Method for producing indole compound

Abstract

To provide a method for producing an indole compound by which a desired product can be obtained at high yield in an indole cyclization reaction using sodium dithionite.SOLUTION: A compound represented by formula (1) is reacted with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent to produce an indole compound represented by formula (2). In formula (1) and formula (2), R1 represents methyl, methoxy, or ethoxy, R2 represents a halogen atom, and n represents an integer of 1, 2, 3, or 4.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a process for producing an indole compound. [Background technology]

[0002] Indole compounds are useful as intermediates for various fine chemicals including physiologically active substances such as medicines, agrochemicals, etc. Various methods for producing the indole compounds are known, for example, as described in Patent Documents 1 to 8. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2003 / 082860 [Patent Document 2] International Publication No. 2005 / 000812 [Patent Document 3] International Publication No. 2006 / 057354 [Patent Document 4] International Publication No. 2007 / 092751 [Patent Document 5] International Publication No. 2010 / 108651 [Patent Document 6] International Publication No. 2005 / 049559 [Patent Document 7] International Publication No. 2008 / 053221 [Patent Document 8] China Patent Application Publication No. 110590739 Summary of the Invention [Problem to be solved by the invention]

[0004] However, the above-mentioned conventional techniques have various problems. For example, in the manufacturing method using heavy metals such as iron, iron complexes, or palladium on carbon, the disposal of waste liquid and waste is a problem. Also, in the manufacturing method using carbon monoxide under high pressure, there are manufacturing problems such as the operation of high-pressure equipment.

[0005] Furthermore, in the production method using sodium dithionite, depending on the target compound, the yield may be low in the reaction in water or a polar solvent, or in the reaction in the presence of a basic compound.

[0006] An object of one embodiment of the present invention is to provide a method for producing an indole compound, which can provide a target product in high yield through an indole cyclization reaction using sodium dithionite. [Means for solving the problem]

[0007] In order to solve the above problems, a method for producing an indole compound according to one embodiment of the present invention comprises reacting a compound represented by the following formula (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent to produce an indole compound represented by the following formula (2). In formulas (1) and (2), R1 represents methyl, methoxy, or ethoxy, R2 represents a halogen atom, and n represents an integer of 1, 2, 3, or 4.

[0008] [ka]

[0009] In order to solve the above problems, a method for producing an indole compound according to one embodiment of the present invention includes a first step of producing a compound represented by the following formula (2) by reacting a compound represented by the following formula (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent, and a second step of producing an indole compound represented by the following formula (3) from the compound represented by the formula (2), the second step including a step of heating the compound represented by the formula (2) in the presence of water and an acidic compound or a basic compound. In formulas (1) and (2), R1 represents methyl, methoxy, or ethoxy, and in formulas (1) to (3), R2 represents a halogen atom, and n represents an integer of 1, 2, 3, or 4.

[0010] [ka] Effect of the Invention

[0011] According to one embodiment of the present invention, a target indole compound can be obtained in high yield in an indole cyclization reaction using sodium dithionite. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] A first production method for an indole compound according to an embodiment of the present invention is a method for producing an indole compound represented by the following formula (2) (hereinafter also referred to as "compound (2)") using a compound represented by the following formula (1) (hereinafter also referred to as "compound (1)") as a starting material.

[0013] [ka] [In formulas (1) and (2), R1 represents methyl, methoxy, or ethoxy; in formulas (1) and (2), R2 represents a halogen atom; and n represents an integer of 1, 2, 3, or 4].

[0014] In addition, a second production method for an indole compound according to an embodiment of the present invention is a method of producing the following compound (2) using the following compound (1) as a starting material, and further producing an indole compound represented by the following formula (3) (hereinafter also referred to as "compound (3)") using compound (2) as a starting material.

[0015] [ka] [In formulas (1) and (2), R1 represents methyl, methoxy, or ethoxy, and in formulas (1) to (3), R2 represents a halogen atom, and n represents an integer of 1, 2, 3, or 4].

[0016] The above first and second manufacturing methods will be described in more detail below.

[0017] [First manufacturing method] The first production method in an embodiment of the present invention is a method for producing an indole compound, comprising reacting compound (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent to produce compound (2).

