JP2009242244A - Method for producing pyrazine derivative and intermediate of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing a pyrazine derivative useful as a synthetic intermediate of a medicine, agrochemical or the like. <P>SOLUTION: This method for producing the pyrazine derivatives is characterized by reacting amino acid ester derivatives or their acid salts with ammonia to produce α-amino-α-haloalkylamide derivatives, reacting the above with a glyoxate to produce pyrazinol derivatives and then halogenating it. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing 3-haloalkyl-2-halogenopyrazine derivatives useful as intermediates for pharmaceuticals and 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 and the like, in particular, an agricultural and horticultural acaricide (see, for example, Patent Document 1) and a fungicide (see, for example, Patent Document 2). It is useful as an intermediate. 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. (See, for example, Non-Patent Document 3).
JP 2006-008675 A International Publication No. 2007/072999 Pamphlet J. et al. Heterocyclic Chem. , 34 (2), 551-556 (1997)

  In the method of Non-Patent Document 3, it is necessary to introduce an iodine atom at an appropriate position of the heterocyclic ring in advance, an expensive 2-chloro-2,2-difluoroacetic acid methyl ester is used, The above copper iodide is necessary, its removal is difficult, and the reaction temperature is high, so that it is not necessarily an industrially advantageous synthesis method. An object of the present invention is to provide a novel method for producing 3-haloalkyl-2-halogenopyrazine derivatives useful as intermediates for pharmaceuticals and agricultural chemicals.

  As a result of intensive studies to solve the above problems, the present inventors have obtained novel α-amino-α-haloalkylamide derivatives using readily available α-amino-α-haloalkylcarboxylic acid ester derivatives. Then, cyclization with glyoxal leads to novel pyrazinol derivatives, and further industrially useful 3-haloalkyl-2-halogenopyrazine derivatives can be produced efficiently by halogenating the hydroxyl group. The headline and the present invention have been completed.

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示し、Ｒ^２は（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるアミノ酸エステル誘導体類又はその酸塩とアンモニアとを反応させることにより、一般式（III）

（式中、Ｒ^１は前記に同じ。）で表されるα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩を製造し、該アミド誘導体類（III）又はその酸塩を塩基又はその酸塩の存在下、グリオキサールと反応させることにより、一般式（II）

（式中、Ｒ^１は前記に同じ。）で表されるピラジノール誘導体類を製造し、該ピラジノール誘導体類をハロゲン化することを特徴とする一般式（I）

（式中、Ｒ^１は前記に同じくし、Ｙはハロゲン原子を示す。）
で表されるピラジン誘導体類の製造方法、
（２）Ｒ^１がフルオロ（Ｃ_１−Ｃ_６）アルキル基である前記（１）に記載のピラジン誘導体類の製造方法、
（３）Ｒ^１がパーフルオロ（Ｃ_１−Ｃ_６）アルキル基である前記（１）に記載のピラジン誘導体類の製造方法、
（４）Ｒ^１がパーフルオロ（Ｃ_１−Ｃ_３）アルキル基である前記（１）に記載のピラジン誘導体類の製造方法、
（５）Ｒ^１がトリフルオロメチル基である前記（１）に記載のピラジン誘導体類の製造方法、
（６）一般式（III）

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩、
（７）Ｒ^１がフルオロ（Ｃ_１−Ｃ_６）アルキル基である前記（６）に記載のα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩、
（８）Ｒ^１がパーフルオロ（Ｃ_１−Ｃ_６）アルキル基である前記（６）に記載のα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩、
（９）Ｒ^１がパーフルオロ（Ｃ_１−Ｃ_３）アルキル基である前記（６）に記載のα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩、
（１０）Ｒ^１がトリフルオロメチル基である前記（６）に記載のα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩、
（１１）一般式（II）

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるピラジノール誘導体類、
（１２）Ｒ^１がフルオロ（Ｃ_１−Ｃ_６）アルキル基である前記（１１）に記載のピラジノール誘導体類、
（１３）Ｒ^１がパーフルオロ（Ｃ_１−Ｃ_６）アルキル基である前記（１１）に記載のピラジノール誘導体類、
（１４）Ｒ^１がパーフルオロ（Ｃ_１−Ｃ_３）アルキル基である前記（１１）に記載のピラジノール誘導体類、および
（１５）Ｒ^１がトリフルオロメチル基である前記（１１）に記載のピラジノール誘導体類、
に関する。 That is, the present invention provides (1) the 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), or an amino acid ester derivative thereof or an acid salt thereof and ammonia By reacting with general formula (III)

