Patent Application
20080108686
The present invention relates to N-(ortho-phenyl)-1-methyl-3-difluoromethylpyrazole-4-carboxanilides of the formula I
in which the substituents are as defined below:
R1 and R2 independently of one another are halogen, C1-C6-alkyl, C1-C6-haloalkyl, cyano, nitro, methoxy, trifluoromethoxy or difluoromethoxy.
Moreover, the invention relates to a method for controlling harmful fungi using the compounds I and to the use of the compounds I for preparing fungicidal compositions.
N-(ortho-Phenyl)-1-methyl-3-difluoromethylpyrazole-4-carboxanilides are known from EP-A 0589301, which also discloses a process for their preparation and a list of possible mixing partners from the group of the fungicides, bactericides, acaricides, nematicides and insecticides.
WO 01/42223 likewise discloses N-(ortho-phenyl)-1-methyl-3-difluoromethylpyrazole4-carboxanilides which are monosubstituted at the phenyl ring.
However, the 1-methyl-3-difluoromethylpyrazole-4-carboxanilides described are, in particular at low application rates, not entirely satisfactory.
It was an object of the present invention to provide novel 1-methyl-3-difluoromethyl-pyrazole4-carboxanilides having improved fungicidal action, in particular at low application rates.
Accordingly, we have found the compounds of the formula I defined at the outset.
Preference is given to N-(ortho-phenyl)-1-methyl-3-difluoromethylpyrazole-4-carboxanilides of the formula I
in which the substituents are as defined below:
R2 and R2 independently of one another are fluorine, chlorine, cyano, methyl, methoxy or trifluoromethyl.
Preference is furthermore given to compounds of the formula I in which R1 and R2 independently of one another are fluorine, chlorine, cyano or methoxy.
Particular preference is given to compounds of the formula I in which R1 and R2 independently of one another are fluorine or chlorine.
Very particular preference is given to compounds of the formula I in which R1 and R2 are located in the 3- and 4-positions of the phenyl ring.
From among the compounds I according to the invention, preference is given to compounds of the formulae Ia to If listed in the tables below.
In the context of the present invention, halogen denotes fluorine, chlorine, bromine and iodine and in particular fluorine and chlorine.
The term “alkyl” comprises straight-chain and branched alkyl groups. They are preferably straight-chain or branched C1-C6-alkyl groups. Examples of alkyl groups are alkyl such as, in particular, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.
Haloalkyl is an alkyl group as defined above which is partially or fully halogenated by one or more halogen atoms, in particular fluorine and chlorine. Preferably, 1 to 3 halogen atoms are present, and the difluoromethyl and the trifluoromethyl groups are particularly preferred.
Processes for preparing the compounds of the formula F are known from EP-A 0 589 301.
For example, 1-methyl-3-difluoromethylpyrazolecarbonyl halides of the formula II are reacted with an aniline of the formula III to give the compounds of the formula I:
The radical Hal in the formula II denotes a halogen atom, such as chlorine, bromine and iodine, in particular chlorine or bromine.
This reaction is usually carried out at temperatures of from −20° C. to 100° C., preferably from 0° C. to 50° C.
Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as methylene chloride, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol and also dimethyl sulfoxide and dimethylformamide, particularly preferably toluene and tetrahydrofuran.
It is also possible to use mixtures of the solvents mentioned.
Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide und calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides, such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, and organometallic compounds, in particular alkali metal alkyls, such as methyllithium, butyllithium and phenyllithium, alkylmagnesium halides, such as methyl-magnesium chloride, and also alkali metal und alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and dimethoxymagnesium, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, triisopropylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and also bicyclic amines.
Particular preference is given to using triethylamine and pyridine.
The bases are generally employed in equimolar amounts, based on the compound II. However, they can also be employed in an excess of from 5 mol-% to 30 mol-%, preferably 5 mol-% to 10 mol-%, or—in the case of tertiary amines—as solvents, if appropriate.
The starting materials are generally reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ II in an excess of from 1 mol-% to 20 mol-%, preferably 1 mol-% to 10 mol-%, based on III.
The compounds I according to the invention can, in the application form as fungicides, also be present together with other active compounds, e.g. with herbicides, insecticides, growth regulators, fungicides or else with fertilizers. On mixing the compounds I or the compositions comprising them in the application form as fungicides with other fungicides, in many cases an expansion of the fungicidal spectrum of activity is obtained.
