JP2003221377A - Method for producing trifluoromethylbenzene sulfonyl chloride compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a production method capable of producing a trifluoromethylbenzene sulfonyl chloride compound in a high yield and with high purity. <P>SOLUTION: A benzotrifluoride compound represented by formula (1) (X and Y are same or different and are each hydrogen or a halogen atom) is reacted with sulfur trioxide and the resulted sulfonic compound represented by formula (2) (X and Y are the same as the above) is chlorinated to form the trifluoromethylbenzene sulfonyl chloride compound represented by formula (3) (X and Y are the same as the above). <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a trifluoromethylbenzenesulfonyl chloride compound.

[0002]

2. Description of the Related Art General formula (3)

[0003]

[Chemical 4]

[Wherein X and Y are the same or different,
Indicates a hydrogen atom or a halogen atom. ] The trifluoromethylbenzenesulfonyl chloride compound represented by the formula is for use in synthesizing pharmaceuticals as described in, for example, Journal of Medicinal Chemistry Vol. 41, pp. 4885-4889 (1998). It is a compound useful as an intermediate.

As a method for producing a trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3), for example, a method of directly converting a trifluoromethylbenzene compound into a chlorosulfonyl group is known (Japanese Patent Publication No. Sho 5).
4-9191). In this method, as shown in the reaction formula below, a trifluoromethylbenzene compound is added dropwise to a mixed liquid of chlorosulfonic acid and fuming sulfuric acid to carry out a chlorosulfonylation reaction, and then the reaction liquid is added to a large amount of ice. Then, the excess chlorosulfonic acid is hydrolyzed and the fuming sulfuric acid is diluted, and then the target compound is isolated and purified.

[0006]

[Chemical 5]

[In the formula, X and Y are the same as above. However, in this method, when the reaction liquid is added to ice, the target compound is contacted with water and decomposed into a sulfonic acid compound, so that a decrease in the yield of the target compound cannot be avoided. Further, since a large amount of sulfuric acid is produced as a waste liquid, it becomes necessary to treat the waste liquid, which is disadvantageous as an industrial manufacturing method.

As an improvement of the production method described in Japanese Patent Publication No. 54-9191, a trifluoromethylbenzene compound is subjected to a sulfonation reaction at 30 to 70 ° C. with fuming sulfuric acid, and then chlorsulfone is added. A method has been developed in which an acid is added to carry out a chlorosulfonylation reaction at 20 to 60 ° C. (JP-A-63-104952).

However, JP-A-63-104952
Even in the method described in the publication, the reaction liquid is added to a large amount of ice, so the decomposition of the target compound is unavoidable, and therefore the effect of improving the yield of the target compound is insufficient.

Further, Japanese Patent Laid-Open No. 2-157257 discloses
A method of reacting a trifluoromethylbenzene compound with fuming sulfuric acid and chlorosulfonic acid, adding an inert solvent to the resulting reaction solution, extracting the target compound into an inert solvent, and isolating and purifying the target compound from the extract. Is. Since this method does not add the reaction solution to a large amount of ice,
The aim is to avoid decomposition of the target compound and improve the yield of the target compound.

However, in the method described in Japanese Patent Application Laid-Open No. 2-157257, the reaction solution is directly added with an inert solvent for extraction, so that the extraction efficiency is extremely poor and it is necessary to perform extraction with a large amount of inert solvent many times. Therefore, not only the cost becomes high, but also the operation becomes complicated. Moreover, since fuming sulfuric acid and chlorosulfonic acid used in the reaction are incorporated into the extract of the inert solvent, it is necessary to remove fuming sulfuric acid and chlorosulfonic acid from the extract. Therefore, this method is extremely unsuitable as an industrial manufacturing method.

