RU2070197C1 - Thiazolyl-5-carbonamide derivatives, fungicidal agent for controlling fungal diseases of plants, and process for controlling fungal diseases of plants - Google Patents

Abstract

FIELD: agriculture. SUBSTANCE: product: thiazolyl-5-carbonamide derivatives of formula:

wherein R₃ is 2-furanyl, 2- thienyl, 3-furanyl, 3-thienyl; R₁R₂ are cyclopropyl, C₁-C₄- alkyl, CH₂-O-R₄; R₄ is C₁-C₄-alkyl. Reagent 1:

. Reagent 2:

Description

 The invention relates to new thiazolyl-5-carbonamide derivatives containing these compounds with a fungicidal agent and to a fungus control method in which these compounds are used.

(I) В этой формуле R₃ обозначает 2-фуранил, 2-тиенил, 3-фуранил или 3-тиенил; R₁ и R₂ независимо друг от друга обозначают циклопропил, алкил С₁-C₄ или группу СН₂-O-R₄, где R₄ означает алкил С₁-C₄, который может быть незамещенным или замещенным галогеном.The invention therefore relates to thiazolyl-5-carbonamide derivatives of the general formula

(I) In this formula, R ₃ is 2-furanyl, 2-thienyl, 3-furanyl or 3-thienyl; R ₁ and R _{2 are} independently cyclopropyl, C ₁ -C ₄ alkyl or a CH ₂ -OR ₄ group, where R ₄ is C ₁ -C ₄ alkyl, which may be unsubstituted or substituted with halogen.

By alkyl alone or as a component of another substituent, like halide alkyl, depending on the number of carbon atoms, it is understood, for example, methyl, ethyl, propyl, butyl, as well as their isomers isopropyl, isobutyl, tert-butyl or sec-butyl . Halogen is fluoro, chloro, bromo or iodo. Halogen alkyl denotes residues from simple to perhalogenated, such as CHCl ₂ , CH ₂ F, CCl ₃ , CH ₂ Cl, CHF ₂ , CF ₃ , CH ₂ CH ₂ Br, C ₂ Cl ₅ , CH ₂ Br, CHBrCl and etc. Cycloalkyl, depending on the number of carbon atoms mentioned, means, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

 The compounds of formula I are oils or solids at room temperature that exhibit valuable fungicidal properties. They can be used in the agricultural sector or in related fields prophylactically or curatively to combat fungi harmful to plants. The active substances of the formula I according to the invention at low concentrations of use are distinguished not only by their exceptional fungicidal action, but also by their particularly good tolerance to plants.

 Adjacent to the nitrile group in the compounds of formula I is an asymmetric carbon atom. Therefore, they can be conventionally split into optical antipodes. These antipodes have different fungicidal effects.

(V)
или галоидангидрида кислоты, сложного эфира или ангидрида кислоты с аминоацетонитрилом формулы II

(II)
в присутствии или при отсутствии конденсирующего средства или акцептора кислотного типа, причем заместители R₁, R₂ и R₃ имеют указанное для формулы I значение.Compounds of formula I are prepared by reaction of a thiazolyl-5-carboxylic acid of formula V

(V)
or acid halide, ester or acid anhydride with aminoacetonitrile of formula II

(Ii)
in the presence or absence of a condensing agent or acid type acceptor, wherein the substituents R ₁ , R ₂ and R ₃ have the meaning indicated for formula I.

 It is advisable to use amine component II in a slight excess relative to component V (for example, up to 2 molar equivalents).

As an acid halide, it is primarily understood as chloride, bromide or iodide, as acid esters it is easy to understand the easily reactive derivatives of C ₁ -C ₆ alcohols, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, amyl ethers and others. The reaction of V with II is carried out in the absence or preferably in the presence of an acid type condensing agent or acceptor (proton acceptor).

An acid halide of formula V can be prepared in situ from thiazolyl-5-carboxylic acid by reacting the latter with reagent 11 in the presence of thionyl halide, for example SOCl ₂ , and imidazole. This method variant is included in the above process.

The reaction temperature range is from -20 ^o C to 150 ^o C, preferably from -5 ^o C to +80 ^o C.

 Suitable proton acceptors are, for example, inorganic or organic bases, such as, for example, alkali or alkaline earth metal compounds, for example, hydroxides, oxides or carbonates of lithium, sodium, potassium, magnesium, calcium, strontium and barium, or also hydrides, such as sodium hydride. As organic bases, for example, tertiary amines such as triethylamine, triethylenediamine, pyridine, 4-dimethylaminopyridine.

