WO1998056777A1 - Isoxazol-5-yl-substituted benzenes and process for producing the same - Google Patents

Abstract

Compounds of general formula (I): (wherein R is chlorine or methyl; and R?1, R2 and R3¿ are each independently hydrogen or C¿1-4?alkyl), and a process for producing the same. The compounds of general formula (I) are useful as intermediates for pesticides and medicines, particularly as intermediates for herbicides.

Description

 SPECIFICATIONS Soxazole-5-yl-substituted benzenes and production method

 The present invention relates to novel isoxazole-5-yl-substituted benzenes useful as intermediates for agricultural chemicals and pharmaceuticals, and a method for producing the same. Background art:

 Compounds derived from the isooxazole-5-yl-substituted benzenes of the present invention include W096 / 26206, W0997 / 4111, W0997 / 4 No. 118 discloses that compounds represented by the following formula [A] are useful as herbicides.

]

 (Z = Hetero-yl) WO97 / 35850 describes benzoic acid derived from the compound of the present invention. Disclosure of the invention:

 The present invention provides a compound represented by the general formula [I]:

(Wherein, R represents a chlorine atom or a methyl group; R ¹ , R ² and R ³ represent Each independently represents a hydrogen atom or a C, -4 alkyl group. ), And the production method thereof.

 Manufacturing method 1.

 General formula [Π]

(Wherein, R, R ¹ and R ² have the same meanings as described above), and a general formula [一般]: R ³ SH (wherein, R ³ has the same meaning as described above) A method for producing a compound represented by the above general formula [I], which comprises reacting a compound represented by the following formula:

 Manufacturing method 2.

 General formula (IV)

(IV)

(Wherein, R, R ′, R ² and R ³ have the same meanings as described above.) Wherein the compound represented by the general formula [I] is subjected to a deamination reaction. This is a method for producing a compound to be produced.

BEST MODE FOR CARRYING OUT THE INVENTION

In the compound of the present invention, the alkyl groups for R ′, R ² and R ³ include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like. Is mentioned. The production method of the compound of the present invention and various intermediate compounds will be described in more detail. Production Method 1

 C I] [m] [I]

(Wherein, R, R ^1, R ² and R ^3, _c as defined above)

 Compound [I] of the present invention can be produced by reacting compound [H] with alkanethiol [IE] in a suitable solvent in the presence of a base at a temperature between 0 and the boiling point of the solvent used. .

 Examples of the alkanthiol used in the reaction include methyl menolecaptan, ethyl mercaptan, n-propylmercaptan, and isopropylmercaptan, and the base is sodium methanol. Chlorates, sodium ethyl chloride, potassium t-alcohols such as butoxide, sodium hydroxide, alkali metal hydroxides such as hydration power rim, carbonates Examples include carbonates such as sodium and potassium carbonate, tertiary amines such as triethylamine and diisopropylethylamine, and organic bases such as pyridine. In addition, salts of sodium, potassium and the like of the previously prepared alkanol [IE] can also be used.

 Examples of the solvent used include alcohols such as methanol, ethanol and isopropanol, ethers such as THF and dioxane, and aromatic hydrocarbons such as bemben, toluene, and xylene. And nitriles such as acetate, and amides such as DMF and dimethyl acetate.

In addition, using aqueous solutions of sodium and potassium salts of alkanthiol [ΙΠ], hydrocarbons such as benzene and toluene, and chlorine-based carbon dioxide such as methylene chloride and cross-hole form are used. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used in the presence of a quaternary ammonium salt such as tetra-n-butylammonium bromide without using hydrogens or an organic solvent. Can also produce compound [I]. Manufacturing method 2

 [IV] CI]

(Wherein, R, R ′, R ² and R ³ have the same meaning as described above.)

Compound [I] is prepared by converting compound [IV] into Na N02 or a general formula: in a suitable solvent, in the presence of an organic acid such as acetic acid or a mineral acid such as hydrochloric acid or sulfuric acid, at a temperature from room temperature to 0 ° C. R 0 N 0 (R is, C, -. indicating an _e alkyl group) by reacting, after the Jiazo two ©厶塩, meta Nord, ethanol, in an alcohol such as propanol Lumpur, heating hydrolysis It can be manufactured by decomposition.

 Examples of the solvent used include water, acids such as acetic acid, alcohols such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, acetate and methylethylketo. Ketones such as methane, ethers such as THF and dioxane, esters such as ethyl acetate, DMF and the like, or a mixed solvent of two or more of these.

Hydrolysis in alcohol is more mild in the presence of copper, aluminum, copper oxide, zinc dust or a large excess of hypophosphorous acid, or using a catalyst such as copper sulfate. The reaction can also be performed under conditions. As a modification, compound [IV] is converted to an alcohol such as methanol, ethanol or propanol in an appropriate solvent in the presence of an organic acid such as acetic acid or a mineral acid such as hydrochloric acid or sulfuric acid. It can be added and reacted under heating with NaN 02 or R ¹ ON〇. The compound [H] and the compound [IV] in the above Production Method 1 and Production Method 2 are both novel compounds, and can be produced, for example, by the following method. Method for producing compound [H] Process a

l

 (1) (2) (4) Step b:

工程 c ：

Process c:

(Wherein, R, R ¹ and have the same meaning as described above, R ⁵ and have an optionally branched ₆ alkyl group, and X has a halogen atom. In the compound (4), R ⁵ represents R ⁵ ′ because it may scramble with R ⁶ of Mg (OR ⁶ ).)

