Methods for producing acylated benzene derivatives or salts thereof, acid salts of acylated benzene derivatives, and iguratimod, and compositions

Abstract

The present invention provides acylated benzene derivatives or salts thereof with few impurities, salts of acylated benzene derivatives, methods for producing iguratimod, and compositions thereof. [Solution] According to the embodiment, a method for producing an acylated benzene derivative or a salt thereof is provided. This production method includes contacting a benzene derivative represented by formula (2) with aminoacetonitrile or a salt thereof in the presence of a Lewis acid to obtain a first mixture, contacting the first mixture with a protic solvent to obtain a second mixture, and then contacting the second mixture with hydrogen chloride to obtain a crude acylated benzene derivative represented by formula (1) or a salt thereof, or contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting the third mixture with a protic solvent to obtain a crude acylated benzene derivative represented by formula (1) or a salt thereof.

Description

[Technical Field]

[0001] The present invention relates to acylated benzene derivatives or salts thereof, acid salts of acylated benzene derivatives, and methods for producing iguratimod, as well as compositions thereof. [Background technology]

[0002] The acylated benzene derivative represented by formula (1) below is useful as a production intermediate for 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod), which is useful as an anti-inflammatory agent. For example, iguratimod can be produced by the method described in Patent Document 1.

[0003] [ka]

[0004] In equation (1), R 1 R is a phenyl group which may be substituted with a halogen atom, 2 R is an alkyl group having 1 to 5 carbon atoms. 3 This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0005] Iguratimod is represented by the following formula (I).

[0006] [ka]

[0007] As a method for producing an acid salt of the above acylated benzene derivative (1), the method disclosed in Patent Document 1 is known. Specifically, a crude product of the acylated benzene derivative (1) is obtained by bringing a benzene derivative into contact with a nitrile derivative or a salt thereof in the presence of a Lewis acid such as aluminum chloride and an inorganic acid such as hydrogen chloride. Then, crystals of the acid salt of the acylated benzene derivative (1) can be produced by bringing a liquid containing this crude product into contact with an aqueous inorganic acid solution to precipitate crystals. Here, when hydrochloric acid is used as the aqueous inorganic acid solution, the crystals of the acid salt of the acylated benzene derivative (1) are produced as a hydrochloride salt. [Prior Art Document] [Patent Document]

[0008] [Patent Document 1] Japanese Unexamined Patent Publication No. Hei 5-97840 [Summary of the Invention] [Problem to be Solved by the Invention]

[0009] An object of the present invention is to provide an acylated benzene derivative or a salt thereof with less impurities, an acid salt of the acylated benzene derivative, a method for producing iguratimod, and a composition. [Means for Solving the Problem]

[0010] According to an embodiment, a method for producing an acylated benzene derivative or a salt thereof is provided. This production method comprises: bringing a benzene derivative represented by the following formula (2) into contact with aminoacetonitrile or a salt thereof in the presence of a Lewis acid to obtain a first mixture; and after bringing the first mixture into contact with a protic solvent to obtain a second mixture, bringing the second mixture into contact with hydrogen chloride to obtain a crude product of the acylated benzene derivative represented by the following formula (1) or a salt thereof; or, after bringing the first mixture into contact with hydrogen chloride to obtain a third mixture, bringing the third mixture into contact with a protic solvent to obtain a crude product of the acylated benzene derivative represented by the formula (1) or a salt thereof.

[0011]

Chemical

[0012] In Formula (2), R 1 is a phenyl group optionally substituted by a halogen atom. R 2 is an alkyl group having 1 to 5 carbon atoms. R 3 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0013]

Chemical

[0014] In Formula (1), R 1 , R 2 , and R 3 have the same definitions as those in Formula (2).

[0015] According to an embodiment, there is provided a method for producing an acid salt of an acylated benzene derivative. This production method comprises bringing a crude product of the acylated benzene derivative represented by Formula (1) or a salt thereof obtained by the method according to the embodiment into contact with a first inorganic acid to obtain an acid salt of the acylated benzene derivative represented by Formula (1).

Effects of the Invention

[0016] According to the production method of the present invention, there are provided a low-impurity acylated benzene derivative or a salt thereof, an acid salt of an acylated benzene derivative, a method for producing iguratimod, and a composition.

Mode for Carrying Out the Invention

[0017] The manufacturing method according to the embodiment includes: contacting a benzene derivative represented by formula (2) with aminoacetonitrile or a salt thereof in the presence of a Lewis acid to obtain a first mixture; contacting the first mixture with a protic solvent to obtain a second mixture, and then contacting the second mixture with hydrogen chloride to obtain a crude acylated benzene derivative represented by formula (1) or a salt thereof; or contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting the third mixture with a protic solvent to obtain a crude acylated benzene derivative represented by formula (1) or a salt thereof.

[0018] This method yields highly pure acylated benzene derivatives or their salts. This is thought to be due to the contact between the first or third mixture and a protic solvent. In other words, the inventors have found that in a method that does not use a protic solvent and instead contacts the first mixture with hydrogen chloride to obtain the crude acylated benzene derivative or its salt represented by formula (1), an impurity, acylated aniline derivative or its salt represented by formula (3), is generated. The reason for this is not clear, but it is thought that the protic solvent inactivates Lewis acids, making demesylation of the benzene derivative represented by formula (2) less likely and thus less likely to generate the impurity represented by formula (3).