[0018] [ka]

[0019] [Compound (1)] Compound (1) has a keto-enol tautomer represented by formula (1') or formula (1''). The structures of formula (1') and formula (1'') are shown below. Compound (1) is a normal 1 In H-NMR, etc., a mixture of keto-enol tautomers is observed. In this specification, compound (1) represents one or both of these isomers unless otherwise specified.

[0020] [ka]

[0021] In formula (1) and formula (2), R1 represents methyl, methoxy, or ethoxy; R2 represents a halogen atom; and n represents an integer of 1, 2, 3, or 4.

[0022] The halogen atom may be any of fluorine, chlorine, bromine and iodine, and when n is 2 or more, the halogen atoms in R2 may be the same or different.

[0023] Compound (1) is preferably a compound represented by the following formula (1A). In the first production method, since the structure of compound (2) corresponds to the structure of compound (1), compound (2) is preferably a compound represented by the following formula (2A). In the following formulas (1A) and (2A), R1 represents methyl, methoxy, or ethoxy, and R2 represents a fluorine atom.

[0024] [ka]

[0025] [Aromatic hydrocarbon solvents] The aromatic hydrocarbon solvent is a solvent in the synthesis reaction in the first production method. The aromatic hydrocarbon solvent may be one or more kinds. In the first production method, by using an aromatic hydrocarbon as a solvent, it becomes possible to produce the target compound (2) in a high yield. Examples of the aromatic hydrocarbon solvent include benzene, toluene, ortho-xylene, meta-xylene, para-xylene, ethylbenzene, chlorobenzene, ortho-dichlorobenzene, meta-dichlorobenzene, para-dichlorobenzene, nitrobenzene, and tetrahydronaphthalene. Among them, it is preferable that the aromatic hydrocarbon solvent is toluene or ortho-xylene from the viewpoint of increasing the yield of compound (2).

[0026] The amount of the aromatic hydrocarbon solvent used in the first production method may be appropriately determined within the range in which compound (2) is produced. For example, the amount of the aromatic hydrocarbon solvent used in the first production method may be 0.1 to 20 parts by mass per part by mass of compound (1).

[0027] [Acidic compounds] Various acids can be used as the acidic compound. The acid may be one or more kinds. Examples of the acid include mineral acids, aliphatic carboxylic acids, and organic sulfonic acids. Examples of the mineral acids include sulfuric acid, nitric acid, phosphoric acid, and hydrochloric acid. Examples of the aliphatic carboxylic acids include formic acid, acetic acid, trifluoroacetic acid, and propionic acid. Examples of the organic sulfonic acids include methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Among them, it is preferable that the acidic compound is acetic acid or propionic acid from the viewpoint of increasing the yield of compound (2).

[0028] The amount of the acidic compound used in the first production method can be appropriately determined within the range in which compound (2) is produced in the first production method. For example, the amount of the acidic compound used in the first production method may be 0.01 to 50 molar equivalents relative to compound (1), and is preferably 0.1 to 20 molar equivalents from the viewpoint of increasing the yield of compound (2).

[0029] [Sodium dithionite] Sodium dithionite acts as a reducing agent in the first production method. The amount of sodium dithionite used in the first production method can be appropriately determined within the range in which compound (2) is produced in the first production method. For example, the amount of sodium dithionite used in the first production method may be 1 to 10 molar equivalents relative to compound (1).

[0030] [Other ingredients] In the first production method, other components than the above-mentioned components may be further added to the reaction system as long as compound (2) is produced. The other components may be one or more, and may be used as long as compound (2) is produced and the effects of the other components can be obtained.

[0031] For example, in the first production method, a base may be used in combination with an acidic compound. The base may be one or more types. Examples of the base include sodium formate, sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The use of the base in combination can favorably act on the reduction of compound (1). The amount of the base used in the first production method is preferably 0.01 to 5 molar equivalents relative to compound (1), more preferably 0.1 to 2 molar equivalents.

[0032] [Reaction temperature] The reaction temperature in the first production method can be appropriately determined within the range in which compound (2) is produced in the first production method under heating. If the reaction temperature is too high, the components in the reaction mixture in the first production method may be thermally decomposed. From the viewpoint of reaction time and yield, the reaction temperature in the first production method is preferably 50 to 150°C.

