WO2019163731A1 - Production method for oxazolidinone compound - Google Patents

Abstract

A method for producing the compound represented by formula (3), the production method comprising steps 1 and 2 and being capable of efficiently yielding the oxazolidinone compound (3), which is an intermediate of rivaroxaban, which is useful as a medicine. Step 1: a step in which the compound represented by formula (1) is reacted with the compound represented by formula (2) in acetonitrile in the presence of a trifluoromethanesulfonate. Step 2: a step in which the mixture obtained in step 1 is reacted with 1,1'-carbonyldiimidazole to obtain the compound represented by formula (3). The present invention further provides: a method for producing a hydrochloride of the compound represented by formula (4) from the obtained compound represented by formula (3); and a method for producing the compound represented by formula (6) from the hydrochloride of the compound represented by formula (4).

Description

Method for producing oxazolidinone compound

The present invention relates to a method for producing an oxazolidinone compound.

Rivaroxaban, ie, formula (6)

(Hereinafter referred to as compound (6)) is one of oral anticoagulants that directly inhibits factor Xa.

AU2004313694B includes a compound represented by formula (1) as a method for producing compound (6).

(Hereinafter referred to as compound (1)) and formula (2)

Is reacted with a compound represented by the following formula (hereinafter referred to as compound (2)), followed by reaction with a phosgene equivalent, that is, an oxazolidinone compound that is a production intermediate, that is, formula (3)

(Hereinafter referred to as compound (3)), and from compound (3) to formula (4)

A method for producing rivaroxaban via the hydrochloride of a compound represented by the formula (hereinafter referred to as compound (4)) is described. Moreover, as a manufacturing method of compound (3) which is a manufacturing intermediate, specifically, compound (1) and compound (2) were reacted as a first step in a mixed solvent of ethanol and water. Formula (7)

And the compound (7) is then cyclized using 1,1′-carbonyldiimidazole in N-methylpyrrolidone or toluene as the second step. To obtain compound (3) by reacting compound (3) and methylamine in ethanol to obtain compound (4) and adding hydrochloric acid to obtain hydrochloride of compound (4); and compound (4) ) To obtain compound (6) from the hydrochloride salt thereof.

However, in this method, in the production of compound (3), although 1,1′-carbonyldiimidazole having a property of decomposing by reacting with water in the second step is used, ethanol is used as a solvent in the first step. Since a mixed solvent of water and water is used, it is necessary to isolate and dry the compound (7) generated in order to remove water after the completion of the reaction in the first step. In addition, since the compound (2) used in the first step is gradually decomposed in the presence of water, the decomposed product itself can be an impurity, and the decomposed product reacts with the target product or other impurities to generate new impurities. This is not preferred in the production of rivaroxaban, a pharmaceutical product.

Furthermore, since the solvent used in the second step for obtaining the compound (3) and the step for obtaining the compound (4) from the compound (3) are different, it is necessary to isolate the compound (3) also in the second step.

The present invention relates to an efficient production method in which water is not used as a solvent in the production of compound (3) which is a production intermediate of rivaroxaban useful as a pharmaceutical, and the hydrochloride of compound (4) using the same And an efficient method for producing rivaroxaban.

The present invention is as follows.
[1] Method for producing compound (3) comprising step 1 and step 2:
Step 1: A step of reacting Compound (1) and Compound (2) in acetonitrile in the presence of trifluoromethanesulfonate;
Step 2: A step of reacting the mixture obtained in Step 1 with 1,1′-carbonyldiimidazole to obtain Compound (3).
[2] Method for producing hydrochloride of compound (4) comprising step 3 and step 4 in addition to step 1 and step 2 according to [1]:
Step 3: A step of obtaining a compound (4) by reacting a compound (3) with methylamine;
Step 4: A step of reacting compound (4) with hydrogen chloride to obtain hydrochloride of compound (4).
[3] Method for producing hydrochloride of compound (4) including step 1, step 2 ′, step 3 ′ and step 4:
Step 1: A step of reacting Compound (1) and Compound (2) in acetonitrile in the presence of trifluoromethanesulfonate;
Step 2 ′: reacting the mixture obtained in Step 1 with 1,1′-carbonyldiimidazole;
Step 3 ′: a step of reacting the mixture obtained in Step 2 ′ with methylamine to obtain compound (4);
Step 4: A step of reacting compound (4) with hydrogen chloride to obtain hydrochloride of compound (4).
[4] Method for producing hydrochloride of compound (4) according to [2] or [3], and method for producing compound (6) comprising step 5:
Step 5: Hydrochloride of compound (4) and formula (5)

A compound represented by the formula (hereinafter referred to as compound (5)) in the presence of a base to obtain compound (6).
[5] The trifluoromethanesulfonate is any one of [1] to [4], which is zinc (II) trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate (III), or aluminum (III) trifluoromethanesulfonate. Production method.

Hereinafter, the present invention will be described in detail.
Process 1
Step 1 will be described. In step 1, compound (1) and compound (2) are reacted in acetonitrile in the presence of trifluoromethanesulfonate.

