Method for producing formamide compound

Abstract

To provide a method for producing a formamide compound with high production efficiency.SOLUTION: According to an embodiment, a method for producing a formamide compound is provided. The production method comprises contacting a crude formamide compound represented by formula (1), an aqueous solution of a reducing agent, and a lower alcohol having 1 to 5 carbon atoms, to precipitate crystals of the formamide compound represented by formula (1). In formula (1), R1 is a phenyl group optionally substituted with a halogen atom, and R2 is an alkyl group having 1 to 5 carbon atoms.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a formamide compound. [Background technology]

[0002] The formamide compound represented by the following formula (1) is useful as a production intermediate for iguratimod, which is useful as an anti-inflammatory agent.

[0003] [ka]

[0004] In formula (1), R 1 is a phenyl group optionally substituted with a halogen atom, R 2 is an alkyl group having 1 to 5 carbon atoms.

[0005] A known method for producing the formamide compound is described in Patent Document 1. Specifically, a crude formamide compound (1) is obtained by contacting a benzene derivative represented by the following formula (2) with sodium iodide in the presence of aluminum chloride using a nitrile compound as a solvent, and then a liquid containing the crude form is contacted with an aqueous solution of a reducing agent to precipitate crystals, thereby producing crystals of formamide compound (1).

[0006] [ka]

[0007] In equation (2), R 1 is a phenyl group optionally substituted with a halogen atom, R 2 is an alkyl group having 1 to 5 carbon atoms, R 3 is an alkyl group having 1 to 5 carbon atoms. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 5-97840 [Patent Document 2] Japanese Patent Application Publication No. 2-49778 Summary of the Invention [Problem to be solved by the invention]

[0009] The formamide compound was produced by the method described in Patent Document 1, and a solution containing the crude formamide compound was added dropwise to an aqueous solution of a reducing agent. As the addition proceeded, the precipitated microcrystals of the formamide compound aggregated, visually confirming the formation of coarse, agglomerated crystals with a longest side of 5.0 mm or more. Agglomerated crystals can clog pipes during production, potentially resulting in production problems. Furthermore, because the crystals can absorb impurities from the mixed solution as they form, agglomerated crystals can result in a decrease in purity and an increase in apparent yield. A decrease in purity may require additional purification or adversely affect the reaction in the next step due to impurities. An increase in apparent yield would require the use of more reagents in the next step, which is disadvantageous in terms of side reactions and production costs. [Means for solving the problem]

[0010] According to an embodiment, there is provided a method for producing a formamide compound, which comprises contacting a crude formamide compound represented by the following formula (1) with an aqueous solution of a reducing agent and a lower alcohol having 1 to 5 carbon atoms to precipitate crystals of the formamide compound represented by formula (1):

[0011] [ka]

[0012] In formula (1), R 1is a phenyl group optionally substituted with a halogen atom, R 2 is an alkyl group having 1 to 5 carbon atoms.

[0013] According to the production method of the embodiment, crystals of a formamide compound having a small particle size can be obtained. In order to solve the above-mentioned problem, the present inventors focused on the precipitation behavior of crystals when a solution containing a crude formamide compound (1) is brought into contact with an aqueous solution of a reducing agent. When a solution containing a crude formamide compound (1) is added dropwise to an aqueous solution of a reducing agent, the precipitated fine crystals are dispersed in the solution at the beginning of the addition. However, as the addition proceeds and the amount of precipitated crystals increases, the precipitated crystals aggregate, and eventually, coarse crystals of formamide compound (1) measuring 5.0 mm or more on a side are formed as visually observed. The present inventors considered that, since the crystals aggregate as the addition of the solution containing a crude formamide compound proceeds, changes in the dielectric constant of the solvent significantly affect the precipitation state of the crystals. Therefore, it was expected that by contacting another organic solvent with a liquid containing crude formamide compound (1) and an aqueous solution of a reducing agent and changing the dielectric constant of the mixed liquid, aggregation of the crystals could be suppressed during crystal precipitation. In the method according to the embodiment, a lower alcohol having 1 to 5 carbon atoms is mixed when crude formamide compound (1) is contacted with an aqueous solution of a reducing agent. By precipitating crystals of formamide compound (1) under these conditions, the crystals are formed in a suspended state. As a result, coarsening of the above-mentioned crystals of formamide compound (1) can be suppressed, and crystals of formamide compound (1) can be produced in a state where the crystals are dispersed in the liquid. [Effects of the Invention]

