JPH10291973A - Production of aminophenyl alkyl sulfide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for medicines, agrochemicals, dyes, and so on in a simple reactor by a simple method in a high yield purity by reacting an aminothiophenol with an alkylating agent in a specific solvent followed by specific purification treatment. SOLUTION: This compound is obtained by reacting an aminothiophenol with an alkylating agent in a liquid containing a hydrophobic organic solvent, and purifying the reaction producty adding water into the reaction liquor containing the reaction product to separate the reaction liquor into two layers, adding an acidic aqueous solution to the organic layer, and separating the aqueous layer. The aminothiophenol is preferably a compound of the formula (X is H or a 1-4C alkyl) especially 2-aminothiophenol, 4-aminothiophenol, and so on. The organic solvent includes pref. chlorobenzene, dichlorobenzene, and so on.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing aminophenylalkyl sulfides by reacting aminothiophenols with an alkylating agent. Aminophenylalkyl sulfides are useful as intermediates for pharmaceuticals, agricultural chemicals, dyes and the like.

[0002]

BACKGROUND OF THE INVENTION Aminophenylalkyl sulfides are usually produced by reacting an aminothiophenol with an alkylating agent. However, alkylating agents have the property of reacting with amino groups and hydroxyl groups in addition to mercapto groups,
It was difficult to selectively obtain the target compound with high purity. In addition, in the case of an alkylating agent having another functional group in the alkylating agent, side reactions of these functional groups must be considered, and it is difficult to selectively obtain a target compound with a higher purity. It was difficult.

[0003] The aminothiophenols are usually produced by starting from the corresponding halogenated nitrobenzenes and simultaneously mercapto-forming and reducing with a sulfur compound. If the above alkylation is carried out without performing purification such as distillation and / or recrystallization, the compound can be produced at a lower cost, which is convenient. However, contamination of by-products during production of aminothiophenol,
A side reaction between the compound contaminated during the production of aminothiophenols and the alkylating agent occurs, and it has been desired to purify the compound by a simple method.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing aminophenylalkyl sulfides in high yield and high purity.

[0005]

SUMMARY OF THE INVENTION The present invention relates to a method of reacting an aminothiophenol with an alkylating agent in a liquid containing at least one water-immiscible organic medium, followed by alkaline water extraction and acidic water extraction. And a method for producing aminophenylalkyl sulfides by purification.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail. Specifically, the present invention relates to a method comprising reacting an aminophenol with an alkylating agent in a liquid containing an organic medium immiscible with water, and then adding water to a reaction liquid containing aminophenylalkylsulfides. After separating the aqueous layer and then adding an acidic aqueous solution to the remaining organic layer, separating and purifying the aqueous layer, and removing the organic medium from the remaining organic layer to produce aminophenylalkyl sulfides. is there. Aminothiophenols: The raw material aminothiophenols are compounds having one or more mercapto groups and amino groups in the benzene ring, for example, compounds of the formula (I)

[0007]

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Wherein X represents hydrogen or an alkyl group having 1 to 4 carbon atoms. ] It is a compound represented by these. Specific examples include 2-aminothiophenol, 3-aminothiophenol, 4-aminothiophenol, 2-amino-5-methylthiophenol, and 3-methyl-4-aminothiophenol. Of these, 2-aminothiophenol and 4-aminothiophenol are preferred.

Aminothiophenols are usually produced by starting from the corresponding halogenated nitrobenzene as a starting material and simultaneously carrying out mercapto-formation and reduction with a sulfur compound.
In this reaction, hydrogen sulfide, sodium hydrogen sulfide, sodium sulfide, sodium polysulfide, thiourea, etc. are used as sulfur compounds, and a nitrobenzene halide is heat-treated in the presence of an alkaline compound and water as necessary, and after the reaction, if necessary. It is performed by adding an alkaline compound and hydrolyzing to obtain an aqueous solution of S-alkali salt of aminothiophenols.

As described above, aminothiophenols are present in an aqueous medium as alkali salts, but elemental sulfur, hydrogen sulfide, sodium sulfide, ammonia and the like coexist in the reaction mixture in addition to the reaction starting materials. In this state, side reactions with the alkylating agent increase, so that aminothiophenols are actually separated and purified by distillation, recrystallization, etc. to obtain aminothiophenols of high purity.

