JPS6364429B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is based on the general formula [In the formula, R ₁ and R ₃ represent a lower alkyl group or a phenyl group (the phenyl may be optionally substituted with 1 to 3 lower alkyl groups, lower alkoxy groups, halogen atoms, or nitro groups)] ,
R ₂ represents a hydrogen atom, a lower alkyl group or a phenyl group (the phenyl may be optionally substituted with 1 to 3 lower alkyl groups, lower alkoxy groups, halogen atoms or nitro groups). This invention relates to a novel isoxazole compound having the following properties. In the definition of the above general formula (), examples of lower alkyl groups for R ₁ , R ₂ and R ₃ include methyl, ethyl, n-propyl, isopropyl, n-
Examples include straight-chain or branched alkyl groups having 1 to 4 carbon atoms such as butyl, isobutyl, and tert-butyl. When R ₁ , R ₂ and R ₃ are phenyl groups having a lower alkyl group as a substituent, the lower alkyl group has 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl. Examples include alkyl groups. When R ₁ , R ₂ and R ₃ are phenyl groups having a lower alkoxy group as a substituent, examples of the lower alkoxy group include methoxy, ethoxy, n
- Examples include alkoxy groups having 1 to 3 carbon atoms such as propoxy or isopropoxy. Further, when R ₁ , R ₂ and R ₃ are phenyl groups having a halogen atom as a substituent, examples of the halogen atom include chlorine, bromine and fluorine. In the general formula (), the compound ( _H ) in which R ₂ is a hydrogen atom can exist as an equilibrium mixture with a tautomer (' _H ). (In the above formula, R ₁ and R ₃ have the same meanings as described above.) The novel isoxazole compound () of the present invention is a compound useful as an agricultural and horticultural fungicide or a paddy field herbicide. Examples of the novel isoxazole compounds of the present invention include the following. 1 4-(2,4-dichlorobenzoyl)-5-
Methyl-2-phenyl-4-isoxazolin-3-one 2 5-methyl-2-phenyl-4-p-toluoyl-4-isoxazolin-3-one 3 5-methyl-2-phenyl-4-m- Toluoyl-4-isoxazolin-3-one 4 4-benzoyl-5-methyl-2-phenyl-4-isoxazolin-3-one 5 4-(2,4-dimethylbenzoyl)-5-
Methyl-2-phenyl-4-isoxazoline-3-one 6 4-(2-chlorobenzoyl)-5-methyl-2-phenyl-4-isoxazoline-3-
On7 4-(4-brombenzoyl)-5-methyl-2-phenyl-4-isoxazoline-3-
8 -methyl-2-phenyl-4-(3,4,5
-trimethoxybenzoyl-4-isoxazolin-3-one 9 4-(3,5-dinitrobenzoyl)-5-
Methyl-2-phenyl-4-isoxazolin-3-one 10 5-Methyl-4-(2-methoxybenzoyl)-2-phenyl-4-isoxazoline-
3-one 11 4-benzoyl-2-(4-chlorophenyl)-5-methyl-4-isoxazoline-3
-one 12 4-benzoyl-5-methyl-2-p-tolyl-4-isoxazolin-3-one 13 4-benzoyl-5-methyl-2-m-tolyl-4-isoxazolin-3-one 14 4 -benzoyl-2-(3-chlorophenyl)-5-methyl-4-isoxazoline-3
-one 15 4-benzoyl-2-(3,5-dichlorophenyl)-5-methyl-4-isoxazoline-3-one 16 4-benzoyl-2-(4-bromphenyl)-5-methyl-4-isoxazoline -3
-on17 4-(2,4-dichlorobenzoyl)-2,
5-dimethyl-4-isoxazolin-3-one 18 4-acetyl-5-methyl-2-phenyl-
4-Isoxazolin-3-one 19 4-acetyl-2,5-diphenyl-4-isoxazolin-3-one 20 4-acetyl-2-(4-chlorophenyl)
-5-phenyl-4-isoxazoline-3-
21 4-acetyl-5-phenyl-2-p-tolyl-4-isoxazolin-3-one 22 4-acetyl-5-phenyl-2-m-tolyl-4-isoxazolin-3-one 23 4- Acetyl-2-(3,5-dichlorophenyl)-5-phenyl-4-isoxazolin-3-one24 4-acetyl-2-(4-bromphenyl)
