A preparation method of rivaroxaban

Abstract

The present invention relates to a pharmaceutical chemical synthesis method, and in particular to a preparation method of rivaroxaban, which is used to solve the shortcomings of the existing rivaroxaban preparation method or the low purity of the rivaroxaban finished product, or the inability to separate the intermediate from the by-product. The preparation method of rivaroxaban uses an ethylamine aqueous solution as an ammonolysis reagent, and its by-product can be removed by hydrochloric acid, and its main impurities can be controlled by adjusting the amount of ethylamine aqueous solution added, solving the problem that the intermediate and the by-product cannot be separated; in the refining step of the rivaroxaban crude product, the method adopts formic acid for dissolution, and then adds poor solvent water for crystallization, which ensures the purity and yield of rivaroxaban, and leaching with acetone can remove the moisture content in the material, reduce the pressure of the subsequent drying step, and recrystallization avoids the disadvantages of low column chromatography yield and long time consumption.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical chemical synthesis method, and in particular to a preparation method of rivaroxaban. Background Art

[0002] Rivaroxaban, whose chemical name is 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide, has a molecular formula of C 19 H 18 ClN3O5S. Rivaroxaban tablets were launched by Bayer Pharmaceuticals in the United States in July 2011 and were registered as imported tablets in China in March 2009. Currently, rivaroxaban has gradually replaced the old anticoagulant warfarin and is expected to become a new blockbuster in the cardiovascular field after clopidogrel.

[0003] The synthesis route of rivaroxaban disclosed by Bayer Pharmaceuticals is as follows:

[0004]

[0005] The specific preparation process of (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione (Formula 1) to rivaroxaban (Formula 2) is as follows: MeNH2, H2O (40%, 10.2 ml, 0.142 mol) was added dropwise to a suspension of (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione (4.45 g, 10.6 mol) in EtOH (102 ml) at room temperature, the reaction mixture was refluxed for 1 hour and concentrated under reduced pressure to obtain (S)-4-(4-(5-(aminomethyl)- 5-Chloro-thiophene-2-carboxamide (2.29 g, 12.7 mol) was added dropwise to a pyridine solution (90 ml) of (S)-4-(4-(5-(aminomethyl)-2-oxoxazolidin-3-yl)phenyl)morpholin-3-one at 0°C under an argon atmosphere. The reaction mixture was stirred at room temperature for 1 hour and then mixed with water. Dichloromethane was added and the phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The compound of formula 1 was purified by flash chromatography (eluted with a dichloromethane-methanol mixture) in a total yield of 3.92 g, 86% of the theoretical amount.

[0006] In the above process, MeNH2 is used as the ammonolysis reagent, but even if MeNH2 and H2O are aqueous solutions, they still have the characteristics of low boiling point, low available concentration, flammability and explosion. As the reaction progresses, the purity of the obtained rivaroxaban product will eventually be low.

[0007] In the Gabriel amine synthesis method, hydrazine hydrate is used as the ammonolysis reagent, and the by-product obtained is 2,3-dihydrophthalazine-1,4-dione (Formula 4), which is extremely difficult to separate from the intermediate by crystallization. In theory, whether the intermediate is in the salt state or in the free base state, there will be an equal number of moles of by-products accompanying crystallization, resulting in the inability to control the quality of the intermediate.

[0008] Summary of the invention

[0009] The purpose of the present invention is to solve the shortcomings of the existing rivaroxaban preparation method or the low purity of the rivaroxaban finished product or the inability to separate the intermediate and the by-product, and to provide a rivaroxaban preparation method.