However, for the purpose of the present invention, complicated high-purity purification methods such as distillation, recrystallization and the like are not adopted, and the apparatus used in the following simple method is substantially high-purity in a small number of methods. Can also be used as aminothiophenols. That is, a reaction mixture of aminothiophenols produced by simultaneously performing mercapto-formation and reduction with a sulfur compound using halogenated nitrobenzenes as a starting material can be used only by the following simple method of washing and extraction.

The reaction mixture is mixed and brought into contact with an organic medium immiscible with water, and the starting materials, such as halogenated nitrobenzenes, elemental sulfur, and diphenyl sulfides as by-products, are extracted and separated into the organic medium. ,Remove. Examples of the organic medium used include benzene, toluene, methyl isobutyl ketone, chlorobenzene, and dichlorobenzene. Among them, a medium having a higher specific gravity than water, such as chlorobenzene and dichlorobenzene, extracts and removes impurities from the aqueous layer. However, it is preferable for the operation of the apparatus.

Next, the aqueous layer is neutralized with an acid such as hydrochloric acid, sulfuric acid or acetic acid to release aminothiophenols. In this neutralization, if the acidity is too strong, it is not preferable because it is dissolved again in the aqueous layer as a salt of an amino compound. The preferred pH control range is 3 to 11, preferably 4 to 10, and more preferably 5 to 9. It is also preferable to use an acid such as acetic acid, which hardly forms a water-soluble salt with an amino group. At this time, it is preferable to add salt or the like to improve the liberation rate by utilizing the salting out effect. The target substance is further washed, extracted and removed of water-soluble impurities contaminated with water and, if necessary, saline. In this series of operations, it is preferable that an organic medium such as benzene, toluene, methyl isobutyl ketone, chlorobenzene, and dichlorobenzene coexist as an extraction medium. In this case, unlike the case described above, a medium having a lower specific gravity than water such as benzene and toluene can easily extract the target substance from the aqueous layer, and can be easily washed with water.
It is preferable for the operation of the device. When the aminothiophenols liberated by neutralization are solid, they can be isolated by a method such as filtration, but when alkylation is to be continued, it is preferable to handle as a solution dissolved in a medium. .

Next, a trace amount of hydrogen sulfide remaining in the liquid,
In order to remove ammonia, an inert gas is blown into the obtained solution of aminothiophenols to remove low-boiling volatile compounds. The inert gas is a gas that does not react with aminothiophenols, and usually, a gas such as nitrogen, helium, or argon is used. The aminothiophenols purified by the above simple methods can be used as substantially high-purity aminothiophenols for the present invention.

Reaction medium: In the present invention, the above-mentioned aminothiophenols are reacted with an alkylating agent in a liquid containing at least one water-immiscible (water-immiscible) organic medium to form an aminophenylalkyl sulfide. Manufacturing. Examples of the organic medium that does not mix with water include benzene, toluene, methyl isobutyl ketone, chlorobenzene, and dichlorobenzene, which are the above-mentioned extractants for aminothiophenols, and methyl isobutyl ketone is used to obtain reaction activity. preferable.

The aqueous medium used as required includes an organic medium miscible with water, and a mixture thereof. Examples of the organic medium that can be mixed with water include lower alcohols such as methanol, ethanol, and propanol;
Ketones such as acetone and diacetone alcohol, N, N
Amides such as -dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; and sulfoxides such as dimethyl sulfoxide. −
Amides such as dimethylformamide and N-methylpyrrolidone are preferred. When using a mixture of these water-miscible organic mediums, it is not preferable in terms of operability in the post-treatment even if the amount is too large, and the amount of the water-miscible organic medium is not more than the same amount as the water-immiscible organic medium. is there.

