JP3076675B2 - Method for producing pyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a pyridine derivative useful as a synthetic intermediate such as a herbicide or an insecticide.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a pyridine derivative, a halopyridine and a hydrazine are reacted to form a corresponding hydrazinopyridine, and then an oxidizing agent is allowed to act thereon to remove the halogen. There is known a method for obtaining a converted pyridine derivative.

For example, synthetic intermediates such as pesticides,
3,5-Trichloropyridine is prepared by reacting 2,3,5,6-tetrachloropyridine with hydrazine in a methanol or ethanol solvent, and reacting and mixing the produced 2,3,5-trichloro-6-hydrazinopyridine. It is isolated by crystallization from a liquid, and is produced by reacting an oxidizing agent such as hypochlorite in an aqueous solvent.

However, in this method, as a means for removing impurities and a solvent in the reaction mixture, the 2,3,5-
The isolation operation by crystallization of trichloro-6-hydrazinopyridine is employed. Therefore, after completion of the reaction between 2,3,5,6-tetrachloropyridine and hydrazine, complicated operation steps such as crystallization operation by cooling the reaction mixture, centrifugation, extraction operation of wet crystal and charging operation are required. Therefore, it cannot be said that the method is industrially satisfactory.

Accordingly, an object of the present invention is to provide a simple operation,
An object of the present invention is to provide an industrial method for efficiently producing a pyridine derivative with a high yield.

[0006]

The present inventor has set out the following in order to achieve the above object.
As a result of diligent studies, when the reaction of halopyridine having at least one halogen atom with hydrazine is performed in an alcohol solvent having 3 or more carbon atoms, impurities can be easily removed by subjecting the reaction mixture to an extraction operation with water, The inventors have found that the solvent can be easily replaced with water from alcohol by distillation, and that the pyridine derivative can be obtained with a high yield by a simple operation, and the present invention has been completed.

That is, the present invention provides a method for reacting a halopyridine having at least one halogen atom with hydrazine to form a corresponding hydrazinopyridine, and then reacting with an oxidizing agent to convert the dehalogenated pyridine derivative. A method for obtaining the halopyridine and hydrazine in an alcohol solvent having 3 or more carbon atoms,
The reaction mixture was subjected to an extraction operation with water to collect an organic layer, water was added to the organic layer, and the alcohol was distilled off by distillation to obtain a mixed solution of hydrazinopyridine and water.
A method for producing a pyridine derivative, wherein an oxidizing agent is allowed to act on the mixture.

In the method of the present invention, halopyridine having at least one halogen atom and hydrazine are used as raw material components.

[0009] Halogen atoms include fluorine, chlorine, bromine and iodine atoms. Of these, chlorine and bromine atoms, particularly chlorine atoms, are preferred.

The halopyridines include monohalopyridines such as 2-chloropyridine, 4-chloropyridine, 2-bromopyridine and 4-bromopyridine; 2,3-dichloropyridine, 2,4-dichloropyridine, 2,6 Dihalopyridines such as -dichloropyridine, 3,4-dichloropyridine, 2,3-dibromopyridine, 2,4-dibromopyridine, 2,6-dibromopyridine and 3,4-dibromopyridine; 2,3,4-trichloropyridine , 2,3
5-trichloropyridine, 2,3,6-trichloropyridine, 2,4,6-trichloropyridine, 3,4,5-
Trihalopyridines such as trichloropyridine;
Tetrahalopyridines such as 4,5-tetrachloropyridine, 2,3,4,6-tetrachloropyridine, 2,3,5,6-tetrachloropyridine; and 2,3,4,5,6
Pentahalopyridines such as pentachloropyridine.

In the halopyridine having two or more halogen atoms, the halogen atoms may be the same or different.

The halopyridine may have a substituent other than a halogen atom. As such a substituent,
Lower alkyl groups such as methyl and ethyl; lower alkoxy groups such as methoxy and ethoxy; halogenated lower alkyl groups such as trifluoromethyl; and nitro groups.

[0013] Of these halopyridines, trihalopyridine, tetrahalopyridine, pentahalopyridine,
In particular, tetrahalopyridines such as 2,3,5,6-tetrachloropyridine are frequently used.

The hydrazine may be hydrazine or hydrazine hydrate. It can also be used as a hydrazine salt. Hydrazine salts include sulfates and the like. When used as a salt, usually, a base necessary to liberate the salt is added to the reaction system.