Although not absolutely necessary, it is advantageous to use solvents or diluents for the reaction, for example, halide hydrocarbons, especially chloro derivatives of hydrocarbons such as tetrachlorethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, 1,2 1,1-dichloroethane, 1,2-cis-dichloroethylene, chlorobenzene, fluorobenzene, bromobenzene, dichlorobenzene, dibromobenzene, chlorotoluene, trichlorotoluene; ethers such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, di-n-butyl ether, di-isobutyl ether, diisoamyl ether, diisopropyl ether, anisole, cyclohexyl methyl ether, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, thioanisole, dichlorodiethyl ether; nitrocarbons, such as nitromethane, nitroethane, nitrobenzene, chloronitrobenzene, o-nitrotoluene; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, benzonitrile, m-chlorobenzonitrile; aliphatic or cycloaliphatic hydrocarbons such as heptane, hexane, octane, nonane, zymol, gasoline fractions within the range of boiling points from 70 ^o C to 190 ^o C, cyclohexane, methylcyclohexane, decalin, petroleum ether ligroin, trimethyl pentane, like 2, 3, 3 trimethylpentane; esters such as ethyl acetate, acetoacetate, isobutyl acetate; amides, for example formamide, methylformamide, dimethylformamide; ketones like acetone, methyl ethyl ketone; if necessary also water. Mixtures of these solvents and diluents are also taken into account.

Целесообразно применять бинарную систему растворителей, состоящую, во-первых, из простого эфира (простой диэтиловый эфир, диоксан, тетрагидрофуран и т. д. ) или ароматического углеводорода (бензол, толуол, ксилол) и, во-вторых, из воды, и работают при температуре от 0^oC до 100^oC.The starting products of formula II can be obtained by Strecker synthesis by reacting aldehyde III with hydrocyanic acid or alkaline cyanide (e.g. NaCN) in the presence of ammonia or an ammonium salt:

It is advisable to use a binary solvent system consisting, firstly, of ether (diethyl ether, dioxane, tetrahydrofuran, etc.) or an aromatic hydrocarbon (benzene, toluene, xylene) and, secondly, of water, and they work at a temperature of from 0 ^o C to 100 ^o C.

причем R' обозначает С₁-C₆-углеводород, и затем, если желательно, омылением переводят в карбоновую кислоту V. Реакцию можно осуществлять в протонном растворителе, таком, как спирт, или в апротонном растворителе, таком, как бензол, толуол, циклогексан и т. д. В некоторых случаях можно добавлять протонный акцептор, как Na-ацетат/уксусная кислота или третичное основание (например, пиридин, триэтиламин и т. д.). Реакцию проводят сначала при температурах между -60^oC и +40^oC, предпочтительно при -20^oC до +20^oC. Затем нагревают до температуры от +30^oC до +140^oC, предпочтительно от +50^oC до +110^oC. Если работают, например, в бензоле, толуоле или циклогексане, можно удалять образующуюся воду при помощи водоотделителя.The starting materials of formula V are obtained by converting the thioamide of formula VI with the α-halogen-b-keto ester of formula VII to the thiazolyl-5-carboxylic acid ester Va:

moreover, R 'is a C ₁ -C ₆ hydrocarbon, and then, if desired, saponification is transferred to carboxylic acid V. The reaction can be carried out in a protic solvent, such as alcohol, or in an aprotic solvent, such as benzene, toluene, cyclohexane etc. In some cases, you can add a proton acceptor, such as Na-acetate / acetic acid or a tertiary base (for example, pyridine, triethylamine, etc.). The reaction is carried out first at temperatures between -60 ^o C and +40 ^o C, preferably at -20 ^o C to +20 ^o C. Then they are heated to a temperature of +30 ^o C to +140 ^o C, preferably from +50 ^o C to +110 ^o C. If you work, for example, in benzene, toluene or cyclohexane, you can remove the resulting water using a water separator.

При этом целесообразно работать в инертном растворителе, таком, как ацентонитрил или тетрагидрофуран. В качестве протонного акцептора служит предпочтительно третичное основание, такое, как пиридин, триэтиламин, 4-диметиламинопиридин и др. Реакция должна была протекать в области температур от -40^oC до +80^oC, предпочтительно от -20^oC до +20^oC. После этого IX конденсируют со сложным галоидным эфиром Х до сложного эфира тиазолил-5-карбоновой кислоты и затем, если желательно, переводят обычным образом в V:

