JPH082864B2 - Method for producing 4-halogenothiophenol - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing 4-halogenothiophenol, which is useful as a raw material for medicines, agricultural chemicals and the like, and as an intermediate for dyes. More specifically, it relates to a method for producing high-purity 4-halogenothiophenol containing almost no isomer 2-halogenothiophenol.

(Prior art and problems to be solved) In order to use 4-halogenothiophenol as a raw material for pharmaceuticals, a high-purity product containing almost no impurities is required.

However, 4-halogenobenzenesulfonyl chloride obtained by sulfonation of a halogenobenzene such as monochlorobenzene or monobromobenzene with a sulfonating agent such as chlorosulfonic acid and then chlorination with a chlorinating agent such as thionyl chloride is 2- as an isomer as an impurity
It usually contains 1 to 3% of halogenobenzenesulfonyl chloride.

When 4-halogenobenzenesulfonyl chloride containing this isomer is reduced with zinc and / or tin and a mineral acid, the isomer is also similarly reduced, and 4-halogenothiophenol and 2- Separation from halogenothiophenol is extremely difficult. For example, the boiling points of 4-chlorothiophenol and 2-chlorothiophenol are close to 205 to 207 ° C. and 205 to 206 ° C., and it is extremely difficult to distill and separate them.

Separation and purification of 4-chlorothiophenol and 2-chlorothiophenol by recrystallization is a commonly used method, but it cannot be said to be an advantageous method because of loss to the solvent. Further, in order to prevent deterioration of purity due to oxidation of the product, filtration, drying and the like must be carried out in an inert gas atmosphere. In the case of 4-chlorothiophenol, the melting point is 52-
Since it is 53 ° C. and the temperature cannot be set high during drying, it takes a long time to remove the solvent, which is not industrially advantageous.

From these facts, in order to obtain 4-halogenothiophenol containing almost no isomer as an impurity, a non-isomer-containing 4-halogenobenzenesulfonyl chloride as a raw material is used in the reduction reaction which is the preceding step. Is a good idea.

As a method for purifying 4-halogenobenzenesulfonyl chloride, conventionally known is a method in which a reaction solution containing 4-halogenobenzenesulfonyl chloride is added to water to crystallize 4-halogenobenzenesulfonyl chloride. However, this method can remove unreacted sulfonic acid and excess chlorinating agent, sulfonating agent, etc., but it is almost impossible to remove isomers. Further, it is very difficult to separate and purify these by distillation because the boiling points of both are similar.

In view of such a situation, the present inventors have diligently studied a method for improving the drawbacks of the conventional method and producing a 4-halogenothiophenol containing almost no isomer 2-halogenothiophenol in a high yield. . As a result, the reaction solution containing 4-halogenobenzenesulfonyl chloride was added not only to water but also to a mixed solution containing an organic solvent to cause crystallization, and this was filtered to obtain the isomer 2-halogenobenzene. The inventors have found that the content of sulfonyl chloride can be remarkably reduced, and by reducing it, 4-halogenothiophenol containing almost no 2-halogenothiophenol can be produced in high yield, and the present invention has been completed.

MEANS FOR SOLVING THE PROBLEMS The present invention relates to sulfonation of halogenobenzene to 4-halogenobenzenesulfonic acid, followed by chlorination to form 4-halogenobenzenesulfonyl chloride, and zinc and / or tin and a mineral acid. Upon reduction to obtain 4-halogenothiophenol, a reaction solution containing 4-halogenobenzenesulfonyl chloride was added to a mixed solution of water and an organic solvent, crystallized, and collected by filtration, followed by addition of zinc and / or tin. The present invention provides a method for producing high-purity 4-halogenothiophenol, which is characterized by reduction with a mineral acid.

Even if the reaction liquid containing 4-halogenobenzenesulfonyl chloride is added to water, crystals are precipitated, but in this case, the product becomes viscous and easily aggregated, and the filterability is poor, and even if washed, the isomers The effect of reducing the content is small.

In the present invention, crystals having good filterability can be obtained by adding a reaction liquid containing 4-halogenobenzenesulfonyl chloride to a mixed liquid of water and an organic solvent. Therefore, 4-halogenobenzenesulfonyl chloride containing less isomers can be obtained. Crystals are obtained. By reducing the 4-halogenobenzenesulfonyl chloride thus obtained, it is possible to obtain 4-halogenothiophenol having a very low content of the isomeric 2-halogenothiophenol.