The following list of fungicides, with which the compounds according to the invention can be used in conjunction, is intended to illustrate the possible combinations but does not limit them:
The compounds of the formula I are distinguished by being highly active against a wide range of phytopathogenic fungi, in particular from the classes of the Ascomycetes, Basidiomycetes, Phycomycetes and Deuteromycetes. Some of them act systemically and can therefore also be used as foliar and soil-acting fungicides. They can also be employed for seed-dressing.
They are particularly important in the control of a multitude of fungi on various cultivated plants, such as cotton, vegetable species (for example cucumbers, beans, tomatoes, potatoes and cucurbits), barley, grass, oats, bananas, coffee, corn, fruit species, rice, rye, soya, grapevines, wheat, ornamental plants, sugar cane and also on a large number of seeds.
They are particularly suitable for controlling the following phytopathogenic fungi: Blumeria graminis (powdery mildew) on cereals, Erysiphe cichoracearum and Sphaerotheca fuliginea on cucurbits, Podosphaera leucotricha on apples, Uncinula necator on grapevines, Puccinia species on cereals, Rhizoctonia species on cotton, rice and lawns, Ustilago species on cereals and sugar cane, Venturia inaequalis (scab) on apples, Helminthosporium species on cereals, Septoria nodorum on wheat, Botrytis cinerea (gray mold) on strawberries, vegetables, ornamental plants and grapevines, Cercospora arachidicola on peanuts, Pseudocercosporella herpotrichoides on wheat and barley, Pyricularia oryzae on rice, Phytophthora infestans on potatoes and tomatoes, Plasmopara viticola on grapevines, Pseudoperonospora species on hops and cucumbers, Alternaria species on fruit and vegetables, Mycosphaerella species on bananas and also Fusarium and Verticillium species, Phakopsora pachyrhizi and also P. meibomiae on soya.
Depending on the desired effect, the application rates of the compounds of the formula I according to the invention are, in particular in the case of areas under agricultural cultivation, from 0.01 to 8 kg/ha, preferably from 0.1 to 5 kg/ha, in particular from 0.1 to 3.0 kg/ha.
For the compound 1, the application rates are in particular from 0.01 to 1 kg/ha, preferably from 0.05 to 0.5 kg/ha, in particular from 0.05 to 0.3 kg/ha.
In seed-dressing, application rates of mixture are generally from 0.001 to 250 g/kg of seed, preferably from 0.01 to 100 g/kg, in particular from 0.01 to 50 g/kg.
In the control of phytopathogenic harmful fungi, the application of the compound I is carried out by spraying or dusting the seeds, the plants or the soils before or after sowing of the plants or before or after emergence of the plants.
The fungicidal compounds I according to the invention can be prepared, for example, in the form of directly sprayable solutions, powders and suspensions or in the form of highly concentrated aqueous, oily or other suspensions, dispersions, emulsions, oil dispersions, pastes, dustable products, compositions for broadcasting or granules and be applied by spraying, atomizing, dusting, broadcasting or pouring. The use form depends on the particular intended purpose; in each case, it should ensure as fine and even a distribution as possible of the mixture according to the invention.
The formulations are prepared in a manner known per se, for example by adding solvents and/or carriers, if desired using emulsifiers and dispersants. Solvents/auxiliaries suitable for this purpose are essentially:
emulsifiers, such as nonionic and anionic emulsifiers (for example polyoxyethylene fatty alcohol ethers, alkylsulfonates and arylsulfonates), and dispersants, such as lignosulfite waste liquors and methylcellulose.
Suitable surfactants are alkali metal, alkaline earth metal and ammonium salts of aromatic sulfonic acids, for example lignosulfonic acid, phenolsulfonic acid, naphthalenesulfonic acid and dibutylnaphthalenesulfonic acid, and also of alkylarylsulfonates, alkyl sulfates, fatty acids, alkylsulfonates and lauryl ether sulfates, fatty alcohol sulfates, and salts of sulfated hexa-, hepta- and octadecanols or fatty alcohol glycol ethers, condensates of sulfonated naphthalene and naphthalene derivatives with formaldehyde, condensates of naphthalene or of naphthalenesulfonic acid with phenol and formaldehyde, polyoxyethylene octylphenol ethers, ethoxylated isooctylphenol, octylphenol or nonylphenol, alkylphenyl polyglycol ethers or tributylphenyl polyglycol ethers, alkylaryl polyether alcohols, isotridecyl alcohol, fatty alcohol ethylene oxide condensates, ethoxylated castor oil, polyoxyethylene alkyl ethers or polyoxypropylene, lauryl alcohol polyglycol ether acetate, sorbitol esters, lignosulfite waste liquors or methylcellulose.
