KR860000061B1 - Process for preparing 3-(n-1,3,4-thiadiazolyl-2)-aminoalkyl-alkylacrylates - Google Patents

Abstract

A method for the preparation of 3-(N-1,3,4-Thiadiazolyl-2) - aminoalkyl-alkylacylates of formula I(R1 = H or Cl-4 alkyl; R2 = Cl-4 alkyl; R3 = H or -CO-R4; R4 = methoxymethyl, cyclopropyl methylphenyl, or furyl was described. Thus, 2-amino-1,3,4thiadiazol, 303g, in the presence of methyl cellosolve, 2 L, was reacted with methyl-α-formyl-propionate at 120≰C for 16 hrs to give the title compds. The title compds. are used as antibacterial agents for plant protection.

Description

Method for preparing 3- (N-1,3,4-thiadiazolyl-2) -aminoalkyl-alkylacrylate

The present invention relates to a process for preparing the compound of formula (I).

In the above formula,

R ₁ is hydrogen or C ₁ -C ₄ alkyl,

R ₂ is C ₁ -C ₄ alkyl,

R ₃ is hydrogen or a -CO-R ₄ group,

R ₄ is a pyridyl or phenyl group unsubstituted or monosubstituted or disubstituted with methyl or halogen or is methoxymethyl, cyclopropyl, methyl, halomethyl or furyl.

Depending on the number of carbon atoms, the alkyl group, by itself or as part of another substituent, means the following.

That is, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the like and their isomers such as isopropyl, isobutyl, tert-butyl, isopentyl and the like.

In addition, examples of the halogen include fluorine, chlorine, bromine or iodine.

The compounds of formula (I) are stable substances. This compound has a very useful bactericidal activity spectrum and is particularly resistant to phytopathogenic microorganisms, in particular bacteria, which harm plants.

Thus, the preferred group of fungicides consists of the compounds of formula (I) wherein R ₃ is hydrogen, each of which is particularly preferred since these compounds act as very useful fungicides.

3- (N-1,3,4-thiadiazolyl-2) -amino-2-methylacrylate,

3- (N-1,3,4-thiadiazolyl-2) -amino-2-methyl-ethyl-acrylate,

3- (N-1,3,4-thiadiazolyl-2) -amino-2-methyl-n-propylacrylate,

3- (N-1,3,4-thiadiazolyl-2) -amino-2-ethyl-ethylacrylate,

3- (N-1,3,4-thiadiazolyl-2) -amino-2-isopropyl-ethylacrylate.

The compounds of formula (I) can be prepared by the methods described below, and the intermediates formed through this reaction can be separated before further reaction, but the reaction can proceed without separating the intermediates. . In R ₄ COOH of the following formulas (II) and (III), the substituents R ₁ , R ₂ , R ₃ and R ₄ are as defined in the formula (I) above.

The compound of formula (I) can be produced by the following method.

After 2-amino-1,3,4-thiadiazole of formula (II) is condensed with a compound of formula (III) and water is removed, the condensate is acid R ₄ COOH, preferably a reactive acid. N-acylation with derivative.

Wherein R ' ₃ is hydrogen.

It is preferred that all reactions proceed in the presence of an inert diluent or organic solvent.

As a diluent, an excess of reactant, such as an excess of acylation reagent, is used in the N-acylation reaction.

In the reaction of the compound of formula (II) with the compound of formula (III), examples of suitable reaction media include aliphatic and aromatic hydrocarbons such as benzene, toluene, xylene, petroleum ether; Halogenated hydrocarbons such as chlorobenzenes, carbon tetrachloride and tetrachloroethylene; Esters such as ethyl acetate, propyl acetate and butyl acetate; Ethers and ethereal compounds such as dialkyl ethers (diisopropyl ether, tert-butyl methyl ether, etc.), anisole, dioxane, dimethoxy ethane; Alcohols such as ethanol, propanol, butanol and methylcellosolve; Nitriles such as acetonitrile, propionitrile and the like or a mixture of the above solvents.

In condensation reactions it is advantageous to have acids, bases or neutral condensing agents or acid acceptors present. Examples of suitable condensing agents include strong acids such as sulfonic acid (P-toluenesulfonic acid, benzenesulfonic acid), phosphoric acid; Amines such as pyridine, piperidine, triethylamine, triethylenediamine, N, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidylpyridine; Anhydrides such as acetic anhydride, and compounds such as dicyclohexyl-carbodiimide.

The reaction temperature in the condensation reaction to produce enamine is generally 0 ° -180 ° C., preferably 50 ° -150 ° C. or the boiling point of the solvent or solvent mixture.