Examples of the trifluoromethanesulfonate include zinc (II) trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate (III), aluminum trifluoromethanesulfonate (III), lithium trifluoromethanesulfonate, calcium trifluoromethanesulfonate, and trifluoromethanesulfone. Trifluoromethanesulfonic acid metal salts such as iron (II) acid, copper (II) trifluoromethanesulfonate and bismuth (III) trifluoromethanesulfonate, and triethylsilyl trifluoromethanesulfonate, and zinc trifluoromethanesulfonate (II ), Ytterbium trifluoromethanesulfonate (III) and aluminum (III) trifluoromethanesulfonate are preferred. , Zinc trifluoromethanesulfonate (II) and trifluoromethanesulfonic acid ytterbium (III) are more preferable. Trifluoromethanesulfonate may be an anhydride or a hydrate, and a commercially available product can be used as it is.

The amount of trifluoromethanesulfonate to be used is generally 0.01 mol to 0.20 mol, preferably 0.02 mol to 0.07 mol, per 1 mol of compound (1).

The amount of compound (2) to be used is generally 1 mol to 1.5 mol, preferably 1.00 mol to 1.05 mol, per 1 mol of compound (1).

The acetonitrile used in step 1 is more preferably one having a low water content. When the water content of acetonitrile is large, the compound (2) may be decomposed by water, and 1,1′-carbonyldiimidazole used in Step 2 is hydrolyzed, which is not preferable. Therefore, the water content of acetonitrile used in Step 1 is usually 0% to 0.05%, preferably 0% to 0.02%, more preferably 0% to 0.01%. The water content of acetonitrile can be measured by the Karl Fischer method.

The amount of acetonitrile used may be 3 parts by weight or more with respect to 1 part by weight of the compound (1), and is usually 5 parts by weight to 20 parts by weight, preferably 7 parts by weight to 15 parts by weight.

The reaction is carried out by mixing compound (1), compound (2), trifluoromethanesulfonate and acetonitrile. The mixing order of compound (1), compound (2), trifluoromethanesulfonate and acetonitrile is not particularly limited. For example, after mixing acetonitrile, compound (1) and compound (2), trifluoromethanesulfonate is mixed. The compound (1), the compound (2) and trifluoromethanesulfonate are mixed and then acetonitrile is added.

The reaction temperature is usually in the range of 1 ° C to 80 ° C, preferably in the range of 5 ° C to 55 ° C.

The reaction time is usually 1 to 60 hours.

By this reaction, a mixture containing the compound (7) is obtained.

The mixture obtained in step 1 can be directly used in step 2.
Process 2
Step 2 will be described. In step 2, the mixture obtained in step 1 is reacted with 1,1′-carbonyldiimidazole to obtain compound (3).

The amount of 1,1'-carbonyldiimidazole to be used is generally 1 mol-3 mol, preferably 1.0 mol-1.5 mol, per 1 mol of compound (1) used in Step 1.

The reaction is carried out by mixing the mixture obtained in step 1 and 1,1'-carbonyldiimidazole. From the viewpoint of operability, 1,1′-carbonyldiimidazole is preferably added to the mixture obtained in Step 1. In order to add 1,1′-carbonyldiimidazole to the mixture obtained in Step 1, the entire amount of 1,1′-carbonyldiimidazole may be added all at once, or 1,1′-carbonyldiimidazole may be added. May be divided and added in multiple portions.

The addition is usually performed within a range of 1 ° C to 80 ° C, preferably within a range of 5 ° C to 55 ° C.

The reaction temperature is usually in the range of 1 ° C to 80 ° C, preferably in the range of 40 ° C to 80 ° C.

The reaction time is usually 1 minute to 10 hours.

After completion of the reaction in Step 2, for example, the compound (3) can be precipitated and isolated by mixing the reaction mixture and a poor solvent.

Examples of the poor 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 toluene, and toluene, methanol or ethanol is preferably used.

The amount of the poor solvent used is usually 2 to 20 parts by weight, preferably 5 to 15 parts by weight, based on 1 part by weight of the compound (1) used in Step 1.

The mixing is usually performed within a range of 1 ° C to 60 ° C, preferably within a range of 20 ° C to 60 ° C. From the viewpoint of operability, it is preferable to carry out by adding a poor solvent to the reaction mixture.

The compound (3) is usually precipitated as crystals by the mixing. In order to promote the precipitation of the compound (3), a seed crystal of the compound (3) may be added as necessary.

When seed crystals are added, the amount added is 0.001 parts by weight to 0.01 parts by weight with respect to 1 part by weight of the compound (1) used in Step 1, and the addition is usually 1 ° C. to 70 ° C. Is preferably within the range of 20 ° C to 60 ° C.

Crystals are precipitated by mixing the reaction mixture with a poor solvent and, if necessary, seed crystals, usually at −20 ° C. to 60 ° C., preferably −5 ° C. to 20 ° C., usually 1 minute to 24 hours, preferably 1 hour. By holding for ~ 15 hours.

The precipitated compound (3) can be obtained according to a solid-liquid separation technique. Specific examples include solid-liquid separation operations such as filtration and decantation. If necessary, the compound (3) obtained by the solid-liquid separation operation may be washed with a solvent. Examples of the solvent used for washing include hydrocarbon solvents such as heptane, toluene and xylene; and alcohol solvents such as methanol, ethanol and isopropyl alcohol. Toluene, methanol and ethanol are preferably used.

