CN118580183A - A method for preparing an edoxaban intermediate - Google Patents

Abstract

The invention discloses a preparation method of an ideoxaban intermediate, in particular to a preparation method of a compound shown in a formula (I) or salt or hydrate thereof, which ensures that the obtained product has high yield and low impurity content, the whole reaction process system is smoothly stirred, solidification and sticky phenomena can not occur, difficult treatment or toxic reagents are not used, the preparation method is environment-friendly, the reaction time is short, the cost is low, the post-treatment process is simplified, the preparation method is more suitable for industrialized large-scale production,

Description

A method for preparing an edoxaban intermediate

Technical Field

The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing an edoxaban intermediate.

Background Art

Edoxaban tosylate tablets were developed by Daiichi Sankyo of Japan. They are selective factor Xa inhibitors and were launched in Japan in April 2011 for venous thromboembolism (VTE). They were approved in the United States in January 2015 to reduce the risk of stroke and dangerous thrombosis (systemic embolism) in patients with atrial fibrillation caused by non-valvular heart disease. They entered China in December 2018 for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors (such as congestive heart failure, hypertension, age ≥75 years, diabetes, previous history of stroke or transient ischemic attack (TIA)). They are used to treat deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults, as well as to prevent recurrence of deep vein thrombosis and pulmonary embolism in adults. Its structure is as follows:

The compound of formula (I) tert-butyl N-((1R,2S,5S)-2-(2-(5-chloropyridin-2-yl)amino)-2-oxyacetyl)amino)-5-(dimethylcarbamoyl)cyclohexyl)carbamate is an important intermediate in the synthesis of edoxaban:

The prior art CN103214414A, CN102348688A, CN104761571A, CN107641131A, CN112940012A, CN104761571A, CN106459087A, CN104936961A, CN111763169A, US9809546B2, etc. all adopt the method of reacting the compound of formula (2) with the compound of formula (3) in the presence of triethylamine:

However, the methods disclosed in the above-mentioned prior art all have the problem of difficulty in uniform stirring and poor reaction uniformity, resulting in low yield and purity. For example, the reaction system disclosed in CN103214414A contains a large amount of salt, which causes the reaction to solidify and makes stirring difficult. The reaction uniformity is poor in industrial scale-up production, resulting in a low yield of the product of formula (I), which is not satisfactory at the industrial level. The method disclosed in CN111763169A has a too long reaction time. After reacting at 50-60°C for 5-6h, it is necessary to react at room temperature for 4-24h. The reaction time is long and the reaction conditions are unstable, which is not conducive to industrial production.

Prior art CN105399667A discloses a preparation method of formula (I), which is prepared by condensing a compound of formula (4) with a compound of formula (5):

However, the reaction requires first adding the compound of formula (4) to a solvent to adjust the pH, and then conducting a condensation reaction with the compound of formula (5). The condensation reaction requires the addition of an organic bismuth catalyst. The use of the catalyst increases the production cost on the one hand, and also causes metal bismuth residue on the other hand, affecting the product quality and being unfavorable for industrial production.

Prior art CN113968813A and IN202041026059A disclose a preparation method of formula (I), which is prepared by condensing a compound of formula (6) with a compound of formula (7):

However, the reaction disclosed in CN113968813A uses N,N-dimethylformamide as the reaction solvent, and the purity of the precipitated product is poor. It needs to react at 85°C to 95°C for more than 6 hours and needs to be filtered while hot at high temperature. However, even so, the purity does not reach more than 99%, and high-temperature hot filtration is difficult to achieve industrial production, which poses a great safety hazard. In addition, N,N-dimethylformamide may decompose to produce dimethylamine impurities under high temperature alkaline conditions for a long time. The crude product yield of the process disclosed in IN202041026059A is less than 80%, and the post-treatment adds the process of methanol and water refining, and the total yield is less than 75%.

Summary of the invention

The object of the present invention is to develop a method for preparing an edoxaban intermediate, so that the obtained product has a high yield and a low impurity content, the whole reaction process system is stirred smoothly, no solidification and viscosity phenomena occur, no difficult or toxic reagents are used, the method is environmentally friendly, the reaction time is short, the cost is low, the post-processing process is simplified, and the method is more suitable for industrialized scale-up production.

Specifically, the present invention provides a method for preparing a compound of formula (I) or a salt or hydrate thereof, comprising reacting a compound of formula (7) with a compound of formula (2) under the action of a base to obtain:

In one embodiment, the compound of formula (7) can be placed in an organic solvent first, then a base is added, the temperature is raised and stirred, and then the compound of formula (2) is added to react.

