JP5631741B2 - Process for producing pyrazine derivatives and intermediates thereof - Google Patents

Description

  The present invention relates to a method for producing 3-haloalkyl-2-halogenopyrazine derivatives useful as intermediates for pharmaceuticals or agricultural chemicals, particularly as intermediates for producing agricultural and horticultural acaricides and fungicides.

A 3-haloalkyl-2-halogenopyrazine derivative is used as an intermediate for pharmaceuticals, agricultural chemicals, etc., especially between agricultural and horticultural acaricides (for example, see Patent Document 1) and fungicides (for example, see Patent Document 2). Useful as a body.
As a production method thereof, a method is known in which 2-chloro-3-iodopyrazine is substituted with 2-chloro-2,2-difluoroacetic acid methyl ester, potassium fluoride and copper iodide, and the iodine atom is substituted with a trifluoromethyl group. (For example, see Non-Patent Document 1).
In addition, a method has been reported in which a phenylglyoxylic acid ester derivative and ethylenediamine are reacted to lead to a dihydropyrazinone derivative, which is converted to a hydroxypyrazine derivative by oxidation (see, for example, Non-Patent Document 2). However, there is no specific disclosure or suggestion regarding a compound into which a haloalkyl group is introduced as in the present invention.

JP 2006-008675 A International Publication No. 2007/072999 Pamphlet

J. et al. Heterocyclic Chem. , 34 (2), 551-556 (1997) Acta Chemica Scandinavia, 1997, 51, 742

In the method of Non-Patent Document 1, it is necessary to introduce an iodine atom at an appropriate position of the heterocyclic ring in advance, use of expensive 2-chloro-2,2-difluoroacetic acid methyl ester, equivalent number The above copper iodide is necessary and difficult to remove, and the reaction temperature is high, so that it is not necessarily an industrially advantageous production method.
In addition, the report of Non-Patent Document 2 does not disclose or suggest the derivatives according to the present invention and the production method thereof. Furthermore, even when the derivatives according to the present invention were dehydrogenated according to the method disclosed in Non-Patent Document 2, no corresponding hydroxypyrazine derivative could be produced.
An object of the present invention is to provide a novel and industrially advantageous production method of 3-haloalkyl-2-halogenopyrazine derivatives useful as intermediates for pharmaceuticals or agricultural chemicals.

As a result of diligent research, the present inventors have led to novel dihydropyrazinone derivatives by reacting pyruvate substituted with a halogen atom and ethylenediamine or a salt thereof. Next, by examining various oxidation reactions, it was found that novel hydroxypyrazine derivatives were obtained, and further industrially useful 3-haloalkyl-2-halogenopyrazine derivatives were efficiently produced by halogenating the hydroxyl group. It was. Furthermore, it has been found that the compounds represented by the general formulas (II) and (III) are novel compounds not described in the literature, and the present invention has been completed.
That is, the present invention
[1] General formula (III)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). A dihydropyrazinone derivative represented by the general formula is dehydrogenated in the presence of an organic base. (II)

(Wherein R ¹ is the same as above), a method for producing hydroxypyrazine derivatives represented by:
[2] General formula (IV)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group, and R ² represents a (C ₁ -C ₆ ) alkyl group) and a pyruvate derivative represented by ethylenediamine or a salt thereof And the general formula (III)

(Wherein R ¹ is the same as above), and the dihydropyrazinone derivative (III) is dehydrogenated in the presence of an organic base. General formula (II)

(Wherein R ¹ is the same as above), a method for producing hydroxypyrazine derivatives represented by:
[3] General formula (III)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group) and the dihydropyrazinone derivatives represented by the general formula (II) are dehydrogenated in the presence of an organic base.

(Wherein R ¹ is the same as above), and the hydroxypyrazine derivative (II) is halogenated.

(Wherein R ¹ is the same as described above, and X represents a halogen atom), a method for producing a pyrazine derivative represented by:
[4] General formula (IV)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group, and R ² represents a (C ₁ -C ₆ ) alkyl group) and a pyruvate derivative represented by ethylenediamine or a salt thereof And the general formula (III)

(Wherein R ¹ is the same as above), and the dihydropyrazinone derivative (III) is dehydrogenated in the presence of an organic base to give a general formula (II )

(Wherein R ¹ is the same as above), and the hydroxypyrazine derivative (II) is halogenated.

