KR800000625B1 - Method for preparing aniline derivative - Google Patents

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Description

Method for preparing aniline derivative

The present invention relates to a process for the preparation of the aniline derivatives of the following formula (I) useful as fungicides and plant growth regulators.

In the above structural formula

R ₁ is alkyl having 1 to 4 carbon atoms, alkoxy or halogen having 1 to 4 carbon atoms,

R ₂ is hydrogen, alkyl of 1 to 3 carbon atoms or halogen,

R ₅ is hydrogen, alkyl of 1 to 3 carbon atoms or halogen,

R ₆ is hydrogen or methyl,

The total number of carbon atoms of the substituents R ₁ , R ₂ , R ₅ and R ₆ in the phenyl ring should not exceed 8,

이고,X is -CH ₂ or

ego,

이고, 여기서 R′,R″ 및 R″′는 각각 수소, 메틸 또는 에틸이고,R ₃ is -COOR ′ or

Wherein R ′, R ″ and R ″ ′ are each hydrogen, methyl or ethyl,

R ₄ is a 5 or 6 membered heterocyclic group unsubstituted or substituted with methyl and / or halogen, having 1 to 2 heteroatoms,

Provided that when the 2,6 or 2,3,6-position is substituted with a methyl group and R ₄ is a 2-furanyl group and -XR ₃ is an α-propionic acid methyl ester, the phenyl ring further contains a substituent. Alkyl moieties of alkyl and alkoxy groups represent methyl, ethyl, n-propyl, isopropyl, or n-, iso-, secondary- or tertiary butyl groups, and halogen is fluorine, chlorine, bromine or iodine.

Heterocyclic groups of 5 to 6 atoms are, for example, furan, thiophene, pyridine, pyrimidine, 2,3-dihydro-4H-pyran, 1,4-oxathi- (2)-phosphorus, tetrahydrofuran, mor Pauline or piperidine, all of which may be substituted with methyl and / or halogen.

German Publication No. 2,006,471 discloses (2'-methylfuranyl-3 ')-carbonyl as an active substance with adequate action against some fungi (uromises paceoli, alterna solani, lizatonia solani). -2,6-dimethyl aniline and (2'-methylfuranyl-3 ')-carbonyl-2-methyl-6-chloro aniline are disclosed.

The present invention is based on the surprising finding that compounds having structures significantly different from formula (I) have a particularly effective bactericidal spectrum for protecting cultivated plants. Cultivated plants within the scope of the present invention include, for example, cereals, corn, rice, vegetables, beets, soybeans, peanuts, fruit trees, ornamental plants, vines, hops, cucumbers, cucumbers, zucchini, melon potatoes, tobacco , Tomato bananas, cocoa and natural rubber plants.

The active ingredient of structural formula (I) according to the present invention can inhibit or kill fungi occurring in plants or parts of plants (fruit, flowers, leaves, stems, roots, etc.), and also the parts of plants that grow afterwards from these fungi You can also protect. Effective substances of formula (I) include ascomycetes (eg, Erysipaceae); Bassidiomycetes, in particular phytopathogenic fungi such as rust fungi, in particular Omycetes belonging to Pycomycetes, for example, phytopotora, peronospora, pseudoferonospora, phytium or plasmo Acts on para and so on. Moreover, the compounds of formula (I) have an infiltration action and can also be used as an antiseptic to protect seeds (fruit, stems, seams) and to protect plant wounds from fungal infections as well as phytopathogenic fungi in the soil. .

의 그룹이며, R₄,R₅,R₆및 R′가 전술한 바와 같은 구조식(I) 화합물들이며, 이들 화합물을 그룹(Ia)로 나타낸다. 이들 화합물(Ia) 가운데 우수한 것은 R₄가 메틸기로 치환되거나 바람직하게는 치환되지 않은 2-푸라닐기인 화합물이다.Preferred fungicides are R ₁ is methyl, R ₂ is methyl, ethyl or chlorine at the ortho position relative to the amino group and -XR ₃ is

R ₄ , R ₅ , R ₆ and R ′ are the compounds of formula (I) as described above, and these compounds are represented by group (Ia). Among these compounds (Ia), excellent is a compound in which R ₄ is a 2-furanyl group which is substituted or preferably unsubstituted with a methyl group.

