IL275443B - Production method for oxazolidinone compound - Google Patents

Description

S426 DESCRIPTION PRODUCTION METHOD FOR OXAZOLIDINONE COMPOUND Technical Field [0001] The present invention relates to a method for producing an oxazolidinone compound. Background Art [0002] Rivaroxaban, i.e., a compound of formula (6): id="p-3" id="p-3" id="p-3" id="p-3" id="p-3"

[0003] (hereinafter referred to as compound (6)) is one of oral anticoagulants which directly inhibit factor Xa. [0004] AU2004313694B mentions, as a method for producing the compound (6), a method in which a compound of formula (1): id="p-5" id="p-5" id="p-5" id="p-5" id="p-5"

[0005] (hereinafter referred to as compound (1)) is reacted with a compound of formula (2): S426 id="p-6" id="p-6" id="p-6" id="p-6" id="p-6"

[0006] (hereinafter referred to as compound (2)), followed by a reaction with a phosgene equivalent to produce an oxazolidinone compound which is a production intermediate, i.e., a compound of formula (3): id="p-7" id="p-7" id="p-7" id="p-7" id="p-7"

[0007] (hereinafter referred to as compound (3)) and further production of rivaroxaban from compound (3) through hydrochloride of a compound of formula (4): id="p-8" id="p-8" id="p-8" id="p-8" id="p-8"

[0008] (hereinafter referred to as compound (4)). Specific examples of the method for producing compound (3) which is a production intermediate include a method comprising a first step of reacting compound (1) with compound (2) in a mixture of ethanol and water as a solvent, and isolating the thus produced compound of formula (7): S426 id="p-9" id="p-9" id="p-9" id="p-9" id="p-9"

[0009] (hereinafter referred to as compound (7)) and a second step of cyclizing compound (7) in N-methylpyrrolidone or toluene using 1,1’-carbonyldiimidazole to obtain compound (3); a method in which compound (3) is reacted with methylamine in ethanol to obtain compound (4), and hydrochloric acid is added to obtain hydrochloride of compound (4); and a method in which compound (6) is obtained from hydrochloride of compound (4). [0010] However, in this method, despite the fact that 1,1′-carbonyldiimidazole, which is susceptible to decomposition by reaction with water is to be used in the second step in the production of compound (3), a mixture of ethanol and water is used as a solvent in the first step, which necessitated isolation and sufficient drying of the resulting compound (7) to remove water after completion of the reaction in the first step. Since compound (2) used in the first step gradually decomposes in the presence of water, there has been a concern that the resulting decomposition products themselves can be impurities, and may react with the target product or other impurities to generate new impurities in the production of rivaroxaban as pharmaceutical. [0011] Moreover, the solvent to be used in the second step of obtaining compound (3) is different from that to be used in the step of obtaining compound (4) from compound (3), so that compound (3) must be isolated also in the second step. Disclosure of the Invention 30 S426 id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"

