Method for producing acid salt of acylated benzene derivative

Abstract

To provide a method that enables production of an acylated benzene derivative with high purity.SOLUTION: According to an embodiment, a method for producing an acylated benzene derivative or a salt thereof is provided. The production method comprises contacting a crude acylated benzene derivative represented by formula (1), an aqueous inorganic acid solution, and a first organic solvent, to precipitate crystals of the acylated benzene derivative represented by formula (1) or a salt thereof. The first organic solvent contains at least one selected from the group consisting of lower alcohols having 1 to 5 carbon atoms, esters, ethers, and nitriles. In formula (1), R1 is a phenyl group optionally substituted with a halogen atom, R2 is an alkyl group having 1 to 5 carbon atoms, and R3 is a hydrogen atom or 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 an acid salt of an acylated benzene derivative. [Background technology]

[0002] The acylated benzene derivative represented by the following formula (1) 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 formula (1), R 1 is a phenyl group optionally substituted with a halogen atom, and R 2 is an alkyl group having 1 to 5 carbon atoms, and R 3 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0005] The method described in Patent Document 1 is known as a method for producing the acid salt of the acylated benzene derivative (1). Specifically, a crude product of the acylated benzene derivative (1) is obtained by contacting a benzene derivative 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, and then a liquid containing the crude product is contacted with an aqueous inorganic acid solution to precipitate crystals, thereby producing a crystal of the acid salt of the acylated benzene derivative (1). When hydrochloric acid is used as the aqueous inorganic acid solution, the crystal of the acid salt of the acylated benzene derivative (1) is produced as the hydrochloride salt. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 5-97840 [Patent Document 2] Japanese Patent Application Publication No. 2-49778 [Non-patent literature]

[0007] [Non-Patent Document 1] Chemical Pharmaceutical Bulletin [Chem.Pharm.Bull.,13,1319~1325(1965)] Summary of the Invention [Problem to be solved by the invention]

[0008] The present inventors have produced N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate by contacting N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide with aminoacetonitrile hydrochloride in the presence of aluminum chloride and hydrogen chloride gas according to the method described in Patent Document 1.

[0009] Chlorine and sulfur are elements constituting the acid salt, and the theoretical sulfur-to-chlorine mass ratio is 1.00:1.10. In contrast, when the inventors performed X-ray fluorescence analysis on the N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate, the aluminum, chlorine, and sulfur contents were 1.52 mass%, 13.60 mass%, and 6.20 mass%, respectively. That is, the sulfur-to-chlorine mass ratio in this N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate was 1.00:2.19, and 6.74 mass% of excess chlorine was contained. The presence of these impurities increases the apparent yield, necessitating the use of large amounts of reactants in the subsequent step, which is industrially disadvantageous. [Means for solving the problem]

[0010] According to an embodiment, there is provided a method for producing an acid salt of an acylated benzene derivative. This method comprises contacting a crude acylated benzene derivative represented by the following formula (1), an aqueous inorganic acid solution, and a first organic solvent to precipitate crystals of the acid salt of the acylated benzene derivative represented by formula (1). The first organic solvent comprises at least one selected from the group consisting of lower alcohols having from 1 to 5 carbon atoms, esters, ethers, and nitriles.

[0011] [ka]

[0012] In formula (1), R 1 R is a phenyl group which may be substituted with a halogen atom. 2 is an alkyl group having 1 to 5 carbon atoms. 3 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0013] The production method according to the embodiment provides a method for producing a highly pure acid salt of an acylated benzene derivative. Specifically, in order to address the aforementioned problem, the inventors focused on the precipitation behavior of crystals after contacting a liquid containing crude acylated benzene derivative (1) with an aqueous inorganic acid solution. Initially, upon contact between the crude acylated benzene derivative (1) and the aqueous inorganic acid solution, precipitated small crystals were dispersed within the liquid. However, as the amount of precipitated crystals increased, the precipitated crystals aggregated, ultimately forming large, clumped crystals of the hydrochloride salt of the acylated benzene derivative (1). It is believed that impurities such as aluminum and chlorine were incorporated into the clumps during the process in which the initial small crystals aggregated to form clumps, resulting in the crude acid salt of the acylated benzene derivative (1) containing these impurities. These impurities are believed to originate from the reagents used in the synthesis of the crude acylated benzene derivative (1). In the method according to the embodiment, an organic solvent is present when the crude acylated benzene derivative (1) is contacted with the inorganic acid. Precipitating crystals of the acylated benzene derivative (1) under these conditions is thought to prevent aggregation of the crystals, possibly due to a change in the dielectric constant of the solvent. As a result, coarsening of the crystals of the acid salt of the acylated benzene derivative (1) can be suppressed, enabling the production of an acid salt of the acylated benzene derivative (1) with reduced impurities such as aluminum and chlorine. [Effects of the Invention]