 Step a:

 The diketoester (4) can be produced from the benzoic acid halide (3) and the magnesium salt of the / 3-ketoester (2) by a known method.

That is, the / 3-ketoester (1) and the magnesium alcoholate (2) are reacted in a suitable solvent at a temperature between 0 ° C and the boiling point of the solvent used for 0.5 to 10 hours, To a magnesium salt of a ketoester and then reacting with benzoic acid halide (4) at a temperature between 110 ° C and the boiling point of the solvent used. You.

 By removing the alcohol by-produced during the production of magnesium salt in this reaction, the reaction can be carried out smoothly and the by-product can be reduced.

 Examples of the solvent used in this reaction include aromatic hydrocarbons such as benben, toluene, and xylene; aliphatic hydrocarbons such as n-hexane and cyclohexane; ethers and tetrahydrofuran ( Ethers such as THF) and dioxane.

 Step b:

 By heating compound (4) in a suitable solvent in the presence of a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as p-toluenesulfonic acid at a temperature up to the boiling point of the solvent used, (5) can be manufactured.

 Compound (5) exists as a tautomer of keto and enol, and at room temperature, rather, exists mostly as an enol form.

 Examples of the solvent used include aromatic hydrocarbons such as benben, toluene, and xylene; aliphatic hydrocarbons such as n-hexane and cyclohexane; ethers such as ether, THF and dioxane; and chlorobenzene. And the like, and halogenated hydrocarbons.

 The reaction time varies depending on the substituents, but is generally from several hours to 48 hours. The amount of the acid catalyst used is from 0.001 to 1 mol per 1 mol of the compound (4).

 Further, compound (5) can also be produced by acid-catalyzed hydrolysis. That is, it can be produced by hydrolyzing compound (4) in the presence of a mineral acid such as hydrochloric acid or sulfuric acid at a temperature between room temperature and the boiling point of the solvent used for several hours to 48 hours. In this reaction, water-soluble ethers such as acetic acid, THF, and dioxane; alcohols such as methanol, ethanol, and isopropanol; and a mixed solvent of two or more of these are used together with water. Can be performed smoothly.

 Process c:

The compound [Π] is reacted by reacting the diketone compound (5) with hydroxylamin in a suitable solvent at 0 ° C. and at the boiling point of the solvent used for i 0 minutes to 24 hours. Can be manufactured.

 In this reaction, the hydroxylamine can be used in the form of a hydrochloride or a sulfate, or an acid such as hydrogen chloride, sulfuric acid or P-toluenesulfonic acid can be used as a catalyst.

 Examples of the solvent include alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as benzene and toluene; ethers such as THF and dioxane; Examples include nitriles such as nitrile, dimethylformamide (DMF), pyridine, acetic acid, water, etc., and a mixed solvent of two or more of these solvents. Method for producing compound [IV] Step d

R 'CC

 (1) (2) (7) Step e:

NO i

 (7) (8) Step f:

(8) (9) Process g:

 (9) (10) Step h:

 (10) (11) Step i:

 (1 1) CIV]

(Wherein, R, R ¹ , R ² , R ⁵ , R ⁶ , R ⁵ ′ and have the same meanings as described above.

R ⁷ represents SCN, chlorine atom or bromine atom. ) Step d:

 The diketoester (7) can be produced from the benzoic acid halide (6) and the magnesium salt of the -ketoester (1) in the same manner as in the step a).

 Process e:

 The compound (7) is heated in a suitable solvent in the presence of a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as p-toluenesulfonic acid at a temperature up to the boiling point of the solvent to be used. 8) can be manufactured.

The compound (8) exists as a tautomer of a ketone and an enol, and at room temperature, rather, exists mostly as an enol form. Examples of the solvent to be used include aromatic hydrocarbons such as benzene and toluene and xylene, aliphatic hydrocarbons such as n-hexane and cyclohexane, ethers such as ether, THF, and dioxane; Halogenated hydrocarbons such as chlorobenzene;

 The reaction time varies depending on the substituents, but is generally from several hours to 48 hours. The amount of the acid catalyst used is from 0.001 to 2 mol per 1 mol of the compound (7).

 Further, compound (8) can also be produced by acid-catalyzed hydrolysis. That is, it can be produced by hydrolyzing compound (7) in the presence of a mineral acid such as hydrochloric acid or sulfuric acid at a temperature between room temperature and the boiling point of the solvent used for several hours to 48 hours. In this reaction, water and water-soluble ethers such as acetic acid, THF, and dioxane; alcohols such as methanol, ethanol, and isopropanol; or a mixture of two or more of these, with water. The reaction can be carried out smoothly by using a solvent.

 However, in the case of hydrolysis, the reaction is preferably carried out in an anhydrous system using toluene sulphonic acid or the like, since it is easy to produce by-produced acetone. Process f:

 Compound (9) is reacted with diketone (8) and hydroxylamin in a suitable solvent at a temperature of from 0 ° C to the boiling point of the solvent to be used for 10 minutes to 24 hours, whereby compound (9) is obtained. Can be manufactured.