(Wherein R ¹ is the same as described above, and X represents a halogen atom), a method for producing a pyrazine derivative represented by:
[5] Organic bases are pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine, 2,3-lutidine, 2,4-lutidine, 2 , 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3,6-lutidine,
[6] The production method according to any one of [1] to [4], wherein the organic base is pyridine.
[7] The method for producing a hydroxypyrazine derivative according to [1], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group,
[8] The method for producing a hydroxypyrazine derivative according to [2], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group, and R ² is a (C ₁ -C ₆ ) alkyl group,
[9] The method for producing a pyrazine derivative according to [3], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group, and X is a halogen atom.
[10] The pyrazine derivatives according to [4], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group, R ² is a (C ₁ -C ₆ ) alkyl group, and X is a halogen atom. Production method,
[11] Organic bases are pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine, 2,3-lutidine, 2,4-lutidine, 2 , 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3,6-lutidine, the production method according to [7] to [10],
[12] The production method according to [7] to [10], wherein the organic base is pyridine,
[13] The method for producing a hydroxypyrazine derivative according to [1], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group,
[14] The method for producing a hydroxypyrazine derivative according to [2], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group and R ² is a (C ₁ -C ₆ ) alkyl group,
[15] The method for producing a pyrazine derivative according to [3], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group, and X is a halogen atom.
[16] The pyrazine derivatives according to [4], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group, R ² is a (C ₁ -C ₆ ) alkyl group, and X is a halogen atom. Production method,
[17] The organic base is pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine, 2,3-lutidine, 2,4-lutidine, 2 , 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3,6-lutidine, [13] to [16],
[18] The production method according to [13] to [16], wherein the organic base is pyridine,
[19] The method for producing a hydroxypyrazine derivative according to [1], wherein R ¹ is a trifluoromethyl group,
[20] The method for producing hydroxypyrazine derivatives according to [2], wherein R ¹ is a trifluoromethyl group and R ² is a (C ₁ -C ₆ ) alkyl group,
[21] The method for producing a pyrazine derivative according to [3], wherein R ¹ is a trifluoromethyl group, and X is a halogen atom.
[22] The method for producing a pyrazine derivative according to [4], wherein R ¹ is a trifluoromethyl group, R ² is a (C ₁ -C ₆ ) alkyl group, and X is a halogen atom.
[23] Organic bases are pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine, 2,3-lutidine, 2,4-lutidine, 2 , 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3,6-lutidine, [19] to [22],
[24] The production method according to [19] to [22], wherein the organic base is pyridine.
[25] General formula (III)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group), dihydropyrazinone derivatives represented by:
[26] Dihydropyrazinone derivatives according to [25], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group,
[27] The dihydropyrazinone derivatives according to [25], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group,
[28] Dihydropyrazinone derivatives according to [25], wherein R ¹ is a trifluoromethyl group,
[29] General formula (II)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group),
[30] The hydroxypyrazine derivatives according to [29], wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group,
[31] The hydroxypyrazine derivatives according to [29], wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group,
[32] The hydroxypyrazine derivative according to [29], wherein R ¹ is a trifluoromethyl group.

  According to the present invention, an objective compound can be produced efficiently and economically advantageously on an industrial scale by using an easily available reagent and without using conventionally used copper iodide.

A preferred embodiment of the present invention will be described. R ¹ is preferably a halo (C ₁ -C ₆ ) alkyl group, preferably a halo (C ₁ -C ₃ ) alkyl group, more preferably a fluoro (C ₁ -C ₃ ) alkyl group, most preferably trifluoromethyl. It is a group. R ² is preferably a (C ₁ -C ₆ ) alkyl group. X is preferably a halogen atom, preferably a bromine atom or a chlorine atom, and most preferably a chlorine atom.
Next, each substituent described in this specification is demonstrated. In the definition of the substituents of the compounds represented by the general formulas (I) to (IV) of the present invention, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and “(C ₁ -C _“6 ) alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, An alkyl group such as s-butyl, t-butyl, n-pentyl, n-hexyl, etc., which may be the same as or different from the “halo (C ₁ -C ₆ ) alkyl group” and substituted with one or more halogen atoms And a “fluoro (C ₁ -C ₃ ) alkyl group” is 1 to 6 carbon atoms substituted with one or more fluorine atoms. 3 linear or branched alkyl groups are shown.
The salt may be an acid salt. Examples of the acid in the acid salt 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, methanesulfonic acid, and trifluoroacetic acid. Examples thereof include sulfonic acids such as romethanesulfonic acid and p-toluenesulfonic acid.

