Method for Evaluating Activity of Fluorinating Agent and Method for Producing Ester Compound

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

Technical Field

[0001] The present invention relates to a method for evaluating the activity of a fluorinating agent and a method for producing an ester compound.

Background Art

[0002] Fluorine is an element attracting attention in the forefront technical fields such as the fields of medical and agricultural chemicals and materials, and a method for efficiently obtaining a fluorinated compound is required. As a simple method for obtaining a fluorinated compound, a method of fluorinating a non-fluorinated compound using a fluorinating agent can be mentioned. In recent years, various fluorinating agents such as (diethylamino)sulfur trifluoride (DAST (registered trademark)) and 2,6-dimethyl-4-t-butyl-trifluorothiosulfanylbenzene (Fluolead (registered trademark)) have been reported and sold, and it has become possible to efficiently introduce fluorine into a non-fluorinated compound (for example, see Patent Document 1). When using a fluorinating agent, it is necessary to grasp its activity in advance. As a method for estimating the activity of a fluorinating agent, a method using NMR (for example, see Patent Document 2) and a method for quantifying the fluorine content by titration or an ion electrode are known (for example, see Patent Document 3). Further, for a fluorinating agent having a trifluorothiosulfanyl aromatic compound such as Fluolead as a skeleton, a fluorosulfinyl aromatic compound which is an impurity contained in the fluorinating agent is converted into a sulfinamide compound by an amine, and further the trifluorothiosulfanyl aromatic compound is converted into a sulfinic acid ester compound by an alcohol, and then a method for evaluating the activity by measuring the content of the sulfinic acid ester compound by HPLC or the like (see Patent Document 4) is known.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

[0004] Most fluorinating agents are unstable in water and gradually decompose when exposed to moisture in the air, etc., resulting in a decrease in the activity as a fluorinating agent. Therefore, it is necessary to examine the activity level before using the fluorinating agent. In the NMR measurement described in Patent Document 2, it is possible to determine the content rate of active species contained in the fluorinating agent, and the obtained content rate is considered to correspond to the activity level. However, this evaluation method requires a nuclear magnetic resonance apparatus that is expensive and requires maintenance and management, 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 rate may not directly represent the activity level in some cases. When measuring the fluorine content by titration or ion electrode as described in Patent Document 3, impurities such as hydrogen fluoride in the fluorinating agent are also detected, making it difficult to accurately define the activity level as a fluorinating agent. 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 trifluorothiol aromatic compound into a sulfinic acid ester compound. However, a part of it is also converted into a sulfinamide compound, resulting in poor reproducibility of the evaluation results. In view of the above, an object of the present invention is to provide a method for evaluating the activity of a fluorinating agent that is economical, simple, and reproducible. [Means for Solving the Problems]

[0005] The above problems are solved by the following present invention.

[0006] 1. A method for evaluating the activity as a fluorinating agent, comprising: subjecting the fluorinating agent to a reaction with a carboxylic acid represented by the following formula (1) to convert it into a carboxylic acid fluoride represented by the following formula (2) (fluorination step); subjecting the mixture after the fluorination step to a reaction with an alcohol represented by R 1 OH (wherein R 1 represents an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituents are an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, 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, an acyloxy group having 1 to 18 carbon atoms, 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.) to convert the carboxylic acid fluoride into an ester compound represented by the following formula (3) (esterification step); and quantitatively analyzing the concentration of the ester compound contained in the mixture after the esterification step, and comparing it with the theoretically obtained concentration of the ester compound from the fluorinating agent and the carboxylic acid, thereby evaluating the activity as a fluorinating agent. A method for evaluating the activity of a fluorinating agent, comprising the above steps.

[0007]

Chemical formula

[0008]

Chemical formula

[0009]

Chemical formula

[0010] 2.R a , R b , R c , R d and R e are each a methyl group or a hydrogen atom, and R 1 3. The method for evaluating the activity of a fluorinating agent according to 1 above, wherein is an ethyl group or a methyl group.