[0019] When a composition of an acylated benzene derivative represented by formula (1) or its salt and an acylated aniline derivative represented by formula (3) or its salt, which contains a small amount of the impurity (3), is used as a raw material, a highly pure iguratimod can be obtained.

[0020] The present invention will be described in detail below.

[0021] (Method for producing acylated benzene derivatives or salts thereof) The method for producing an acylated benzene derivative or a salt thereof according to the embodiment includes: contacting a benzene derivative represented by formula (2) with aminoacetonitrile or a salt thereof in the presence of a Lewis acid to obtain a first mixture; contacting the first mixture with a protic solvent to obtain a second mixture, and then contacting the second mixture with hydrogen chloride to obtain a crude acylated benzene derivative or a salt thereof represented by formula (1); or contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting the third mixture with a protic solvent to obtain a crude acylated benzene derivative or a salt thereof represented by formula (1).

[0022] In other words, the method for producing an acylated benzene derivative or a salt thereof according to the embodiment includes a first production method and a second production method. The first production method involves contacting a first mixture with a protic solvent to obtain a second mixture, and then contacting the second mixture with hydrogen chloride to obtain a crude acylated benzene derivative or salt thereof represented by formula (1). In contrast, the second production method involves contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting this third mixture with a protic solvent.

[0023] First, the preparation of the first mixture will be described. The first mixture is obtained by contacting a benzene derivative represented by formula (2) with aminoacetonitrile or a salt thereof in the presence of a Lewis acid.

[0024] Benzene derivatives are represented by the following formula (2). Benzene derivatives represented by formula (2) can be produced, for example, by known methods.

[0025] [ka]

[0026] In equation (2), R 1 R is a phenyl group which may be substituted with a halogen atom. The halogen atom is, for example, a chlorine atom, a bromine atom, or an iodine atom. 1 It is preferable that it is a phenyl group.

[0027] R 2 R is an alkyl group having 1 to 5 carbon atoms. 2 It is preferably a methyl group or an ethyl group, and more preferably a methyl group.

[0028] R 3 This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. It is preferably a methyl group or an ethyl group, and more preferably a methyl group.

[0029] The Lewis acid is not particularly limited, but for example, at least one selected from the group consisting of aluminum chloride, aluminum bromide, zinc chloride, zinc bromide, iron chloride, tin chloride, boron tribromide, boron trichloride, and titanium chloride is used. 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.

[0030] The amount of Lewis acid used is 1.0 to 4.0 moles per mole of benzene derivative, preferably 1.1 to 3.0 moles.

[0031] The amount of aminoacetonitrile or its salt used is 1 to 3.0 moles, preferably 1 to 1.5 moles, per mole of the benzene derivative of general formula (2). It is preferable to use aminoacetonitrile hydrochloride as the aminoacetonitrile or its salt.

[0032] Contact between a benzene derivative of general formula (2) and aminoacetonitrile or a salt thereof in the presence of a Lewis acid is carried out, for example, at 0 to 40°C, preferably at 10 to 35°C.

[0033] The contact between the benzene derivative of general formula (2) and aminoacetonitrile or its salt in the presence of a Lewis acid is preferably carried out in the presence of a reaction solvent.

[0034] The reaction solvent is not particularly limited as long as it does not adversely affect the reaction, but examples include nitro compounds such as nitrobenzene, nitromethane, and nitroethane; sulfolanes; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; esters such as diethyl oxalate and ethyl acetate; and nitriles such as acetonitrile, and these may be mixed as appropriate. Preferred solvents include solvents obtained by mixing nitro compounds such as nitrobenzene, nitromethane, or nitroethane with halogenated hydrocarbons such as methylene chloride. The amount of organic solvent used is not particularly limited, but preferably 3 to 5 mL per 1 g of the benzene derivative of general formula (2).

[0035] When using a reaction solvent, it is preferable to prepare the first mixture by the following method. First, a Lewis acid is mixed with the reaction solvent, then aminoacetonitrile or a salt thereof is added, and the mixture is heated to, for example, 30-50°C to obtain a solution. After cooling this solution to 0-20°C, a benzene derivative represented by formula (2) is added to obtain the first mixture.

[0036] Next, in the first manufacturing method, the first mixture is brought into contact with a protic solvent to obtain the second mixture.

[0037] The protic solvent includes, for example, at least one selected from the group consisting of water, primary alcohols having 1 to 5 carbon atoms, and carboxylic acids having 1 to 3 carbon atoms. Preferably, the protic solvent includes at least one selected from the group consisting of water and primary alcohols having 1 to 5 carbon atoms, and more preferably, at least one selected from the group consisting of water and methanol.

[0038] The amount of protic solvent relative to 1 mole of the benzene derivative represented by formula (2) is, for example, 0.01 moles or more and 1.0 moles or less. A larger amount of protic solvent tends to reduce the amount of impurities. A smaller amount of protic solvent tends to increase the yield of the acylated benzene derivative represented by formula (1). The amount of protic solvent is preferably 0.05 moles or more and 0.50 moles or less, and more preferably 0.1 moles or more and 0.4 moles or less.