Particularly important among these are -XR _{3, which} is an α-propionic acid methyl ester group, and the total of the substituents R ₁ , R ₂ , R _3, and R ₆ do not exceed 4, for example, the third substituent in the phenyl nucleus. 2,6-dimethylaniline derivatives further containing R ₅ and R ₆ , as well as 2,3,5,6-tetramethylaniline, 2,6-dimethyl-3-ethylaniline or 2,6-dimethyl aniline derivatives. Group (Ia) contains compounds wherein R ₄ is a 3-furanyl group which may be substituted with one or two methyl groups as a fungicide which is beneficial to the special field. Compounds of group (Ia) in which R ₄ is 2-thienyl are also particularly interesting fungicides.

Other preferred compounds for regulating plant growth are R ₁ is methyl or ethyl, R ₂ is methyl, ethyl or chlorine at the ortho position relative to the amino group and -XR ₃ is -CH ₂ -CON (R ″) (R ″ ′) And R ₄ , R ₅ , R ₆ , R ″ and R ″ ′ are structural formula (I) compounds as described above.

Plant growth regulation primarily refers to the delayed regulation of the growth of natural plants, especially to the desired plant size in terms of growth height. Such growth can be found in monocots and dicotyledons, in particular grass, cereals, soybeans and ornamentals.

The preparation method of the present invention is characterized in that the compound of formula (II) is acylated with a carboxylic acid of formula (III) or one of its acid halides, acid anhydrides, esters or acid amides thereof. It is.

In the above formulas (II) and (III)

R ₁ -R ₆ and X are as defined in formula (I) above, “acid halide” preferably denotes acid chloride or acid bromide. The reaction can be carried out in the presence or absence of a solvent or diluent that is inert to the reactants. Examples of such solvents or diluents include aliphatic or aromatic hydrocarbons such as benzene, toluene, xylene, petroleum ether; Halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride and chloroform; Ether or ethereal compounds such as dialkyl ether, dioxane and tetrahydrofuran; Nitriles such as acetonitrile; N, N-dialkylated amides such as dimethylformamide; Acetic anhydride and dimethyl sulfoxide; Ketones such as methyl ethyl ketone and mixtures of these solvents.

The reaction temperature is from 0 ° to 180 ° C, preferably from 20 ° to 120 ° C. In most cases it is advantageous to use acceptors or condensates, for example tertiary amines such as trialkylamines (e.g. triethylamine), pyridine and pyridine bases such as oxides and hydroxides, alkali metals and alkaline earth metals. Bicarbonates and deacidates as well as sodium acetate. Furthermore, an aniline derivative of the formula (II) may be used as the acid acceptor. The method for preparing using the compound of formula II as starting material may be carried out without an acid acceptor. In some cases it may be convenient to pass nitrogen gas to build up the produced hydrogen halide, and in other cases it is very advantageous to use dimethylformamide as the reaction catalyst.

인 구조식(I) 화합물은 비대칭 탄소원자(^*)를 가지고 있으며 통상의 방법에 따라 광학적인 대장체로 분리시킬 수 있다. 이러한 점에서 볼 때 광학적 대장체 D-형에서는 상술한 바와 같은 살균작용이 현저하다. 따라서 본 발명의 범주내에서 이들 화합물은 구조식(I)의 D-배위가 바람직하다. 에탄올 또는 아세톤에서 이들 D-형은 마이너스 각도로 회전하는 규칙을 갖는다.The details of the preparation of the intermediate formula (II) can be seen in particular from the preparation of the anilino-alkanoic acid esters described in the literature (J. Org. Chem. 30, 4101 (1965), Tetrahedron). 1967, 487, Tetrahedron 1967, 493). X

Phosphorus (I) compound has an asymmetric carbon atom ( ^* ) and can be separated into an optical colon according to a conventional method. From this point of view, the bactericidal action as described above is remarkable in the optical colon D-form. Therefore, within the scope of the present invention, these compounds preferably have the D-configuration of formula (I). In ethanol or acetone these D-forms have the rule of rotating at negative angles.

Pure optical D-colliders are obtained by preparing the racemic compound of formula (VI) and then reacting with an optically active base containing nitrogen according to conventional methods to produce the corresponding salts.

