Method for producing trifluoromethanesulfonamide compound

Abstract

The present disclosure provides a method for producing a trifluoromethanesulfonamide compound, the method comprising reacting a trifluoromethanesulfonylating agent composition containing a compound represented by general formula (1) described in the specification, with an aromatic amino compound represented by general formula (2) described in the specification and / or an acid salt thereof in the presence of a solvent under acidic conditions.

Description

Method for producing trifluoromethanesulfonamide compounds

[0001] The present disclosure relates to a method for producing a trifluoromethanesulfonamide compound using a trifluoromethanesulfonylating agent composition capable of trifluoromethanesulfonylation of a substrate containing a functional group such as an anilinic amino group.

[0002] In the synthesis of pharmaceutical active ingredients or intermediates, trifluoromethanesulfonylation of substrates having various functional groups is carried out. Trifluoromethanesulfonamide compounds are often found in the partial structures of pharmaceutical and agrochemical molecules (e.g., Example 1 of Patent Document 1). Trifluoromethanesulfonamide compounds are produced using trifluoromethanesulfonic anhydride (Patent Document 1, Non-Patent Documents 1-3) or trifluoromethanesulfonyl chloride (Non-Patent Documents 4 and 5) as trifluoromethanesulfonylating agents.

[0003] Japanese Patent Application Laid-Open No. 2022-184796

[0004] J. Am. Chem. Soc. 2021,143,7604. Supporting InformationRussian Journal of Organic Chemistry 2011,47,510Tetrahedron Letters 2008, 49, 6300-6303Bioorganic & Medicinal Chemistry 2017, 25, 3989. Bioorganic & Medicinal Chemistry 2015, 23, 6673.

[0005] As a result of investigations by the present inventors, it has been found that the methods described in Patent Document 1 and Non-Patent Documents 1 to 5 have room for improvement in terms of selectively trifluoromethanesulfonylating an aniline amino group when a nucleophilic functional group such as a hydroxyl group is present in addition to the aniline amino group.

[0006] The present disclosure has been made in view of the above circumstances, and an object of the present disclosure is to provide a method for producing a trifluoromethanesulfonamide compound, which can selectively trifluoromethanesulfonylate the aniline amino group of a substrate having a functional group such as an aniline amino group.

[0007] In view of the above problems, the present inventors have conducted extensive research and found that, by reacting a substrate having a functional group such as an aniline amino group with a trifluoromethanesulfonylating agent composition containing a specific trifluoromethanesulfonylating agent according to the present disclosure under acidic conditions, it is possible to selectively trifluoromethanesulfonylate the aniline amino group in the substrate having a functional group such as an aniline amino group.

[0008] That is, the present disclosure provides the disclosures described in [1] to [9] below.

[0009] [1] A trifluoromethanesulfonylating agent composition containing a compound represented by the following general formula (1): (In general formula (1), R １ is a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 6 carbon atoms; R ２ is a hydrogen atom, a halogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, a nitro group, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms, and X is a nitrogen atom or C(R ３ ), and Y is a nitrogen atom or C(R ４ ) and R ３ is a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms; ４ is a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms; ２ and R ３ may be bonded to form a ring, and R ２ and R ４ may be bonded to form a ring, and n is an integer of 1 to 3. ２ R when there are multiple２ may be the same or different, R ３ R when there are multiple ３ may be the same or different.) General formula (2): (in general formula (2), Ar represents an aromatic ring group or a substituted aromatic ring group) and / or an acid salt thereof, in the presence of a solvent under acidic conditions.

[0010] [2] The method for producing a trifluoromethanesulfonamide compound according to [1], wherein the trifluoromethanesulfonylating agent composition contains: a compound represented by general formula (1); and a heterocyclic group-containing organic base and / or an acid salt thereof.

[0011] [3] In the general formula (1), X is C(R ３ ) and R １ , R ２ , and R ３ are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0012] [4] The method for producing a trifluoromethanesulfonamide compound according to [2], wherein the heterocyclic group-containing organic base is an organic base having a nitrogen atom and a heterocyclic group having 4 or more carbon atoms.

[0013] [5] The method for producing a trifluoromethanesulfonamide compound according to [2], wherein the heterocyclic group-containing organic base is any one selected from the group consisting of pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

[0014] [6] The method for producing a trifluoromethanesulfonamide compound according to any one of [1] to [5], wherein, in the general formula (2), Ar represents an aromatic ring group, and the aromatic ring group is an aromatic hydrocarbon group.

[0015] [7] The method for producing a trifluoromethanesulfonamide compound according to any one of [1] to [5], wherein, in the general formula (2), Ar represents a substituted aromatic ring group, and the substituted aromatic ring group has a substituent that is a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a β-D-glucopyranoside group, an amino group, a lower alkylamino group, or a hydroxyl group.

[0016] [8] The method for producing a trifluoromethanesulfonamide compound according to any one of [1] to [7], wherein the reaction is carried out at a reaction temperature of 150° C. or less.

[0017] [9] The method for producing a trifluoromethanesulfonamide compound according to any one of [1] to [8], wherein the reaction solution after completion of the reaction is post-treated with water, an acidic aqueous solution, or an alkaline aqueous solution.

[0018] According to the present disclosure, it is possible to provide a method for producing a trifluoromethanesulfonamide compound, which can selectively trifluoromethanesulfonylate the aniline amino group of a substrate having a functional group such as an aniline amino group.

[0019] The present disclosure will be described in detail below. Hereinafter, embodiments of the present disclosure will be described, but the present disclosure is not limited to the following embodiments and can be appropriately implemented based on the ordinary knowledge of those skilled in the art within the scope of the present disclosure.

[0020] In the method for producing a trifluoromethanesulfonamide compound of the present disclosure, a trifluoromethanesulfonylating agent composition containing a specific trifluoromethanesulfonylating agent (also referred to as a triflating agent or Tf agent) of the present disclosure is reacted with a substrate having a functional group such as an aniline amino group in the presence of a solvent under acidic conditions, thereby selectively trifluoromethanesulfonylated (also referred to as Tf-conversion) the aniline amino group in the substrate having a functional group such as an aniline amino group. More specifically, in the method for producing a trifluoromethanesulfonamide compound of the present disclosure, a trifluoromethanesulfonylating agent composition containing a compound represented by general formula (1) is reacted with an aromatic amino compound represented by general formula (2) in the presence of a solvent under acidic conditions, thereby selectively trifluoromethanesulfonylated the aniline amino group in the aromatic amino compound represented by general formula (2), which is a substrate having a functional group such as an aniline amino group.

