JP2001288168A - Method for producing indole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing indoles substituted at the 4-position which is an intermediate for various kinds of medicines, dyestuffs and the like without using a specific raw material by a simple process In high yield and high quality. SOLUTION: This method for producing the indole derivative is characterized as the amino group of 2-aminotoluene having an arbitrary substituent at the 6-position is once protected with an aclyating agent such as an acetyl group, and the amino group protected intermediate is reacted with dimethylformamide dialkyl acetal in an organic solvent in the presence (or absence) of an organic secondary amine.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel method for producing an indole derivative.

BACKGROUND OF THE INVENTION Indole derivatives are extremely important compounds as intermediates of medicinal and agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION 4-Substituted indoles are used in medicines, pesticides,
It is important as a raw material for electronic materials and the like. As a method for producing this compound, a method of forming an indole ring by a Fischer reaction via a 3-substituted phenylhydrazine synthesized from a 3-substituted aniline, followed by a decarboxylation reaction {J. Org. Chem. 30, 3457 (196)
5) A method of closing a ring using a styrene derivative as a starting material or a 2-substituted-6-nitrotoluene and using TiCl3 as a catalyst {Chem. Pharm. Bull. , 29 (3),
726, (1981)}, or a method of performing reductive ring closure using a Pd or Ni catalyst (US Pat. No. 3,976,639)
Similarly, a method for obtaining indole via a phenylethanol derivative and indoline using 2-substituted-6-nitrotoluene as a raw material {J. Heterocyclic. Che
m. , 25 (2), 361, (1988)}, a method of closing a 2-amino-6-substituted toluene as a raw material to an indole ring via an imidate derivative {Orgnic. S
ynthesis. , 65, 146 (1987)},
Lysate method for ring closure to indole ring via o-nitrophenylpyruvate derivative {Ber. , 30,
1030, (1897)} and the like.

[0003] However, these conventional methods have the following disadvantages in the raw materials, the reaction rate, and the reaction operation. The method (1) has a large problem that the regioselectivity at the time of ring closure by the Fischer reaction is low and the yield is low. In the method (1), TiCl3 used as a catalyst has a risk that it may be ignited by contact with air or moisture, is difficult to handle, and has a low yield, which is not preferable as an industrial production method. However, there remains a problem in the use and treatment of expensive noble metal catalysts. Paraformaldehyde used in the above method is harmful to deleterious substances and powerful drugs, and its use in large quantities is not preferred. Is difficult to obtain reproducibility of the reaction and quality, and the method is not easy to synthesize the o-nitrophenylpyruvate ester derivative. The problem is that the process is long.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, starting from 2-amino-6-substituted toluene, this amino group was once acylated with an acylating agent. Later, this is reacted with N, N-dimethylformamide dialkylacetals in an organic solvent in the presence (or absence) of an organic secondary amine, thereby performing two steps of simple reactions of acylation and ring closure, which is troublesome. It has been found that the indole derivative is produced almost quantitatively in high yield without any waste release and the present invention.

[0005] That is, the method of the present invention uses the general formula (1)