As the organic solvent, any organic solvent that does not react with 4-halogenobenzenesulfonyl chloride can be used. For example, alcohols such as methanol, ethanol and propanol, ethers such as dioxane and tetrahydrofuran, aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as toluene and xylene, and halogenated aromatic hydrocarbons such as chlorobenzene. Is used.
In particular, when alcohols such as methanol, ethanol and propanol, and aliphatic hydrocarbons such as hexane and heptane are used, the effect of removing isomers is large and the recovery rate is high and good results are obtained.

The temperature at which the reaction solution containing 4-halogenobenzenesulfonyl chloride is added to the mixed solution of water and the organic solvent is preferably 0 to 30 ° C, particularly preferably 5 to 15 ° C. When the temperature is higher than 30 ° C, 4-halogenobenzenesulfonyl chloride is decomposed and the loss of dissolution in the filtrate is increased, so that the recovery rate is lowered.

The mixing ratio of water and the organic solvent is 0.1 to 3.0 parts by weight, preferably 0.5 to 2.0 parts by weight, of the organic solvent to 1 part by weight of water. If it is less than 0.1 part by weight, the effect of mixing an organic solvent cannot be obtained, and if it is more than 3.0 parts by weight, the content of the impurity 2-halogenobenzenesulfonyl chloride is reduced, but it is the desired product. This is not preferable because the amount of halogenobenzenesulfonyl chloride dissolved in the solution increases and the yield decreases.

In order to obtain preferable results regarding the purity and yield of 4-halogenobenzenesulfonyl chloride, it is necessary to use the mixing ratio of water and the organic solvent within the above range.

The precipitated 4-halogenobenzenesulfonyl chloride has good filterability and can be used for the reduction reaction in the next step without drying after washing.

The reduction reaction is carried out using zinc and / or tin in the presence of mineral acid such as hydrochloric acid or acid. Preference is given to using zinc in the presence of hydrochloric acid.

When zinc is used, 1.05 times the theoretical amount is sufficient.

The reduction reaction is usually carried out by adding an organic solvent, and as the organic solvent, aromatic hydrocarbons such as toluene and xylene are preferably used.

After completion of the reduction reaction, the organic layer and the aqueous layer are separated, and the organic layer is washed with a dilute acid to remove unreacted metal.

The organic layer was washed with water and then distilled to obtain 4,4 ′ other than 2-halogenothiophenol existing as impurities.
-Dihalogenodiphenyl sulfone, 4,4'-dihalogenodiphenyl disulfide and the like can be easily separated because they have a high boiling point, and 4-halogenothiophenol having a purity of 99.5% or more can be obtained.

Thus, for purification of 4-halogenothiophenol, which is easily oxidized, purification by distillation as described above is better than purification by recrystallization which requires complicated operations such as crystallization, filtration and washing. At this time, the isomer 2-
When halogenothiophenol is mixed, since the boiling points of both are similar, it is extremely difficult to separate them, but in the method of the present invention, 2-halogenothiophenol mixed in is extremely small, It is possible to easily obtain highly pure 4-halogenothiophenol.

(Example) Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Production Example 1 32.8 g of sodium sulfate was added to 652.4 g (5.6 mol) of chlorosulfonic acid, and the temperature was raised to 50 ° C. To this, 450.4 g (4.0 mol) of monochlorobenzene was added dropwise over 3 hours. 70 ° C
After the temperature was raised to 1 hour, 499.4 g (4.2 mol) of thionyl chloride was added dropwise over 3 hours and the temperature was maintained for 1 hour. 1069.6 g of the obtained reaction liquid containing 4-chlorobenzenesulfonyl chloride was divided and used as a raw material liquid for Examples 1 to 4 and Comparative Example 1 below.

