WO1998046561A1 - Benzene derivatives, benzofuran derivatives, and processes for producing these - Google Patents

Abstract

Compounds useful as intermediates for industrially advantageously producing (thio)semicarbazide derivatives used as feedstocks for herbicides. The benzene derivatives and the benzofuran derivatives are respectively represented by general formulae (I) and (II), wherein R?1 and R2¿ are the same or different and each represents a halogeno, a lower alkyl, a lower haloalkyl, a lower alkoxy, or cyano; R4 represents a lower alkyl; R?3 and R5¿ are the same or different and each represents hydrogen or a lower alkyl; and Z represents nitro, amino, or a group YCN (wherein Y represents sulfur or oxygen).

Description

 Specification

 Benzene derivative, Benzofuran derivative

 And their manufacturing methods

 The present invention relates to a benzene derivative, a benzofuran derivative and a method for producing them. Background art

 General formula (6)

Wherein 1 ^ ¹ and 1¾ ² represents a halogen atom, a lower alkyl group, lower haloalkyl group, lower alkoxy group or Shiano group the same or different. ³ and ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. R ⁶ represents a lower alkyl group. Y represents an oxygen atom or a sulfur atom. The benzofuranyl triazole derivative represented by the formula is a compound useful as a herbicide. This benzofuranyl triazole derivative is a compound discovered by the present inventors for the first time. Patent applications have already been filed as Japanese Patent Application Laid-Open Nos. Hei 8-25083 and Hei 9-71583. JP Hei 8

According to JP-A-2005-8383 and JP-A-9-171583, the benzofuranyltriazole derivative of the general formula (6) can be prepared by the method shown in the following reaction formula-1. More manufactured.

Reaction formula 1

[Wherein, RR ² , R ³ , R \ R ⁶ and Y are the same as above. Further, according to JP-A-8-20583 and JP-A-9171583, in the above-mentioned reaction formula 11, the general formula (5) used as a starting material is used. The (thio) semicarbazide derivative of the present invention can be easily produced from the corresponding aniline according to a known method, for example, the method described in US Pat. No. 4,514,419. It has been.

However, an industrially advantageous method for producing the (thio) semicarbazide derivative of the general formula (5) has not been found yet. Further, the compound represented by the general formula (6) is derived from the (thio) semicarbazide derivative represented by the general formula (5) described in JP-A-8-20583 and JP-A-9-71583. Although the method for producing the benzofurantriazole derivative described above is practical, there is still room for improvement. That is, trifluoroacetic anhydride used in this method has a low boiling point (40 ° C.), is highly hygroscopic, and reacts quickly with moisture to produce highly corrosive trifluoroacetic acid. Even if trifluoroacetic anhydride does not react with water, trifluoroacetic acid remains in the reaction mixture after completion of the reaction with the (thio) chemical pad'zide derivative. Need to be collected or treated and disposed of.

 The present invention provides a novel benzene derivative and a benzofuran derivative which are intermediates for industrially advantageously producing the (thio) semicarbazide derivative of the general formula (5). Aim.

 Another object of the present invention is to provide a method for producing such a benzene derivative and a benzofuran derivative.

Still another object of the present invention is to provide an industrially advantageous method for producing a benzofuranyl triazole derivative represented by the general formula (6). Disclosure of the invention

 The benzene derivative and the benzofuran derivative of the present invention are novel compounds which have not been described in the literature, and are represented by the following general formulas (1), (2), (3) and (3), respectively. 4) in

¾C O ₀

General formula (1):

[In the formula, ¹ and ² are the same or different and represent a halogen atom. A lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. 1 ³ and 1 ^ ^4, the same or different One hydrogen atom or a lower alkyl group. ]

General formula (2):

[Wherein, RRR ³ is the same as above. R ⁵ represents hydrogen or a lower alkyl group. ]

General formula (3):

[Wherein, R ¹ R ² , R ³ and R ⁵ are the same as above. ]

General formula (4):

[Wherein, RR ² , R ³ , and R ⁵ are the same as above. Y represents an oxygen atom or a sulfur atom. ]

 The present invention relates to a novel benzene derivative represented by the general formula (1) and a novel benzofuran derivative represented by the general formulas (2), (3) and (4). It relates to these manufacturing methods.

Further, the present invention relates to a method for producing a (thio) semicarbazide derivative represented by the general formula (5) and a benzofuranyl triazole derivative represented by the general formula (6) using these derivatives. Best form to harm ^ a Examples of the halogen atom shown in the present specification include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

As the lower alkyl group shown in the present specification, a straight or branched chain alkyl group having 1 to 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, i Seo heptyl, tert - 1 to 4 carbon atoms, such as butyl (C -! ₄₎ of Ru can and this include linear or branched alkyl group.

 Examples of the lower haloalkyl group shown in the present specification include, for example, triphenylenomethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, and fluoromethyl. -Dometyl, diphnolelomethyl, jib mouth momechinore, 2—chloroechinole, 2, 2, 2—trifluroethyl, 2, 2, 2—trichloroechinole, 3—bromopropinole, 3 — Chloropropinole, 2, 3 — dichloropropine, 4,4,4 _ trichlorobutyl, 4 1 halogeno atom as a substituent such as fluorobutyl group A straight-chain or branched-chain haloalkyl group having 1 to 4 carbon atoms having 1 to 3 carbon atoms can be exemplified. Here, as the halogen atom, those described above can be mentioned.

As the lower alkoxy group shown in the present specification, for example, a C 1 -C 4 group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy group, etc. A straight-chain or branched-chain alkoxy group can be exemplified. According to the present invention, the benzene derivative represented by the general formula (1) is produced according to the method shown in the following reaction formula 12.

 Reaction Formula 1 2

[Wherein, R ¹ R ² , R ³ and R ⁴ are as defined above. X represents a halogen atom. Preferably, R ¹ and X are each a halogen atom, and R ² , R ³ and R ⁴ are each a C- ₄ alkyl group. ]

 According to Reaction Scheme-2, the benzene derivative of the general formula (1) is produced by reacting the benzene of the general formula (7) with the oxime of the general formula (8). You.

The reaction between the benzene derivative of the general formula (7) and the oxime of the general formula (8) is carried out in a two-phase solvent of water and a suitable hydrophobic solvent in the presence of a phase transfer catalyst and a base. . Examples of the hydrophobic solvent used include aromatic solvents such as benzene, toluene, chlorobenzene, etc .; dichloromethane, dichloroethane, and chlorofluoronom Halogen such as carbon tetrachloride System solvents; mixed solvents of these, and the like; among them, aromatic solvents are preferred. As the phase transfer catalyst, conventionally known ones can be widely used, and examples thereof include tetramethylammonium bromide, tetramethyl bromide-n-butynolemonium, and yo-i-dila tetran — Butynoleammonium, tetrachloride — n — Butylammonium, bromide tetra — n-pentylammonium, bromide tetra n — hexizoleammonium, bromide tetra — N — octyl ammonium, bromide tetra n — hexadecyl ammonium, benzylinoletriethyl ammonium, trichloride n — octyl methyl ammonium, etc. Ammonium salt; tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, methyltriphenylphosphonium bromide, tetrahydrochloride-n-butyl Quaternary phosphonium Honiu salt-free, such as a host Honiu beam, and the like. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; and carbonic acid. Examples of such metals include sodium hydroxide and metal hydroxides. Such a base is usually used in the form of an aqueous solution or suspension, and its concentration is usually about 5 to 60%, preferably about 10 to 40%. The reaction temperature of this reaction can be appropriately selected from the range of room temperature to 100 ° C, and is 50 to 8 Performing at 0 ° C is preferred in terms of reaction time and yield. The ratio of the benzene derivative of the general formula (7) to the oxam of the general formula (8) is usually 1 to 5 moles, preferably 1.5 to 1 mole of the former. It is better to use up to 3.5 moles. The phase transfer catalyst is used usually in an amount of 0.1 to 0.5 mol, preferably 0.15 to 0.3 mol, per 1 mol of the benzene derivative of the general formula (7). The base is used in an amount of usually 1 to 4 mol, preferably 1.5 to 2.5 mol, per 1 mol of the benzene derivative of the general formula (7).

 The amount of the reaction solvent used is 100 to 100 parts by weight of the benzene derivative of the general formula (7), usually 150 to 100 parts by weight, preferably 300 to 100 parts by weight. It is recommended to be 700 parts by weight. The ratio of water and hydrophobic solvent used is preferably 0.5 to 20 and more preferably 1 to 10 with respect to water 1 by weight.

 Thus, the benzene derivative of the general formula (1) can be produced with a high yield.

The benzene derivative of the general formula (7), which is a starting material for this reaction, is a known compound. For example, as described in Japanese Patent Application Laid-Open No. Sho 56-169651, formula

[Wherein, RR ² and X are the same as above. ]

It can be easily produced by converting the compound represented by

 On the other hand, the oxime of the general formula (8), which is a starting material, can be easily produced from hydroxylamin or its hydrochloride and a ketone such as acetone. The oxime of general formula (8) produced in this way may be used after purification, but the crude product obtained by distilling low-boiling substances from the reaction solution under reduced pressure may be used as it is. It is also possible. When hydroxylamine hydrochloride is used as a raw material, an oxime hydrochloride of the general formula (8) is obtained, but when this salt is used in Reaction Formula 12, the amount of base is adjusted to the amount of hydrochloric acid. It is desirable to increase the amount required for salt neutralization.

The benzene derivative of the general formula (7) is reacted with the oxime of the general formula (8) in dimethylformamide in the presence of sodium hydride, potassium butoxide and other bases. Although the benzene derivative of the general formula (1) could not be obtained or the yield was extremely low, the reaction system was By forming a two-phase system with a neutral solvent and reacting with a base using a phase transfer catalyst, it is possible to obtain the corresponding benzene derivative of the general formula (1) in good yield. Was.

The synthesis of the benzene derivative represented by the general formula (1) into the benzofuranyltriazole derivative represented by the general formula (6) can be performed according to the method shown in the following reaction formula-13.

Reaction formula 1 3

(4) (29)

[Wherein, RR ² , R ³ , RR ^5, R ⁶ and Y are the same as above. The preferred and rather R ¹ is Ri Oh halogen ^{atom, R 2, R 3, R} 4 and R ⁶ are C〗 - are _four alkyl groups der, R ⁵ is a hydrogen atom or a C - a ₃ alkyl group. ] According to step 1, when the benzene derivative of the general formula (1) and hydrogen halide are mixed and heated, the 5-nitrobenzofuran derivative of the general formula (2) is produced. The reaction solvent used in this reaction includes, for example, methanol, ethanol, n-prono, ⁰ -nor, 2-propanol, n-butanol, and methanol. Alcohol-based solvents such as tilcello sonolev; carboxylic acid-based solvents such as acetic acid; mixed solvents thereof; among others, alcohol-based solvents are preferred. The amount of the reaction solvent to be used is usually 100 to 300 parts by weight, preferably 400 to 300 parts by weight, per 100 parts by weight of the benzene derivative of the general formula (1). 150 parts by weight is preferred.

As the hydrogen halide, conventionally known ones can be widely used, and examples thereof include hydrogen chloride and hydrogen bromide. Such hydrogen halide can be used as it is dissolved in the reaction solvent as it is, but an aqueous solution of hydrogen halide can also be used by adding it to the reaction solvent. The amount of hydrogen halide to be used is generally 1 to 15 mol, preferably 5 to 10 mol, per 1 mol of the benzene derivative of the general formula (1). The reaction temperature can be appropriately selected from the range of 40 ° C. to the boiling point of the reaction solvent, but the reaction is preferably carried out at 60 to 100 ° C. from the viewpoint of the reaction time and the yield. Hydrogen halide aqueous solution When used, the concentration thereof is not particularly limited, but usually an aqueous solution of 20 to 60% by weight is used, and more preferably, an aqueous solution of 30 to 50% by weight is used.

Also, the 5-dibenzobenzofuran derivative represented by the general formula (2) can be produced by a method other than the above step 1 ₍ for example, the 5-nitrobenzofuran derivative (2) can be produced by the following reaction. Manufactured according to the methods shown in Formula 1, 4, Formula 5 and Formula 6

 Reaction formula 1 4

(2b) [Wherein, RR ² and R ⁵ are the same as above. R ^3b represents a lower alkyl group. R ⁷ represents a hydrogen atom or a lower alkyl group. C X ¹ and X ² each represent a nitrogen atom. ]

 According to Reaction Scheme-4, first, a 2,5-disubstituted phenol (9) is reacted with a 2,3-dihalogenopropene derivative (10) in an inert solvent in the presence of a base. Thus, the ether derivative (11) is obtained.

Examples of the inert solvent include non-protonic polar solvents such as aceton, acetonitril and dimethylformamide; ethers such as getyl ether and tetrahydrofuran; Solvents: alcohol solvents such as methanol and the like. The amount of the solvent used is usually 100 to 200 parts by weight per 100 parts by weight of 2,5-disubstituted phenol (9), preferably 200 to 200 parts by weight; 0 0 0 parts by weight. Examples of the base include carbonates such as potassium carbonate and sodium carbonate; hydroxides such as sodium hydroxide, calcium hydroxide and calcium hydroxide; and triethyla Tertiary amines such as mine, pyridin, triethylenediamine, etc .; metal hydrides such as sodium hydride, hydrogen hydride and the like. The amount of the base to be used is generally 0.5 to 50 equivalents, preferably 1 to 10 equivalents, relative to 2,5-disubstituted phenol (9). 2, 3 — The amount of the dihalogenopropene derivative (10) used is It is usually 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of 2,5-disubstituted phenol (9). The reaction temperature can be appropriately selected from the melting point to the boiling point of the solvent, but it is usually preferable to carry out the reaction within the range from room temperature to the boiling point of the solvent. The reaction usually completes in 1 to 100 hours.

 By heating the ether derivative (11) to 150 to 250 ° C. in the absence of a solvent or in the presence of a high-boiling solvent, a Claisen rearranged trisubstituted phenol derivative is obtained. (12) is obtained. Examples of the high-boiling solvent include alkylanilines such as dimethylylaniline and getylaniline; tetralin, mesitylene, diphenylether, snoreholane, etc. However, among these, alkylanilines are preferred. The amount of the high boiling point solvent to be used is generally 0 to 1000 parts by weight, preferably 20 to 200 parts by weight, per 100 parts by weight of the ether derivative (11). This reaction usually completes in 1 to 40 hours.