[0011] 3. The method for evaluating the activity of a fluorinating agent according to 1 or 2 above, wherein the fluorinating agent is at least one selected from the group consisting of 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), difluoro(morpholino)sulfonium tetrafluorochloride, difluoro(morpholino)sulfonium tetrafluoroborate, hexafluoropropene diethylamine, 1,1,2,2-tetrafluoro-N,N-dimethylethylamine, a mixture of N,N'-1,3-bis(2,6-diisopropylphenyl)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'-1,3-bis(2,6-diisopropylphenyl)fluoroimidazolium borate.

[0012] [Chemical formula] (In the formula, R f , R g , R h , R i and R j each represent a hydrogen atom, 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, 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, an acyloxy group having 1 to 18 carbon atoms, 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. R f , R g , R h , R i and R j may be the same or different, and adjacent substituents may be bonded to each other to form a ring.)

[0013] [Chemical formula] (In the formula, R k represents 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, 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.)

[0014] [Chemical formula] (In the formula, R l and R mEach represents 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, 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. R l and R m may be the same or different. X - represents a halide ion or a tetrafluoroborate ion.)

[0015] [Chemical formula] (In the formula, R n represents 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, an alkoxycarbonyl group having 2 to 18 carbon atoms, or an aryloxycarbonyl group having 7 to 30 carbon atoms.)

[0016] 4. The method for evaluating the activity of the fluorinating agent according to 3 above, wherein the fluorinating agent is a compound represented by the above formula (4).

[0017] 5. The mixture containing the ester compound represented by the above formula (3) contains hydrogen fluoride. After the esterification step, the mixture is subjected to a reaction with a tertiary amine represented by (R 2 )3N (R 2 is an alkyl group having 1 to 4 carbon atoms) to form a salt of the hydrogen fluoride and the tertiary amine. The method for evaluating the activity of the fluorinating agent according to any one of 1 to 4 above further includes this step.

[0018] 6. A fluorination step of subjecting the fluorinating agent to a reaction with a carboxylic acid represented by the following formula (1) to convert it into a carboxylic acid fluoride represented by the following formula (2), and after the fluorination step, the mixture is treated with R 1 OH (R 1represents an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituents include an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, 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, an acyloxy group having 1 to 18 carbon atoms, 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. It is subjected to a reaction with an alcohol represented by the following formula to convert the carboxylic acid fluoride into an ester compound represented by the following formula (3), including an esterification step: A method for producing an ester compound.

[0019]

Chemical formula

[0020]

Chemical formula

[0021]

Chemical formula

[0022] 7. R a , R b , R c , R d and R e are each a methyl group or a hydrogen atom, and R 1 is an ethyl group or a methyl group, and the method for producing the ester compound according to the above 6

[0023] 8. The method for producing the ester compound according to the above 6 or 7, wherein the fluorinating agent is represented by the following formula (4).

[0024]

Chemical formula

Advantages of the Invention

[0025] According to the present invention, the activity as a fluorinating agent can be easily and reproducibly evaluated. Further, the activity as a fluorinating agent can be evaluated by an economical and industrially excellent method. Furthermore, an ester compound can be produced in good yield.

Embodiments for Carrying Out the Invention

[0026] [Method for Evaluating Activity of Fluorinating Agent] The inventors of the present invention 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 thus have completed the present invention. The present invention is a method for evaluating the activity as a fluorinating agent, a fluorination step of subjecting a fluorinating agent to a reaction with a carboxylic acid represented by the following formula (1) to convert it into a carboxylic acid fluoride represented by the following formula (2), the mixture after the fluorination step is subjected to a reaction with an alcohol represented by R 1 OH (wherein R 1 represents an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituents are an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, 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, an acyloxy group having 1 to 18 carbon atoms, 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.) to convert the carboxylic acid fluoride into an ester compound represented by the following formula (3), and a step of quantitatively analyzing the concentration of the ester compound contained in the mixture after the esterification step and comparing it with the theoretically obtained concentration of the ester compound from the fluorinating agent and the carboxylic acid, thereby evaluating the activity as a fluorinating agent. This is a method for evaluating the activity of a fluorinating agent.

