Process for preparing edoxaban and its intermediates

Abstract

The present invention provides a method for preparing edoxaban, or its salt or hydrate. This method involves step 1: removing the N-Boc protecting group from compound 1 in a polar solvent under acidic conditions to produce compound 2; and step 2: adding triethylamine, a protic solvent, a condensing agent, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof to the reaction mixture obtained in step 1 to produce edoxaban. Adding a certain amount of protic solvent to the reaction system accelerates the reaction process, shortens the reaction time, improves reaction efficiency, and reduces the content of impurities in the resulting edoxaban. The purification method is simple, allowing for high-purity production, making the compound suitable for industrial mass production.

Description

[Technical Field]

[0001] The present invention is in the field of chemical synthesis, and specifically relates to a method for preparing edoxaban and its intermediates. [Background technology]

[0002] Edoxaban is an oral blood coagulation factor X (FXa) inhibitor developed by Daiichi Sankyo Co., Ltd. This drug was approved by the US FDA and launched in 2015 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (arrhythmia). Edoxaban is also approved for the treatment of deep vein thrombosis and pulmonary embolism after 5 to 10 days of parenteral anticoagulant use. Edoxaban is the fourth novel oral anticoagulant (NOAC) approved by the FDA, following dabigatran, rivaroxaban, and apixaban.

[0003] The chemical name of edoxaban is N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-C]pyridin-2-ylcarbonylamino)cyclohexyl]oxamide, and the structural formula is: [ka]

[0004] In recent years, the incidence of cardiovascular disease has been on the rise, increasing patients' need for anticoagulants, and anticoagulant factor Xa drugs have become the mainstream of anticoagulants, so edoxaban has very broad commercial prospects.

[0005] Daiichi Sankyo's Patent CN1826333 discloses a synthetic route for edoxaban, with the compound of formula 1 being a key intermediate. Reference Example 434 discloses for the first time a method for obtaining edoxaban, in which methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride is dissolved in tetrahydrofuran and converted to a lithium salt with aqueous lithium hydroxide. This is then reacted with t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate in the presence of HOBT and EDC condensing agents to obtain Compound 1, an intermediate for edoxaban. The Boc protecting group of Compound 1, an intermediate for edoxaban, is then removed by hydrolysis, followed by condensation with 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-C]pyridine-2-carboxylic acid or its salt to obtain edoxaban. [ka]

[0006] This method requires purification by silica gel column chromatography, and is therefore not suitable for industrial mass production.

[0007] Chinese Patent CN103214414 discloses a method for preparing edoxaban. This method includes the following steps: Triethylamine is added to a suspension of t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate in acetonitrile at 60°C, followed by the addition of ethyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride at the same temperature. The mixture is stirred for 6 hours and then at room temperature for 16 hours. Water is then added to the reaction mixture, which is cooled to 10°C to precipitate crystals. The crystals are then filtered to obtain Compound 1, an intermediate for edoxaban. Methanesulfonic acid is then added to an acetonitrile solution of compound 1, an intermediate for edoxaban, for deprotection. Triethylamine, EDCI, HOBT, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride are then added to the reaction mixture, which is then stirred for 16 hours. After the reaction is complete, triethylamine and water are added, and the mixture is cooled to precipitate crystals, yielding edoxaban. In the step of preparing compound 1, an intermediate for edoxaban, the reaction system instantly solidifies and becomes unstirrable, resulting in reduced product yield, reduced purity, and a longer condensation reaction time after deprotection.

[0008] Chinese Patent CN102348688 addresses the problem of solidification during large-scale preparation of Compound 1, an intermediate for edoxaban, by changing the order of raw material addition and adding triethylamine in portions. Specifically, ethyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride is first pretreated with a portion of triethylamine in acetonitrile. Then, t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate and the remaining triethylamine are added and reacted.

[0009] Chinese Patent CN108484641 discloses a method for preparing Compound 1, an intermediate for edoxaban. This method involves the following steps: 1-butyl-3-methylimidazolium hydroxide, t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate, ethyl[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride, and acetonitrile are added and stirred, followed by the addition of triethylamine and pyridine. The resulting turbid solution is heated with stirring. The reaction mixture is heated to 45-60°C, where the viscosity of the reaction mixture increases, making stirring difficult. However, the mixture is gradually cooled and the viscosity is reduced by adding acetonitrile in portions. The mixture is then allowed to react for 4 hours, yielding an acetonitrile solution of Compound 1, an intermediate for edoxaban. Then, 1-butyl-3-methylimidazolium hydroxide and methanesulfonic acid are added to this acetonitrile solution, cooled to 10°C in an ice bath, triethylamine and pyridine are added with stirring, and then EDCI, HOBT, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride are added and reacted for 20 hours or more to obtain edoxaban.

