JP2002241361A - Method for producing diphenyl disulfide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for extremely safely producing a diphenyl disulfide derivative in high yield and selectivity. SOLUTION: A diphenyl disulfide derivative expressed by general formula (II) (R is a 1-6C alkyl, a 1-6C alkoxy, a halogen atom or hydrogen atom) is produced directly from a benzenesulfonyl chloride derivative expressed by general formula (I) (R is a 1-6C alkyl, a 1-6C alkoxy, a halogen atom or hydrogen atom) by reducing the starting compound in a binary phase system composed of water and an organic solvent in the presence of a mineral acid using 2-3 times mol of metallic zinc based on the benzenesulfonyl chloride derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an industrial direct production method capable of providing a diphenyl disulfide derivative useful as a synthetic intermediate or a raw material for agricultural chemicals, pharmaceuticals, electronic materials, etc. in a high yield and with high selectivity. .

[0002]

2. Description of the Related Art Conventionally, a method for synthesizing a diphenyl disulfide derivative from an aromatic thiol has been known as an oxidation reaction using hydrogen peroxide (Organic Synthesis).
III, 86) is generally known. For example, it can be easily inferred that the method can be applied to 4-methoxybenzenethiol, but the raw material 4-methoxybenzenethiol is generally difficult to obtain. Moreover, it is expensive and is not suitable as a method for industrially producing a diphenyl disulfide derivative.

Therefore, as a method for producing a benzenethiol derivative, a method disclosed in Japanese Patent Application Laid-Open No. Sho 57-62252 has been proposed. However, the use of an equimolar amount of triphenylphosphine and the treatment of a waste liquid containing phosphorus are also required. However, this method is not always industrially advantageous.

As a method for synthesizing a diphenyl disulfide derivative, for example, a method using 4-methoxybenzenesulfonyl chloride as a raw material is known.
Org. Chem. , 1990, 55, 3728,
The use of expensive tungsten in equivalent molar amounts with the raw material 4-methoxybenzenesulfonyl chloride enables a 61%
To give bis (4-methoxyphenyl) disulfide in a yield of In addition, Chem. Ph
arm. Bull. , 1987, 35, 1770,
For example, by using a 6-fold molar excess of sodium borohydride relative to the starting 4-methoxybenzenesulfonyl chloride, the bis (4-
It is known that (methoxyphenyl) disulfide is obtained. However, none of these documents is suitable for industrial production.

[0005] Further, a method of synthesizing a benzenethiol derivative by reacting a benzenesulfonyl chloride derivative with zinc metal and a mineral acid (sulfuric acid) in water (Tetrahe)
dron, 1994, 50, 4775). However, since this method involves rapid generation of hydrogen during the reaction, it is difficult to control the reaction temperature and is not necessarily an industrially advantageous method. In addition, there are problems that the reaction proceeds heterogeneously and that diphenyl disulfide derivatives cannot be directly synthesized.

[0006]

SUMMARY OF THE INVENTION The present invention solves the above-mentioned problems relating to the method for producing a diphenyl disulfide derivative from a benzenesulfonyl chloride derivative, and provides a high yield, high selectivity and industrially excellent diphenyl. An object of the present invention is to provide a method for directly producing a disulfide derivative.

[0007]

The present invention provides a compound represented by the following general formula (I):

[0008]

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(Wherein, R represents an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom or a hydrogen atom), and a benzenesulfonyl chloride derivative represented by the following general formula: (II),

[0010]

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(Wherein R represents an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom or a hydrogen atom). The present invention relates to a direct method for producing a diphenyl disulfide derivative, which comprises reducing in a two-phase solution of water and an organic solvent using 2 to 4 times the molar amount of zinc metal with respect to the benzenesulfonyl chloride derivative in the presence of an acid.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formulas (1) and (II) of the present invention, the substituent R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec. A straight-chain alkyl group having 1 to 6 carbon atoms or a branched alkyl group such as -butyl group, tert-butyl group, n-pentyl group, iso-pentyl group, tert-pentyl group, and n-hexyl group. . Further, as the substituent R, a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group, an n-butoxy group, a sec-
A linear alkoxyl group having 1 to 6 carbon atoms such as a butoxy group, a tert-butoxy group, an n-pentyloxy group, an iso-pentyloxy group, a tert-pentyloxy group, and an n-hexyloxy group, or a branched alkoxyl group Is mentioned. Further, examples of the substituent R include a halogen atom and a hydrogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The metal zinc used in the present invention is preferably used in an amount of 2 to 4 moles per mole of the benzenesulfonyl chloride derivative. In the case of 2 to 4 moles, the diphenyl disulfide derivative is directly and selectively synthesized. If the amount is excessively less than 2 times, the starting benzenesulfonyl chloride derivative and the reaction intermediate S-phenylbenzenethiosulfonate derivative remain, and the desired diphenyl disulfide derivative is synthesized with high yield and high selectivity. Can not do. If the molar ratio is excessively higher than 4 times, only the benzenethiol derivative which is a by-product of the diphenyl disulfide derivative is synthesized with high selectivity, and the diphenyl disulfide derivative cannot be synthesized directly.