  The reaction involved in the present invention is illustrated as follows.

(Wherein R ¹ , R ² and X are the same as above)
That is, a pyruvic acid ester derivative represented by the general formula (IV) is reacted with ethylenediamine or a salt thereof to obtain a dihydropyrazinone derivative represented by the general formula (III), and the dihydropyrazinone derivative (III ) Is isolated or unisolated to convert to hydroxypyrazine derivatives represented by the general formula (II), and the hydroxypyrazine derivatives (II) are halogenated with a halogenating agent Thus, pyrazine derivatives represented by the general formula (I) can be produced.

General formula (IV) → General formula (III)
In this reaction, pyruvic acid ester derivatives represented by general formula (IV) are reacted with ethylenediamine or a salt thereof in an inert solvent to produce dihydropyrazinone derivatives represented by general formula (III). . Ethylenediamine or a salt thereof can be used in the range of 0.1 to 10 times mol, preferably 0.5 to 5 times mol for the pyruvate derivatives represented by the general formula (IV). More preferably, it is 0.9 to 1.2 times mol. The inert solvent to be used may be any one that does not significantly inhibit the progress of this reaction. For example, aliphatic hydrocarbons such as hexane, cyclohexane, and methylcyclohexane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chain or cyclic ethers such as diethyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, n- Propanol, alcohols such as i-propanol, amides such as dimethylformamide, dimethylacetamide, nitriles such as acetonitrile, or inert solvents such as 1,3-dimethyl-2-imidazolidinone or water, These solvents Alone or in combination of two or more inert solvents can be used.

  The reaction temperature may be appropriately selected from the range of 0 ° C. to the reflux temperature of the inert solvent used, but is preferably selected from the range of 0 ° C. to the boiling point of the inert solvent. 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. The reaction proceeds even in the presence of oxygen in the air, but the reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas.

Depending on the type of R ¹ , the reaction may stop in the state of hemiaminal represented by general formula (III ′). In this case, hemiaminal may be heated and dehydrated in the presence of an acid catalyst. As the acid used, sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid; inorganic acids such as sulfuric acid and hydrochloric acid; Lewis acids such as iron chloride are preferably used. Although the usage-amount of the acid used can be used in 0.01-1 times mole range with respect to hemiaminal, Preferably it is the range of 0.02-0.2 times mole. The solvent used is preferably a solvent that does not mix with water, and is more preferably an inert solvent such as aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride. . The time required for dehydration is not constant, but may be appropriately selected within the range of several minutes to 100 hours.
After completion of the reaction, the target product may be isolated from the reaction system by a conventional method, and the target product can be produced by further purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.

General formula (III) → General formula (II)
The dihydropyrazine derivatives represented by the general formula (III) are dehydrogenated by heating and stirring in the presence of a base such as pyridine in an inert solvent or without a solvent, and represented by the general formula (II). Hydroxypyrazine derivatives can be prepared. The inert solvent may be any solvent that does not significantly inhibit the progress of this reaction. For example, aliphatic hydrocarbons such as hexane, cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, xylene and toluene, diethyl Ether, t-butyl methyl ether, dioxane, tetrahydrofuran, linear or cyclic ethers such as 1,2-dimethoxyethane, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile and propionitrile, acetone, methyl Linear or cyclic ketones such as isobutyl ketone and cyclohexanone, esters such as ethyl acetate and butyl acetate, alcohols such as methanol, ethanol, n-propanol and i-propanol, 1,3-dimethyl-2-imidazo Jin Won, sulfolane, can be exemplified inert solvent such as dimethyl sulfoxide and water, these inert solvents may be mixed and used alone or in combination.

