Method for producing 2-chloro-5,6-diphenylpyrazine

Abstract

This invention provides a method for producing 2-chloro-5,6-diphenylpyrazine in high yield. [Solution] In one aspect, a method for producing 2-chloro-5,6-diphenylpyrazine is provided. This method includes contacting 2-hydroxy-5,6-diphenylpyrazine and phosphoryl chloride at a temperature of 70°C or higher and less than 120°C to obtain a first mixture. The first mixture contains 2-chloro-5,6-diphenylpyrazine. The contact temperature is preferably 80°C or higher and 100°C or lower.

Description

Technical Field

[0001] The present invention relates to a method for producing 2-chloro-5,6-diphenylpyrazine.

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 2-chloro-5,6-diphenylpyrazine with a high yield.

Means for Solving the Problems

[0006] According to one aspect, a method for producing 2-chloro-5,6-diphenylpyrazine is provided. This production method includes contacting 2-hydroxy-5,6-diphenylpyrazine with phosphoryl chloride at a temperature of 70°C or higher and lower than 120°C to obtain a first mixture. The first mixture contains 2-chloro-5,6-diphenylpyrazine.

Effects of the Invention

[0007] The present invention provides a method for producing 2-chloro-5,6-diphenylpyrazine in high yield. [Modes for carrying out the invention]

[0008] According to the embodiment, a method for producing 2-chloro-5,6-diphenylpyrazine is provided. This method includes contacting 2-hydroxy-5,6-diphenylpyrazine with phosphoryl chloride at a temperature of 70°C or higher and less than 120°C to obtain a first mixture. The first mixture contains 2-chloro-5,6-diphenylpyrazine.

[0009] 2-Chloro-5,6-diphenylpyrazine can be used as an intermediate for selexipag as described above. That is, selexipag can be obtained, for example, by the synthesis method shown below.

[0010] [ka]

[0011] First, benzyl (SX-A01) and glycinamide hydrochloride (SX-D01) are reacted in reflux methanol in the presence of sodium hydroxide to obtain 2-hydroxy-5,6-diphenylpyrazine (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). SX-A04 is reacted with t-butyl bromoacetate to obtain 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetate tert-butyl (SX-A05Boc). SX-A05Boc is hydrolyzed to obtain 2-{4-[N-(5,6-diphenylpyrazine-2-yl)-N-isopropylamino]butyloxy}acetic acid (SX-A06). Selexipag (SXP) is obtained by reacting SX-A06 with a sulfonamide.

[0012] According to the manufacturing method of the embodiment, 2-chloro-5,6-diphenylpyrazine (SX-A03Cl) can be obtained in high yield. This is thought to be because when 2-hydroxy-5,6-diphenylpyrazine (SX-A02) and phosphoryl chloride (POCl3) are reacted at a temperature of 70°C or higher but less than 120°C, hydrolysis of the intermediate and side reactions are less likely to occur. That is, as shown in the formula below, when SX-A02 and phosphoryl chloride are reacted, it is thought that SX-A03Cl is synthesized via the intermediate SX-A02PCl. The intermediate SX-A02PCl can be hydrolyzed back to SX-A02.

[0013] [ka]

[0014] As a result of the intensive research by the present inventors, when the temperature during this reaction is 120°C or higher, as shown by the following formula, it is found that a phosphoric acid diester (I) in which two SX-A02 are bonded and a phosphoric acid triester (II) in which three SX-A02 are bonded are likely to be formed. These phosphoric acid esters to which a plurality of SX-A02 are bonded are more stable than the intermediate SX-A02PCl and are considered to produce a phosphoric acid diester (III) by hydrolysis. And the phosphoric acid diester (III) is further hydrolyzed to produce a phosphoric acid monoester (IV), and this phosphoric acid monoester (IV) is further hydrolyzed to produce SX-A02. Therefore, when SX-A02 and phosphoryl chloride are reacted at a high temperature of 120°C or higher, it is considered that the yield of SX-A03Cl decreases.

[0015]

Chemical formula

[0016] In the method according to the embodiment, since SX-A02 and phosphoryl chloride are brought into contact at a temperature of 70°C or higher and lower than 120°C, the above phosphoric acid esters (I) and (II) are unlikely to be formed. Therefore, according to the method according to the embodiment, SX-A03Cl can be obtained in a high yield. In addition, since it can be converted to SX-A03Cl in a short time, the production efficiency can be increased.

