WO2003064380A1 - Process for production of trifluoromethylbenzenesulfonyl chlorides - Google Patents

Abstract

Trifluoromethylbenzenesulfonyl chlorides represented by the general formula (3): (3) [wherein X and Y are each independently hydrogen or halogeno] are produced by reacting a benzotrifluoride represented by the general formula (1): (1) [wherein X and Y are each as defined above] with sulfur trioxide to form a sulfonic acid represented by the general formula (2): (2) [wherein X and Y are each as defined above] and then reacting the sulfonic acid with a chlorinating agent. According to the invention, trifluoromethylbenzene- sulfonyl chlorides can be produced in high yield and at high purity.

Description

 Specification

 Method for producing trifluoromethylbenzenesulfonyl chloride compound

 Technical field

 The present invention relates to a method for producing a trifluoromethylbenzenesulfol chloride compound.

 Background technology

 General formula (3)

[Wherein, X and Y are the same or different and each represent a hydrogen atom or a halogen atom. For example, the trifluoromethylbenzenesulfonyl chloride compound represented by the following formula is described in, for example, the journal “Ob Medicinal” Chemistry, Vol. 41, No. 4885-48889 (pp. 1989) It is a compound useful as an intermediate for synthesizing pharmaceuticals, as described in.

 As a method for producing the trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3), for example, a method of directly converting a trifluoromethylbenzene compound into a chloromethyl sulfonyl compound is known (Japanese Patent Publication No. — 9 191 issue). In this method, as shown in the following reaction formula, a trifluorosulfonylation reaction is carried out by dropping a trifluoromethylbenzene compound into a mixture of chlorosulfonic acid and fuming sulfuric acid, and then the reaction is carried out in a large amount of ice. This is a method in which the target compound is isolated and purified after the addition of a liquid to hydrolyze the excess cloulosulfonic acid and dilute fuming sulfuric acid.

 (13)

 [Wherein, X and Y are the same as above. ]

However, in this method, when the reaction solution is added to ice, the target compound is not dissolved in water. , It is decomposed into a sulfonic acid conjugate, so that the yield of the target compound is inevitably reduced. Also, since a large amount of sulfuric acid is generated as a waste liquid, it is necessary to treat the waste liquid, which is disadvantageous as an industrial production method.

 As an improvement of the production method described in Japanese Patent Publication No. 54-9-1191, a sulfonation reaction of a trifluoromethylbenzene compound with fuming sulfuric acid at 30 to 70 ° C is performed. After that, a method has been developed in which chlorosulfonic acid is subsequently added to carry out a chlorosulfonylation reaction at 20 to 60 ° C (Japanese Patent Application Laid-Open No. 63-14952). However, even with the method described in Japanese Patent Application Laid-Open No. 63-14952, the target compound is isolated by adding the reaction solution to a large amount of ice after completion of the chlorosulfonylation. Therefore, the effect of improving the yield of the target compound is insufficient.

 Further, Japanese Patent Application Laid-Open No. 2-15772 / 57 discloses that a trifluoromethylbenzene compound is reacted with fuming sulfuric acid and chlorosulfonic acid, and an inert solvent is added to the obtained reaction solution to convert the target compound into an inert solvent. This is a method in which the target compound is extracted and extracted from the extract. Since this method does not add the reaction solution to a large amount of ice, it aims at avoiding decomposition of the target compound and improving the yield of the target compound.

 However, the method described in Japanese Patent Application Laid-Open No. 2-15772 / 57 involves extraction with the addition of an inert solvent directly to the reaction solution, so that the extraction efficiency is extremely poor, and the extraction is repeated many times with a large amount of the inert solvent. This not only increases the cost but also complicates the operation. Moreover, since fuming sulfuric acid and chlorosulfonic acid used in the reaction are taken 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 production method.

Further, the inventors of the present invention have examined the methods described in JP-A-63-149492 and JP-A-2-157257, and found that the general formula (3) Among the trifluoromethylbenzenesulfonyl chloride compounds represented by the formula, especially when at least one of X and Y is a fluorine atom, the trifluoromethylbenzenesulfur present on the benzene ring of the starting compound during the reaction. Most of the methyl groups are hydrolyzed and converted to hepoxyl groups, and as a result, the target compound is obtained in a low yield of only about 10%. It was found that the product could not be manufactured (see Comparative Examples 1 and 2 described below).

 Disclosure of the invention

 An object of the present invention is to provide a new process for industrially advantageously producing a trifluoromethylbenzenesulfonyl chloride compound of the general formula (3).

 Another object of the present invention is to provide a method for producing the trifluoromethylbenzenesulfonyl chloride compound in high yield and high purity. The present inventor has made intensive studies to achieve the above object. As a result, they have found that the above object can be achieved by reacting a benzotrifluoride compound with sulfur trioxide and then chlorinating the resulting compound. The present invention has been completed based on such findings.