Powders, compositions for broadcasting and dustable products can be prepared by mixing or concomitantly grinding the compound I with a solid carrier. Granules (for example coated granules, impregnated granules and homogeneous granules) are usually prepared by binding the active compound(s) onto a solid carrier.
Examples of fillers and solid carriers are mineral earths, such as silica gels, silicas, silicates, talc, kaolin, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic materials, and fertilizers, such as, ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas, and products of vegetable origin, such as cereal meal, tree bark meal, wood meal and nutshell meal, cellulose powders and other solid carriers.
In general, the formulations comprise from 0.1 to 95% by weight, preferably from 0.5 to 90% by weight, of the compound 1.
The active compounds are employed in a purity of from 90% to 100%, preferably 95% to 100% (according to the NMR spectrum or HPLC).
The following are examples of formulations: 1. Products for dilution with water
A) Water-soluble concentrates (SL)
10 parts by weight of the active compounds are dissolved in water or in a water-soluble solvent. As an alternative, wetters or other auxiliaries are added. The active compound dissolves upon dilution with water.
B) Dispersible concentrates (DC)
20 parts by weight of the active compounds are dissolved in cyclohexanone with addition of a dispersant, for example polyvinylpyrrolidone. Dilution with water gives a dispersion.
C) Emulsifiable concentrates (EC)
15 parts by weight of the active compounds are dissolved in xylene with addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5%). Dilution with water gives an emulsion.
D) Emulsions (EW, EO)
40 parts by weight of the active compounds are dissolved in xylene with addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5%). This mixture is introduced into water by means of an emulsifying machine (Ultraturvax) and made into a homogeneous emulsion. Dilution with water gives an emulsion.
E) Suspensions (SC, OD)
In an agitated ball mill, 20 parts by weight of the active compounds are comminuted with addition of dispersants and wetters and water or an organic solvent to give a fine active compound suspension. Dilution with water gives a stable suspension of the active compound.
F) Water-dispersible granules and water-soluble granules (WG, SG)
50 parts by weight of the active compounds are ground finely with addition of dispersants and wetters and prepared as water-dispersible or water-soluble granules by means of technical appliances (for example extrusion, spray tower, fluidized bed). Dilution with water gives a stable dispersion or solution of the active compound.
G) Water-dispersible powders and water-soluble powders (WP, SP)
75 parts by weight of the active compounds are ground in a rotor-stator mill with addition of dispersants and wetters and silica gel. Dilution with water gives a stable dispersion or solution of the active compound.
2. Products to be applied undiluted
H) Dustable powders (DP)
5 parts by weight of the active compounds are ground finely and mixed intimately with
95% of finely divided kaolin. This gives a dustable product.
I) Granules (GR, FG, GG, MG)
0.5 part by weight of the active compounds is ground finely and combined with 95.5% of carriers. Current methods are extrusion, spray-drying or the fluidized bed. This gives granules to be applied undiluted.
J) ULV solutions (UL)
10 parts by weight of the active compounds are dissolved in an organic solvent, for example xylene. This gives a product to be applied undiluted.
The active compounds can be used as such, in the form of their formulations or the use forms prepared therefrom, for example in the form of directly sprayable solutions, powders, suspensions or dispersions, emulsions, oil dispersions, pastes, dustable products, compositions for broadcasting, or granules, by means of spraying, atomizing, dusting, broadcasting or pouring. The use forms depend entirely on the intended purposes; they are intended to ensure in each case the finest possible distribution of the active compounds according to the invention.
Aqueous use forms can be prepared from emulsion concentrates, pastes or wettable powders (sprayable powders, oil dispersions) by adding water. To prepare emulsions, pastes or oil dispersions, the substances, as such or dissolved in an oil or solvent, can be homogenized in water by means of a wetter, tackifier, dispersant or emulsifier. However, it is also possible to prepare concentrates composed of active substance, wetter, tackifier, dispersant or emulsifier and, if appropriate, solvent or oil which are suitable for dilution with water.
The active compound concentrations in the ready-to-use preparations can be varied within relatively wide ranges. In general, they are from 0.0001 to 10%, preferably from 0.01 to 1%.
