WO2021200640A1 - Method for evaluating activity of fluorinating agent and method for manufacturing ester compound - Google Patents

Method for evaluating activity of fluorinating agent and method for manufacturing ester compound Download PDF

Info

Publication number
WO2021200640A1
WO2021200640A1 PCT/JP2021/012828 JP2021012828W WO2021200640A1 WO 2021200640 A1 WO2021200640 A1 WO 2021200640A1 JP 2021012828 W JP2021012828 W JP 2021012828W WO 2021200640 A1 WO2021200640 A1 WO 2021200640A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
carbon
groups
fluorinating agent
Prior art date
Application number
PCT/JP2021/012828
Other languages
French (fr)
Japanese (ja)
Inventor
悟 森
Original Assignee
宇部興産株式会社
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 宇部興産株式会社 filed Critical 宇部興産株式会社
Priority to JP2022512112A priority Critical patent/JPWO2021200640A1/ja
Priority to CN202180026895.4A priority patent/CN115427386A/en
Publication of WO2021200640A1 publication Critical patent/WO2021200640A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters

Definitions

  • the present invention relates to a method for evaluating the activity of a fluorinating agent and a method for producing an ester compound.
  • Fluorine is an element that is attracting attention in cutting-edge technology fields such as medical and agricultural chemicals and materials, and there is a need for a method for efficiently obtaining fluorinated compounds.
  • a simple method for obtaining a fluorinated compound is a method for fluorinating a non-fluorinated compound using a fluorinating agent.
  • various fluorinating agents such as (diethylamino) sulfatrifluoride (DAST®) and 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene (Fluolead®) have been introduced.
  • fluorinating agents are unstable to water and gradually decompose when exposed to moisture in the air, reducing their activity as fluorinating agents. Therefore, it is necessary to check the activity of the fluorinating agent before using it.
  • NMR measurement described in Patent Document 2 it is possible to determine the content of the active species contained in the fluorinating agent, and it is considered that the determined content corresponds to the activity.
  • the evaluation method requires a nuclear magnetic resonance apparatus that is expensive and requires maintenance, and is not economical. Therefore, a simpler evaluation method is required.
  • impurities in the fluorinating agent may inhibit the fluorination reaction, and the content may not be the activity as it is.
  • an object of the present invention is to provide a method for evaluating the activity as an economical, simple and reproducible fluorinating agent.
  • a fluorination step in which a fluorinating agent is subjected to a reaction with a carboxylic acid represented by the following formula (1) to be converted into a carboxylic acid fluoride represented by the following formula (2).
  • the mixture after the fluorination step is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and 1 carbon number.
  • R a , R b , R c , R d and Re respectively, have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively.
  • R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.
  • the fluorinating agent is a compound represented by the following formula (4), a compound represented by the following formula (5), a compound represented by the following formula (6), a compound represented by the following formula (7), and difluoro (morpholino) sulfonium.
  • a mixture of chloroimidazolium chloride and cesium fluoride in a weight ratio of 1: 2, 1,3-bis (2,6-diisopropylphenyl) -2,2-difluoro-4-imidazoline and N, N' The method for evaluating the activity of a fluorinating agent according to 1 or 2 above, which is at least one selected from the group consisting of -1,3-bis (2,6-diisopropylphenyl) fluoroimidazolium borate.
  • R f , R g , R h , R i and R j are hydrogen atoms, alkyl groups having 1 to 18 carbon atoms, aryl groups having 6 to 30 carbon atoms and 1 to 18 carbon atoms, respectively.
  • R f , R g , R h , Ri and R j may be the same or different, and adjacent substituents may be bonded to each other to form a ring.
  • R k is an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a dialkylamino group having 1 to 18 carbon atoms, an arylamino group having 6 to 30 carbon atoms, and carbon.
  • a bis (alkoxyalkyl) amino group having 1 to 18 carbon atoms, a morpholino group, an acyloxy group having 1 to 18 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms. show.
  • R l and R m are an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a bis (2-alkoxyethyl) amino group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively. Indicates an acyloxy group having 1 to 18, an alkoxycarbonyl group having 2 to 18 carbon atoms, or an aryloxycarbonyl group having 7 to 30 carbon atoms. R l and R m may be the same or different.
  • X - indicates a halide ion or a tetrafluoroborate ion.
  • R n is an alkyl group having 1 to 18 carbon atoms, a fluoroalkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 5 to 30 carbon atoms, and carbon. Indicates an alkoxycarbonyl group having a number of 2 to 18 or an aryloxycarbonyl group having a carbon number of 7 to 30.
  • the mixture containing the ester compound represented by the formula (3) contains hydrogen fluoride, and after the esterification step, the mixture is subjected to (R 2 ) 3 N (R 2 is an alkyl group having 1 to 4 carbon atoms).
  • R 1 OH R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and an alkoxy group having 1 to 18 carbon atoms.
  • the carboxylic acid fluoride is subjected to a reaction with an alcohol represented by the following formula (3), and includes an esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3).
  • Method for producing ester compound is a reaction with an alcohol represented by the following formula (3), and includes an esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3).
  • R a , R b , R c , R d and Re respectively, have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively.
  • R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.
  • R f , R g , R h , R i and R j are hydrogen atoms, alkyl groups having 1 to 18 carbon atoms, aryl groups having 6 to 30 carbon atoms and 1 to 18 carbon atoms, respectively.
  • the activity as a fluorinating agent can be evaluated easily and with good reproducibility.
  • the activity as a fluorinating agent can be evaluated by an economically and industrially excellent method.
  • the ester compound can be produced in high yield.
  • the present inventors have found that the present invention can evaluate the activity as a fluorinating agent by inducing a carboxylic acid into another compound using a fluorinating agent, and the present inventions are made. It came to.
  • the present invention is a method for evaluating the activity as a fluorinating agent.
  • a fluorination step in which a fluorinating agent is subjected to a reaction with a carboxylic acid represented by the following formula (1) to be converted into a carboxylic acid fluoride represented by the following formula (2).
  • R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and 1 carbon number.
  • the fluorination step and esterification step are as shown in the following formula.
  • the fluorinating agent used in the present invention is a material capable of introducing a fluorine atom into an organic compound, and deoxidizes an alcohol group or a carbonyl group in the organic compound to replace the fluorine atom. .. Specifically, the compound represented by the following formula (4), the compound represented by the following formula (5), the compound represented by the following formula (6), the compound represented by the following formula (7), and difluoro (morpholino) sulfonium.
  • fluorinating agents are by-products generated in the process of producing the fluorinating agent, compounds formed by desorption of fluorine atoms after the fluorination reaction, and produced by thermal decomposition or hydrolysis of the fluorinating agent. Decomposed products are also included. Therefore, the content of the active ingredient is not necessarily 100% by mass. Therefore, it is necessary to evaluate the activity as a fluorinating agent.
  • R f , R g , R h , R i and R j are preferably hydrogen atoms or alkyl groups having 1 to 18 carbon atoms, and hydrogen atoms or carbons, from the viewpoint of high accuracy of activity evaluation and availability.
  • Alkyl groups having a number of 1 to 4 are more preferable
  • R f and R j are methyl groups
  • R h is a tert-butyl group
  • R g and Ri are hydrogen atoms.
  • 2,6-dimethyl-4- in which R f and R j are methyl groups
  • R h is a tert-butyl group
  • R g and Ri are hydrogen atoms. It is t-butyl-trifluorosulfanylbenzene and is also referred to as Fluolead®.
  • a compound having a diethylamino group also referred to as DAST
  • a compound having a bis (2-methoxyethyl) amino group also referred to as Deoxo-Fluor (registered trademark)
  • DAST diethylamino group
  • Deoxo-Fluor registered trademark
  • the R n of the formula (7) is an alkyl group having 1 to 18 carbon atoms, a fluoroalkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, and a heteroaryl group having 5 to 30 carbon atoms.
  • Examples thereof include an alkoxycarbonyl group having 2 to 18 carbon atoms and an aryloxycarbonyl group having 7 to 30 carbon atoms.
  • a fluoroalkyl group having 1 to 18 carbon atoms or a heteroaryl group having 5 to 30 carbon atoms is preferable, and a nonafluorobutyl group, a pyridyl group or a pyrimidyl group is more preferable.
  • a mixture of N, N'-1,3-bis (2,6-diisopropylphenyl) chloroimidazolium chloride and cesium fluoride in a weight ratio of 1: 2 is also referred to as PhenoFluor-MIX® (registered trademark) and has the following formula (IV).
  • PhenoFluor-MIX® registered trademark
  • 1,3-Bis (2,6-diisopropylphenyl) -2,2-difluoro-4-imidazoline is also referred to as PhenoFlour (registered trademark) and is represented by the following formula (VI).
  • N, N'-1,3-bis (2,6-diisopropylphenyl) fluoroimidazolium borate, also referred to as AlkylFluor® is represented by the following formula (V).
  • R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.
  • R a , R b , R c , R d and Re are preferably an alkyl group or a hydrogen atom having 1 to 4 carbon atoms, more preferably a methyl group or a hydrogen atom, and particularly preferably a methyl group or a hydrogen atom. It is a hydrogen atom.
  • 1.0 equivalent or more of carboxylic acid may be used for the fluorinating agent, 1.2 to 6.0 equivalent of carboxylic acid is preferably used, and 1.2 to 2.0 equivalent of carboxylic acid is used. Is even more preferable.
  • the reaction is preferably carried out in the presence of a solvent.
  • R 1 is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.
  • SOOR 1 compound a sulfinic acid ester compound
  • the amount of alcohol may be excessive with respect to the COF form, and is preferably the amount of solvent. As described above, since alcohol serves as a solvent in this reaction, no additional solvent is required, but halogenated hydrocarbons such as dichloromethane may be used as the solvent.
  • the amount of the solvent used is appropriately adjusted, but is 0.1 g to 100 g, preferably 0.5 g to 10 g, with respect to 1 g of the COF body.
  • the reaction is preferably carried out at room temperature (15 ° C. to 30 ° C.).
  • the reaction time can be appropriately set and may be about 1 to 60 minutes.
  • a known catalyst or reaction accelerator necessary for esterification may be used in combination.
  • the peak area of the ester compound is determined by analysis by HPLC, and the concentration of the ester compound in the mixture containing the ester compound obtained in the esterification step or the salt forming step is determined from this value.
  • the eluent is preferably a mixed solvent of acetonitrile and water.
  • the correction may be performed using a standard substance.
  • the activity of the fluorinating agent can be determined from the theoretical concentration of the fluorinating agent and the ester compound obtained from the carboxylic acid and the measured concentration.
  • reaction conditions and operating methods of the fluorination step, esterification step and salt formation step, and the fluorinating agent used are the same as the activity evaluation method of the fluorinating agent.
  • the carboxylic acid, carboxylic acid fluoride, and ester compound used in this production method are the same as the method for evaluating the activity of the fluorinating agent, and are represented by the following formulas (1), (2), and (3), respectively.
  • aryloxy groups halogen atoms, nitro groups, cyano groups, alkoxysulfonyl groups with 1-18 carbon atoms, arylsulfonyl groups with 6-30 carbon atoms, acyloxy groups with 1-18 carbon atoms, carbon number Is an alcan sulfonyloxy group having 1 to 18, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms, an aryloxycarbonyl group having 7 to 30 carbon atoms, or a hydrogen atom.
  • a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is preferable, a hydrogen atom or a methyl group is more preferable, and a hydrogen atom is further preferable.
  • R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.
  • the ester compound can be isolated by using, for example, neutralization, extraction, filtration, concentration, distillation, crystallization, column chromatography, HPLC and the like.
  • the activity can be evaluated in the activity evaluation step without post-treatment of the mixture.
  • a preferred embodiment of the method is to subject the mixture containing SF 3 and SOF to a fluorination step, then to an esterification step, and further to a salt forming step. This scheme is shown below.
  • the mixture in the fluorinating agent is mainly a mixture containing SF 3 , SOF and HF
  • the mixture after the fluorination step is mainly a compound described in the above formula (2) and a fluorosulfinyl aromatic compound.
  • It is a mixture containing (SOF) and HF
  • the mixture after the esterification step is mainly a mixture containing the compound of the above formula (3), a sulfinate compound (SOOR 1 ), and HF
  • the obtained mixture is mainly a mixture containing the compound of the above formula (3), a sulfinate compound (SOOR 1 ), hydrogen fluoride and a salt of a tertiary amine.
  • Example 1A The conversion of carboxylic acid to ester compound using a fluorinating agent was carried out according to the following procedure. 2,6-Dimethyl-4-t-butyl-trifluorosulfanylbenzene (Fluoread®) was prepared. The substance is a mixture containing trace amounts of fluorosulfinyl aromatic compounds (SOF) and hydrogen fluoride (HF) produced by decomposition during storage. ⁇ Fluorination process> 1.0 g of Fluororead and 0.8 g of benzoic acid were purified in a glove box under a nitrogen atmosphere (dew point: ⁇ 20 ° C.), and placed in a fluororesin container equipped with a 20 mL rotor.
  • Fluoread® 2,6-Dimethyl-4-t-butyl-trifluorosulfanylbenzene
  • HF hydrogen fluoride
  • Methyl benzoate was prepared as a standard ester compound. Methyl benzoate (100 mg) was calibrated, placed in a 100 mL volumetric flask, and acetonitrile was added to make exactly 100 mL. In this way, a standard solution of the ester compound was prepared.
  • Example 3 Prepare the same lot of Fluid (registered trademark) as that used in Example 1A, and prepare the equivalent number of benzoic acid, the amount of dichloromethane, the stirring time after adding dichloromethane (stirring 1), the amount of methanol, and after adding methanol.
  • a sample solution of the mixture obtained after the salt forming step was prepared by varying the stirring time (stirring 2) of the above, a standard solution of the ester compound was prepared in the same manner as in Example 1B, and HPLC was performed in the same manner as in Example 1C.
  • the activity of Fluoled was determined by the analysis in.
  • Example 4 When preparing a sample solution of the mixture obtained after the salt forming step by preparing the same lot of Fluolead (registered trademark) as that used in Example 1A, water was added to partially decompose the Fluolead (registered trademark). A sample solution of the mixture obtained after the salt forming step was prepared. Then, a standard solution of the ester compound was prepared in the same manner as in Example 1B, and the activity of the decomposed Fluolead (registered trademark) was determined by analyzing by HPLC in the same manner as in Example 1C. In addition, the number of moles of Fluolead (registered trademark) to be decomposed was calculated from the weight of added water, and the theoretical value of activity was calculated.
  • Fluolead (registered trademark) is prepared, and a conventional method for evaluating the activity of a trifluorosulfanyl aromatic compound (described in Patent Document 4), that is, a fluorosulfinyl aromatic compound is converted into a sulfinamide compound by an amine, and further, a trifluorosulfanyl fragrance is obtained.
  • a method for evaluating the activity by measuring the content of the sulfinic acid ester compound by HPLC or the like was carried out by the following procedure.
  • Comparative Example 2 Prepare a Loolead® in the same lot as that used in Comparative Example 1A, prepare a sample solution of the conventional method in the same manner as in Comparative Example 1, and analyze by HPLC in the same manner as in Comparative Example 1B. The operation of determining the area percentage of the peak of the sulfinate ester compound was repeated 5 times. The results are shown in Table 4, including the results obtained in Comparative Example 1B. It was found that the obtained area percentage was 94.9% to 97.2% and the reproducibility was low, and the activity obtained by the method was also low in reproducibility.

