JPH03167173A - Industrial production of pyridine derivatives - Google Patents

Abstract

PURPOSE:To enable industrial production of the subject compounds of high purity useful as an intermediate of medicines and agricultural chemicals in a high yield by adding hydroquinone and a dehydrohalogenating agent in a specified amount based thereon to a mixed solvent and reacting the resultant mixture in a reaction condition. CONSTITUTION:To a mixed solvent composed of a polar non-protonic solvent and an aromatic hydrocarbon solvent, hydroquinone and a dehydrohalogenating agent in an amount of 0.10-0.70 equivalent based on hydroquinone are added and the resultant mixture is heated and refluxed under ordinary pressure for dehydration. To the above-mentioned mixture 2,3-dichloro-5- trifluoromethylpyridine is then added in an amount of 0.20-0.95 equivalent ratio based on the above-mentioned agent and of <=0.95 molar ratio based on hydroquinone and the resultant mixture is reacted at 100-170 deg.C. To the obtained reaction solution hydrogen chloride or hydrochloric acid is added and the solvent is then distilled off. Extraction is subsequently carried out using an aliphatic hydrocarbon solvent heated to >=35 deg.C and <= boiling point, thus obtaining 2-(4'- hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to an industrial method for producing 2-(4=-hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine. 2-(4-hydroxyphenoxy)-3
-Chloro-5-trifluoromethylpyridine is an important compound for Lfr as an intermediate in the production of pharmaceuticals and agricultural chemicals.

<Prior art> As a conventional production method, in dimethyl sulfoxide solvent,
Hydroquinone, 2,3-dichloro-5-trifluoromethylpyridine, and potassium hydroxide were reacted at 150°C for 2 hours with stirring under a nitrogen gas stream, and the resulting reaction solution was allowed to cool and then neutralized with hydrochloric acid. , followed by extraction with methylene chloride, drying, and concentration to obtain the target product 2-(4″-hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine (Japanese Unexamined Patent Publication No. 54-61182, etc.). It is publicly known.

Alternatively, hydroquinone can be dissolved in a polar solvent, heated under low vacuum to degas it, and the hydroquinone 75~
Add enough aqueous sodium or potassium hydroxide to neutralize 100% and dilute the water with heating under low vacuum until less than 1% water remains, based on the total weight of solvent and reactants. vent, release the vacuum with dry inert gas, cool and react with 2,3-dichloro-5-trifluoromethylpyridine to give 2-(
Method for obtaining 4'-hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine (JP-A-58-96
2) is publicly known.

Furthermore, 2,3-dichloro-5-trifluoromethylpyridine and 4-methoxyphenol were reacted in dimethyl sulfoxide at 80-85°C to obtain 2-(4--
methoxyphenoxy)-3-chloro-5-trifluoromethylpyridine was demethylated with a 48% aqueous hydrobromic acid solution to obtain the desired product 2-(4″-hydroxyphenoxy)-3-
Method for obtaining chloro-5-trifluoromethylpyridine (
Japanese Patent Publication No. 63-44747) is publicly known.

<Problems with the Prior Art> In Jikai No. 54-61182, the yield decreases due to the influence of water produced as a by-product from the reaction of hydroquinone and potassium hydroxide. In addition, the post-processing operation is complicated, and although it is suitable for production on a laboratory scale, it cannot be considered an industrial post-processing method.

JP-A-58-962 discloses a method in which hydroquinone is reacted with sodium or potassium hydroxide in advance, and then, after removing by-product water, the reaction is carried out with 2゜3-dichloro-5-trifluoromethylpyridine. ,
Since the reaction solvent is only a polar aprotic solvent, it is very difficult to remove the water dissolved in the polar aprotic solvent and the water produced by the reaction between hydroquinone and the dehalogenation reagent, and it does not adversely affect the reaction. Complicated operations are required to achieve the contamination concentration of water, and water must be removed by distillation under low vacuum conditions. Furthermore, in the examples of this patent, only the analysis results of the reaction mixture are described, and the post-treatment method is unclear.

In the method described in Japanese Patent Publication No. 63-44747, two steps are required to obtain the target product, and industrially,
It is desirable to manufacture with fewer steps.