The active compounds may also be used successfully in the ultra-low-volume process (ULV), it being possible to apply formulations comprising over 95% by weight of active compound, or even to apply the active compound without additives.
Oils of various types, wetters, adjuvants, herbicides, fungicides, other pesticides, bactericides may be added to the active compounds, even, if appropriate, not until immediately prior to use (tank mix). These agents can be admixed with the compositions according to the invention in a weight ratio of from 1:10 to 10:1.
The compound I or the corresponding formulations are applied by treating the harmful fungi, their habitat or the plants, seeds, soils, areas, materials or spaces to be kept free from them with a fungicidally effective amount of the compound I.
Application can be before or after infection by the harmful fungi.
Preparation Examples
1.) Synthesis of Ethyl 4,4-difluoro-3-oxobutyrate 1
13.9 g of sodium hydride were added to 300 ml of absolute tetrahydrofuran. At 35-40° C., a solution of 62 g of ethyl difluoroacetate in 44 g of ethyl acetate was added. After 7 h of stirring at 40° C., the reaction mixture was stirred into 1 I of ice-water, the pH was adjusted to 3 using 10% strength sulfuric acid and the mixture was extracted twice with in each case 300 ml of methyl tert-butyl ether. The combined organic phase was washed twice with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was distilled. This gave 59.1 g of the product as a colorless oil bp(100 mb)=90-94° C.
2.) Synthesis of Ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate 2
A mixture of 30 g of ethyl 4,4-difluoro-3-oxobutyrate 1, 44 g of triethyl ortho-formate and 55 g of acetic anhydride was stirred under reflux for 4 h and then distilled. This gave 35 g of the product as a colorless oil. bp=85-87° C.
3.) Synthesis of Ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate 3
At −40° C., 33.5 g of ethyl 2-ethoxymethylene-4,4-difluoro-3-oxobutyrate 2 were dissolved in 250 ml of abs. ethanol. 7 g of methylhydrazine were added and the mixture was stirred at −40° C. for 1 h and at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from pentane. This gave 29.6 g of the product. M.p.=50-51° C.
4.) Synthesis of 3-difluoromethyl-1-methylpyrazole-4-carboxylic Acid 4
19.3 g of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate 3 and 5.7 g of sodium hydroxide were dissolved in a mixture of 80 ml of ethanol and 40 ml of water. The mixture was stirred at 60° C. for 2 h. The mixture was then concentrated under reduced pressure and the residue was taken up in 500 ml of ice-water and adjusted to pH=3 using 10% strength hydrochloric acid. The mixture was extracted twice with a mixture of 300 ml of THF and methyl tert-butyl ether (2:3). The combined organic phase was washed three times with dilute sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. This gave 14.5 g of the product as a light-yellow powder. M.p.=192-193° C.
5.) Synthesis of ortho-(3,4-dichlorophenyl)aniline 5
0.14 g of tetrakistriphenylphosphinepalladium(0) was added to a solution of 20.47 g of 2-bromoaniline, 24.98 g of 3,4-dichlorophenylboronic acid and 25.23 g of sodium carbonate in a mixture of 150 ml of water and 450 ml of ethylene glycol dimethyl ether. The mixture was stirred under reflux for 48. The mixture was concentrated under reduced pressure. The residue was taken up in methyl tert-butyl ether, washed once with sodium bicarbonate solution and four times with water, dried over sodium sulfate and concentrated under reduced pressure. Chromatographic purification using a mixture of toluene and cyclohexane (1:2) gave 15.5 g of the product as a light-yellow powder.
6.) Synthesis of 3-difluoromethyl-1-methyl-N-(ortho-(3,4-dichlorophenyl)phenyl)-pyrazole-4-carboxamide 6
0.35 g of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid 4, 0.47 g of ortho-(3,4-dichlorophenyl)aniline 5; 0.3 g of triethylamine and 0.55 g of bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride were dissolved in 20 ml of toluene. The mixture was stirred at room temperature for 15 h, 20 ml of methyl tert-butyl ether were then added and the mixture was washed twice with 5% strength aqueous sodium hydroxide solution, twice with 5% strength hydrochloric acid and once with brine. The organic phase was dried over sodium sulfate and dried under reduced pressure. Chromatographic purification using a mixture of toluene and methyl tert-butyl ether (5:1) gave 0.47 g of the product as a colorless powder. M.p.=129-130° C.