-5-phenyl-4-isoxazoline-3-
On25 4-acetyl-2-(3-chlorophenyl)
-Phenyl-4-isoxazolin-3-one26 4-(2,4-dichlorobenzoyl)-5-
Methyl-4-isoxazolin-3-one 27 4-benzoyl-5-methyl-4-isoxazolin-3-one 28 4-benzoyl-5-ethyl-2-phenyl-4-isoxazolin-3-one 29 4 -(2,4-dichlorobenzoyl)-5-
Isopropyl-2-phenyl-4-isoxazolin-3-one30 4-(4-brombenzoyl)-5-tert-
Butyl-2-methyl-4-isoxazoline-
3-one 31 4-(4-chlorobenzoyl)-5-(4-
Chlorphenyl)-2-phenyl-4-isoxazolin-3-one32 4-(3-brombenzoyl)-5-(3-
Bromphenyl)-2-phenyl-4-isoxazolin-3-one33 2-(3,5-dichlorophenyl)-4-p
-Toluoyl-5-p-tolyl-4-isoxazolin-3-one34 4-benzoyl-2-ethyl-5-methyl-
4-Isoxazolin-3-one35 4-(2,4-dichlorobenzoyl)-2-
Isopropyl-5-methyl-4-isoxazolin-3-one 36 2-tert-butyl-4-(3,5-dinitrobenzoyl)-5-methyl-4-isoxazolin-3-one 37 5-ethyl-2 -Phenyl-4-propionyl-4-isoxazolin-3-one38 4-butyroyl-5-n-propyl-2-p
-Tolyl-4-isooxazolin-3-one 39 2-(4-bromphenyl)-4-isobutyroyl-5-isopropyl-4-isooxazolin-3-one 40 5-tert-butyl-2-(4-chlorophenyl) -4-pivaloyl-4-isoxazolin-3-one The novel compound () according to the present invention can be produced as follows. (1) Among the compounds having the general formula (),
When R ₂ is a compound other than a hydrogen atom, the general formula (In the formula, R ₁ and R ₂ have the same meaning as above.) A hydroxamic acid having the general formula R ₃ -COX () (wherein, R ₃ has the same meaning as above),
X represents a halogen atom. ) in the presence of a base. In carrying out the above reaction, the compound having the above general formula () is used in an equimolar to slightly excess amount, and the two are brought into contact in the presence of a double molar to slightly excess base in an inert solvent. It is done by twisting. Bases used include linear tertiary amines such as triethylamine or tri-n-butylamine; cyclic tertiary amines such as triethylenediamine or 1,5-diazabicyclo[5.4.0]undecene-5; potassium tert-butoxide or Alkali metal alkoxides such as sodium isoamylate; organolithium reagents such as n-butyllithium; metal hydrides such as sodium hydride or potassium hydride. The solvent used in the reaction is not particularly limited as long as it is inert to this reaction; for example, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride or chloroform. ; ethers such as tetrahydrofuran or dioxane; nitriles such as acetonitrile, propionitrile or benzonitrile; alcohols such as tert-butanol or isoamyl alcohol; amides such as dimethylformamide or dimethylacetamide; Examples include mixed solvents. The reaction temperature is not particularly limited and is usually carried out at about -40°C to 60°C. The time required for the reaction is usually 1 to 15 hours. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, the reaction mixture is poured into a large amount of ice water, the organic layer is separated, extracted with a solvent such as ethyl ether, benzene, or toluene, and the extract is combined with the organic layer,
It can be obtained by washing with water and then concentrating, and if necessary, it can be further purified by conventional methods such as recrystallization, column chromatography, etc. In addition, the raw material compound of the above general formula () is C.