Furthermore, the inventors of the present invention investigated the methods described in JP-A-63-104952 and JP-A-2-157257, and found that trifluoromethylbenzene represented by the general formula (3) was used. Among the sulfonyl chloride compounds, particularly when at least one of X and Y is a compound showing a fluorine atom, most of the trifluoromethyl group present on the benzene ring of the raw material compound is hydrolyzed during the reaction. Converted to a carboxyl group,
As a result, it was found that the target compound could be produced only in a low yield (see Comparative Examples 1 and 2 below).

[0013]

An object of the present invention is to provide an industrially advantageous method for producing a trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3).

An object of the present invention is to provide a production method capable of producing the above trifluoromethylbenzenesulfonyl chloride compound in high yield and high purity.

[0015]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to develop a method for producing a trifluoromethylbenzenesulfonyl chloride compound that solves the above problems. As a result, they have found that the above problems can be solved by reacting a benzotrifluoride compound with sulfur trioxide and then chlorinating the compound produced. The present invention has been completed based on such knowledge. 1. The present invention has the general formula (1)

[0016]

[Chemical 6]

[In the formula, X and Y are the same as defined above. ] The benzotrifluoride compound represented by

[0018]

[Chemical 7]

[Wherein X and Y are the same as defined above]. ] By chlorinating the sulfonic acid compound represented by the general formula (3)

[0020]

[Chemical 8]

[Wherein X and Y are the same as defined above]. ] The manufacturing method of the trifluoromethyl benzene sulfonyl chloride compound characterized by manufacturing the trifluoromethyl benzene sulfonyl chloride compound represented by these. 2. In the present invention, a benzotrifluoride compound represented by the general formula (1) is reacted with sulfur trioxide, and then a sulfonic acid compound represented by the general formula (2) produced is chlorinated without isolation. The manufacturing method according to the above 1, wherein 3. The present invention is the production method described in the above 1, wherein unreacted sulfur trioxide is taken out from the reaction system prior to chlorination.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the benzotrifluoride compound represented by the general formula (1) used as a starting material is a known compound.

Examples of the benzotrifluoride compound represented by the general formula (1) include benzotrifluoride,
2-fluorobenzotrifluoride, 4-fluorobenzotrifluoride, 2,4-difluorobenzotrifluoride, 2-chlorobenzotrifluoride, 4-chlorobenzotrifluoride, 2,4-dichlorobenzotrifluoride, 2-chloro- 4-fluorobenzotrifluoride, 2-fluoro-4-chlorobenzotrifluoride, 2-bromobenzotrifluoride, 4-bromobenzotrifluoride, 2,4-dibromobenzotrifluoride, 2-bromo-4-fluorobenzotrifluoride Lido, 2-fluoro-4-bromobenzotrifluoride,
2-bromo-4-chlorobenzotrifluoride, 4-bromo-2-chlorobenzotrifluoride and the like can be mentioned.

The reaction between the benzotrifluoride compound represented by the general formula (1) and sulfur trioxide is carried out without solvent or in a suitable inert solvent. Examples of the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride and the like. These inert solvents may be used alone or in combination of 2
Mixtures of two or more can be used.

The ratio of the benzotrifluoride compound represented by the general formula (1) and sulfur trioxide to be used is usually 1 to 10 mol, preferably 1 to 4 mol of the latter with respect to 1 mol of the former.
It is good to set it to about molar.

The reaction between the benzotrifluoride compound represented by the general formula (1) and sulfur trioxide is a sulfonation reaction, and the reaction produces a sulfonic acid compound represented by the general formula (2).

The reaction temperature of this sulfonation reaction is usually −
10 ° C to around the boiling point of the inert solvent, preferably 20 to 50
C., about 30 to 40.degree. C. is more preferable. The reaction time varies depending on the reaction temperature, but is usually about 0.1 to 10 hours, preferably about 1 to 3 hours.

