Triazinedione Compounds

Abstract

To provide a novel compound useful as a dehydration condensation agent.SOLUTION: The present invention relates to a novel triazinedione compound represented by formula (I): [where each symbol is as defined in the specifications] and a method for producing the same. The present invention also relates to the use of the compound as a dehydration condensation agent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel triazinedione compound. The present invention also relates to a dehydration condensation agent comprising the triazinedione compound for efficiently producing an ester or an amide from various carboxylic acids and an alcohol or an amine. [Background technology]

[0002] Carboxylic acid derivatives such as esters and amides are important compounds that form the basic skeletons of various organic compounds such as medicines, agricultural chemicals, and polymer compounds. Therefore, methods for producing carboxylic acid derivatives have been studied for a long time. Among them, carbodiimide-based condensing agents such as dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), which can produce amide compounds under mild reaction conditions, are most widely used industrially. However, carbodiimide-based condensing agents have many compounds that cause problems such as rashes, so they must be handled with care, and when used in a condensation reaction in a protic organic solvent, they have problems such as a decrease in reaction yield. In addition, Mukaiyama et al. reported a pyridinium oxide compound as a condensing agent for producing an ester compound under mild reaction conditions (Non-Patent Document 1). However, when producing the pyridinium oxide compound, methyl iodide, which has been identified as carcinogenic, must be used, which necessitates careful attention to the working environment.

[0003] Meanwhile, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (Non-Patent Documents 2 and 3), reported by Kaminski et al. and the present inventor at roughly the same time, has been attracting attention in recent years as a condensing agent for synthesizing amide compounds that does not cause rashes, etc. However, in the method for producing amide compounds by Kaminski et al., a carboxylic acid compound and a condensing agent were reacted in equimolar amounts to generate a reactive derivative as an intermediate, and then the reactive derivative was reacted with an amine compound to obtain an amide compound, so that the yield of the amide compound was unsatisfactory, fluctuating widely from 17 to 73%.

[0004] The present inventors have reported a method for esterifying and amidating carboxylic acids using a dimethoxytriazine-type quaternary ammonium salt such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (hereinafter sometimes abbreviated as "DMT-MM") as a dehydration condensation agent (Non-Patent Documents 4, 5, Patent Document 1). These are effective methods for producing esters and amides, but it has been found that in certain solvents, DMT-MM is decomposed by a demethylation reaction caused by nucleophilic attack by the counter anion, chloride ion, and converted to 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)morpholine (DMTM), which is inactive as a condensation agent (Non-Patent Documents 4, 5). The present inventors have also reported 1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-3,5-lutidinium chloride (hereinafter sometimes abbreviated as "DMT-3,5-LUT") as another dehydrating condensation agent for esterification of carboxylic acids, and it has been confirmed that in the esterification reaction using DMT-3,5-LUT, carboxylic acid anhydrides are also competitively produced (Non-Patent Document 6). In addition, Non-Patent Document 6 also describes 4-(N,N'-dimethylamino)-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyridinium chloride (hereinafter sometimes abbreviated as "DMT-DMAP") as a condensing agent similar to DMT-3,5-LUT. However, due to the high electron donating property of DMAP, the activity of DMT-DMAP as a condensing agent is significantly reduced compared to DMT-3,5-LUT, and it has been confirmed that the ester can be obtained only in low yield even after a long time has passed (24 hours).

[0005] On the other hand, the present inventors have conducted research and development into a condensing agent obtained by converting the above-mentioned triazine-type condensing agent, DMT-MM, into a more active tautomeric structure. As a result, the triazinedione-type condensing agent, which is considered to be the most active, was too active and decomposed, and could not be prepared. Therefore, the inventors have developed a triazinedione-type condensing agent, which is considered to be the second most active, and has the following formula:

[0006] [ka]

[0007] (wherein R represents methoxy, ethoxy, isopropoxy, or N,N-dimethylamino) is reported to be useful as a dehydration condensation agent in esterification and amidation reactions (Non-Patent Document 7, Patent Document 2). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2000 / 53544 [Patent Document 2] JP 2017-149690 A [Non-patent literature]

[0009] [Non-Patent Document 1] Mukaiyama, T. et al., Bull. Chem. Soc. Jpn., 1977, 50, 1863-1866. [Non-Patent Document 2] Kaminski, ZJ et al., J. Org. Chem., 1998, 63, 4248-4255. [Non-Patent Document 3] Kunishima, M. et al., Tetrahedron Lett., 1999, 40, 5327-5330. [Non-Patent Document 4] Kunishima, M. et al., Tetrahedron, 1999, 55, 13159-13170. [Non-Patent Document 5] Kunishima, M. et al., Chem. Eur. J., 2012, 18, 15856-15867. [Non-Patent Document 6] Yamada, K. et al., Org. Biomol. Chem., 2018, 16, 6569-6575. [Non-Patent Document 7] Yamada, K. et al., J. Org. Chem., 2019, 84, 15042-15051. Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a novel compound which has a different chemical structure from conventional triazine-type quaternary ammonium salts or triazinone-type quaternary ammonium salts, is highly active, and can suppress side reactions, and is useful as a dehydration condensation agent. [Means for solving the problem]

[0011] Under such circumstances, the present inventors have conducted intensive research and have found a novel compound useful as a dehydration condensation agent capable of improving the elimination ability in a dehydration condensation reaction and completely suppressing side reactions derived from counter anions by converting the triazine skeleton (i.e., triazine ring or triazinone ring) of a conventional triazine-type quaternary ammonium salt or triazinone-type quaternary ammonium salt into a triazinedione ring and using a highly electron-donating 4-(N,N-dialkylamino)pyridine derivative as an amine for forming a quaternary salt, thereby completing the present invention.

[0012] That is, the present invention is as follows. [1] Formula (I):

[0013] [ka]

[0014] [In the formula, Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 Represents an aryl group; Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6An alkyl group or an optionally substituted C 6-10 Represents an aryl group; R 1 and R 2 are each independently a hydrogen atom or C 1-4 R represents an alkyl group. 3 and R 4 are each independently 1-4 represents an alkyl group, or R 1 and R 3 , R 3 and R 4 , and / or R 2 and R 4 may each independently form, together with the carbon atom and / or nitrogen atom to which they are attached, an optionally substituted 5- to 8-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom; and X - indicates a counter anion that is non-nucleophilic or has a low nucleophilicity. (hereinafter, also referred to as "compound (I)" or "compound of the present invention". Hereinafter, the same abbreviations may be used for the compounds represented by formula (I') and formulas (II) to (IV).) [2]R 1 and R 2 are both hydrogen atoms, and R 3 and R 4 are both methyl or ethyl groups, or R 3 and R 4 are taken together with the nitrogen atom to which they are bonded to form a 5- or 6-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom, [3] Both R are hydrogen atoms; Two R's are each a hydrogen atom, C 1-4 Alkyl group or haloC 1-4 is an alkyl group, R 1 and R 2 are both hydrogen atoms, R 3 and R4 are both methyl or ethyl groups, or R 3 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl group; and X - is a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkylsulfonate ion, an optionally substituted arylsulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion; [4] R and R' are all hydrogen atoms; R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are both methyl or ethyl groups, and X - fluoride ion, chloride ion, bromide ion, iodide ion, C 1-4 Alkyl sulfonate ion, halo C 1-4 The compound according to the above [1], wherein the counter anion is selected from the group consisting of an alkylsulfonate ion, an optionally substituted phenylsulfonate ion, and a perchlorate ion. [5] A dehydration condensation agent comprising the compound according to any one of [1] to [4] above. [6] A method for dehydration condensation of a nucleophilic compound selected from the group consisting of alcohols, amines, anilines, and phenols with a carboxylic acid, comprising using the dehydration condensation agent according to the above item [5] and a base. [7] Formula (IV):