In the above structural formula

R ₁ , R ₂ , R ₃ and R ₆ are as described above.

Pure D-forms fractionate crystallize the salts and subsequently liberate the acid of formula (VI) with abundant optical D-col, followed by salt formation, crystallization and liberation of α-anilino propionic acid of formula (VI), if appropriate. It is obtained stepwise by repeating several times. Then, if desired, from these D-forms, according to conventional methods, for example, in the presence of hydrochloric acid or sulfuric acid to produce an ester of formula (II) in optical D-coordination or the corresponding structural formula HN (R The amide of formula (II) can be prepared by reaction with an amine of ″) (R ″ ′). Suitable optically active organic bases are, for example, α-phenylethylamine.

Instead of fractional crystallization, the hydroxy group is substituted with halogen in naturally occurring L (+) lactic acid and the product obtained is further reacted with aniline of the following structural formula (VII) having the opposite configuration to It is also possible to obtain an optical colon D-form.

축에서는 아트로프 이성화가 관찰되며 이 경우에 페닐환은 적어도 2,6-위치에서 치환되고 동시에 이 축에 대해 비대칭성이다(즉 더 많은 치환체가 존재함으로써). 이러한 양상은 -X-R₃및 -CO-R₄기의 입체장애에 의해 생긴다. 순수한 이성체를 분리할 목적으로 합성하지 않을 경우 생성물은 보통 2개의 광학적 이성체 또는 2개의 아트로프 이성체의 혼합물로서, 또는 이들 4개의 가능한 이성체의 혼합물로서 생성된다. 광학적 대장체인 D-형의 근본적으로 보다 우수한 살균작용(D,L-형 또는 L-형에 비하여)이 유지되지만 아트로프 이성화에 의하여 현저하게 영향을 받는 것은 아니다. 다음의 실시예는 본 발명을 좀더 상세히 설명한 것이나 본 발명이 이에 국한되지는 않는다. 별다른 언급이 없는한, 광학적으로 활성형인 구조식(I)의 유효물질은 항상 라세미 혼합물이다.Phenyl in addition to optical isomerization

Atrope isomerization is observed at the axis, in which case the phenyl ring is substituted at least in the 2,6-position and at the same time asymmetrical about this axis (ie, due to the presence of more substituents). This aspect is caused by steric hindrance of the -XR ₃ and -CO-R ₄ groups. Unless synthesized for the purpose of separating pure isomers, the product is usually produced as a mixture of two optical isomers or two atropes isomers, or as a mixture of these four possible isomers. The fundamentally better bactericidal action (compared to D, L- or L-form) of the optically cognate D-form is maintained but is not significantly affected by atropisomerization. The following examples illustrate the invention in more detail, but the invention is not limited thereto. Unless stated otherwise, the active substance of formula (I), which is optically active, is always a racemic mixture.

Example 1

Preparation of N- (1′-methoxycarbonylethyl) -N- (furan- (2 ″)-carbonyl) -2,3-dimethyl-6-ethylaniline (Compound 2)

(a) 100 g of 2,3-dimethyl-6-ethylaniline, 223 g of 2-bromopropionic acid methyl ester, and 84 g of sodium bicarbonate were stirred at 140 ° C. for 17 hours, after which the mixture was cooled and diluted with 300 ml of water, Extract with ethyl ether. The extract is washed with a small amount of water, dehydrated with sodium sulfate, filtered and the ether is evaporated. Excess 2-bromopropionic acid methyl ester is distilled off and then distilled at high vacuum of the crude product. Boiling point 88 ° to 90 ° C / 0.04 Torr (b) 13 g of furan-2-carboxylic acid chloride was stirred and added dropwise to 17 g of ester obtained in (a), 2 ml of dimethylformamide and 150 ml of anhydrous toluene and the mixture was stirred for 1 hour. Reflux. The solvent is evaporated and the crude product is triturated with petroleum ether. Melting Point 110.5 ° to 126 ° C. (Ethyl Acetate / Petroleum Ether) Compound 2 is a mixture of two pairs of diastereomers.

D-forms of the atropisomers (compounds 2a and 2b) convert the D-forms of α- (2,3-dimethyl-6-ethylanilino) -propionic acid methyl ester to furan- (2) -carboxylic acid or a reactive derivative thereof Obtained by acylation.