[0021] The present inventors have used trifluoromethanesulfonic anhydride (Tf ２ When trifluoromethanesulfonic anhydride (TFA) was reacted with 4-methoxyphenol (TFA) in the presence of a solvent in the presence of a phenolic hydroxyl group and an aniline amino group (for example, 4-methoxyphenol and 4-methoxyaniline), 53% of 4-methoxyphenol Tf product and 30% of 4-methoxyaniline Tf product were obtained. This indicates that when trifluoromethanesulfonic anhydride is used, there is room for improvement in terms of selectively trifluoromethanesulfonylating an aniline amino group in the presence of a nucleophilic functional group such as a hydroxyl group in addition to the aniline amino group. It is also indicated that there is room for improvement in terms of selectively trifluoromethanesulfonylating an aniline amino group in the case of using trifluoromethanesulfonyl chloride as a trifluoromethanesulfonylating agent.

[0022] On the other hand, as a result of intensive studies, the present inventors have found that when a trifluoromethanesulfonylating agent composition containing a compound represented by the above general formula (1) as a trifluoromethanesulfonylating agent was reacted in the coexistence of a phenolic hydroxyl group and an aniline amino group (for example, 4-methoxyphenol and 4-methoxyaniline) in the presence of a solvent and a base, 82% of 4-methoxyphenol Tf compound and 0% of 4-methoxyaniline Tf compound were obtained, and that when the compound represented by the above general formula (1) was used together with a base, in the presence of a nucleophilic functional group such as a hydroxyl group in addition to an aniline amino group, the hydroxyl group was selectively trifluoromethanesulfonylated.

[0023] Furthermore, as a result of extensive research, the present inventors have found that when a trifluoromethanesulfonylating agent composition containing a compound represented by the above general formula (1) as a trifluoromethanesulfonylating agent was reacted in the coexistence of a phenolic hydroxyl group and an aniline amino group (for example, 4-methoxyphenol and 4-methoxyaniline) under acidic conditions in the presence of a solvent, less than 1% of 4-methoxyphenol Tf compound and 80% of 4-methoxyaniline Tf compound were obtained, and that the aniline amino group was selectively trifluoromethanesulfonylated even in the presence of a nucleophilic functional group such as a hydroxyl group in addition to the aniline amino group. Furthermore, as a result of conducting similar tests using various compounds, the present inventors have found that by reacting a trifluoromethanesulfonylation agent composition containing a compound represented by the general formula (1) above with an aromatic amino compound represented by the general formula (2) above in the presence of a solvent under acidic conditions, trifluoromethanesulfonylation proceeds selectively to the aniline amino group even when a reactive site (e.g., an OH group, etc.) coexists between or within molecules, and that this makes it possible to selectively trifluoromethanesulfonylate the aniline amino group in the aromatic amino compound represented by the general formula (2) above, which is a substrate having a functional group such as an aniline amino group.

[0024] The reason why the above-mentioned effect is obtained in the method for producing a trifluoromethanesulfonamide compound of the present disclosure is not clear, but it is speculated that the compound represented by the general formula (1) has a relatively low elimination ability, so its reactivity toward functional groups depends on the reaction conditions, and the reactivity toward functional groups can be controlled by the reaction conditions. More specifically, it is speculated as follows. First, the compound represented by the general formula (1) is protonated under acidic conditions to become a cationic species. Then, when the aromatic amino compound represented by the general formula (2) reacts, the aniline amino group is more nucleophilic than a hydroxyl group or the like, so it is speculated that the aniline amino group selectively attacks the cationic species with a nucleophilic attack, thereby selectively trifluoromethanesulfonylating the aniline amino group.

[0025] <Trifluoromethanesulfonylating Agent Composition> (Trifluoromethanesulfonylating Agent) The trifluoromethanesulfonylating agent composition of the present disclosure (hereinafter also referred to as the composition of the present disclosure) contains a compound represented by the following general formula (1) as a trifluoromethanesulfonylating agent.

[0026]

[0027] In general formula (1), R １ is a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 6 carbon atoms; R ２ is a hydrogen atom, a halogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, a nitro group, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms, and X is a nitrogen atom or C(R ３ ), and Y is a nitrogen atom or C(R ４ ) and R ３ is a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms; ４ is a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms; ２ and R ３ may be bonded to form a ring, and R ２ and R ４may be bonded to form a ring, and n is an integer of 1 to 3. ２ R when there are multiple ２ may be the same or different, R ３ R when there are multiple ３ may be the same or different.

[0028] In general formula (1), R １ represents a hydrogen atom, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), or an aliphatic hydrocarbon group having 1 to 6 carbon atoms. The aliphatic hydrocarbon group may be linear, branched, or cyclic. When the hydrocarbon group is branched or cyclic, the aliphatic hydrocarbon group has 3 to 6 carbon atoms. Examples of the aliphatic hydrocarbon group include alkyl groups, alkenyl groups, and alkynyl groups, and any of these may be used, but alkyl groups are preferred. Examples of the alkyl group include linear alkyl groups having 1 to 6 carbon atoms, branched alkyl groups having 3 to 6 carbon atoms, and cyclic alkyl groups having 3 to 6 carbon atoms, and any of these may be used, but linear alkyl groups having 1 to 6 carbon atoms and branched alkyl groups having 3 to 6 carbon atoms are preferred.

[0029] Examples of linear alkyl groups having 1 to 6 carbon atoms include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched alkyl groups having 3 to 6 carbon atoms include isopropyl, isobutyl, sec-butyl, and tert-butyl groups. Examples of cyclic alkyl groups having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. In this specification, alkenyl and alkynyl groups include groups obtained by removing two and four hydrogen atoms, respectively, from an alkyl group.

[0030] R １ Among these, a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group is preferred because of ease of synthesis.

[0031] In general formula (1), R ２represents a hydrogen atom, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), an aliphatic hydrocarbon group having 1 to 6 carbon atoms, a nitro group, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms. ２ R when there are multiple ２ may be the same or different. The aliphatic hydrocarbon group having 1 to 6 carbon atoms may be linear, branched, or cyclic. When the hydrocarbon group is branched or cyclic, the aliphatic hydrocarbon group has 3 to 6 carbon atoms. Examples of the aliphatic hydrocarbon group having 1 to 6 carbon atoms include linear aliphatic hydrocarbon groups having 1 to 6 carbon atoms, branched aliphatic hydrocarbon groups having 3 to 6 carbon atoms, and cyclic aliphatic hydrocarbon groups having 3 to 6 carbon atoms. Any of these may be used, but linear aliphatic hydrocarbon groups having 1 to 6 carbon atoms and branched aliphatic hydrocarbon groups having 3 to 6 carbon atoms are preferred.