[0010] In order to solve the deficiencies of the above-mentioned prior art, the present invention provides the following technical solutions:

[0011] A method for preparing rivaroxaban, which is special in that it comprises the following steps:

[0012] Step (1), preparing (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0013] (1.1) dispersing (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidine-5-yl)methyl)isoindole-1,3-dione in an alcohol solvent, adding an ethylamine aqueous solution to form a reaction solution, heating the reaction solution to 45-55° C., and keeping the temperature for at least 5 hours; the molar ratio of the (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidine-5-yl)methyl)isoindole-1,3-dione to the ethylamine in the ethylamine aqueous solution is 1:3-20;

[0014] (1.2) adding hydrochloric acid dropwise to the reaction solution after the reaction in step (1.1) until the pH value of the reaction solution is less than 3, and filtering to obtain a crude product;

[0015] (1.3) The crude product is purified by using an alcohol solvent to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0016] Step (2), preparing a crude product of rivaroxaban;

[0017] (2.1) adding the (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride obtained in step (1.3) and a ketone solvent to an aqueous sodium carbonate solution to form a reaction solution; adding dropwise a mixed solution of 5-chloro-2-acylthiophene and a benzene solvent to the reaction solution at 10 to 20° C., wherein the molar ratio of the (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride to 5-chloro-2-acylthiophene is 1:1 to 1.4;

[0018] (2.2) adding a ketone solvent to the reaction solution after the reaction in step (2.1) and stirring, heating to 45-60° C., keeping the temperature for at least 4 hours, cooling and filtering, washing and filtering with purified water and a ketone solvent in turn, to obtain a crude product of rivaroxaban;

[0019] Step (3), preparing a rivaroxaban finished product;

[0020] The crude product of rivaroxaban was dissolved in formic acid, and purified water was added dropwise for crystallization. After filtering, the product was washed with water and acetone in turn, and dried to obtain the finished product of rivaroxaban.

[0021] Furthermore, the step (1.3) is specifically as follows:

[0022] (1.3.1) washing the crude product obtained in step (1.2) with an alcohol solvent, centrifuging, and filtering to obtain a filtrate;

[0023] (1.3.2) The filtrate obtained in step (1.3.1) is dissolved in an alcohol solvent, heated to 48-54°C, and kept warm for at least 30 minutes; then cooled to 18-22°C, and kept warm for at least 30 minutes; after centrifugation, an alcohol solvent is added for washing, and vacuum drying is performed at 55-65°C to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride.

[0024] Furthermore, the step (3) is specifically as follows:

[0025] (3.1) dissolving the crude rivaroxaban in formic acid, heating to 60-70° C., keeping warm for at least 20 minutes, filtering the insoluble matter to obtain a filter cake and a first filtrate; washing the filter cake with formic acid to obtain a second filtrate, combining the first filtrate and the second filtrate to obtain a combined filtrate; the weight volume ratio of the crude rivaroxaban to formic acid is 1:6-15;

[0026] (3.2) The combined filtrate is heated until it is completely dissolved, purified water is added dropwise, the temperature is lowered for crystallization, and the filtrate is filtered to obtain a filtrate;

[0027] (3.3) The filtrate obtained in step (3.2) is sequentially eluted with purified water and acetone until the pH of the elution solution is ≥ 6; and the rivaroxaban product is obtained after drying.

[0028] Furthermore, in step (1.1), the molar ratio of the (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione to the ethylamine in the ethylamine aqueous solution is 1:14-16.

[0029] Furthermore, in step (2.1), the molar ratio of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride to 5-chloro-2-acylthiophene is 1:1.1 to 1.2.

[0030] Furthermore, in step (3.1), the weight-to-volume ratio of the crude rivaroxaban to formic acid is 1:9-11, with the weight unit being kg and the volume unit being L; in step (3.2), the weight-to-volume ratio of the crude rivaroxaban to purified water in step (3.1) is 1:10-15, with the weight unit being kg and the volume unit being L.

[0031] Furthermore, in step (1.1) and step (1.3), the alcohol solvent is methanol or ethanol; in step (1.1), the reaction solution is heated to 48-54° C. and kept warm for 5-6 hours; in step (1.2), when the pH value of the reaction solution is 1-2, the crude product is filtered.