[0033] [Other conditions] The reaction in the first production method may include further conditions within the range in which compound (2) is produced in the first production method. For example, it is preferable to carry out the reaction in the first production method in an inert gas atmosphere from the viewpoint of suppressing the production of unintended by-products such as oxides. The inert gas may be any gas that is substantially inactive against the reagents and products in the reaction in the first production method. Examples of the inert gas include nitrogen gas and rare gases. From the viewpoint of lower cost, it is preferable that the inert gas is nitrogen gas.

[0034] The end point of the reaction in the first production method can be determined by a conventional method, for example, analysis of the reaction mixture.

[0035] The reaction mixture obtained in the first production method can be isolated by a conventional method. For example, the reaction mixture can be extracted with an aromatic hydrocarbon such as toluene to obtain a solution of the target compound (2).

[0036] [Second manufacturing method] The second production method in the embodiment of the present invention includes a first step of producing compound (2) by reacting compound (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent, and a second step of producing compound (3) from compound (2).

[0037] [ka]

[0038] In formulas (1) and (2), R1 represents methyl, methoxy, or ethoxy; in formulas (1) to (3), R2 represents a halogen atom; and n represents an integer of 1, 2, 3, or 4.

[0039] [First step] The first step is substantially the same as the first production method in the embodiment of the present invention described above. In the second production method, the product of the first step may be isolated, or may be subjected to the second step in the form of a solution, as long as the second step, which is the next step, can be carried out.

[0040] [Second step] The second step is a step of carrying out a deacetylation or deesterification reaction of compound (2). For example, the second step includes a step of heating compound (2) in the presence of water and an acidic or basic compound.

[0041] <Water> The amount of water used in the second step can be appropriately determined within the range in which the deacetylation or deesterification reaction of compound (2) is carried out. For example, the amount of water used in the second step may be 1 to 50 parts by mass relative to 1 part by mass of compound (2).

[0042] <Acidic compounds> The acidic compound in the second step is the same as the acidic compound in the above-mentioned first production method. The acidic compound in the second step may be the same as or different from the acidic compound in the first production method.

[0043] The amount of the acidic compound used in the second step may be appropriately determined in consideration of the valence of the acid within a range that realizes the deacetylation or deesterification reaction of compound (2). For example, the amount of the acidic compound used in the second step, in the case of sulfuric acid, may be 0.1 to 10 molar equivalents relative to compound (2) as the starting material in the second step.

[0044] <Basic compounds> Various bases can be used as the basic compound in the second step. The base may be one or more. Examples of the base include lithium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium isopropoxide, and potassium tert-butoxide. Among them, from the viewpoint of reaction operability and economic efficiency, the basic compound is preferably sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.

[0045] The amount of the basic compound used in the second production method may be appropriately determined in consideration of the valence of the base within a range that realizes the deacetylation or deesterification reaction of compound (2). For example, the amount of the basic compound used in the second step, in the case of sodium hydroxide, may be 0.1 to 10 molar equivalents relative to compound (2) as the starting material in the second step.

[0046] <Reaction temperature> The second step is carried out by heating the reaction mixture. If the reaction temperature is too high, the components in the reaction mixture may be thermally decomposed. From the viewpoint of reaction time and yield, the reaction temperature in the second step is preferably 50 to 150°C.

[0047] From the viewpoint of heating and stabilizing the temperature, the second step preferably contains an aromatic hydrocarbon as a solvent. The aromatic hydrocarbon in the second step is the same as the aromatic hydrocarbon in the first production method described above. The aromatic hydrocarbon in the second step may be the same as or different from the aromatic hydrocarbon in the first production method. From the viewpoint of realizing an appropriate reaction temperature, the aromatic hydrocarbon in the second step is preferably toluene.

[0048] <Other conditions> The second step may include further conditions within the scope of producing compound (3) by deacetylation or deesterification of compound (2). For example, the second step may be carried out in an inert gas atmosphere. The end point of the reaction in the second step may also be determined by a conventional method, and compound (3) may be isolated from the reaction mixture of the second step by a conventional method, for example, extraction with an aromatic hydrocarbon such as toluene.