[0032] Examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms include a linear alkyl group having 1 to 6 carbon atoms, a linear alkenyl group having 2 to 6 carbon atoms, and a linear alkynyl group having 2 to 6 carbon atoms. Examples of the linear alkyl group having 1 to 6 carbon atoms include R １ Examples of the alkyl group include a linear alkyl group having 1 to 6 carbon atoms.

[0033] Examples of the branched aliphatic hydrocarbon group having 3 to 6 carbon atoms include a branched alkyl group having 3 to 6 carbon atoms, a branched alkenyl group having 3 to 6 carbon atoms, and a branched alkynyl group having 3 to 6 carbon atoms. Examples of the branched alkyl group having 3 to 6 carbon atoms include R １ Examples of the cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms include a cyclic alkyl group having 3 to 6 carbon atoms, a cyclic alkenyl group having 3 to 6 carbon atoms, and a cyclic alkynyl group having 3 to 6 carbon atoms. Examples of the cyclic alkyl group having 3 to 6 carbon atoms include R １ Examples of the cyclic alkyl group having 3 to 6 carbon atoms include those described in the above.

[0034] Examples of aromatic hydrocarbon groups having 6 to 14 carbon atoms include a phenyl group, a naphthyl group, an anthryl group, etc. Examples of aromatic heterocyclic groups having 3 to 14 carbon atoms include a pyrrole group, a pyrazine group, a pyrimidine group, a pyridazine group, etc.

[0035] R ２ is preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 6 carbon atoms, or a nitro group, and more preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms. ２ is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a nitro group, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0036] In the general formula (1), X is a nitrogen atom or C(R ３ ), and Y is a nitrogen atom or C(R ４ ) R ３ represents a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms. ３ R when there are multiple ３ may be the same or different.

[0037] Examples of the aliphatic hydrocarbon group having 1 to 6 carbon atoms include a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, and a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms. Any of these may be used, but a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms and a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms are preferred. Examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and an aromatic heterocyclic group having 3 to 14 carbon atoms include R ２Examples of the alkyl group include a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and an aromatic heterocyclic group having 3 to 14 carbon atoms.

[0038] R ３ is preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0039] R ４ represents a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms. ４ R when there are multiple ４ may be the same or different.

[0040] Examples of the aliphatic hydrocarbon group having 1 to 6 carbon atoms include a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, and a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms. Any of these may be used, but a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms and a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms are preferred. Examples of the linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and an aromatic heterocyclic group having 3 to 14 carbon atoms include R ２ Examples of the alkyl group include a linear aliphatic hydrocarbon group having 1 to 6 carbon atoms, a branched aliphatic hydrocarbon group having 3 to 6 carbon atoms, a cyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, and an aromatic heterocyclic group having 3 to 14 carbon atoms.

[0041] R ４ is preferably a hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 3 to 6 carbon atoms, and more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0042] In the general formula (1), X is C(R３ ) and Y is preferably a nitrogen atom.

[0043] n is an integer of 1 to 3. n is preferably 1.

[0044] R ２ and R ３ may be bonded to form a ring. ２ and R ３ The ring formed by the bonding of R is not particularly limited, but examples thereof include aromatic hydrocarbon rings having 6 to 14 carbon atoms (e.g., naphthalene ring, anthracene ring) and aromatic heterocyclic rings having 6 to 14 carbon atoms. ２ and R ４ may be bonded to form a ring. ２ and R ４ The ring formed by bonding is not particularly limited, and examples thereof include an aromatic hydrocarbon ring having 6 to 14 carbon atoms (e.g., a naphthalene ring, an anthracene ring) or an aromatic heterocyclic ring having 6 to 14 carbon atoms.

[0045] In the general formula (1), X is C(R ３ ) and R １ , R ２ , and R ３ are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group (preferably a hydrogen atom). Furthermore, it is more preferable that Y is a nitrogen atom and n is 1.

[0046] Examples of compounds represented by general formula (1) are shown below, but the compounds are not limited to these.

[0047]

[0048] <Aspects of Method for Producing Trifluoromethanesulfonamide Compound> By reacting a trifluoromethanesulfonylating agent composition containing the compound represented by the general formula (1) with a substrate having a functional group such as an aniline amino group under acidic conditions in the presence of a solvent, it is possible to selectively trifluoromethanesulfonylate the aniline amino group in the substrate having a functional group such as an aniline amino group. More specifically, in the method for producing a trifluoromethanesulfonamide compound of the present disclosure, by reacting a trifluoromethanesulfonylating agent composition containing the compound represented by the general formula (1) with an aromatic amino compound represented by the general formula (2) and / or an acid salt thereof under acidic conditions in the presence of a solvent, it is possible to selectively trifluoromethanesulfonylate the aniline amino group in the aromatic amino compound represented by the general formula (2), which is a substrate having a functional group such as an aniline amino group.

[0049] The trifluoromethanesulfonylating agent composition contains the compound represented by the above general formula (1), and two or more of these compounds may be used in combination.

[0050] As used herein, a reaction under acidic conditions refers to a reaction in the presence of a proton donor in the reaction system (reaction solvent). Thus, acidic conditions do not refer to whether the reaction system is acidic or basic, but rather to a state in which a proton donor is present in the reaction system (reaction solvent). That is, acidic conditions simply refer to a state in which a proton donor is added to the reaction system (reaction solvent). Therefore, acidic conditions encompass not only cases in which a proton donor is present in the reaction system (reaction solvent) and the reaction system is acidic, but also cases in which the proton donor is present together with a base or the like in the reaction system (reaction solvent) and the reaction system is not acidic. When a proton donor is present in the reaction system (reaction solvent) together with a base and / or a reaction substrate (e.g., a compound represented by general formula (2)), the proton donor may form a salt with the base and / or the reaction substrate (e.g., a compound represented by general formula (2)). In the present disclosure, it is preferable that the proton donor is present together with a base in the reaction system (reaction solvent), and it is more preferable that the proton donor forms a salt with the base.

[0051] An example of an acidic condition is a condition in which the acid dissociation constant (pKa) of the proton donor itself added to the reaction system is, for example, in the range of 1 to 5. In this specification, the acid dissociation constant (pKa) of the reaction system is measured at 25° C. by dissolving it in dimethyl sulfoxide.

[0052] The proton donor is not particularly limited as long as it is a compound that can donate a proton, and examples thereof include acids such as inorganic acids and organic acids. These compounds can be used alone or in combination.

