JP2012062285A - Method of producing 3-haloalkyl-2-hydroxypyrazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially advantageous method of producing a 3-haloalkyl-2-hydroxypyrazine derivative useful as an intermediate for pharmaceuticals, agrochemicals and the like.SOLUTION: The method of producing a hydroxypyrazine derivative represented by formula (1) (in the formula Rrepresents a 1-6C haloalkyl group) comprises allowing a dihydropyrazinone derivative represented by formula (2) (in the formula Ris the same as defined above) to react with an oxidizing agent in the presence or absence of an acid.

Description

  The present invention relates to a method for producing 3-haloalkyl-2-hydroxypyrazine derivatives useful as intermediates for pharmaceuticals, agricultural chemicals and the like, especially as intermediates for producing agricultural and horticultural acaricides and fungicides.

A 3-haloalkyl-2-hydroxypyrazine derivative is used as an intermediate for pharmaceuticals, agricultural chemicals and the like, in particular, an agrochemical for agricultural and horticultural use (for example, see Patent Document 1) and a bactericide (for example, see Patent Document 2). It is useful as an intermediate.
As its production method, a method of reacting trifluoroalanylamide and glyoxal (see, for example, Patent Document 3), a reaction of a trifluoropyruvic ester derivative with ethylenediamine, leading to a dihydropyrazinone derivative, Thereafter, a method of converting to a hydroxypyrazine derivative by reacting in the presence of an organic base has been reported (see, for example, Patent Document 4).

JP 2006-008675 A International Publication No. 2007/072999 Pamphlet JP 2009-242244 A International Publication No. 2010/055884 Pamphlet

  Patent Documents 3 and 4 disclose methods for producing hydroxypyrazine derivatives. However, in any of the production methods, the reaction time is long, and the production method described in Patent Document 4 is not an industrially advantageous production method because the yield decreases when scaled up. An object of the present invention is to provide an industrially advantageous production method of 3-haloalkyl-2-hydroxypyrazine derivatives represented by the general formula (1) useful as an intermediate for pharmaceuticals, agricultural chemicals and the like.

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるジヒドロピラジノン誘導体類を酸の存在下又は不存在下に酸化剤と反応させることを特徴とする、下記一般式（１）

（式中、Ｒ^１は前記に同じ。）で表されるヒドロキシピラジン誘導体類の製造方法。
［２］下記一般式（３）

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるヘミアミナール誘導体類を脱水することにより、下記一般式（２）

（式中、Ｒ^１は前記に同じ。）で表されるジヒドロピラジノン誘導体類に変換し、該ジヒドロピラジノン誘導体類（２）を酸の存在下又は不存在下に酸化剤と反応させることを特徴とする、下記一般式（１）

（式中、Ｒ^１は前記に同じ。）で表されるヒドロキシピラジン誘導体類の製造方法。
［３］下記一般式（３）

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるヘミアミナール誘導体類を酸存在下、酸化剤と反応させることを特徴とする、下記一般式（１）

（式中、Ｒ^１は前記に同じ。）で表されるヒドロキシピラジン誘導体類の製造方法。
［４］酸化剤が、過酸化水素又は過酸である前記［１］乃至［３］何れか一項に記載のヒドロキシピラジン誘導体類の製造方法。
［５］酸が、硫酸である前記［１］乃至［３］何れか一項に記載のヒドロキシピラジン誘導体類の製造方法。
［６］Ｒ^１が、ハロ（Ｃ_１−Ｃ_３）アルキル基である前記［１］乃至［３］何れか一項に記載のヒドロキシピラジン誘導体類の製造方法。
［７］Ｒ^１が、フルオロ（Ｃ_１−Ｃ_３）アルキル基である前記［１］乃至［３］何れか一項に記載のヒドロキシピラジン誘導体類の製造方法。
［８］Ｒ^１が、トリフルオロメチル基である前記［１］乃至［３］何れか一項に記載のヒドロキシピラジン誘導体類の製造方法。 As a result of intensive studies to solve the above problems, the present inventors have not used an organic base by using various oxidation reactions for the dihydropyrazinone derivatives represented by the general formula (2). Has also found that 3-haloalkyl-2-hydroxypyrazine derivatives represented by the general formula (1) can be efficiently produced, and the present invention has been completed.
That is, the present invention relates to the following inventions.
[1] The following general formula (2)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). A dihydropyrazinone derivative represented by halo is reacted with an oxidizing agent in the presence or absence of an acid. The following general formula (1)