[0049] <Two-step reaction> Alternatively, the second step can be carried out in a two-step reaction process as shown in the following reaction scheme, where R1 is methoxy or ethoxy.

[0050] [ka]

[0051] That is, the second step can also be realized by hydrolysis of the alkoxy of compound (2) and decarboxylation of the carboxy of the compound represented by the above formula (4) (hereinafter also referred to as "compound (4)") thus produced.

[0052] (Hydrolysis reaction) For the hydrolysis reaction, known conditions capable of realizing a hydrolysis reaction in methoxy or ethoxy of R1 can be adopted. For example, the hydrolysis reaction can be carried out by heating in a solvent containing a polar solvent and water in the presence of an acidic or basic compound.

[0053] The polar solvent may be one or more, examples of which include lower alcohols, such as alcohols having up to four carbon atoms, examples of which include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol.

[0054] The solvent for the hydrolysis reaction may further contain an aromatic hydrocarbon from the viewpoint of stabilizing the reaction temperature. The aromatic hydrocarbon for the dehydrolysis reaction is the same as the aromatic hydrocarbon described above. The aromatic hydrocarbon is preferably toluene from the viewpoint of stabilizing the reaction temperature.

[0055] The amount of each of the above components used in the hydrolysis reaction can be appropriately determined within a range in which the hydrolysis reaction can be realized. For example, if the acidic compound or basic compound is monovalent, it may be 0.1 to 10 molar equivalents relative to compound (2), which is the starting material for the hydrolysis reaction. The amount of water used in the solvent may be 1 to 50 parts by mass relative to 1 part by mass of compound (2). The amount of polar solvent used in the solvent may be 0.1 to 20 parts by mass relative to 1 part by mass of compound (2). Furthermore, the amount of aromatic hydrocarbon used in the solvent may be 0.1 to 20 parts by mass relative to 1 part by mass of compound (2).

[0056] The heating temperature in the hydrolysis reaction is preferably 50 to 150° C. from the viewpoint of promoting the hydrolysis reaction and suppressing decomposition of the components in the reaction mixture.

[0057] The reaction product of the hydrolysis reaction (the above compound (4)) can be isolated by neutralizing the reaction mixture or can exist as a salt in the aqueous layer. In carrying out the next step of the decarboxylation reaction, the compound (4) may be isolated or may be dissolved in the aqueous layer as a salt.

[0058] (Decarboxylation reaction) The decarboxylation reaction can be carried out under known conditions capable of eliminating the carboxyl group of compound (4). For example, the decarboxylation reaction can be carried out by heating in a solvent containing a polar solvent and water in the presence of an acidic or basic compound.

[0059] The polar solvent in the decarboxylation reaction is the same as the polar solvent in the hydrolysis reaction, and may be the same as or different from the polar solvent in the hydrolysis reaction. In addition, the solvent in the decarboxylation reaction may further contain an aromatic hydrocarbon from the viewpoint of stabilizing the reaction temperature, as in the hydrolysis reaction, and the aromatic hydrocarbon is preferably toluene.

[0060] The amount of each of the above components used in the decarboxylation reaction can be appropriately determined within a range in which the decarboxylation reaction can be realized. For example, if the acidic compound or basic compound is monovalent, it may be 0.1 to 10 molar equivalents relative to the above compound (4) which is the starting material for the decarboxylation reaction. The amount of water used in the solvent may be 1 to 50 parts by mass relative to 1 part by mass of compound (2). The amount of polar solvent used in the solvent may be 0.1 to 20 parts by mass relative to 1 part by mass of compound (2). Furthermore, the amount of aromatic hydrocarbon used in the solvent may be 0.1 to 20 parts by mass relative to 1 part by mass of compound (2).

[0061] The reaction temperature in the decarboxylation reaction is preferably 50 to 150° C. from the viewpoint of proceeding with the decarboxylation reaction and suppressing decomposition of the components in the reaction mixture.

[0062] Decarboxylation produces compound (3), which can be isolated from the reaction mixture by extraction with an aromatic hydrocarbon.