Compound (3) can be dried under normal pressure or reduced pressure.

The purity of the obtained compound (3) is usually 99% or more. Purity can be confirmed by analytical means such as gas chromatography (GC) and high performance liquid chromatography (HPLC).

The obtained compound (3) may be further washed with a slurry by mixing and stirring with the poor solvent.

Moreover, after completion | finish of reaction of the process 2, a compound (3) can also be used for the process 3 without refine | purifying. That is, the mixture obtained in step 2 can be directly used in step 3.
Process 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 carried out in the same manner as in Step 2. The mixture obtained after completion of the reaction in Step 2 can be subjected to Step 3 ′ without purification. That is, the mixture obtained in step 2 ′ can be directly used in step 3 ′.

The mixture obtained in step 2 ′ contains compound (3).
Process 3
Step 3 will be described. In step 3, compound (4) is obtained by reacting compound (3) with methylamine.

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; tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, cyclopentyl methyl ether and the like. Ether solvents; ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; and water. Methanol, ethanol, acetonitrile, and water are preferably used.

Compound (3) may be a mixture obtained by the reaction in Step 2. When the mixture obtained in Step 2 is directly used in Step 3, the solvent used in Step 2 can be used as it is, but the solvent may be further mixed and used.

Methylamine is usually mixed with a solvent and used as a liquid composition. Examples of such a solvent include methanol, ethanol, isopropyl alcohol, and water, and methanol or water is preferably used. A commercially available liquid composition such as a methylamine aqueous solution may be used as it is.

The amount of methylamine to be used is generally 1 mol to 10 mol, preferably 3 mol to 7 mol, per 1 mol of compound (3).

The reaction is performed by mixing the compound (3) and methylamine. In the mixing, the mixing order is not particularly limited, and examples thereof include a method in which methylamine is added to a mixture of compound (3) and a solvent; compound (3) is added to a mixture of methylamine and a solvent. .

The reaction temperature is usually within the range of 10 ° C to 80 ° C.

The reaction time is usually in the range of 1 minute to 6 hours.

After completion of the reaction, compound (4) can be subjected to step 4 without purification. That is, the mixture obtained in Step 3 can be directly used in Step 4.

Compound (4) can also be isolated and purified by a conventional method. After completion of the reaction, for example, the reaction mixture is concentrated; the reaction mixture and water are mixed and separated, and then the obtained organic layer is washed, dried, concentrated, etc. Can be separated.
Step 3 '
Step 3 ′ will be described. In step 3 ′, the mixture obtained in step 2 ′ is reacted with methylamine to obtain compound (4).

The reaction can be carried out in the same manner as in Step 3, using the mixture obtained in Step 2 ′ (including compound (3)). However, the amount of methylamine used in step 3 ′ is usually 1 to 10 mol, preferably 3 to 7 mol, per 1 mol of compound (1) used in step 1.
Process 4
Step 4 will be described. In step 4, compound (4) is reacted with hydrogen chloride to obtain hydrochloride of compound (4).

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; tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, cyclopentyl methyl ether and the like. Ether solvents; ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; nitrile solvents such as acetonitrile and propionitrile; and water. Methanol, ethanol, isopropyl alcohol, acetonitrile, and water are preferably used.

Compound (4) may be a mixture obtained in Step 3 or Step 3 ′. When the mixture obtained in Step 3 or Step 3 'is directly used in Step 4, the solvent used in Step 3 can be used as it is, but the solvent may be further mixed and used.

As hydrogen chloride, hydrochloric acid (aqueous solution of hydrogen chloride) or hydrogen chloride gas is usually used.

When hydrochloric acid is used, its concentration is not limited, but 5 wt% to 35 wt% hydrochloric acid is preferably used.

The reaction is carried out by mixing compound (4) and hydrogen chloride. In the mixing, the mixing order is not particularly limited. Specifically, hydrochloric acid is added to compound (4); hydrogen chloride gas is blown into a mixture of compound (4) and a solvent; compound (4) is added to hydrochloric acid, and compound (4) is mentioned. A method of adding hydrochloric acid to is preferable.

The amount of hydrogen chloride to be used is usually 3 to 7 mol per 1 mol of compound (4) in which the reaction mixture has a pH of usually 0 to 5, preferably 1 to 4 is mixed.

The reaction temperature is usually in the range of 10 ° C to 70 ° C.

The reaction time is usually in the range of 1 minute to 5 hours.

After completion of the reaction, for example, the reaction mixture is concentrated; by maintaining the reaction mixture at −20 ° C. to 70 ° C., preferably −5 ° C. to 60 ° C. for 1 minute to 20 hours, the hydrochloride of the compound (4) is obtained. Precipitate.

The hydrochloride of the precipitated compound (4) can be obtained according to a solid-liquid separation technique. Specific examples 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 used for washing include methanol, ethanol, isopropyl alcohol, acetonitrile, water, and an aqueous acetonitrile solution, and an acetonitrile or aqueous acetonitrile solution is preferable.

The compound (4) can be dried under normal pressure or reduced pressure.
Process 5
Step 5 will be described. In step 5, compound (4) hydrochloride and compound (5) are reacted in the presence of a base to obtain compound (6).