[0039] The contact temperature between the first mixture and the protic solvent is, for example, 0°C to 30°C. Preferably, the contact temperature is 5°C to 20°C.

[0040] The contact time between the first mixture and the protic solvent is, for example, 1 minute or more and 1 hour or less. Preferably, the contact time is 1 minute or more and 10 minutes or less.

[0041] The protic solvent may be added immediately after obtaining the first mixture, or it may be added several hours later. From the standpoint of suppressing the generation of impurities, it is preferable to add the protic solvent immediately after obtaining the first mixture.

[0042] Next, in the first manufacturing method, the second mixture is brought into contact with hydrogen chloride to obtain a crude acylated benzene derivative or salt thereof represented by formula (1).

[0043] Acyl benzene derivatives are represented by the following formula (1).

[0044] [ka]

[0045] In equation (1), R 1 , R 2 , and R 3 This is equivalent to the one in equation (2).

[0046] Examples of salts of acylated benzene derivatives include salts with hydrochloric acid, sulfuric acid, or methanesulfonic acid, as well as hydrates of these salts.

[0047] Hydrogen chloride is preferably in gaseous form. The amount of hydrogen chloride used is, for example, 1 to 20 moles, preferably 1 to 4 moles, per mole of benzene derivative.

[0048] The contact time between the second mixture and hydrogen chloride is, for example, 1 to 20 hours.

[0049] The crude form of the acylated benzene derivative represented by formula (1) or its salt may contain, as an impurity, the acylated aniline derivative represented by formula (3) or its salt. In other words, the crude form of the acylated benzene derivative represented by formula (1) or its salt may be a composition containing the acylated benzene derivative represented by formula (1) or its salt, and the acylated aniline derivative represented by formula (3) or its salt.

[0050] [ka]

[0051] In equation (3), R 1 and R 3 This is equivalent to the one in equation (2).

[0052] Examples of salts of acylated aniline derivatives include salts with hydrochloric acid, sulfuric acid, or methanesulfonic acid, as well as hydrates of these salts.

[0053] The content of the acylated benzene derivative represented by formula (1) or its salt in the crude product of the acylated benzene derivative represented by formula (1) or its salt, as determined by high-performance liquid chromatography, is, for example, 99.000% or more and 99.500% or less.

[0054] The content of the acylated aniline derivative represented by formula (3) or its salt in the crude acylated benzene derivative represented by formula (1) or its salt, as determined by high-performance liquid chromatography, is, for example, 0.001% or more and 0.150% or less. When the amount of the acylated aniline derivative represented by formula (3) or its salt is 0.150% or less, this compound can be removed by purification treatment, etc., so that iguratimod with a low or no content of the acylated aniline derivative represented by formula (3) or impurities derived from this compound can be produced. The content of the acylated aniline derivative represented by formula (3) or its salt is preferably 0.100% or less, more preferably 0.050% or less, and even more preferably 0.020% or less.

[0055] The crude acylated benzene derivative represented by formula (1) or its salt may contain other impurities, excluding the acylated benzene derivative represented by formula (1) or its salt and the acylated aniline derivative represented by formula (3) or its salt. These other impurities include the unreacted starting material, the benzene derivative represented by formula (2). The content of these other impurities by high-performance liquid chromatography is, for example, 3.50% to 23.00%. The content of impurities excluding the unreacted starting material, the benzene derivative represented by formula (2), and the acylated aniline derivative represented by formula (3) or its salt, by high-performance liquid chromatography is, for example, 2.50% to 6.50%.

[0056] The second manufacturing method involves contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting this third mixture with a protic solvent.

[0057] The contact time between the first mixture and hydrogen chloride is, for example, 1 to 20 hours. The amount of hydrogen chloride is the same as in the first production method.

[0058] The contact temperature and contact time between the third mixture and the protic solvent are the same as those between the first mixture and the protic solvent.

[0059] The protic solvent may be added immediately after obtaining the third mixture, or it may be added several hours later. From the standpoint of suppressing the generation of impurities, it is preferable to add the protic solvent immediately after obtaining the third mixture.

[0060] From the viewpoint of obtaining a crude acylated benzene derivative or salt thereof represented by formula (1) with few impurities, it is preferable to use the first manufacturing method, in which the first mixture is brought into contact with a protic solvent. From the viewpoint of increasing the yield of the crude acylated benzene derivative or salt thereof represented by formula (1), it is preferable to use the second manufacturing method, in which the third mixture is brought into contact with a protic solvent.

[0061] (Method for producing salts of acylated benzene derivatives) A method for producing an acylated benzene derivative salt involves contacting a crude acylated benzene derivative represented by formula (1) or its salt obtained by the above method with a first inorganic acid. The acylated benzene derivative salt represented by formula (1) is useful as an intermediate for the production of iguratimod.