[0063] In both the hydrolysis reaction and the decarboxylation reaction, an acidic compound or a basic compound is used, and either an acidic compound or a basic compound may be used as long as the desired reaction proceeds. In the hydrolysis reaction, it is preferable to use a basic compound, and in the decarboxylation reaction, it is preferable to use an acidic compound.

[0064] 〔summary〕 In the first production method described above, compound (1) is used as a raw material, and reacted in an aromatic hydrocarbon solvent in the presence of sodium dithionite and an acidic compound to obtain the target 2-methyl-1H-indole-3-carbonyl compound (compound (2)) in high yield. This effect is believed to be brought about by using an aromatic hydrocarbon as a solvent for compound (1) and by making the reaction system acidic with the acidic compound.

[0065] In the first and second production methods described above, components containing heavy metals are not required, and therefore waste liquid and waste materials can be easily treated. In addition, the first and second production methods described above can be carried out at normal pressure, and therefore do not require special equipment such as high-pressure equipment, and do not require special operations for operating the equipment. Thus, the first and second production methods described above can produce compound (2) or compound (3) in high yields by using normal equipment for the production of organic compounds in the normal manner.

[0066] In the second production method described above, compound (3) can be obtained in high yield from compound (1) by further applying a conventional deacetylation or deesterification technique. In the second step of the second production method, compound (3) can be obtained in a two-step process from compound (2) via compound (4) by using an acidic compound and a basic compound appropriately and an aromatic hydrocarbon and a polar solvent appropriately as a solvent. In the second step including such two steps, compound (4) can be isolated as a solid by utilizing the difference in solubility between the raw material (compound (2)) and the product (compound (4)). Alternatively, compound (4) can be separated into the aqueous phase as a salt for an oil-soluble raw material. Therefore, such a second step is advantageous from the viewpoint of facilitating the separation of compound (2) and compound (4) and facilitating the purification of compound (4).

[0067] As is apparent from the above description, in the first production method according to an embodiment of the present invention, compound (1) is reacted with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent to produce compound (2).

[0068] A second production method according to an embodiment of the present invention includes a first step of producing compound (2) by reacting compound (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent, and a second step of producing compound (3) from compound (2). The second step includes a step of heating compound (2) in the presence of water and an acidic compound or a basic compound.

[0069] According to these embodiments of the present invention, the target indole compound can be obtained in high yield in the indole cyclization reaction using sodium dithionite.

[0070] In the first production method, the acidic compound may be acetic acid or propionic acid, which is more effective in increasing the yield of compound (2).

[0071] In the first production method, the aromatic hydrocarbon solvent may be toluene or ortho-xylene, which is more effective in increasing the yield of compound (2).

[0072] In the first production method, the reaction temperature may be 50 to 150° C. This is more effective from the viewpoint of suppressing thermal decomposition during the reaction and from the viewpoint of the balance between the reaction time and the yield.

[0073] In the first production method, compound (1) may be a compound represented by the above formula (1A), and compound (2) may be a compound represented by the above formula (2A).

[0074] According to this configuration, it is possible to produce indole compounds useful as intermediates for pharmaceuticals and agrochemicals in high yields. Therefore, the present invention can promote the development and dissemination of pharmaceuticals and agrochemicals. Thus, the present invention is expected to contribute to the achievement of the Sustainable Development Goals (SDGs) for ensuring healthy lives and resolving food problems.

[0075] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in the different embodiments are also included in the technical scope of the present invention. EXAMPLES

[0076] The present invention will be described in more detail below by giving specific examples, but the present invention is not limited to these.

[0077] The conditions for qualitative and quantitative analysis by high performance liquid chromatography (hereinafter referred to as HPLC) are described below.

[0078] [Qualitative analysis] Column: Inertsil ODS-4, 250 mm, 4.6 mm diameter, 5 μm (GL Sciences) Flow rate: 1.0mL / min Column temperature: 40℃ UV detection wavelength: 254 nm Eluent: acetonitrile / 0.1% trifluoroacetic acid aqueous solution = 50 / 50 (0-10 min)-95 / 5 (16-30 min)-50 / 50 (30.01-37 min) (volume ratio) Sample dissolution medium: acetonitrile [Quantitative analysis] For quantitative analysis using HPLC, the internal standard method was used with 1,4-diisopropylbiphenyl as the internal standard substance, and the measurement was carried out under the same measurement conditions as for the qualitative analysis.

