A preparation method of rivaroxaban

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology and specifically discloses a method for preparing rivaroxaban, comprising eight steps: 1) preparing a compound of formula II; 2) preparing a compound of formula III; 3) preparing a compound of formula IV; 4) preparing a compound of formula V; 5) preparing a compound of formula VI; 6) preparing a compound of formula VII; 7) preparing a compound of formula VIII; and 8) preparing a compound of formula IX. The present invention simplifies the post-processing process of rivaroxaban, eliminating the need for cumbersome operating procedures, significantly saving production time and improving production efficiency. The synthetic reaction is milder, avoiding the difficulty of production operations caused by harsh reaction conditions, increasing rivaroxaban production, facilitating purification of intermediates in each step, improving yield and economic benefits, and ensuring the operability and safety of rivaroxaban preparation, thereby making the preparation method suitable for industrial-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing rivaroxaban. Background Art

[0002] Developed by Bayer / Johnson & Johnson, rivaroxaban is the world's first oral direct Factor Xa inhibitor. It highly selectively and competitively inhibits free and bound Factor Xa and prothrombin activity, prolonging the activated partial thromboplastin time (APTT) and prothrombin time (PT) in a dose-dependent manner. Rivaroxaban differs from fondaparinux sodium and heparin in that it does not require the presence of antithrombin III and directly antagonizes free and bound Factor Xa. Heparin, on the other hand, requires antithrombin III to be effective and is ineffective against Factor Xa in the prothrombin complex. In June 2009, the drug was approved for marketing in China under the trade name Xarelto. It was subsequently approved by the FDA for official marketing in the United States in July 2011. Its 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. Its molecular formula is C19H18ClN3O5S, CAS number: 366789-02-8, and its structural formula is as follows:

[0003] .

[0004] Currently, there are many methods for preparing rivaroxaban, i.e., 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide, mainly including the following:

[0005] Method 1: The original research company Bayer of Germany first disclosed the synthesis method of rivaroxaban in patent WO0147919A1. It uses 3-morpholinone and p-fluoronitrobenzene as starting materials. The technical route of rivaroxaban is obtained through six steps of docking, reduction, condensation, cyclization, deprotection and amidation. The reaction equation of this technical route is shown below:

[0006] ;

[0007] This route requires the use of expensive dimethylaminopyridine and palladium on carbon, resulting in high production costs. In addition, the use of sodium hydrogen for hydrogenation requires strict control of moisture, is prone to material impact and explosion, has harsh reaction conditions, and has high requirements for production operations, making it unsuitable for industrial production.

[0008] Method 2: In 2005, Bayer further improved the industrial synthesis route of rivaroxaban in WO2005068456A1. Using 5-chlorothiophene-2-carbonyl chloride and 1,2-dihydroxypropylamine as raw materials, rivaroxaban was obtained through a four-step reaction of amidation, bromination, condensation, and cyclization. The synthesis route is as follows:

[0009] ;

[0010] This route uses hydrobromic acid as a bromination reagent, which has low regioselectivity, many side reactions, and large impurities, which increases the difficulty of purification. In addition, the toxicity of phosgene increases the safety risks in industrial production, making it unsuitable for industrial production.

[0011] Method 3: Patent WO2006055952A2 reports a method for preparing rivaroxaban, and its synthesis route is as follows:

[0012] ;

[0013] This route also uses 5-chlorothiophene-2-carbonyl chloride as the starting material, and obtains racemic rivaroxaban through four steps of amidation, oxidation, condensation, and cyclization, and then obtains rivaroxaban through chiral column separation. The chiral column used in this route is relatively expensive and wastes half of the final product, which is obviously not suitable for industrial production.

[0014] Currently, there are also methods for preparing rivaroxaban, i.e., 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide. For example, Chinese patent CN112159402A discloses a method for preparing rivaroxaban, and its synthetic route is as follows:

[0015] ;

[0016] This route uses p-nitroaniline and (S)-N-glycidylphthalimide as raw materials, and obtains rivaroxaban through seven steps of addition, cyclization, hydrolysis, amidation, reduction, addition, and cyclization. Although the use of cheap and readily available p-nitroaniline reduces costs, the reaction conditions of this route are relatively harsh and the production operation requirements are high, making it unsuitable for industrial production.

[0017] In summary, the synthetic routes reported at present for preparing rivaroxaban have harsh reaction conditions, high production operation requirements, high yield or cost, and cannot meet the requirements of industrial production. Therefore, a new technical solution is needed to solve the above technical problems. Summary of the Invention

[0018] The object of the present invention is to provide a method for preparing rivaroxaban, so as to solve the problems raised in the above-mentioned background technology that the current synthesis route of rivaroxaban has harsh reaction conditions, high production operation requirements, high yield or cost, and cannot meet the requirements of industrial production.

[0019] To achieve the above object, the present invention provides the following technical solution: a method for preparing rivaroxaban, the specific synthesis route is as follows:

[0020] .