  Examples of bases include monoethylamine, diethylamine, triethylamine, tributylamine, pyrrolidine, piperidine, morpholine, pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine, 5-ethyl-2-methyl. Organics such as pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3,6-lutidine, quinoline and pyrrole Bases, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, carbonates such as sodium bicarbonate and potassium carbonate, phosphates such as potassium monohydrogen phosphate and trisodium phosphate, sodium Alkali metal alkoxides such as methoxide and sodium ethoxide Succoth can. Examples of acid salts of bases include acid salts of organic bases such as diethylamine hydrochloride, pyrrolidine hydrochloride and pyridine sulfate, and ammonium salts such as ammonium acetate. Of these, preferably an organic base, more preferably pyridine, 2-picoline, 3-picoline, 4-picoline, 4-dimethylaminopyridine, 5-ethyl-2-methylpyridine, 2,3-lutidine, 2 Substituted pyridines such as 1,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 3,6-lutidine and the like are selected.

These bases or acid salts thereof can be appropriately selected in the range of 0.01 mole to solvent amount with respect to the dihydropyrazine derivatives represented by the general formula (III), preferably 1 to 20 The range is double moles.
The reaction temperature may be appropriately selected within the range of −30 ° C. to the reflux temperature of the inert solvent used, and is preferably selected from the range of 0 to 80 ° 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 200 hours.

An additive may be added to this reaction for the purpose of promoting the reaction. Examples of additives include manganese compounds such as manganese dioxide; chromic acids such as sodium chromate; lead compounds such as lead tetraacetate; mercury compounds such as mercury oxide; oxidations such as osmium tetroxide, ruthenium tetroxide, and selenium dioxide. Agents; metal halides such as iron chloride, copper iodide, copper chloride, magnesium chloride, zinc chloride, boron fluoride; carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, barium carbonate, ammonium carbonate; Metal oxides such as cuprous oxide, cupric oxide, iron oxide and palladium oxide; halogens such as iodine and bromine; haloimides such as N-chlorosuccinimide, N-bromosuccinimide and diiodohydantoin; palladium and platinum , Iridium, rhodium, ruthenium, selenium, rhenium and other transition metal compounds Quinone-based oxidizing agents such as DDQ; peroxides such as hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid; sulfur atoms, oxygen, activated carbon, silica gel, alumina, titanium oxide, diatomaceous earth, pumice, barium sulfate or And polyaniline (JOC, 1997, 62, 1072-1078, TL, 48 (2007) 2729-2732). Transition metal compounds such as palladium, platinum, iridium, rhodium, ruthenium, selenium, rhenium, etc. can be used as metal itself. For example, activated carbon, silica gel, alumina, titanium oxide, diatomaceous earth, pumice, barium sulfate or polyaniline are supported. Can be used, and Pd / C and Pt / C supported on activated carbon are preferred. When the transition metal compound is zero-valent in this way, in order to carry out the reaction while returning the transition metal compound oxidized by the reaction to zero-valent (reduced type), formate such as sodium formate and ammonium formate; hydroquinone, Organic reducing agents such as formaldehyde, formic acid, glucose, and ascorbic acid; reducing gases such as carbon monoxide, ethylene, and methane may be mixed and used. On the other hand, transition metal compounds in an oxidized state can also be used, for example, PdCl ₂ , Pd (OH) ₂ , palladium oxide, palladium sulfide, PtO ₂ , iridium (III) chloride, rhodium (III) chloride, ruthenium chloride (III). ), Inorganic transition metal compounds such as rhenium oxide; palladium (II) acetate, dichlorobis (benzonitrile) palladium (II), carbonyltris (triphenylphosphine) palladium (0), dichlorobis (trialkylphosphine) palladium (II), trans- [iodo (phenyl) bis (dimethylphenylphosphine) palladium (II)], trans- [dimethylbis (triphenylphosphine) palladium (II)], bis (t-butylisocyanide) palladium (0), (two Oxygen) bis (t-butyl isocyanate), Pd ₂ Cl ₄ (C ₂ H ₄ ) ₂ , Pd ₂ Cl ₄ (PPh ₃ ) ₂ , tetrakis (triphenylphosphine) palladium (0), Pd (C ₂ H ₄ ) (PPh ₃ ) ₂ , tris (dibenzylideneacetone) dipalladium (0), PdCl ₂ ( _{C 8 H 12), [PdCl} (C 3 H 5)] 2, Pd (C 3 H 5) (C 5 H 5), Pd (C 3 H 5) 2, [Pd (C 5 H 5) (C _{8 H 12)] BF 4,} [Pd (C 3 H 5) (C 8 H 12)] BF 4, and organic transition metal compounds, such as _{[Pd (acac) (C 8} H 12)] BF 4. Two or more transition metal compounds can also be used in combination, for example, a method such as Wacker oxidation ("Palladium Reagents and Catalysts", First Edition 2004, Wiley, 29-35; Synthesis 1984, 369-384). Can be used. Among these additives, transition metal compounds supported on metal halides, carbonates, halogen molecules, activated carbon or activated carbon, silica gel, alumina, titanium oxide, diatomaceous earth, pumice, sulfuric acid or barium polyaniline are preferable. These additives can be used alone or in admixture of two or more.