Landscapes

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

Abstract

The purpose of the present invention is to provide an economical, convenient and reproducible method for evaluating an activity as a fluorinating agent.　Provided is a method for evaluating an activity of a fluorinating agent, the method including: a fluorinating step for subjecting a fluorinating agent to a reaction with a carboxylic acid represented by formula (1) below to convert the fluorinating agent into a carboxylic acid fluoride; an esterifying step for subjecting the mixture after the above step to a reaction with an alcohol represented by R1OH (wherein R1 is a C1-4 alkyl group) to convert the above carboxylic acid fluoride into an ester compound; and a step for quantitatively analyzing the concentration of the ester compound contained in the mixture after the above esterifying step to evaluate an activity as a fluorinating agent through comparison of same with a theoretical concentration of the ester compound obtained from the above fluorinating agent and carboxylic acid. (Here Ra, Rb, Rc, Rd and Re each represent a given group.)

Description

フッ素化剤の活性評価方法及びエステル化合物の製造方法Method for evaluating activity of fluorinating agent and method for producing ester compound
　本発明はフッ素化剤の活性評価方法及びエステル化合物の製造方法に関する。 The present invention relates to a method for evaluating the activity of a fluorinating agent and a method for producing an ester compound.
　フッ素は医農薬や材料分野等の最先端技術分野において注目を集めている元素であり、フッ素化化合物を効率的に入手する手法が求められている。フッ素化化合物を入手する簡便な手法として、フッ素化剤を用いて非フッ素化化合物をフッ素化する手法が挙げられる。近年では（ジエチルアミノ）サルファートリフルオリド（ＤＡＳＴ（登録商標））や２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼン（Ｆｌｕｏｌｅａｄ（登録商標））等をはじめとした様々なフッ素化剤が報告・販売されており、フッ素を非フッ素化化合物に効率的に導入することが可能となってきている（例えば、特許文献１参照）。
　フッ素化剤を使用する際、その活性度を事前に把握しておく必要がある。フッ素化剤の活性度を見積もる手法としては、ＮＭＲを用いる手法（例えば、特許文献２参照）や、滴定またはイオン電極によるフッ素含量を定量する手法が知られている（例えば、特許文献３参照）。また、Ｆｌｕｏｌｅａｄのようなトリフルオロスルファニル芳香族化合物を骨格とするフッ素化剤であれば、フッ素化剤に含まれる不純物であるフルオロスルフィニル芳香族化合物をアミンによりスルフィンアミド化合物へ変換し、さらにトリフルオロスルファニル芳香族化合物をアルコールによりスルフィン酸エステル化合物へと変換した後、ＨＰＬＣ等によりスルフィン酸エステル化合物の含量を測定することで活性度を評価する手法（特許文献４参照）が知られている。 Fluorine is an element that is attracting attention in cutting-edge technology fields such as medical and agricultural chemicals and materials, and there is a need for a method for efficiently obtaining fluorinated compounds. A simple method for obtaining a fluorinated compound is a method for fluorinating a non-fluorinated compound using a fluorinating agent. In recent years, various fluorinating agents such as (diethylamino) sulfatrifluoride (DAST®) and 2,6-dimethyl-4-t-butyl-trifluorosulfanylbenzene (Fluolead®) have been introduced. It has been reported and sold, and it has become possible to efficiently introduce fluorine into a non-fluorinated compound (see, for example, Patent Document 1).
When using a fluorinating agent, it is necessary to know its activity in advance. As a method for estimating the activity of the fluorinating agent, a method using NMR (see, for example, Patent Document 2) and a method for quantifying the fluorine content by titration or an ionic electrode are known (see, for example, Patent Document 3). .. Further, in the case of a fluorinating agent having a trifluorosulfanyl aromatic compound as a skeleton such as Fluolead, the fluorosulfinyl aromatic compound, which is an impurity contained in the fluorinating agent, is converted into a sulfinamide compound by an amine, and further trifluoro. A method of evaluating activity by converting a sulfanyl aromatic compound into a sulfinate ester compound with alcohol and then measuring the content of the sulfinate ester compound by HPLC or the like is known (see Patent Document 4).
特表２０１５－５０９９０７号公報Special Table 2015-509907 特表２００９－５４４７３５号公報Special Table 2009-544735 特開２００３－０６４０３４号公報Japanese Unexamined Patent Publication No. 2003-064034 国際公開第２０１８／１８６３３１号International Publication No. 2018/186331
　ほとんどのフッ素化剤は水に対して不安定であり、空気中の湿気等に晒されることにより徐々に分解し、フッ素化剤としての活性が低下する。そのため、フッ素化剤を使用する前にその活性度を調べておく必要がある。
　特許文献２に記載のＮＭＲ測定ではフッ素化剤中に含まれる活性種の含有率を求めることが可能であり、求めた含有率が活性度に相当すると考えられる。しかし当該評価方法は高価且つ維持管理が必要な核磁気共鳴装置が必要であり、経済的でないため、より簡便な評価方法が求められている。また、フッ素化剤中の不純物がフッ素化反応を阻害する可能性があり、含有率がそのまま活性度とならない場合もある。
　特許文献３に記載の滴定又はイオン電極によりフッ素含量を測定した場合、フッ素化剤中のフッ化水素等の不純物も検出してしまうため、フッ素化剤としての活性度を正確に規定することは難しい。
　特許文献４に記載のフッ素化剤をスルフィン酸エステル化合物へと変換し、ＨＰＬＣにて定量する手法は、トリフルオロスルファニル芳香族化合物をスルフィン酸エステル化合物へと定量的に変換する必要があるが、一部はスルフィンアミド化合物にも変換されてしまい、評価結果の再現性が乏しいという問題がある。
　以上を鑑み、本発明の課題は経済的で簡便且つ再現性のあるフッ素化剤としての活性を評価する方法を提供することである。 Most fluorinating agents are unstable to water and gradually decompose when exposed to moisture in the air, reducing their activity as fluorinating agents. Therefore, it is necessary to check the activity of the fluorinating agent before using it.
In the NMR measurement described in Patent Document 2, it is possible to determine the content of the active species contained in the fluorinating agent, and it is considered that the determined content corresponds to the activity. However, the evaluation method requires a nuclear magnetic resonance apparatus that is expensive and requires maintenance, and is not economical. Therefore, a simpler evaluation method is required. In addition, impurities in the fluorinating agent may inhibit the fluorination reaction, and the content may not be the activity as it is.
When the fluorine content is measured by the titration or ion electrode described in Patent Document 3, impurities such as hydrogen fluoride in the fluorinating agent are also detected. Therefore, it is not possible to accurately define the activity as the fluorinating agent. difficult.
The method of converting the fluorinating agent described in Patent Document 4 into a sulfinic acid ester compound and quantifying it by HPLC requires quantitatively converting a trifluorosulfanyl aromatic compound into a sulfinic acid ester compound. Some of them are also converted to sulfinamide compounds, and there is a problem that the reproducibility of the evaluation results is poor.
In view of the above, an object of the present invention is to provide a method for evaluating the activity as an economical, simple and reproducible fluorinating agent.
　前記課題は以下の本発明によって解決される。 The above problem is solved by the following invention.
１．フッ素化剤としての活性を評価する方法であって、
　フッ素化剤を、下記式（１）で表されるカルボン酸との反応に供して、下記式（２）で表されるカルボン酸フッ化物に変換するフッ素化工程、
前記フッ素化工程後の混合物をＲ１ＯＨ（Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。）で表されるアルコールとの反応に供して、前記カルボン酸フッ化物を下記式（３）で表されるエステル化合物に変換するエステル化工程、及び
　前記エステル化工程後の混合物中に含まれるエステル化合物の濃度を定量分析し、前記フッ素化剤及び前記カルボン酸から得られるエステル化合物の理論上の濃度と比較することにより、フッ素化剤としての活性を評価する工程を含む、フッ素化剤の活性評価方法。 1. 1. It is a method to evaluate the activity as a fluorinating agent.
A fluorination step in which a fluorinating agent is subjected to a reaction with a carboxylic acid represented by the following formula (1) to be converted into a carboxylic acid fluoride represented by the following formula (2).
The mixture after the fluorination step is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and 1 carbon number. An alkoxy group of ~ 18, an aryloxy group having 6 to 30 carbon atoms, a halogen atom, a nitro group, a cyano group, an alkanesulfonyl group having 1 to 18 carbon atoms, an arylsulfonyl group having 6 to 30 carbon atoms, and a carbon number of carbon atoms. Is an acyloxy group having 1 to 18, an alkanesulfonyloxy group having 1 to 18 carbon atoms, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an alkoxycarbonyl group having 7 to 30 carbon atoms. It is an aryloxycarbonyl group.) After the esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3) by subjecting it to a reaction with an alcohol represented by the following formula (3), and after the esterification step. A step of quantitatively analyzing the concentration of the ester compound contained in the mixture of the above and evaluating the activity as the fluorinating agent by comparing with the theoretical concentration of the fluorinating agent and the ester compound obtained from the carboxylic acid. A method for evaluating the activity of a fluorinating agent, including.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
（Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基、炭素数が７～３０のアリールオキシカルボニル基又は水素原子を示す。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）
Figure JPOXMLDOC01-appb-C000014
(R a , R b , R c , R d and Re , respectively, have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively. 6 to 30 aryloxy groups, halogen atoms, nitro groups, cyano groups, alcoholyl sulfonyl groups with 1 to 18 carbon atoms, aryl sulfonyl groups with 6 to 30 carbon atoms, acyloxy groups with 1 to 18 carbon atoms, carbon Indicates an alkanesulfonyloxy group having 1 to 18, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms, an aryloxycarbonyl group having 7 to 30 carbon atoms or a hydrogen atom. R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
２．Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅがそれぞれメチル基又は水素原子であり、Ｒ１がエチル基又はメチル基である、前記１に記載のフッ素化剤の活性評価方法。 2. The method for evaluating the activity of a fluorinating agent according to 1 above, wherein R a , R b , R c , R d and Re are methyl groups or hydrogen atoms, respectively, and R 1 is an ethyl group or methyl group.
３．フッ素化剤が、下記式（４）で示される化合物、下記式（５）で示される化合物、下記式（６）で示される化合物、下記式（７）で示される化合物、ジフルオロ（モルホリノ）スルホニウムテトラフルオロクロリド、ジフルオロ（モルホリノ）スルホニウムテトラフルオロボラート、ヘキサフルオロプロペンジエチルアミン、１，１，２，２－テトラフルオロ－Ｎ，Ｎ－ジメチルエチルアミン、Ｎ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）クロロイミダゾリウムクロリドとフッ化セシウムの重量比１：２の混合物、１，３－ビス（２，６－ジイソプロピルフェニル）－２，２－ジフルオロ－４－イミダゾリン及びＮ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）フルオロイミダゾリウムボレートからなる群から選ばれる少なくとも１つである、前記１又は２に記載のフッ素化剤の活性評価方法。 3. 3. The fluorinating agent is a compound represented by the following formula (4), a compound represented by the following formula (5), a compound represented by the following formula (6), a compound represented by the following formula (7), and difluoro (morpholino) sulfonium. Tetrafluorochloride, difluoro (morpholino) sulfonium tetrafluoroborate, hexafluoropropenediethylamine, 1,1,2,2-tetrafluoro-N, N-dimethylethylamine, N, N'-1,3-bis (2, 6-Diisopropylphenyl) A mixture of chloroimidazolium chloride and cesium fluoride in a weight ratio of 1: 2, 1,3-bis (2,6-diisopropylphenyl) -2,2-difluoro-4-imidazoline and N, N' The method for evaluating the activity of a fluorinating agent according to 1 or 2 above, which is at least one selected from the group consisting of -1,3-bis (2,6-diisopropylphenyl) fluoroimidazolium borate.
Figure JPOXMLDOC01-appb-C000015
（式中、Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊはそれぞれ水素原子、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）
Figure JPOXMLDOC01-appb-C000015
(In the formula, R f , R g , R h , R i and R j are hydrogen atoms, alkyl groups having 1 to 18 carbon atoms, aryl groups having 6 to 30 carbon atoms and 1 to 18 carbon atoms, respectively. Alkoxy group, aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcan sulfonyl group having 1 to 18 carbon atoms, aryl sulfonyl group having 6 to 30 carbon atoms, carbon number 1 to 1 to 18 acyloxy groups, 1-18 carbon alcan sulfonyloxy groups, 6-30 carbon aryl sulfonyloxy groups, 2-18 carbon alkoxycarbonyl groups or 7-30 carbon aryloxycarbonyl Indicates a group. R f , R g , R h , Ri and R j may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
Figure JPOXMLDOC01-appb-C000016
（式中、Ｒｋは炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のジアルキルアミノ基、炭素数が６～３０のアリールアミノ基、炭素数が１～１８のビス（アルコキシアルキル）アミノ基、モルホリノ基、炭素数が１～１８のアシルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。）
Figure JPOXMLDOC01-appb-C000016
(In the formula, R k is an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a dialkylamino group having 1 to 18 carbon atoms, an arylamino group having 6 to 30 carbon atoms, and carbon. A bis (alkoxyalkyl) amino group having 1 to 18 carbon atoms, a morpholino group, an acyloxy group having 1 to 18 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms. show.)
