Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
  • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/42—Separation; Purification; Stabilisation; Use of additives
  • C07C303/44—Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

• the present invention relates to a method for producing N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide (hereinafter referred to as Compound A).
• the present invention also relates to compound A in which the content of 1-chloro-N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide (hereinafter referred to as compound B) is reduced.
• Iguratimod is known as an excellent anti-rheumatic agent.
• the amount of iguratimod synthesized by the conventional production method is very small, N- (7- (chloromethyl) sulfonamide) -4-oxo-6-phenoxy-4H-chromen-3-yl) formamide (hereinafter, hereafter, Compound C) is contained as an impurity.
• compound A is known as an intermediate for producing iguratimod (Patent Document 1), and is produced from, for example, 2-chloro-5-methoxynitrobenzene (Non-Patent Document 1).
• Iguratimod is produced from compound A (Patent Document 2).
• Compound B which is an impurity contained in compound A, which is a production intermediate, becomes compound C in the production process of iguratimod, and is contained in iguratimod as an impurity. Further, the reaction product of compound B produced in the production process of iguratimod has similar physical characteristics to the reaction product obtained from compound A, and it is extremely difficult to remove the reaction product in the production process of iguratimod. On the other hand, since iguratimod is used as a drug substance for pharmaceuticals, higher purity is desired, and it is desired to use high-purity compound A as a production intermediate.
• An object of the present invention is to provide a high-purity compound A used for producing high-purity iguratimod and a method for producing the same.
• compound A having a low content of compound B using 2-chloro-5-methoxynitrobenzene as a raw material has a high content. It was found that it can be obtained in yield. Furthermore, it has been found that a compound A having a low content of compound B can be obtained in a high yield by a step of decomposing compound B which is a by-product in the process of producing compound A.
• the present invention provides: [1] N- (5-Methoxy-2) comprising reacting 5-methoxy-2-phenoxyaniline with methanesulphonic acid anhydride or methanesulfonyl chloride in the presence or absence of a base. -Phenoxyphenyl) A method for producing methanesulfonamide. [2] The production method according to [1], wherein the methanesulfonic acid anhydride or methanesulfonyl chloride is a methanesulfonic acid anhydride. [3] The production method according to [1] or [2], wherein the solvent is nitriles or ethers.
• the organic base is an organic base selected from 4-dimethylaminopyridine, N, N-dimethyl-1,3-propanediamine, triethylamine and 1,4-diazabicyclo [2,2,2] octane [5]. ] To [7] according to any one of the manufacturing methods. [9] The production method according to any one of [5] to [7], wherein the organic base is 1,4-diazabicyclo [2,2,2] octane.
• N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide having a content of 1-chloro-N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide of less than 10 ppm.
• the production method of the present invention is useful as a production method for compound A in which the content of compound B is reduced. Further, the compound A having a reduced content of the compound B of the present invention is useful as a raw material for a high-purity iguratimod drug substance.
• Examples of aliphatic hydrocarbons include pentane, hexane, heptane, cyclohexane and decahydronaphthalene.
• Examples of halogenated hydrocarbons include methylene chloride, chloroform and dichloroethane.
• Examples of alcohols include methanol, ethanol, propanol, 2-propanol, butanol and 2-methyl-2-propanol.
• Examples of glycols include ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol and diethylene glycol.
• ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether.
• ketones examples include acetone, 2-butanone and 4-methyl-2-pentanone.
• esters examples include methyl acetate, ethyl acetate, propyl acetate and butyl acetate.
• amides examples include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone.
• nitriles examples include acetonitrile and propionitrile.
• sulfoxides examples include dimethyl sulfoxide.
• aromatic hydrocarbons examples include benzene, toluene and xylene.
• the production method of the present invention can produce compound A having a reduced content of compound B.
• the production method of the present invention can produce compound A having a compound B content of less than 10 ppm.
• the content of the compound B may be 30 ppm or less, preferably less than 10 ppm.
• iguratimod having a reduced content of compound C can be produced.
• the compound of the formula [1] is obtained by reacting the compound of the formula [2] with phenol in the presence of (1) a solvent and the presence of a base to obtain the compound of the formula [3], and (2) in the presence of the solvent. In the presence or absence of a catalyst, the compound of the formula [3] is reduced to obtain the compound of the formula [4], (3) in the presence or absence of a base, in the presence or absence of a base, of the formula [4]. It can be obtained by reacting the compound with methanesulfonic anhydride or methanesulfonyl chloride.