[0010] Chinese Patent CN107641131 discloses a method for preparing edoxaban. This method includes the following steps: t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate and ethyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride are reacted in DMF with sodium acetate as a base at 90-110°C for 2-3 hours to yield compound 1. The BOC protecting group of compound 1 is then removed in ethanol with hydrochloric acid to yield compound 2. Separately, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride is condensed in a polar solvent in the presence of a base and a condensing agent, CDI, to yield compound 3, which is then reacted with compound 2 to yield compound 4. Here, the reaction of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride with the condensing agent CDI requires 7 hours, and after the reaction, the reaction with Compound 2 requires 20 hours. [ka]

[0011] Conventional methods for preparing edoxaban basically involve reacting ethyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate or ethyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride with t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate to produce compound 1, followed by elimination of the protecting group from compound 1 and subsequent condensation with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride condensate. However, the above-mentioned conventional methods have problems such as a relatively long reaction time, high impurity content, and the low stability of ethyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride, which requires a large amount of base to neutralize the reaction and participate in the reaction, resulting in viscous solidification of the reaction system or the need for dilution with a large amount of solvent to prevent solidification. Therefore, from the perspective of industrial mass production, it is very important to provide a method for preparing edoxaban that is characterized by simple operation and low cost. Summary of the Invention

[0012] The present invention provides a method for preparing edoxaban to address the shortcomings and deficiencies of the prior art. Specifically, adding a protic solvent during the condensation reaction accelerates the reaction, shortens the reaction time, improves the reaction efficiency, and reduces impurities and improves the mass of the product. Furthermore, the specific reaction step effectively solves the problem of thickening and solidification of the reaction system, eliminates the need to add reaction reagents in portions, and simplifies the production process, making the technical solution of the present invention suitable for industrial production.

[0013] The present invention provides a method for preparing edoxaban, or a salt or hydrate thereof, the method comprising: Step 1 is removing the N-Boc protecting group from compound 1 in a polar solvent under acidic conditions to generate compound 2; [ka] Step 2: adding triethylamine, a protic solvent, a condensing agent, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof to the reaction solution obtained in Step 1 to react with the resulting solution to obtain edoxaban; [ka] Includes:

[0014] In some embodiments, the acidic conditions in step 1 are hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid, preferably methanesulfonic acid.

[0015] In some embodiments, the polar solvent is one or more selected from the group consisting of methanol, ethanol, propanol, and acetonitrile, preferably acetonitrile.

[0016] In some embodiments, the protic solvent in Step 2 is one or more selected from the group consisting of methanol, ethanol, and water.

[0017] In some embodiments, the amount of the protic solvent used is 0.5% to 5% of the weight of all raw materials in the reaction system in Step 1, and all raw materials in the reaction system in Step 1 refer to the total mass of Compound 1, the acidic substance, and the polar solvent.

[0018] In some embodiments, the amount of protic solvent used in Step 1 is 3.5% to 5% of the weight of all raw materials in the reaction system.

[0019] In some embodiments, the condensing agent is EDCI in combination with HOBt.

[0020] In some embodiments, the mass ratio of Compound 1 to the acid used under acidic conditions to the polar solvent is Compound 1:acid used under acidic conditions:polar solvent=1:0.6:15 to 1:0.9:20.

[0021] In some embodiments, the molar ratio of compound 1 to 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof to triethylamine in step 2 is compound 1:5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof:triethylamine in step 2=1:1.1:6 to 1:1.2:8.

[0022] In some embodiments, the mass ratio of Compound 1, EDCI, and HOBT is Compound 1:EDCI:HOBT=1:0.4:0.3 to 1:0.6:0.5.

[0023] In some embodiments, the reaction solution obtained in Step 1 is treated with triethylamine at −5 to 5° C., and then a protic solvent, a condensing agent, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof are further added.

[0024] In some embodiments, in step 2, the reaction temperature is 30 to 50° C. and the reaction time is 6 to 8 hours.