[0032] Furthermore, in step (2.1) to step (2.2), the ketone solvent is acetone or butanone; in step (2.1), a mixed solution of 5-chloro-2-acylchloridothiophene and a benzene solvent is added dropwise to the reaction solution at 12 to 18° C., and the benzene solvent is toluene or xylene; in step (2.2), the ketone solvent is added to the reaction solution after the reaction in step (2.1), stirred, and then heated to 50 to 55° C. and kept warm for at least 4 to 6 hours.

[0033] Further, in step (3.1), in step (3.1), the crude rivaroxaban is dissolved in formic acid and heated to 62-68°C; in step (3.2), the cooling and crystallization and filtering to obtain the filtrate are specifically: cooling to 13-20°C, keeping warm for at least 30 minutes, and centrifuging to obtain the filtrate; in step (3.3), the drying to obtain the finished rivaroxaban is specifically: vacuum drying at 73-80°C for 6-8 hours to obtain the finished rivaroxaban.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The invention discloses a preparation method of rivaroxaban. The method uses an ethylamine aqueous solution as an ammonolysis reagent, and its byproducts can be removed by hydrochloric acid. The main impurities can be controlled by adjusting the amount of the ethylamine aqueous solution added, thereby solving the problem that intermediates and byproducts cannot be separated. In the refining step of the crude rivaroxaban product, the method uses formic acid for dissolution, and then adds poor solvent water for crystallization, thereby ensuring the purity and yield of rivaroxaban. The water content in the material can be removed by eluting with acetone, thereby reducing the pressure of the subsequent drying step, and the recrystallization avoids the disadvantages of low column chromatography yield and long time consumption. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The mass spectrum of rivaroxaban prepared in Example 1 of the present invention;

[0037] Figure 2 for Figure 1 Proton spectrum of rivaroxaban;

[0038] Figure 3 for Figure 1 Carbon spectrum of rivaroxaban. DETAILED DESCRIPTION

[0039] The present invention is further described below in conjunction with the accompanying drawings and exemplary embodiments.

[0040] Example 1

[0041] A method for preparing rivaroxaban comprises the following steps:

[0042] Step (1), preparing (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0043] (1.1) Disperse 60 kg of (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione in 300 L of methanol, start stirring, slowly add 138.2 kg of ethylamine aqueous solution (65% concentration) to form a reaction solution, heat the reaction solution to 48° C., and keep it warm for 6 hours;

[0044] (1.2) Slowly add hydrochloric acid to the reaction solution until the pH value of the reaction solution meets the range of 1 to 2; stir for 15 minutes and then retest to confirm that the pH value of the reaction solution still meets the range of 1 to 2, then keep warm for 30 minutes and filter to obtain a crude product;

[0045] (1.3) The crude product was purified by methanol to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0046] (1.3.1) Wash the crude product obtained in step (1.2) with 100 L of methanol, centrifuge, and filter to obtain a filtrate;

[0047] (1.3.2) The filtrate obtained in step (1.3.1) was dissolved in 372 L of methanol, stirred and heated to 48°C, and kept warm for 30 minutes; then cooled to 18°C ​​and kept warm for 30 minutes; after centrifugation, 80 L of methanol was added for washing, and vacuum dried at 55°C for 4 hours to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride;

[0048] Step (2), preparing a crude product of rivaroxaban;

[0049] (2.1) Add 30 kg of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride obtained in step (1.3) and 80 L of acetone to 180 L of sodium carbonate aqueous solution to form a reaction solution; slowly dropwise add 18.2 kg of a mixed solution of 5-chloro-2-acylthiophene and toluene to the reaction solution at 12° C. over 1 hour;

[0050] (2.2) adding 80 L of ketone solvent to the reaction solution after the reaction in step (2.1) and stirring for 10 minutes, heating to 50° C., keeping warm for 6 hours, cooling to 18° C., stirring for 30 minutes, washing and filtering with 100 L of purified water and 80 L of ketone solvent in turn, to obtain a crude product of rivaroxaban;

[0051] Step (3), preparing a rivaroxaban finished product;