[0012] The present invention provides an efficient method for producing compound (3), which is an intermediate for the production of rivaroxaban useful as pharmaceutical, without using water as a solvent; and an efficient method for producing hydrochloride of compound (4) using the same, and rivaroxaban. [0013] The present invention is as follows. [1] A method for producing compound (3) comprising step 1 and step 2: Step 1: reacting compound (1) with compound (2) in acetonitrile in the presence of trifluoromethanesulfonate; and Step 2: reacting the mixture obtained in the step 1 with 1,1’-carbonyldiimidazole to obtain compound (3). [2] A method for producing hydrochloride of compound (4) comprising, step 1 and step 2 as defined in [1], and further step 3: reacting compound (3) with methylamine to obtain compound (4); and step 4: reacting compound (4) with hydrogen chloride to obtain hydrochloride of the compound of formula (4). [3] A method for producing hydrochloride of compound (4) comprising step 1, step 2’, step 3’ and step 4: step 1: reacting compound (1) with compound (2) in acetonitrile in the presence of trifluoromethanesulfonate; step 2’: reacting the mixture obtained in the step 1 with 1,1’-carbonyldiimidazole; step 3’: reacting the mixture obtained in step 2’ with methylamine to obtain compound (4); and 30 S426 step 4: reacting compound (4) with hydrogen chloride to obtain a hydrochloride of compound (4). [4] A method for producing a compound of formula (6), comprising the method as defined in [2] or [3] for producing hydrochloride of compound (4), and step 5: reacting hydrochloride of compound (4) with a compound of formula (5): (hereinafter referred to as compound (5)) in the presence of a base to obtain compound (6). [0014] [5] The production method according to any one of [1] to [4], wherein trifluoromethanesulfonate is zinc(II) trifluoromethanesulfonate, ytterbium(III) trifluoromethanesulfonate or aluminum(III) trifluoromethanesulfonate. Mode for Carrying Out the Invention [0015] The present invention will be described in detail below. Step Step 1 will be described. In step 1, compound (1) is reacted with compound (2) in acetonitrile in the presence of trifluoromethanesulfonate. [0016] Examples of trifluoromethanesulfonate include trifluoromethanesulfonic acid metal salts such as zinc(II) S426 trifluoromethanesulfonate, ytterbium(III) trifluoromethanesulfonate, aluminum(III) trifluoromethanesulfonate, lithium trifluoromethanesulfonate, calcium trifluoromethanesulfonate, iron(II) trifluoromethanesulfonate, copper(II) trifluoromethanesulfonate and bismuth(III) trifluoromethanesulfonate, and triethylsilyl trifluoromethanesulfonate, of which zinc(II) trifluoromethanesulfonate, ytterbium(III) trifluoromethanesulfonate and aluminum(III) trifluoromethanesulfonate are preferable, and zinc(II) trifluoromethanesulfonate and ytterbium(III) trifluoromethanesulfonate are more preferable. Trifluoromethanesulfonate may be an anhydride or a hydrate, and commercially available products can be directly used. [0017] Trifluoromethanesulfonate is usually used in an amount of 0.01 mol to 0.20 mol, and preferably 0.02 mol to 0.07 mol, per mol of compound (1). [0018] The compound (2) is usually used in an amount of 1 mol to 1.5 mols, and preferably 1.00 mol to 1.05 mols, per mol of compound (1). [0019] Acetonitrile to be used in step 1 more preferably has lower water content. If acetonitrile has higher water content, compound (2) may be decomposed by water, and 1,1′-carbonyldiimidazole to be used in step 2 is hydrolyzed, which is not preferable. Therefore, the water content of acetonitrile to be used in step 1 is usually 0% to 0.05%, 30 S426 preferably 0% to 0.02%, and more preferably 0% to 0.01%. The water content of acetonitrile can be measured by the Karl Fischer method. [0020] Acetonitrile may be used in an amount of 3 parts by weight or more, usually 5 parts by weight to 20 parts by weight, and preferably 7 parts by weight to 15 parts by weight, per part by weight of the compound (1). [0021] The reaction is performed by mixing compound (1), compound (2), trifluoromethanesulfonate and acetonitrile. There is no particular limitation on the mixing order of compound (1), compound (2), trifluoromethanesulfonate and acetonitrile. For example, it is possible to perform the reaction by a method in which acetonitrile, compound (1) and compound (2) are mixed, and then trifluoromethanesulfonate is added; and a method in which compound (1), compound (2) and trifluoromethanesulfonate are mixed, and then acetonitrile is added. [0022] The reaction temperature is usually in a range of 1°C to 80°C, and preferably 5°C to 55°C. [0023] The reaction time is usually 1 hour to 60 hours. [0024] By this reaction, a mixture containing compound (7) can be obtained. [0025] The mixture obtained in step 1 can be directly fed to step 2. 30 S426 Step Step 2 will be described. In step 2, the mixture obtained in step 1 is reacted with 1,1′-carbonyldiimidazole to obtain compound (3). [0026] 1,1’-carbonyldiimidazole is usually used in an amount of 1 mol to 3 mols, and preferably 1.0 mol to 1.5 mols, per mol of compound (1) used in step 1. [0027] The reaction is performed by mixing the mixture obtained in step 1 with 1,1’-carbonyldiimidazole. From the viewpoint of the operability, it is preferable to add 1,1’-carbonyldiimidazole to the mixture obtained in step 1. To add 1,1’-carbonyldiimidazole to the mixture obtained in step 1, the whole amount of 1,1’-carbonyldiimidazole may be added at once, or 1,1’-carbonyldiimidazole may be added in plural portions. [0028] The addition is usually performed in a range of 1°C to 80°C, and preferably 5°C to 55°C. [0029] The reaction temperature is usually in a range of 1°C to 80°C, and preferably 40°C to 80°C. [0030] The reaction time is usually 1 minute to 10 hours. [0031] After completion of the reaction in step 2, for example, compound (3) can be precipitated and isolated by mixing the reaction mixture with an insufficient solvent. [0032] 30 S426 Examples of the insufficient solvent include hydrocarbon solvents such as heptane, toluene and xylene; halogenated hydrocarbon solvents such as monochlorobenzene; ether solvents such as diisopropyl ether and methyl tert-butyl ether; alcohol solvents such as methanol, ethanol and isopropyl alcohol; and water, of which toluene, methanol or ethanol is preferably used. [0033] The insufficient solvent is usually used in an amount of 2 parts by weight to 20 parts by weight, and preferably 5 parts by weight to 15 parts by weight, per part by weight of compound (1) used in step 1. [0034] The mixing is usually performed in a range of 1°C to 60°C, and preferably 20°C to 60°C. From the viewpoint of the operability, the mixing is preferably performed by adding the insufficient solvent to the reaction mixture. [0035] By the mixing, compound (3) is usually precipitated as crystals. To accelerate the precipitation of compound (3), seed crystals of compound (3) may be added, if necessary. [0036] When the seed crystals are added, the amount thereof is 0.001 part by weight to 0.01 part by weight per part by weight of compound (1) used in step 1. The addition is usually performed in a range of 1°C to 70°C, and preferably 20°C to 60°C. [0037] Crystals are precipitated by mixing the reaction mixture with the insufficient solvent and, if necessary, seed 30 S426 crystals, followed by holding usually at -20°C to 60°C, preferably -5°C to 20°C, usually for 1 minute to 24 hours, preferably 1 hour to 15 hours. [0038] The precipitates of compound (3) can be obtained in accordance with the solid-liquid separation method. Specific examples thereof include solid-liquid separation operations such as filtration and decantation. Compound (3) obtained by the solid-liquid separation operation may be washed with a solvent, if necessary. Examples of the solvent to be used for washing include hydrocarbon solvents such as heptane, toluene and xylene; and alcohol solvents such as methanol, ethanol and isopropyl alcohol; of which toluene, methanol or ethanol is preferably used. [0039] Compound (3) can be dried under normal pressure or reduced pressure. [0040] Compound (3) thus obtained usually has a purity of 99% or more. The purity can be confirmed by analytical means such as gas chromatography (GC) and high performance liquid chromatography (HPLC). [0041] Compound (3) thus obtained may be further slurry washed by mixing with the insufficient solvent under stirring. [0042] After completion of the reaction in step 2, compound (3) can also be fed to step 3 without purification. That is, the mixture obtained in step 2 can be directly fed to step 3. 30 S426 Step 2’ Step 2’ will be described. In step 2’, the mixture obtained in step 1 is reacted with 1,1’-carbonyldiimidazole. The reaction can be performed in the same manner as in step 2. The mixture obtained after completion of the reaction in step 2 can be fed to step 3’ without purification. That is, the mixture obtained in step 2’ can be directly fed to step 3’. [0043] The mixture obtained in step 2’ includes the compound (3). Step Step 3 will be described. In step 3, compound (3) is reacted with methylamine to obtain compound (4). [0044] The reaction is usually performed in a solvent. Examples of the solvent include hydrocarbon solvents such as toluene and xylene; halogenated hydrocarbon solvents such as monochlorobenzene; alcohol solvents such as methanol, ethanol and isopropyl alcohol; ether solvents such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and cyclopentyl methyl ether; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; and water, of which methanol, ethanol, acetonitrile or water is preferably used. [0045] Compound (3) may be obtained as a mixture in the reaction of step 2. When the mixture obtained in step 2 is S426 fed to step 3 as it is, the solvent used in step 2 can be used as it is, or the solvent may be further added thereto. [0046] Methylamine is usually used as a liquid composition after mixing with a solvent. Examples of the solvent include methanol, ethanol, isopropyl alcohol and water, of which methanol or water is preferably used. Commercially available liquid compositions such as an aqueous methylamine solution may be used as it is. [0047] Methylamine is usually used in an amount of 1 mol to mols, and preferably 3 mols to 7 mols, per mol of compound (3). [0048] The reaction is performed by mixing compound (3) with methylamine. In the mixing, the order of mixing is not particularly limited, and examples thereof include a method in which methylamine is added to a mixture of compound (3) and a solvent; and a method in which compound (3) is added to a mixture of methylamine and a solvent. [0049] The reaction temperature is usually in a range of 10°C to 80°C. [0050] The reaction time is usually in a range of 1 minute to 6 hours. [0051] After completion of the reaction, compound (4) can be directly fed to step 4 without purification. That is, the mixture obtained in step 3 can be directly fed to step 4. 30 S426 id="p-52" id="p-52" id="p-52" id="p-52" id="p-52"