In order to promote the reaction rate, it is preferable to proceed with this reaction in the phase transfer catalyst. Examples of these catalysts are as follows.

Tetraalkylammonium halides, tetraalkylhydrogensulfates and tetraalkyl hydroxides (such as tetrabutyl ammonium chloride, tetrabutylammonium bromide and tetrabutylammonium iodine); Triethylbenzylammonium chloride and triethylbenzeneammonium bromide; Tetrapropylammonium chloride, tetrapropyl ammonium bromide and tetrapropylammonium iodine.

Also suitable are phosphonium salts as suitable phase transfer catalysts.

The N-acylation reaction is carried out by reacting with R ₄ COOH or with reactive acid derivatives such as esters, acid anhydrides or acid halides preferably acid chlorides or acid bromide. This acylation reaction is preferably carried out in the presence of a reaction catalyst such as dimethylformamide.

The reaction temperature is between 0 ° and 180 ° C., preferably between 0 ° and 150 ° C. or the boiling point temperature of the solvent or mixture of these solvents. It is sometimes desirable to use acid acceptors or condensers, suitable examples of which include: trialkylamines (trimethylamine, triethylamine, tripropylamine), pyridine and pyridine bases (4-dimethylaminopyridine, 4- Amines such as pyrrolidylaminopyridine), hydrogen carbonates, carbonates, hydroxides and oxides of alkali metals and alkaline earth metals, and alkali metal acetates.

Hydrogen halides formed during the reaction can be removed from the reaction mixture by injecting a combination of inert gas (eg nitrogen gas) or molecular sieves. All of these reactions proceed under normal pressure.

The starting materials of the above formulas (II) and (III) are known or can be prepared by known methods.

The scope of the present invention also includes all partial steps of the specified process.

Among the compounds associated with compounds of formula (II), 2-amino-1,3,4-thiadiazole derivatives are known from US Pat. No. 3891762. Their fungicide action on plants is also specified. However, the fires specified in the patent application have been observed to have a teratogenic action (see Teratology 7, 65 (1973); 9, 179 (1974) and 10, 90 (1964)]. However, the compounds of the present invention do not have such side effects (see Biological Examples). Moreover, several compounds known compared to the compounds of the present invention have vegetable toxicity.

It can be seen that the compounds of formula (I) have a very desirable bactericidal activity spectrum in practical use, the field of their use being in the inhibition of harmful microorganisms, in particular phytopathogenic bacteria.

The compounds of formula (I) can be used to protect cultivated crops without side effects such as phytotoxicity.

Cultivated crops that fall within the scope of the present invention are as follows: grains, rice, citrus fruits, fruits, cotton, vegetables (e.g. tomatoes, paprika, cabbage, potatoes, carrots, etc.), hawthorn, fruit trees (e.g .; Plums, apples, pears and cherry trees, and horticultural plants (eg geranium, begonia, etc.).

The plants listed above are composed of the most important and cultivating plants, of course, which may also cover related species.

The compounds of the formula (I) are especially Xanthomonadae (e.g., chisantomonas obi ash, chisantomonas citris, chisantomonas competis, chisantomonas malvasium, etc.) and Pseudomonas genus, er. It can be used in all ranges in which such diseases are found, including Winia, Agrobacterium, Corynebacterium, host plants on mixed plants.

The compounds of formula (I) can destroy or inhibit bacteria that are transmitted to parts of plants or plants (fruit, flowers, leaves, stems, tubers, roots) in useful plants, and at the same time, It can protect against transmission of the same fungus.

In addition, the compound of formula (I) has a systemic action.

The double bonds in the molecular structure form cis and trans isomers that differ in their biological properties. Compounds in which the thiadiazolyl amine group and the carboxyl group are in trans position act as particularly effective fungicides.

The compounds of formula (I) may be used alone or in combination with a carrier or a suitable adjuvant. Depending on the method of use, these carriers and auxiliaries are solid or liquid, corresponding to the materials used. For example, natural or regenerated inorganics, organic solvents, dispersion media, humectants, adhesives, thickening agents, binders or fertilizers and the like.

In practical use, the compounds of formula (I) are formulated as active ingredients in the following formulations, where the percentage corresponds to the effective amount of the active ingredient:

Solid form: Dust, tracking agents (up to 10%), granules (coated granules, saturated granules, homogeneous granules), pellets (1-80%)

Liquid formulations: a) active ingredient concentrates which can be dispersed in water: wet powder, ointments (25-90% in commercial packings, 0.01 to 15% in ready-to-use solutions); Concentrated emulsion and solution (10 to 50%; 0.01 to 15% for immediate use).

b) solution, aerosol: The content of the active ingredient described above is from 0.1 to 95% by weight. Such compositions are also included within the scope of the present invention.

