WO2003082860A1 - Processes for producing indole compound - Google Patents

Abstract

A process for producing an indole compound represented by the formula (2) which comprises reducing a 2-nitrobenzylcarbonyl compound represented by the formula (1) (wherein R1 and R2 each independently represents hydrogen or optionally substituted alkyl or phenyl; R3 represents alkyl, halogeno, etc.; and n is an integer of 0 to 4) with a hydrogen donor in the presence of a reduction catalyst, characterized in that an acylating agent and a base are caused to coexist in the reduction step; the process in which the 4-fluoro-2-nitrophenylacetone produced from 2-chloro-4-fluoronitrobenzene is used; and a process for producing a sulfamoyltriazole compound which comprises reacting the indole compound with 1-(N,N-dimethylsulfamoyl)-3-chlorosulfonyl-1,2,4-triazole.

Description

 Description Method for producing indole compound

 The present invention relates to a method for producing an indole compound useful as various fine chemical intermediates including physiologically active substances such as pharmaceuticals and agricultural chemicals, and a novel 2--2-mouth phenylaceton as an intermediate in the production method. For compounds. Technology background

 The following methods are known as methods for producing indole compounds.

 DE 262327 gives an example of reacting N-o-tolyl-acetoamide with barium oxide at 36 to give 2-methylindole. Similarly, sodium methoxide and sodium amide (Buricin de la Lavob Societe Cimiche de France) (Bui 1. Soc. Chim. Fr.), 4, 1039 (1924)) There are examples using organic synthesis (Org. Syn.), 27, 94 (1942)), but all require high reaction temperatures, large amounts of by-products, and low yields.

 There is an example in which phenylhydrazone of acetone is reacted with sodium hydroxide at 240 to give 2 _methylindole, but the yield is low due to many by-products (Chem. Be r. ), 81, 266, 270 (1948)).

 2-Nitro-1- (2-nitrophenyl) propene is reacted with hydrogen in the presence of 10% activated carbon-supported palladium catalyst to produce 2-methylindole, but the yield is 81% (heterogeneous). Heterocycles, 55, 95 (2001)).

The reaction of aniline with tris (2-hydroxypropyl) amine hydrochloride in the presence of tin dichloride, ruthenium trichloride, and triphenylphosphine with 18 O: yields 2-methylindole in a yield of 64%. Low yield (Tetrahedron, 3321 (2001)). As a method for producing from 2-trobenzylcarbonyl compound, for example, 2-nitrophenethylacetone is reduced with iron in the presence of acetic acid and sodium acetate to give 2-methylindole in a yield of 68%. The resulting description (Journal of Organic Chemistry (J. Org. Chem.), 48, 2066 (1983)) and the reaction of 4-fluoro-2-nitofenylphenylacetone with zinc in an aqueous acetic acid solution. (Japanese Patent Application Laid-Open No. 47-38963) that a 6-fluoro-2-methylindole was obtained with a yield of 95%. And have a large environmental impact. Further, the latter mentions that a similar product can be obtained by catalytic reduction in the presence of a catalyst such as palladium, Raney nickel, platinum, etc., but there is no corresponding example.

 As described above, there is no example of producing a 2-substituted indole compound in a single step with a high yield by an environmentally friendly method using a reducing catalyst such as a supported noble metal catalyst and a hydrogen donor. In practice, when 4-fluoro-2-nitrophenylacetone is reduced with hydrogen gas in the presence of a palladium catalyst on activated carbon, 6-fluoro-2-methylindoline is produced as a by-product, and the yield of 6-fluoro-2-methylindole is increased. Is about 70%. This is because 1-hydroxy-2-methylindole produced as a reaction intermediate has a tautomeric relationship with 2-methylindolenine Ν-oxide, and this 2-methylindolenine ォ -oxide is further reduced. This is to produce 6-fluoro-2-methylindrin.

Examples of the synthesis of 1-hydroxy-2-alkylindole, a reduction intermediate, include the synthesis of 1-hydroxy-2-methylindole by reducing 2-nitrophenylacetone with zinc and ammonium chloride (Brutin de La Rob Societe Chimike * de * France (Bu i 1. Soc. Chim. Fr.), 1 296 (1967)) and electrochemical a— (o-hydroxyaminophenyl) ) There is a synthesis from propene (Bulchin de la Rob, Society, Cimique, France) (Bu 11 1. Soc. Chim. Fr.), 121 (1974)). It is also known that 1-hydroxy-12-methylindole has a tautomeric relationship with 2-methylindolenin peroxoside (Journal of the Chemical Society (J. Chem. Soc.), 1067 (1970)), ぺ Spectroch im. Acta, 23, 717 (1967)) „

 Then, as an example of the acylation, 1-hydroxy-2-phenylindole or 1-benzoyloxy-2-phenylindole is synthesized from 1-hydroxy-2-phenylindole with acetic anhydride or benzoyl chloride. Examples ((Journal of the Chemical Society (J. Chem. Soc.), 3466 (I960)) and 1-Acetoxy 2 _methylindole (Burctin de la ブ ob) There is an example of synthesis of "Sosaikote", "Chimike" and "De" France (Bull. Soc. Chim. Fr.), 3040 (1973).

 Further, as an example of a reduction reaction from the acylated product, 1-benzoyloxy-2-phenylindole or 1-acetoxy-3-cyano-2-phenylindole is reduced in ethanol with a palladium catalyst supported on activated carbon. Examples of obtaining 2-phenylindole or 3-cyano-2-phenylindole (Journal of the Chemical Society (J. Chem. Soc.), 34 66 (1960 However, this method requires multiple steps to obtain the target indole compound from the starting 2-nitrobenzyl carbonyl compound, and is not an efficient method.

 In addition, various compounds and production methods of phenylacetone compounds have been developed as important intermediates in the production of fine chemicals. 2-Ditrophenyl-2-acetone compounds are important intermediates in the production of various heterocyclic compounds due to having two kinds of functional groups, ie, di- and carbonyl groups in the molecule. Luaceton (Tetrahedron Letters, 42, 1387 (2001)), 4-chloro-2-nitrophenylacetone (Chemical 'and Pharmaceutical Burtin) ( Chem. Pharm. Bull.), 17, 605 (1969)) and 4-fluoro-2-nitrophenylacetone (Japanese Patent Laid-Open No. 47947/1987).

In particular, various indole compounds derived from this group of compounds have been synthesized mainly from physiologically active compounds since ancient times.

International Patent Application Publication No. WO 99/21851 The usefulness of a group of compounds using the obtained indole compounds as fungicides is described. In particular, 6-fluoro-2-methylindole is one of the intermediates for the production of highly useful indole compounds, and the production of 3- (4-fluoro-2-nitrophenyl) acetone which is a correspondingly important raw material As a method, a method described in the above-mentioned JP-A-47-38947 is known. However, since multiple steps are required, a simpler and more excellent production method is required.

In addition, by reacting an indole compound with 1- (N, N-dimethylsulfamoyl) -3-chlorosulfonyl-1,2,4-triazole, International Patent Application Publication No. WO99 / 21851 is disclosed. As a method for producing a fungicide described in bread fret, in addition to the pamphlet of International Patent Application Publication No.W09921851, a method described in Japanese Patent Application Laid-Open No. 2001-187787 is described. Although it is known, a production method with a higher yield is required.