[0014] According to the production method of the present invention, formamide compound (1) having a small particle size is precipitated in a dispersed state in a liquid, thereby preventing the crystals from forming clumps and enabling the production of crystals of formamide compound (1) with good operability. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention is a method for producing a formamide compound, which comprises contacting a crude formamide compound with an aqueous solution of a reducing agent and a lower alcohol having from 1 to 5 carbon atoms to precipitate crystals of formamide compound (1).

[0016] The present invention will be described in detail below.

[0017] (Crude formamide compound) The formamide compound is represented by the following formula (1).

[0018] [ka]

[0019] In formula (1), R 1 R is a phenyl group optionally substituted with a halogen atom. The halogen atom is, for example, a chlorine atom, a bromine atom, or an iodine atom. 1 is preferably a phenyl group.

[0020] R 2 is an alkyl group having 1 to 5 carbon atoms. 2 is preferably a methyl group or an ethyl group, more preferably a methyl group.

[0021] The crude formamide compound (1) can be produced by contacting a benzene derivative of the following general formula (2) with a halide salt in the presence of a Lewis acid.

[0022] [ka]

[0023] In equation (2), R 1 , R 2 , has the same meaning as in formula (1). 3 is an alkyl group having 1 to 5 carbon atoms, and is preferably a methyl group.

[0024] The Lewis acid is not particularly limited, but examples thereof include aluminum chloride, aluminum bromide, zinc chloride, zinc bromide, iron chloride, tin chloride, boron tribromide, boron trichloride, and titanium chloride. The Lewis acid preferably contains at least one selected from the group consisting of aluminum chloride, aluminum bromide, zinc chloride, tin chloride, and titanium chloride, and more preferably contains aluminum chloride. The amount of the Lewis acid used is 2.0 to 4.0 mol, preferably 2.0 to 3.0 mol, per mol of the benzene derivative of general formula (2).

[0025] The halide salt is not particularly limited, but preferably contains at least one selected from the group consisting of sodium iodide, lithium iodide, potassium iodide, sodium bromide, lithium bromide, and potassium bromide, and most preferably contains potassium iodide. The amount of the halide salt used is 1.0 to 4.0 mol, preferably 1.1 to 2.0 mol, per 1 mol of the benzene derivative of general formula (2).

[0026] The contact of the benzene derivative of general formula (2) with the halide salt is preferably carried out in the presence of an organic solvent. The organic solvent used is not particularly limited as long as it does not adversely affect the reaction. Examples include nitrile compounds such as acetonitrile, benzonitrile, and propionitrile; and halogenated hydrocarbon compounds such as methylene chloride and 1,2-dichloroethane. These may be mixed appropriately. A nitrile compound is preferred, and acetonitrile is more preferred, because it provides high solubility for the starting benzene derivative (2), is highly reactive, and does not inhibit the desired reaction. The amount of organic solvent used can be selected appropriately, but is preferably 2 mL to 5 mL per 1 g of the benzene derivative of general formula (2).

[0027] The reaction time can be appropriately selected depending on the Lewis acid used and the reaction temperature, but is usually 1 to 10 hours.

[0028] The compound of general formula (2) can be produced by the method described in Patent Document 2, for example.

[0029] (aqueous solution of reducing agent) The purpose of using a reducing agent is to reduce elemental halogens. In the reaction of the benzene derivative of formula (2) with a halide salt, the halide salt is consumed, and an alkyl halide can be produced as a by-product. The resulting alkyl halide is oxidized by oxygen in the air and converted to an elemental halogen. This elemental halogen can be contained in the crude formamide compound (1). If the elemental halogen remains in the crystals of the target formamide compound (1), it may react as an oxidizing agent and cause the decomposition of formamide compound (1). By using a reducing agent, the elemental halogen produced is reduced to hydrogen halide, preventing the decomposition of formamide compound (1). Furthermore, hydrogen halide tends to be more water-soluble than elemental halogen, making it easier to remove.