[0062] The first inorganic acid is not particularly limited as long as it does not affect the stability of the salt of the acylated benzene derivative (1), but examples of aqueous solutions of hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid are available due to their low cost and availability. Preferably, it is an aqueous solution of hydrogen chloride, i.e., hydrochloric acid. Its concentration is not particularly limited, but is preferably 0.5 to 4 mol / L, and more preferably 1 mol / L. The amount of 1 mol / L first inorganic acid used is 1.5 to 10 mL, preferably 5 to 10 mL, per 1 g of crude acylated benzene derivative.

[0063] The contact temperature and time between the crude acylated benzene derivative or salt thereof represented by formula (1) and the first inorganic acid are not particularly limited, but are usually 0 to 40°C, preferably 0 to 30°C, for 1 to 6 hours.

[0064] The contact between the crude form of the acylated benzene derivative represented by formula (1) or its salt and the first inorganic acid may be carried out in the presence of the first organic solvent. Carrying out the contact in the presence of the first organic solvent can suppress the coarsening of the crystals of the acid salt of the acylated benzene derivative represented by formula (1), thereby obtaining a highly pure acid salt of the acylated benzene derivative represented by formula (1). It is preferable to contact the crude form of the acylated benzene derivative represented by formula (1) or its salt with a mixture of the first inorganic acid and the first organic solvent.

[0065] The first organic solvent includes, for example, at least one selected from the group consisting of lower alcohols having 1 to 5 carbon atoms, esters, ethers, and nitriles.

[0066] Specific examples of lower alcohols having 1 to 5 carbon atoms include methanol, ethanol, n-propanol, isopropanol, isobutyl alcohol, and tert-butyl alcohol.

[0067] Specific examples of esters include diethyl oxalate, ethyl formate, butyl acetate, isopropyl acetate, ethyl acetate, and methyl acetate.

[0068] Specific examples of ethers include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, dimethoxyethane, diglyme, and diethyl ether.

[0069] Specific examples of nitriles include acetonitrile, benzonitrile, and propionitrile.

[0070] These organic solvents can be used individually or as a mixture of two or more solvents in any mixing ratio. The first organic solvent preferably contains at least one selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol (IPA), ethyl acetate, acetonitrile, and tetrahydrofuran (THF), and more preferably contains isopropyl alcohol.

[0071] The amount of the first organic solvent used can be arbitrarily selected, but for example, it is 0.75 mL to 10 mL per gram of crude material of general formula (1), preferably 1 mL to 6 mL, and more preferably 3 mL to 5 mL.

[0072] The ratio V1 / V2 of the volume V1 of the 1 mol / L first inorganic acid to the volume V2 of the first organic solvent is, for example, 0.15 to 13.3, and preferably 1 to 4.

[0073] A specific example of an acid salt of an acylated benzene derivative represented by formula (1) is N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate, represented by formula (1a) below. This N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate can be obtained by using hydrochloric acid as the first inorganic acid.

[0074] [ka]

[0075] If the acid salt of the acylated benzene derivative represented by formula (1) or its salt precipitates as a solid after contact with the first inorganic acid, crystals of the acid salt can be obtained by known operations such as filtration. If the acid salt does not precipitate, the acid salt can be precipitated by adding a solvent in which the acid salt has low solubility, and the desired acid salt of the acylated benzene derivative can be obtained by the same operation. The obtained crystals of the acid salt of the acylated benzene derivative may be dried or washed. The drying temperature and time are not particularly limited as long as they do not affect the stability of the acid salt of the acylated benzene derivative, but are usually around 6 hours at 40°C.

[0076] The purity of the crystalline acid salt of the obtained acylated benzene derivative (1) can be confirmed by X-ray fluorescence analysis. There are no particular restrictions on the sample preparation method for performing X-ray fluorescence analysis, and samples formed by hydraulic molding may be used for measurement.

[0077] In the crystal (1a) which is an acid salt of an acylated benzene derivative, the ratio M1 / M2, where M1 is the mass percentage of chlorine and M2 is the mass percentage of sulfur, is, for example, 1.10 to 2.18, and preferably 1.10 to 1.25. Also, if M3 is the mass percentage of aluminum contained in the crystal which is an acid salt of an acylated benzene derivative, the ratio M3 / M2, where M2 is the mass percentage of aluminum, is, for example, 0.002 to 0.240, and preferably 0.002 to 0.020.

[0078] If the resulting acylated benzene derivative salt is sufficiently pure, it may be used directly in the next reaction, or it may be further purified. In such cases, a method of production is to wash the filtered acylated benzene derivative salt with water and / or an alcohol such as isopropyl alcohol.

[0079] (Method for manufacturing Iguratimod) Specifically, a method for producing 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod) is known, which involves three steps from N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate produced by the above-mentioned method.

[0080] First, N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate is subjected to a formylation reaction to obtain formylaminomethyl=2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone. Subsequently, a demethylation reaction is performed to obtain formylaminomethyl=2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone. Finally, a ring-closing reaction is performed to obtain 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod).

[0081] According to this manufacturing method, since a crude acylated benzene derivative or salt represented by formula (1), which has a low content of the acylated aniline derivative or salt represented by formula (3) above, is used as an intermediate, an iguratimod with a low or no content of the impurity represented by formula (II) below can be obtained. The impurity represented by formula (II) is a compound obtained by demesylating iguratimod, as shown below. This impurity is thought to originate from the acylated aniline derivative or salt represented by formula (3) above.