[0052] (3.1) Dissolve 37 kg of crude rivaroxaban in 333 L of formic acid, stir and heat to 62° C. until the crude rivaroxaban is completely dissolved. After keeping warm for 20 minutes, filter out the insoluble matter to obtain a filter cake and a first filtrate; wash the filter cake with 40 L of formic acid to obtain a second filtrate, and combine the first filtrate and the second filtrate to obtain a combined filtrate;

[0053] (3.2) The combined filtrate was heated to complete dissolution, 370 L of purified water was added dropwise, and the temperature was lowered to 13°C, kept warm for 30 minutes, and centrifuged to obtain the filtrate;

[0054] (3.3) The filtrate obtained in step (3.2) was rinsed with 2100 L of purified water until the pH of the eluent was ≥6; after drying, it was rinsed with 80 L of acetone, dried, and vacuum dried at 73° C. for 8 hours to obtain the finished product of rivaroxaban.

[0055] Reference Figures 1 to 3 , Figure 1The mass spectrum of rivaroxaban prepared in this example shows that the molecular weight corresponding to the rivaroxaban molecule has an obvious mass spectrum peak, proving the existence of the molecule with the corresponding molecular weight; Figure 2 and Figure 3 are respectively the hydrogen spectrum and carbon spectrum of rivaroxaban prepared in this embodiment, Figure 2 and Figure 3 The corresponding structure of rivaroxaban can be solved, which confirms the successful extraction of rivaroxaban. Figure 2 and Figure 3 No obvious NMR peaks other than rivaroxaban were found in the sample, which proved that the prepared rivaroxaban had a relatively ideal molecular purity.

[0056] Example 2

[0057] A method for preparing rivaroxaban comprises the following steps:

[0058] Step (1), preparing (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0059] (1.1) Disperse 60 kg of (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione in 300 L of methanol, start stirring, slowly add 157.9 kg of ethylamine aqueous solution (65% concentration) to form a reaction solution, heat the reaction solution to 50° C., and keep it warm for 6 hours;

[0060] (1.2) Slowly add hydrochloric acid to the reaction solution until the pH value of the reaction solution meets the range of 1 to 2; stir for 15 minutes and then retest to confirm that the pH value of the reaction solution still meets the range of 1 to 2, then keep warm for 30 minutes and filter to obtain a crude product;

[0061] (1.3) The crude product was purified by methanol to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0062] (1.3.1) Wash the crude product obtained in step (1.2) with 100 L of methanol, centrifuge, and filter to obtain a filtrate;

[0063] (1.3.2) The filtrate obtained in step (1.3.1) was dissolved in 372 L of methanol, stirred and heated to 52°C, and kept warm for 30 minutes; then cooled to 22°C and kept warm for 30 minutes; after centrifugation, 80 L of methanol was added for washing, and vacuum dried at 60°C for 4 hours to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride;

[0064] Step (2), preparing a crude product of rivaroxaban;

[0065] (2.1) Add 30 kg of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride obtained in step (1.3) and 80 L of acetone to 180 L of sodium carbonate aqueous solution to form a reaction solution; slowly dropwise add 19.8 kg of a mixed solution of 5-chloro-2-acylthiophene and toluene to the reaction solution at 14° C. over 1 hour;

[0066] (2.2) adding 80 L of ketone solvent to the reaction solution after the reaction in step (2.1) and stirring for 10 minutes, heating to 52° C., keeping warm for 6 hours, cooling to 18° C., stirring for 30 minutes, washing and filtering with 100 L of purified water and 80 L of ketone solvent in turn, to obtain a crude product of rivaroxaban;

[0067] Step (3), preparing a rivaroxaban finished product;

[0068] (3.1) Dissolve 37 kg of crude rivaroxaban in 407 L of formic acid, stir and heat to 64° C. until the crude rivaroxaban is completely dissolved. After keeping warm for 20 minutes, filter out the insoluble matter to obtain a filter cake and a first filtrate; wash the filter cake with 40 L of formic acid to obtain a second filtrate, and combine the first filtrate and the second filtrate to obtain a combined filtrate;

[0069] (3.2) The combined filtrate was heated to complete dissolution, 444 L of purified water was added dropwise, and the temperature was lowered to 15°C, kept warm for 30 minutes, and centrifuged to obtain the filtrate;

[0070] (3.3) The filtrate obtained in step (3.2) was rinsed with 2100 L of purified water until the pH of the eluent was ≥6; after drying, it was rinsed with 80 L of acetone, dried, and vacuum dried at 75° C. for 8 hours to obtain the finished product of rivaroxaban.