[0021] The specific synthesis steps are as follows:

[0022] S1. Using the compound of formula I as the starting material, the compound is heated to 60-80°C in a protic solvent to carry out a condensation reaction with S-epichlorohydrin to obtain the compound of formula II. The synthetic route is as follows:

[0023] ,

[0024] wherein the molar ratio of the compound of formula I to S-epichlorohydrin is 1:1.5-3.0, and the protic solvent is one or a combination of methanol, ethanol, isopropanol, and water;

[0025] S2, the compound of formula II is dispersed in the reaction solvent I, and a cyclization reaction is carried out under the action of CDI to form the compound of formula III. The synthesis route is as follows:

[0026] ,

[0027] Wherein, the reaction solvent I is one of toluene and isopropyl acetate, and the molar ratio of the compound of formula II to CDI is 1:1.1-1.5;

[0028] S3, the compound of formula III is dissolved in the reaction solvent II, and reacted with potassium phthalimide in the presence of a metal catalyst at 80-100° C. to produce the compound of formula IV. The synthesis route is as follows:

[0029] ,

[0030] wherein the reaction solvent II is one of N,N-dimethylformamide, ethylene glycol, and N-methylpyrrolidone, and the metal catalyst is one of cuprous chloride, cuprous bromide, and cuprous iodide;

[0031] S4. The compound of formula IV is dissolved in the reaction solvent III, and a reduction reaction is carried out at 50-80° C. under the action of a metal catalyst and an acid to obtain the compound of formula V. The synthesis route is as follows:

[0032] ,

[0033] Wherein, the reaction solvent III is one or more of ethanol, acetic acid, and concentrated hydrochloric acid, the metal catalyst is one of iron powder and zinc powder, and the acid is one of hydrochloric acid and acetic acid;

[0034] S5. The compound of formula V is dissolved in the reaction solvent IV and docked with 2-bromoethanol in the presence of an acid binding agent to obtain the compound of formula VI. The synthetic route is as follows:

[0035] ,

[0036] Wherein, the reaction solvent IV is one of N,N-dimethylformamide, N-methylpyrrolidone, and acetonitrile, and the acid binding agent is one of sodium carbonate, potassium carbonate, and cesium carbonate;

[0037] S6. The compound of formula VI is dispersed in the reaction solvent V and reacts with chloroacetyl chloride in the presence of an acid-binding agent to produce a compound of formula VII. The synthesis route is as follows:

[0038] ,

[0039] Wherein, the molar ratio of the compound of formula VI, chloroacetyl chloride, and the acid-binding agent is 1:3-5:6-10, the acid-binding agent is one of sodium hydroxide, potassium hydroxide, and sodium methoxide, and the reaction solvent V is one of methanol, ethanol, and isopropanol;

[0040] S7. The compound of formula VII is dissolved in the reaction solvent VI, dephthalated in a methylamine solution, and then salified in hydrochloric acid to obtain the compound of formula VIII. The synthesis route is as follows:

[0041] ,

[0042] Wherein, the molar ratio of the compound of formula VII to the methylamine solution is 1:4-6, the methylamine solution is one of a methylamine aqueous solution and a methylamine ethanol solution, and the reaction solvent VI is one of ethanol and N,N-dimethylformamide;

[0043] S8. The compound of formula VIII is dispersed in the reaction solvent VII and reacted with 5-chlorothiophene-2-carbonyl chloride in the presence of an acid-binding agent to obtain the compound of formula IX, which is the target product, rivaroxaban. The synthesis route is as follows:

[0044] ,

[0045] The reaction solvent VII is one of acetone, tetrahydrofuran and acetonitrile, and the acid-binding agent is one of sodium carbonate, potassium carbonate and sodium hydroxide.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] 1. The present invention utilizes the eight-step synthesis process of condensation-cyclization-substitution-reduction-docking-cyclization-deprotection-amination to prepare rivaroxaban, which effectively simplifies the process of rivaroxaban post-treatment, does not require complicated operating procedures, greatly saves production time, improves production efficiency, and also makes the synthesis reaction of rivaroxaban more gentle, effectively avoids the problem of difficulty in production operation due to harsh reaction conditions, reduces the requirements for production operation, effectively improves the production volume of rivaroxaban, adopts cheap and easily available raw materials and auxiliary materials, effectively reduces the cost of preparing rivaroxaban, makes each step of intermediate purification more convenient, effectively improves the yield and economic benefit of rivaroxaban, ensures the operability and safety of rivaroxaban preparation, thereby making the preparation method suitable for industrial-scale production.

[0048] 2. The present invention utilizes iron powder and acid or zinc powder and acid to reduce nitro groups to amino groups, which is more economical than palladium carbon. In addition, the zinc or iron in the reduction reaction can be completely removed, and the residual hazard is smaller than that of palladium carbon. It is more in line with the concept of green chemistry. By using a metal catalyst to intervene in the reaction, the problem of generating a large amount of gas and heat due to the use of sodium hydrogen is effectively avoided, thereby ensuring the safety of industrial production.

