SI7510828A8 - Process for preparing substituted 2,6-dimethylanilides of furan-2-carboxylic acid - Google Patents

Description

The present invention relates to the preparation of substituted 2,6-dimethyl-anilides of furan-2-carboxylic acid of formula I

in which R is hydrogen or methyl further to the microbicidal agents contained in these compounds as effective substances, as well as to the use of these compounds as microbicides, preferably for the control of phytopathogenic fungi.

Bacterial and fungal diseases on cultivated plants are accelerated by two factors. When growing plants, we want to first and foremost increase yield and improve quality. Often, however, part of the plant's natural resistance to parasites is loss. In addition, experience has shown that bacteria and harmful fungi have developed resistance to known pesticides over the years.

Therefore, there is a great need for microbicides that are transmitted live behind the crop and that destroy their direct parasites.

Cultured plants are within the scope of the present isuip e.g. cereals, corn, rice, vegetables, beets, soybeans, groundnuts, fruit trees, ornamental plants, and especially vines, hops, plants of the cucumber (cucumber, pumpkin, melon) species, solanacea as potatoes, tobacco and tomatoes, as well as bananas, cocoa and gum.

It has now been surprisingly found that by using effective Formula I substances on plants or plant parts (fruits, leaves, stems, tubers, roots) of these and related cultivated plants, the emerging fungi can be restricted or destroyed, with parts of the plant being protected from such fungi as well. that grow later. The active substances are effective against phytopathogenic fungi belonging to the following classes: Ascomycetes (eg Erysiphaceae); Basidiomycetes as primarily rust fungi; Fungi imperfekti; and especially against Oomycetes such as Phytophtori, Perctaospora, Pseudoperonospora, Pythium, or Piamopari, belonging to the class Phycomycetes. In addition, compounds of formula I are systemically active.

They can also be used as puddles for the treatment of seeds (fruits, tubers, grains) and seedlings for protection against fungal infections, as well as against phytopathogenic fungi in the soil.

The N- (substituted phenyl) -N-furanoyl-alanine-methyl esters of Formula I represent a hitherto unknown class of novel microbitide active substances that clearly outperform conventional commercial products in their scope.

The compounds of formula I are prepared according to the process of the invention, for example, such that the compound of formula II

R CH ₃ ch ₃ in which R has the foregoing meaning is acylated with furan- (2) -carboxylic acid, its acid halide, acid anhydride or ester, and in some cases also furan- (2) -carboxamide (preamidation).

According to another method according to the invention, the compounds of formula I can be obtained from the acyl anilides of formula III

R CH ₃

N-CO- ^ ojl (ΠΙ) H

which are converted with the appropriate alkali salt with butyl lithium or sodium hydroxide, which is then converted into the desired end product with the methyl ester of α-halogenpropionic acid, or prepared with methyl ester of cZ-halogenpropionic acid in the presence of alkali carbonate as (KjCOs as acceptor) protons, preferably from the addition of catalytic amounts of alkali iodide, e.g.

KJ.

In formulas II and III, R stands for hydrogen or methyl, and the term acid halide means especially acid chloride or acid bromide and the halogen atom in the methyl ester of <Z -halogenpropionic acid is preferably chlorine or bromine. The metabolism can be carried out in the presence or absence of solvents or diluents inert to the participants in the reaction. For example, e.g. the following: aliphatic or aromatic hydrocarbons such as benzene, toluene, xylenes, five rolls; halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride, chloroform; ethers and ethereal compounds such as dialkyl ether dioxane, tetrahydrofuran; nitriles such as acetonitrile; N, N-dialkylated amides as dimethylformamide; anhydrous acetic acid, dimethylsulfoxide, ketones as methylethyl ketone and mixtures of these solvents.

The reaction temperatures are between 0 ° and 180 ° C, preferably between 20 ° and 120 °. In some cases, acidic or acid binding agents are advantageously used. condensing agents. As such, they come in handy. tert.amines such as trialkylamines (e. g. triethylamine), natural and adhering. bases or inorganic bases such as oxides and hydroxides, hydrogen carbonates and carbonates of alkali and alkaline earth metals as well as sodium acetate. In addition, the excess of each aniline derivative 8 of formula II may serve as an acid-binding agent.

The preparation method starting from the compounds of formula II can also be carried out without an acid-binding agent, in which case it is then advantageous to pass nitrogen through the reaction mixture in order to expel the resulting halogen. In other cases, the addition of dimethylformamide as a reaction catalyst is very advantageous.