Embedded image [Wherein R1 represents a nitro group, a cyano group, a C1-C6 substituted or unsubstituted alkyl group, a C2-C6 substituted or unsubstituted alkenyl group, a C2-C6 substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a C1 -C6 alkoxy group, substituted or unsubstituted aryloxy group, formyl group, halogen,
Mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amino group, hydroxy group, mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted Amide group, N-substituted or unsubstituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbamoyl group, unsubstituted or mono- or di- or tri (C1-C6 substituted or unsubstituted alkyl or substituted or An unsubstituted aryl) -substituted ureido group, (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) An aryl) oxysulfonyl group, (C1-
C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thiocarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxythiocarbonyl group, thiol group, (C1-C6 substituted or unsubstituted alkyl) Or substituted or unsubstituted aryl) thio group, unsubstituted or mono-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfamoyl group unsubstituted or mono- or di-N-substituted (C
1-C6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfonamide group, unsubstituted or mono- or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonylamino group, Unsubstituted or mono- or di-N substituted (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonylamino group, carboxyl group,
(C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarboxyl group, C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfoxyl group, C3-C6 substituted or unsubstituted cycloalkyl group 5- or 6-membered substituted or unsubstituted heteroaromatic ring containing at least one substituted or unsubstituted aralkyl group, O atom or S atom or N atom 5- or 6-membered containing at least one O atom or S atom or N atom
Represents a member-substituted or unsubstituted hetero-saturated ring. Where R2, R3,
R4 is the same or different and each represents a hydrogen atom, a nitro group, a cyano group, a C1-C6 substituted or unsubstituted alkyl group,
C2-C6 substituted or unsubstituted alkenyl group, C2-C6 substituted or unsubstituted alkynyl group, substituted or unsubstituted aryl group, C1-C6 alkoxy group, substituted or unsubstituted aryloxy group, formyl group, halogen, mono- or di- ―
(C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amino group, hydroxy group, mono-
Or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amide group, N-substituted or unsubstituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbamoyl group, unsubstituted Or mono- or di- or tri (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted ureido group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) An aryl) oxycarbonyl group, (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonyl group (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thiocarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) Aryl) oxythiocarbonyl group, thiol group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thio group, unsubstituted or mono-N substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) Aryl) sulfamoyl group, unsubstituted or mono- or di-N substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfonamide group, unsubstituted or mono- or di-N substituted (C
1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonylamino group, unsubstituted or mono- or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonylamino group Carboxyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarboxyl group, C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfoxyl group, C3-C6 substituted or unsubstituted Substituted cycloalkyl group, substituted or unsubstituted aralkyl group, O atom or S atom or N
A 5- or 6-membered substituted or unsubstituted heteroaromatic ring containing at least one atom, a 5- or 6-membered substituted or unsubstituted heterocyclic ring containing at least one O atom or S atom or N atom. Further, R2 and R3 or R3 and R4 may be bonded to each other to form a 5- or 6-membered ring. Where R
5 is a hydrogen atom, nitro group, cyano group, C1-C6 substituted or unsubstituted alkyl group, C2-C6 substituted or unsubstituted alkenyl group, C2-C6 substituted or unsubstituted alkynyl group, substituted or unsubstituted aryl group, C1- C6 alkoxy group, substituted or unsubstituted aryloxy group, formyl group, halogen,
Mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amino group, hydroxy group, mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted Amide group, N-substituted or unsubstituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbamoyl group, unsubstituted or mono- or di- or tri (C1-C6 substituted or unsubstituted alkyl or substituted or An unsubstituted aryl) -substituted ureido group, (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) An aryl) oxysulfonyl group, (C1-
C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thiocarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxythiocarbonyl group, thiol group, (C1-C6 substituted or unsubstituted alkyl) Or substituted or unsubstituted aryl) thio group, unsubstituted or mono-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfamoyl group, unsubstituted or mono- or di-N-substituted (C1-C6 Substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfonamide group, unsubstituted or mono-
Or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonylamino group, unsubstituted or mono- or di-N-substituted (C1
-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonylamino group, carboxyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarboxyl group, C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfoxyl group, C3-C6 substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aralkyl group, O
Containing at least one atom or S atom or N atom 5
Represents a 5- or 6-membered substituted or unsubstituted heteroaromatic ring containing at least one O or S atom or at least one N atom. ] Toluidines represented by the acylating agent (the acylating agent used herein is not only a group derived by removing -OH from the carboxyl group of a carboxylic acid, but also an inorganic agent such as sulfuric acid, nitric acid, and phosphoric acid. This includes groups derived from acids in a broad sense by removing -OH, including groups derived from acids or organic acids such as carbamic acid, carbonic acid, sulfonic acid, and phosphonic acid by removing -OH.) The following general formula (2) obtained by reacting

Embedded image [Wherein R1, R2, R3, R4 and R5 are the same as described above] in an organic solvent in the presence of N, N-dimethylformamide dialkylacetals and an organic secondary amine ( Or in the absence of) the following general formula (3):

Embedded image [Wherein R1, R2, R3, R4, and R5 are the same as described above].

According to the present invention, the production of the indole derivative is carried out in two steps of acylation and ring closure, and the operability is improved without troublesome release of waste and the desired product can be obtained in good yield. Therefore, its industrial utility value is extremely high.