[0015] [ka]

[0016] [In the formula, Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 Represents an aryl group; Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 represents an aryl group; and Y represents a leaving group. In the presence of a divalent palladium catalyst, a compound represented by the formula (III):

[0017] [ka]

[0018] [Each symbol in the formula has the same meaning as defined above.] and converting the compound represented by the formula: The compound represented by formula (III) is reacted with a compound represented by formula (II):

[0019] [ka]

[0020] [In the formula, R 1 and R 2 are each independently a hydrogen atom or C 1-4 R represents an alkyl group. 3 and R 4 are each independently 1-4 represents an alkyl group, or R 1 and R 3 , R 3 and R 4 , and / or R 2 and R 4may each independently form, together with the carbon atom and / or nitrogen atom to which they are bonded, an optionally substituted 5- to 8-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom. With a compound represented by formula (I'):

[0021] [ka]

[0022] [In the formula, Y - represents a counter anion derived from a leaving group, and the other symbols are as defined above. to a compound represented by formula (I):

[0023] [ka]

[0024] [In the formula, X - represents a counter anion having no or low nucleophilicity, and the other symbols are as defined above. A method for producing a compound represented by the formula: [8] Y - But X - The manufacturing method according to the above [7], [9] The present invention relates to the production method according to the above [7], further comprising a step of a counter anion exchange reaction from the compound of the formula (I') to the compound of the formula (I). Effect of the Invention

[0025] According to the present invention, it is possible to provide a novel dehydration condensation agent having the most excellent condensation ability among dehydration condensation agents having a triazine skeleton that have been developed so far. Specifically, according to the present invention, it is possible to provide a compound useful as a practical dehydration condensation agent capable of producing a target carboxylic acid derivative (ester, amide, etc.) under mild conditions in a short time and in high yield in a condensation reaction between a nucleophilic compound selected from the group consisting of alcohols, amines, anilines, and phenols and a carboxylic acid, and a method for producing the same. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention will be described in detail below. (definition)

[0027] In this specification, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0028] In the present specification, the term "alkyl group" refers to a linear or branched alkyl group having one or more carbon atoms. When there is no particular limitation on the range of the carbon number, the alkyl group is preferably one of the following: 1-12 is an alkyl group, C 1-6 Alkyl groups are more preferred, C 1-4 Alkyl groups are particularly preferred.

[0029] In this specification, "C 1-6 Specific examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 1-4 Specific examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Among these, methyl or ethyl is particularly preferred.

[0030] As used herein, "HaloC 1-6 "Alkyl group" means C 1-6 It means a group in which one or more hydrogen atoms of an alkyl group are replaced with a halogen atom.1-6 Specific examples of the "alkyl group" include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl. 1-4 "Alkyl group" is preferred.

[0031] As used herein, "HaloC 1-4 "Alkyl group" means C 1-4 It means a group in which one or more hydrogen atoms of an alkyl group are replaced with a halogen atom. 1-4 Specific examples of the "alkyl group" include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, chloromethyl, bromomethyl, 2,2,2-trichloromethyl, etc. Among them, trifluoromethyl or 2,2,2-trifluoroethyl is preferable, and trifluoromethyl is more preferable.

[0032] In the present specification, the term "alkoxy group" refers to a linear or branched alkoxy group having one or more carbon atoms. When there is no particular limitation on the range of the carbon number, it is preferably C 1-12 is an alkoxy group, C 1-6 An alkoxy group is more preferred.

[0033] In this specification, "C 1-6The term "alkoxy group" refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy. Among these, C alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy are particularly preferred. 1-4 Alkoxy groups are preferred, more preferably methoxy or ethoxy.

[0034] As used herein, "HaloC 1-6 The "alkoxy group" refers to the C 1-6 "HaloC" means an alkoxy group in which one or more hydrogen atoms have been replaced with a halogen atom. 1-6 Specific examples of the "alkoxy group" include, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, trichloromethoxy, 2-chloroethoxy, bromomethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy. Among them, haloC 1-4 Alkoxy groups are preferred, more preferably trifluoromethoxy or 2,2,2-trifluoroethoxy.

[0035] In this specification, "C 3-8 The term "cycloalkyl group" means a cyclic alkyl group having 3 to 8 carbon atoms. 3-8 Specific examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 Cycloalkyl groups are preferred.

[0036] In this specification, "C 2-6The term "alkenyl group" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms, and examples thereof include ethenyl, 1-propenyl (allyl), 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. Among these, C 2-4 Alkenyl groups are preferred.

[0037] In this specification, "C 2-6 The term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. Of these, ethynyl is preferred.

[0038] In this specification, "C 6-10 The term "aryl group" refers to a monocyclic or bicyclic (fused) hydrocarbon group exhibiting aromaticity, and specific examples include phenyl, 1-naphthyl, and 2-naphthyl. Of these, phenyl is preferred.

[0039] In the present specification, the term "aralkyl group" refers to a group in which the "alkyl group" is substituted with the "aryl group", and preferably refers to a group in which the "C 1-4 "Alkyl group" to the above "C 6-10 "C" substituted with "aryl group" 7-14 aralkyl group".

[0040] "C 7-14Specific examples of the "aralkyl group" include benzyl, 1-phenylethyl, 2-phenylethyl, (naphthyl-1-yl)methyl, (naphthyl-2-yl)methyl, 1-(naphthyl-1-yl)ethyl, 1-(naphthyl-2-yl)ethyl, 2-(naphthyl-1-yl)ethyl, 2-(naphthyl-2-yl)ethyl, and the like, and among these, benzyl is preferred.

[0041] In the present specification, the term "aralkyloxy group" refers to a group in which the above-mentioned "aralkyl group" is bonded to an oxygen atom. Examples of the "aralkyloxy group" include C aryloxy groups such as benzyloxy, 1-naphthylmethyloxy, and 2-naphthylmethyloxy. 7-14 Examples thereof include aralkyloxy groups, and among these, a benzyloxy group is preferable.

[0042] In the present specification, the term "acyl group" refers to an alkanoyl or aroyl group, and the carbon number range is not particularly limited, but preferably is 1-7 Alkanoyl group or C 7-11 It is Aroil.

[0043] In this specification, "C 1-7 The term "alkanoyl group" refers to a linear or branched formyl or alkylcarbonyl group having 1 to 7 carbon atoms (i.e., C 1-6 alkyl-carbonyl), such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, and the like.

[0044] In this specification, "C 7-11 The term "aroyl group" refers to an arylcarbonyl group having 7 to 11 carbon atoms (i.e., C 6-10 aryl-carbonyl), such as benzoyl.

[0045] In the present specification, the term "haloacyl group" refers to a group in which one or more hydrogen atoms of the above-mentioned acyl group are substituted with halogen atoms. Specific examples of the "haloacyl group" include trifluoroacetyl, trichloroacetyl, 4-chlorobenzoyl, etc.

[0046] In the present specification, the term "acyloxy group" refers to a group in which the above-mentioned alkanoyl group or aroyl group is bonded to an oxygen atom. The carbon number range is not particularly limited, but preferably, 1-7 Alkanoyloxy group or C 7-11 It is an aroyloxy group.