 An object of the present invention is to provide a method for producing an industrially advantageous indole compound and an intermediate thereof. Disclosure of the invention

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, in the step of reducing a 2-2 trobenzyl carbonyl compound with a hydrogen donor in the presence of a reduction catalyst, the coexistence of an acylating agent and a base Indole compounds are found to be able to be produced in a single step with good yield, and at the same time, they are important raw materials for the production of 6-fluoro-2-methylindole, one of the indole compounds. As a result of studying various methods for producing acetone, a novel 2--2-toluene phenylacetone compound as a key intermediate and 3_ (4-fluoro-2-nitrophenyl) via the compound were investigated. A new method for producing acetone was found, and the indole compound was converted to an alkali metal salt, followed by 1- (N, N-dimethylsulfur Yl) — 3-chlorosulfonyl — 1,2,4-triazole to produce a compound described in International Patent Application Publication WO99 / 21851 Pamphlet in good yield. They have found and completed the present invention. That is, the present invention provides the following [1] to [23]

 (1) Equation (2)

(Wherein, and R ₂ each independently represent a hydrogen atom, an optionally substituted alkyl group or a phenyl group, and R ₃ represents an optionally substituted alkyl group, a phenyl group, an alkoxy group Represents an alkoxycarbonyl group or a halogen atom, and n represents an integer of 0 to 4.)

The indole compound represented by the formula is converted into an alkali metal salt, and then reacted with 1- (N, N-dimethylsulfamoyl) -3-chlorosulfonyl-1,2,4-triazole to obtain the formula (3 )

(In the formula, R ₂ , R ₃ and n represent the same meaning as described above.)

A method for producing a sulfamoyl triazole compound represented by the formula:

 [2] Equation (1)

(Wherein, and R ₂ are each independently a hydrogen atom or an optionally substituted R ₃ represents an alkyl group, a phenyl group, an alkoxy group, an alkoxycarbonyl group, or a halogen atom which may be substituted; n represents an integer of 0 to 4; )

In the step of reducing the 2-nitrobenzylcarbonyl compound represented by the formula (2) with a hydrogen donor in the presence of a reduction catalyst, the above formula (2) produced by coexisting an acylating agent and a base is used. The production method according to [1], wherein the indole compound represented is used.

 [3] The step of reducing the 2-nitrobenzylcarbonyl compound represented by the above formula (1) with a hydrogen donor in the presence of a reducing catalyst is characterized by coexisting an acylating agent and a base. A method for producing an indole compound represented by the above formula (2).

 [4] The method for producing an indole compound according to claim 3, wherein the acylating agent is an organic acid anhydride.

 [5] The method for producing an indole compound according to [3], wherein the acylating agent is acetic anhydride.

 [6] The method for producing an indole compound according to [3], wherein the base is an alkali metal salt or an alkali metal hydroxide.

 [7] The method for producing an indole compound according to [3], wherein the base is an organic acid salt, carbonate, hydrogencarbonate or hydroxide of an alkali metal.

 [8] The method for producing an indole compound according to [3], wherein the reduction catalyst is a supported noble metal catalyst.

 [9] The method for producing an indole compound according to [3], wherein the reduction catalyst is palladium on activated carbon.

 [10] The method for producing an indole compound according to [3], wherein the hydrogen donor is hydrogen gas.

[11] After halogenating an indole compound represented by the above formula (2) (wherein R ₂ represents a hydrogen atom), and then converting it to an alkali metal salt, 1- (N, N-dimethylsulfur) is obtained. Famoyl) represented by the above formula (3) (wherein R ₂ represents a chlorine atom, a bromine atom or an iodine atom) by reacting with 13-chlorosulfonyl-1,2,4-triazole. A method for producing a sulfamoyltriazole compound to be used.

[1 2] The indole compound is 2-methyl-6-fluoroindole [11] The production method according to [1].

 [13] The method according to claim 12, wherein the halogenation is bromination.

 [14] The method according to [13], wherein the bromination is caused by sodium hypobromite.

 [15] The production method according to [13], wherein the bromination is caused by bromine in the presence of sodium hydroxide.

 [16] 3-Methyl-6 produced by coexisting an acylating agent and a base in the step of reducing 3- (4-fluoro-2-ditrophenyl) acetone with a hydrogen donor in the presence of a reduction catalyst. —The production method according to [12], wherein a fluoroindole is used.

 [17] In the step of reducing 3- (4-fluoro-2-nitrophenyl) acetone with a hydrogen donor in the presence of a reducing catalyst, the method is characterized by coexisting an acylating agent and a base. —Methyl— 6-Fluoroindole production method.

 [18] Formula (I)

(Wherein, R represents a methyl group, a methoxy group, or an ethoxy group.) 3- (4-monofluoro-2) produced by treating a 2-nitrophenylacetone compound represented by the following formula in the presence of an acid or a base. —Ditrophenyl) The production method according to [16], wherein acetone is used.

 [19] Use of 3- (4-fluoro-2-nitrophenyl) acetone produced by treating the 2-nitrophenylacetone compound represented by the formula (I) in the presence of an acid or a base. 17] The production method described above.

[20] A method for producing 3- (4-monofluoro-2-nitrophenyl) acetone by treating a 2-nitrophenylacetone compound represented by the above formula (I) in the presence of an acid or a base. [21] Formula (II)

(Wherein, X represents a fluorine atom, a chlorine atom or a bromine atom).

(Wherein, R represents a methyl group, a methoxy group or an ethoxy group.) A 2-nitrophenylacetone compound represented by the above formula (I) produced by reacting the compound with a dicalponyl compound represented by the following formula: The method according to [18], [19] or [20].

 [22] A method for producing a 2-nitrophenylacetone compound represented by the formula (I) by reacting a nitrobenzene represented by the formula (II) with a dicarbonyl compound represented by the formula (III) .

 [23] A 2-nitrophenylacetone compound represented by the formula (I).

About.

 The method for producing the indole compound represented by the formula (2) from the 2-nitrobenzylcarbonyl compound represented by the formula (1) will be described in more detail.

(Wherein 1 ^ and R ₂ each independently represent a hydrogen atom, an optionally substituted alkyl group or a phenyl group, and R ₃ represents an optionally substituted alkyl group, a phenyl group, Represents an alkoxy group, an alkoxycarbonyl group or a halogen atom, and n represents an integer of 0 to 4.) In the step of reducing the 2-nitrobenzyl carbonyl compound represented by the formula (1) with a hydrogen donor in the presence of a reduction catalyst, the intermediate compound of formula (3)

で表される 1—ヒドロキシインドールおよびその互変異性体の式 （4 )

Formula of 1-hydroxyindole and its tautomer represented by the formula (4)

The indolenine N-oxide represented by the formula is acylated to give the formula (5)

(Wherein, R ₄ represents an acyl group of the above-mentioned acylating agent.) A compound represented by the formula (2):

This is a method for producing an indole compound represented by the formula:

According to the present invention, an indole compound can be produced at a high yield with almost no by-product of an indoline compound as a reduction by-product. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the compound to which the present invention is applied include a 2-nitrobenzyl carbonyl compound represented by the formula (1) and an indole compound represented by the formula (2), and R ₂ are each independently a hydrogen atom, R ₃ represents an optionally substituted alkyl group, a phenyl group, an alkoxy group, an alkoxycarbonyl group or a halogen atom, and n represents 0 to 4. And R ₂ each independently represents a hydrogen atom or an optionally substituted alkyl group; R ₃ represents a halogen atom; and n represents an integer of 0 or 1. Represents a methyl group, R ₂ represents a hydrogen atom, R ₃ represents a fluorine atom, and n represents an integer of 0 or 1. The 2-nitrobenzylcarbonyl compound represented by the formula (1), which is a starting material of the present invention, is produced by a known method. For example, 2-nitrophenylacetone (Tetrahedrone's Letters, 42, 1387 (2001)), 4-chloro-2-nitrophenylacetone (chemical's) Pharmaceutical Burtin) (Chem. Pharm. Bull.), 17, 605 (1969)), and 4-fluoro-2-nitrophenylacetone (JP-A-47-38947).

 2. The reagents and reaction conditions used in the step of reducing the 12-trobenzylcarbonyl compound are as follows, but are not limited thereto.