Example 1 267.4 g of a reaction solution containing 4-chlorobenzenesulfonyl chloride corresponding to 1.0 mol in Production Example 1 was added dropwise to a mixed solution of 240 g of methanol and 160 g of water in 20 minutes. During this time,
The temperature was kept at 10 ° C. After stirring at the same temperature for 2 hours, the mixture was filtered under reduced pressure and washed with a mixed solution of 60 g of methanol and 40 g of water. 219 g of a wet cake of 4-chlorobenzenesulfonyl chloride, 50 g of toluene and 657 g of concentrated hydrochloric acid (6.3 mol)
Then, 196.2 g (3.0 mol) of zinc was added in 1 hour while the temperature was raised from 20 ° C to 80 ° C.

After keeping at 85 ℃ for 2 hours, add 150g of toluene,
Separated after cooling to.

The toluene layer was washed with 100 g of 10% hydrochloric acid and then with 100 g of water to obtain 330.6 g of an organic layer. The production rate of 4-chlorothiophenol was 90.8%, and the content of 2-chlorothiophenol was 0.12%.

The organic layer was distilled under reduced pressure to obtain 127.1 g of 4-chlorothiophenol as a fraction of 94 to 97 ° C / 15 to 20 mmHg ° C.

Physical yield is 87.9% (vs chlorobenzene), purity is 99.7
%, The content of 2-chlorothiophenol was 0.12%.

Example 2 133.7 g of the reaction solution containing 0.5 mol of 4-chlorobenzenesulfonyl chloride in Preparation Example 1 was added dropwise to a mixed solution of 80 g of 2-propanol and 120 g of water over 15 minutes. During this time, the temperature was kept at 15 ° C. After stirring at the same temperature for 1 hour and 45 minutes, the mixture was filtered under reduced pressure and washed with a mixed solution of 20 g of 2-propanol and 30 g of water.

Wet cake of 4-chlorobenzenesulfonyl chloride 11
3.5 g was added to 25 g of toluene and 334 g (3.2 mol) of concentrated hydrochloric acid, and 98.1 g (1.5 mol) of zinc was added in 30 minutes while raising the temperature from 20 ° C to 80 ° C. After holding at 85 ℃ for 1 hour and 30 minutes,
100 g of toluene was added, the mixture was cooled to 30 ° C., and then the layers were separated.

The toluene layer was washed with 50 g of 10% hydrochloric acid and further with 50 g of water to obtain 186.7 g of an organic layer.

The production rate of 4-chlorothiophenol is 88.3%,
The content of 2-chlorothiophenol was 0.11%. The organic layer was distilled in the same manner as in Example 1 to obtain 62.0 g of 4-chlorothiophenol having a purity of 99.8%. The yield based on chlorobenzene was 85.8% and contained 0.11% 2-chlorothiophenol.

Example 3 267.4 g of a reaction solution containing 4-chlorobenzenesulfonyl chloride obtained in Production Example 1 was added to 200 g of n-hexane and 200 g of water.
It was added dropwise to the mixed solution of 30 minutes. During this time, the temperature was kept at 10 ° C. After stirring for 1 hour 30 minutes at the same temperature, vacuum filtration,
Wash with n-hexane 50g and water 50g, wet cake 177.0g
I got Thereafter, in the same manner as in Example 1, the reaction mixture was added to toluene and concentrated hydrochloric acid to carry out a reduction reaction.

The production rate of 4-chlorothiophenol is 86.9%.
The content of chlorothiophenol was 0.04%.

It was distilled in the same manner as in Example 1 to obtain 122.6 g of 4-chlorothiophenol having a purity of 99.8%. The yield based on chlorobenzene was 84.8% and contained 0.04% of 2-chlorothiophenol.

Example 4 133.7 g of the reaction solution containing 4-chlorobenzenesulfonyl chloride obtained in Preparation Example 1 was added dropwise to a mixed solution of 80 g of dioxane and 120 g of water over 15 minutes. During this time, the temperature was kept at 5 ° C. After stirring at the same temperature for 1 hour and 45 minutes, the mixture was filtered under reduced pressure and washed with 25 g of dioxane and 25 g of water to obtain 93.9 g of a wet cake.

Thereafter, in the same manner as in Example 2, the reaction mixture was added to toluene and concentrated hydrochloric acid to carry out a reduction reaction.

The production rate of 4-chlorothiophenol is 87.5%.
The content of chlorothiophenol was 0.18%.