[0047] In this specification, "C 1-7 Examples of the "alkanoyloxy group" include formyloxy, acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy (pivaloyloxy), pentylcarbonyloxy, isopentylcarbonyloxy, neopentylcarbonyloxy, hexylcarbonyloxy and the like, and preferably acetoxy or pivaloyloxy.

[0048] In this specification, "C 7-11 Examples of the "aroyloxy group" include benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, and the like.

[0049] In the present specification, the term "haloacyloxy group" refers to the above-mentioned acyloxy group in which one or more hydrogen atoms have been substituted with halogen atoms. Specific examples of the "haloacyloxy group" include trifluoroacetoxy, trichloroacetoxy, 4-chlorobenzoyloxy, etc.

[0050] In this specification, "R 1 and R 3 , R 3 and R 4 , and R 2 and R 4are each independently formed together with the carbon atom and / or nitrogen atom to which they are bonded to form an "optionally substituted 5- to 8-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom", but is not particularly limited thereto, and examples thereof include compounds having the following formula, in which the 5- to 8-membered ring may be further substituted:

[0051] [ka]

[0052] [Each symbol in the formula has the same meaning as defined above.] and compound (I) prepared from compound (II).

[0053] In the present specification, the term "leaving group" is not particularly limited as long as it is one that is eliminated during a reaction. Suitable examples of the "leaving group" include, for example, a halogen atom, an optionally substituted alkylsulfonyloxy group, an optionally substituted arylsulfonyloxy group, and the like.

[0054] In the present specification, the "alkylsulfonyloxy group" in the "optionally substituted alkylsulfonyloxy group" means a group in which the above-mentioned "alkyl group" is bonded to the sulfur atom of -S(O)2-O-, and examples thereof include C alkylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, neopentylsulfonyloxy, hexylsulfonyloxy, and other C alkylsulfonyloxy groups. 1-6 Alkyl sulfonyloxy groups are also included. 1-4 An alkylsulfonyloxy group is preferred. As the "optionally substituted alkylsulfonyloxy group", a methylsulfonyloxy group optionally substituted by a halogen atom (e.g., a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group) is particularly preferred.

[0055] In the present specification, the term "optionally substituted arylsulfonyloxy group" refers to a group in which an "aryl group" is bonded to the sulfur atom of -S(O)2-O-, and examples thereof include phenylsulfonyloxy, 1-naphthylsulfonyloxy, and 2-naphthylsulfonyloxy. Among these, the phenylsulfonyloxy group is preferred. As the "optionally substituted arylsulfonyloxy group", a phenylsulfonyloxy group optionally substituted with a methyl group (e.g., benzenesulfonyloxy group, p-toluenesulfonyloxy group, o-nitrobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, and 2,4-dinitrobenzenesulfonyloxy) is particularly preferred.

[0056] In the present specification, the term "alkylsulfonate ion" in the term "optionally substituted alkylsulfonate ion" refers to -SO3 - It means an anion in which an "alkyl group" is bonded to C, and examples thereof include methylsulfonate ion, ethylsulfonate ion, propylsulfonate ion, isopropylsulfonate ion, butylsulfonate ion, isobutylsulfonate ion, sec-butylsulfonate ion, tert-butylsulfonate ion, pentylsulfonate ion, isopentylsulfonate ion, neopentylsulfonate ion, and hexylsulfonate ion. 1-4 Alkyl sulfonate ion (e.g., methanesulfonate ion), or haloC 1-4 Alkyl sulfonate ions (eg, trifluoromethanesulfonate ion) are preferred.

[0057] In the present specification, the term "arylsulfonate ion" in the term "optionally substituted arylsulfonate ion" refers to -SO3 - An anion having an "aryl group" bonded to the aryl group, such as phenylsulfonate ion, 1-naphthylsulfonate ion, 2-naphthylsulfonate ion, etc. 6-10Examples of the arylsulfonate ion include arylsulfonate ions. Among them, phenylsulfonate ions are preferred. As the "arylsulfonate ion" in the "arylsulfonate ion which may be substituted", phenylsulfonate ions which may be substituted with a methyl group (e.g., benzenesulfonate ion, p-toluenesulfonate ion, o-nitrobenzenesulfonate ion, p-nitrobenzenesulfonate ion, 2,4-dinitrobenzenesulfonate ion) are particularly preferred.

[0058] In the present specification, the term "tri-substituted silyl group" refers to a silyl group having three identical or different substituents (e.g., C 1-6 Alkyl group, C 6-10 aryl group, and examples of the group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, and a triphenylsilyl group.

[0059] In the present specification, the term "optionally substituted" means that, unless otherwise specified, one or more substituents may be present. The "substituents" include, for example, (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) a C 1-6 Alkyl group, (5) haloC 1-6 Alkyl group, (6) C 1-6 Alkoxy group, (7) haloC 1-6 Alkoxy group, (8) C 1-6 Alkoxy-C 1-6 Alkoxy group, (9) C 3-8 Cycloalkyl groups, (10)C 7-14 Aralkyl group, (11)C 7-14 Aralkyloxy group, (12)C 2-6 Alkenyl group, (13)C 2-6 Alkynyl group, (14)C 1-6 (15) an alkylenedioxy group, (16) an acyl group, (17) an acyloxy group, (18) a haloacyloxy group, (19) a C 1-6Examples of the substituents include an alkoxy-carbonyl group, (20) a tri-substituted silyl group, etc. Among these, preferred are a halogen atom, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxy, methylenedioxy, acetyl, trifluoroacetyl, acetoxy, trifluoroacetoxy, benzyl, benzyloxy, etc. In addition, when a plurality of substituents are present, the respective substituents may be the same or different.

[0060] The above-mentioned substituent may be further substituted with the above-mentioned substituent. The number of the substituents is not particularly limited as long as it is a substitutable number, but is preferably 1 to 5, more preferably 1 to 3. When a plurality of substituents are present, each of the substituents may be the same or different.

[0061] (Compounds of the Invention) The compound of the present invention (compound (I)) has the following formula (I):

[0062] [ka]

[0063] [In the formula, Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 Represents an aryl group; Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 Represents an aryl group; R 1 and R 2 are each independently a hydrogen atom or C 1-4 R represents an alkyl group. 3 and R 4 are each independently 1-4 represents an alkyl group, or R 1 and R 3, R 3 and R 4 , and / or R 2 and R 4 may each independently form, together with the carbon atom and / or nitrogen atom to which they are attached, an optionally substituted 5- to 8-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom; and X - indicates a counter anion that is non-nucleophilic or has a low nucleophilicity. It is a triazinedione compound represented by the formula:

[0064] Each group in compound (I) will be explained below.

[0065] Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 This represents an aryl group (e.g., a phenyl group).

[0066] Preferably, both of R are hydrogen atoms.

[0067] Each of the two R's is independently a hydrogen atom or C 1-6 Alkyl group, haloC 1-6 An alkyl group or an optionally substituted C 6-10 This represents an aryl group (e.g., a phenyl group).

[0068] Preferably, both R' are hydrogen atoms, C 1-4 Alkyl group or haloC 1-4 They are preferably both an alkyl group and more preferably both are hydrogen atoms.

[0069] R 1 and R 2 are each independently a hydrogen atom or C 1-4 Indicates an alkyl group.

[0070] R 1 and R 2 are preferably both hydrogen atoms.

[0071] R 3 and R 4 are each independently 1-4 Indicates an alkyl group.

[0072] R 3 and R 4 are preferably both a methyl group or an ethyl group, and more preferably both are a methyl group.