 As the acylating agent, an organic acid anhydride having a reactive active acyl group is effective, and acetic anhydride, trifluoroacetic anhydride, propionic anhydride, butyric anhydride, cabronic anhydride, crotonic anhydride, maleic anhydride, and benzoic anhydride. An acid, succinic anhydride, or a mixed acid anhydride synthesized from acetic anhydride and formic acid is preferred, and a mixture of these can also be used. Of these, acetic anhydride is particularly preferred in terms of economy.

 The amount of the acylating agent to be used is preferably 0.01 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the 2-nitrobenzylcarbonyl compound.

Examples of the base include organic bases such as amine pyridine and organic acid salts, carbonates, bicarbonates, phosphates, sulfites, and hydroxides of metals such as alkali metals and alkaline earth metals. And inorganic bases such as oxides, but preferably reacts with an organic acid salt of an alkali metal or an organic acid anhydride or an organic acid generated therefrom in a reaction solution to form an organic acid salt of an alkali metal. Bases such as carbonates, bicarbonates, and hydroxides of alkali metals are exemplified. Of these, sodium formate, potassium formate, sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and the like are particularly preferable. Mixed use of these bases is also possible.

 The amount of the base used is preferably from 0.01 to 5 mol, more preferably from 0.1 to 2 mol, per 1 mol of the 2-nitrobenzylcarbonyl compound.

 As the reduction catalyst, a metal catalyst such as a nickel catalyst, a palladium catalyst, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst, which are usually used for hydrogenation, are preferable. Among them, a supported noble metal catalyst is particularly preferable, and palladium on activated carbon is more preferable in terms of economy.

 The amount of the reduction catalyst to be used is preferably 0.01% to 50%, more preferably 1% to 10%.

 Examples of the hydrogen donor include, in addition to hydrogen gas, sodium formate, potassium formate, ammonium formate, sodium phosphite, potassium phosphite, potassium diphosphite, sodium diphosphite, etc. which can be a hydrogen donor in the reaction system. Of these, hydrogen gas is particularly preferred in terms of economy.

 The amount of the hydrogen donor to be used is 2 to 5 mol, preferably 3 to 4 mol, per 1 mol of the 2-nitrobenzylcarbonyl compound.

The solvent is not particularly limited as long as it is inert to the reaction. For example, aromatics such as benzene, toluene, xylene, getyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane Ethers such as tan, diethylene diol glycol dimethyl ether, esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, ethyl propionate, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone , Hydrocarbons such as hexane, heptane, octane, and nonane; organic acids such as formic acid, acetic acid, and propionic acid; N, N-dimethylformamide; N, N-dimethylacetate Examples thereof include polar solvents such as amide and N-methylpyrrolidone, and water, and a mixed solvent thereof can also be used.

 The amount of the solvent to be used is preferably 1 to 20 times, more preferably 3 to 10 times the amount of the 2-nitropentylcarbonyl compound.

 The reaction is carried out by reacting a mixture of a 2-nitrobenzylcarbonyl compound, an acylating agent, a base, a reduction catalyst and a solvent with a hydrogen donor.

 The reaction can be carried out at a temperature ranging from a low temperature of room temperature or lower to several hundred degrees, preferably from room temperature to a boiling point of the reaction solvent or lower.

The reaction can be carried out under normal pressure to a high pressure of 100 kg / cm ² or the like, but it is preferably in the range of normal pressure to 10 kg / cm ² , and preferably as a hydrogen partial pressure. Is in the range of 0.01 to 10 kg / cm ² , and the higher the pressure, the faster the reaction.

 The reaction time is affected by the stirring speed, and the reaction is completed within 4 to 50 hours under normal pressure under normal stirring conditions and within several hours under pressurized conditions.

 As a method for treating the reaction solution after the reaction, a solution of the indole compound can be obtained by removing the reduction catalyst by filtration and then washing the reaction solution with water. The reagents and by-products used in the reaction can be removed by washing the reaction solution with an alkaline aqueous solution such as sulfuric acid and hydrochloric acid. The recovered reduction catalyst can be used over and over again without being poisoned.

 The novel 2-nitofene phenylaceton compound provided by the present invention has the formula (I)

(In the formula, R represents a methyl group, a methoxy group, or an ethoxy group.)

The novel 2-nitrophenylacetone compound has a keto-enol tautomer, which can be observed in a mixed form by ordinary ¹ H-NMR. In the present application, the structure of the formula (I) is unified as including the enol form.

In addition, the above 2-nitrophenylacetone compound is

Equation (I I)

(Wherein X represents a fluorine atom, a chlorine atom or a bromine atom.) And a nitrobenzene represented by the formula (III)

(Wherein R represents a methyl group, a methoxy group or an ethoxy group.) The compound of the formula (III) can also be produced by a novel method by reacting a dikarponyl compound represented by the formula: The reaction described in the same manner as above is usually performed in the presence of a base.

 Various bases can be used for the reaction, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, Various substances such as potassium bicarbonate, lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium isopropoxide, and potassium tert-butoxide are included, but the operability of the reaction and the economical efficiency For example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like are preferable. These bases can be used alone or in combination.

 The amount of the base to be used is generally 0.3 to 10 mol, particularly preferably 0.5 to 5 mol, per 1 mol of the dicarbonyl compound of the formula (III).

It is also possible to add an additive to the reaction system to make the reaction proceed smoothly. . Additives include tetramethylammonium chloride, tetramethylammonium chloride, tetramethylammonium chloride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium bromide, tetraethylammonium chloride Zide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltolylchloride Quaternary ammonium salts such as thiammonium bromide, triphenylmethylphosphonium chloride, triphenylmethylphosphonium chloride, triphenylmethylphosphonium chloride, triphenylmethylphosphonium chloride, triphenylarylphosphonate Phosphonide such as mozide, triphenylphenylphosphonium bromide, triphenylphenylphosphonium bromide, tetraphenylphosphonium methoxide, tetraphenylphosphonium bromide, tetraphenylphosphonium bromide, etc. Salt and the like.

 The amount of these additives is usually 0.001 to 1 mol, preferably 0.001 to 0.5 mol, per 1 mol of the dicarbonyl compound of the formula (III).

The reaction is preferably performed by diluting with a solvent in order to smoothly carry out the reaction including the dispersion and mixing of the reagents used in the reaction. The solvent used in the reaction is not particularly limited as long as it is an inactive solvent in the reaction. For example, dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, dimethoxymethane, diethoxymethane, and ethylene glycol dimethyl ester Ethers such as ethylene glycol dimethyl ether, ethylene glycol dibutyl ether, diethylene diol glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, 1,4-dioxane, and methanol , Ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, 2-methyl-2-propanol, methyl-solvent, ethyl-solve, i-solvent Alcohols such as ropyl cellosolve, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol monobutyl ether, cyclohexanol, benzyl alcohol, pentane, hexane, cyclohexane, methylcyclohexyl Aliphatic hydrocarbons such as sun, heptane, octane, decane, benzene, and toluene

Benzene, xylene, cyclobenzene, o-cyclobenzene, m-cyclobenzene, p-cyclobenzene, nitrobenzene, aromatic hydrocarbons such as tetrahydronaphthalene, nitriles such as acetonitrile and propionitrile, and acetic acid Esters such as methyl, ethyl acetate, butyl acetate, and ethyl propionate; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; 1,3-dimethylimidazolide Ureas such as non-, N, N, N ', N'-tetramethyl urea, iodium-containing polar solvents such as dimethyl sulfoxide and sulfolane, pyridine, 2-picoline, 3-picoline, 4-picoline, 5-ethyl-1 — Pyridines such as picolin and water; These can be used alone or in combination.