Figure JPOXMLDOC01-appb-C000017
（式中、Ｒｌ及びＲｍはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のビス（２-アルコキシエチル）アミノ基、炭素数が１～１８のアシルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。Ｒｌ及びＲｍは同一であっても異なっていてもよい。Ｘ－はハロゲン化物イオン又はテトラフルオロホウ酸イオンを示す。）
Figure JPOXMLDOC01-appb-C000017
(In the formula, R l and R m are an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a bis (2-alkoxyethyl) amino group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively. Indicates an acyloxy group having 1 to 18, an alkoxycarbonyl group having 2 to 18 carbon atoms, or an aryloxycarbonyl group having 7 to 30 carbon atoms. R l and R m may be the same or different. X - indicates a halide ion or a tetrafluoroborate ion.)
Figure JPOXMLDOC01-appb-C000018
（式中、Ｒｎは炭素数が１～１８のアルキル基、炭素数が１～１８のフルオロアルキル基、炭素数が６～３０のアリール基、炭素数が５～３０のヘテロアリール基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。）
Figure JPOXMLDOC01-appb-C000018
(In the formula, R n is an alkyl group having 1 to 18 carbon atoms, a fluoroalkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 5 to 30 carbon atoms, and carbon. Indicates an alkoxycarbonyl group having a number of 2 to 18 or an aryloxycarbonyl group having a carbon number of 7 to 30.)
４．フッ素化剤が前記式（４）で示される化合物である、前記３に記載のフッ素化剤の活性評価方法。 4. The method for evaluating the activity of a fluorinating agent according to 3 above, wherein the fluorinating agent is a compound represented by the formula (4).
５．前記式（３）で表されるエステル化合物を含む混合物がフッ化水素を含み、エステル化工程の後に、当該混合物を（Ｒ２）３Ｎ（Ｒ２は炭素数１～４のアルキル基）で表される３級アミンとの反応に供して、当該フッ化水素と３級アミンの塩を形成する工程をさらに含む、前記１～４のいずれか１つに記載のフッ素化剤の活性評価方法。 5. The mixture containing the ester compound represented by the formula (3) contains hydrogen fluoride, and after the esterification step, the mixture is subjected to (R 2 ) 3 N (R 2 is an alkyl group having 1 to 4 carbon atoms). The method for evaluating the activity of a fluorinating agent according to any one of 1 to 4, further comprising a step of forming a salt of the hydrogen fluoride and the tertiary amine in preparation for the reaction with the represented tertiary amine. ..
６．フッ素化剤を、下記式（１）で表されるカルボン酸との反応に供して、下記式（２）で表されるカルボン酸フッ化物に変換するフッ素化工程、及び
前記フッ素化工程後の混合物をＲ１ＯＨ（Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。）で表されるアルコールとの反応に供して、前記カルボン酸フッ化物を下記式（３）で表されるエステル化合物に変換するエステル化工程を含む、
エステル化合物の製造方法。 6. After the fluorination step of converting the fluorinating agent into the carboxylic acid fluoride represented by the following formula (2) by subjecting it to the reaction with the carboxylic acid represented by the following formula (1), and after the fluorination step. The mixture is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and an alkoxy group having 1 to 18 carbon atoms. Aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcansulfonyl group having 1 to 18 carbon atoms, arylsulfonyl group having 6 to 30 carbon atoms, acyloxy having 1 to 18 carbon atoms A group, an alkanesulfonyloxy group having 1 to 18 carbon atoms, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms. ), The carboxylic acid fluoride is subjected to a reaction with an alcohol represented by the following formula (3), and includes an esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3).
Method for producing ester compound.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
（Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基、炭素数が７～３０のアリールオキシカルボニル基又は水素原子である。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）
Figure JPOXMLDOC01-appb-C000021
(R a , R b , R c , R d and Re , respectively, have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively. 6 to 30 aryloxy groups, halogen atoms, nitro groups, cyano groups, alcoholyl sulfonyl groups with 1 to 18 carbon atoms, aryl sulfonyl groups with 6 to 30 carbon atoms, acyloxy groups with 1 to 18 carbon atoms, carbon It is an alkanesulfonyloxy group having 1 to 18, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms, an aryloxycarbonyl group having 7 to 30 carbon atoms or a hydrogen atom. R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
７．Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅがそれぞれメチル基又は水素原子であり、Ｒ１がエチル基又はメチル基である、前記６記載のエステル化合物の製造方法。 7. The method for producing an ester compound according to the above 6, wherein R a , R b , R c , R d and Re are methyl groups or hydrogen atoms, respectively, and R 1 is an ethyl group or methyl group.
８．フッ素化剤が、下記式（４）で示される、前記６又は７に記載のエステル化合物の製造方法。 8. The method for producing an ester compound according to 6 or 7, wherein the fluorinating agent is represented by the following formula (4).
Figure JPOXMLDOC01-appb-C000022
（式中、Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊはそれぞれ水素原子、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）
Figure JPOXMLDOC01-appb-C000022
(In the formula, R f , R g , R h , R i and R j are hydrogen atoms, alkyl groups having 1 to 18 carbon atoms, aryl groups having 6 to 30 carbon atoms and 1 to 18 carbon atoms, respectively. Alkoxy group, aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcan sulfonyl group having 1 to 18 carbon atoms, aryl sulfonyl group having 6 to 30 carbon atoms, carbon number 1 to 1 to 18 acyloxy groups, 1-18 carbon alcan sulfonyloxy groups, 6-30 carbon aryl sulfonyloxy groups, 2-18 carbon alkoxycarbonyl groups or 7-30 carbon aryloxycarbonyl Indicates a group. R f , R g , R h , Ri and R j may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
　本発明により、フッ素化剤としての活性を簡便且つ再現性良く評価することができる。また、経済的かつ工業的に優れた方法によりフッ素化剤としての活性を評価することができる。さらに、エステル化合物を収率よく製造することができる。 According to the present invention, the activity as a fluorinating agent can be evaluated easily and with good reproducibility. In addition, the activity as a fluorinating agent can be evaluated by an economically and industrially excellent method. Further, the ester compound can be produced in high yield.
　［フッ素化剤の活性評価方法］
　本発明者らは、本発明はフッ素化剤を用いて、カルボン酸を別化合物に誘導することにより、そのフッ素化剤としての活性を評価することが可能であることを見出し、本発明をするに至った。
　本発明はフッ素化剤としての活性を評価する方法であって、
　フッ素化剤を、下記式（１）で表されるカルボン酸との反応に供して、下記式（２）で表されるカルボン酸フッ化物に変換するフッ素化工程、
　前記フッ素化工程後の混合物をＲ１ＯＨ（Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。）で表されるアルコールとの反応に供して、前記カルボン酸フッ化物を下記式（３）で表されるエステル化合物に変換するエステル化工程、及び
　前記エステル化工程後の混合物中に含まれるエステル化合物の濃度を定量分析し、前記フッ素化剤及び前記カルボン酸から得られるエステル化合物の理論上の濃度と比較することにより、フッ素化剤としての活性を評価する工程を含む、フッ素化剤の活性評価方法である。 [Method for evaluating the activity of fluorinating agent]
The present inventors have found that the present invention can evaluate the activity as a fluorinating agent by inducing a carboxylic acid into another compound using a fluorinating agent, and the present inventions are made. It came to.
The present invention is a method for evaluating the activity as a fluorinating agent.
A fluorination step in which a fluorinating agent is subjected to a reaction with a carboxylic acid represented by the following formula (1) to be converted into a carboxylic acid fluoride represented by the following formula (2).
The mixture after the fluorination step is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and 1 carbon number. An alkoxy group of ~ 18, an aryloxy group having 6 to 30 carbon atoms, a halogen atom, a nitro group, a cyano group, an alkanesulfonyl group having 1 to 18 carbon atoms, an arylsulfonyl group having 6 to 30 carbon atoms, and a carbon number of carbon atoms. Is an acyloxy group having 1 to 18, an alkanesulfonyloxy group having 1 to 18 carbon atoms, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an alkoxycarbonyl group having 7 to 30 carbon atoms. It is an aryloxycarbonyl group.) After the esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3) by subjecting it to a reaction with an alcohol represented by the following formula (3), and after the esterification step. A step of quantitatively analyzing the concentration of the ester compound contained in the mixture of the above and evaluating the activity as the fluorinating agent by comparing with the theoretical concentration of the fluorinating agent and the ester compound obtained from the carboxylic acid. It is a method for evaluating the activity of a fluorinating agent.
　前記フッ素化工程及びエステル化工程は下式に示す通りである。 The fluorination step and esterification step are as shown in the following formula.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
＜フッ素化剤＞
　本発明で使用されるフッ素化剤は、有機化合物にフッ素原子を導入することができる材料であり、有機化合物中のアルコール基やカルボニル基に対して脱酸素的にフッ素原子への置換反応を行う。具体的には、下記式（４）で示される化合物、下記式（５）で示される化合物、下記式（６）で示される化合物、下記式（７）で示される化合物、ジフルオロ（モルホリノ）スルホニウムテトラフルオロクロリド、ジフルオロ（モルホリノ）スルホニウムテトラフルオロボラート、ヘキサフルオロプロペンジエチルアミン、１，１，２，２－テトラフルオロ－Ｎ，Ｎ－ジメチルエチルアミン、Ｎ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）クロロイミダゾリウムクロリドとフッ化セシウムの重量比１：２の混合物、１，３－ビス（２，６－ジイソプロピルフェニル）－２，２－ジフルオロ－４－イミダゾリン及びＮ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）フルオロイミダゾリウムボレートからなる群から選ばれる少なくとも１つであり、より再現性よく活性を評価する観点から、下記式（４）又は下記式（５）で示される化合物が好ましく、下記式（４）で示される化合物がより好ましい。
　また、フッ素化剤の中には、フッ素化剤の製造の過程で生じる副生成物、フッ素化反応後にフッ素原子が脱離して生成する化合物、フッ素化剤の熱分解や加水分解等により生成する分解物等も含まれる。そのため、活性成分の含有量が必ずしも１００質量％ではない。したがって、フッ素化剤としての活性を評価する必要がある。 <Fluorinating agent>
The fluorinating agent used in the present invention is a material capable of introducing a fluorine atom into an organic compound, and deoxidizes an alcohol group or a carbonyl group in the organic compound to replace the fluorine atom. .. Specifically, the compound represented by the following formula (4), the compound represented by the following formula (5), the compound represented by the following formula (6), the compound represented by the following formula (7), and difluoro (morpholino) sulfonium. Tetrafluorochloride, difluoro (morpholino) sulfonium tetrafluoroborate, hexafluoropropenediethylamine, 1,1,2,2-tetrafluoro-N, N-dimethylethylamine, N, N'-1,3-bis (2, 6-Diisopropylphenyl) A mixture of chloroimidazolium chloride and cesium fluoride in a weight ratio of 1: 2, 1,3-bis (2,6-diisopropylphenyl) -2,2-difluoro-4-imidazoline and N, N' It is at least one selected from the group consisting of -1,3-bis (2,6-diisopropylphenyl) fluoroimidazolium borate, and from the viewpoint of evaluating the activity with better reproducibility, the following formula (4) or the following formula ( The compound represented by 5) is preferable, and the compound represented by the following formula (4) is more preferable.
In addition, some of the fluorinating agents are by-products generated in the process of producing the fluorinating agent, compounds formed by desorption of fluorine atoms after the fluorination reaction, and produced by thermal decomposition or hydrolysis of the fluorinating agent. Decomposed products are also included. Therefore, the content of the active ingredient is not necessarily 100% by mass. Therefore, it is necessary to evaluate the activity as a fluorinating agent.
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　前記式（４）のＲｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊとしてはそれぞれ水素原子、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基が挙げられ、Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊは、活性評価の精度の高さや入手容易性等の観点から、水素原子又は炭素数が１～１８のアルキル基が好ましく、水素原子又は炭素数が１～４のアルキル基がより好ましく、Ｒｆ及びＲｊがメチル基、Ｒｈがｔｅｒｔ－ブチル基、Ｒｇ及びＲｉが水素原子であることがさらに好ましい。
　前記式（４）において、実施態様の一つとしては、Ｒｆ及びＲｊがメチル基、Ｒｈがｔｅｒｔ－ブチル基、Ｒｇ及びＲｉが水素原子である２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼンであり、Ｆｌｕｏｌｅａｄ（登録商標）とも称する。 The R f , R g , R h , Ri and R j of the above formula (4) are a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, and 1 carbon atom, respectively. Alkoxy group of ~ 18, aryloxy group of 6-30 carbons, halogen atom, nitro group, cyano group, alcansulfonyl group of 1-18 carbons, arylsulfonyl group of 6-30 carbons, carbon number 1 to 18 acyloxy group, 1 to 18 carbon number alcan sulfonyloxy group, 6 to 30 carbon number aryl sulfonyloxy group, 2 to 18 carbon number alkoxycarbonyl group or 7 to 30 carbon number Aryloxycarbonyl groups are mentioned, and R f , R g , R h , R i and R j may be the same or different, and adjacent substituents are bonded to each other to form a ring. May be good. R f , R g , R h , R i and R j are preferably hydrogen atoms or alkyl groups having 1 to 18 carbon atoms, and hydrogen atoms or carbons, from the viewpoint of high accuracy of activity evaluation and availability. Alkyl groups having a number of 1 to 4 are more preferable, R f and R j are methyl groups, R h is a tert-butyl group, and R g and Ri are hydrogen atoms.