The manufacturing method of the present invention will be described in detail. In the present invention, first, N-acylation of toluidines is performed using an acylating agent. The raw material toluidines used in the production method of the present invention is a compound represented by the general formula (1). Examples of such compounds include the following compounds.

[0008]

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[0009]

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[0010]

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[0011]

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[0012]

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[0013]

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[0014]

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[0015]

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[0016]

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[0017]

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[0018]

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[0019]

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[0020]

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The acylating agent used in the present invention includes:
Acetic acid, acetic anhydride, acetyl halide benzoyl halide, p-toluenesulfonic acid halide, ethyl halogenocarbonate, diethylcarbamyl halide, cinnamoyl halide, 2-furoyl halide propionyl halide,
Methanesulfonyl halide, diethyl phosphate halide and the like can be mentioned. In particular, use of acetic anhydride and acetyl chloride is advantageous from an industrial point of view.

The amount of the acylating agent to be used is 0.1 to 10 times, preferably 1 to 1.2 times the mol of the toluidines. If it is less than equimolar, a large amount of the raw material remains, which is not practical, and if it is more than 1.2 times, a side reaction (diacylation) occurs, which is not preferable.

In the acylation reaction of the present invention, it is preferable to use a reaction solvent, and as the reaction solvent, a solvent usually used for an acylation reaction is used. Specific examples thereof include ethyl acetate, methyl acetate, dioxane, CCl4,
CHCl3, CH2Cl2, THF, hexane, ligroin, methyl ethyl ketone, methyl isobutyl ketone acetone, toluene, benzene, xylene, acetonitrile and the like, preferably acetone, toluene,
Acetonitrile. These may be used alone or in a mixture of two or more.

The amount of the reaction solvent used in the acylation reaction is not fixed depending on the type of toluidines, but is usually in the range of 1 to 100 times (volume), preferably 2 to 10 times (volume).

The reaction temperature of the acylation reaction is not particularly limited, but is preferably in the range of 10 ° C. to 100 ° C. If the temperature is lower than 10 ° C., the reaction rate is small and not practical.

The reaction time is not fixed depending on the type of toluidine or the reaction temperature, but is usually 0.1 to 10
Time.

The N-acyl compound represented by the general formula (2) thus obtained is isolated by subjecting the reaction solution to general filtration, extraction or / and concentration and distillation.

The N-acyl compound represented by the general formula (2) is converted to an indole derivative by a ring closing reaction. In the ring closure reaction of the present invention, it is preferable to use a reaction solvent. Examples of the reaction solvent include lower aliphatic alcohols such as methanol, ethanol and propanol, methyl cellosolve, ethyl cellosolob, ethyl acetate, methyl acetate, butyl acetate, dioxane and DMF , DMSO (dimethyl sulfoxide), CCl4, CHCl3, CH2Cl2, T
Examples include HF, hexane, ligroin, methyl ethyl ketone, methyl isobutyl ketone, acetone, toluene, benzene, xylene, acetonitrile and the like, and preferably high-boiling solvents such as DMF, DMSO, toluene and xylene.

The amount of the reaction solvent used for the ring closure reaction is not fixed depending on the type of the N-acyl compound, but is usually in the range of 1 to 100 times (volume), preferably 2 to 10 times (volume).

The N, N-dimethylformamide dialkyl acetals used for the ring closure reaction include N, N-
Dimethylformamide bis ｛2- (trimethylsilyl)
Ethyl diacetal, N, N-dimethylformamide dibenzyl acetal, N, N-dimethylformamide di-t-butyl acetal, N, N-dimethylformamide dicyclohexyl acetal, N, N-dimethylformamide diethyl acetal, N, N-dimethyl Formamide diisopropyl acetal, N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide dineopentyl acetal, N, N-dimethylformamide dipropyl acetal, N, N-dimethylformamide, etc., are particularly industrial aspects. The use of N, N-dimethylformamide dimethyl acetal is advantageous.

The amount of the N, N-dimethylformamide dialkyl acetal used is 0.1% based on the N-acyl compound.
1 to 10 moles, preferably equimolar to 1.5 moles
The range is twice as high. If it is less than equimolar, a large amount of raw material remains, which is not practical. If it is more than 1.5 times, it is not preferable in view of economic efficiency.