[0082] [ka] [Examples]

[0083] The present invention will be described in detail below with reference to examples, but the present invention is not limited in any way by these examples.

[0084] The example uses N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide, which is obtained by the reaction of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide with aminoacetonitrile hydrochloride, represented by the following formula. As an acylated aniline derivative, 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)ethanone, represented by formula (III), is produced.

[0085]

Chem.

[0086]

Chem.

[0087] In addition, the conversion rate from N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide to an N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide derivative or a salt thereof, and the yield of 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone were measured under the following conditions.

[0088] <HPLC Condition 1> Apparatus: Liquid chromatograph (manufactured by Waters Corporation) Detector: Ultraviolet absorption spectrophotometer Measurement wavelength: 240 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm, packed with 5 μm octadecylsilylated silica gel for liquid chromatography Mobile phase A: Acetonitrile Mobile phase B: A mixed solution prepared by adding 8.16 g of potassium dihydrogen phosphate to 3000 mL of water to dissolve it, then adding phosphoric acid to adjust the pH to 2.5 Mobile phase feeding: Concentration gradient control is performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0089]

Table 1

[0090] Flow rate: 0.8 mL per minute Column temperature: Constant temperature around 30°C Measurement time: 50 minutes Retention time: N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide: 9.8 min 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone: 11.0 min N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide: 36.0 min <HPLC Condition 2> Measurement wavelength: 254 nm Mobile phase delivery: gradient elution is performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

[0091]

Table 2

[0092] Flow rate: 1.2 mL per minute Measurement time: 70 minutes Other measurements are performed under the same conditions as the above Condition 1.

[0093] Retention time: iguratimod: 26.0 min N-(3-formamido-4-oxo-6-phenoxy-chromen-7-yl)formamide: 22.8 min The production rate (%) of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and the production rate (%) of 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)etanone (impurity), as well as their content in the crystal, are the ratios of their respective area values ​​to the sum of the area values ​​of all peaks (excluding solvent peaks) measured under condition 1 above. Furthermore, the conversion rate (%) from N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide to N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide is the ratio of the peak area value of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide to the sum of the peak area values ​​of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide and N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide.

[0094] [Comparative Example 1] 43.6 g of anhydrous aluminum chloride was added in portions to 120 mL of nitrobenzene, followed by the addition of 15.16 g of aminoacetonitrile hydrochloride. The mixture was stirred for 1 hour while maintaining a temperature of 40°C. After the reaction mixture was cooled to 10-15°C, 40.0 g of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide was added to obtain the first mixture. Under stirring, 12 g of hydrogen chloride gas was introduced into this first mixture over 80 minutes while maintaining a temperature of 10-15°C. The reaction mixture was then stirred at 20°C. After confirming that the reaction was complete by HPLC, this mixture was added dropwise to a mixture of 200 mL of 1N hydrochloric acid and 80 mL of methanol. The mixture was stirred at 10°C for 2 hours, and the precipitate was filtered off. The obtained precipitate was washed with ethyl acetate, water, and isopropyl alcohol, then dried to obtain 46.8 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate. Table 3 shows the production rates and content of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (the target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)ethanone (an impurity) during the reaction.

[0095] [Comparative Example 2] The reaction mixture obtained by adding hydrogen chloride gas to the first mixture was stirred at 10°C instead of 20°C in the same manner as in Comparative Example 1 to obtain 46.8 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate. Table 3 shows the production rates of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)ethanone (impurity) during the reaction, as well as their content in the obtained crystals.

[0096] [Comparative Example 3] 16.5 g of sodium formate and 146.4 g of pivalic acid chloride were sequentially added to 120 mL of acetone, and the mixture was vigorously stirred at room temperature for 5 hours. Then, 40.00 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate, prepared in Comparative Example 1, was added, and the mixture was stirred at room temperature for 3 hours. 360 mL of water was added dropwise to the reaction suspension, and the precipitated crystals were filtered off. The obtained precipitated crystals were sequentially washed with water and isopropanol, and then dried to obtain 34.82 g of formylaminomethyl=2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone.

[0097] 21.2 g of anhydrous aluminum chloride was added in portions to 90 mL of acetonitrile while maintaining the temperature below 20°C. Then, 30.00 g of the prepared formylaminomethyl=2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone and 13.1 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature below 20°C. The reaction suspension was added dropwise to 270 mL of 1% sodium sulfite aqueous solution, cooled to 10°C, and the precipitated crystals were filtered off. The obtained precipitated crystals were sequentially washed with water and ethanol, dried, and 27.40 g of formylaminomethyl=2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone was obtained.

[0098] 75 mL of N,N-dimethylformamide was mixed with 20.5 g of N,N-dimethylformamide dimethyl acetal 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 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 homogeneously dissolved solution was added dropwise to 250 mL of water to adjust the pH to 5.0. The precipitated crystals were filtered, washed sequentially with methylene chloride, water, and ethanol, and then dried. The resulting crystals were then dissolved in aqueous acetone with potassium hydroxide, neutralized with hydrochloric acid, and the crystals were filtered. The obtained crystals were washed with water and dried to obtain 22.2 g of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod). Analysis of the obtained crystals by HPLC showed that the purity of iguratimod was 99.972%, and the content of N-(3-formamido-4-oxo-6-phenoxy-chromen-7-yl)formamide was 0.006%.