[0025] In some embodiments, the post-treatment of edoxaban obtained in step 2 involves adding an aqueous solution of sodium bicarbonate at 0 to 20°C dropwise to the reaction solution obtained in step 2, and stirring the solution while controlling the temperature to precipitate crystals.

[0026] In this step, the present inventors have unexpectedly found that adding a small amount of a protic solvent to the reaction system promotes the reaction and reduces the production of impurities.

[0027] In some embodiments, Compound 1 is Step A, in which methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate and t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate are added to a polar solvent, respectively, to obtain a reaction mixture; and Step B: heating the reaction mixture obtained in Step A to 60±5°C, and then adding triethylamine all at once to react to prepare Compound 1; [ka] It is prepared by

[0028] In some embodiments, the polar solvent is one or more selected from the group consisting of methanol, ethanol, propanol, and acetonitrile, preferably acetonitrile.

[0029] In some embodiments, the molar ratio of t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate, methyl[(5-chloropyridin-2-yl)amino]-2-oxoacetate, and the triethylamine in Step B is t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate:methyl[(5-chloropyridin-2-yl)amino]-2-oxoacetate:triethylamine in Step B=1.0:1.0:2.8 to 1.0:1.1:3.5.

[0030] In some embodiments, the ratio of the mass of t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate to the volume of the polar solvent is 1.0:4.5 to 1.0:5.5 g / ml.

[0031] In some embodiments, the methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate is (1) reacting 2-amino-5-chloropyridine and methyl oxalyl chloride in tetrahydrofuran to obtain methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride; and (2) adding methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride to tetrahydrofuran, and adding sodium bicarbonate in portions to liberate methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate; It is prepared by

[0032] The inventors of the present invention discovered the following in the course of their research: When methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride was left at room temperature for 13 days, its purity decreased from 95.28% to 90.52%, and the content of its decomposition products increased from 2.5% to 7.4%, making methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride unstable and unsuitable for storage. In contrast, when methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride was used as a free base, After isolation, the stability improves, and purity does not decrease after 13 days of storage. Furthermore, by reacting methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate free base with t-butyl ((1R,2S,5S)-2-amino-5-(dimethylaminocarbonyl)cyclohexyl)carbamate oxalate in acetonitrile, heating to 60±5°C, and then adding triethylamine all at once at this temperature, the problem of viscosity and solidification of the reaction system can be effectively solved.

[0033] Compared with the prior art, the present invention has the following excellent technical effects:

[0034] 1. The preparation method provided by the present invention adds a certain amount of protic solvent to the reaction system to promote the reaction, shorten the reaction time, improve the reaction efficiency, and reduce the content of impurities in the obtained edoxaban, simplify the purification method, and increase the purity, which is suitable for industrial mass production.

[0035] 2. The present invention effectively solves the problem of thickening and solidification of the reaction system through a specific reaction step, making it easier to stir, allowing the reaction to proceed fully, improving the yield, and improving the stability of the starting materials, which is convenient for storage.

[0036] 3. The preparation method provided by the present invention eliminates the need to add triethylamine in portions, and reduces the amount of triethylamine and reaction solvent used, thereby saving operation time and raw material costs. DETAILED DESCRIPTION OF THE INVENTION

[0037] The following examples are provided to further illustrate specific embodiments of the present invention, but are not intended to limit the scope of the present invention.

[0038] Reference Example 1: t-Butyl [(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate Triethylamine (169 ml) was added to a suspension of t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate (100.1 g) in acetonitrile (550 ml) at 60°C. Ethyl [(5-chloropyridin-2-yl)amino] (oxo)acetate hydrochloride (84.2 g) was added at the same temperature and stirred for 6 hours, followed by stirring at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was stirred at 10°C for 1.5 hours. The crystals were then filtered to give a white solid.

