JP3965787B2 - Process for producing 2-chloro-5-hydroxypyridine - Google Patents

Description

【０００７】
【化４】

【０００８】
【発明実施の形態】
以下、本発明を詳細に説明する。
本発明で原料として使用する２−クロロ−５−アミノピリジンは、２−クロロ−５−ピリジンカルボキサミドを次亜塩素酸ナトリウム水溶液中で反応させることにより容易に製造することができる。
【０００９】
２−クロロ−５−アミノピリジンと亜硝酸または亜硝酸塩との反応は、通常、無機酸水溶液に２−クロロ−５−アミノピリジンを溶解した後、亜硝酸または亜硝酸塩水溶液を添加することにより行われる。
このうち、亜硝酸または亜硝酸塩としては、亜硝酸アルカリ金属塩が好ましく、特に好ましくは、亜硝酸ナトリウムである。
上記亜硝酸化合物は、原料２−クロロ−５−アミノピリジンに対し1.0 倍モル以上用いられ、1.0 〜2.0 倍モルの範囲が収率及び経済的にも好ましい。
この反応により、２−クロロ−５−アミノピリジンのジアゾ化化合物が得られていると考えられる。
【００１０】
無機酸としては、硫酸の他、塩酸等が使用され、他に酢酸も使用される。酸水溶液の濃度は収率面から１０％以上、好ましくは３０〜６０％である。酸水溶液の量は、２−クロロ−５−アミノピリジン１重量に対し２倍重量以上、経済的な観点から２〜６倍重量程度が好ましい。反応温度は通常０〜２０℃、好ましくは０〜１０℃である。
【００１１】
２−クロロ−５−ヒドロキシピリジンの製造は、上記反応により生成した化合物の水溶液をカルボン酸溶液に添加することにより行われる。
亜硝酸または亜硝酸塩との反応で得られる化合物は、通常、水溶液として得られるので、そのまま、カルボン酸溶液中に徐々に添加ないしは滴下する方法が最も簡便で好ましいが、該化合物が水溶液以外の状態、例えば、有機溶媒の溶液である場合には、カルボン酸と水の混合溶液中に該化合物を添加する方法、カルボン酸溶液中に該化合物を添加後、水を添加する方法等が挙げられる。この場合、水の添加量は、原料の２−クロロ−５−アミノピリジンに対して、１〜５０倍モル、中でも特に１〜２０倍モルが好ましい。
亜硝酸または亜硝酸塩との反応で得られる化合物の水溶液をカルボン酸溶液中に徐々に添加ないしは滴下する方法を採用する場合には、添加の速度は、カルボン酸溶液１００重量部に対して０．１〜１０重量部／分が好ましい。
【００１２】
カルボン酸としては、酢酸、プロピオン酸、ブタン酸、乳酸等のカルボン酸類、これらカルボン酸類のナトリウムまたはカリウム等のアルカリ金属塩等のカルボン酸塩類、および、これらの混合溶媒を用いることができるが、特にカルボン酸類が好ましい。中でも特に、経済性の面から酢酸単独溶媒が好ましい。
カルボン酸の量は２−クロロ−５−アミノピリジン１重量に対し３倍重量以上、好ましくは５〜５０倍重量が生産性の面で好適である。反応温度は、通常５０℃以上、好ましくは６０〜１２０℃である。
【００１３】
反応により生成した２−クロロ−５−ヒドロキシピリジンは、反応液を濃縮した後、水を添加し食塩等の塩を添加して塩析することにより容易に単離することが出来る。さらに、水を添加した濃縮液を有機溶媒により抽出処理した後、抽出液から有機溶媒を蒸留分離する方法も採用することが出来る。また、単離した目的物が着色している場合は、活性炭等により容易に脱色することができる。
【００１４】
【実施例】
以下、本発明を実施例によって更に詳細に説明するが、本発明は、その要旨を越えない限り、以下の実施例に限定されるものではない。
【００１５】
実施例１
５０％硫酸水溶液１２５．０ｇに２−クロロ−５−アミノピリジン２５．０ｇ（０．１９５ｍｏｌ）を溶解し０〜５℃に冷却した。その溶液に３９％亜硝酸ナトリウム水溶液４１．１ｇ（０．２３４ｍｏｌ）を上記温度を保持しながら、１．５時間で滴下した。この反応液を、１００℃の酢酸５００ｇに３０分間で滴下し、２時間撹拌を続行して反応を終了した。反応終了後、液体クロマトグラフィーで反応液を分析した結果、２−クロロ−５−ヒドロキシピリジンが２１．４ｇ（収率８５％）で生成していることがわかった。
【００１６】
実施例２
実施例１において、カルボン酸としてプロピオン酸５００ｇを使用した以外は、実施例１と同様に反応を行った。２−クロロ−５−ヒドロキシピリジンが２１．０ｇ生成していることがわかった。収率は８３％であった。
【００１７】
比較例１
実施例１において、カルボン酸として８５％乳酸５００ｇを使用した以外は、実施例１と同様に反応を行った。２−クロロ−５−ヒドロキシピリジンが１５．２ｇ生成していることがわかった。収率は６０％であった。
【００１８】
比較例２