Example 2

Preparation of N- (dimethylaminocarbonylmethyl) -H- (furan- (2 ″)-carbonyl) -2,6-dimethylaniline (Compound 47)

28 g of N- (1′-methoxycarbonylmethyl) -N- (furan- (2 ″)-carbonyl) -2, -6-dimethylaniline (melting point 98 ° to 28 g) prepared in a similar manner to Example 1 99 ° C.) is stirred with 150 ml of 40% aqueous dimethylamine solution and 0.5 g of triethylenediamine for 1 day at room temperature. Unreacted starting material is removed by extraction twice with ether and the aqueous layer is concentrated by rotary evaporation. The residue on viscous oil is triturated with hexane. The melting point of the final product after recrystallization in hexane / tetrahydrofuran is 142 ° -145 ° C.

Example 3

Preparation of N- (1′-methoxycarbonylethyl) -N- (2 ″, 4 ″ -dichloropyrimidine- (5 ″)-carbonyl) -2,6-dimethylaniline (Compound 114)

20.7 g of N- (1'-methoxycarbonylethyl) -2,6-dimethylaniline, 2 ml of a solution of 25.4 g of 2,4-dichloropyrimidine-5-carboxylic acid chloride dissolved in 50 ml of chlorobenzene To the mixture of dimethylformamide and 150 ml of chlorobenzene was added dropwise with stirring over 20 minutes. The temperature is raised to 10 ℃. The reaction compound is then heated to 110 ° C. and the resulting hydrogen chloride is removed by passing it through a stream of nitrogen. The solvent is removed by rotary evaporation and the crude product is triturated with petroleum ether. The final product, recrystallized and purified from dizopropanol, has a melting point of 136 ° to 137 ° C. The following compound of formula (Ib), wherein R ₁ is in the 2-position, having three or four substituents in the phenyl nucleus, is prepared by this method or by one of the methods described above.

The compounds listed below are mono- or di-substituted in the phenyl nucleus and have the following structural formula.

Among these compounds are compounds of the following structural formulas.

Among these compounds are compounds of the following structural formulas.

There is also a compound of the following structural formula.

Compounds of formula (I) may be used alone or in combination with appropriate carriers and / or other additives. Suitable carriers and additives are in the form of solids or liquids conventionally used in formulating preparations, and include, for example, natural or recycled inorganic solvents, dispersants, wetting agents, tackifiers, extenders, binders, or fertilizers. Typically the amount of active ingredient in useful compositions is from 0.1 to 90%.

The compound of formula (I) is used in the following preparation. (The weight percentage in parentheses indicates the amount of active ingredient):

Solid preparation: powder and tracking preparation (less than 10%); Granulated and Coated Granules, Penetrated Granules and Uniform Granules (1 to 80%)

Liquid formulations:

(a) Concentrates of active ingredients that can be dispersed in water:

Hydrating and pasta (25-95% in commercial packaging,

0.01-15% when used)

Emulsifiers and concentrated solutions (10-50%,

0.01-15% when used)

(b) solution (0.1-20%)

The active ingredient of the structural formula (I) can be formulated as follows.

Powder:

Prepare powders a) 50% and b) 2% using the following ingredients:

a) 5 active ingredients

95 parts talc

b) active ingredients in two parts;

1 part highly dispersed silicic acid

97 parts talc

The active ingredient is mixed with the carrier, milled and then formulated by milling.

Mouth:

5% granules are prepared using the following ingredients.

5 active ingredients

0.25 parts and epichlorohydrin

0.25 parts cetylpolyglycol ether

3.50 parts of polyethylene glycol

91 parts kaolin (particle size 0.3 to 0.8 mm)

The active ingredient is mixed with epichlorohydrin and dissolved in 6 parts of acetone. Polyethyleneglycol and cetylpolyglycol ether are added thereto and the resulting solution is sprayed on kaolin and the acetone is evaporated under vacuum. These microparticles are advantageously used to remove fungi in the soil.