• the compounds of the formulas [3] and [4] obtained by this production method may be isolated or may be used in the next step without isolation.
• the compound of the formula [3] can be produced by reacting the compound of the formula [2] with phenol in the presence of a solvent and the presence of a base.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but for example, aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers and ketones. , Esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, water and the like, and these may be mixed and used.
• Preferred solvents include amides and aromatic hydrocarbons, with N, N-dimethylacetamide and toluene being more preferred, and N, N-dimethylacetamide and toluene mixed solvents being even more preferred.
• the amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w), more preferably 5 to 10 times (v / w) with respect to the compound of the formula [2].
• the amount of phenol used in this reaction may be 1 to 100 times mol, preferably 1 to 10 times mol, with respect to the compound of the formula [2].
• Bases used in this reaction include, for example, organic bases such as pyridine, dimethylaminopyridine, triethylamine and N, N-diisopropylethylamine; and sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate and sodium carbonate.
• organic bases such as pyridine, dimethylaminopyridine, triethylamine and N, N-diisopropylethylamine
• sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate and sodium carbonate inorganic bases and the like can be mentioned.
• Preferred bases include inorganic bases, with sodium hydroxide and potassium hydroxide being more preferred, and potassium hydroxide being even more preferred.
• the amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, and more preferably 1 to 2 times mol with respect to the compound of the formula [2]. This reaction may be carried out at 0 to 150 ° C., preferably 100 to 120 °
• the compound of the formula [3] obtained by this production method can be continuously used in the next step without isolation.
• the compound of the formula [4] can be produced by reducing the compound of the formula [3] in the presence of a solvent, in the presence or absence of a catalyst, and in the presence of a reducing agent.
• Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but for example, aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers and ketones. , Esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, water and the like, and these may be mixed and used.
• Preferred solvents include aromatic hydrocarbons and alcohols, with toluene and 2-propanol more preferred.
• the amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w), more preferably 5 to 10 times (v / w) with respect to the compound of the formula [3].
• Examples of the catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metals such as lane nickel and platinum salts such as platinum oxide. ..
• the amount of the catalyst used may be 0.001 to 5 times (W / W), preferably 0.01 to 1 times (W / W) with respect to the compound of the formula [3].
• Examples of the reducing agent include hydrogen; formic acid; formate such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene; and cyclohexadiene.
• the amount of the reducing agent used may be 2 to 100 times mol, preferably 2 to 10 times mol, with respect to the compound of the formula [3].
• This reaction may be carried out at 0 to 150 ° C., preferably 50 to 120 ° C., more preferably 70 to 80 ° C. for 30 minutes to 48 hours, preferably 2 to 12 hours.
• the compound of the formula [4] obtained by this production method can be continuously used in the next step without isolation.
• the compound of the formula [1] can be obtained by reacting the compound of the formula [4] with a methanesulfonic anhydride in the presence of a solvent, in the presence or absence of a base.
• the obtained compound of the formula [1] can be crystallized if desired.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but for example, aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers and ketones. , Esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and the like, and these may be mixed and used.
• Preferred solvents include nitriles and ethers, with acetonitrile being more preferred.
• the amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w), more preferably 1 to 10 times (v / w) with respect to the compound of the formula [4].
• the amount of methanesulfonic anhydride used in this reaction may be 1 to 100 times mol, preferably 1 to 10 times mol, with respect to the compound of the formula [4].
• the bases optionally used in this reaction include, for example, organics such as pyridine, 2-picoline, 2,6-lutidine, 2,4,6-cholidine, dimethylaminopyridine, triethylamine and N, N-diisopropylethylamine.
• Bases; as well as inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate and sodium carbonate.
• Preferred bases include organic bases, with pyridine and 2-picoline being more preferred, and pyridine being even more preferred.
• the amount of the base used may be 1 to 100 times by mole, preferably 1 to 10 times by mole, more preferably 1 to 2 times by mole with respect to the compound of the formula [4].
• This reaction may be carried out at 0 to 150 ° C., preferably 0 to 30 ° C., more preferably 0 to 10 ° C. for 30 minutes to 48 hours, preferably 1 to 10 hours.