The present invention provides a compound represented by the general formula (1) 2

[Wherein, X and Y are the same or different and each represent a hydrogen atom or a halogen atom. A benzotrifluoride compound represented by the general formula (2)

[Wherein, X and Y are the same as above. ]

[式中、 X及び Yは前記に同じ。 ] By reacting a chlorinating agent with the sulfonic acid compound represented by the general formula (3)

[Wherein, X and Y are the same as above. ]

The present invention provides a method for producing a trifluoromethylbenzenesulfonide compound represented by the formula:

 In the present invention, the benzotrifluoride compound represented by the general formula (1) used as a starting material is an easily available known compound.

 Examples of the benzotrifluoride compound represented by the general formula (1) include benzotrifluoride, 2-fluorobenzotrifluoride, 4-fluorobenzobenzofluoride, and 2,4-difluorobenzotrifluoride. , 2-chloro benzotrifluoride, 4-chloro benzotrifluoride, 2,4-dichlorobenzotrifluoride, 2-chloro 4-fluorobenzotrifluoride, 2-fluoro 4-fluor Benzotrifluoride, 2-bromobenzotrifluoride, 4-bromobenzotrifluoride, 2,4-dibromobenzotrifluoride, 2-bromo-14-fluorobenzotrifluoride, 2-fluoro-4-bromobenzotrif Fluoride, 2-bromo-4-benzobenzotrifluoride, 4-promo 2-chlorobenzotrifluoride, etc. be able to.

 The reaction between the benzotrifluoride compound represented by the general formula (1) and sulfur trioxide is carried out without a solvent or in a suitable inert solvent, preferably in an inert solvent.

 Examples of the inert solvent include chloroform, dichloromethane, 1,2-dichloroethane, and halogenated hydrocarbons such as carbon tetrachloride. These inert solvents can be used alone or in combination of two or more.

 The use ratio of the benzotrifluoride compound represented by the general formula (1) to sulfur trioxide is usually about 1 to 10 mol, preferably about 1 to 4 mol per 1 mol of the former.

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

 This sulfonation reaction is carried out usually at a temperature of about 10 ° C. to about the boiling point of the inert solvent, preferably about 20 to 50 ° C., and more preferably about 30 to 40 ° C. The reaction is completed in about 0.1 to 10 hours, preferably about 1 to 3 hours, depending on the reaction temperature.

 In a preferred embodiment of the sulfonation reaction, for example, the benzotrifluoride compound of the general formula (1) is gradually added to a predetermined amount of sulfur trioxide, or the benzene of the general formula (1) is added. It is advisable to gradually add sulfur trioxide to the zotrifluoride compound. When an inert solvent is used, sulfur trioxide may be dissolved in the inert solvent, or the benzotrifluoride compound of the general formula (1) may be dissolved in the inert solvent.

 When the benzotrifluoride compound of the general formula (1) is mixed with sulfur trioxide, the temperature of the mixture gradually increases. In the present invention, the addition rate when mixing the benzotrifluoride compound of the general formula (1) with sulfur trioxide is adjusted so that the temperature of the mixture is maintained in the range of 30 to 40 ° C. Is more preferred.

 In the present invention, the resulting sulfonic acid compound represented by the general formula (2) is then chlorinated. The sulfonic acid compound of the general formula (2) formed by the sulfonation reaction may be once isolated and subjected to the next chlorination, but from the viewpoint of the efficiency of the reaction, the general formula (2) It is preferred that the sulfonic acid compound is subjected to the next chlorination reaction as it is without isolation.

 Further, in the present invention, it is desirable to remove unreacted sulfur trioxide or sulfur trioxide and an inert solvent present in the reaction mixture before chlorination. Known removal means can be widely applied to these removals. Examples of such a removing means include distillation under reduced pressure. The sulfur trioxide removed from the reaction mixture can be recovered and reused, which is advantageous in terms of production cost, waste liquid treatment, and the like.

 The chlorination of the sulfonic acid compound of the general formula (2) is performed, for example, by allowing a chlorinating agent to act on the sulfonic acid compound of the general formula (2).

As the chlorinating agent, known chlorinating agents can be widely used, and examples thereof include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, chlorosulfonic acid, and sulfuryl chloride. Can be. These chlorinating agents can be used alone or in combination of two or more. Among these chlorinating agents, thiol chloride is preferred.

 The chlorination of the sulfonic acid compound of the general formula (2) is carried out without a solvent or in a suitable inert solvent, preferably without a solvent.

 Examples of the inert solvent include halogenated hydrocarbons such as methylene chloride, dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as toluene, cyclobenzene, and xylene; and aliphatic hydrocarbons such as n-hexane and n-heptane. And the like. 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, at least one selected from the group consisting of an amide compound and a pyridine compound may be present in the reaction system as a catalyst.