(Wherein R ¹ is the same as defined above).
[2] The following general formula (3)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). Dehydrating hemiaminal derivatives represented by the following general formula (2)

(Wherein R ¹ is the same as above), and the dihydropyrazinone derivative (2) is reacted with an oxidizing agent in the presence or absence of an acid. The following general formula (1)

(Wherein R ¹ is the same as defined above).
[3] The following general formula (3)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group) and a hemiaminal derivative represented by the following general formula (1):

(Wherein R ¹ is the same as defined above).
[4] The method for producing a hydroxypyrazine derivative according to any one of [1] to [3], wherein the oxidizing agent is hydrogen peroxide or peracid.
[5] The method for producing a hydroxypyrazine derivative according to any one of [1] to [3], wherein the acid is sulfuric acid.
[6] The method for producing a hydroxypyrazine derivative according to any one of [1] to [3], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group.
[7] The process for producing a hydroxypyrazine derivative according to any one of [1] to [3], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group.
[8] The method for producing a hydroxypyrazine derivative according to any one of [1] to [3], wherein R ¹ is a trifluoromethyl group.

  According to the present invention, a target compound can be produced efficiently and economically on an industrial scale in a short time using a commercially available reagent.

Hereinafter, the present invention will be described in detail.
In the general formulas (1) to (3), the substituent represented by R ¹ is preferably a halo (C ₁ -C ₆ ) alkyl group, preferably a halo (C ₁ -C ₃ ) alkyl group, more preferably Is a fluoro (C ₁ -C ₃ ) alkyl group, most preferably a trifluoromethyl group. In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom unless otherwise specified.

The “halo (C ₁ -C ₆ ) alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms which may be the same or different. The linear or branched alkyl group having 1 to 6 carbon atoms is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, and s. -Butyl group, t-butyl group, i-butyl group, pentyl group, hexyl group and the like. In addition, the “halo (C ₁ -C ₃ ) alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms substituted with one or more halogen atoms which may be the same or different. The “fluoro (C ₁ -C ₃ ) alkyl group” refers to a linear or branched alkyl group having 1 to 3 carbon atoms substituted with one or more fluorine atoms. Although it does not specifically limit as a C1-C3 linear or branched alkyl group, For example, a methyl group, an ethyl group, n-propyl group, i-propyl group etc. are mentioned.

（式中、Ｒ^１は前記に同じ。）
即ち、本発明によると、前記一般式（３）で表されるヘミアミナール誘導体類を脱水し、前記一般式（２）で表されるジヒドロピラジノン誘導体類とし、当該ジヒドロピラジノン誘導体類を単離又は単離せずして酸化することにより、前記一般式（１）で表されるヒドロキシピラジン誘導体類を製造することができる。また、原料として使用する、前記一般式（３）で表されるヘミアミナール誘導体類及び前記一般式（２）で表されるジヒドロピラジノン誘導体類は、公知の方法により製造することができる（例えば、前記特許文献４を参照。）。 One aspect of the present invention is illustrated as follows.

(In the formula, R ¹ is the same as above.)
That is, according to the present invention, the hemiaminal derivatives represented by the general formula (3) are dehydrated to obtain dihydropyrazinone derivatives represented by the general formula (2), and the dihydropyrazinone derivatives are isolated. Alternatively, the hydroxypyrazine derivatives represented by the general formula (1) can be produced by oxidation without isolation. Moreover, the hemiaminal derivatives represented by the general formula (3) and the dihydropyrazinone derivatives represented by the general formula (2) used as raw materials can be produced by a known method (for example, (See Patent Document 4).

General formula (3) → General formula (2)
The dihydropyrazinone derivatives represented by the general formula (2) can be produced by dehydrating the hemiaminal derivatives represented by the general formula (3). Although this dehydration reaction is not specifically limited, For example, it can carry out by heating in presence of an acid.