These additives can be appropriately selected in the range of 0.001 to 10-fold moles with respect to the dihydropyrazine derivatives represented by the general formula (III), but preferably 0.01 to 2-fold moles. A range is preferred.
The reaction is preferably in an oxidative atmosphere such as oxygen or air bubbling.
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purifying it by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.

General formula (II) → General formula (I)
The pyrazine derivatives represented by the general formula (I) of the present invention can be produced by reacting the hydroxypyrazine derivatives represented by the general formula (II) with a halogenating agent. The reaction is not particularly required to use a solvent, but can be carried out in the presence of a catalyst or in an inert solvent, if necessary. Examples of the catalyst include basic solvents such as dimethylformamide and dimethylacetamide, and organic bases such as N, N-dimethylaniline and N, N-diethylaniline. The amount of these catalysts used depends on the halogenating agent. On the other hand, it is appropriately selected within a range of 0.01 to 1 molar equivalent. The inert solvent may be any solvent that does not significantly inhibit the progress of this reaction. For example, aliphatic hydrocarbons such as hexane, cyclohexane and methylcyclohexane, aromatic hydrocarbons such as benzene, xylene and toluene, diethyl Ether, t-butyl methyl ether, dioxane, tetrahydrofuran, linear or cyclic ethers such as 1,2-dimethoxyethane, amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile and propionitrile, acetone Linear or cyclic ketones such as methyl isobutyl ketone and cyclohexanone, esters such as ethyl acetate and butyl acetate, amide-based inert solvents such as dimethylformamide and dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, Can be exemplified inert solvent such as fine sulfolane, these inert solvents may be mixed and used alone or in combination.

Examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phenylphosphonic dichloride, phosgene, phosphorus tribromide and the like. These halogenating agents can be appropriately selected in the range of 1 to 20 times molar equivalents relative to the hydroxypyrazine derivatives represented by the general formula (II), but preferably in the range of 1 to 3 times mol. is there.
The reaction temperature may be appropriately selected within the range of the reflux temperature of the inert solvent or halogenating agent used from 0 ° C, but is preferably selected from the range of 50 to 180 ° 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. The reaction proceeds even in the presence of oxygen 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 target product may be isolated from the reaction system by a conventional method, and the target product can be produced by further purification by recrystallization, column chromatography or the like, if necessary.

The compound of the present invention produced in each step can be obtained from the reaction solution by a conventional method. If desired, it can be separated and purified by any purification method such as distillation, suspension washing, recrystallization, column chromatography and the like. Can do. Moreover, it can also be separated into a salt and purified using an inorganic acid such as hydrochloric acid.
The 3-haloalkyl-2-halogenopyrazine 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, By amidation, compounds useful as agricultural and horticultural acaricides (Patent Document 1) and fungicides (Patent Document 2) can be produced.

  Typical examples of the present invention are shown below, but the present invention is not limited thereto. In the following, “v” represents “volume” and “w” represents “weight”.

Example 1. Preparation of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one To a toluene solution (100 ml) of ethylenediamine (4.2 g, 70.6 mmol), ethyl trifluoropyruvate (12 g, 70.6 mmol) was added dropwise and stirred at room temperature for 15 hours. Thereafter, P-toluenesulfonic acid monohydrate (0.7 g, 0.37 mmol) was added and azeotropic dehydration was performed for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with a mixed solvent of t-butyl methyl ether / n-hexane, and air-dried to obtain the title compound as a yellow 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 Production of 2-hydroxy-3-trifluoromethylpyrazine-Part 1
A pyridine solution (6 ml) of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (0.6 g, 3.6 mmol) was heated and stirred at 60 ° C. for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the residue concentrated under reduced pressure was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1 (v / v)) to give the title compound as a brown solid.
Yield; 0.42g
Yield; 43%
Physical properties: ¹ H-NMR [CDCl ₃ / TMSδ value (ppm)]
7.67 (1H, d), 7.58 (1 H, d).
Melting point: 138-139 ° C