 In this reaction, hydroxylamin can be used in the form of a hydrochloride or a sulfate, or an acid such as hydrogen chloride, sulfuric acid or p-toluenesulfonic acid can be used as a catalyst.

Examples of the solvent include alcohols such as methanol, ethanol and isopropanol; hydrocarbons such as benzene and toluene; ethers such as THF and dioxane; and acetates such as acetonitril. Examples include nitriles, DMF, pyridine, acetic acid, water, and the like, and a mixed solvent of two or more of these solvents. Process g Compound (9) in an appropriate solvent at a temperature between 0 ° C and the boiling point of the solvent used. However, if the temperature is too high, the isoxazole ring may open, so the temperature is too high. Undesirably, preferably 0 to 50, the compound (10) is obtained by reduction with a metal and an acid or catalytic reduction using a catalyst. As the metal, Fe, Zn, Sη or the like or a compound thereof is used, and is used in the form of powder, granules or rods. As the acid, an organic acid such as acetic acid and a spreading acid such as hydrochloric acid and sulfuric acid are used.

 Examples of the solvent used include water, acids such as acetic acid, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methylethylketone, THF, dioxane and the like. And DMF and the like, or a mixed solvent of two or more thereof.

 Catalytic reduction is performed under normal pressure or pressurization of hydrogen gas. As a catalyst, 0.1 to 10% of PdZC, PdZBaSO ,,, Pt / C, or the like is used.

 Examples of the solvent used include water, acids such as acetic acid, alcohols such as methanol, ethanol, and isopropanol; ketones such as acetate and methylethylketone; and ethers such as THF and dioxane. And the like.

 If the activity of the catalyst is too strong, the isooxazole ring may be opened. In such a case, it is necessary to use a less active catalyst. In some cases, the compound in which the isoxazole ring has been opened can be reacted again with NH 2 OH.HCl to close the isoxazole ring. Step h:

Compound (11) is produced by reacting 1 to 2 moles of (R ⁸ ) ₂ with respect to 1 mole of compound (10) in an appropriate solvent at a temperature between 0 and the boiling point of the solvent used. it can.

Examples of (R ⁷ ) ₂ include (SCN) ₂ , (Br) ₂ , (C 1) 2 and the like, and (SCN) 2 is converted into Na SCN, KSCN or NH ₄ SCN during the reaction. It is also possible to use those that have been reacted with halogens such as Br ₂ and C 12, N-chloroamide, calcium hypochlorite, and the like.

Solvents used include water, acids such as acetic acid, methanol, ethanol, Examples thereof include alcohols such as propanol, ketones such as acetone and methylethyl ketone, ethers such as THF and dioxane, DMF and the like, and a mixed solvent of two or more of these. Process i:

Compound (IV) is prepared by subjecting compound (11) to an appropriate solvent at a temperature between 0 ° C. and the boiling point of the solvent to be used. Alternatively, KS can be produced by reacting R ³ Z or (R ³⁰ ) SO ₂ (R ³ , Z has the same meaning as described above).

 Examples of the solvent used include water, acids such as acetic acid, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methylethylketone, THF, dioxane and the like. Ethers, DMF and the like, or a mixed solvent of two or more thereof. The benzoic acid represented by the general formula [V] can be produced from the compound of the present invention by the method shown below.

 With this benzoic acid, a useful herbicide can be produced by the method described in the aforementioned W097 / 358,550. Step j

[I] (1 2) (1 3) Process k

 (1 3) [V]

(Wherein, R, R ¹ , R ² , and R ³ have the same meanings as described above, R ⁸ represents a halogen atom or an optionally substituted methyl group, and Y represents a halogen atom or R ⁸ represents a CO〇 group, and n represents 1 or 2.)

 The compound (13) is obtained by adding 1 to 2 mol of the compound (12) to 1 mol of the compound [I] without solvent or in an appropriate solvent, and mixing 1 to 5 mol of a Louis acid such as aluminum chloride. And at a temperature between 110 and the boiling point of the solvent used.

 Examples of the compound (12) include acid halides such as acetyl chloride and propionyl chloride, and acid anhydrides such as acetic anhydride and butyric anhydride.

 Examples of the solvent to be used include chlorinated hydrocarbons such as methylene chloride and chloroform.

 Compound [V] can be produced by reacting compound (13) with 5- to 10-fold molar hypohalogenate in an appropriate solvent at —10 to 80.

 Examples of the used hypohalite include sodium hypochlorite, sodium hypobromite, potassium hypochlorite, calcium hypochlorite, and the like. Water is generally used as the reaction solvent, but a mixed solvent with dioxane or the like can also be used for smooth reaction.