The organic secondary amine used for the ring closure reaction includes dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-2-ethylhexylamine, diallylamine, diethanolamine. , N-methylethanolamine, diisopropanolamine, 3,
3′-iminodipropionitrile, iminodiacetic acid, ethyleneimine, dicyclohexylamine, dibenzylamine, N-methylaniline, N-ethylaniline, diphenylamine, piperidine, 2-pipecoline, 3-pipecoline, 4-pipecoline, piperazine, N -Methylpiperazine, morpholine, pyrrolidine, imidazole, triazole and the like can be mentioned, and from the industrial point of view, use of diethylamine, diisobutylamine, 2-pipecoline, 3-pipecoline, 4-pipecoline, morpholine and pyrrolidine is particularly advantageous.

The organic secondary amine may not be used depending on the reactivity in some cases, but when used, the amount used is not particularly limited, but is preferably in the range of equimolar to 1.5-fold molar. . There is no problem even if it is less than equimolar due to reactivity,
If the molar ratio is 1.5 times or more, it is not preferable in view of economy.

The reaction temperature of the ring closure reaction is not particularly limited, but is preferably in the range of 50 ° C. to 150 ° C. If the temperature is lower than 50 ° C., the reaction rate is small and not practical, and if it is higher than 150 ° C., a side reaction occurs, which is not preferable.

The reaction time is not fixed depending on the type of N-acyl compound or the reaction temperature, but is usually 0.1 to 10
Time.

The general formula (3) thus obtained in the present invention
The indole derivative represented by is a general filtration of the reaction solution,
It is isolated by extraction or / and concentration and distillation. If desired, known methods such as column chromatography, distillation,
It can be purified by recrystallization or the like.

[0037]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

Comparative Example 1 In a 200 ml flask equipped with a stirrer, a reflux condenser and a thermometer, 30.4 g of 2-amino-6-nitrotoluene was placed.
(0.2 mol), 35.7 g (0.3 mol) of N, N-dimethylformamide dimethyl acetal, 21.3 g (0.3 mol) of pyrrolidine and 150 ml of DMF
After stirring, the mixture was stirred at an internal temperature of 100 ° C. for 3 hours. Thereafter, the mixture was concentrated, and the concentrated residue was analyzed with a gas chromatography mass spectrometer. As a result, traces of 4-nitroindole were obtained.

Example 1 2 equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel
In a 00 ml flask, 45.6 g (0.3 mol) of 2-amino-6-nitrotoluene and acetonitrile 90
Then, 33.7 g (0.33 mol) of acetic anhydride placed in a dropping funnel was added in about 10 minutes while stirring at room temperature. After completion of the addition, the temperature was raised to around 60 ° C. during the cooling and stirring, and crystals were precipitated at this time. The mixture was cooled on ice for 1 hour from the time when the internal temperature returned to room temperature, and filtered to obtain 50.7 g of 2- (N-acetylamino) -6-nitrotoluene having a gas chromatography purity of 100.0%. 2
The yield of 2- (N-acetylamino) -6-nitrotoluene based on -amino-6-nitrotoluene was 87.1%.
Met.

Example 2 In a 500 ml flask equipped with a stirrer, reflux condenser and thermometer, 48.5 g (0.25 mol) of 2- (N-acetylamino) -6-nitrotoluene, N, N-dimethylformamide 44.6 g of dimethyl acetal (0.37
5 mol), 26.6 g of pyrrolidine (0.375 mol)
l) and 250 ml of DMF were charged and the internal temperature was 100
Stirred at C for 7 hours. Thereafter, the mixture was concentrated to obtain a brown oil. This oil was recrystallized from a mixed solvent of methanol and water to obtain 33.0 g of 4-nitroindole having a gas chromatography purity of 100.0%. The yield from 2- (N-acetylamino) -6-nitrotoluene is 86.
8%. 206-207 ° C.