Example 3 Production of 2-hydroxy-3-trifluoromethylpyrazine-2
Iron chloride (4 g, 24.6 mmol) was added to a pyridine solution (40 ml) of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (4 g, 24.1 mmol) for 9 hours at 55 ° C. Stir with heating. After completion of the reaction, the reaction mixture was cooled to room temperature, and the residue concentrated under reduced pressure was purified by silica gel chromatography (n-hexane: ethyl acetate = 1: 1 (v / v)) to give the title compound as a brown solid.
Yield; 2.7g
Yield; 68%

Example 4 2.8 g of 2-hydroxy-3-trifluoromethylpyrazine was obtained in exactly the same manner except that the iron chloride in Example 3 was replaced with magnesium chloride. Yield: 71%

Example 5 FIG. Production of 2-hydroxy-3-trifluoromethylpyrazine-3
Iodine (0.9 g, 3.5 mmol) was added to a pyridine solution (40 ml) of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (4 g, 24.1 mmol) at 55 ° C. for 9 hours. Stir with heating for hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from n-hexane / ethyl acetate to give the title compound as a brown solid.
Yield: 3.6g
Yield; 89%

Example 6 Production of 2-hydroxy-3-trifluoromethylpyrazine-Part 4
To a pyridine solution (40 ml) of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (4 g, 24.1 mmol) was added 50% water content 5% (w / w) Pd / C (1 g). The mixture was vigorously heated and stirred at 60 ° C. for 24 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 4: 1) to obtain the title compound as a yellow solid. .
Yield: 3.7g
Yield: 93%

Example 7 Preparation of 2-hydroxy-3-trifluoromethylpyrazine-Part 5
A pyridine solution (40 ml) of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (4 g, 24.1 mmol) and activated carbon (1 g) was vigorously heated and stirred at 60 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 4: 1) to give the title compound as a yellow solid. Got.
Yield: 2.9g
Yield: 73%

Example 8. Preparation of 2-hydroxy-3-trifluoromethylpyrazine-Part 6
Pyridine solution of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (2.2 g, 13.2 mmol), activated carbon (0.55 g), calcium carbonate (0.3 g, 3.4 mmol) (22 ml) was vigorously heated and stirred at 60 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 4: 1) to give the title compound. Obtained as a yellow solid.
Yield: 1.9g
Yield: 86%

Example 9 Preparation of 2-hydroxy-3-trifluoromethylpyrazine-Part 7
4-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (2.2 g, 13.2 mmol), activated carbon (0.55 g), barium carbonate (0.67 g, 3.4 mmol) 4- The picoline solution (22 ml) was vigorously heated and stirred at 60 ° C. for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane / ethyl acetate = 4: 1) to give the title compound as a yellow solid. Got.
Yield: 1.8g
Yield: 81%

Example 10 Preparation of 2-chloro-3-trifluoromethylpyrazine-Part 1
2-hydroxy-3-trifluoromethylpyrazine (61.4 g, 374 mmol) was added to 90% purity 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, the aqueous layer was removed, the organic layer was washed with water, and then washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and suction filtered through a Buchner funnel with celite and silica gel. The 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%
Physical properties: ¹ H-NMR [DMSO-d ₆ / TMSδ value (ppm)]
8.62 (2H, d).

Example 11 Production of 2-chloro-3-trifluoromethylpyrazine-2
Dimethylformamide (0.3 ml, 4 mmol) was added to a thionyl chloride (1.5 ml, 20.5 mmol) solution of 2-hydroxy-3-trifluoromethylpyrazine (1.45 g, 10.3 mmol) for 2.5 hours. Heated to reflux. The reaction solution was poured into ice and extracted with 30 ml of methyl-t-butyl ether. The organic layer was washed successively with water, aqueous sodium bicarbonate, and saturated brine. As a result of quantitative analysis by gas chromatography, the obtained organic layer contained 0.77 g of 2-chloro-3-trifluoromethylpyrazine.
Yield: 48%