[0049] 3. The present invention utilizes an eight-step synthesis process of condensation-cyclization-substitution-reduction-docking-cyclization-deprotection-amination with relatively mild reaction conditions to make the production operation process of rivaroxaban safer and more reliable, effectively avoids the problem of difficult production operation due to harsh reaction conditions, effectively improves the production volume of rivaroxaban, adopts commonly used reagents in the chemical industry as auxiliary materials, effectively reduces the cost of preparing rivaroxaban, makes each step of intermediate purification more convenient, effectively improves the yield and economic benefit of rivaroxaban, ensures the operability and safety of rivaroxaban preparation, thereby making the preparation method suitable for industrial-scale production. DETAILED DESCRIPTION

[0050] The following examples are used to further illustrate the present invention but are not intended to limit its application.

[0051] Example 1:

[0052] Step 1, preparation of compound of formula II:

[0053] First, the compound of formula I (4-nitroaniline) is selected as the starting material for the compound of formula II, and methanol is used as the protic solvent;

[0054] Then, the compound of formula I (4-nitroaniline) (200 g, 1.45 mol), methanol (2.4 L), water (800 ml), and S-epichlorohydrin (200.9 g, 2.17 mol) were added sequentially to a 5 L reaction flask, stirred evenly, and heated to 60-70°C for 20 hours for condensation reaction. After the reaction, the temperature was cooled to room temperature and filtered. The filter cake was dried with air at 50°C to obtain the compound of formula II (325.6 g, molar yield 97.5%).

[0055] Step 2: Preparation of the compound of formula III:

[0056] First, the compound of formula II obtained in step 1 is used as the starting material of the compound of formula III, and isopropyl acetate is used as the reaction solvent I;

[0057] Then, the compound of formula II (100 g, 0.43 mol), isopropyl acetate (600 ml) and CDI (N,N'-carbonyldiimidazole) (77.3 g, 0.48 mol) were added sequentially to a 1 L reaction flask, stirred evenly, heated to 89°C, and refluxed for 3 hours for cyclization reaction. After the reaction, the temperature was lowered to 50°C, ethanol (100 ml) was added, and the mixture was stirred at this temperature for 0.5 hour. After cooling to room temperature for 0.5 hour, the mixture was filtered and the filter cake was dried with air at 50°C to obtain the compound of formula III (107.2 g, molar yield 96.3%).

[0058] Step 3, preparation of compound of formula IV:

[0059] First, the compound of formula III obtained in step 2 is selected as the starting material of the compound of formula IV, N,N-dimethylformamide is used as the reaction solvent II, and cuprous chloride is used as the metal catalyst;

[0060] Then, the compound of formula III (100 g, 0.39 mol), N,N-dimethylformamide (1 L), potassium phthalimide (108.3 g, 0.58 mol), and cuprous chloride (3.9 g, 0.039 mol) were added sequentially to a 2 L reaction flask. Under nitrogen protection, the mixture was stirred evenly and heated to 80-90°C for 24 hours for a substitution reaction. After the reaction, the mixture was cooled to room temperature and the reaction solution was slowly added dropwise to 10°C water (1.5 L). The temperature was controlled below 30°C during the addition of water. After stirring at room temperature for 0.5 hour, the mixture was filtered and rinsed with water (300 ml). The filter cake was air-dried at 50°C to obtain the compound of formula IV (135.1 g, molar yield 94.4%).

[0061] Step 4: Preparation of the compound of formula V:

[0062] First, the compound of formula IV obtained in step 3 is selected as the starting material of the compound of formula V, ethanol is used as the reaction solvent III, iron powder is used as the metal catalyst, and acetic acid is used as the acid;

[0063] Then, the compound of formula IV (100 g, 0.27 mol), ethanol (800 ml) and acetic acid (64.8 g, 1.08 mol) were added to a 2 L reaction flask in sequence and heated to 50-60 ° C for stirring and dissolution. At this temperature, iron powder (39.7 g, 0.71 mol) was added in batches. After the addition, the mixture was kept warm and stirred for 2 hours for reduction reaction. After the reaction was completed, the mixture was filtered while hot, the filtrate was taken, and most of the solvent was evaporated. Dichloromethane (600 ml) and water (300 ml) were added to the remaining portion, stirred to dissolve, and then the layers were separated. The organic layer was taken and washed once with water (100 ml). Anhydrous sodium sulfate (5 g) was added to the organic layer and dried for 0.5 hours. The mixture was filtered with suction, and the filtrate was taken and evaporated to dryness to obtain the compound of formula V (86.2 g, molar yield 93.9%).

[0064] Step 5, preparation of compound of formula VI:

[0065] First, the compound of formula V obtained in step 4 is selected as the starting material of the compound of formula VI, acetonitrile is used as the reaction solvent IV, and cesium carbonate is used as the acid-binding agent;

[0066] Then, the compound of formula V (100 g, 0.30 mol), acetonitrile (900 ml), 2-bromoethanol (112 g, 0.90 mol), cesium carbonate (194.2 g, 0.60 mol) and water (300 ml) were added to a 2 L reaction flask in sequence, stirred evenly, heated to 80-90 ° C for 48 hours for heat preservation and docking reaction. After the reaction, it was cooled to 40 ° C, ethyl acetate (1 L) and water (500 ml) were added, stirred for 0.5 hours, and then separated. The aqueous layer was extracted twice with ethyl acetate (200 ml * 2), and the organic layers were combined and washed twice with 5% brine (400 ml * 2). The organic layer was separated and then concentrated under reduced pressure at 50 ° C to obtain the compound of formula VI (103.8 g, molar yield 91.8%).