As a preferred embodiment of the sulfonation reaction, for example, a benzotrifluoride compound of the general formula (1) is gradually added to a predetermined amount of sulfur trioxide, or a benzotrifluoride compound of the general formula (1) is added. It is advisable to gradually add sulfur trioxide to the trifluoride compound. When an inert solvent is used, sulfur trioxide may be dissolved in the inert solvent, or the benzotrifluoride compound represented by the general formula (1) may be dissolved in the inert solvent. When the benzotrifluoride compound of the general formula (1) and sulfur trioxide are mixed,
The temperature of the mixture gradually rises. In the present invention, it is preferable to adjust the addition rate when mixing the benzotrifluoride compound of the general formula (1) and sulfur trioxide so that the temperature of the mixture is maintained in the range of 30 to 40 ° C.

In the present invention, the following general formula (2) is generated.
The sulfonic acid compound represented by is chlorinated. The sulfonic acid compound of the general formula (2) produced by the sulfonation reaction may be isolated and then chlorinated, but from the viewpoint of reaction efficiency, the sulfonic acid compound of the general formula (2) produced by the sulfonation reaction may be used. It is preferable to use the reaction mixture as it is for the next chlorination reaction without isolation of the sulfonic acid compound.

Further, in the present invention, it is desirable to isolate unreacted sulfur trioxide or sulfur trioxide and an inert solvent present in the reaction mixture prior to chlorination. As the isolation means, known isolation means can be widely applied. Examples of such isolation means include vacuum distillation and the like.
Since the isolated sulfur trioxide can be recovered and reused,
It is advantageous in terms of manufacturing cost and waste liquid treatment.

Chlorination of the sulfonic acid compound of the general formula (2) is carried out, for example, by reacting the sulfonic acid compound of the general formula (2) with a chlorinating agent.

A wide variety of known chlorinating agents can be used, and examples thereof include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, chlorosulfonic acid and sulfuryl chloride. These chlorinating agents may be used alone or in combination of two or more. Among these chlorinating agents, thionyl chloride is preferable.

Chlorination of the sulfonic acid compound of the general formula (2) is carried out without solvent or in a suitable inert solvent, preferably without solvent. Examples of the inert solvent include halogen-based solvents such as methylene chloride, dichloroethane and carbon tetrachloride, aromatic hydrocarbon-based solvents such as toluene, chlorobenzene and xylene, and aliphatic hydrocarbon-based solvents such as n-hexane and n-heptane. Etc. can be mentioned. These inert solvents can be used alone or in combination of two or more.

In the present invention, in order to allow the reaction to proceed smoothly, dimethylformamide or the like may be present in the reaction system.

The ratio of the sulfonic acid compound of the general formula (2) to the chlorinating agent is usually 1 to 1 mol of the former and 1 to 2 mol of the latter.
It is about 5 mol, preferably about 1.2 to 2.2 mol.

The reaction temperature of the chlorination reaction is usually 0 to 160.
C., preferably 60 to 110.degree. C., more preferably 65 to 100.degree. C., and particularly preferably 70 to 90.degree. The reaction time of the chlorination reaction varies depending on the reaction temperature, but is usually about 1 to 10 hours, preferably about 2 to 5 hours.

By chlorinating the sulfonic acid compound of the general formula (2), the desired trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3) is produced.

After completion of the chlorination reaction, in the present invention, the trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3) can be isolated by concentrating the reaction solution under reduced pressure. The obtained trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3) can be used as it is as an intermediate for synthesizing a drug or the like.

Further, in the present invention, the reaction solution after completion of the reaction is concentrated under reduced pressure, an inert solvent is added to the resulting concentrated solution, and trifluoromethylbenzenesulfonyl chloride represented by the general formula (3) is added. By extracting the compound in an inert solvent, washing the extract with water, and concentrating it, the target trifluoromethylbenzenesulfonyl chloride compound compound represented by the general formula (3) can be isolated.