Example 3 2 equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel
In a 00 ml flask, 42.6 g (0.3 mol) of 2-amino-6-chlorotoluene and acetonitrile 90
Then, 33.7 g (0.33 mol) of acetic anhydride placed in a dropping funnel was added in about 10 minutes while stirring at room temperature. After completion of the addition, the temperature was raised to around 60 ° C. during the cooling and stirring, and crystals were precipitated at this time. The mixture was cooled on ice for 1 hour from the time when the internal temperature returned to room temperature, and filtered to obtain 46.9 g of 2- (N-acetylamino) -6-chlorotoluene having a gas chromatography purity of 100.0%. 2
The yield of 2- (N-acetylamino) -6-chlorotoluene based on -amino-6-chlorotoluene is 85.2%.
Met.

Example 4 In a 500 ml flask equipped with a stirrer, a reflux condenser and a thermometer, 45.9 g (0.25 mol) of 2- (N-acetylamino) -6-chlorotoluene and N, N-dimethylform Amide dimethyl acetal 44.6 g (0.37
5 mol), 26.6 g of pyrrolidine (0.375 mol)
l) and 230 ml of DMF were charged and the internal temperature was 100
Stirred at C for 7 hours. Thereafter, the mixture was concentrated to obtain a brown oil. The oil is purified by distillation and 4-chloroindole 3 having a gas chromatography purity of 100.0%.
1.5 g were obtained. 2- (N-acetylamino) -6
The yield from -chlorotoluene was 83.2%. Boiling point 129-130 ° C / 4mm.

[0043]

According to the method of the present invention, an indole derivative having a substituent which is difficult to obtain can be obtained in a short step,
Production can be performed selectively and with good yield, thereby enabling industrial production thereof, and greatly reducing the production cost.

Claims (9)