[0014] According to the production method of the present invention, an acid salt of an acylated benzene derivative can be produced with high purity. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides a method for producing an acid salt of an acylated benzene derivative, which comprises contacting a crude acylated benzene derivative with an aqueous inorganic acid and a first organic solvent to precipitate crystals of an acid salt of the acylated benzene derivative (1), wherein the first organic solvent contains at least one selected from the group consisting of lower alcohols having from 1 to 5 carbon atoms, esters, ethers, and nitriles.

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

[0017] (Crude acylated benzene derivatives) The acylated benzene derivative 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] R 3 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. 3 is preferably a methyl group or an ethyl group, more preferably a methyl group.

[0022] The crude acylated benzene derivative (1) can be produced by contacting a benzene derivative of the following general formula (2) with aminoacetonitrile or a salt thereof.

[0023] [ka]

[0024] In equation (2), R 1 , R 2 , and R 3 has the same meaning as in formula (1).

[0025] The amount of aminoacetonitrile or a salt thereof used is 1 to 3.0 mol, preferably 1 to 1.5 mol, per 1 mol of the benzene derivative of general formula (2). As aminoacetonitrile or a salt thereof, it is preferable to use aminoacetonitrile hydrochloride.

[0026] The contact of the benzene derivative of the general formula (2) with aminoacetonitrile or a salt thereof is preferably carried out in the presence of a Lewis acid and an acidic gas.

[0027] The Lewis acid is not particularly limited as long as it does not affect the reaction, and 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 Lewis acid used is 1.0 to 4.0 mol, preferably 1.1 to 3.0 mol, per mol of aminoacetonitrile or a salt thereof.

[0028] The acidic gas to be introduced may be hydrogen chloride or hydrogen bromide, with hydrogen chloride being preferred.

[0029] The amount of the acidic gas used is 1 to 20 moles, preferably 1 to 4 moles, per mole of aminoacetonitrile or a salt thereof.

[0030] The benzene derivative of the general formula (2) is contacted with aminoacetonitrile or a salt thereof in an organic solvent used as a reaction solvent, usually at 0 to 40°C, preferably 10 to 35°C.

[0031] The organic solvent used is not particularly limited as long as it does not adversely affect the reaction. Examples include nitro compounds such as nitrobenzene, nitromethane, and nitroethane; sulfolane; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; esters such as diethyl oxalate and ethyl acetate; and nitriles such as acetonitrile, which may be mixed appropriately. A preferred solvent is a mixture of a nitro compound such as nitrobenzene, nitromethane, or nitroethane with a halogenated hydrocarbon such as methylene chloride. The amount of organic solvent used is not particularly limited, but is preferably 3 to 5 mL per 1 g of the benzene derivative of general formula (2).

[0032] The reaction time can be appropriately selected depending on the Lewis acid used, the amount of acidic gas introduced, and the reaction temperature, but is usually 4 to 20 hours.

[0033] The compound of general formula (2) can be produced, for example, by the method described in Patent Document 2. Aminoacetonitrile or a salt thereof can be produced, for example, by the method described in Non-Patent Document 1.

[0034] (Inorganic acid aqueous solution) An inorganic acid is used to generate the acid salt of the acylated benzene derivative (1).