The particulars of the preparation of intermediates of formula II can be summarized by the methods generally stated for the preparation of anilinoalkanoic acid esters in the following publications:

J. Org. Chem 30, 4101 (1965),

Tetrahedron 1967, 487,

Tetrahedon 1967, 493.

NH-CH-COOCH 3

CH

The compounds of formula I have an asymmetric carbon atom in the propionic acid ester chain and can be cleaved in the usual way into optical antipodes. The enantiomeric D-form has a stronger microbicidal effect.

- 39 026 - eg.

Accordingly, those compounds, their agents and their use, which refer to the D-configurations of Formula I, are preferred in the context of the invention. These products have a negative rotational angle in ethanol or acetone.

In the preparation of pure optical D-antipodes, the coupling compound of formula IV is conditioned by the ethereal inhibition of both residues additionally introduced to the N-atom of trimethylaniline. Unless synthesis directed at isolation of pure isomers is carried out, the following compound LL 2 is obtained when prepared as a mixture of 4 isomers. The more favorable fungicidal effect of the enantiomeric D-form (compared to the D, L-form ab with the L-form) is maintained, and its atropisomerism has no significant effect on it.

The preparation of the active compounds of formula I is illustrated by the following examples (temperature indications are given in

CH-j nh-ch-cooh (R = H al i CH ₃ ) and then, in a known manner, the N-containing optically active base is metabolized to the corresponding salt. By fractional crystallization of the salt and subsequent release of the acid of formula. IV, which is enriched with the optical D-antipode, and optionally, by repeated (also multiple) salt formation, crystallization -and release of Z-anilino-propionic acid of formula IV, a gradually pure D-form is obtained. From this, then, in the usual way, e.g. in the presence of HCl or HjSO, methanol gives the optical D-configuration of the ester of formula II. As an optically active organic base, e.g. Z-Phenyl-ethylamine.

Instead of 'fractional crystallization', the enantiomeric D-form of Formula IV can also be obtained by exchanging the hydroxyl group in naturally occurring L (+) lactic acid with halogen and by further reacting this product in the reverse of the configuration with the desired 2,6-dimethylaniline, or. 2,3,6 trimethylaniline.

In addition to optical isomerism, if R = CHj, at aturanylation of compound II (or by reaction of compound III with methyl ester-halogenpropionic acid), atropisomerism occurs around the phenyl-N axis, which is

(compound # 1)

N- (V-methoxycarbonylethyl) -N- (furan- (2) -carbonyl) -2,6-dimethylaniline

18.2 g of N- (1-methoxycarbonylethyl) -2,6-dimethylaniline in 10 ml of anhydrous toluene and 0.2 ml of dimethylformamide are added dropwise while stirring 12.6 g of furan- (2) -carboxylic acid chloride. When the weakly exothermic reaction has ceased, it is heated at reflux for 5 hours and the resulting hydrogen chloride is completely removed by conducting nitrogen. After removal of the solvent, distill in vacuo, boiling. = 166 to 168 ° / 0.08 mg <The solidified final product melts between 81 and 84 ° after recrystallization from petroleum ether toluene. X-ray powder diagrams indicate that the compound is polymorphic. One of the two modifications melts at 85 °.

The D-config enantiome and its prodrugs have the following physical information:

(D) -form (a) Q ° = + 10.7 + 0.3 °;

C = 1.56% w / v ethanol (D) -form (ot) g ° = +29.8 + 0, 5 ⁰ ;

C = 1.52% w / v in methanol - 33 026 Compound no.

(D) - o bi i ka _; m.p. 102 to 103 ° ω ² 0 ° - -47.0 ± 0.7 °

C = 1.73 7o w / v in acetone

Example 2

Preparation

(compound # 2)

N- (r-methoxycarbonyl-ethyl) -N- (furan- (2 ') - carbonyl-2,3,6-trimethylaniline.

a) A suspension of 51.5 g (0.382 mol) of 2,3,6-trimethylaniline, 35.3 g of NaHCO, and 126 ml (1.15 mol) of 2-bromopropionic acid methyl ester were stirred for 6 hours at a bath temperature of 130 °, then cooled, the salt filtered off and distilled off. 67.3 g of methyl (Lr (2,3,6-trimethylanilino) -propionic acid methyl ester are obtained, boiling 144 to 146 ° C / 12 mb.

b) To a suspension of 33.5 g (0.152 mol) of a) the ester obtained and 18 g (0.17 mol) of soda in 200 ml of absolute benzene are added dropwise 16.7 ml (0.17 mol) of furan-2-carboxylic acid chloride at 60 to 70 ° and maintained for 4 hours at this temperature. After cooling, filtration and evaporation, the filtrate crystallizes the isopropyl ether end product, m.p. 98 to 102 ° C.