It was distilled in the same manner as in Example 2 to obtain 61.5 g of 4-chlorothiophenol having a purity of 99.6%.

Yield to chlorobenzene is 85.1%, 0.18%
Of 2-chlorothiophenol.

Comparative Example 1 133.7 g of a reaction solution containing 0.5 mol of 4-chlorobenzenesulfonyl chloride in Preparation Example 1 was added dropwise to 200 g of water over 20 minutes. During this time, the temperature was kept at 15 ° C. The mixture was stirred at the same temperature for 1 hour and 45 minutes, filtered under reduced pressure, and washed with 50 g of water. To the resulting wet cake 118.2 g, toluene 25 g, concentrated hydrochloric acid 313
g (3.0 mol) and add 98.1 g (1.5 mol) zinc at 20 ° C
The temperature was raised from 1 to 80 ° C, and the mixture was added in 1 hour. 2 at 85 ° C
After maintaining for a time, 100 g of toluene was added, the mixture was cooled to 30 ° C., and then the layers were separated. The toluene layer was washed with 50 g of 10% hydrochloric acid and then with 50 g of water to obtain 188.5 g of an organic layer. 4-
The production yield of chlorothiophenol was 88.1% and the content of 2-chlorothiophenol was 0.92%. It was distilled in the same manner as in Example 2 to obtain 61.4 g of 4-chlorothiophenol.
Physical yield is 84.9% (versus monochlorobenzene), purity is 9
It contained 0.93% of 2-chlorothiophenol at 8.9%.

Production Example 2 16.4 g of anhydrous sodium sulfate was added to 326.3 g (2.8 mol) of chlorosulfonic acid, and the temperature was raised to 50 ° C. To this, 314.0 g (2.0 mol) of monobromobenzene was added dropwise over 3 hours. After holding at the same temperature for 30 minutes, the temperature was raised to 80 ° C., and 249.8 g (2.1 mol) of thionyl chloride was added dropwise over 3 hours. After the dropping, the temperature was maintained for 1 hour at the same temperature to obtain 622.0 g of a reaction liquid containing 4-bromobenzenesulfonyl chloride. This reaction liquid was divided and used as the raw material liquids of Example 5 and Comparative Example 2 below.

Example 5 311.0 g of a reaction solution containing 4-bromobenzenesulfonyl chloride corresponding to 1.0 mol in the reaction solution of Production Example 2 was added dropwise to a mixed solution of 200 g of methanol and 200 g of water over 15 minutes. During this time, the temperature was kept at 15 ° C. 45 at the same temperature for 1 hour
After stirring for minutes, vacuum filtration was performed, and 50 g of methanol and 50 g of water were added.
It was washed with the mixed solution of.

Wet cake of 4-bromobenzenesulfonyl chloride 26
3.0 g was added to 50 g of toluene and 689 g of concentrated hydrochloric acid (6.6 mol), and 206.0 g (3.15 mol) of zinc was added over 1 hour while raising the temperature from 20 ° C to 80 ° C. After holding at 85 ° C. for 1 hour, 400 g of toluene was added, the mixture was cooled to 30 ° C., and then the layers were separated.
The toluene layer was washed with 100 g of 10% hydrochloric acid and further washed with 100 g of water to obtain 618.4 g of an organic layer. The production yield of 4-bromothiophenol was 91.0%, and the content of 2-bromothiophenol was 0.11%. The organic layer was distilled to obtain 166.6 g of 4-bromothiophenol. The physical yield was 88.1% (relative to brombenzene) and the purity was 99.7%.
It contained 0.11%.

Comparative Example 2 311.0 g of a reaction liquid containing 4-bromobenzenesulfonyl chloride obtained in Production Example 2 as in Example 5 was added to 50 g of toluene.
And added to 689 g (6.6 mol) of concentrated hydrochloric acid at 20 to 80 ° C.
235.4 g (3.6 mol) of zinc was added while the temperature was raised to. The time required for the addition was 1 hour. After holding at 85 ° C for 1 hour, 400 g of toluene was added, and the mixture was cooled to 30 ° C and separated.
After washing the toluene layer with 10% hydrochloric acid, wash with 100 g of water,
612.6 g of an organic layer was obtained. The production yield of 4-bromothiophenol was 88.1%, and the content of 2-bromothiophenol was 0.76.
%Met. The organic layer was distilled in the same manner as in Example 5 to obtain 163.7 g of 4-bromothiophenol in a yield of 86.6% (relative to brombenzene). The purity was 98.2% and contained 0.96% 2-bromothiophenol. When recrystallization was performed using the same amount of hexane to remove 2-bromothiophenol, the content of 2-bromothiophenol decreased to 0.21%, but the recovery rate was 82%.