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; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl- Amide solvents such as 2-imidazolidinone; heterocyclic aromatic solvents such as 1-methylimidazole; ether solvents such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, cyclopentyl methyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, etc. Examples thereof include ketone solvents; nitrile solvents such as acetonitrile and propionitrile; and water. Toluene, acetonitrile or water is preferably used.

The reaction is carried out by mixing the hydrochloride of compound (4), compound (5) and a base. In the mixing, the order of mixing is not particularly limited, and for example, a base is added to a mixture of the hydrochloride salt of the compound (4), the compound (5) and the solvent; to the mixture of the hydrochloride salt of the compound (4), the base and the solvent The method of adding a compound (5) is mentioned.

Compound (5) is usually mixed with a solvent and used as a liquid composition. Examples of such a solvent include the same solvents as those used in the above reaction (excluding water).

The amount of compound (5) to be used is generally 1 mol to 1.5 mol with respect to 1 mol of hydrochloride of compound (4).

Examples of the base include lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, diazabicycloundecene (DBU) and pyridine. And triethylamine is preferably used.

The amount of the base used is generally 2 mol to 4 mol with respect to 1 mol of the hydrochloride of compound (4).

The reaction temperature is usually in the range of 0 ° C to 60 ° C.

The reaction time is usually in the range of 1 minute to 4 hours.

After completion of the reaction, for example, the reaction mixture is concentrated; by maintaining the reaction mixture at −20 ° C. to 50 ° C., preferably −5 to 30 ° C. for 1 minute to 15 hours, the compound (6) is precipitated.

The precipitated compound (6) can be obtained according to a solid-liquid separation technique. Specific examples include solid-liquid separation operations such as filtration and decantation. If necessary, the compound (6) obtained by the solid-liquid separation operation may be washed with a solvent. Examples of the solvent used for washing include methanol, ethanol, acetonitrile, and water, and acetonitrile or water is preferably used.

Compound (6) can be dried under normal pressure or reduced pressure.

The purity of the obtained compound (6) is usually 99% or more. Purity can be confirmed by analytical means such as gas chromatography (GC) and high performance liquid chromatography (HPLC).

The obtained compound (6) is dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, 1,4-dioxane. Further purity is achieved by recrystallization using a solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, chloroform, methanol, ethanol, butanol, 1-pentanol, acetonitrile, acetic acid, water, or a mixed solvent of the above solvents. Can also be increased. If necessary, the compound (6) obtained by recrystallization may be washed with a solvent. Examples of the solvent used for washing include methanol, ethanol, acetonitrile, and water, and methanol or water is preferably used.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

In the following examples, “%” related to concentration means weight% unless otherwise specified.

In the following examples, unless otherwise specified, the purity of a compound was analyzed by high performance liquid chromatography (hereinafter referred to as HPLC) and determined by an area percentage method. The analysis conditions are as follows.
[HPLC analysis condition 1]
Measuring equipment: LC-10Avp manufactured by Shimadzu Corporation
Mobile phase: A liquid: acetonitrile, B liquid: acetonitrile column: CHIRALPAK (registered trademark) IC, particle size 5 μm, 4.6 mm D. × 250mm (manufactured by Daicel Corporation)
UV measurement wavelength: 250 nm
Flow rate: 0.7 mL / min
Column oven: 30 ° C
[HPLC analysis condition 2]
Measuring equipment: LC-10Avp manufactured by Shimadzu Corporation
Mobile phase: Liquid A: 0.1% trifluoroacetic acid aqueous solution, liquid B: 0.1% trifluoroacetic acid-containing acetonitrile gradient conditions: Table 1 below
Column: L-column 2 ODS, particle size 3 μm, 4.6 mm I.D. D. × 150mm (Chemicals Evaluation and Research Institute)
UV measurement wavelength: 240 nm
Flow rate: 1.0 mL / min
Column oven: 35 ° C
<Gradient condition>

Table 1

Example 1
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 15.0 g (0.078 mol) 4- (4-aminophenyl) morpholin-3-one, 15.9 g (0.078 mol) (S) -N-glycidylphthalimide, trifluoromethanesulfone 1.2 g (2.5 mol%) of ytterbium (III) acid hydrate and 105.0 g of acetonitrile were mixed and stirred at 40 ° C. for 20 hours. To the resulting mixture, 17.1 g (0.105 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 7.5 hours. 105.0 g of methanol was added dropwise at 50 ° C. and stirred for 0.5 hour, then cooled to 0 ° C. and stirred for 6 hours, and then the precipitated crystals were isolated by filtration. The obtained crystals were washed with methanol and then dried under reduced pressure at a bath temperature of 50 ° C. to give 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (88% yield) (HPLC purity (HPLC analysis condition 2)): 99 .6%).

Example 2
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 15.0 g (0.078 mol) 4- (4-aminophenyl) morpholin-3-one, 15.9 g (0.078 mol) (S) -N-glycidylphthalimide, trifluoromethanesulfone 1.2 g (2.5 mol%) of ytterbium acid (III) hydrate and 105.0 g of acetonitrile were mixed and stirred at 30 ° C. for 25 hours. To the obtained mixture, 15.8 g (0.098 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 4.5 hours. 105.0 g of methanol was added dropwise at 50 ° C. and stirred for 0.5 hour, then cooled to −10 ° C. and stirred for 1.5 hours, and then the precipitated crystals were isolated by filtration. The obtained crystals were washed with methanol and then dried under reduced pressure at a bath temperature of 50 ° C. to give 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (29.3 g, yield 89%) was obtained (HPLC purity (HPLC analysis condition 2)): 99 .7%).