[0052] Compound (4) can also be isolated and purified by a conventional method. After completion of the reaction, compound (4) can be isolated, for example, by concentrating the reaction mixture; or by mixing the reaction mixture with water and performing liquid separation, followed by washing, drying and further concentration of the organic layer thus obtained. Step 3’ Step 3’ will be described. In step 3’, the mixture obtained in step 2’ is reacted with methylamine to obtain compound (4). [0053] The reaction can be performed in the same manner as in step 3 using the mixture obtained in step 2’ (including compound (3)). Methylamine is usually used in step 3’ in an amount of 1 mol to 10 mols, and preferably 3 mols to 7 mols, per mol of the compound (1) used in step 1. Step Step 4 will be described. In step 4, compound (4) is reacted with hydrogen chloride to obtain hydrochloride of compound (4). [0054] The reaction is performed in a solvent or in the absence of a solvent. Examples of the solvent include hydrocarbon solvents such as toluene and xylene; halogenated hydrocarbon solvents such as monochlorobenzene; alcohol solvents such as methanol, ethanol and isopropyl alcohol; ether solvents such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and cyclopentyl methyl ether; ketone 30 S426 solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; and water, of which methanol, ethanol, isopropyl alcohol, acetonitrile or water is preferably used. [0055] Compound (4) may be obtained as a mixture in step 3 or step 3’. When the mixture obtained in step 3 or step 3’ is directly fed to step 4, the solvent used in step 3 can be used as it is, or the solvent may be further added thereto. [0056] As hydrogen chloride, hydrochloric acid (an aqueous solution of hydrogen chloride) or a hydrogen chloride gas is usually used. [0057] When using hydrochloric acid, the concentration thereof is not particularly limited, and hydrochloric acid having the concentration of 5% by weight to 35% by weight is preferably used. [0058] The reaction is performed by mixing compound (4) with hydrogen chloride. In the mixing, the order of mixing order is not particularly limited, and specific examples thereof include a method in which hydrochloric acid is added to compound (4); a method in which a hydrogen chloride gas is blown into a mixture of compound (4) and a solvent; and a method in which compound (4) is added to hydrochloric acid, and a preferred is the method in which hydrochloric acid to is added to compound (4). [0059] S426 Hydrogen chloride is used in such an amount that the pH of the reaction mixture is usually 0 to 5, and preferably to 4, and is usually in an amount of 3 mols to 7 mols per mol of the compound (4). [0060] The reaction temperature is usually in a range of 10°C to 70°C. [0061] The reaction time is usually in a range of 1 minute to hours. [0062] After completion of the reaction, a hydrochloride of compound (4) is precipitated, for example, by concentrating the reaction mixture; or by holding the reaction mixture at -20°C to 70°C, preferably -5°C to 60°C, for 1 minute to 20 hours. [0063] The precipitated hydrochloride of compound (4) can be obtained in accordance with the solid-liquid separation method. Specific examples thereof include solid-liquid separation operations such as filtration and decantation. The hydrochloride of compound (4) obtained by the solid-liquid separation operation may be washed with a solvent, if necessary. Examples of the solvent to be used for washing include methanol, ethanol, isopropyl alcohol, acetonitrile, water and an aqueous acetonitrile solution, of which acetonitrile or an aqueous acetonitrile solution is preferable. [0064] S426 Compound (4) can be dried under normal pressure or reduced pressure. Step Step 5 will be described. In step 5, hydrochloride of compound (4) is reacted with compound (5) in the presence of a base to obtain compound (6). [0065] The reaction is usually performed in a solvent. Examples of the solvent include hydrocarbon solvents such as toluene and xylene; halogenated hydrocarbon solvents such as monochlorobenzene; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone; heterocyclic aromatic solvents such as 1-methylimidazole; ether solvents such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and cyclopentyl methyl ether; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; and water, of which toluene, acetonitrile or water is preferably used. [0066] The reaction is performed by mixing hydrochloride of compound (4), compound (5) and a base. In the mixing, the order of mixing is not particularly limited, and examples thereof include a method in which the base is added to a mixture of hydrochloride of compound (4), compound (5) and a solvent; and a method in which compound (5) is added to a mixture of hydrochloride of compound (4), the base and a solvent. [0067] 30 S426 Compound (5) is usually used as a liquid composition after mixing with a solvent. The solvent is the same as that to be used in the above reaction (water is excluded). [0068] Compound (5) is usually used in an amount of 1 mol to 1.5 mols per mol of hydrochloride of the compound (4). [0069] Examples of the base include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, diazabicycloundecene (DBU) and pyridine, of which triethylamine is preferably used. [0070] The base is usually used in an amount of 2 mols to 4 mols per mol of hydrochloride of compound (4). [0071] The reaction temperature is usually in a range of 0°C to 60°C. [0072] The reaction time is usually in a range of 1 minute to hours. [0073] After completion of the reaction, compound (6) is precipitated, for example, by concentrating the reaction mixture; or by holding the reaction mixture at -20°C to 50°C, preferably -5 to 30°C, for 1 minute to 15 hours. [0074] The precipitates of compound (6) can be obtained in accordance with the solid-liquid separation method. Specific 30 S426 examples thereof include solid-liquid separation