[0035] The inorganic acid aqueous solution used is not particularly limited as long as it does not affect the stability of the acid salt of the acylated benzene derivative (1). Examples include aqueous solutions of hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, etc., which are inexpensively available. Aqueous hydrogen chloride solution, i.e., hydrochloric acid, is preferred. Its concentration is not particularly limited, but is preferably 0.5 to 4 mol / L, more preferably 1 mol / L. The amount of 1 mol / L inorganic acid aqueous solution used is 1.5 to 10 mL, preferably 5 to 10 mL, per 1 g of crude acylated benzene derivative.

[0036] (First organic solvent) The first organic solvent is used to suppress coarsening of crystals in the step of producing the acid salt of the acylated benzene derivative (1).

[0037] The first organic solvent used contains at least one selected from the group consisting of lower alcohols having 1 to 5 carbon atoms, esters, ethers, and nitriles.

[0038] Specific examples of lower alcohols having 1 to 5 carbon atoms include methanol, ethanol, normal propanol, isopropanol, isobutyl alcohol, and tert-butyl alcohol.

[0039] Specific examples of esters include diethyl oxalate, ethyl formate, butyl acetate, isopropyl acetate, ethyl acetate, and methyl acetate.

[0040] Specific examples of ethers include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, dimethoxyethane, diglyme, and diethyl ether.

[0041] Specific examples of nitriles include acetonitrile, benzonitrile, and propionitrile.

[0042] These organic solvents can be used alone or as a mixed solvent of two or more kinds at 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.

[0043] The amount of the first organic solvent used can be selected arbitrarily, but is, for example, 0.75 mL to 10 mL, preferably 1 mL to 6 mL, and more preferably 3 mL to 5 mL per gram of the crude compound of general formula (1).

[0044] 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.

[0045] The ratio V1 / V2 of the volume V1 of the 1 mol / L aqueous inorganic acid solution to the volume V2 of the first organic solvent is 0.15-13.3, and preferably 1-4.

[0046] (Contacting Crude Acylated Benzene Derivative with Aqueous Inorganic Acid Solution and First Organic Solvent) It is preferable that the inorganic acid aqueous solution and the first organic solvent are mixed in advance before being brought into contact with the crude acylated benzene derivative. The temperature and time when the inorganic acid aqueous solution and the first organic solvent are brought into contact with the liquid of the crude acylated benzene derivative are not particularly limited, but are usually 0 to 40°C, preferably 0 to 30°C, for 1 to 6 hours.

[0047] (Operations after contact) If the acid salt of the acylated benzene derivative precipitates as a solid in the dispersion after contacting the crude acylated benzene derivative with the inorganic acid aqueous solution and the first organic solvent, the desired crystals of the acid salt of the acylated benzene derivative can be easily obtained by known procedures such as filtration. If the acid salt of the acylated benzene derivative 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 procedures. 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 typically about 6 hours at 40°C. When hydrogen chloride is used as the inorganic acid, the hydrochloride hemihydrate of the acylated benzene derivative is obtained. This hydrochloride hemihydrate of the acylated benzene derivative retains a certain amount of water even after drying. Sufficient drying can be confirmed using a thermogravimetric differential thermal analyzer (TG-DTA). In the crystals of the hydrochloride hemihydrate of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide represented by the following formula (1a), a weight loss equivalent to 2.27% by mass of the theoretical value was observed at around 155° C. This weight loss suggests that it is a hemihydrate.

[0048] [ka]

[0049] (acid salts of acylated benzene derivatives) The purity of the resulting crystals of the acid salt of the acylated benzene derivative (1) can be confirmed by X-ray fluorescence analysis. There are no particular limitations on the sample preparation method for X-ray fluorescence analysis, and measurements can be performed using hydraulically molded samples.

[0050] Since the acid salt of the acylated benzene derivative (1) contains sulfur in the molecule, the content of impurities such as aluminum and chlorine can be estimated by checking the ratio of the mass % of sulfur to that of impurities such as aluminum and chlorine.