Means for Solving the Problems〉 The present inventors have discovered that 2-(4”-hydroxyphenoxy)-
As a result of intensive studies on the production method of 3-chloro-5-trifluoromethylpyridine, we found that by using a mixed solvent of a polar aprotic solvent and an aromatic hydrocarbon solvent as the reaction solvent for hydroquinone and a dehydrohalogenation reagent, It is possible to remove the water in the polar aprotic solvent as well as the water produced by the reaction between hydroquinone and the dehydrohalogenation reagent by heating and refluxing the product under pressure. I found that there were no negative effects. Furthermore, as a post-treatment method for the obtained reaction solution, after neutralizing the excess dehydrohalogenating reagent with hydrogen chloride or hydrochloric acid, the solvent was distilled off, and then the aliphatic carbonization was carried out by heating to a temperature above 35°C and below the boiling point. By extracting with hydrogen solvent, the desired 2-(4'-hydroxyphenoxy)-3-chloro-
The present inventors have discovered that 5-trifluoromethylpyridine can be obtained in high yield and purity with easy post-treatment operations, and have completed the present invention.

That is, in the present invention, in a mixed solvent of a polar aprotic solvent and an aromatic hydrocarbon solvent, hydroquinone and a dehydrohalogenating reagent in an amount of 0.10 to 0.70 equivalent to the hydroquinone are added, and the mixture is heated at normal pressure. After refluxing and dehydration, 2.3-dichloro-5-trifluoromethylpyridine in an equivalent ratio of 0.20 to 0.95 with respect to the added dehydrohalogenating agent and 0.95 molar ratio or less with respect to hydroquinone. Add hydrogen chloride or hydrochloric acid to the resulting reaction solution, then distill off the solvent, and then extract with an aliphatic hydrocarbon solvent heated to above 35°C and below the boiling point. The present invention provides an industrial method for producing 2-(4''-hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine characterized by the following.

Effect〉 The present invention will be explained in detail below.

Examples of polar aprotic solvents applicable to the reaction of the present invention include N,N-dimethylformamide, NIN-dimethylacetamide, dimethylsulfoxide, hexamethylphosphorotriamide, and N-methylpyrrolidone, but the stability of the solvent In addition, dimethyl sulfoxide is preferred because of its ease of handling.

Aromatic hydrocarbon solvents used in the reaction include benzene,
Toluene, xylene, ethylbenzene, cumene, mesitylene, etc. can be fried, but those with a boiling point of 100° C. or higher are preferred, and the product can be dehydrated by heating under reflux at normal pressure.

The mixing ratio of the polar aprotic solvent and the aromatic hydrocarbon solvent used in the reaction can be any ratio, but if the concentration of the polar aprotic solvent is too high, the dehydration will take a long time and the dehydration will be difficult. This is not desirable as it may be incomplete. On the other hand, if the concentration of the polar aprotic solvent is too low, a large amount of the salt compound produced by the reaction between the dehydrohalogenating agent and hydroquinone will precipitate, resulting in the formation of a large amount of salt compound during the subsequent reaction with 2゜3-dichloro-5-trifluoromethylpyridine. This is not preferable because the reaction rate may decrease.

Therefore, the weight ratio of the polar aprotic solvent to the aromatic hydrocarbon solvent is preferably in the range of 95:5 to 20:80 (wt/wt).

If the concentration of hydroquinone in the reaction solvent is 0.5 wt% or less, the solvent is too excessive and is not economical;
If it exceeds t%, a large amount of hydroquinone salt compound produced by the reaction between hydroquinone and the dehydrohalogenation agent may precipitate, which may reduce the rate of the subsequent reaction with 2゜3-dichloro-5-trifluoromethylpyridine. . Therefore, a concentration range of 0.5 to 30 wt% is preferred.

Examples of dehydrohalogenation reagents include lithium hydroxide, sodium hydroxide, potassium hydroxide, rubyram hydroxide, cesium hydroxide, beryllium hydroxide, magnesium hydroxide,
Alkali metal or alkaline earth metal hydroxides such as calcium hydroxide and strontium hydroxide, lithium carbonate,
Carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, rubyrum carbonate, cesium carbonate, beryllium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, bicarbonate Although alkali metal hydrogen carbonates such as rubyrum and cesium hydrogen carbonate are fried, sodium hydroxide, potassium hydroxide, sodium carbonate, Potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate are preferred.

Regarding the amount of the dehydrohalogenation reagent added, if it is less than 0.10 equivalents of hydroquinone, a large amount of surplus hydroquinone will be present and it is not economical, and if it is more than 0.70 equivalents, the yield will decrease due to side reactions. This may occur.

Therefore, the amount of the dehydrohalogenation agent added is preferably in the range of 0.10 to 0.70 equivalents relative to hydroquinone.