In the above formula (4), as one of the embodiments, 2,6-dimethyl-4- , in which R f and R j are methyl groups, R h is a tert-butyl group, and R g and Ri are hydrogen atoms. It is t-butyl-trifluorosulfanylbenzene and is also referred to as Fluolead®.
　フッ素化剤として式（４）で示される化合物（以下、ＳＦ３又はＳＦ３体と称することもある）は空気中の湿気等によりＳＦ３基がＳＯＦ基に分解されるため（以下、生成したＳＯＦ基を有する化合物をＳＯＦ又はＳＯＦ体ともいう）、当該式（４）で示される化合物はＳＯＦ体を含んでいてもよい。ＳＦ３がＳＯＦに分解される際にフッ化水素を生成するので、当該式（４）で示される化合物はフッ化水素を含んでいてもよい。これらの成分の混合比率は任意であるが、ＳＦ３体が主成分であることが好ましい。ＳＦ３体が保存中に分解することによって得られる、ＳＦ３及びＳＯＦを含む混合物におけるＳＦ３体の濃度は９０％質量以上であり、９３質量％以上であることが好ましい。 As a fluorinating agent, the compound represented by the formula (4) (hereinafter, also referred to as SF 3 or SF 3 body) is produced because 3 SF groups are decomposed into SOF groups due to humidity in the air or the like (hereinafter, produced. A compound having an SOF group is also referred to as SOF or SOF form), and the compound represented by the formula (4) may contain a SOF form. Since hydrogen fluoride is produced when SF 3 is decomposed into SOF, the compound represented by the formula (4) may contain hydrogen fluoride. The mixing ratio of these components is arbitrary, but it is preferable that three SFs are the main components. The concentration of SF 3 in the mixture containing SF 3 and SOF obtained by decomposing the SF 3 during storage is 90% by mass or more, preferably 93% by mass or more.
　前記式（５）のＲｋとしては炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のジアルキルアミノ基、炭素数が６～３０のアリールアミノ基、炭素数が１～１８のビス（アルコキシアルキル）アミノ基、モルホリノ基、炭素数が１～１８のアシルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基が挙げられ、炭素数が６～３０のアリール基、炭素数が１～１８のジアルキルアミノ基、炭素数が１～１８のビス（２-アルコキシエチル）アミノ基又はモルホリノ基であることが好ましく、炭素数が６～１６のアリール基、炭素数が１～４のジアルキルアミノ基、炭素数が１～８のビス（２-アルコキシエチル）アミノ基又はモルホリノ基であることがより好ましい。中でも、ジエチルアミノ基を有する化合物（ＤＡＳＴとも称する）、ビス（２－メトキシエチル）アミノ基を有する化合物（Ｄｅｏｘｏ－Ｆｌｕｏｒ（登録商標）とも称する）がさらにより好ましい。 The alkyl group as the R k carbon atoms 1 to 18 in the formula (5), an aryl group having a carbon number of 6 to 30, a dialkylamino group having a carbon number of 1 to 18, arylamino of 6 to 30 carbon atoms Group, bis (alkoxyalkyl) amino group having 1 to 18 carbon atoms, morpholino group, acyloxy group having 1 to 18 carbon atoms, alkoxycarbonyl group having 2 to 18 carbon atoms or aryloxy having 7 to 30 carbon atoms. The carbonyl group may be an aryl group having 6 to 30 carbon atoms, a dialkylamino group having 1 to 18 carbon atoms, a bis (2-alkoxyethyl) amino group having 1 to 18 carbon atoms or a morpholino group. More preferably, it is an aryl group having 6 to 16 carbon atoms, a dialkylamino group having 1 to 4 carbon atoms, a bis (2-alkoxyethyl) amino group having 1 to 8 carbon atoms or a morpholino group. Among them, a compound having a diethylamino group (also referred to as DAST) and a compound having a bis (2-methoxyethyl) amino group (also referred to as Deoxo-Fluor (registered trademark)) are even more preferable.
　前記式（６）のＲｌ及びＲｍとしてはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のビス（２-アルコキシエチル）アミノ基、炭素数が１～１８のアシルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基が挙げられ、炭素数が１～１８のアルキル基が好ましく、炭素数が１～４のアルキル基がより好ましく、エチル基であることがさらに好ましい。Ｒｌ及びＲｍは同一であっても異なっていてもよい。
　前記式（６）のＸ－はハロゲン化物イオン又はテトラフルオロホウ酸イオンを示し、塩化物イオン又はテトラフルオロホウ酸イオンであることが好ましい。 The R l and R m of the formula (6) are an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, and a bis (2-alkoxyethyl) amino group having 1 to 18 carbon atoms, respectively. Examples thereof include an acyloxy group having 1 to 18 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms, and an alkyl group having 1 to 18 carbon atoms is preferable. Alkyl groups having a number of 1 to 4 are more preferable, and ethyl groups are even more preferable. R l and R m may be the same or different.
X in the formula (6) - represents a halide ion or tetrafluoroborate ion, preferably a chloride ion or a tetrafluoroborate ion.
　前記式（７）のＲｎとしては炭素数が１～１８のアルキル基、炭素数が１～１８のフルオロアルキル基、炭素数が６～３０のアリール基、炭素数が５～３０のヘテロアリール基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基が挙げられる。中でも、炭素数が１～１８のフルオロアルキル基、または炭素数が５～３０のヘテロアリール基が好ましく、ノナフルオロブチル基、ピリジル基又はピリミジル基であることがより好ましい。 The R n of the formula (7) is an alkyl group having 1 to 18 carbon atoms, a fluoroalkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, and a heteroaryl group having 5 to 30 carbon atoms. Examples thereof include an alkoxycarbonyl group having 2 to 18 carbon atoms and an aryloxycarbonyl group having 7 to 30 carbon atoms. Of these, a fluoroalkyl group having 1 to 18 carbon atoms or a heteroaryl group having 5 to 30 carbon atoms is preferable, and a nonafluorobutyl group, a pyridyl group or a pyrimidyl group is more preferable.
　また、ジフルオロ（モルホリノ）スルホニウムテトラフルオロクロリドやジフルオロ（モルホリノ）スルホニウムテトラフルオロボラートはＸｔａｌＦｌｕｏｒ－Ｍ（登録商標）とも称し、下記式（Ｉ）で示される。
　ヘキサフルオロプロペンジエチルアミンは下記式（ＩＩ）で示される。
　１，１，２，２－テトラフルオロ－Ｎ，Ｎ－ジメチルエチルアミンは下記式（ＩＩＩ）で示される。
　Ｎ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）クロロイミダゾリウムクロリドとフッ化セシウムの重量比１：２の混合物は、ＰｈｅｎｏＦｌｕｏｒ－ＭＩＸ（登録商標）とも称し、下記式（ＩＶ）で示される。
　１，３－ビス（２，６－ジイソプロピルフェニル）－２，２－ジフルオロ－４－イミダゾリンは、ＰｈｅｎｏＦｌｏｕｒ（登録商標）とも称し、下記式（ＶＩ）で示される。
　Ｎ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）フルオロイミダゾリウムボレートは、ＡｌｋｙｌＦｌｕｏｒ（登録商標）とも称し、下記式（Ｖ）で示される。 Further, difluoro (morpholino) sulfonium tetrafluorochloride and difluoro (morpholino) sulfonium tetrafluoroborate are also referred to as XtalFluor-M (registered trademark) and are represented by the following formula (I).
Hexafluoropropenediethylamine is represented by the following formula (II).
1,1,2,2-tetrafluoro-N, N-dimethylethylamine is represented by the following formula (III).
A mixture of N, N'-1,3-bis (2,6-diisopropylphenyl) chloroimidazolium chloride and cesium fluoride in a weight ratio of 1: 2 is also referred to as PhenoFluor-MIX® (registered trademark) and has the following formula (IV). ).
1,3-Bis (2,6-diisopropylphenyl) -2,2-difluoro-4-imidazoline is also referred to as PhenoFlour (registered trademark) and is represented by the following formula (VI).
N, N'-1,3-bis (2,6-diisopropylphenyl) fluoroimidazolium borate, also referred to as AlkylFluor®, is represented by the following formula (V).
Figure JPOXMLDOC01-appb-C000028
（式（Ｉ）中、Ｘ－は塩化物イオン又はテトラフルオロホウ酸イオンを示す。）
Figure JPOXMLDOC01-appb-C000028
(In the formula (I), X - represents a chloride ion or a tetrafluoroborate ion.)
＜フッ素化工程＞
　本工程は、フッ素化剤を前記式（１）で表されるカルボン酸との反応に供して、前記式（２）で表されるカルボン酸フッ化物に変換する工程である。
　式（１）及び（２）のＲａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは、それぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基、炭素数が７～３０のアリールオキシカルボニル基又は水素原子である。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅとして、好ましくは、炭素数が１～４のアルキル基又は水素原子であり、更に好ましくは、メチル基又は水素原子であり、特に好ましくは、水素原子である。
　フッ素化剤に対し、１．０当量以上のカルボン酸を用いればよく、１．２～６．０当量のカルボン酸を用いることが好ましく、１．２～２．０当量のカルボン酸を用いることがさらに好ましい。
　また、反応は溶媒存在下で実施することが好ましい。アルコールやカルボニル化合物とはフッ素化反応が進行するため、水酸基やカルボニル基を有する溶媒は好ましくない。特に水と反応するとフッ化水素が発生するため好ましくない。副反応を生じない限り溶媒は限定されないが、溶解性等を考慮するとジクロロメタン等のハロゲン化炭化水素が好ましい。使用する溶媒量は、適宜調節されるが、フッ素化剤１ｇに対して、０．１ｇ～１００ｇであり、０．５ｇ～１０ｇが好ましい。
　また、反応は室温（１５～３０℃）で実施することが好ましい。反応時間は適宜設定でき、１～６０分程度としてよい。さらに、フッ素化に必要な公知の触媒や反応促進剤を併用してもよい。 <Fluorination process>
This step is a step of subjecting the fluorinating agent to a reaction with the carboxylic acid represented by the formula (1) to convert it into the carboxylic acid fluoride represented by the formula (2).
R a , R b , R c , R d, and Re of the formulas (1) and (2) have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, and 1 carbon atom, respectively. Alkoxy group of ~ 18, aryloxy group of 6-30 carbons, halogen atom, nitro group, cyano group, alcansulfonyl group of 1-18 carbons, arylsulfonyl group of 6-30 carbons, carbon number 1-18 acyloxy groups, 1-18 carbon alcan sulfonyloxy groups, 6-30 carbon aryl sulfonyloxy groups, 2-18 carbon alkoxycarbonyl groups, 7-30 carbon carbons It is an aryloxycarbonyl group or a hydrogen atom. R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring. R a , R b , R c , R d and Re are preferably an alkyl group or a hydrogen atom having 1 to 4 carbon atoms, more preferably a methyl group or a hydrogen atom, and particularly preferably a methyl group or a hydrogen atom. It is a hydrogen atom.
1.0 equivalent or more of carboxylic acid may be used for the fluorinating agent, 1.2 to 6.0 equivalent of carboxylic acid is preferably used, and 1.2 to 2.0 equivalent of carboxylic acid is used. Is even more preferable.
Further, the reaction is preferably carried out in the presence of a solvent. A solvent having a hydroxyl group or a carbonyl group is not preferable because the fluorination reaction proceeds with the alcohol or the carbonyl compound. In particular, it is not preferable because hydrogen fluoride is generated when it reacts with water. The solvent is not limited as long as a side reaction does not occur, but a halogenated hydrocarbon such as dichloromethane is preferable in consideration of solubility and the like. The amount of the solvent used is appropriately adjusted, but is 0.1 g to 100 g, preferably 0.5 g to 10 g, with respect to 1 g of the fluorinating agent.
The reaction is preferably carried out at room temperature (15 to 30 ° C.). The reaction time can be appropriately set and may be about 1 to 60 minutes. Further, a known catalyst or reaction accelerator necessary for fluorination may be used in combination.
＜エステル化工程＞
　本工程では、前記工程で得られた式（２）で示されるカルボン酸フッ化物（ＣＯＦ体ともいう）をアルコールとの反応に供して、一般式（３）で表されるエステル化合物に変換する工程である。
　本工程で用いるアルコールはＲ１ＯＨで表される。Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。Ｒ１として好ましくは、炭素数１～４のアルキル基であり、更に好ましくは、メチル基又はエチル基であり、特に好ましくは、メチル基である。
　また本工程においてフッ素化工程後の混合物中に含まれるＳＯＦ体は、前記アルコールと反応してスルフィン酸エステル化合物（以下、ＳＯＯＲ１体又はＳＯＯＲ１という）へと変換される。アルコールの量はＣＯＦ体に対して過剰であればよく、溶媒量とすることが好ましい。このように本反応ではアルコールが溶媒となるので追加の溶媒は不要であるが、例えばジクロロメタン等のハロゲン化炭化水素を溶媒として用いてもよい。使用する溶媒量は、適宜調節されるが、ＣＯＦ体１ｇに対して、０．１ｇ～１００ｇであり、０．５ｇ～１０ｇが好ましい。
　反応は室温（１５℃～３０℃）で実施することが好ましい。反応時間も適宜設定でき、１～６０分程度としてよい。さらに、エステル化に必要な公知の触媒や反応促進剤を併用してもよい。 <Esterification process>
In this step, the carboxylic acid fluoride (also referred to as COF compound) represented by the formula (2) obtained in the above step is subjected to a reaction with an alcohol to be converted into an ester compound represented by the general formula (3). It is a process.
The alcohol used in this step is represented by R 1 OH. R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and 6 to 30 carbon atoms. Aryloxy group, halogen atom, nitro group, cyano group, alkylsulfonyl group having 1 to 18 carbon atoms, arylsulfonyl group having 6 to 30 carbon atoms, acyloxy group having 1 to 18 carbon atoms, 1 carbon number. It is an alkanesulfonyloxy group having a carbon number of 18 to 18, an arylsulfonyloxy group having a carbon number of 6 to 30, an alkoxycarbonyl group having a carbon number of 2 to 18, or an aryloxycarbonyl group having a carbon number of 7 to 30. R 1 is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.
Further, in this step, the SOF compound contained in the mixture after the fluorination step is reacted with the alcohol and converted into a sulfinic acid ester compound (hereinafter referred to as SOOR 1 compound or SOOR 1 ). The amount of alcohol may be excessive with respect to the COF form, and is preferably the amount of solvent. As described above, since alcohol serves as a solvent in this reaction, no additional solvent is required, but halogenated hydrocarbons such as dichloromethane may be used as the solvent. The amount of the solvent used is appropriately adjusted, but is 0.1 g to 100 g, preferably 0.5 g to 10 g, with respect to 1 g of the COF body.