[0073] R 1 , R 2 , R 3 and R 4 As another embodiment of the present invention, R 1 and R 3 , R 3 and R 4 , and / or R 2 and R 4 may each independently form, together with the carbon atom and / or nitrogen atom to which they are bonded, an optionally substituted 5- to 8-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom.

[0074] R 3 and R 4 preferably form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring which may further contain a heteroatom selected from oxygen and sulfur atoms, in which case R 1 and R 2 are preferably both hydrogen atoms.

[0075] R 3 and R 4 more preferably, together with the nitrogen atom to which they are attached, form a pyrrolidinyl or piperidyl group, in which case R 1 and R 2 More preferably, both are hydrogen atoms.

[0076] R 1 and R 3 , and / or R 2 and R 4preferably each independently form, together with the carbon atom and the nitrogen atom to which they are attached, an optionally substituted 5- or 6-membered partially unsaturated nitrogen-containing heterocycle, not forming a ring; R 1 and R 3 , or R 2 and R 4 When R is present, it is not forming a ring. 1 or R 2 is preferably a hydrogen atom, and R 3 and R 4 and are preferably both a methyl group or an ethyl group.

[0077] R 1 and R 3 , and R 2 and R 4 more preferably, together with the carbon atom and nitrogen atom to which they are attached, form an optionally substituted 6-membered partially unsaturated nitrogen-containing heterocycle.

[0078] X - indicates a non-nucleophilic or less nucleophilic counteranion.

[0079] X - is preferably a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkylsulfonate ion, an optionally substituted arylsulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion.

[0080] X - is more preferably C optionally substituted with a fluoride ion, a chloride ion, a bromide ion, an iodide ion, or a halogen atom. 1-4 The counter anion is selected from the group consisting of an alkylsulfonate ion, an optionally substituted phenylsulfonate ion, and a perchlorate ion.

[0081] X - is more preferably a counter anion selected from the group consisting of a chloride ion, a trifluoromethanesulfonate ion, a methanesulfonate ion, a benzenesulfonate ion, a p-toluenesulfonate ion, an o-nitrobenzenesulfonate ion, a p-nitrobenzenesulfonate ion, a 2,4-dinitrobenzenesulfonate ion, and a perchlorate ion.

[0082] As compound (I), the following compounds are preferred:

[0083] [Compound (IA)] Two R's are both hydrogen atoms, Two R's are each a hydrogen atom, C 1-4 Alkyl group or haloC 1-4 is an alkyl group, R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are both methyl or ethyl groups, and X - is a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkylsulfonate ion, an optionally substituted arylsulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion.

[0084] [Compound (IB)] Two R's are both hydrogen atoms, Two R's are each a hydrogen atom, C 1-4 Alkyl group or haloC 1-4 is an alkyl group, R 1 and R 2 are both hydrogen atoms, R3 and R 4 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which may further contain heteroatoms selected from oxygen and sulfur atoms; and X - is a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkylsulfonate ion, an optionally substituted arylsulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion.

[0085] [Compound (IC)] Two R's are both hydrogen atoms, Two R's are both hydrogen atoms, R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are both methyl or ethyl groups, and X - may be substituted with a fluoride ion, a chloride ion, a bromide ion, an iodide ion, or a halogen atom. 1-4 Compound (I), wherein the counter anion is selected from the group consisting of an alkylsulfonate ion, an optionally substituted phenylsulfonate ion, and a perchlorate ion.

[0086] [Compound (ID)] Two R's are both hydrogen atoms, Two R's are both hydrogen atoms, R 1 and R 2 are both hydrogen atoms, R 3 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl group; and X -may be substituted with a fluoride ion, a chloride ion, a bromide ion, an iodide ion, or a halogen atom. 1-4 Compound (I), wherein the counter anion is selected from the group consisting of an alkylsulfonate ion, an optionally substituted phenylsulfonate ion, and a perchlorate ion.

[0087] [Compound (IE)] Two R's are both hydrogen atoms, Two R's are both hydrogen atoms, R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are both methyl groups, and X - is a counter anion (preferably a chloride ion) selected from the group consisting of a chloride ion, a trifluoromethanesulfonate ion, a methanesulfonate ion, a benzenesulfonate ion, a p-toluenesulfonate ion, an o-nitrobenzenesulfonate ion, a p-nitrobenzenesulfonate ion, a 2,4-dinitrobenzenesulfonate ion, and a perchlorate ion.

[0088] [Compound (IF)] Two R's are both hydrogen atoms, Two R's are each a hydrogen atom, C 1-4 Alkyl group or haloC 1-4 is an alkyl group, R 1 and R 3 , and / or R 2 and R 4 each independently forms, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 5- or 6-membered partially unsaturated nitrogen-containing heterocycle (provided that R 1 and R 3 , or R 2 and R 4 When R is present, it is not forming a ring. 1 or R 2is a hydrogen atom and does not form a ring. 3 and R 4 are both methyl or ethyl groups, and X - is a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkylsulfonate ion, an optionally substituted arylsulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion.

[0089] [Compound (IG)] Two R's are both hydrogen atoms, Two R's are both hydrogen atoms, R 1 and R 3 , and R 2 and R 4 together with the carbon atom and nitrogen atom to which they are attached form an optionally substituted 6-membered partially unsaturated nitrogen-containing heterocycle; and X - may be substituted with a fluoride ion, a chloride ion, a bromide ion, an iodide ion, or a halogen atom. 1-4 Compound (I), wherein the counter anion is selected from the group consisting of an alkylsulfonate ion, an optionally substituted phenylsulfonate ion, and a perchlorate ion.

[0090] As compound (II) used in the production of compound (I), the following compounds are suitable.

[0091] [Compound (II-A)] R 1 and R 2 are both hydrogen atoms, R 3 and R 4 and are both a methyl group or an ethyl group (preferably a methyl group).

[0092] [Compound (II-B)] R 1 and R 2 are both hydrogen atoms, R 3 and R 4 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring which may further contain a heteroatom selected from oxygen and sulfur atoms.

[0093] [Compound (II-C)] R 1 and R 2 are both hydrogen atoms, R 3 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidinyl group or a piperidyl group.

[0094] [Compound (II-D)] R 1 and R 3 , and / or R 2 and R 4 each independently forms, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 5- or 6-membered partially unsaturated nitrogen-containing heterocycle (provided that R 1 and R 3 , or R 2 and R 4 When R is present, it is not forming a ring. 1 or R 2 is a hydrogen atom and does not form a ring. 3 and R 4 are both methyl or ethyl groups), compound (II).

[0095] [Compound (II-E)] R 1 and R 3 , and R 2 and R 4 together with the carbon atom and nitrogen atom to which they are attached form an optionally substituted 6-membered partially unsaturated nitrogen-containing heterocycle.

[0096] Specific examples of suitable compounds (II) include, for example, N,N-dimethyl-4-aminopyridine (DMAP), N,N-diethyl-4-aminopyridine, and The formula:

[0097] [ka]

[0098] [Each symbol in the formula has the same meaning as defined above.] and the like.

[0099] As compound (III) used in the production of compound (I), the following compounds are suitable.

[0100] [Compound (III-A)] Two R's are both hydrogen atoms, Two R's are each a hydrogen atom, C 1-4 Alkyl group or haloC 1-4 is an alkyl group, and Compound (III), wherein Y is a leaving group selected from the group consisting of a halogen atom, an optionally substituted alkylsulfonyloxy group, and an optionally substituted arylsulfonyloxy group.

