CN116137814A

CN116137814A - New process for the preparation of apixaban

Info

Publication number: CN116137814A
Application number: CN202180059664.3A
Authority: CN
Inventors: 堀瑶平; 忠田悠
Original assignee: Da Tong Co ltd
Current assignee: Da Tong Co ltd
Priority date: 2020-06-26
Filing date: 2021-05-28
Publication date: 2023-05-19
Also published as: JP2022022550A; WO2021261172A1

Abstract

The present invention provides a simple method for manufacturing apixaban which can be applied industrially. Specifically, formamide and sodium methoxide are added as a base to a compound represented by the following formula (I) with preferable acetonitrile, methanol or ethanol as a reaction solvent to react them. The method can directly prepare the target apixaban through a one-pot reaction without separating intermediate products.

Description

New process for the preparation of apixaban

Technical Field

The invention relates to a novel manufacturing method of apixaban.

Background

As an orally active blood coagulation factor X (FXa) inhibitor, apixaban (INN) is a drug which is clinically used for treatment of venous thromboembolism (deep venous thrombosis and pulmonary thromboembolism) and for suppressing recurrence (non-patent document 1) under the name of Ai Letuo (registered trademark) tablets, and has the chemical name: 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide and is represented by the formula:

[ chemical 1]

Heretofore, a known production method for apixaban is shown in the following chemical reaction formula:

[ chemical 2]

< step 1 (equation 1) >)

< step 2 (equation 2) >)

< step 1 (equation 1) >)

Adding a strong base and a phase transfer catalyst to the compound (I) to react to obtain a compound (II) after crystallization (patent document 1),

< step 2 (equation 2) >)

To the obtained compound (II), formamide and a base are added to react, thereby obtaining apixaban (patent document 2).

In addition, as another known method of step 2, there is a method of obtaining apixaban by blowing ammonia gas into compound (II) to perform a reaction (patent document 3).

In the above-described production method, it is necessary to convert the compound (I) into the intermediate compound (II) and to crystallize and separate the compound (II) to further convert it into apixaban. In addition, the following disadvantages exist in the production of compound (II): it is necessary to use methylene chloride, which is an environmentally heavy material, as a reaction solvent, and in post-treatment operation after the reaction, concentration operation and the like are required.

Prior art literature

Patent literature

Patent document 1: CN104045637A

Patent document 2: WO2003049681A2

Patent document 3: WO2016035007A2

Non-patent literature

Non-patent document 1: to a pair of the same piece of equipment, i.e. a piece of the same piece of equipment Shang, i.e. a piece of equipment, modified by the year 2020 1 month (10 th edition)

Disclosure of Invention

Technical problem to be solved by the invention

In view of the above-described state of the art, the present invention has an object to provide a simple method for producing apixaban which can be industrially applied.

In order to solve the above problems, the present inventors have intensively studied to find that the objective apixaban can be directly produced by a one-pot reaction without isolating the compound (II) as an intermediate by adding formamide to the compound (I) as the starting compound of the above step 1 in the presence of a base, thereby completing the present invention.

Technical means for solving the technical problems

The present invention provides a process for producing apixaban, which comprises adding formamide and a base to a compound represented by the following formula (I) in the presence of a reaction solvent,

[ chemical 3]

Wherein apixaban is represented by the formula:

[ chemical 4]

Specifically, in the above production method, the equivalent of the formamide used is 1.5 to 30.0 equivalents relative to 1 equivalent of the compound (I).

Next, in the above production method, the base used is a base selected from sodium methoxide, potassium tert-butoxide, sodium amide, sodium hydride, potassium hydroxide or sodium hydroxide.

In the above production method, the reaction solvent used is an organic solvent selected from acetonitrile, methanol, ethanol, formamide, N-dimethylformamide, dimethyl sulfoxide, acetone, toluene, and a mixed solvent thereof.

Finally, the manufacturing method of the invention is treated as a one-pot reaction.

Effects of the invention

The invention provides a simple and easy manufacturing method of apixaban which can be applied to industry, in particular to a manufacturing method for directly synthesizing apixaban from a compound (I) by a one-pot synthesis method.