[0030] The aqueous solution of the reducing agent used is not particularly limited as long as it does not affect the stability of the formamide compound (1). However, from the viewpoint of inexpensive procurement, an aqueous solution containing at least one compound selected from the group consisting of sodium sulfite, sodium thiosulfate, and sodium hydrogen sulfite is preferred. An aqueous sodium sulfite solution is preferred. Its concentration is not particularly limited, but is preferably 1 to 5%. The amount of reducing agent is preferably 0.25 to 0.6 mol per mol of the halide salt used. The amount of water can be appropriately selected based on the solubility of the formamide compound (1), but is preferably 3 mL to 10 mL per 1 g of the benzene derivative of general formula (2).

[0031] (lower alcohol) The lower alcohol used is a lower alcohol having 1 to 5 carbon atoms, and specific examples include methanol, ethanol, normal propanol, isopropanol, normal butyl alcohol, isobutyl alcohol, and tertiary butyl alcohol.

[0032] These lower alcohols can be used alone or as a mixed solvent of two or more kinds at any mixing ratio. Among these, it is preferable to use at least one selected from the group consisting of methanol, ethanol, normal propanol, and isopropanol, because they have a relatively low boiling point and are easily removed from the formamide compound.

[0033] The amount of the lower alcohol used can be selected arbitrarily, but is, for example, 0.5 mL to 10 mL, preferably 1 mL to 5 mL, per 1 g of the crude compound of general formula (1).

[0034] The weight of the crude product can be estimated, for example, by using high performance liquid chromatography (HPLC) and a calibration curve prepared from a standard substance of general formula (1), from the weight of the liquid containing the crude product and the detected area value.

[0035] (Contacting a crude formamide compound with an aqueous solution of a reducing agent and a lower alcohol) It is preferable that the aqueous solution of the reducing agent and the lower alcohol are mixed in advance before being brought into contact with the crude formamide compound. The temperature and time when the aqueous solution of the reducing agent and the lower alcohol are brought into contact with the liquid containing the crude formamide compound are not particularly limited, but are usually 0 to 40°C, preferably 0 to 30°C, for 1 to 6 hours.

[0036] (Operations after contact) After contacting the crude formamide compound with an aqueous solution of a reducing agent and a lower alcohol, if the formamide compound precipitates as a solid in the dispersion, the target formamide compound crystals can be easily obtained by known procedures such as filtration. If the formamide compound does not precipitate, it can be precipitated by adding a solvent in which the compound has low solubility, and the target formamide compound crystals can be obtained by the same procedures. The drying temperature and time are not particularly limited as long as they do not affect the stability of the formamide compound, but are usually about 6 hours at 40°C.

[0037] (formamide compounds) The purity of the obtained formamide compound can be confirmed, for example, by high performance liquid chromatography (HPLC). If the formamide compound is sufficiently pure, it may be used in the next reaction as is, or may be further purified. In such a case, a production method may include washing the acylated benzene derivative after filtration with water and / or an alcohol such as isopropyl alcohol.

[0038] The formamide compound, particularly formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, can be suitably used as a production intermediate for 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod). Specifically, a known method for producing 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one is a one-step production method from formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, which is produced by the production method of the present invention. 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one can be obtained by subjecting the resulting compound to a ring-closure reaction. [Example]

[0039] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0040] The examples are examples of the case where crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone obtained from formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, represented by the following formula, is used.

[0041] [ka]

[0042] The evaluations in the examples were carried out by the following methods.

[0043] <Quantitative determination of crude substance (HPLC measurement conditions)> Apparatus: Liquid chromatograph (Waters Corporation) Detector: UV absorption photometer Measurement wavelength: 240nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm, packed with 5 μm octadecyl silica silica gel for liquid chromatography. Mobile phase A: 8.16 g of potassium dihydrogen phosphate was dissolved in 3000 mL of water, and then phosphoric acid was added to adjust the pH to 2.5. Mobile phase B: acetonitrile Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows:

[0044] [Table 1]

[0045] Flow rate: 0.8 mL per minute Column temperature: constant temperature around 30°C Measurement time: 50 minutes A calibration curve was prepared using a standard substance of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.

