A preparation method of high-purity rivaroxaban

Abstract

The invention belongs to the field of organic synthesis, and in particular to a method for preparing high-purity rivaroxaban. In the existing process for synthesizing rivaroxaban, there are many types of solvents, large environmental pressure, difficult centrifugation of intermediates, and large impurity quality problems. It is urgent to solve these problems in industry to improve the industrialization capacity of rivaroxaban. In order to solve the above problems, the present invention provides a method for industrial production of high-purity rivaroxaban. The present invention only uses a single solvent of acetonitrile to synthesize from starting material 4-(4-aminophenyl)-3-morpholinone to rivaroxaban crude product, greatly reducing the reaction solvent type, economic and environmental protection, while improving the crystallization particle size of each step intermediate, solving the problem that the product is sticky, difficult to centrifuge, and the impurity content is high, improving product quality and production efficiency, and being suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing high-purity rivaroxaban. Background Art

[0002] The chemical name of rivaroxaban is 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide, which corresponds to the general formula (1):

[0003]

[0004] The general formula (1) is used as an inhibitor of coagulation factor Xa, which selectively blocks the active site of factor Xa, and can also be used as a drug for preventing and / or treating thromboembolic disorders, especially myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass surgery, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

[0005] The existing conventional technology for preparing rivaroxaban is to use three key intermediates, namely, 4-(4-aminophenyl)-3-morpholinone, (S)-(+)-N-(2,3-epoxypropyl)phthalimide and 5-chlorothiophene-2-carbonyl chloride, for synthesis.

[0006] Patent WO2005068456A1 reports a method for preparing rivaroxaban, which is an improvement on the gram-scale preparation method reported in Patent WO0147919A1. Compounds 4-(4-aminophenyl)-3-morpholinone (2) and (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) are prepared in a mixture of water and ethanol to prepare the intermediate (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1, 3-dione (4), intermediate (4) is used in toluene solvent to prepare (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5), which is further hydrolyzed under methylamine conditions in ethanol to obtain intermediate (S)-4-(4-(5-(aminomethyl)-2-oxoxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6), and further in acetone aqueous solution, 5-chlorothiophene-2-carbonyl chloride toluene solution is added to prepare rivaroxaban crude product. This synthesis process uses multiple solvents such as ethanol, toluene, and acetone until the synthesis of the crude product is completed, which has the problems of multiple solvent types and large amount of three wastes, which is not conducive to environmental protection. At the same time, when the intermediate (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) and the intermediate (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) are synthesized under the conditions of an ethanol-water mixture, the material has a high viscosity and is difficult to centrifuge, which also leads to impurities being wrapped and adsorbed, affecting production efficiency and product quality.

[0007] Patent CN202210006184.6 reports a method for preparing rivaroxaban, wherein compounds 4-(4-aminophenyl)-3-morpholinone (2) and (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) are prepared in isopropanol solvent as intermediate (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4), and then reacted in dichloromethane, ethanol, N,N -Dimethylformamide is used to prepare the intermediate (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5), the intermediate (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) and rivaroxaban crude product. The process uses a wide variety of solvents, which puts great pressure on environmental protection. In addition, the problems of high viscosity, difficulty in centrifugation and poor quality of the intermediates are not solved.

[0008] The existing process for synthesizing rivaroxaban generally has many solvent types, large amount of three wastes, difficult centrifugation of intermediates, high impurity content, poor product quality and other problems. The industry urgently needs to solve these problems to improve the industrialization capacity of rivaroxaban. In order to solve the above problems, the present invention provides a method for producing high-purity rivaroxaban with high efficiency and high environmental protection. Summary of the invention

[0009] The present invention aims to provide a method for preparing high-purity rivaroxaban to solve the problems raised in the above background technology. The technical solution of the present invention is as follows:

[0010] Step 1: 4-(4-aminophenyl)-3-morpholinone (2) and (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) are reacted in an aqueous acetonitrile solvent at 50-70° C. for 8-12 hours to prepare (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4);

[0011]

[0012] Step 2: (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) is reacted with N,N-carbonyldiimidazole in acetonitrile solvent at 60-80° C. for 6-10 hours to prepare (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5);