Use Example
Preparation of Active Compound
The active compounds, separately or jointly, were prepared as a stock solution comprising 25 mg of active compound which was made up to 10 ml using a mixture of acetone and/or DMSO and the emulsifier Uniperol® EL (welting agent having an emulsifying and dispersing action based on ethoxylated alkylphenols) in a ratio by volume of solvent/emulsifier of 99:1. The mixture was then made up to 100 ml with water. This stock solution was diluted with the solvent/emulsifier/water mixture described to give the concentration of active compound stated below. Alternatively, the active compounds were employed as a commercial finished formulation and diluted with water to the stated concentration of active compound.
Use Example 1
Curative Activity Against Brown Rust of Wheat Caused by Puccinia recondita
Leaves of polted wheat seedlings of the cultivar “Kanzler” were inoculated with a spore suspension of brown rust (Puccinia recondita). The pots were then placed into a chamber with high atmospheric humidity (90-95%) at 20-22° C. for 24 hours. During this time, the spores germinated and the germ tubes penetrated into the leaf tissue. The next day, the infected plants were sprayed to runoff point with an aqueous suspension having the concentration of active compound stated below. The suspension or emulsion was prepared as described above. After the spray coating had dried on, the test plants were cultivated in a greenhouse at temperatures between 20 and 22° C. and at 65 to 70% relative atmospheric humidity for 7 days. The extent of the rust fungus development on the leaves was then determined.
Use Example 2a
Activity against gray mold on bell pepper leaves caused by Botrytis cinerea, protective application Bell pepper seedlings of the cultivar “Neusiedler Ideal Elite” were, after 2-3 leaves were well developed, sprayed to runoff point with an aqueous suspension having the concentration of active compound stated below. The next day, the treated plants were inoculated with a spore suspension of Botrytis cinerea which comprised 1.7×106 spores/ml in a 2% strength aqueous biomalt solution. The test plants were then placed into a dark climatized chamber at 22-24° C. and high atmospheric humidity. After 5 days, the extent of the fungal infection on the leaves could be determined visually in %.
Use Example 2b
Activity Against Net Blotch of Barley Caused byPyrenophora teres, 1 day Protective Application
Leaves of potted barley seedlings were sprayed to runoff point with an aqueous suspension having the concentration of active compound stated below. 24 hours after the spray coating had dried on, the test plants were inoculated with an aqueous spore suspension of Pyrenophora [syn. Drechslera] teres, the net blotch pathogen. The test plants were then placed into a greenhouse at temperatures between 20 and 24° C. and 95 to 100% relative atmospheric humidity. After 6 days, the extent of the development of the disease was determined visually in % infection of the total leaf area.
Comparative Test 1
Curative Activity Against Brown Rust of Wheat Caused by Puccinia recondita
Comp. 35 of EP-A 0 589301 was compared to the compounds 67.1-67.14 according to the invention of table 67. Leaves of potted wheat seedlings of the cultivar “Kanzler” were inoculated with a spore suspension of brown rust (Puccinia recondita). The pots were then placed into a chamber with high atmospheric humidity (90-95%) at 20-22° C. for 24 hours. During this time, the spores germinated and the germ tubes penetrated into the leaf tissue. The next day, the infected plants were sprayed to runoff point with an aqueous suspension having the concentration of active compound stated below. The suspension or emulsion was prepared as described above. After the spray coating had dried on, the test plants were cultivated in a greenhouse at temperatures between 20 and 22° C. and at 65 to 70% relative atmospheric humidity for 7 days. The extent of the rust fungus development on the leaves was then determined.
Comparative Test 2
Activity Against Leaf Blotch on Wheat Caused by Leptosphaeria nodorum
Comp. 35 of EP-A 0 589301 was compared to the compounds 67.1-67.14 according to the invention of table 67. Pots of wheat plants of the cultivar “Kanzler” was sprayed to runoff point with an aqueous suspension having the concentration of active compound stated below. The next day, the pots were inoculated with an aqueous spore suspension of Leptosphaeria nodorum (syn. Stagonospora nodorum, Septoria nodorum). The plants were then placed into a chamber at 20° C. and maximum atmospheric humidity. After 8 days, the leaf blotch on the untreated but infected control plants had developed to such an extent that the infection could be determined visually in %.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2004 029 469.0 | Jun 2004 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP05/06479 | 6/16/2005 | WO | 00 | 12/4/2006 |