In the conventional production method, it is necessary to use a phase transfer catalyst such as tetrabutylammonium bromide under a strongly basic condition and to use dichloromethane with a large environmental load as a reaction solvent for synthesizing the compound (II) from the compound (I).

The manufacturing method of the invention can avoid using methylene dichloride, thereby reducing the environmental load during industrial production.

In addition, in the conventional production method, since the separation of the compound (II) is required, it takes 2 days to obtain apixaban from the compound (I) at the minimum, and the total yield is only 76.6%.

The production method of the present invention requires only about 8 hours from the production of compound (I) to the production of apixaban (see examples described later), and significantly shortens the production time, and the yield is as high as 87.8%.

In summary, since the reaction from the compound (I) to apixaban can be quantitatively carried out and the operation time is short, the simple production method of apixaban provided by the present invention is a production method with extremely high efficiency and good industrial applicability.

Detailed Description

The present invention will be described in detail below by sequentially describing what the inventors have studied.

First, there are only reported examples using formamide or ammonia from the reaction of compound (II) to give apixaban (patent documents 1 and 2).

When formamide is used (patent document 1), it is presumed that apixaban is protected by the formyl group (III) represented by the following formula, and therefore, a multi-step reaction is required, and the reaction path is complicated:

[ chemical 5]

Formyl protected form (III) of apixaban.

In addition, in the method using ammonia (patent document 2), since ammonia is a gas, it is necessary to perform a blowing operation into a reaction vessel and to control the ammonia concentration, which is troublesome.

From these reports, we conceived that the reaction from compound (II) to apixaban might be carried out by using solid sodium amide as shown in the following reaction formula (3).

[ chemical 6]

< reaction No. 3>

Further, since sodium amide has basicity enough to remove protons of the amide structure, as shown in the following reaction formula (4), if sodium amide is applied to the compound (I), the reaction of intramolecular formation of a 6-membered ring and the reaction from the ester skeleton to the amide skeleton, both, may proceed, and apixaban can be directly obtained without isolation of the compound (II). However, although these attempts were made, the desired reaction did not proceed, and the desired result could not be obtained.

[ chemical 7]

< reaction formula (4) >

That is, in these reactions, hydrolysis reaction proceeds preferentially because of the high alkalinity of sodium amide. For example, as shown in the following reaction scheme (5), upon reaction with a compound of formula (I), an A is obtained

Hydrolyzate of pipaban (IV):

[ chemical 8]

< reaction formula (5) >

In view of the above results, we further conceived that apixaban could be directly obtained from compound (I) by using as a base a carboxamide anion which is less nucleophilic and capable of forming an amide bond (following equation 6).

[ chemical 9]

< reaction formula (6) >

Although it is possible for the reaction to proceed via the formyl protected form (III) of apixaban, it should be able to be easily converted into apixaban since the formyl protected form (III) is easily hydrolyzed.

In addition, we speculate that the reaction of the shift from compound (II) to apixaban in patent document 2 is the carboxamide anion used.

Based on the above, various attempts have been made to directly convert to apixaban under the reaction conditions using the compound (I) instead of the compound (II), and it has finally been found that the desired product apixaban can be successfully obtained by reacting the compound (I) with formamide and a base in the presence of a reaction solvent, thereby completing the present invention.

As described above, the present invention is a process for producing apixaban, characterized in that formamide and a base are added to compound (I) in the presence of a reaction solvent to react them.

The equivalent of formamide used in the reaction is 1.5 to 30.0 equivalents, preferably 10.0 to 20.0 equivalents, relative to 1 equivalent of compound (I).

The base used may be selected from sodium methoxide, potassium tert-butoxide, sodium hydride, sodium amide, sodium hydroxide, and potassium hydroxide, but is not limited thereto.

Among them, sodium methoxide and potassium methoxide are preferable, and sodium methoxide is more preferable.