The nitration of the tri-substituted phenol derivative (12) gives the 412 phenol derivative (13). Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane and chlorophonolem; acids such as sulfuric acid and acetic acid; water; and a mixed solvent thereof. Is used in the general formula (1 2) 100 to 500 parts by weight, preferably 100 to 200 parts by weight, per 100 parts by weight of the trisubstituted phenol derivative. As the nitrifying agent, nitric acid, acetyl chloride and the like are used. When nitric acid is used as the nitrating agent, its concentration is usually from 10 to L 0%, preferably from 50 to L 0%. The amount of the nitrating agent used is usually 0.5 to 5 moles, preferably 0.9 to 1.5 moles per monolayer of the trisubstituted phenol derivative (12). Is good. The reaction temperature can be appropriately selected from 130 ° C. to the boiling point of the solvent, but is usually preferably in the range of 0 to 50 ° C. This reaction is usually completed in 1 to 10 hours.

4 The 12-nitrobenzofuran derivative (2b) can be obtained by heating the 12-tropininol derivative (13) in an acidic solution. Examples of the acid include mineral acids such as hydrogen chloride and hydrogen bromide. The amount of the acid to be used is generally 0.5 to 100 mol, preferably 1 to 20 mol, per 1 mol of 4-nitrophenol derivative (13). Solvents include carboxylic acids such as acetic acid; methanol, 2-prono. Alcohols such as ethanol; water and the like; these may be used alone or as a mixture of two or more. Preferably, hydrogen bromide is used as the acid and acetic acid is used as the solvent. The amount of the solvent used is the 4-nitrophenol derivative (13) It is usually from 100 to 500 parts by weight, preferably from 100 to 100 parts by weight, per 100 parts by weight. The reaction temperature is usually preferably in the range from room temperature to the boiling point of the solvent. This reaction is usually completed in 1 to 100 hours.

 Reaction formula 1 5

(14) (16) Rearrangement ring closure

 (2b)

[Wherein, RR ² , R ^3b , R ⁵ , R ⁷ and X ² are the same as above. According to Reaction Scheme 15, 2,5-disubstituted-4-nitronitrinoyl derivative (14) is converted to propargyl halide derivative (15) in the presence of a base in an inert solvent. To give the propargyl ether derivative (16).

Examples of the inert solvent include non-protonic polar solvents such as aceton, acetonitril, dimethylformamide and the like; Etenole-based solvents such as jetinole ether and tetrahydrofuran; alcohol-based solvents such as methanol; and the like. The amount of solvent used is 2,5-disubstituted-4-nitrophenol (14) 100 to 100 parts by weight Normally 100 to 200 parts by weight, preferably 100 parts by weight Or 200 to 100 parts by weight. Examples of the base include carbonates such as potassium carbonate and sodium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; Tertiary amines such as triethylamine, pyridin and triethylene diamine; metal hydrides such as sodium hydride and calcium hydride; The amount of the base used is usually 0.5 to 50 equivalents, preferably 1 to 10 equivalents, based on 2,5-disubstituted-4- 4-nitrophenol (14). It is. The amount of the propargyl halide derivative (15) to be used is usually 1 to 10 moles, preferably 1 to 10 moles, per mole of the 2,5-disubstituted-412 trophenol (14). Or 1 to 5 moles. The reaction temperature is preferably in the range from room temperature to the boiling point of the solvent. This reaction usually completes in 1 to 50 hours.

The propargyl ether derivative (16) is rearranged and ring-closed in the presence or absence of a catalyst in the presence of an inert solvent to give the 5-nitrobenzofuran derivative (2b). Examples of inert solvents include dimethylylaniline and getylaniline. Alkylanilines such as phosphorus; tetralin, mesitylene, diphenyl ether, sulfolane, etc. can be used, but among these, alkylanilins are preferred. The amount of the inert solvent used is usually from 0 to 100 parts by weight, preferably from 50 to 500 parts by weight, per 100 parts by weight of the propargyl-ter derivative of the general formula (16). It is. Cesium fluoride is used as the catalyst. The amount of the catalyst used is usually 0.0001 to 50 moles, preferably 1 mole of prono and the argyl ether derivative (16). Or 0.01 to 5 moles. The reaction temperature is preferably in the range of 100 to 300 ° C. The reaction is usually completed in 1 to 20 hours.

Reaction formula—6

(2c) [wherein, RR ² and R ⁵ are the same as above. R ⁸ represents a hydrogen atom or a lower alkyl group. ]

According to Reaction Scheme 16, the 2,5-disubstituted phenol (9) is represented by the general formula (17) in the presence of sulfuric acid; 9 monoketo acid or 3— By reacting with a keto acid ester, a coumarin derivative (18) is obtained. ) Examples of the 3-keto acid include acetoacetic acid and propionylacetic acid. Also, as a 3-keto acid ester, for example, acetate Ethyl acetate, propionyl acetate, and the like. The / 3—keto acid or 3—keto acid ester of the general formula (17) is usually from 1 to 5 moles per mole of 2,5—disubstituted phenol (9). It is 10 moles, preferably 1 to 5 moles. In the present invention, lingic acid may be used in place of the; 3—keto acid or / 3—keto acid ester of the general formula (17). The amount of _c- sulfuric acid, which is converted to 3-keto acid in the reaction system, is 100 parts by weight of 2,5-disubstituted phenol of general formula (9). Usually 100 to 100 parts by weight, preferably 100 to 500 parts by weight. The reaction temperature is usually in the range of room temperature to 200 ° C., preferably 100 to 160 ° C. This reaction usually completes in 1 to 10 hours.

 Nitrotization of the coumarin derivative (18) gives the 6-dicyclomaline derivative (19). The nitration reaction was carried out in the same manner as in the above-mentioned method of di-troying the trisubstituted phenol (12) to obtain a 4--2- phenol derivative (13). can do.

The benzofuran carboxylic acid derivative (20) can be obtained by adding a 6-nitrocoumarin derivative (19) to a halogen and then reacting with a base. As a reaction solvent for the addition of halogen, for example, dichloromethane, Halogenated hydrocarbons such as rum are used. The amount of the solvent to be used is generally 100 to 500 parts by weight, preferably 200 to 200 parts by weight, per 100 parts by weight of the 6-dicyclomaline derivative of the general formula (19). 0 0 0 parts by weight. As the halogen, for example, chlorine, bromine, or the like is used. The amount of the halogen is usually 1 to 10 mol, preferably 1 to 1 mol of the 6-nitocumaline derivative (19). ~ 3 moles. The reaction temperature can be selected from 0 ° C to the boiling point of the solvent, but it is usually preferable to carry out the reaction within the range of 0 to 50 ° C. This reaction usually completes in 1 to 50 hours. When an alkali metal hydroxide is allowed to act on a halogenated 6-nitrocoumarin derivative in an alcohol solvent, a benzofurancarboxylic acid derivative (20) is obtained. Examples of alcohol solvents include methanol, ethanol, and 2-prono. Knol and the like. The amount of the alcohol-based solvent to be used is generally 100 to 500 parts by weight, preferably 200 to 500 parts by weight, per 100 parts by weight of the halogenated 6-nitrocoumarin derivative. Examples of the aluminum hydroxide, which is 200 parts by weight, include sodium hydroxide, potassium hydroxide, and the like. It is usually 3 to 30 mol, preferably 3 to 12 mol, per 1 mol of the trokumalin derivative. The reaction temperature can be selected from 0 ° C to the boiling point of the solvent, but it is usually 0 to 5 It is preferable to carry out within the range of 0 ° C. This reaction is usually completed in 1 to 30 hours.

 The benzofurancarboxylic acid derivative (20) is decarboxylated in a quinoline solvent by the action of a copper catalyst to give the 5-nitrobenzofuran derivative (2c). The amount of quinoline used is usually 100 to 200 parts by weight, preferably 100 to 500 parts by weight, per 100 parts by weight of the benzofurancarboxylic acid derivative (20). It is. The amount of the copper catalyst to be used is generally 0.05 to 10 mol, preferably 0.1 to 1 mol, per 1 mol of the benzofuran canolevonic acid derivative (20). The copper catalyst can be used in various forms such as powder and granules, but is preferably used in powder form. The reaction temperature is usually preferably in the range of 150 to 250 ° C. This reaction is usually completed in 0.5 to 10 hours.

 The 5-nitrobenzofuran derivative represented by the general formula (2) thus obtained is used as an intermediate for producing the compounds of the general formulas (5) and (6). Importantly, it can itself be an intermediate for other pesticides, pharmaceuticals, etc.

Table 1 shows specific examples of the compound of the 5-nitrobenzofuran derivative (2), which was synthesized by any one of the methods of Step 1, Reaction Scheme 4, 5, and 6 of Reaction Scheme 13 above. . 1>

R ¹ R ² R ³ R ⁵ so-C ₃ H ₇ H

^CH 3 ^CH 3

 C 1 C 1 H

^CH 3

 C 1 C 1

^CH 3

 C 1 H

^CH 3

 C 1 H

^CH 3 ^CH 3

 B r H

^CH 3 ^CH 3

 C 1 H

^CF 3 ^CH 3

 H

^CH 3 ^CH 3

 C 1 C N H

^C 3

 C 1 C 1 H

 C 1 C 1 H H

C 1 H

^CH 3 ° ^CH 3

 F H

^CH 3 ^CH 3

 C 1 F H

^CH 3

 C 1 F

^CH 3

 H H

^CH 3

 H

^CH 3 ^iS ° ^-C 3 ^H 7 ^CH 3

C 1 iso- C ₃ H end H

^CH 3

CH 0 H 3 ^CH 3 ^CH 3

 C 1 H

^CF 3 ° ^CH 3

tert-C _t U _n H

4 9 ^CH 3 ^CH 3

 C 1 C 1 H

H5 Further, according to step 2 of Reaction formula-3, the 5-aminobenzobenzofuran derivative of the general formula (3) reduces the corresponding 5-dibenzobenzofuran derivative of the general formula (2) It is manufactured by this. In this reaction, various methods for reducing a nitro group to an amino group, for example, reduction of a nitro group using a metal noic acid, a metal hydride, a metal hydride complex compound, hydrazine, etc. Or the catalytic reduction method can be applied.

 Among these, the reduction method using metal Z-acid is excellent in terms of industrial use from the viewpoint that inexpensive reagents can be used and no special equipment is required.

In the reduction method using a metal / acid, the reaction solvent is water; methanol, ethanol, or 2-prono. Examples include alcohol solvents such as ethanol; ether solvents such as tetrahydrofuran and dioxane; ester solvents such as ethyl acetate; acetic anhydride; and acetate. These solvents can be used alone or in combination of two or more. As a preferred solvent, a mixed solvent of alcoholic solvent and water is mentioned, and the mixing ratio is usually 1/1/10 to 10Z1, preferably IZSSZI. The amount of the solvent to be used is as follows: 100 parts by weight of the 5-dibenzobenzofuran derivative of the general formula (2), usually 200 to 1000 parts by weight, preferably Is preferably 500 to 500 parts by weight. As the acid, mineral acids such as hydrochloric acid and hydrobromic acid; and organic acids such as acetic acid are used. These acids may also be used as solvents. The amount of the acid to be used is generally 0.5 to 100 mol, preferably 1.0 to 20 mol, per 1 mol of the 5-to-2-benzobenzofuran derivative of the general formula (2). Is good. Examples of the metal include iron, zinc, and tin, and examples of the metal salt include iron sulfate (11) and tin (II) chloride hydrate. The amount of the metal or salt thereof to be used is generally 1.0 to 50 mol, preferably 2.0 to 10 mol, per 1 mol of the 5-dibenzobenzofuran derivative (2). There are no particular restrictions on the combination of the _c- metal and acid, which should be in moles.

 The temperature of this reduction reaction is preferably selected from the range of room temperature to the boiling point of the solvent, and is preferably from 50 ° C. to the boiling point of the solvent in view of the reaction time and the yield.

 In this reaction, the order in which the solvent, substrate, acid and metal are added to the reaction vessel is not particularly limited. Since this reaction is exothermic, to control the reaction temperature and reaction rate, the substrate or metal should be added as a solid or in a solution or slurry using a solvent and then gradually added. You can do it.

From the viewpoint of the mildness of the reaction and the ease of the purification process, It is preferable to employ a catalytic reduction method.

 Examples of a reaction solvent in the catalytic reduction method include methanol, ethanol, and 2-prono. Alcohol solvents such as ethanol, butanol and methyl sorb; ether solvents such as getyl ether and tetrahydrofuran; cyclohexane, benzene Hydrocarbon solvents such as chlorofonolem, dichloroethane, cyclobenzene, dichlorobenzen, etc .; Any ester solvents and the like can be mentioned. Preference is given to methanol, 2-propanol, tonolene, black mouth benzene, and the like. These solvents are used alone or in combination of two or more. The amount of the solvent used may be 5—nitrobenzene zofuran derivative (2), usually 100 to 100 parts by weight per 100 parts by weight, preferably 5 to 500 parts by weight. The content is preferably from 0 to 500 parts by weight.

As the catalyst used in the catalytic reduction, those widely known in the art can be widely used, such as Raney alloy, Raney catalyst, activated carbon-supported palladium, silica-supported palladium, and aluminum. Palladium-supported palladium, calcium carbonate-supported palladium, barium sulfate-supported palladium, platinum oxide, activated carbon-supported platinum, activated carbon-supported platinum sulfide, activated carbon-supported ruthenium, alumina-supported ruthenium, etc. And preferably active Palladium on charcoal and platinum sulfide on activated carbon are listed. In the case of Raney alloys and Raney catalysts, the amount of these catalysts used is usually 0.0005 to 5 mol, preferably 1 mol, of 5-nitrobenzofuran derivative (2). 0.005 to 0.5 mol, for other catalysts, 5—2-benzobenzofuran derivative (2) Usually 0.000 to 0.05 to 0. It is preferably 5 moles, preferably 0.005 to 0.05 moles.

The temperature of the above reduction reaction can be appropriately selected from the range of 0 to 200 ° C, and preferably, the temperature is from room temperature to 100 ° C, in view of the reaction time and the yield. Preferred from. Further, the reduction reaction can be carried out at a hydrogen pressure of 1 to 300 kg / cm ² . From the viewpoint of reaction time and yield, it is preferable to carry out the reaction in the range of 2 to 20 kg / cm ² .

Among the above methods, a more preferred method is a catalytic reduction method. C The 5-aminobenzobenzofuran derivative (3) can also be produced by a method other than the step 2 shown in Reaction Formula 13. For example, the 5-amino benzofuran derivative (3) can be produced by following the methods shown in the following reaction formulas -7 and -8.