[0051] When the mass percentage of chlorine contained in the crystal (1a) which is an acid salt of an acylated benzene derivative is M1 and the mass percentage of sulfur contained in the crystal (1a) is M2, the ratio M1 / M2 is 1.10 to 2.18, preferably 1.10 to 1.25. When the mass percentage of aluminum contained in the crystal (1a) which is an acid salt of an acylated benzene derivative is M3, the ratio M3 / M2 is 0.002 to 0.240, preferably 0.002 to 0.020.

[0052] When the obtained acid salt of the acylated benzene derivative is of sufficiently high purity, it may be used in the next reaction as it is, or may be further purified. In such a case, a production method includes washing the acid salt of the acylated benzene derivative after filtration with water and / or an alcohol such as isopropyl alcohol.

[0053] A known method for producing 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod) is a three-step process starting with N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate, which is produced by the method of the present invention. First, N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate is formylated to yield formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. Subsequently, formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone is obtained by demethylation. Finally, a ring closure reaction can be carried out to obtain 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one (iguratimod). [Example]

[0054] 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.

[0055] The examples are examples using crude N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide, which is obtained by treating the reaction product of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide and aminoacetonitrile hydrochloride, represented by the following formula, with hydrochloric acid.

[0056] [ka]

[0057] The evaluations in the examples were carried out by the following methods.

[0058] <X-ray fluorescence analysis> Approximately 0.5 g of the solid acid salt of the acylated benzene derivative was weighed and placed inside an aluminum ring for powder samples, with an outer diameter of 23 mm, an inner diameter of 20 mm, and a thickness of 1.5 mm.

[0059] For the hydraulically molded samples, the samples were prepared by applying pressure of 7 tons for 2 minutes using a hydraulic molding machine.

[0060] The obtained samples were analyzed using a Rigaku ZSX Primus IV scanning X-ray fluorescence analyzer to determine the semi-quantitative atomic concentrations of the samples using the scattered radiation fundamental parameter method. The target material of the X-ray tube was Rh, the output power was 4.0 kW, and the analyzing crystals were LiF, PET, RX25, and Ge. Other suitable target materials and analyzing crystals were used depending on the elements contained in the composition.

[0061] The purities of the samples were compared using the values (M1 / M2, M3 / M2) obtained by dividing the measured chlorine mass percentage M1 and aluminum mass percentage M3 by the sulfur mass percentage M2 of the same sample.

[0062] <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:

[0063] [Table 1]

[0064] Flow rate: 0.8 mL per minute Column temperature: constant temperature around 30°C Measurement time: 50 minutes A calibration curve was prepared using N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate as a standard substance.

[0065] <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.

[0066] <Crude mass quantification method> 100 mg of the liquid containing the crude N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide was weighed out and made up to exactly 20 mL with a 1:1 mixture of water and acetonitrile. The solution was analyzed by HPLC, and the content of the crude product was calculated using the calibration curve from the detected area value and the total weight of the liquid containing the crude product.

[0067] [Comparative Example 1] To 120 mL of nitrobenzene, 43.6 g of anhydrous aluminum chloride was added in portions, followed by the addition of 15.16 g of aminoacetonitrile hydrochloride, and the mixture was stirred for 1 hour while maintaining the temperature at 40°C. The reaction mixture was cooled to 10-15°C, and then 40.0 g of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide was added. Next, 12 g of hydrogen chloride gas was introduced into the stirred reaction mixture over 10 hours while maintaining the temperature at 25-30°C. Completion of the reaction was confirmed by HPLC, and the crude product was quantified to obtain a liquid containing crude N-[4-(2-aminoacetyl)5-methoxy-2-phenoxyphenyl]methanesulfonamide. The quantitative yield of the crude product was 49.64 g. This mixture was added dropwise to 200 mL of 2N hydrochloric acid, stirred at 25-30°C for 1 hour, and then at 10°C for another 1 hour. The precipitate was then collected by filtration. The resulting precipitated crystals were washed with ethyl acetate, water, and isopropyl alcohol, and then dried to give 51.4 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate. The content of this compound determined from the calibration curve was 65.4%, and the yield was 62.3%.

[0068] Comparative Example 2 Except for changing 200 mL of 2N hydrochloric acid to 400 mL of 1N hydrochloric acid, the same procedure as in Comparative Example 1 was repeated to obtain 45.4 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate. The content of this compound was 88.4%, and the yield was 74.4%.