The amount of hydrazine to be used is usually 1.0 mol or more, preferably about 1.2 to 1.7 mol, in consideration of reaction efficiency and economy, per 1 mol of the halopyridine. When two or more halogen atoms are substituted with a hydrazino group, the amount of hydrazine used can be appropriately increased according to the number of halogen atoms to be substituted.

The reaction between the above-mentioned halopyridine and hydrazine is usually carried out in the presence of a base in order to make the reaction proceed smoothly.

The base is not particularly limited as long as it can capture by-product hydrogen halide, and may be an organic base, but is preferably an inorganic base. Inorganic bases include carbonates of alkali metals such as sodium carbonate, potassium carbonate and lithium carbonate; carbonates of alkaline earth metals such as magnesium carbonate, calcium carbonate and barium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate And alkali metal bicarbonates. Of these bases, alkali metal carbonates such as sodium carbonate are preferably used.

The amount of the base used is usually at least 1.0 equivalent, preferably at least 1.0 equivalent, per equivalent of halopyridine.
It is about 2.0 equivalents. The base may be added to the reaction system as it is, or may be charged after being dissolved or dispersed in a solvent such as water. Usually, it is often used as an aqueous solution.

In the case where the halopyridine as a raw material component contains an acid catalyst such as ferric chloride as an impurity, the above-mentioned base, for example, sodium carbonate or the like is reacted at least in an equivalent amount before or before the extraction operation with water. It is preferably added to the system. Metal halides such as ferric chloride are changed to hydroxides by sodium carbonate or the like, and are easily transferred to the aqueous layer side as colloids during extraction. For example, the partition coefficient of ferric chloride (iron (%) in aqueous layer / iron (%) in organic layer) is 1
, Whereas the distribution coefficient of ferric hydroxide is 3-4.
About.

The reaction between the halopyridine and the hydrazine can be carried out usually in the range of room temperature to the reflux temperature of the solvent, preferably at the reflux temperature of the solvent.

The main feature of the present invention is that an alcohol having 3 or more carbon atoms is used as a reaction solvent in the reaction between the above-mentioned halopyridine and hydrazine.

The alcohol having 3 or more carbon atoms includes 1-
Propanol, 2-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 4-methyl-1-butanol, 1-pentanol, 2-pentanol, 1-hexanol, 2-hexanol, 1- Alkanols such as heptanol, 1-octanol and 2-octanol; cycloalkanols such as cyclohexanol; aralkyl alcohols such as benzyl alcohol;
And alkoxyalkanols such as 2-methoxyethanol.

Of these alcohols, preferably
Alcohols having 4 to 8 carbon atoms, especially 2-methyl-
Alcohols having 4 carbon atoms such as 1-propanol and 1-butanol are frequently used.

The amount of the alcohol to be used is appropriately determined within a range in which the stirring operation is smoothly performed, and usually 30 to 1000 parts by weight based on 100 parts by weight of the halopyridine.
Preferably it is about 100 to 500 parts by weight.

By using such an alcohol, impurities can be removed by liquid separation in an extraction step with water, and solvent replacement can be performed by distillation. More specifically, as described below.

That is, in the present invention, after the above-mentioned halopyridine and hydrazine are reacted, the reaction mixture is subjected to an extraction operation with water to recover an organic layer.

In general, the halopyridine used as a raw material component often contains, as impurities, a metal compound or the like used as a catalyst during the production. For example, unpurified 2,3,5,6-tetrachloropyridine obtained by chlorination of 2-chloropyridine contains several percent of a metal chloride such as ferric chloride. Unreacted hydrazine remains in the reaction mixture of halopyridine and hydrazine.

When these metal compounds and hydrazine are subjected to the next oxidation step together with the intermediate product hydrazinopyridine, they react violently with the oxidizing agent or lower the purity of the pyridine derivative as the target compound. Cause.
In order to remove the impurities, in the conventional method, a purified high-purity halopyridine is used, or, as described above, the halopyridine and hydrazine are reacted in a methanol or ethanol solvent, and then the crystallization is performed from the reaction mixture by crystallization. Hydrazinopyridine is isolated and purified.

On the other hand, when an alcohol having 3 or more carbon atoms is used as a reaction solvent between the above-mentioned halopyridine and hydrazine as in the present invention, unlike the conventional method using methanol or ethanol, the reaction mixture can be easily prepared with water. Separate. On the other hand, the impurities contained in the raw material components easily migrate to the aqueous layer. Therefore, these impurities can be easily removed from the reaction mixture by the above-mentioned extraction operation with water without performing complicated operations such as crystallization and centrifugation. Therefore, even if unpurified halopyridine is used as a raw material component, the target compound can be efficiently obtained with a simple operation in a high yield.