卜 卜 ィ

[Wherein, RRR ^{3 b} , R ⁵ , R ⁷ and X ¹ are the same as above. According to Reaction Formula-7, the 4-substituted phenol derivative (13) obtained by di- or di-torosification of the tri-substituted phenol form (12) is a 4-to-12-phenol derivative (13 ) Or 4-nitrosophenol derivative (21) reduces to 4-aminophenol. The derivative (22) is obtained, and the 4-aminophenol derivative (22) is heated in an acidic solution to give the 5-aminobenzobenzofuran derivative (3). b) or a salt thereof is obtained.

 The reaction to obtain a 4-nitrophenol derivative (13) by subjecting the trisubstituted phenol form (12) to two-trough bonding is as described above.

Nitrosation of the trisubstituted phenol form (12) to a 412 torosophenol derivative (21) is carried out using nitrite and an acid. Examples of the nitrite include sodium nitrite and potassium nitrite. The amount of nitrite to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the trisubstituted phenol compound (12). As the acid, for example, hydrochloric acid, acetic acid or the like is used, and these can also serve as a solvent. The amount of the acid to be used is generally 1 to: 100 mol, preferably 2 to 10 mol, per 1 mol of the trisubstituted phenol compound (12). May be used in larger quantities. Examples of the reaction solvent include phenol-based solvents such as methanol, ethanol, and 2-propanol; water; and the amount of tri-substituted phenol. Usually 100 to 500 parts by weight, preferably 100 to 2000 parts by weight, per 100 parts by weight of the body (12). You. This reaction is usually carried out at a temperature of from 30 to 50 ° C, preferably at a temperature of 0 ° (: to room temperature.) The reaction proceeds quickly after the addition of the reagents (nitrite and acid). Usually, it is preferable to react for about 0.5 to 10 hours after the introduction of the reagent.

 The reduction of the 4—nitrophenol derivative (13) force to the 4—aminophenol derivative (22) is achieved by the reaction of 5—nitro in Reaction Scheme 13. The reaction can be carried out under the same reaction conditions as in the reaction (step 2) for reducing the benzofuran derivative (2) to the 5- (aminobenzofuran derivative (3).

 The reduction of the 42-nitrophenol derivative (21) to the 41-aminophenol derivative (22) is carried out by the reaction of 5-5-nitrobenzene in Reaction Formula 13 The same reaction conditions as in the reaction (Step 2) for the reduction of the benzofuran derivative (2) to the 5-amino benzobenzofuran derivative (3) can be used, and the same reducing agent is used. However, the amount used may be two-thirds of the reducing agent used in the step 2.

The 4—aminophenol derivative (22) is ring-closed in a suitable solvent in the presence of an acid to give the 5—aminobenzofuran derivative (3b). . Examples of the acid include mineral acids such as hydrochloric acid and hydrobromic acid. The amount of the acid to be used is usually 0.5 to: L00 mol, preferably 1 to 20 mol, per 1 mol of the -aminophenol derivative (22), Instead of these mineral acids, hydrogen chloride, hydrogen bromide, etc. may be added to the reaction system. Solvents include carboxylic acids such as acetic acid; methanol, 2-proha. Alcohols such as ethanol; water and the like; these may be used alone or as a mixture of two or more. The amount of the solvent used is usually from 100 to 500 parts by weight, preferably from 100 to 100 parts by weight, per 100 parts by weight of the 4-aminophenol derivative (22). 0 parts by weight. The reaction temperature is usually preferably in the range from room temperature to the boiling point of the solvent. This reaction is usually completed in 1 to 100 hours.

Reaction Formula 1 8

 (26) (27)

[Wherein, RRR ³ , R ⁵ and X are the same as above. According to Reaction Formula-8, 2,5-disubstituted 41-aminophenol derivative (23) is subjected to acetylation of the amino group to acetoanilide derivative (23). 2 4) and then —

By reacting with (25), a 5-keto ether derivative (26) is obtained. / 9—The benzofuranylamide derivative (27) force when the ketoether derivative (26) is closed The resulting benzofuranylamide derivative (27) is further deacetylated to give the 5-aminobenzobenzofuran derivative (3).

 The protecting group for the amino group of the 2,5-disubstituted-41-aminophenol derivative (23) is not limited to the acetyl group, but may be a honoleminole group or a chloroacetyl group. Various commonly used protecting groups such as trichloroacetyl group, benzoyl group and the like can be used.

The 2,5-disubstituted-41-aminophenol derivative (23) is reacted with an acetylating agent in a solvent to form an acetoanilide derivative (24). Is obtained. For this acetylation, the reaction conditions for normal N-acetylation can be widely applied. As the acetylating agent, those conventionally known can be widely used, and examples thereof include acetic anhydride, acetic halide, and acetic ester. For example, when acetic anhydride is used as the acetylating agent, the amount of the acetic anhydride used is based on 1 mol of the 2,5-disubstituted-4-aminophenol derivative (23). Usually, it is 1 to 10 moles, preferably 1 to 5 moles. As the solvent, for example, aromatic solvents such as benzene, toluene, and benzene are preferable. The amount of the solvent to be used is generally 100 to 500 parts by weight, preferably 100 to 500 parts by weight of 2,5-disubstituted-41-aminophenol derivative (23). H is 20 0 to 2000 parts by weight. The reaction temperature is usually preferably in the range from room temperature to the boiling point of the solvent. This reaction usually completes in 1 to 50 hours.

 By reacting the acetoanilide derivative (24) with α-haloketone (25), yS-ketoether derivative is obtained.

(26) is obtained. α-Haloketone (25) is, for example, 3—Black mouth 2—Butanone, 3—Black mouth 2—Pentanone, 2—Black mouth 1— Pentannone and the like can be used in an amount of usually 0.5 to 10 mol, preferably 1 to 3 mol, per 1 mol of the acetoanilide derivative (24). is there. Examples of the solvent include non-protonic polar solvents such as aceton, acetonitril, and dimethylformamide; ethers such as getylether and tetrahydrofuran; And the like. The amount of the solvent used is usually 100 to 200 parts by weight per 100 parts by weight of the acetoanilide derivative (24), preferably 200 to 100 parts by weight. 0 parts by weight. Examples of the base include carbonates such as potassium carbonate and sodium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; Tertiary amines such as triethylamine, pyridin and triethylene diamine; sodium hydride; metal hydrides such as calcium hydride; The amount of the base used is usually determined by deriving the acetate hydride of the general formula (24). It is usually 0.5 to 50 equivalents, preferably 1 to 10 equivalents, relative to the conductor. The reaction temperature is usually preferably in the range from room temperature to the boiling point of the solvent. The reaction usually completes in 1 to 100 hours.

 A benzofuranylamide derivative (27) is obtained by ring-closing the 3-ketoether derivative (26) in a solvent in the presence of an acid. Concentrated sulfuric acid is preferable as the acid and the solvent, and the amount of the sulfuric acid used is usually from 100 to 500,000 parts by weight per 100 parts by weight of the / 3-ketoether derivative (26). Or 2000 to 2000 parts by weight. The reaction temperature is preferably in the range of 0 to 150 ° C. This reaction is usually completed in 1 to 20 hours.

By heating a benzofuranylamide derivative (27) with a base in a polar solvent, a 5-aminobenzobenzofuran derivative (3) is obtained. Examples of the polar solvent include alcohol solvents such as methanol, ethanol, and 2-propanol, and water, and these may be used alone or in combination of two or more. it can. The amount of the solvent used is generally 100 to 100,000 parts by weight, preferably 500 to 500 parts by weight, per 100 parts by weight of the benzofuranylamide derivative of the general formula (27). 0 parts by weight. As the base, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferable. Better. The amount of base used is benzofuranylamide derivative

(27) Usually 1 to 1 mol: L00 mol, preferably 2 to 20 tomol per 1 mol. The reaction temperature is usually in the range of room temperature to the boiling point of the solvent. Heating is preferred to shorten the reaction time. This reaction is usually completed in 1 to 50 hours.

 The thus obtained 5-amino benzofuran derivative of the general formula (3) is important as an intermediate for producing the compounds of the general formulas (5) and (6). It can itself be an intermediate for other pesticides, medicines and the like.

 Table 2 shows specific examples of the 5-amino benzofuran derivative (3) obtained by the reaction of any one of Step 2, Reaction Formula 17 and Reaction Formula 18 in Reaction Formula 13. Table 2>

R ¹ R ² R ³ R ⁵

 H

^CH 3 ^CH 3

 C 1 C 1 H

^CH 3

 C 1 C 1

^CH 3

 C 1 H

^CH 3

 C 1 H

^CH 3 ^CH 3

 B r H

^CH 3 ^CH 3 Continued from Table 2>

Also, according to step 3 of Reaction formula-3, the benzofuranilyso (thio) cyanate derivative of the general formula (4) can be converted to Alternatively, it is produced by reacting with thiophosgene. Specifically, in general formula (4), benzo in which Y is an oxygen atom The furanyl isocyanate derivative is produced by reacting the corresponding 5-aminobenzofuran derivative (3) with phosphene, phosgene dimer or phosgene trimer. In addition, in the general formula (4), the benzofuranilusisothiocyanate derivative in which Y is a sulfur atom is a thiophosgene in the corresponding 5-aminoaminobenzofuran derivative (3). It is produced by reacting

 The reaction solvent that can be used in this reaction is not particularly limited as long as it is inactive under the reaction conditions, but specific examples include dichloromethane and chloroform. Halogenated hydrocarbon solvents such as honolem, dichloroethane, and chlorobenzene; hydrocarbon solvents such as n-hexane, cyclohexane, benzene, and toluene; Examples include ester solvents such as ethyl acetate and water. Among these solvents, preferred solvents are dichloromethane, dichloroethane, toluene, ethyl acetate and the like. These solvents are used alone or in combination of two or more. The amount of the solvent to be used is preferably from 200 to 100,000 parts by weight per 100 parts by weight of the 5- (aminobenzobenzofuran derivative) of the general formula (3), and is preferably used. Is preferably from 500 to 300 parts by weight.

Phosgene and tiophosgene also include these equivalents, for example, trichloromethanetinolechlorohonolate, Phosgene and the like can be mentioned.

 The use ratio of the 5-aminobenzofuran derivative (3) and phosgene or tiophosgene is not particularly limited, but the latter is usually 0.5 equivalent to 1 equivalent of the former. ~ 2 equivalents, preferably 0.1 to 1.5 equivalents.

 In the reaction using phosgene or its equivalent, a base is not required, and the 5-aminobenzobenzofuran derivative (3) and phosgene or its equivalent may be heated in the presence of a solvent.

The reaction using thiophosgene is preferably performed in the presence of a base. As the base, conventionally known bases can be widely used. For example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, or sodium carbonate Aqueous solutions or suspensions of alkali metal carbonates such as lime and potassium carbonate; and tertiary amines such as triethylamine and pyridin. Preferably, it is an aqueous solution of an alkali metal hydroxide. In the case of an aqueous solution of an alkali metal hydroxide or an alkali metal carbonate, the concentration varies depending on the type of the base, but is usually 1 to 50% by weight, preferably 5 to 25% by weight. Good to use. The amount of the base to be used is generally 1-10 mol, preferably 2-5 mol, per 1 mol of 5-aminobenzobenzofuran derivative (3). This reaction can be performed at a reaction temperature of 0 to 50 ° C.

 In this reaction, the desired benzofuraniluiso (thio) cyanate derivative of the general formula (4) is obtained in a good yield and the reaction operation is simple. Phosgene or thiophosgene is highly toxic and requires special equipment when used in large quantities. In addition, there are few factories that can handle phosgene or thiophosgene, and there are many restrictions on industrial production due to transportation problems.

 Therefore, as a result of studying a method for synthesizing a benzofuraniluisothiocyanate derivative without using thiophosgene, the presence of a base in the presence of a base in the 5- (aminobenzofuran derivative of the general formula (3) was investigated. By reacting carbon disulfide to form a dithiocarbamate and then reacting with a halogen-based oxidizing agent, the benzofuranite in which Y is a sulfur atom in the general formula (4) is obtained. Established a method to produce Louiso thiocyanate derivatives in good yields ο

Examples of the solvent used in the reaction to produce dithiocarbamate include hydrocarbon solvents such as benzene, tonolene, cyclohexane, and n-hexane; dichloromethan; Halogenated hydrocarbons such as chlorofluoronom, chlorochloroethane, trichloromethane, crozen benzene, crozen toluene, etc. Medium: Ether solvents such as ethynoleate and tetrahydrofuran, etc. Among them, hydrocarbon solvents are preferable. These solvents can be used alone or in combination of two or more. The amount of the solvent used is usually from 100 to 400 parts by weight, preferably from 200 to 100 parts by weight, based on 100 parts by weight of the 5-aminobenzobenzofuran derivative of the general formula (3). It is about 2000 parts by weight.

 Examples of usable bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; sodium acetate, potassium acetate and the like. Acetates such as uranium; triethinoreamin, trimethinoreamin, diisopropyretinoreamin, 1-methinolebiperidine, 1-methinolemonorephorin, 1-methylpyroline , Lysine, 4-dimethinorea minopyridine, 4-pyrrolidinopyridin, 1,4_ diazabisik mouth [2.2.2] octane, 1 , 8 — Jaza Bisikro

[5.4.0] Tertiary amines such as decenyl-1-ene and the like are preferred, and tertiary amines are preferably used. These bases can be used alone or in combination of two or more. When an inorganic base or acetate is used, a phase transfer catalyst is preferably present in the reaction system. Examples of the phase transfer catalyst include quaternary ammonium salts and quaternary phosphonium salts. Quaternary Ammonium Examples of the salt include tetramethylammonium bromide, tetramethyl bromide n-butynoleammonium, tetrachloroammonium n-butylammonium, and bromide tetrammonium. Examples include butyl ammonium and benzyl triethyl ammonium chloride. Examples of the quaternary phosphonium salts include tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, methyltriphenylphosphonium bromide, and chloride chloride. Tetra-n-butylphosphonium etc. can be exemplified. The amount of the base to be used is generally about 1 to 20 mol, preferably about 1 to 5 mol, per 1 mol of the 5-amino benzofuran derivative of the general formula (3).

 The amount of carbon disulfide to be used is generally about 1 to 20 mol, preferably about 1 to 5 mol, per 1 mol of the 5-amino benzofuran derivative (3).

 This reaction is usually performed at a temperature in the range of 0 to 50 ° C, and is generally completed in about 1 to 20 hours.

