JP2022022550A - Novel production method for apixaban - Google Patents

Abstract

To provide a simple production method that can be industrially applied and that enables direct production of apixaban.SOLUTION: Through usage of the production method, the target apixaban is directly prepared from a one-pot reaction without involving isolation of production intermediates, by causing a reaction to a compound represented by formula (I) after adding thereto formamide, and a base, preferably sodium methoxide in the presence of a reaction solvent, preferably acetonitrile, methanol, or ethanol.SELECTED DRAWING: None

Description

The present invention relates to a novel method for producing apixaban.

The following formula:

Chemical name indicated by: 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] Apixaban (INN) with pyridine-3-carboxamide is a clinically named Eliquis® tablet as an orally activated blood coagulation factor X (FXa) inhibitor, and is a venous thrombosis. It is a drug used for the treatment of embolism (deep vein thrombosis and pulmonary thromboembolism) and suppression of recurrence (Non-Patent Document 1).

So far, the method for producing apixaban has been described in the following chemical reaction formula:

As shown in
<Step 1 (reaction formula 1)>
After adding a strong base and a phase transfer catalyst to compound (I) and reacting to obtain compound (II) as crystals (Patent Document 1),
<Step 2 (reaction formula 2)>
A method for obtaining apixaban by adding formamide and a base to the obtained compound (II) and reacting with the obtained compound (II) is known (Patent Document 2).

Further, as another production method in step 2, a production method for obtaining apixaban by blowing ammonia into compound (II) and reacting with the compound (II) is known (Patent Document 3).

In the above production method, the intermediate compound (II) is once produced from the compound (I), the compound (II) is isolated as a crystal, and the compound (II) is induced into apixaban, and the compound (II) is also used. ), It is necessary to use dichloromethane as a reaction solvent, which has a large environmental load, and there is a drawback that a concentration operation or the like is also required in the post-treatment operation after the reaction.

CN1040455637A WO200349481A2 WO2016305007A2

Eliquis® Tablets Drug Interview Form Revised January 2020 (10th Edition)

In view of the present situation, it is an object of the present invention to provide a simple method for producing apixaban that can be applied industrially.
As a result of diligent studies to solve this problem, the present inventors have added formamide in the presence of a base to the compound (I) which is the starting compound of the above step 1 to simply add the compound (II) as an intermediate product. We have found that the target apixaban can be directly produced by a one-pot reaction without separation, and have completed the present invention.

Therefore, the present invention has the following formula (I):

The compound represented by (1) is reacted by adding formamide and a base in the presence of a reaction solvent.

It is a manufacturing method of apixaban shown by.

More specifically, it is the above-mentioned production method in which 1.5 to 30.0 equivalents are used with respect to 1 equivalent of compound (I) as the equivalent of formamide to be used.

More specifically, in the above production method, the base to be used is a base selected from sodium methoxydo, potassium methoxyd, potassium tert-butoxide, sodium amide, sodium hydride, potassium hydroxide or sodium hydroxide. be.

Further, in the present invention, the reaction solvent used is an organic solvent selected from acetonitrile, methanol, ethanol, formamide, N, N-dimethylformamide, dimethyl sulfoxide, acetone, toluene or a mixed solvent thereof. It is a manufacturing method of the above, and further, it is a manufacturing method of processing as a one-pot reaction.

INDUSTRIAL APPLICABILITY The present invention provides a simple method for producing apixaban that can be applied industrially, particularly a method for directly synthesizing apixaban from compound (I) by one-pot synthesis.
In the conventional production method obtained by isolating compound (II) from compound (I), a phase transfer catalyst such as tetrabutylammonium bromide is used under strong basic conditions, and dichloromethane having a large environmental load is used as a reaction solvent. There is.
In the production method according to the present invention, the use of dichloromethane can be avoided, which leads to a reduction in the environmental load during industrial production.