[0079] Example 1 Preparation of 1-(6-fluoro-2-methyl-1H-indol-3-yl)ethanone (hereinafter referred to as compound (2-1)) 0.50 g of 3-(4-fluoro-2-nitrophenyl)-4-hydroxy-3-penten-2-one (hereinafter referred to as compound (1-1)), 1.88 g of acetic acid, 1.09 g of sodium dithionite, and 2.50 g of toluene were added to a reaction vessel, and the mixture was stirred at 100°C for 22 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to 70°C, diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a toluene solution containing compound (2-1). Quantitative analysis of this toluene solution confirmed that it contained 0.29 g of compound (2-1) (yield 72.0%).

[0080] Example 2 Preparation of methyl 6-fluoro-2-methyl-1H-indole-3-carboxylate (hereinafter referred to as compound (2-2)) 0.50 g of 2-(4-fluoro-2-nitrophenyl)-3-hydroxy-2-butenoic acid methyl ester (hereinafter referred to as compound (1-2)), 1.77 g of acetic acid, 1.02 g of sodium dithionite, and 2.50 g of toluene were added to a reaction vessel, and the mixture was stirred at 100° C. for 22 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to 70° C., diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a toluene solution containing compound (2-2). Quantitative analysis of this toluene solution confirmed that it contained 0.36 g of compound (2-2) (yield 89.0%).

[0081] Example 3 Preparation of ethyl 6-fluoro-2-methyl-1H-indole-3-carboxylate (hereinafter referred to as compound (2-3)) 0.50 g of ethyl 2-(4-fluoro-2-nitrophenyl)-3-hydroxy-2-butenoate (hereinafter referred to as compound (1-3)), 1.67 g of acetic acid, 0.97 g of sodium dithionite, and 2.50 g of toluene were added to a reaction vessel, and the mixture was stirred at 100°C for 22 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to 70°C, diluted with 5.0 mL of water, and extracted with 5.7 mL of toluene to obtain a toluene solution containing compound (2-3). Quantitative analysis of this toluene solution confirmed that it contained 0.36 g of compound (2-3) (yield 88.3%).

[0082] Example 4 Preparation of compound (2-2) A reaction was carried out under the same conditions as in Example 2, except that acetic acid was replaced with 2.18 g of propionic acid, to obtain a toluene solution containing compound (2-2). Quantitative analysis of this toluene solution confirmed that it contained 0.31 g of compound (2-2) (yield 75.2%).

[0083] Example 5 Preparation of compound (2-1) A reaction was carried out under the same conditions as in Example 1, except that toluene was replaced with ortho-xylene, to obtain an ortho-xylene solution containing compound (2-1). Quantitative analysis of this ortho-xylene solution confirmed that it contained 0.32 g of compound (2-1) (yield 80.4%).

[0084] Example 6 Preparation of compound (2-2) A reaction was carried out under the same conditions as in Example 2, except that toluene was replaced with ortho-xylene, to obtain an ortho-xylene solution containing compound (2-2). Quantitative analysis of this ortho-xylene solution confirmed that it contained 0.35 g of compound (2-2) (yield 85.8%).

[0085] Example 7 Preparation of compound (2-3) A reaction was carried out under the same conditions as in Example 3, except that toluene was replaced with ortho-xylene, to obtain an ortho-xylene solution containing compound (2-3). Quantitative analysis of this ortho-xylene solution confirmed that it contained 0.35 g of compound (2-3) (yield 85.7%).

[0086] Example 8 Preparation of 6-fluoro-2-methyl-1H-indole (hereinafter referred to as compound (3-1)) 0.50 g of compound (2-2), 0.43 g of sodium hydroxide, 7.50 g of water, and 1.50 g of toluene were added to a reaction vessel and stirred under heating and reflux for 26 hours. After the reaction was completed, the reaction mixture was cooled to 40°C and extracted with 1.7 mL of toluene. The resulting organic layer was washed with 1.5 mL of water, and a toluene solution containing compound (3-1) was obtained. Quantitative analysis of this toluene solution confirmed that it contained 0.36 g of compound (3-1) (yield 98.8%).