It is to be understood that the compounds of formula (I) may be used in conjunction with other fungicides, herbicides and the like to expand the activity spectrum.

Accordingly, the present invention also relates to the use of a compound of formula (I) above for the inhibition of phytopathological bacteria. The following examples illustrate the present invention in detail, and the present invention is not limited by the following examples. The parts and percentages used in this example are parts by weight and parts by weight.

Preparation Example

Example 1

Preparation of 3- (N-1,3,4-thiadiazolyl-2) -amino-2-methyl-methylacrylate of the following formula

303 g (3.0 moles) of 2-amino-1,3,4-thiadiazole in 2 l of methyl cellosolve together with 352.8 g (3.18 moles) of methyl α-formyl-propionate were 16 at 120 ° C. Keep for hours.

P-toluenesulfonic acid is added while maintaining. The reaction mixture is cooled and the precipitated crystals are filtered by suction method and then recrystallized in ethanol. The white crystals thus formed are dissolved at 176 ° -179 ° C. Concentration and recrystallization of the mother liquor will yield more of the title compound.

Example 2

Preparation of 3- (N-1,3,4-thiadiazolyl-2-N-cyclopropyl carbonyl) -amino-2-methyl-methylacrylate of the following formula

16.6 g (0.83 mole) of 3- (N-1,3,4-thiadiazolyl-2) -amino-2-methyl-methylacrylate (Compound 1) was added to 200 ml of toluene, followed by the presence of dimethylformamide. 10.35 g (0.1 mole) of cyclo propanecarboxylic acid chloride is added again. The mixture is heated at reflux for 18 h, after addition of a small amount of activated carbon, it is filtered under hot condition. Crystallize after adding petroleum ether and recrystallize once again in ethanol.

Melting Point: 116-118 ℃

The following compounds can be prepared by the same method as in Examples 1 and 2.

TABLE 1

Formulation Example

Example 3

Dust: The following materials are used to make a) 5%, b) 2%, c) 80% dust:

a) 5 parts active ingredient: 96 parts talc (talc)

b) 2 parts active ingredient: 1 part highly dispersed silicic acid, 97 parts talc (talc)

c) 80 parts of active ingredient: 17 parts of talc, 3 parts of highly dispersed silica.

After mixing and polishing the carrier and the active ingredient, it can be processed into powder in this state for use.

Example 4

Granules: The following materials are used to formulate 5% granules.

5 parts active ingredient, 0.25 parts epoxidized vegetable oil, 0.25 parts cetylpolyglycol ether, 3.25 parts polyethylene glycol, 91 parts kaolin (particle size 0.3-0.8 mm).

The active ingredient is mixed with epoxidized vegetable oil and dissolved in 6 parts of acetone. Polyethylene glycol and cetylpolyglycol ether are added. The resulting solution is sprayed onto kaolin and the acetone is evaporated in vacuo.

Example 5

Wet powder: The following components are used for the manufacture of wet powders: a) 70%, b) 40%, c) 25%, d) 25%, e) 10%.

a) 70 parts active ingredient: 5 parts sodium dibutylnaphthyl sulfonate, 3 parts naphthalenesulfonic acid / phenolsulfonic acid / formaldehyde concentrate (3: 2: 1), 10 parts kaolin, 12 parts caffeine chalk.

b) 40 parts active ingredient: 5 parts sodium ligninsulfonate, 1 part sodium dibutylnaphthalenesulfonic acid, 54 parts silicic acid.

c) 25 parts of active ingredient: 4.5 parts of calcium lignin sulfate, 1.9 parts of champagne choke / hydroxyethylcellulose mixture (1: 1), 1.5 parts of sodium dibutylnaphthalenesulfonate, 19.5 parts of silicic acid, 19.5 parts of champagne choke, 28.1 parts of kaolin .

d) 25 parts active ingredient; 2.5 parts isooctylphenoxypolyethylene ethanol, 1.7 parts champagne choke / hydroxyethyl cellulose mixture (1: 1), 8.3 parts sodium aluminum silicate, 16.5 parts diatomaceous earth, 46 parts kaolin.

e) 10 parts active ingredient: sodium salt mixture of 3 parts saturated fatty alcohol sulfate, 5 parts naphthalenesulfonic acid / formaldehyde concentrate, 82 parts kaolin.

The active ingredient is mixed homogeneously together with the additives in a suitable mixer and ground with a grinder and roller. The wettable powder and suspension powder are obtained. This wet powder can be diluted with water to obtain a suspension of the desired concentration, and can be used especially for the treatment of leaves.

Example 6

Emulsifying Concentrates The following materials are used in the 25% emulsifying concentrate formulations.