 By reacting the thus obtained dithiolbasamic acid derivative salt with a halogen-based oxidizing agent in a suitable solvent with stirring, washing the reaction solution with water, drying and concentrating, the general formula ( In 4), a benzofuranylisothiocyanate derivative in which Y is a sulfur atom can be obtained.

Solvents that can be used include, for example, cyclohexane, Hydrocarbon solvents such as toluene and toluene; halogenated hydrocarbon solvents such as dichloromethane, chlorophorenolem, dichloroethane, trichloroethane, and chlorobenzene; methanol Le, ethanol, 2-prono. And alcohol-based solvents such as ethanol; water and the like. Of these, halogenated hydrocarbon-based solvents are preferred. The amount of the solvent to be used is generally about 200 to about 200 parts by weight, preferably about 500 to about 100 parts by weight, based on 100 parts by weight of the dithiolamine derivative salt. Examples of the halogen-based oxidizing agent include alkyl carbonates such as methyl methyl carbonate and potassium ethyl carbonate; phosgene, oxalyl chloride, sodium hypochlorite, and the like. However, among them, black carbonate alkyl esters are preferred. The amount of the halogen-based oxidizing agent to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the dithiol rubbamate derivative salt.

 This reaction is usually carried out at a temperature in the range of 0 to 50 ° C, and is generally completed in about 1 to 10 hours.

In the present invention, the halogenated oxidizing agent is added to the reaction solution without isolating the salt of the dithiocarboxylic acid derivative from the inside of the reaction system, whereby the compound represented by the general formula (4) is obtained. Benzofuranyi sothiocyanate derivative where Y is a sulfur atom Can be obtained all at once.

 Table 3 shows specific examples of the benzofuraniluiso (thio) cyanate derivative (4) obtained by step 3 of Reaction formula-3.

<Table 3>

R ¹ R ² R ³ R ⁵ Y

 H S

is ^s ° ^-C 3 ^H 7 ^CH 3 ^CH 3

iso— C _n HH 〇

3 7 ^CH 3 ^CH 3

 C 1 C 1 H S

^CH 3

 C 1 C 1 H 0

^CH 3

 C 1 C 1 s

^CH 3 ^CH 3

 C 1 C I 0

^CH 3 ^CH 3

 C 1 H s

^CH 3 ^CH 3

 C 1 H 0

^CH 3 ^CH 3

 C 1 H s

^CH 3 ^CH 3

 C 1 H 0

^CH 3 ^CH 3

 B r H s

^CH 3 ^CH 3

 B r H 0

^CH 3 ^CH 3

 C 1 H s

^CF 3 ^CH 3

 C 1 H 0

^CF 3 ^CH 3

 H s

^CH 3 ^CH 3 ^CH 3

 H 0

^CH 3 ^CH 3 ^CH 3 Continuation of <Table 3>

R ¹ R ² R ³ R ⁵ Y

C 1 CN H S

^CH 3

 C 1 CN H 0

^CH _Three

 C 1 C 1 H s

^CH _Three

 C 1 C 1 H 0

^CH 3

 C 1 C 1 H H s

C 1 C 1 H H 0

C 1 H s

^CH 3 ° ^CH 3

 C 1 H 0

^CH 3 °

 F H s

^CH _Three ^{C H} _Three

 F H 0

^{C H} _Three

 C 1 F H s

^CH 3

 C 1 F H 0

^CH 3

 C 1 F s

^CH 3 ^CH 3

 C 1 F 0

^CH 3 ^CH 3

 H H s

^CH 3 ^CH 3

 H H 0

^CH 3 ^CH 3

 H s

^CH 3 ^iS ° ^-C 3 ^H 7 ^CH 3

 H 0

^CH 3 ^is ° ^-C 3 ^H 7 ^CH 3

C 1 H si ^S ° ^-C 3 ^H 7 ^CH 3

C 1 iso-C ₃ H ₇ H 0

^CH 3

 H s

^CH 3 ° ^CH 3 ^CH 3

 H 0

^CH 3 ° ^CH 3 ^CH 3 Continued from Table 3>

In addition, according to Step 4 of Reaction Scheme 13, the benzofuranilyso (thio) cyanate derivative of the general formula (4)

R ⁶ NHNH 2 (2 8)

[Wherein, R ⁸ represents a lower alkyl group. ]

 By reacting with the alkyl hydrazine represented by the formula, a benzofuranyl (thio) semicarbazide derivative represented by the general formula (5) is produced.

The reaction solvent that can be used in this reaction is not particularly limited as long as it is inert under the reaction conditions, and, specifically, dichloromethane, Halogenated hydrocarbon solvents such as chloro-honolem, dichloroethane, and black benzene, and aromatics such as n-hexane, cyclohexane, benzene, tonolenene Group hydrocarbon solvents and the like. The amount of the solvent used is preferably from 200 to 100,000 parts by weight, per 100 parts by weight of the benzofuranyliso (thio) cyanate derivative of the general formula (4). The amount is preferably 500 to 300 parts by weight.

 As the alkyl hydrazine of the general formula (28), conventionally known alkyl hydrazines can be widely used, and examples thereof include methyl hydrazine, ethynole hydrazine, π-propynole hydrazine, Isopropynolehydrazine, n-butylhydrazine and the like. The phenolic hydrazine (28) may not contain water, or may be in the form of an aqueous solution. General formula

The use ratio of the benzofuranyliso (thio) cyanate derivative of (4) and the alkyl hydrazine of the general formula (28) is not particularly limited but is within a wide range. Although it can be appropriately selected from the above, it is usually preferable that the amount of the latter is 0.8 to 3 moles, preferably 1.0 to 2 moles per mole of the former. This reaction can be performed at a reaction temperature of 0 to 50 ° C.

 In the present invention, an organic layer obtained by washing and separating the reaction solution of the benzofuraniliso (thio) cyanate derivative (4) produced in Step 3 of Reaction Scheme 13 is directly used in the step. It can also be used for 4.

Without using phosgene, in general formula (5), Y is As a method for obtaining a semicarbazide derivative which is an oxygen atom, there is a method via a phenylcaprate derivative (29) (Steps 5 and 5 in Reaction Scheme-3). 6).

 According to step 5 of Reaction formula-3, the reaction of 5-aminobenzofuran derivative of the general formula (3) with a phenylcycloformate in the presence of a base yields the general formula It is possible to produce the vinyl acetate derivative of (29). Solvents used in this reaction include, for example, hydrocarbon solvents such as benzene, toluene, cyclohexane and n-hexane; dichloromethane, chloroform Halogenated hydrocarbon solvents such as honolem, dichloroethane, trichloroethane, black benzene, chlorotonolene, etc .; Jethyl ether, tetrahydrofuran Ether solvents such as lan; ester solvents such as ethyl acetate; These solvents can be used alone or in combination of two or more. The amount of the solvent to be used is usually 100 to 400 parts by weight, preferably 200 to 200 parts by weight, per 100 parts by weight of the 5-amino benzofuran derivative (3). It is about 0 parts by weight.

Examples of usable bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; sodium acetate, and acetic acid. Acetates such as potassium; triethinoreamin, trimethinoreamin, 1-methinoreperi Gin, 1—Methylmonorephorin, 1—Methinolepyrrolidine, 4—Dimethinorea Minopyridine, 41 Pyrrolidinopyridin, 1,4—Zazabicyclo [2. 2.2] octane, 1,8- diazabicyclo [5.4.0] organic base such as indecen-17-ene. These bases can be used alone or in combination of two or more. The amount of the base to be used is generally about 1 to 20 mol, preferably about 1 to 5 mol, per 1 mol of the 5-aminobenzobenzofuran derivative (3).

 The amount of phenylcycloform used is usually 1 to 20 mol, preferably about 1 to 5 mol, per 1 mol of the 5-amino benzobenzofuran derivative (3). is there.

 This reaction is usually performed at a temperature in the range of 0 to 50 ° C, and is generally completed in about 1 to 20 hours.

 According to step 6 of Reaction formula-3, by reacting the phenylcarbamate derivative of the general formula (29) with the alkylhydrazine of the general formula (28), In the general formula (5), a semicarbazide derivative in which Y is an oxygen atom is obtained.

Solvents that can be used include, for example, hydrocarbon solvents such as cyclohexane, benzene, and toluene; dichloromethane, chlorofluoronom, dichloroethane, and trichloromethane. Halogenated hydrocarbon solvents such as chloroethane and chlorobenzen; Ether solvents such as ether and tetrahydrofuran; ditrino solvents such as acetonitrile; methanol, ethanol, 2-propanol and the like; Alcohol solvents; water and the like. The amount of the solvent used is usually from 100 to 400 parts by weight, preferably from 200 to 200 parts by weight, based on 100 parts by weight of the phenylcarbamate derivative (29). It is about parts by weight. The amount of the alkynolehydrazine (28) to be used is generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the phenyl carbamate derivative.

 This reaction is usually carried out within a range of room temperature to the boiling point of the solvent, and is generally completed in about 1 to 30 hours.

 Also, according to Step 7 of Reaction formula-3, the benzofuranylthiosemicarbazide derivative (5b) in which Y is a sulfur atom in the general formula (5) is converted into an inert solvent in the presence of a base. By reacting with trifluoroacetic acid alkyl ester, it is possible to obtain a benzofuran-l-oxotoxytriazole derivative (6b) in which Y is a sulfur atom in the general formula (6). .

Solvents that can be used in this reaction include, for example, alcoholic solvents such as methanol, ethanol, 2-prono, and ⁰ -nor; carbonized solvents such as cyclohexane, benzene, and toluene. Hydrogen solvents; dichloromethane, chlorophonolem, dichloroeta Halogenated hydrocarbon solvents such as benzene, trichloroethane, and chlorobenzene. The amount of the solvent used is generally 100 to 200 parts by weight based on 100 parts by weight of the benzofuranylthiosemicarbazide derivative (5b) in which Y is a sulfur atom in the general formula (5). It is preferably about 200 to 100 parts by weight.

 Bases that can be used in this reaction include, for example, alkali metal alcoholates such as sodium methoxide and potassium ethoxide; and alkali metals such as sodium hydroxide and potassium hydroxide. Alkaline metal hydroxides; alkaline metal hydroxides such as calcium hydroxide and magnesium hydroxide; and the like. The amount of the base to be used is generally about 2 to 10 mol, preferably about 0.5 to 3 mol, per 1 mol of the benzofuranylthiosemicarbazide derivative (5b).

 As the trifluoroacetic acid alkyl ester, those conventionally known can be widely used. For example, methyl trifluoroacetate, ethyl tritrifluoroacetate, etc. are preferred. The amount of the alkyl trifluoroacetate to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the benzofuranylthiosemicarbazide derivative (5b).

This reaction is usually performed in the range of room temperature to the boiling point of the solvent, Generally, it is completed in about 0.5 to 10 hours.

 Also, in step 7 of Reaction Formula 13, from the semicarbazide derivative in which Y is an oxygen atom in the general formula (5), a benzofurantrile in which Y is an oxygen atom in the general formula (6) In producing the azole derivative, for example, known methods described in JP-A-8-20583, JP-A-917583, and the like can be employed. That is, by heating a semicarbazide derivative in which Y is an oxygen atom in the general formula (5) in trifluoroacetic anhydride, Y should be an oxygen atom in the general formula (6). Nzofuranyl triazole derivatives can be produced. At this time, it is preferable to add a catalyst such as Lewis acids such as titanium tetrachloride, organic acids such as p-toluenesulfonic acid, and inorganic acids such as concentrated sulfuric acid. The amount of the catalyst used is usually from 0.0001 to 10 mol, preferably from 0.01 to 1 mol, per mol of the semicarbazide derivative in which Y is an oxygen atom in the general formula (5). It may be 1 mole. The reaction conditions such as the amount of trifluoroacetic anhydride used, the heating temperature and the time may be the same as those described in the above patent publication.

The reaction product obtained in each of the above reactions is isolated and purified from the reaction mixture by ordinary isolation and purification means. Such isolation and purification means include, for example, extraction, filtration, distillation, and power. Ram chromatograph etc. can be mentioned.

 The benzene derivative (1), 5-nitrobenzofuran derivative (2), 5-amino benzobenzofuran derivative (3) and benzofuraniliso (chio) cyanate derivative (5) obtained above 4) is a benzofuran (thio) semicarbazide derivative of the general formula (5) and an intermediate for producing a benzofuranyl triazole derivative of the general formula (6) useful as a herbicide. However, it can also be an intermediate for other pesticides, medicines, etc. by itself.

 Further, according to the method of the present invention, on an industrial scale, the general formula

(5) The benzofuran (thio) semicarba and zide derivatives of (5) can be produced in a small number of steps and using raw materials that are industrially easily available. Example

 Examples are given below to further clarify the present invention.o

Example 1

Acetonoxime 0 — (2 — 1-methyl chloro-5-methylolone 4-nitrophenyl) ether (compound of general formula (1): R 1 = CR ² = R ³ = R ⁴ = CH ₃ ) Manufacture

25% sodium hydroxide in 100 ml 1 volume flask 3.33 g (0.02 mole) of aqueous solution, 7.5 ml of benzene at the mouth, 4.5, dicyclo-1,2-nitro-2-enole 2.06 g (0.01 mol) Monole), 2.19 g (0.03 mol) of acetonoxime and 0.849 g (0.025 mol) of tetramethyl bromide-n-butylammonium at room temperature The mixture was added sequentially, and heated and stirred at an internal temperature of 65 ° C for 4 hours. After allowing the reaction solution to cool, ethyl acetate and water were added thereto, and the organic layer was separated. After the aqueous layer was extracted twice with ethyl acetate, the extract and the organic layer were combined, washed twice with water and once with a saturated saline solution, and dried over anhydrous magnesium sulfate. The crude product obtained by concentrating to dryness is suspended in 2-propanol, filtered, washed, dried and dried with acetonoxime 0-(2-black 1-5-nitro 4-nitrite 1.71 (Yield: 71%, purity: 96%) was obtained.

Melting point: 13 0-13 1 ° C

 'H-NMR (CDC 13, ό ppm): 2.09 (3Hs), 2.16 (3H, s), 2.63 (3H, s), 7.46 ( 1 H, s), 8.16 (1 H, s)

Example 2

Acetonoxime 0 — (2 — Bromo 5 — Methinole 4 12-trophenyl) ether (Compound of general formula (1): R ¹ = Br, R ² = R ³ = R ⁴ = CH ₃ ) Manufacturing of 4, 5 — Jikro mouth 1 2 — Nitroth noren instead of 4,5 — Jibo mouth Mo 2 — Nitroth noren 2.95 g (0.01 mol) The procedure of Example 1 was repeated except that acetic acid was used, to give 1.49 g of acetonoxime 0- (2-bromo-5-methyl_412-nitrophenyl) ether (1.49 g, yield 55%). %, Purity 95%).

