Method for producing and purifying selexipag

Abstract

This invention provides a method for producing and purifying selexipag with few impurities. [Solution] In one aspect, a method for producing selexipag is provided. This method comprises contacting a first mixture with aluminum oxide particles to obtain a second mixture. The first mixture comprises 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid, and a solvent. The second mixture comprises 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.

Description

Technical Field

[0001] The present invention relates to a method for producing and purifying selexipag.

Background Art

[0002] 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, also known as selexipag (SXP), is a therapeutic agent for pulmonary hypertension. Selexipag is represented by the following formula.

[0003]

Chemical Formula

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a method for producing and purifying selexipag with less impurities.

Means for Solving the Problems

[0006] In one aspect, a method for producing selexipag is provided. This method comprises contacting a first mixture with aluminum oxide particles to obtain a second mixture. The first mixture comprises 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid, and a solvent. The second mixture comprises 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.

[0007] According to another aspect, a method for purifying selexipag is provided. This purification method comprises contacting a first mixture with aluminum oxide particles. The first mixture comprises 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid, and a solvent. [Effects of the Invention]

[0008] According to the present invention, a method for producing and purifying selexipag with fewer impurities is provided. [Modes for carrying out the invention]

[0009] According to the embodiment, a method for producing or purifying 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is provided. Hereinafter, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide will also be referred to as selexipag or SXP.

[0010] The manufacturing method according to this embodiment involves contacting a first mixture containing selexipag and impurities with aluminum oxide particles to obtain a second mixture containing selexipag. This manufacturing method yields selexipag with fewer impurities. The reason for this is thought to be as follows.

[0011] First, selexipag, or crude selexipag, used as a raw material, can be obtained, for example, by the synthesis method shown below.

[0012] [ka]

[0013] First, benzyl (SX-A01) and glycinamide hydrochloride (SX-D01) are reacted in reflux methanol in the presence of sodium hydroxide to obtain 5,6-diphenyl-1H-pyrazine-2-one (SX-A02). SX-A02 is reacted with reflux phosphoryl chloride to obtain 2-chloro-5,6-diphenylpyrazine (SX-A03Cl). SX-A03Cl and 4-(isopropylamino)-1-butanol (SX-E01) are reacted in n-methylpyrrolidone to obtain 4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]-1-butanol (SX-A04). AX-A04 is reacted with t-butyl bromoacetate to obtain tert-butyl 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetate (SX-A05Boc). SX-A05Boc is hydrolyzed to obtain 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetate (SX-A06). Selexipag (SXP) is obtained by reacting SX-A06 with a sulfonamide.

[0014] The crude selexipag obtained by such a method may contain impurities. As a result of the intensive research by the present inventors, it has been found that these impurities include 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid (SX-A06), which is a precursor of selexipag. And as a result of further research by the present inventors, it has been found that SX-A06 can be significantly removed by using aluminum oxide particles, that is, alumina, as an adsorbent, compared with the case of using other types of adsorbents. Therefore, according to the method according to the embodiment, selexipag with a reduced amount of the impurity SX-A06 can be obtained.

[0015] Hereinafter, the manufacturing method according to the embodiment will be described in detail.

[0016] The manufacturing method according to the embodiment includes contacting a first mixture containing selexipag, SX-A06 and a solvent with aluminum oxide particles to obtain a second mixture containing selexipag.

[0017] Also, the purification method according to the embodiment includes contacting a first mixture containing selexipag, SX-A06 and a solvent with aluminum oxide particles.

[0018] The aluminum oxide particles may be composed only of aluminum atoms and oxygen atoms, or may contain other atoms. Examples of other atoms include hydrogen, carbon, sodium, silicon, and iron. The aluminum oxide particles may be a composite oxide of A12O3 and at least one oxide selected from the group consisting of Na2O3, Fe2O3, and SiO2. In the composite oxide, the proportion occupied by A12O3 is, for example, 90% by mass or more.

[0019] The aluminum oxide particles may be in any form of powder, lump, or sphere. The average particle size of the aluminum oxide particles by the laser diffraction / scattering method is, for example, 0.05 mm or more and 0.3 mm or less. The average particle size is preferably 0.1 mm or more and 0.2 mm or less.

[0020] As the aluminum oxide particles, it is preferable to use activated alumina. The activated alumina may be acidic, basic or neutral. As the activated alumina, it is preferable to use basic alumina. The pH of the basic alumina is preferably 8 or more and 12 or less.

[0021] The aluminum oxide particles are porous. The specific surface area of the aluminum oxide particles by the BET method is, for example, 100 m 2 / g or more and 300 m 2 / g or less. The specific surface area is preferably 150 m 2 / g or more and 250 m 2 / g or less.