This reaction may be carried out in a single step, but in some cases, the reaction may be carried out under milder conditions, for example, by reacting the first step with aqueous hydrogen peroxide and then with a hypohalite. it can. In the present invention, the target product can be obtained by performing ordinary post-treatment after completion of any of the reactions. The structure of the compound of the present invention was determined from IR, NMR, MS and the like. In the present invention, the R ⁴ C, is as one _Β alkyl group, methylation, Echiru, pro Pi Le, i Sopuro pills, heptyl, I Sopuchiru, s - heptyl, t - like butyl cited et al is, R Examples of the C i-optionally branched alkyl group of ⁵ , R ⁶ and R ⁵ ′ include methyl, ethyl, propyl, isopropyl, butyl, isoptyl, s-butyl, t-butyl, Examples include amimil, isoamyl, hexyl, isohexyl, 4-methyl-2-pentyl, and 2-ethylbutyl. Examples of halogen atoms for X and Y include chlorine and bromine. Examples of the methyl group which may be substituted with the halogen atom of R ⁷ include methyl, chloromethyl, bromomethyl, fluoromethyl, trimethyl, dichloromethyl, and trimethyl. Lorometyl and the like

EXAMPLES Next, the present invention will be described more specifically with reference to Examples, Reference Examples, and Application Examples. Reference Example 12 Production of 2,6 dichlorobenzoyl acetate

マグネシウムェチラ一 卜 5 4. 4 gを トルエン 5 0 O m l に懸濁させ、 室温でァ セ ト酢酸メ チルエステル 6 2. 0 5 gを加え、 2 時間加熱還流した後、 低沸点のァ ルコールを除去し、 室温まで冷却した。 その温度で 2 , 6 ジク ロロベンゾィル ク ロ リ ド 1 0 0. 0 gを加え、 8 0 °Cで 2 時間攪拌した。 室温まで冷却し、 反応混 合物を希塩酸に注加して、 酢酸ェチルで抽出を行い、 有機層を水洗後、 無水硫酸 マグネシウムで乾燥した。 溶媒を減圧濃縮して、 2 — （2， 6 ジク ロ口べンゾ ィル） ァセ ト酢酸エステルをメ チルおよびェチルエステルの混合物と して、 1 4 8. 9 g得た。 Three

Magnesium ethyl acetate 54.4 g was suspended in toluene 50 O ml, and methyl acetate acetate 62.05 g was added at room temperature. The mixture was heated under reflux for 2 hours, and then a low-boiling alcohol was added. Was removed and cooled to room temperature. At that temperature, 100.0 g of 2,6-dichlorobenzoyl chloride was added, and the mixture was stirred at 80 ° C for 2 hours. After cooling to room temperature, the reaction mixture was poured into dilute hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 148.9 g of 2-((2,6-dichlorobenzene) acetate) as a mixture of methyl and ethyl esters.

 Ethyl ester Melting point 40 — 43 ° C

This 2— (2,6 dichlorobenzoyl) acetate acetate An acid (135 ml), concentrated sulfuric acid (26 ml) and water (104 ml) were added, and the mixture was stirred under heating and reflux for 18 hours. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 10,4.6 g of 2,6-dichloromouth benzoylaceton. n _D ²⁵ 1. 5 6 9 3 Reference Example 1 2, 6-Dichloro 11- (3-methylisoxazolyl 5-yl) Production of benzene

2, 6—Dichlorobensyl acetate 104.06 g was dissolved in 330 ml of ethanol, and 35.8 g of hydroxylamin hydrochloride was added. The mixture was heated under reflux for 1 hour. Stirred. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 90.3 g of 2,6-dichloro-1- (3-methylisoxazolyl-5-yl) benzene. n D ²⁵ 1.57 2 9 Example 1 2—Cross mouth—6—Methylthio (3—methylisoxazolyl 5—yl) Production of benzene

2, 6-Dichloro-1- (3-methylisoxazolyl-5-yl) Dissolve 40 g of benzene in 160 ml of DMF and add 21.6 g of potassium t-butoxide at room temperature. After addition, the reaction solution was cooled to 0 ° C., gas was passed through 13.0 g of methyl mercaptan, and the mixture was stirred at room temperature for 3 hours. Pour the reaction mixture into ice water and extract with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 34.8 g of 2-chloro-1-6- (3-methylisosazozo-1-yl-5-yl) benzene. m. p. 7 2-7 4 ° C Reference Example 3 2 —Cross — 6 —Methylbenzuretone

 2—Cross mouth 6—Methyl benzoic acid 11.2 Suspend 1.2 g in 12 O ml of benzene, add 1 drop of pyridine at room temperature, then add 15.6 g of thionyl chloride g was dropped. After heating under reflux for 3 hours, the solvent was concentrated under reduced pressure to obtain 1-3.0 g of 2-chloro-6-methylbenzoyl chloride.

 8.4 g of magnesium ethyl ether was suspended in 120 ml of toluene, 8.4 g of methyl acetate acetate was added at room temperature, and the mixture was heated under reflux for 2 hours, and then a low-boiling alcohol was added. Removed and cooled to room temperature. At that temperature, 13.0 g of 2-chloro-6-methylbenzoyl chloride was added, and the mixture was stirred at 80 ° C for 2 hours. After cooling to room temperature, the reaction mixture was poured into dilute hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure to give 2- (2-cyclo-6-methylbenzoyl) acetate acetate as a mixture of methyl and ethyl esters.

17.8 g were obtained.