[0069] [Example 1] The procedure was repeated as in Comparative Example 1 until crude N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide was obtained. The liquid containing the crude product was added dropwise to a premix of 400 mL of 1N hydrochloric acid and 200 mL of isopropyl alcohol (IPA) as a first organic solvent. The mixture was stirred at 25-30°C for 1 hour and then at 10°C for 1 hour, after which the precipitated crystals were collected by filtration. The precipitated crystals were washed with ethyl acetate, water, and isopropyl alcohol and then dried to obtain 41.4 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate. The content of this compound determined from the calibration curve was 95.7%, and the yield was 73.4%.

[0070] [Examples 2 to 6] The same operation as in Example 1 was carried out except for the conditions shown in Table 2. Tetrahydrofuran (THF) was used in Example 4. 200 mL of 1N hydrochloric acid was used in Example 6. The yield, purity, and X-ray fluorescence analysis results for the organic solvents tested are shown in Table 2.

[0071] [Example 7] The procedure was repeated as in Comparative Example 1 until crude N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide was obtained. 200 mL of ethyl acetate was added to the liquid containing the crude product at 0°C and stirred for 30 minutes. This mixture was added dropwise to a premix of 200 mL of 1N hydrochloric acid and 80 mL of methanol as a first organic solvent. The mixture was stirred at 10°C for 2 hours, and the precipitated crystals were collected by filtration. The precipitated crystals were washed with ethyl acetate, water, and isopropyl alcohol and then dried to obtain 46.8 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate. The content of this compound calculated from the calibration curve was 97.2%, and the yield was 86.7%. As in Examples 2 to 6, the yield, purity, and X-ray fluorescence analysis results are shown in Table 2.

[0072] [Table 2]

[0073] [Example 8] To 120 mL of acetone, 16.5 g of sodium formate and 146.4 g of pivaloyl chloride were added sequentially and stirred vigorously at room temperature for 5 hours. Then, 40.00 g of N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide hydrochloride hemihydrate (prepared in Example 6) was added and stirred at room temperature for 3 hours. 360 mL of water was added dropwise to the reaction suspension, and the precipitated crystals were collected by filtration. The precipitated crystals were washed sequentially with water and isopropanol and then dried to obtain 34.79 g of formylaminomethyl 2-methoxy-4-methylsulfonylamino-5-phenoxyphenyl ketone (yield: 91.0%).

[0074] 21.2 g of anhydrous aluminum chloride was added in portions to 90 mL of acetonitrile while maintaining the temperature below 20°C. Next, 30.00 g of the resulting 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% aqueous sodium sulfite solution, cooled to 10°C, and the precipitated crystals were collected by filtration. The precipitated crystals were washed successively with water and ethanol and then dried to obtain 27.45 g of formylaminomethyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone (yield: 95.0%).

[0075] 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 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 homogeneously dissolved. The solution was then 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).

[0076] Preferred embodiments are described below.

[0077] The method includes contacting a crude acylated benzene derivative represented by the following formula (1) with an aqueous inorganic acid solution and a first organic solvent to precipitate a crystal of an acid salt of the acylated benzene derivative represented by the formula (1): the first organic solvent includes at least one selected from the group consisting of lower alcohols having 1 to 5 carbon atoms, esters, ethers, and nitriles; Method for preparing acid salts of acylated benzene derivatives:

[0078] [ka]

[0079] 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, R 3 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

[0080] The crude acylated benzene derivative represented by the formula (1) can be obtained by contacting a benzene derivative represented by the following formula (2) with aminoacetonitrile or a salt thereof, in the production method described in [1]:

[0081] [ka]

[0082] In the formula (2), R 1 , R 2 , and R 3 has the same meaning as in the above formula (1).

[0083] The production method according to [2], wherein the benzene derivative represented by the formula (2) is contacted with the aminoacetonitrile or a salt thereof in the presence of a Lewis acid and an acidic gas.