operations such as filtration and decantation. Compound (6) obtained by the solid-liquid separation operation may be washed with a solvent, if necessary. Examples of the solvent to be used for washing include methanol, ethanol, acetonitrile and water, of which acetonitrile or water is preferably used. [0075] Compound (6) can be dried under normal pressure or reduced pressure. [0076] Compound (6) thus obtained usually has a purity of 99% or more. The purity can be confirmed by analytical means such as gas chromatography (GC) and high performance liquid chromatography (HPLC). [0077] It is also possible to further increase the purity of compound (6) thus obtained by recrystallizing using solvents such as dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2- imidazolidinone, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, chloroform, methanol, ethanol, butanol, 1-pentanol, acetonitrile, acetic acid and water, or a mixed solvent of the above solvents. Compound (6) obtained by recrystallization may be washed with a solvent, if necessary. Examples of the solvent to be used for washing include methanol, ethanol, acetonitrile and water, of which methanol or water is preferably used. Examples [0078] 30 S426 The present invention will be described in more detail by way of Examples, but the present invention is not limited thereto. [0079] In the following Examples, percentages relating to the concentration are by weight unless otherwise specified.[0080] In the following Examples, the purity of the compound was determined by the area percentage method after an analysis using high performance liquid chromatography (hereinafter referred to as HPLC) unless otherwise specified. The analysis conditions are as follows.[HPLC analysis condition 1] Measuring instrument: Shimadzu LC-10Avp Mobile phase: solution A: acetonitrile, solution B: acetonitrile Column: CHIRALPAK (registered trademark) IC, particle size of μm, 4.6 mm I.D. × 250 mm (manufactured by Daicel Co., Ltd.) UV measurement wavelength: 250 nm Flow rate: 0.7 mL/min Column oven: 30°C [HPLC analysis condition 2] Measuring instrument: Shimadzu LC-10 Avp Mobile phase: solution A: aqueous 0.1% trifluoroacetic acid solution, solution B: acetonitrile containing 0.1% trifluoroacetic acid Gradient conditions: Table 1 below Column: L-column2 ODS, particle size of 3 μm, 4.6 mm I.D. × 150 mm (manufactured by Chemicals Evaluation and Research Institute, Japan) UV measurement wavelength: 240 nm 30 S426 Flow rate: 1.0 mL/min Column oven: 35°C [0081] Table 1 Time (min) Concentration of solution B (%) 5 35 40 40.1 50 stop [0082] Example Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)- dione 15.0 g (0.078 mol) of 4-(4-aminophenyl)morpholin-3-one, 15.9 g (0.078 mol) of (S)-N-glycidyl phthalimide, 1.2 g (2.5 mol%) of ytterbium(III) trifluoromethanesulfonate hydrate and 105.0 g of acetonitrile were mixed, followed by stirring at 40°C for 20 hours. To the mixture thus obtained, 17.1 g (0.105 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 7.5 hours. 105.0 g of methanol was added dropwise at 50°C, followed by stirring for 0.5 hour. After cooling to 0°C and stirring for 6 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained was washed with methanol and then dried at a bath temperature of 50°C under reduced pressure to obtain 28.8 g (yield: 88%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H- 25 S426 isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.6%). [0083] Example Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4- yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 15.0 g (0.078 mol) of 4-(4-aminophenyl)morpholin-3-one, 15.9 g (0.078 mol) of (S)-N-glycidyl phthalimide, 1.2 g (2.5 mol%) of ytterbium(III) trifluoromethanesulfonate hydrate and 105.0 g of acetonitrile were mixed, followed by stirring at 30°C for 25 hours. To the mixture thus obtained, 15.8 g (0.098 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 4.5 hours. 105.0 g of methanol was added dropwise at 50°C, followed by stirring for 0.5 hour. After cooling to -10°C and stirring for 1.5 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained was washed with methanol and then dried at a bath temperature of 50°C under reduced pressure to obtain 29.3 g (yield: 89%) of 2-({(5S)-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.7%). [0084] Example 3 Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 15.0 g (0.078 mol) of 4-(4-aminophenyl)morpholin-3-one, 15.9 g (0.078 mol) of (S)-N-glycidyl phthalimide, 2.4 g 30 S426 (5 mol%) of ytterbium(III) trifluoromethanesulfonate hydrate and 105.0 g of acetonitrile were mixed, followed by stirring at 10°C for 54 hours. To the mixture thus obtained, 17.1 g (0.105 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 2 hours. 105.0 g of water was added dropwise at 50°C, followed by stirring for 0.5 hour. After cooling to 0°C and stirring for 7 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained were washed with water and then dried at a bath temperature of 50°C under reduced pressure to obtain 27.9 g (yield: 85%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.7%). [0085] Example 4 Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 15.0 g (0.078 mol) of 4-(4-aminophenyl)morpholin-3-one, 15.9 g (0.078 mol) of (S)-N-glycidyl phthalimide, 1.2 g (2.5 mol%) of ytterbium(III) trifluoromethanesulfonate hydrate and 150.0 g of acetonitrile were mixed, followed by stirring at 30°C for 48 hours. To the mixture thus obtained, 17.7 g (0.109 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure to distill off 130 g of acetonitrile. Subsequently, 180.0 g of methanol was added at 50°C, followed by stirring for 0.hour. After cooling to 0°C and stirring for 8 hours, the precipitated crystals were isolated by filtration. The 30 S426 crystals thus obtained was washed with methanol and then dried at a bath temperature of 50°C under reduced pressure to obtain 28.9 g (yield: 88%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.7%). [0086] Example Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)- dione 