[0017] Hereinafter, the manufacturing method according to the embodiment will be described in detail. The manufacturing method according to the embodiment includes bringing 2-hydroxy-5,6-diphenylpyrazine and phosphoryl chloride into contact at a temperature of 70°C or higher and lower than 120°C to obtain a first mixture.

[0018] This contact temperature is preferably 80 °C or higher, more preferably 90 °C or higher. When the contact temperature is high, the solubility of 2-hydroxy-5,6-diphenylpyrazine increases, and the conversion rate tends to increase. On the other hand, when the contact temperature exceeds 120 °C, impurities may be generated, and the yield of SX-A03Cl may decrease. This contact temperature is preferably 110 °C or lower, more preferably 100 °C or lower.

[0019] This contact time is, for example, 30 minutes or longer and 24 hours or shorter. According to the method according to the embodiment, since the conversion rate to 2-chloro-5,6-diphenylpyrazine is high, 2-chloro-5,6-diphenylpyrazine can be obtained in a high yield even with a short contact time. The contact time is preferably 1 hour or longer and 20 hours or shorter, more preferably 3 hours or longer and 12 hours or shorter.

[0020] In this contact, the amount of phosphoryl chloride relative to 1 g of 2-hydroxy-5,6-diphenylpyrazine is, for example, 0.1 mL or more and 10 mL or less. Phosphoryl chloride is both a reactant and functions as a reaction solvent. Therefore, when the amount of phosphoryl chloride is large, the reaction efficiency tends to increase. The amount of phosphoryl chloride relative to 1 g of 2-hydroxy-5,6-diphenylpyrazine is preferably 0.3 mL or more, more preferably 0.5 mL or more. On the other hand, according to the method according to the embodiment, since by-products are unlikely to occur, a high yield can be achieved even if the amount of phosphoryl chloride is reduced. Therefore, from the viewpoint of cost reduction, the amount of phosphoryl chloride relative to 1 g of 2-hydroxy-5,6-diphenylpyrazine is preferably 5.0 mL or less, more preferably 3.0 mL or less, and even more preferably 1.5 mL or less.

[0021] The amount of phosphoryl chloride relative to 1 mol of 2-hydroxy-5,6-diphenylpyrazine is, for example, 1 mol or more and 20 mol or less, preferably 1 mol or more and 10 mol or less, and more preferably 1.5 mol or more and 5 mol or less.

[0022] This contact may be carried out in the presence of an organic solvent other than phosphoryl chloride. As the organic solvent, for example, at least one compound selected from the group consisting of toluene, tetrachloroethane (TCE), and xylene is used. Preferably, at least one compound selected from the group consisting of toluene and TCE is used as the organic solvent, and more preferably, toluene is used.

[0023] The amount of organic solvent per 1 g of 2-hydroxy-5,6-diphenylpyrazine is, for example, 0.1 mL to 10 mL. Preferably, the amount of organic solvent is 0.5 mL to 5 mL, and more preferably 1 mL to 4 mL.

[0024] This contact is preferably carried out in the presence of a reaction accelerator. For example, N,N-dimethylformamide (DMF) is used as the reaction accelerator. The amount of reaction accelerator per mole of 2-hydroxy-5,6-diphenylpyrazine is, for example, 0.01 moles or more and 1 mole or less. More preferably, the amount of reaction accelerator is 0.1 moles or more and 0.5 moles or less.

[0025] In the first mixture, the area percentage of 2-chloro-5,6-diphenylpyrazine determined by high-performance liquid chromatography (HPLC) is, for example, 80% or more. According to the method of the embodiment, impurities are less likely to be generated, and high-purity 2-chloro-5,6-diphenylpyrazine can be obtained. This area percentage is preferably 90% or more, and more preferably 95% or more. There is no particular upper limit to this area percentage, but in one example it is 100% or less, and in another example it is 99% or less. Details of the method for measuring this area percentage will be described later in the examples.