(In the formula, R ¹ is the same as defined above) α-amino-α-haloalkylamide derivatives represented by the following formulas or acid salts thereof are produced, and the amide derivatives (III) or acid salts thereof are converted into bases or acids thereof. By reacting with glyoxal in the presence of a salt, general formula (II)

(Wherein R ¹ is the same as defined above) and a pyrazinol derivative represented by the general formula (I), wherein the pyrazinol derivative is halogenated.

(Wherein R ¹ is the same as above, and Y is a halogen atom.)
A process for producing pyrazine derivatives represented by:
(2) The method for producing a pyrazine derivative according to (1), wherein R ¹ is a fluoro (C ₁ -C ₆ ) alkyl group,
(3) The method for producing a pyrazine derivative according to (1), wherein R ¹ is a perfluoro (C ₁ -C ₆ ) alkyl group,
(4) The method for producing a pyrazine derivative according to (1), wherein R ¹ is a perfluoro (C ₁ -C ₃ ) alkyl group,
(5) The method for producing a pyrazine derivative according to (1), wherein R ¹ is a trifluoromethyl group,
(6) General formula (III)

(In the formula, R ¹ represents a halo (C ₁ -C ₆ ) alkyl group.) Α-amino-α-haloalkylamide derivatives represented by the following:
(7) The α-amino-α-haloalkylamide derivative or the acid salt thereof according to (6), wherein R ¹ is a fluoro (C ₁ -C ₆ ) alkyl group,
(8) α-amino-α-haloalkylamide derivatives or acid salts thereof according to (6) above, wherein R ¹ is a perfluoro (C ₁ -C ₆ ) alkyl group,
(9) α-amino-α-haloalkylamide derivatives or acid salts thereof according to the above (6), wherein R ¹ is a perfluoro (C ₁ -C ₃ ) alkyl group,
(10) α-amino-α-haloalkylamide derivatives or acid salts thereof according to (6), wherein R ¹ is a trifluoromethyl group,
(11) General formula (II)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group), pyrazinol derivatives represented by:
(12) The pyrazinol derivatives according to (11), wherein R ¹ is a fluoro (C ₁ -C ₆ ) alkyl group,
(13) The pyrazinol derivatives according to (11), wherein R ¹ is a perfluoro (C ₁ -C ₆ ) alkyl group,
(14) The pyrazinol derivatives according to the above (11), wherein R ¹ is a perfluoro (C ₁ -C ₃ ) alkyl group, and (15) the above described (11), wherein R ¹ is a trifluoromethyl group. Pyrazinol derivatives,
About.

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

Each substituent described in this specification will be described.
“Halogen atom” and “halogeno” represent 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 group having 1 to 6 carbon atoms. A branched alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, etc. A “halo (C ₁ -C ₆ ) alkyl group” which may be the same or different and represents a linear or branched alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms. The “perfluoro (C ₁ -C ₆ ) alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms in which all hydrogen atoms are substituted with fluorine atoms.
Examples of the acid in the acid salt include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and the like. And sulfonic acids.

（式中、Ｒ^１、Ｒ^２及びＹは前記に同じ。）
即ち、一般式（IV）で表されるアミノ酸エステル誘導体類又はその酸塩とアンモニアとを反応させ、一般式（III）で表されるα−アミノ−α−ハロアルキルアミド誘導体類又はその酸塩とし、該α−アミノ−α−ハロアルキルアミド誘導体類（III)又はその酸塩を単離又は単離することなく塩基又はその酸塩存在下、グリオキサールと反応させ、一般式（II）で表されるピラジノール誘導体類とし、該ピラジノール誘導体類（II)を単離又は単離することなく、ハロゲン化剤でハロゲン化することにより一般式（I）で表されるピラジン誘導体類を製造することができる。 The present invention is illustrated as follows.