Production Example 3 To 14.3 g (2.8 mol) of chlorosulfonic acid, 14.2 g of anhydrous sodium sulfate was added, and monofluorobenzene 19
2.2 g (2.0 mol) was added dropwise over 3 hours. 30 at the same temperature
After maintaining the temperature for 30 minutes, the temperature was raised to 70 ° C and 249.8 g (2.
1 mol) was added dropwise over 3 hours. After the dropping, the temperature was maintained at the same temperature for 1 hour to obtain 496.4 g of a reaction liquid containing 4-fluorobenzenesulfonyl chloride. This reaction liquid was divided and used as the raw material liquids of Example 6 and Comparative Example 3 below.

Example 6 248.2 g of a reaction liquid containing 4-fluorobenzenesulfonyl chloride corresponding to 1.0 mol in the reaction liquid of Production Example 3.
Was added dropwise to a mixed solution of 30 g of 2-propanol and 270 g of water in 30 minutes. During this time, the temperature was kept at 10 ° C. After stirring at the same temperature for 1 hour, the mixture was filtered under reduced pressure and washed with 100 g of water.

Wet cake of 4-fluorobenzenesulfonyl chloride
218.2 g was added in 50 g of cyclohexane and 615 g (5.9 mol) of concentrated hydrochloric acid, and 196.1 g (3.0 mol) of zinc was added from 20 ° C to 8 ° C.
The temperature was raised to 0 ° C., and the mixture was added in 1 hour. After holding at 80 ° C for 1 hour, the mixture was cooled to 30 ° C, and then separated. The cyclohexane layer was washed with 100 g of water to obtain 159.0 g of an organic layer. 4-
The production yield of fluorothiophenol was 87.4%, and the content of 2-fluorothiophenol was 0.20%. The organic layer was distilled to obtain 108.4 g of 4-fluorothiophenol. Physical yield is 84.6% (vs. monofluorobenzene), purity 99.3
% Of 2-fluorothiophenol.

Comparative Example 3 248.2 g of the reaction liquid containing 4-fluorobenzenesulfonyl chloride obtained in Production Example 3 was added to 50 g of cyclohexane and 646 g of concentrated hydrochloric acid (6.2 mol) at 20 ° C.
Then, 202.7 g (3.1 mol) of zinc was added while heating to 80 ° C. The time required for the addition was 1 hour. After holding at 80 for 1 hour, it was cooled to 30 ° C. and separated. The cyclohexane layer was washed with 100 g of water to obtain 161.3 g of an organic layer. The production yield of 4-fluorothiophenol was 90.5%, and the content of 2-fluorothiophenol was 2.02%. The organic layer was distilled in the same manner as in Example 6 to give 112.5 g of 4-fluorothiophenol.
Was obtained in a physical yield of 87.8% (relative to monofluorobenzene).
The purity was 98.6% and contained 2.00% 2-fluorothiophenol.

Production Example 4 14.2 g of anhydrous sodium sulfate was added to 326.3 g (2.8 mol) of chlorosulfonic acid, and the temperature was raised to 40 ° C. To this, 408.0 g (2.0 mol) of monoiodobenzene was added dropwise over 3 hours. After heating to 70 ℃ for 1 hour, 249.8g of thionyl chloride
(2.1 mol) was added dropwise over 3 hours, and the temperature was maintained for 1 hour. 686.2 g of the obtained reaction liquid containing 4-iodobenzenesulfonyl chloride was divided and provided as a raw material liquid for Example 7 and Comparative Example 4 below.

Example 7 343.1 g of a reaction solution containing 4-iodobenzenesulfonyl chloride corresponding to 1.0 mol in the reaction solution of Preparation Example 4 was added dropwise to a mixed solution of 150 g of ethanol and 150 g of water over 30 minutes. During this time, the temperature was kept at 10 ° C. The mixture was stirred at the same temperature for 1 hour and 30 minutes, filtered under reduced pressure, and washed with 100 g of water.