[0046] <How to create a calibration curve> 10 mg, 20 mg, and 30 mg of the standard substance were precisely weighed into three 20 mL volumetric flasks, and a 1:1 mixture of water and acetonitrile was added to make exactly 20 mL for dissolution. These three standard solutions were analyzed by HPLC, and a calibration curve was created based on the area values of the detected peaks.

[0047] <Crude mass quantification method> 100 mg of the liquid containing the crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone is weighed out and made into exactly 20 mL with a 1:1 mixture of water and acetonitrile. The solution is analyzed by HPLC, and the content of the crude product is calculated using the calibration curve from the detected area value and the total weight of the liquid containing the crude product.

[0048] (Comparative Example 1) 35.3 g of anhydrous aluminum chloride was added in portions to 150 mL of acetonitrile while maintaining the temperature below 20°C. Next, 50.0 g of formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 21.8 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature at 20°C. The quantitative yield of crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone calculated using the above quantitative method was 46.2 g. The reaction suspension containing crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was added dropwise to 450 mL of 2.0% aqueous sodium sulfite solution and then cooled to 10°C. Crystals of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone precipitated in the mixture. Visual inspection revealed that the longest side of the crystals was 5.0 mm or longer. The precipitated crystals were then collected by filtration, washed with water and ethanol in that order, and then dried to obtain 43.0 g (yield 89.3%) of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.

[0049] Example 1 35.3 g of anhydrous aluminum chloride was added in portions to 150 mL of acetonitrile while maintaining the temperature below 20°C. Next, 50.0 g of formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 21.8 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature at 20°C. The quantitative yield of crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone calculated using the above quantitative method was 46.2 g. The reaction suspension containing crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was added dropwise to a mixture of 450 mL of 2.0% aqueous sodium sulfite and 100 mL of isopropyl alcohol, and then cooled to 10°C. Visual inspection revealed that crystals of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone were precipitated as a suspension in the mixture. The longest side of the crystals was 0.5 mm or less. The precipitated crystals were then collected by filtration. The precipitated crystals were washed with water and ethanol, and then dried to obtain 44.9 g (yield 93.3%) of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.

[0050] Example 2 35.3 g of anhydrous aluminum chloride was added in portions to 150 mL of acetonitrile while maintaining the temperature below 20°C. Next, 50.0 g of formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 21.8 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature at 20°C. The quantitative yield of crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone calculated using the above quantitative method was 46.3 g. To the reaction suspension containing crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 100 mL of isopropyl alcohol and 450 mL of 2.0% aqueous sodium sulfite solution were added dropwise, in that order, at 10°C. Visual inspection revealed that crystals of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone were precipitated in a suspended state within the mixture. The longest side of the crystals was 0.5 mm or less. The precipitated crystals were then collected by filtration. The precipitated crystals were washed with water and ethanol, and then dried to obtain 46.3 g (yield 96.4%) of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.

[0051] Example 3 35.3 g of anhydrous aluminum chloride was added in portions to 150 mL of acetonitrile while maintaining the temperature below 20°C. Next, 50.0 g of formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 21.8 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature at 20°C. The quantitative yield of crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone calculated using the above quantitative method was 46.3 g. To the reaction suspension containing crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 100 mL of ethanol and 450 mL of 2.0% aqueous sodium sulfite solution were added dropwise, in that order, at 10°C. Visual inspection revealed that crystals of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone were precipitated as a suspension in the mixture. The longest side of the crystals was 0.5 mm or less. The precipitated crystals were then collected by filtration. The precipitated crystals were washed with water and ethanol, and then dried to obtain 45.2 g (yield 94.0%) of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.

[0052] Example 4 35.3 g of anhydrous aluminum chloride was added in portions to 150 mL of acetonitrile while maintaining the temperature below 20°C. Next, 50.0 g of formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone and 21.8 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature at 20°C. The quantitative yield of crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone calculated using the above quantitative method was 46.3 g. To the reaction suspension containing crude formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 100 mL of methanol and 450 mL of 2.0% aqueous sodium sulfite solution were added dropwise, in that order, at 10°C. Visual inspection revealed that crystals of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone were precipitated as a suspension in the mixture. The longest side of the crystals was 0.5 mm or less. The precipitated crystals were then collected by filtration. The precipitated crystals were washed with water and ethanol, and then dried to obtain 43.2 g (89.7% yield) of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone.