Melting point: 1 27-1 28 ° C

 ^ -NMRCCDC ls, 5 ppm): 2.09 (3Hs), 2.17 (3H, s), 2.62 (3H, s), 7.43 (1H, s) ), 8.32 (1 H, s)

Comparative Example 1

60% oily sodium hydride 0.30 g (8.56 mmol) in a 100 ml 3-volume flask fitted with a dropping funnel, calcium chloride tube and septum Then, 6 ml of dehydrated hexane was added, and the mixture was stirred for 5 minutes. After leaving the solution to stand still, the hexane was removed by suction with a syringe. Add 10 ml of dehydrated dimethylformamide, and dissolve 0.63 g (8.56 mmol) of acetonoxime in 10 ml of dehydrated dimethylformamide with stirring. Was added, and the mixture was stirred at room temperature for 10 minutes. Then, from the dropping funnel, 4.68 g (2-5.6) of dichloro-2-en-2-northrene was added to dehydrated dimethylformamide (10 m). 1 Dissolve the solution It was dropped. After the addition, the mixture was stirred at room temperature for 6 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. After the aqueous layer was extracted twice with ethyl acetate, the extract and the organic layer were combined, washed three times with water and once with a saturated saline solution, and dried over anhydrous magnesium sulfate.

 When this solution was subjected to silica gel thin-layer chromatography (developing solvent: hexanenoether = 51), the raw material 4,5-dichloro1-2-nitro Noreen and the desired product, acetonoxime 0 — (2 — 1-methyl-5 — methyl — 4 _ nitrofininole) ether were not observed. Example 3

7 - click B port one 2, 4 - dimethyl Chinore one 5 - Two preparative Robenzofura emissions (compound of the general formula (2): R i C l R 2 = R 3 = CH 3, R 5 = H) prepared in

2-Prono2 was cooled in a 100 ml eggplant flask. Take 10 ml of the paste, and dissolve 1.10 g (30 mmol) of hydrogen chloride gas. To this solution was added 2.42 g (10 millimoles) of acetonoxime di- (2-cyclomethyl-5-methinole-4-nitrophenyl) ether, and the mixture was heated under reflux for 8 hours. After cooling the reaction mixture, the crude product was collected by filtration, washed twice with 20 ml of 2-propanol, twice with 30 ml of water, and once with 20 ml of 2-propanol. After, vacuum drying As a result, 1.42 g (yield: 63%, purity: 97%) of 7-chloro-1,2,4-dimethinole-5-nitrobenzofuran was obtained. Melting point: 1 4 2 — 1 4 3 ° C

 'H-NMRCCDC ls, δ ppm): 2.55 (3H, s), 2.69 (3H, s), 6.60 (1H, s), 7.97 (1H) , s)

Example 4

7 - Bed B mode one 2, 4-di-menu Chinore -5 _ D filtrated base emissions Zoff run-(I匕合of the general formula (2): RL - B r ^ R 2 = R 3 = CH, R ⁵ = H)

 Acetonoxime 0 — (2 — black mouth 1 5 —

4 — Nitrofluoroninole) Instead of ether, acetonoxime 0 — (2 — Bromo 5 — Methinole 4 — Nitropheninole) ether 2.87 g (1 The same operation as in Example 3 was carried out except that 0 mm was used to obtain 7-promo 2,4-dimethyinole 5 —nitrobenzofuran 1.46 g ( yield

54%, purity 97%).

Melting point: 15 1-15 2 ° C

^{X H - NMR (CDC 1 a} , 5 ppm): 2. 5 5 (3 H, s), 2. 6 9 (3 H, s), 6. 6 2 (1 H, s), 8. 1 1 (1 H, s)

Example 5 !!.! 4, 7 - di-click B B one 2 - methylation over 5 - two-door Lobbe down Zoff La emissions (I匕合of the general formula ^{(2): ^ 1 ^ ^} 2 ^, R 3 = CH _3, the production of R ⁵ = H)

 [1] 1,4-Dichloro-2- (2-cyclo-1-2-propenyloxy) benzene (compound of the general formula (11): R

¹ = R ² = X ¹ = C 1 _Λ R ⁵ = R ⁷ = H)

 2 lit-sole four-mouthed flasks with 2,5 — dichlorophenol 1 in. 250 g (l.53 monole), 2,3 — dichlorone Add 213 g (l.92 mol) of pen, 265 g (1.92 monole) of potassium carbonate and 1.3 liters of acetonitrile and add 20 liters. The mixture was stirred and refluxed for hours. After standing to cool, the mixture was filtered by suction, and the obtained filtrate was concentrated under reduced pressure to give 1,4-dichloro-

2 — (2 — Black mouth 1 2 — Propaninoleux) Benzene 3

45 g (95% yield) were obtained.

[II] 3,6-Dichloro-2- (2-cyclo-1-2-propyl) phenol (compound of general formula (12): R ^{1 =} R

² = X ¹ = CR ⁵ = R ⁷ = H)

 2 1,4-Dichloro mouth 1 _ (2—chloro-2-propidinoxy) benzene obtained in [I] on eggplant flask of 2 liters l. 45 mol) and 330 g of N, N-ethylaniline at 220 ° C under a nitrogen atmosphere.

Stir for 4 hours. After cooling down, with 1.2 liters of ethyl acetate It was extracted and washed sequentially with 10% hydrochloric acid and water. The ethyl acetate extract was dried over magnesium sulfate, filtered, and the ethyl acetate was distilled off under reduced pressure, and then purified by vacuum distillation to obtain 3,6-dichloro-2- (2-cyclo 1-2-3). 300 g (yield 87%) of a colorless liquid was obtained.

!!. [III] 4, 7 - di click B B one 2 - Main Chinore -5 - Two collected by filtration Baie emissions Zoff run-in (formula (2) ^{Compound: ^ 1 ^ ^ 2: 1} , R 3 = CH ₃ , R ⁵ = H)

 3, 6-Dichloro-2 — (2 — Kuroguchi 1 2 — Propaninole) phenol 2 9 2 obtained in [II] on 3 liters of eggplant flask g (l.23 monole) and kuro honolem 1.

 Two liters were added and cooled in an ice-water bath. Under stirring, 83 g (l.29 mol) of fuming nitric acid was gradually added dropwise. After the addition was completed, the mixture was further stirred for 1.5 hours. The reaction mixture is washed with water, and the solvent is distilled off under reduced pressure to give 3,6-dichloro-2 (2-cyclopropyl-2-2-propyl) -14-nitrophenol (general) Expression

Compound of (13): R ¹ = R ² = X ¹ = C 1, R ⁵ = R ⁷ = H) A crude product was obtained.

This crude product was placed in a 3-liter flask, 1 kg of 47% hydrobromic acid and 0.5 liter of acetic acid were added, and the mixture was stirred and refluxed overnight. The reaction solution was cooled, and ice water was added, and the precipitated crystals were filtered by suction. Transfer the resulting solid to a beaker, 2 — Prono,. After suspending and washing with ethanol, suction filtration was performed. The solid was dried to give the title 4,7-dichloro-2-methyltin-5-nitrobenzofuran as a yellow solid (174 g, yield 57%).

Melting point: 1 3 7 — 1 3 8 ° C

 ^ -MRCCCDCls, 5ppm): 2.57 (3H, s), 6.70 (1H, s), 7.92 (1H, s) Example 6

7 — Bromo 2,4 — Dimethinole 1 5 —Nitrobenzofuran (Compound of general formula (2): R i Br R ² = R ³ = CH ₃ , R ⁵ = H ) Manufacturing of

[I] 4 one Bed B mode one 2 - D filtrated one 5 - Pro Bruno, ⁰ Ruginoreoki collected by Rue emissions (formula (1 6) ^{compounds: R i- B i ^ R 2} = CH 3, R 5 = R ⁷ = H)

In a 200 ml flask, add 2-bromo-5-methyl-5-nitrophenol 12 g (52 mimol), propargyl bromide 7.8 g (6 5 millimoles), 9.0 g (65 milliliters of carbonic acid) and 60 ml of acetonitrile were added, and the mixture was heated under reflux with stirring for 2 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with n-hexane and filtered by suction. The solid is dried and 4-Bromo 1-2 Tro 5-Proha. Noregino Leoxy Site Nore 10.6 g (yield 76%) was obtained.

[II] 7-Bromo-1,4, -dimethinol-5-Nitrobenzofuran (Compound of general formula (2): R ¹ = Br, R ² = R ³ = CH a. R ⁵ = H)

Under a nitrogen stream, one 4 was obtained in [I] bromo - 2 - Two collected by filtration -5 - Purono, ⁰ Rugiruokishi Tonoreen 2. 5 g (9. 2 9 millimeter Mosore), full tool I匕Se shea c arm A mixture of 1.97 g (13.01 mimol) and N, N-getylaniline (10 g) was stirred at 210 ° C for 1.5 hours. After cooling, ethyl acetate was added, and insolubles were removed by celite filtration. The filtrate

Washed sequentially with 10% hydrochloric acid and saturated saline. The ethyl acetate solution was dried over magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained solid was washed with petroleum ether, filtered by suction, dried and dried to give 1.0 g (yield 40%) of the title 7-promo 2,4-dimethyl-5-nitrobenzofuran. The melting point and ¹ H-NMR (CDC 13, 5 ppm) value of the obtained compound corresponded to those of the compound obtained in Example 4.

Example 7

4, 7 — dimethyl-1 5 — nitrobenzofuran (compound of general formula (2):! ^ ¹ :! ^ ² ^^. !!! ^ R ³ = R ⁵ = H) 6 A

[I] 5, 8 - dimethyl Chiru 6 - Two filtrated click Mali down (!.! General formula (1-9) ^{compounds: ^ 1 ^ ^ 2: ^} ^ R 5 = H) of Preparation 2 0 0 20 ml of concentrated sulfuric acid was added to an m 1 flask, and the mixture was cooled in an ice-monosalt bath. 5,8-Dimethylcoumarin (12 g, 69.0 mmol) was added in small portions. Under cooling and stirring, fuming nitric acid (5.21 g, 82.8 mmol) was gradually added dropwise. After completion of the dropwise addition, the mixture was further stirred in an ice-water bath for 1 hour. When the reaction solution was poured into ice water, a yellow solid precipitated. After filtration, the solid was dissolved in 400 ml of ethyl acetate, washed sequentially with dilute aqueous sodium hydroxide, water and saturated saline, and then dried over magnesium sulfate. After filtration, the filtrate was concentrated until a slurry was formed, followed by suction filtration to obtain 7.24 g (yield: 48%) of 5,8-dimethyl-16-dicyclomaline. .

[II] 4, 7 - dimethyl Chinore 5 - D filtrated one 2 - Ben Zoff La Nkarubon acid (!!. Formula (2 0) of ^{Compound: ^ 1 ^ ^ 2: H} 3, R 6 = H) of Manufacturing,

Bromine was added to a solution of 5,8-dimethysol 6-nitrocyclomalin 2.19 g (10 mimol) obtained in [I] and 20 ml of 20 ml of cross-linked form. 4 g (15 mmol) was added little by little and stirred at room temperature for 1 day. Add 4% of 20% sodium sulfite aqueous solution, stir for 30 minutes, and then close the mouth form 30 m 1 was added, and the organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. When 5 ml of ethanol was added, a solid precipitated and became slurry.

 While cooling and stirring a solution of 4.5 g (80 mmol) of potassium hydroxide and 10 ml of ethanol in a water bath, the slurry was added little by little. After stirring overnight, 12 ml of 6N hydrochloric acid was added. The precipitated solid was filtered off with suction, washed with water and dried, and the title 4,7-dimethinole-5-nitro-2-benzofurancarboxylic acid yellow solid 1.65 g (yield 7 0%).

[III] 4, 7 - dimethyl Chiru 5 - Two collected by filtration base Nzofura down production of (!!. One general formula (2) ^{compounds: ^ 1:: ^ 2 !!} ^ R 3 = R 5 = H)

4, 7 — Dimethinole 5 — Nitro 2 — Benzofurancanolevonic acid 0.70 g (3.0 mimol), quinoline 1.5 g and copper powder 0 . 15 g were mixed and stirred at 200 ° C. for 1 hour. The mixture was extracted with 100 ml of ethyl acetate and washed several times with 1N hydrochloric acid. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting solid was purified by column chromatography (developing solvent: n-hexane / ethyl acetate = 8/1) to give 4,7-dimethyl-5-dibenzobenzene. 0.4 lg (72% yield) of yellow solid Got O

 'H-NMRCCDC la, <5 ppm): 2.51 (3H, s), 2.70 (3H, s), 6.86 (1H, d), 7.67 (1 H, d), 7.76 (1H, s)

 The following compounds were obtained in the same manner as in Examples 3 to 7. The NMR spectrum data and melting point of the obtained compound are also shown.