[0067] Step 6: Preparation of the compound of formula VII:

[0068] First, the compound of formula VI obtained in step 5 is used as the starting material of the compound of formula VII, ethanol is used as the reaction solvent V, and sodium hydroxide is used as the acid binding agent;

[0069] Then, the compound of formula VI (100 g, 0.26 mol), ethanol (800 ml) and water (200 ml) were added to a 2 L reaction flask in sequence and stirred evenly. The pH was adjusted to 11 with a solution of sodium hydroxide (93.6 g, 2.34 mol) and water (200 ml). Chloroacetyl chloride (88.1 g, 0.78 mol) was then added dropwise. During the addition of chloroacetyl chloride, the pH was kept at 11 and the temperature was kept at 30°C. After the addition was completed, the mixture was stirred at room temperature for 12 minutes. The cyclization reaction was carried out for 2 hours. After the reaction was completed, the filter cake was filtered and rinsed with water (100 ml). The filter cake was taken, and the filter cake and ethanol (500 ml) were added to a 1 L single-necked bottle and stirred. The mixture was then heated to reflux, kept warm for 10 minutes, then cooled to 25-30° C., kept warm and stirred for 1 hour, and the filter cake was filtered and dried with air at 50° C. to obtain the compound of formula VII (99.1 g, molar yield 89.7%). The mass spectrum and H-NMR spectrum data of the prepared compound of formula VII are as follows:

[0070] ;

[0071] Step 7, preparation of compound of formula VIII:

[0072] First, the compound of formula VII obtained in step 6 is used as the starting material of the compound of formula VIII, ethanol is used as the reaction solvent VI, and 40% methylamine aqueous solution is used as the methylamine solution;

[0073] The compound of formula VII (100 g, 0.24 mol), ethanol (800 ml) and 40% methylamine aqueous solution (74.4 g, 0.96 mol) were added sequentially to a 2 L reaction flask, stirred evenly, heated to 60-70°C and stirred for 6 hours (i.e., dephthalylation). The temperature was then lowered to 40°C, maintaining T < 60°C, and hydrochloric acid (88 ml) was added dropwise. After the addition, the pH value was 2, and a large amount of solid precipitated. The temperature was lowered to 25-30°C, filtered, and the filter cake was collected. The filter cake and dichloromethane (400 ml) were then added to a single-necked flask, slurried for 1 hour, filtered, and dried with air at 40°C to obtain the compound of formula VIII (69.2 g, molar yield 88.9%). The mass spectrum and H-NMR spectrum data of the prepared compound of formula VIII are as follows:

[0074] ;

[0075] Step 8. Preparation of the compound of formula IX:

[0076] First, the compound of formula VIII obtained in step 7 is used as the starting material of the compound of formula IX, acetone is used as the reaction solvent VII, and sodium carbonate is used as the acid binding agent;

[0077] Sodium carbonate (64.7 g, 0.61 mol) and water (700 ml) were added to a 2 L reaction flask, stirred to dissolve, and the temperature was controlled at 10-20°C. The compound of formula VIII (100 g, 0.305 mol) was added, and the mixture was stirred for 10 minutes. Acetone (400 ml) was then added, and 5-chlorothiophene-2-carbonyl chloride (66.25 g, 0.366 mol) was added dropwise at the same temperature. After the addition was completed, the mixture was stirred for 3 hours to carry out an amination reaction. After the reaction was completed, the mixture was filtered and the filter cake was washed with water. The filter cake was taken and air-dried at 50°C to obtain the compound of formula IX (i.e., the target product, rivaroxaban) (126.5 g, molar yield 95.1%).

[0078] Example 2:

[0079] Step 1, preparation of compound of formula II:

[0080] First, the compound of formula I (4-nitroaniline) is selected as the starting material for the compound of formula II, and ethanol is used as the protic solvent;

[0081] The compound of formula I (4-nitroaniline) (200 g, 1.45 mol), ethanol (2.4 L), water (800 ml), and S-epichlorohydrin (301.4 g, 3.26 mol) were added sequentially to a 5 L reaction flask, stirred evenly, and heated to 65-75°C for 20 hours for condensation reaction. After the reaction, the mixture was cooled to room temperature and filtered. The filter cake was dried with air at 50°C to obtain the compound of formula II (326.9 g, molar yield 97.9%).