Examples of the inert solvent used for extracting the reaction solution include halogen solvents such as methylene chloride, dichloroethane and carbon tetrachloride, aromatic hydrocarbon solvents such as toluene, chlorobenzene and xylene, n-hexane, n-
Examples thereof include aliphatic hydrocarbon solvents such as heptane. These inert solvents can be used alone or in combination of two or more.

When the method of concentrating the reaction solution under reduced pressure after the chlorination reaction is adopted, the unreacted chlorinating agent can be recovered and reused, which is advantageous in terms of manufacturing cost, waste liquid treatment, and the like.

In the method of the present invention, since the sulfur trioxide used in the sulfonation reaction and the inert solvent and the chlorinating agent used in the chlorination reaction are removed from the reaction solution, it is possible to extract the target compound. The amount of the inert solvent used can be greatly suppressed.

The amount of the inert solvent used is usually 1 to 10 times the volume of the reaction liquid to be extracted, preferably 2 times.
Up to 5 times capacity is sufficient.

The inert solvent from which the target compound has been extracted may be mixed with a small amount of chlorinating agent or the like which has not been recovered. By washing the solvent with water, the mixed impurities can be removed. it can. Thus, the trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3), which is the object of the present invention, can be produced with high purity.

[0045]

INDUSTRIAL APPLICABILITY According to the method of the present invention, the trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3) can be obtained in a high yield (eg 90% or more) and a high purity (eg 95
% Or more) can be provided. The method of the present invention is particularly suitable for producing a fluorine-substituted trifluoromethylbenzenesulfonyl chloride compound such as 2-fluoro-5-trifluoromethylbenzenesulfonyl chloride and 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride.

In the method of the present invention, the sulfur trioxide used in the sulfonation reaction and the chlorinating agent used in the chlorination reaction can be recovered and reused. For this reason, the waste liquid treatment becomes unnecessary, and the amounts of sulfur trioxide and the chlorinating agent can be reduced, so that the manufacturing cost can be suppressed.

In the method of the present invention, the amount of the inert solvent used for extracting the target compound can be greatly suppressed.

Therefore, the method of the present invention is extremely advantageous as an industrial method for producing the trifluoromethylbenzenesulfonyl chloride compound of the general formula (3).

[0049]

EXAMPLES The present invention will be further clarified with reference to the following examples.

Example 1 In a mixed solution of 30 g of sulfur trioxide and 30 g of methylene chloride,
15 g of 4-fluorobenzotrifluoride was added dropwise at 20 ° C. Although the temperature of the reaction solution gradually rises as the dropping proceeds, the dropping rate was adjusted so that the temperature of the reaction solution was maintained in the range of 30 to 35 ° C. After completion of dropping, the mixture was stirred for 2 hours.
From the NMR spectrum of the reaction solution, disappearance of 4-fluorobenzotrifluoride as a raw material was confirmed.

Next, methylene chloride and sulfur trioxide were distilled from the reaction solution under reduced pressure to recover them. Further, 24 ml of thionyl chloride and a few drops of dimethylformamide were added to the reaction solution, and the mixture was heated under reflux for 5 hours. After the reaction solution was cooled to 40 ° C., thionyl chloride was distilled under reduced pressure to collect it.
After cooling the reaction solution to 10 ° C, 100 ml of n-hexane was added, and water was added while cooling so that the solution temperature did not exceed 10 ° C.
0 ml was added and the n-hexane solution was separated. After drying the n-hexane solution, it was concentrated under reduced pressure to give 2-fluoro-5.
-Trifluoromethylbenzenesulfonyl chloride 2
2.8 g (yield 95%, purity 96%) was obtained. Boiling point: 80 to 85 ° C./5 mmHg NMR spectrum (δ ppm): 8.26-8.28
(1H, m), 8.01 to 8.05 (1H, m), 7.
51 (1H, t, 9Hz).