Alkylating agents: Alkylating agents include alkyl esters such as acetate, methyl sulfonate, benzene sulfonate, p-toluene sulfonate, dialkyl sulfate, alkyl chloride, alkyl bromide and iodide. And alkyl halides such as alkyl. As the alkyl group, a methyl group,
Examples thereof include an alkyl group having about 1 to 20 carbon atoms, which may be branched, such as an ethyl group, a propyl group, a butyl group, an octyl group, and an octadecanyl group. These alkyl groups may have a fluorine atom, an amino group, a cycloalkyl group, or an aromatic group. Specific examples of these alkylating agents include ethyl p-toluenesulfonate, dimethyl sulfate,
Examples include ethyl iodide, butyl iodide, ethyl bromide, butyl bromide, pentafluoroethyl iodide, nonafluorobutyl iodide and the like.

Reaction: The aminothiophenol is reacted with an alkylating agent in a liquid containing at least one water-immiscible organic medium to produce aminophenylalkyl sulfides. Alkylation is for aminothiophenols 1
The aminothiophenol is dissolved in 1 to 100 parts by weight of a water-immiscible organic medium in which 1 to 5 stoichiometric amount of an alkali auxiliary is dispersed, if necessary.
C. to 150.degree. C., if necessary, under pressure, if necessary, adding the alkylating agent over 0.1 to 10 hours.
Further, the reaction is carried out at the same temperature for 0.3 to 10 hours.

As the alkaline auxiliary, sodium carbonate,
Examples thereof include alkali metal carbonates such as potassium carbonate and the like, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The above compounds are preferable from the viewpoint of dispersibility in an organic medium. Organic alkaline compounds such as alkaline earth metal hydroxides, alkaline earth metal carbonates, and tetramethylammonium hydroxide can also be used, but the former compound is preferred from the viewpoint of cost.

In the reaction, if necessary, methanol,
Lower alcohols such as ethanol and propanol; ketones such as acetone and diacetone alcohol; amides such as N, N-dimethylformamide and N-methylpyrrolidone; ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; An organic medium miscible with water (miscible with water) such as sulfoxides such as dimethyl sulfoxide may be allowed to coexist. The coexisting amount of the water-miscible organic medium is preferably 1 to 100 parts by weight based on the aminothiophenol.

The alkylating agent may be added by dissolving it in an organic medium in advance or, in the case of a gaseous compound, may be directly blown into the reaction system. The amount of the alkylating agent used is 0.3 to 1 equivalent of aminothiophenols.
It is common to use two chemical equivalents. After the reaction,
Water is added in an amount of 1 to 10 with respect to 1 part by weight of aminothiophenols.
Add 0 parts by weight, dissolve the unreacted alkali auxiliary and the generated inorganic salts to make them alkaline, then stand still, separate the alkaline aqueous layer, and dissolve in unreacted aminothiophenols and contaminated alkaline aqueous solution Impurities are removed.

Next, an aqueous solution of an acid was added to the organic layer containing the remaining aminophenylalkyl sulfides in an amount of 1 to 100 parts by weight based on 1 part by weight of the aminothiophenols used as the raw material.
After the addition in parts by weight, the mixture is allowed to stand and the aqueous layer is separated to remove disulfides as by-products and impurities soluble in contaminating acidic aqueous solution. After the purification treatment, the desired aminophenylalkyl sulfide is further purified and isolated by a method such as distillation and recrystallization.

The target aminophenylalkyl sulfides extracted and separated by the purification method of the present invention have high purity, and when they are used in the next reaction, the extracted state or simply the organic medium is distilled off. It can also be used in a concentrated state. In the method of the present invention, the reaction between the amino group and the alkylating agent and the hydrolysis reaction of the alkylating agent are suppressed to a low level, and the target product can be obtained in high yield and high purity.

[0024]

EXAMPLES The contents of the present invention will be described below in more detail with reference to examples. The yield and purity of the reaction were measured by high performance liquid chromatography after dispersing a very small part of the reaction solution. REFERENCE EXAMPLE 1 <Synthesis of p-aminothiophenol> 2500 g of water and sodium sulfide were placed in a 5,000-ml separatory funnel type four-necked flask equipped with a liquid outlet at the bottom and a jacket for heating and cooling on the peripheral wall. 600 g of (9-hydrate) and 158 g of p-chloronittobenzene were added, and the mixture was reacted at 90 ° C. for 3 hours with stirring. The reaction solution was cooled to 30 ° C., 100 g of o-dichlorobenzene was added, and the mixture was stirred to dissolve and extract a water-insoluble oil-soluble organic substance. The mixture was allowed to stand and separated, and the lower organic layer was extracted from the bottom. , Discarded.