As specific examples of the mineral acid used in the present invention,
Examples thereof include phosphoric acid, nitric acid, sulfuric acid, and hydrochloric acid, and among them, sulfuric acid is preferable. The amount of the mineral acid is:
Usually, 1 to 3 moles are preferable. If the amount is excessively less than this range, the starting benzenesulfonyl chloride derivative and the reaction intermediate S-phenylbenzenethiosulfonate derivative remain, and the desired diphenyl disulfide derivative is synthesized with high yield and high selectivity. Can not. On the other hand, if the amount is excessively large, the intended diphenyl disulfide derivative can be synthesized, but there is no point in increasing the amount in consideration of waste liquid treatment.

The specific organic solvent used in the present invention is not particularly limited as long as it is an organic solvent inert to the above reaction. Any organic solvent in which a benzenesulfonyl chloride derivative is dissolved can be used. It can be used as appropriate. Examples thereof include diethyl ether, dimethoxyethane, diethoxyethane, n-hexane, n-heptane, benzene, toluene and (o, m, p-) xylene. These organic solvents may be used alone,
Mixing may be used.

The solvent used in the present invention is a mixed solvent of water and an organic solvent, and the volume ratio of water to the organic solvent (water / organic solvent) is preferably 1/5 to 5/1, and water and the organic solvent are preferably used. Is 0.05 to 20 times the weight of the starting benzenesulfonyl chloride derivative, preferably 0.2 to 1 time.
Five weight times are used. If the absolute amount of the organic solvent excessively contained is smaller than this range, the precipitation of organic substances as by-products becomes remarkable, the reduction reaction stops halfway, and a large amount of unreacted metallic zinc remains. The reaction solution can be heated to complete the reaction. At this time, unreacted zinc reacts violently with mineral acid (sulfuric acid) at around 30 ° C., causing an exothermic reaction accompanied by generation of hydrogen. . For this reason, there is a problem that control of the reaction becomes impossible, and it is not possible to selectively synthesize a target diphenyl disulfide derivative. On the other hand, if the absolute amount of water is excessively small, the desired diphenyl disulfide derivative will be formed, but the salt generated during the reaction will be precipitated, resulting in poor stirring efficiency and waste liquid treatment. Therefore, the absolute amount of water is preferably larger than the amount that dissolves all the salts generated during the reaction.

The temperature range of the present invention is preferably from -10 to 20 ° C, more preferably from -5 to 12 ° C, from the start of the addition of zinc metal to 1 to 2 hours after the addition. Also,
30 minutes from 1-2 hours after the addition of zinc metal to the end of the reaction
110 ° C is preferred, and more preferably 70 to 90 ° C.

As a method for extracting the desired diphenyl disulfide derivative from the reaction mixture, the reaction mixture is cooled, the organic layer is separated, made basic with an aqueous alkali hydroxide solution, and the diphenyl disulfide derivative, water A small amount of benzenethiol derivative can be separated on the layer side. On the organic layer side, the diphenyl disulfide derivative can be easily taken out by distilling off the organic solvent.
The aqueous layer side is made acidic again and extracted with an organic solvent such as toluene, and then a small amount of a benzenethiol derivative can be taken out by distilling off the organic solvent. Further, by combining these operations with means such as distillation or recrystallization, a higher-purity diphenyl disulfide derivative can be obtained.

When a diphenyl disulfide derivative is selectively obtained, an oxidation reaction can be carried out without purification after the above-mentioned reduction reaction. That is, after the completion of the above reduction reaction, the organic layer is separated from the reaction mixture, and the benzenethiol derivative, which is a small amount of by-product, is isolated and separated without being separated from the reaction mixture. And oxidation reaction with hydrogen peroxide
Only a diphenyl disulfide derivative can be selectively obtained. In this case, an aqueous solution of 10% to 35% of hydrogen peroxide can be used, and it is preferable that the molar amount be 2.0 times or less the benzenethiol derivative as a by-product.