The reaction is preferably carried out at room temperature (15 ° C. to 30 ° C.). The reaction time can be appropriately set and may be about 1 to 60 minutes. Further, a known catalyst or reaction accelerator necessary for esterification may be used in combination.
＜塩形成工程＞
　本工程は、前記式（３）で表されるエステル化合物を含む混合物がフッ化水素を含み、前記混合物を（Ｒ２）３Ｎ（Ｒ２は炭素数１～４のアルキル基）で表される３級アミンとの反応に供して、前記フッ化水素と３級アミンの塩を形成する工程である。
　本工程を行わなくてもフッ素化剤の活性評価を行うことはできるが、前述のとおりエステル化工程後の混合物にはフッ化水素が含まれている場合があるため、本工程を行う方が好ましい。フッ化水素は腐食性を有するため、塩形成工程を行うことにより、分析時に用いる機器や容器の腐食等を防止することができる。そこで、本方法においては前記エステル化工程後の混合物に３級アミンを加え、当該混合物中に含まれるフッ化水素を選択的に塩に変換することが好ましい。 <Salt formation process>
In this step, the mixture containing the ester compound represented by the formula (3) contains hydrogen fluoride, and the mixture is represented by (R 2 ) 3 N (R 2 is an alkyl group having 1 to 4 carbon atoms). This is a step of forming a salt of the hydrogen fluoride and the tertiary amine by subjecting it to a reaction with the tertiary amine.
Although the activity of the fluorinating agent can be evaluated without performing this step, it is better to perform this step because the mixture after the esterification step may contain hydrogen fluoride as described above. preferable. Since hydrogen fluoride is corrosive, it is possible to prevent corrosion of equipment and containers used during analysis by performing a salt forming step. Therefore, in this method, it is preferable to add a tertiary amine to the mixture after the esterification step and selectively convert hydrogen fluoride contained in the mixture into a salt.
　使用する塩基としてはフッ化水素と塩を形成するものならば特に制限されないが、生成した塩の有機溶媒への溶解性を向上させ、後処理を簡便化する観点から、有機塩を使用することが好ましく、（Ｒ２）３Ｎで表される３級アミンを使用することがより好ましい。（Ｒ２）３Ｎ中のＲ２は炭素数１～４のアルキル基であり、炭素数２または３のアルキル基であることが好ましく、エチル基であることがより好ましい。また、フッ化水素の中和はＫＦ等の無機塩を用いても実施可能であるが、当該塩は有機溶媒に不溶であり、塩を含む溶液が不均一になる。しかし、３級アミンから形成される塩は有機溶媒に可溶であるのでこのような不具合が生じない。
　本工程は、使用する塩基がフッ化水素に対して過剰量あればよい。反応は室温（１５℃～３０℃）で実施することが好ましい。反応時間も適宜設定でき、１～６０分程度としてよい。 The base to be used is not particularly limited as long as it forms a salt with hydrogen fluoride, but an organic salt should be used from the viewpoint of improving the solubility of the produced salt in an organic solvent and simplifying the post-treatment. preferably, it is more preferable to use a tertiary amine represented by (R 2) 3 N. (R 2) R 2 in 3 N is an alkyl group having 1 to 4 carbon atoms, preferably an alkyl group having 2 or 3 carbon atoms, and more preferably an ethyl group. Neutralization of hydrogen fluoride can also be carried out by using an inorganic salt such as KF, but the salt is insoluble in an organic solvent and the solution containing the salt becomes non-uniform. However, since the salt formed from the tertiary amine is soluble in the organic solvent, such a problem does not occur.
In this step, the amount of base used may be excessive with respect to hydrogen fluoride. The reaction is preferably carried out at room temperature (15 ° C. to 30 ° C.). The reaction time can be appropriately set and may be about 1 to 60 minutes.
＜活性評価工程＞
　本工程で、エステル化工程又は塩形成工程で得られた混合物中に含まれるエステル化合物の濃度を定量分析し、前記フッ素化剤及び前記カルボン酸から得られるエステル化合物の理論上の濃度と比較することにより、フッ素化剤としての活性を評価する工程である。
　定量分析は、エステル化合物を定量することができれば、内部標準法や絶対検量線法等のいずれの定量方法でもよく、ＮＭＲ、ＨＰＬＣ、ＧＣ等のいずれの測定機器を用いてもよいが、再現性よく簡便に分析する観点から、ＨＰＬＣを用いることが好ましい。
　例えば、ＨＰＬＣを用いる場合、ＨＰＬＣで分析してエステル化合物のピーク面積を決定し、この値からエステル化工程又は塩形成工程で得られるエステル化合物を含む混合物中のエステル化合物の濃度を決定する。この場合、溶離液はアセトニトリルと水の混合溶媒が好ましい。さらに標準物質を用いて補正を行ってもよい。前記フッ素化剤及び前記カルボン酸から得られるエステル化合物の理論上の濃度と実測の濃度よりフッ素化剤の活性度が求められる。 <Activity evaluation process>
In this step, the concentration of the ester compound contained in the mixture obtained in the esterification step or the salt forming step is quantitatively analyzed and compared with the theoretical concentration of the ester compound obtained from the fluorinating agent and the carboxylic acid. This is a step of evaluating the activity as a fluorinating agent.
The quantitative analysis may be performed by any quantification method such as an internal standard method or an absolute calibration curve method as long as the ester compound can be quantified, and any measuring instrument such as NMR, HPLC or GC may be used, but the reproducibility. From the viewpoint of good and simple analysis, it is preferable to use HPLC.
For example, when HPLC is used, the peak area of the ester compound is determined by analysis by HPLC, and the concentration of the ester compound in the mixture containing the ester compound obtained in the esterification step or the salt forming step is determined from this value. In this case, the eluent is preferably a mixed solvent of acetonitrile and water. Further, the correction may be performed using a standard substance. The activity of the fluorinating agent can be determined from the theoretical concentration of the fluorinating agent and the ester compound obtained from the carboxylic acid and the measured concentration.
　［製造方法］
　本発明の製造方法は、
　フッ素化剤を、下記式（１）で表されるカルボン酸との反応に供して、下記式（２）で表されるカルボン酸フッ化物に変換するフッ素化工程、及び
前記フッ素化工程後の混合物をＲ１ＯＨ（Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。）で表されるアルコールとの反応に供して、前記カルボン酸フッ化物を下記式（３）で表されるエステル化合物に変換するエステル化工程を含む、
エステル化合物の製造方法である。
さらに、エステル化工程の後に、前記塩形成工程を含んでいてもよい。 [Production method]
The manufacturing method of the present invention
After the fluorination step of converting the fluorinating agent into the carboxylic acid fluoride represented by the following formula (2) by subjecting it to the reaction with the carboxylic acid represented by the following formula (1), and after the fluorination step. The mixture is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and an alkoxy group having 1 to 18 carbon atoms. Aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcansulfonyl group having 1 to 18 carbon atoms, arylsulfonyl group having 6 to 30 carbon atoms, acyloxy having 1 to 18 carbon atoms A group, an alkanesulfonyloxy group having 1 to 18 carbon atoms, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms. ), The carboxylic acid fluoride is subjected to a reaction with an alcohol represented by the following formula (3), and includes an esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3).
This is a method for producing an ester compound.
Further, the salt forming step may be included after the esterification step.
　フッ素化工程、エステル化工程及び塩形成工程の反応条件や操作方法、使用するフッ素化剤については前記フッ素化剤の活性評価方法と同じである。 The reaction conditions and operating methods of the fluorination step, esterification step and salt formation step, and the fluorinating agent used are the same as the activity evaluation method of the fluorinating agent.
　本製造方法で使用するカルボン酸、カルボン酸フッ化物、エステル化合物は、前記フッ素化剤の活性評価方法と同じで、それぞれ下記式（１）、（２）、（３）で示される。 The carboxylic acid, carboxylic acid fluoride, and ester compound used in this production method are the same as the method for evaluating the activity of the fluorinating agent, and are represented by the following formulas (1), (2), and (3), respectively.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基、炭素数が７～３０のアリールオキシカルボニル基又は水素原子であるが、活性評価の精度の高さや入手容易性等の観点から、水素原子又は炭素数１～４のアルキル基が好ましく、水素原子又はメチル基がより好ましく、水素原子がさらに好ましい。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。 R a , R b , R c , R d and Re have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and 6 carbon atoms, respectively. ~ 30 aryloxy groups, halogen atoms, nitro groups, cyano groups, alkoxysulfonyl groups with 1-18 carbon atoms, arylsulfonyl groups with 6-30 carbon atoms, acyloxy groups with 1-18 carbon atoms, carbon number Is an alcan sulfonyloxy group having 1 to 18, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms, an aryloxycarbonyl group having 7 to 30 carbon atoms, or a hydrogen atom. From the viewpoint of high accuracy of activity evaluation, availability, and the like, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is preferable, a hydrogen atom or a methyl group is more preferable, and a hydrogen atom is further preferable. R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.
　エステル化工程又は塩形成工程で得られる混合物から、例えば、中和、抽出、濾過、濃縮、蒸留、晶析、カラムクロマトグラフィー、ＨＰＬＣ等を用いて、エステル化合物を単離することができる。
　また、前記混合物の後処理をすることなく、前記活性評価工程にて活性評価することができる。 From the mixture obtained in the esterification step or the salt forming step, the ester compound can be isolated by using, for example, neutralization, extraction, filtration, concentration, distillation, crystallization, column chromatography, HPLC and the like.
In addition, the activity can be evaluated in the activity evaluation step without post-treatment of the mixture.
　本方法の好ましい態様として、ＳＦ３及びＳＯＦを含む混合物をフッ素化工程に供し、次いでエステル化工程に供し、さらに塩形成工程に供することが挙げられる。このスキームを以下に示す。 A preferred embodiment of the method is to subject the mixture containing SF 3 and SOF to a fluorination step, then to an esterification step, and further to a salt forming step. This scheme is shown below.
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　当該スキームにおいて、各記号の説明は前記と同じである。よって、より好ましいスキームは以下のとおりである。
　なお、当該スキームにおいて、フッ素化剤中の混合物とは主にＳＦ３、ＳＯＦ及びＨＦを含む混合物、フッ素化工程後の混合物とは主に前記式（２）記載の化合物、フルオロスルフィニル芳香族化合物（ＳＯＦ）及びＨＦを含む混合物であり、エステル化工程後の混合物とは主に前記式（３）記載の化合物、スルフィン酸エステル化合物（ＳＯＯＲ１）、ＨＦを含む混合物であり、塩形成工程で得られる混合物とは主に前記式（３）記載の化合物、スルフィン酸エステル化合物（ＳＯＯＲ１）、フッ化水素と３級アミンの塩を含む混合物である。 In the scheme, the description of each symbol is the same as above. Therefore, a more preferred scheme is as follows.
In the scheme, the mixture in the fluorinating agent is mainly a mixture containing SF 3 , SOF and HF, and the mixture after the fluorination step is mainly a compound described in the above formula (2) and a fluorosulfinyl aromatic compound. It is a mixture containing (SOF) and HF, and the mixture after the esterification step is mainly a mixture containing the compound of the above formula (3), a sulfinate compound (SOOR 1 ), and HF, and is a mixture containing HF in the salt forming step. The obtained mixture is mainly a mixture containing the compound of the above formula (3), a sulfinate compound (SOOR 1 ), hydrogen fluoride and a salt of a tertiary amine.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　次に、実施例を挙げて本発明を具体的に説明するが、本発明はこれら実施例に制限されるものではない。 Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.
［実施例１Ａ］
　フッ素化剤を用いて、カルボン酸からエステル化合物への変換を、以下の手順に従い実施した。
　２，６－ジメチル－４－ｔ－ブチル－トリフルオロスルファニルベンゼン（Ｆｌｕｏｌｅａｄ（登録商標））を準備した。当該物質は保存中の分解によって生じた微量なフルオロスルフィニル芳香族化合物（ＳＯＦ）およびフッ化水素（ＨＦ）を含む混合物である。
＜フッ素化工程＞
　窒素雰囲気下のグローブボックス内（露点：－２０℃）にてＦｌｕｏｌｅａｄを１．０ｇと安息香酸０．８ｇを精量し、２０ｍＬの回転子を備えたフッ素樹脂製容器に入れた。
　２ｍＬのジクロロメタンを前記容器に加え、スターラーに載置し、室温（１９～２４℃）で撹拌した。
＜エステル化工程＞
　３０分経過後に、２ｍＬのメタノールを前記容器に加え攪拌した。
＜塩形成工程＞
　さらに３０分経過後に反応溶液に対して３ｍＬのトリエチルアミンを１分かけて添加した。
　攪拌を終了し、反応液全量を５０ｍＬのメスフラスコに入れ、アセトニトリルを加えて正確に５０ｍＬとした。
　この溶液５ｍＬをとり、５０ｍＬのメスフラスコに入れ、アセトニトリルを加えて正確に５０ｍＬとした。
　このようにして塩形成工程後に得られた変性混合物の試料溶液を調製した。 [Example 1A]
The conversion of carboxylic acid to ester compound using a fluorinating agent was carried out according to the following procedure.
2,6-Dimethyl-4-t-butyl-trifluorosulfanylbenzene (Fluoread®) was prepared. The substance is a mixture containing trace amounts of fluorosulfinyl aromatic compounds (SOF) and hydrogen fluoride (HF) produced by decomposition during storage.
<Fluorination process>
1.0 g of Fluororead and 0.8 g of benzoic acid were purified in a glove box under a nitrogen atmosphere (dew point: −20 ° C.), and placed in a fluororesin container equipped with a 20 mL rotor.
2 mL of dichloromethane was added to the container, placed on a stirrer and stirred at room temperature (19-24 ° C.).
<Esterification process>
After 30 minutes, 2 mL of methanol was added to the container and stirred.
<Salt formation process>
After a further 30 minutes, 3 mL of triethylamine was added to the reaction solution over 1 minute.
Stirring was completed, the total volume of the reaction solution was placed in a 50 mL volumetric flask, and acetonitrile was added to make exactly 50 mL.
5 mL of this solution was taken, placed in a 50 mL volumetric flask, and acetonitrile was added to make exactly 50 mL.