Example 12 Production of 2-chloro-3-trifluoromethylpyrazine-3
5% (w / w) Pd / C (3 g) was added to a pyridine solution (120 ml) of 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (12 g, 72 mmol) at 55 ° C. The mixture was heated and stirred for 16 hours. The filtrate obtained by filtration was concentrated under reduced pressure, 90% (w / w) phenylphosphonic dichloride (20 g, 0.102 mol) was added to the residue, and the mixture was stirred at 160 ° C. for 1.5 hours. After cooling to 50 ° C., t-butyl methyl ether was added and poured into ice water. The pH was adjusted to 7-8 with NaHCO ₃ , filtered through Celite, the filtrate was separated, and the organic layer was washed successively with water and saturated brine. It was dried over Na ₂ SO _4, the solvent was distilled off, and the residue was purified by distillation under reduced pressure (65 ° C./20 mmHg) to obtain the title compound as a colorless liquid.
Yield: 9.6 g
Yield; 73%

Comparative Example 1 Preparation of 2-hydroxy-3-trifluoromethylpyrazine 3-trifluoromethyl-5,6-dihydropyrazin-2 (1H) -one (0.6 g, 3.6 mmol) and m-chloroperbenzoic acid (70% The reaction was performed according to the method described in Non-Patent Document 2 using a purity of 0.89 g, 3.6 mmol), but tarring occurred and the target product could not be obtained.

Reference Example 1 Preparation of methyl 3-trifluoromethylpyrazine-2-carboxylate 66.5 g (366 mmol) 2-chloro-3-trifluoromethylpyrazine, 370 ml methanol, 40.7 g in a 2 L autoclave substituted with argon gas. (403 mmol) triethylamine, 1.16 g (2.7 mmol) 1,4-bis (diphenylphosphino) butane and 0.95 g (1.4 mmol) dichlorobis (triphenylphosphine) palladium (II). 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. After completion of the reaction, the temperature was returned to room temperature, the catalyst was removed, 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. The inorganic material was filtered and concentrated. The 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 (1H, d), 4.05 (3H, s)
Physical properties: ¹⁹ F-NMR [CDCl ₃ / TMSδ value (ppm)]
65.7 (s)

Reference Example 2 Preparation of 3-trifluoromethylpyrazine-2-carboxylic acid 700 mg (3.4 mmol) of methyl 3-trifluoromethylpyrazine-2-carboxylate was dissolved in ethanol-water (1: 1 (v / v), 10 ml). Then, 300 mg of potassium hydroxide was added and heated to reflux for 1 hour. After completion of the reaction, the reaction solution 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 the ethyl acetate layer was washed with saturated brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give 409 mg of the desired product as crystals.
Yield: 63%
Physical properties: melting point 130-134 ° C.

Reference Example 3. Preparation of N- {3-isobutyl-4- [2,2,2-trifluoro-1- (trifluoromethyl) ethyl] phenyl} -3-trifluoromethylpyrazine-2-carboxylic acid amide 3-trifluoromethyl 2-pyrazinecarboxylic acid 192 mg (1 mmol), 3-isobutyl-4- [2,2,2-trifluoro-1- (trifluoromethyl) ethyl] aniline 199 mg (1 mmol), 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. After completion of the reaction, the reaction solution 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 (v / v)) to paste 293 mg of the desired product as a paste. Got as.
Yield: 62%
Physical properties: n _D 1.4825 (27.7 ° C.)

Claims (10)

Formula (III)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). The dihydropyrazinone derivatives represented by halo are selected from the group consisting of halogens, metal halides, carbonates, activated carbon and palladium. Dehydrogenation in the presence of one or more additives and pyridine and in the absence of manganese dioxide and potassium hydroxide ,

(Wherein R ¹ is the same as defined above). The production method according to claim 1, wherein the additive is one or more selected from the group consisting of iodine, iron chloride, magnesium chloride, calcium carbonate, barium carbonate, activated carbon, and palladium carbon . Formula (III)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group), dihydropyrazinone derivatives represented by: The dihydropyrazinone derivatives according to claim 3, wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group. The dihydropyrazinone derivatives according to claim 3, wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group. The dihydropyrazinone derivatives according to claim 3, wherein R ¹ is a trifluoromethyl group. Formula (II)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). The hydroxypyrazine derivatives according to claim 7, wherein R ¹ is a halo (C ₁ -C ₃ ) alkyl group. The hydroxypyrazine derivatives according to claim 7, wherein R ¹ is a fluoro (C ₁ -C ₃ ) alkyl group. The hydroxypyrazine derivatives according to claim 7, wherein R ¹ is a trifluoromethyl group.