The dehydrohalogenation reagent may be added as a solid or as an aqueous solution without any problem.

Dehydration of a mixed solution containing a salt compound of hydroquinone produced by the reaction between a dehydrohalogenation agent and hydroquinone is achieved by heating the mixed solution containing a salt compound of hydroquinone at normal pressure to a temperature at which the aromatic hydrocarbon solvent refluxes, and then distilling the solution together with the aromatic hydrocarbon solvent. The water is separated and removed using a moisture meter.

The dehydration time of the reaction solution of a dehydrohalogenating agent and hydroquinone depends on the type of dehydrohalogenating agent added, the type of polar aprotic solvent, the type of aromatic hydrocarbon solvent,
Although it varies depending on the mixing ratio of the polar aprotic solvent and the aromatic hydrocarbon solvent and the reflux conditions due to heating, it is usually completed within 10 hours.

2. The amount of 3-dichloro-5-trifluoromethylpyridine added is 0.9 based on the added dehydrohalogenation reagent.
If the molar ratio is more than 5 equivalents, the yield will decrease based on 2,3-dichloro-5-trifluoromethylpyridine, which is undesirable, and if the molar ratio is less than 0.20, it is not only uneconomical but also has no significant effect on improving the yield. unacceptable. Moreover, addition of 0.95 molar ratio or more to hydroquinone is not preferable because the yield decreases.

The addition temperature of 2.3-dichloro-5-trifluoromethylpyridine is within the range of room temperature to 170'C without any problem.

If the reaction temperature of the hydroquinone salt compound and 2,3-dichloro-5-trifluoromethylpyridine is below 100°C, the reaction will require a long time, which is undesirable. If it is above 170°C, a side reaction will occur, resulting in 2,3-dichloro-5-trifluoromethylpyridine. This is not preferable since a decrease in yield based on 5-trifluoromethylpyridine may occur.

Therefore, reaction at 100-170°C is preferred.

The reaction time after addition of 2,3-dichloro-5-trifluoromethylpyridine is usually within 20 hours at the above reaction temperature.

After the predetermined reaction, the reaction solution is cooled to 100° C. or lower, and then hydrogen chloride or an aqueous hydrochloric acid solution is added for the purpose of neutralizing the excess dehydrohalogenation reagent.

The amount of hydrogen chloride or hydrochloric acid to be added is theoretically sufficient if it is equivalent to the excess dehydrohalogenation reagent, but if it is too small, the target product 2-(4'-hydroxyphenoxy)-3- A salt compound of chloro-5-trifluoromethylpyridine may remain and may not be extracted in the subsequent hot aliphatic hydrocarbon solvent extraction, resulting in a decrease in yield. Also, the use of too much excess will not provide the same benefits. Therefore, it is preferable to use hydrogen chloride or hydrochloric acid aqueous solution in an amount of 1.1 to 5.0 times the molar amount of the excess dehydrohalogenation reagent present in the reaction-completed solution.

In addition, when using an aqueous hydrochloric acid solution, the concentration of hydrochloric acid is 1 to
If it is 36 wt%, it can be used in the present invention, but if it is too dilute, the amount of liquid to be added will be large.
If the concentration is as high as wt%, smoke may be generated during addition and workability may deteriorate, so it is usually 5wt% to 25wt%.
An aqueous solution of hydrochloric acid is used. Further, if the addition of hydrogen chloride or hydrochloric acid aqueous solution is carried out at 100° C. or lower, no problem will arise.

When removing the solvent from the reaction solution neutralized with hydrogen chloride or hydrochloric acid, if hydrogen chloride is used to neutralize the excess dehydrohalogenation reagent, there will be no problem if the temperature is below 200°C. It is possible to do so. On the other hand, when an aqueous hydrochloric acid solution is used for neutralization, decomposition of the target product may occur at temperatures above 120° C., which is undesirable. Therefore, the solvent is distilled off under reduced pressure.

Distillation of the solvent can be carried out with the same problem as long as it is carried out within the above temperature conditions, and after distillation of the solvent, a black living eye oil containing an inorganic salt is obtained.

The aliphatic hydrocarbon solvent used to extract the target product from the obtained black live eye oil containing inorganic salts may include pentane, hexane, petroleum benzine, ligroin, etc., and any industrially available solvent may be used. Anything can be used.

The amount of aliphatic hydrocarbon solvent to be used varies depending on the type of solvent, but the total amount is usually about JO to 300 times the content of the target substance, and batch or continuous extraction is performed. When performing batch extraction, the number of extractions is preferably about 3 to 10 times.