[0084] The production method according to [3], wherein the Lewis acid includes at least one selected from the group consisting of aluminum chloride, aluminum bromide, zinc chloride, tin chloride, and titanium chloride.

[0085] The method according to any one of [1] to [4], wherein the first organic solvent comprises at least one selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, ethyl acetate, acetonitrile, and tetrahydrofuran.

[0086] The production method according to any one of [1] to [5], wherein the ratio V1 / V2 of the volume V1 of the 1 mol / L inorganic acid aqueous solution to the volume V2 of the first organic solvent is 0.15 or more and 13.3 or less.

[0087] [6] The method according to any one of [1] to [6], wherein the amount of the 1 mol / L aqueous inorganic acid solution relative to 1 g of the crude acylated benzene derivative represented by the formula (1) is 1.5 mL or more and 10 mL or less.

[0088] [7] The method according to any one of [1] to [7], wherein the amount of the first organic solvent per 1 g of the crude acylated benzene derivative represented by the formula (1) is 0.75 mL or more and 10 mL or less.

[0089] The production method according to any one of [1] to [8], wherein the ratio M1 / M2 of the mass M1 of chlorine to the mass M2 of sulfur contained in the crystals of the acid salt of the acylated benzene derivative represented by the formula (1) as determined by X-ray fluorescence analysis is 1.10 or more and 2.18 or less.

[0090] The production method according to any one of [1] to [9], wherein the ratio M3 / M2 of the mass of aluminum M3 to the mass of sulfur M2 in the crystals of the acid salt of the acylated benzene derivative represented by the formula (1) as determined by X-ray fluorescence analysis is 0.240 or less.

[0091]

[10] 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 hemihydrate obtained by the production method according to any one of

[11] to

[12] .

Claims

1. The method includes contacting a crude acylated benzene derivative represented by the following formula (1) with an aqueous inorganic acid solution and a first organic solvent to precipitate a crystal of an acid salt of the acylated benzene derivative represented by the formula (1): the first organic solvent includes at least one selected from the group consisting of lower alcohols having 1 to 5 carbon atoms, esters, ethers, and nitriles; Method for producing acid salts of acylated benzene derivatives: 【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, R ３ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.

2. The method according to claim 1, wherein the crude acylated benzene derivative represented by formula (1) is obtained by contacting a benzene derivative represented by the following formula (2) with aminoacetonitrile or a salt thereof: 【Chemistry 2】 In the formula (2), R １ , R ２ , and R ３ has the same meaning as in the formula (1).

3. The method according to claim 2, wherein the benzene derivative represented by formula (2) is contacted with the aminoacetonitrile or a salt thereof in the presence of a Lewis acid and an acidic gas.

4. The method according to claim 3, 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.

5. 2. The method according to claim 1, wherein the first organic solvent comprises at least one selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, ethyl acetate, acetonitrile, and tetrahydrofuran.

6. 2. The method according to claim 1, wherein a ratio V1 / V2 of a volume V1 of the 1 mol / L inorganic acid aqueous solution to a volume V2 of the first organic solvent is 0.15 or more and 13.3 or less.

7. 2. The method according to claim 1, wherein the amount of the 1 mol / L aqueous inorganic acid solution relative to 1 g of the crude acylated benzene derivative represented by formula (1) is 1.5 mL or more and 10 mL or less.

8. 2. The method according to claim 1, wherein the amount of the first organic solvent relative to 1 g of the crude acylated benzene derivative represented by formula (1) is 0.75 mL or more and 10 mL or less.

9. 2. The production method according to claim 1, wherein a ratio M1 / M2 of a mass M1 of chlorine to a mass M2 of sulfur contained in the crystals of the acid salt of the acylated benzene derivative represented by the formula (1) as determined by fluorescent X-ray analysis is 1.10 or more and 2.18 or less.

10. 2. The production method according to claim 1, wherein the ratio M3 / M2 of the mass M3 of aluminum to the mass M2 of sulfur in the crystals of the acid salt of the acylated benzene derivative represented by formula (1) as determined by X-ray fluorescence analysis is 0.240 or less.

11. 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 hemihydrate obtained by the production method according to claim 1.

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