① Compound of general formula (2): R i RZ ^ RSCHR ⁵ = H

Melting point: 95-96. C

^{X H - NMR (CDC 1 3} , (5 ppm): 2. 5 0 (6 H, s), 2. 6 7 (3 H, s), 6. 5 2 (1 H, s), 7. 7 5 (1 H, s)

② General formula (2) compounds: R '- C 1, R 2 = CH 3 0, R 3 = CH 3, R 5 = H

 'H-NMR (CDC13, ό ppm): 2.60 (3H, s), 4.15 (3H, s), 6.72 (1H, s), 7.74 (1 H, s)

③ Compound of the general formula (2): ¹ :. 1, R ² = F, R ³ = CH ₃ , R ⁵ = H

'H-NMRCCDC la, 5 ppm): 2.55 (3Hs), 6.65 (1H, s), 7.94 (1H, d) 化合物 Compound of general formula (2): R i-

CR ³ = C 2 H ₅ , R ⁵ = H

 'H-NMRCCDC ls, (5 ppm): 1.39 (3H, t), 2.89 (2H, q), 6.60 (1H, s), 7-82 (1 H, s) Example 8

5 - A Mi node on 7 - click B B - 2, 4 - dimethyl Chinorebenzofu run-: Production of (formula (3) compound ^{R i C 1, R 2 =} R 3 = CH 3, R 5 = H)

7 for crochet 7 — chloro 2, 4 — dimethinolate 5 — nitrobenzofuran 0.45 g (2 mimol), 2 — 20 ml of propanol and Raney alloy (AlZN i = 50/50 (wt%)) 0. After adding lg and replacing the inside of the vessel with hydrogen, adjust the pressure to 10 kg / cm ² , and press Stirred for hours. After the reaction mixture was filtered through celite, the filtrate was concentrated and concentrated to 5 -amino 7 -chloro 2,4 -dimethylbenzofuran 0.38 g (quantitative, purity 97%) I got Melting point: 1 4 2 — 1 4 3 ° C

^-NMRCCCDCla, 5ppm): 2.21 (3H, s), 2.45 (3H, s), 3.48 (2H, bs),

6.3 2 (1 H, s), 6.6 2 (1 H, s) Example 9

5 — Amino 1 7 — Chloro 2, 4 — Dimethinolenbenzofuran (Compound of general formula (3): R ¹ = C 1, R ² = R ³ = CH ₃ , R ⁵ = H)

 7 in the crotch — 1 in the mouth 2, 4 — dime

— Nitrobenzofuran 0.90 g (4.0 milliliters), methanol 9 ml and 5% platinum-sulfide carbon 45 mg Was replaced with hydrogen, the pressure was adjusted to 30 kg / cm ² , and the mixture was stirred at 80 ° C for 1 hour. After the reaction mixture was filtered through celite, the filtrate was concentrated to give 5-amino-1 7-chloro-1,2,4-dimethinobenzobenzofuran 0.78 g (quantitative, purity 9 9%).

The melting point and ¹ H_NMR (CDC 13, 5 ppm) value of the obtained compound were consistent with those of the compound obtained in Example 8.

Example 10

5—Amino 7—Cro- mouth 1,2,4 Preparation of dimethinolevenzofuran (compound of general formula (3): R ¹ C 1, R ² = R ³ -CH 3, R ⁵ = H)

To a microcleave (volume of 100 ml), add 7-1,2,4,1-dimethyl-5- nitrobenzofuran 1. Og (4.43 milliliters) ), 10 ml of ethyl acetate and —Catalyst (NDHT — 90: manufactured by Kawaken Fine Chemicals Co., Ltd.) 0.1 g is added, and the inside of the vessel is replaced once with hydrogen. It was adjusted to cm ^2.

The mixture was stirred at 40 ° C for 2 hours. After the reaction was filtered through celite, the filtrate was concentrated to obtain a crude product of 5- (amino-7) -crobox_2,4-dimethylbenzofuran 0.81 (quantitative).

Example 1 1

5 — Amino 1 7 — Bromo 1,2,4-dimethinolenbenzofuran (a compound of general formula (3): R ¹ = Br, R ² = R ³ = CH ₃ , R ⁵ = H)

 7 — Chlores 2, 4 — Dimethinoles 5 — Instead of ditrovenzofuran 7 — Bromo-1, 2, 4-dimethinoles 5 — Ditrobenzofuran 0. 5—Amino 7—Blomo 1,2,4—Dimethyl benzofuran The same operation as in Example 8 except that 4 g (2 milliliters) is used. 0.48 g (quantitative, purity: 96%) was obtained.

Melting point: 15 1 — 15 2 ° C

 ^ -NMRCCDC ls, δ ppm): 2.21 (3H, s), 2.45 (3H, s), 3.47 (2H, bs), 6.34 (1H, s), 6.77 (1 H, s)

Implementation J [1 2 5—Amino-1,4—7-Dichloro2—Production of methinolevene zofuran (compound of general formula (3): R i RZC1, R ³ = CH ₃ , R ⁵ = H)

 In a 300 ml flask, 4,7-dichloro-2-methyl 5-nitrobenzofuran 4.92 g (20 mi monole), methanol Add 45 ml of Reno water (2 1), concentrated hydrochloric acid 2.0 g (20 mmol) and reduced iron 4.48 g (80 mmol), and stir for 1.5 hours. Refluxed. The reaction solution was filtered through hot celite, the filtrate was concentrated under reduced pressure, and the precipitated solid was washed with water and filtered by suction. The solid is washed twice with water, dried and dried to give 5—amino 4,7—dichloro-2-methylphenylzofuran, a yellow solid 3.76 g (98% purity, yield Rate of 85%).

Melting point: 1 4 1 1 1 4 2 ° C

'H-NMRCCDC ^, δ ppm): 2.46 (3H, s), 3.91 (2H, bs), 6.40 (1H, s), 6.69 (1H , s)

Example 13

5 — Amino 2, 4, 7 — Preparation of trimethinolenbenzofuran (compound of general formula (3): R i RZ ^ RSCH s R ⁵ = H)

[I] 2 — (2 — Black mouth 1 2 _ Propaninole) 1 3, 6 — Manufacture of dimethyl-14-nitrobenzene (compound of general formula (21): R ¹ = R ² = CH ₃ , R ⁶ = R ⁷ = H, X ¹ = C 1)

500 ml of beaker 2 — (2 — black mouth — 2 — propionyl) 1, 3,6 _ dimethyl phenol 9.83 g (50 milliliters), 95% ethanol 50 ml of ethanol and 50 ml of concentrated hydrochloric acid were added, and the mixture was cooled in an ice-monosalt bath. While stirring, 5.52 g (80 mmol) of sodium nitrite was added little by little. After the addition, the mixture was stirred for 1 hour. The reaction solution was poured into 1.5 liters of water, and the precipitated solid was collected by suction filtration and washed thoroughly with water. Dry and dry 2-(2-black mouth-2-probe) 1, 3, 6-dimethyltinole 4-nitroso feno-nole yellow solid 9.3 2 ₈ (yield 83 %).

[II] 4 — Amino 1 2 — (2 — Chlorine 2 — Propaninole) — 3, 6 — Dimethyltinole (Compound of general formula (2 2):! ^ ¹ : ^{! ^ 2:..! !!} ^ R 5 = R 7 = H, 1) Made in

2— (2—Chloro2—Propenyl) -1,3,6—Dimethyltinole 1—Nitrosofe obtained in [I] in a 300 ml four-neck flask Roh Nore 6. 9 0 g (3 1 millimeter Monore), 2 - Purono, ⁰ Bruno Lumpur 5 0 ml, water 5 0 ml, concentrated hydrochloric acid 1 0 m 1 and the reduced iron 8. 6 8 g (1 5 5 Millimol) and stirred. Heat with stirring and reflux for 1 hour. 200 ml of ethyl acetate was added and the mixture was filtered through celite. The filtrate was separated, and the organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and filtered. The organic layer was concentrated under reduced pressure, and n-hexane was added before drying to dryness. The precipitated solid was filtered by suction, washed with n-hexane, and washed with 4—amino 2— (2—clo 5.60 g (yield 87%) of a yellow solid of 1 2 -propinole 1, 3,6 -dimethylphenol was obtained.

[III] 5 - § Mi Bruno - 2, 4, 7 - Application Benefits main Chirube Nzofu run-Preparation of (compound of the general formula (3) R i - - RZ ^ RS CH ^ R 5 = H)

4—Amino 1 2— (2—Cro mouth 1 2—Propaninole) 1,3,6—Dimethyltinole 6) obtained in 200 ml of flask with 6. To the mixture were added 00 g (28.4 mmol), 47% hydrobromic acid (25 ml) and acetic acid (25 ml), and the mixture was stirred and refluxed for 2 hours. After cooling, 150 ml of ethyl acetate and 100 ml of water were added, and the mixture was neutralized by dropwise addition of an aqueous sodium hydroxide solution. The organic layer was washed successively with water and a saturated saline solution, and then dried over magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure to obtain 4.39R (yield: 88%) of the title 5—amino-1,2,4,7—trimethylbenzofuran as a pale yellow solid. . Melting point: 1 1 1 — 1 1 2 ° C

 ^ -NMR (CDC 13, 5 ppm): 2.22 (3 H, s), 2.39 (3 H, s), 2.42 (3 H, s), 3.40 ( 2 H, bs), 6.28 (1 H, s), 6.42 (1 H, s)

Example 14

5 — Amino 4, 7 — Dichloro 2, 3 — Preparation of dimethinolevene zofuran (compound of general formula (3): F ^ RSCR ³ -R ⁵ = CH ₃ )

[I] 5—Acetinoleamino 1,4,7—Dichloro-1,2, -dimethylbenzofuran (Compound of the general formula (27): R ¹ = R ² = C 1 R ³ = R ⁵ = CH ₃ )

 N- [2,5-Dichloro-4- (2_oxo-1: 1-methylprobosiki) phenyl] acetamide in 10 O ml of flask 2.71 g (9.34 mmol) was added, and 24 ml of concentrated sulfuric acid was added little by little while stirring in an ice water bath. The ice bath was replaced with an oil bath, and the temperature was gradually raised to 100 ° C. After cooling, the reaction solution was poured into ice water, whereupon a gray solid precipitated. After suction filtration, the solid is washed with water and air-dried to give 2.0 g (yield: 79%) of 5-acetinolemino 4,7-dicyclo-1,2,3 -dimethylbenzofuran. Obtained.

“II” 5—Amino 4, 7—Dichloro 1, 2, 3—Dimethyl Preparation of Rubenzofuran (Compound of General Formula (3): R ¹ = R ² = C 1, R ³ = R ⁵ = CH ₃ )

 5-I-acetylinorea 4,7-dichloro-1,2,3-dimethinobenzofran obtained in [I] 1.71 g (6.29 mimol), etano-1 30 ml of Nore and 20 ml of 5N sodium hydroxide aqueous solution were added to 100 ml of flask, and the mixture was stirred and refluxed for 2 hours. The reaction solution was cooled and concentrated under reduced pressure. The brown residue obtained was washed with ice water and saturated saline, and then filtered by suction. The obtained solid was washed three times with water, dried, and dried under the title 5—Amino 4,7—Dichloro-2,3-dimethylbenzofuran yellow solid 1.03 g (Yield 72%) was obtained.

 'H-NMR (CDC 13, <5 ppm): 2.32 (6H, s), 3.31 (2H, bs), 6.64 (1H, s) Example 1 above The following compounds were obtained in the same manner as in Examples 1 to 14. The NMR spectrum data and physical properties of the obtained compound are also shown.

① Compound of general formula (3): R i -iso—C ₃ H ₇ , R ² = R ³ = CH ₃ , R ⁵ = H

Oil

^{n D 2 1 - 9 = 1.} 5 7

'H-NMRCCDC ls, 5 ppm): 1.32 (6 H d), 2.23 (3H, s), 2.42 (3H, s). 3.32 (1H, m), 3.41 (2H, bs :), 6. 2 8 (1 H, s), 6.48 (1 H, s)

② Compound of general formula (3): R i R S- CHR ² = C 1 R ⁵ -H

_{^{X H - NMR (CDC 1 3}} > 5 ppm): 2. 3 4 (3 H, s), 2. 3 9 (3 H, s), 3. 6 8 (2 H, bs), 6. 2 7 (1 H, s), 6.40 (1 H, s)

③ Compound of general formula (3): 1, 1, R ² = CH ₃₀ , R ³ = CH _3> R ⁵ = Η

 'H-NMRCCDC la, 5 ρ ρ m): 2.40 (3 Η, s), 3.68 (2 Η, bs), 3.90 (3 Η, s), 6.38 ( 1Η, s), 6.58 (1Η, s)

化合物 Compound of general formula (3): R i = F, R ² = R ³ = CH 3, R ⁵ = H

_{'H - NMR (CDC 1 3} , ά ppm): 2. 1 5 (3 H, s), 2. 3 9 (3 H, s), 3. 4 4 (2 H, bs), 6. 2 0 (1H, s), 6.34 (1H, d)

化合物 Compound of general formula (3):! ^ ¹ :! ^ ² ^. ! ^ ^ R ³ = R ⁵ = H

_{- NMR (CDC 1 3, δ} ppm): 2. 2 4 (3 H, s), 2. 4 0 (3 H, s), 3. 3 7 (2 H, bs), 6.44 (1H, s), 6.61 (1H, s), 7.47 (1H, s)

化合物 Compound of general formula (3): R '= R ³ = CH ₃ , R ² = iso — to C ₃ H R ⁵ = H

'H-NMRCCDC ls, δ ppm): 1.35 (6H, d), 2.37 (3H, s), 2.38 (3H, s), 3.17 (1H , m), 3.35 (2 H, bs), 6.

3 6 (1 H, s), 6.38 (1 H, s)

化合物 Compound of general formula (3): R ¹ = tert—C ₄ H ₉ , R ² = R ³ = CH ₃ , R ⁵ = H

 ^ -NMRCCDC ls, δ ppm): 1.50 (9H, s), 2.20 (3H, s), 2.40 (3H, s), 3.38 (2H, s) bs), 6.20 (1H, s), 6.

4 0 (1 H, s)

⑧ the formula (3) compounds: R i ^ RS - C 1 , R 3 = C 2 H

₅ , R ⁵ = H

¹ H-NMR (CDC 13, δ ppm): 1.29 (3 H, t), 2.74 (2 H, q) 4.80 (2 H, bs),

6.30 (1 H, s), 6.64 (1 H, s) Example 15

7 — Black mouth 2, 4 — Dimethylinobenzene Zofran 1 5 — Inole Lee Seo thio Shiana preparative (compound of the general formula ^{(4): 1:. 1} , R 2 = R 3 = CH 3, R 5 = H, Y = S) preparation of

 In 20 O ml of eggplant flask, 5 — Amino 7 — Black mouth — 2,4 — Dimethizoleben Zofran 3.92 g (20 mimol), Toluene 62 ml A solution prepared by dissolving 4.24 g (40 milliliters) of anhydrous sodium carbonate in 62 ml of water was added thereto, and the mixture was stirred in a water bath to obtain 1.83 ml of tiophosgene. 4 mmol) was added dropwise. After stirring for 1 hour, the organic layer was separated from the aqueous layer and washed with saturated saline. After the organic layer was dried over magnesium sulfate, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. 7—Cross port—2,4—Dimethylenbenzofuran 1— 4.57 g (yield: 96%, purity: 97%) of isopropyl thiothiocyanate was obtained.