Next, 500 g of sodium chloride, 300 g of acetic acid and 750 g of methyl isobutyl ketone were added to the aqueous layer remaining in the flask, and the mixture was stirred to dissolve and extract p-aminothiophenol in methyl isobutyl ketone. , And the lower aqueous layer was withdrawn from the bottom and discarded. Further, the operation of adding 200 g of a 20% saline solution, stirring, washing the organic layer, and discarding the aqueous layer was repeated twice. At 25 ° C., 30 liters of nitrogen gas was introduced into the organic layer remaining in the flask, and bubbling was performed by introducing 30 liters of nitrogen gas. The dissolved gas component was removed together to obtain a solution of p-aminothiophenol in methyl isobutyl ketone. [Amount of p-aminothiophenol: 81.4 g, yield: 65.0% (based on p-chloronitobenzene)].

Example 1 The same apparatus as in Reference Example 1 was continuously used to obtain p
300 g of N, N-dimethylformamide and 135 g of anhydrous potassium carbonate were added to the total amount of the solution of -aminothiophenol.
Was added. The mixture was cooled to 0 ° C., and pentafluoroethyl iodide gas was added at 0 to 5 ° C. for 2 hours to give 143.
9 g was blown into it to carry out the alkylation reaction. After the completion of the blowing, the temperature was raised and the mixture was stirred at 10 ° C. for 12 hours to complete the reaction. (Purity of p-aminophenylpentafluoroethyl sulfide: 83.7%, yield: 89.6%).

Then, 860 g of water was added to the above reaction solution,
After stirring, unreacted potassium carbonate and inorganic salts produced as a by-product were dissolved, and the aqueous layer was made alkaline. Then, the mixture was allowed to stand and separated, and the lower aqueous layer was extracted from the bottom and discarded.
(Purity of p-aminophenyl pentafluoroethyl sulfide: 84.0%, yield 89.6%). In addition, 4%
864 g of aqueous hydrochloric acid was added, the mixture was stirred, the organic layer was washed, and the aqueous layer was discarded. The remaining organic layer was concentrated by distilling off methyl butyl ketone to obtain 119.7 g of the objective p-aminophenylpentafluoroethyl sulfide.
(Purity: 98.7%, yield 84.1% / based on pentafluoroethyl iodide).

Comparative Example 1 The solvent methyl isobutyl ketone was distilled off from the p-aminothiophenol methyl isobutyl ketone solution obtained in Reference Example 1, and then 800 g of ethanol and 28.7 g of sodium hydroxide were added. The mixture was heated to 30 ° C., and pentafluoroethyl iodide gas was added to the mixture.
Over a period of time, 143.9 g was blown in to carry out the alkylation reaction. After completion of blowing, 2 hours at 30 ° C, then 5 hours
The mixture was stirred at 0 ° C. for 2 hours to complete the reaction. At the end of the reaction, the purity of p-aminophenyl pentafluoroethyl sulfide was 26.3%, and the yield was only 23.7% (based on pentafluoroethyl iodide).

Comparative Example 2 In the same manner as in Comparative Example 1, the solvent was distilled off from the solution of p-aminothiophenol in methyl isobutyl ketone obtained in Reference Example 1, and 800 g of N, N-dimethylformamide and 135 g of anhydrous potassium carbonate were added. added. This mixture was cooled to 0 ° C., and 143.9 g of pentafluoroethyl iodide gas was blown in at 0 to 5 ° C. over 2 hours to carry out an alkylation reaction. After the completion of the blowing, the mixture was stirred at 0 to 5 ° C. for 4 hours to complete the reaction. (Purity of p-aminophenyl pentafluoroethyl sulfide: 75.2%, yield 8)
6.2%). After completion of the reaction, 1,300 g of water was added while maintaining the temperature at 0 to 5 ° C., and the mixture was stirred to dissolve unreacted potassium carbonate and by-product inorganic salts in water, thereby making the aqueous layer alkaline. Next, 800 g of toluene was added and mixed and stirred. The mixture was allowed to stand and separated, and the lower aqueous layer was withdrawn from the bottom and discarded. (Purity of p-aminophenyl pentafluoroethyl sulfide: 84.8%, yield 85.
1%). Then, toluene as a solvent was distilled off, and the desired p-aminophenylpentafluoroethyl sulfide was isolated by steam distillation. Although the purity of the product after isolation was 96.7%, the yield was only 76.3% (based on pentafluoroethyl iodide).