15.0 g (0.078 mol) of 4-(4-aminophenyl)morpholin-3-one, 5.3 g (0.026 mol) of (S)-N-glycidyl phthalimide, 1.2 g (2.5 mol%) of ytterbium(III) trifluoromethanesulfonate hydrate and 105.0 g of acetonitrile were mixed, followed by stirring at 30°C for 5 hours. Subsequently, 5.3 g (0.0mol) of (S)-N-glycidyl phthalimide was added, followed by stirring at 30°C for 5 hours, the addition of 5.3 g (0.0mol) of (S)-N-glycidyl phthalimide and further stirring at 30°C for 20 hours. To the mixture thus obtained at the same temperature, 14.6 g (0.090 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 1 hour. After cooling to 50°C, the reaction mixture was concentrated under reduced pressure to distill off 75 g of acetonitrile. Subsequently, 180.0 g of toluene was added at 50°C. After stirring for 0.5 hour and cooling to 0°C, the precipitated solid was isolated by filtration. The solid thus obtained was washed with toluene and then dried at a bath temperature of 50°C under reduced pressure to obtain crude 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- 30 S426 yl}methyl)-1H-isoindole-1,3(2H)-dione. The thus obtained crude 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione, 150.0 g of toluene and 15.0 g of ethanol were mixed, followed by stirring at 25°C for 1 hour. After cooling to 0°C and stirring for 8 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained were washed with toluene and then dried at a bath temperature of 50°C under reduced pressure to obtain 30.5 g (yield: 93%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl}methyl)-1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.6%). [0087] Example Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4- yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 15.0 g (0.078 mol) of 4-(4-aminophenyl)morpholin-3-one, 15.9 g (0.078 mol) of (S)-N-glycidyl phthalimide, 1.4 g (5 mol%) of zinc(II) trifluoromethanesulfonate and 200.3 g of acetonitrile were mixed, followed by stirring at 40°C for hours. To the mixture thus obtained, 17.08 g (0.105 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 2.5 hours. After cooling to 50°C, the reaction mixture was concentrated under reduced pressure to distill off 170 g of acetonitrile. Subsequently, 180.0 g of methanol was added at 50°C, followed by stirring for 0.5 hour. After cooling to 0°C and stirring for 8 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained was washed with methanol and then dried at a bath 30 S426 temperature of 50°C under reduced pressure to obtain 28.1 g (yield: 86%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.5%). [0088] Example Synthesis of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride To a mixture of 30.0 g (0.071 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl}methyl)-1H-isoindole-1,3(2H)-dione and 177.6 g of acetonitrile, 24.3 g (0.313 mol) of an aqueous 40% methylamine solution was added dropwise at 25°C, followed by heating to 60°C and further stirring for 4 hours. To the mixture thus obtained, 36.0 g of isopropyl alcohol was added. After cooling to 55°C, 46.0 g of 20% hydrochloric acid was added until the pH became 1.5, followed by stirring for 0.hour. After cooling to 20°C and stirring for 13.5 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained were washed with an aqueous 90% acetonitrile solution and then with acetonitrile, and then dried at a bath temperature of 50°C under reduced pressure to obtain 18.1 g (yield: 77.6%) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (HPLC purity (HPLC analysis condition 2): 99.8%). [0089] Reference Example Synthesis of 5-chlorothiophene-2-carbonyl chloride To a mixture of 12.4 g (0.076 mol) of 5-chlorothiophene-2-carboxylic acid and 0.1 g (1.779 mmol) of 30 S426 N,N-dimethylformamide, 32.4 g of toluene was added, followed by heating to 60°C. 9.1 g (0.076 mol) of thionyl chloride was added dropwise over 3 hours at 60°C, followed by stirring for 6 hours. After cooling to room temperature, the reaction mixture was concentrated at a bath temperature of 60°C or less under reduced pressure, and then thionyl chloride and toluene were distilled off until a solution of about 40% or more of 5-chlorothiophene-2-carbonyl chloride in toluene was obtained (the concentration of toluene was confirmed by gas chromatography). After cooling, toluene was added to obtain 39.5 g of a solution of about 35% of 5-chlorothiophene-2-carbonyl chloride in toluene. [0090] Example Synthesis of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4- yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide 15.0 g (0.046 mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride, 10.5 g of water and 75.0 g of acetonitrile were mixed at room temperature and then 11.6 g (0.114 mol) of triethylamine was added dropwise at 25°C. After cooling to 10°C, 29.6 g (0.0mol) of a solution of about 35% of 5-chlorothiophene-2-carbonyl chloride in toluene and 4.8 g of toluene were added dropwise at 10°C, followed by heating to 20°C and further stirring for 2 hours. Subsequently, the mixture thus obtained was heated to 50°C, followed by stirring for hours. After cooling to 25°C and stirring for 11.5 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained were sequentially washed with acetonitrile and water, and then dried at a bath temperature 30 S426 of 50°C under reduced pressure to obtain 18.5 g (yield: 93%) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (HPLC purity (HPLC analysis condition 2): 99.96% or more). [0091] Reference Example Recrystallization of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide To 15.0 g (0.034 mol) of 5-chloro-N-({(5S)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, 60.0 g of dimethyl sulfoxide (hereinafter referred to as DMSO) was added, followed by heating to 70°C, the addition of 0.5 g of activated carbon and further stirring for 0.5 hour. Subsequently, the solid obtained by filtration was washed with 22.5 g of DMSO to