[0027] The fluorination step and the esterification step are as shown in the following formula.

[0028] [Chem.]

[0029] <fluorinating agent> The fluorinating agent used in the present invention is a material capable of introducing fluorine atoms into organic compounds, and performs a substitution reaction of an oxygen atom with a fluorine atom in a deoxygenating manner with respect to an alcohol group or a carbonyl group in the organic compound. Specifically, 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), difluoro(morpholino)sulfonium tetrafluorochloride, difluoro(morpholino)sulfonium tetrafluoroborate, hexafluoropropene diethylamine, 1,1,2,2-tetrafluoro-N,N-dimethylethylamine, a mixture of N,N'-1,3-bis(2,6-diisopropylphenyl)chloroimidazolium chloride and cesium fluoride at a weight ratio of 1:2, 1,3-bis(2,6-diisopropylphenyl)-2,2-difluoro-4-imidazoline, and at least one selected from the group consisting of N,N'-1,3-bis(2,6-diisopropylphenyl)fluoroimidazolium borate. From the viewpoint of evaluating the activity with better reproducibility, a compound represented by the following formula (4) or the following formula (5) is preferable, and a compound represented by the following formula (4) is more preferable. In addition, the fluorinating agent includes by-products generated in the process of manufacturing the fluorinating agent, compounds generated by the elimination of fluorine atoms after the fluorination reaction, decomposition products generated by thermal decomposition or hydrolysis of the fluorinating agent, etc. 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.

[0030] [Chem.]

[0031] [Chem.]

[0032]

Chem.

[0033]

Chem.

[0034] R in the formula (4) above f , R g , R h , R i and R j are each a hydrogen atom, 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, 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, an acyloxy group having 1 to 18 carbon atoms, 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. R f , R g , R h , R i and R j 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 preferably a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, more preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, from the viewpoints of high accuracy of activity evaluation, easy availability, etc. It is even more preferable that R f and R j are methyl groups, R h is a tert-butyl group, and R g and R i are hydrogen atoms. In the formula (4) above, as one of the embodiments, R fand R j is a methyl group, R h is a tert-butyl group, R g and R i is 2,6-dimethyl-4-t-butyl-trifluorothiobenzene where is a hydrogen atom, and is also referred to as Fluolead (registered trademark).

[0035] The compound represented by formula (4) (hereinafter, may also be referred to as SF3 or SF3 species) as a fluorinating agent decomposes the SF3 group into a SOF group due to moisture in the air or the like (hereinafter, the compound having the generated SOF group is also referred to as SOF or SOF species), and the compound represented by the formula (4) may contain a SOF species. Since hydrogen fluoride is generated when SF3 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 the SF3 species is the main component. The concentration of the SF3 species in the mixture containing SF3 and SOF obtained by the decomposition of the SF3 species during storage is 90% by mass or more, and preferably 93% by mass or more.

[0036] R in the formula (5) k includes 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, 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, and preferably 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, and more preferably 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.

[0037] R in the formula (6) above l and R m are each 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, 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. An alkyl group having 1 to 18 carbon atoms is preferred, an alkyl group having 1 to 4 carbon atoms is more preferred, and an ethyl group is even more preferred. R l and R m may be the same or different. X in the formula (6) above - represents a halide ion or a tetrafluoroborate ion, and is preferably a chloride ion or a tetrafluoroborate ion.

[0038] R in the formula (7) above 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, an alkoxycarbonyl group having 2 to 18 carbon atoms, or an aryloxycarbonyl group having 7 to 30 carbon atoms. Among them, a fluoroalkyl group having 1 to 18 carbon atoms or a heteroaryl group having 5 to 30 carbon atoms is preferred, and a nonafluorobutyl group, a pyridyl group, or a pyrimidyl group is more preferred.