The water used for the extraction operation may be present in the reaction system from the beginning of the reaction, or part or all of it may be added to the reaction system during or after the reaction. For example, when the raw material component halopyridine contains the metal component, and when the inorganic base is used as a hydrogen halide scavenger, the reaction and the stirring operation are performed smoothly from the beginning of the reaction so that the reaction and the stirring operation are performed smoothly. Preferably, an appropriate amount of water is present in the system. Usually, about 5 to 200 parts by weight of water can be present in the reaction system from the beginning of reaction based on 100 parts by weight of halopyridine.

The amount of water used in the extraction operation varies depending on the type of alcohol used as a solvent, and can be appropriately selected within a range in which the mixture is separated when mixed with the reaction mixture. Usually, it is about 10 to 500 parts by weight, preferably about 20 to 200 parts by weight, based on 100 parts by weight of alcohol.

The temperature of the reaction mixture at the time of the extraction operation can be appropriately selected within a temperature range from the temperature at which the formed hydrazinopyridine precipitates to the temperature below the reflux temperature of the solvent.
Usually, it is in the range of 50 ° C. or higher and lower than the reflux temperature. For example, when 2,3,5,6-tetrachloropyridine is used as the halopyridine and butanol is used as the alcohol, the temperature is preferably about 85 to 93 ° C.

The extraction operation may be repeated by further adding water to the organic layer obtained by the extraction. In addition, in order to completely remove the metal component, an alkali such as sodium carbonate can be dissolved in water, and the extraction operation can be repeated.

In the method of the present invention, water is then added to the organic layer recovered by the extraction operation, the alcohol is distilled off by distillation, and the solvent is replaced to obtain a mixed solution of hydrazinopyridine and water. . Such solvent replacement has the following advantages.

The oxidation reaction of hydrazinopyridine is carried out in an aqueous solvent. In this oxidation reaction, the presence of alcohol tends to cause side reactions such as the formation of an alkoxy compound. Therefore, it is necessary to replace the alcohol used as a solvent in the reaction between halopyridine and hydrazine with water. According to the method of the present invention, by utilizing the azeotropic distillation of the alcohol and water, the solvent can be easily replaced with water from the alcohol without isolating the hydrazinopyridine as crystals. Therefore, it is possible to shift to the next oxidation step without performing complicated operations and operations, and the manufacturing process is extremely simplified.

The amount of water to be added to the organic layer is appropriately determined in consideration of the azeotropic composition of water and alcohol and the amount required as a solvent for a subsequent oxidation reaction.

The method of adding water is not particularly limited, and the whole amount may be added before distillation, but preferably the whole amount or a part thereof is sequentially added during distillation.

Further, according to the above-mentioned solvent substitution method, there is an advantage that the alcohol distilled off by azeotropic distillation can be recycled as a reaction solvent between the above-mentioned halopyridine and hydrazine. In particular, when a mixed liquid of azeotropic water and alcohol is separated, alcohol can be recycled as the reaction solvent and water can be refluxed into the distillation system.

In the present invention, an oxidizing agent is allowed to act on a mixture of hydrazinopyridine and water obtained by distilling off alcohol to obtain a dehalogenated pyridine derivative.

As the oxidizing agent, known oxidizing agents such as hydrogen peroxide and hypochlorite can be used. The reaction can also be carried out by a commonly used method. For example, when hydrogen peroxide is used as the oxidizing agent, the pyridine derivative can be obtained by the following method.

That is, an alkali such as sodium hydroxide is added to the mixture of hydrazinopyridine and water so as to have a concentration of, for example, 1 to 40% by weight, preferably about 8 to 15% by weight. If the alkali concentration is too low, the reaction rate will be slow, and if the alkali concentration is too high, the viscosity of the reaction mixture will increase, and the load in the subsequent filtration step will tend to increase.

Next, an aqueous solution of hydrogen peroxide is slowly dropped to cause a reaction. The concentration of the aqueous hydrogen peroxide solution is usually about 35% by weight or less from the viewpoint of safety. The amount of hydrogen peroxide to be added is generally 1.0 to 1.5 mol, preferably about 1.1 to 1.3 mol, per 1 mol of hydrazinopyridine. Further, the reaction temperature is usually about 50 to 100 ° C, preferably about 70 to 80 ° C.

The pyridine derivative produced by the oxidation reaction can be isolated and purified by, for example, concentration, filtration, crystallization, recrystallization, solvent extraction, distillation, sublimation, column chromatography, or a conventional separation means combining these. Can be.