[0053] Example 5 20.5 g of N,N-dimethylformamide dimethyl acetal was added to 75 mL of N,N-dimethylformamide and cooled to 10-15°C. 4.12 g of glacial acetic acid and 25.0 g of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone (prepared in Example 1) were added sequentially to this mixture. The mixture was stirred at 15-20°C for 5 hours. 125 mL of methylene chloride was added to the reaction suspension, and the resulting solution was uniformly dissolved. The resulting solution was added dropwise to 250 mL of water, and the pH was adjusted to 5.0. The precipitated crystals were collected by filtration, washed sequentially with methylene chloride, water, and ethanol, and then dried. The resulting crystals were then dissolved in aqueous acetone with potassium hydroxide, neutralized by adding hydrochloric acid, and collected by filtration. The obtained crystals were washed with water and then dried to obtain 22.2 g (yield 86.4%) of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod).

[0054] Preferred embodiments are listed below.

[0055] A method for producing a formamide compound, comprising contacting a crude formamide compound represented by the following formula (1) with an aqueous solution of a reducing agent and a lower alcohol having 1 to 5 carbon atoms to precipitate crystals of the formamide compound represented by the formula (1):

[0056] [ka]

[0057] In the formula (1), R 1 is a phenyl group optionally substituted with a halogen atom, R 2 is an alkyl group having 1 to 5 carbon atoms.

[0058] The crude formamide compound represented by the formula (1) can be obtained by contacting a benzene derivative represented by the following formula (2) with a halide salt in the presence of a Lewis acid, according to the production method described in [1]:

[0059] [ka]

[0060] In the formula (2), R 1 and R 2 has the same meaning as in the formula (1), R 3 is an alkyl group having 1 to 5 carbon atoms.

[0061] The production method according to [2], wherein the benzene derivative represented by the formula (2), the Lewis acid, and the salt of the halide are contacted in the presence of a nitrile compound.

[0062] The method according to [3], wherein the amount of the nitrile compound per 1 g of the benzene derivative represented by the formula (2) is 2 mL or more and 5 mL or less.

[0063] The production method according to any one of [1] to [4], wherein the lower alcohol includes at least one selected from the group consisting of methanol, ethanol, normal propanol, and isopropyl alcohol.

[0064] The method according to any one of [1] to [5], wherein the amount of the lower alcohol per 1 g of the crude formamide compound represented by the formula (1) is 1 mL or more and 5 mL or less.

[0065]

[0023] A method for producing formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone by the production method according to any one of [1] to [6], and then using the resulting formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone to produce 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

Claims

1. A method for producing a formamide compound, comprising contacting a crude formamide compound represented by the following formula (1) with an aqueous solution of a reducing agent and a lower alcohol having 1 to 5 carbon atoms to precipitate crystals of the formamide compound represented by the formula (1): 【Chemical 1】 In the formula (1), R １ is a phenyl group optionally substituted with a halogen atom, R ２ is an alkyl group having 1 to 5 carbon atoms.

2. The crude formamide compound represented by formula (1) is obtained by contacting a benzene derivative represented by formula (2) below with a halide salt in the presence of a Lewis acid, according to the production method of claim 1: 【Chemistry 2】 In the formula (2), R １ and R ２ has the same meaning as in the formula (1), R ３ is an alkyl group having 1 to 5 carbon atoms.

3. 3. The production method according to claim 2, wherein the benzene derivative represented by formula (2), the Lewis acid, and the halide salt are contacted in the presence of a nitrile compound.

4. The method according to claim 3, wherein the amount of the nitrile compound per 1 g of the benzene derivative represented by the formula (2) is 2 mL or more and 5 mL or less.

5. The method according to claim 1, wherein the lower alcohol comprises at least one selected from the group consisting of methanol, ethanol, normal propanol, and isopropyl alcohol.

6. 2. The method according to claim 1, wherein the amount of the lower alcohol relative to 1 g of the crude formamide compound represented by formula (1) is 1 mL or more and 5 mL or less.

7. A method for producing formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone by the production method according to claim 1, and then using the resulting formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone to produce 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.

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