[0039] Also, 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). Hexafluoropropene diethylamine 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 with a weight ratio of 1:2 is also referred to as PhenoFluor-MIX(registered trademark) and is represented by 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 is also referred to as AlkylFluor(registered trademark) and is represented by the following formula (V).

[0040] [Chemical formula] (In formula (I), X - represents a chloride ion or a tetrafluoroborate ion.)

[0041] [Fluorination step] This step is a step of subjecting a fluorinating agent to a reaction with the carboxylic acid represented by the above formula (1) to convert it into the carboxylic acid fluoride represented by the above formula (2). R in formulas (1) and (2) a , R b , R c , R d and R e are each 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, 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, an acyloxy group having 1 to 18 carbon atoms, 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, an aryloxycarbonyl group having 7 to 30 carbon atoms or a hydrogen atom. R a , R b , R c , R d and R emay be the same or different, and the substituents adjacent to each other may be bonded to each other to form a ring. R a 、R b 、R c 、R d and R e are preferably an alkyl group having 1 to 4 carbon atoms or a hydrogen atom, more preferably a methyl group or a hydrogen atom, and particularly preferably a hydrogen atom. For the fluorinating agent, a carboxylic acid in an amount of 1.0 equivalent or more may be used, preferably 1.2 to 6.0 equivalents of the carboxylic acid, and more preferably 1.2 to 2.0 equivalents of the carboxylic acid. Also, the reaction is preferably carried out in the presence of a solvent. Since a fluorination reaction proceeds with an alcohol or a carbonyl compound, a solvent having a hydroxyl group or a carbonyl group is not preferred. In particular, since hydrogen fluoride is generated when reacting with water, it is not preferred. The solvent is not limited as long as side reactions do not occur, but considering solubility and the like, halogenated hydrocarbons such as dichloromethane are preferred. The amount of the solvent used is appropriately adjusted, but is 0.1 g to 100 g, preferably 0.5 g to 10 g, per 1 g of the fluorinating agent. Also, the reaction is preferably carried out at room temperature (15 to 30 °C). The reaction time can be set as appropriate and may be about 1 to 60 minutes. Further, a known catalyst or reaction accelerator necessary for fluorination may be used in combination.

[0042] <Esterification step> In this step, the carboxylic acid fluoride (also referred to as the COF form) represented by the formula (2) obtained in the above step is subjected to a reaction with an alcohol to convert it into an ester compound represented by the general formula (3). The alcohol used in this step is R 1 represented by OH. R 1represents an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituents include an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, 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, an acyloxy group having 1 to 18 carbon atoms, 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. 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. In this step, the SOF compound contained in the mixture after the fluorination step reacts with the alcohol to be converted into a sulfinic acid ester compound (hereinafter referred to as SOOR 1 compound or SOOR 1 ). The amount of the alcohol only needs to be in excess relative to the COF compound, and it is preferably used as the amount of the solvent. Since the alcohol serves as the solvent in this reaction, an additional solvent is not necessary, but a halogenated hydrocarbon such as dichloromethane may be used as the solvent. The amount of the solvent used is appropriately adjusted, but it is 0.1 g to 100 g, preferably 0.5 g to 10 g, per 1 g of the COF compound. The reaction is preferably carried out at room temperature (15°C to 30°C). The reaction time can also be set as appropriate and can be about 1 to 60 minutes. Further, a known catalyst or reaction accelerator necessary for the esterification may be used in combination.

[0043] <Salt formation step> In this step, the mixture containing the ester compound represented by the formula (3) contains hydrogen fluoride, and the mixture is subjected to a reaction with a tertiary amine represented by (R 2 )3N (R 2 is an alkyl group having 1 to 4 carbon atoms) to form a salt of the hydrogen fluoride and the tertiary amine. Although the activity of the fluorinating agent can be evaluated without performing this step, since the mixture after the esterification step may contain hydrogen fluoride as described above, it is preferable to perform this step. Since hydrogen fluoride is corrosive, performing the salt formation step can prevent corrosion of the equipment and containers used during analysis. Therefore, in this method, it is preferable to add a tertiary amine to the mixture after the esterification step to selectively convert the hydrogen fluoride contained in the mixture into a salt.