При циклизации N-ацилтиоамида IX в протонном растворителе (как, например, в низшем спирте) или апротонном растворителе обрабатывают алкоголятом (например, СН₃-O-Na) или NaOH при температурах от -40^oC до +20^oC, предпочтительно от -30^oC до 0^oC и затем смешивают со сложным галоидным эфиром Х при -20^oC до +20^oC, предпочтительно при -10^oC до +10^oC. После этого для удаления реакционной воды нагревают несколько часов до температуры от +40^oC до +120^oC, предпочтительно от +60^oC до 100^oC.In another embodiment of the process, an intermediate of formula V can also be prepared in such a way that the thioamide of formula VI is first acylated with an acid halide of formula VIII to an N-acylthioamide of formula IX:

It is advisable to work in an inert solvent, such as acentonitrile or tetrahydrofuran. The proton acceptor is preferably a tertiary base, such as pyridine, triethylamine, 4-dimethylaminopyridine, etc. The reaction should take place in the temperature range from -40 ^o C to +80 ^o C, preferably from -20 ^o C to +20 ^o C. Thereafter, IX is condensed with the halide ester X to the thiazolyl-5-carboxylic acid ester and then, if desired, converted in the usual manner into V:

Upon cyclization of N-acylthioamide IX in a protic solvent (such as lower alcohol) or an aprotic solvent, it is treated with an alcoholate (e.g. CH ₃ -O-Na) or NaOH at temperatures from -40 ^° C to +20 ^° C, preferably from -30 ^o C to 0 ^o C and then mixed with a complex of halide ester X at -20 ^o C to +20 ^o C, preferably at -10 ^o C to +10 ^o C. After that, to remove the reaction water is heated for several hours to a temperature from +40 ^o C to +120 ^o C, preferably from +60 ^o C to 100 ^o C.

In the above formulas, Va-X R ₁ and R ₂ have the meaning indicated for formula I.

 The compounds of formula I have a fungicidal activity which is very favorable for practical needs. They have very beneficial therapeutic, prophylactic and especially systemic properties and are used to protect numerous cultivated plants. Using active substances of the formula I on plants or on parts of plants (fruits, flowers, foliage, stems, tubers, roots) of various beneficial crops, it is possible to localize or destroy emerging pests, and later parts of plants also protect against phytopathogenic microorganisms, for example.

 The compounds of formula I are effective, for example, against the following classes of phytopathogenic fungi: Fungiumperfecti (especially Botrytis, hereinafter Pyricularia, Helminthosporium, Fusarium, Sertoria, Cercospora u Alternaria); Basidiomyceten (e.g. Rhizoctonia, Hemileia, Puccinia). In addition, they act against the class Ascomyceten (e.g. Venturia u Erysiphe, Podosphaera, Monilinia, Uncinula), but primarily against the class Oomyceten (e.g. Phytophthora, Peronospora, Bremia, Pythium, Plasmopara). Further, the compounds of formula I can be used as dressing agents for the treatment of seeds (fruits, tubers, grains) and plant plugs for protection against fungal infections, as well as against phytopathogenic fungi that appear in the soil.

 Therefore, the invention also relates to a fungicidal agent which contains compounds of the formula I as a component of the active substance. The preparation of this agent consists in thoroughly mixing the active substance with one or more of the substances or groups of substances described herein. Also included in the scope of the invention is a method for controlling fungi that infect plants by treating plants with new compounds of formula I or a agent containing them.

 The crops that are protected by the use of the compounds of the invention are, for example, the following plant species: cereals (wheat, barley, rye, oats, rice, corn, sorghum and related species); beets (sugar beets and fodder beets); pome fruit, stone fruit and berries (apples, pears, plums, peaches, almonds, cherries, strawberries, gooseberries, raspberries and blackberries); leguminous fruits (beans, lentils, peas, soybeans); oilseeds (rapeseed, mustard, poppy, olives, sunflower, coconut palm, castor oil, cocoa, peanut); cucumber plants (pumpkin, cucumbers, melons); fibrous plants (cotton, flax, hemp, jute); citrus fruits (oranges, lemons, pampelmus, tangerines); varieties of vegetables (spinach, lettuce, asparagus, types of cabbage, carrots, onions, tomatoes, potatoes, red peppers); bay plants (avocado, cinnamon, camphor) or plants such as tobacco, nuts, coffee, sugarcane, tea, pepper, grapes, hops, eggplant, banana plants and natural rubber, as well as decorative plants.

 The active substances of the formula I are usually used in the form of compositions, and they can be applied simultaneously or in turn with other active substances on the treated area or on plants. These other substances can be both fertilizers, agents for the dissolution of trace elements, and other drugs that affect plant growth. In this case, selective herbicides can also be used, as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, together with others, if necessary, conventional carrier substances, surfactants or other accelerating additives in the formulation technique.