Melting point: 90-91 ° C

_{'H - NMR (CDC 1 3} , δ ppm): 2. 4 4 (3 H, s), 2. 5 0 (3 H, s), 6. 4 3 (1 H, s), 7. 1 0 (1 H, s)

Example 16

7 — Promoter 2, 4 — Dimethyl benzofuran 1 5 — lysothiocyanate (Compound of general formula (4): R i = Br, R ² = R ³ = CH ₃ , R ⁵ = H , Y = S)

5 — Amino 7 — Black mouth 2, 4 — Jim Tilben Zoff Example 15 except that 5-amino 7-bromo 2,4-dimethylbenzofuran 4.82 g (20 milliliters) was used instead of lan Perform the same procedure as in 7-Bromo-2,4-dimethinolenbenzofuran-1.5-g-inoisoisothiocyanate 5.30 g (94% yield, 97% purity) %).

Melting point: 1 2 2 _ 1 2 3 ° C

 H — NMRCDC ", 5 ppm): 2.45 (3H, s), 2.51 (3H, s), 6.45 (1H, s), 7.25 (1H, s) s)

Example 17

7 — Black mouth 1,2,4-Dimethynolebenzofuran 1 5 — Inoleisocyanoate (compound of general formula (4): R ¹ = C 1, R ² = R ³ = CH 3 s R ⁵ = H, Y = O)

 To 200 m1 of eggplant flask, 5 — Amino 1 7 — Black mouth 2, 4 — Dimethylbenzofuran 5.0 g (25.6 mimol), ethyl acetate Add 40 ml, stir under ice-cooling, and mix a mixture of trichloromethinochloroformate 2.16 ml (17,9 mimol) and 10 ml of ethyl acetate. Was added dropwise. After the dropwise addition, the mixture was heated under reflux for 2.5 hours. After removing insolubles by celite filtration, the filtrate was concentrated and the crude product obtained was reconstituted with n-hexane-ethyl acetate.

B says, 7 — Black mouth 1, 2, 4 — Dimethylinobenzene Zofran 5 — 4. O g (71% yield, 95% purity) was obtained as a white solid of Inoleic acid.

Melting point: 80-81 ° C

 'H-NMR (CDC 13.5 ppm): 2.40 (3H, s), 2.49 (3H, s), 6.40 (1H, s), 6.97 (1 H, s)

Example 18

7 _ Bromo 1, 2, 4 — Dimethylinobenzobenzofuran 1, 5 — Inoleisocyanoate (compound of general formula (4): R i -B i ^ R ² = R ³ == CH 3. R ⁵ = H, Y = O)

 5 — Amino 7 — Black mouth _ 2, 4 — Instead of dimethino benzobenzene 5 — Amino 7 — Bromo 1, 2, 4 — Dimethylbenzofuran 4 The same operation as in Example 17 was carried out except that 8 g (20 milliliters) was used, and 7-bromo-2,4-dimethylbenzofuran-15-isolate was obtained. 4. Og (yield 75%, purity 94%) was obtained.

Melting point: 8 5-8 6 ° C

 'H-NMR (CDC 13, <5 ppm): 2.36 (3H, s), 2.49 (3H, s), 6.42 (1H, s), 7.1 1 (1 H, s)

 Example 19

4, 7 — Cyclo mouth 1 2 — Methynorenzofuran 1 5 — yl Preparation of isothiocyanate (compound of general formula (4): R ¹ ! ^ ² -C 1, R ³ = CH ₃ , R ⁵ = H, Y = S)

 5 _ Amino 7-Black mouth 1,2,4-Dimethyl benzofuran Instead of 5-Amino 1,4,7-Dichloro mouth 1 2-Methylbenzofuran 4.32 Except for using g (20 mm), the same operation as in Example 15 was performed to obtain 4,7-dichloro-1 2-methinobenzo-zofran-1-5-inoiso 4.95 g (96% yield) of thiocyanoate was obtained.

Melting point: 103-104 ° C

'H-NMR C C D Cla, <5 ppm): 2.52 (3H, s), 6.53 (1H, s), 7.15 (1H, s) Example 20

7 — Black mouth 1,2,4 — Dimethinolenbenzofuran 1 5 —ylisothiocyanate (Compound of general formula (4): R ¹ = C 1, R ² = R ³ = CH ₃ , R ⁵ = H, Y = S)

5—Amino—7—Chloro 2,4—dimension on a 200-m1 four-necked flask with a dropping funnel, calcium chloride tube, and mechanical stirrer 1.95 g (10 mimol) of tilbenzofuran, 20 ml of toluene and 1,3-diazabicyclo [2.2.2] octane 3.36 g (30 mi) ), And 2.28 g (30 mmol) of carbon disulfide was added dropwise while stirring at room temperature. After dropping, The mixture was stirred at room temperature for 5 hours. The precipitated salt was filtered off with suction and washed with a small amount of toluene. The residue was dried under reduced pressure to obtain 3.75 g (yield: 98%) of dithiolbamate.

 3.75 g (9.78 mimol) of the obtained dithiocarnominate and 40 ml of dry methylene chloride were put into 200 ml of Nasflasco and cooled in an ice-water bath. While stirring, a solution of 0.83 ml (10.8 milliliters) of ethyl chlorocarbonate dissolved in 10 ml of dry methylene chloride was added dropwise. After the addition was completed, the mixture was further cooled and stirred in an ice-water bath for 1.5 hours. Water was added to the reaction solution, and the organic layer was washed successively with water and saturated saline. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to give 7—black mouth—2,4—dimethylbenzofuran-5—ylisothiocyanate, a white solid. 2.21 g (yield 90%, purity 97%) was obtained.

The melting point of the obtained compound and _{^{1 H- NMR (CDC 1 3,}} 6 ppm) values were agreed with those of the compound obtained in Example 1 5.

 The following compounds were obtained in the same manner as in Examples 15 to 20 described above. The NMR data and melting point of the obtained compound are also shown.

① Compound of general formula (4):! ^ ¹ :! ^ ² ^! ^ ³ :. ! ! ^ R ⁵ = H, Y = S Melting point: 8 7-8 8 ° C

 'H-NMR (CDC 13, δ ppm): 2.42 (3H, s), 2.43 (3H, s), 2.46 (3H, s), 6.36 (1 H, s), 6.88 (1 H, s)

② Compound of general formula (4):! ^ ¹ :! ^ ² ^! ^ ³ :. ! ! ^ R ⁵ = H, Y = 0

Melting point: 28-29. C

^{X H - NMR (CDC 1 3} , 5 ppm): 2. 3 5 (3 H, s), 2. 4 0 (3 H, s), 2. 4 4 (3 H, s), 6. 3 3 (1 H, s), 6.72 (1 H, s)

③ Compound of general formula (4): R i-RZC 1, R ³ = CH ₃ , R ⁵ = H, Y = 0

Melting point: 95_96 ° C

^: H-NMR (CDC 13 _> ό ppm): 2.51 (3H, s), 6.50 (1H, s), 7.01 (1H, s)

化合物 Compound of general formula (4): R i ^ iso—C ₃ H ₇ , R ² = R ³ = CH ₃ , R ⁵ = H, Y = S

¹ H-NMR (CDC 13, <5 ppm): 1.32 (6H _: d), 2.34 (3H, s), 2.48 (3H, s), 3.3 5 (1 H, m), 6.36 (1 H, s), 6.93 (1 H, s) Example 2 1

4-(7-1,2,4-dimethinonorbenzofuran-15-ynole)-1-2-methylthiosemicarbazide (Compound of general formula (5): R1 ⁼ C1, R ² = R ³ = R ⁶ = CH ₃ , R ⁵ = H, Y = S)

 To 10 O ml of eggplant flask, add 7 — black mouth 1, 2, 4 — dimethinolenbenzofuran 1 5 — diisoquinone. 1.19 g (5 millimolar) Add 15 ml of toluene and 15 ml of toluene, and stir in a water bath while stirring 0.26 g (5.5 mimol) of monomethylhydrazine in 5 ml of toluene solution. Was added dropwise. After stirring for 1 hour, the precipitated solid was filtered off with suction, washed with a small amount of toluene, dried, and dried. 4_ (7—Cross port—2,4—Dimethylinobenzophenone-5—Innole 1.32 g of 1-methylthiosemicarnozide (94% yield, 92% purity) was obtained.

Melting point: 18 1-18 2 ° C

^{X H - NMR (DMSO - de} , <5 ppm): 2. 3 3 (3 H, s), 2. 5 7 (3 H, s), 3. 6 3 (3 H, s), 5. 2 5 (2H, bs), 6.82 (1H, s), 7.28 (1H, s), 9.90 (1H, bs)

 Example 22

4 1 (7—Bromo-1,2,4—Dimethinolenbenzofuran 1 5 1 2 — methylthiosemicarnozide (a compound of the general formula (5): R i -B r ^ R ² = R ³ = R ⁶ = CH ₃ , R ⁵ = H, Y = S)

 7 — Chloro 2, 4 — Dimethylinobenzophenone 1 5 — Instead of dinoleisothiocyanate 7 — Bromo2, 4 — Dimethylbenzofuran I 5 — レ ソ ソ チ オ シ 一 1. 1. 1. 操作 操作 操作 操作 操作 操作 操作 操作 操作 操作 操作 操作 操作 5 操作 操作 操作 5 操作 5 操作 5 5 操作 操作 5 操作 操作 操作 5 5 5 5 5 5 以外 5 操作 5 5 以外 以外. Dimethylinobenzofuran-1-5-inole) 1-2-methinoretiosemicanolenos and zide 1.55 g (yield 95%, purity 93%) were obtained. Melting point: 180-180 ° C

^{X H - NMR (DMSO - de} , δ ppm): 2. 2 3 (3 H, s), 2. 4 8 (3 H, s), 3. 5 5 (3 H, s), 5. 1 6 (2H, bs), 6.77 (1H, s), 7.29 (1H, s), 9.73 (1H, bs)

Example 23

4 — (7 — chloro 2, 4 — dimethylbenzofuran-1-quinolene) 1 2-methysemicanolenoxide (compound of general formula (5): R ^{1 =} C 1) , R ² = R ³ = R ⁶ = CH ₃ , R ⁵ = H, Y = O)

7 — Black mouth 1, 4 — Dimethyltilben Zofran 1 5 — In place of dilysothiocyanate 7 — Black mouth 1, 2, 4 — Dimethyl benzophenone 5 — In the same manner as in Example 21 except that 110 g (5 millimoles) was used, 4 — (7 — Black mouth — 2, 4 — Dimethylbenzofuran 1-5 — yl) 1 2 — Methinoresemi-force Norrenozide 1. 25 g (94% yield, 93% purity) I got

Melting point: 180-18 1 ° C

'H - NMR (DMSO - d 6, δ ppm): 2. 0 9 (3 H, s), 2. 3 3 (3 H, s), 2. 8 9 (3 H, s), 4. 6 9 (2H, bs), 6.54 (1H, s), 7.59 (1H, s), 8.63 (1H, bs)

Example 2 4

4 1 (7-Bromo 1, 2, 4-Dimethinolene Zofran-1-5-Inole) 1 2-Methinolesemicarnodide (Compound of general formula (5): R ^{1 =} = (Br, R ² = R ³ = R ⁶ = CH ₃ , R ⁵ = H, Y = O)

 7-Black mouth 1, 2, 4-Dimethino benzophenone 5-In place of quinolone isothiocyanate 7-Blomo 2, 4-Dimethino benzophenone One 5 — 1. ソ 1.

Except that 33 g (5 mmol) was used, the same operation as in Example 21 was carried out to obtain 41- (7-bromo-2,4-dimethylbenzofuran-5-a). Sole) _ 2 — Metilsemi Canolenozide 1,

43 g (92% yield, 94% purity) were obtained. Melting point: 19 3 — 19 4 ° C

_{^ - NMR (DMSO - d 6} , 5 ppm): 2. 2 4 (3 H, s), 2. 4 4 (3 H, s), 3. 0 4 (3 H, s), 4. 8 5 (2H, bs), 6.74 (1H, s), 7.86 (1H, s), 8.78 (1H, bs)

Example 2 5

4 — (7 — Black mouth 1, 2, 4 — Dimethyltinole benzofuran 1 5 — Dinole) 1 2 — Methinolethiosemicarnozide (Compound of general formula (5): R ^{1 =} C 1 , R ² RR ⁶ = CHR = H, Y = S)

 10-100 m] in eggplant flask-7-black 2,4-dimethylbenzofuran 5-lysothiocyaniana h 2.0 g (8.4 mimol) And 30 ml of tonoleene, and while stirring in a water bath, 2.20 ml (16.8 mmol) of a 35% aqueous solution of monomethylhydrazine was added dropwise.

 After stirring for 2 hours, the precipitated solid was filtered off with suction, washed with a small amount of toluene, dried and dried. 4 — (7 — 口 D 1-2, 4 — dimethylbenzofuran 1 — 2.27 g (yield: 94%, purity: 9.9%) of 121-methylthiosemicarboxide was obtained.

Example 26

4 1 (2, 4, 7 — Trimethyltinolbenzofuran 1 — 5) One 2 - main Chiruse Mi Karubaji de (compound of the general formula (5): R] ^{= R 2 = R 3 = R} e = CH 3, R 5 = H, Y = 0) the production of [I] off We Ninore 2 , 4, 7 — Trimethyltilbenzofuran — 5 — Preparation of ylcarbamate (compound of general formula (29): R ^ R ^ R ^ CH a. R ⁵ = H)

 5—Amino 2,4,7—Trimethyltin Benzofuran HBr salt in 200 ml of flask 5.12 g (20 mmol) of ethinole acetate 80 ml and 3.95 g (50 mmol) of pyridine were added, and the mixture was stirred while cooling in a water bath. Then, a mixed solution of 3.44 g (22 mmol) of phenyl carbonate and 10 ml of ethyl acetate was added dropwise. After stirring for 2 hours, 50 ml of n-hexane was added, and the precipitated solid was filtered by suction. The solid was washed with water and dried to obtain 5.50 g (yield: 93%) of phenyl 2,4,7-trimethylbenzofuran-15-ylcanomate as a white solid.

[11] 4 — (2, 4, 7 — trimethyl benzophenone 1 5 — yl) 1 2 — methisoresemicarnoxide (a compound of general formula (5): R i R ^ RSRSCHR ⁵ = H, Y = 0)

In 200 ml of flask, the phenyl 2,4,7-trimethylbenzofuran obtained in [I] was added to 5.90 g of quinolecanoate 5.90 g ( 20 mm), acetonitrile 1 To the mixture were added 0. 0 ml and 1.38 g (30 millimoles) of methylhydrazine, and the mixture was stirred at 80 ° C under reduced pressure. After cooling, the reaction solution was concentrated under reduced pressure, and the precipitated solid was washed with a mixed solvent of 10 ml of ethyl acetate and 10 ml of n-hexane, followed by suction filtration. The solid is further washed with a small amount of n-hexane and the title 4 _ (2,4,7—trimethinolebenzofuran 1-5—inole) 1 2—white solid of methylsemicarbazide 3 .84 g (77% yield) were obtained.