[0053] Examples of inorganic acids include hydrochloric acid (hydrogen chloride), sulfuric acid, fluorosulfuric acid, nitric acid, phosphoric acid, hydrogen iodide, hydrogen bromide, etc. Among these, hydrochloric acid (hydrogen chloride), sulfuric acid, hydrogen iodide, and hydrogen bromide are preferred, and hydrochloric acid (hydrogen chloride) is more preferred.

[0054] Examples of organic acids include monocarboxylic acids such as formic acid, acetic acid, propionic acid, acrylic acid, methacrylic acid, benzoic acid, trifluoroacetic acid, and difluoroacetic acid; dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, and phthalic acid; polycarboxylic acids such as polyglutamic acid, polyacrylic acid, and polymethacrylic acid; hydroxycarboxylic acids such as glycolic acid, lactic acid, hydroxyacrylic acid, glyceric acid, malic acid, tartaric acid, and citric acid; acidic amino acids such as glutamic acid and aspartic acid; sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and trifluoromethanesulfonic acid; and sulfonimides such as trifluoromethanesulfonimide. Among these, sulfonic acids are preferred.

[0055] The proton donor is preferably an acid, more preferably an inorganic acid, and even more preferably hydrochloric acid (hydrogen chloride).

[0056] To carry out the reaction under acidic conditions, a proton donor (preferably an acid) may be added to the reaction system (reaction solvent). The amount of the proton donor (preferably an acid) used is not particularly limited, but is usually preferably 0.1 to 5.0 mol, more preferably 0.5 to 2.0 mol, and particularly preferably 0.9 to 1.1 mol, relative to 1 mol of the compound represented by the general formula (1).

[0057] In the production method of the present disclosure, a trifluoromethanesulfonylation agent composition containing the compound represented by the above-mentioned general formula (1) is reacted with a substrate having a functional group such as an aniline amino group in the presence of a solvent under acidic conditions, thereby selectively trifluoromethanesulfonylating the aniline amino group in the substrate having a functional group such as an aniline amino group. This reaction proceeds even in the absence of a base in the reaction system (reaction solvent). This is presumably because, when the compound represented by the general formula (1) is protonated by a proton donor (preferably an acid), it becomes a cationic species that can undergo nucleophilic attack by the aniline amino group.

[0058] On the other hand, the reaction proceeds even in the absence of a base in the reaction system (reaction solvent), but the presence of a base in the reaction system (reaction solvent) is preferred because the effects of the present disclosure tend to be more favorably obtained. Note that, since the base may form a salt, it is preferred that the base and / or its acid salt be present in the reaction system (reaction solvent).

[0059] First Aspect One preferred aspect of the present disclosure is a trifluoromethanesulfonylating agent composition comprising a compound represented by the above-described general formula (1) and a heterocyclic group-containing organic base and / or an acid salt thereof. The trifluoromethanesulfonylating agent composition comprising a compound represented by the general formula (1) and a specific base and / or an acid salt thereof (hereinafter referred to as the "first trifluoromethanesulfonylating agent composition," or simply the "first composition") enables selective trifluoromethanesulfonylation of an aniline amino group while suppressing the production of by-products. Furthermore, the trifluoromethanesulfonamide compound can be isolated from the reaction solution following the trifluoromethanesulfonylation reaction by simply performing a general post-treatment, enabling industrially feasible and efficient production of the trifluoromethanesulfonamide compound.

[0060] In this specification, the expression "selectively reacts" a trifluoromethanesulfonylation agent with an anilinic amino group means that the trifluoromethanesulfonylation reaction proceeds preferentially with the anilinic amino group. Furthermore, in this specification, an aniline amino group refers to an amino group bonded to an aromatic ring. The first composition of the present disclosure contains a compound represented by general formula (1). Two or more types of compounds represented by general formula (1) may be combined. The first composition preferably contains 40% or more, and more preferably 55% or more, of the compound represented by general formula (1) relative to the total mass of the first composition.

[0061] (Base) The first trifluoromethanesulfonylating agent composition of the present disclosure preferably contains a base and / or an acid salt thereof. Note that, by using a base in the form of an acid salt, such as pyridine hydrochloride, as the base, it becomes possible to more easily add an acid serving as a proton donor to the reaction system (reaction solvent), and it becomes possible to more easily carry out the reaction under acidic conditions. Here, the acid of the acid salt is the same as the acid described for the proton donor, including preferred embodiments.

[0062] Examples of the base used in the first trifluoromethanesulfonylating agent composition include heterocyclic group-containing organic bases. Two or more types of bases may be combined. Furthermore, when the base is an acid salt, two or more types of acids that form a salt with the base may be combined. Inorganic bases such as potassium carbonate have low solubility in reaction solvents and may contain water such as water of crystallization, which may lead to reduced reproducibility. However, it is believed that the use of a heterocyclic group-containing organic base will result in good reproducibility and excellent yield.

[0063] The heterocyclic group-containing organic base is preferably a compound having a heterocyclic group with 4 or more carbon atoms, more preferably a compound having a nitrogen atom and a heterocyclic group with 4 or more carbon atoms, and even more preferably a compound having a nitrogen atom and a heterocyclic group with 4 to 9 carbon atoms. Specific examples include pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5,6-collidine, quinoline, isoquinoline, pyrazine, pyridazine, pyrimidine, etc. Among these, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, and 3,5-lutidine are preferred, and pyridine is more preferred. Acid salts of these are also preferred, with pyridine acid salts being more preferred, and pyridine hydrochloride being even more preferred.

[0064] The organic base is preferably a heterocyclic group-containing organic base, which tends to provide a method for producing a trifluoromethanesulfonamide compound with better reproducibility and excellent yield.

[0065] The organic base is preferably liquid at 25°C. Inorganic bases such as potassium carbonate are solid at 25°C and therefore have low solubility in reaction solvents, which may lead to reduced reproducibility. However, by using an organic base that is liquid at 25°C, the reaction system tends to become more homogeneous, and a method for producing a trifluoromethanesulfonamide compound that is more suitable, has good reproducibility, and is excellent in yield tends to be provided. Examples of organic bases that are liquid at 25°C include the compounds exemplified above as heterocyclic group-containing organic bases. In this specification, "liquid at 25°C" refers to a compound that has fluidity at 25°C, and includes a cream-like or paste-like compound.

[0066] In the first trifluoromethanesulfonylating agent composition of the present disclosure, the content of the heterocyclic group-containing organic base, relative to 100 mol% of base, is preferably 80 mol% or more, more preferably 90 mol% or more, even more preferably 95 mol% or more, particularly preferably 98 mol% or more, and most preferably 100 mol%, for reasons that allow the effects of the present disclosure to be more suitably obtained.