 Suitable carriers and additives may be solid or liquid, such as, for example, natural or regenerated minerals, solvents, dispersants, wetting agents, adhesion promoters, thickeners, binders or fertilizers.

 A preferred method for applying an active substance of formula I or an agrochemical agent that contains at least one of these active substances is applying to the foliage (applying to the leaves). In this case, the frequency of application and the rate of application depend on the degree of damage to the corresponding pathogen. But the active substances of formula I can also enter the plants through the soil and through the roots (systemic effect), where the location of the plants is impregnated with a liquid preparation or substances in solid form are introduced into the soil, for example, in the form of granules (application to the soil). In aquatic rice crops, such granules can be introduced into a flooded rice field. But the compounds of formula I can also be applied to seed grains, the grains either being impregnated with a liquid preparation of the active substance or coated with a solid preparation.

 In this case, the compounds of formula I are used in an unchanged form or, preferably, together with adjuvants customary in the prescription technique. To do this, it is advisable to process them, for example, in emulsion concentrates, spreadable pastes, sprayable directly or dilute solutions, diluted emulsions, wettable powders, soluble powders, dusting agents, granules, encapsulation, for example, of polymeric substances in a known manner. Methods of application, such as spraying, spraying, dusting, scattering, coating or pouring, as well as the type of product, are selected respectively depending on the desired goals and on these conditions. Favorable consumption rates are usually from 25 g to 2 kg of active substance per ha.

 Formulations containing the active substance of the formula I and, if necessary, a solid or liquid additive, formulations or formulations are prepared in a known manner, for example, by thoroughly mixing and / or grinding the active substances with fillers, such as, for example, solvents, carrier solids and, if necessary with surfactant compounds (surfactants).

As solvents take into account: aromatic hydrocarbons, preferably C ₈ -C ₁₂ fractions, such as xylene mixtures or substituted naphthalenes, phthalic acid esters like dibutyl or dioctyl phthalate, aliphatic hydrocarbons like cyclohexane or paraffins, alcohols and glycols, as well as their ethers and esters like ethanol, ethylene glycol, ethylene glycol monomethyl or ethyl ether, ketones like cyclohexanone, highly polar solvents like N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, epoxidized also if necessary vegetable oils such as epoxidised coconut oil or soybean oil; or water.

 As carrier solids, for example, for dusting and dispersible powders, natural stone flour, such as calcite, talc, kaolin, montmorillonite or attapulgite, is used.

 Further, particularly beneficial accelerating application additives, which can lead to a significant reduction in the consumption rate, are natural (animal or vegetable) or synthetic phospholipids from a number of cephalins and lecithins, which can be obtained, for example, from soybeans.

 As surface-active compounds, depending on the type of formulation of the active substance of the formula I, nonionic, cationic and / or anionic surfactants with good emulsification, dispersion and wetting properties are taken into account. Surfactants should also be understood as mixtures of surfactants.

 Suitable anionic surfactants may be both so-called water-soluble soaps and water-soluble synthetic surface-active compounds.

As types of soap, mention should be made of alkali metal salts, alkaline earth metal salts or, if necessary, substituted ammonium salts of higher fatty acids (C ₁₀ -C ₂₂ ), such as salts a or K of oleic acid or stearic acid, or natural mixtures of fatty acids, which can be obtained, for example, from coconut oil or melted animal fat. Further, mention is also made of the methylauric fatty acid salts.

 As nonionic surfactants, derivatives of polyglycol ethers of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and alkyl phenols, which may contain from 3 to 30 groups of simple glycol ethers and from 9 to 20 carbon atoms in the (aliphatic) hydrocarbon, are taken into account. the remainder and from 6 to 18 carbon atoms in the alkyl part of the alkyl phenols.

 Examples of nonionic surfactants include nonylphenolpolyethoxyethanol, castor oil polyglycol ether, polypropylene oxide adducts of polyethylene oxide, tributylphenoxypolyethylene ethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.

 Further, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan trioleate are also taken into account.

 With cationic surfactants, it is primarily a question of quaternary ammonium salts, which as N substituents contain at least an alkyl residue with 8 22 C atoms and as other substituents lower, optionally halogenated alkyl, benzyl or lower hydroxyalkyl leftovers.

 Other conventional surfactants in the prescription technique are known to those skilled in the art or may be borrowed from the corresponding specialist literature.

 Agrochemical preparations contain according to the invention from 3 to 75 weight. the active substance of the compounds of General formula I.