[0099] [Example 1] 43.6 g of anhydrous aluminum chloride was added in portions to 120 mL of nitrobenzene, followed by the addition of 15.16 g of aminoacetonitrile hydrochloride. The mixture was stirred for 1 hour while maintaining a temperature of 40°C. After cooling the reaction mixture to 10-15°C, 40.0 g of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide was added to obtain the first mixture. To this first mixture, 0.2 moles of water were added to 1 mole of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide to obtain the second mixture. Under stirring, 12 g of hydrogen chloride gas was introduced into the second mixture over 80 minutes while maintaining a temperature of 10-15°C. The reaction mixture was then stirred at 10°C. After confirming that the reaction was complete by HPLC, this mixture was added dropwise to a mixture of 200 mL of 1N hydrochloric acid and 80 mL of methanol. The mixture was stirred at 10°C for 2 hours, and the precipitated layer was filtered off. The obtained precipitated crystals were washed with ethyl acetate, water, and isopropyl alcohol, and then dried to obtain 48.0 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)ethanone (impurity) during the reaction.

[0100] [Example 2] N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate was obtained in the same manner as in Example 1, except that the amount of water added was 0.4 moles per mole of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone (impurity) during the reaction.

[0101] [Example 3] 46.3 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate was obtained in the same manner as in Example 1, except that 0.2 moles of methanol were added to the first mixture per mole of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide instead of water. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone (impurity) during the reaction.

[0102] [Example 4] 40.1 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate was obtained in the same manner as in Example 1, except that 0.4 moles of methanol were added to the first mixture per mole of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide instead of water. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone (impurity) during the reaction.

[0103] [Example 5] Except that hydrogen chloride gas was added to the second mixture to obtain the reaction mixture, the stirring temperature of the mixture was raised from 10°C to 20°C, and 47.6 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate was obtained in the same manner as in Example 1. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone (impurity) during the reaction.

[0104] [Example 6] A first mixture was obtained in the same manner as in Example 1. While stirring this first mixture, 12 g of hydrogen chloride gas was introduced over 80 minutes at a temperature of 10-15°C to obtain a third mixture. To this third mixture, 0.2 moles of water were added per mole of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide, and the reaction mixture was heated to 20°C. After confirming that the reaction was complete by HPLC, this mixture was added dropwise to a mixture of 200 mL of 1N hydrochloric acid and 80 mL of methanol, stirred at 10°C for 2 hours, and the precipitated layer was filtered off. The obtained precipitated crystals were washed with ethyl acetate, water, and isopropyl alcohol, and then dried to obtain 49.6 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (the target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)ethanone (an impurity) during the reaction.

[0105] [Example 7] 48.0 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate was obtained by the same method as in Example 6, except that the reaction mixture obtained by adding 0.2 moles of water to 1 mole of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide was stirred at a temperature of 10°C. Table 3 shows the production rates and content in the crystals of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide (target product) and 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone (impurity) during the reaction.

[0106] [Table 3]

[0107] [Manufacturing Example 1] <Synthesis of 2-amino-1-(4-amino-2-methoxy-5-phenoxyphenyl)ethanone standard> 2 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate was dissolved in 10 mL of 90% aqueous methanesulfonic acid, and the solution was stirred at 80°C for two days. The mixture was added dropwise to 60 mL of 10% aqueous sodium hydroxide solution, stirred at 5°C for 2 hours, and the precipitated crystals were collected by filtration. The obtained precipitated crystals were washed with 4 mL of water and dried, to give 1.12 g of methanesulfonic acid salt of 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone.

[0108] The physical property data of the obtained methanesulfonic acid salt of 2-amino-1-(4-amino-2-methoxy-5-phenoxy-phenyl)ethanone are as follows.

[0109] 1 H-NMR (500 MHz, DMSO-d₆) δ values: 2.30 (3H, s), 3.86 (3H, s), 4.02 (1H, s), 6.23 (2H, s), 6.49 (1H, s), 6.54 (3H, br), 6.91 (2H, m), 7.05 (1H, m), 7.30 (1H, s), 7.34 (2H, m) 13 C-NMR (500 MHz, DMSO-d₆) δ values: 39.73, 49.52, 55.83, 96.87, 111.25, 116.71, 121.40, 122.51, 129.77, 135.70, 148.31, 157.67, 159.03, 190.89 Further, the HPLC retention time measured under Condition 1 above was 11.0 minutes.