Wet cake of 4-iodobenzenesulfonyl chloride 30
2.8 g was added to 50 g of toluene and 646 g (6.2 mol) of concentrated hydrochloric acid, and 196.1 g (3.0 mol) of zinc was added over 1 hour while raising the temperature from 20 ° C to 80 ° C. After holding at 85 ° C. for 2 hours, 400 g of toluene was added, the mixture was cooled to 30 ° C., and then the layers were separated. The toluene layer was washed with 100 g of 10% hydrochloric acid, and further washed with 100 g of water to obtain 652.3 g of an organic layer. The production yield of 4-iodothiophenol was 87.8%, and the content of 2-iodothiophenol was
It was 0.13%. The organic layer was distilled to obtain 203.7 g of 4-iodothiophenol. The organic yield was 86.3% (relative to monoiodobenzene), the purity was 99.6%, and 2-iodothiophenol was contained at 0.13%.

Comparative Example 4 343.1 g of a reaction liquid containing 4-iodobenzenesulfonyl chloride corresponding to 1.0 mol in the reaction liquid of Production Example 4 was added dropwise to 300 g of water over 30 minutes. During this time, the temperature was kept at 10 ° C. The mixture was stirred at the same temperature for 1 hour and 30 minutes, filtered under reduced pressure, and washed with 100 g of water. 307.8 g of the obtained wet cake was added to 50 g of toluene and 646 g (6.2 mol) of concentrated hydrochloric acid, and 202.7 g (3.1 mol) of zinc was added over 1 hour while the temperature was raised from 20 ° C to 80 ° C. After keeping at 85 ℃ for 2 hours, add 400g of toluene,
It was cooled to 30 ° C. and then separated. The toluene layer was washed with 100 g of 10% hydrochloric acid and then with 100 g of water to obtain 659.5 g of an organic layer. The production yield of 4-iodothiophenol is 89.8%.
The content of 2-iodothiophenol was 2.50%. 4-iodothiophenol was distilled as in Example 7.
205.6g was obtained. The physical yield is 87.1% (vs. monoiodobenzene), the purity is 98.8%, and 2-iodothiophenol is 2.
It contained 50%.

(Effect of the Invention) According to the present invention, a reaction solution containing 4-halogenobenzenesulfonyl chloride is added to a mixed solution of water and an organic solvent to cause crystallization, and this is filtered to obtain two isomers of isomers.
-The halogenobenzenesulfonyl chloride can be easily removed, and 4-halogenobenzenesulfonyl chloride containing almost no isomer can be obtained. Then, by reducing this, 4-halogenothiophenol having an extremely low content of 2-halogenothiophenol, which is difficult to separate by a usual method, can be obtained in a high yield never before.

Claims (10)

[Claims] 1. A 4-halogenobenzenesulfonyl chloride derived from a halogenobenzene by sulfonation and chlorination is reduced with zinc and / or tin and a mineral acid to produce 4-halogenobenzenesulfonyl chloride.
Upon obtaining the halogenothiophenol, the reaction solution containing 4-halogenobenzenesulfonyl chloride was added to a mixed solution of water and an organic solvent, crystallized and collected by filtration, and then reduced with zinc and / or tin and a mineral acid. And a method for producing 4-halogenothiophenol. 2. The method according to claim 1, wherein the mixing ratio in the mixed liquid of water and the organic solvent is 0.1 to 3.0 parts by weight with respect to 1 part by weight of water. 3. The method according to claim 1, wherein the organic solvent is an alcohol. 4. The alcohol is methanol, ethanol,
The method according to claim (3), which is selected from the group consisting of propanol. 5. The method according to claim 1, wherein the organic solvent is an aliphatic hydrocarbon. 6. The method according to claim 5, wherein the aliphatic hydrocarbon is hexane or heptane. 7. The organic solvent is ethers (1).
The described method. 8. The method according to claim 7, wherein the ether is dioxane. 9. The method according to claim 1, wherein the halogenobenzene is monochlorobenzene. 10. The method according to claim 1, wherein the halogenobenzene is monobromobenzene.