[0087] Example 9 Preparation of compound (3-1) 0.50 g of compound (2-1), 2.57 g of 50% by mass aqueous sulfuric acid solution, and 2.50 g of toluene were added and stirred under heating and reflux for 9 hours. After the reaction was completed, the reaction mixture was cooled to 70°C, diluted with 3.5 mL of water, and then extracted with 1.2 mL of toluene. The resulting organic layer was washed with 1.5 mL of water to obtain a toluene solution containing compound (3-1). Quantitative analysis of this toluene solution confirmed that it contained 0.36 g of compound (3-1) (yield 91.8%).

[0088] [Examples 10 and 11] Preparation of compound (3-1) Except for changing the type of raw material, the amount of 50% by mass aqueous sulfuric acid solution used, and the reaction time, the reaction was carried out under the same conditions as in the method described in Example 9. The amount of each reagent used, the reaction time, and the yield are shown in Table 1 below.

[0089] [Table 1]

[0090] Example 12 Preparation of compound (3-1) A reaction was carried out under the same conditions as in Example 8, except that 0.87 g of sodium hydroxide, 12.50 g of water, and the reaction time were changed to 23 hours, to obtain a toluene solution containing compound (3-1). Quantitative analysis of this toluene solution confirmed that it contained 0.35 g of compound (3-1) (yield 97.8%).

[0091] Example 13 Preparation of compound (3-1) 2.00 g of compound (2-2), 6.01 g of methanol, 2.90 g of 40% by mass aqueous sodium hydroxide solution, and 4.27 g of water were added to a reaction vessel, and the mixture was stirred for 16 hours under heating and reflux. After the reaction was completed, the reaction mixture was cooled to 30°C, diluted with 13.8 mL of toluene, and then extracted with 6.0 mL of water. The resulting aqueous layer was washed with 13.8 mL of toluene, and then 6.0 mL of water was added. The reaction mixture was cooled to 10°C, and 3.52 g of 35% by mass hydrochloric acid was added dropwise, and the mixture was stirred for 0.5 hours. The precipitated solid was filtered, washed with 12.01 g of water, and then dried to obtain 1.57 g of 6-fluoro-2-methyl-1H-indole-3-carboxylic acid (hereinafter referred to as compound (4-1)) (yield 84.3%).

[0092] 1.01 g of compound (4-1), 5.04 g of toluene, 1.01 g of methanol, 4.86 g of water, and 0.27 g of 35% by mass hydrochloric acid were added to a reaction vessel and stirred at 60° C. for 2 hours. The reaction solution was cooled to 30° C., and the organic layer and the aqueous layer were separated. The obtained aqueous layer was extracted with 5.8 mL of toluene, and the organic layer was mixed to obtain 10.26 g of a toluene solution containing compound (3-1). Quantitative analysis of this toluene solution confirmed that it contained 0.77 g of compound (3-1) (yield 98.6%).

[0093] Example 14 Preparation of compound (3-1) 1.00 g of compound (2-2), 3.02 g of toluene, 3.02 g of methanol, 2.42 g of 40% by mass aqueous sodium hydroxide solution, and 1.55 g of water were added to a reaction vessel, and the mixture was stirred under heating and reflux for 22 hours. The reaction solution was cooled to room temperature, and the organic layer and the aqueous layer were separated. The obtained aqueous layer was washed with 3.4 mL of toluene, and then 3.00 g of water, 4.63 g of 35% by mass hydrochloric acid, and 4.63 g of toluene were added to the washed aqueous layer, and the mixture was stirred at 60° C. for 4 hours. After cooling to room temperature, the organic layer and the aqueous layer were separated. The obtained aqueous layer was extracted with 5.3 mL of toluene, and then mixed with the organic layer to obtain 9.80 g of a toluene solution containing compound (3-1). Quantitative analysis of this toluene solution confirmed that it contained 0.54 g of compound (3-1) (yield 80.2%).