  Examples of the acid include organic acids such as formic acid, acetic acid and trifluoroacetic acid, sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, inorganic acids such as sulfuric acid and hydrochloric acid, and Lewis acids such as iron chloride. Etc., and p-toluenesulfonic acid, trifluoroacetic acid, and sulfuric acid are preferably used. These acids can be used in the range of 0.001 to 5 molar equivalents with respect to the hemiaminal derivatives represented by the general formula (3), and the range of 0.01 to 3 molar equivalents is preferable.

  A solvent can be used for the dehydration reaction. The solvent may be any solvent that does not inhibit the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, heptane, and the like. Inert solvents such as chain or cyclic aliphatic hydrocarbons such as xane and cyclohexane, and alcohols such as methanol, ethanol, n-propanol and i-propanol can be used. These inert solvents can be used alone or in admixture of two or more.

  The reaction temperature in the dehydration reaction may be in the range from room temperature to the boiling point of the solvent used. The time required for dehydration is not constant depending on the reaction scale or the like, but may be appropriately selected within the range of several minutes to 100 hours. Although this reaction proceeds even in the presence of oxygen or the like in the air, the reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas. Moreover, in order to accelerate | stimulate reaction, the operation | movement and apparatus which remove | eliminate the produced | generated water can also be used. After completion of the reaction, the target dihydropyrazinone derivative represented by the general formula (2) may be isolated by a conventional method, and may be purified by recrystallization, column chromatography or the like as necessary. it can. It can also be used in the next reaction without isolation.

General formula (2) → General formula (1)
Hydroxy represented by the general formula (1) by reacting the dihydropyrazinone derivatives represented by the general formula (2) with an oxidizing agent in an inert solvent in the presence or absence of an acid. Pyrazine derivatives can be produced.

  The inert solvent is not particularly limited as long as it does not significantly inhibit the progress of the reaction, and examples thereof include chain or cyclic aliphatic hydrocarbons such as hexane, cyclohexane, and methylcyclohexane, benzene, xylene, toluene, chlorobenzene, and the like. Aromatic hydrocarbons, diethyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, linear or cyclic ethers such as 1,2-dimethoxyethane, amides such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, Nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate and butyl acetate, organic acids such as formic acid, acetic acid and trifluoroacetic acid, alcohols such as methanol, ethanol, n-propanol and i-propanol, 3-dimethyl-2-imida Rijinon, and inert solvents such as water can be cited, these inert solvents may be mixed and used alone or in combination.

  Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. In particular, sulfuric acid is preferably used. These acids can be appropriately selected and used in the range of 0.01 mole equivalent to solvent amount with respect to the dihydropyrazinone derivatives represented by the general formula (2), preferably 0.1 to 20 moles. It is the range of equivalent, More preferably, it is the range of 0.5-5 molar equivalent.

Examples of the oxidizing agent include hydrogen peroxide, sodium perborate tetrahydrate, sodium percarbonate, hydrogen peroxide derivatives such as urea / hydrogen peroxide adduct, and persulfates such as potassium persulfate and ammonium persulfate, inorganic oxidizing agents represented by _{2KHSO 5 · KHSO 4 · K 2} SO 4 and the like, peracetic acid, trifluoroperacetic acid, often an organic peracid such as m-CPBA, preferably, hydrogen peroxide, sodium perborate 4 Hydrate, sodium percarbonate, urea / hydrogen peroxide adduct, potassium persulfate, ammonium persulfate, 2KHSO ₅ · KHSO ₄ · K ₂ SO ₄ , or trifluoroperacetic acid, more preferably hydrogen peroxide, perborate sodium tetrahydrate, sodium percarbonate, urea-hydrogen peroxide _{adduct, 2KHSO 5 · KHSO 4 · K} 2 SO 4, or trifluoroacetic excessive vinegar , And most preferably a good hydrogen peroxide. Further, since peracetic acid and trifluoroperacetic acid are unstable, those prepared from hydrogen peroxide and acetic acid or trifluoroacetic acid in the system can be used. These oxidizing agents can be appropriately selected in the range of 0.1 to 20 molar equivalents relative to the dihydropyrazinone derivatives represented by the general formula (2), preferably 0.3 to 10 molar equivalents More preferably, it is in the range of 0.5 to 3 molar equivalents.