[0082] Step 2: Preparation of the compound of formula III:

[0083] First, the compound of formula II obtained in step 1 is used as the starting material of the compound of formula III, and toluene is used as the reaction solvent I;

[0084] Then, the compound of formula II (100 g, 0.43 mol), toluene (600 ml) and CDI (N,N'-carbonyldiimidazole) (91.3 g, 0.56 mol) were added sequentially to a 1 L reaction flask, stirred evenly, heated to 110°C, and refluxed for 3 hours for cyclization reaction. After the reaction, the temperature was lowered to 50°C, ethanol (100 ml) was added, and the mixture was stirred at this temperature for 0.5 hours. After cooling to room temperature and stirring for 0.5 hours, the mixture was filtered and the filter cake was dried with air at 50°C to obtain the compound of formula III (108.4 g, molar yield 97.4%).

[0085] Step 3, preparation of compound of formula IV:

[0086] First, the compound of formula III obtained in step 2 is selected as the starting material of the compound of formula IV, ethylene glycol is used as the reaction solvent II, and cuprous bromide is used as the metal catalyst;

[0087] Then, the compound of formula III (100 g, 0.39 mol), ethylene glycol (1 L), potassium phthalimide (108.3 g, 0.58 mol), and cuprous bromide (5.6 g, 0.039 mol) were added sequentially to a 2 L reaction flask. Under nitrogen protection, the mixture was stirred evenly and heated to 90-100°C for 24 hours for the substitution reaction. After the reaction, the temperature was cooled to room temperature, and the reaction solution was slowly added dropwise to 10°C water (1.5 L). The temperature was controlled below 30°C during the addition of water. After the addition was completed, the mixture was stirred at room temperature for 0.5 hours, filtered, and rinsed with water (300 ml). The filter cake was air-dried at 50°C to obtain the compound of formula IV (136.3 g, molar yield 95.2%).

[0088] Step 4: Preparation of the compound of formula V:

[0089] First, the compound of formula IV obtained in step 3 is selected as the starting material of the compound of formula V, ethanol is used as the reaction solvent III, zinc powder is used as the metal catalyst, and acetic acid is used as the acid;

[0090] Then, the compound of formula IV (100 g, 0.27 mol), ethanol (800 ml) and acetic acid (64.8 g, 1.08 mol) were added sequentially to a 2 L reaction flask, heated to 60-70°C, stirred and dissolved, and zinc powder (46.4 g, 0.71 mol) was added in batches at this temperature. After the addition, the mixture was kept warm and stirred for 2 hours for reduction reaction. After the reaction was completed, the mixture was filtered while hot, the filtrate was taken, and most of the solvent was evaporated. Dichloromethane (600 ml) and water (300 ml) were added to the remaining portion, stirred and dissolved, and the layers were separated. The organic layer was taken and washed once with water (100 ml). Anhydrous sodium sulfate (5 g) was added to the organic layer and dried for 0.5 hours. The mixture was filtered with suction, and the filtrate was taken and evaporated to dryness to obtain the compound of formula V (85.7 g, molar yield 93.3%).

[0091] Step 5, preparation of compound of formula VI:

[0092] First, the compound of formula V obtained in step 4 is selected as the starting material of the compound of formula VI, N,N-dimethylformamide is used as the reaction solvent IV, and sodium carbonate is used as the acid binding agent;

[0093] Then, the compound of formula V (100 g, 0.30 mol), N,N-dimethylformamide (500 ml), 2-bromoethanol (112 g, 0.90 mol), sodium carbonate (63.2 g, 0.60 mol) and water (200 ml) were added to a 2 L reaction flask in sequence, stirred evenly, heated to 90-100 ° C, and subjected to a 48-hour heat-insulated docking reaction. After the reaction, the mixture was cooled to 40 ° C, ethyl acetate (1 L) and water (500 ml) were added, and the mixture was stirred for 0.5 hours, and then the layers were separated. The aqueous layer was extracted twice with ethyl acetate (200 ml * 2), and the organic layers were combined and washed twice with 5% brine (400 ml * 2). The organic layer was separated and concentrated under reduced pressure at 50 ° C to obtain the compound of formula VI (102.5 g, molar yield 90.6%).

[0094] Step 6: Preparation of the compound of formula VII:

[0095] First, the compound of formula VI obtained in step 5 is used as the starting material of the compound of formula VII, methanol is used as the reaction solvent V, and sodium methoxide is used as the acid binding agent;

[0096] The compound of formula VI (100 g, 0.26 mol), methanol (500 ml) and water (400 ml) were added sequentially to a 2 L reaction flask and stirred uniformly. The pH was adjusted to >11 with a solution of sodium methoxide (168.5 g, 3.12 mol) and methanol (400 ml), and chloroacetyl chloride (117.4 g, 1.04 mol) was then added dropwise. During the addition of chloroacetyl chloride, the pH was maintained at >11 and the temperature was maintained at <30°C. After the addition, the cyclization reaction was carried out at room temperature with stirring for 12 hours. After the reaction was completed, the mixture was filtered and the filter cake was rinsed with water (100 ml). The filter cake was taken and added to a 1 L single-necked flask with ethanol (500 ml) and stirred. The mixture was then heated to reflux, kept warm for 10 minutes, then cooled to 25-30°C, kept warm and stirred for 1 hour, and the filter cake was filtered and dried with air at 50°C to obtain the compound of formula VII (97.9 g, molar yield 88.6%).