 This reaction can be performed in a wide temperature range. In consideration of economical production, a preferable temperature range is usually 0 to 150, particularly preferably 10 to 100.

 The reaction time varies depending on the amount, concentration, reaction temperature, etc. of the reagent used, but conditions are usually set so that the reaction is completed within a range of 0.1 to 200 hours, preferably 1 to 70 hours. preferable.

 After completion of the reaction, the solvent is distilled off if necessary, and then the crude reaction product is extracted by adding water and a solvent immiscible with water, and then subjected to ordinary methods such as distillation, recrystallization, and column chromatography from the organic layer. As a result, it is possible to purify and isolate the desired 2-nitrotrophenylasetone compound of the formula (I).

 The 2-nitrophenylacetone compound of the formula (I) obtained by the above reaction can be treated in the presence of an acid or a base to give an important intermediate such as indole production. 2--2-trophenyl) Can be easily derived into acetone.

Various bases can be used for the reaction, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate , Potassium bicarbonate, etc., but from the viewpoint of reaction operability, economical efficiency, etc. Lium and potassium hydroxide are preferred.

 Examples of the acid that can be used in this reaction include mineral acids such as sulfuric acid, nitric acid, and hydrochloric acid, aliphatic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and benzenesulfonic acid. Examples thereof include acids and organic sulfonic acids such as toluenesulfonic acid. From the viewpoint of practicality and economy, it is preferable to use sulfuric acid and hydrochloric acid alone or in combination with other acids based on these.

 The base or acid is usually used in an amount of 0.01 to 50 mol, preferably 0.1 to 20 mol, per 1 mol of 2-nitrophenylacetone of the formula (I).

The reaction is preferably performed by diluting with a solvent from the viewpoint of operability. The solvent used for the reaction is not particularly limited as long as it is an inert solvent for this reaction.Examples include getyl ether, methyl-t-butyl ether, tetrahydrofuran, dimethoxymethane, ethoxymethane, ethylene glycol dimethyl ether, and ethylene. Ethers such as glycol getyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, 1,4-dioxane, methanol, ethanol, 1- Propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, 2-methyl-12-propanol, methylaceto-solve, ethylsil-solve, i- Ropyrcellosolve, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, cyclohexanol, alcohols such as benzyl alcohol, acetone, methyl ethyl ketone, diethyl ketone, 2-pentanone, methyl isobutyl ketone, cyclohexane Ketones such as xanone, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, methylcyclohexane, heptane, octane, and decane; halogenated hydrocarbons such as chloroform, dichloroethane, and tetrachloroethylene; benzene , Toluene, xylene, benzene, o-dichlorobenzene, m-dichlorobenzene, ρ-dichlorobenzene, nitrobenzene, tetrahydronaphthalene, etc. Aromatic hydrocarbons Motorui, formic acid, acetic acid, organic acids or water, such as propionic acid. These are Can be used alone or in combination.

 This reaction can be performed in a wide temperature range. However, in consideration of economical production including the use amount of the reaction reagent, a preferable temperature range is usually 20 to 200: particularly preferably 50 to 150. .

 The reaction time varies depending on the amount, concentration, reaction temperature, etc. of the reagents used, but conditions are usually set so that the reaction is completed within a range of 0.1 to 50 hours, preferably 1 to 30 hours. preferable.

 After completion of the reaction, the solvent is distilled off, if necessary, and then the desired product is directly obtained by distillation, or water and a solvent that is immiscible with water are added to the crude reaction product, washed thoroughly, and distilled from the organic layer. It is possible to purify and isolate the target 3- (4-fluoro-2-nitrophenyl) acetone by performing a conventional method such as chromatography.

 The reaction of the above two steps of the present invention can be continually operated, and there is a great merit such as an improvement in productivity.

 For example, after the completion of the reaction in the first step, if a solvent that freely dissolves in water is used, the solvent is distilled off and replaced with a solvent that does not mix with water. Then, water is added to extract the new intermediate 2-nitrophenylacetone compound into an organic solvent. If further purification is required here, the compound is transferred from the organic solvent solution containing the 2-nitrophenylacetone compound to the aqueous solution with the required amount and concentration of an alkaline aqueous solution, then acidified, and then the organic solvent is newly added. And the compound is again dissolved in an organic solvent. Then, the desired 3- (4-fluoro-2-nitrophenyl) acetone can be obtained in good yield by directly reacting the solution containing the 2-nitrophenylacetone compound or by concentrating the solution and adding an appropriate acid or base. Can be obtained at According to this method, the two-step reaction can be carried out by a continuous operation substantially in a solution state without using a technique such as recrystallization or chromatography.

Converting the indole compound represented by the formula (2) into an alkali metal salt, followed by reacting with an 1- (N, N-dimethylsulfamoyl) -3-chlorosulfonyl-1,2,4-triazole compound; From equation (3)

で表される化合物を製造することができる。

Can be produced.

 The compound represented by the formula (3) is a fungicide described in International Patent Application Publication No. WO99Z21851 Panfret.

 As a method for converting the indole compound represented by the formula (2) into an alkali metal salt, for example, a method of stirring with an alkali metal compound in a solvent can be mentioned.

 Examples of the solvent at that stage include cyclic or non-cyclic solvents such as getyl ether, dipropyl ether, diglyme, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol getyl ether, tetrahydrofuran, tetrahydropyran, and 1,4-dioxane. Cyclic ether solvents are mentioned.

 Alkali metal compounds include sodium hydroxide, sodium hydroxide hydroxide and other alkali metal hydroxides, sodium carbonate and potassium carbonate metal such as lithium carbonate, sodium methoxide, potassium—t— Alkoxides such as butoxide, sodium hydride and the like.

 At that stage, in order to bias the equilibrium in the reaction system toward the metal salt of indole, it is preferable to carry out the reaction while removing water, acid, alcohol, etc. derived from the alkali metal compound generated during the reaction out of the system. However, from such a viewpoint and from an economic viewpoint, the alkali metal compound is preferably an alkoxide, for example, sodium methoxide is particularly preferable.

The amount of the alkali metal compound to be used is 0.5 to 1 mol of the indole compound. Although it is 20 mol, 1-2 mol is particularly preferred.

 The reaction temperature depends on the kind of the indole compound and the reaction material to be used, but is usually selected from the range of 0 to 10 and is preferably 20 to 5 Ot.

 As the reaction conditions, for example, reflux under reduced pressure is preferable.

 The reaction time varies depending on the substrate used, but is usually 5 minutes to 24 hours, preferably 1 hour to 3 hours. However, if the reaction is not performed until the salt is sufficiently formed in the reaction system, the subsequent condensation reaction may not proceed well.

 Further, a phase transfer catalyst can be used for the reaction. Examples of the phase transfer catalyst at this stage include quaternary ammonium salts such as tetrabutylammonium chloride and the like, and 18 crown 6 and the like.

 Examples of the solvent used in the step of reacting the obtained alkali metal salt with 1- (N, N-dimethylsulfamoyl)-3-clothrosulfonyl-1,2,4-triazole include, for example, dimethyl ether, dipropyl ether And cyclic or acyclic ether solvents such as diglyme, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol getyl ether, tetrahydrofuran, tetrahydropyran, and 1,4-dioxane.

 In the reaction, an alkali metal salt is formed in the system, and then the reaction solution is mixed in a system containing 1 _ (N, N-dimethylsulfamoyl) -3 -chlorosulfonyl-1,2,4-triazole compound. It is preferable that the reaction is performed while dropping the solution.