 While concentrated products are preferred in trade, the end user uses, as a rule, diluted products.

 The agents may also contain other additives, such as stabilizers, defoamers, viscosity regulators, binders, adhesion promoters, as well as fertilizers or other active substances to achieve special effects.

 The following examples serve to provide a more detailed explanation of the invention without limiting the latter.

 Production Example 1.

31,3 г сложного этилового эфира 2-хлорацетуксусной кислоты в 400 мл бензола смешивают при комнатной температуре и при интенсивном перемешивании с 20 г метокситиоацетамида и нагревают затем при применении водоотделителя 4 1/2 часа при температуре флегмы. После охлаждения до комнатной температуры реакционный раствор в бензоле разбавляют 500 мл этилацетата, промывают дважды, каждый раз 80 мл 10%-ного раствора соды, и дважды, каждый раз 50 мл воды, сушат над сульфатом натрия и фильтруют. Смесь растворителей выпаривают. Оставшееся желтое масло растиранием с простым диизопропиловым эфиром доводят до кристаллизации. Бежевые кристаллы плавятся при 36-37^oC.a) Preparation of 2-methoxymethyl 4-methylthiazole-5-carboxylic acid ethyl ester

31.3 g of ethyl 2-chloroacetacetic acid ethyl ester in 400 ml of benzene are mixed at room temperature and with vigorous stirring with 20 g of methoxythioacetamide and then heated using a water separator for 4 1/2 hours at reflux temperature. After cooling to room temperature, the reaction solution in benzene was diluted with 500 ml of ethyl acetate, washed twice, each time with 80 ml of 10% soda solution, and twice, each time with 50 ml of water, dried over sodium sulfate and filtered. The solvent mixture was evaporated. The remaining yellow oil was triturated with diisopropyl ether and crystallized. Beige crystals melt at 36-37 ^o C.

22,1 г сложного этилового эфира 2-метоксиметил-4- метилтиазол-5-карбоновой кислоты смешивают при комнатной температуре с 6,7 г 85%-ной гидроокиси калия в 100 мл этанола и затем нагревают 18 часов при температуре флегмы. После охлаждения этанол выпаривают и остаток растворяют в 200 мл воды. После перемешивания с активированным углем смесь фильтруют через гифло и фильтрат, подкисляют при интенсивном перемешивании концентрированной хлористоводородной кислоты. Осажденные желтоватые кристаллы отфильтровывают, промывают водой и сушат. После перекристаллизации из тетрагидрофурана/петролейного эфира (30 45^oC) (= 10:1) желтоватые кристаллы плавятся при 168 169,5^oC.c) Preparation of 2-methoxymethyl-4-methylthiazole-5-carboxylic acid

22.1 g of 2-methoxymethyl-4-methylthiazole-5-carboxylic acid ethyl ester was mixed at room temperature with 6.7 g of 85% potassium hydroxide in 100 ml of ethanol and then heated for 18 hours at reflux temperature. After cooling, ethanol was evaporated and the residue was dissolved in 200 ml of water. After stirring with activated carbon, the mixture is filtered through hyphlo and the filtrate, acidified with vigorous stirring of concentrated hydrochloric acid. Precipitated yellowish crystals are filtered off, washed with water and dried. After recrystallization from tetrahydrofuran / petroleum ether (30 45 ^o C) (= 10: 1), yellowish crystals melt at 168 169.5 ^o C.

соединение 68
В 3,5 г метоксиметил-4-метилтиазол-5-карбоновой кислоты в 40 мл пиридина закапывают при перемешивании при 0^oC в течение 1/4 часа 2,38 г хлористого тионила. После одночасового перемешивания при 0^oC добавляют 3,5 г (2-(3-тиенил)-аминоацетонитрилгидрохлорида и перемешивают 18 часов при пропускании азота. После добавки 200 мл ледяной воды и 100 мл этилацетата при перемешивании подкисляют 50 мл концентрированной соляной кислоты, отделяют органическую фазу и еще раз экстрагируют 70 мл этилацетата. Соединенные экстракты дважды промывают, каждый раз 100 мл 1 н соляной кислоты, и один раз 100 мл насыщенного раствора бикарбоната натрия, сушат над сульфатом натрия, фильтруют и выпаривают растворитель. Остающееся желтоватое масло растиранием с простым диизопропиловым эфиром доводят до кристаллизации. Бледно-желтые кристаллы плавятся при 111 113^oC.c) Preparation of 2- (2-methoxymethyl-3-methylthiazolyl-5-carbonylamino) -2- (3-thienyl) acetonitrile