Example 3
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 15.0 g (0.078 mol) 4- (4-aminophenyl) morpholin-3-one, 15.9 g (0.078 mol) (S) -N-glycidylphthalimide, trifluoromethanesulfone 2.4 g (5 mol%) of ytterbium (III) acid hydrate and 105.0 g of acetonitrile were mixed and stirred at 10 ° C. for 54 hours. To the resulting mixture, 17.1 g (0.105 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 2 hours. 105.0 g of water was added dropwise at 50 ° C. and stirred for 0.5 hour, then cooled to 0 ° C. and stirred for 7 hours, and then the precipitated crystals were isolated by filtration. The obtained crystals were washed with water and dried under reduced pressure at a bath temperature of 50 ° C. to give 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (yield 85%) was obtained (HPLC purity (HPLC analysis condition 2)): 99 .7%).

Example 4
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 15.0 g (0.078 mol) 4- (4-aminophenyl) morpholin-3-one, 15.9 g (0.078 mol) (S) -N-glycidylphthalimide, trifluoromethanesulfone 1.2 g (2.5 mol%) of ytterbium (III) acid hydrate and 150.0 g of acetonitrile were mixed and stirred at 30 ° C. for 48 hours. To the obtained mixture, 17.7 g (0.109 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and 130 g of acetonitrile was distilled off. Subsequently, 180.0 g of methanol was added at 50 ° C. and stirred for 0.5 hour, then cooled to 0 ° C. and stirred for 8 hours, and then the precipitated crystals were isolated by filtration. The obtained crystals were washed with methanol and then dried under reduced pressure at a bath temperature of 50 ° C. to give 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (yield 88%) was obtained (HPLC purity (HPLC analysis condition 2)): 99 .7%).

Example 5
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 4- (4-aminophenyl) morpholin-3-one 15.0 g (0.078 mol), (S) -N-glycidylphthalimide 5.3 g (0.026 mol), trifluoromethanesulfone 1.2 g (2.5 mol%) of ytterbium (III) acid hydrate and 105.0 g of acetonitrile were mixed and stirred at 30 ° C. for 5 hours. Next, 5.3 g (0.026 mol) of (S) —N-glycidylphthalimide was added and stirred at 30 ° C. for 5 hours, and then 5.3 g (0.026 mol) of (S) —N-glycidylphthalimide was further added. And stirred at 30 ° C. for 20 hours. To the mixture obtained at the same temperature, 14.6 g (0.090 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 1 hour. After cooling to 50 ° C., the reaction mixture was concentrated under reduced pressure, and 75 g of acetonitrile was distilled off. Next, 180.0 g of toluene was added at 50 ° C., and the mixture was stirred for 0.5 hour, then cooled to 0 ° C. and the precipitated solid was isolated by filtration. The obtained solid was washed with toluene, dried under reduced pressure at a bath temperature of 50 ° C., and crude 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl ] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione was obtained. The resulting crude 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-iso Indole-1,3 (2H) -dione, 150.0 g of toluene and 15.0 g of ethanol were mixed and stirred at 25 ° C. for 1 hour, further cooled to 0 ° C. and stirred for 8 hours. Isolated by filtration. The obtained crystals were washed with toluene, dried under reduced pressure at a bath temperature of 50 ° C., and 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (yield 93%) was obtained (HPLC purity (HPLC analysis condition 2)): 99 .6%).

Example 6
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 15.0 g (0.078 mol) 4- (4-aminophenyl) morpholin-3-one, 15.9 g (0.078 mol) (S) -N-glycidylphthalimide, trifluoromethanesulfone Zinc (II) acid (1.4 g, 5 mol%) and acetonitrile (200.3 g) were mixed and stirred at 40 ° C. for 28 hours. To the resulting mixture, 17.08 g (0.105 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 2.5 hours. After cooling to 50 ° C., the reaction mixture was concentrated under reduced pressure, and 170 g of acetonitrile was distilled off. Next, 180.0 g of methanol was added at 50 ° C., and the mixture was stirred for 0.5 hour, further cooled to 0 ° C. and stirred for 8 hours, and the precipitated crystals were isolated by filtration. The obtained crystals were washed with methanol and then dried under reduced pressure at a bath temperature of 50 ° C. to give 2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (yield 86%) (HPLC purity (HPLC analysis condition 2)): 99 .5%).

Example 7
Synthesis of 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 2-({(5S)- 2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidin-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione30. To a mixture of 0 g (0.071 mol) and 177.6 g of acetonitrile, 24.3 g (0.313 mol) of an aqueous methylamine solution (40%) was added dropwise at 25 ° C. Subsequently, it heated at 60 degreeC and stirred for 4 hours. 36.0 g of isopropyl alcohol was added to the obtained mixture, and after cooling to 55 ° C., 46.0 g of 20% hydrochloric acid was added dropwise until the pH reached 1.5, followed by stirring for 0.5 hour. Then, after cooling to 20 ° C. and stirring for 13.5 hours, the precipitated crystals were isolated by filtration. The obtained crystals were washed with 90% acetonitrile aqueous solution and then with acetonitrile, and then dried under reduced pressure at a bath temperature of 50 ° C. to give 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1, 18.1 g (yield 77.6%) of 3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride was obtained (HPLC purity (HPLC analysis condition 2): 99.8%).