• the crystallization method for crystallization of the obtained compound of the formula [1] as desired is not particularly limited, but after preparing a solution of the compound of the formula [1], crystallization by distilling off the solvent and cooling of the solvent are performed. Examples thereof include crystallization by addition of a poor solvent and crystallization by addition of a poor solvent, and crystallization by cooling the solvent is preferable.
• the solvent used in the crystallization is not particularly limited as long as it does not adversely affect the reaction, but for example, aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers and ketones. , Esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and the like, and these may be mixed and used.
• Preferred solvents include aromatic hydrocarbons and alcohols, with toluene and 2-propanol more preferred, and a mixed solvent of toluene and 2-propanol even more preferred.
• the amount of the solvent used is not particularly limited, but the amount of toluene is preferably 0.5 to 10 times (v / w), more preferably 1 to 3 times (v / w) with respect to the compound of the formula [4].
• 2-propanol is preferably 0.5 to 10 times the amount (v / w), and more preferably 1 to 5 times the amount (v / w).
• the volume ratio of toluene and 2-propanol is not particularly limited, but 2-propanol / toluene is preferably 1 to 5, and more preferably 1 to 2.
• the compound of the formula [1] is prepared by reacting the compound of the formula [4] with a methanesulfonyl chloride in the presence or absence of a base, a quenching agent, and then a solvent. It can be obtained by reacting with an organic base and crystallization in the presence or absence of an inorganic base. The obtained compound of the formula [1] can be crystallized if desired.
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and is, for example, aliphatic hydrocarbons, halogenated hydrocarbons, and alcohols. Classes, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and the like, and these may be mixed and used. Preferred solvents include nitriles and ethers, with acetonitrile being more preferred.
• the amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w), more preferably 1 to 10 times (v / w) with respect to the compound of the formula [4].
• the amount of methanesulfonyl chloride used in this reaction may be 1 to 100 times mol, preferably 1 to 10 times mol, with respect to the compound of the formula [4].
• the bases optionally used in this reaction include, for example, organic bases such as pyridine, 2-picoline, 2,6-lutidine, 2,4,6-cholidine, dimethylaminopyridine, triethylamine and N, N-diisopropylethylamine.
• organic bases such as pyridine, 2-picoline, 2,6-lutidine, 2,4,6-cholidine, dimethylaminopyridine, triethylamine and N, N-diisopropylethylamine.
• examples include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate and sodium carbonate.
• Preferred bases include organic bases, with pyridine and 2-picoline being more preferred, and pyridine being even more preferred.
• the amount of the base used may be 1 to 100 times mol, preferably 1 to 10 times mol, and more preferably 1 to 2 times mol with respect to the compound of the formula [4].
• This reaction may be carried out at 0 to 150 ° C., preferably 0 to 50 ° C., more preferably 20 to 30 ° C. for 30 minutes to 48 hours, preferably 1 to 24 hours.
• Examples of the quenching agent used in the quench treatment include alcohols such as methanol, ethanol, propanol, butanol and 2-propanol, amines such as methylamine, ethylamine, morpholine and N, N-diisopropylethylamine, and ammonia. Be done.
• Preferred quenching agents include alcohols and amines, with methanol and N, N-diisopropylethylamine being more preferred, and N, N-diisopropylethylamine being even more preferred.
• the amount of the quenching agent used may be 1 to 100 times mol, preferably 1 to 10 times mol, more preferably 1 to 2 times mol, of the compound of the formula [4].
• the solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but for example, aliphatic hydrocarbons, halogenated hydrocarbons and alcohols. , Glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and the like, and these may be mixed and used.
• Preferred solvents include amides, with N, N-dimethylacetamide being more preferred.
• the amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v / w), more preferably 1 to 10 times (v / w) with respect to the compound of the formula [4].
• Examples of the organic base used in this reaction include pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, N, N. -Dimethyl-1,3-propanediamine, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] -7-undecene, 1,5-diazabicyclo [4,3] , 0] -5-nonen, triethylamine, N, N-diisopropylethylamine, 4-methylmorpholin and the like.
• Preferred organic bases include 4-dimethylaminopyridine, N, N-dimethyl-1,3-propanediamine, triethylamine and 1,4-diazabicyclo [2,2,2] octane, and 1,4-diazabicyclo [ 2,2,2] Octane is more preferable.