[0044] The base to be used is not particularly limited as long as it forms a salt with hydrogen fluoride, but from the viewpoint of improving the solubility of the formed salt in an organic solvent and simplifying the post-treatment, it is preferable to use an organic salt, and it is more preferable to use a tertiary amine represented by (R 2 )3N. R 2 in (R 2 )3N 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. Also, the neutralization of hydrogen fluoride can be carried out 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 a tertiary amine is soluble in an organic solvent, such a problem does not occur. For this step, it is sufficient that the base used is in an excess amount with respect to hydrogen fluoride. The reaction is preferably carried out at room temperature (15°C to 30°C). The reaction time can also be set appropriately and can be about 1 to 60 minutes.

[0045] <Activity Evaluation Step> In this step, the concentration of the ester compound contained in the mixture obtained in the esterification step or the salt formation step is quantitatively analyzed and compared with the theoretically calculated concentration of the ester compound obtained from the fluorinating agent and the carboxylic acid, thereby evaluating the activity as a fluorinating agent. For the quantitative analysis, any quantitative method such as the internal standard method or the absolute calibration curve method may be used as long as the ester compound can be quantified, and any measuring instrument such as NMR, HPLC, or GC may be used, but from the viewpoint of analyzing simply with good reproducibility, it is preferable to use HPLC. For example, when using HPLC, analyze by HPLC to determine the peak area of the ester compound, and determine the concentration of the ester compound in the mixture containing the ester compound obtained in the esterification step or the salt formation step from this value. In this case, the eluent is preferably a mixed solvent of acetonitrile and water. Further, correction may be performed using a standard substance. The activity of the fluorinating agent is determined from the theoretical concentration and the measured concentration of the ester compound obtained from the fluorinating agent and the carboxylic acid.

[0046] [Production Method] The production method of the present invention is a fluorination step of subjecting a fluorinating agent to a reaction with a carboxylic acid represented by the following formula (1) to convert it into a carboxylic acid fluoride represented by the following formula (2), and subjecting the mixture after the fluorination step to R 1 OH (wherein R 1 represents an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituents are an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, 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, an acyloxy group having 1 to 18 carbon atoms, 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.)) and subjecting it to a reaction with an alcohol represented by the following formula (3) to convert the carboxylic acid fluoride into an ester compound represented by the following formula (3), which is a method for producing an ester compound. Furthermore, after the esterification step, the salt formation step may be included.

[0047] The reaction conditions, operation methods, and the fluorinating agent used in the fluorination step, esterification step, and salt formation step are the same as those in the method for evaluating the activity of the fluorinating agent.

[0048] The carboxylic acid, carboxylic acid fluoride, and ester compound used in this manufacturing method are the same as those in the method for evaluating the activity of the fluorinating agent, and are represented by the following formulas (1), (2), and (3), respectively.

[0049]

Chemical formula

[0050]

Chemical formula

[0051]

Chemical formula

[0052] R a 、R b 、R c 、R d and R e are each 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, 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, an acyloxy group having 1 to 18 carbon atoms, 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, an aryloxycarbonyl group having 7 to 30 carbon atoms, or a hydrogen atom. From the viewpoints of high accuracy of activity evaluation and easy availability, a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is preferred, a hydrogen atom or a methyl group is more preferred, and a hydrogen atom is even more preferred. R a 、R b 、R c 、R d and R e may be the same or different, and adjacent substituents may be bonded to each other to form a ring.

[0053] From the mixture obtained in the esterification step or the salt formation step, the ester compound can be isolated using, for example, neutralization, extraction, filtration, concentration, distillation, crystallization, column chromatography, HPLC, etc. Further, without performing post-treatment of the mixture, the activity can be evaluated in the activity evaluation step.

