JPH01242562A - Production of aminophenol alkyl ether - Google Patents

Abstract

PURPOSE:To obtain the subject substance by reacting an aminophenol with an alkali metal hydroxide in a mixed consisting of an aprotic polar solvent and a solvent forming an azeotropic mixture with water and reacting the resultant alkali metal salt with an alkyl halide. CONSTITUTION:The subject substance can be produced by (1) reacting an aminophenol with an alkali metal hydroxide in a mixed solvent consisting of an aprotic polar solvent (preferably N,N-dialkyl-acetamide) and a solvent forming an azeotropic mixture with water (e.g., benzene or cyclohexane) at 65-125 deg.C for 2-3hr while removing the water distilled as an azeotropic mixture and (2) reacting the resultant aminophenol alkali metal salt with an alkyl halide at 60-80 deg.C. The amounts of the aprotic polar solvent and the alkali metal hydroxide can be decreased by the use of the present process and the objective compound useful as an intermediate for pharmaceuticals and agricultural chemicals, etc., can be obtained in high yield without causing the corrosion problem.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing aminophenol alkyl ether, which is useful as an intermediate for pharmaceuticals, agricultural chemicals, dyes, etc., and as a raw material for various chemicals.

[Conventional technology]

As a method for producing aminophenol alkyl ether,
An aminophenol alkyl ether is produced by reacting an aminophenol with an alkyl halide in an aprotic polar solvent such as N,N-dimethylacetamide or N,N-diethylacetamide in the presence of an alkali metal hydroxide. Methods are known (for example,
-15468, JP-A-56-99448, etc.).

Both of the above conventional methods are one-stage reactions to directly produce aminophenol alkyl ether, and both methods use N,N-dimethylacetamide, N
The amount of aprotic polar solvents such as , N-diethylacetamide, etc. used is about 7 times the amount of aminophenol, so the productivity is low for industrial production, leading to an increase in production costs. was there. In addition, all alkali metal hydroxides must be in solid form, such as powder or granules, and industrially, it is easier to handle and cheaper to use aqueous solutions of alkali metal hydroxides. There was a problem that aminophenol alkyl ether could not be obtained in a satisfactory manner.

[Problem to be solved by the invention]

An object of the present invention, in order to solve the above problems, is to reduce the amount of aprotic polar solvent used, and to produce aminophenol alkyl ether in high yield using an aqueous solution of alkali metal hydroxide. The purpose of the present invention is to propose a possible method for producing aminophenol alkyl ethers.

[Means to solve the problem]

The present invention aims to combine an aminophenol and an alkali metal hydroxide while removing azeotropic water in a mixed solvent of an aprotic polar solvent and an azeotropic solvent that can be azeotropically distilled with water and separable from water. This is a method for producing aminophenol alkyl ether, which comprises reacting to form an aminophenol alkali salt, and then reacting the produced aminophenol alkali salt with an alkyl halide.

The aprotic polar solvent used in the present invention is
Examples include N,N-dialkylacetamides such as N,N-dimethylacetamide and N,N-diethylacetamide, tetramethylurea, hexamethylphosphoramide, dimethylsulfoxide, and N-methylpyrrolidone, but in particular N,N- Dialkyl acetamides are preferred.

In the present invention, the azeotropic solvent used together with these aprotic polar solvents is a hydrocarbon solvent that can be azeotropically distilled with water and separable from water, and preferably has a boiling point of 60 to 150°C. Examples of such azeotropic solvents include aromatic hydrocarbons such as benzene and toluene, alicyclic hydrocarbons such as cyclohexane, and chain hydrocarbons such as n-hexane. Toluene is preferred.

In the conventional one-stage reaction, reducing the amount of aprotic polar solvent such as N,N-dialkyl acetamide,
N-alkylaminophenol alkyl ether, N-
By-products such as dialkylaminophenol alkyl ether increase, the selectivity for aminophenol alkyl ether worsens, and the yield decreases; however, in the present invention, an azeotrope is formed with the aprotic polar solvent and water. While separating and removing azeotropic water in a mixed solvent with a solvent,
By reacting aminophenol with an alkali metal hydroxide to form an aminophenol alkali salt, and then reacting it with an alkyl halide, it is possible to reduce the amount of aprotic polar solvent such as N,N-dialkylacetamide. Aminophenol alkyl ether can be obtained with high selectivity and yield.

The first stage reaction in the present invention is represented by the following formula.

In the reaction of formula (1), aminophenol and an alkali metal hydroxide are reacted in a mixed solvent of an aprotic polar solvent and an azeotropic solvent. The amount of aprotic polar solvent used is usually 1 to 2 times the weight of the alkylphenol, preferably 1
．． It is 4 to 1.6 times the weight.

The amount of azeotropic solvent is usually 0.0% relative to the aprotic polar solvent.
The amount is 5 to 2.0 times by weight, preferably 0.8 to 1.5 times by weight. As the alkali metal hydroxide, sodium hydroxide, potassium hydroxide, etc. can be used, and both can be used in the form of an aqueous solution.Industrially, it is desirable to use one with a concentration of about 500 wt. You may also use one. The amount of alkali metal hydroxide used is usually 1 to 1.5 times the amount of aminophenol, preferably 1.
．． The amount is 1 to 1.2 moles.