実施例１において、カルボン酸類に換えて硫酸銅４８．７ｇ（０．１９５モル）含む１０％硫酸５００ｇを使用した以外は、実施例１と同様に反応を行った。２−クロロ−５−ヒドロキシピリジンが３．５ｇ生成していることがわかった。収率は１４％であった。
【００１９】
【発明の効果】
本発明の製造方法によれば、医薬や農薬などの原料として有用な２−クロロ−５−ヒドロキシピリジンを工業的に有利に製造することが出来る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 2-chloro-5-hydroxypyridine, which is useful as a raw material for synthesis of pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
In “J. of Med. Chem., 16, 4, 319 (1973)”, an aqueous diazo compound synthesized by reacting 2-chloro-5-aminopyridine with sodium nitrite in a 2N aqueous sulfuric acid solution is further added to sulfuric acid. It has been reported that the target 2-chloro-5-hydroxypyridine is obtained in a yield of 20% by reacting dropwise with a 2N sulfuric acid aqueous solution containing copper at a temperature of 85 to 98 ° C.
[0003]
[Problems to be solved by the invention]
However, the above method is not industrially advantageous because the yield is extremely low and a large amount of aqueous sulfuric acid solution is required. Actually, when the present inventors carried out the above method, a large amount of polymer was formed, and the yield during the reaction was only 14%.
[0004]
The present invention has been made in view of the above circumstances, and an object thereof is to provide a method for producing 2-chloro-5-hydroxypyridine more inexpensively and more efficiently.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to achieve the above object, the present inventors have hydrolyzed a compound obtained by reacting 2-chloro-5-aminopyridine with a nitrite compound in an inorganic acid aqueous solution. The knowledge that the target 2-chloro-5-hydroxypyridine can be produced in a higher yield than the conventional method by carrying out in the presence of carboxylic acid was obtained.
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 an inorganic acid or acetic acid , and then the reaction solution is carboxylic acid. The method lies in a method for producing 2-chloro-5-hydroxypyridine represented by the following (2), wherein the compound obtained is added to or dropped thereinto and the resulting compound is reacted with water .
[0006]
[Chemical 3]