A preferred method is, for example, to add an organic solvent to a reaction mixture obtained by an oxidation reaction, and then filter the mixture.
In this method, a high-purity pyridine derivative is obtained from the separated organic layer by, for example, distillation.

Examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane; pentane, hexane, heptane and octane. Aliphatic hydrocarbons such as cyclohexane and methylcyclohexane;
Esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, cellosolve acetate, and ethyl propionate; and ethers such as diethyl ether, dibutyl ether, dioxane, and tetrahydrofuran. Of these, hydrocarbons, especially aromatic hydrocarbons such as toluene, are frequently used.

The filtration method is not particularly limited, and a conventional filtration method using filter paper, various woven fabrics, wire mesh, a packed layer, a porous body, etc. as a filter material can be employed.
It is preferable to use a membrane or a filter having pores of about 0 μm. Usually, even if an organic solvent such as toluene is added to the reaction mixture and allowed to stand, the interface is not clear because of the scum, but when the filtration is performed by the membrane or the like, the scum is removed, and the interface is extremely reduced. It becomes clear and liquid separation becomes possible.

The dehalogenated pyridine derivative thus obtained can be suitably used as a synthetic intermediate such as a herbicide or an insecticide.

[0048]

According to the method of the present invention, removal of impurities and solvent replacement can be easily performed by extraction and distillation, so that a pyridine derivative can be produced with a simple operation, efficiently and in a high yield. .

[0049]

EXAMPLES The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Unpurified 2,3,5,6-tetrachloropyridine obtained by chlorination of 2-chloropyridine (purity 92.5
%; As impurities, ferric chloride 2.6%, tar content 3.
140.8 g (including 0.5%, 1.2% pentachloropyridine and 0.2% 2,3,6-trichloropyridine).
60 mol), 36.1 g (0.72 mol) of hydrazine hydrate, 38.2 g (0.36 mol) of sodium carbonate, 1
-A mixture of 459.8 ml of butanol and 140.8 ml of water was reacted under reflux for 16 hours.

The reaction mixture is allowed to stand at about 90 ° C.
Separated. After removing the aqueous layer, the organic layer was treated with water 343.4.
1-butanol was distilled off by azeotropic distillation with water. During the distillation, water was added to the bottom of the column at about 3 ml / min. Distillation was terminated when the temperature at the top of the column reached 100 ° C.

149 ml of a 25% by weight aqueous sodium hydroxide solution was added to about 360 ml of the bottom liquid obtained,
35% aqueous hydrogen peroxide solution 6 at a temperature of 75 ° C. with stirring
2.5 ml (0.72 mol) was added dropwise over 10 hours. After the addition, 136 ml of toluene was added and mixed.

Next, the mixture was filtered using a diatomaceous earth filter having pores having an average pore diameter of 19 μm, the filtrate was separated, and the organic layer was distilled to obtain 2,3,5-trichloropyridine having a purity of 98.5%. 78.2 g were obtained. The yield was 71% based on 2,3,5,6-tetrachloropyridine.

Comparative Example 1 A reaction was carried out in the same manner as in Example 1 except that ethanol was used instead of 1-butanol. The reaction mixture was allowed to stand, but not separated. Therefore, complicated operation steps such as a crystallization operation by cooling the reaction mixture, a centrifugal separation operation, an operation for taking out and charging a wet crystal, and the like are required.

────────────────────────────────────────────────── ─── Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 213/00-213/61 CA (STN)

Claims (3)

(57) [Claims] 1. A method for reacting a halopyridine having at least one halogen atom with hydrazine to form a corresponding hydrazinopyridine, and then reacting with an oxidizing agent to obtain a dehalogenated pyridine derivative. Then, the halopyridine and hydrazine were reacted in an alcohol solvent having 3 or more carbon atoms, the reaction mixture was subjected to an extraction operation with water to collect an organic layer, water was added to the organic layer, and the organic layer was distilled. A method for producing a pyridine derivative, wherein an alcohol is distilled off to obtain a mixture of hydrazinopyridine and water, and an oxidizing agent is allowed to act on the mixture. 2. A pyridine derivative is obtained from an organic layer obtained by adding an organic solvent to a reaction mixture obtained by reacting an oxidizing agent with a mixture of hydrazinopyridine and water and then filtering and separating the separated organic layer. A method for producing the pyridine derivative described above. 3. The method for producing a pyridine derivative according to claim 1, wherein the alcohol distilled off by distillation is recycled to the reaction system.