JPH05339235A - Production of pyridine derivative - Google Patents

Abstract

PURPOSE:To efficiently obtain a pyridine derivative in high yield according to simple operation. CONSTITUTION:A halopyridine having at least one halogen atom is made to react with hydrazine in a >=3C alcoholic solvent and the resultant reactional mixture is then subjected to extracting operation with water. Since impurities such as metallic compounds or the unreacted hydrazine migrate to an aqueous layer, they can readily be removed. Water is added to an organic layer and the alcohol is distilled away by distillation to provide a mixture of hydrazinopyridine with water. An oxidizing agent such as hydrogen peroxide is allowed to react with the resultant mixture solution and an organic solvent such as toluene is then added thereto. The prepared mixture solution is subsequently filtered through a membrane. Thereby, the objective dehalogenated pyridine derivative is obtained from the separated organic layer by distillation, etc. This method is useful for obtaining, e.g. 2,3,5-trichloropyridine from 2,3,5,6- tetrachloropyridine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a pyridine derivative useful as a synthetic intermediate for herbicides, insecticides and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a pyridine derivative, halopyridine and hydrazine are reacted with each other to give a corresponding hydrazinopyridine, which is then treated with an oxidizing agent to remove halogen. There is known a method for obtaining a condensed pyridine derivative.

For example, 2, which is a synthetic intermediate for agricultural chemicals, etc.
3,5-trichloropyridine is prepared by reacting 2,3,5,6-tetrachloropyridine with hydrazine in a solvent of methanol or ethanol, and mixing the resulting 2,3,5-trichloro-6-hydrazinopyridine. It is isolated from the liquid by crystallization and produced by reacting it with an oxidizing agent such as hypochlorite in a water solvent.

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

Therefore, the object of the present invention is to provide a simple operation,
It is to provide an industrial method for efficiently producing a pyridine derivative in a high yield.

[0006]

In order to achieve the above object, the present inventor has
As a result of diligent study, if the reaction of halopyridine having at least one halogen atom and hydrazine is carried out 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 present invention has been completed by finding that the solvent can be easily replaced with water from alcohol by distillation, and thus a pyridine derivative can be obtained in a high yield by a simple operation.

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

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

Halogen atoms include fluorine, chlorine, bromine and iodine atoms. Of these, chlorine and bromine atoms, particularly chlorine atom, are preferable.

The halopyridines include monochloropyridines such as 2-chloropyridine, 4-chloropyridine, 2-bromopyridine and 4-bromopyridine; 2,3-dichloropyridine, 2,4-dichloropyridine and 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; 2,3
Tetrahalopyridines such as 4,5-tetrachloropyridine, 2,3,4,6-tetrachloropyridine, 2,3,5,6-tetrachloropyridine; and 2,3,4,5,6
-Includes 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,
Examples thereof include 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 group.

Among these halopyridines, trihalopyridine, tetrahalopyridine and pentahalopyridine,
In particular, tetrahalopyridines such as 2,3,5,6-tetrachloropyridine are often used.

As the hydrazine, either hydrazine or hydrazine hydrate may be used. It can also be used as a salt of hydrazine. The salt of hydrazine includes sulfate and the like. When used as a salt, a base necessary for liberating the salt is usually added to the reaction system.

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

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

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

The amount of the base used is usually 1.0 equivalent or more, preferably 1.0 to 10 equivalents, relative to 1 equivalent of halopyridine.
It is about 2.0 equivalents. The base may be added to the reaction system as it is, or may be prepared by dissolving or dispersing it in a solvent such as water. Usually, it is often used as an aqueous solution.

When the raw material component halopyridine contains an acid catalyst such as ferric chloride as an impurity, the above-mentioned base such as sodium carbonate is reacted in an equivalent amount or more during or before the extraction operation with water. It is preferably added to the system. A metal halide such as ferric chloride is converted to a hydroxide by sodium carbonate or the like, and is easily transferred to the aqueous layer side as a colloid during extraction. For example, the distribution coefficient of ferric chloride (iron content (%) in water layer / iron content (%) in organic layer) is 1
~ 2, while the distribution coefficient of ferric hydroxide is 3-4
It becomes a degree.

The reaction between halopyridine and 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 halopyridine and hydrazine.

For the alcohol having 3 or more carbon atoms, 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;
Alkoxyalkanols such as 2-methoxyethanol are included.

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

The amount of the alcohol used is appropriately determined within a range where the stirring operation is smoothly carried out, but is usually 30 to 1000 parts by weight, relative to 100 parts by weight of the halopyridine.
It is preferably about 100 to 500 parts by weight.

By using such an alcohol, impurities can be removed by liquid separation in the extraction step with water, and the solvent can be replaced by distillation. The details will be described below.

That is, in the present invention, after reacting the halopyridine with hydrazine, the reaction mixture is subjected to an extraction operation with water to recover the 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 its production. For example, unpurified 2,3,5,6-tetrachloropyridine obtained by chlorination of 2-chloropyridine contains a few% of a metal chloride such as ferric chloride. Further, unreacted hydrazine remains in the reaction mixture of the halopyridine and hydrazine.