Further, in the conventional production method for isolating compound (II), it took at least two days to obtain apixaban from compound (I), and the total yield was 76.6%.
The production method according to the present invention requires only about 8 hours to obtain apixaban from compound (I) (see Examples below), and a significant reduction in production time can be expected. Furthermore, the yield is as high as 87.8%.
Therefore, the simple method for producing apixaban provided by the present invention is extremely efficient and highly industrially useful because the reaction from compound (I) to apixaban proceeds quantitatively and the reaction time is short. Is.

Hereinafter, the present invention will be described in detail by sequentially describing the contents examined by the present inventors.

First, the reaction for obtaining apixaban from compound (II) was only reported using formamide or ammonia gas (Patent Documents 1 and 2).
When formamide is used (Patent Document 1), apixaban formyl-protected body (III) represented by the following formula:

Since it is presumed to go through, the process requires multiple steps, and it is considered that the reaction path is not smooth.
Further, in the method using ammonia gas (Patent Document 2), since the ammonia gas is a gas, it is necessary to blow it into the reaction vessel and adjust the ammonia gas concentration, which is difficult to handle.
Therefore, as shown in the reaction formula (3) below, it was predicted that the reaction from compound (II) to apixaban would proceed by using sodium amide which is a solid.

Furthermore, since sodium amide has sufficient basicity to extract protons having an amide structure, if sodium amide is allowed to act on compound (I) as shown in the following reaction formula (4), It was considered that both intramolecular 6-membered ring formation and the reaction from the ester skeleton to the amide skeleton proceeded, and apixaban could be obtained directly without isolating compound (II). The desired reaction did not proceed and the expected result could not be obtained.

That is, in these reactions, since the basicity of sodium amide is high, the hydrolysis reaction proceeds preferentially, and for example, in the case of a reaction with the compound of the formula (I), the following reaction formula is used. (5):

As shown in, the hydrolyzate (IV) of apixaban was obtained.

Therefore, it was considered that apixaban could be directly converted from compound (I) by using a formamide anion as a base capable of suppressing nucleophilicity and forming an amide bond (reaction formula 6 below).

At this time, there is a possibility that the apixaban may pass through the formyl protectant (III), but since the formyl protectant (III) is easily hydrolyzed, it is considered that the apixaban can be easily induced.
Further, it is considered that formamide anion is used as the reaction condition for converting compound (II) to apixaban (Patent Document 2).
Based on the above, various reaction conditions for directly inducing apixaban using compound (I) instead of compound (II) were investigated, and formamide and a base were allowed to act on compound (I) in the presence of a reaction solvent. Therefore, we succeeded in obtaining the desired apixaban, which led to the present invention.

As described above, the present invention is a method for producing apixaban, which comprises adding formamide and a base to the compound (I) in the presence of a reaction solvent to cause a reaction.
The equivalent of formamide used in the reaction is 1.5 to 30.0 equivalents, more preferably 10.0 to 20.0 equivalents, relative to 1 equivalent of compound (I).

The base to be used can be selected from, but is not limited to, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium hydride, sodium amide, sodium hydroxide, and potassium hydroxide. ..
Of these, sodium methoxide or potassium methoxide is preferable as the base, and sodium methoxide is more preferable.

The reaction is carried out in the presence of a solvent, which may be selected from acetonitrile, methanol, ethanol, formamide, N, N-dimethylformamide, toluene, dimethyl sulfoxide, acetone, dichloromethane, tetrahydrofuran or a mixture of these. It can, but is not limited to these.
Considering the yield and purity of apixavan and the reduction of environmental load, acetonitrile, methanol, ethanol, formamide, N, N-dimethylformamide, toluene, acetone and dimethyl sulfoxide are preferable, and acetonitrile, methanol and ethanol are more preferable. preferable.

The reaction time cannot be unconditionally limited depending on the solvent used and the like, but is in the range of about 0.5 to 24 hours. In order to suppress hydrolysis, it is preferable to add the base at 10 ° C. or lower. The subsequent reaction temperature cannot be unconditionally limited, but it is preferably about 0 ° C. to 60 ° C., preferably 15 ° C. to 45 ° C. or lower, and more preferably 25 ° C. to 35 ° C.