[0054] As a preferred embodiment of the present method, a mixture containing SF3 and SOF is subjected to a fluorination step, then to an esterification step, and further to a salt formation step. This scheme is shown below.

[0055] [Chemical formula]

[0056] In this scheme, the description of each symbol is the same as above. Therefore, a more preferred scheme is as follows. In this scheme, the mixture in the fluorinating agent mainly contains a mixture of SF3, SOF and HF, the mixture after the fluorination step mainly contains the compound described in the above formula (2), a fluorosulfinyl aromatic compound (SOF) and a mixture containing HF, and the mixture after the esterification step mainly contains the compound described in the above formula (3), a sulfinic acid ester compound (SOOR 1 ), a mixture containing HF, and the mixture obtained in the salt formation step mainly contains the compound described in the above formula (3), a sulfinic acid ester compound (SOOR 1 ), a mixture containing a salt of hydrogen fluoride and a tertiary amine.

[0057] [Chemical formula] [Examples]

[0058] Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[0059] [Example 1A] Using a fluorinating agent, the conversion of a carboxylic acid to an ester compound was carried out according to the following procedure. 2,6-Dimethyl-4-t-butyl-trifluorothiobenzene (Fluolead (registered trademark)) was prepared. This substance is a mixture containing trace amounts of fluorosulfinyl aromatic compound (SOF) and hydrogen fluoride (HF) generated by decomposition during storage. <Fluorination step> Under a nitrogen atmosphere in a glove box (dew point: -20 °C), 1.0 g of Fluolead and 0.8 g of benzoic acid were accurately weighed 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 step> After 30 minutes, 2 mL of methanol was added to the container and stirred. <Salt formation step> After another 30 minutes, 3 mL of triethylamine was added dropwise to the reaction solution over 1 minute. Stirring was terminated, and the entire amount of the reaction solution was placed in a 50 mL volumetric flask, and acetonitrile was added to make it exactly 50 mL. 5 mL of this solution was taken, placed in a 50 mL volumetric flask, and acetonitrile was added to make it exactly 50 mL. In this way, a sample solution of the modified mixture obtained after the salt formation step was prepared.

[0060] [Example 1B] Methyl benzoate was prepared as a standard product of the ester compound. 100 mg of methyl benzoate was accurately weighed, placed in a 100 mL volumetric flask, and acetonitrile was added to make it exactly 100 mL. In this way, a standard solution of the ester compound was prepared.

[0061] [Example 1C] <Activity evaluation step> 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 5μm, 4.6×150mm Eluent: MeCN:H2O = 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 Fluolead (registered trademark).

[0062] When GC-MS was measured under the above conditions, the peak of methyl benzoate contained only methyl benzoate, and no peaks of other compounds were detected. From this, it is clear that this reaction proceeds quantitatively and contains no impurities that inhibit the analysis.

[0063] [Example 2] The same lot of Fluolead (registered trademark) as used in Example 1A was prepared, and a sample solution of the mixture obtained after the salt formation step was prepared in the same manner as in Example 1A. A standard solution of the ester compound was prepared in the same manner as in Example 1B, and the operation of determining the activity of Fluolead (registered trademark) by analyzing with HPLC in the same manner as in Example 1C was repeated 4 times. The results including those obtained in Example 1C are shown in Table 1. The range of the obtained activity was 92.3% - 93.5%, and it was found that the evaluation could be made with good reproducibility.

[0064]

Table 1

[0065] [Example 3] The same lot of Fluolead (registered trademark) as that used in Example 1A was prepared, and the number of equivalents of benzoic acid, the amount of dichloromethane, the stirring time after adding dichloromethane (stirring 1), the amount of methanol, and the stirring time after adding methanol (stirring 2) were varied to prepare a sample solution of the mixture obtained after the salt formation step. A standard solution of the ester compound was prepared in the same manner as in Example 1B, and the activity of Fluolead (registered trademark) was determined by analyzing it by HPLC in the same manner as in Example 1C. These results are summarized in Table 2. Except when the number of equivalents of benzoic acid is less than 1 equivalent relative to Fluolead (registered trademark), it was found that even when each parameter was varied, there was no significant change in the evaluation result of the activity. From this, it was found that it is a method that can be quantitatively determined simply and with good reproducibility without depending on the reaction conditions or the amount of reagents.