(Wherein R ¹ , R ² and Y are the same as above)
That is, an amino acid ester derivative represented by the general formula (IV) or an acid salt thereof is reacted with ammonia to form an α-amino-α-haloalkylamide derivative represented by the general formula (III) or an acid salt thereof. The α-amino-α-haloalkylamide derivative (III) or its acid salt is reacted with glyoxal in the presence of a base or its acid salt without isolation or isolation, and is represented by the general formula (II) Pyrazine derivatives represented by the general formula (I) can be produced by converting to pyrazinol derivatives and halogenating with a halogenating agent without isolating or isolating the pyrazinol derivatives (II).

General formula (IV) → General formula (III)
An amino acid ester derivative represented by the general formula (IV) or an acid salt thereof is reacted with ammonia in an inert solvent to produce an α-amino-α-haloalkylamide derivative represented by the general formula (III) or a derivative thereof. Acid salts can be produced. In this reaction, ammonia can be used in excess of the amino acid ester derivative represented by the general formula (IV) or its acid salt, and the amino acid ester derivative represented by the general formula (IV) or its acid salt The range is 2 to 100 times mol, preferably 2 to 10 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 carbonization such as benzene, toluene, and xylene. Hydrogen, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc., linear or cyclic ethers such as diethyl ether, t-butyl methyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, acetic acid Esters such as butyl, chain or cyclic ketones such as acetone, methyl isobutyl ketone and cyclohexanone, alcohols such as methanol, ethanol, n-propanol and i-propanol, amides such as dimethylformamide and dimethylacetamide , Nitriles such as acetonitrile, or inert solvents such as 1,3-dimethyl-2-imidazolidinone, and these solvents may be used alone or in admixture of two or more inert solvents. it can.
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 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. 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.
After completion of the reaction, it may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by 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)
It can be produced by reacting an α-amino-α-haloalkylamide derivative represented by the general formula (III) or an acid salt thereof with glyoxal in an inert solvent in the presence of a base or an acid salt thereof. 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, inert solvent such as dimethyl sulfoxide and water can show, these inert solvents may be mixed and used alone or in combination.

Examples of the base include organic bases such as monoethylamine, diethylamine, triethylamine, tributylamine, pyrrolidine, piperidine, morpholine, pyridine, 4-dimethylaminopyridine, and hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide. Examples include alkali metals, carbonates such as sodium bicarbonate and potassium carbonate, phosphates such as potassium monohydrogen phosphate and trisodium phosphate, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide. . Examples of base acid salts include diethylamine hydrochloride, pyrrolidine hydrochloride, organic base acid salts such as pyridine sulfate, and ammonium salts such as ammonium acetate. Of these, diethylamine, lithium hydroxide, pyrrolidine hydrochloride and the like are preferably selected. These bases or acid salts thereof can be appropriately selected within a range of 0.01 to 5 times molar equivalent to the amino acid ester derivatives represented by the general formula (IV) or acid salts thereof, preferably It is the range of 1 to 1.2 times mole.
The reaction temperature may be appropriately selected within the range of −30 ° C. to the reflux temperature of the inert solvent used, but 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. 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.
After completion of the reaction, it may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification 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 pyrazinol 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 carried out 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. It is selected in the range of 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 show 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 and the like. These halogenating agents can be appropriately selected in the range of 1 to 20 times molar equivalent to the pyrazine derivatives represented by the general formula (II), but preferably in the range of 1 to 3 times mol. .
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 the reaction may be performed in an inert gas atmosphere such as nitrogen gas or argon gas.

The compound of the present invention produced in each step can be obtained from the reaction solution by a conventional method. However, when it is necessary to purify the compound, any of distillation, suspension washing, recrystallization, column chromatography, etc. It can be separated and purified by the purification method. 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-ylcarboxylate derivatives by, for example, the method shown in Reference Examples, and further amidated. By doing so, useful compounds such as agricultural and horticultural acaricides (Patent Document 1) and fungicides (Patent Document 2) can be produced.