[0071] Example 3

[0072] A method for preparing rivaroxaban comprises the following steps:

[0073] Step (1), preparing (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0074] (1.1) Disperse 60 kg of (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione in 300 L of methanol, start stirring, slowly add 138.2 kg of ethylamine aqueous solution (65% concentration) to form a reaction solution, heat the reaction solution to 52° C., and keep it warm for 5 hours;

[0075] (1.2) Slowly add hydrochloric acid to the reaction solution until the pH value of the reaction solution meets the range of 1 to 2; stir for 15 minutes and then retest to confirm that the pH value of the reaction solution still meets the range of 1 to 2, then keep warm for 30 minutes and filter to obtain a crude product;

[0076] (1.3) The crude product was purified by methanol to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0077] (1.3.1) Wash the crude product obtained in step (1.2) with 100 L of methanol, centrifuge, and filter to obtain a filtrate;

[0078] (1.3.2) The filtrate obtained in step (1.3.1) was dissolved in 372 L of methanol, stirred and heated to 54°C, and kept warm for 30 minutes; then cooled to 20°C and kept warm for 30 minutes; after centrifugation, 80 L of methanol was added for washing, and vacuum dried at 65°C for 4 hours to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride;

[0079] Step (2), preparing a crude product of rivaroxaban;

[0080] (2.1) Add 30 kg of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride obtained in step (1.3) and 80 L of acetone to 180 L of sodium carbonate aqueous solution to form a reaction solution; slowly dropwise add 18.2 kg of a mixed solution of 5-chloro-2-acylthiophene and toluene to the reaction solution at 16° C. over 1 hour;

[0081] (2.2) adding 80 L of ketone solvent to the reaction solution after the reaction in step (2.1) and stirring for 10 minutes, heating to 54° C., keeping warm for 5 hours, then to 18° C., stirring for 30 minutes, washing and filtering with 100 L of purified water and 80 L of ketone solvent in turn, to obtain a crude product of rivaroxaban;

[0082] Step (3), preparing a rivaroxaban finished product;

[0083] (3.1) Dissolve 37 kg of crude rivaroxaban in 333 L of formic acid, stir and heat to 66° C. until the crude rivaroxaban is completely dissolved. After keeping warm for 20 minutes, filter out the insoluble matter to obtain a filter cake and a first filtrate; wash the filter cake with 40 L of formic acid to obtain a second filtrate, and combine the first filtrate and the second filtrate to obtain a combined filtrate;

[0084] (3.2) The combined filtrate was heated to complete dissolution, 481 L of purified water was added dropwise, and the temperature was lowered to 18°C, kept warm for 30 minutes, and centrifuged to obtain the filtrate;

[0085] (3.3) The filtrate obtained in step (3.2) was rinsed with 2100 L of purified water until the pH of the eluent was ≥6; after drying, it was rinsed with 80 L of acetone, dried, and vacuum dried at 78° C. for 6 hours to obtain the finished product of rivaroxaban.

[0086] Example 4

[0087] A method for preparing rivaroxaban comprises the following steps:

[0088] Step (1), preparing (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0089] (1.1) Disperse 60 kg of (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione in 300 L of methanol, start stirring, slowly add 157.9 kg of ethylamine aqueous solution (65% concentration) to form a reaction solution, heat the reaction solution to 54° C., and keep it warm for 5 hours;

[0090] (1.2) Slowly add hydrochloric acid to the reaction solution until the pH value of the reaction solution meets the range of 1 to 2; stir for 15 minutes and then retest to confirm that the pH value of the reaction solution still meets the range of 1 to 2, then keep warm for 30 minutes and filter to obtain a crude product;