[0097] Step 7, preparation of compound of formula VIII:

[0098] First, the compound of formula VII obtained in step 6 is used as the starting material of the compound of formula VIII, N,N-dimethylformamide is used as the reaction solvent VI, and 40% methylamine aqueous solution is used as the methylamine solution;

[0099] The compound of formula VII (100 g, 0.24 mol), N,N-dimethylformamide (600 ml) and 40% methylamine aqueous solution (93.0 g, 1.20 mol) were added sequentially to a 2 L reaction flask, stirred evenly, heated to 60-70°C and stirred for 6 hours (i.e., dephthalylation), then cooled to 40°C, maintaining T < 60°C, and hydrochloric acid (108 ml) was added dropwise. After the addition, the pH value was 2, and a large amount of solid precipitated. The temperature was cooled to 25-30°C, filtered, and the filter cake was collected. The filter cake and dichloromethane (400 ml) were then added to a single-necked flask, slurried for 1 hour, filtered, and dried with air at 40°C to obtain the compound of formula VIII (66.9 g, molar yield 86.0%).

[0100] Step 8. Preparation of the compound of formula IX:

[0101] First, the compound of formula VIII obtained in step 7 is used as the starting material of the compound of formula IX, acetonitrile is used as the reaction solvent VII, and potassium carbonate is used as the acid-binding agent;

[0102] Potassium carbonate (84.3 g, 0.61 mol) and water (700 ml) were added to a 2 L reaction flask, stirred to dissolve, and the temperature was controlled at 10-20°C. The compound of formula VIII (100 g, 0.305 mol) was added, and the mixture was stirred for 10 minutes. Acetonitrile (400 ml) was then added, and 5-chlorothiophene-2-carbonyl chloride (66.25 g, 0.366 mol) was added dropwise at this temperature. After the addition was completed, the mixture was stirred for 3 hours to carry out an amination reaction. After the reaction was completed, the mixture was filtered and the filter cake was washed with water. The filter cake was taken and air-dried at 50°C to obtain the compound of formula IX (i.e., the target product, rivaroxaban) (125.2 g, molar yield 94.1%).

[0103] Example 3:

[0104] Step 1, preparation of compound of formula II:

[0105] First, the compound of formula I (4-nitroaniline) is selected as the starting material for the compound of formula II, and isopropyl alcohol is used as the protic solvent;

[0106] The compound of formula I (4-nitroaniline) (200 g, 1.45 mol), isopropyl alcohol (2.4 L), water (800 ml), and S-epichlorohydrin (401.8 g, 4.34 mol) were added sequentially to a 5 L reaction flask, stirred evenly, and heated to 70-80°C for 20 hours for condensation reaction. After the reaction, the mixture was cooled to room temperature and filtered. The filter cake was dried with air at 50°C to obtain the compound of formula II (327.4 g, molar yield 98.0%).

[0107] Step 2: Preparation of the compound of formula III:

[0108] First, the compound of formula II obtained in step 1 is used as the starting material of the compound of formula III, and toluene is used as the reaction solvent I;

[0109] Then, the compound of formula II (100 g, 0.43 mol), toluene (600 ml) and CDI (N,N'-carbonyldiimidazole) (105.4 g, 0.65 mol) were added sequentially to a 1 L reaction flask, stirred evenly, heated to 110°C, and refluxed for 3 hours for cyclization reaction. After the reaction, the temperature was lowered to 50°C, ethanol (100 ml) was added, and the mixture was stirred at this temperature for 0.5 hours. After cooling to room temperature and stirring for 0.5 hours, the mixture was filtered and the filter cake was dried with air at 50°C to obtain the compound of formula III (108.9 g, molar yield 97.8%).

[0110] Step 3, preparation of compound of formula IV:

[0111] First, the compound of formula III obtained in step 2 is selected as the starting material of the compound of formula IV, N-methylpyrrolidone is used as the reaction solvent II, and cuprous iodide is used as the metal catalyst;

[0112] Then, the compound of formula III (100 g, 0.39 mol), N-methylpyrrolidone (1 L), potassium phthalimide (108.3 g, 0.58 mol), and cuprous iodide (7.4 g, 0.039 mol) were added sequentially to a 2 L reaction flask. Under nitrogen protection, the mixture was stirred evenly and heated to 85-95°C for 24 hours for a substitution reaction. After the reaction, the mixture was cooled to room temperature and the reaction solution was slowly added dropwise to 10°C water (1.5 L). The temperature was controlled below 30°C during the addition of water. After stirring at room temperature for 0.5 hour, the mixture was filtered and rinsed with water (300 ml). The filter cake was air-dried at 50°C to obtain the compound of formula IV (135.4 g, molar yield 94.6%).