A. 59 , 10058g (1963). (2) Among the compounds having the general formula (),
A compound ( _H ) in which R ₂ is a hydrogen atom can be produced by the following series of reactions. (In the formula, R ₁ and R ₃ have the same meanings as described above, R ₄ represents an acid residue, and X represents a halogen atom.) That is, after ring-closing β-ketoester () with hydroxylamine, the obtained The hydroxyl group of the obtained isoxazole is protected, and the methylene at the 4-position is halogenated and then hydrolyzed to obtain a secondary alcohol (2). After oxidation of (), the protecting group can then be removed to yield ( _H ). Each step will be explained below. The first step is to produce a compound having the above general formula (), in which hydroxylamine is used in the ester () in an equimolar to slightly excess amount, and a base in an equimolar to twice the molar amount as the ester is added to the ester in an inert solvent. This is achieved by bringing the two into contact in the presence of. Preferred bases include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or magnesium hydroxide. The reaction is preferably carried out in the presence of a solvent. The solvent to be used is not particularly limited unless it is related to this reaction, and examples include water; lower alcohols such as methanol or ethanol; ketones such as acetone or methyl ethyl ketone; amides such as dimethylformamide or dimethylacetamide; Examples include mixed solvents. The reaction temperature is not particularly limited and is usually -
It is carried out at a temperature of about 50°C to 0°C. The time required for the reaction is about 2 to 5 hours. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, after pouring the reaction mixture into a large amount of water, if the target compound precipitates as crystals, remove it, or if it does not precipitate, extract with a solvent such as ethyl ether and then distill off the solvent from the extract. obtained by. The crude target compound can also be purified by conventional methods such as recrystallization, column chromatography, etc. The second step is a step of producing a compound having the general formula (), and is achieved by protecting the hydroxyl group of the compound having the general formula ().The reaction is to produce a compound having the general formula (). This is carried out by contacting the hydroxyl-protecting group-forming compound () in the presence of a base. Examples of the hydroxyl-protecting group-forming compound used include acids such as carboxylic acid, sulfonic acid, or phosphoric acid. Bases used include, for example, linear tertiary amines such as triethylamine or tributylamine; cyclic tertiary amines such as triethylenediamine or 1,5-diazabicyclo[5.4.0]undecene-5. etc. are used without particular limitation.The reaction is suitably carried out in the presence of a solvent.The solvent to be used is not particularly limited as long as it does not participate in this reaction, for example aromatic hydrocarbons such as benzene or toluene. halogenated hydrocarbons such as methylene chloride or chloroform; ethers such as tetrahydrofuran or dioxane; nitriles such as acetonitrile or propionitrile; ethyl acetate or a mixed solvent of these solvents are preferably used. The reaction temperature is not particularly limited and is usually carried out at room temperature to about 60°C.The time required for the reaction is usually 1 to 4 hours.After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method.For example, reaction It can be obtained by pouring the mixture into a large amount of water, separating the organic layer, washing it with water, drying it with an appropriate desiccant, and distilling off the solvent.The third step is based on the above general formula (). This is a process for producing a compound having the general formula (), and is achieved by bringing the compound having the general formula () into contact with a halogenating agent in a suitable solvent. Examples of the halogenating agent used include N-- N-halosuccinimide such as bromsuccinimide, N-chlorosuccinimide, halogen molecules, etc. are preferably used.The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction. Examples include aromatic hydrocarbons such as benzene or chlorobenzene; halogenated hydrocarbons such as carbon tetrachloride or dichloroethane.The reaction is carried out with a stoichiometric amount of halogenating agent; In order to carry out the reaction quickly, it is usually preferable to use an excess amount (about 1.1 to 1.5 times the mole).In addition, the reaction is carried out by adding a catalytic amount of a radical initiator such as benzoyl peroxide or azoisobutyronitrile. Alternatively, the reaction is advantageously carried out by irradiation with light, and completed by heating at the reflux temperature of the solvent for 0.5 to 4 hours. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, it can be obtained as a solid by removing insoluble matter from the reaction mixture and concentrating the liquid, but in this series of methods, it can be used as it is as a solution of the raw material compound for the next step without isolation and purification. can. The fourth step is a step of producing a compound having the general formula (), and is achieved by hydrolyzing the compound having the general formula (). The reaction is carried out using an equimolar to slight excess of a silver agent such as silver nitrate or silver trifluoroacetate; a copper agent such as copper chloride or copper acetate; a mercury agent such as mercury chloride or mercury acetate; and 2 to 4 times the weight of the substrate. is carried out in the presence of silica gel. The solvent used is
Alcohols such as tert-butanol or isoamyl alcohol; ketones such as acetone or methyl isobutyl ketone; nitrites such as acetonitrile or propionitrile; and mixing with water with water-miscible organic solvents such as ethyl acetate. A solvent is preferably used. The reaction may be accelerated by adding dropwise a catalytic amount of an acid, for example a mineral acid such as hydrochloric acid or sulfuric acid. The reaction temperature is not particularly limited, but the reaction is usually carried out around room temperature. The time required for the reaction is 15 to 50 hours. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, it can be obtained by removing insoluble matter from the reaction mixture, diluting the liquid with a large amount of water, extracting with a solvent such as methylene chloride, and distilling off the solvent from the extract. This product can be further purified by conventional methods such as recrystallization and column chromatography to obtain a blunt product. The fifth step is a step of producing a compound having the general formula (), and is achieved by oxidizing the compound having the general formula (). The reaction is carried out in the presence of an oxidizing agent. Examples of oxidizing agents used include chromic acid, chromic anhydride, chromic anhydride-pyridine complex salt, chromic anhydride-concentrated sulfuric acid-water, chromic acids such as sodium dichromate; especially chromic acid-sulfuric acid and pyridine-chromic acid. - A hydrochloric acid system is preferably used. The solvent used is not particularly limited as long as it does not participate in this reaction, but for example, acetic acid, an organic acid such as acetic acid-acetic anhydride, or a mixed solvent of an organic acid and an organic acid anhydride; dichloromethane, chloroform, carbon tetrachloride. Preferred are halogenated hydrocarbons, such as, and ketones, such as acetone and methyl isobutyl ketone. The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and the reaction is usually carried out at 0°C to room temperature. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture under reduced pressure. This product can be purified by conventional methods such as recrystallization. The sixth step is a step of producing a compound having the general formula ( _H ), and is achieved by removing the hydroxyl protecting group _R4 of the compound having the general formula (). The reaction is carried out in the presence of a base. Bases used include amines such as ammonia, monomethylamine or diethylamine; alkali metal alkoxides such as sodium methoxide or sodium ethoxide; alkali metals and alkaline earth metals such as sodium hydroxide or calcium hydroxide. hydroxides and the like are preferably used. The reaction is carried out in the presence or absence of a solvent, but in order to carry out the reaction smoothly, it is preferable to use a solvent.The solvent to be used is not particularly limited as long as it does not participate in the reaction, for example, water; Lower alcohols such as methanol or ethanol; ketones such as acetone or methyl isobutyl ketone; and mixed solvents of these solvents are preferably used. The reaction temperature is not particularly limited and is carried out at room temperature to the reflux temperature of the solvent. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, it can be obtained by acidifying the reaction mixture, extracting it with a solvent such as ethyl acetate, and distilling off the solvent from the extract. The crude target compound can be purified by conventional methods such as recrystallization, column chromatography, etc. The method for producing the novel isoxazole compound () of the present invention will be explained in more detail with reference to Examples and Reference Examples, but these examples do not limit the present invention. Example 1 4-(2,4-dichlorobenzoyl)-5-methyl-2-phenyl-4-isoxazoline-
3-one N-phenylacetoacetohydroxamic acid 1.0
After dissolving g in 40ml of benzene, add triethylamine.