[0022] The aluminum oxide may be α-aluminum oxide or γ-aluminum oxide.

[0023] The amount of the aluminum oxide particles with respect to 1 g of seligustat is, for example, 0.01 g or more and 10 g or less. The amount of the aluminum oxide particles is preferably 0.1 g or more and 5.0 g or less, and more preferably 0.2 g or more and 1.0 g. When the amount of the aluminum oxide particles is large, the concentration of impurities tends to decrease.

[0024] The amount of the aluminum oxide particles with respect to 1 g of the first mixture is, for example, 0.001 g or more and 0.5 g or less. The amount of the aluminum oxide particles is preferably 0.01 g or more and 0.1 g or less, and more preferably 0.03 g or more and 0.05 g or less.

[0025] As the solvent contained in the first mixture, water, an organic solvent, or a mixed solvent thereof is used. As the solvent, it is preferable to use an organic solvent. The organic solvent preferably contains at least one selected from the group consisting of acetone, ethyl acetate, and acetonitrile, and more preferably contains acetone.

[0026] The amount of solvent is, for example, 1 mL to 60 mL per 1 g of the mixture of selexipag and SX-A06. Preferably, the amount of solvent per 1 g of the mixture is 10 mL to 50 mL, and more preferably 15 mL to 40 mL.

[0027] Contact between the first mixture and the aluminum oxide particles is carried out, for example, within a temperature range of 0°C to 40°C. This contact may also be carried out at room temperature between 20°C and 40°C.

[0028] Contact between the first mixture and the aluminum oxide particles is carried out, for example, within a range of 10 minutes to 3 hours. Preferably, this contact time is within a range of 30 minutes to 2 hours. During this contact time, it is preferable that the mixture of the first mixture and the aluminum oxide particles is continuously stirred.

[0029] In the first mixture, the area percentage of selexipag determined by high-performance liquid chromatography is, in one example, 90% or more, and in other examples, 95% or more. There is no particular upper limit to this percentage, but in one example, it is 99% or less. The method for calculating this area percentage will be described in detail in the examples.

[0030] In the first mixture, the area percentage of SX-A06 determined by high-performance liquid chromatography is, in one example, 10% or less, and in another example, 5% or less. There is no particular lower limit to this percentage, but in one example, it is 1% or more.

[0031] In the second mixture, the area percentage of selexipag determined by high-performance liquid chromatography is preferably 98% or higher, and more preferably 99% or higher. There is no particular upper limit to this percentage, but for example, it is 100%.

[0032] In the second mixture, the area percentage of SX-A06 determined by high-performance liquid chromatography is 2% or less in one example and 1% or less in another. There is no particular lower limit to this percentage, but it is 0% in one example and 0.1% or more in another.

[0033] In the first mixture, the ratio A1 / A2 of the peak area A1 of SX-A06 obtained by high-performance liquid chromatography to the peak area A2 of selexipag obtained by high-performance liquid chromatography is, in one example, between 0.01 and 0.05, and in another example, between 0.015 and 0.03.

[0034] In the second mixture, the ratio A1 / A2 of the peak area A1 of SX-A06 obtained by high-performance liquid chromatography to the peak area A2 of selexipag obtained by high-performance liquid chromatography is, for example, 0.01 or less. According to the method of the embodiment, SX-A06 can be selectively removed, so a second mixture with a low ratio can be obtained. It is more preferable that this ratio A1 / A2 is 0.007 or less. The lower limit of this ratio A1 / A2 is, in one example, 0, and in another example, 0.001.

[0035] Selexipag may be filtered off from the second mixture obtained by the above method. The filtered selexipag may be subjected to a washing treatment or further to an adsorbent treatment. Examples of adsorbents used in the adsorbent treatment include activated carbon, porous silica, aluminum hydroxide, and hydrotalcite. These adsorbents may be used in combination with the aluminum oxide particles in contact with the first mixture, or aluminum oxide particles may be used alone. [Examples]

[0036] The present invention will be described in detail below with reference to examples, but the present invention can be controlled by these examples. It is not limited.

[0037] <Example 1> (Manufacturing of crude selexipag) 20 g of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid (SX-A06) was mixed with 320 mL of super-dehydrated THF to obtain a solution. 11.6 g of 1,1'-carbonyldiimidazole was added to this solution and the mixture was stirred for several hours. 6.8 g of methanesulfonamide was added to the stirred solution, followed by 14.5 g of diazabicycloundecene, and the mixture was stirred for several hours to obtain the reaction mixture. After the reaction was complete, water was added to the reaction mixture, and it was concentrated under reduced pressure and washed three times with methyl t-butyl ether. The pH of the reaction mixture after washing was adjusted to 5 or less using hydrochloric acid, and then extracted twice with ethyl acetate. The resulting organic layer was concentrated under reduced pressure to obtain crude selexipag.