[0094] Comparative Example 1 0.30 g of compound (1-1) was used, and 0.66 g of sodium dithionite, 2.62 g of water, and 3.00 g of toluene were added to a reaction vessel, and the mixture was stirred at 100° C. for 5 hours under a nitrogen atmosphere. The organic layer after the reaction was qualitatively analyzed by HPLC. As a result, the peak area (S 2-1 ) and the peak area of ​​compound (1-1) (S 1-1 ) area ratio (S 2-1 / S 1-1 ) was 25 / 75 (Rt = 6.4 min / 13.8 min). In addition, the sum of the relative area percentages of compound (2-1) and compound (1-1), after removing the peak of the solvent toluene, was 98.6%.

[0095] Comparative Example 2 The reaction was carried out under the same conditions as in Comparative Example 1, except that compound (1-2) was used instead of compound (1-1). After the reaction, the organic layer was subjected to qualitative analysis using HPLC. As a result, the peak area (S 2-2 ) and the peak area of ​​compound (1-2) (S 1-2 ) area ratio (S 2-2 / S 1-2 ) was 20 / 80 (Rt = 10.2 min / 8.8 min, 15.0 min). In addition, the sum of the relative area percentages of compound (2-2) and compound (1-2), after removing the peak of the solvent toluene, was 79.6%.

[0096] Comparative Example 3 0.20 g of 3-(4-fluoro-2-nitrophenyl)acetone (hereinafter also referred to as "FNPA") was used, and 0.60 g of acetic acid, 0.53 g of sodium dithionite, 1.00 g of toluene, and 0.04 g of sodium acetate were added to a reaction vessel, and the mixture was stirred at 100°C for 4.5 hours under a nitrogen atmosphere. The solution after the reaction was qualitatively analyzed by HPLC. As a result, the peak area (S 3-1 ) and the FNPA peak area (S FNPA The area ratio (S 3-1 / S FNPA) was 73 / 27 (Rt = 12.6 min / 7.5 min). In addition, the sum of the relative area percentages of compound (3-1) and FNPA, excluding the peak of the solvent toluene, was 40.5%.

[0097] Example 15 The reaction was carried out under the same conditions as in Comparative Example 3, except that compound (1-2) was used instead of FNPA. After the reaction, the solution was subjected to qualitative analysis using HPLC. 2-2 / S 1-2 The peak area was 100 / 0 (Rt = 10.2 min / 8.8 min, 15.0 min). In addition, the sum of the relative area percentages of compound (2-2) and compound (1-2), after removing the peak of the solvent toluene, was 65.4%. [Industrial Applicability]

[0098] The present invention can be utilized for efficient production of pharmaceuticals and agrochemicals, and is expected to contribute to the further development and popularization of pharmaceuticals and agrochemicals.

Claims

1. A method for producing an indole compound, comprising reacting a compound represented by the following formula (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent to produce an indole compound represented by the following formula (2): [Case 1] (In formula (1) and formula (2), R １ represents methyl, methoxy, or ethoxy; R ２ represents a halogen atom, and n represents an integer of 1, 2, 3, or 4.

2. The method according to claim 1 , wherein the acidic compound is acetic acid or propionic acid.

3. The method according to claim 1 or 2, wherein the aromatic hydrocarbon solvent is toluene or orthoxylene.

4. The method according to any one of claims 1 to 3, wherein the reaction temperature is 50 to 150°C.

5. The method according to any one of claims 1 to 4, wherein the compound represented by formula (1) is a compound represented by the following formula (1A), and the indole compound represented by formula (2) is a compound represented by the following formula (2A). [Case 2] (In formula (1A) and formula (2A), R １ represents methyl, methoxy, or ethoxy; R ２ represents a fluorine atom)

6. A first step of producing a compound represented by the following formula (2) by reacting a compound represented by the following formula (1) with an acidic compound and sodium dithionite under heating in an aromatic hydrocarbon solvent; A second step of producing an indole compound represented by the following formula (3) from the compound represented by the formula (2), The second step comprises heating the compound represented by formula (2) in the presence of water and an acidic compound or a basic compound. [C3] (In formula (1) and formula (2), R １ represents methyl, methoxy, or ethoxy; in formulas (1) to (3), R ２ represents a halogen atom, and n represents an integer of 1, 2, 3, or 4.

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