1.10 g and then 1.19 g of 2,4-dichlorobenzoyl chloride were added. After stirring the reaction solution at room temperature for 6 hours, it was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: n-hexane: acetone = 30:1) to give a melting point of 141.5 ~
1.60g of the target compound having a temperature of 143°C was obtained (yield
88.9%). Elemental analysis value (%) As C ₁₇ H ₁₁ Cl ₂ NO ₃ Calculated value C, 58.64; H, 3.18; N, 4.02 Actual value C, 58.62; H, 2.93; N, 3.95 According to the method of Example 1 above The following compounds were prepared.

【table】

[Table] Example 2 4-(2,4-dichlorobenzoyl)-5-methyl-4-isoxazolin-3-one 3-benzenesulfonyloxy-4-(2,4
After dissolving 507 mg of -dichlorobenzoyl)-5-methylisoxazole in 16 ml of methanol, 204 mg of sodium methoxide was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was acidified with hydrochloric acid, extracted with ether, washed with water, dried, concentrated to dryness, and reconsolidated with methylene chloride to determine the melting point.
282 mg of the target compound having a temperature of 160-161°C was obtained (yield 84.2%). Elemental analysis value (%) As C ₁₁ H ₇ Cl ₂ NO ₃ Calculated value C, 48.56; H, 2.59; N, 5.15 Actual value C, 48.86; H, 2.77; N, 4.80 Example 3 4-benzoyl-methyl -4-Isoxazolin-3-one After dissolving 1.05 g of 3-benzenesulfonyloxy-4-benzoyl-5-methylisoxazole in 25 ml of acetone, 11 ml of 29% ammonia water was added under water cooling, and the mixture was stirred at room temperature for 4 hours. . Next, acetone was distilled off, the mixture was acidified with hydrochloric acid, and extracted with ether. The ether layer was extracted with an aqueous sodium bicarbonate solution, acidified, and then re-extracted with methylene chloride to obtain 0.63 g of the target compound having a melting point of 148-150°C. (100% yield). Elemental analysis value (%) As C ₁₁ H ₉ NO ₃ Calculated value C, 65.02; H, 4.43; N, 6.90 Actual value C, 65.14; H, 4.61; N, 6.90 Reference example 1 4-(2,4-di (chlorobenzyl)-3-hydroxy-5-methylisoxazole 1.43g of sodium hydroxide, 15ml of water and methanol
After dissolving in 30ml of the mixture, add ethyl 2 at -25 to -30℃.
-(2,4-dichlorobenzyl)acetoacetate 10g, then hydroxylamine hydrochloride 2.89g
5 ml of an aqueous solution neutralized by adding 1.71 g of sodium hydroxide was added dropwise. After stirring for 2 hours, add 20ml of hydrochloric acid.
Heat at 80℃ for 1 hour, concentrate to 1/2 volume, then add 50% water.