[0039] N-(5-chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(dimethylaminocarbonyl)-2-{[(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-C]pyridin-2-yl)carbonyl]amino}cyclohexyl]ethanediamide (edoxaban)

[0040] 316g of acetonitrile and 20g of t-butyl [(1R,2S,5S)-2-({[(5-chloropyridin-2-yl)amino](oxo)acetyl}amino)-5-(dimethylaminocarbonyl)cyclohexyl]carbamate were added to a reaction bottle, stirring was started, the temperature was controlled at 15-25°C, 16.4g of methanesulfonic acid was added dropwise, and after the dropwise addition was completed, the temperature was maintained at 15-25°C and the reaction was carried out for 4-6 hours. After the reaction was completed, cooling was started, the temperature was controlled at -5-5°C, and 30.2g of triethylamine was added dropwise. After the dropwise addition was completed, 12g of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride, 10.6g of EDCI, and 7.06g of HOBt were added in this order. The raw materials were After the addition, the temperature was raised. The reaction was continued for 16 hours while maintaining the temperature at 35-45°C. After the reaction was completed, the reaction system was concentrated to approximately 1 / 5 of its original volume by vacuum distillation at 35-45°C. Next, 400 g of a 5% aqueous solution of sodium bicarbonate was added dropwise. After the addition was completed, the mixture was stirred for 1.5-3.0 hours while maintaining the temperature at 5-15°C to precipitate crystals. The mixture was suction filtered and the filter cake was washed with 40 g of water. An off-white solid was obtained by suction drying. The off-white solid was obtained by vacuum drying at 40-50°C for 10-12 hours. The yield was 78.9%, the purity was 95.5%, and the content of the above compound 2, the deprotected impurity, was 2.93%.

[0041] Reference Example 2: The temperature was controlled at 15-30°C. 39 mL of acetonitrile was added to the reaction bottle, followed by 2.0 g of methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate and 0.93 g of triethylamine. After stirring for 30 minutes, 2.9 g of t-butyl ((1R,2S,5S)-2-amino-5-(dimethylaminocarbonyl)cyclohexyl)carbamate oxalate and 1.86 g of triethylamine were added. The reaction mixture was heated to 60°C. As the reaction progressed, the mixture became viscous. After completion of the reaction, the mixture was concentrated to remove most of the acetonitrile. 34 mL of water was added, stirred for 1-2 hours, and then suction filtered. The solid was dried in a vacuum oven at 45°C to obtain compound 1, an intermediate for edoxaban. The yield was 91.7% and the purity was 97.4%.

[0042] Example 1 Preparation of methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate Tetrahydrofuran (225 ml) and 15 g of 2-amino-5-chloropyridine were stirred until completely dissolved, and the temperature was raised to 40 to 50° C. 18.6 g of methyl oxalyl chloride was added dropwise to the reaction solution, and after the dropwise addition was completed within 1 hour, the solution was cooled to 0 to 5° C., kept at the same temperature for 14 to 15 hours, and then suction filtered to obtain methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride.

[0043] Methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride was added to 300 ml of tetrahydrofuran, 11.7 g of sodium bicarbonate was added, and the mixture was stirred for 3 hours. The mixture was then suction filtered and washed with tetrahydrofuran. The filtrate was concentrated to approximately 1 / 8 of its original volume, cooled to 10-15°C, 375 ml of water was added, and the mixture was stirred for 1-2 hours. The solid was then suction filtered and dried in vacuo for 24 hours to obtain methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate.

[0044] Example 2 The temperature was controlled between 15 and 30°C. 350 mL of acetonitrile was added to the reaction bottle, followed by 42.0 g of methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate and 70.0 g of t-butyl ((1R,2S,5S)-2-amino-5-(dimethylaminocarbonyl)cyclohexyl)carbamate oxalate, in that order. The reaction mixture was heated to 60°C, and 56.6 g of triethylamine was added in one portion at the same temperature. The reaction mixture remained a turbid, stirrable liquid without thickening or solidification. After completion of the reaction, the reaction mixture was cooled to 10-20°C, 1050 mL of water was added, and the mixture was stirred for 1-2 hours. The mixture was then suction filtered and the solid was dried in a vacuum oven at 45°C to obtain compound 1, an intermediate for edoxaban. The yield was 98.2%, the purity was 99.8%, and the total impurities content was 0.2%.

[0045] Example 3 The temperature was controlled at 15 to 30°C, and 350 mL of acetonitrile was added to the reaction bottle, followed by 42.0 g of methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate and 70.0 g of t-butyl ((1R,2S,5S)-2-amino-5-(dimethylaminocarbonyl)cyclohexyl)carbamate oxalate in this order. The reaction solution was then cooled to 55°C. The mixture was heated to 10°C, and 56.6 g of triethylamine was added in one portion at the same temperature. The reaction mixture was a turbid liquid that could be stirred normally without thickening or solidification. After the reaction was completed, the mixture was cooled to 10-20°C, 1050 mL of water was added, and the mixture was stirred for 1-2 hours. The mixture was then suction filtered, and the solid was dried in a vacuum oven at 45°C to obtain compound 1, an intermediate for edoxaban, in 98.9% yield, 99.7% purity, and 0.3% total impurities.