（式中、Ｒ^１はハロ（Ｃ_１−Ｃ_６）アルキル基を示し、Ｒ^２は（Ｃ_１−Ｃ_６）アルキル基を示す。）で表されるα-ケトカルボン酸エステル誘導体類と式（VII）

で表されるヒドロキシルアミン又はその酸塩とを反応させ、一般式（Ｖ）

（式中、Ｒ^１及びＲ^２は前記に同じくし、波線はヒドロキシル基がＲ^１に関して（Ｅ）または（Ｚ）の位置にあることを示す。）で表されるα−ヒドロキシイミノカルボン酸エステル誘導体類とし、該α−ヒドロキシイミノカルボン酸エステル誘導体類（Ｖ）を還元することを特徴とする一般式（IV）

（式中、Ｒ^１及びＲ^２は前記に同じ。）で表されるα−アミノ酸エステル誘導体類又はその酸塩の製造方法によって工業的有利に製造されうる。 The compound represented by the general formula (IV) or an acid salt thereof is
General formula (VI)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group and R ² represents a (C ₁ -C ₆ ) alkyl group) and α-ketocarboxylic acid ester derivatives represented by the formula ( VII)

Is reacted with a hydroxylamine represented by the general formula (V)

(Wherein R ¹ and R ² are the same as described above, and the wavy line indicates that the hydroxyl group is at the position (E) or (Z) with respect to R ¹ ). Derivatives, wherein the α-hydroxyiminocarboxylic acid ester derivative (V) is reduced.

(Wherein, R ¹ and R ² are the same as above) and can be produced industrially advantageously by a method for producing α-amino acid ester derivatives represented by the formula:

  According to this production method, an α-amino acid ester derivative (IV) or a salt thereof can be efficiently produced using an industrially inexpensive reagent, without discharging unnecessary benzyl alcohol and carbon dioxide, which have been conventionally produced. Can be manufactured economically and economically.

Each substituent described in the above description of the method for producing α-amino acid ester derivatives (IV) or salts thereof will be described.
“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 having 1 to 6 carbon atoms. A group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl and the like; The term “(C ₁ -C ₆ ) alkyl group” may be the same or different, and represents a linear or branched alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms, “Fluoro (C ₁ -C ₆ ) alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms in which all hydrogen atoms are substituted with fluorine atoms.
Examples of the acid in the acid salt include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and the like. And sulfonic acids.

（式中、Ｒ^１、Ｒ^２及び波線は前記に同じ。）
即ち、一般式（VI）で表されるα−ケトカルボン酸エステル誘導体類と式（VII）で表されるヒドロキシルアミン又はその酸塩とを反応させ、一般式（Ｖ）で表されるα−ヒドロキシイミノカルボン酸エステル誘導体類とし、該α−ヒドロキシイミノカルボン酸エステル誘導体類を単離又は単離することなくヒドロキシイミノ部分を還元することにより一般式（IV）で表されるα−アミノ酸エステル誘導体類又はその酸塩を製造することができる。 This manufacturing method is illustrated as follows.

(In the formula, R ¹ , R ² and the wavy line are the same as above.)
That is, the α-ketocarboxylic acid ester derivative represented by the general formula (VI) is reacted with the hydroxylamine represented by the formula (VII) or an acid salt thereof, and the α-hydroxy represented by the general formula (V). Α-amino acid ester derivatives represented by the general formula (IV) by reducing the hydroxyimino moiety without isolating or isolating the α-hydroxyiminocarboxylic acid ester derivatives as iminocarboxylic acid ester derivatives Alternatively, the acid salt thereof can be produced.

General formula (VI) → General formula (V)
A hydroxylamine derivative represented by the general formula (VII) and an α-ketocarboxylic acid ester derivative represented by the general formula (VI) are added in an inert solvent, if necessary, by adding a base or an acid, Α-Hydroxyiminocarboxylic acid ester derivatives represented by the general formula (V) can be produced. Since this reaction is an equimolar reaction, the hydroxylamine of the formula (VII) or its acid salt and the α-ketocarboxylic acid ester derivative represented by the general formula (VI) may be used in an equimolar amount. The agent can be used in excess, and preferably the hydroxylamine derivative represented by the general formula (VII) or its acid salt is used in excess, and the amount used is represented by the general formula (VI). The amount is in the range of 1 to 5 times mol, preferably in the range of 1 to 1.2 times mol, relative to the α-ketocarboxylic acid ester derivative. 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 carbonization such as benzene, toluene, and xylene. Hydrogens, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chain or cyclic ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, esters such as ethyl acetate, butyl acetate, Ketones such as acetone, methyl isobutyl ketone and cyclohexanone; alcohols such as methanol, ethanol, n-propanol and i-propanol; amides such as dimethylformamide and dimethylacetamide; nitriles such as acetonitrile; - can show inert solvent or water, such as dimethyl-2-imidazolidinone, these inert solvents may be used alone or as a mixture of two or more solvents.