[0013]

[0014] Step 3: (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5) is reacted in acetonitrile or aqueous acetonitrile solvent with 40% monomethylamine at 50-70°C for 2-6 hours, and separated as a hydrochloride to prepare (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6);

[0015]

[0016] Step 4: (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) is subjected to amidation reaction with 5-chlorothiophene-2-carbonyl chloride at 50-70° C. for 2-6 hours in acetonitrile or aqueous acetonitrile solvent under triethylamine condition to prepare crude rivaroxaban, which is then recrystallized from acetic acid to obtain rivaroxaban (1).

[0017]

[0018] In the preparation method of the present invention, the volume ratio of acetonitrile: water in the aqueous acetonitrile in step 1 is 2 to 4:1.

[0019] In the preparation method of the present invention, the water content of the acetonitrile in step 2 is less than 1 volume %.

[0020] In the preparation method of the present invention, the water content of acetonitrile in the aqueous acetonitrile in step 3 is less than 15%.

[0021] In the preparation method of the present invention, the water content of the acetonitrile in the water-containing acetonitrile in step 4 is less than 20%. In the preparation method of the present invention, the optimal reaction temperature in step 1 is 55-60° C., and the reaction time is 9-10 hours, the optimal reaction temperature in step 2 is 70-75° C., and the reaction time is 7-8 hours, the optimal reaction temperature in step 3 is 60-65° C., and the reaction time is 3-4 hours, and the optimal reaction temperature in step 4 is 60-65° C., and the reaction time is 3-4 hours.

[0022] In the preparation method of the present invention, the molar ratio of 4-(4-aminophenyl)-3-morpholinone and (S)-(+)-N-(2,3-epoxypropyl)phthalimide in step 1 is 1:1.2.

[0023] In the preparation method of the present invention, the molar ratio of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione and N,N-carbonyldiimidazole in step 2 is 1:1.2.

[0024] In the preparation method of the present invention, the molar ratio of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride, triethylamine and 5-chlorothiophene-2-carbonyl chloride in step 4 is 1:3:1.5.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) In the present invention, acetonitrile is used as the solvent in the synthesis of the starting material 4-(4-aminophenyl)-3-morpholinone (2) to the crude product of rivaroxaban. The solvent is single and recyclable, which reduces the number of solvents and is economical and environmentally friendly.

[0027] (2) The intermediate (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4), (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) and the crude product of rivaroxaban synthesized in acetonitrile solvent have good crystal particle size, are easy to centrifuge, have low moisture content, are not easily encapsulated by impurities, and thus have improved product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 HPLC chart of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) synthesized in Reference Example a;

[0029] Figure 2 HPLC chart of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) synthesized in Reference Example c;

[0030] Figure 3 This is the HPLC chart of the crude product of rivaroxaban (1) synthesized in Reference Example d;

[0031] Figure 4 HPLC chart of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) synthesized in Example 1;

[0032] Figure 5 HPLC chart of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) synthesized in Example 5;

[0033] Figure 6 This is the HPLC chart of the crude product of rivaroxaban (1) synthesized in Example 8;

[0034] Figure 7 This is the HPLC profile of the rivaroxaban (1) synthesized in Example 11; DETAILED DESCRIPTION

[0035] The following will be combined with the drawings and tables in the embodiments of the present invention and the reference examples to clearly and completely describe the technical solutions in the embodiments of the present invention and the reference examples. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Reference example

[0037] Preparation of rivaroxaban using the technical solution disclosed in patent WO2005068456A1

[0038] a)(R)-2-(2-Hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4)

[0039]

[0040] 117.3 g of 4-(4-aminophenyl)-3-morpholinone (2) and 139.3 g of (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) were stirred at 20°C with 670 ml of water and 1440 ml of ethanol, and the suspension was heated to 58-60°C and stirred for 36 hours. After 2 hours, 5 g of crystalline (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) was added to the reaction mixture, and the product began to crystallize. After cooling to 26°C, the mixture was filtered and washed with ethanol to obtain 252 g of the target product as a wet product, which was dried to obtain 149 g of the target product with a yield of 79.7%.