Hydration:

The following components are used to prepare a) 70%, b) 40%, c) and d) 25%, and e) 10% hydrating agent.

a) 70 parts of active ingredient

5 parts sodium dibutyl naphthylsulfonate

3 parts naphthalenesulfonic acid / phenolsulfonic acid / formaldehyde condensate (3: 2: 1)

10 kaolins

12 Champagne Chokes

b) 40 parts of active ingredient

5 parts sodium lignin sulfonate

1 part sodium dibutylnaphthalenesulfonic acid

54 parts silicic acid

c) 25 active ingredients

4.5 parts calcium lignin sulfonate

1.9 parts champagne choke / hydroxyethyl cellulose mixture (1: 1)

1.5 parts sodium dibutylnaphthalenesulfonate

19.5 parts silicic acid

19.5 Champagne Chokes

28.1 kaolin

d) 25 active ingredients

2.5 parts isooctylphenoxy-polyethylene-ethanol

1.7 parts champagne choke / hydroxyethyl cellulose mixture (1: 1)

8.3 parts sodium aluminum silicate

16.3 diatomaceous earth

46 kaolins

e) 20 parts of active ingredient

A mixture of sodium salt of 3 parts saturated fatty alcohol sulfate

5 parts naphthalenesulfonic acid / formaldehyde condensate

82 parts kaolin.

The active ingredient is mixed well with the additives in a suitable mixer and then pulverized with a suitable mill and roller to obtain a wettable powder and a suspension powder having excellent wettability. It can be diluted with water to form a suspension of the desired concentration, especially for leaves.

Emulsifier:

25% of an emulsifier is prepared using the following ingredients.

25 active ingredients

2.5 parts epoxidized vegetable oil

10 parts alkylarylsulfonate / fatty alcohol polyglycol ether mixture

5 parts dimethyl formamide

57.5 parts xylene

The emulsifier is diluted with water to produce an emulsion of the desired concentration, which is particularly suitable for use on leaves.

Example 4

Action of Tomato (Solanum lycopersicum) on Phytophora infestans

Ia) Residue-prevention

The solution obtained from the hydrating agent is sprayed and infected with the yeast suspension of the late blight bacteria so that the tomato crop of the “Rotor Gnom” variety grown for about three weeks contains 0.05% of the active compound, and then dried. This is then maintained for 6 days in a room with high humidity and 18 to 20 ° C, artificially moistened with fog, and after this period, the number and size of typical spots on the leaves are measured to test the efficacy of the test substance. .

Ib) therapeutic action

After spraying the rotator suspension of the late blight on the "rotor nom" tomato crop grown for about three weeks, it is incubated in a room maintained at a temperature of 18 to 20 ℃ and saturated humidity. Humidity is stopped after 24 hours. After the plants are dried, the liquid containing the active substance prepared as a hydrating agent is sprayed to a concentration of 0.05%. After the spray coat has dried, the crop is grown for four days in a damp room. During this period, the efficacy of the material is tested by measuring the number and size of typical spots on the leaves.

II) preventive penetration

The soil surface in the pot where the “rotor norm” tomato crop is grown for 3 weeks is treated with an active ingredient of 0.05% concentration (volume to soil) as a wetting agent. After 3 days, the lower lobe of the crop was spray-infected with the injector suspension of the late blight, stored in a spray chamber maintained at a temperature of 18-20 ° C. and saturated humidity for 5 days, and then the size and number of spots on the leaves were measured and tested. Assay the efficacy of the substance.

From the test results of Example 4, it can be seen that the compound of formula (I) shows a potent action against the fungus of leaves.

[table]

Compounds 1,4,8,53,65,74 and 112 reduce the infection rate of fungi to less than 20% when tested in the same test using only 0.02% concentration and compound 54 (D-form of Compound 53) is only 0 To 5%.

Example 6

Action of Vine on Plasmapara viticola

a) residue-prevention

Vine cuttings of the “Chasselas” variety are grown in greenhouses. Three 10 leafed vines are sprayed with a 0.05% solution of the active compound formulated in the form of a hydrate. After the coating layer is dried, it is infected with the spore suspension of the Bacillus spp. On the lower part of the leaves of the plant and then maintained for 8 days in a damp room. After this period, symptoms of disease appear in the control crop. The effect of the tested active ingredient is assayed by measuring the size and number of infected areas present in the treated crop.

b) therapeutic action

Vine cuttings of the “Chasellas” strain are grown in greenhouses to infect the spore suspension of the Bacillus fungi at and below 10 leaves. After 24 hours of storage in a damp room, it is sprayed with a 0.05% solution prepared from an active ingredient hydrating agent.