25 parts active ingredient, 2.5 parts epoxidized vegetable oil, 10 parts alkylarylsulfonate / fatty alcohol polyglycol ether mixture, 5 parts dimethylformamide, 57.5 parts xylene.

This concentrate can be diluted with water to produce an emulsion of the desired concentration that is easy to use on the leaves for treatment.

The compound of formula (I) may also be used in the form of a dispersion suspension as a spray injector.

Biological Example

Example 7

Effect of Rice on Chisantomonas Duckwood

a) persistent protection

Rice of the "calo" or "S ₆ " variety is grown on warm for three weeks and sprayed with the test substance in the form of a spray mixture (0.06% active ingredient).

Allow the spray coating to dry for one day, place the treated plants in a thermostat at 75-85% relative humidity and 24 ° C, and cut off the ends of the leaves with scissors previously soaked in Chisantomonas duck resuspension. Infect. After growing for 10 days in the same room as above, the cut leaves run necrotic withered and twisted.

The residual action of the test substance is determined by assessing the extent of these symptoms. That is, less than 20% of these plants were affected by the action of compounds 1,2,3,4,6,7,8,9,11,12,13,14. However, it can be seen that untreated, infected control plants develop about 100%, or almost all of them.

b) systematic action

After cultivation of rice of the "calo" or "S ₆ " variety in the hotbed for three weeks, a suspension of the test substance (0.006% active ingredient, based on soil volume) is sprayed. Three days after this treatment, the crops are stored in a thermostat at 75-85% relative humidity and 24 ° C. Scissors that have been soaked in Chisantomo Nasuori material suspension are used to cut off the tip of the leaf and spread the bacteria.

After culturing for 10 days in the room, the cut leaves will wither and dry, and run necrotic. By measuring the extent of these symptoms, the phylogenetic action of the test substance can be measured. In these experiments, compounds of formula (I), including compounds 1,2,3,4,6,7,8,9,11,12,12,14, were treated with untreated and infected control plants (100% onset). Less than 20% of cases).

Example 8

Paprika's Action on Chisantomonas Besicataria

a) persistent protection

Paprika plants of the "California Wonder" variety are incubated in the greenhouse for three weeks, followed by spraying test substances in the form of a spray mixture (0.06% active ingredient). The spray coating is dried for one hour, then stored in a thermostat at 95-100% relative humidity and 26 ° C, and the base of the leaves is spread with a Chisantomonas Besiccataria standardized suspension.

After 6 days of incubation, round, initially wet and later necrotic spots form on the leaves. The persistence of the test substance is determined by the size and number of spots.

Compounds of formula (I), encompassing compounds 1,2,4,6,8,9,12,13,14, showed that less than 20% of the untreated infected control plants (100% invention) developed. Can be.

b) phylogenetic

Paprika plants of the "California Wonder" variety are grown in greenhouses for three weeks, then sprayed with a test mixture (0.006% active ingredient, based on soil volume) in the form of a spray mixture. After 3 days of treatment, it is stored in a thermostat at 26-100C relative humidity and 26 ° C, and the bottom surface of the leaves is sprayed with Chisantomonas Besicataria suspension.

After incubation for 6 days in the thermostat, round spots that are initially wet and then necrotic are formed on the leaves. The systematic behavior of the test substance can be determined by the size and number of these spots. In this experiment, the compounds of formula (I) encompassing compounds 1,2,4,7,9,11,14 were found to be invented less than 20% compared to untreated infected control plants (100% invention). Able to know.

Example 9

Experiments on possible embryonic malformations

Experimental substance

US Pat. ) With 0.2% solution (solution in sodium carboxymethylcellulose / physiological sodium chloride solution) or only with carrier solution (control).

Killed on the 21st day of pregnancy, counting the number of malformed fetuses.

Claims (1)

Condensation reaction of 2-amino-1,3,4-thiadiazole of formula (II) with a compound of formula (III) at a temperature of 0 ° -180 ° C. removes water, and the resulting condensate is R 4- (N-1,3,4-thiadiazolyl-2) -aminoalkyl-alkylacrylic compound of formula (I), characterized in that it comprises acylation with a reactive derivative thereof, such as ₄ COOH or an acid halide. Method of producing a rate.

Wherein R ₁ is hydrogen or C ₁ -C ₄ alkyl, R ₂ is C ₁ -C ₄ alkyl, R ₃ is hydrogen or —CO-R ₄ , and R ₄ is methoxymethyl, cyclopropyl, methyl , Chloromethyl, furyl, monochlorophenyl, dichlorophenyl, methylphenyl or dichloropyridyl, and R ' ₃ is hydrogen.