To 17.8 g of this 2— (2—black mouth 6—methylbenzoinole) acetate acetate, add 48 ml of acetic acid, 3.2 ml of concentrated sulfuric acid, and 12.4 ml of water, and heat. The mixture was stirred under reflux for 6 hours. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 13.6 g of 2-chloro-6-methylbenzoylaceton. n ²⁷ 1. 5 4 8 7 Reference Example 4 2 — Black mouth 1 — Methyl — 1 — (3 — Yl) Production of benzene

2—Cross-mouth 6—Methylbenzoylaceton 1 Dissolve 3.6 g in 6 O ml of ethanol, add 5.5 g of hydroxylamine hydrochloride, and heat to reflux. Stirred for hours. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 12.7 g of 2-chloro-6-methyl-1- (3-methylisosoxazolu-5-yl) benzene. n D ²⁷ 1.5 5 7 5 Example 22 Production of 2-Methyl-6-Methylthio-11- (3-methylisoxazolyl-5-yl) benzene

2-Chlor 6-methyl 1-11 (3-methyl 5-yl) Benzene 2.0 g is dissolved in DMF 10 m 1, and at room temperature, potassium t- 1.34 g of butoxide was added, and the reaction solution was cooled to 0 ° C. After passing through 0.7 g of methanethiol gas, the mixture was stirred at 70 to 80 ° C for 2 hours. did. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (solvent: n-hexane: ethyl acetate = 9: 3), and 2_methyl-16-methylthio-1- (3- (methylisoxazole-15-yl) benzene 1. 0.8 g was obtained. n D ²⁷ 1. 5 9 2 9 Reference Example 5 2—Methyl—3—2

2—Methyl 1 3 2 Trobenzoids meth- od 18 1 g is suspended in benzene 1000 m 1, 1 drop of pyridine is added at room temperature, and then thionyl chloride 100 m 1 Was added dropwise. After heating under reflux for 2 hours, the solvent was concentrated under reduced pressure to obtain 200 g of 2-methyl-3-nitrobenzoyl chloride.

 Magnesium ethyl acetate (125.4 g) was suspended in toluene (150 Oml), and from 80 to 90, acetic acid t-butyl ester (173,8 g) was added, followed by heating under reflux for 2 hours. Thereafter, the alcohol having a low boiling point was removed, and the mixture was cooled to room temperature. 2-Methyl at that temperature

 200 g of nitrobenzoyl chloride was dissolved in 400 ml of benzene and added, followed by stirring at 70 ° C for 1 hour. After cooling to room temperature, the reaction mixture was poured into dilute sulfuric acid and ice, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 330 g of t-butyl 2-((2-methyl-3-nitrobenzoyl)) acetate.

 To 300 g of t-butyl 2- (2-methyl-3-nitrobenzene) acetate was added 150 g of P-toluenesulfonate monohydrate and 160 ml of benzene, and The mixture was stirred under reflux with heating for 2 hours. After cooling, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 2 — 1.2-g of 2-methyl-3-nitrobenzoylaceton.

m.p. 106-107.5 ° C

_{Ή - NMR (CDC 1 3,} 5 ρ ρ m): 2.20 (3Η, s), 2.55 (. 3Η s), 5.79 (1Η, s) .7 .35-7, 87 (3Η, m), 15.70 ( 1Η, brs)

2 —メ チルー 3 —ニ ト ロベンゾィルアセ ト ン 1 8 7 gにエタ ノ ール 2 8 0 0 m 1 、 塩酸ヒ ドロキシルァ ミ ン 9 0 gを添加後、 加熱還流下に 3時間攪拌した。 反 応液を冷却後、 氷水に注加して、 酢酸ェチルで抽出を行い、 有機層を水洗後、 無 水硫酸マグネシゥムで乾燥した。 溶媒を減圧濃縮して、 2 —メチルー 3 —ニ トロ 一 1 一 （ 3 —メ チルイ ソォキサゾ一ルー 5 —ィル） ベンゼン 1 86. 7 gを得た。 Reference Example 6 Production of 2-methyl-3-2-methyl-1- (3-methylisoxazole-5-yl) benzene;

To 187 g of 2-methyl-3-nitrobenzoylaceton, 280 ml of ethanol and 90 g of hydroxylamine hydrochloride were added, and the mixture was stirred under heating and reflux for 3 hours. After cooling the reaction solution, it was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 186.7 g of 2-methyl-3-nitro-5-yl (3-methylisosazozol-1-yl) benzene.

m. p. 73. 5-75. C

_{'H- NMR (CDC 1 3,} 0 ppm): 2.40 (3H, s) .2.51 (3H, s), 6.31 (1H, s), 7 .37-7.84 (3H, m) Reference Example 7 3 - § 2 — Methyl-1 (3 — Methyli soxazole-5 — yl) Production of benzene

 7 — 1) Under stirring, 70 ml of water and 51.4 g of iron powder, under stirring, add 5.1 g of acetic acid i, and then add 2-methyl-3-nitro-11- (3 — Methyl i-oxoxazolu-5-yl) A solution of 5 Og of benzene in 35 Oml of acetate was added dropwise over 30 minutes. After maintaining at 40 to 45 for 1 hour, cooling, adding water and ethyl acetate, filtering through celite, separating liquid, washing with water, drying with anhydrous magnesium sulfate, concentrating the solvent under reduced pressure, and adding 3-amino -2-Methyl-1 (3-Methyl-soxazo-1-5-yl) Benzene 38.9 g was obtained.