If the D-form of methyl ester <b- (2,3,6-trimethylanilino) -propionic acid is acylated with furan-2-carboxylic acid or one of its reaction-capable derivatives, the D-form of compound 2 is obtained as a mixture of atropisomers.

The percentage of each of the isomers obtained depends on the respective conditions of preparation.

Example 3

A mixture of 51.7 g of N- (1-methoxycarbonylethyl) -2,6-dimethylaniline, 30.2 g of furan-2-carboxylic acid and 25.3 g of pyridine in 250 ml of dioxane was added at 0 ° C and stirred dropwise. 46 g of POCI3 (phosphorus oxychloride), with the temperature rising to about 20 ° C. The reaction mixture was then stirred for 2 hours, 2 liters of water added and stirred well. The organic phase was separated, diluted with 500 ml of ethyl acetate, washed successively with 100 ml of water, 100 ml of 10% sodium carbonate solution and again with 100 ml of water, dried over sodium sulfate, filtered and the solvent evaporated. The residue was recrystallized from ligroim to give crystalline colorless N- (1'-methoxycarbonylethyl) -N- (furan- (2) -carbonyl) -2,6-dimethylaniline. Tal. 81 to 83 “C.

Example 4

A solution of 23 g of anhydrous furan-2-carboxylic acid in 100 ml of dipxane was added dropwise at room temperature and 20.7 g of N- (1-methoxycarbonyl-ethyl) -2,6-dimethylaniline in 300 'was added dropwise over 30 minutes. ml of anhydrous toluene. The mixture was stirred at 80 ° C for 2 hours, the solution was cooled to room temperature, 300 ml of water was added and the mixture was stirred well. The organic phase was separated, washed with 200 ml of saturated sodium carbonate solution and twice with 100 ml of water, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product melts at 40 to 60 ° C. Recrystallization from ethanol / petroleum ether (1: 1) gave a colorless crystalline N- (r-methoxycarbonylethyl) N-(furan- (2) -carbonyl) -2,6-dimethyl-aniline, mp 79 to 82 ° C.

Example 5

To a mixture of 37 g of aqueous sodium hydroxide solution (30%) and 55.2 g of Z- (2,3,6-trimethylanilino-propionic acid methyl ester in 300 ml of toluene was added over 2 hours while stirring at 0 ° to 5 ° C dropwise a solution of 49 g of furan-2 carboxylic acid bromide in toluene The organic phasel is separated, washed twice with 200 ml of water, dried over sodium sulfate and filtered, and after removal of the excess solvent, an oily residue which is left after crystallization from ligroin is removed. / petroleum ether to 54.4 g of N- (1'-methoxycarbonylethyl) -N- (furan- (2) -1carbonyl) -2,3,6-trimethylaniline, mp 99 to 102 ° C.

Example 6

110.5 g of N- (2,3,6-trimethylanilino) -propionic acid methyl ester and 69.3 g of furan-2-carboxylic acid methyl ester were stirred at about 120 ° C for 4 hours and the reaction mixture was then cooled to room temperature. The viscous reaction product was recrystallized 3 times from isopropanol (petroleum ether) to give 37.8 g of N- (r-methoxycarbonylethyl-N- (furan (2) -carbonyl) -2,3,6-trimethylamine) m.p. C.

- 39 026 -

S

The compounds of formula I may be used in combination with other pesticidal substances or active substances that promote plant growth to broaden their effect spectrum.

The compounds of formula I can be used alone or together with suitable carriers and / or other additives. Suitable carriers and excipients may be solid or liquid and correspond to substances customary in the art of preparation, e.g. natural or regenerated minerals, solvents, dispersants, wetting agents, adhesives, thickeners, binders or fertilizers.

The content of the active substance in marketable agents is between 0.1 and. 90%.

The compounds of formula I may be used in the following processed forms (with the indicated weight percentages of the effective substance in parentheses): solid processed forms: dusting agents, earthquakes (up to 10%), granules, coating granules, impregnating granules and homogeneous granules (1 to 80%) of the liquid formulation:

a) concentrates of water-dispersible active substances: wettable powder and paste (25 to 90% in commercial preparations, 0.01 to 15% in solution ready for use); emulsion and solution concentrates (10 to 50%, 0.01 to 15% in solution ready for use);

b) solutions (0.1 to 20%);

The active substances of formula-1 can be converted into preparations as follows:

Spraying agents

The following substances are used to prepare a) 5 S and b) 2% powder:

a) 5 parts of active substance no. 2 parts of talc

b) 2 parts of active substance no. 1 part of high dispersion silica powder.