ml and extracted with n-hexane to recover raw materials, which were further extracted with ether. The extract was dried and concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: n-hexane: isopropyl ether = 2:1) to obtain 4.20 g of the target compound having a melting point of 175-177°C (yield rate 47.4%). Elemental analysis value (%) As C ₁₁ H ₇ Cl ₂ NO ₂ Calculated value C, 51.56; H, 3.49; N, 5.46 Actual value C, 51.57; H, 3.65; N, 5.29 According to the method of Reference Example 1 above The following compounds were prepared. 4-Benzyl-3-hydroxy-5-methylisoxazole, mp100-104℃ Reference example 2 3-benzenesulfonyloxy-4-(2,4
-dichlorobenzyl)-5-methylisoxazole After dissolving 0.5 g of 4-(2,4-dichlorobenzyl)-3-hydroxy-5-methylisoxazole in 30 ml of tetrahydrofuran, add 0.22 g of triethylamine under ice cooling, then benzene. 0.38 g of sulfonyl chloride was added. After stirring at room temperature for 3.5 hours, the mixture was concentrated under reduced pressure, a large amount of water was added, and the mixture was extracted with ether. The extract was washed successively with water, 1% hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then water, and then concentrated. The residue was purified by silica gel column chromatography (eluent: benzene) to form an oil (n ²⁴ _D 1.5750). 0.57 g of the target compound was obtained (yield 74.1%). Elemental analysis value (as % C ₁₇ H ₁₃ Cl ₂ NO ₄ S Calculated value C, 51.27; H, 3.29; N, 3.52 Actual value C, 51.04; H, 3.34; N, 3.38 According to the method of Reference Example 2 above The following compound was produced: 3-benzenesulfonyloxy-4-benzyl-5-methylisoxazole, n ²⁴ _D 1.5642 Reference example 3 3-benzenesulfonyloxy-4-(α-hydroxy-2,4-dichloro benzyl) -5-
Methylisoxazole 3-benzenesulfonyloxy-4-(2,4
After dissolving 1.02 g of -dichlorobenzyl)-5-methylisoxazole in 15 ml of carbon tetrachloride, 0.48 g of N-bromsuccinimide was added and heated to 80°C.
Next, 0.03 g of benzoyl peroxide was added, heated under reflux for 1 hour, and filtered. 3 ml of an aqueous solution in which 1.09 g of silver nitrate was dissolved was added to the solution, and acetone was further added until both became a homogeneous solution, followed by stirring at room temperature for 48 hours. The reaction solution was concentrated and extracted with ether, and the extract was washed with water, dried, and purified by silica gel column chromatography (eluent: benzene: chloroform = 5:1) to obtain 0.58 g of the target compound with a melting point of 98-103°C. (yield 55.3%). Elemental analysis value (%) As C ₁₇ H ₁₃ Cl ₂ NO ₅ S Calculated value C, 49.29; H, 3.16; N, 3.38 Actual value C, 49.17; H, 3.15; N, 3.40 According to the method of Reference Example 3 above The following compound was produced. 3-benzenesulfonyloxy-4-(α-hydroxybenzyl)-5-methylisoxazole, n ²⁴ _D 1.5682 Reference example 4 3-benzenesulfonyloxy-4-(2,4
-dichlorobenzoyl)-5-methylisoxazole To a solution of 1.24 g of 3-benzenesulfonyloxy-4-(α-hydroxy-2,4-dichlorobenzyl)-5-methylisoxazole dissolved in 20 ml of acetone, add sulfuric acid. 0.8ml and chromic acid 0.81g
A solution prepared by dissolving this in 4 ml of water was added dropwise under ice cooling. After stirring at room temperature for 2.5 hours, it was poured into 120 ml of ice water, extracted with methylene chloride, the extract was washed with water, dried, and concentrated, and the residue was subjected to silica gel column chromatography (eluent: benzene: chloroform = 4:1).
1.23g of the target compound with a melting point of 90-91℃ purified by
was obtained (yield 100%). Elemental analysis value (%) As C ₁₇ H ₁₁ Cl ₂ NO ₅ S Calculated value C, 49.53; H, 2.69; N, 3.40 Actual value C, 49.23; H, 2.77; N, 3.49 According to the method of Reference Example 4 above The following compound was produced. 3-benzenesulfonyloxy-4-benzoyl-5-methylisoxazole, mp84.5-85.5℃

Claims (1)

[Claims] 1 formula [In the formula, R ₁ and R ₃ represent a lower alkyl group or a phenyl group (the phenyl may be optionally substituted with 1 to 3 lower alkyl groups, lower alkoxy groups, halogen atoms, or nitro groups)] ,
R ₂ represents a hydrogen atom, a lower alkyl group, or a phenyl group (the phenyl may be optionally substituted with 1 to 3 lower alkyl groups, lower alkoxy groups, halogen atoms, or nitro groups). ] An isoxazole compound represented by