  In this reaction, when an acid salt of hydroxylamine is used, a base can be used for the purpose of neutralizing the acid. Examples of the base to be used include organic bases such as triethylamine, tributylamine, pyridine and 4-dimethylaminopyridine, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium hydrogen carbonate and potassium carbonate. Examples thereof include salts, phosphates such as potassium monohydrogen phosphate and trisodium phosphate, organic acid salts such as sodium acetate and potassium acetate, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and the like. These bases can be appropriately selected in the range of 0.01 to 5 times the molar equivalent to the hydroxylamine represented by the formula (VII) or its acid salt, preferably 1 to 1.2 times the mole. Range.

Also, a catalytic amount of acid can be used for the purpose of accelerating the reaction as is known in normal oximation. Examples of the acid to be used include organic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid. Can be shown. These acids can be appropriately selected in the range of 0.01 to 1 molar equivalent with respect to the α-ketocarboxylic acid ester derivatives represented by the general formula (VI), and preferably 0.02 to 0.00. The range is 3 moles.
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 50 to 150 ° 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. After completion of the reaction, it may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography or the like, if necessary. It can also be used in the next reaction without isolation.

General formula (V) → General formula (IV)
A compound represented by the general formula (IV) can be produced from the α-hydroxyiminocarboxylic acid ester derivatives represented by the general formula (V) under the reduction reaction conditions. As the reduction reaction conditions, the reduction reaction conditions for oxime compounds described in publicly known literature (edited by Chemical Society of Japan, “New Experimental Chemistry Course”, Vol. 15, p.16-17, 1977, Maruzen Co., Ltd.). However, it is necessary to select reduction reaction conditions that do not affect the ester functional group present in the molecule of the α-hydroxyiminocarboxylic acid ester derivatives represented by the general formula (V), and catalytic reduction. Reaction conditions are preferred. The catalytic reduction reaction can be performed in a hydrogen atmosphere in the presence of a catalyst, under normal pressure or under pressure. Examples of the catalytic reduction catalyst include palladium catalysts such as palladium-carbon and palladium hydroxide-carbon, nickel catalysts such as Raney nickel, cobalt catalysts, platinum catalysts, ruthenium catalysts, and rhodium catalysts. The reaction temperature may be appropriately selected within the range of −20 ° C. to the reflux temperature of the solvent used, but is preferably selected from the range of 20 to 50 ° C. The reaction time may be appropriately selected within the range of several minutes to 100 hours.

The reaction pressure may be appropriately selected from the range of 1 atm to 100 atm, but is preferably selected from the range of 1 atm to 10 atm. 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, 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 isobutyl ketone, cyclohexanone Ketones such as ethyl acetate, esters such as ethyl acetate and butyl acetate, alcohols such as methanol, ethanol, n-propanol and i-propanol, 1,3-dimethyl-2-imidazolidinone, sulfolane, dimethylsulfoxy Can exhibit an inert solvent such as water, these inert solvents may be mixed and used alone or in combination.
When reducing reaction conditions other than the catalytic reduction reaction are used, 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.

  Compound (IV) or a salt thereof produced in each step can be isolated from the reaction solution by a conventional method. However, when it is necessary to purify the compound, distillation, suspension washing, recrystallization, It can be separated and purified by any purification method such as column chromatography. Moreover, it can also be separated and purified to an acid salt using an inorganic acid such as hydrochloric acid.