The reaction temperature for the formula (1) is usually 60 to 130°C, preferably 65 to 125°C, and the reaction time is usually 2 to 6 hours, preferably 2 to 3 hours. The reaction pressure may be normal pressure or may be under reduced pressure. During the reaction, the water contained in the aqueous alkali metal hydroxide solution and the water produced by the reaction are azeotroped together with the azeotropic solvent, and when the azeotropic vapor is cooled, the azeotropic solvent and water are separated. Therefore, the azeotropic solvent is returned to the reaction system, and the reaction is carried out while removing water from the reaction system to form an aminophenol alkali salt.

By removing water by azeotropy, the production of the alkali metal salt of aminophenol in the reaction system can be completed, thereby making it possible to maintain high reaction efficiency.

In the second stage reaction of the present invention, the aminophenol alkali salt formed as described above is reacted with an alkyl halide to produce an aminophenol alkyl ether according to the following formula.

(R in the formula is a lower alkyl group having 1 to 6 carbon atoms, and
is a halogen atom. ) In the reaction of formula (II), it is preferable that the alkyl halide is reacted after water produced as a by-product during the formation of the aminophenol alkali salt and water contained in the alkali metal hydroxide are removed from the system. The reaction temperature is usually 40-10
0°C, preferably 60-80°C, reaction time usually 1-80°C
6 hours, preferably 2 to 3 hours. The amount of alkyl halide used is usually 0.5 to 0.5 to aminophenol.
The amount is 2.0 molar times, preferably 1.0 to 1.5 molar times.

The reaction product of formula (II) is obtained by filtration.
Solid contents such as alkali halide represented by X are removed, and after solvent removal, purification distillation is performed to obtain the target product, aminophenol alkyl ether.

If water is present in the reaction system at this time, unreacted alkali metal hydroxide and by-product alkali halide will dissolve in the water and corrode the equipment, but by removing water in the first stage reaction, , such corrosion problems do not occur.

〔Effect of the invention〕

According to the present invention, an aminophenol and an alkali metal hydroxide are reacted in a mixed solvent of a solvent that forms an azeotrope with water and an aprotic polar solvent while removing azeotropic water, By reacting the alkyl halide after forming the aminophenol alkali salt, it is possible to reduce the amount of aprotic polar solvent and alkali metal hydroxide used, and it is also possible to reduce the amount of aprotic polar solvent and alkali metal hydroxide used. It has the advantage of being able to produce aminophenol alkyl ether in good yield and with less corrosion during production.

〔Example〕

Examples of the present invention will be described below.

Example 1 32.7g (0.3 mol) of m-aminophenol, N,N -diethylacetamide 49.1 g
.

26.4 g of 50% by weight aqueous sodium hydroxide solution (0.3
3 moles) and 49.1 g of toluene were taken and gradually heated while stirring.

Toluene-water mixed vapor is generated from 107°C.

The generated steam is cooled, the toluene phase is returned to the flask, and the aqueous phase is discharged from the system. The total amount of water generated.

When the total amount of water in the 50% sodium hydroxide solution added at the beginning and the reaction product water reaches 18.6 g, stop heating and cool to 65°C (the reaction up to this point can also be carried out under reduced pressure). can). 7.7 Q (0.34 mol) of methyl chloride is bubbled in while maintaining the temperature at 65°C.

When the blowing of methyl chloride is completed, the reaction solution is cooled and then filtered, a portion of the filtrate is taken, and after neutralization, it is subjected to gas chromatography [Gas chromatography analysis conditions: Column 5P-1000, length 2 m, diameter 3 mm, column Temperature 200°C → 270°C (temperature increase at a rate of 3°C per minute),
When analyzed using detector FID and carrier gas nitrogen,
m-N-dimethylaminophenol methyl nityl 0.
4 mol%, m-N-methylaminophenol methyl ether 2.2 mol%, and m-aminophenol methyl ether 97.3 mol%.

After this filtration, the reaction solution was desolvented and subjected to purification distillation to obtain highly pure m-aminophenol methyl ether.

Example 2 In the same apparatus as in Example 1, 32.0 m-aminophenol was added.
7g (0.3 mol), N,N-diethylacetamide 4
9.1&, 50% sodium hydroxide (-lium aqueous solution 26.
4 g (0.33 mol) and 49.1 g of benzene were taken and gradually heated while stirring.

A mixed vapor of Hensen-water is generated from 95°C.

The generated steam is cooled, the benzene phase is returned to the flask, and the aqueous phase is discharged from the system. When the total amount of water generated reaches the sum of the water in the 50 wt% aqueous sodium hydroxide solution added at the beginning and the reaction product water (18.6 g), stop heating and heat to 65°C.
(The reaction up to this point can also be carried out under reduced pressure). Methyl chloride 7.7 while maintaining 65℃
0 (0,.34 mol) is blown into the solution.