The reaction is carried out in the presence of a solvent, and as the solvent, acetonitrile, methanol, ethanol, formamide, N-dimethylformamide, toluene, dimethyl sulfoxide, acetone, methylene chloride, tetrahydrofuran, or a mixed solvent thereof may be selected, but is not limited thereto.

In view of the yield and purity of apixaban and the reduction of environmental load, acetonitrile, methanol, ethanol, formamide, N-dimethylformamide, toluene, acetone, dimethyl sulfoxide are preferable, and among them, acetonitrile, methanol, ethanol are more preferable.

The reaction time is not generally limited depending on the solvent used, but is in the range of about 0.5 to 24 hours. In order to suppress hydrolysis, it is preferable to add a base at 10℃or lower. The reaction temperature thereafter is not generally limited, but is preferably about 0℃to 60℃and preferably 15℃to 45℃or less, more preferably 25℃to 35 ℃.

After the reaction, the target product apixaban can be crystallized, separated from the reaction mixture by filtration, and then dried under reduced pressure to form white crystals, whereby apixaban having a good purity can be obtained.

Therefore, the method for producing apixaban according to the present invention can be carried out as a one-pot reaction, and is an excellent industrial production method of apixaban.

Examples

The present invention will be described in more detail by describing examples/comparative examples, but the present invention is not limited to these examples.

In addition, the reaction rate analysis conditions in the following examples/comparative examples were as follows.

< analysis conditions for reaction Rate >

High performance liquid chromatography: shimazu LC-2010HT

A detector: ultraviolet absorbance photometer (measurement wavelength: 224 nm)

Column: YMC-Pack ODS-AQ 250X 4.6mm 5.0 μm

Column temperature: 30 DEG C

Mobile phase: 600mL buffer and 400mL acetonitrile mixture

Buffer solution: 1.36g of potassium dihydrogen phosphate was dissolved in 1000mL of water, and the pH was adjusted to 6.0 by adding a potassium hydroxide solution

Flow rate: 1.0 mL/min

Measurement time: 70 minutes

Sample injection amount: 10 mu L

Sample dilution: mobile phase

Sample concentration: adding mobile phase to 1 drop of reaction solution to dilute to 5mL

Example 1:

to a mixed solvent of acetonitrile (70 mL) and methanol (10 mL) were added compound (I) (10.0 g,19.1 mmol) and formamide (8.6 g,190.3mmol;10 eq.) and cooled to below 5 ℃.

Then, 28% sodium methoxide in methanol (11.0 g,57.4mmol;3 eq.) was added at the same temperature and stirred for 30 minutes, then heated to 30℃and stirred for 2 hours.

After confirming the reaction rate by HPLC, the reaction solution was cooled to 5℃and water (140 mL) was added thereto, followed by stirring for 1 hour and filtration. After washing the filtrate with water (20 mL) and ethanol (20 mL), it was dried under reduced pressure at 40℃to give 7.7g of apixaban white crystals.

The yield was 87.8% (calculated as anhydrous apixaban). The purity was 99.1%.

Example 2:

to a mixed solvent of acetonitrile (14 mL) and methanol (2 mL), compound (I) (2.0 g,3.8 mmol) and formamide (1.5 to 30.0 equivalents, table 1 below) were added, and the mixture was cooled to 5℃or lower.

Then, 28% sodium methoxide in methanol (2.2 g,11.4mmol;3 eq.) was added at the same temperature and stirred for 30 minutes, then heated to 30℃and stirred for 2 hours.

After confirming the reaction rate by HPLC, the reaction solution was cooled to 5℃and water (28 mL) was added thereto, followed by stirring for 1 hour and filtration. After washing the filtrate with water (4 mL) and ethanol (4 mL), it was dried under reduced pressure at 40℃to give apixaban white crystals.

The reaction rates, yields of apixaban (calculated as anhydrous apixaban) and purities obtained for the use of different equivalents of formamide are summarized in table 1 below.