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

Example 1. Preparation of 3,3,3-trifluoro-alaninamide 410 ml (2.8 mol) of 7N ammonia / methanol solution was cooled to 5 ° C. 110 g (530 mmol) of trifluoroalanine ethyl ester hydrochloride was added to the solution so that the internal temperature was kept at 8 to 10 ° C., and the resulting suspension was reacted at room temperature for 24 hours. After completion of the reaction, ammonia and methanol were distilled off under reduced pressure. The residue was suspended in 200 ml of ethyl acetate, and the insoluble material was filtered off. The unwanted matter was again suspended in 100 ml of ethyl acetate, and the insoluble matter was filtered off. The obtained filtrates were combined and concentrated to obtain 70.1 g of 3,3,3-trifluoroalaninamide as a yellow solid.
Yield: 94%
Physical properties: ¹ H-NMR [DMSO-d ₆ / TMSδ value (ppm)]
7.70 (1H, brs), 7.46 (1H, brs), 3.86 (1H, q), 2.25 (2H, brs)

Example 2 Preparation of 2-hydroxy-3-trifluoromethylpyrazine 6.0 ml (53 mmol) of an 8.8M-glyoxal aqueous solution was cooled to 0 ° C. A 30 ml methanol solution of 4.96 g (35.2 mmol) of 3,3,3-trifluoroalaninamide was added dropwise so that the reaction solution temperature was kept at 4 to 6 ° C. After 10 minutes under ice cooling, 70 ml of methanol was further added for dilution. 1.48 g (35.2 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred for 15 hours while gradually warming to room temperature. The reaction solution was concentrated to pH 4 by adding 1.5 ml of concentrated hydrochloric acid, further concentrated by adding ethanol, and further concentrated by adding toluene to obtain a brown oil. To this, 50 ml of ethyl acetate and 3 g of celite were added, and suction filtration was performed through 25 g of silica gel. The residue was thoroughly washed with ethyl acetate, and the filtrates were combined and concentrated to obtain 4.14 g of the desired product as a yellow solid.
Yield: 72%
Physical property: ¹ H-NMR [CDCl 3 / TMSδ value (ppm)]
7.67 (1H, d), 7.58 (1 H, d).

Example 3 FIG. Preparation of 2-chloro-3-trifluoromethylpyrazine 61.4 g (374 mmol) of 2-hydroxy-3-trifluoromethylpyrazine was added to 145 g (699 mmol) of 90% phenylphosphonic dichloride and an oil bath at 155 ° C. Stir above 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 containing 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 residue was washed with 900 ml methyl-t-butyl 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 54 g (297 mmol) of 2-chloro-3-trifluoromethylpyrazine and 14 g of methyl-t-butyl ether.
Yield: 80%
Physical properties: ¹ H-NMR [DMSO-d ₆ / TMSδ value (ppm)]
8.62 (2H, d).

Reference Example 1 Preparation of ethyl 3,3,3-trifluoro-2-hydroxyiminopropionate A mixture of 44.1 g (635 mmol) hydroxylamine hydrochloride, 60 ml water, 300 ml toluene and 54.6 g (665 mmol) sodium acetate Was cooled to 5 ° C. 102.95 g (605 mmol) of ethyl trifluoropyruvate was added dropwise to the solution so that the internal temperature was kept at 8 to 10 ° C.
A Dean-Stark was attached, and water was distilled off by heating under reflux for 1 hour. To the reaction mixture, 5.17 g (27 mmol) of p-toluenesulfonic acid monohydrate was added, and water was further distilled off by heating under reflux for 4 hours. After completion of the reaction, the reaction solution was poured into 100 ml of water, the target product was extracted with 200 ml of ethyl acetate, the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 180 g of a yellow oil. This oily substance was determined by gas chromatography and consisted of 104 g (564 mmol) of the desired product (E-form: Z-form = 9: 1), 38 g of toluene and 38 of ethyl acetate, and can be used as it is for the next reaction. (Yield 93%).
Physical property: ¹ H-NMR [CDCl 3 / TMSδ value (ppm)]
E-form; 12.64 (1H, brs), 4.45 (2H, q), 1.40 (3H, t),
Z form; 10.56 (1H, brs), 4.37 (2H, q) 1.37 (3H, t)

Reference Example 2. Preparation of 3,3,3-trifluoroalanine ethyl ester hydrochloride 104 g (564 mmol) ethyl 3,3,3-trifluoro-2-hydroxyiminopropionate and 2.20 g 10% palladium on carbon Powder (containing 50% water) and 300 ml of ethanol were placed in a reaction vessel, and hydrogenated at 4 kgf / cm ² at room temperature for 24 hours. After the theoretical amount of hydrogen was absorbed, the catalyst was removed from the reaction solution by filtration, and the filtrate was ice-cooled. 200 ml of a 3.3 mol / L-hydrogen chloride / ethanol solution was added dropwise to the solution. Ethanol was distilled off, toluene was further added and distilled off twice to obtain 110 g (530 mmol) of 3,3,3-trifluoroalanine ethyl ester hydrochloride as a colorless powder (yield 94%). .
Physical properties: ¹ H-NMR [DMSO-d ₆ / TMSδ value (ppm)]
5.42 (1H, q), 4.33 (2H, m), 1.26 (3H, t)

Reference Example 3. 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. 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 properties: boiling point 74-75 ° C./2.5-2.8 mmHg)

Reference Example 4 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, 10 ml) to prepare potassium hydroxide. 300 mg was added and 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. 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 5 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. 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 293 mg of the desired product as a paste.
Yield: 62%
Physical properties: n _D 1.4825 (27.7 ° C.)

Reference Example 6 Preparation of N- (3 ′, 4′-difluorobiphenyl-2-yl) -3-trifluoromethylpyrazine-2-carboxamide 10.1 g (49 mmol) of 3 ′, 4′-difluorobiphenyl-2-ylamine A mixture of 10 ml N, N-dimethylacetamide and 30 ml 28% sodium methoxide in methanol was cooled in a water bath. 11.0 g (53.4 mmol) of methyl 3-trifluoromethylpyrazine-2-carboxylate was added dropwise to the solution so that the internal temperature was kept at 25 ° C. or lower, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into a mixture consisting of 150 ml of 1N hydrochloric acid and 100 g of ice and extracted with 300 ml of t-butyl-methyl ether. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 16.5 g (43 mmol) of the desired product.
Yield: 89%
Physical property: Melting point 119-121 ° C

Claims (15)

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), or an amino acid ester derivative thereof or an acid salt thereof and ammonia By reacting with general formula (III)

(In the formula, R ¹ is the same as defined above) α-amino-α-haloalkylamide derivatives represented by the following formulas or acid salts thereof are produced, and the amide derivatives (III) or acid salts thereof are converted into bases or acids thereof. By reacting with glyoxal in the presence of a salt, general formula (II)

(Wherein R ¹ is the same as defined above) and a pyrazinol derivative represented by the general formula (I), wherein the pyrazinol derivative is halogenated.

(Wherein R ¹ is the same as above, and Y is a halogen atom.)
The manufacturing method of pyrazine derivatives represented by these. The method for producing pyrazine derivatives according to claim 1, wherein R ¹ is a fluoro (C ₁ -C ₆ ) alkyl group. The method for producing pyrazine derivatives according to claim 1, wherein R ¹ is a perfluoro (C ₁ -C ₆ ) alkyl group. The method for producing pyrazine derivatives according to claim 1, wherein R ¹ is a perfluoro (C ₁ -C ₃ ) alkyl group. The method for producing pyrazine derivatives according to claim 1, wherein R ¹ is a trifluoromethyl group. General formula (III)

(In the formula, R ¹ represents a halo (C ₁ -C ₆ ) alkyl group.) Α-amino-α-haloalkylamide derivatives represented by the above or acid salts thereof. The α-amino-α-haloalkylamide derivatives or acid salts thereof according to claim 6, wherein R ¹ is a fluoro (C ₁ -C ₆ ) alkyl group. The α-amino-α-haloalkylamide derivatives or acid salts thereof according to claim 6, wherein R ¹ is a perfluoro (C ₁ -C ₆ ) alkyl group. The α-amino-α-haloalkylamide derivative or the acid salt thereof according to claim 6, wherein R ¹ is a perfluoro (C ₁ -C ₃ ) alkyl group. The α-amino-α-haloalkylamide derivatives or acid salts thereof according to claim 6, wherein R ¹ is a trifluoromethyl group. Formula (II)

(Wherein R ¹ represents a halo (C ₁ -C ₆ ) alkyl group). The pyrazinol derivatives according to claim 11, wherein R ¹ is a fluoro (C ₁ -C ₆ ) alkyl group. The pyrazinol derivatives according to claim 11, wherein R ¹ is a perfluoro (C ₁ -C ₆ ) alkyl group. The pyrazinol derivatives according to claim 11, wherein R ¹ is a perfluoro (C ₁ -C ₃ ) alkyl group. The pyrazinol derivatives according to claim 11, wherein R ¹ is a trifluoromethyl group.