[0113] Step 4: Preparation of the compound of formula V:

[0114] First, the compound of formula IV obtained in step 3 is selected as the starting material of the compound of formula V, ethanol is used as the reaction solvent III, zinc powder is used as the metal catalyst, and concentrated hydrochloric acid is used as the acid;

[0115] The compound of formula IV (100 g, 0.27 mol), ethanol (800 ml) and concentrated hydrochloric acid (90 ml, 1.08 mol) were added to a 2 L reaction flask in sequence, heated to 70-80 ° C, stirred and dissolved, and zinc powder (46.4 g, 0.71 mol) was added in batches at this temperature. After the addition, the mixture was kept warm and stirred for 2 hours for reduction reaction. After the reaction was completed, the mixture was filtered while hot, the filtrate was taken, and most of the solvent was evaporated. Dichloromethane (600 ml) and water (300 ml) were added to the remaining portion, stirred and dissolved, and the pH value was adjusted to 6-7 with 5% sodium bicarbonate aqueous solution. The organic layer was taken and washed once with water (100 ml). The organic layer was taken, anhydrous sodium sulfate (5 g) was added, and dried for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 50 ° C to obtain the compound of formula V (84.5 g, molar yield 92.0%).

[0116] Step 5, preparation of compound of formula VI:

[0117] First, the compound of formula V obtained in step 4 is selected as the starting material of the compound of formula VI, N-methylpyrrolidone is used as the reaction solvent IV, and potassium carbonate is used as the acid binding agent;

[0118] Then, the compound of formula V (100 g, 0.30 mol), N-methylpyrrolidone (500 ml), 2-bromoethanol (112 g, 0.90 mol), potassium carbonate (82.4 g, 0.60 mol) and water (200 ml) were added to a 2 L reaction flask in sequence, stirred evenly, heated to 100-110°C, and subjected to a 48-hour heat-insulated docking reaction. After the reaction, the mixture was cooled to 40°C, ethyl acetate (1 L) and water (500 ml) were added, stirred for 0.5 hours, and then separated. The aqueous layer was extracted twice with ethyl acetate (200 ml*2), the organic layers were combined, and then washed twice with 5% brine (400 ml*2). The organic layers were separated and concentrated under reduced pressure at 50°C to obtain the compound of formula VI (104.6 g, molar yield 92.5%).

[0119] Step 6: Preparation of the compound of formula VII:

[0120] First, the compound of formula VI obtained in step 5 is used as the starting material of the compound of formula VII, ethanol is used as the reaction solvent V, and potassium hydroxide is used as the acid-binding agent;

[0121] The compound of formula VI (100 g, 0.26 mol), ethanol (1000 ml) and water (100 ml) were added sequentially to a 2 L reaction flask and stirred uniformly. The pH was adjusted to >11 with a solution of potassium hydroxide (218.8 g, 3.90 mol) and water (400 ml), and chloroacetyl chloride (146.8 g, 1.3 mol) was then added dropwise. During the addition of chloroacetyl chloride, the pH was maintained at >11 and the temperature was maintained at <30°C. After completion of the dropwise addition, the cyclization reaction was carried out under stirring at room temperature for 12 hours. After completion of the reaction, the mixture was filtered and the filter cake was rinsed with water (100 ml). The filter cake was taken and added to a 1 L single-necked flask with ethanol (500 ml) and stirred. The mixture was then heated to reflux, kept warm for 10 minutes, then cooled to 25-30°C, kept warm and stirred for 1 hour, and the filter cake was filtered and dried with air at 50°C to obtain the compound of formula VII (101.2 g, molar yield 91.6%).

[0122] Step 7, preparation of compound of formula VIII:

[0123] First, the compound of formula VII obtained in step 6 is used as the starting material of the compound of formula VIII, ethanol is used as the reaction solvent VI, and 30% methylamine ethanol solution is used as the methylamine solution;

[0124] The compound of formula VII (100 g, 0.24 mol), N,N-dimethylformamide (600 ml) and 40% methylamine aqueous solution (93.0 g, 1.20 mol) were added sequentially to a 2 L reaction flask, stirred evenly, heated to 60-70°C and stirred for 6 hours (i.e., dephthalylation), then cooled to 40°C, maintaining T < 60°C, and hydrochloric acid (108 ml) was added dropwise. After the addition, the pH value was 2, and a large amount of solid precipitated. The temperature was cooled to 25-30°C, filtered, and the filter cake was collected. The filter cake and dichloromethane (400 ml) were then added to a single-necked flask, slurried for 1 hour, filtered, and dried with air at 40°C to obtain the compound of formula VIII (66.9 g, molar yield 86.0%).

[0125] The compound of formula VII (100 g, 0.24 mol), ethanol (700 ml) and 30% methylamine ethanol solution (148.8 g, 1.44 mol) were added sequentially to a 2 L reaction flask, stirred evenly, heated to 60-70°C and stirred for 6 hours (i.e., dephthaloyl protection), then cooled to 40°C, maintaining T < 60°C, and hydrochloric acid (128 ml) was added dropwise. After the addition, the pH value was 2, and a large amount of solid precipitated. The temperature was cooled to 25-30°C, filtered, and the filter cake was taken. The filter cake and dichloromethane (400 ml) were then added to a single-necked flask, beaten for 1 hour, and the filter cake was filtered and dried with air at 40°C to obtain the compound of formula VIII (70.4 g, molar yield 90.5%).