[0020]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist.

Example 1 Concentrated sulfuric acid (95%, 28.1 g, 272) was added to ice (100 g).
mmol) was added in four portions, and 4-methoxybenzenesulfonyl chloride (15.0 g, 72 mmol) in toluene (7 mmol) was added while stirring in an ice bath (inner temperature 10 ° C. or less).
0 ml) solution was added. Add zinc powder (1
(1.8 g, 181 mmol) was added little by little over 30 minutes, and the mixture was stirred for 1.5 hours while maintaining the internal temperature at 10 ° C or lower. The mixture was gradually heated, heated to reflux for 1 hour, and further stirred. The reaction solution became transparent and stirred for 3 hours from the start of reflux. After cooling the reaction mixture to 40 ° C., the organic layer was separated, shaken with a 2N aqueous solution of caustic soda, and bis (4
(-Methoxyphenyl) disulfide was extracted into the organic layer and 4-methoxybenzenethiol was extracted into the aqueous phase. After the aqueous phase was acidified with 2N hydrochloric acid, 4-methoxybenzenethiol was extracted into the organic layer with toluene. The solution of bis (4-methoxyphenyl) disulfide and the solution of 4-methoxybenzenethiol are dried over sodium sulfate, respectively,
The solvent was distilled off under reduced pressure to obtain 8.53 g of bis (4-methoxyphenyl) disulfide, a yield of 85.2%, and 0.68 g of 4-methoxybenzenethiol, a yield of 6.7%.

Comparative Example 1 Concentrated sulfuric acid (95%, 77.3 g, 750) was added to ice (250 g).
mmol) was added in four portions, and 4-methoxybenzenesulfonyl chloride (20.7 g, 100 mmol) was added while stirring in an ice bath (inner temperature 10 ° C. or lower). Zinc powder (32.5 g, 500 mmol) under vigorous stirring
Was added little by little over 30 minutes, and the mixture was further stirred for 1 hour while maintaining the internal temperature at 10 ° C or lower. When heated gradually, it reacted violently at about 25 ° C. and generated hydrogen while generating heat. Heat the mixture to reflux and continue stirring.
The mixture was stirred for 6 hours from the start of reflux. After cooling the reaction mixture to 40 ° C., it was extracted with toluene and dried over sodium sulfate.
After distilling off the solvent under reduced pressure, liquid chromatography analysis revealed that the yield was 2.0% for bis (4-methoxyphenyl) disulfide and 80.3% for 4-methoxybenzenethiol.
Met.

Comparative Example 2 Concentrated sulfuric acid (95%, 28.1 g, 272) was added to ice (100 g).
mmol) was added in four portions, and 4-methoxybenzenesulfonyl chloride (15.0 g, 72 mmol) was added while stirring in an ice bath (inner temperature 10 ° C. or lower). Under vigorous stirring, zinc powder (11.8 g, 181 mmol) was added little by little over 30 minutes, and the mixture was further stirred for 1.5 hours while maintaining the internal temperature at 10 ° C or lower. When heated gradually, it reacted violently at about 25 ° C. and generated hydrogen while generating heat. When the mixture was heated to reflux and further stirred, the reaction solution became transparent and stirred for 5 hours from the start of reflux. Reaction mixture at 40 ° C
After cooling to room temperature, the mixture was extracted with toluene and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 15 g of an oily mixture. According to liquid chromatography analysis, the yield was 9.9% for bis (4-methoxyphenyl) disulfide, 18.4% for 4-methoxybenzenethiol, and 63% for S- (4-methoxyphenyl) 4-methoxybenzenethiosulfonate.
It was 0%.

Comparative Example 3 Concentrated sulfuric acid (95%, 77.4 g, 750) was added to ice (250 g).
mmol) was added in four portions, and a solution of 4-methoxybenzenesulfonyl chloride (20.7 g, 100 mmol) in toluene (100 ml) was added while stirring in an ice bath (inner temperature 10 ° C. or lower). Under vigorous stirring, zinc powder (32.5 g, 500 mmol) was added little by little over 30 minutes, and the mixture was further stirred for 1 hour while keeping the internal temperature at 10 ° C or lower. The mixture was gradually heated, heated to reflux for 1 hour, and further stirred. The reaction solution became transparent and stirred for 3 hours from the start of reflux. After cooling the reaction mixture to 40 ° C., the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
By liquid chromatography analysis, the yield was bis (4-
(Methoxyphenyl) disulfide was 0.7%, and 4-methoxybenzenethiol was 91.4%.