[0038] (Purification of crude selexipag) 1.0 g of crude selexipag was dissolved in 20 mL of acetone to obtain the first mixture. 0.1 g of basic alumina was added to the first mixture and stirred for 1 hour. Then, the first mixture was filtered to remove dust and obtain the second mixture.

[0039] The average particle size of basic alumina determined by laser diffraction / scattering is 0.15 mm, and the specific surface area determined by BET is 200 m². 2 The concentration was / g, and the pH was 10.

[0040] <Examples 2, 3, Comparative Examples 1-4> The second mixture was obtained in the same manner as in Example 1, except that the manufacturing conditions were changed as shown in Table 1.

[0041] <Evaluation Test> The purity of SX-A06 contained in the second mixture obtained in the examples and comparative examples was measured using high-performance liquid chromatography. Specifically, for the measurement sample, the purity of SX-A06 was defined as the ratio of the area value of SX-A06 to the total area value of SXP and SX-A06 obtained under the following conditions. The results are shown in Table 3.

[0042] Use a solution prepared by dissolving 20 μL of the first mixture and the second mixture in 1.5 mL of acetonitrile. Equipment: e2695 (manufactured by Waters) Detector: 2489 UV / Vis Detector Wavelength: 296nm Column: X Bridge C18 5μm 4.6×150mm Column temperature: 40℃ Sample temperature: 25℃ Sample injection volume: 10 μL Mobile phase A: Acetonitrile / buffer = 4 / 6 mixture Mobile phase B: Acetonitrile / buffer = 7 / 3 mixture Buffer: 20 mM dipotassium hydrogen phosphate aqueous solution (adjusted to pH 5.6 with phosphoric acid) Mobile phase delivery: The mobile phase was switched as shown in the table below.

[0043] [Table 1]

[0044] retention time

[0045] [Table 2]

[0046] [Table 3]

[0047] Preferred embodiments of the invention are described below. [1] A method for producing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, comprising contacting a first mixture containing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide with aluminum oxide particles to obtain a second mixture containing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide. [2] The manufacturing method according to [1], wherein the aluminum oxide is basic. [3] The method for producing aluminum oxide particles according to [1], wherein the amount of aluminum oxide particles per 1 g of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is 0.01 g or more and 10 g or less. [4] The method for producing the product according to [1], wherein the solvent comprises at least one organic solvent selected from the group consisting of acetone, ethyl acetate, and acetonitrile. [5] The method for producing the product according to [1], wherein the amount of the solvent relative to 1 g of the mixture of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid is 1 mL or more and 60 mL or less. [6] The manufacturing method according to [1], wherein the contact is carried out within a temperature range of 0°C to 40°C. [7] The manufacturing method according to [1], wherein the contact is performed within a range of 10 minutes to 3 hours. [8] The production method according to [1], wherein in the second mixture, the ratio A1 / A2 of the peak area A1 of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid and the peak area A2 of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide obtained by high-performance liquid chromatography is 0.01 or less. [9] A method for purifying 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, comprising contacting a first mixture containing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid, and a solvent with aluminum oxide particles.

Claims

1. A method for producing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, comprising contacting a first mixture containing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid and a solvent with aluminum oxide particles to obtain a second mixture containing 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide.

2. The manufacturing method according to claim 1, wherein the aluminum oxide is basic.

3. The manufacturing method according to claim 1, wherein the amount of aluminum oxide particles per 1 g of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide is 0.01 g or more and 10 g or less.

4. The manufacturing method according to claim 1, wherein the solvent comprises at least one organic solvent selected from the group consisting of acetone, ethyl acetate, and acetonitrile.

5. The production method according to claim 1, wherein the amount of the solvent relative to 1 g of the mixture of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid is 1 mL or more and 60 mL or less.

6. The manufacturing method according to claim 1, wherein the contact is performed within a temperature range of 0°C to 40°C.

7. The manufacturing method according to claim 1, wherein the contact is performed within a range of 10 minutes to 3 hours.

8. The production method according to claim 1, wherein in the second mixture, the ratio A1 / A2 of the peak area A1 of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid and the peak area A2 of 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide obtained by high-performance liquid chromatography is 0.01 or less.

9. A method for purifying 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide, 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid, and a solvent, and aluminum oxide particles, comprising contacting these with a first mixture.

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