The reaction temperature may be appropriately selected within the range from −30 ° C. to the reflux temperature of the inert solvent used, and is preferably selected from the range of 0 to 50 ° C. The reaction time varies depending on the reaction scale, reaction temperature, and the like, and is not constant, but may be appropriately selected within the range of several minutes to 100 hours.
This reaction proceeds even in the presence of oxygen or the like in the air, but may be performed in an inert gas atmosphere such as nitrogen gas or argon gas.
After completion of the reaction, the hydroxypyrazine derivative represented by the general formula (1), which is the target product, may be isolated from the reaction system by a conventional method, and purified by recrystallization, column chromatography, distillation or the like as necessary. can do.

General formula (3) → General formula (1)
The hydroxypyrazine derivatives represented by the general formula (1) can be produced by reacting the hemiaminal derivatives represented by the general formula (3) with an oxidizing agent in the presence of an acid in an inert solvent. Can be manufactured. The inert solvent, acid, and oxidizing agent to be used can be produced in the same manner as described for the reactions (3) → (2) and (2) → (1).

  The 3-haloalkyl-2-hydroxypyrazine derivatives obtained by the production method of the present invention are easily derived into 3-haloalkylpyrazin-2-ylcarboxylic acid ester derivatives by, for example, the method shown in Reference Examples, and further the amide Thus, useful compounds such as agricultural and horticultural acaricides (for example, see Patent Document 1) and fungicides (for example, see Patent Document 2) can be produced.

Typical examples of the present invention are shown below, but the present invention is not limited thereto.

(Synthesis Example 1: Synthesis of hemiaminal derivatives)
To a toluene solution (60 ml) of ethylenediamine (20.0 g, 333 mmol), ethyl trifluoropyruvate (56.6 g, 333 mmol) was added dropwise at 22-29 ° C. over 0.6 hours under ice-cooling, and then 20- Stir at 25 ° C. for 2 hours. The precipitated crystals were collected by filtration, washed with toluene, and then air-dried to obtain 3-hydroxy-3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one as a yellow solid.
Yield: 60.1g
Yield: 98%
Melting point: 117-119 ° C

Example 1: Synthesis of dihydropyrazinone derivatives
3-hydroxy-3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (10.9 g) synthesized in Synthesis Example 1 and p-toluenesulfonic acid monohydrate (0.7 g, 0.37 mmol) was added to a toluene solution (100 ml) and subjected to azeotropic dehydration for 3 hours. Thereafter, the mixture was cooled to room temperature, insolubles were filtered through Celite, and the filtrate was concentrated. The precipitated crystals were collected by filtration, washed with a mixed solvent of t-butyl methyl ether / n-hexane, then air-dried, and 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one was yellow. Obtained as a solid.
Yield: 10.9g
Yield: 93%
Physical properties: ¹ H-NMR [CDCl ₃ / TMSδ value (ppm)]
3.56 (2H, m), 4.04 (2H, m), 6.7 (1H, brs)
Melting point: 98-99 ° C

(Example 2: Synthesis 1 of hydroxypyrazine derivatives)
To a methanol solution (0.40 ml) of 97% sulfuric acid (0.73 g, 7.23 mmol) under ice cooling, 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (0.40 g, 2.41 mmol) was added, 35% hydrogen peroxide (0.26 g, 2.65 mmol) was further added, and the mixture was stirred at 20 to 25 ° C. for 3 hours to obtain a 2-hydroxy-3-trifluoromethylpyrazine solution. As a result of analyzing the solution by liquid chromatography, the yield of 2-hydroxy-3-trifluoromethylpyrazine was 90%.

(Example 3: Synthesis 2 of hydroxypyrazine derivatives)
To a solution of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (0.40 g, 2.41 mmol) in dimethylacetamide (4.00 ml) was added 2KHSO ₅ · KHSO ₄ · K ₂ SO ₄ ( 0.89 g, 1.45 mmol) was added, and the mixture was stirred at 20 to 25 ° C. for 3 hours to obtain a 2-hydroxy-3-trifluoromethylpyrazine solution. As a result of analyzing the solution by liquid chromatography, the yield of 2-hydroxy-3-trifluoromethylpyrazine was 66%.