Furthermore, the organic solvent is selected from acetonitrile, N,N-dimethylformamide or a mixture thereof, preferably acetonitrile; the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine or a mixture thereof, preferably triethylamine.

Furthermore, the molar ratio of the compound of formula (2) to the base is 1:3.5-5.5, preferably 1:4.0-5.2.

Furthermore, the molar ratio of the compound of formula (2) to the compound of formula (7) is 1:1.1 to 1.5, preferably 1:1.1 to 1.2.

Furthermore, the heating is to 45°C to 55°C.

In another embodiment, the compound of formula (7) is placed in an organic solvent, and then a base is added in a molar ratio of 1.0 to 2.0:1 to the compound of formula (2), the temperature is raised and stirred, and then a base in a molar ratio of 2.0 to 4.0:1 to the compound of formula (2) and the compound of formula (2) are added to react; the total molar ratio of the compound of formula (2) to the base is 1:3.5 to 5.5, preferably 1:4.0-5.2.

In another embodiment, the compound of formula (7) is placed in an organic solvent, and then a base is added in a molar ratio of 1.2 to 1.5:1 to the compound of formula (2), the temperature is raised and stirred, and then a base in a molar ratio of 3.0 to 4.0:1 to the compound of formula (2) and the compound of formula (2) are added to react; the total molar ratio of the compound of formula (2) to the base is 1:3.5 to 5.5, preferably 1:4.0-5.2.

In another embodiment, the compound of formula (7) is placed in an organic solvent, and then a base is added in a molar ratio of 1.4:1 to the compound of formula (2), the temperature is raised and stirred, and then a base in a molar ratio of 3.8:1 to the compound of formula (2) and the compound of formula (2) are added to react; the total molar ratio of the compound of formula (2) to the base is 1:3.5-5.5, preferably 1:4.0-5.2.

Furthermore, the organic solvent is selected from acetonitrile, N,N-dimethylformamide or a mixture thereof, preferably acetonitrile; the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine or a mixture thereof, preferably triethylamine.

Furthermore, the molar ratio of the compound of formula (2) to the compound of formula (7) is 1:1.1 to 1.5, preferably 1:1.1 to 1.2.

Furthermore, the heating is to 45°C to 55°C.

In one embodiment, the compound of formula (2) is added and then the temperature is raised to react. After the reaction, the temperature is lowered and water is added and stirred.

Furthermore, the heating is to 70°C to 80°C; and the cooling is to 30°C to 50°C.

Furthermore, the mass ratio of the amount of water to the amount of the organic solvent is 1.0 to 1.5:1; preferably, the mass ratio of the amount of water to the amount of acetonitrile is 1.0 to 1.5:1.

In order to avoid the problem that dissociation first and then reaction generate more salts, so that the system solidifies, thereby affecting the stirring and reaction uniformity, the present invention first adds a solvent and a compound of formula (7) 2-[(5-chloropyridine)amino]-2-oxoethyl acetate, and adds a base in batches or all at once under stirring, and after heating and stirring, adds a compound of formula (2) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate to react. After the reaction is completed, after the system is cooled, an appropriate amount of purified water is added and stirred for crystallization to obtain the target product. The yield can be stabilized at more than 90%, and the total impurities of the product can be controlled below 0.5%.

The solvent used in the preparation method of the present invention is miscible with water, the whole reaction process system is stirred smoothly, no solidification and viscosity phenomena occur, the product is not easy to wrap the solvent, even if a small amount of solvent remains, it can be removed by the drying process; the reaction does not need to add a metal catalyst, which is more in line with the concept of green chemistry; the free base 2-[(5-chloropyridine)amino]-2-oxoethyl acetate is directly used to avoid the problem of first dissociating the material to generate a large amount of salt; the product prepared by the preparation method of the present invention has high yield and low impurity content, does not use difficult-to-treat or toxic reagents, is environmentally friendly, does not need to stir for a long time in the reaction process, has a short reaction time, is low in cost, simplifies the post-processing process, and is more suitable for industrialized scale-up production.

DETAILED DESCRIPTION

The following representative examples are intended to better illustrate the present invention, but are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the materials used in the following examples were commercially available.