 Examples of the amide compound include dimethylformamide, getylformamide, dimethylacetamide, N-methylpyrrolidone, and the like.

 Examples of the pyridine compound include pyridine, 4-dimethylaminopyridine and the like.

 The usage of at least one selected from the group consisting of amide compounds and pyridine compounds is usually about 0.001 to 0.1 mol per 1 mol of the sulfonic acid compound of the general formula (2). .

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

 The chlorination reaction is usually performed at about 0 to 160 ° C., preferably about 60 to 11 O, more preferably about 65 to 100 ° C., and particularly preferably about 70 to 90 ° C. . The chlorination reaction varies depending on the reaction temperature, but is usually completed in about 1 to 10 hours, preferably in about 2 to 5 hours.

 By chlorination of the sulfonic acid compound of the general formula (2), the desired trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3) is formed. After completion of the chlorination reaction, in the present invention, the reaction solution is concentrated under reduced pressure to obtain the general formula

Isolate the trifluoromethylbenzenesulfonyl chloride compound represented by (3) it can. 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.

 In the present invention, the reaction solution after completion of the reaction is concentrated under reduced pressure, and then an inert solvent is added to the obtained concentrated solution to inactivate the trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3). It is preferable to dissolve in a solvent, wash the solution with water, and concentrate. In this way, the target trifluoromethylbenzenesulfoerck sulfide compound represented by the general formula (3) can be isolated with even higher purity.

 The inert solvent used for the extraction of the reaction solution is preferably the same as the inert solvent used for the chlorination reaction, for example, halogenated hydrocarbons such as methylene chloride, dichloroethane, carbon tetrachloride, toluene, and the like. Examples thereof include aromatic hydrocarbons such as benzene and xylene, and aliphatic hydrocarbons such as n-hexane and n-heptane. These inert solvents can be used alone or in combination of two or more.

 If a method of concentrating the reaction solution under reduced pressure after completion of the chlorination reaction is employed, the unreacted chlorinating agent can be recovered and reused, which is advantageous in terms of production cost, waste liquid treatment, and the like. In the method of the present invention, since the sulfur trioxide used in the sulfonation reaction, the inert solvent, and the chlorinating agent used in the chlorination reaction are removed from the reaction solution, the target compound is extracted for extraction. The amount of the inert solvent used can be greatly reduced.

 The amount of the inert solvent used may be generally 1 to 10 times, preferably 2 to 5 times, the volume of the reaction solution to be subjected to the extraction treatment.

 The inert solvent from which the target compound has been extracted may contain a small amount of a chlorinating agent that has not been recovered. However, the mixed impurities can be removed by washing the solvent with water. 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.

 The invention's effect

According to the method of the present invention, the trifluoromethylbenzenesulfonyl chloride compound represented by the general formula (3) can be obtained in high yield (for example, 90% or more) and high purity (for example, 95% or less). The above method can be provided. The method of the present invention is particularly suitable for the production of fluorine-substituted trifluoromethylbenzenesulfonyl chloride compounds such as 2-fluoro-5-trifluoromethylbenzenesulfonyl chloride and 4-fluoro-3_trifluoromethylbenzenesulfonyl chloride. I have.

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

 According to the method of the present invention, the amount of an inert solvent used for extracting a target compound can be significantly reduced.

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

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be further clarified with reference to examples.

Example 1

 To 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. As the addition proceeded, the temperature of the reaction solution gradually increased, but the addition speed was adjusted so that the temperature of the reaction solution was maintained in the range of 30 to 35. After completion of the dropwise addition, the mixture was stirred for 2 hours. From the NMR spectrum of the reaction solution, it was confirmed that 4-fluorobenzotrifluoride as the raw material had disappeared.

 Next, methylene chloride and sulfur trioxide were distilled from the reaction solution under reduced pressure, and these were recovered. Further, to the reaction solution were added 24 ml of Shiridani Thionyl and several drops of dimethylformamide, and the mixture was heated under reflux for 5 hours. After cooling the reaction solution to 40, thionyl chloride was distilled off under reduced pressure and collected. After cooling the reaction mixture to 100, 100 ml of n-hexane was added, and 100 ml of water was added while cooling so that the liquid temperature did not exceed 10 ° C. separated. After drying the n-hexane solution, the solution was concentrated under reduced pressure to obtain 22.8 g of 2-fluoro-5-trifluoromethylbenzenesulfonyl chloride (95% yield, 96% purity).