_{'Η- NMR (CDC 1 3,} 5 ppm): 2.22 (3H, s), 2.35 (3H, s), 4.35 (2H, brs), 6.17 (1H, s), 6.73-7.12 (3H, m)

7 - 2) 2 - methyltransferase one 3 - Two-Toro one 1 - (3 - main horst Sookisazoru - 5 one I le) benzene 1 g was dissolved in ethanol 1 0 ml, 0. 5% P dZB a S 0 4 0.1 g was added, and the mixture was catalytically reduced at room temperature and normal pressure. After reacting at room temperature for 7 hours, the mixture was filtered and the solvent was concentrated under reduced pressure to obtain 86 g of 3-amino-2-methyl-1- (3-methylisoxazolyl-5-yl) benzene. Reference Example 8 3—Amino 1 2—Methyl 6—Thyocyanato 1 i 1 (3—Methyl ioxoxazo 1-5)

、0 CH _:

, 0

 , SCN

3—Amino 2—Methyl 1— (3—Methyl Soxazolu-5-yl) Dissolve 3 g of benzene in 5 ml of methanol 2 and add sodium thiocyanate. 2.5 g was added. Then, after adding 10 ml of methanol saturated with sodium bromide, 2.7 g of bromine was added dropwise over 15 minutes. After reacting at 0 to room temperature for 3 hours, pour into water, neutralize with sodium bicarbonate, extract with chloroform, dry over anhydrous magnesium sulfate, concentrate under reduced pressure, add ethyl acetate, crystallize, filter, and add No. 2-methyl-6-thiocyanato-1-1 (3-methylisoxazole-5-yl) benzene 1.18 g was obtained. Further, the mother liquor was concentrated under reduced pressure, a small amount of ethanol was added, crystallization and filtration were performed. Further, 0.94 g of 3-amino-2-methyl-6-thiocyanato 1— was added. (3—Methyl Louis Soxazole—5—yl) Benzene was obtained.

¹ H-NMR (CDC 1, .0 ppm): 1.98 (3H, s), 2.44 (3H, s), 4.09 (2H, brs), 6.3K1H, s), 6.8K1H, d), 7.48 (1H, d) Reference example 9 Production of 3-amino-2-methyl-6-methylthio (3-methylisoxazole-5-yl) benzene

Sodium sulphide 9-hydrate 1.25 g, 3.5-m1 water, stirring, 3 — amino 2 — methyl — 6 — thiocyanato 1 — (3 — methylisoxazole 5 — yl) ba Senzen 1. A suspension of 6 g of I in 15 ml of ethanol was added. After stirring at room temperature for 1.5 hours, the mixture was cooled to 5 ° C., and 6 g of methyl iodide was added dropwise over 30 minutes. After reacting at 5 to 4 hours at room temperature, concentrate under reduced pressure, add water and ethyl acetate, separate, extract 1N-HC1, extract 1N-NaH, neutralize ethyl acetate, wash with water, anhydrous magnesium sulfate After drying under reduced pressure, the solvent was concentrated under reduced pressure to obtain 0.96 g of 3_amino-2-methyl-6-methylthio-1- (3-methylisosoxazole-15-yl) benzene.

_{Ή - NMR (CDC 1 3,} 5 ppm): 1.9K3H, s), 2.27 (3H, s), 2.39 (3H, s), 3 • 71 (2H, brs), 6.17 (1H, s), 6.76 ( 1H, d), 7.14C1H, d) Example 3 2—Methyl-6-methylthio-1 (3—methylisoxazolyl 5—yl) Production of benzene

3 To 33.3 g of a 6% aqueous sulfuric acid solution, add 5.3 g of 3 —amino — 2 — methyl — 6 — methylthio-1--1- (3 — methylyisoxazole — 5 — yl) benzene, and add 0 g. To — cooled to 5 ° C. Dissolve _{N a N 0 2 2. 1 2} g of water 5 m 1, was added in 5 minutes. After stirring for 30 minutes, 250 ml of ethanol and 1 g of copper sulfate were added dropwise to the mixture while being heated to 70 under stirring. After reacting at 70 T; for 1 hour, cool, concentrate under reduced pressure, add water and ethyl acetate, separate, wash with water, dry over anhydrous magnesium sulfate, concentrate the solvent under reduced pressure, and remove the column chromatography. (Benzene solvent) to give 2 g of 2-methyl-6-methylthio-i- (3-methylisoxazolyl-5-yl) benzene.