[0110] [Production Example 2] <Synthesis of a standard preparation of N-(3-formamido-4-oxo-6-phenoxy-chromen-7-yl)formamide (the above formula (3))> 5 g of iguratimod was dissolved in 10 mL of 90% methanesulfonic acid aqueous solution and stirred at 80°C for two days. This mixture was added dropwise to 50 mL of water and stirred at 5°C for 2 hours, after which the precipitated crystals were filtered off. The obtained precipitated crystals were washed with 10 mL of water and dried. Next, 4.35 g of sodium formate was added to 40 mL of acetonitrile, followed by 3.86 g of pivaloyl chloride, and the mixture was stirred at 5°C for 5 hours. The obtained crystals were added to this mixture, the temperature was raised to 20°C and stirred for 2 hours. After that, it was cooled to 5°C, 90 mL of water was added, and the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were filtered off, washed with 10 mL of water and 10 mL of isopropanol, and then dried to obtain 2.5 g of N-(3-formamido-4-oxo-6-phenoxychromen-7-yl)formamide.

[0111] The physical properties of the obtained N-(3-formamide-4-oxo-6-phenoxychromen-7-yl)formamide are as follows.

[0112] 1 H-NMR (500MHz, DMF-d7) δ value 7.24 (2H, d), 7.30 (1H, t), 7.40 (1H, s), 7.52 (2H, t) , 8.52(1H, s), 8.67(1H, s), 8.74(1H, s), 9.38(1H, s), 9.86(1H, s), 10.6(1H, s) 13 C-NMR (500MHz, DMF-d7) δ value 109.25, 111.14, 118.18, 120.30, 124.49, 125.50 , 131.05, 135.81, 145.43, 145.99, 152.75, 156.57, 161.11, 161.94, 170.51 Furthermore, the retention time measured by HPLC under condition 2 above was 22.8 minutes.

[0113] [Example 8] 16.5 g of sodium formate and 146.4 g of pivalic acid chloride were sequentially added to 120 mL of acetone, and the mixture was vigorously stirred at room temperature for 5 hours. Then, 40.00 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate, prepared in Example 7, was added, and the mixture was stirred at room temperature for 3 hours. 360 mL of water was added dropwise to the reaction suspension, and the precipitated crystals were filtered off. The obtained precipitated crystals were sequentially washed with water and isopropanol, and then dried to obtain 34.87 g of formylaminomethyl=2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone.

[0114] 21.2 g of anhydrous aluminum chloride was added in portions to 90 mL of acetonitrile while maintaining the temperature below 20°C. Then, 30.00 g of formylaminomethyl=2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone prepared in Example 8 and 13.1 g of sodium iodide were added sequentially, and the mixture was stirred for 3 hours while maintaining the temperature below 20°C. The reaction suspension was added dropwise to 270 mL of 1% sodium sulfite aqueous solution, cooled to 10°C, and the precipitated crystals were filtered off. The obtained precipitated crystals were sequentially washed with water and ethanol, and then dried to obtain 27.52 g of formylaminomethyl=2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl=ketone.

[0115] 75 mL of N,N-dimethylformamide was mixed with 20.5 g of N,N-dimethylformamide dimethyl acetal 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 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 homogeneously dissolved solution was added dropwise to 250 mL of water to adjust the pH to 5.0. The precipitated crystals were filtered, washed sequentially with methylene chloride, water, and ethanol, and then dried. The resulting crystals were then dissolved in aqueous acetone with potassium hydroxide, neutralized with hydrochloric acid, and the crystals were filtered. The obtained crystals were washed with water and dried to obtain 22.4 g of 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod). Analysis of the obtained crystals by HPLC showed that the purity of iguratimod was 99.974%, and N-(3-formamido-4-oxo-6-phenoxy-chromen-7-yl)formamide was not detected.

[0116] Preferred embodiments are described below.

[0117] [1] In the presence of a Lewis acid, a benzene derivative represented by the following formula (2) is contacted with aminoacetonitrile or a salt thereof to obtain a first mixture, and, After contacting the first mixture with a protic solvent to obtain a second mixture, the second mixture is contacted with hydrogen chloride to obtain a crude acylated benzene derivative or its salt represented by the following formula (1), or, The method includes contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting the third mixture with the protic solvent to obtain a crude acylated benzene derivative represented by formula (1) or a salt thereof. Method for producing acylated benzene derivatives or salts thereof:

[0118] [ka]

[0119] In the above equation (2), R 1 This is a phenyl group which may be substituted with a halogen atom, R 2 This is an alkyl group having 1 to 5 carbon atoms. R 3 This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0120] [ka]

[0121] In the above formula (1), R 1 , R 2 , and R 3 This is equivalent to the one in equation (2) above.

[0122] [2] The protic solvent is selected from the group consisting of water and primary alcohols having 1 to 5 carbon atoms, according to the manufacturing method described in [1].

[0123] [3] The method for producing the product according to [1] or [2], wherein the amount of the protic solvent relative to 1 mole of the benzene derivative represented by formula (2) is 0.1 moles or more and 0.4 moles or less.

[0124] [4] The crude acylated benzene derivative represented by formula (1) or a salt thereof comprises the acylated aniline derivative represented by formula (3) below or a salt thereof, according to any one of [1] to [3]:

[0125] [ka]

[0126] In the above equation (3), R 1 and R 3This is equivalent to the one in equation (2) above.

[0127] [5] The method for producing the product according to [4], wherein the content of the acylated aniline derivative represented by formula (3) or its salt, as determined by high-performance liquid chromatography, in the crude acylated benzene derivative represented by formula (1) or its salt is 0.001% or more and 0.200% or less.