The active substances and the carrier are mixed and ground and can be dusted in this form.

Granulate

The following substances are used to prepare the 5% granulate:

parts of the active substance no. 1

0.25 parts of epichlorohydrin

0.25 parts of cetylpolyglycol ether

3.50 parts of polyethylene glycol parts of kaolin (grain size 0.3 to 0.8 mm). The active substance is mixed with epichlorohydrin and dissolved in 6 parts of acetone, then polyethylene glycol and cetylpoi glycol ether are added. The solution thus obtained is then injected with kaolin and the acetone is then evaporated in vacuo. Such microgranules are advantageously used to suppress soil fungi.

Spray powder

The following ingredients are used to prepare a) 70%, b) 40%, c) and d) 25% and e) 10% spray powder:

a) 70 parts of N- (1'-methoxycarbonyl-ethyl) -N- (furan- (2) -carbonyl) -2,6-dimethylaniline, effective compounds of no. la (D-form), according to the present invention, parts of sodium dibutylnaphthyl sulfonate parts of naphthalenesulfonic acid-phenol-sulfonic acid-formaldehyde condensate (3: 2: 1) kaolin parts of champagne chalk parts

b) 40 parts of active substance no. 2 parts Na-salts of ligninsulfonic acid 1 parts Na-salts of dibutylnaphthalenesulfonic acid 54 parts of silica c, 25 parts of active substance no. 2a (D-shape)

4.5 parts of calcium ligninsulfonate

1.9 parts of champagne-hydroxyethylcellulose (1: 1)

1.5 parts of sodium dibutyl naphthalenesulfonate

19.5 parts of silica

19.5 parts champagne chalk 28.1 parts kaolin

d) 25 parts of active substance no. 2

2.5 parts of isooctylphenoxy-polyoxyethylene-ethanol 1.7 parts of a mixture of champagne chalk-hydroxyethylcellulose (1: 1)

8.3 parts of sodium aluminum silicate

16.5 parts silica foam 46 parts kaolin

e) 10 parts of active substance no. 1a (D-form) portions of a mixture of sodium salts of sulphates of saturated fatty alcohols of the condensate parts of naphthalenesulfonic acid-formaldehyde of parts of kaolin.

The active substances in suitable mixers are thoroughly mixed with additional substances and ground on suitable mills and rollers. Spray powders are obtained with excellent wetting and hovering ability, which can be diluted with suspensions of any desired concentration with water and used especially on leaves.

Emulsion concentrate

The following substances are used to prepare the 25% emulsion concentrate:

parts of the active substance no. 1

2.5 parts epoxidized vegetable oil parts alkylaryl sulfonate-polyglycol ether fatty alcohol mixture 5 parts dimethylformamld

57.5 parts of xylene.

From these concentrates, an emulsion of any desired concentration, particularly suitable for application to the leaves, can be prepared by dilution with water.

Example 3

Effect against Phytophthora infestana on Solanum lycopersicum (- tomatoes) la) Residual preventive effect

Solanum lycopersicum plants of the "Roter Gnom" variety grown for 3 weeks were sprayed with a spray containing 0.05% of the active substance (prepared from an effective substance processed into a spray powder), dried and infected with a Phytophthora infestans zoo spore suspension. They are then left for 6 days in an air conditioning chamber at 18 to 20 ⁰ and high humidity is created by means of artificially dispersed mist. After this time, characteristic spots appear on the leaves. Their number and size are the criterion for the substance tested.

lb) Curative effect

Tomato plants of the "Roter Gnom" variety grown for 3 weeks are sprayed with a fungal zoo-spore suspension and incubated in a chamber at 18 to 20 ⁰ - 29 026 - and with saturated air humidity. Moisture is stopped after 24 hours. After drying, the plants are sprayed with a spray containing an active substance at a concentration of 0.05%, prepared as a spray powder. After drying the spray coating, plants are placed in a humid chamber for 4 days. The number and size of characteristic spots on leaves that appear after this time are a measure of the effectiveness of the substances tested.

II Preventive-systemic effect

The active substance prepared as a spray powder is placed at a concentration of 0.05% (based on soil volume) on ρρντέϊηο soil of 3-week-old Roter Gnom tomatoes in pots. After waiting for 3 days, spray the phytophthora infestans suspension on the back of the leaves of the plants. They are then placed in a spray chamber with 18 to 20 ⁰ and saturated air humidity for 5 days. After this time, characteristic spots are formed on the leaves, the number and size of which serves as an eye for the efficacy of the substances tested.