TABLE 1

Formamide equivalent	Reaction Rate	Yield rate	Purity of
				1.5 equivalent	97.1％	34.8％	97.0％
10.0 equivalent	99.6％	87.8％	99.1％
				20.0 equivalent	99.5％	80.6％	97.9％
30.0 equivalent	99.4％	81.1％	98.6％

Example 3:

to the solvent shown in Table 2 below were added compound (I) (1.0 g,1.9 mmol) and formamide (0.9 g,19.1mmol,10 equivalents), and the mixture was cooled to 5℃or lower.

Then, 28% sodium methoxide in methanol (1.1 g,5.7mmol;3 equivalents) was added thereto at the same temperature, and after stirring for 30 minutes, it was stirred at 30℃to 45 ℃.

After confirming the reaction rate by HPLC, the reaction solution was cooled to 5℃and was stirred with water for 1 hour and then filtered. After washing the filtrate with water (2 mL) and ethanol (2 mL), it was dried under reduced pressure at 40 ℃ to obtain apixaban white crystals.

The reaction rates, yields of apixaban (calculated as anhydrous apixaban) and purities obtained with the different solvents are summarized in table 2 below.

TABLE 2

Example 4:

to a mixed solvent of acetonitrile (14 mL) and methanol (2 mL) were added compound (I) (2.0 g,3.8 mmol) and formamide (1.7 g,38.2mmol;10 eq.) and cooled to below 5 ℃.

Then, the base (3 equivalents) described in Table 3 below was added at the same temperature, stirred for 30 minutes, and then heated to 30℃and stirred for 2 hours.

The reaction rates, yields of apixaban (calculated as anhydrous apixaban) and purities obtained with the different bases are summarized in table 3 below.

TABLE 3

Comparative example 1: production of Compound (II) (see patent document 1)

To dichloromethane (90 mL) was added compound (I) (1.8 g,3.4 mmol), tetrabutylammonium bromide (0.2 g,0.7mmol;0.2 eq.) and sodium hydroxide (0.3 g,6.8mmol;2.0 eq.) and, after stirring at room temperature for 3 hours, 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. To the obtained oily substance was added ethyl acetate (18 mL), and the mixture was recrystallized and the crystals were filtered. The filtrate was dried under reduced pressure at 40℃to obtain 1.4g of compound (II) as white crystals in powder form. The yield was 86.4%. The purity was 99.2%.

Comparative example 2: production of apixaban (see patent document 2)

To N, N-dimethylformamide (6.0 mL) was added compound (II) (1.2 g,2.5 mmol), formamide (1.1 g,24.4mmol;10 eq.) and 28% sodium methoxide in methanol (1.0 g,4.9mmol;2.0 eq.) and, after stirring at 25℃for 1 hour, water (25 mL) was added to the reaction solution and filtration was performed. The filtrate was dried under reduced pressure at 40℃to give 1.0g of apixaban as white crystals in powder form. The yield was 88.6% (calculated as anhydrous apixaban). The purity was 98.3%.

Industrial applicability

As described above, the present invention provides a simple production method of apixaban which can be industrially applied, and in particular, a production method for directly synthesizing apixaban from compound (I) by a one-pot synthesis method.

Compared with the prior art, the method for producing apixaban provided by the invention can realize the production of apixaban with high purity and high yield under extremely simple conditions, and has great industrial applicability.

Claims

1. A process for producing apixaban, which comprises adding formamide and a base to a compound represented by the following formula (I) in the presence of a reaction solvent,

[ chemical 1]

Wherein apixaban is represented by the formula:

[ chemical 2]

2. The production process according to claim 1, wherein the amount of formamide used is 1.5 to 30.0 equivalents relative to 1 equivalent of the compound (I).

3. The process according to claim 1, wherein the base is selected from the group consisting of sodium methoxide, potassium tert-butoxide, sodium amide, sodium hydride, potassium hydroxide and sodium hydroxide.

4. The process according to claim 1, wherein the reaction solvent used is an organic solvent selected from acetonitrile, methanol, ethanol, formamide, N-dimethylformamide, dimethyl sulfoxide, acetone, toluene and a mixed solvent thereof.

5. The method of claim 1, wherein the method is performed as a one-pot reaction.