JPS6318585B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides high quality 3,5-
The present invention relates to a method for obtaining dichloro-2,6-dimethyl-4-pyridinol.

3,5-dichloro-2,6-dimethyl-4-pyridinol (hereinafter referred to as clopidol according to its common name) is effective in preventing and treating coccidiosis in poultry, and is therefore used as a feed additive for poultry. Its quality is required to be of a high standard, and in particular, 4-amino-3,5-dichloro-2,6-dimethylpyridine as an impurity causes secondary phytotoxic damage. -3,5-dichlor-2,
The content of 6-dimethylpyridine is strictly regulated at 10 ppm or less.

Now, clopidol can be obtained by chlorinating 2,6-dimethyl-4-pyridinol, but clopidol separated from the reaction solution after this chlorination reaction is 4-amino-3,5-dichloro-2,
The reality is that it contains about 200 to 1000 ppm of 6-dimethylpyridine. Japanese Patent Publication No. 40-20977 (Patent No. 40-20977) is the basic patent for clopidol production.
467992) teaches that clopidol after over-separation can be purified by recrystallizing it from an organic solvent or washing it with water, but clopidol has very low solubility in ordinary organic solvents. Because of their small size, recrystallization using organic solvents cannot be a practical means of purification, and washing with water or organic solvents cannot effectively remove impurities inside the crystals.

However, as a result of intensive research by the present inventors,
When an aqueous alkaline solution of clopidol is brought into contact with activated carbon and then the aqueous alkali solution separated from the activated carbon is neutralized to precipitate clopidol, 4-amino-3,5-dichloro-2,
It was discovered that white clopidol with an extremely low content of 6-dimethylpyridine can be obtained, and the present invention was completed.

Clopidol is produced industrially by reacting dehydroacetic acid with aqueous ammonia to produce 2,6-dimethyl-
4-pyridinol was obtained, and the 2,6-dimethyl-
Produced by chlorinating 4-pyridinol. In this first step reaction, 4-amino-
2,6-dimethylpyridine is produced as a by-product, which becomes harmful 4-amino-3,5-dichloro-2,6-dimethylpyridine in the next chlorination step. Therefore, either add acid to the slurry reaction liquid after the first stage reaction to make a homogeneous solution, or dissolve the 2,6-dimethyl-4-pyridinol obtained by filtering the slurry reaction liquid in water under acidic conditions. By contacting this solution with activated carbon, 4-amino-3,
One possible method is to remove 4-amino-2,6-dimethylpyridine, which is a precursor of 5-dichloro-2,6-dimethylpyridine. However, 4-amino-2,6-dimethylpyridine could not be removed sufficiently by this method, and the clopidol obtained in the next chlorination step still contained a considerable amount of 4-amino-3,5-dichloro. -2,6-dimethylpyridinol is included, and the amount of 2,6-dimethyl-4-pyridinol adsorbed to activated carbon and lost cannot be ignored.

In the present invention, after obtaining clopidol by the chlorination reaction of 2,6-dimethyl-4-pyridinol,
Only by carrying out activated carbon treatment under alkaline conditions could the intended purpose be achieved.

The alkaline aqueous solution of clopidol in the present invention is prepared by subjecting 2,6-dimethyl-4-pyridinol to a chlorination reaction in an acidic or alkaline aqueous medium,
If the obtained reaction solution is a homogeneous solution, continue as is.
When in slurry form, add alkali to make an aqueous solution. (Generally, when the above chlorination reaction is carried out in an acidic or neutral environment, the reaction solution becomes a slurry in which clopidol is dispersed in fine particles, whereas when the reaction is carried out in an alkaline environment, it becomes a homogeneous solution. (Depending on the degree of reaction or the amount of water in the system, the reaction solution may become a slurry.) The clopidol produced is separated from the reaction solution after the chlorination reaction of 2,6-dimethyl-4-pyridinol. Dissolve in an alkaline aqueous solution.

Clopidol, which has been purified by other suitable methods but whose impurities have not been sufficiently removed, is dissolved in an aqueous alkaline solution.

prepared by.

As the alkali, alkali hydroxides such as sodium hydroxide and potassium hydroxide are preferably used.
In addition, sodium carbonate, potassium carbonate, ammonia, etc. are also used. It is sufficient to use an amount of alkali that uniformly dissolves clopidol, but
There is no problem in using more than that.

Contact between the alkaline aqueous solution of clopidol and activated carbon can be achieved by adding the activated carbon to the aqueous alkaline clopidol solution and stirring, then separating the activated carbon and repeating this operation as necessary. Any method can be used, such as passing the It is preferable that the temperature at the time of contact is low, and for example, a temperature condition of about 5° C. to room temperature is adopted.