[0041] b) (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5)

[0042]

[0043] 264.1 g of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) was suspended in 2200 ml of toluene, 130 g of N,N-carbonyldiimidazole was added at 19° C., the mixture was heated under reflux for 1 hour, the temperature was lowered to 60° C., 450 ml of ethanol was added, the mixture was cooled to 25-30° C., the mixture was filtered, washed with ethanol, and dried to obtain 270 g of the target product with a yield of 95.9%.

[0044] c) (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6)

[0045]

[0046] At 22°C, 136g of (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5) was suspended in 1020ml of ethanol, and 110.3g of 40% methylamine solution was added. The reaction mixture was then heated to 60-65°C, stirred for reaction for 2 hours, cooled to 55-60°C, and about 235g of 20% hydrochloric acid was added until the pH was 2-3, after which crystallization began. After cooling to 20°C, the mixture was filtered and washed with methanol to obtain 124g of the target product as a wet product, which was dried to obtain 88g of the target product with a yield of 83.2%.

[0047] d) Rivaroxaban (1) crude product

[0048]

[0049] At 10°C, 116 g of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6), 35 ml of water and 270 ml of acetone were added to 46.4 g of sodium carbonate solution in 595 ml of water. At 8-12°C, a mixed solution of 253.5 g of 5-chlorothiophene-2-carbonyl chloride and 800 ml of toluene was added, the mixture was heated to 50°C, 270 ml of acetone was added, the mixture was stirred and reacted at 50-53°C for 30 minutes, cooled to 26°C, filtered, and washed with a mixed solution of acetone and water to obtain 188 g of the target product in wet form, which was dried to obtain 139 g of the target product in dry form.

[0050] e) Recrystallization of Rivaroxaban (1)

[0051] 212 g of the crude product containing solvent was suspended in 1200 g of acetic acid and heated to 110-115°C. The resulting solution was stirred at this temperature for 10 minutes, clarified and filtered, cooled to 20°C, filtered, rinsed with ethanol and water, and dried to obtain 178 g.

[0052] Example 1

[0053] Preparation of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4)

[0054] 117.3 g of 4-(4-aminophenyl)-3-morpholinone (2) and 139.3 g of (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) were stirred at 20°C with 350 ml of water and 1050 ml of acetonitrile. The suspension was heated to 55-60°C and stirred for 10 hours. After cooling to 25-30°C, it was filtered and rinsed with acetonitrile aqueous solution to obtain 189 g of the target product as a wet product. After drying, 155 g of the target product was obtained with a yield of 83.0%.

[0055] Example 2

[0056] Preparation of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4)

[0057] 117.3 g of 4-(4-aminophenyl)-3-morpholinone (2) and 139.3 g of (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) were stirred at 20°C with 450 ml of water and 1050 ml of acetonitrile. The suspension was heated to 55-60°C and stirred for 10 hours. After cooling to 25-30°C, it was filtered and rinsed with acetonitrile aqueous solution to obtain 190 g of the target product as a wet product. After drying, 154 g of the target product was obtained with a yield of 82.5%.

[0058] Example 3

[0059] Preparation of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4)

[0060] 117.3 g of 4-(4-aminophenyl)-3-morpholinone (2) and 139.3 g of (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) were stirred at 20°C with 260 ml of water and 1050 ml of acetonitrile. The suspension was heated to 55-60°C and stirred for 9 hours. After cooling to 25-30°C, it was filtered and rinsed with acetonitrile aqueous solution to obtain 187 g of the target product as a wet product. After drying, 157 g of the target product was obtained with a yield of 84.0%.

[0061] Compare the quality with reference example a:

[0062] source Total Miscellaneous Key single Moisture content Example 1 1.216％ 0.330％ 18％ Example 2 1.277％ 0.413％ 19％ Example 3 1.097％ 0.298％ 16％ Reference example a 2.657％ 1.411％ 41％

[0063] In reference example a, in the process of synthesizing (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4), a larger amount of solution was used, seed crystals were added, and the reaction time was prolonged to control the crystal particle size, but it did not have a very good effect. The moisture content of the product was still relatively high and it was not easy to centrifuge, resulting in a high impurity content.