Reference example 1
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 N, N-dimethylformamide in toluene 32. 4 g was added and heated to 60 ° C. At 60 ° C., 9.1 g (0.076 mol) of thionyl chloride was added dropwise over 3 hours and stirred for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure with a bath temperature of 60 ° C. or less, and thionyl chloride and toluene were distilled off until a toluene solution of about 40% or more of 5-chlorothiophene-2-carbonyl chloride was obtained ( The concentration of toluene was confirmed by gas chromatography.) After cooling, toluene was added to obtain 39.5 g of a toluene solution of about 35% 5-chlorothiophene-2-carbonyl chloride.

Example 8
5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2- Synthesis of carboxamide 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 15.0 g (0.046 mol) ), 10.5 g of water and 75.0 g of acetonitrile were mixed at room temperature, and 11.6 g (0.114 mol) of triethylamine was added dropwise at 25 ° C. After cooling to 10 ° C., 29.6 g (0.057 mol) of a toluene solution of about 35% concentration of 5-chlorothiophene-2-carbonyl chloride and 4.8 g of toluene were added dropwise at 10 ° C. and heated to 20 ° C. Stir for 2 hours. The resulting mixture was then heated to 50 ° C. and stirred for 3 hours, then cooled to 25 ° C. and stirred for 11.5 hours, and the precipitated crystals were isolated by filtration. The obtained crystals were washed successively with acetonitrile and water and then dried under reduced pressure at a bath temperature of 50 ° C. to give 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholine -4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide (18.5 g, yield 93%) was obtained (HPLC purity (HPLC analysis condition 2): 99.96. %that's all).

Reference example 2
5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2- Recrystallization of carboxamide 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) 60.0 g of dimethyl sulfoxide (hereinafter referred to as DMSO) is added to 15.0 g (0.034 mol) of thiophene-2-carboxamide, heated to 70 ° C., 0.5 g of activated carbon is added, and the mixture is stirred for 0.5 hours. did. Subsequently, the solid obtained by filtration was washed with 22.5 g of DMSO to obtain a mixed solution of the filtrate and the washing solution. After 82.5 g of methanol was slowly added dropwise at 50 ° C. to the resulting mixture, 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) 0.02 g of crystals of [phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide were added. Then, it cooled to 5 degreeC and stirred for 14 hours, and the precipitated crystal | crystallization was filtered. The obtained crystals were washed successively with methanol and water and then dried under reduced pressure at a bath temperature of 50 ° C. to give 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholine -4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide (14.2 g, yield 94%) was obtained (HPLC purity (HPLC analysis condition 2): 99.96. % Or more, optical purity (HPLC analysis condition 1): 99.99% or more).

Reference example 3
5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2- Recrystallization of carboxamide 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) To 31.0 g (0.071 mol) of thiophene-2-carboxamide, 124.0 g of DMSO was added, heated to 70 ° C., 0.9 g of activated carbon was added, and the mixture was stirred for 0.5 hours. Subsequently, the solid obtained by filtration was washed with 46.5 g of DMSO to obtain a mixed solution of the filtrate and the washing solution.
94.7 g of the obtained mixed solution (5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5 -Yl} methyl) thiophene-2-carboxamide (containing 0.034 mol equivalent) at 50 ° C. was slowly added dropwise with 4.2 g of methanol, and then 5-chloro-N-({(5S) -2-oxo-3- [ 0.02 g of 4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide crystal was added and stirred for 4 hours. Thereafter, 78.3 g of methanol was slowly added dropwise at 50 ° C., cooled to 5 ° C., stirred for 10.5 hours, and the precipitated crystals were filtered. The obtained crystals were washed successively with methanol and water and then dried under reduced pressure at a bath temperature of 50 ° C. to give 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholine -4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide (14.2 g, yield 95%) was obtained (HPLC purity (HPLC analysis condition 2): 99.96. % Or more, optical purity (HPLC analysis condition 1): 99.99% or more).
As a result of analyzing the obtained crystal by a near infrared (NIR) analysis method, it was found that 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxo Consistent with modification I of morpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide.

Example 9
Synthesis of 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 4- (4-aminophenyl) 20.0 g (0.104 mol) of morpholin-3-one, 21.1 g (0.104 mol) of (S) —N-glycidylphthalimide, 1.9 g (5 mol%) of zinc (II) trifluoromethanesulfonate, and 267. 0 g was mixed and stirred at 45 ° C. for 18 hours. To the obtained mixture, 19.4 g (0.120 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 2 hours. After cooling to 25 ° C., 35.4 g (0.458 mol) of an aqueous methylamine solution (40%) was added dropwise at 25 ° C. Next, the mixture was heated to 60 ° C. and stirred for 4 hours. Then, 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 adjusted to pH 2.0. And stirred for 0.5 hour. Then, it cooled to 20 degreeC, stirred for 11 hours, and isolate | separated the crystal | crystallization which precipitated. The obtained crystals were washed with 90% acetonitrile aqueous solution and then with acetonitrile, and then dried under reduced pressure at a bath temperature of 50 ° C. to give 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1, 19.1 g (yield 56.1%) of 3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride was obtained (HPLC purity (HPLC analysis condition 2): 99.8%).