Example 1: Preparation of the compound of formula (I)

170 g of acetonitrile was added to the reaction flask, stirring was started, 20.1 g (87.9 mmol, 1.1 eq) of ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, and 11.3 g (111.7 mmol, 1.4 eq) of triethylamine was added. After the addition was completed, the temperature was raised to 50°C and stirred for 15 min. Then 30.7 g (303.4 mmol, 3.8 eq) of triethylamine and 30 g (79.9 mmol, 1.0 eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate were added, the temperature was raised to 80°C and stirred for 4 h. The system temperature was lowered to below 50°C. 250 g of purified water was added to the above reaction solution, and the solution was cooled to 10°C and stirred for 2 h. The filter cake was filtered and rinsed with 30 g of purified water. After drying, 34.9 g of white solid was obtained with a yield of 93.4% and a purity of 99.5%.

Example 2: Preparation of the compound of formula (I)

170 kg of acetonitrile was added to the reaction kettle, stirring was started, 21.9 kg (95.8 mol, 1.2 eq) of ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, and 11.3 kg (111.7 mol, 1.4 eq) of triethylamine was added. After the addition was completed, the temperature was raised to 50°C and stirred for 15 min. Then 30.7 kg (303.4 mol, 3.8 eq) of triethylamine and 30 kg (79.9 mol, 1.0 eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate were added, the temperature was raised to 70°C and stirred for 4 h. The system temperature was lowered to below 50°C. 250 kg of purified water was added to the above reaction solution, and the reaction solution was cooled to 10°C and stirred for 2 h. The filter cake was filtered and rinsed with 30 kg of purified water. After drying, 34.8 kg of white solid was obtained with a yield of 93.1% and a purity of 99.9%.

Example 3: Preparation of the compound of formula (I)

170g acetonitrile was added to the reaction bottle, stirring was started, 21.9g (95.8mmol, 1.2eq) ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, 32g (316.2mmol, 4.0eq) triethylamine was added, the temperature was raised to 50°C and stirred for 15min, 30g (79.9mmol, 1.0eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate was added under stirring, the temperature was raised to 75°C and stirred for 4h, the system temperature was lowered to below 50°C, 250g purified water was added to the above reaction solution, the mixture was cooled to 10°C and stirred for 2h. Filter, rinse the filter cake with 30g purified water, and dry to obtain 34.2g white solid with a yield of 91.5% and a purity of 99.6%.

Experimental Example 4: Preparation of the compound of formula (I)

170g acetonitrile was added to the reaction bottle, stirring was started, 21.9g (95.8mmol, 1.2eq) ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, 42g (415.1mmol, 5.2eq) triethylamine was added, the temperature was raised to 50°C and stirred for 15min, 30g (79.9mmol, 1.0eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate was added under stirring, the temperature was raised to 75°C and stirred for 4h, the system temperature was lowered to below 50°C, 250g purified water was added to the above reaction solution, the mixture was cooled to 10°C and stirred for 2h. Filter, rinse the filter cake with 30g purified water, and dry to obtain 34.7g white solid with a yield of 92.7% and a purity of 99.7%.

Comparative Example 1: Preparation of the compound of formula (I)

170g acetonitrile was added to the reaction bottle, stirring was started, 25.4g (95.8mmol, 1.2eq) ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate hydrochloride was added, and then 42g (415.1mmol, 5.2eq) triethylamine and 30g (79.9mmol, 1.0eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate were added. The system solidified and stirring was difficult. The temperature was raised to 75°C (the system was still very viscous after heating and contained a lot of blocky solids), and the temperature was kept and stirred for 4h. The system temperature was lowered to below 50°C, 250g purified water was added to the above reaction solution, and the mixture was cooled to 10°C and stirred for 2h. Filter, rinse the filter cake with 30g purified water, and dry to obtain 31.0g white solid, with a yield of 82.9% and a purity of 97.8%. Comparative Example 2: Preparation of the compound of formula (I)

170g acetonitrile was added to the reaction bottle, stirring was started, 18.3g (79.9mmol, 1.0eq) ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, 42g (415.1mmol, 5.2eq) triethylamine was added, 30g (79.9mmol, 1.0eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate was added under stirring, the temperature was raised to 65°C and stirred for 4h, the system temperature was lowered to below 50°C, 250g purified water was added to the above reaction solution, and the mixture was cooled to 10°C and stirred for 2h. Filter, rinse the filter cake with 30g purified water, and dry to obtain 29.5g white solid, with a yield of 78.9% and a purity of 98.3%.

