JP2000026420A - Production of 2-chloro-5-hydroxypyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply producing 2-chloro-5-aminopyridine in high yield. SOLUTION: 2-Chloro-5-aminopyridine represented by the following formula (1) is reacted with nitrous acid or a nitrous salt in an aqueous solution of an inorganic acid and the resultant compound is then reacted with water in the presence of a carboxylic acid to produce 2-chloro-5-hydroxypyridine represented by the following formula (2).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2-chloro-5-hydroxypyridine, which is useful as a raw material for synthesizing medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art "J. of Med. Chem., 1
6,4,319 (1973) ", an aqueous solution of a diazo compound synthesized by reacting 2-chloro-5-aminopyridine with sodium nitrite in a 2N aqueous sulfuric acid solution is further added to a 2N aqueous sulfuric acid solution containing copper sulfate in an amount of 85 to 85%. It is reported that the desired 2-chloro-5-hydroxypyridine is obtained in a yield of 20% by dropping and reacting at a temperature of 98 ° C.

[0003]

However, the above method is not industrially advantageous because the yield is extremely low and a large amount of sulfuric acid aqueous solution is required. In fact, when the present inventors carried out the above method, a large amount of polymer was produced, and the yield during the reaction was only 14%.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing 2-chloro-5-hydroxypyridine at lower cost and more efficiently.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above object, and as a result, have obtained 2-chloro-5.
-Hydrolyzing a compound obtained by reacting aminopyridine with a nitrite compound in an aqueous solution of an inorganic acid, in the presence of a carboxylic acid, to obtain the desired 2-chloro-5 in a higher yield than in the conventional method. -It was found that hydroxypyridine can be produced. That is, the gist of the present invention is that 2-chloro-5-aminopyridine represented by the following formula (1) is reacted with nitrous acid or nitrite in an aqueous solution of inorganic acid, and the obtained compound is treated with water in the presence of carboxylic acid. 2-chloro-5 shown in the following (2):
The present invention relates to a method for producing hydroxypyridine.

[0006]

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[0007]

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[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The 2-chloro-5-aminopyridine used as a raw material in the present invention can be easily produced by reacting 2-chloro-5-pyridinecarboxamide in an aqueous sodium hypochlorite solution.

The reaction of 2-chloro-5-aminopyridine with nitrous acid or nitrite is usually carried out by adding 2-
After dissolving the chloro-5-aminopyridine, the reaction is carried out by adding nitrous acid or an aqueous solution of nitrite. Among them, nitrite or nitrite is preferably an alkali metal nitrite, and particularly preferably sodium nitrite. The above-mentioned nitrite compound is used in an amount of 1.0-fold or more with respect to the raw material 2-chloro-5-aminopyridine, and is used in an amount of 1.0 to 2.
A molar range of 0 times is preferable in terms of yield and economy. It is considered that a diazotized compound of 2-chloro-5-aminopyridine was obtained by this reaction.

As the inorganic acid, sulfuric acid, hydrochloric acid, acetic acid and the like are used. The concentration of the acid aqueous solution is 10% or more in terms of yield,
Preferably it is 30 to 60%. The amount of the aqueous acid solution is 2-
The weight is preferably at least 2 times the weight of chloro-5-aminopyridine and about 2 to 6 times the weight from the economical viewpoint. The reaction temperature is usually 0-20 ° C, preferably 0-10 ° C.

The production of 2-chloro-5-hydroxypyridine is carried out by adding an aqueous solution of the compound produced by the above reaction to a carboxylic acid solution. The compound obtained by the reaction with nitrous acid or nitrite is usually obtained as an aqueous solution, and as such, a method of gradually adding or dropping it into the carboxylic acid solution is the most simple and preferable method.
When the compound is in a state other than an aqueous solution, for example, when it is a solution of an organic solvent, a method of adding the compound to a mixed solution of carboxylic acid and water, adding the compound to a carboxylic acid solution, and then adding water And the like. In this case, the amount of water to be added is preferably 1 to 50 times, especially 1 to 20 times the mol of the raw material 2-chloro-5-aminopyridine. When adopting a method in which an aqueous solution of the compound obtained by the reaction with nitrous acid or nitrite is gradually added or dropped into the carboxylic acid solution, the rate of addition is 0.1 to 100 parts by weight of the carboxylic acid solution. 1 to 10 parts by weight / minute is preferred.