compound 68
2.35 g of thionyl chloride are instilled in 3.5 ml of methoxymethyl-4-methylthiazole-5-carboxylic acid in 40 ml of pyridine with stirring at 0 ^° C. for 1/4 hour. After stirring for one hour at 0 ^° C., 3.5 g of (2- (3-thienyl) aminoacetonitrile hydrochloride are added and stirred for 18 hours under nitrogen flow. After adding 200 ml of ice-cold water and 100 ml of ethyl acetate, acidify 50 ml of concentrated hydrochloric acid with stirring and separate the organic phase is extracted again with 70 ml of ethyl acetate.The combined extracts are washed twice, each time with 100 ml of 1 N hydrochloric acid, and once with 100 ml of saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and the solvent is evaporated. ltovatoe oil trituration with diisopropyl ether until crystallization is adjusted. Pale yellow crystals melting at 111 113 ^o C.

соединение 2
8,75 г 2-(3-тиенил)-аминоацетонитрилгидрохлорида суспендируют в 200 мл этилацетата и после охлаждения до +5^oC при перемешивании в течение 5 минут смешивают с 12 г триэтиламина. При интенсивном перемешивании закапывают в течение 1 часа 10 г хлорангидрида 2-метил-4-циклопропилтиазол-5- карбоновой кислоты в 100 мл этилацетата при -5^oC и затем дополнительно перемешивают 2 часа при комнатной температуре, смешивают с 100 мл воды и отделяют водную фазу. Раствор этилацетата промывают еще дважды, каждый раз 50 мл воды, сушат над сульфатом натрия, фильтруют и выпаривают растворитель. Остающееся масло очищают хроматографией на колонке через силикагель (тетрагидрофуран:гексан 1: 1). После выпаривания смеси растворителей коричневатое сначала масло растиранием с петролейным эфиром (50 70^oC) доводят до кристаллизации и перекристаллизовывают из гексана/дихлорметана. Бежевые кристаллы плавятся при 108 110^oC.Production Example 2
Preparation of 2- (2-methyl-4-cyclopropylthiazole-5-carbonylamino) -2- (3-thienyl) acetonitrile

compound 2
8.75 g of 2- (3-thienyl) aminoacetonitrile hydrochloride is suspended in 200 ml of ethyl acetate and, after cooling to +5 ^° C, it is mixed with 12 g of triethylamine with stirring for 5 minutes. With vigorous stirring, 10 g of 2-methyl-4-cyclopropylthiazole-5-carboxylic acid chloride in 100 ml of ethyl acetate at -5 ^° C are instilled for 1 hour and then further stirred for 2 hours at room temperature, mixed with 100 ml of water and the aqueous solution is separated phase. The ethyl acetate solution was washed twice more, each time with 50 ml of water, dried over sodium sulfate, filtered and the solvent was evaporated. The remaining oil is purified by column chromatography through silica gel (tetrahydrofuran: 1: 1 hexane). After evaporation of the solvent mixture, the brownish oil is first triturated with petroleum ether (50 ^° -70 ^° C.), crystallized and recrystallized from hexane / dichloromethane. Beige crystals melt at 108 110 ^o C.

 In a similar manner, the following compounds can be obtained (see table. 1).

In the presence of an acid catalyst, such as HCl, from the acids of Table 2 by esterification with methanol, ethanol or with one of the isomeric alcohols propanol, pentanol or hexanol, the corresponding C ₁ -C ₆ alkyl esters of carboxylic acid can be easily obtained.

2. Examples of formulations for the active substances of formula 1 (% weight percent); see table 3
The active substance is well mixed with additives and well ground in a suitable mill. Wettable powders are obtained which can be diluted with water to suspensions of any desired concentration.

2.2 Emulsion concentrate
The active substance from table 1 10%
Octylphenolpolyethylene glycol ether (4 5 moles of ethylene oxide) 3%
Ca-dodecylbenzenesulfonate 3%
Castor oil polyglycol ether (35 moles of ethylene oxide) 4%
Cyclohexanone 30%
A mixture of xylenes 50%
Emulsions of any desired concentration can be obtained from this concentrate by dilution with water (see table 4).

 Ready-to-use dusting agents are obtained, the active substance being mixed with a carrier and ground in an appropriate mill.

2.4. Extruded granulate
The active substance from table 1 10%
M-ligninsulfonate 2%
Carboxymethyl cellulose 1%
Kaolin 87%
The active substance is mixed with additives, crushed and moistened with water. This mixture is extruded and then dried in a stream of air.