[0026] In the first mixture, the area percentage of 2-hydroxy-5,6-diphenylpyrazine determined by high-performance liquid chromatography is, for example, 20% or less. According to the method of the embodiment, the formation of phosphate esters that hydrolyze to produce 2-hydroxy-5,6-diphenylpyrazine is unlikely, so a first mixture with a low proportion of 2-hydroxy-5,6-diphenylpyrazine is obtained. This area percentage is preferably 10% or less, more preferably 5% or less, and even more preferably 3% or less. There is no particular lower limit to this area percentage, but in one example it is 0%, and in another example it is 0.1% or more.

[0027] In the first mixture, the yield of 2-chloro-5,6-diphenylpyrazine is, for example, 70% or more. According to the method of the embodiment, impurities are less likely to be generated, so 2-chloro-5,6-diphenylpyrazine can be obtained in high yield. This yield is preferably 90% or more, and more preferably 95% or more. There is no particular upper limit to this yield, but according to one example it is 110% or less, and according to another example it is 100% or less.

[0028] In the first mixture, the yield of 2-hydroxy-5,6-diphenylpyrazine is, for example, 25% or less. This yield is preferably 15% or less, more preferably 5% or less, and even more preferably 3% or less. There is no particular lower limit to this yield, but in one example it is 0.1% or more, and in another example it is 0.5% or more.

[0029] The first mixture obtained by the method according to the embodiment may be further subjected to liquid-liquid extraction, concentration, or purification. [Examples]

[0030] 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.

[0031] <Example 1> 1 g of SX-A02 was placed in a reactor, 8.8 mL of phosphoryl chloride was added, and the mixture was heated to 70°C and stirred for several hours to obtain the first mixture. After the first mixture was allowed to cool, the phosphoryl chloride was removed by distillation under reduced pressure to obtain a residue. 10 mL of ethyl acetate was carefully added to the black tar residue at 0°C to obtain a suspension. 10 mL of water at 0°C was slowly added dropwise to this suspension to separate it into an oil layer and an aqueous layer. The aqueous layer was re-extracted using ethyl acetate. The oil layer obtained by re-extraction and the previously obtained oil layer were combined and dried over sodium sulfate, then filtered and concentrated to obtain crude SX-A03Cl as a black solid. 3 mL of a mixed solvent of ethyl acetate and heptane was added to the crude SX-A03Cl to form a slurry, stirred at 0°C for 1 hour, and then filtered using 2 mL of a mixed solvent of ethyl acetate and heptane at 0°C. The volume ratio of the mixed solvent of ethyl acetate and heptane was ethyl acetate:heptane = 2:1. The obtained solid was dried overnight under full vacuum at 40°C to obtain SX-A03Cl as a white-brown solid. <Examples 2-7, Comparative Example 1> SX-A03Cl was manufactured in the same manner as in Example 1, except that the manufacturing conditions were changed as shown in Table 3. <Example 8> 10 g of SX-A02 was placed in a reactor, 20 mL of toluene, 7.5 mL of phosphoryl chloride, and 0.62 mL of N,N-dimethylformamide were added, and the mixture was heated to 95°C and stirred for several hours to obtain the first mixture. After cooling, the first mixture was diluted with 20 mL of dichloromethane and filtered while washing to obtain the filtrate. The filtrate was carefully added dropwise to 64.9 g of 10% sodium hydroxide aqueous solution at 0°C over 1 hour at a temperature below 15°C, and then 50 mL of dichloromethane and 50 mL of water were added to separate the oil and water. The aqueous layer was re-extracted with 25 mL of dichloromethane. The oil layer obtained by re-extraction and the previously obtained oil layer were combined and concentrated to obtain crude SX-A03Cl as a yellow solid. Crude SX-A03Cl was mixed with 60 mL of ethanol and water to form a slurry, which was stirred at 0°C for 1 hour. The slurry was then filtered using 15 mL of ethanol and water mixed at 0°C. The volume ratio of the ethanol and water mixture was ethanol:water = 3:1. The resulting solid was dried overnight at 60°C under full vacuum to obtain SX-A03Cl as a wheat-colored solid. <Examples 9-12> SX-A03Cl was manufactured in the same manner as in Example 8, except that the manufacturing conditions were changed as shown in Table 3.

[0032] <Evaluation Method> (Calculation of conversion rate) For the examples and comparative examples, the conversion rates were calculated at 1 hour, 3 hours, 6 hours, and 24 hours. The following formula was used to calculate the conversion rate. Each area value was calculated using the same method as for purity, which will be described later. The results are shown in Table 4.