Melting point: 1 8 3 — 18 4 ° C

_{XH - NMR (DMSO - d 6} , <5 ppm): 2. 2 7

(3H, s), 2.38 (3H, s), 2.44 (3H, s), 3.14 (3H, s), 4.56 (2H, bs) , 6.40 (1H, s), 7.36 (1H, s), 8.54 (1H, bs)

4 — (7 — Black mouth 1, 2, 4 — Dimethylbenzofuran 1 5 — Innole) 1 1 — Mechinore 1 3 — Trifnoreo lo Metinole 1, 2, 4 — Triazole 5 (1 H) - thio down (. compounds of general formula ^{(6): 1: 1,} R 2 = R 3 = R 6 = CH 3, R 5 = H, Y = S) preparation of

Add 4 — (7 — Black mouth 2, 4 — to 200 ml of flask. Dimethylbenzofuran-15-yl) 1-2-Methylthiosemicanolebazide 4.0 g (14.1 millimonole) and 50 ml of methanol were added and stirred. . 2 8% sodium methoxide solution (4.3 ml, 21.2 millimonole) and 3.35 ml (28.2 millimol) ) Was added successively, and the mixture was stirred at room temperature for 30 minutes and then refluxed for 1 hour. After cooling the reaction solution, 50 ml of toluene was added, and methanol was distilled off under reduced pressure. After washing the toluene layer several times with water, a small amount of insoluble matter was removed by suction filtration, and toluene was distilled off under reduced pressure. A small amount of n-hexane is added, and the precipitated crystals are suction-filtered and dried, and then dried. 4- (7-chloro-2,4-dimethylbenzofuran-15-inole) 1-1-1 Methyl phenol 3 — Trifnorolelomethyl 1, 2,4,1 Triazo phenol 5 (1 H) — Thion white solid 4.85 g (93% yield, purity 93%) 98%).

Comparative Example 2

4 — (7 — Black mouth 2, 4 — Dimethylbenzofuran 1 — 5 — Innole) 1 1 — Mechinore 1 3 — Trif Noreo lo Mechinore 1, 2, 4 — Triazole 5 (1 H) - on-preparation of (compound of the general formula ^{(6) R 1 = C 1} , R 2 = R 3 = R 6 = CH 3, R 5 = H, Y = 0)

7 — Crawl 2, 4 — Dimetries on 100 m 1 flask go Ruben Zofran-1 5 — Izole 2 — Methynoresemicanoleva'zide 2. Add 28 g (8.52 milimonole) and 30 ml of xylene, and stir anhydrously with stirring. Trifluoroacetic acid (1.44 ml, 10.0 millimol) was added dropwise, and the mixture was stirred for 1 hour. 0.19 g (l.0 millimol) of p-toluenesulfonate was added, and the mixture was stirred at 150 ° C for 2 hours. During this time, low-boiling substances distilled out were removed from the system. After cooling, the solvent was distilled off under reduced pressure. The crude product obtained is purified by silica gel column chromatography (developing solvent: n-hexane Z-getyl ether = 2: 1), and 4 — (7 — macropore — 2, 4 —) Dimethinobenzene Benzofuran 1 5 — Innole) 1 1 — Methynole 3 — Trifnoreolo Methynolay 1, 2, 4 — Triazonole 1 5 (1H) — On white solid 2 .15 g (72% yield, 98% purity) were obtained.

Comparative Example 3

4 1 (7 — Black mouth 1, 2, 4 1 Dimethyltinolbenzofuran 1 5 — Innole) 1 1 — Methinoré 3 — Trifluoro Metinole 1, 2, 4 — Triazole 5 (1 ^! H) - oN (formula (6) ^{compounds: R = C 1, R 2} = R 3 = R 6 = CH 3, R 5 = H, Y = 0) preparation of

4 1 (7—Black mouth 2,4—Dimethyltin benzofuran 5—Innole) 1 2—Methyl semi-force 1.73 g of norenozide (6.48 milliliter) and 15 ml of methanol were added and stirred. 2.8 g (9.72 mimol) of sodium methoxide solution in 8% sodium methoxide, 1.16 g (9.72 mi) of ethyl trifluoroacetate Was added successively, and the mixture was stirred at room temperature for 30 minutes and then refluxed for 1 hour. After the reaction solution was cooled, it was subjected to thin-layer chromatography to confirm the product, and it was confirmed that the target product was 4 — (7 — 1,2-, 4-dimethyltinbenzobenzoff). Lan 1 5 — innole) 1 1 — methino 1 3 — trifnorole methino 1, 2, 2, 4-triazole — 5 (1H) — spot equivalent to on A lot of power. Industrial applicability

 The benzene derivative represented by the general formula (1) and the benzofuran derivative represented by the general formulas (2), (3) and (4) of the present invention are represented by the general formula (5) And a benzofuranyltriazole derivative of the general formula (6), which are useful as intermediates for industrially advantageous production of the (thio) semicarbazide derivative represented by .

According to the present invention, in the general formula (5), a benzofuranylthiosemicarbazide derivative (5b) in which Y is a sulfur atom is reacted with an alkyl trifluoracetate, In the general formula (6), there is provided a method for producing a benzofuranyloxo-triazole derivative (6b) wherein Y is a sulfur atom. This method does not require the use of trifluoroacetic anhydride, so that highly corrosive trifluoroacetic acid is not generated and trifluoroacetic acid remaining in the final reaction is not collected and discarded. This method is useful in that it does not have the drawbacks of the conventional method that it does not work.

Claims

The scope of the claims

General formula (1)

[Wherein, the lengths ¹ and ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. 1¾ ³ and 1 ^ ⁴ is a hydrogen atom or a lower alkyl group Te same or different dates. ]

A benzene derivative represented by

2. General formula (1a)

Wherein, R ^la represents a halogen atom, R ^{2 a,} R ^{3 a} and R a each is C i - shows a 4 alkyl group. ]

The benzene derivative according to claim 1, which is represented by:

3. In the presence of a phase transfer catalyst and a base, the general formula

[Wherein, R ¹ and R ² are the same or different and represent a halogen atom. A lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. X represents a halogen atom. The benzene derivative represented by the general formula

[Wherein, the lengths ³ and ⁴ are the same or different and represent a hydrogen atom or a lower alkyl group. ]

A general formula (1) characterized by reacting an oxime represented by

[Wherein, RR ² , R ³ and R ⁴ are the same as above. ]

A method for producing a benzene derivative represented by the formula:

4. In the presence of a phase transfer catalyst and a base, the general formula

[In the formula, R ^la and X represent a halogen atom, and R ^2a represents a C ₄ alkyl group. ]

The benzene derivative represented by the general formula OH

[Wherein, R ^3a and R ^4a represent a C alkyl group. Wherein the oxime represented by the general formula (1a) is reacted:

[Wherein, R ^la , R ² R ^3a and R ^4a are as defined above. A method for producing a benzene derivative represented by the formula: 5 General formula (2)

[In the formula, ¹ and 1 ^ ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. R ³ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group. ]

5 — a dibenzobenzofuran derivative.

Wherein, R ^{1 a} represents a halogen atom, R ^{2 a} and R ^{3 a} is, respectively it C i - ₄ alkyl groups indicates, R ^{5 a} is a hydrogen atom or a C 1 one 3 alkyl group. ]

The 5--2-trovenzofuran derivative according to claim 5, which is represented by the following formula: θ 7

7. A general formula (2) characterized by reacting the benzene derivative (1) according to claim 1 with hydrogen halide.

[Wherein, ¹ and 1 ^ ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. ³ and ⁶ are the same or different and represent a hydrogen atom or a lower alkyl group. ]

A method for producing a 5-dibenzobenzofuran derivative represented by the formula:

8. The general formula (2a), wherein the benzene derivative (la) according to claim 2 is reacted with hydrogen halide.

Wherein, R ^{1 a} represents a halogen atom, R ^{2 a} and R ^{3 a} represents a, respectively it C physician ₄ alkyl group, R ^{5 a} is a hydrogen atom or a C i - shows the 3 alkyl groups. ]

A method for producing a 5-nitrotobenzofuran derivative represented by the formula:

9. General formula (3)

[Wherein, R ¹ and R ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. R ³ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group. ]

5-amino benzofuran derivative represented by

1 0. —General formula (3a)

Wherein, R ^la is indicates a halogen atom, scale ²⁴ and 1 ^ ³ 3, respectively it C i - Indicates ₄ alkyl group, R ^{5 a} is a hydrogen atom or a C i - shows the 3 alkyl groups. ]

The 5-amino benzofuran derivative according to claim 9, which is represented by the following formula:

The 5-nitrobenzofuran derivative according to claim 5 Wherein (2) is reduced or catalytically reduced in a system of a metal-noic acid;

[Wherein, ¹ and ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. ³ and ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group. ]

A method for producing a 5-amino benzofuran derivative represented by the formula:

1 2. A method for producing a 5- (aminobenzobenzofuran derivative) according to claim 11, wherein the 5—2 trobenzofuran derivative (2) according to claim 5 is catalytically reduced. Production method.

1 3. A general formula (3a) characterized in that the 5-nitrobenzofuran derivative (2a) according to claim 6 is reduced or catalytically reduced in a metal acid system. )

(3 a)

Wherein, R ^la represents a halogen atom, R ^{2 a} and R ^{3 a} is their respective C i - indicates ₄ alkyl group, R ^{6 a} is hydrogen atom or a C 1 - shows a 3 alkyl group. ]

Method for producing 5-amino benzofuran derivative represented by the formula: 1 4. General formula (4)

Wherein 1 ^ ¹ and 1¾ ² are the same or halogen atom me different, a lower alkyl group, lower haloalkyl group, lower alkoxy group or Shiano group. ³ and ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. Y represents an oxygen atom or a sulfur atom. ]

A benzofuranyliso (chio) cyanate derivative represented by

1 5. — General formula (4a)

Wherein, R ^{1 a} represents a halogen atom, R ^za and R ^{3 a} is, respectively it C - indicates 4 alkyl group, R "is indicates hydrogen atom or a C one 3 alkyl group, Y is an oxygen atom Or a sulfur atom.] The benzofuranyliso (thio) cyanate derivative according to claim 14, which is represented by the following formula:

Wherein 1 ^ ¹ and 1¾ ² represents a halogen atom, a lower alkyl group, lower haloalkyl group, lower alkoxy group or Shiano group the same or different. Scales ³ and ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. ]

15. The benzofuranilo thiothiocyanate derivative according to claim 14, represented by the formula:

1 7. A general formula (4) characterized by reacting the 5-amino benzofuran derivative (3) according to claim 9 with phosgene or thiophosgene.

[Wherein, R ¹ and R ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. The scales ³ and 1 ^ ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. Y represents an oxygen atom or a sulfur atom. ]

A method for producing a benzofuraniliso (thio) cyanate derivative represented by the formula:

1 8. A general formula (4a) characterized by reacting the 5-amino benzofuran derivative (3a) according to claim 10 with phosgene or thiophosgene.

Wherein, R ^{1 a} represents a halogen atom, R ^{2 a} and R ^{3 a} is, respectively it C, - 4 alkyl group indicates, R ^{5 a} is a hydrogen atom or a C i - shows the 3 alkyl groups. Y represents an oxygen atom or a sulfur atom. A method for producing a benzofuraniliso (thio) cyanate derivative represented by the formula:

1 9. The 5- (aminobenzobenzofuran derivative (3) according to claim 9 is reacted with carbon disulfide in the presence of a base, and then reacted with a halogen-based oxidizing agent. , The general formula (4b)

Wherein ¹ and 1¾ ² are the same or halogen atom me different, a lower alkyl group, lower haloalkyl group, lower alkoxy group or Shiano group. ³ and 1 to ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. ]

A method for producing a benzofuranilo sothiocyanate derivative represented by the formula:

20. The benzofuranyliso according to claim 14 04 Cyanate derivative (4) and general formula

R ⁶ NHNH 2

[In the formula, R ⁶ represents a lower alkyl group. ]

General formula (5) characterized by reacting with an alkylhydrazine represented by

[Wherein, ¹ and 1 ^ ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. 1 ^ ³ and ⁵ are the same or different and represent hydrogen or a lower alkyl group. Y represents an oxygen atom or a sulfur atom. R ⁶ is the same as above. ]

A method for producing a benzofuranyl (thio) semicarnozide derivative represented by the formula:

2 1. The benzofuranyliso (thio) cyanate derivative (4a) according to claim 15 and a general formula

R ^{6 a} NHNH 2

[Wherein, R ^6a represents a C ₄ alkyl group. ]

Reacting with an alkylhydrazine represented by General formula (5a)

Wherein, R ^{1 a} is Ri Oh halogen atom, R ^{2 a} and R ^{3 a} is Ri, respectively it C i ₄ alkyl der, R represents a hydrogen atom or a C i - are three alkyl groups der, Y Is an oxygen atom or a sulfur atom.

R ^6a is the same as above. ]

A method for producing a benzofuranyl (thio) semicarbazide derivative represented by the formula:

2 2. General formula (5b)

(5 b)

[Wherein the lengths ¹ and ² are the same or different and represent a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group or a cyano group. The scales ³ and ⁵ are the same or different and represent a hydrogen atom or a lower alkyl group. R ⁶ represents a lower alkyl group. ] Wherein a benzofuranylthiosemicarbazide derivative represented by the following formula is reacted with an alkyl triacetate: (6b)

[Wherein, RR \ R ³ , R ⁵ and R ⁶ are the same as above. A method for producing a benzofuranyloxotriazole derivative represented by the formula:

2 3. — General formula (5c)

[Wherein, R ^lc represents a halogen atom, R ^{2 e} , R ^{3 e} and R ^{6 e} each represent a Ci- ₄ alkyl group, and R ^{5 e} represents a hydrogen atom or a Ci- ₃ alkyl group. . Wherein the benzofuranyl thiosemicarbazide derivative represented by the general formula (6c) is reacted with an alkyl trifluoracetate.

[Wherein, R ^lc , R ^2c , R ³ R ^5e and R ^6c are the same as described above. ] A method for producing a benzofuranyloxotriazole derivative represented by the formula: