JP2009143850A - Method of preparing pyrazolinone derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of preparing a pyrazolinone derivative (1-[(2-propenylthio)carbonyl]-4-(2-methylphenyl)-5-amino-1H-pyrazole-3-one, for example). <P>SOLUTION: A pyrazolinone derivative is prepared by causing a pyrazolinone compound represented by formula (1) (3-amino-4-(2-methylphenyl)-pyrazoline-5-one, for example) to react with an acid halide represented by formula (2) (acrylchlorothioformate, for example) in the presence of an alkali in a mixed liquid of water and an organic solvent, subjecting the resulting reaction mixture to an oil/water separation treatment, neutralizing the separated water phase by adding an acid thereinto to cause the resulting pyrazolinone derivative to precipitate, and isolating the precipitate. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵はそれぞれ水素原子、ハロゲン原子又はハロゲン原子で置換されていてもよいメチル基を表す。Ｒ⁶は水素原子又は炭素数１〜５のアルキル基を表す。）
で示される化合物〔以下、ピラゾリノン化合物（１）ということがある。〕と、一般式（２）

（式中、Ｘは塩素原子又は臭素原子を表し、Ｙは酸素原子又は硫黄原子を表す。Ｒ⁷は炭素数１〜５のアルキル基、炭素数３〜５のアルケニル基又は炭素数３〜５のアルキニル基を表す。）
で示される化合物〔以下、酸ハロゲン化物（２）ということがある。〕を塩基存在下で反応させ、一般式（３）

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷及びＹはそれぞれ前記と同じ意味を表す。）
で示される化合物〔以下、ピラゾリノン誘導体（３）ということがある。〕を製造する方法に関する。ピラゾリノン誘導体（３）は、例えば、農薬の原料として有用である。 The present invention relates to a general formula (1)

^{(Wherein, R 1, R 2, R} 3, R 4 and R ⁵ are each a hydrogen atom, .R ⁶ is 1 hydrogen atom or a carbon atoms of a halogen atom or a halogen atom which may be substituted methyl group 5 represents an alkyl group.)
[Hereinafter, it may be called a pyrazolinone compound (1). ] And general formula (2)

(Wherein, X represents a chlorine atom or a bromine atom, Y is .R ⁷ is an alkyl group having 1 to 5 carbon atoms, 3-5 alkenyl group carbon atoms or 3 to 5 carbon atoms an oxygen atom or a sulfur atom Represents an alkynyl group of
[Hereinafter, referred to as acid halide (2). ] In the presence of a base to give a general formula (3)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Y have the same meanings as described above).
[Hereinafter, it may be referred to as a pyrazolinone derivative (3). ] About the method of manufacturing. The pyrazolinone derivative (3) is useful as a raw material for agricultural chemicals, for example.

As a method for producing the pyrazolinone derivative (3), for example, Japanese Patent Application Laid-Open No. 2000-226374 (Patent Document 1) discloses that a pyrazolinone compound (1) and an acid halide (2) are mixed in water and a hydrophobic organic solvent. The reaction is carried out in the presence of a base, and the resulting reaction mixture is subjected to acid treatment without oil-water separation and solvent extraction to produce a pyrazolinone derivative (3).

JP 2000-226374 A

In the above conventional method, the yield is not always satisfactory. In the reaction, in addition to the target pyrazolinone derivative (3), a urea compound having a structure in which two molecules of the pyrazolinone compound (1) are connected by a carbonyl group is produced as a by-product. It is easily taken into the precipitate of the derivative (3), the quality is lowered, and is not preferable for the post-process using the pyrazolinone derivative (3).

Therefore, an object of the present invention is to provide a method capable of producing the pyrazolinone derivative (3) with good quality by suppressing the incorporation of the above-mentioned by-product with good yield.

As a result of intensive studies, the present inventors reacted the pyrazolinone compound (1) and the acid halide (2) in a mixed solution of water and a hydrophobic organic solvent in the presence of a base, and obtained the reaction mixture. The oil-water separation is carried out, and by adding an acid to the aqueous layer and neutralizing it, the pyrazolinone derivative (3) is precipitated and separated, and it is found that the yield can be improved and the incorporation of the by-product can be suppressed. It came to be completed.

That is, in the present invention, the pyrazolinone compound (1) and the acid halide (2) are reacted in a mixed solution of water and a hydrophobic organic solvent in the presence of a base, and the resulting reaction mixture is separated into oil and water to form an aqueous layer. The present invention provides a method for producing a pyrazolinone derivative characterized by adding an acid to neutralize to precipitate and separate the pyrazolinone derivative (3).

According to the present invention, the pyrazolinone derivative (3) can be produced with good quality in good yield.

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵はそれぞれ水素原子、ハロゲン原子又はハロゲン原子で置換されていてもよいメチル基を表す。Ｒ⁶は水素原子又は炭素数１〜５のアルキル基を表す。）
において、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴及びＲ⁵の少なくとも１つがハロゲン原子又はハロゲン原子で置換されたメチル基である場合、このハロゲン原子は、フッ素原子、塩素原子、臭素原子又はヨウ素原子であることができる。また、ハロゲン原子で置換されたメチル基は、モノフルオロメチル基やモノクロロメチル基の如きモノハロメチル基であってもよいし、ジフルオロメチル基やジクロロメチル基の如きジハロメチル基であってもよいし、トリフルオロメチル基やトリクロロメチル基の如きトリハロメチル基であってもよい。Ｒ⁶が炭素数１〜５のアルキル基である場合、このアルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基等が挙げられる。 The present invention is described in detail below. General formula (1) showing the pyrazolinone compound (1)

^{(Wherein, R 1, R 2, R} 3, R 4 and R ⁵ are each a hydrogen atom, .R ⁶ is 1 hydrogen atom or a carbon atoms of a halogen atom or a halogen atom which may be substituted methyl group 5 represents an alkyl group.)
In this case, when at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is a halogen atom or a methyl group substituted by a halogen atom, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine Can be an atom. The methyl group substituted with a halogen atom may be a monohalomethyl group such as a monofluoromethyl group or a monochloromethyl group, a dihalomethyl group such as a difluoromethyl group or a dichloromethyl group, or a trihalomethyl group. It may be a trihalomethyl group such as a fluoromethyl group or a trichloromethyl group. When R ⁶ is an alkyl group having 1 to 5 carbon atoms, examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, Examples thereof include a tert-butyl group and an n-pentyl group.

（式中、Ｘは塩素原子又は臭素原子を表し、Ｙは酸素原子又は硫黄原子を表す。Ｒ⁷は炭素数１〜５のアルキル基、炭素数３〜５のアルケニル基又は炭素数３〜５のアルキニル基を表す。）
において、Ｒ⁷が炭素数１〜５のアルキル基である場合、このアルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基等が挙げられる。Ｒ⁷が炭素数３〜５のアルケニル基である場合、このアルケニル基としては、例えば、アリル基（２−プロペニル基）、メタリル基（２−メチル−２−プロペニル基）、クロチル基（２−ブテニル基）等が挙げられる。Ｒ⁷が炭素数３〜５のアルキニル基である場合、このアルキニル基としては、例えば、２−プロピニル基、２−ブチニル基又は３−ブチニル基等が挙げられる。 General formula (2) showing acid halide (2)

(Wherein, X represents a chlorine atom or a bromine atom, Y is .R ⁷ is an alkyl group having 1 to 5 carbon atoms, 3-5 alkenyl group carbon atoms or 3 to 5 carbon atoms an oxygen atom or a sulfur atom Represents an alkynyl group of
When R ⁷ is an alkyl group having 1 to 5 carbon atoms, examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and an isobutyl group. Group, tert-butyl group, n-pentyl group and the like. When R ⁷ is an alkenyl group having 3 to 5 carbon atoms, examples of the alkenyl group include an allyl group (2-propenyl group), a methallyl group (2-methyl-2-propenyl group), a crotyl group (2- Butenyl group) and the like. When R ⁷ is an alkynyl group having 3 to 5 carbon atoms, examples of the alkynyl group include a 2-propynyl group, a 2-butynyl group, and a 3-butynyl group.

The reaction between the pyrazolinone compound (1) and the acid halide (2) is carried out in the presence of a base. Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, sodium carbonate and potassium carbonate. Examples thereof include inorganic bases such as alkali metal carbonates, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and organic bases such as pyridine, 4- (dimethylamino) pyridine and triethylamine. When using the said inorganic base, it can also be used as aqueous solution. Preferably, an aqueous solution of an alkali metal hydroxide is used.

The usage-amount of the acid halide (2) used for reaction is 0.5-5 mol normally with respect to 1 mol of pyrazolinone compounds (1), Preferably it is 0.9-1.5 mol. The usage-amount of the base used for reaction is 1-5 mol normally with respect to 1 mol of pyrazolinone compounds (1), Preferably it is 1.5-2.5 mol.

In the reaction, the pyrazolinone compound (1) and the acid halide (2) are carried out in a mixture of water and an organic solvent in the presence of a base.

Examples of the hydrophobic organic solvent include aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene, aliphatic hydrocarbons such as n-hexane and n-heptane, and alicyclic rings such as cyclopentane and cyclohexane. And hydrocarbons such as formula hydrocarbons, ketones such as methyl ethyl ketone and methyl isobutyl ketone, ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and tetrahydropyran, and these can be used alone or in combination of two or more. .

Simultaneously with the hydrophobic organic solvent, a hydrophilic organic solvent such as alcohol such as methanol, ethanol and propanol can be used.

Water and the hydrophobic organic solvent may be added to the reactor in advance, or may be added in combination with the pyrazolinone compound (1) or the acid halide (2).

The total amount of the water, the hydrophobic organic solvent and the hydrophilic organic solvent is usually 1 to 20 parts by weight, preferably 1 to 10 parts by weight with respect to 1 part by weight of the pyrazolinone compound (1).

The reaction temperature is usually 0 to 100 ° C., preferably 10 to 50 ° C. In addition, the reaction is usually performed near normal pressure, but may be performed under pressure or under reduced pressure as necessary. As the reaction system, any of a continuous system, a semi-continuous system, and a batch system can be employed.

The pH during the reaction is usually 10 or more, and it is usually adjusted by adding a base or an acid such as hydrochloric acid.

The order of preparation is not particularly limited, and the acid halide (2) may be added to the mixture of the pyrazolinone compound (1) and the base, and the mixture of the pyrazolinone compound (1) and the base may be added to the acid halide (2). May be added.

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ⁷及びＹはそれぞれ前記と同じ意味を表す。）
で示されるピラゾリノン誘導体（３）を固体として析出させ、分離する。 After completion of the reaction, the reaction mixture is separated into oil and water, neutralized by adding an acid to the aqueous layer, and the target compound of the general formula (3)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Y have the same meanings as described above).
Is precipitated as a solid and separated.

Examples of the acid added to the aqueous layer include hydrogen chloride and sulfuric acid, and an aqueous solution thereof is preferably used. The usage-amount of an acid is 0.5-5 mol normally with respect to 1 mol of pyrazolinone compounds (1), Preferably it is 0.7-1.5 mol. The pH of the aqueous layer after addition of the acid is preferably 5 or more from the aspect of quality and operation, and the pH of the aqueous layer after addition of the acid is sufficient to precipitate the pyrazolinone derivative (3) sufficiently. It is preferably 9 or less. The pH can be adjusted by adjusting the amount of acid used.

Moreover, it is preferable that the aqueous layer before adding an acid is a state in which the pyrazolinone derivative (3) is dissolved.

The time for adding the acid to the aqueous layer is 3 hours or more in order to suppress the incorporation of the by-product into the precipitated pyrazolinone derivative (3). On the other hand, the upper limit is not particularly limited, but is usually 20 hours or less from the viewpoint of productivity.

After adding an acid to precipitate the pyrazolinone derivative (3), the aqueous layer containing the precipitate is separated from the pyrazolinone derivative (3) by a known separation means such as filtration. By washing the separated precipitate with water or an organic solvent, the target pyrazolinone derivative (3) can be obtained as a solid.

Thus, the pyrazolinone derivative (3) can be obtained with good quality, in good yield, with reduced uptake of the by-product. Furthermore, it can be purified by means such as recrystallization or column chromatography, if necessary.

Examples of the present invention will be described below, but the present invention is not limited thereto.

Example 1
A glass reactor equipped with a reflux condenser, a thermometer, a stirrer, and a dropping funnel was charged with 3-amino-4- (2-methylphenyl) -pyrazolin-5-one [in the general formula (1), R ¹ represents methyl Group, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen atoms] 45.00 g (0.238 mol), methanol 45.00 g, water 16.16 g, xylene 45.00 g and 25% Sodium hydroxide aqueous solution 39.96g was put and stirred. 10% hydrochloric acid is added to this aqueous solution to adjust the pH to about 12.0, and at 15 ° C. allyl chlorothioformate [in the general formula (2), X is a chlorine atom, Y is a sulfur atom, R ⁷ is an allyl group. A mixed solution of 34.44 g (0.252 mol) and xylene 29.52 g was added dropwise over 2 hours, and after completion of the addition, the mixture was further stirred at the same temperature for 2 hours. During the dropwise addition of allyl chlorothioformate and subsequent warming, a 10% sodium hydroxide solution was added together to maintain the pH in the reaction system at about 10.7. Thereafter, the reaction mixture was allowed to stand for 30 minutes to separate oil and water, and 82.34 g of 10% hydrochloric acid was added dropwise to the aqueous layer at 25 ° C. over 3 hours to give 1-[(2-propenylthio) carbonyl] -4- (2-Methylphenyl) -5-amino-1H-pyrazol-3-one [in the general formula (3), R ¹ is a methyl group, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen] A compound in which an atom, Y is a sulfur atom, and R ⁷ is an allyl group] was deposited. The pH at this time was 6.5. The aqueous layer containing this precipitate was filtered. The filtered product was washed with n-hexane and then with methanolic water to give 1-[(2-propenylthio) carbonyl] -4- (2-methylphenyl) -5-amino-1H-pyrazol-3-one. Obtained .61 g. This was analyzed by high performance liquid chromatography, the purity was calculated by an absolute calibration curve method, and the yield relative to the starting material 3-amino-4- (2-methylphenyl) -pyrazolin-5-one was determined. As a result, the purity was 95.9% and the yield was 85.2%. Moreover, when the content of the urea compound as a by-product was calculated by the area percentage method, the content was 1.1%.

Comparative Example 1
In the same reactor as in Example 1, 15.00 g (0.079 mol) of 3-amino-4- (2-methylphenyl) -pyrazolin-5-one, 15.00 g of methanol, 7.49 g of water, xylene 15 0.000 g and 25% aqueous sodium hydroxide solution 13.32 g were added and stirred. 10% hydrochloric acid was added to this aqueous solution to adjust the pH to 12.0, and at 15 ° C. allyl chlorothioformate [in general formula (2), X is a chlorine atom, Y is a sulfur atom, R ⁷ is an allyl group. A certain compound] A mixed solution of 10.61 g (0.078 mol) and 9.10 g of xylene was added dropwise over 2 hours. After completion of the addition, the mixture was further stirred at the same temperature for 2 hours. During the dropwise addition of allyl chlorothioformate and subsequent warming, a 10% sodium hydroxide solution was added together to maintain the pH in the reaction system at about 10.7. Thereafter, 28.57 g of 10% hydrochloric acid was added dropwise to the reaction mixture at 0.5 ° C. over 0.5 hour, and 1-[(2-propenylthio) carbonyl] -4- (2-methylphenyl) -5-amino- 1H-pyrazol-3-one was precipitated. The pH at this time was 6.5. To this was added 30.00 g of n-hexane, and the mixture was stirred for 1 hour and filtered. The filtered product was washed with n-hexane and then with aqueous methanol, and 1-[(2-propenylthio) carbonyl] -4- (2-methylphenyl) -5-amino-1H-pyrazol-3-one was converted to 19 .28 g was obtained. When analyzed in the same manner as in Example 1, the purity was 95.3% and the yield was 85.9%. The urea compound content was 1.8%.

Claims (3)

General formula (1)

^{(Wherein, R 1, R 2, R} 3, R 4 and R ⁵ are each a hydrogen atom, .R ⁶ is 1 hydrogen atom or a carbon atoms of a halogen atom or a halogen atom which may be substituted methyl group And a pyrazolinone compound represented by the general formula (2):

(In the formula, X represents a chlorine atom or a bromine atom, Y represents an oxygen atom or a sulfur atom. R ⁷ represents an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or 3 to 5 carbon atoms. In the presence of a base in a mixed solution of water and a hydrophobic organic solvent, the resulting reaction mixture is separated into oil and water, and an acid is added to the aqueous layer. General formula (3) by neutralization

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Y each have the same meaning as described above) are precipitated and separated. And a method for producing a pyrazolinone derivative. The production method according to claim 1, wherein the hydrophobic organic solvent is toluene and / or xylene. The pyrazolinone compound represented by the general formula (1) is 3-amino-4- (2-methylphenyl) -pyrazolin-5-one, and the acid halide represented by the general formula (2) is allyl chlorothioformate, The product pyrazolinone derivative represented by the general formula (3) is 1-[(2-propenylthio) carbonyl] -4- (2-methylphenyl) -5-amino-1H-pyrazol-3-one The manufacturing method of Claim 1 characterized by these.