(Example 4: Synthesis 3 of hydroxypyrazine derivatives)
To a solution of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (0.40 g, 2.41 mmol) in trifluoroacetic acid (4.00 ml) was added disodium carbonate / hydrogen peroxide (. 38 g, 3.62 mmol) was added, and the mixture was stirred at 20 to 25 ° C. for 4 hours to obtain a 2-hydroxy-3-trifluoromethylpyrazine solution. As a result of analyzing the solution by liquid chromatography, the yield of 2-hydroxy-3-trifluoromethylpyrazine was 86%.

Examples 5 to 16: Synthesis of hydroxypyrazine derivatives 4 to 15
Hydroxypyrazine derivatives were synthesized in the same manner as in Examples 1 to 4 except that part of the conditions were changed to those described in Table 1. The changed conditions and the results obtained are shown in Table 1.

Example 17 Synthesis 16 of Hydroxypyrazine Derivatives
To a methanol solution (0.40 ml) of 97% sulfuric acid (0.73 g, 7.23 mmol) under ice-cooling, 3-hydroxy-3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one ( 0.44 g, 2.41 mmol), 35% hydrogen peroxide (0.26 g, 2.66 mmol) was added, and the mixture was stirred at 20 to 25 ° C. for 3 hours to give 2-hydroxy-3-trifluoromethylpyrazine. Obtained. As a result of analyzing the solution by liquid chromatography, the yield of 2-hydroxy-3-trifluoromethylpyrazine was 89%.

(Example 18. Synthesis 17 of hydroxypyrazine derivatives)
To an aqueous solution (10.0 ml) of 98% sulfuric acid (18.0 g, 180.9 mmol) under ice-cooling, 3-hydroxy-3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (11 0.1 g, 60.3 mmol) was added. Next, 30% hydrogen peroxide (7.33 g, 65.1 mmol) was added dropwise at 15 to 20 ° C. over 1 hour under ice cooling, and then stirred at 20 to 25 ° C. for 3 hours. Furthermore, 35% sodium bisulfite aqueous solution (8.91 g) was added dropwise over 15 hours at 15 to 20 ° C. under ice cooling, and then 20% aqueous sodium hydroxide solution (60.0 g) was added at 20 to 25 ° C. The reaction solution was obtained dropwise over 0.5 hour. The reaction solution was extracted with ethyl acetate (25 ml × 3 times), and the obtained organic layer was concentrated to give 2-hydroxy-3-trifluoromethylpyrazine as a yellow solid.
Yield: 8.9g
Yield: 90%
Melting point: 138-140 ° C

(Comparative Example 1: Synthesis 18 of hydroxypyrazine derivatives)
Preparation of 2-hydroxy-3-trifluoromethylpyrazine 20 g of 3-hydroxy-3-trifluoromethyl-5,6-dihydropyrazine-2 according to the conditions of Example 5 of Patent Document 4 (55 ° C., 16 hours) The reaction was carried out using (1H) -one, but the yield was less than 40%.

Reference Example 1: Synthesis of 2-chloro-3-trifluoromethylpyrazine
2-hydroxy-3-trifluoromethylpyrazine (61.4 g, 374 mmol) was added to 90% phenylphosphonic dichloride (145 g, 699 mmol), and the mixture was stirred on an oil bath at 155 ° C. for 1.5 hours. The reaction solution was cooled to 50 ° C., diluted with 200 ml of methyl-t-butyl ether, and poured into 200 ml of ice water. This was poured into 50 g of sodium bicarbonate, and suction filtered through a Buchner funnel with celite. The filtrate was transferred to a separatory funnel to remove the aqueous layer, washed with water, and then washed with saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and suction filtered through a Buchner funnel with celite and silica gel. The obtained residue was washed with 900 ml of t-butyl methyl ether. The obtained filtrate and washings were combined and concentrated on a warm water bath at 40 ° C. at 150 mmHg to obtain 68 g of a brown oil. As a result of quantitative analysis by gas chromatography, this oily substance was composed of 2-chloro-3-trifluoromethylpyrazine (54 g, 297 mmol) and 14 g of t-butyl methyl ether.
Yield: 80% (2-chloro-3-trifluoromethylpyrazine)
Physical properties: ¹ H-NMR [DMSO-d ₆ / TMSδ value (ppm)]
8.62 (2H, d)