'H-NMR CCDC l.,, 5 ppm): 2.17 (3H, s), 2.38 (3H, s), 2.39 (3H, s), 6 • 22 (1H, s), 7.03-7.36 (3H, m ) Application Example 1 2 —Black mouth— 3 — (3 —Methylisoxazole-5 —yl) — 4 Manufacture of methanesulfonyl pentzoids

2 — Black mouth 6 — Methylthio 1 — (3 — Methylisoxazolyl 5 — yl) 20 g of benzene is dissolved in methylene chloride, and the aluminum chloride is cooled and cooled. g, and then 9.83 g of acetyl chloride was added dropwise, followed by stirring at room temperature for 4 hours. The reaction solution was poured into ice water, extracted with chloroform, extracted, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 1-8.9 g of 3-acetyl-2-chloro-6-methylthio-1- (3-methylisoxazolyl-5-yl) benzene. m.p. 9 6-10 1 ° C

 3 — acetyl-2 — chloro 6-methylthio 1-1 (3-methylyl soxazo-lu 5-yl) benzene 1. Dissolve Og in 5 ml of 1,4-dioxane and add 10% at room temperature. When the aqueous solution of sodium chlorite was added dropwise, the internal temperature rose to 45 ° C. After the dropwise addition, the mixture was continuously stirred at that temperature for 2 hours, and then poured into ice water. The mixture was adjusted to pH with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, washed with n-hexane-ether, and 2-chloro-3-

(3-Methylisoxazole-15-yl) 1.4-methanesulfonylbenzoic acid 0.89 g was obtained. m.p.2 25-2 28 ° C

 Application Example 2 2—Methyl 3— (3—Methyl Soxazo 1—5—yl) 1—4—Methanesulfonyl Benzoic Acid

2 —メ チル一 6 —メ チルチオ一 1 一 （ 3 — メ チルイ ソォキサゾ一ルー 5 —ィル ) ベンゼン 0. 5 gを塩化メ チ レン 1 0 m 1 に溶解し、 冷却下、 塩化アルミ ニウム 0. 9 1 を添加し、 次いで、 ァセチルクロ リ ド 0. 2 7 gを滴下後、 室温で 1 時間 攪拌した。 反応液を氷水に注加して、 ク ロ口ホルムを加え、 抽出を行い、 有機層 を飽和食塩水で洗浄後、 無水硫酸マグネシウムで乾燥した。 溶媒を減圧濃縮して 、 3 —ァセチルー 2 —メ チル一 6 —メ チルチオ一 1 一 （ 3 —メ チルイ ソォキサゾ ール— 5 —ィル） ベンゼン 0. 4 8 gを得た。 m . p . 1 0 7 - 1 0 9 °C

2 —Methyl 1 6 —Methylthio 1 1 1 (3 —Methyl oxoxazolu-5-yl) Benzene 0.5 g is dissolved in methylene chloride 10 m 1, and cooled with aluminum chloride 0 Then, 0.27 g of acetyl chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice-water, and the mixture was extracted with chloroform and extracted. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 0.48 g of 3-acetyl-2-methyl-16-methylthio-11- (3-methylisosoxazole-5-yl) benzene. m.p. 1 0 7-1 0 9 ° C

 (F) 2 — Methyl 3 — (3 — Methyl soxazo 1-5-yl) 1-4-Methanesulfonyl benzoic acid liquid (Process f)

 3-acetyl-2-methyl-6-methylthio 1-11 (3-methyl-soxazo-1-5-yl) Dissolve 40 g of benzene in 3 ml of 1,4-dioxane, and add 10% sodium hydroxide at room temperature. When 8.0 g of aqueous sodium chlorate solution was added dropwise, the internal temperature rose to 45 ° C. After the dropwise addition, the mixture was continuously stirred at 80 ° C. for 3 hours, and then poured into ice water. The mixture was adjusted to pH with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Concentrate the solvent under reduced pressure, wash with n-hexane-ether, and wash with 2-methyl-3- (3-methylthiosoxazolu-5-yl) -14-methanesulfonylbenzzoic acid 0 30 g were obtained. m. p. 2 4 3-2 45 ° C Application 3

 4-[2-Chiroichione 3-(3-Methylisosoxazole-5-yl)-4- Methanesulfonylbenzoyl] 1-1-ethyl-5-Manufacture of hydroxypyrazole

Les 2

1 —ェチル— 5 — ヒ ドロキン ビラゾ一ル塩酸塩 0. 7 g (0. 0 0 4 7モル） と ト リ ヱチルァ ミ ン 0. 9 5 g (0. 0 0 9 4モル） を塩化メ チレン 2 0 m l に溶解 し、 2 —ク ロロー 4 —メ タ ンスルホ二ルー 3 — ( 3 — メ チルイ ソォキサゾ一ルー 5 —ィル） ベンゾィルク ロ リ ド 1. 5 8 g (0. 0 0 4 7モル） の塩化メ チ レ ン溶 液 5 m 1 を室温で滴下し、 さ らに室温で 1 時間撹拌した。 反応混合物を 1 N—塩 酸、 次いで飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥後、 溶媒を減圧下 留去した。 残留物をァセ 卜二 ト リ ル 2 0 m 1 に溶解し、 卜 リエチルァ ミ ン 0. 4 7 g ( 0. 0 0 4 7モル） とアセ ト ンシアンヒ ドリ ン 0. 1 g (0. 0 0 1 1 モル） を加 え、 室温で一夜撹拌した。 溶媒を減圧下留去し、 残留物を酢酸ェチルに溶解し、 1 N—塩酸、 次いで飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥後、 溶媒 を留去した。 残留物をシ リ カゲルカラムク ロマ ト グラフ ィ ーで精製し、 結晶と し て目的化合物 0. 7 3 gを得た。 m. p . 2 3 0 - 2 3 3 °C