Example 2 In a mixed solution of 37 g of sulfur trioxide and 37 g of methylene chloride,
19 g of 2-fluorobenzotrifluoride was added dropwise at 20 ° C. Although the temperature of the reaction solution gradually rises as the dropping proceeds, the dropping rate was adjusted so that the temperature of the reaction solution was maintained in the range of 30 to 35 ° C. After completion of dropping, the mixture was stirred for 2 hours.
From the NMR spectrum of the reaction solution, the disappearance of the starting material 2-fluorobenzotrifluoride was confirmed.

Next, the reaction solution was depressurized to distill methylene chloride and sulfur trioxide, and these were recovered. Further, 24 ml of thionyl chloride and a few drops of dimethylformamide were added to the reaction solution, and the mixture was heated under reflux for 5 hours. After the reaction solution was cooled to 40 ° C., thionyl chloride was distilled under reduced pressure to collect it. After cooling the reaction solution to 10 ° C., 100 ml of 1,2-dichloroethane was added, and 100 ml of water was added while cooling so that the liquid temperature did not exceed 10 ° C. to separate a 1,2-dichloroethane solution. After the 1,2-dichloroethane solution was dried, it was concentrated under reduced pressure to give 28 g of 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (yield 99%,
Purity 98%) was obtained. Boiling point: 85 to 89 ° C./5 mmHg NMR spectrum (δ ppm): 8.2-8.4 (2
H, m), 7.50 (1H, t, J = 9 Hz).

Comparative Example 1 4-Fluoro-3-trifluoromethylbenzenesulfonyl chloride was produced according to the method described in JP-A-63-104952.

That is, 33 g of 4-fluorobenzotrifluoride was added dropwise to 20 ml of 60% fuming sulfuric acid at 50 ° C. over 1 hour, and the mixture was further stirred at the same temperature for 1 hour. Then, chlorosulfonic acid (67 ml) was gradually added dropwise to this mixture at 50 ° C. The mixture was stirred for 2 hours while cooling to 20 ° C. The reaction solution was poured into 500 g of ice and stirred. n-Hexane was added, the precipitated crystals were filtered off, the n-hexane layer was taken in a separating funnel, concentrated and dried to give 5.2 g of 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (yield 10%. ) Got.

Comparative Example 2 According to the method described in JP-A-2-157257,
4-Fluoro-3-trifluoromethylbenzenesulfonyl chloride was prepared.

That is, a mixed solution of 15 ml of 60% fuming sulfuric acid and 30 ml of chlorosulfonic acid was cooled to -5 ° C., and 4-fluorobenzotrifluoride was added thereto at a temperature of 0.
The mixture was added dropwise while cooling so that the temperature did not rise above ℃. The reaction was stirred at 0 ° C for a further 4 hours. N-hexane 1 in the reaction solution
After adding 00 ml, the mixture was stirred for 1 hour and the n-hexane layer was separated. Furthermore, the same operation was repeated twice.

The n-hexane layers obtained were combined and washed with water 30
The extract was washed with 0 ml of water, dried over magnesium sulfate, and then concentrated to obtain 5 g (yield 10%) of 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): [In the formula, X and Y are the same or different and each represents a hydrogen atom or a halogen atom. ] The benzotrifluoride compound represented by the following formula is reacted with sulfur trioxide, and then formed by the general formula (2): [In the formula, X and Y are the same as defined above. ] By chlorinating the sulfonic acid compound represented by the general formula (3) [In the formula, X and Y are the same as defined above. ] The trifluoromethylbenzene sulfonyl chloride compound represented by these is manufactured, The manufacturing method of the trifluoromethyl benzene sulfonyl chloride compound characterized by the above-mentioned. 2. A benzotrifluoride compound represented by the general formula (1) is reacted with sulfur trioxide, and then a sulfonic acid compound represented by the general formula (2) produced is chlorinated without isolation. The manufacturing method according to claim 1, wherein: 3. The production method according to claim 1, wherein unreacted sulfur trioxide is taken out from the reaction system prior to chlorination.