[0007]
[Formula 4]

[0008]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
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.
[0009]
The reaction between 2-chloro-5-aminopyridine and nitrous acid or nitrite is usually performed by dissolving 2-chloro-5-aminopyridine in an inorganic acid aqueous solution and then adding nitrous acid or an aqueous nitrite solution. Is called.
Among these, as nitrous acid or nitrite, alkali metal nitrite is preferable, and sodium nitrite is particularly preferable.
The nitrous acid compound is used in an amount of 1.0-fold mol or more with respect to the raw material 2-chloro-5-aminopyridine, and a range of 1.0 to 2.0-fold mol is preferable also in terms of yield and economy.
It is considered that a diazotized compound of 2-chloro-5-aminopyridine is obtained by this reaction.
[0010]
As an inorganic acid , hydrochloric acid or the like is used in addition to sulfuric acid , and acetic acid is also used. The concentration of the aqueous acid solution is 10% or more, preferably 30 to 60% from the viewpoint of yield. The amount of the acid aqueous solution is preferably about 2 to 6 times by weight with respect to 1 weight of 2-chloro-5-aminopyridine and about 2 to 6 times by weight from an economical viewpoint. The reaction temperature is usually 0 to 20 ° C., preferably 0 to 10 ° C.
[0011]
The production of 2-chloro-5-hydroxypyridine is carried out by adding an aqueous solution of the compound produced by the above reaction to the carboxylic acid solution.
Since the compound obtained by the reaction with nitrous acid or nitrite is usually obtained as an aqueous solution, the method in which it is gradually added or dropped as it is into the carboxylic acid solution is the simplest and preferred, but the compound is in a state other than the aqueous solution. For example, in the case of a solution of an organic solvent, a method of adding the compound to a mixed solution of carboxylic acid and water, a method of adding water after adding the compound to the carboxylic acid solution, and the like can be mentioned. In this case, the amount of water added is preferably 1 to 50 times mol, particularly preferably 1 to 20 times mol for the raw material 2-chloro-5-aminopyridine.
In the case of adopting a method in which an aqueous solution of a compound obtained by reaction with nitrous acid or nitrite is gradually added or dropped into the carboxylic acid solution, the rate of addition is set to 0. 1 to 10 parts by weight / minute is preferred.
[0012]
As the carboxylic acid, carboxylic acids such as acetic acid, propionic acid, butanoic acid and lactic acid, carboxylates such as alkali metal salts such as sodium or potassium of these carboxylic acids, and mixed solvents thereof can be used. Carboxylic acids are particularly preferred. Among these, an acetic acid single solvent is particularly preferable from the viewpoint of economy.
The amount of the carboxylic acid is 3 times or more, preferably 5 to 50 times the weight with respect to 1 weight of 2-chloro-5-aminopyridine. The reaction temperature is usually 50 ° C. or higher, preferably 60 to 120 ° C.
[0013]
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 sodium chloride, and salting out. Furthermore, it is also possible to employ a method in which the concentrated solution to which water has been added is extracted with an organic solvent, and then the organic solvent is distilled off from the extracted solution. Moreover, when the isolated target object is colored, it can be easily decolorized with activated carbon or the like.
[0014]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention still in detail, this invention is not limited to a following example, unless the summary is exceeded.
[0015]
Example 1
25.0 g (0.195 mol) of 2-chloro-5-aminopyridine was dissolved in 125.0 g of 50% aqueous sulfuric acid solution and cooled to 0 to 5 ° C. To the solution, 41.1 g (0.234 mol) of 39% sodium nitrite aqueous solution was added dropwise over 1.5 hours while maintaining the above temperature. This reaction solution was added dropwise to 500 g of acetic acid at 100 ° C. over 30 minutes, and stirring was continued for 2 hours to complete the reaction. After completion of the reaction, the reaction solution was analyzed by liquid chromatography. As a result, it was found that 2-chloro-5-hydroxypyridine was produced in 21.4 g (yield 85%).
[0016]
Example 2
In Example 1, the reaction was performed in the same manner as in Example 1 except that 500 g of propionic acid was used as the carboxylic acid. It was found that 21.0 g of 2-chloro-5-hydroxypyridine was produced. The yield was 83%.
[0017]
Comparative Example 1
In Example 1, the reaction was performed in the same manner as in Example 1 except that 500 g of 85% lactic acid was used as the carboxylic acid. It was found that 15.2 g of 2-chloro-5-hydroxypyridine was produced. The yield was 60%.
[0018]
Comparative Example 2
In Example 1, except for using 10% sulfuric acid 500g containing copper sulfate 48.7 g (0.195 mol) instead of the carboxylic acids, the reaction was carried out in the same manner as in Example 1. It was found that 3.5 g of 2-chloro-5-hydroxypyridine was produced. The yield was 14%.
[0019]
【The invention's effect】
According to the production method of the present invention, 2-chloro-5-hydroxypyridine useful as a raw material for pharmaceuticals and agricultural chemicals can be advantageously produced industrially.

Claims (7)

After reacting 2-chloro-5-aminopyridine represented by the following formula (1) with nitrous acid or nitrite in an aqueous solution of an inorganic acid or acetic acid , the reaction solution is added or dropped into a carboxylic acid to obtain A method for producing 2-chloro-5-hydroxypyridine represented by the following (2), wherein the obtained compound is reacted with water .

  The production method according to claim 1, wherein the carboxylic acid is acetic acid.   The production method according to claim 1, wherein the carboxylic acid is propionic acid.   The method according to any one of claims 1 to 3, wherein the inorganic acid is sulfuric acid.   The method according to any one of claims 1 to 3, wherein the inorganic acid is hydrochloric acid. After reacting 2-chloro-5-aminopyridine with nitrous acid or nitrite in an aqueous solution of an inorganic acid or acetic acid , the reaction solution is added or dropped into the carboxylic acid, and the resulting compound is reacted with water . The manufacturing method according to any one of claims 1 to 5, wherein the hourly temperature is 60 to 120 ° C.   Nitrous acid or nitrite is alkali metal nitrite, The manufacturing method of any one of Claims 1-6 characterized by the above-mentioned.