[0066] [Table 2]

[0067] In Table 2, "eq" means the number of equivalents of benzoic acid relative to Fluolead (registered trademark), "hr" means the stirring time (hours), and "min" means the stirring time (minutes).

[0068] [Example 4] The same lot of Fluolead (registered trademark) as that used in Example 1A was prepared. When preparing a sample solution of the mixture obtained after the salt formation step, water was added to partially decompose Fluolead (registered trademark) to prepare a sample solution of the mixture obtained after the salt formation step. Thereafter, 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 it by HPLC in the same manner as in Example 1C. Further, the number of moles of Fluolead (registered trademark) decomposed was calculated from the weight of the added water, and the theoretical value of the activity was calculated. Table 3 shows the results of comparing the theoretical value with the measured value. From Table 3, it was found that the theoretical value and the measured value were almost the same, and a decrease in activity corresponding to the amount of decomposed Fluolead (registered trademark) was observed. Therefore, it was found that this method can accurately evaluate the activity of Fluolead (registered trademark).

[0069]

Table 3

[0070] [Comparative Example 1A] Fluolead (registered trademark) was prepared, and the conventional method for evaluating the activity of trifluorothiolanyl aromatic compounds (described in Patent Document 4), that is, the method of converting a fluorosulfinyl aromatic compound into a sulfinamide compound with an amine and further converting the trifluorothiolanyl aromatic compound into a sulfinic acid ester compound with an alcohol, and then measuring the content of the sulfinic acid ester compound by HPLC or the like to evaluate the activity, was carried out according to the following procedure. 1) 0.5 g of Fluolead was precisely weighed 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 - 24°C). 3) After 30 minutes, 0.018 g of diethylamine was added to the container and stirred. 4) After another 30 minutes, 5 mL of methanol was added to the container and stirred. 5) After another 60 minutes, the entire reaction solution was placed in a 100 mL volumetric flask, and methanol was added to make it exactly 100 mL. The sample solution of the conventional method was prepared in this way.

[0071] [Comparative Example 1B] The sample solution obtained in Comparative Example 1 was analyzed by HPLC. The analysis conditions are as follows. Column: Xbridge C8 5μm, 4.6×150mm Eluent: MeCN:H2O = 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%.

[0072] [Comparative Example 2] Prepare the same lot of Fluolead (registered trademark) as used in Comparative Example 1A, prepare the sample solution of the conventional method in the same manner as in Comparative Example 1, and analyze it by HPLC in the same manner as in Comparative Example 1B to determine the area percentage of the peak of the sulfinic acid ester compound. This operation was repeated 5 times. Including the results obtained in Comparative Example 1B, the results are shown in Table 4. It was found that the obtained area percentages were 94.9% - 97.2%, with low reproducibility, and the activity determined by this method also had low reproducibility.

[0073]

Table 4

[0074] [Comparative Example 3] Prepare the same lot of Fluolead (registered trademark) as used in Example 1A, 19F-NMR was measured. The content of the SF3 form was calculated from the area ratio of the peak attributed to the obtained SF3 form and the peak attributed to the SOF form. Table 5 shows the results of four measurements. It was found that the values obtained were higher than the activity results shown in Example 2. Elemental analysis of the Fluolead (registered trademark) of this lot revealed that it contained approximately 5% by mass of inorganic substances. 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 Fluolead (registered trademark) by NMR measurement. Since inorganic substances can be similarly mixed in fluorinating agents other than Fluolead (registered trademark), it was found that it is difficult to evaluate the activity of fluorinating agents in the same way by this method.