[0046] Example 4 The temperature was controlled between 15 and 30°C. 350 mL of acetonitrile was added to the reaction bottle, followed by 42.0 g of methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate and 70.0 g of t-butyl ((1R,2S,5S)-2-amino-5-(dimethylaminocarbonyl)cyclohexyl)carbamate oxalate, in that order. The reaction mixture was heated to 65°C, and 56.6 g of triethylamine was added in one portion at the same temperature. The reaction mixture remained a turbid, stirrable liquid without thickening or solidification. After completion of the reaction, the reaction mixture was cooled to 10-20°C, 1050 mL of water was added, and the mixture was stirred for 1-2 hours. The mixture was then suction filtered and the solid was dried in a vacuum oven at 45°C to obtain compound 1, an intermediate for edoxaban. The yield was 97.8%, the purity was 99.9%, and the total impurities content was 0.1%.

[0047] Example 5: Preparation of Edoxaban (Addition of 3.5% Methanol) 20 g of Compound 1, an intermediate for edoxaban obtained in Example 2, was dissolved in 316 g of acetonitrile, the temperature was controlled at 15-25°C, and 16.4 g of methanesulfonic acid was added dropwise. The reaction was completed after 2-3 hours of stirring. Cooling was initiated, the temperature was controlled at -5-5°C, and 30.2 g of triethylamine was added dropwise. After the addition was complete, 12.3 g of methanol, 12 g of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride, 10.6 g of EDCI, and 12.3 g of HOBt were added in this order. After the raw materials were added, the temperature was raised. The reaction was continued for 7 hours while maintaining the temperature at 35-45°C. After the reaction was completed, the reaction system was distilled under reduced pressure at 35-45°C and concentrated to approximately 1 / 5 of its original volume. Next, 400 g of a 5% aqueous solution of sodium bicarbonate was added dropwise. After the dropwise addition was completed, the mixture was stirred for 1.5 to 3.0 hours while maintaining the temperature at 5 to 15°C to precipitate crystals. The mixture was filtered under suction, and the filter cake was washed with 40 g of water. The solid was dried under suction to obtain an off-white solid. The solid was dried under reduced pressure at 40 to 50°C for 10 to 12 hours. The yield was 77.6%, the purity was 98.11%, and the content of the deprotected impurity was 1.52%.

[0048] Example 6: Preparation of Edoxaban (Addition of 5% Methanol) 20 g of Compound 1, an intermediate for edoxaban obtained in Example 2, was dissolved in 316 g of acetonitrile, the temperature was controlled at 15-25°C, and 16.4 g of methanesulfonic acid was added dropwise. The reaction was completed after 2-3 hours of stirring. Cooling was initiated, the temperature was controlled at -5-5°C, and 30.2 g of triethylamine was added dropwise. After the addition was complete, 17.6 g of methanol, 12 g of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride, 10.6 g of EDCI, and 12.3 g of HOBt were added in this order. After the raw materials were added, the temperature was raised. The reaction was continued for 7 hours while maintaining the temperature at 35-45°C. After the reaction was completed, the reaction system was distilled under reduced pressure at 35-45°C and concentrated to approximately 1 / 5 of its original volume. Next, 400 g of a 5% aqueous solution of sodium bicarbonate was added dropwise. After the dropwise addition was completed, the mixture was stirred for 1.5 to 3.0 hours while maintaining the temperature at 5 to 15°C to precipitate crystals. The mixture was filtered under suction, and the filter cake was washed with 40 g of water. The mixture was dried under suction to obtain an off-white solid. The product was dried under reduced pressure at 40 to 50°C for 10 to 12 hours. The off-white solid was obtained in a yield of 78.3%, with a purity of 98.25% and a deprotected impurity content of 1.32%.