[0033] Conversion rate (%) = Area value of SX-A03Cl / (Area value of SX-A02 + Area value of SX-A03Cl) × 100 (Yield calculation) For the examples and comparative examples, the amount of SX-A03Cl in the first mixture was quantified from the calibration curve data obtained by HPLC. The yield of SX-A02 was calculated using the same method. The results are shown in Table 4.

[0034] (purity) The purity of SX-A03Cl obtained in the examples and comparative examples was measured using high-performance liquid chromatography. Specifically, the purity of SX-A03Cl was defined as the ratio of the area value of SX-A03Cl to the total area value of SX-A03Cl and SX-A02 obtained under the following conditions. The results are shown in Table 4.

[0035] The measurement conditions are as follows. Method for preparing the measurement sample: Use a solution prepared by dissolving 10 μL of the first mixture in 0.1 mL of water and 1.4 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.

[0036] [Table 1]

[0037] retention time

[0038] [Table 2]

[0039] [Table 3]

[0040] [Table 4]

[0041] Preferred embodiments of the invention are described below. [1] A method for producing 2-chloro-5,6-diphenylpyrazine, comprising contacting 2-hydroxy-5,6-diphenylpyrazine and phosphoryl chloride at a temperature of 70°C or higher and less than 120°C to obtain a first mixture containing 2-chloro-5,6-diphenylpyrazine. [2] The manufacturing method according to [1], wherein the contact temperature is 80°C or higher and 100°C or lower. [3] The method for producing phosphoryl chloride per 1 g of 2-hydroxy-5,6-diphenylpyrazine is 0.1 mL or more and 10 mL or less, as described in [1] or [2]. [4] The manufacturing method according to any one of [1] to [3], wherein the contact is carried out in an organic solvent. [5] The method for producing organic solvents according to [4], wherein the organic solvent comprises at least one selected from the group consisting of toluene, tetrachloroethane, and xylene. [6] The method for producing the organic solvent per 1 g of 2-hydroxy-5,6-diphenylpyrazine is 0.1 mL or more and 10 mL or less, as described in [4] or [5]. [7] The aforementioned contact is carried out in the presence of N,N-dimethylformamide, according to any one of [1] to [6]. [8] The method for producing the product according to [7], wherein the amount of N,N-dimethylformamide per mole of 2-hydroxy-5,6-diphenylpyrazine is 0.01 moles or more and 1 mole or less. [9] The manufacturing method according to any one of [1] to [8], wherein the contact time is 30 minutes or more and 24 hours or less.

[10] The method for producing the first mixture according to any one of [1] to [9], wherein the area proportion of 2-chloro-5,6-diphenylpyrazine determined by high-performance liquid chromatography is 80% or more.

Claims

1. A method for producing 2-chloro-5,6-diphenylpyrazine, comprising contacting 2-hydroxy-5,6-diphenylpyrazine and phosphoryl chloride at a temperature of 70°C or higher and less than 120°C to obtain a first mixture containing 2-chloro-5,6-diphenylpyrazine.

2. The manufacturing method according to claim 1, wherein the contact temperature is 80°C or higher and 100°C or lower.

3. The manufacturing method according to claim 1, wherein the amount of phosphoryl chloride per 1 g of 2-hydroxy-5,6-diphenylpyrazine is 0.1 mL or more and 10 mL or less.

4. The manufacturing method according to claim 1, wherein the contact is carried out in an organic solvent.

5. The production method according to claim 4, wherein the organic solvent comprises at least one selected from the group consisting of toluene, tetrachloroethane, and xylene.

6. The manufacturing method according to claim 4, wherein the amount of the organic solvent per 1 g of 2-hydroxy-5,6-diphenylpyrazine is 0.1 mL or more and 10 mL or less.

7. The manufacturing method according to claim 1, wherein the contact is carried out in the presence of N,N-dimethylformamide.

8. The manufacturing method according to claim 7, wherein the amount of N,N-dimethylformamide per mole of 2-hydroxy-5,6-diphenylpyrazine is 0.01 moles or more and 1 mole or less.

9. The manufacturing method according to claim 1, wherein the contact time is 30 minutes or more and 24 hours or less.

10. The production method according to claim 1, wherein in the first mixture, the area ratio of 2-chloro-5,6-diphenylpyrazine determined by high-performance liquid chromatography is 80% or more.

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