[0067] The amount of the base and / or its acid salt (total amount of the base and its acid salt) used is not particularly limited, but is usually preferably 0.01 to 20 mol, and more preferably 0.05 to 5 mol, per 1 mol of the compound to be trifluoromethanesulfonylated, which will be described later.

[0068] The first composition of the present disclosure may further contain a solvent. The solvent is not particularly limited as long as it dissolves the compound represented by the general formula (1) and the base and / or its acid salt, and examples thereof include the reaction solvents for trifluoromethanesulfonylation described below. The first composition of the present disclosure may or may not contain a solvent.

[0069] <Method for Producing Trifluoromethanesulfonamide Compound> A method for producing a trifluoromethanesulfonamide compound using the first composition of the present disclosure (hereinafter also referred to as the first production method) includes a step of reacting the above-described first trifluoromethanesulfonylating agent composition with a compound represented by the following general formula (2) in the presence of a solvent under acidic conditions:

[0070] (Compound to be trifluoromethanesulfonylated) The compound to be trifluoromethanesulfonylated with the first trifluoromethanesulfonylation agent composition (hereinafter also referred to as the compound to be trifluoromethanesulfonylated) is an aromatic amino compound represented by the following general formula (2): Note that the aromatic amino compound represented by the following general formula (2) may form a salt, and therefore the compound to be trifluoromethanesulfonylated is an aromatic amino compound represented by the following general formula (2) and / or its acid salt. Note that by using the compound to be trifluoromethanesulfonylated in the form of an acid salt, such as aniline hydrochloride, as the compound to be trifluoromethanesulfonylated, it becomes possible to more easily add an acid, which is a proton donor, to the reaction system (reaction solvent), and it becomes possible to more easily carry out the reaction under acidic conditions. Here, the acid of the acid salt is the same as the acid described for the proton donor, including preferred embodiments. Furthermore, when an acid salt of an aromatic amino compound represented by the following general formula (2) is used as the compound to be trifluoromethanesulfonated, the reaction of selectively trifluoromethanesulfonylating an anilinic amino group in a substrate having a functional group such as an anilinic amino group tends to proceed favorably even in the absence of a base in the reaction system (reaction solvent).

[0071]

[0072] In formula (2), Ar represents an aromatic ring group or a substituted aromatic ring group.

[0073] In the aromatic amino compound represented by general formula (2), Ar represents an aromatic ring group or a substituted aromatic ring group. The aromatic ring group is not particularly limited, but may be monocyclic or polycyclic. An aromatic ring group having 1 to 18 carbon atoms is preferred. Examples include aromatic hydrocarbon groups such as phenyl, naphthyl, and anthryl, and aromatic heterocyclic groups containing a heteroatom such as a nitrogen atom, oxygen atom, or sulfur atom, such as pyrrolyl (including nitrogen-protected forms), pyridyl, pyrazyl, pyrimidyl, pyridazyl, triazyl, furyl, thienyl, indolyl (including nitrogen-protected forms), indazolyl, quinolyl, carbazolyl, pyrrolopyridyl, benzofuryl, and benzothienyl. In general formula (2), Ar represents an aromatic ring group, and the aromatic ring group is preferably an aromatic hydrocarbon group, more preferably a monocyclic aromatic hydrocarbon group.

[0074] The substituted aromatic ring group has any number and any combination of substituents on any carbon or nitrogen atom of the aromatic ring group. Such substituents include halogen atoms such as fluorine, chlorine, bromine, and iodine, lower alkyl groups such as methyl, ethyl, and propyl, lower unsaturated groups such as vinyl, allyl, and propargyl, lower haloalkyl groups such as fluoromethyl, chloromethyl, and bromomethyl, C(CF ３ ) ２OH group (including protected hydroxyl groups), lower alkoxy groups such as methoxy, ethoxy and propoxy groups, lower haloalkoxy groups such as fluoromethoxy, chloromethoxy and bromomethoxy groups, lower acyloxy groups such as formyloxy, acetyloxy, propionyloxy and butyryloxy groups, cyano group, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups, methoxycarbonylmethyl group, ethoxycarbonylethyl group and propoxycarbonyl group, Examples of the substituent include lower alkoxycarbonyl lower alkyl groups such as phenylpropyl group, β-D-glucopyranoside group, phenyl group, naphthyl group, anthryl group, pyrrolyl group (including nitrogen-protected groups), pyridyl group, furyl group, thienyl group, indolyl group (including nitrogen-protected groups), quinolyl group, aromatic ring groups such as benzofuryl group and benzothienyl group, protected carboxyl groups, amino groups, protected amino groups, lower alkylamino groups, lower alkylamino lower alkyl groups, hydroxyl groups, protected hydroxyl groups, and X'-Ar'-OH group. These substituents may be further substituted, for example, with the substituents of "such substituents" above.

[0075] In the above general formula (2), Ar represents a substituted aromatic ring group, and the substituent of the substituted aromatic ring group may be a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a β-D-glucopyranoside group, an amino group, a lower alkylamino group, or a hydroxyl group.

[0076] X' in the X'-Ar'-OH group is C(CH ３ ) ２ group, C (CF ３ ) ２ group, oxygen atom, nitrogen atom (including nitrogen-protected atoms), sulfur atom, SO group or SO ２ group, and Ar' represents a phenylene group or a substituted phenylene group. The substitution position of the phenylene group is the 2-, 3-, or 4-position relative to the amino group. The substituent of the substituted phenylene group is the same as the substituent of the substituted aromatic ring group described above. Specific examples of aromatic amino compounds represented by general formula (2) substituted with an X'-Ar'-OH group include the following compounds.

[0077]

[0078] In this specification, "lower" means a straight or branched chain or cyclic (when the number of carbon atoms is 3 or more) group having 1 to 6 carbon atoms. The aromatic ring group in the above "substituents" includes halogen atoms, lower alkyl groups, lower unsaturated groups, lower haloalkyl groups, C(CF ３ ) ２ Substitution can also be made with an OH group (including a protected hydroxyl group), a lower alkoxy group, a lower haloalkoxy group, a formyloxy group, a lower acyloxy group, a cyano group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, a protected carboxyl group, a protected amino group, a hydroxyl group, a protected hydroxyl group, an X'-Ar'-OH group, etc. Furthermore, protecting groups for pyrrolyl, indolyl, hydroxyl, carboxyl, and amino groups are protecting groups described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc., etc. Among these, aromatic ring groups and substituted aromatic ring groups excluding "amino groups", "aromatic ring groups", and "X'-Ar'-OH groups" as substituents are preferred, and aromatic hydrocarbon groups and substituted aromatic hydrocarbon groups (aromatic hydrocarbon groups having a substituent) excluding "amino groups", "aromatic ring groups", and "X'-Ar'-OH groups" as substituents are particularly preferred. In aromatic amino compounds having multiple amino groups, multiple fluorosulfonylation reactions may proceed depending on the reaction conditions used.