When the blowing of methyl chloride was completed, the reaction solution was cooled and filtered, and a portion of the filtrate was taken, neutralized, and then analyzed by gas chromatography. As a result, m-N-dimethylaminophenol methyl ether was found to be 0.5 mol%, m -N-
Methylaminophenol methyl ether 2.3 mol%,
The m-aminophenol methyl ether content was 9762 mol%.

Example 3 In the same apparatus as in Example 1, 32.0 m-aminophenol was added.
7g (0.3 mol), N,N-dimethylacetamide 4
9.1 g, 50% by weight aqueous sodium hydroxide solution 26.4
g (0.33 mol) and 49.1 g of toluene were taken and gradually heated while stirring. When the total amount of water generated in the same manner as in Example 1 reaches 18.6 g, heating is stopped, the mixture is cooled to 65° C., and 7.7 Q (0.34 mol) of methyl chloride is blown in while maintaining that temperature. When the blowing of methyl chloride was completed, it was cooled and filtered, and a portion of the filtrate was taken, neutralized, and then analyzed by gas chromatography. It was found that m-N-dimethylaminophenol methyl ether was 0.2 mol%, m-N -methylaminophenol methyl ether was 2.9 mol%, and m-aminophenol methyl ether was 96.9 mol%.

Comparative Example 1 32.7 g (0.3 mol) of m-aminophenol, 49.1 g of N,N-diethylacetamide, and Take 26.4 g (0.33 mol) of Jusha% sodium hydroxide aqueous solution and heat at 65°C.
While maintaining that temperature, 7.7 Q (0.34 mol) of methyl chloride was blown into the reactor, then cooled and the reaction solution was filtered. A portion of the filtrate was taken, and after neutralization, it was subjected to gas chromatography. As a result of analysis, m-N-dimethylaminophenol methyl ether 2.2 mol%, m-N
-Methylaminophenol methyl ether 10.5 mol%, m-aminophenol methyl ether 30.4 mol%, m-aminophenol 56.9 mol% Comparative Example 2 Methyl chloride blowing tube, thermometer insertion tube, 32.7 g (0.3 mol) of m-aminophenol, 49.1 g of N,N-diethylacetamide, 49.1 g of toluene, and
0% sodium hydroxide aqueous solution 26.4g (0,3
3 mol), heated to 65°C and while maintaining that temperature, methyl chloride 7.7 Q, (0.34 mol)
After blowing.

After cooling, the reaction solution was filtered, a portion of the filtrate was taken, and after neutralization, it was analyzed by gas chromatography, and it was found that m-N-
Dimethylaminophenol methyl ether 2.4 mol%
, m -N-methylaminophenol methyl ether 1
1.8 mol%, m-aminophenol methyl ether 3
0.4 mol%, m-aminophenol 57.2 mol%.

Comparative Example 3 32.7 g (0.3 mol) of m-aminophenol, 49.1 g of N,N-diethylacetamide, and 49 g of benzene were placed in a three-piece flask equipped with a methyl chloride blowing tube, a thermometer insertion tube, a stirrer, etc. .1g, and 5
0% sodium hydroxide aqueous solution 26.4g (0,3
7.7 Q (0.34 mol) of methyl chloride was heated to 65°C and maintained at that temperature.
After blowing in, the reaction solution was cooled and filtered, and a portion of the filtrate was taken, and after neutralization, analysis by gas chromatography revealed that 2.3 mol% of m-N-dimethylaminophenol methyl ether, m-N -Methylaminophenol methyl ether 11.5 mol%, m-aminophenol methyl ether 30.4 mol%, m-aminophenol 58
．． It was 2 mol%.

Example 4 In the same apparatus as in Example 1, 32.0 m-aminophenol was added.
7g (0.3 mol), N,N-diethylacetamide 4
9.1 g, 50% by weight aqueous sodium hydroxide solution 26.4
g (0.33 mol) and 49.1 g of toluene were taken and gradually heated while stirring. As in Example 1, when the total amount of water generated reached 18.6 g, heating was stopped and 6
Cool to 5°C, and while maintaining that temperature, blow in ethyl chloride door, 7Q (0.34 mol). After blowing in ethyl chloride, filter after cooling, take a part of the filtrate, and neutralize. After analysis by gas chromatography, m-N-diethylaminophenol ethyl ether was 0.4 mol%, m-N-ethylaminophenol ethyl ether was 3.5 mol%, and m-aminophenol ethyl ether was 96.1 mol%. there were.

Agent: Patent attorney Sei Yanagi Hara

Claims (1)

[Claims] (1) React aminophenol and alkali metal hydroxide while removing azeotropic water in a mixed solvent of an azeotropic solvent and an aprotic polar solvent that can be azeotropically distilled with water and separable from water. A method for producing an aminophenol alkyl ether, which comprises: forming an alkali salt of aminophenol, and then reacting the alkali salt of aminophenol produced with an alkyl halide.