A method for preparing an ethyl apixabanate

Abstract

The application belongs to the field of medicine and chemical industry, and relates to a preparation method of apixaban ethylate. The application reacts a compound of formula (1) with a compound of formula (2) in an inorganic base, an iodide and a non-hydrophilic organic solvent, and then reacts with an acid to obtain apixaban ethylate. The preparation method significantly improves the yield, reduces the reaction time, and is simple in post-treatment, and is very suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing apixaban ethyl ester, which belongs to the field of pharmaceutical and chemical engineering. Background Technology

[0002] Apixaban is a novel direct inhibitor of factor Xa that can be used for the prevention and treatment of thrombosis. The structural formula of apixaban is shown below:

[0003]

[0004] Apixaban ethyl ester is a key intermediate in the synthesis of apixaban, with the structure shown below:

[0005]

[0006] Patent document WO2014108919 reports the reaction of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridone (formula (1)) with ethyl chloro[(4-methoxyphenyl)hydrazino]chloroacetate (formula (2)) under conditions of sodium carbonate and acetone to obtain apixaban ethyl ester. The synthetic route is shown below:

[0007]

[0008] The patented method was found to be unstable during repeated experiments, with product yields generally below 60% and purity below 97%. Post-processing was also cumbersome, which was not conducive to large-scale industrial production.

[0009] Patent document CN101967145 reports a method for preparing apixaban ethyl esters from formulas (1) and (2) under conditions of organic bases and metal iodides. The synthetic route is shown below:

[0010]

[0011] The patented method, during repeated experiments, revealed that the process typically requires more than 20 hours and the product yield is generally below 80%, which is not conducive to large-scale industrial production. Summary of the Invention

[0012] The purpose of this invention is to provide a method for preparing apixaban ethyl esters with high yield, high purity, and short reaction time.

[0013] This invention provides a method for preparing apixaban ethyl ester, the reaction formula of which is as follows:

[0014]

[0015] 1) React the compound of formula (1) with the compound of formula (2) in an inorganic base, an iodide, and a non-hydrophilic organic solvent;

[0016] 2) After the reaction in step 1) is completed, it reacts with acid to obtain apixaban ethyl ester.

[0017] In this invention, the inorganic base can be hydroxides, carbonates, bicarbonates, or acetates of alkali metals and alkaline earth metals, preferably carbonates, and more preferably sodium carbonate.

[0018] In this invention, the iodide can be an organic iodide, an alkali metal or alkaline earth metal iodide, preferably tetrabutylammonium iodide and potassium iodide.

[0019] In this invention, the non-hydrophilic organic solvent is selected from acetonitrile, dichloromethane, tetrahydrofuran, toluene, ethyl acetate, 2-methyltetrahydrofuran, and mixed solvents thereof, preferably tetrahydrofuran and ethyl acetate.

[0020] In this invention, the molar ratio of the iodide to formula (1) is 0.05 to 2.0, preferably 0.1 to 1.0, and more preferably 0.1 to 0.5.

[0021] In this invention, the molar ratio of the inorganic base to formula (1) is 1.0 to 10.0, preferably 1.0 to 4.0, and more preferably 1.5 to 3.5.

[0022] In this invention, the molar ratio of the compound represented by formula (2) to that represented by formula (1) is 1.0 to 2.0, preferably 1.05 to 1.4; the mass ratio of the non-hydrophilic organic solvent to that represented by formula (1) is 3 to 30, preferably 8 to 15.

[0023] In this invention, the reaction temperature is 50℃~110℃, preferably 60℃~100℃; the reaction time is 5~12 hours, preferably 5~10 hours.

[0024] In this invention, the acid can be an inorganic acid or an organic acid, preferably hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid, and more preferably hydrochloric acid.

[0025] In this invention, the molar ratio of the acid to the compound of formula (1) is 2.0 to 12.0, preferably 3.0 to 6.0.

[0026] In this invention, after the acid reaction in step 2), the following steps are also included: cooling, filtering, drying; or distillation, adding water to form a slurry, and recrystallization.

[0027] This invention provides a method for preparing apixaban ethyl ester, which significantly improves the yield of apixaban ethyl ester, and the process is stable, with short reaction time, few impurities, and simple post-processing, making it very suitable for industrial production. Detailed Implementation

[0028] The technical solution of the present invention and its resulting technical effects will be further explained below with reference to embodiments, so as to fully understand the purpose, technical features and effects of the present invention.

[0029] Example 1:

[0030] At room temperature, 10g of formula (1), 10g of formula (2), 10g of sodium carbonate, and 1g of potassium iodide were sequentially added to a four-necked reaction flask. 100g of ethyl acetate was added, and the reaction flask was heated to 70℃~80℃ and reacted for 5 hours. The temperature was then lowered to 0℃~10℃, and 90mL of 2N dilute hydrochloric acid was added dropwise. The temperature was raised to 20℃~30℃ and stirred for 1 hour. The mixture was then cooled to 0℃~10℃, kept warm and stirred for 2 hours, and filtered. The filter cake was washed with a small amount of ethyl acetate and dried to obtain the target product, a light yellow solid. Yield: 87.1%, HPLC purity: 97.4%.

