentyl, 4-methylcoumarin (I2), be dissolved in 5mL E-C mixed solution, slowly drip Glacial acetic acid, stir, to generating without white precipitate, filtration is dry afterwards obtains white solid 0.350g, productive rate: 74.4%, fusing point: 133 ~ 135 DEG C.
Embodiment 12
Extracorporeal antifungal activity is tested
Compound uses coubling dilution and standard microtiter technique, tests for several frequently seen agriculture fungi.Experimental result judges with minimum inhibitory concentration (MIC) value.
Test adopts the clinical experiment standard (NationalCommitteeforClinicalLaboratoryStandards, NCCLS) meeting United States National Committee and formulate.
Minimum inhibitory concentration (MIC) operates:
Agar dilution is by certain density antibacterials, add and melt and be chilled in the quantitative MH agar of about 50 DEG C, make in the test tube containing finite concentration antibacterials, inoculate tested bacterium, hatch rear observation bacterial growth situation, with lowest concentration of drug contained by the agar test tubes of bacteria growing inhibiting for MIC.
The in vitro anti-microbial activity of table 1 tonka bean camphor-triazole class compounds
Test concentrations is about 125mg/L, and positive reference substance is that triazolone concentration is about 125mg/L
By preliminary active testing, find that the compound surveyed has reasonable effect to the wheat scab that typical BotrytiscinereaParsexFr. causes, wherein comparatively positive control is good for I-1, I-2, I-3, I-4 and I-7 effect; The inhibit activities of compound to the wheat gray mold that typical Fusariumgramineaum causes synthesized outward except I-6, I-8 is similar to reference substance; In the rice sheath blight disease inhibit activities test caused typical Rhizoctoniace-realis, there is larger difference in compound activity, and the activity of I-3, I-7, I-8 is suitable with triazolone, and I-1 effect is better than triazolone.
The present invention is described with as above preferred embodiment, but it will be appreciated by those skilled in the art that the various changes that can use these preferred embodiments, and the present invention can to carry out with diverse ways described herein.Therefore the present invention includes all improvement in spirit and scope that claim defines.
Claims (9)
1. tonka bean camphor-triazole class compounds, is characterized in that, be specially 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3,4-substituting group tonka bean camphors, its structural formula is as shown in (I):
R
1, R
2respectively be selected from hydrogen, alkyl, aryl, halogen and polyhalohydrocarbon base;
R
3, R
4respectively be selected from hydrogen, alkyl, halogen and alkoxyl group.
2. tonka bean camphor-3-triazole compounds as claimed in claim 1, is characterized in that, described R
1methyl or halogenated methyl, R
2halogen or n-pentyl; R
3, R
4hydrogen.
3. tonka bean camphor-triazole class compounds, at an agriculturally acceptable salt, is characterized in that, comprises hydrochloride, vitriol, nitrate, acetate as claimed in claim 1.
4. the preparation method of tonka bean camphor-triazole class compounds as claimed in claim 1, it is characterized in that, with the ethylphosphonoacetate of the phenols replaced, replacement for starting raw material, under the condition of sulphuric acid catalysis, temperature controls room temperature to 0 DEG C reaction 6 ~ 12 hours, obtain intermediate 3,4-substituting groups-umbelliferone; Under the existence of alkaline catalysts triethylamine, in optional inert solvent, add 1,2,4-triazole, at 70 DEG C, add a chlorine pinacolone participate in reaction, obtain intermediate 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane; 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane reacts with bromine in optional inert solvent, obtains bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane; 3,4-substituting group-umbelliferone again with bromo 3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butane, obtain tonka bean camphor-triazole class compounds in inert organic solvents condensation reaction.
5. the preparation method of tonka bean camphor-triazole class compounds as claimed in claim 4, it is characterized in that, the phenols of replacement comprises Resorcinol, the chloro-Resorcinol of 4-; The ethylphosphonoacetate replaced comprises 2-amyl group methyl aceto acetate, 4-chloroacetyl acetacetic ester, 2-methyl-acetoacetic ester.
6. one kind as claimed in claim 3 tonka bean camphor-triazole class compounds in the preparation method of agriculturally acceptable salt, it is characterized in that, by 7-(3,3-dimethyl-2-carbonyl-1-(1,2,4-triazol radical) butanols base)-3,4-substituting group tonka bean camphor and acid are under normal temperature condition, be dissolved in E-C mixed solution, slow dropping Glacial acetic acid, be stirred to till generating without white precipitate, dry that white solid reacts preparation and obtains after filtering, described acid comprises hydrochloric acid, sulfuric acid, nitric acid, acetic acid.
7. tonka bean camphor triazole class compounds according to claim 1 or their agriculturally acceptable salt or their solvate or their mixture are for the preparation of the application of agricultural antibacterials.
8. coumarin azole compound according to claim 1 (I) or their agriculturally acceptable salt or their solvate or their mixture are for the preparation of the application of agricultural antifungal drug.
9. coumarin azole compound according to claim 1 (I) or their agriculturally acceptable salt or their solvate or their mixture are preparing the application in plant protection product.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080269051A1 (en) * | 2004-10-12 | 2008-10-30 | Bayer Corpscience Ag | Fungicidal Active Compound Combinations |
| CN102796085A (en) * | 2012-09-04 | 2012-11-28 | 西南大学 | Coumarin triazole, and preparation method and application thereof |
| CN103848824A (en) * | 2012-12-05 | 2014-06-11 | 江苏七洲绿色化工股份有限公司 | Coumarin-triazole compound as well as preparation method and application thereof |
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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080269051A1 (en) * | 2004-10-12 | 2008-10-30 | Bayer Corpscience Ag | Fungicidal Active Compound Combinations |
| CN102796085A (en) * | 2012-09-04 | 2012-11-28 | 西南大学 | Coumarin triazole, and preparation method and application thereof |
| CN103848824A (en) * | 2012-12-05 | 2014-06-11 | 江苏七洲绿色化工股份有限公司 | Coumarin-triazole compound as well as preparation method and application thereof |
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