Example 10
Synthesis of 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 4- (4-aminophenyl) 40.0 g (0.208 mol) of morpholin-3-one, 42.3 g (0.208 mol) of (S) —N-glycidylphthalimide, 3.8 g (5 mol%) of zinc (II) trifluoromethanesulfonate, and 534. 0 g was mixed and stirred at 45 ° C. for 17 hours. To the obtained mixture, 38.8 g (0.239 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 2 hours. After cooling to 25 ° C., 70.7 g (0.915 mol) of an aqueous methylamine solution (40%) was added dropwise at 25 ° C. Subsequently, it heated at 60 degreeC and stirred for 4 hours. 12.0 g of acetonitrile and 48.0 g of isopropyl alcohol were added to the obtained mixture, and after cooling to 55 ° C., 128.6 g of 35% hydrochloric acid was added dropwise until the pH reached 1.8, followed by stirring for 0.5 hours. Then, it cooled to 20 degreeC and stirred for 11.5 hours, and the crystal | crystallization which precipitated was isolated by filtration. The obtained crystals were washed with 90% acetonitrile aqueous solution and then with acetonitrile, and then dried under reduced pressure at a bath temperature of 50 ° C. to give 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1, There was obtained 51.3 g (yield 74.3%) of 3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride (HPLC purity (HPLC analysis condition 2): 97.7%).

Example 11
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 4- (4-aminophenyl) morpholin-3-one 8.0 g (0.042 mol), (S) -N-glycidylphthalimide 8.5 g (0.042 mol), trifluoromethanesulfone 0.7 g (3.5 mol%) of aluminum (III) acid and 80.0 g of acetonitrile were mixed and stirred at 40 ° C. for 21 hours. To the obtained mixture, 7.8 g (0.048 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 1.5 hours. 40.0 g of methanol was added dropwise at 50 ° C., cooled to 20 ° C., stirred for 1 hour, and the resulting crystals were isolated by filtration, washed with methanol, dried under reduced pressure at a bath temperature of 50 ° C., 2- ({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 ( 2H) -dione (13.0 g, yield 74%) was obtained (HPLC purity (HPLC analysis condition 2): 99.9%).

Example 12
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 2- (4-aminophenyl) morpholin-3-one 20.0 g (0.104 mol), (S) -N-glycidylphthalimide 21.1 g (0.104 mol), trifluoromethanesulfone A mixture of 1.0 g (2.5 mol%) of zinc acid (II) and 267.0 g of acetonitrile was stirred at 50 ° C. for 23 hours. To the obtained mixture, 19.4 g (0.120 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 2 hours. Acetonitrile 13.0g was added to the obtained mixture, and methanol 140.0g was dripped at 50 degreeC. The crystals obtained after cooling to 0 ° C. and stirring for 6.5 hours were isolated by filtration, washed with methanol, dried under reduced pressure at a bath temperature of 50 ° C., and 2-({(5S) -2-oxo -3- [4- (3-Oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (35.8 g) 82%) (HPLC purity (HPLC analysis condition 2): 99.7%).

Example 13
2-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1, Synthesis of 3 (2H) -dione 4- (4-aminophenyl) morpholin-3-one 40.0 g (0.208 mol), (S) -N-glycidylphthalimide 42.3 g (0.208 mol), trifluoromethanesulfone 3.8 g (5 mol%) of zinc (II) acid and 534.0 g of acetonitrile were mixed and stirred at 45 ° C. for 17 hours. To the obtained mixture, 38.8 g (0.239 mol) of 1,1′-carbonyldiimidazole was added and stirred at 75 ° C. for 2 hours. Next, 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, dried under reduced pressure at a bath temperature of 50 ° C., and 2-({(5S) -2-oxo-3 71.1 g of-[4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione (yield 81 %) (HPLC purity (HPLC analysis condition 2): 99.7%).

Example 14
Synthesis of 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 2-({(5S)- 2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidin-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione To a mixture of 0 g (0.142 mol) and 337.2 g of acetonitrile, 48.7 g (0.626 mol) of an aqueous methylamine solution (40%) was added dropwise at 25 ° C. Subsequently, it heated at 60 degreeC and stirred for 4 hours. 30.0 g of acetonitrile and 72.0 g of isopropyl alcohol were added to the obtained mixture, and after cooling to 55 ° C., 54.0 g of 35% hydrochloric acid was added dropwise until the pH reached 1.7, followed by stirring for 0.5 hours. Thereafter, the crystal obtained by cooling to 0 ° C. and stirring for 9.5 hours is isolated by filtration, washed with 90% acetonitrile aqueous solution and then with acetonitrile, dried under reduced pressure at a bath temperature of 50 ° C., and 4- { 43.5 g (yield 93.0%) of 4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride was obtained. (HPLC purity (HPLC analysis condition 2): 98.2%).