[0031] Example 2:

[0032] At room temperature, 10g of formula (1), 10g of formula (2), 10g of sodium carbonate, and 2g of tetrabutylammonium iodide were sequentially added to a four-necked reaction flask. 100g of tetrahydrofuran was added, and the reaction flask was heated to 70℃~80℃ and reacted for 8 hours. The temperature was then lowered to 0℃~10℃, and 90mL of 2N dilute hydrochloric acid was added dropwise. The temperature was raised to 20℃~30℃ and stirred for 1 hour. The mixture was then cooled to 0℃~10℃, and 20mL of water was added. After stirring and maintaining the temperature for 2 hours, the mixture was filtered. The filter cake was washed with a small amount of tetrahydrofuran and dried to obtain the target product, a light yellow solid. Yield: 90.1%, HPLC purity: 98.0%.

[0033] Example 3:

[0034] At room temperature, 10g of formula (1), 9g of formula (2), 10g of sodium carbonate, and 1g of potassium iodide were sequentially added to a four-necked reaction flask. 100g of tetrahydrofuran was added, and the reaction flask was heated to 60℃~70℃ and reacted for 6 hours. The temperature was then lowered to 0℃~10℃, and 90mL of 2N dilute hydrochloric acid was added dropwise. The temperature was then raised to 20℃~30℃ and stirred for 1 hour. The tetrahydrofuran was removed by distillation, and 100g of water was added to form a slurry. The mixture was filtered, and the filter cake was recrystallized from toluene and dried to obtain the target product, a light yellow solid. Yield: 86.2%, HPLC purity: 98.3%.

[0035] Example 4:

[0036] At room temperature, 10g of formula (1), 8.3g of formula (2), 5g of sodium carbonate, and 1.5g of potassium iodide were sequentially added to a four-necked reaction flask. 100g of ethyl acetate was added, and the reaction flask was then heated to 80℃~90℃ and reacted for 10 hours. The temperature was then lowered to 0℃~10℃, and 90mL of 2N dilute hydrochloric acid was added dropwise. The temperature was then raised to 20℃~30℃ and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate and dried to obtain the target product, a light yellow solid. Yield: 86.8%, HPLC purity: 97.6%.

[0037] Comparative Example 1

[0038] At room temperature, 10g of formula (1), 11g of formula (2), and 9g of sodium carbonate were added to a four-necked flask. 50mL of acetone was added, and the reaction was carried out at 50℃ for 3 hours. After cooling to 25℃, 50mL of dilute hydrochloric acid (15mL purified hydrochloric acid + 35mL water) was added, followed by stirring for 2 hours. Then, 30mL of water was added, and the mixture was stirred for 0.5 hours. The mixture was filtered and dried. The filter cake was recrystallized from 50mL of toluene, filtered, and dried. 8g of the product was obtained, with a yield of 58.4% and an HPLC purity of 94.2%.

Claims

1. A method for preparing apixaban ethyl ester, the reaction formula of which is as follows: 1) React the compound of formula (1) with the compound of formula (2) in an inorganic base, an iodide, and a non-hydrophilic organic solvent; 2) After the reaction in step 1) is completed, it reacts with acid to give apixaban ethyl ester. The inorganic base is a carbonate, and the iodide is selected from tetrabutylammonium iodide and potassium iodide. The non-hydrophilic organic solvent is selected from acetonitrile, dichloromethane, tetrahydrofuran, toluene, ethyl acetate, 2-methyltetrahydrofuran, and mixed solvents thereof. The molar ratio of the iodide to formula (1) is 0.1 to 0.

5. The molar ratio of the inorganic base to formula (1) is 1.5 to 3.

5. The molar ratio of the compound represented by formula (2) to that represented by formula (1) is 1.05 to 1.

4. The reaction temperature is 60℃~100℃, and the reaction time is 5~10 hours.

2. The preparation method according to claim 1, characterized in that... The inorganic base is sodium carbonate.

3. The preparation method according to claim 1, characterized in that... The non-hydrophilic organic solvent is selected from tetrahydrofuran and ethyl acetate.

4. The preparation method according to claim 1, characterized in that... The mass ratio of the non-hydrophilic organic solvent to formula (1) is 3 to 30.

5. The preparation method according to claim 4, characterized in that... The mass ratio of the non-hydrophilic organic solvent to formula (1) is 8-15.

6. The preparation method according to claim 1, characterized in that... The acid is an inorganic acid or an organic acid.

7. The preparation method according to claim 6, characterized in that... The acid is hydrochloric acid, sulfuric acid, acetic acid, or trifluoroacetic acid.

8. The preparation method according to claim 1, characterized in that... The molar ratio of the acid to the compound of formula (1) is 2.0 to 12.

0.

9. The preparation method according to claim 8, characterized in that... The molar ratio of the acid to the compound of formula (1) is 3.0 to 6.

0.

10. The preparation method according to claim 1, characterized in that... Step 2) after the acid reaction also includes the following steps: cooling, filtering, drying; or distillation, adding water to make a slurry, recrystallization.

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