obtain a mixed liquid of the filtrate and the washing liquid. To the mixed liquid thus obtained, 82.5 g of methanol was slowly added dropwise at 50°C and then 0.02 g of crystals of 5-chloro-N-({(5S)-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide were added. After cooling to 5°C, crystals precipitated by stirring for 14 hours were filtered. The crystals thus obtained were sequentially washed with methanol and water, and then dried at a bath temperature of 50°C under reduced pressure to obtain 14.2 g (yield: 94%) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (HPLC purity (HPLC analysis condition 2): 99.96% S426 or more, optical purity (HPLC analysis condition 1): 99.99% or more). [0092] Reference Example Recrystallization of 5-chloro-N-({(5S)-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide To 31.0 g (0.071 mol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, 124.0 g of DMSO was added, followed by heating to 70°C, the addition of 0.9 g of activated carbon and further stirring for 0.5 hour. Subsequently, the solid obtained by filtration was washed with 46.5 g of DMSO to obtain a mixed liquid of the filtrate and the washing liquid. To 94.7 g of the thus obtained mixed liquid (including about 0.034 mol of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide), 4.2 g of methanol was slowly added dropwise at 50°C and 0.02 g of crystals of 5- chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide were added, followed by stirring for 4 hours. Subsequently, 78.3 g of methanol was slowly added dropwise at 50°C, and then crystals obtained by cooling to 5°C and stirring for 10.5 hours were filtered. The crystals thus obtained were sequentially washed with methanol and water, and then dried at a bath temperature of 50°C under reduced pressure to obtain 14.2 g (yield: 95%) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2- 30 S426 carboxamide (HPLC purity (HPLC analysis condition 2): 99.96% or more, optical purity (HPLC analysis condition 1): 99.99% or more). The crystals thus obtained were analyzed by the near infrared (NIR) analysis method and found to be in an agreement with modification I of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide mentioned in JP 5416408 B1. [0093] Example 9 Synthesis of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride 20.0 g (0.104 mol) of 4-(4-aminophenyl)morpholin-3-one, 21.1 g (0.104 mol) of (S)-N-glycidyl phthalimide, 1.9 g (5 mol%) of zinc(II) trifluoromethanesulfonate and 267.0 g of acetonitrile were mixed, followed by stirring at 45°C for hours. To the mixture thus obtained, 19.4 g (0.120 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 2 hours. After cooling to 25°C, 35.4 g (0.458 mol) of an aqueous 40% methylamine solution was added dropwise at 25°C. To the mixture obtained by heating to 60°C and stirring for 4 hours, 13.2 g of acetonitrile and 52.6 g of isopropyl alcohol were added. After cooling to 55°C, 110.9 g of 20% hydrochloric acid was added dropwise until the pH became 2.0, followed by stirring for 0.5 hour. After cooling to 20°C and stirring for 11 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained were washed with an aqueous 90% acetonitrile solution and then with acetonitrile, and then dried at a bath temperature of 50°C under reduced pressure to obtain 19.1 g (yield: 56.1%) 30 S426 of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (HPLC purity (HPLC analysis condition 2): 99.8%). [0094] Example 10 Synthesis of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride 40.0 g (0.208 mol) of 4-(4-aminophenyl)morpholin-3-one, 42.3 g (0.208 mol) of (S)-N-glycidyl phthalimide, 3.8 g (5 mol%) of zinc(II) trifluoromethanesulfonate and 534.0 g of acetonitrile were mixed, followed by stirring at 45°C for hours. To the mixture thus obtained, 38.8 g (0.239 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 2 hours. After cooling to 25°C, 70.7 g (0.915 mol) of an aqueous 40% methylamine solution was added dropwise at 25°C, followed by heating to 60°C and further stirring for hours. To the mixture thus obtained, 12.0 g of acetonitrile and 48.0 g of isopropyl alcohol were added. After cooling to 55°C, 128.6 g of 35% hydrochloric acid was added dropwise until the pH became 1.8, followed by stirring for 0.5 hour. After cooling to 20°C and stirring for 11.5 hours, the precipitated crystals were isolated by filtration. The crystals thus obtained were washed with an aqueous 90% acetonitrile solution and then with acetonitrile, and then dried at a bath temperature of 50°C under reduced pressure to obtain 51.3 g (yield: 74.3%) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (HPLC purity (HPLC analysis condition 2): 97.7%). [0095] Example 11 30 S426 Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 8.0 g (0.042 mol) of 4-(4-aminophenyl)morpholin-3-one, 8.5 g (0.042 mol) of (S)-N-glycidyl phthalimide, 0.7 g (3.5 mol%) of aluminum(III) trifluoromethanesulfonate and 80.0 g of acetonitrile were mixed, followed by stirring at 40°C for hours. To the mixture thus obtained, 7.8 g (0.048 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 1.5 hours. Crystals obtained by adding dropwise 40.0 g of methanol at 50°C, cooling to 20°C and stirring for hour were isolated by filtration, washed with methanol and then dried at a bath temperature of 50°C under reduced pressure to obtain 13.0 g (yield: 74%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)- 1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.9%). [0096] Example Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4- yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 20.0 g (0.104 mol) of 4-(4-aminophenyl)morpholin-3-one, 21.1 g (0.104 mol) of (S)-N-glycidyl phthalimide, 1.0 g (2.5 mol%) of zinc(II) trifluoromethanesulfonate and 267.0 g of acetonitrile were mixed, followed by stirring at 50°C for hours. To the mixture thus obtained, 19.4 g (0.120 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 2 hours. To the mixture thus obtained, 13.0 g of acetonitrile