After completion of the reaction, the target apixaban is collected by filtration from the reaction mixture as crystals and dried under reduced pressure to obtain apixaban as white crystals with high purity.
Therefore, the method for producing apixaban of the present invention can prepare a target apixaban as a one-pot reaction, and is particularly excellent as an industrial production method.

Hereinafter, the present invention will be described in detail by describing Examples / Comparative Examples, but the present invention is not limited to these Examples.

The reaction rate analysis conditions in the following Examples / Comparative Examples are as follows.
<Reaction rate analysis conditions>
High Performance Liquid Chromatograph: Shimazu LC-2010HT
Detector: Ultraviolet absorptiometer (measurement wavelength: 224 nm)
Column: YMC-Pack ODS-AQ 250 x 4.6 mm 5.0 μm
Column temperature: 30 ° C
Mobile phase: A mixed solution of 600 mL of buffer and 400 mL of acetonitrile Buffer: 1.36 g of potassium dihydrogen phosphate is dissolved in 1000 mL of water, and potassium hydroxide test solution is added to adjust the pH to 6.0. Flow rate: 1.0 mL / min Area measurement range: 70 minutes Sample injection volume: 10 μL
Sample diluted solution: Mobile phase Sample concentration: Add the mobile phase to 1 drop of the reaction solution and dilute to 5 mL.

Example 1:
Compound (I) (10.0 g, 19.1 mmol) and formamide (8.6 g, 190.3 mmol; 10 eq) were added to a mixed solvent of acetonitrile (70 mL) and methanol (10 mL), and the mixture was cooled to 5 ° C. or lower.
Then, a methanol solution of 28% sodium methoxide (11.0 g, 57.4 mmol; 3 equivalents) was added at the same temperature, and the mixture was stirred for 30 minutes, then heated to 30 ° C. and stirred for 2 hours.
After confirming the reaction rate by HPLC, the reaction solution was cooled to 5 ° C., water (140 mL) was added, the mixture was stirred for 1 hour, and then filtered. The filtrate was washed with water (20 mL) and ethanol (20 mL) and then dried under reduced pressure at 40 ° C. to obtain 7.7 g of apixaban as white crystals.
The yield was 87.8% (calculated as apixaban anhydride). The purity was 99.1%.

Example 2:
Add compound (I) (2.0 g, 3.8 mmol) and formamide (1.5 to 30.0 equivalents, Table 1 below) to a mixed solvent of acetonitrile (14 mL) and methanol (2 mL), and cool to 5 ° C or lower. did.
Then, a methanol solution of 28% sodium methoxide (2.2 g, 11.4 mmol; 3 equivalents) was added at the same temperature, and the mixture was stirred for 30 minutes, then heated to 30 ° C. and stirred for 2 hours.
After confirming the reaction rate by HPLC, the reaction solution was cooled to 5 ° C., water (28 mL) was added, the mixture was stirred for 1 hour, and then filtered. The filtrate was washed with water (4 mL) and ethanol (4 mL) and then dried under reduced pressure at 40 ° C. to obtain apixaban as white crystals.

The reaction rate to the equivalent amount of formamide used, the yield of apixaban (calculated as apixaban anhydride) and the purity are summarized in Table 1 below.

Example 3:
Compound (I) (1.0 g, 1.9 mmol) and formamide (0.9 g, 19.1 mmol; 10 eq) were added to the solvents listed in Table 2 below, and the mixture was cooled to 5 ° C. or lower.
Then, a methanol solution of 28% sodium methoxide (1.1 g, 5.7 mmol; 3 equivalents) was added at the same temperature, and the mixture was stirred for 30 minutes and then stirred at 30 ° C to 45 ° C.
After confirming the reaction rate by HPLC, the reaction solution was cooled to 5 ° C., water was added, the mixture was stirred for 1 hour, and then filtered. The filtrate was washed with water (2 mL) and ethanol (2 mL) and then dried under reduced pressure at 40 ° C. to obtain apixaban as white crystals.