In this way, a sample solution of the modified mixture obtained after the salt forming step was prepared.
［実施例１Ｂ］
　エステル化合物の標準品として安息香酸メチルを準備した。安息香酸メチル１００ｍｇを精量し、１００ｍＬのメスフラスコに入れ、アセトニトリルを加えて正確に１００ｍＬとした。このようにしてエステル化合物の標準溶液を調製した。 [Example 1B]
Methyl benzoate was prepared as a standard ester compound. Methyl benzoate (100 mg) was calibrated, placed in a 100 mL volumetric flask, and acetonitrile was added to make exactly 100 mL. In this way, a standard solution of the ester compound was prepared.
［実施例１Ｃ］
＜活性評価工程＞
　実施例１Ａで得た試料溶液と実施例１Ｂで得た標準溶液をＨＰＬＣで分析した。分析条件は以下のとおりである。
カラム：ＹＭＣ－ＯＤＳ－ＡＭ　５μｍ、４．６×１５０ｍｍ
溶離液：ＭｅＣＮ：Ｈ２Ｏ＝７：３
流速：１ｍＬ／ｍｉｎ
検出波長：２５４ｎｍ
注入量：１０μＬ
　得られた分析結果から、試料溶液中のエステル化合物のピーク面積と標準溶液中のエステル化合物のピーク面積を求めた。試料溶液中のエステル化合物のピーク面積を、標準溶液中のエステル化合物のピーク面積によって補正し、試料溶液中のエステル化合物の濃度を算出した。この濃度の理論上の濃度に対する割合は９３．１％であった。この値はＦｌｕｏｌｅａｄ（登録商標）の活性度に相当する。 [Example 1C]
<Activity evaluation process>
The sample solution obtained in Example 1A and the standard solution obtained in Example 1B were analyzed by HPLC. The analysis conditions are as follows.
Column: YMC-ODS-AM 5 μm, 4.6 × 150 mm
Eluent: MeCN: H 2 O = 7: 3
Flow rate: 1 mL / min
Detection wavelength: 254 nm
Injection volume: 10 μL
From the obtained analysis results, the peak area of the ester compound in the sample solution and the peak area of the ester compound in the standard solution were determined. The peak area of the ester compound in the sample solution was corrected by the peak area of the ester compound in the standard solution, and the concentration of the ester compound in the sample solution was calculated. The ratio of this concentration to the theoretical concentration was 93.1%. This value corresponds to the activity of Fluoled®.
　上記条件で、ＧＣ－ＭＳを測定したところ、安息香酸メチルのピークには安息香酸メチルのみが含まれ、他の化合物のピークが検出されなかった。このことから本反応は定量的に反応が進み、分析を阻害する不純物が含まれないことが明らかである。 When GC-MS was measured under the above conditions, the peak of methyl benzoate contained only methyl benzoate, and the peaks of other compounds were not detected. From this, it is clear that this reaction proceeds quantitatively and does not contain impurities that hinder the analysis.
［実施例２］
　実施例１Ａで用いたものと同一のロットのＦｌｕｏｌｅａｄ（登録商標）を準備して、実施例１Ａと同様にして塩形成工程後に得られた混合物の試料溶液を調製し、実施例１Ｂと同様にしてエステル化合物の標準溶液を調製し、実施例１Ｃと同様にしてＨＰＬＣで分析することによりＦｌｕｏｌｅａｄ（登録商標）の活性度を求める操作を４回繰り返した。実施例１Ｃで得られた結果も含め、表１に結果を示す。求められた活性度の範囲は９２．３％～９３．５％であり、再現性良く評価ができていることがわかった。 [Example 2]
Prepare a Loolead® in the same lot as that used in Example 1A, prepare a sample solution of the mixture obtained after the salt formation step in the same manner as in Example 1A, and make it the same as in Example 1B. A standard solution of the ester compound was prepared and analyzed by HPLC in the same manner as in Example 1C to determine the activity of Fluolead®, which was repeated four times. The results are shown in Table 1, including the results obtained in Example 1C. The range of activity required was 92.3% to 93.5%, and it was found that the evaluation was possible with good reproducibility.
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
［実施例３］
　実施例１Ａで用いたものと同一のロットのＦｌｕｏｌｅａｄ（登録商標）を準備して、安息香酸の当量数、ジクロロメタンの量、ジクロロメタン添加後の攪拌時間（攪拌１）、メタノールの量、メタノール添加後の攪拌時間（攪拌２）を変動させて塩形成工程後に得られた混合物の試料溶液を調製し、実施例１Ｂと同様にしてエステル化合物の標準溶液を調製し、実施例１Ｃと同様にしてＨＰＬＣで分析することによりＦｌｕｏｌｅａｄ（登録商標）の活性度を求めた。これらの結果を表２にまとめた。
　安息香酸の当量数がＦｌｕｏｌｅａｄ（登録商標）に対して１当量を下回る場合を除き、各パラメータを変動させても、活性度の評価結果に大きな変化はないことがわかった。これより、反応条件や試薬量に依存することなく、再現性よく、簡便に定量できる方法であることがわかった。 [Example 3]
Prepare the same lot of Fluid (registered trademark) as that used in Example 1A, and prepare the equivalent number of benzoic acid, the amount of dichloromethane, the stirring time after adding dichloromethane (stirring 1), the amount of methanol, and after adding methanol. A sample solution of the mixture obtained after the salt forming step was prepared by varying the stirring time (stirring 2) of the above, a standard solution of the ester compound was prepared in the same manner as in Example 1B, and HPLC was performed in the same manner as in Example 1C. The activity of Fluoled (registered trademark) was determined by the analysis in. These results are summarized in Table 2.
It was found that there was no significant change in the activity evaluation result even if each parameter was changed, except when the equivalent number of benzoic acid was less than 1 equivalent with respect to Fluoled (registered trademark). From this, it was found that the method can be easily quantified with good reproducibility without depending on the reaction conditions and the amount of reagents.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
　なお、表２において、「ｅｑ」は、Ｆｌｕｏｌｅａｄ（登録商標）に対する安息香酸の当量数、「ｈｒ」は撹拌時間（時間）、「ｍｉｎ」は撹拌時間（分）を意味する。 In Table 2, "eq" means the equivalent number of benzoic acid with respect to Fluoled (registered trademark), "hr" means the stirring time (hours), and "min" means the stirring time (minutes).
［実施例４］
　実施例１Ａで用いたものと同一のロットのＦｌｕｏｌｅａｄ（登録商標）を準備して、塩形成工程後に得られた混合物の試料溶液を調製する際、水を加えてＦｌｕｏｌｅａｄ（登録商標）を一部分解させて塩形成工程後に得られた混合物の試料溶液を調製した。その後実施例１Ｂと同様にしてエステル化合物の標準溶液を調製し、実施例１Ｃと同様にしてＨＰＬＣで分析することにより分解させたＦｌｕｏｌｅａｄ（登録商標）の活性度を求めた。また加えた水の重量から分解するＦｌｕｏｌｅａｄ（登録商標）のモル数を計算し、活性度の理論値を計算した。理論値と実測値を比較した結果を表３に示す。表３より、理論値と実測値はほぼ同一の値となり、分解したＦｌｕｏｌｅａｄ（登録商標）の量に応じた活性度の低下が観測された。よって本手法はＦｌｕｏｌｅａｄ（登録商標）の活性度を正確に評価できていることがわかった。 [Example 4]
When preparing a sample solution of the mixture obtained after the salt forming step by preparing the same lot of Fluolead (registered trademark) as that used in Example 1A, water was added to partially decompose the Fluolead (registered trademark). A sample solution of the mixture obtained after the salt forming step was prepared. Then, a standard solution of the ester compound was prepared in the same manner as in Example 1B, and the activity of the decomposed Fluolead (registered trademark) was determined by analyzing by HPLC in the same manner as in Example 1C. In addition, the number of moles of Fluolead (registered trademark) to be decomposed was calculated from the weight of added water, and the theoretical value of activity was calculated. Table 3 shows the results of comparing the theoretical value and the measured value. From Table 3, the theoretical value and the measured value were almost the same, and a decrease in activity was observed according to the amount of decomposed Fluoled (registered trademark). Therefore, it was found that this method can accurately evaluate the activity of Fluoled (registered trademark).
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
［比較例１Ａ］
　Ｆｌｕｏｌｅａｄ（登録商標）を準備して、従来のトリフルオロスルファニル芳香族化合物の活性評価方法（特許文献４記載）、すなわちフルオロスルフィニル芳香族化合物をアミンによりスルフィンアミド化合物へ変換し、さらにトリフルオロスルファニル芳香族化合物をアルコールによりスルフィン酸エステル化合物へと変換した後、ＨＰＬＣ等によりスルフィン酸エステル化合物の含量を測定することで活性度を評価する手法を、以下の手順で実施した。
１）窒素雰囲気下のグローブボックス内（露点：－２０℃）にてＦｌｕｏｌｅａｄ０．５ｇを精量し、２０ｍＬの回転子を備えたフッ素樹脂製容器に入れた。
２）５ｍＬのジクロロメタンとトリエチルアミン０．４０ｇを容器に加え、スターラーに載置し、室温（１９～２４℃）で撹拌した。
３）３０分経過後に、ジエチルアミン０．０１８ｇを容器に加え攪拌した。
４）さらに３０分経過後に５ｍＬのメタノールを容器に加え攪拌した。
５）さらに６０分経過後に反応液全量を１００ｍＬのメスフラスコに入れ、メタノールを加えて正確に１００ｍＬとした。
　このようにして従来法の試料溶液を調製した。 [Comparative Example 1A]
Fluolead (registered trademark) is prepared, and a conventional method for evaluating the activity of a trifluorosulfanyl aromatic compound (described in Patent Document 4), that is, a fluorosulfinyl aromatic compound is converted into a sulfinamide compound by an amine, and further, a trifluorosulfanyl fragrance is obtained. After converting the group compound to a sulfinic acid ester compound with alcohol, a method for evaluating the activity by measuring the content of the sulfinic acid ester compound by HPLC or the like was carried out by the following procedure.
1) 0.5 g of Fluororead was purified in a glove box under a nitrogen atmosphere (dew point: −20 ° C.) and placed in a fluororesin container equipped with a 20 mL rotor.
2) 5 mL of dichloromethane and 0.40 g of triethylamine were added to the container, placed on a stirrer, and stirred at room temperature (19 to 24 ° C.).
3) After 30 minutes, 0.018 g of diethylamine was added to the container and stirred.
4) After a further 30 minutes, 5 mL of methanol was added to the container and stirred.
5) After another 60 minutes, the total amount of the reaction solution was placed in a 100 mL volumetric flask, and methanol was added to make exactly 100 mL.
In this way, the sample solution of the conventional method was prepared.
［比較例１Ｂ］
　比較例１で得た試料溶液をＨＰＬＣで分析した。分析条件は以下のとおりである。
カラム：Ｘｂｒｉｄｇｅ Ｃ　８ ５μｍ、４．６×１５０ｍｍ
溶離液：ＭｅＣＮ：Ｈ２Ｏ＝７：３
流速：１ｍＬ／ｍｉｎ
検出波長：２５４ｎｍ
注入量：２０μＬ
得られた分析結果から、試料溶液中のスルフィン酸エステル化合物のピークの面積百分率を求めた。スルフィン酸エステル化合物のピークの面積百分率は９７．２％であった。 [Comparative Example 1B]
The sample solution obtained in Comparative Example 1 was analyzed by HPLC. The analysis conditions are as follows.
Column: Xbridge C 85 μm, 4.6 × 150 mm
Eluent: MeCN: H 2 O = 7: 3
Flow rate: 1 mL / min
Detection wavelength: 254 nm
Injection volume: 20 μL
From the obtained analysis results, the area percentage of the peak of the sulfinic acid ester compound in the sample solution was determined. The area percentage of the peak of the sulfinic acid ester compound was 97.2%.
［比較例２］
　比較例１Ａで用いたものと同一のロットのＦｌｕｏｌｅａｄ（登録商標）を準備して、比較例１と同様にして従来法の試料溶液を調製し、比較例１Ｂと同様にしてＨＰＬＣで分析することによりスルフィン酸エステル化合物のピークの面積百分率を求める操作を５回繰り返した。比較例１Ｂで得られた結果も含め、表４に結果を示す。求められた面積百分率が９４．９％～９７．２％と再現性が低く、当該手法で求める活性度も同様に再現性が低いことがわかった。 [Comparative Example 2]
Prepare a Loolead® in the same lot as that used in Comparative Example 1A, prepare a sample solution of the conventional method in the same manner as in Comparative Example 1, and analyze by HPLC in the same manner as in Comparative Example 1B. The operation of determining the area percentage of the peak of the sulfinate ester compound was repeated 5 times. The results are shown in Table 4, including the results obtained in Comparative Example 1B. It was found that the obtained area percentage was 94.9% to 97.2% and the reproducibility was low, and the activity obtained by the method was also low in reproducibility.
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
［比較例３］
　実施例１Ａで用いたものと同一のロットのＦｌｕｏｌｅａｄ（登録商標）を準備して、１９Ｆ－ＮＭＲを測定した。得られたＳＦ３体に帰属されるピークとＳＯＦ体に帰属されるピークの面積比からＳＦ３体の含量を計算した。４回測定を行った結果を表５に示す。実施例２で示した活性度の結果よりも高い数値が出ていることがわかった。当該ロットのＦｌｕｏｌｅａｄ（登録商標）の元素分析を行ったところ、約５質量％の無機物を含有していることが判明した。ＮＭＲでこれらの無機不純物が検出できていないため、含量が実際の含有量より大きく算出された。この結果からＮＭＲ測定でＦｌｕｏｌｅａｄ（登録商標）の活性を正確に評価することは困難であることがわかった。Ｆｌｕｏｌｅａｄ（登録商標）以外のフッ素化剤においても同様に無機物が混合し得ることから、同様にフッ素化剤の活性度評価を行うことは本方法では困難であることがわかった。 [Comparative Example 3]
The same lot of Fluoride® as used in Example 1A was prepared and 19 F-NMR was measured. From the area ratio of the peak attributed to the peak attributable to SF 3 body obtained and SOF body were calculated content of SF 3 body. The results of the four measurements are shown in Table 5. It was found that the numerical value was higher than the result of the activity shown in Example 2. Elemental analysis of Fluolead® of the lot revealed that it contained approximately 5% by mass of inorganic material. Since these inorganic impurities could not be detected by NMR, the content was calculated to be larger than the actual content. From this result, it was found that it is difficult to accurately evaluate the activity of Fluoled (registered trademark) by NMR measurement. Since inorganic substances can be similarly mixed with fluorinating agents other than Fluoled (registered trademark), it was found that it is difficult to evaluate the activity of the fluorinating agent in the same manner by this method.
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
　本発明により、フッ素化剤としての活性を簡便且つ再現性良く評価する手法を提供することができる。また、経済的かつ工業的に優れた方法によりフッ素化剤としての活性を評価することができる。さらに、エステル化合物を収率よく製造することができる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a method for easily and reproducibly evaluating the activity as a fluorinating agent. In addition, the activity as a fluorinating agent can be evaluated by an economically and industrially excellent method. Further, the ester compound can be produced in high yield.