[0075]

Table 5

Industrial Applicability

[0076] According to the present invention, a method for simply and reproducibly evaluating the activity as a fluorinating agent can be provided. In addition, the activity as a fluorinating agent can be evaluated by an economically and industrially excellent method. Furthermore, an ester compound can be produced in good yield.

Claims

1. A method for evaluating the activity of a fluorinating agent, comprising: a fluorination step of subjecting a fluorinating agent to a reaction with a carboxylic acid represented by the following formula (1) to convert it into a carboxylic acid fluoride represented by the following formula (2); subjecting the mixture after the fluorination step to a reaction with an alcohol represented by R １ OH (R １ represents an optionally substituted alkyl group having 1 to 8 carbon atoms, and the substituents include an aryl group having 6 to 30 carbon atoms, an alkoxy group having 1 to 18 carbon atoms, 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, an acyloxy group having 1 to 18 carbon atoms, 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.) to convert the carboxylic acid fluoride into an ester compound represented by the following formula (3), and quantitatively analyzing the concentration of the ester compound contained in the mixture after the esterification step, and comparing it with the theoretically obtained concentration of the ester compound from the fluorinating agent and the carboxylic acid, thereby evaluating the activity of the fluorinating agent. A method for evaluating the activity of a fluorinating agent, comprising the above steps. 【Chemical formula 23】 【Chemical formula 24】 【Chemical formula 25】 (R ａ , R ｂ , R ｃ , R ｄ and R ｅeach represents 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, 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, an acyloxy group having 1 to 18 carbon atoms, 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, an aryloxycarbonyl group having 7 to 30 carbon atoms or a hydrogen atom. R ａ , R ｂ , R ｃ , R ｄ and R ｅ may be the same or different, and adjacent substituents may be bonded to each other to form a ring. )

2. R ａ , R ｂ , R ｃ , R ｄ and R ｅ are each a methyl group or a hydrogen atom, and R １ is an ethyl group or a methyl group, The method for evaluating the activity of the fluorinating agent according to claim 1.

3. The fluorinating agent is at least one selected from the group consisting of 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), difluoro (morpholino) sulfonium tetrachloride, difluoro (morpholino) sulfonium tetrafluoroborate, hexafluoropropene diethylamine, 1,1,2,2-tetrafluoro-N,N-dimethylethylamine, a mixture of N,N'-1,3-bis(2,6-diisopropylphenyl)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'-1,3-bis(2,6-diisopropylphenyl)fluoroimidazolium borate, The method for evaluating the activity of the fluorinating agent according to claim 1 or 2. 【Chemical formula 26】 (In the formula, R ｆ , R ｇ , R ｈ , R ｉ and R ｊ each represents a hydrogen atom, 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, 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, an acyloxy group having 1 to 18 carbon atoms, 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. R ｆ , R ｇ , R ｈ , R ｉ and R ｊ may be the same or different, and the adjacent substituents may be bonded to each other to form a ring. ) 【Chemical formula 27】 (In the formula, R ｋ represents 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, 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. ) 【Chemical formula 28】 (In the formula, R ｌ and R ｍ each represents 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, 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. R ｌ and R ｍ may be the same or different. X － represents a halide ion or a tetrafluoroborate ion. ) 【Chemical formula 29】 (wherein R ｎ represents 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, an alkoxycarbonyl group having 2 to 18 carbon atoms, or an aryloxycarbonyl group having 7 to 30 carbon atoms.)

4. The method for evaluating the activity of a fluorinating agent according to claim 3, wherein the fluorinating agent is a compound represented by the formula (4).

5. The mixture containing the ester compound represented by the formula (3) contains hydrogen fluoride, and after the esterification step, the mixture is treated with (R ２ ) ３ N(R ２ is an alkyl group having 1 to 4 carbon atoms) and subjected to a reaction with a tertiary amine represented thereby to further include a step of forming a salt of the hydrogen fluoride and the tertiary amine. The method for evaluating the activity of a fluorinating agent according to any one of claims 1 to 4.

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