• the amount of the organic base used may be 1 to 100 times mol, preferably 1 to 10 times mol, and more preferably 1 to 2 times mol with respect to the compound of the formula [4].
• Inorganic bases optionally used in this reaction include, for example, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate and dipotassium hydrogen phosphate. Can be mentioned. Preferred inorganic bases include sodium hydrogen carbonate, potassium carbonate and sodium carbonate, with potassium carbonate being more preferred.
• the amount of the inorganic base used may be 1 to 100 times mol, preferably 1 to 10 times mol, and more preferably 1 to 2 times mol with respect to the compound of the formula [4].
• This reaction may be carried out at 0 to 200 ° C., preferably 50 to 150 ° C., more preferably 70 to 100 ° C. for 30 minutes to 48 hours, preferably 5 to 24 hours.
• the crystallization method for crystallization of the obtained compound of the formula [1] as desired is not particularly limited, but after preparing a solution of the compound of the formula [1], crystallization by distilling off the solvent and cooling of the solvent are performed. Examples thereof include crystallization by addition of a poor solvent and crystallization by addition of a poor solvent, and crystallization by cooling the solvent is preferable.
• the solvent used in the crystallization is not particularly limited as long as it does not adversely affect the reaction, but for example, aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers and ketones. , Esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and the like, and these may be mixed and used.
• Preferred solvents include aromatic hydrocarbons and alcohols, with toluene and 2-propanol more preferred, and a mixed solvent of toluene and 2-propanol even more preferred.
• the amount of the solvent used is not particularly limited, but the amount of toluene is preferably 0.5 to 10 times (v / w), more preferably 1 to 3 times (v / w) with respect to the compound of the formula [4].
• 2-propanol is preferably 0.5 to 10 times the amount (v / w), and more preferably 1 to 5 times the amount (v / w).
• the volume ratio of toluene and 2-propanol is not particularly limited, but 2-propanol / toluene is preferably 1 to 5, and more preferably 1 to 2.
• This production method does not require column purification, does not use dangerous reagents, and can produce compound A non-isolated from 2-chloro-5-methoxynitrobenzene, resulting in high yield and production. It is a manufacturing method with extremely high productivity. Further, this production method can produce compound A having a low content of compound B and extremely high purity, and is extremely useful from the viewpoint of safety.
• Detector Ultraviolet absorptiometer Measurement wavelength: 230nm
• Column TSKgel OSD-80T M, particle size 5 [mu] m, an inner diameter of 4.6 ⁇ length 150mm
• Mobile phase A mixture of water / acetonitrile / 1 mol / L acetic acid / 1 mol / L acetic acid / triethylamine solution (volume ratio 99: 90: 10: 1) Flow rate: 1.0 mL / min
• Test Example 1 The purity of the compound A obtained in Example 1, Example 2, Example 3, Example 4 and Comparative Example 1 and the content of the compound B contained in the compound A were measured. The purity of compound A was quantified using the area percentage method and the ratio of the area of compound A to the total area of the obtained peaks. The content of compound B was determined by the following formula using the area% of the results measured by high performance liquid chromatography of compound A and compound B. The retention time of compound A was 10.4 minutes, and the retention time of compound B was 16.9 minutes.
• Comparative Example 1 was carried out in the same manner as in the production method described in Reference Example 5 (2) of Patent Document 1.
• As the seed crystal a crystal obtained in the same manner as in the method described in Patent Document 1 was used.
• Example 1 A mixture of 2-chloro-5-methoxynitrobenzene 51.00 g, phenol 38.38 g, 48% potassium hydroxide aqueous solution 41.32 g, N, N-dimethylacetamide 51 mL and toluene 255 mL was heated under a nitrogen atmosphere until reflux was performed. At the same temperature, the mixture was stirred for 9 hours and 30 minutes while removing water using a Dean-Stark apparatus. The reaction mixture was cooled to 80 ° C., 102 mL of water was added, the mixture was stirred at 60-80 ° C. for 10 minutes, and the organic layer was separated.