1 —Ethyl— 5 — 0.7 g (0.047 mol) of hydroquinone benzoyl hydrochloride and 0.95 g (0.0094 mol) of tritylamine in methylene chloride Dissolve in 20 ml and add 2 — chloro 4 — methanesulfonyl 3 — (3 — methyl thioxoxazolu 5 — yl) benzoyl chloride 1.58 g (0.04 7 mol 5 ml) of the methylene chloride solution of 1) was added dropwise at room temperature, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was washed with 1N-hydrochloric acid and then with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of acetonitrile, and 0.47 g (0.047 mol) of triethylamine and 0.1 g of acetonitrile (0.04 mol) were added. (0.11 mol) and stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with 1 N hydrochloric acid and then with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 0.73 g of the desired compound as crystals. m.p. 2 3 0-23 3 ° C

 This compound showed strong herbicidal activity.

Application example 4

 4 1 [2 — methyl 1 3 — (3 — methyl soxazolyl 5 — yl) — 4 — methyl sulfonylbenzoyl] — 1-methyl 5- 5 — Manufacture of hydroxypyrazole

塩酸 1 —メ チル一 5 — ヒ ドロキシピラゾール 0. 3 6 g ( 0. 0 0 2 6モル） と ト リ ェチルァ ミ ン 0. 5 1 g (0. 0 0 5 1 モル） を塩化メ チ レン 1 0 m i に溶解し 、 2 —メ チルー 4 —メ タ ンスルホ二ルー 3 — （ 3 — メ チルイ ソォキサゾ一ルー 5 —ィル） ベンゾイルク ロ リ ド 0. 7 1 g (0. 0 0 2 3モル） の塩化メ チ レン溶液 2 m 1 を室温で滴下し、 さ らに室温で 1時間撹拌した。 反応混合物を 1 N—塩酸 、 次いで飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥後、 溶媒を減圧下留 去した。 残留物をァセ トニ ト リル 1 0 m 1 に溶解し、 卜 リエチルァ ミ ン 0. 4 7 g (0. 0 0 4 7モル） とアセ ト ンシアン ヒ ドリ ン 0. 0 6 g (0. 0 0 0 7モル） を加 え、 室温で一夜撹拌した。 溶媒を減圧下留去し、 残留物を酢酸ェチルに溶解し、 1 N -塩酸、 次いで飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥後、 溶媒 を留去した。 残留物をシ リ カゲルカラムクロマ 卜グラフィ 一で精製し、 結晶と し て目的化合物 0. 5 0 gを得た。 m. p . 2 0 1 - 2 0 4 °C 上記実施例を含めて、 本発明の製造方法で得られる化合物の代表例を第 1表〜 第 1 2表に示した。 第 1 表

Hydrochloric acid 1—methyl mono 5—hydroxypyrazole 0.36 g (0.0026 mol) and triethylamine 0.51 g (0.0051 mol) are mixed with methyl chloride. Dissolved in 10 mi of ren, and 2-methyl 4-methanesulfonyl 3-(3-methylisoxazolo 1-5-yl) benzoyl chloride 0.71 g (0.02) 3 mol) methylene chloride solution 2 ml was added dropwise at room temperature, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was washed with 1N hydrochloric acid and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of acetonitrile, and 0.47 g (0.047 mol) of triethylamine and 0.06 g (0.06 g) of acetonitrile hydride were dissolved. (0.7 mol) was added and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with 1N-hydrochloric acid and then with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 0.50 g of the desired compound as crystals. m.p. 201-204 ° C. Tables 1 to 12 show typical examples of the compounds obtained by the production method of the present invention including the above Examples. Table 1

* (Ryu R): Indicates that NMR data is described in the examples ₍

same as below 2nd 0

R ¹ (4)

Table 3

Table 4

Table 5

第 7 表

Table 7

^ 8 3¾

No.

 9

第 1 0 表 table

Table 10

第 1 i 表

Table 1i

Table 12

産業上の利用可能性 ：

Industrial applicability:

 As described above, the production method of the present invention can be easily produced with a high yield, and various intermediates are industrially used as intermediates for agricultural chemicals and pharmaceuticals, for example, as intermediates for herbicides. It is a useful compound.

Claims

The scope of the claims 1. A compound represented by the general formula [I].

(In the formula, R represents a chlorine atom or a methyl group, and R ¹ , R ² and R ³ each independently represent a hydrogen atom or a C i-4 alkyl group.) 2. —General formula [Π]

(Wherein, R, R ¹ and R ² have the same meanings as in the first term.) And a general formula [ΠΙ]: R ³ SH (where R ³ is the first term) Wherein the compound represented by the general formula [I] is reacted:

(Wherein, R, R ¹ , R ² and R ³ have the same meanings as described above.). 3. General formula [IV] (IV)

(Wherein, R, R ¹ , R and R ³ have the same meaning as in the first item.) General formula [I] characterized in that the compound is subjected to a deamination reaction.

(Wherein, R, R ¹ , R ² and R ³ have the same meanings as described above.).