(Reference Example 2: Synthesis of methyl 3-trifluoromethylpyrazine-2-carboxylate)
In a 2 L autoclave purged with argon gas, 66.5 g (366 mmol) 2-chloro-3-trifluoromethylpyrazine, 370 ml methanol, 40.7 g (403 mmol) triethylamine, 1.16 g (2.7 mmol). 1,4-bis (diphenylphosphino) butane and 0.95 g (1.4 mmol) of dichlorobis (triphenylphosphine) palladium (II) were added. The inside of the reaction vessel was replaced twice with argon gas and twice with carbon monoxide gas, and then charged with carbon monoxide gas at an initial pressure of 20 kg / cm ² and reacted at 120 ° C. for 2 hours. The temperature was returned to room temperature, the catalyst was filtered, and the filtrate was concentrated. The residue was extracted with t-butyl-methyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the inorganic substance, the concentrated residue was distilled under reduced pressure to obtain 54.5 g of methyl 3-trifluoromethylpyrazine-2-carboxylate.
Yield: 72%
Physical property: Boiling point 74-75 ° C / 2.5-2.8mmHg
Physical properties: ¹ H-NMR [CDCl ₃ / TMSδ value (ppm)]
8.85 (1H, d), 8.82 (1 H, d), 4.05 (3H, s)
Physical properties: ¹⁹ F-NMR [CDCl ₃ / TMSδ value (ppm)]
65.7 (s)

Reference Example 3: Synthesis of 3-trifluoromethylpyrazine-2-carboxylic acid
700 mg (3.4 mmol) of methyl 3-trifluoromethylpyrazine-2-carboxylate was dissolved in ethanol-water (1: 1, 10 ml), 300 mg of potassium hydroxide was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. After drying with magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 409 mg of the objective compound, 3-trifluoromethylpyrazine-2-carboxylic acid, as crystals.
Yield: 63%
Physical properties: melting point 130-134 ° C.

Reference Example 4: Synthesis of N- {3-isobutyl-4- [2,2,2-trifluoro-1- (trifluoromethyl) ethyl] phenyl} -3-trifluoromethylpyrazine-2-carboxylic acid amide )
192 mg (1 mmol) of 3-trifluoromethyl-2-pyrazinecarboxylic acid, 199 mg (1 mmol) of 3-isobutyl-4- [2,2,2-trifluoro-1- (trifluoromethyl) ethyl] aniline, 2- Chloro-1-methylpyridinium iodide (255 mg, 1 mmol) and triethylamine (303 mg, 3 mmol) were dissolved in 10 ml of tetrahydrofuran and heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the target compound N- {3-isobutyl. 293 mg of -4- [2,2,2-trifluoro-1- (trifluoromethyl) ethyl] phenyl} -3-trifluoromethylpyrazine-2-carboxylic acid amide was obtained as a paste.
Yield: 62%
Physical properties: n _D 1.4825 (27.7 ° C.)

Claims (8)

The following general formula (2)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). A dihydropyrazinone derivative represented by halo is reacted with an oxidizing agent in the presence or absence of an acid. The following general formula (1)

(Wherein R ¹ is the same as defined above). The following general formula (3)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). Dehydrating hemiaminal derivatives represented by the following general formula (2)

(Wherein R ¹ is the same as above), and the dihydropyrazinone derivative (2) is reacted with an oxidizing agent in the presence or absence of an acid. The following general formula (1)

(Wherein R ¹ is the same as defined above). The following general formula (3)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group) and a hemiaminal derivative represented by the following general formula (1):

(Wherein R ¹ is the same as defined above).   The method for producing a hydroxypyrazine derivative according to any one of claims 1 to 3, wherein the oxidizing agent is hydrogen peroxide or peracid.   The method for producing a hydroxypyrazine derivative according to any one of claims 1 to 3, wherein the acid is sulfuric acid. The method for producing a hydroxypyrazine derivative according to any one of claims 1 to ₃ , wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group. The method for producing a hydroxypyrazine derivative according to any one of claims 1 to ₃ , wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group. The method for producing a hydroxypyrazine derivative according to any one of claims 1 to 3, wherein R ¹ is a trifluoromethyl group.