2.5. Shell granulate
The active substance from table 1 3%
Polyethylene glycol (molecular weight 200) 3%
Kaolin 94%
Finely ground active substance in the mixer is uniformly applied to kaolin moistened with polyethylene glycol. In this way dust-free granules in the shell are obtained.

2.6. Suspension concentrate
The active substance from table 1 40%
Ethylene glycol 10%
Nonylphenolpolyethylene glycol ether (15 mol ethylene oxide) 6%
N-ligninsulfonate 10%
Carboxymethyl cellulose 1%
37% aqueous formaldehyde solution 0.2%
Silicone oil in the form of a 75% aqueous emulsion of 0.8%
Water 32%
Finely ground active substance is thoroughly mixed with additives. In this way, a suspension concentrate is obtained from which suspensions of any desired concentration can be obtained by dilution with water.

3. Biological examples
I. Action against Phytophthora infestans on tomatoes.

a) Therapeutic effect
After three weeks of cultivation, tomato plants of the Red Gnome variety are sprayed with a zoospore suspension of the fungus and incubated at 18 ^° -20 ^° C. and at saturated air humidity for 24 hours. After drying the plants, the latter are sprayed with a solution that contains the active substance at a concentration of 600, 200 or 60 ppm as a wettable powder. After drying the wettable coating, the plants are again kept in a humid chamber for 4 days. The number and size of typical stains on leaves that appear after this time are the basis for evaluating the activity of the test substances.

b) Preventive-systemic action
The active substance of the formulation as a wettable powder at a concentration of 60 ppm (in terms of soil volume) is applied to the soil surface in pots with tomato plants three weeks old of the variety "Red Gnome". After three days of aging, the underside of the leaf of the plants is sprayed with a suspension of Phytophthora infestans zoospores. Then they are kept for 5 days in a humidification chamber at 18 20 ^o C and at saturated humidity. After this time, typical spots form on the leaves, the number and size of which serve as the basis for assessing the activity of the tested substances.

 From table 1, the following compounds achieved inhibition of disease damage below 10% 2, 3, 5, 8, 9, 12, 18, 24, 32, 34, 35, 39, 48, 54, 55, 63, 68, 77, 78, 90, 93, 95, 98, 104, 107, 110, 111, 113, 116, 118 130 and 138 156.

II. Action against Plasmopara viticola (Bert. Et Curt.) (Bert. Et De Toni) on grapes
a) The residual preventive effect
In the greenhouse, Shasselas grapevine plugs are grown. In the 10 leaf stage 3, the plants were sprayed with a solution obtained from the active substance of the formulation as a wettable powder (200 ppm of the active substance). After drying the wettable coating, the plants on the underside of the leaf were uniformly infected with a suspension of fungal spores. Then the plants are kept for 8 days in a humidification chamber. After this time, distinct symptoms of the disease appear on the control plants. The number and size of infection sites on treated plants provide the basis for evaluating the activity of test substances.

b) therapeutic effect
Shasselas grapevine shteklings are grown in a greenhouse and, in the 10-leaf stage, they are infected with a Plasmopara viticola spore suspension on the underside of a leaf. After 24 hours in the humidification chamber, the plants are sprayed with a solution of the active substance, which was obtained from a wettable powder of the active substance (500 ppm of the active substance). Then the plants are kept for 7 days in a humidification chamber. After this time, the symptoms of the disease appear on the control plants. The number and size of infection sites on treated plants is an estimate of the activity of the tested substances.

And here all the compounds named in example 1 achieve inhibition of disease damage below 10%
III. Action against Pythium debaryanum on sugar beets.

a) Action after application to the soil
The fungus is cultivated on sterile oats and a mixture of earth-sand is added. The soil infected in this way is poured into flower pots and sown with sugar beet seeds. Immediately after sowing, the earth is watered with an aqueous suspension of preparations in the form of a wettable powder (20 ppm of the active substance in terms of the volume of land). After that, the pots are kept for 2 3 weeks in a greenhouse at 20 24 ^o C. The earth is maintained uniformly moist by constant weak spraying with water. When evaluating the test, the germination of sugar beet plants and the number of healthy and diseased plants are determined.

b) Effect after mordant application
The fungus is cultivated on sterile oats and a mixture of earth-sand is added. The soil infected in this way is poured into flower pots and sown with sugar beet seeds, which were pickled with the preparations as dressing powder (1000 ppm of the active substance, calculated on the weight of the seeds). Sown pots were placed for 2 3 weeks in a greenhouse at 20 - 24 ^o C. At the same time, the ground was maintained uniformly moist with weak spraying with water.

 When assessing, the germination of sugar beet plants and the number of healthy and diseased plants are determined.