As the carboxylic acid, carboxylic acids such as acetic acid, propionic acid, butanoic acid and lactic acid; carboxylic acid salts such as alkali metal salts such as sodium and potassium of these carboxylic acids; and a mixed solvent thereof can be used. However, carboxylic acids are particularly preferred. Among them, acetic acid single solvent is particularly preferable from the viewpoint of economy. The amount of the carboxylic acid is at least 3 times the weight, preferably 5 to 50 times the weight of 1-chloro-5-aminopyridine in terms of productivity. The reaction temperature is usually 50 ° C or higher, preferably 60 to 120 ° C.

The 2-chloro-5-hydroxypyridine produced by the reaction can be easily isolated by concentrating the reaction solution, adding water, adding a salt such as salt, and salting out. Furthermore, a method of extracting the concentrated solution to which water has been added with an organic solvent and then distilling off the organic solvent from the extracted solution can also be employed. When the isolated target is colored, it can be easily decolored with activated carbon or the like.

[0014]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples unless it exceeds the gist of the invention.

Example 1 25.0 g (0.195 mol) of 2-chloro-5-aminopyridine was dissolved in 125.0 g of a 50% aqueous sulfuric acid solution to obtain a solution.
Cool to ５5 ° C. To the solution, 41.1 g (0.234 mol) of a 39% aqueous sodium nitrite solution was added dropwise over 1.5 hours while maintaining the above temperature. This reaction solution is
The mixture was added dropwise to 500 g of acetic acid at 00 ° C. over 30 minutes, and stirring was continued for 2 hours to complete the reaction. After completion of the reaction, the reaction mixture was analyzed by liquid chromatography to find that 2-chloro-5-
It was found that hydroxypyridine was produced in 21.4 g (yield 85%).

Example 2 In Example 1, propionic acid 50 was used as the carboxylic acid.
The reaction was carried out in the same manner as in Example 1 except that 0 g was used. 21.0 g of 2-chloro-5-hydroxypyridine
It turned out that it was generating. The yield was 83%.

Example 3 In Example 1, 85% lactic acid 500% was used as the carboxylic acid.
The reaction was carried out in the same manner as in Example 1 except that g was used.
It was found that 15.2 g of 2-chloro-5-hydroxypyridine was produced. The yield was 60%.

Comparative Example 1 In Example 1, copper sulfate was used instead of carboxylic acids.
Example 1 was repeated except that 500 g of 10% sulfuric acid containing 7 g (0.195 mol) was used. 2-chloro-5-
It was found that 3.5 g of hydroxypyridine was produced. The yield was 14%.

[0019]

According to the production method of the present invention, 2-chloro-5-hydroxypyridine useful as a raw material for medicines, agricultural chemicals and the like can be produced industrially advantageously.

Claims (7)

[Claims] 1. 2-chloro-5 represented by the following formula (1)
-Aminopyridine is reacted with nitrite or nitrite in an aqueous inorganic acid solution, and the obtained compound is reacted with water in the presence of a carboxylic acid. -A method for producing hydroxypyridine. Embedded image Embedded image 2. The method according to claim 1, wherein the carboxylic acid is acetic acid. 3. The method according to claim 1, wherein the carboxylic acid is propionic acid. 4. The production method according to claim 1, wherein the inorganic acid is sulfuric acid. 5. The method according to claim 1, wherein the inorganic acid is hydrochloric acid. 6. The reaction temperature of 2-chloro-5-aminopyridine with nitrous acid or nitrite in an aqueous solution of inorganic acid and the reaction of the obtained compound with water in the presence of carboxylic acid is 80 to 120. ℃.
6. The method according to any one of items 5 to 5. 7. The method according to claim 1, wherein the nitrite or the nitrite is an alkali metal nitrite.
The production method according to the paragraph.