Claims (8)

  1. 　フッ素化剤としての活性を評価する方法であって、
    　フッ素化剤を、下記式（１）で表されるカルボン酸との反応に供して、下記式（２）で表されるカルボン酸フッ化物に変換するフッ素化工程、
    前記フッ素化工程後の混合物をＲ１ＯＨ（Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。）で表されるアルコールとの反応に供して、前記カルボン酸フッ化物を下記式（３）で表されるエステル化合物に変換するエステル化工程、及び
    　前記エステル化工程後の混合物中に含まれるエステル化合物の濃度を定量分析し、前記フッ素化剤及び前記カルボン酸から得られるエステル化合物の理論上の濃度と比較することにより、フッ素化剤としての活性を評価する工程を含む、フッ素化剤の活性評価方法。
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    （Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアルールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基、炭素数が７～３０のアリールオキシカルボニル基又は水素原子を示す。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）     It is a method to evaluate the activity as a fluorinating agent.
    A fluorination step in which a fluorinating agent is subjected to a reaction with a carboxylic acid represented by the following formula (1) to be converted into a carboxylic acid fluoride represented by the following formula (2).
    The mixture after the fluorination step is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and 1 carbon number. An alkoxy group of ~ 18, an aryloxy group having 6 to 30 carbon atoms, a halogen atom, a nitro group, a cyano group, an alkanesulfonyl group having 1 to 18 carbon atoms, an arylsulfonyl group having 6 to 30 carbon atoms, and a carbon number of carbon atoms. Is an acyloxy group having 1 to 18, an alkanesulfonyloxy group having 1 to 18 carbon atoms, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an alkoxycarbonyl group having 7 to 30 carbon atoms. It is an aryloxycarbonyl group.) After the esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3) by subjecting it to a reaction with an alcohol represented by the following formula (3), and after the esterification step. A step of quantitatively analyzing the concentration of the ester compound contained in the mixture of the above and evaluating the activity as the fluorinating agent by comparing with the theoretical concentration of the fluorinating agent and the ester compound obtained from the carboxylic acid. A method for evaluating the activity of a fluorinating agent, including.
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    (R a , R b , R c , R d and Re , respectively, have an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively. 6 to 30 aryloxy groups, halogen atoms, nitro groups, cyano groups, alcan sulfonyl groups with 1 to 18 carbon atoms, allul sulfonyl groups with 6 to 30 carbon atoms, acyloxy groups with 1 to 18 carbon atoms, carbon Indicates an alkanesulfonyloxy group having 1 to 18, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms, an aryloxycarbonyl group having 7 to 30 carbon atoms or a hydrogen atom. R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
  2. 　Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅがそれぞれメチル基又は水素原子であり、Ｒ１がエチル基又はメチル基である、請求項１記載のフッ素化剤の活性評価方法。 The method for evaluating the activity of a fluorinating agent according to claim 1 , wherein R a , R b , R c , R d and Re are methyl groups or hydrogen atoms, respectively, and R 1 is an ethyl group or methyl group.
  3. 　フッ素化剤が、下記式（４）で示される化合物、下記式（５）で示される化合物、下記式（６）で示される化合物、下記式（７）で示される化合物、ジフルオロ（モルホリノ）スルホニウムテトラフルオロクロリド、ジフルオロ（モルホリノ）スルホニウムテトラフルオロボラート、ヘキサフルオロプロペンジエチルアミン、１，１，２，２－テトラフルオロ－Ｎ，Ｎ－ジメチルエチルアミン、Ｎ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）クロロイミダゾリウムクロリドとフッ化セシウムの重量比１：２の混合物、１，３－ビス（２，６－ジイソプロピルフェニル）－２，２－ジフルオロ－４－イミダゾリン及びＮ，Ｎ’－１，３－ビス（２，６－ジイソプロピルフェニル）フルオロイミダゾリウムボレートからなる群から選ばれる少なくとも１つである、請求項１又は２に記載のフッ素化剤の活性評価方法。
    Figure JPOXMLDOC01-appb-C000004
    （式中、Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊはそれぞれ水素原子、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）
    Figure JPOXMLDOC01-appb-C000005
    （式中、Ｒｋは炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のジアルキルアミノ基、炭素数が６～３０のアリールアミノ基、炭素数が１～１８のビス（アルコキシアルキル）アミノ基、モルホリノ基、炭素数が１～１８のアシルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。）
    Figure JPOXMLDOC01-appb-C000006
    （式中、Ｒｌ及びＲｍはそれぞれ炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のビス（２-アルコキシエチル）アミノ基、炭素数が１～１８のアシルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。Ｒｌ及びＲｍは同一であっても異なっていてもよい。Ｘ－はハロゲン化物イオン又はテトラフルオロホウ酸イオンを示す。）
    Figure JPOXMLDOC01-appb-C000007
    （式中、Ｒｎは炭素数が１～１８のアルキル基、炭素数が１～１８のフルオロアルキル基、炭素数が６～３０のアリール基、炭素数が５～３０のヘテロアリール基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。）     The fluorinating agent is a compound represented by the following formula (4), a compound represented by the following formula (5), a compound represented by the following formula (6), a compound represented by the following formula (7), and difluoro (morpholino) sulfonium. Tetrafluorochloride, difluoro (morpholino) sulfonium tetrafluoroborate, hexafluoropropenediethylamine, 1,1,2,2-tetrafluoro-N, N-dimethylethylamine, N, N'-1,3-bis (2, 6-Diisopropylphenyl) A mixture of chloroimidazolium chloride and cesium fluoride in a weight ratio of 1: 2, 1,3-bis (2,6-diisopropylphenyl) -2,2-difluoro-4-imidazoline and N, N' The method for evaluating the activity of a fluorinating agent according to claim 1 or 2, which is at least one selected from the group consisting of -1,3-bis (2,6-diisopropylphenyl) fluoroimidazolium borate.
    Figure JPOXMLDOC01-appb-C000004
    (In the formula, R f , R g , R h , R i and R j are hydrogen atoms, alkyl groups having 1 to 18 carbon atoms, aryl groups having 6 to 30 carbon atoms and 1 to 18 carbon atoms, respectively. Alkoxy group, aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcan sulfonyl group having 1 to 18 carbon atoms, aryl sulfonyl group having 6 to 30 carbon atoms, carbon number 1 to 1 to 18 acyloxy groups, 1-18 carbon alcan sulfonyloxy groups, 6-30 carbon aryl sulfonyloxy groups, 2-18 carbon alkoxycarbonyl groups or 7-30 carbon aryloxycarbonyl Indicates a group. R f , R g , R h , Ri and R j may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
    Figure JPOXMLDOC01-appb-C000005
    (In the formula, R k is an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a dialkylamino group having 1 to 18 carbon atoms, an arylamino group having 6 to 30 carbon atoms, and carbon. A bis (alkoxyalkyl) amino group having 1 to 18 carbon atoms, a morpholino group, an acyloxy group having 1 to 18 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms. show.)
    Figure JPOXMLDOC01-appb-C000006
    (In the formula, R l and R m are an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a bis (2-alkoxyethyl) amino group having 1 to 18 carbon atoms, and a carbon number of carbon atoms, respectively. Indicates an acyloxy group having 1 to 18, an alkoxycarbonyl group having 2 to 18 carbon atoms, or an aryloxycarbonyl group having 7 to 30 carbon atoms. R l and R m may be the same or different. X - indicates a halide ion or a tetrafluoroborate ion.)
    Figure JPOXMLDOC01-appb-C000007
    (In the formula, R n is an alkyl group having 1 to 18 carbon atoms, a fluoroalkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 5 to 30 carbon atoms, and carbon. Indicates an alkoxycarbonyl group having a number of 2 to 18 or an aryloxycarbonyl group having a carbon number of 7 to 30.)
  4. 　フッ素化剤が前記式（４）で示される化合物である、請求項３に記載のフッ素化剤の活性評価方法。 The method for evaluating the activity of a fluorinating agent according to claim 3, wherein the fluorinating agent is a compound represented by the above formula (4).
  5. 　前記式（３）で表されるエステル化合物を含む混合物がフッ化水素を含み、エステル化工程の後に、当該混合物を（Ｒ２）３Ｎ（Ｒ２は炭素数１～４のアルキル基）で表される３級アミンとの反応に供して、当該フッ化水素と３級アミンの塩を形成する工程をさらに含む、請求項１～４のいずれか一項に記載のフッ素化剤の活性評価方法。 The mixture containing the ester compound represented by the formula (3) contains hydrogen fluoride, and after the esterification step, the mixture is subjected to (R 2 ) 3 N (R 2 is an alkyl group having 1 to 4 carbon atoms). Evaluation of activity of the fluorinating agent according to any one of claims 1 to 4, further comprising a step of forming a salt of the hydrogen fluoride and the tertiary amine in the reaction with the represented tertiary amine. Method.
  6. 　フッ素化剤を、下記式（１）で表されるカルボン酸との反応に供して、下記式（２）で表されるカルボン酸フッ化物に変換するフッ素化工程、及び
    前記フッ素化工程後の混合物をＲ１ＯＨ（Ｒ１は炭素数１～８の置換されていても良いアルキル基を示し、置換基としては炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基である。）で表されるアルコールとの反応に供して、前記カルボン酸フッ化物を下記式（３）で表されるエステル化合物に変換するエステル化工程を含む、
    エステル化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000008
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
    （Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは炭素数がそれぞれ１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基、炭素数が７～３０のアリールオキシカルボニル基又は水素原子である。Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）     After the fluorination step of converting the fluorinating agent into the carboxylic acid fluoride represented by the following formula (2) by subjecting it to the reaction with the carboxylic acid represented by the following formula (1), and after the fluorination step. The mixture is R 1 OH (R 1 represents an alkyl group having 1 to 8 carbon atoms which may be substituted, and the substituents are an aryl group having 6 to 30 carbon atoms and an alkoxy group having 1 to 18 carbon atoms. Aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcansulfonyl group having 1 to 18 carbon atoms, arylsulfonyl group having 6 to 30 carbon atoms, acyloxy having 1 to 18 carbon atoms A group, an alkanesulfonyloxy group having 1 to 18 carbon atoms, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms or an aryloxycarbonyl group having 7 to 30 carbon atoms. ), The carboxylic acid fluoride is subjected to a reaction with an alcohol represented by the following formula (3), and includes an esterification step of converting the carboxylic acid fluoride into an ester compound represented by the following formula (3).
    Method for producing ester compound.
    Figure JPOXMLDOC01-appb-C000008
    Figure JPOXMLDOC01-appb-C000009
    Figure JPOXMLDOC01-appb-C000010
    (R a, R b, R c, R d and R e is an alkyl group of 1 to 18 carbon atoms, an aryl group having a carbon number of 6 to 30, an alkoxy group having a carbon number of 1 to 18, carbon atoms 6 to 30 aryloxy groups, halogen atoms, nitro groups, cyano groups, alcoholyl sulfonyl groups with 1 to 18 carbon atoms, aryl sulfonyl groups with 6 to 30 carbon atoms, acyloxy groups with 1 to 18 carbon atoms, carbon It is an alkanesulfonyloxy group having 1 to 18, an arylsulfonyloxy group having 6 to 30 carbon atoms, an alkoxycarbonyl group having 2 to 18 carbon atoms, an aryloxycarbonyl group having 7 to 30 carbon atoms or a hydrogen atom. R a , R b , R c , R d and Re may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
  7. 　Ｒａ、Ｒｂ、Ｒｃ、Ｒｄ及びＲｅがそれぞれメチル基又は水素原子であり、Ｒ１がエチル基又はメチル基である、請求項６記載のエステル化合物の製造方法。 The method for producing an ester compound according to claim 6, wherein R a , R b , R c , R d and Re are methyl groups or hydrogen atoms, respectively, and R 1 is an ethyl group or methyl group.
  8. 　フッ素化剤が、下記式（４）で示される、請求項６又は７に記載のエステル化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000011
    （式中、Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊはそれぞれ水素原子、炭素数が１～１８のアルキル基、炭素数が６～３０のアリール基、炭素数が１～１８のアルコキシ基、炭素数が６～３０のアリールオキシ基、ハロゲン原子、ニトロ基、シアノ基、炭素数が１～１８のアルカンスルホニル基、炭素数が６～３０のアリールスルホニル基、炭素数が１～１８のアシルオキシ基、炭素数が１～１８のアルカンスルホニルオキシ基、炭素数が６～３０のアリールスルホニルオキシ基、炭素数が２～１８のアルコキシカルボニル基又は炭素数が７～３０のアリールオキシカルボニル基を示す。Ｒｆ、Ｒｇ、Ｒｈ、Ｒｉ及びＲｊは同一であっても異なっていてもよく、隣同士の置換基が互いに結合して環を形成していてもよい。）     The method for producing an ester compound according to claim 6 or 7, wherein the fluorinating agent is represented by the following formula (4).
    Figure JPOXMLDOC01-appb-C000011
    (In the formula, R f , R g , R h , R i and R j are hydrogen atoms, alkyl groups having 1 to 18 carbon atoms, aryl groups having 6 to 30 carbon atoms and 1 to 18 carbon atoms, respectively. Alkoxy group, aryloxy group having 6 to 30 carbon atoms, halogen atom, nitro group, cyano group, alcan sulfonyl group having 1 to 18 carbon atoms, aryl sulfonyl group having 6 to 30 carbon atoms, carbon number 1 to 1 to 18 acyloxy groups, 1-18 carbon alcan sulfonyloxy groups, 6-30 carbon aryl sulfonyloxy groups, 2-18 carbon alkoxycarbonyl groups or 7-30 carbon aryloxycarbonyl Indicates a group. R f , R g , R h , Ri and R j may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)
PCT/JP2021/012828 2020-03-31 2021-03-26 Method for evaluating activity of fluorinating agent and method for manufacturing ester compound WO2021200640A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2022512112A JPWO2021200640A1 (en) 2020-03-31 2021-03-26
CN202180026895.4A CN115427386A (en) 2020-03-31 2021-03-26 Method for evaluating activity of fluorinating agent and method for producing ester compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020062760 2020-03-31
JP2020-062760 2020-03-31