The reaction temperature is preferably from 0 to 100, particularly preferably from 0 to 20. In the formula (2), for a compound in which R ₂ is a halogen group, after halogenating an indole compound in which R ₂ is a hydrogen atom, 1_ (N, N-dimethylsulfamoyl) —3 —Chlorosulfonyl— Can be produced by reacting with 1,2,4-triazole. · Examples of the solvent in the halogenation step include halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloromethane, ethers such as dimethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, acetone, Ketones such as methylethyl ketone and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide; Solvents that are not affected by halogenating agents such as acid amides such as N and N, N-dimethylacetamide can be used, but aromatic hydrocarbon solvents such as benzene, toluene, and xylene that are subject to halogenation can also be used. For example, toluene is a preferable solvent from the viewpoint of industrial handling.

 Examples of the halogenating agent include chlorine, bromine, iodine, N-chloro succinimide, N-bromosuccinimide, N-odosuccinimide, sodium hypobromite and the like.

 The halogenation is preferably performed under alkaline conditions in the presence of an alkali metal compound. As the alkali metal compound at that stage, for example, sodium hydroxide is preferable.

 The amount of the halogenating agent to be used is, for example, preferably 1 mol or around 1 mol of the indole compound.

 The amount of sodium hydroxide is preferably, for example, 1.1 mol or about 1 mol per 1 mol of the indole compound.

 When sodium hypobromite is used as the halogenating agent, it is preferable that sodium hydroxide and bromine coexist in the reaction system, and that sodium hypobromite be generated in the system before the reaction. .

 The reaction temperature depends on the kind of the indole compound and the reaction material to be used, but is usually selected from the range of 0 to 100, preferably 0 to 10.

 The reaction time varies depending on the substrate used, but is usually 5 minutes to 24 hours, preferably 1 hour to 3 hours.

 The obtained halide can be used in the form of a solution, if necessary, washed with an aqueous solution of sodium hydrogen sulfite or the like, and then subjected to the next reaction for producing an alkali metal salt. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

 Example 1

In a reaction flask purged with nitrogen, 5.0 g (0.0254 mole) of 4-fluoro-2-nitrophenylacetone, 35 g of toluene, 2.10 g of sodium acetate (0.0254) Mol), acetic anhydride 10.4 g (0.101 mol) and activated carbon supported 0.25 g of 5% palladium [manufactured by NE Chemcat, Inc. (50% water-containing product)] was added, and the atmosphere was replaced with hydrogen. Then, at 50, a hydrogen gas was supplied at normal pressure and reacted for 6 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, the atmosphere was replaced with nitrogen, and the catalyst was filtered through celite. The reaction mixture was washed sequentially with 35 g of water, 10 g of water, 14 g of a 5% aqueous sodium hydroxide solution, 10 g of water and 10 g of water. After separation, a toluene solution of 6-fluoro-2-methylindole was obtained. Was As a result of quantitative analysis by liquid chromatography, it was confirmed that 6.60 g (yield 95.0%) of 6-fluoro-2-methylindole was produced.

 Example 2

 In a reaction flask purged with nitrogen, 500 g (2.54 mol) of 4-fluoro-2-nitrophenylacetone, 3500 g of toluene, 208 g (2.54 mol) of sodium acetate, 1036 g (10.1 mol) of acetic anhydride ) And 25 g of activated carbon-supported 5% palladium [made by NE Chemcat (50% water-containing product)] were added and replaced with hydrogen. Then, at 50, hydrogen gas was supplied at normal pressure and reacted for 30 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, the atmosphere was replaced with nitrogen, 2,000 g of water and 2705 g of a 30% aqueous sodium hydroxide solution were dropped, and the mixture was stirred for 1 hour and then celite. The catalyst was filtered, and then the aqueous layer was separated. The mixture was further washed with 1000 g of water, 1000 g of a 0.5% aqueous sulfuric acid solution, 1000 g of water, and 1000 g of water in that order, and separated to obtain a toluene solution of 6-fluoro-2-methylindole. Quantitative analysis by liquid chromatography confirmed that 353 g (yield 93.4%) of 6_fluoro-2-methylindole was produced.

 Example 3

In a reaction flask purged with nitrogen, 0.50 g (0.200254 mol) of 4-fluoro-2-nitrophenylacetone, 3.5 g of toluene, 0.21 g (0.200254 mol) of sodium acetate, and propionic anhydride 1 32 g (0.0102 mol) and 5% palladium on activated carbon [NE Chemcat (50% water-containing product)] 0.025 g was added, and the atmosphere was replaced with hydrogen. The mixture was supplied and reacted for 5 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, the atmosphere was replaced with nitrogen, and the catalyst was filtered through celite. The reaction solution was quantitatively analyzed by liquid chromatography, and it was confirmed that 0.36 g (95% yield) of 6-fluoro-2-methylindole was produced.

 Example 4

 In a reaction flask purged with nitrogen, 0.50 g (0.200254 mol) of 4-fluoro-2-nitophenyl phenylaceton, 3.5 g of toluene, 0.21 g (0.200254 mol) of sodium acetate, and 1 part of butyric anhydride 61 g (0.0102 mol) and activated carbon-supported 5% palladium [NE Chemcat (50% water-containing product)] 0.025 g was added and replaced with hydrogen. And reacted for 5 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, the mixture was replaced with nitrogen and the catalyst was filtered through celite. The reaction mixture was quantitatively analyzed by liquid chromatography, and it was confirmed that 0.37 g (97% yield) of 6-fluoro-2-methylindole was produced.

 Example 5

 In a reaction flask purged with nitrogen, 0.50 g (0.0000254 mol) of 4-fluoro-2-nitrophenylacetone, 3.5 g of toluene, 0.18 g (0.00127 mol) of potassium carbonate, and acetic anhydride 1. After charging 29 g (0.0127 mol) and 5% palladium on activated carbon [NE Chemcat (50% water-containing product)] 0.025 g, and replacing with hydrogen, hydrogen gas was supplied at normal pressure in step 5. For 7.5 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, it was replaced with nitrogen, and the catalyst was filtered through celite. The reaction solution was quantitatively analyzed by liquid chromatography, and it was confirmed that 0.36 g (95% yield) of 6-fluoro-2-methylindole was produced.

 Example 6

In a reaction flask purged with nitrogen, 4-fluoro-2-nitrophenylacetone 0 • 50 g (0.200254 mol), toluene 3.5 g, sodium hydrogencarbonate 0.21 g (0.200254 mol), acetic anhydride 1 29 g (0.0127 mol) and 5% palladium on activated carbon [NE Chemcat, Inc. (50% water content)] 0.025 g was added and replaced with hydrogen. The reaction was carried out for 7.5 hours by supplying pressure. 4-fluoro-2-nitrophene by liquid chromatography After confirming the disappearance of nylacetone, the atmosphere was replaced with nitrogen, and the catalyst was filtered through Celite. The reaction solution was quantitatively analyzed by liquid chromatography to confirm that 0.37 g (yield 97%) of 6_fluoro-2-methylindole was produced.

 Example 7

 In a reaction flask purged with nitrogen, 0.50 g (0.100254 mol) of 4-fluoro-2-nitrophenylacetone, 3.5 g of toluene, 0.13 g (0.00127 mol) of sodium carbonate, and acetic anhydride 1. 29 g (0.0127 mol) and activated carbon-supported 5% palladium [NE Chemcat (50% water-containing product)] 0.025 g was added, and the atmosphere was replaced with hydrogen. The mixture was supplied and reacted for 8 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, the mixture was replaced with nitrogen and the catalyst was filtered through celite. The reaction mixture was quantitatively analyzed by liquid chromatography to confirm that 0.35 g (yield 92%) of 6-fluoro-2-methylindole was produced.

