WO2003064380A1 - Chlorures de trifluoromethylbenzenesulfonyle - Google Patents

Chlorures de trifluoromethylbenzenesulfonyle Download PDF

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Publication number
WO2003064380A1
WO2003064380A1 PCT/JP2003/000782 JP0300782W WO03064380A1 WO 2003064380 A1 WO2003064380 A1 WO 2003064380A1 JP 0300782 W JP0300782 W JP 0300782W WO 03064380 A1 WO03064380 A1 WO 03064380A1
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WIPO (PCT)
Prior art keywords
general formula
reaction
compound
sulfonic acid
chlorinating agent
Prior art date
Application number
PCT/JP2003/000782
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English (en)
Japanese (ja)
Inventor
Masatoshi Hayashi
Hirofumi Nakagawa
Original Assignee
Otsuka Chemical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Chemical Co., Ltd. filed Critical Otsuka Chemical Co., Ltd.
Publication of WO2003064380A1 publication Critical patent/WO2003064380A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
    • C07C303/06—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfuric acid or sulfur trioxide

Definitions

  • the present invention relates to a method for producing a trifluoromethylbenzenesulfol chloride compound.
  • X and Y are the same or different and each represent a hydrogen atom or a halogen atom.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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
  • the present invention provides a method for producing a trifluoromethylbenzenesulfonide compound represented by the formula:
  • the benzotrifluoride compound represented by the general formula (1) used as a starting material is an easily available known compound.
  • benzotrifluoride compound represented by the general formula (1) examples include benzotrifluoride, 2-fluorobenzotrifluoride, 4-fluorobenzobenzofluoride, and 2,4-difluorobenzotrifluoride.
  • 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.
  • inert solvent examples 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.
  • 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.
  • 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.
  • the temperature of the mixture gradually increases.
  • 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.
  • 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.
  • 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).
  • 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.
  • the inert solvent examples 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.
  • 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.
  • amide compound examples include dimethylformamide, getylformamide, dimethylacetamide, N-methylpyrrolidone, and the like.
  • pyridine compound examples 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.
  • trifluoromethylbenzenesulfonyl chloride compound represented by (3) 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.
  • 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.
  • halogenated hydrocarbons such as methylene chloride, dichloroethane, carbon tetrachloride, toluene, and the like.
  • aromatic hydrocarbons such as benzene and xylene
  • aliphatic hydrocarbons such as n-hexane and n-heptane.
  • the unreacted chlorinating agent can be recovered and reused, which is advantageous in terms of production cost, waste liquid treatment, and the like.
  • 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.
  • the mixed impurities can be removed by washing the solvent with water.
  • 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 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.
  • 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.
  • the amount of an inert solvent used for extracting a target compound can be significantly reduced.
  • the process of the present invention is extremely advantageous as an industrial process for producing a trifluoromethylbenzenesulfonyl chloride compound of the general formula (3).
  • 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%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des chlorures de trifluorométhylbenzènesulfonyle représentés par la formule générale (3): (dans laquelle X et Y représentent chacun, de manière indépendante, un hydrogène ou un halogèno) qui sont produits par mise en réaction d'un benzotrifluorure représenté par la formule générale (1): (dans laquelle X et Y sont définis tels que ci-dessus) et de trioxyde de soufre afin de former un acide sulfonique représenté par la formule générale (2): ( dans laquelle X et Y sont définis tels que ci-dessus) puis par mise en réaction de cet acide sulfonique avec un agent de chloration. Selon l'invention, les chlorures de trifluorométhylbenzènesulfonyle peuvent être produits avec des rendements élevés et une grande pureté.
PCT/JP2003/000782 2002-01-29 2003-01-28 Chlorures de trifluoromethylbenzenesulfonyle WO2003064380A1 (fr)

Applications Claiming Priority (2)

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JP2002-20039 2002-01-29
JP2002020039A JP2003221377A (ja) 2002-01-29 2002-01-29 トリフルオロメチルベンゼンスルホニルクロリド化合物の製造方法

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02169561A (ja) * 1988-12-23 1990-06-29 Mitsui Toatsu Chem Inc ３‐トリフルオロメチルベンゼンスルホニルクロリド類の製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02169561A (ja) * 1988-12-23 1990-06-29 Mitsui Toatsu Chem Inc ３‐トリフルオロメチルベンゼンスルホニルクロリド類の製造方法

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