[0049] Example 7: Preparation of Edoxaban (addition of 2% water) 20 g of Compound 1, an intermediate of edoxaban obtained in Example 2, was dissolved in 316 g of acetonitrile, and the temperature was controlled to 15 to 25°C. 16.4 g of methanesulfonic acid was added. The reaction was completed after 2-3 hours of stirring. Cooling was initiated, the temperature was controlled at -5-5°C, and 30.2 g of triethylamine was added dropwise. After the addition was complete, 7.04 g of water, 12 g of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride, 10.6 g of EDCI, and 7.06 g of HOBt were added in that order. After the addition of the raw materials, the temperature was raised and the reaction was continued for 8 hours while maintaining the temperature at 35-45°C. After the reaction was completed, the reaction system was distilled under reduced pressure at 35-45°C and concentrated to approximately 1 / 5 of its original volume. Next, 400 g of a 5% aqueous solution of sodium bicarbonate was added dropwise. After the addition was complete, the mixture was stirred for 1.5-3.0 hours while maintaining the temperature at 5-15°C, allowing crystals to precipitate. The mixture was suction filtered, the filter cake was washed with 40 g of water, and suction dried to obtain an off-white solid. After drying under reduced pressure at 40-50°C for 10-12 hours, an off-white solid was obtained in 76.3% yield with a purity of 97.21% and a deprotected impurity content of 2.26%.

[0050] Example 8: Preparation of Edoxaban (addition of 0.5% water) 20 g of Compound 1, an intermediate for edoxaban obtained in Example 2, was dissolved in 316 g of acetonitrile, the temperature was controlled at 15-25°C, and 16.4 g of methanesulfonic acid was added dropwise. The reaction was then completed after 2-3 hours of stirring. Cooling was initiated, the temperature was controlled at -5-5°C, and 30.2 g of triethylamine was added dropwise. After the addition was complete, 1.76 g of water, 12 g of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride, 10.6 g of EDCI, and 7.06 g of HOBt were added in this order. After the addition of the raw materials, the temperature was raised. The reaction was continued for 6 hours while maintaining the temperature at 35-45°C. After the reaction was completed, the reaction system was concentrated to approximately 1 / 5 of its original volume by vacuum distillation at 35-45°C. Next, 400 g of a 5% aqueous solution of sodium bicarbonate was added dropwise, and after the addition was complete, the mixture was stirred for 1.5 to 3.0 hours while maintaining the temperature at 5 to 15°C to precipitate crystals. The mixture was filtered by suction, and the filter cake was washed with 40 g of water and dried by suction to obtain an off-white solid. The solid was dried under reduced pressure at 40 to 50°C for 10 to 12 hours. The yield of the off-white solid was 78%, the purity was 97.24%, and the deprotected impurity content was 2.32%.

[0051] Example 9: Preparation of Edoxaban (addition of 5% water) 20 g of Compound 1, an intermediate for edoxaban obtained in Example 2, was dissolved in 316 g of acetonitrile, the temperature was controlled at 15-25°C, and 16.4 g of methanesulfonic acid was added dropwise. After stirring for 2-3 hours, the reaction was completed. After the reaction was completed, cooling was initiated, the temperature was controlled at -5-5°C, and 30.2 g of triethylamine was added dropwise. After the addition was completed, 17.6 g of water, 12 g of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid hydrochloride, 10.6 g of EDCI, and 7.06 g of HOBt were added in this order. After the raw materials were added, the temperature was raised. The reaction was continued for 8 hours while maintaining the temperature at 35-45°C. After the reaction was completed, the reaction system was distilled under reduced pressure at 35-45°C and concentrated to approximately 1 / 5 of its original volume. Next, 400 g of a 5% aqueous solution of sodium bicarbonate was added dropwise. After the dropwise addition was completed, the mixture was stirred for 1.5 to 3.0 hours while maintaining the temperature at 5 to 15°C to precipitate crystals. The mixture was filtered under suction, and the filter cake was washed with 40 g of water. The mixture was dried under suction to obtain an off-white solid. The product was dried under reduced pressure at 40 to 50°C for 10 to 12 hours. An off-white solid was obtained. The yield was 78.4%, the purity was 98.7%, and the deprotected impurity content was 1.19%.

[0052] Table 1 shows the reaction phenomena and results of synthesizing Compound 1, an intermediate for edoxaban in Reference Examples 1 and 2 and Example 2.

[0053] [Table 1]

[0054] Table 2 shows a comparison of the experimental results of Reference Example 1 and Examples 5 to 8.