[0091] (1.3) The crude product was purified by methanol to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride;

[0092] (1.3.1) Wash the crude product obtained in step (1.2) with 100 L of methanol, centrifuge, and filter to obtain a filtrate;

[0093] (1.3.2) The filtrate obtained in step (1.3.1) was dissolved in 372 L of methanol, stirred and heated to 54°C, and kept warm for 30 minutes; then cooled to 20°C and kept warm for 30 minutes; after centrifugation, 80 L of methanol was added for washing, and vacuum dried at 60°C for 4 hours to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride;

[0094] Step (2), preparing a crude product of rivaroxaban;

[0095] (2.1) Add 30 kg of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride obtained in step (1.3) and 80 L of acetone to 180 L of sodium carbonate aqueous solution to form a reaction solution; slowly dropwise add 19.8 kg of a mixed solution of 5-chloro-2-acylthiophene and toluene to the reaction solution at 18° C. over 1 hour;

[0096] (2.2) adding 80 L of ketone solvent to the reaction solution after the reaction in step (2.1) and stirring for 10 minutes, heating to 55° C., keeping warm for 4 hours, then to 18° C., stirring for 30 minutes, washing and filtering with 100 L of purified water and 80 L of ketone solvent in turn, to obtain a crude product of rivaroxaban;

[0097] Step (3), preparing a rivaroxaban finished product;

[0098] (3.1) Dissolve 37 kg of crude rivaroxaban in 407 L of formic acid, stir and heat to 68° C. until the crude rivaroxaban is completely dissolved. After keeping warm for 20 minutes, filter out the insoluble matter to obtain a filter cake and a first filtrate; wash the filter cake with 40 L of formic acid to obtain a second filtrate, and combine the first filtrate and the second filtrate to obtain a combined filtrate;

[0099] (3.2) The combined filtrate was heated to complete dissolution, 555 L of purified water was added dropwise, and then the temperature was lowered to 20°C, kept warm for 30 minutes, and centrifuged to obtain the filtrate;

[0100] (3.3) The filtrate obtained in step (3.2) was rinsed with 2100 L of purified water until the pH of the eluent was ≥6; after drying, it was rinsed with 80 L of acetone, dried, and vacuum dried at 80° C. for 6 hours to obtain the finished product of rivaroxaban.

[0101] The present invention adopts an aqueous solution of ethylamine as an ammonolysis reagent, and the obtained by-product is N1, N2 diethylphthalamide (Formula 5). The amino group is affected by the carbonyl group, the electron cloud shifts toward the carbonyl group, the alkalinity of the N atom becomes weak, and it cannot form a salt with hydrochloric acid, while the intermediate (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one can form a salt with hydrochloric acid, and the intermediate hydrochloride is finally precipitated, and the by-product remains in the mother liquor.

[0102]

[0103] When the aqueous solution of ethylamine is insufficient, impurities 1 (Formula 6) and impurities 2 (Formula 7) are generated during the reaction, which are insufficient to meet the established standards after crystallization.

[0104]

[0105] Multiple batches of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride obtained in step (1.3.2) of Example 1 to Example 4 were tested, and the purity of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholine-3-one hydrochloride, the content of impurity 1, the content of impurity 2 and the actual yield thereof were calculated, as shown in Table 1;

[0106] Table 1

[0107] Intermediate batch number purity(%) Formula 4 (%) Formula 5 (%) Yield (%) 1 99.40 0.48 0.05 81.5 2 99.53 0.40 0.05 82.6 3 99.23 0.59 0.07 82.8 4 99.47 0.43 0.06 80.3 5 99.45 0.43 0.04 80.5 6 99.31 0.49 0.05 79.4

[0108] Multiple batches of rivaroxaban finished products obtained in step (3.3) of Example 1 to Example 4 were tested, and the purity of rivaroxaban, the content of impurity 1, the content of impurity 2, the content of other impurities except impurity 1 and impurity 2, and the actual yield of rivaroxaban were calculated. The results are shown in Table 2.