Table 2 below summarizes the reaction rate to the solvent used, the yield of apixaban (calculated as apixaban anhydride), and the purity.

Example 4:
Compound (I) (2.0 g, 3.8 mmol) and formamide (1.7 g, 38.2 mmol; 10 eq) were added to a mixed solvent of acetonitrile (14 mL) and methanol (2 mL), and the mixture was cooled to 5 ° C. or lower.
Then, the bases (3 equivalents) shown in Table 3 below were added at the same temperature, and the mixture was stirred for 30 minutes, then heated to 30 ° C. and stirred for 2 hours.
After confirming the reaction rate by HPLC, the reaction solution was cooled to 5 ° C., water (28 mL) was added, the mixture was stirred for 1 hour, and then filtered. The filtrate was washed with water (4 mL) and ethanol (4 mL) and then dried under reduced pressure at 40 ° C. to obtain apixaban as white crystals.

Table 3 below summarizes the reaction rate to the base used, the yield of apixaban (calculated as apixaban anhydride), and the purity.

Comparative Example 1: Production of compound (II) (see Patent Document 1)
Compound (I) (1.8 g, 3.4 mmol), tetrabutylammonium bromide (0.2 g, 0.7 mmol; 0.2 eq) and sodium hydroxide (0.3 g, 6.8 mmol) in dichloromethane (90 mL); 2.0 eq) was added, the mixture was stirred at room temperature for 3 hours, and then water (15 mL) was added.
The dichloromethane layer and the aqueous layer were separated, and the dichloromethane layer was washed with water (15 mL). The dichloromethane layer was concentrated to dryness under reduced pressure. Ethyl acetate (18 mL) was added to the obtained oily substance, recrystallized, and the crystals were filtered. The filtrate was dried under reduced pressure at 40 ° C. to obtain 1.4 g of compound (II) as a white crystalline powder. The yield was 86.4%. The purity was 99.2%.

Comparative Example 2: Production of apixaban (see Patent Document 2)
Methanol solution of compound (II) (1.2 g, 2.5 mmol), formamide (1.1 g, 24.4 mmol; 10 eq) and 28% sodium methoxide (1) in N, N-dimethylformamide (6.0 mL). (0.0 g, 4.9 mmol; 2.0 eq) was added, and the mixture was stirred at 25 ° C. for 1 hour, water (25 mL) was added to the reaction solution, and the mixture was filtered. The filtrate was dried under reduced pressure at 40 ° C. to obtain 1.0 g of apixaban as a powder of white crystals. The yield was 88.6% (calculated as apixaban anhydride). The purity was 98.3%.

As described above, the present invention provides a simple method for producing apixaban that can be industrially applied, particularly a method for directly synthesizing apixaban from compound (I) by one-pot synthesis.
The method for producing apixaban provided by the present invention can be produced with high purity and high yield under extremely simple conditions as compared with the conventional method, and its industrial applicability is great.

Claims (5)

Equation (I)

The compound represented by the following formula is characterized by adding formamide and a base in the presence of a reaction solvent to cause a reaction.

The method for producing apixaban shown in. The production method according to claim 1, wherein 1.5 to 30.0 equivalents are used with respect to 1 equivalent of compound (I) as the equivalent of formamide. The production method according to claim 1, wherein the base used is a base selected from sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium amide, sodium hydride, potassium hydroxide or sodium hydroxide. The production method according to claim 1, wherein the reaction solvent used is acetonitrile, methanol, ethanol, formamide, N, N-dimethylformamide, dimethyl sulfoxide, acetone, toluene or an organic solvent selected from a mixed solvent thereof. The production method according to claim 1, which is treated as a one-pot reaction.