This is then maintained for 7 more days in a damp room and the symptoms of the disease appearing in the control crops are observed. The therapeutic effect of the test substance is tested by measuring the size and number of infected sites.

In these tests, the compound of formula (I) shows significant bactericidal activity on the leaves. Unexpectedly, the compounds listed in the table of Example 4 reduce the infection of fungi by up to 20% and in some cases, for example, compounds 1, 53 and 54 rarely cause infection (0-5%).

Example 6

Action against Hordeum vu1gare powdery mildew (Erisiphe graminis)

Residual protection

After spraying the spraying solution (0.05% of active substance) from the hydrating agent of the active compound to barley about 8 cm high, it was infected with conidia of fungi after 48 hours and left in the greenhouse at about 22 ° C. Measure Compounds of formula (I), such as compounds 76 and 77, reduce the infection rate to 20% or less.

Example 6

Action on Pyathium debaryanum in Beet vulgaris

a) Action after soil treatment

Fungi are incubated in sterile oat grains and added to a mixture of soil and sand. Pot soil contaminated with germs and seed the beet seeds. Immediately after sowing, the preparation of the test compound, prepared as a hydrate, is poured into the soil in the form of an aqueous suspension (ratio of 0.002% of the active compound relative to the volume of the soil). This pot is then stored in a silver chamber at 20-24 ° C. for 2-3 weeks. The soil is kept in a uniform wet state by spraying the water still. The efficacy of the test compound is assayed by measuring the germination rate of sugar beet and healthy and diseased plants.

b) after treatment of seed fractions;

Fungi are incubated in oat grains and added to a mixture of soil and sand. The soil contaminated with bacteria is filled in pots, and the beet seeds are treated with a test formulation formulated with powder for powder (containing 0.1% active ingredient by weight of the seed) and sown in the soil. Pots are stored in a greenhouse at 20-24 ° C. for two to three weeks and then gently sprayed with water to keep the moisture uniform. Test the efficacy of the test compound by measuring the germination rate of sugarcane and healthy and diseased plants.

Under the test conditions of (a) and (b) above, as a result of treatment with the active substance of formula (I), more than 85% of the sugar beet germinated and all were healthy. Only 20% or less germinated in the untreated control, some of which were diseased.

Example 8

Paul's growth inhibition

An aqueous formulation of the active substance of formula (1) is sprayed onto a 3 m ² bath lawn consisting of Lolium perenne, Poa pratensis and Festuca rubra. However, two days after we cut lawn first in spring. The amount of active substance is 5 kg per hectare, and the untreated area is used as a control. Six weeks after treatment, the extent of growth of treated and untreated areas is measured as height. Lawns treated with active compounds grew uniformly and their appearance was healthy. Significant or nearly complete growth inhibition is carried out in particular by the active compounds of formula (I) in which XR ₃ is a -CO-N (R ″) (R ″ ′).

Claims (1)

A process for preparing the aniline derivative of formula (I) wherein the compound of formula (II) is acylated with a carboxylic acid of formula (I) or one of its acid halides, acid anhydrides, esters, or acidamides.

In the above structure, R ₁ is alkyl having 1 to 4 carbon atoms, alkoxy or halogen having 1 to 4 carbon atoms, R ₂ is hydrogen, alkyl having 1 to 3 carbon atoms or halogen, R ₅ is hydrogen, alkyl having 1 to 3 carbon atoms or Halogen, R ₆ is hydrogen or methyl, wherein the total carbon number of the substituents R ₁ , R ₂ , R ₅ and R ₆ of the phenyl ring must not exceed 8, and X is -CH ₂ or

And R ₃ is -COOR ′ or

Wherein R ′, R ″ and R ″ ′ are hydrogen, methyl or ethyl and R ₄ is a 5-6 membered heterocyclic group substituted with methyl and / or halogen, having 1 to 2 heteroatoms, provided The phenyl ring further contains a substituent when the 2,6- or 2,3,6-position is substituted with a methyl group and R ₄ is a 2-furanyl group and -XR ₃ is an α-propionic acid methyl ester.