Publications (1)

Publication Number Publication Date
WO2021200640A1 true WO2021200640A1 (en) 2021-10-07

Family

ID=77928876

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/012828 WO2021200640A1 (en) 2020-03-31 2021-03-26 Method for evaluating activity of fluorinating agent and method for manufacturing ester compound

Country Status (3)

Country Link
JP (1) JPWO2021200640A1 (en)
CN (1) CN115427386A (en)
WO (1) WO2021200640A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000103748A (en) * 1998-09-29 2000-04-11 Air Prod And Chem Inc Package for safe storage of electrophilic fluorinating agent and packaging thereof
JP2003064034A (en) * 2001-08-28 2003-03-05 Mitsubishi Gas Chem Co Inc Fluorine compound and fluorinating agent consisting of the same compound
JP2009544735A (en) * 2006-07-28 2009-12-17 アイエム・アンド・ティー・リサーチ・インコーポレーテッド Substituted phenyl sulfur trifluoride and other similar fluorinating agents
JP2011157292A (en) * 2010-01-29 2011-08-18 Fujifilm Corp Method for producing fluorine-containing ester compound, and polyfunctional fluorine-containing ester compound
WO2018186331A1 (en) * 2017-04-03 2018-10-11 宇部興産株式会社 Modification method and analysis method for mixture containing trifluorosulfanyl aromatic compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000103748A (en) * 1998-09-29 2000-04-11 Air Prod And Chem Inc Package for safe storage of electrophilic fluorinating agent and packaging thereof
JP2003064034A (en) * 2001-08-28 2003-03-05 Mitsubishi Gas Chem Co Inc Fluorine compound and fluorinating agent consisting of the same compound
JP2009544735A (en) * 2006-07-28 2009-12-17 アイエム・アンド・ティー・リサーチ・インコーポレーテッド Substituted phenyl sulfur trifluoride and other similar fluorinating agents
JP2011157292A (en) * 2010-01-29 2011-08-18 Fujifilm Corp Method for producing fluorine-containing ester compound, and polyfunctional fluorine-containing ester compound
WO2018186331A1 (en) * 2017-04-03 2018-10-11 宇部興産株式会社 Modification method and analysis method for mixture containing trifluorosulfanyl aromatic compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MIEKO ARISAWA; YUI IGARASHI; HARUKI KOBAYASHI; TORU YAMADA; KENTARO BANDO; TAKUYA ICHIKAWA; MASAHIKO YAMAGUCHI;: "Equilibrium shift in the rhodium-catalyzed acyl transfer reactions", TETRAHEDRON, ELSEVIER SIENCE PUBLISHERS, AMSTERDAM, NL, vol. 67, no. 40, 12 July 2011 (2011-07-12), AMSTERDAM, NL , pages 7846 - 7859, XP028282082, ISSN: 0040-4020, DOI: 10.1016/j.tet.2011.07.031 *
TERUO UMEMOTO, SINGH RAJENDRA P., XU YONG, SAITO NORIMICHI: "Discovery of 4- tert -Butyl-2,6-dimethylphenylsulfur Trifluoride as a Deoxofluorinating Agent with High Thermal Stability as Well as Unusual Resistance to Aqueous Hydrolysis, and Its Diverse Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation with High Stereoselectivity", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ¬AMERICAN CHEMICAL SOCIETY|, vol. 132, no. 51, 29 December 2010 (2010-12-29), pages 18199 - 18205, XP055083243, ISSN: 00027863, DOI: 10.1021/ja106343h *

Also Published As

Publication number Publication date
CN115427386A (en) 2022-12-02
JPWO2021200640A1 (en) 2021-10-07

Similar Documents

Publication Publication Date Title
CN1430592A (en) Production of fluormethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether
US20060089514A1 (en) Anhydrous flouride salts and reagents and methods for their production
US20050197514A1 (en) Highly branched perfluoroolefins, super-stable perfluoroalkyl radicals and production methods thereof
US4828764A (en) N-Fluoro-N-Perfluoromethyl sulfonamides
EP2157078B1 (en) Fluorine compound and fluorinating agent comprising the compound
WO2021200640A1 (en) Method for evaluating activity of fluorinating agent and method for manufacturing ester compound
WO2018186331A1 (en) Modification method and analysis method for mixture containing trifluorosulfanyl aromatic compound
JP3954363B2 (en) Low molecular radical supply method, radical carrying molecule, polymer production method and polymer
JPWO2020012913A1 (en) Vinyl sulfonic acid anhydride, its production method, and vinyl sulfonyl fluoride production method
JP2020515487A (en) Process for producing highly pure iridium(III) chloride hydrate
Kitagawa et al. Nucleophilic substitution of alkylchlorodihydro [60] fullerenes: thermodynamic stabilities of alkylated C 60 cation intermediates
JP2022070145A (en) Method for producing fluorinated carboxylate
EP4349819A2 (en) Composition
Kyba et al. Linked bis (. mu.-phosphido) and related ligands for metallic clusters. 3. Synthesis and chemistry of a bis (. mu.-phosphido)(. mu.-carbonyl) dimolybdenum (Mo. tplbond. Mo) system
Bardin et al. A well feasible and general route to (organoethynyl) difluoroboranes, RHCCBF2, and their perfluorinated analogues, RFCCBF2
CN111351780A (en) Analysis method for electrolyte components in trifluoromethyl sulfonyl fluoride electrolytic cell
Pospelova et al. NMR Analysis in the technology of perfluoro (vinyloxy) butanoic acid ester production
Naulet et al. In Situ Generated DBU⋅ HF Acts as a Fluorinating Agent in a Hexafluoroisobutylation Tandem Reaction: An Effective Route to 5, 5, 5, 5’, 5’, 5’‐Hexafluoroleucine
Frohn et al. A Widely Applicable Synthetic Approach to Alk‐1‐yn‐1‐yl (polyfluoroorganyl)‐iodonium Salts [(RC≡ C)(R′) I][BF4]
CN110066255B (en) Synthetic method of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone
JP4333147B2 (en) Method for producing fluorinated alkyl group-containing sulfonic acid
RU2550139C1 (en) Method for producing trimethyl(trifluoromethyl)silane
JP2022070144A (en) Method for producing fluorinated cyclic compound
EP1723091B1 (en) Synthesis of carbon-labeled perfluoroalkyl compounds
Zhu et al. Chemical transformation of bis ((perfluoroalkyl) sulfonyl) methanes and 1, 1, 3, 3‐tetraoxopolyfluoro‐1, 3‐dithiaycloalkanes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21779523

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022512112

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21779523

Country of ref document: EP

Kind code of ref document: A1