Comparative Example 3: Preparation of the compound of formula (I)

170g acetonitrile was added to the reaction bottle, stirring was started, 30g (79.9mmol, 1.0eq) (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate and 42g (415.1mmol, 5.2eq) triethylamine were added, and the temperature was raised to 50°C and stirred for 15min, and then 21.9 (95.8mmol, 1.2eq) ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, the system solidified, the temperature was raised to 75°C and stirred for 4h, the system temperature was lowered to below 50°C, 250g purified water was added to the above reaction solution, and the mixture was cooled to 10°C and stirred for 2h. Filter, rinse the filter cake with 30g purified water, and dry to obtain 26.6g white solid, with a yield of 71.1% and a purity of 99.2%.

Comparative Example 4: Preparation of the compound of formula (I)

170 g of acetonitrile was added to the reaction flask, stirring was started, 21.9 g (95.8 mmol, 1.2 eq) of ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, and 11.3 g (111.7 mmol, 1.4 eq) of triethylamine was added. After the addition was completed, the temperature was raised to 50°C and stirred for 15 min. Then 14.5 g (143.3 mmol, 1.8 eq) of triethylamine and 30 g (79.9 mmol, 1.0 eq) of (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate were added, the temperature was raised to 70°C and stirred for 4 h. The system temperature was lowered to below 50°C. 250 g of purified water was added to the above reaction solution, and the solution was cooled to 10°C and stirred for 2 h. The filter cake was filtered and rinsed with 30 g of purified water, and dried to obtain 30.9 g of a white solid with a yield of 82.6% and a purity of 98.9%. Comparative Example 5: Preparation of the compound of formula (I)

170 g of acetonitrile was added to the reaction flask, stirring was started, 18.3 g (79.9 mmol, 1.0 eq) of ethyl 2-[(5-chloropyridine)amino]-2-oxoacetate was added, and 11.3 g (111.7 mmol, 1.4 eq) of triethylamine was added. After the addition was completed, the temperature was raised to 50°C and stirred for 15 min. Then 30.7 g (303.4 mmol, 3.8 eq) of triethylamine and 30 g (79.9 mmol, 1.0 eq) of (1S, 2R, 4S)-1-amino-4-(dimethylaminocarbonyl)-cyclohexyl-2-carbamic acid tert-butyl ester oxalate were added, the temperature was raised to 70°C and stirred for 4 h. The system temperature was lowered to below 50°C. 250 g of purified water was added to the above reaction solution, and the solution was cooled to 10°C and stirred for 2 h. The filter cake was filtered and rinsed with 30 g of purified water. After drying, 31.4 g of white solid was obtained with a yield of 84.0% and a purity of 99.2%.

Although the present invention has been described in detail above, it is understood by those skilled in the art that various changes, substitutions and modifications may be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above, but should be attributed to the claims.

Claims (10)

1. A method for preparing a compound of formula (I) or a salt or hydrate thereof, characterized in that a compound of formula (7) is reacted with a compound of formula (2) under the action of a base to obtain: 2. The preparation method according to claim 1, characterized in that the compound of formula (7) is first placed in an organic solvent, then a base is added, the temperature is raised and stirred, and then the compound of formula (2) is added to react. 3. The preparation method according to claim 1 is characterized in that the compound of formula (7) is first placed in an organic solvent, then a base is added in a molar ratio of 1.0 to 2.0:1 to the compound of formula (2), the temperature is raised and stirred, and then a base is added in a molar ratio of 2.0 to 4.0:1 to the compound of formula (2) and the compound of formula (2) to react. 4. The preparation method according to any one of claims 2 to 3, characterized in that the organic solvent is selected from acetonitrile, N,N-dimethylformamide or a mixture thereof, preferably acetonitrile; the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine or a mixture thereof, preferably triethylamine. 5. The preparation method according to any one of claims 1-2, characterized in that the molar ratio of the compound of formula (2) to the base is 1:3.5-5.5, preferably 1:4.0-5.2. 6. The preparation method according to any one of claims 1 to 4, characterized in that the molar ratio of the compound of formula (2) to the compound of formula (7) is 1:1.1 to 1.5, preferably 1:1.1 to 1.2. 7. The preparation method according to any one of claims 2-3, characterized in that the temperature is raised to 45°C to 55°C. 8. The preparation method according to any one of claims 2 to 7, characterized in that the temperature is raised after the compound of formula (2) is added, and after the reaction, the temperature is lowered and water is added with stirring. 9 . The preparation method according to claim 8 , characterized in that the heating is to 70° C. to 80° C.; and the cooling is to 30° C. to 50° C. 10 . The preparation method according to claim 8 , characterized in that the mass ratio of the amount of water to the amount of the organic solvent is 1.0 to 1.5:1.