 Example 8

 In a reaction flask purged with nitrogen, 4-fluoro-2-nitrophenylacetone 0-50 g (0.00254 mol), toluene 3.5 g, sodium hydroxide 10 g (0.00254 mol), acetic anhydride 1. 29 g (0.0127 mol) and 5% palladium on activated carbon [NE Chemcat (50% water-containing product)] 0.025 g was added and replaced with hydrogen. At 50, hydrogen gas was supplied at normal pressure And reacted for 9 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, the atmosphere was replaced with nitrogen, and the catalyst was filtered through celite. The reaction solution was quantitatively analyzed by liquid chromatography, and it was confirmed that 0.36 g (95% yield) of 6-fluoro-2-methylindole was produced.

 Comparative example

In a reaction flask purged with nitrogen, 0.30 g (0.0000152 mol) of 4-fluoro-2-nitrophenylacetone, 2.1 g of ethanol and 5% palladium on activated carbon [NE Chemcat (50% water content) ], And hydrogen gas was supplied at normal pressure at 20 to react for 90 hours. After confirming the disappearance of 4-fluoro-2-nitrophenylacetone by liquid chromatography, And the catalyst was filtered through Celite. The reaction solution was quantitatively analyzed by liquid chromatography, and it was confirmed that 0.16 g (yield 72%) of 6_fluoro-2-methylindole was produced.

 Example 9

 Production of 3- (4-monofluoro-2-nitrophenyl) -1-hydroxy-3-penten-2-one

 To a mixed solution of 5.00 g of 2,5-difluoronitrobenzene and 50 mL of dimethyl sulfoxide, 3.45 g of acetylethylacetone and subsequently 9.09 g of potassium carbonate were added. After stirring at room temperature for 43 hours, 15 OmL of toluene was added to the reaction mixture, followed by stirring, and this was added to 15 OmL of water. The toluene phase was separated, and then extraction was performed twice by adding 10 OmL of toluene to the aqueous phase. The obtained toluene phases were combined, washed with 15 OmL of water three times, then with 10 OmL of saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the resulting crude product was washed with a mixed solvent of 15 mL of hexane and 2 mL of getyl ether, and dried under vacuum to give 3- (4-fluoro-2-nitrophenyl) — 4.81 g (yield; 64%) of 4-hydroxy-3-penten-2-one was obtained.

_{Ή-NMR (CDC 1 3)} : 1. 86 p pm (s, 6H, CH 3), 7. 3- 7. 8 p pm (m, 3H, A r H), 16. 55 p pm (s, 1 H, OH) Melting point: 98-10 Ot:

 Example 10

 Preparation of 3- (4-fluoro-2-nitrophenyl) -1-hydroxy-3-pentene-1-one

A mixed suspension of 7.65 g of powdered potassium carbonate, 4.00 g of 2,5-difluoronitrobenzene and 2 OmL of N, N-dimethylformamide was heated at 40 to 40, and 2.90 g of acetylacetone was added. Was. The reaction solution was heated to 80 and stirred overnight under a nitrogen atmosphere. After cooling, 2 OmL of toluene was added to the reaction mixture, and the mixture was stirred, and then added to 5 OmL (10) of cold water. The toluene phase was separated, and then an extraction operation was performed three times by adding 3 OmL of toluene to the aqueous phase. The obtained toluene phases were combined, washed three times with 5 OmL of water, and passed through silica gel (10.0 g) (4 Washed with OmL of toluene). The crude product obtained by evaporating the solvent was washed with a mixed solvent of hexane (30 mL) and dimethyl ether (2 mL), filtered (the filtrate was washed with hexane), and dried in vacuo to obtain 3- ( Example 11: 4-fluoro-2-nitrophenyl) -4-hydroxy-3-penten-2-one was obtained in an amount of 4.07 g (yield; 68%).

 Production of 2- (4-fluoro-2-nitrophenyl) -1-hydroxy-2-butenoic acid methyl ester [2- (4-fluoro-2-nitrophenyl) _3-oxobutyric acid methyl ester]

A mixture of powdered potassium carbonate (19.0 g), 2,5-difluoronitrobenzene (10 Og) and N, N-dimethylformamide (5 OmL) was heated to 50X :, and then acetate acetate methyl ester 8. 39 g were added. Thereafter, the mixture was stirred at 49-51 for 19 hours in a nitrogen atmosphere, and then allowed to cool to 22. To the reaction mixture was added 15 OmL of toluene and stirred, and this was added to 30 OmL of cold water of 10. The toluene phase was separated and extracted twice with 15 OmL of toluene added to the aqueous phase. The obtained toluene phases were combined, washed three times with 15 OmL of water, and then extracted with an aqueous phase by adding 15 OmL of a 5% sodium hydroxide solution (twice). To the obtained aqueous phase, 35 mL of 35% hydrochloric acid was added to adjust the pH to 3, and extraction was performed twice with 15 OmL of toluene. The obtained toluene solution is washed three times with 20 OmL of water, then filtered through a liquid phase separation filter paper, the filter paper is washed with 2 OmL of toluene, and the solvent is distilled off and dried to obtain 2- (4 -Fluoro-2-nitrophenyl) _3-hydroxy-2-butenoic acid methyl ester [2- (4-fluoro-2-nitrophenyl) -3-oxobutanoic acid methyl ester] 'in 12.1 g (yield: 76 %) of Compound (keto form in a CDC 1 _3: eno - le body = 1: 9).

_{Ή-NMR (CDC 1 3)} : 1. 83 p pm (s, 3H, phenol body _{C = C (OH) CH 3} ), 2. 38 p pm (s, keto form COCHs), 3. 64 p pm ( s, 3H, enol form C0 ₂ CH ₃ ), 3.79 ppm (s, 3H, keto form C ₂ CH ₃ ), 5.35 ppm (s, 1 H, keto form CH ₃ COCHC0 ₂ CH ₃ ), 7.2-8.0 ppm (m, 3H, ArH), 12.95 ppm (s, 1H, enol Body OH),

 Melting point: 72_75

 Example 12

 Production of 2- (4-fluoro-2-nitrophenyl) -1-hydroxy-2-butenoic acid ethyl ester [2- (4-fluoro-2-nitrophenyl) -13-oxobutyric acid ethyl ester]

To a mixed solution of 5.00 g of 2,5-difluoronitrobenzene and 3 OmL of N, N-dimethylformamide at room temperature was added 4.49 g of acetoacetic acid ethyl ester, and subsequently 9.09 g of potassium carbonate. After stirring at room temperature for 67 hours, 10 OmL of toluene was added to the reaction mixture, followed by stirring, and this was added to 20 OmL of ice water. The toluene phase was separated, and then an extraction operation was performed twice by adding 10 OmL of toluene to the aqueous phase. The obtained toluene phases were combined, and an extraction operation into an aqueous phase by adding 10 OmL of a 1 N aqueous potassium hydroxide solution was performed twice. To the obtained aqueous phase, 25 mL of 35% hydrochloric acid was added to adjust the pH to 2, and extraction was performed twice with 15 OmL of toluene. The obtained toluene phase was washed with 15 OmL of water three times, then with 10 OmL of saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent is distilled off under reduced pressure to give 2_ (4-fluoro-2-nitrophenyl) -1-hydroxy-2-butenoic acid ester [2- (4-fluoro-2-nitrophenyl) —3-oxobutane acid Echiruesuteru] 7. 10 g (yield: 84%) of Compound (keto form in a CDC 1 _3: perilla Ichiru body = 1: 9).