[0101] [Compound (III-B)] Two R's are both hydrogen atoms, Two R's are both hydrogen atoms, and Y is a halogen atom or a C optionally substituted with a halogen atom. 1-4 Compound (III), wherein the leaving group is selected from the group consisting of an alkylsulfonyloxy group and an optionally substituted phenylsulfonyloxy group.

[0102] When compound (I), compound (II) or compound (III) has isomers such as optical isomers, stereoisomers, positional isomers, etc., either one of the isomers or a mixture thereof is included in compound (I), compound (II) or compound (III). For example, when compound (I), compound (II) or compound (III) has optical isomers, the optical isomers resolved from the racemate are also included in compound (I), compound (II) or compound (III). These isomers can be obtained as single products by known synthesis and separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization).

[0103] Compound (I), compound (II) or compound (III) may be a solvate or a non-solvate.

[0104] Compound (I), compound (II) or compound (III) may also be isotoped (e.g., 3 H, 14 C, etc.) may be used. Furthermore, compound (I), compound (II) or compound (III) may be a deuterium-converted form.

[0105] (Method for producing compound (I)) The method for producing compound (I) is not particularly limited, but for example, compound (I) can be synthesized via the following reactions.

[0106] Unless otherwise specified, the starting compounds are readily available as commercial products or can be produced according to known methods or methods equivalent thereto.

[0107] The compounds obtained in each step in the following reaction schemes can be used in the next reaction either as the reaction solution or as a crude product. Alternatively, the compounds can be isolated from the reaction mixture in a conventional manner and easily purified by conventional separation means such as recrystallization, distillation, and chromatography. (Manufacturing method)

[0108] [ka]

[0109] [Each symbol in the formula has the same meaning as defined above.]

[0110] (Process 1) This step is a step of producing compound (IV) by reacting compound (VI) with compound (V). The reaction can be carried out according to a method known per se (e.g., Recl. Trav. Chim. Pays-Bas. 2010, 79, 83-89; Eur. J. Org. Chem. 2019, 4436-4446) or a method similar thereto. Specifically, for example, the reaction is carried out by using cyanuric chloride, in which Y is a chlorine atom, as compound (VI) and mixing it with compound (V) in a solvent that does not affect the reaction in the presence of a base. Moreover, as compound (VI), compounds other than cyanuric chloride can also be prepared from cyanuric acid and used in the same manner.

[0111] The amount of compound (V) used is usually 2 to 5 moles, preferably 2.5 to 3.5 moles, per mole of compound (VI). Suitable examples of compound (V) include compounds that correspond to the definitions of R and R' in the above-mentioned compounds (III-A) and (III-B).

[0112] The base to be used is not particularly limited, and examples thereof include organic bases such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 2,6-lutidine, and 2,6-di-tert-butylpyridine; and inorganic bases such as sodium hydride. Among these, N,N-diisopropylethylamine is preferred. The amount of the base used is usually 2 to 5 mol, preferably 2.5 to 3.5 mol, per mol of compound (VI).

[0113] Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as 1,4-dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hydrocarbons such as hexane, benzene, and toluene; nitriles such as acetonitrile; and mixed solvents thereof. Among these, dichloromethane, chloroform, and THF are preferred, and dichloromethane is particularly preferred.

[0114] The reaction temperature is usually from -40°C to 80°C, preferably from -20°C to room temperature. The reaction time is usually 0.5 to 48 hours.

[0115] (Process 2) This step is a step of producing compound (III) by heating compound (IV) under reflux in the presence of a divalent palladium catalyst, in a solvent that does not influence the reaction, and optionally in the presence of a base.

[0116] Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; and ethers such as 1,4-dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme, with chloroform or THF being preferred.

[0117] Examples of the divalent palladium catalyst include bis(benzonitrile)palladium(II) dichloride, palladium(II) chloride, palladium(II) acetate, and the like. Among these, bis(benzonitrile)palladium(II) dichloride is preferred. The amount of the divalent palladium catalyst used is usually 0.001 to 0.2 mol, and preferably 0.01 to 0.01 mol, per 1 mol of compound (IV).

[0118] When a base is used, examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium carbonate, and cesium carbonate, and organic bases such as triethylamine, N,N-diisopropylethylamine, 2,6-lutidine, and collidine, and among these, sodium hydrogen carbonate or potassium carbonate is preferred. The amount of the base used is usually 0.001 to 0.2 mol, preferably 0.01 to 0.01 mol, per 1 mol of compound (IV).

[0119] The reaction temperature is not particularly limited as long as it is the reflux temperature of the solvent used, but is usually 50°C to 100°C, preferably 60°C to 80°C. The reaction time is usually 0.5 to 24 hours.

[0120] (Step 3) This step is a step of producing compound (I') by reacting compound (III) obtained in step 2 with compound (II) in a solvent that does not influence the reaction.

[0121] The amount of compound (II) used is usually 1 to 2 moles, preferably 1 to 1.5 moles, per mole of compound (III). Suitable examples of compound (II) include the compounds corresponding to the above-mentioned compounds (II-A) to (II-E).

[0122] Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; ethers such as 1,4-dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hydrocarbons such as hexane, benzene, and toluene; nitriles such as acetonitrile; and mixed solvents thereof. Among these, THF is preferred.

[0123] The reaction temperature is usually 0° C. to 80° C., preferably room temperature. The reaction time is usually 0.5 to 24 hours.

[0124] (Step 4) In this step, the compound (I') obtained in the step 3 is mixed with MX in a solvent that does not affect the reaction to form a counter anion Y - to other counter anion X - to synthesize compound (I). This step can be omitted when Y and X are the same group.

[0125] M in the reactant represented by MX represents a metal atom or a quaternary ammonium group, and specific examples thereof include alkali metals such as lithium, potassium, sodium, and cesium; alkaline earth metals such as magnesium and calcium; noble metals such as gold and silver; heavy metals such as thallium; and a tetramethylammonium group. Among these, lithium, sodium, or silver is preferable.

[0126] X in the reactant represented by MX is Y in compound (I'). - Among the groups corresponding to the above, those which have no nucleophilicity or have low nucleophilicity other than groups which can be Y, such as halogen atoms (e.g., chlorine atoms), optionally substituted alkylsulfonyloxy groups, and optionally substituted arylsulfonyloxy groups, are mentioned. Specific examples thereof include perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate, arsenate, and the like.

[0127] The amount of MX used is usually 1 to 10 mol, preferably 1 to 3 mol, per mol of compound (I').

[0128] Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and trichloroethylene; nitriles such as acetonitrile; ethers such as 1,4-dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; hydrocarbons such as hexane, benzene, and toluene; alcohols such as methanol and ethanol; esters such as ethyl acetate; ureas such as 1,3-dimethyl-2-imidazolidinone; water; and mixed solvents thereof (e.g., mixed organic solvents, two-layer systems of water and organic solvent, etc.). Among these, dichloromethane or acetonitrile is particularly preferred.

[0129] The reaction temperature is usually from -30 to 100°C, preferably from 0 to 40°C. The reaction time is usually 0.1 to 30 hours.

[0130] (Method for producing an amide compound or an ester compound using the compound (I) of the present invention as a dehydration condensation agent) The compound (I) of the present invention can be suitably used as a dehydration condensation agent in producing an ester compound or an amide compound from a compound having a carboxy group (hereinafter, also referred to as a carboxylic acid compound) and a nucleophilic compound selected from the group consisting of an alcohol, an amine, an aniline, and a phenol.