Comparative Example 4 Concentrated sulfuric acid (95%, 23.2 g, 225 m) was added to ice (85 g).
mol) was added in four portions, and a solution of 4-methoxybenzenesulfonyl chloride (20.7 g, 100 mmol) in toluene (100 ml) was added while stirring in an ice bath (inner temperature 10 ° C or lower). Under vigorous stirring, zinc powder (9.8 g, 150 mmol) was added little by little over 30 minutes, and the mixture was further stirred for 1.5 hours while maintaining the internal temperature at 10 ° C or lower. When heated gradually, it reacted violently at about 25 ° C. and generated hydrogen while generating heat. When the mixture was heated to reflux and further stirred, the reaction solution became transparent and stirred for 5 hours from the start of reflux. The reaction mixture was cooled to 40 ° C., extracted with toluene, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 15 g of an oily mixture. According to liquid chromatography analysis, the yield was 47.0% for bis (4-methoxyphenyl) disulfide and 2.70% for 4-methoxybenzenethiol.
2% and 32.0% of S- (4-methoxyphenyl) 4-methoxybenzenethiosulfonate.

Example 2 Concentrated hydrochloric acid (36%, 76 g, 760 mm) was added to ice (150 g).
ol) in 4 portions and add in an ice bath (internal temperature 10 ° C or less)
While stirring with 4-methoxybenzenesulfonyl chloride (20.7 g, 100 mmol) in toluene (10
0 ml) solution was added. Zinc powder (2
(2.8 g, 350 mmol) was added little by little over 30 minutes, and the mixture was stirred for 1.5 hours while maintaining the internal temperature at 10 ° C or lower. The mixture was gradually heated, heated to reflux for 1 hour, and further stirred. The reaction solution became transparent and stirred for 3 hours from the start of reflux. After cooling to 40 ° C., the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 15 g of a mixture of bis (4-methoxyphenyl) disulfide and 4-methoxybenzenethiol. According to liquid chromatography analysis, the yield was 82.3% for bis (4-methoxyphenyl) disulfide and 8.3% for 4-methoxybenzenethiol.

Example 3 Concentrated sulfuric acid (95%, 43.0 g, 417) was added to ice (100 g).
mmol) was added in four portions, and a solution of 4-methoxybenzenesulfonyl chloride (25.0 g, 121 mmol) in dimethoxyethane (100 ml) was added while stirring in an ice bath (inner temperature 10 ° C. or lower). Under vigorous stirring, add zinc powder (22.6 g, 348 mmol) in small portions 30
The mixture was added over minutes, and the mixture was further stirred for 1.5 hours while maintaining the internal temperature at 10 ° C. or lower. The mixture was gradually heated, heated to reflux for 1 hour, and further stirred. The reaction solution became transparent and stirred for 3 hours from the start of reflux. After cooling to 40 ° C., the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 18 g of a mixture of bis (4-methoxyphenyl) disulfide and 4-methoxybenzenethiol. According to liquid chromatography analysis, the yield was 85.6% for bis (4-methoxyphenyl) disulfide and 3.7% for 4-methoxybenzenethiol. Examples 1-3
Table 1 shows the production conditions and yields of Comparative Examples 1 to 4.
Shown in

[0028]

[Table 1]

Example 4 After the reaction of Example 1, a 2N aqueous solution of caustic soda (7 m
, 14 mmol), and the mixture was stirred at 65 ° C, and 30% aqueous hydrogen peroxide (0.30 ml, 2.7 mmol) was added dropwise so that the internal temperature was maintained at 65 to 70 ° C. After cooling the reaction mixture to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain bis (4-methoxyphenyl).
A yield of 91.7% was obtained from 9.18 g of disulfide and 4-methoxybenzenesulfonyl chloride.

Example 5 After the reaction of Example 1, a 2N aqueous solution of caustic soda (7 m
1, 14 mmol), and the mixture was stirred at 65 ° C, and 30% aqueous hydrogen peroxide (0.22 ml, 1.94 mmol) was added dropwise so that the internal temperature was maintained at 65 to 70 ° C. After cooling the reaction mixture to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain bis (4-methoxyphenyl).
A yield of 89.1% was obtained from 8.92 g of disulfide and 4-methoxybenzenesulfonyl chloride.