_{Ή-NR (CDC 1 3)} : 1. 13 ppm (t, J = 7. 2Hz, 3H, enol Lumpur body _{C0 2 CH 2 CH 3),} 0. 9- 1. 5 p pm ( keto form CO ₂ CH ₂ CH ₃ ), 1.87 p pm (s, 3H, phenolic COCH, 2.42 p pm (s, 3 H, keto COCH ₃ ), 3.8--4.6 p pm (m, 2H _{, C0 2 CH 2 CH 3)} , 5. 33 p pm (s, 1H, keto form CH ₃ COCHC_〇 _{2 E t), 7. 2- 8.} lp pm (m, 3H, ArH), 13. 05 p pm (s, 1H, enol body 〇H),

 Melting point: 48-49

Example 13 Preparation of 1- (4-fluoro-2-nitrophenyl) acetone (Preparation from 3- (4-fluoro-2-nitrophenyl) -4-hydroxy-3-penten-1-one)

 To 1.03 g of 3- (4-fluoro-2-nitrophenyl) -1-4-hydroxy-3-penten-2-one was added 10 g of acetic acid at room temperature, followed by 8.0 g of a 50% aqueous sulfuric acid solution. The mixture was heated gradually with stirring and finally reacted at reflux for 3 hours. After cooling the reaction mixture to room temperature, water and acetic acid were partially distilled off, and 2 OmL of toluene and then 4 OmL of water were added. After separating the toluene phase, the aqueous phase was extracted twice with 3 OmL of toluene. The obtained toluene phases were combined, washed three times with 3 OmL of water and once with 2 OmL of saturated saline, and then dried over anhydrous sodium sulfate. After the filtration operation, the solvent was distilled off to obtain 0.76 g of 1-1 (4-fluoro-2-nitrophenyl) acetone (89% yield).

_{Ή-NMR (CDC 1 3)} : 2. 32 ppm (s, 3H, CH 2 C (O) CH 3), 4. llp pm (s, CH 2 C (O) CH 3), 7. 2- 7 .9 p pm (m, 3H, Ar H)

 Melting point: 49-50 "

 Example 14

 Preparation of 1- (4-fluoro-2-nitrophenyl) acetone (2- (4-fluoro-2-nitrophenyl) —3-hydroxy-2-butenoic acid methyl ester [2- (4-fluoro-2-nitrophenyl) —3 —Oxobutanoic acid methyl ester])

2- (4-Fluoro-2-nitrophenyl) — 3-hydroxy-2-butenoic acid methyl ester [2- (4-fluoro-2-nitrophenyl) —3-oxobutyric acid methyl ester] 18.1 g of acetic acid 1 10 g was added at room temperature, and then 26. O g of a 50% aqueous sulfuric acid solution was added. The mixture was heated gradually with stirring and finally reacted at reflux temperature for 4.7 hours. Water and acetic acid were partially distilled off from the reaction mixture, and 10 OmL of toluene was added. Then, the mixture was gradually poured into 10 OmL of water. After separating the toluene phase, 10 OmL of toluene was added to the aqueous phase, and the toluene phase was separated again. The obtained toluene phase was washed four times with 10 OmL of water, and then filtered through celite. Reduce solvent After distilling off under reduced pressure and adding 10 OmL of n-hexane to form a slurry, the crystals obtained by filtration are dried under reduced pressure to obtain 1- (4-fluoro-2-nitrophenyl) acetone. g was obtained (yield 92%).

 Example 15

 Preparation of 1- (4-fluoro-2-nitrophenyl) acetone (2- (4-fluoro-2-nitrophenyl) —3-hydroxy-2-butenoic acid ethyl ester [2- (4-fluoro-2-nitrophenyl) -1,3-oxobutane (Ethyl ester))

 2- (4-Fluoro-2-nitrophenyl) —3-hydroxy-2-butenoic acid ethyl ester [2- (4-fluoro-2-nitrophenyl) —3-oxobutanoic acid ester] 4.00 g of acetic acid (24 g) at room temperature Then, 6. O g of a 50% aqueous sulfuric acid solution was added. The mixture was heated gradually with stirring and finally reacted at reflux temperature for 4.6 hours. Water and acetic acid were partially distilled off from the reaction mixture, 4 OmL of toluene was added, and then 4 OmL of water was added. After separating the toluene phase, the aqueous phase was extracted twice with 4 OmL of toluene. The obtained toluene phase was washed three times with 4 OmL of water and once with 4 OmL of saturated saline, and then passed through silica gel. The solvent was distilled off under reduced pressure to obtain 2.40 g of 1- (4-fluoro-2-nitrophenyl) acetone (yield: 82%).

 Example 16

Preparation of 1- (4-fluoro-2-nitrophenyl) acetone [Continuous method] A mixture of 10.0 g of 2,5-difluoronitrobenzene, 19.O g of powdered potassium carbonate and 52 mL of N, N-dimethylformamide was prepared. After heating at 53, 8.4 g of acetoacetic acid methyl ester was continuously added, and the mixture was stirred at 48-53 for 15 hours under a nitrogen atmosphere. After cooling, 15 OmL of toluene was added to the reaction mixture, followed by stirring, and the mixture was added to 30 OmL of cold water (6). The toluene phase was separated, and then the aqueous phase was extracted twice with 15 OmL of toluene. The obtained toluene phases were combined, washed three times with 15 OmL of water, filtered through a liquid phase separation filter paper (washing the filter paper with 2 OmL of toluene), and the solvent was distilled off. Was added to obtain 56 g of a toluene solution of the 2-nitrophenylacetone compound shown in Example 11. This solution was continuously subjected to the next decarboxylation step. 20 mL of acetic acid and 2 OmL of a 50% aqueous solution of sulfuric acid were added, the temperature was gradually raised, and the mixture was heated and refluxed for 45 hours. Further, 2 OmL each of acetic acid and 50% sulfuric acid aqueous solution was added, and reacted at reflux temperature for 25 hours. After cooling (22), 15 OmL of toluene and 20 OmL of water were added and stirred. After separating the toluene phase, the aqueous phase was extracted twice with 15 OmL of toluene. The obtained toluene phases were combined, 20 OmL of a 5% aqueous thorium hydroxide solution was added, and the mixture was stirred and filtered through Celite. After separating the toluene phase and washing with water, liquid phase separation was filtered with filter paper, and the solvent was distilled off. After the precipitated solid was dissolved in 33 mL of toluene, the solid was poured into hexane (30 OmL), stirred overnight, and the resulting solid was filtered. The filtrate was concentrated, purified with 1 mL of toluene and 3 OmL of hexane, combined with the previous solid, dried in vacuo, and 9.8 g of 1- (4-fluoro-2-ditrophenyl) acetone (79% (2 , 5-difluoronitrobenzene).

 Example 17

 Preparation of 3_bromo-6-fluoro-2-methylindole

 To 0.58 g (3.9 mmo 1) of 6-fluoro-2-methylindole, 8.7 g of toluene and 0.17 g (4.25 mmo 1) of sodium hydroxide were added under a nitrogen atmosphere. Cool. To this solution, 0.6 g (3.9 mmo 1) of bromine was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. After confirming by HPLC that the desired product was formed, the solution was washed once with 8.7 g of 0.2 mO1 ZL aqueous sodium bisulfite solution and once with 8.7 g of pure water. Led to the process. Quantitative yield 96.6%

^J HNMR (CDC 1a)

 2.40 (s, 3H), 6.90-7.00 (m, 2H), 7.45-7.51 (m, 1H), 7.85-8.05 (br s, 1H)

1- (N, N-dimethylsulfamoyl) -3- (3-promo 6-fluoro-12-methylindole-11-yl) sulfonyl- 1,2,4-triazole Obtained in Example 17 3-bromo-6-fluoro-2-methylindole 0.17 g (4.25 mmo 1) of sodium hydroxide, 0.1 llg (0.39 mmo 1) of tetrabutylammonium chloride and 5.8 g of diglyme were added to the luene solution under a nitrogen atmosphere.30, 3 OmmHg The mixture was stirred under reflux under reduced pressure for 2 hours to synthesize sodium salt of 3-bromo-6-fluoro-2-methylindole. This solution was prepared separately under a nitrogen atmosphere under a nitrogen atmosphere 5 from 1- (N, N-dimethylsulfamoyl) -3-chlorosulfonyl-1,2,4-triazole 1.04 g (3.9 mmo 1). Diglyme was added dropwise to the 5.8 g solution over 15 minutes, and the mixture was further stirred for 1 hour to obtain the desired 11- (N, N-dimethylsulfamoyl) _3- (3-bromo-6-fluoro-2-methyl It was confirmed by HPLC that indole-1_) sulfonyl-1,2,4-triazole was formed. Quantitative yield 94.0%