was added and 140.0 g of methanol was added 30 S426 dropwise at 50°C. Crystals obtained by cooling to 0°C and stirring for 6.5 hours were isolated by filtration, washed with methanol and then dried at a bath temperature of 50°C under reduced pressure to obtain 35.8 g (yield: 82%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3- oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.7%). [0097] Example Synthesis of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4- yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione 40.0 g (0.208 mol) of 4-(4-aminophenyl)morpholin-3-one, 42.3 g (0.208 mol) of (S)-N-glycidyl phthalimide, 3.8 g (5 mol%) of zinc(II) trifluoromethanesulfonate and 534.0 g of acetonitrile were mixed, followed by stirring at 45°C for hours. To the mixture thus obtained, 38.8 g (0.239 mol) of 1,1’-carbonyldiimidazole was added, followed by stirring at 75°C for 2 hours. Subsequently, 26.0 g of acetonitrile was added and 280.0 g of methanol was added dropwise at 50°C. Crystals obtained by cooling to 0°C and stirring for 12 hours were isolated by filtration, washed with methanol and then dried at a bath temperature of 50°C under reduced pressure to obtain 71.1 g (yield: 81%) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H- isoindole-1,3(2H)-dione (HPLC purity (HPLC analysis condition 2): 99.7%). [0098] Example Synthesis of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin- 30 S426 3-yl]phenyl}morpholin-3-one hydrochloride To a mixture of 60.0 g (0.142 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione and 337.2 g of acetonitrile, 48.7 g (0.626 mol) of an aqueous 40% methylamine solution was added dropwise at 25°C, followed by heating to 60°C and further stirring for 4 hours. To the mixture thus obtained, 30.0 g of acetonitrile and 72.0 g of isopropyl alcohol were added. After cooling to 55°C, 54.0 g of 35% hydrochloric acid was added dropwise until the pH became 1.7, followed by stirring for 0.5 hour. Subsequentially, crystals obtained by cooling to 0°C and stirring for 9.5 hours were isolated by filtration, washed with an aqueous 90% acetonitrile solution and then with acetonitrile, and then dried at a bath temperature of 50°C under reduced pressure to obtain 43.5 g (yield: 93.0%) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (HPLC purity (HPLC analysis condition 2): 98.2%). [0099] Example Synthesis of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride To a mixture of 30.0 g (0.071 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5- yl}methyl)-1H-isoindole-1,3(2H)-dione and 168.6 g of acetonitrile, 24.2 g (0.313 mol) of an aqueous 40% methylamine solution was added dropwise at 25°C, followed by heating to 60°C and further stirring for 4 hours. To the mixture thus obtained, 9.0 g of acetonitrile and 36.0 g of 30 S426 methanol were added. After cooling to 55°C, 28.5 g of 35% hydrochloric acid was added dropwise until the pH became 1.6, followed by stirring for 0.5 hour. Subsequentially, crystals obtained by cooling to 0°C and stirring for 14.5 hours were isolated by filtration, washed with an aqueous 90% acetonitrile solution and then with acetonitrile, and then dried at a bath temperature of 50°C under reduced pressure to obtain 20.2 g (yield: 86.5%) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (HPLC purity (HPLC analysis condition 2): 99.6%). [0100] Example Synthesis of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide 15.0 g (0.046 mol) of 4-{4-[(5S)-5-(aminomethyl)-2- oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride, 10.5 g of water and 75.0 g of acetonitrile were mixed at room temperature, and 12.2 g (0.120 mol) of triethylamine was added dropwise at 25°C. After cooling to 10°C, 32.0 g (0.0mol) of a solution of about 35% of 5-chlorothiophene-2- carbonyl chloride in toluene and 4.8 g of toluene were added dropwise at 10°C, followed by heating to 20°C and further stirring for 2 hours. Subsequently, the mixture thus obtained was heated to 50°C, followed by stirring for 2 hours and further addition of 10.5 g of acetonitrile. Crystals obtained by cooling to 0°C and stirring for 11 hours were isolated by filtration, sequentially washed with acetonitrile and water, and then dried at a bath temperature of 50°C under reduced pressure to obtain to obtain 18.0 g (yield: 90%) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]- 30 S426 1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (HPLC purity (HPLC analysis condition 2): 99.95% or more). [0101] Reference Example 4 Recrystallization of 5-chloro-N-({(5S)-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide To 15.0 g (0.034 mol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide, 67.5 g of dimethyl sulfoxide (hereinafter referred to as DMSO) was added, followed by heating to 60°C. Then, 0.5 g of activated carbon was added, followed by heating to 70°C and further stirring for 0.5 hour. Subsequently, the solid separated by filtration was washed with 10.5 g of DMSO to obtain a mixed liquid of the filtrate and the washing liquid. The mixed liquid thus obtained and 4.5 g of DMSO were slowly added dropwise to a mixture of 82.5 g of methanol and 0.02 g of crystals of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide at 45°C, followed by heating to 60°C and further stirring for hours. Subsequentially, crystals precipitated by cooling to 5°C and stirring for 9.5 hours were filtered. The crystals thus obtained were sequentially washed with methanol and water, and then dried at a bath temperature of 50°C under reduced pressure to obtain 14.3 g (yield: 95%) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (HPLC purity (HPLC analysis condition 2): 99.97% or more, optical purity (HPLC analysis condition 1): 99.99% or more). 30 S426 Industrial Applicability [0102] According to the present invention, hydrochlorides of compound (3) and compound (4), which are intermediates for the production of rivaroxaban useful as pharmaceutical, and rivaroxaban can be efficiently produced.