Comparative Example 5 After the reaction of Example 1, a 2N aqueous solution of caustic soda (7 m
1, 14 mmol), and the mixture was stirred at 65 ° C, and 30% aqueous hydrogen peroxide (5.50 ml, 48.6 mmol) was added dropwise so that the internal temperature was maintained at 65 to 70 ° C. After cooling the reaction mixture to room temperature, the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain bis (4-methoxyphenyl).
A yield of 63.2% was obtained from 6.33 g of disulfide and 4-methoxybenzenesulfonyl chloride. Examples 4 and 5
Table 2 below shows the production conditions and the yields of Comparative Example 5.

[0032]

[Table 2]

Example 6 In place of 4-methoxybenzenesulfonyl chloride as a raw material, benzenesulfonyl chloride (12.7 g, 72 m
mol)), and the reaction was conducted in the same manner as in Example 1. According to liquid chromatography analysis, the yields were 73.4% of diphenyl disulfide and 10.1% of thiophenol.

Example 7 Example 1 was repeated except that 4-isopropoxybenzenesulfonyl chloride (17.0 g, 72 mmol) was used in place of 4-methoxybenzenesulfonyl chloride as a raw material.
The reaction was carried out in the same manner as described above. According to liquid chromatography analysis, the yields were 88.4% of bis (4-isopropoxyphenyl) disulfide and 3.6% of 4-isopropoxybenzenethiol.

Example 8 In place of 4-methoxybenzenesulfonyl chloride as a raw material, 4-toluenesulfonyl chloride (13.8 g, 7
The reaction was carried out in the same manner as in Example 1 except that 2 mmol) was used. According to liquid chromatography analysis, the yield was 74.3% for di (4-tolyl) disulfide,
Methylthiophenol was 11.5%.

Example 9 Example 1 was repeated, except that 4-tert-butylbenzenesulfonyl chloride (16.8 g, 72 mmol) was used in place of the raw material 4-methoxybenzenesulfonyl chloride.
The reaction was carried out in the same manner as described above. Liquid chromatography analysis showed that the yields were 86.0% of bis (4-tert-butylphenyl) disulfide and 6.8% of 4-tert-butylbenzenethiol.

Example 10 In place of 4-methoxybenzenesulfonyl chloride as a raw material, 4-chlorobenzenesulfonyl chloride (15.2) was used.
g, 72 mmol), and the reaction was carried out in the same manner as in Example 1. Liquid chromatography analysis showed that the yields were 82.9% of bis (4-chlorophenyl) disulfide and 8.8% of 4-chlorothiophenol.

[0038]

According to the present invention, by causing a reaction in a two-phase liquid of water and an organic solvent, there is no rapid generation of hydrogen and no reaction thermal runaway as compared with the conventional method.
High yield, high selectivity and high safety could be established. In addition, by reducing the amount of metal zinc used, it is possible to selectively produce diphenyl disulfide derivatives,
The load of waste liquid treatment was reduced.

Claims (4)

[Claims] 1. A compound represented by the following general formula (I): (Where R is an alkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms)
6 represents an alkoxyl group, a halogen atom or a hydrogen atom. From the benzenesulfonyl chloride derivative represented by the following general formula (II): (Where R is an alkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms)
6 represents an alkoxyl group, a halogen atom or a hydrogen atom. In the method for producing a diphenyl disulfide derivative represented by the formula (2), a metal zinc is used in an amount of 2 to 4 times the molar amount of the benzenesulfonyl chloride derivative in the presence of a mineral acid, and reduction is carried out in a two-phase liquid of water and an organic solvent. A method for directly producing a diphenyl disulfide derivative. 2. The method for directly producing a diphenyl disulfide derivative according to claim 1, wherein the amount of said mineral acid is 1 to 3 times mol with respect to said metallic zinc. 3. A volume ratio of the water and the organic solvent (water / water).
The organic solvent) is 1/5 to 5/1, and the weight ratio of the total weight of the water and the organic solvent to the benzenesulfonyl chloride derivative is 0.05 to 20. A method for producing a diphenyl disulfide derivative according to the above. 4. An organic layer containing a diphenyl disulfide derivative and a benzenethiol derivative as a by-product is fractionated from the reaction mixture obtained by the reduction, and the organic layer is 2.0 moles or less of the benzenethiol derivative. 4. The method for directly producing a diphenyl disulfide derivative according to claim 1, wherein the benzene thiol derivative is oxidized to diphenyl disulfide derivative by adding hydrogen peroxide.