Comparative Example 3 To the total amount of the p-aminothiophenol solution obtained in Reference Example 1, 750 g of methyl isobutyl ketone was added, and 135 g of anhydrous potassium carbonate was further added. This mixture was cooled to 0 ° C., and 143.9 g of pentafluoroethyl iodide gas was blown in at 0 to 5 ° C. over 2 hours to carry out an alkylation reaction. After the completion of the blowing, the temperature was raised and the mixture was stirred at 10 ° C. for 18 hours. The reaction was not completed, but about 5% of unreacted raw material p-aminothiol remained. (Purity of p-aminophenylpentafluoroethyl sulfide: 76.5%, yield: 82.9%). Then, 860 g of water is added and mixed with stirring to dissolve unreacted potassium carbonate and inorganic salts produced as a by-product, and after making the aqueous layer alkaline, the mixture is allowed to stand and separated, and the lower aqueous layer is extracted from the bottom. Discarded.
(Purity of p-aminophenylpentafluoroethyl sulfide: 79.0%, yield: 82.9%). In addition, 4%
864 g of aqueous hydrochloric acid was added and stirred, the organic layer was washed, and the aqueous layer was discarded. Although the purity of p-aminophenylpentafluoroethyl sulfide after the extraction and purification was 97.4%, the yield was only 79.6% (based on pentafluoroethyl iodide).

[0031]

According to the method of the present invention, aminophenylalkyl sulfides can be obtained in high yield and high purity with a small number of devices and a simple method.

Claims (8)

[Claims] Claims: 1. A method comprising reacting an aminothiophenol with an alkylating agent in a liquid containing an organic medium immiscible with water, adding water to a reaction solution containing aminophenylalkylsulfides, and forming a layer. A method for producing aminophenylalkyl sulfides, comprising separating and then adding an acidic aqueous solution to the remaining organic layer, followed by separating and purifying the aqueous layer. 2. An aminothiophenol represented by the formula (I): [In the formula, X represents hydrogen or an alkyl group having 1 to 4 carbon atoms. The production method according to claim 1, which is a compound represented by the formula: 3. The method according to claim 1, wherein the aminothiophenols are produced by simultaneously performing mercapto-forming and reduction with a sulfur compound using halogenated nitrobenzenes as a starting material. 4. An aminothiophenol is contacted with an organic reaction medium that is not mixed with water, by contacting an alkaline reaction solution obtained by simultaneous mercapto-formation and reduction with an organic medium that is not mixed with water, thereby extracting and removing a side reaction product soluble in the organic medium. The method for producing a sulfide according to claim 3, wherein the aminothiophenol is an aminothiophenol obtained by neutralizing the reaction solution and insolubilizing the aminothiophenol with water. 5. An aminothiophenol obtained by blowing an inert gas into a liquid of the obtained aminothiophenol to remove volatile components having a low boiling point. 5. The method for producing a sulfide according to 4. 6. The method according to claim 2, wherein the aminothiophenol is selected from 2-aminothiophenols and 4-aminothiophenols. 7. The alkylating agent is selected from an alkyl acetate, an alkyl methyl sulfonate, an alkyl benzene sulfonate, an alkyl p-toluene sulfonate, a dialkyl sulfate, and an alkyl halide (provided that the alkylating agent is an alkylating agent). The alkyl group has 1 to 20 carbon atoms and may be substituted with a fluorine atom, an amino group, a cycloalkyl group, or an aromatic group.),
The production method described in 1. 8. The method according to claim 1, wherein the reaction between the aminothiophenol and the alkylating agent is carried out in the presence of an alkali auxiliary.