 With compounds from table 1, germination rates above 80% were achieved. The corresponding control plants had a germination rate of less than 30% and an unhealthy appearance.

 To compare the fungicidal activity of thiazolyl-5-carbonamide derivatives, compounds of the invention and the prior art were taken.

соединение 43, таблица 1

соединение 122, таблица 1

соединение 48, таблица 1

соединение 124, таблица 1

соединение 68, таблица 1

соединение 54, таблица 1

соединение 12, таблица 1

соединение 130, таблица 1

соединенеи 123, таблица 1
Соединения по патенту 4918089 (известный уровень техники)

соединение 1, таблица 1

соединение 3, таблица 1

соединение 4, таблица 1
Все соединения брали в форме смачивающихся порошков и испытывали в виде разбавленных водных растворов. Испытания проводили согласно описанным ниже методикам.Compounds according to the invention:

compound 43, table 1

compound 122, table 1

compound 48, table 1

compound 124, table 1

compound 68, table 1

compound 54, table 1

compound 12, table 1

compound 130, table 1

connections 123, table 1
Compounds of Patent 4918089 (prior art)

compound 1, table 1

compound 3, table 1

compound 4, table 1
All compounds were taken in the form of wettable powders and tested in the form of dilute aqueous solutions. The tests were carried out according to the methods described below.

The results of the action of the drugs were evaluated according to the following scale:
fungal infection scores
1 0 5% (no visible lesion)
3 5 20%
6 20 50%
9> 50% (lesion similar to untreated but infected control plants)
Each test at one concentration was carried out on three plants. The scores shown in the tables below are the average of the results of three trials.

 A series of dilutions began with a concentration of 200 million shares of the active component and followed the procedure described in the text of the initial description.

Test: action on Phytophthora infestans on tomatoes
Systematic action
After a cultivation period of 3 weeks, Roter Gnom tomato plants were treated with spray mixtures (200, 60, 20 or 6 million parts of the active ingredient per soil volume) prepared from the preparations of the test compounds in the form of a wettable powder. At the same time, caution was taken so that the spray mixtures did not fall on those parts of plants that are above the soil. After 72 hours, plant leaves on the reverse side were infected from suspensions with fungal spores. The defeat of the fungi was evaluated 5 days after infection, and the plants were kept at 20 ^o C and a relative humidity of 90 to 100%
The results are shown in table. 5.

Test: action on Plasmopara viticola on grapes
Residual protective effect
Chasselas grape cuttings in the developmental stage of 10 leaves were sprayed with spray mixtures (200, 60, 20 or 6 million shares of the active component) prepared from preparations of the test compounds taken in the form of wettable powders. After 24 hours, leaves on the reverse side were infected from suspensions with fungal spores. Then the plants were kept for 8 days at a relative humidity of 90 to 100%. The degree of fungal damage was evaluated 15 days after infection.

 The results are shown in table. 6.

Systematic action
Grape cuttings at the stage of development of 4–5 leaves were sprayed with spray mixtures (200, 60, 20, or 6 million shares of the active component per soil volume) obtained from preparations of the test compounds taken in the form of wettable powders. At the same time, it was ensured that the sprayed mixtures did not fall on the plants. After 48 hours, the leaves of the plants on the reverse side were infected with fungal spores from suspensions. Then the infected plants were kept for 5 days at 20 ^o C and a relative humidity of 90 to 100%. After that, the degree of damage to plants by fungi was evaluated.

 The results are shown in table. 7.

Claims (2)

1. Derivatives of thiazolyl-5-carbonamide of the formula I

where R ₃ 2-furanyl, 2-thienyl, 3-furanyl or 3-thienyl;
R ₁ and R ₂ independently from each other cyclopropyl or a group - (CH ₂ -OR ₄ ), or one of the substituents R ₁ or R ₂ - C ₁ C ₄ -alkyl, and R ₄ C ₁ C ₄ -alkyl.  2. A fungicidal agent for combating fungal diseases of plants, comprising an active substance derived from thiazolyl-5-carbonamide and target additives, characterized in that as a derivative of thiazolyl-5-carbonamide, it contains a compound of formula I according to claim 1 with the following ingredients, wt. Active substance 3 75
Target Supplements Else
3. A method of combating fungal diseases of plants or preventing the defeat of their disease by treating plants, their growing places, parts of plants or plant propagation material with a thiazolyl-5-carbonamide derivative, characterized in that a compound of the formula is used as a thiazolyl-5-carbonamide derivative I according to claim 1 with a consumption rate of 0.025 2 kg of active compound per 1 ha.

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