Claims (6)

1.S426 - 37 - CLAIMS 1. A method for producing a compound of formula (3): comprising step 1 and step 2: step 1: reacting a compound of formula (1): with a compound of formula (2): in acetonitrile in the presence of trifluoromethanesulfonate; and step 2: reacting the mixture obtained in step 1 with 1,1’-carbonyldiimidazole to obtain a compound of formula (3).

2. A method for producing hydrochloride of a compound of formula (4): comprising, in addition to step 1 and step 2 according to claim 1, step 3 and step 4: S426 - 38 - Step 3: reacting a compound of formula (3) with methylamine to obtain a compound of formula (4); and Step 4: reacting the compound of formula (4) with hydrogen chloride to obtain a hydrochloride of the compound of formula (4).

3. A method for producing hydrochloride of a compound of formula (4): comprising step 1, step 2’, step 3’ and step 4: step 1: reacting a compound of formula (1): with a compound of formula (2): in acetonitrile in the presence of trifluoromethanesulfonate; step 2’: reacting the mixture obtained in step 1 with 1,1’-carbonyldiimidazole; step 3’: reacting the mixture obtained in step 2’ with methylamine to obtain a compound of formula (4); and step 4:reacting the compound of formula (4) with hydrogen chloride to obtain a hydrochloride of the compound of formula (4).

4. A method for producing a compound of formula (6): S426 - 39 - comprising the method as defined in claim 2 for producing hydrochloride of the compound of formula (4): , and Step 5: reacting hydrochloride of the compound of formula (4) with a compound of formula (5): in the presence of a base to obtain a compound of formula (6).

5. A method for producing a compound of formula (6): comprising the method as defined in claim 3 for producing hydrochloride of the compound of formula (4): , and Step 5: reacting hydrochloride of the compound of formula (4) with a compound of formula (5): S426 - 40 - in the presence of a base to obtain a compound of formula (6).

6. The production method according to any one of claims to 5, wherein trifluoromethanesulfonate is zinc(II) trifluoromethanesulfonate, ytterbium(III) trifluoromethanesulfonate or aluminum(III) trifluoromethanesulfonate.