The type of activated carbon is not particularly limited, but among commercially available products, Shirasagi and Shirasagi C manufactured by Takeda Pharmaceutical Company Limited are preferred. The amount of activated carbon used varies depending on the content of impurities in clopidol, but in the case of a batch method, it is usual to use activated carbon in an amount of several percent to several tens of percent of clopidol. If the content of impurities cannot be reduced to below the target value in one treatment, this treatment may be repeated one more time or more.

After the activated carbon treatment, the activated carbon is separated, and the aqueous alkali solution is neutralized with an acid such as hydrochloric acid, sulfuric acid, or acetic acid. The target product, clopidol, is precipitated. This is separated, and if necessary, washed with water. If it is then dried, high quality clopidol with significantly lower impurity content can be obtained.

Note that it is also possible to add a water-insoluble organic solvent (benzene, toluene, isopropyl ether, ethylene dichloride, etc.) to the alkaline aqueous solution before or after activated carbon treatment and shake it to extract and remove impurities. .

Next, the method of the present invention will be further explained with reference to Examples. Hereinafter, the term "%" refers to % by weight.

Example 1 Purity 97.5%, 4-amino-3,5-dichloro-
10.0 g of pale brown crude clopidol containing 240 ppm of 2,6-dimethylpyridine was dispersed in 250 g of water.
% aqueous sodium hydroxide solution was added to dissolve. PH
became 12.5. 1.5 g of activated carbon (Shirasagi C, manufactured by Takeda Pharmaceutical Co., Ltd.) was added to this aqueous alkali solution, and after stirring at room temperature for 1 hour, the activated carbon was separated. When the liquid was neutralized with 10% hydrochloric acid, crystals were precipitated, which were filtered, washed with water, and dried to obtain white clopidol. The purity of this clopidol is 99.8%, 4-amino-3,5-dichlor-
The content of 2,6-dimethylpyridine was 8.3 ppm.

In addition, when the operation of adding 1.0 g of activated carbon to an aqueous alkaline solution, stirring it at room temperature for 1 hour, and then separating the activated carbon was repeated twice, the amount of 4-amino-3,5-dichloro-2,6-dimethylpyridine in clopidol was The content was 2.7ppm.

Example 2 From 128.7 g (1.0 mol in pure amount) of 2,6-dimethyl-4-pyridinol with a purity of 95.7% obtained by reacting dehydroacetic acid with aqueous ammonia, 1000 g of water, and 52.1 g (0.5 mol) of concentrated hydrochloric acid. When the solution was kept at 5° C. and chlorine was passed through it, it immediately became cloudy, and the system gradually became cloudy. 2 hours
After passing through 163.1 g (2.3 mol) of chlorine, the slurry-like reaction solution was diluted with 4400 g of water, and further 10
% aqueous sodium hydroxide solution was added until the precipitated clopidol in the reaction solution was dissolved. Add 24.0g of activated carbon (Shirasagi C) to this alkaline aqueous solution and let it stand at room temperature.
After stirring for an hour, the activated carbon was separated. When the liquid was neutralized with 10% hydrochloric acid, crystals precipitated, which were filtered and
After washing with water and drying, 167.7 g of white clopidol was obtained. The purity of this clopidol is 99.8
%, 4-amino-3,5-dichloro-2,6-
The content of dimethylpyridine was 9.8 ppm.

Control Example Crude 2,6-dimethyl-4-amino-2,6-dimethylpyridine with a purity of 95.7% and a content of 0.10% obtained by reacting dehydroacetic acid with aqueous ammonia.
4-pyridinol 128.7g, water 1000g and concentrated hydrochloric acid
When 52.1 g was added, a homogeneous solution was obtained, and 24.0 g of activated carbon (Shirasagi C) was added thereto, and after stirring at room temperature for 1 hour, the activated carbon was separated.

Next, keep this solution at 5℃ and add 163.1g of chlorine to 2
The mixture was allowed to pass for some time, and a slurry-like reaction solution was obtained. By filtering the reaction solution, washing with water, and drying, 164.3 g of gray-white powder was obtained. The purity of this clopidol was 99.7%, and the content of 4-amino-3,5-dichloro-2,6-dimethylpyridine was is 120ppm
It was hot.

Claims (1)

[Claims] 1 3,5-dichloro-2,6-dimethyl-4-
3,5-dichloro-2,6-dimethyl-4 by contacting an alkaline aqueous solution of pyridinol with activated carbon, and then neutralizing the alkali aqueous solution after separation from the activated carbon.
High quality 3,5-dichloro-2,6-dimethyl-4- characterized by precipitating pyridinol
Method for producing pyridinol.