[0131] In the method for producing an ester compound or an amide compound using compound (I) of the present invention as a condensing agent, the type and amount of compound (I) to be used are not particularly limited, but are suitably usually 0.9 to 1.5 mol, preferably 1.1 to 1.2 mol, per mol of carboxylic acid.

[0132] The carboxylic acid compound used in the method for producing an ester compound or an amide compound can be any compound having a carboxy group without any limitation.

[0133] (Method of Producing Amide Compound) The amine compound used in the method for producing an amide compound can be any compound having a primary amino group or a secondary amino group without any limitation.

[0134] The dehydration condensation reaction (amidation reaction) in the method for producing an amide compound is suitably carried out in a solvent that does not affect the reaction.

[0135] As the solvent, any solvent that does not affect the reaction can be used without any restrictions. Specific examples of the solvent include ethers such as tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, and tert-butyl methyl ether; esters such as ethyl acetate, propyl acetate, and butyl acetate; nitriles such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated aromatic hydrocarbons such as chlorobenzene; and amides such as dimethylformamide and dimethylacetamide. Among these, THF, ethyl acetate, acetonitrile, dichloromethane, chloroform, and the like are preferably used because they are expected to produce a high reaction yield. These solvents may be used alone or in combination of two or more solvents.

[0136] The reaction temperature is usually room temperature.

[0137] The reaction time varies slightly depending on the types of the carboxylic acid compound and the amine compound used, but is usually 5 minutes to 3 hours, preferably 10 minutes.

[0138] The procedure for the amidation reaction using compound (I) as a condensing agent (e.g., the order of adding the reaction substrate and compound (I)) is not particularly limited, but it is preferable to mix three types of reaction reagents (i.e., compound (I), a carboxylic acid compound, and an amine compound) in a solvent and react them. The method for mixing the above three types of reaction reagents is not particularly limited, and each reaction reagent may be added to the reaction system and mixed simultaneously, or each reaction reagent may be added to the reaction system and mixed sequentially. However, from the viewpoints of operability and reaction yield, it is particularly preferable to add and mix each reaction reagent sequentially and without time intervals in the reaction solvent at room temperature.

[0139] The amide compound obtained by the above amidation reaction can be isolated from the reaction mixture in a conventional manner, and can be easily purified by a conventional separation means such as recrystallization, distillation, or chromatography.

[0140] (Production method of ester compound) The alcohol compound used in the method for producing an ester compound can be any primary alcohol, secondary alcohol, or phenol without any limitation.

[0141] The dehydration condensation reaction (esterification reaction) in the method for producing an ester compound is suitably carried out in the presence of a base in a solvent that does not affect the reaction.

[0142] As the solvent, the same solvent as that used in the amidation reaction can be used.

[0143] The reaction temperature in the esterification reaction is usually room temperature.

[0144] The base used in the esterification reaction is not particularly limited, but is preferably N-methylmorpholine (NMM), triethylamine or N,N-diisopropylethylamine, and more preferably NMM or N,N-diisopropylethylamine. The amount of the base used is not particularly limited, but is usually 1 to 1.5 mol, preferably 1.2 mol, per 1 mol of the carboxylic acid compound.

[0145] The reaction time varies slightly depending on the type of carboxylic acid compound, base, and / or solvent used, but is usually 5 minutes to 3 hours, preferably 10 minutes.

[0146] Compound (I) of the present invention has extremely high activity as a dehydration condensation agent, and therefore has the advantage that, as shown in the experimental examples described below, the reaction which requires a long time, has a low yield, or shows side reactions when a conventionally known dehydration condensation agent having a similar triazine skeleton (DMT-MM, DMT-DMAP, DMT-3,5-LUT) is used, can be completed in good yield within 10 minutes under mild reaction conditions (room temperature). EXAMPLES

[0147] The present invention will be explained in more detail below by way of examples and experimental examples. However, the present invention is not limited to these examples and may be modified without departing from the scope of the present invention. Reactions were monitored by thin layer chromatography using Merck 60 F254 silica gel plates (0.25 mm thickness). 1 H and 13 C-NMR spectra were measured using a JEOL ECS400 in deuterated chloroform as a solvent. 1 Data for H-NMR are reported as chemical shifts (δ ppm), multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, brs = broad singlet, sep = septet), coupling constants (Hz), integrals and assignments. High-resolution mass spectral analysis (HRMS) was performed using a JEOL JMS-T100TD (DART). The melting point (mp) was measured using a Yanagimoto micro melting point apparatus. Elemental analyses were performed using a Yanaco CHN Corder MT-5. Preparative thin-layer chromatography was performed using Merck 60 F254 silica gel plates (0.5 mm thick). Flash chromatography was performed using silica gel 60N from Kanto Chemical Co., Ltd. (Tokyo, Japan). In this specification, "room temperature" generally refers to about 10° C. to about 30° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified.

[0148] In the following examples, 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) (a compound in which Y in formula (VI) is a chlorine atom), which is a raw material compound used in the synthesis of compound (I), compound (I'), compound (III), or compound (IV), was used as is as a commercially available product (manufactured by Tokyo Chemical Industry Co., Ltd.). Other raw material compounds may be used as is as commercially available products, or may be produced according to a method known per se (e.g., Recl. Trav. Chim. Pays-Bas. 2010, 79, 83-89; Eur. J. Org. Chem. 2019, 4436-4446; J. Org. Chem. 2019, 84, 15042-45054; Angew. Chem. Int. Ed. 2004, 43, 5436-5441) or a method similar thereto. Chloroform and ethyl acetate were distilled from reagent grade. Dichloromethane, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran (THF) were purchased as anhydrous solvent grade and used as is. Other reagents were purified as necessary before use.

[0149] Example 1 Synthesis of 1-(1,5-diallyl-4,6-dioxo-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)-4-(N,N-dimethylamino)pyridin-1-ium chloride (compound (I-1))

[0150] [ka]

[0151] In a 200 mL two-necked eggplant flask, 2,4-diallyloxy-6-chloro-1,3,5-triazine (compound (IV-1)) (1.0 g, 4.39 mmol) synthesized according to a method described in a publicly known method (Eur. J. Org. Chem. 2019, 4436-4446) and THF (6 mL) were added. Bis(benzonitrile)palladium(II) dichloride (7.1 mg, 18.3 μmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was heated to reflux for 4 hours and then allowed to cool to room temperature. A solution of N,N-dimethyl-4-aminopyridine (DMAP) (446.9 mg, 3.66 mmol) in THF (6 mL) was added to the reaction solution without isolating or purifying the product (1,3-diallyl-6-chloro-1,3,5-triazine-2,4(1H,3H)-dione (compound (III-1)). The reaction mixture was stirred at room temperature for 2 hours, and the precipitate was filtered by centrifugation and washed with THF to obtain compound (I-1) (1.19 g, yield 93%) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 8.82-8.80 (d, J=7.8 Hz, 2H), 7.27-7.25 (d, J=7.8 Hz, 2H), 5.95-5.80 (m, 2H), 5.44-5.39 (d, J=17.0 Hz, 1H), 5.28-5.21 (d, J=17.9 Hz, 1H), 5.26-5.21 (d, J=17.9 Hz, 1H), 5.15-5.11 (d, J=17.0 Hz, 1H), 4.71-4.70 (d, J=5.0 Hz, 2H), 4.54-4.52 (d, J=5.0 Hz, 2H), 3.46 (s, 6H); 13 C NMR (100 MHz, CDCl3): δ 157.50, 154.88, 152.86, 149.94, 140.31, 130.51, 130.11, 119.64, 118.75, 108.17, 49.88, 45.32, 41.50; HRMS (ESI + ) Calcd for C 16 H20 N5O2 + ([M] + ): 314.1617; found: 314.1631.