Example 15
Synthesis of 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 2-({(5S)- 2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidin-5-yl} methyl) -1H-isoindole-1,3 (2H) -dione30. To a mixture of 0 g (0.071 mol) and 168.6 g of acetonitrile, 24.2 g (0.313 mol) of an aqueous methylamine solution (40%) was added dropwise at 25 ° C. Subsequently, it heated at 60 degreeC and stirred for 4 hours. To the obtained mixture, 9.0 g of acetonitrile and 36.0 g of methanol were added. After cooling to 55 ° C., 28.5 g of 35% hydrochloric acid was added dropwise until the pH reached 1.6, followed by stirring for 0.5 hours. After cooling to 0 ° C. and stirring for 14.5 hours, the crystals obtained were isolated by filtration, washed with 90% acetonitrile aqueous solution and then with acetonitrile, and then dried under reduced pressure at a bath temperature of 50 ° C. There was obtained 20.2 g (yield 86.5%) of 4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride. (HPLC purity (HPLC analysis condition 2): 99.6%).

Example 16
5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2- Synthesis of carboxamide 4- {4-[(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride 15.0 g (0.046 mol) ), 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 (0.062 mol) of a toluene solution of 5-chlorothiophene-2-carbonyl chloride having a concentration of about 35% at 10 ° C. and 4.8 g of toluene were added dropwise and heated to 20 ° C. Stir for 2 hours. The resulting mixture was then heated to 50 ° C. and stirred for 2 hours, after which 10.5 g of acetonitrile was added, cooled to 0 ° C. and stirred for 11 hours, and the resulting crystals were isolated by filtration, acetonitrile and water And then dried under reduced pressure at a bath temperature of 50 ° C. to give 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl]- 18.0 g (90% yield) of 1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide was obtained (HPLC purity (HPLC analysis condition 2): 99.95% or more).

Reference example 4
5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2- Recrystallization of carboxamide 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) 67.5 g of dimethyl sulfoxide (hereinafter referred to as DMSO) is added to 15.0 g (0.034 mol) of thiophene-2-carboxamide, heated to 60 ° C., 0.5 g of activated carbon is added, and heated to 70 ° C. And stirred for 0.5 hour. Next, the solid separated by filtration was washed with 10.5 g of DMSO to obtain a mixed solution of the filtrate and the washing solution. The resulting mixture and 4.5 g DMSO at 45 ° C., 82.5 g methanol and 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) Phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide was slowly added dropwise to a mixture of 0.02 g of crystals, heated to 60 ° C., and stirred for 2 hours. Then, it cooled to 5 degreeC and stirred for 9.5 hours, and the precipitated crystal | crystallization was filtered. The obtained crystals were washed successively with methanol and water and then dried under reduced pressure at a bath temperature of 50 ° C. to give 5-chloro-N-({(5S) -2-oxo-3- [4- (3-oxomorpholine -4-yl) phenyl] -1,3-oxazolidine-5-yl} methyl) thiophene-2-carboxamide (14.3 g, yield 95%) was obtained (HPLC purity (HPLC analysis condition 2): 99.97. % Or more, optical purity (HPLC analysis condition 1): 99.99% or more).

According to the present invention, the hydrochloride of compound (3) and compound (4), which are production intermediates of rivaroxaban useful as a pharmaceutical, and rivaroxaban can be efficiently produced.

Claims (6)

Formula (3) including Step 1 and Step 2

A method for producing a compound represented by:
Step 1: Formula (1) in acetonitrile

And a compound represented by formula (2)

A step of reacting a compound represented by formula (II) in the presence of trifluoromethanesulfonate;
Step 2: A step of reacting the mixture obtained in Step 1 with 1,1′-carbonyldiimidazole to obtain a compound represented by Formula (3). Formula (4) including step 3 and step 4 in addition to step 1 and step 2 according to claim 1

A method for producing a hydrochloride salt of a compound represented by:
Step 3: A step of obtaining a compound represented by Formula (4) by reacting a compound represented by Formula (3) with methylamine;
Process 4: The process of obtaining the hydrochloride of the compound represented by Formula (4) by making the compound represented by Formula (4) and hydrogen chloride react. Formula (4) including Step 1, Step 2 ′, Step 3 ′ and Step 4

A method for producing a hydrochloride salt of a compound represented by:
Step 1: Formula (1) in acetonitrile

And a compound represented by formula (2)

A step of reacting a compound represented by formula (II) 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 represented by Formula (4);
Process 4: The process of obtaining the hydrochloride of the compound represented by Formula (4) by making the compound represented by Formula (4) and hydrogen chloride react. Formula (4) according to claim 2

And a process for producing a hydrochloride salt of the compound represented by formula (6):

A method for producing a compound represented by:
Step 5: Hydrochloride of the compound represented by the formula (4) and the formula (5)

A step of reacting the compound represented by formula (6) in the presence of a base to obtain the compound represented by formula (6). Formula (4) according to claim 3

And a process for producing a hydrochloride salt of the compound represented by formula (6):

A method for producing a compound represented by:
Step 5: Hydrochloride of the compound represented by the formula (4) and the formula (5)

A step of reacting the compound represented by formula (6) in the presence of a base to obtain the compound represented by formula (6). The production method according to any one of claims 1 to 5, wherein the trifluoromethanesulfonate is zinc (II) trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate (III) or aluminum (III) trifluoromethanesulfonate.