[0064] The key monomer in (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) is shown in the following formula (7):

[0065]

[0066] The impurity of formula (7) is inevitably produced in large quantities during the synthesis of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4). The researchers found that if the reaction is prolonged as in reference example a, the impurity will increase significantly. If the crystallization process cannot be well controlled, it is very easy to be wrapped and remain.

[0067] Example 4

[0068] Preparation of (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5)

[0069] 105 g of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) was suspended in 1575 ml of acetonitrile, 52.5 g of N,N-carbonyldiimidazole was added, and the mixture was heated at 70-75° C. for 7 hours. The mixture was cooled to 20-30° C., filtered, washed with acetonitrile and dried to obtain 105 g of the target product with a yield of 93.8%.

[0070] Example 5

[0071] Preparation of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6)

[0072] 105 g of (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5) (the wet product can be directly used for feeding) is suspended in 665 ml of acetonitrile and 35 ml of water, and 73.5 g of 40% methylamine solution is added. The reaction mixture is then heated to 60-65° C. and stirred for reaction for 3 hours. The mixture is cooled to 20-30° C. and about 98 g of concentrated hydrochloric acid is added to a pH of 2-3. Crystallization is then started for 1 hour. The mixture is filtered and washed with acetonitrile aqueous solution to obtain 91.5 g of the wet product of the target product. The wet product of the target product is dried to obtain 83.8 g of the target product with a yield of 90.2%.

[0073] Example 6

[0074] Preparation of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6)

[0075] 105 g of (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5) was suspended in 700 ml of acetonitrile, and 73.5 g of 40% methylamine solution was added. The reaction mixture was then heated to 60-65° C. and stirred for reaction for 3 hours. The mixture was cooled to 20-30° C. and about 98 g of concentrated hydrochloric acid was added to a pH of 2-3. Crystallization was then started for 1 hour. The mixture was filtered and washed with acetonitrile aqueous solution to obtain 98.2 g of the target product as a wet product. The target product was dried to obtain 86.4 g of the target product with a yield of 93.0%.

[0076] Example 7

[0077] Preparation of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6)

[0078] 105 g of (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5) was suspended in 665 ml of acetonitrile and 115 ml of water, and 73.5 g of 40% methylamine solution was added. The reaction mixture was then heated to 60-65° C. and stirred for 4 hours. The mixture was cooled to 20-30° C. and about 98 g of concentrated hydrochloric acid was added until the pH was 2-3. Crystallization was then started for 1 hour. The mixture was filtered and washed with acetonitrile aqueous solution to obtain 87.2 g of the target product as a wet product. The target product was dried to obtain 81.3 g of the target product with a yield of 87.5%.

[0079] Compare the quality with reference example c:

[0080] source Total Miscellaneous Maximum single impurity Moisture content Example 5 0.188％ 0.058％ 8.4％ Example 6 0.252％ 0.078％ 12％ Example 7 0.156％ 0.043％ 6.8％ Reference example c 1.221％ 0.378％ 29％

[0081] The (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) crystallized in an aqueous acetonitrile solvent has a better particle size and can be quickly filtered and separated, which is beneficial to improving the product quality. Since the solvent is uniform and does not affect the next step reaction, the drying procedure of this step can be eliminated, thereby improving production efficiency.

[0082] Example 8

[0083] Preparation of crude rivaroxaban (1)

[0084] 100 g of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride (6) (the wet product can be directly used for feeding) is suspended in 120 ml of water and 480 ml of acetonitrile, 93.3 g of triethylamine is added, the temperature is lowered to 5-10° C., 82.8 g of 5-chlorothiophene-2-carbonyl chloride is added dropwise, the temperature is raised to 60-65° C., the reaction is carried out for 4 hours, the temperature is lowered to 20-25° C., the reaction is centrifuged, and the filter cake is washed with drinking water to obtain 137 g of a crude wet product of rivaroxaban (1), which is dried to obtain 119 g of a crude product of rivaroxaban (1), with a yield of 94.5%.