• Example 2 A mixture of 0.50 g of 5-methoxy-2-phenoxyaniline and 2.5 mL of acetonitrile is cooled to 0 to 10 ° C. under a nitrogen atmosphere, 282 ⁇ L of pyridine is added, and then a 2.5 mL solution of 0.42 g of methanesulfonic anhydride is added dropwise. , Stirred at 0-10 ° C for 2 hours and 40 minutes. 40 mg of methanesulfonic acid anhydride was added to the reaction mixture, and the mixture was stirred at 0 to 10 ° C. for 5 hours and 20 minutes.
• Example 3 A mixture of 2-chloro-5-methoxynitrobenzene 20.00 g, phenol 15.05 g, 48% potassium hydroxide aqueous solution 16.20 g, N, N-dimethylacetamide 20 mL and toluene 100 mL is heated under a nitrogen atmosphere until reflux is performed. At the same temperature, the mixture was stirred for 9 hours while removing water using a Dean-Stark apparatus. The reaction mixture was cooled to 80 ° C., 40 mL of water was added, the mixture was stirred at 60-80 ° C. for 10 minutes, and the organic layer was separated.
• reaction mixture is cooled to 0-10 ° C., 16.34 g of N, N-dimethyl-1,3-propanediamine is added dropwise over 40 minutes, stirred at 0-10 ° C. for 1 hour and 30 minutes, overnight at the same temperature. It was left still. 200 mL of ethyl acetate, 200 mL of 10% aqueous sodium chloride solution and 30 mL of concentrated hydrochloric acid were added to the reaction mixture, the pH was adjusted to 1.05, and the mixture was stirred at 15 to 25 ° C. for 30 minutes to separate the organic layer.
• the reaction mixture was cooled to 20-30 ° C and then stirred at the same temperature for 1 hour and 30 minutes.
• the reaction mixture was cooled to 0-10 ° C. and then stirred at the same temperature for 2 hours.
• the reaction mixture was cooled to ⁇ 25 to ⁇ 15 ° C. and then stirred at the same temperature for 1 hour.
• the solid was collected by filtration and washed with 40 mL of 2-propanol to obtain 29.32 g of N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide as a pale red solid.
• Example 4 A mixture of 0.50 g of 5-methoxy-2-phenoxyaniline, 301 ⁇ L of pyridine and 2.5 mL of acetonitrile was added under a nitrogen atmosphere at 20 to 30 ° C., 216 ⁇ L of methanesulfonyl chloride was added, and the mixture was stirred at the same temperature for 17 hours. The reaction mixture was cooled to 0-10 ° C., 440 ⁇ L of N, N-dimethyl-1,3-propanediamine was added dropwise over 6 minutes, and the mixture was stirred at 0-10 ° C. for 2 hours and 50 minutes.
• the obtained organic layer was washed with a 10% aqueous sodium chloride solution and a 5% aqueous sodium hydrogen carbonate solution, and then magnesium sulfate was added to remove solids.
• the solvent was distilled off from the obtained solution under reduced pressure, 3 mL of 2-propanol was added, and the mixture was stirred at room temperature for 1 hour and 20 minutes.
• the reaction mixture was cooled to 0-10 ° C. and then stirred at the same temperature.
• the solid was collected by filtration and washed 3 times with 1 mL of 2-propanol to obtain 0.57 g of N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide as a white solid.
• Comparative Example 1 A mixture of 10.00 g of 5-methoxy-2-phenoxyaniline, 16.61 g of pyridine and 100 mL of methylene chloride was cooled to 5 ° C under a nitrogen atmosphere, and 9.10 g of methanesulfonyl chloride was added dropwise at 5-10 ° C over 10 minutes. The mixture was stirred at ⁇ 10 ° C. for 1 hour and 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, 100 mL of ethyl acetate and 50 mL of water were added, the pH was adjusted to 1.92 with 4 mol / L hydrochloric acid, and the mixture was stirred at 20 to 30 ° C. for 10 minutes to separate the organic layer. bottom.
• reaction mixture was cooled to 0-10 ° C. and then stirred at the same temperature for 1 hour and 20 minutes.
• the solid was collected by filtration and washed with 20 mL of 2-propanol to obtain 13.05 g of N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide as a pale red solid.
• the production method of the present invention is useful as a production method for N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide having a reduced impurity content. Furthermore, the N- (5-methoxy-2-phenoxyphenyl) methanesulfonamide with reduced impurities of the present invention is useful as a raw material for a high-purity drug substance of iguratimod.

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