[0126] Step 8. Preparation of the compound of formula IX:

[0127] First, the compound of formula VIII obtained in step 7 is used as the starting material of the compound of formula IX, tetrahydrofuran is used as the reaction solvent VII, and sodium hydroxide is used as the acid binding agent;

[0128] Sodium hydroxide (36.6 g, 0.915 mol) and water (700 ml) were added to a 2 L reaction flask, stirred to dissolve, and the temperature was controlled at 10-20° C. The compound of formula VIII (100 g, 0.305 mol) was added, and the mixture was stirred for 10 minutes. Tetrahydrofuran (400 ml) was then added, and 5-chlorothiophene-2-carbonyl chloride (66.25 g, 0.366 mol) was added dropwise at this temperature. After the addition was completed, the mixture was stirred for 3 hours to carry out an amination reaction. After the reaction was completed, the mixture was filtered and the filter cake was washed with water. The filter cake was taken and dried with air at 50° C. to obtain the compound of formula IX (i.e., the target product rivaroxaban) (126.1 g, molar yield 94.8%). The mass spectrum and nuclear magnetic resonance spectroscopy data of the prepared compound of formula IX are as follows:

[0129] .

Claims

1. A method for preparing rivaroxaban, characterized in that: The preparation steps include: S1. Using the compound of formula I as a starting material, heating with S-epichlorohydrin in a protic solvent to carry out a condensation reaction to obtain a compound of formula II, wherein the protic solvent is a combination of methanol and water, ethanol and water, or isopropanol and water; S2, the compound of formula II is dispersed in the reaction solvent I, and a cyclization reaction is carried out under the action of CDI to form the compound of formula III, wherein the reaction solvent I is one of toluene and isopropyl acetate; S3, the compound of formula III is dissolved in reaction solvent II, and a substitution reaction is carried out with potassium phthalimide in the presence of a metal catalyst to obtain a compound of formula IV, wherein the reaction solvent II is one of N,N-dimethylformamide, ethylene glycol, and N-methylpyrrolidone, and the metal catalyst is one of cuprous chloride, cuprous bromide, and cuprous iodide; S4, dissolving the compound of formula IV in a reaction solvent III, and performing a reduction reaction in the presence of a metal catalyst and an acid to obtain a compound of formula V, wherein the reaction solvent III is ethanol, the metal catalyst is one of iron powder and zinc powder, and the acid is one of hydrochloric acid and acetic acid; S5, dissolving the compound of formula V in a reaction solvent IV and docking with 2-bromoethanol in the presence of an acid-binding agent to obtain a compound of formula VI, wherein the reaction solvent IV is one of N,N-dimethylformamide, N-methylpyrrolidone, and acetonitrile, and the acid-binding agent is one of sodium carbonate, potassium carbonate, and cesium carbonate; S6, the compound of formula VI is dispersed in a reaction solvent V, and undergoes a cyclization reaction with chloroacetyl chloride in the presence of an acid-binding agent to obtain a compound of formula VII, wherein the reaction solvent V is one of methanol, ethanol, and isopropanol; S7, dissolving the compound of formula VII in a reaction solvent VI, removing the phthaloyl protection in a methylamine solution, and then salifying with hydrochloric acid to obtain a compound of formula VIII, wherein the reaction solvent VI is one of ethanol and N,N-dimethylformamide; S8, the compound of formula VIII is dispersed in a reaction solvent VII, and in the presence of an acid-binding agent, reacted with 5-chlorothiophene-2-carbonyl chloride to obtain a compound of formula IX, wherein the reaction solvent VII is one of acetone, tetrahydrofuran, and acetonitrile, and the acid-binding agent is one of sodium carbonate, potassium carbonate, and sodium hydroxide; The process route is as follows: 。 2. The method for preparing rivaroxaban according to claim 1, wherein In S1, the molar ratio of the compound of formula I to S-epichlorohydrin is 1:1.5-3.

0.

3. The method for preparing rivaroxaban according to claim 1, wherein In S1, the temperature of the condensation reaction is 60 to 80°C.

4. The method for preparing rivaroxaban according to claim 1, wherein In S2, the molar ratio of the compound of formula II to CDI is 1:1.1-1.

5.

5. The method for preparing rivaroxaban according to claim 1, wherein In S3, the temperature of the substitution reaction is 80 to 100°C.

6. The method for preparing rivaroxaban according to claim 1, wherein In S4, the temperature of the reduction reaction is 50 to 80°C.

7. The method for preparing rivaroxaban according to claim 1, wherein In S6, the molar ratio of the compound of formula VI, chloroacetyl chloride, and the acid-binding agent is 1:3-5:6-10, wherein the acid-binding agent is one of sodium hydroxide, potassium hydroxide, and sodium methoxide.

8. The method for preparing rivaroxaban according to claim 1, wherein In S7, the molar ratio of the compound of formula VII to the methylamine solution is 1:4-6, wherein the methylamine solution is one of a methylamine aqueous solution and a methylamine ethanol solution.

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