[0128] [6] The manufacturing method according to any one of [1] to [5], wherein the contact between the first mixture and the protic solvent, or the contact between the third mixture and the protic solvent, is carried out at a temperature of 0°C or higher and 30°C or lower.

[0129] [7] The method for producing the Lewis acid according to any one of [1] to [6], wherein the Lewis acid comprises at least one selected from the group consisting of aluminum chloride, aluminum bromide, zinc chloride, tin chloride, and titanium chloride.

[0130] [8] A method for producing an acylated benzene derivative salt, comprising contacting a crude acylated benzene derivative represented by formula (1) or a salt thereof obtained by any of the methods in [1] to [7] with a first inorganic acid to obtain an acylated benzene derivative salt represented by formula (1).

[0131] [9] A method for producing 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod) using N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate obtained by the manufacturing method described in [8].

[0132]

[10] A composition comprising an acylated benzene derivative represented by formula (1) below or a salt thereof, and an acylated aniline derivative represented by formula (3) below or a salt thereof:

[0133] [ka]

[0134] In the above formula (1), R 1 This is a phenyl group which may be substituted with a halogen atom, R 2 This is an alkyl group having 1 to 5 carbon atoms. R 3 This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0135] [ka]

[0136] In the above equation (3), R 1 and R 3 This is equivalent to the one in equation (2) above.

[0137]

[11] The composition according to

[10] , wherein the content of the acylated benzene derivative represented by formula (1) or a salt thereof, as determined by high-performance liquid chromatography, is 99.000% or more and 99.500% or less, and the content of the acylated aniline derivative represented by formula (3) or a salt thereof, as determined by high-performance liquid chromatography, is 0.001% or more and 0.200% or less.

Claims

1. In the presence of a Lewis acid, a benzene derivative represented by the following formula (2) is brought into contact with aminoacetonitrile or a salt thereof to obtain a first mixture, and After contacting the first mixture with a protic solvent to obtain a second mixture, the second mixture is contacted with hydrogen chloride to obtain a crude acylated benzene derivative or salt thereof represented by the following formula (1), or, The method includes contacting the first mixture with hydrogen chloride to obtain a third mixture, and then contacting the third mixture with the protic solvent to obtain a crude acylated benzene derivative represented by formula (1) or a salt thereof. Method for producing acylated benzene derivatives or salts thereof: 【Chemistry 1】 In the above formula (2), R １ This is a phenyl group which may be substituted with a halogen atom, R ２ This is an alkyl group having 1 to 5 carbon atoms. R ３ This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. 【Chemistry 2】 In the above formula (1), R １ , R ２ , and R ３ This is equivalent to the one in formula (2) above.

2. The production method according to claim 1, wherein the protic solvent is selected from the group consisting of water and primary alcohols having 1 to 5 carbon atoms.

3. The manufacturing method according to claim 1, wherein the amount of the protic solvent relative to 1 mole of the benzene derivative represented by formula (2) is 0.1 moles or more and 0.4 moles or less.

4. The manufacturing method according to claim 1, wherein the crude acylated benzene derivative or salt thereof represented by formula (1) comprises an acylated aniline derivative or salt thereof represented by the following formula (3): 【Transformation 3】 In the above formula (3), R １ and R ３ This is equivalent to the one in formula (2) above.

5. The manufacturing method according to claim 4, wherein the content of the acylated aniline derivative represented by formula (3) or its salt in the crude acylated benzene derivative represented by formula (1) or its salt, as determined by high-performance liquid chromatography, is 0.001% or more and 0.050% or less.

6. The manufacturing method according to claim 1, wherein the contact between the first mixture and the protic solvent, or the contact between the third mixture and the protic solvent, is carried out at a temperature of 0°C or higher and 30°C or lower.

7. The manufacturing method according to claim 1, wherein the Lewis acid comprises at least one selected from the group consisting of aluminum chloride, aluminum bromide, zinc chloride, tin chloride, and titanium chloride.

8. A method for producing an acylated benzene derivative salt, comprising contacting a crude acylated benzene derivative represented by formula (1) or a salt thereof obtained by the method of claim 1 with a first inorganic acid to obtain an acylated benzene derivative salt represented by formula (1).

9. A method for producing 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod) using N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride 1 / 2 hydrate obtained by the manufacturing method described in claim 8.

10. A composition comprising an acylated benzene derivative represented by the following formula (1) or a salt thereof, and an acylated aniline derivative represented by the following formula (3) or a salt thereof: 【Chemistry 4】 In the above formula (1), R １ is a phenyl group optionally substituted by a halogen atom, R ２ This is an alkyl group having 1 to 5 carbon atoms. R ３ This is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. 【Transformation 5】 In the above formula (3), R １ and R ３ This is equivalent to the one in formula (2) above.

11. The composition according to claim 10, wherein the content of the acylated benzene derivative represented by formula (1) or a salt thereof, as determined by high-performance liquid chromatography, is 99.000% or more and 99.850% or less, and the content of the acylated aniline derivative represented by formula (3) or a salt thereof, as determined by high-performance liquid chromatography, is 0.001% or more and 0.200% or less.

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