[0055] [Table 2]

[0056] The above experimental results show that the method for preparing edoxaban provided by the present invention can effectively solve the problem of thickening and solidification of the reaction system, reduce the amount of triethylamine used, and in the step of preparing edoxaban, the reaction can be accelerated by adding a protic solvent to the reaction system, thereby shortening the reaction time, improving the reaction efficiency, increasing the purity of the obtained edoxaban, and improving the quality of the product.

[0057] The specific embodiments described in the present invention are merely illustrative of the spirit of the present invention, and those skilled in the art may make various amendments, supplements, or substitutions in similar ways to the described specific embodiments without departing from the spirit of the present invention and without exceeding the scope defined in the appended claims.

Claims

1. 1. A method for preparing edoxaban, or a salt or hydrate thereof, comprising: The preparation method comprises: Step 1 is removing the N-Boc protecting group from compound 1 in a polar solvent under acidic conditions to generate compound 2; 【Chemistry 1】 Step 2: adding triethylamine, a protic solvent, a condensing agent, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof to the reaction solution obtained in Step 1 to react with the resulting solution to obtain edoxaban; 【Chemistry 2】 A preparation method comprising:

2. The acidic conditions in step 1 are hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid, preferably methanesulfonic acid; the polar solvent is at least one selected from the group consisting of methanol, ethanol, propanol, and acetonitrile, and is preferably acetonitrile; The method according to claim 1, wherein the mass ratio of the compound 1 to the acid used under acidic conditions and the polar solvent is compound 1: acid used under acidic conditions: polar solvent=1:0.6:15 to 1:0.9:

20.

3. 2. The method according to claim 1, wherein the protic solvent in step 2 is one or more selected from the group consisting of methanol, ethanol, and water.

4. 2. The method according to claim 1, wherein the condensing agent is a combination of EDCI and HOBt.

5. The molar ratio of the compound 1 to 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof to triethylamine in step 2 is The preparation method according to claim 1, characterized in that the ratio of compound 1: 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or its salt: triethylamine in step 2 is 1:1.1:6 to 1:1.2:

8.

6. The preparation method according to claim 1, characterized in that the amount of the protic solvent used is 0.5% to 5% by weight of all raw materials in the reaction system in Step 1, preferably 3.5% to 5%.

7. The method according to claim 1, wherein the mass ratio of compound 1, EDCI, and HOBT is compound 1:EDCI:HOBT=1:0.4:0.3 to 1:0.6:0.

5.

8. The method according to claim 1, characterized in that the reaction solution obtained in step 1 is treated with triethylamine at -5 to 5°C, and then a protic solvent, a condensing agent, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof are further added.

9. The preparation method according to claim 1, characterized in that in step 2, the reaction temperature is 30-50°C and the reaction time is 6-8 hours.

10. The method of claim 1, wherein the post-treatment of edoxaban obtained in step 2 comprises adding dropwise an aqueous solution of sodium bicarbonate at 0 to 20°C to the reaction solution obtained in step 2, and stirring the mixture while controlling the temperature to precipitate crystals.

11. The compound 1 is Step A: adding methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate and t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate to a polar solvent, respectively, to obtain a reaction mixture; and Step B: Heat the reaction mixture obtained in Step A to 60±5°C, add triethylamine all at once, and react to prepare Compound 1. 【Transformation 3】 2. The method according to claim 1, characterized in that it is prepared by:

12. 12. The preparation method according to claim 11, characterized in that the polar solvent is one or more selected from the group consisting of methanol, ethanol, propanol and acetonitrile, preferably acetonitrile.

13. The molar ratio of the t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate to methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate to the triethylamine in Step B is The preparation method according to claim 11, characterized in that the ratio of t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate:methyl[(5-chloropyridin-2-yl)amino]-2-oxoacetate:triethylamine in Step B is 1.0:1.0:2.8 to 1.0:1.1:3.

5.

14. The ratio of the mass of the t-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate to the volume of the polar solvent is The preparation method according to claim 11, characterized in that the mass of t-butyl{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate oxalate:volume of polar solvent=1.0:4.5 to 1.0:5.5 g / ml.

15. The methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate is (1) reacting 2-amino-5-chloropyridine with methyl oxalyl chloride in tetrahydrofuran to obtain methyl [(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride; and (2) adding methyl[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride to tetrahydrofuran, and adding sodium bicarbonate in portions to liberate methyl[(5-chloropyridin-2-yl)amino]-2-oxoacetate; 12. The method according to claim 11, characterized in that it is prepared by:

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