[0085] Example 9

[0086] Preparation of crude rivaroxaban (1)

[0087] 100 g of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride (6) was suspended in 600 ml of acetonitrile, 93.3 g of triethylamine was added, the temperature was lowered to 5-10°C, 82.8 g of 5-chlorothiophene-2-carbonyl chloride was added dropwise, the temperature was raised to 60-65°C, the reaction was continued for 4 hours, the temperature was lowered to 20-25°C, the reaction was continued by centrifugation, the filter cake was washed with drinking water to obtain 145 g of crude rivaroxaban (1) wet product, and the crude rivaroxaban (1) was dried to obtain 122 g of crude product, with a yield of 97.0%.

[0088] Example 10

[0089] Preparation of crude rivaroxaban (1)

[0090] 100 g of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride (6) was suspended in 60 ml of water and 540 ml of acetonitrile, 93.3 g of triethylamine was added, the temperature was lowered to 5-10°C, 82.8 g of 5-chlorothiophene-2-carbonyl chloride was added dropwise, the temperature was raised to 60-65°C, the reaction was continued for 3 hours, the temperature was lowered to 20-25°C, the reaction was carried out by centrifugation, and the filter cake was washed with drinking water to obtain 136 g of crude rivaroxaban (1) wet product, which was dried to obtain 119.5 g of crude rivaroxaban (1), with a yield of 95.0%.

[0091] Compare the quality with reference example d:

[0092] source Total Miscellaneous Maximum single impurity Moisture content Example 8 0.176％ 0.029％ 13％ Example 9 0.431％ 0.055％ 16％ Example 10 0.212％ 0.033％ 12％ Reference example c 1.038％ 0.285％ 26％

[0093] Similarly, the crude product of rivaroxaban (1) crystallized in an aqueous acetonitrile solvent has a better particle size and can be quickly filtered and separated, which is beneficial to improving product quality and production efficiency.

[0094] Embodiment 11

[0095] Rivaroxaban (1) Recrystallization

[0096] Suspend 120 g of the dry crude product (the wet product can be directly used for feeding) in 750 g of acetic acid, heat to 110-115°C, stir until clear, filter, cool to 20-25°C, filter and dry to obtain 114 g.

[0097] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing rivaroxaban, characterized in that: The following steps are involved: Step 1: 4-(4-aminophenyl)-3-morpholinone (2) and (S)-(+)-N-(2,3-epoxypropyl)phthalimide (3) are reacted in an aqueous acetonitrile solvent at 55-60°C for 9-10 hours to prepare (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4); the molar ratio of 4-(4-aminophenyl)-3-morpholinone to (S)-(+)-N-(2,3-epoxypropyl)phthalimide is 1:1.2; ； Step 2: (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione (4) is reacted with N,N-carbonyldiimidazole in acetonitrile solvent at 70-75° C. for 7-8 hours to prepare (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5); the molar ratio of (R)-2-(2-hydroxy-3-((4-(3-oxo-4-morpholinyl)phenyl)amino)propyl)isoindole-1,3-dione to N,N-carbonyldiimidazole is 1:1.2; ； Step 3: (S)-2-((2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-5-oxazolidinyl)methyl)isoindole-1,3-dione (5) is reacted in acetonitrile or aqueous acetonitrile solvent at 60-65°C for 3-4 hours under 40% methylamine conditions, and separated as a hydrochloride to prepare (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6); ； Step 4: (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride (6) is subjected to amidation reaction with 5-chlorothiophene-2-carbonyl chloride at 60-65° C. for 3-4 hours in acetonitrile or aqueous acetonitrile solvent under triethylamine condition to prepare crude rivaroxaban, and then recrystallized from acetic acid to obtain rivaroxaban (1); the molar ratio of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride to triethylamine to 5-chlorothiophene-2-carbonyl chloride is 1:3:1.5; 。 2. A method for preparing rivaroxaban according to claim 1, characterized in that: The volume ratio of acetonitrile to water in the aqueous acetonitrile in step 1 is 2 to 4:1.

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