[0079] In a preferred embodiment, the aromatic amino compound represented by the general formula (2) has at least one substituent selected from an aniline amino group and a hydroxyl group. These substituents may be further substituted, for example, with the substituents described above as "such substituents."

[0080] Examples of compounds represented by general formula (2) are shown below, but the compounds are not limited to these.

[0081]

[0082] In the trifluoromethanesulfonylation reaction, the aromatic amino compound represented by the general formula (2) and / or its acid salt is preferably used in an amount of 0.7 mol to 1.2 mol, more preferably 0.8 mol to 1.0 mol, per 1.0 mol of the trifluoromethanesulfonyl compound represented by the general formula (1).

[0083] (Solvent) The above-mentioned trifluoromethanesulfonylation reaction is preferably carried out using a reaction solvent. Examples of the reaction solvent for trifluoromethanesulfonylation include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, amide solvents, nitrile solvents, and sulfoxide solvents.

[0084] Specific examples of these reaction solvents include ether solvents such as diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 1,4-dioxane, and cyclopentyl methyl ether. Examples of aliphatic hydrocarbon solvents include n-hexane, n-heptane, n-pentane, n-nonane, and n-decane. Examples of aromatic hydrocarbon solvents include toluene, xylene, mesitylene, and ethylbenzene. Examples of halogenated hydrocarbon solvents include methylene chloride, chloroform, and 1,2-dichloroethane. Examples of ester solvents include ethyl acetate, isopropyl acetate, n-butyl acetate, and γ-butyrolactone. Examples of amide solvents include N,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), etc. Examples of nitrile solvents include acetonitrile, propionitrile, benzonitrile, etc. Examples of sulfoxide solvents include dimethyl sulfoxide, etc. Among these, amide solvents are preferred because they dissolve the substrate and the reactant well and more suitably enable selective trifluoromethanesulfonylation of the aniline amino group in a substrate having a functional group such as an aniline amino group. Among amide solvents, N-methylpyrrolidone (NMP) is more preferred because the solvent itself is less likely to cause side reactions, allowing the production of the target trifluoromethanesulfonamide compound in high yield while suppressing the generation of by-products. These reaction solvents can be used alone or in combination.

[0085] The amount of the reaction solvent used for trifluoromethanesulfonylation is not particularly limited, but it is sufficient to use 0.05 L (liters) or more per mole of the compound to be trifluoromethanesulfonated, and usually 0.1 to 20 L is preferred, and particularly 0.1 to 10 L is more preferred.

[0086] (Reaction Temperature) The reaction temperature for trifluoromethanesulfonylation is not particularly limited, but is preferably carried out at a reaction temperature of 150° C. or lower, more preferably in the range of −100 to 150° C., and even more preferably −78 to 100° C. In order to produce the target trifluoromethanesulfonamide compound in high yield while suppressing the production of by-products, the upper limit of the temperature is particularly preferably 70° C. or lower, most preferably 50° C. or lower, and even more preferably 35° C. or lower, and the lower limit of the temperature is particularly preferably −5° C. or higher, and most preferably 10° C. or higher.

[0087] (Reaction Time) The reaction time for trifluoromethanesulfonylation is not particularly limited, but may be in the range of 0.1 to 72 hours. Since the reaction time varies depending on the raw materials and reaction conditions, it is preferable to follow the progress of the reaction by analytical means such as gas chromatography, liquid chromatography, or NMR, and determine the end point as the time when the raw materials have almost completely disappeared.

[0088] (Post-Treatment Procedure: Liquid Separation) After the above reaction, a post-treatment procedure for isolating the trifluoromethanesulfonamide compound may be performed using procedures commonly used in organic synthesis. For example, it is preferable to post-treat the reaction solution containing the trifluoromethanesulfonamide compound after the completion of the reaction with water, an acidic aqueous solution, or an alkaline aqueous solution. That is, the post-treatment procedure may be performed by diluting the reaction solution after the completion of the reaction with an organic solvent, washing with water, an aqueous solution of a mineral acid (inorganic acid), or an aqueous solution of an alkali metal salt, and concentrating the reaction mixture (organic phase). Examples of organic solvents for post-treatment include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, and ester solvents.

[0089] Specific examples of organic solvents for post-treatment include diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, cyclopentyl methyl ether, n-hexane, n-heptane, n-pentane, n-nonane, n-decane, toluene, xylene, mesitylene, ethylbenzene, methylene chloride, chloroform, 1,2-dichloroethane, ethyl acetate, and n-butyl acetate. Among these, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, toluene, xylene, mesitylene, ethylbenzene, methylene chloride, chloroform, 1,2-dichloroethane, ethyl acetate, and n-butyl acetate are preferred, with ethyl acetate being particularly preferred. These reaction solvents can be used alone or in combination.

[0090] The amount of solvent used in the post-treatment is not particularly limited, but it is sufficient to use 0.05 L (liters) or more per mole of the compound to be trifluoromethanesulfonylated, and usually 0.1 to 20 L is preferred, and particularly 0.1 to 10 L is more preferred.

[0091] Specific examples of mineral acids for post-treatment include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Among these, hydrochloric acid and sulfuric acid are preferred, with hydrochloric acid being particularly preferred. Specific examples of alkali metal salts for post-treatment include sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and potassium carbonate.

[0092] The obtained trifluoromethanesulfonamide compound can be suitably used, for example, in a coupling reaction using a transition metal, etc. As described above, the trifluoromethanesulfonamide compound obtained by the first production method of the present disclosure can be isolated from the reaction solution after completion of the reaction by simply performing a simple post-treatment operation, making it industrially feasible, and as a result, it becomes possible to produce a coupling reaction product much more efficiently than by conventional methods.

[0093] Hereinafter, the present disclosure will be described in detail with reference to examples, but the present disclosure is not limited to these examples. In the examples and comparative examples, the yield (%) refers to the percentage of the product obtained by the nuclear magnetic resonance spectrum １９ This value was obtained by quantification using the internal standard method (benzotrifluoride as the internal standard substance) through F-NMR analysis.

[0094] Comparative Example 1: A composition containing 124 mg (1.00 mmol, 1.0 eq.) of 4-methoxyphenol as a substrate and 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, as well as 5 mL of acetonitrile as a reaction solvent, were collected and placed in a 30 mL eggplant-shaped flask equipped with a stirrer, which served as a reactor. Subsequently, a composition containing 200 mg (1.00 mmol, 1.0 eq.) of 1-trifluoromethanesulfonylimidazole and 30.4 mg (0.20 mmol, 0.2 eq.) of 1,8-diazabicyclo[5.4.0]undecene was added to the reactor, and the mixture was stirred at room temperature (25°C) for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from 4-methoxyphenyl trifluoromethanesulfonate at −72.7 ppm, and the quantitative yield was 82%, but no signal derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide could be confirmed.