[Claims] 1. The following general formula (1) [Wherein R1 represents a nitro group, a cyano group, a C1-C6 substituted or unsubstituted alkyl group, a C2-C6 substituted or unsubstituted alkenyl group, a C2-C6 substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a C1 -C6 alkoxy group, substituted or unsubstituted aryloxy group, formyl group, halogen,
Mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amino group, hydroxy group, mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted Amide group, N-substituted or unsubstituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbamoyl group, unsubstituted or mono- or di- or tri (C1-C6 substituted or unsubstituted alkyl or substituted or An unsubstituted aryl) -substituted ureido group, (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) An aryl) oxysulfonyl group, (C1-
C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thiocarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxythiocarbonyl group, thiol group, (C1-C6 substituted or unsubstituted alkyl) Or substituted or unsubstituted aryl) thio group, unsubstituted or mono-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfamoyl group unsubstituted or mono- or di-N-substituted (C
1-C6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfonamide group, unsubstituted or mono- or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonylamino group, Unsubstituted or mono- or di-N substituted (C1-C
6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonylamino group, carboxyl group,
(C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarboxyl group, C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfoxyl group, C3-C6 substituted or unsubstituted cycloalkyl group 5- or 6-membered substituted or unsubstituted heteroaromatic ring containing at least one substituted or unsubstituted aralkyl group, O atom or S atom or N atom 5- or 6-membered containing at least one O atom or S atom or N atom
Represents a member-substituted or unsubstituted hetero-saturated ring. Where R2, R3,
R4 is the same or different and each represents a hydrogen atom, a nitro group, a cyano group, a C1-C6 substituted or unsubstituted alkyl group, a C2-C6 substituted or unsubstituted alkenyl group, a C2-C6 substituted or unsubstituted alkynyl group, a substituted or unsubstituted group; Substituted aryl group, C1-C6 alkoxy group, substituted or unsubstituted aryloxy group, formyl group, halogen, mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amino group, hydroxy group A mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amide group, an N-substituted or unsubstituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbamoyl group , Unsubstituted or mono- or di- or tri- (C1-C6 substituted or unsubstituted Alkyl or substituted or unsubstituted aryl) substituted ureido group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonyl group A (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonyl group (C1-C6
A substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thiocarbonyl group, a (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxythiocarbonyl group, a thiol group, a (C1-C6 substituted or unsubstituted alkyl) A substituted or unsubstituted aryl) thio group, an unsubstituted or mono-N-substituted (C1-C6 substituted or unsubstituted alkyl or a substituted or unsubstituted aryl) sulfamoyl group, an unsubstituted or mono- or di-N-substituted (C1-
C6-substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfonamide group, unsubstituted or mono- or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonylamino group, unsubstituted Or mono- or di-N substitution (C1-C6
Substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonylamino group, carboxyl group, (C
1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarboxyl group, C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfoxyl group, C3-C6 substituted or unsubstituted cycloalkyl group, Substituted or unsubstituted aralkyl group, 5- or 6-membered substituted or unsubstituted heteroaromatic ring containing at least one O or S atom or N atom, 5- or 6-membered containing at least one O or S atom or N atom Represents a member-substituted or unsubstituted hetero-saturated ring. Further, R2 and R3 or R3 and R4 may be bonded to each other to form a 5- or 6-membered ring. In the formula, R5 represents a hydrogen atom, a nitro group, a cyano group,
C1-C6 substituted or unsubstituted alkyl group, C2-C6 substituted or unsubstituted alkenyl group, C2-C6 substituted or unsubstituted alkynyl group, substituted or unsubstituted aryl group, C1-C6 alkoxy group, substituted or unsubstituted aryloxy group , Formyl, halogen, mono- or di- (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl)
Substituted amino group, hydroxy group, mono- or di- (C
1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted amide group, N-substituted or unsubstituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbamoyl group, unsubstituted or mono- or Di- or tri (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) substituted ureido group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) carbonyl group, (C1-C6
Substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarbonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted) Aryl) thiocarbonyl group, (C1
-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxythiocarbonyl group, thiol group, (C
1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) thio group, unsubstituted or mono-N substituted (C
1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfamoyl group, unsubstituted or mono- or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) sulfonamide group, unsubstituted Or mono- or di-N-substituted (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfonylamino group, unsubstituted or mono- or di-N substituted (C1-C6 substituted or unsubstituted alkyl or substituted) Or unsubstituted aryl) oxycarbonylamino group,
Carboxyl group, (C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxycarboxyl group, C1-C6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl) oxysulfoxyl group, C3-C6
A substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aralkyl group, a 5- or 6-membered substituted or unsubstituted heteroaromatic ring containing at least one O atom or S atom or N atom, an O atom or S atom or N atom. It represents a 5- or 6-membered substituted or unsubstituted heterocyclic saturated ring containing at least one. ] Toluidines represented by the acylating agent (the acylating agent used herein is not only a group derived by removing -OH from the carboxyl group of a carboxylic acid, but also an inorganic agent such as sulfuric acid, nitric acid, and phosphoric acid. Acid or carbamic acid, carbonic acid,
It means a group derived from a broadly defined acid except for -OH, including a group derived from organic acids such as sulfonic acid and phosphonic acid by removing -OH. The following general formula (2) obtained by reacting [Wherein R1, R2, R3, R4, and R5 are the same as described above] in an organic solvent, in the presence of N, N-dimethylformamide dialkylacetals and an organic secondary amine, or Reacting in the absence of the following general formula (3) [Wherein R1, R2, R3, R4, and R5 are the same as described above]. 2. The process for producing an indole derivative according to claim 1, wherein R2, R4 and R5 are hydrogen atoms. 3. R2, R4, and R5 are hydrogen atoms;
1. The method for producing an indole derivative according to claim 1, wherein R3 is an electron-withdrawing group. 4. R2, R4, and R5 are hydrogen atoms;
2. The method for producing an indole derivative according to claim 1, wherein when one of R1 and R3 is a hydrogen atom, the other is an electron-withdrawing group. 5. R2, R4, R5 are hydrogen atoms, and R
2. The method for producing an indole derivative according to claim 1, wherein when one of R1 and R3 is a hydrogen atom, the other is a nitro group. 6. The method for producing an indole derivative according to claim 1, wherein R2, R3, R4 and R5 are hydrogen atoms and R1 is a nitro group. 7. The process according to claim 1, wherein the acylating agent used for obtaining the N-acyl compound is acetic anhydride. 8. The method according to claim 1, wherein the N, N-dimethylformamide dialkyl acetal is N, N-dimethylformamide dimethyl acetal. 9. The method according to claim 1, wherein when an organic secondary amine is used, it is pyrrolidine or piperidine.