 Example 19

 Production of 3-promo-6-fluoro-2-methylindole

 To 1 g (6.7 mmo 1) of 6_fluoro-2-methylindole, 7 g of toluene and 0.3 g (7.5 mmo 1) of sodium hydroxide were added under a nitrogen atmosphere, and the mixture was cooled to 5. To this solution, 1. 1 g (6.7 mmo 1) of bromine was added dropwise over 1 hour, and the mixture was further stirred for 1 hour. After confirming by HPLC that the target substance was produced, the solution was washed once with 8 g of a 0.2 mol / L aqueous sodium bisulfite solution and once with 8 g of pure water, and then led to the next step. Was. Quantitative yield 95.5%.

 Example 20

1- (N, N-Dimethylsulfamoyl) -3- (3-bromo-6-fluoro-2-methylindole-1-yl) Sulfonyl 1,2,4-triazole obtained in Example 19 The obtained benzene solution of 3-promo-6-fluoro-2-methylindole was cooled to 5 under a nitrogen atmosphere, and 0.8 g (7.2 mmo 1) of potassium t-butoxide was dissolved in 11.8 g of diglyme. Was added dropwise, and the potassium salt of 3-bromo-6-fluoro-2-methylindole was synthesized over 30 minutes. This solution was prepared separately under a nitrogen atmosphere at 5 in 1- (N, N-dimethylsulfamoyl) -3-chlorosulfonyl-1,2,4-triazole 1.8 g (6.7 mmo The diglyme of 1) was added dropwise over a period of 15 minutes to a solution of 10.7 g of diglyme, and the mixture was further stirred for 30 minutes to obtain the desired 11- (N, N-dimethylsulfamoyl) -13- (3-promo_6_ Fluoro-2-methylindole-1-yl) The formation of sulfonyl 1,2,4-triazole was confirmed by HPLC. Quantitative yield 95.2% Industrial applicability

 According to the present invention, 1- (4-fluoro-2-nitrophenyl) acetone, which is a useful intermediate for indole production and the like, which has been conventionally difficult to produce, can be easily used as an intermediate with novel 2_nitrophenylacetones. Indole compounds can be produced from 2-nitrobenzylcarbonyl compounds in very high yields, and sulfamoyltriazole compounds useful as fungicides can be produced from indole compounds in high yields. Can be obtained at

Claims

The scope of the claims 1. Equation (2)

(Wherein, and R ₂ each independently represent a hydrogen atom, an optionally substituted alkyl group or a phenyl group, and R ₃ represents an optionally substituted alkyl group, a phenyl group, an alkoxy group Represents an alkoxycarbonyl group or a halogen atom, and n represents an integer of 0 to 4.) An indole compound represented by the formula (3) is converted into an alkali metal salt, and then reacted with 11- (N, N-dimethylsulfamoyl) -13-chlorosulfonyl-1,2,4-triazole to obtain the formula (3 )

(In the formula, R, R ₂ , R ₃ and n have the same meanings as described above.) A method for producing a sulfamoyl triazole compound represented by the formula: 2. Equation (1)

(Wherein, and R 2 each independently represent a hydrogen atom, an optionally substituted alkyl group or a phenyl group, and R ₃ represents an optionally substituted alkyl group, a phenyl group, an alkoxy group Represents an alkoxycarbonyl group or a halogen atom, and n represents an integer of 0 to 4.) In the step of reducing the 2-nitrobenzylcarbonyl compound represented by the formula (2) with a hydrogen donor in the presence of a reduction catalyst, the above formula (2) produced by coexisting an acylating agent and a base is used. The production method according to claim 1, wherein the indole compound represented is used.  3. The step of reducing the 2-nitrobenzyl carbonyl compound represented by the formula (1) with a hydrogen donor in the presence of a reduction catalyst, wherein an acylating agent and a base are allowed to coexist. A method for producing an indole compound represented by the above formula (2). 4. The method for producing an indole compound according to claim 3, wherein the acylating agent is an organic acid anhydride.  5. The method according to claim 3, wherein the acylating agent is acetic anhydride.  6. The method for producing an indole compound according to claim 3, wherein the base is an alkali metal salt or an alkali metal hydroxide.  7. The method for producing an indole compound according to claim 3, wherein the base is an organic acid salt, carbonate, bicarbonate or hydroxide of an alkali metal.  8. The method for producing an indole compound according to claim 3, wherein the reduction catalyst is a supported noble metal catalyst.  9. The method for producing an indole compound according to claim 3, wherein the reduction catalyst is palladium on activated carbon. 10. The production of the indole compound according to claim 3, wherein the hydrogen donor is hydrogen gas. Method. 1 1. After halogenating the indole compound represented by the above formula (2) (wherein R ₂ represents a hydrogen atom) and then converting it to an alkali metal salt, 1_ (N, N-dimethylsulfamoyl) Sulfamoyl represented by the above formula (3) (wherein R ₂ represents a chlorine atom, a bromine atom or an iodine atom) by reacting with 1,3-chlorosulfonyl-1,2,4-triazole. A method for producing a triazole compound. 12. The production method according to claim 11, wherein the indole compound is 2-methyl-6-fluoroindole.  13. The production method according to claim 12, wherein the halogenation is bromination.  14. The production method according to claim 13, wherein the bromination is caused by sodium hypobromite.  15. The method according to claim 13, wherein the bromination is caused by bromine in the presence of sodium hydroxide.  16. 2-Methyl-6-furane prepared by coexisting an acylating agent and a base in the step of reducing 3-(4-fluoro-2-nitrophenyl) acetone with a hydrogen donor in the presence of a reducing catalyst. 13. The production method according to claim 12, wherein oroindole is used.  17. The step of reducing 3- (4-fluoro-2-nitrophenyl) acetone with a hydrogen donor in the presence of a reduction catalyst, wherein a co-existing acylating agent and a base are present, wherein 2-methyl is used. —6—Method of producing fluoroindole.  18. Equation (I)

(Wherein, R represents a methyl group, a methoxy group or an ethoxy group.) 3- (4-fluoro-2) produced by treating a 2-nitrophenylacetone compound represented by the following formula in the presence of an acid or a base. —Nitrophenyl) Claims using acetone Item 18. The production method according to Item 16.  19. A method of using 3- (4-fluoro-2-nittophenyl) acetone produced by treating the 2-ditrophenylacetone compound represented by the formula (I) in the presence of an acid or a base. 17. The production method according to 17. 20. A process for producing 3- (4-fluoro-2-nitrophenyl) acetone by treating the 2_nitrophenylacetone compound represented by the formula (I) in the presence of an acid or a base. 21. Equation (II)

(Wherein X represents a fluorine atom, a chlorine atom or a bromine atom.) And nitrobenzene represented by the formula (III)

(Wherein R represents a methyl group, a methoxy group or an ethoxy group.) A 2_ nitrophenylacetone compound represented by the above formula (I) produced by reacting the compound with a dicalponyl compound represented by the following formula: 21. The production method according to claim 18, 19 or 20, which is used.  22. A method for producing a 2-to-2 port phenylacetone compound represented by the above formula (I) by reacting a nitrobenzene represented by the above formula (II) with a dicarbonyl compound represented by the above formula (III) .  23. A 2-nitrophenylacetone compound represented by the formula (I).