[0095] [Physical properties] 4-methoxyphenyl trifluoromethanesulfonate; １ H-NMR (400MHz, CDCl ３ ) δ: 7.19 (d, J = 9.1 Hz, 2H), 6.91 (d, J = 9.6 Hz, 2H), 3.80 (s, 3H). １９ F-NMR (376MHz, CDCl ３ ) δ: -72.7 (3F).

[0096] Comparative Example 2: A composition containing 124 mg (1.00 mmol, 1.0 eq.) of 4-methoxyphenol as a substrate and 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, and 5 mL of dichloromethane as a reaction solvent, were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, a composition containing 282 mg (1.00 mmol, 1.0 eq.) of trifluoromethanesulfonic anhydride and 506 mg (5.00 mmol, 5.0 eq.) of triethylamine was added to the reactor, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ F-NMR analysis confirmed signals at −72.7 ppm and −76.1 ppm derived from 4-methoxyphenyl trifluoromethanesulfonate and N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yields were 53% and 30%, respectively.

[0097] [Physical properties] N-(4-methoxyphenyl)trifluoromethanesulfonamide; １ H-NMR (400MHz, CDCl ３ ) δ: 7.22 (d, J=9.0Hz, 2H), 6.89 (d, J=9.1Hz, 2H), 6.14 (s, 1H), 3.81 (s, 3H). １９ F-NMR (376MHz, CDCl ３ ) δ: -76.1 (3F).

[0098] Comparative Example 3 was carried out in the same manner as in Comparative Example 2, except that the reaction temperature was changed to −78° C. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ F-NMR analysis confirmed signals at −72.7 ppm and −76.1 ppm derived from 4-methoxyphenyl trifluoromethanesulfonate and N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yields were 48% and 30%, respectively.

[0099] Comparative Example 4 Comparative Example 4 was carried out in the same manner as in Comparative Example 2, except that 282 mg (1.00 mmol, 1.0 eq.) of trifluoromethanesulfonic anhydride was changed to 168 mg (1.00 mmol, 1.0 eq.) of trifluoromethanesulfonyl chloride. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from 4-methoxyphenyl trifluoromethanesulfonate at −72.7 ppm, and the quantitative yield of each compound was 90%.

[0100] Example 1 A composition containing 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide at −76.1 ppm, and the quantitative yield was 84%.

[0101] The reaction in Example 1 is shown below.

[0102]

[0103] Example 2: A composition containing 109 mg (1.00 mmol, 1.0 eq.) of p-aminophenol as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９Analysis by F-NMR confirmed a signal at −77.1 ppm derived from N-(4-hydroxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 81%, but no signal derived from 4-aminophenyltrifluoromethanesulfonate could be confirmed.

[0104] The reaction in Example 2 is shown below.

[0105]

[0106] Example 3: 137 mg (1.00 mmol, 1.0 eq.) of 2-(4-aminophenyl)ethanol as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −77.5 ppm derived from N-(4-(2-hydroxyethyl)phenyl)trifluoromethanesulfonamide, and the quantitative yield was 81%, but no signal derived from 4-aminophenethyl trifluoromethanesulfonate could be confirmed.

[0107] The reaction in Example 3 is shown below.

[0108]

[0109] Example 4: A composition containing 93.1 mg (1.00 mmol, 1.0 eq.) of aniline as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from N-phenyltrifluoromethanesulfonamide at −77.3 ppm, and the quantitative yield was 78%.

[0110] The reaction in Example 4 is shown below.

[0111]

[0112] Comparative Example 5: A composition containing 137 mg (1.00 mmol, 1.0 eq.) of tyramine as a substrate and 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride as both components, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ When analyzed by F-NMR, no signal derived from N-(4-hydroxyphenethyl)trifluoromethanesulfonamide could be confirmed.

[0113] The reaction in Comparative Example 5 is shown below. The substrates used in Example 3 and Comparative Example 5 have similar structures. Comparison of Example 3 and Comparative Example 5 clearly demonstrates that, in the method for producing a trifluoromethanesulfonamide compound of the present disclosure, as shown in Comparative Example 5, the reaction does not proceed with a substrate that does not have an aniline amino group, whereas, as shown in Example 3, with a substrate that has an aniline amino group, the trifluoromethanesulfonylation reaction proceeds preferentially with respect to the aniline amino group.

[0114]

[0115] Example 5: A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol and 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine as substrates, and 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, as well as 5 mL of N,N-dimethylformamide as a reaction solvent, were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide at −76.1 ppm, and the quantitative yield was 63%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0116] Example 6: A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol and 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine as substrates, and 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, as well as 5 mL of 1,3-dimethyl-2-imidazolidinone as a reaction solvent, were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −76.1 ppm derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 62%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0117] Example 7: A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol and 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine as substrates, and 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, as well as 5 mL of N-methylpyrrolidone as a reaction solvent, were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −76.1 ppm derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 71%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0118] Example 8 A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol as substrates, 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, and 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride as substrates, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −76.1 ppm derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 80%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0119] The reaction in Example 8 is shown below.

[0120]

[0121] [Physical properties] N-(4-methoxyphenyl)trifluoromethanesulfonamide; １ H-NMR (400MHz, CDCl ３ ) δ: 7.22 (d, J=9.0Hz, 2H), 6.89 (d, J=9.1Hz, 2H), 6.14 (s, 1H), 3.81 (s, 3H). １９ F-NMR (376MHz, CDCl ３ ) δ: -76.1 (3F).

[0122] Example 9: A composition containing 132 mg (1.00 mmol, 1.0 eq.) of 5-aminoindole as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from N-(5-indolyl)trifluoromethanesulfonamide at −76.8 ppm, and the quantitative yield was 68%.

[0123] The reaction in Example 9 is shown below.

[0124]

[0125] Example 10: 162 mg (1.00 mmol, 1.0 eq.) of 4-aminophthalimide as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from N-(4-phthalimidyl)trifluoromethanesulfonamide at −76.9 ppm, and the quantitative yield was 79%.

[0126] The reaction in Example 10 is shown below.

[0127]

[0128] Example 11 A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol as substrates, 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, and 377 mg (1.50 mmol, 1.5 eq.) of pyridine p-toluenesulfonate as substrates, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −76.1 ppm derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 38%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0129] The reaction in Example 11 is shown below.