[0152] Experimental Example 1 Method for producing the ester compound of the present invention using compound (I-1) as a dehydration condensation agent (esterification reaction)

[0153] [ka]

[0154] (Experimental Procedure Example) Dichloromethane (solvent) (2 mL), 3-phenylpropionic acid (60 mg, 0.40 mmol), 2-phenethyl alcohol (58 μL, 0.48 mmol) and N-methylmorpholine (NMM) (53 μL, 0.48 mmol) were added to a 10 mL eggplant flask. Compound (I-1) (167.9 mg, 0.48 mmol) was added to the solution and stirred at room temperature for 10 minutes. The reaction mixture was washed successively with 1 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain phenethyl 3-phenylpropionate (101.6 mg, yield 98%). 1 H NMR (400 MHz, CDCl3): δ 7.35-7.10 (m, 10H), 4.28 (t, J = 6.9 Hz, 2H), 2.95-2.87 (m, 4H), 2.61 (t, J = 7.8 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 172.9, 140.6, 137.9, 129.0, 128.6, 128.4, 126.7, 126.4, 65.1, 36.0, 35.2,31.0; HRMS (DART + ) Calcd for C 17 H 19O2([M+H] + ): 255.1385; found: 255.1379.

[0155] Experimental Example 2 Examination of optimization of dehydration condensation agent and reaction conditions in the esterification reaction of Experimental Example 1 In the esterification reaction of the above Experimental Example 1, the dehydration condensation agent, the base, and / or the solvent were changed, and the results are shown in Table 1.

[0156] [Table 1]

[0157] According to Table 1, in the esterification reaction using compound (I-1), the addition of a base is essential for completing the reaction, but it was found that the reaction was completed within 10 minutes regardless of the type of base or solvent, and the target ester compound was given in high yield. In contrast, when DMT-MM, DMT-DMAP, or DMT-3,5-LUT, which have a similar triazine structure, were used as the dehydration condensation agent instead of compound (I-1), it was found that a long time was required to complete the reaction and the yield of the ester was significantly reduced, as described in Non-Patent Document 6.

[0158] [ka]

[0159] Experimental Examples 3-9 According to the method of the above-mentioned Experimental Example 1, condensation reactions were carried out between various carboxylic acid compounds and alcohol compounds (primary alcohols, secondary alcohols or phenols) using compound (I-1). The results are shown in Table 2.

[0160] [Table 2]

[0161] According to Table 2, it was found that the esterification reaction using compound (I-1) was completed within 10 minutes and gave the desired ester compound in high yield, regardless of the type of carboxylic acid compound and alcohol compound used as the substrate. It was also confirmed that the esterification reaction proceeded in a similarly good yield when phenol was used as the alcohol compound.

[0162] The ester compounds obtained in Experimental Examples 3 to 9 are all described in Non-Patent Document 6 (Org. Biomol. Chem., 2018, 16, 6569-6575), and their instrumental analysis data are shown below.

[0163] Experimental Example 3: 1,3-diphenylpropan-2-yl 3-phenylpropionate 1 H NMR (400 MHz, CDCl3): δ 7.30-7.13 (m, 13H), 7.12-7.07 (m, 2H), 5.31 (quint, J = 6.4 Hz, 1H), 2.87-2.82 (m, 4H), 2.78 (t, J = 7.8 Hz, 2H), 2.49 (t, J = 7.8 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 172.3, 140.7, 137.6, 129.6, 128.6, 128.5, 128.4, 126.7, 126.3, 75.4, 40.1, 36.1, 31.0; HRMS (DART + ) Calcd for C 24 H 24 O2([M+H] + ): 345.1855; found: 345.1844.

[0164] Experimental Example 4: Phenethyl cyclohexane carboxylate 1H NMR (400 MHz, CDCl3): δ 7.33-7.27 (m, 2H), 7.26-7.19 (m, 3H), 4.28 (t, J = 6.9 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 2.23-2.31 (tt, J = 12.0,4.0 Hz, 1H), 1.98-1.58 (m, 5H) 1.47-1.30 (m, 2H) 1.32-1.1.13 (m, 2H); 13 C NMR (100 MHz, CDCl3): δ 176.2, 138.2, 129.1, 128.6, 126.6, 64.7, 43.3, 35.3, 29.1, 25.9, 25.6; HRMS (DART + ) Calcd for C 15 H 20 O2([M+H] + ): 233.1542; found: 233.1538.

[0165] Example 5: シクロヘキサンカボン acid 1,3-ジフェニルプロパン-2-イル 1 H NMR (400 MHz, CDCl3): δ 7.24-7.31 (m, 5H), 7.23-7.15 (m, 5H), 5.31 (quint, J = 6.4 Hz, 1H), 2.86 (d, J = 6.4 Hz, 4H), 2.11-2.18 (m, 1H), 1.58-1.71 (m, 5H), 1.13-1.30 (m, 5H); 13 C NMR (100 MHz, CDCl3): δ 175.6, 137.7, 129.6, 128.4, 126.6, 74.7, 43.5, 40.2, 29.0, 25.9, 25.5; HRMS (DART + ) Calcd for C 22 H 26 O2([M+H] + ): 323.2011; found: 323.2017.

[0166] Experimental Example 6: Phenyl 3-phenylpropionate 1 H NMR (400 MHz, CDCl3): δ 7.42 - 7.18 (m, 8H), 7.04 - 6.98 (m, 2H), 3.08 (t, J = 7.8 Hz, 2H), 2.89 (d, J = 7.8 Hz, 2H); 13 C NMR (100 MHz, CDCl3): δ 171.6, 150.8, 140.3, 129.5, 128.7, 128.6, 126.6, 126.0, 121.7, 36.1, 31.1; HRMS (DART + ) Calcd for C 15 H 15 O2([M+H] + ): 227.1072; found: 227.1078.

[0167] Experimental Example 7: Phenethyl benzoate 1 H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 7.8, 2H), 7.52 - 7.57 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.23 - 7.25 (m, 5H), 4.54 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 7.1, 2H); 13 C NMR (100 MHz, CDCl3): δ 166.6, 138.1, 133.1, 129.7, 129.1, 128.7, 128.5, 126.7, 65.6, 35.4; HRMS (DART + ) Calcd for C 15 H 14 O2([M+H] + ): 227.1072; found: 227.1065.

[0168] Example 8: Benzyl (tert-butoxycarbonyl)-L-alaninate 1 H NMR (400 MHz, CDCl3): δ 7.42-7.30 (m, 5H), 5.20 (d, J = 12.4 Hz, 2H), 5.14 (d, J = 12.4 Hz, 2H), 5.04 (brs, 1H), 4.37 (quint, J = 7.2 Hz, 1H), 1.44 (s, 9H), 1.39 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 173.4, 155.2, 135.6, 128.7, 128.5, 128.3, 80.0, 67.1, 49.4, 28.4, 18.8; HRMS (DART + ) Calcd for C 15 H 22 NO4([M+H] + ): 280.1549; found: 280.1545.