[0109] Table 2

[0110]

[0111] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. For ordinary professional and technical personnel in the field, the specific technical solutions recorded in the aforementioned embodiments can be modified, or some of the technical features therein can be replaced by equivalents, and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions protected by the present invention.

Claims

1. A method for preparing rivaroxaban, characterized in that: The following steps are involved: Step (1), preparing (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride; (1.1) Dispersing (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione in an alcohol solvent, adding an ethylamine aqueous solution to form a reaction solution, heating the reaction solution to 48-54° C., and keeping the temperature for 5-6 hours; the molar ratio of the (S)-2-((2-oxo-3-(4-(3-oxomorpholine)phenyl)oxazolidin-5-yl)methyl)isoindole-1,3-dione to the ethylamine in the ethylamine aqueous solution is 1:14-16; (1.2) Add hydrochloric acid dropwise to the reaction solution after the reaction in step (1.1) until the pH value of the reaction solution is less than 3, and filter to obtain a crude product; (1.3) The crude product is purified by using an alcohol solvent to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride; (1.3.1) washing the crude product obtained in step (1.2) with an alcohol solvent, centrifuging, and filtering to obtain a filtrate; the alcohol solvent is methanol or ethanol; (1.3.2) dissolving the filtrate obtained in step (1.3.1) in an alcohol solvent, heating to 48-54°C, and keeping warm for at least 30 minutes; then cooling to 18-22°C, and keeping warm for at least 30 minutes; after centrifugation, adding an alcohol solvent for washing, and vacuum drying at 55-65°C to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride; Step (2), preparing a crude product of rivaroxaban; (2.1) Adding the (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride obtained in step (1.3) and a ketone solvent to an aqueous sodium carbonate solution to form a reaction solution; adding dropwise a mixed solution of 5-chloro-2-acylthiophene and a benzene solvent to the reaction solution at 12 to 18° C., wherein the molar ratio of the (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride to 5-chloro-2-acylthiophene is 1:1 to 1.4; and the benzene solvent is toluene or xylene; (2.2) adding a ketone solvent to the reaction solution after the reaction in step (2.1), stirring, heating to 50-55° C., keeping the temperature for at least 4-6 hours, cooling and filtering, washing and filtering with purified water and a ketone solvent in turn, to obtain a crude product of rivaroxaban; In step (2.1) to step (2.2), the ketone solvent is acetone or butanone; Step (3), preparing a rivaroxaban finished product; The crude product of rivaroxaban was dissolved in formic acid, and purified water was added dropwise for crystallization. After filtering, it was washed with water and acetone in turn, and dried to obtain the finished product of rivaroxaban, which is as follows: (3.1) Dissolve the crude rivaroxaban in formic acid, raise the temperature to 62-68°C, keep the temperature for at least 20 minutes, filter out the insoluble matter to obtain a filter cake and a first filtrate; wash the filter cake with formic acid to obtain a second filtrate, and combine the first filtrate and the second filtrate to obtain a combined filtrate; the weight-to-volume ratio of the crude rivaroxaban to formic acid is 1:9-11, the weight unit is kg, and the volume unit is L; (3.2) Raise the temperature of the combined filtrate until it is completely dissolved, add purified water dropwise, cool to 13-20°C, keep warm for at least 30 minutes, and centrifuge to dry to obtain the filtrate; the weight-to-volume ratio of crude rivaroxaban to purified water is 1:10-15, with the weight unit being kg and the volume unit being L; (3.3) The filtrate obtained in step (3.2) is sequentially eluted with purified water and acetone until the pH of the eluent is ≥ 6; and vacuum dried at 73-80°C for 6-8 hours to obtain the finished product of rivaroxaban.

2. A method for preparing rivaroxaban according to claim 1, characterized in that: In step (2.1), the molar ratio of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrochloride to 5-chloro-2-acyl chloride thiophene is 1:1.1-1.

2.

3. A method for preparing rivaroxaban according to claim 2, characterized in that: In step (1.2), when the pH value of the reaction solution is 1-2, the crude product is obtained by filtration.

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