[0130]

[0131] Example 12 A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol as substrates, 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, and 215 mg (1.50 mmol, 1.5 eq.) of 3,5-lutidine hydrochloride as substrates, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −76.1 ppm derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 65%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0132] The reaction in Example 12 is shown below.

[0133]

[0134] Example 13 A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol as substrates, 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, and 215 mg (1.50 mmol, 1.5 eq.) of 2,6-lutidine hydrochloride as substrates, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal at −76.1 ppm derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide, and the quantitative yield was 60%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0135] The reaction in Example 13 is shown below.

[0136]

[0137] Example 14 A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol as substrates, 123 mg (1.00 mmol, 1.0 eq.) of p-anisidine, and 236 mg (1.50 mmol, 1.5 eq.) of 2,4,6-collidine hydrochloride as substrates, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at 60°C for 2 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９Analysis by F-NMR confirmed a signal derived from N-(4-methoxyphenyl)trifluoromethanesulfonamide at −76.1 ppm, and the quantitative yield was 43%, but no signal derived from 4-methoxyphenyltrifluoromethanesulfonate could be confirmed.

[0138] The reaction in Example 14 is shown below.

[0139]

[0140] Example 15: 130 mg (1.00 mmol, 1.0 eq.) of aniline hydrochloride as a substrate and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 200 mg (1.00 mmol, 1.0 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from N-phenyltrifluoromethanesulfonamide at −77.3 ppm, and the quantitative yield was 78%.

[0141] The reaction in Example 15 is shown below.

[0142]

[0143] Example 16: 174 mg (1.00 mmol, 1.0 eq.) of 2-(4-aminophenyl)ethanol hydrochloride as a substrate and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 200 mg (1.00 mmol, 1.0 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, １９ Analysis by F-NMR confirmed a signal derived from N-(4-(2-hydroxyethyl)phenyl)trifluoromethanesulfonamide at −77.5 ppm, and the quantitative yield was 43%.

[0144] The reaction in Example 16 is shown below.

[0145]

[0146] Comparative Example 6 A composition containing 124 mg (1.00 mmol, 1.0 eq.) of p-methoxyphenol as a substrate and 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and charged into a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR failed to confirm any signal derived from 4-methoxyphenyl trifluoromethanesulfonate.

[0147] The reaction in Comparative Example 6 is shown below.

[0148]

[0149] Example 17: A composition containing 111 mg (1.00 mmol, 1.0 eq.) of 4-fluoroaniline as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ F-NMR analysis confirmed signals at −77.0 ppm and −117.4 ppm derived from N-(4-fluorophenyl)trifluoromethanesulfonamide, and the quantitative yield was 88%.

[0150] The reaction in Example 17 is shown below.

[0151]

[0152] Example 18: A composition containing 151 mg (1.00 mmol, 1.0 eq.) of methyl 4-aminobenzoate as a substrate, 173 mg (1.50 mmol, 1.5 eq.) of pyridine hydrochloride, and 5 mL of N-methylpyrrolidone as a reaction solvent were collected and placed in a 30 mL recovery flask equipped with a stirrer, which served as a reactor. Subsequently, 300 mg (1.50 mmol, 1.5 eq.) of 1-trifluoromethanesulfonylimidazole was added to the reactor, and the mixture was stirred at room temperature (25°C) for 24 hours to obtain a reaction solution. Benzotrifluoride was added to the reaction solution as an internal standard, and １９ Analysis by F-NMR confirmed a signal derived from methyl 4-trifluoromethanesulfonamidobenzoate at −77.7 ppm, and the quantitative yield was 33%.

[0153] The reaction in Example 18 is shown below.

[0154]

[0155] The method for producing trifluoromethanesulfonamide compounds of the present disclosure can be used in the synthesis of pharmaceutical active ingredients or intermediates.

[0156] Although the present disclosure has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the disclosure.

Claims

1. A method for producing a trifluoromethanesulfonamide compound, which comprises reacting a trifluoromethanesulfonylating agent composition containing a compound represented by the following general formula (1): (In general formula (1), R １ is a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and R ２ is a hydrogen atom, a halogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, a nitro group, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms. X is a nitrogen atom or C(R ３ ), Y is a nitrogen atom or C(R ４ ), R ３ is a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms. R ４ is a hydrogen atom, an aliphatic hydrocarbon group having 1 to 6 carbon atoms, an aromatic hydrocarbon group having 6 to 14 carbon atoms, or an aromatic heterocyclic group having 3 to 14 carbon atoms. R ２ and R ３ may combine to form a ring, and R ２ and R ４ may combine to form a ring. n is an integer of 1 to 3. When there are a plurality of R ２ , R ２ may be the same or different from each other. When there are a plurality of R ３ , R ３ may be the same or different from each other.) General formula (2): (In general formula (2), Ar represents an aromatic ring group or a substituted aromatic ring group.) with an aromatic amino compound represented by the formula and / or its acid salt in the presence of a solvent under acidic conditions.

2. The method for producing a trifluoromethanesulfonamide compound according to claim 1, wherein the trifluoromethanesulfonylating agent composition contains the compound represented by the general formula (1) and a heterocyclic group-containing organic base and / or its acid salt.

3. In the general formula (1), X is C(R ３ ), and R １ , R ２ , and R ３ are each independently a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. The method for producing a trifluoromethanesulfonamide compound according to claim 1.

4. The method for producing a trifluoromethanesulfonamide compound according to claim 2, wherein the heterocyclic group-containing organic base is an organic base having a heterocyclic group having a nitrogen atom and 4 or more carbon atoms.

5. The method for producing a trifluoromethanesulfonamide compound according to claim 2, wherein the heterocyclic group-containing organic base is any one selected from the group consisting of pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, and 3,5,6-collidine.

6. The method for producing a trifluoromethanesulfonamide compound according to claim 1, wherein in the general formula (2), Ar represents an aromatic ring group, and the aromatic ring group is an aromatic hydrocarbon group.

7. The method for producing a trifluoromethanesulfonamide compound according to claim 1, wherein in the general formula (2), Ar represents a substituted aromatic ring group, and the substituent of the substituted aromatic ring group is a lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a β-D-glucopyranoside group, an amino group, a lower alkylamino group, or a hydroxyl group.

8. The method for producing a trifluoromethanesulfonamide compound according to claim 1, wherein the reaction is carried out at a reaction temperature of 150 °C or lower.

9. The method for producing a trifluoromethanesulfonamide compound according to claim 1, wherein the reaction solution after completion of the reaction is post-treated with water, an acidic aqueous solution, or an alkaline aqueous solution.

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