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

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

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 scavenger of hydrogen halide, the reaction is performed from the beginning of the reaction so that the reaction and the stirring operation are smoothly performed. Water is preferably present in the system in an appropriate amount. Usually, about 5 to 200 parts by weight of water can be present in the reaction system from the beginning of the reaction with respect to 100 parts by weight of halopyridine.

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

The temperature of the reaction mixture during the extraction operation can be appropriately selected within a temperature range not lower than the temperature at which the hydrazinopyridine to be formed is deposited and lower than 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, a temperature of about 85 to 93 ° C. is preferable.

Water may be further added to the organic layer obtained by the extraction, and the extraction operation may be repeated. Further, in order to completely remove the metal component, the extraction operation can be repeated by dissolving an alkali such as sodium carbonate in water.

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 to replace the solvent, and a mixed solution of hydrazinopyridine and water is obtained. .. Such solvent substitution brings about the following advantages.

The hydrazinopyridine oxidation reaction is carried out in a water solvent. In this oxidation reaction, when alcohol is present, a side reaction such as formation of an alkoxy compound is likely to occur. Therefore, it is necessary to replace the alcohol used as the solvent for 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 alcohol without isolating hydrazinopyridine as crystals. Therefore, it is possible to shift to the next oxidation step without performing complicated work and operation, and the manufacturing process is extremely simplified.

The amount of water 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 the subsequent oxidation reaction.

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

Further, according to the solvent substitution method, the alcohol distilled by azeotropic distillation has an advantage that it can be recycled as a reaction solvent for the halopyridine and hydrazine. Particularly, when the mixed liquid of azeotropic water and alcohol separates, the alcohol can be recycled as the reaction solvent and the water can be refluxed into the distillation system.

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

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 an oxidizing agent, the pyridine derivative can be obtained by the following method.

That is, an alkali such as sodium hydroxide is added to the mixed solution of hydrazinopyridine and water so as to have a concentration of, for example, 1 to 40% by weight, preferably 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 easily increase.

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

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

A preferred method is, for example, adding an organic solvent to the reaction mixture obtained by the oxidation reaction, followed by filtration,
In this method, a highly pure 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; cycloaliphatic hydrocarbons such as cyclohexane and methylcyclohexane;
Examples thereof include esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, cellosolve acetate, and ethyl propionate; ethers such as diethyl ether, dibutyl ether, dioxane, and tetrahydrofuran. Of these, hydrocarbons, especially aromatic hydrocarbons such as toluene, are commonly used.

The filtration method is not particularly limited, and a conventional filtration method using a filter paper, various woven fabrics, a wire net, a packing layer, a porous material and the like as a filter material can be employed. For example, the average pore diameter is 5 to 12
It is preferable to use a membrane or filter having pores of about 0 μm. Usually, even if an organic solvent such as toluene is added to the reaction mixture and the mixture is allowed to stand, the interface is not clear because of scum content. However, when filtration is performed using the membrane or the like, the scum content is removed and the interface becomes extremely It becomes clear and liquid separation is possible.

The dehalogenated pyridine derivative thus obtained can be suitably used as a synthetic intermediate for herbicides, insecticides and the like.

[0048]

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

[0049]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited by 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.
5%, pentachloropyridine 1.2%, 2,3,6-trichloropyridine 0.2%) 140.8 g (0.
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 was kept at about 90 ° C. and allowed to stand,
Separated. After removing the aqueous layer, water 343.4 was added to the organic layer.
ml was added, and 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. The distillation was terminated when the temperature at the top of the column reached 100 ° C.

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

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

Comparative Example 1 The 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 it was not separated. Therefore, complicated work steps such as a crystallization operation by cooling the reaction mixture, a centrifugal separation operation, a wet crystal extraction operation, and a charging operation are required.

Claims (3)

[Claims] 1. A method for obtaining a dehalogenated pyridine derivative by reacting a hydrazine having at least one halogen atom with hydrazine to form a corresponding hydrazinopyridine and then reacting with an oxidizing agent. And reacting the halopyridine with hydrazine in an alcohol solvent having 3 or more carbon atoms, subjecting the reaction mixture to an extraction operation with water to recover an organic layer, adding water to the organic layer, and distilling A method for producing a pyridine derivative, which comprises distilling alcohol off to obtain a mixed solution of hydrazinopyridine and water, and reacting the mixed solution with an oxidizing agent. 2. A pyridine derivative is obtained from the separated organic layer after adding an organic solvent to a reaction mixture obtained by reacting an oxidant with a mixture of hydrazinopyridine and water and filtering the mixture. A method for producing the described pyridine derivative. 3. The method for producing a pyridine derivative according to claim 1, wherein the alcohol distilled by distillation is recycled to the reaction system.