In these three experiments, the compounds of formula I show a strong leaf-fungicidal effect, i. fungal infection is below .5% '. In the D-forms of the compounds, i. in the case of the effective substances la and 2a, the infection with fungi even at the amount used was 0.02% in all three experiments below. 5%.

Example 4

Effect on Plasmopara viticola (Bert. Et Curt.) (BerL et De Toni) on Vine

a) Residual-preemptive effect

In the greenhouse we grow seedlings of the vine variety "Chasselas". In a 10-leaf stage, spray 3 plants with broth prepared from an effective substance formulated as a spray powder. After the spray coating has dried, the plants on the underside of the leaf with the fungal spore suspension are evenly infested. The plants were then maintained for 8 days in a humid chamber. After this time, clear disease symptoms appear on the control plants. The number and size of infection sites on treated plants serve as a benchmark for the effectiveness of the test substances.

b) Curative effect

Vineyard seedlings of the variety "Chasselas <are grown in a greenhouse and are infected at the stage of 10 leaves with an e suspension of spores of Plasmopara viticola on the underside of the leaves: After 24 hours, the plants are sprayed with a broth of the active substance prepared from the spray powder of the active substance in a moist chamber. Then we keep the plants in the humid chamber for 7 days. After this time, the disease symptoms appear on the control plants. the number and size of infection sites on treated plants serve as a benchmark for the effectiveness of the test substances.

In both experiments of Example 4, the compounds of formula I show a strong fungicidal effect at the following concentrations:

1 2 3 la 0.02% 0 to 5% 2 0.05% 0 to 5% 0.02% 0 to 5% 2a 0.02% 0 to 5% control - + 100%

Example 5

Effect against Pythium debaryanum on Beta vulgaris (beet)

a) Effect after application on soil

The fungus is grown on sterile oat grains and added to the soil / sand mixture. The infected herb is then filled into flower pots and the sugar beet seeds are sown. Immediately after sowing, pour the soil with aqueous suspensions of the test preparations formulated as offending powders (0.002% (effective soil volume)) and then place the pots in a greenhouse at 20 to 24 ° C for 2 to 3 weeks. In the evaluation of the test we determine the germination of plants, beetroot, as well as the proportion of healthy and diseased plants.

b) Effect after leaching.

The fungus is grown on sterile oat grains and added to the soil / sand mixture. The infected soil is then stuffed into flower pots and seeded with sugar beet seeds, which have been puddled with experimental preparations, in the form of a puddle (0.1% of the active substance by weight of the seed). Place the seed pots in the greenhouse at 20 to 24 ° C for 2 to 3 weeks.

Keep your finger evenly important with a light spray of water. In the assessment, we determine that germ is a beet plant and the length of healthy and diseased plants.

Under the conditions of Experiments a) and b), after treatment with one of the active substances 1, 1a, 2 or 2a, more than 85% of beet plants sprouted and had an equally healthy appearance. In the untreated control, less than 20% of plants with partially diseased appearance sprouted.

The Applicant declares that the best known method for the economic exploitation of the claimed invention is described in Embodiment 1. The Applicant notes that the addition of demethylformamide or the addition of any other Base is not necessary.

Claims (6)

A process for the preparation of substituted 2,6-dimethyl-anilides of furan-2-carboxylic acid of formula I Effective substance no. concentration fungal infection in a) and b) 1 2 3 R • - · z \ • a _z ch ₃ CH3 OH-COOCH: 0.05% 0 to 5% 0.02% 0 to 5% CH, (I), - 39 926 - in which R represents a hydrogen atom or a methyl group, characterized in that the compound of formula II in ^{R 1} with ^CH 3 CH, | «J · <) —NH-CH-COOCH3 (Ul, 'ch _{3 of} which R has the above meaning, in the presence or absence of a reaction-inert solvent and / or organic or inorganic base and / or catalyst, is acylated at a temperature of O to 180 ° C with furan (2) -carboxylic acid, its acid halide, acid anhydride or ester. Process according to claim 1, characterized in that the reaction is carried out at a temperature of from 20 ° to 120 ° C. Process according to claim 1, characterized in that toluene, benzene or dioxane are used as the organic, reaction internal solvent. The process of claim 1, wherein pyridine or sodium hydroxide is used as the base. Process according to claim 1, characterized in that dimethylfonnamide is added as catalyst. Process according to claim 1, characterized in that furan-2-carboxylic acid, its acid chloride, acid bromide, acid anhydride or its methyl ester is used as the acylating reagent.