The present invention can be applied as long as the extraction temperature is below the boiling point of the aliphatic hydrocarbon solvent used; however, if the extraction temperature is below 35°C, the solubility of the target product in the aliphatic hydrocarbon solvent used will be significantly reduced. .

Therefore, the extraction temperature is 35°C or higher and lower than the boiling point of the aliphatic hydrocarbon solvent used.

The obtained extract is concentrated to obtain the desired 2-(
, 4m-hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine to give a white to pale yellow solid.

<Effects of the Invention> According to the present invention, an industrial method for producing 2-(4-hydroxyphenoxy)-3-chloro-5-trifluoromethylpyridine has been established.

<Examples> The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these Examples.

[Example 1] 30 equipped with a stirrer and a water metering receiver with a Libig cooling tube
Hydroquinone 2.99 in a 0m1 round bottom 3 flask
g, potassium hydroxide 1.37 g.

15 g of dimethyl sulfoxide and 15 g of toluene were charged and heated while stirring on an oil bath. When the internal temperature reached 110°C, reflux of toluene started.
Dehydration has begun.

Add 2.99 g of hydroquinone and 1.37 g of potassium hydroxide to a 30(') ml round-bottom three-bottle flask.

5 g of dimethyl sulfoxide] and 15 g of toluene were charged and heated while stirring on an oil bath. When the internal temperature reached 110° C., reflux of toluene started and dehydration began.

After 3 hours, dehydration was no longer visually observed, but reflux was continued for another 2 hours, for a total of 5 hours.

After cooling the obtained hydroquinone salt solution to 40°C with stirring, 5.00 g of 2,3-dichloro-5-trifluoromethylpyridine was added dropwise over 0.5 hours, and then heated to 110°C again. The reaction was carried out under reflux for 8.0 hours.

After the reaction is complete, cool to 100°C and add 0.0% hydrogen chloride gas.
The excess base was neutralized by bubbling and supplying 6 g (0° C.: 36.8 ml) over 30 minutes. Then, a vacuum distillation apparatus was attached, and the solvent was distilled off under reduced pressure over 2 hours.

After cooling the black viscous oil obtained by distilling off the solvent to 59°C, 300g of hexane was added and stirred, and the mixture was heated at the same temperature for 50 minutes.
A hexane layer was obtained by settling and then decantation. The residue was further extracted three times with 300 g each of hexane, and the hexane layers were combined and concentrated to obtain a pale yellow solid 6.
42g was obtained.

As a result of analysis by gas chromatography, the conversion rate of 2゜3-dichloro-5-trifluoromethylpyridine was 99.
%, purity was 98% and yield was 94%.

[Examples 2 to 5] Reactions were carried out using the same reaction apparatus as in Example 1 under the conditions shown in Table 1.

The results are shown in Table 1.

Note that in Example 2.3, a 300 ml reaction vessel was used, and in Example 5, a 2000 ml reaction vessel was used.

In addition, in Example 4, after the reaction in a 300 m1 reaction vessel, 1
Extraction was performed in a 0100O vessel.

[Comparative Example 1] Using a 1000 ml reactor, the reaction was carried out under the conditions shown in Table 1 in the same manner as in Example 1, using dimethyl sulfoxide as the sole solvent.

For dehydration, use dimethyl sulfoxide 470 under reduced pressure.
g was distilled off.

The results are shown in Table 1.

[Comparative Example 2.3] Using the same apparatus as in Example 1, a reaction was carried out under the conditions shown in Table 1.

The results are shown in Table 1.

Claims (1)

[Claims] 0.0 for hydroquinone and hydroquinone in a mixed solvent of polar aprotic solvents and aromatic hydrocarbon solvents.
Add 10 to 0.70 equivalents of a dehydrohalogenation reagent, and after dehydration by heating under reflux at normal pressure, at an equivalent ratio of 0.20 to 0.95 to the added dehydrohalogenation reagent and to hydroquinone. Add 2,3-dichloro-5-trifluoromethylpyridine at a molar ratio of 0.95 or less,
After adding hydrogen chloride or hydrochloric acid to the reaction solution obtained by reacting at ℃ to 170℃, and then distilling off the solvent, at 35℃ or higher,
2-(4'-hydroxyphenoxy)-3, which is extracted with an aliphatic hydrocarbon solvent heated below its boiling point.
- Industrial method for producing chloro-5-trifluoromethylpyridine.