[0169] Example 9: Benzyl ((benzyloxy)carbonyl)-L-phenylalaninate 1 H NMR (400 MHz, CDCl3): δ 7.42-7.15 (m, 13H), 7.05-6.96 (m, 2H), 5.23 (d, J = 7.7 Hz, 1H), 5.16 (d, J = 11.9 Hz, 1H), 5.11 (d, J = 11.9 Hz, 1H), 5.15 (d, J = 12.8 Hz, 1H), 5.07 (d, J = 12.8 Hz, 1H), 4.71 (td, J = 5.96, 7.7 Hz, 1H), 3.15-3.06 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 171.5, 155.7, 136.3, 135.6, 135.2, 129.5, 128.75, 128.71, 128.66, 128.3, 128.2, 127.2, 67.4, 67.1, 54.9, 38.3; HRMS (DART + ) Calcd for C 24 H 24 NO4([M+H] + ): 390.1705; found: 390.1702.

[0170] Experimental Example 10 Method for producing the amide compound of the present invention using compound (I-1) as a dehydration condensation agent (amidation reaction)

[0171] [ka]

[0172] (Experimental Procedure Example) Dichloromethane (solvent) (2 mL), 3-phenylpropionic acid (60 mg, 0.40 mmol) and 2-phenethylamine (56 μL, 0.44 mmol) were added to a 10 mL eggplant flask. Compound (I-1) (153.9 mg, 0.44 mmol) was added to the solution and stirred at room temperature for 10 minutes. The reaction mixture was washed successively with 1 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline. The obtained organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain N-phenethyl-3-phenylpropanamide (94.5 mg, yield 93%). The instrumental analysis data of the obtained N-phenethyl-3-phenylpropanamide showed good agreement with the instrumental analysis data described in the literature (Tetrahedron, 1999, 55, 13159-13170).

[0173] Experimental Examples 11-22 According to the method of the above-mentioned Experimental Example 10, condensation reactions of various carboxylic acid compounds and amine compounds were carried out using the compound (I-1), and the results obtained are shown in Table 3. In addition, Table 3 also shows the results of a reaction carried out under the same conditions (in the absence of a base) using DMT-3,5-LUT (Comparative Example), which gave relatively good results in the esterification reaction of Experimental Example 1.

[0174] [Table 3]

[0175] According to Table 3, it was found that in the amidation reaction using compound (I-1), regardless of the type of carboxylic acid compound and amine compound, the reaction was completed in 10 minutes in all cases without the need for the addition of an additional base, and the desired amide compound was obtained in high yield. It was also confirmed that the amidation reaction proceeded in a similarly good yield even when aniline was used as the amine compound, although it took some time to complete the reaction. On the other hand, as shown in the comparative example, when DMT-3,5-LUT was used as the dehydration condensation agent, and no additional base (e.g., NMM) was added, the yield of the desired amide compound was significantly reduced, and 31% of the compound in which an amine compound was introduced into the triazine ring derived from the dehydration condensation agent was by-produced.

[0176] The amide compounds obtained in Experimental Examples 11 to 22 were all known compounds, and each showed good agreement with the instrumental analysis data described in the literature (Tetrahedron, 1999, 55, 13159-13170).

[0177] As shown in Tables 1 to 3, it has been confirmed that by using compound (I) of the present invention as a dehydration condensation agent in the condensation reaction of various carboxylic acid compounds with amine compounds or alcohol compounds, the corresponding amide compounds or ester compounds can be obtained in a short time (within 10 minutes) and in high yield under mild reaction conditions without causing side reactions, regardless of the types of reaction substrates, solvents, and / or bases. [Industrial Applicability]

[0178] According to the present invention, it is possible to provide a novel dehydration condensation agent having the most excellent condensation ability among dehydration condensation agents having a triazine skeleton that have been developed so far. Specifically, according to the present invention, it is possible to provide a compound useful as a practical dehydration condensation agent capable of producing a target carboxylic acid derivative (ester, amide, etc.) under mild conditions in a short time and in high yield in a condensation reaction between a nucleophilic compound selected from the group consisting of alcohols, amines, anilines, and phenols and a carboxylic acid, and a method for producing the same.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Two R's each represent a hydrogen atom; Two R's together represent a hydrogen atom, a C1-4 alkyl group, or a haloC1-4 alkyl group; R １ and R ２ Both represent a hydrogen atom; R ３ and R ４ are each independently １－４ represents an alkyl group, or R ３ and R4 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom; and X － represents a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a C 1-4 alkylsulfonate ion, a halo C 1-4 alkylsulfonate ion, a benzenesulfonate ion, a p-toluenesulfonate ion, an o-nitrobenzenesulfonate ion, a p-nitrobenzenesulfonate ion, a 2,4-dinitrobenzenesulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion.] A compound represented by the formula:

2. R ３ and R ４ The compound according to claim 1 , wherein both are methyl or ethyl groups.

3. R ３ and R ４ The compound of claim 1 , wherein together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl group.

4. R and R' are all hydrogen atoms; R １ and R ２ are both hydrogen atoms, R ３ and R ４ are both methyl or ethyl groups, and X － fluoride ion, chloride ion, bromide ion, iodide ion, C １－４ Alkyl sulfonate ion, halo C １－４ 2. The compound according to claim 1, wherein the counter anion is selected from the group consisting of an alkylsulfonate ion, a benzenesulfonate ion, a p-toluenesulfonate ion, an o-nitrobenzenesulfonate ion, a p-nitrobenzenesulfonate ion, a 2,4-dinitrobenzenesulfonate ion, and a perchlorate ion.

5. A dehydration condensation agent comprising the compound according to any one of claims 1 to 4.

6. A method for dehydration condensation of a nucleophilic compound selected from the group consisting of alcohols, amines, anilines, and phenols with a carboxylic acid, comprising using the dehydration condensation agent according to claim 5 and a base.

7. Formula (IV): 【Chemistry 2】 [In the formula, Two R's each represent a hydrogen atom; Two R's together represent a hydrogen atom, a C1-4 alkyl group, or a haloC1-4 alkyl group; and Y represents a leaving group selected from the group consisting of a halogen atom, a C 1-4 alkylsulfonyloxy group optionally substituted by a halogen atom, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, an o-nitrobenzenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, and a 2,4-dinitrobenzenesulfonyloxy group.] In the presence of a divalent palladium catalyst, a compound represented by the formula (III): 【Chemistry 3】 [Each symbol in the formula has the same meaning as defined above.] and converting the compound represented by the formula: The compound represented by formula (III) is reacted with a compound represented by formula (II): 【Chemistry 4】 [In the formula, R １ and R ２ Both represent a hydrogen atom; R ３ and R ４ are each independently １－４ represents an alkyl group, or R ３ and R4 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom. With a compound represented by formula (I'): 【Chemistry 5】 [In the formula, Y － represents a counter anion derived from the leaving group Y, and the other symbols are as defined above. to a compound represented by formula (I): 【Chemistry 6】 [In the formula, X － represents a counter anion selected from the group consisting of a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a C 1-4 alkylsulfonate ion, a halo C 1-4 alkylsulfonate ion, a benzenesulfonate ion, a p-toluenesulfonate ion, an o-nitrobenzenesulfonate ion, a p-nitrobenzenesulfonate ion, a 2,4-dinitrobenzenesulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion, and an arsenate ion, and the other symbols are as defined above.] A method for producing a compound represented by the formula:

8. Y － But, X － The method of claim 7, wherein the process is the same as

9. The method according to claim 7, further comprising a step of counter anion exchange reaction from the compound of formula (I') to the compound of formula (I).

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