Boiling point: 80 to 85 ° CZ 5 mmH g NMR spectrum (δ p pm):

 8.26 -8.28 (1H, m), 8.01-8.05 (1H, m), 7.51 (1H, t, 9 Hz)

Example 2

 To a mixture of 37 g of sulfur trioxide and 37 g of methylene chloride, 19 g of 2-fluorobenzotrifluoride was added dropwise at 20 ° C. The temperature of the reaction solution gradually increased as the dropwise addition proceeded, but the dropping speed was adjusted so that the temperature of the reaction solution was maintained in the range of 30 to 35 ° C. After completion of the dropwise addition, the mixture was stirred for 2 hours. From the NMR spectrum of the reaction solution, disappearance of the starting material, 2-fluorobenzotrifluoride, was confirmed.

 Next, the reaction solution was depressurized to distill methylene chloride and triacid sulfur, and these were recovered. Further, 24 ml of thionyl chloride and several drops of dimethylformamide were added to the reaction solution, and the mixture was heated under reflux for 5 hours. After cooling the reaction solution to 4 Ot, thionyl chloride was distilled off under reduced pressure and collected. After cooling the reaction solution to 10, 100 ml of 1,2-dichloroethane was added, and 10 Om1 of water was added while cooling so that the liquid temperature did not exceed 10, to separate a 1,2-dichloroethane solution. The 1,2-dichloroethane solution was dried and concentrated under reduced pressure to obtain 28 g of 4-monofluoro-3-trifluoromethylbenzenesulfonyl chloride (yield 99%, purity 98%).

Boiling point: 85-89 5 mmH g

NMR spectrum (δ p pm):

 8.2-8.4 (2H, m), 7.50 (1 Η, t, J == 9Hz)

Comparative Example 1

 According to the method described in JP-A-63-104952, 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride was prepared.

That is, 33 g of 4-fluorobenzotrifluoride was added dropwise to 2 Oml of 60% fuming sulfuric acid at 50 over 1 hour, followed by stirring at the same temperature for 1 hour. Next, chlorosulfonic acid (67 ml) was gradually added dropwise to the mixture at 50. 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, and the precipitated crystals were separated by filtration. The n-hexane layer was taken with a separatory funnel, concentrated and dried to obtain 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride 5. 2 g (10% yield) were obtained.

Comparative Example 2

 According to the method described in JP-A-2-157257, 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride was produced.

-That is, a mixture of 15 ml of 60% fuming sulfuric acid and 30 ml of chlorosulfonic acid is cooled to 15 ° C, and 4-fluorobenzotrifluoride is added to the mixture so that the temperature of the mixture does not exceed 0 ° C. While cooling. The reaction was stirred at 0 ° C for another 4 hours. 100 ml of n-hexane was added to the reaction solution, and after stirring for 1 hour, the n-hexane layer was separated. Further, the same operation was repeated twice.

 The obtained n-hexane layers were combined, washed with water (300 ml), dried over magnesium sulfate, and concentrated to obtain 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride (5 g, yield 10%). Was.

Claims

The scope of the claims  1. General formula (1)

[Wherein, X and Y are the same or different and each represent a hydrogen atom or a halogen atom. ] To the benzotrifluoride compound represented by the general formula (2)

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

[Wherein, X and Y are the same as above. ] A method for producing a trifluoromethylbenzenesulfonyl chloride compound represented by the formula:  2. The method according to claim 1, wherein 1 to 10 mol of sulfur trioxide is used per 1 mol of the benzotrifluoride compound represented by the general formula (1). 3. The method according to claim 1, wherein the reaction between the benzotrifluoride compound and sulfur trioxide is performed in an inert solvent.  4. The method according to claim 1, wherein the reaction between the benzotrifluoride compound and sulfur trioxide is performed at 20 to 50 ° C. 5. Prior to the reaction of the sulfonic acid compound represented by the general formula (2) with the chlorinating agent, 2. The method according to claim 1, wherein unreacted sulfur triacid is removed from the reaction mixture. 6. The method according to claim 1, wherein prior to reacting the sulfonic acid compound with the chlorinating agent, unreacted sulfur trioxide and an inert solvent are removed from the reaction mixture. 7. The method according to claim 1, wherein the chlorinating agent is used in an amount of 1 to 5 mol per 1 mol of the sulfonic acid compound.  8. The method according to claim 1, wherein the chlorinating agent is at least one selected from the group consisting of thionyl chloride, phosphorus oxychloride, pentachloride, chlorosulfonic acid and sulfuryl chloride.  9. The method according to claim 1, wherein the reaction between the sulfonic acid compound and the chlorinating agent is performed in the presence of at least one member selected from the group consisting of an amide compound and a pyridine compound.  10. The method according to claim 1, wherein the reaction between the sulfonic acid conjugate and the chlorinating agent is carried out at 60 to 110 ° C.  11. After the reaction between the benzotrifluoride compound and the sulfur trioxide, the chlorinating agent is allowed to react with the reaction mixture without isolating the resulting sulfonic acid compound represented by the general formula (2). The method according to paragraph 1 above. ' 12. The method according to claim 1, wherein one or both of X and Y in the general formula (1) is a fluorine atom.