JP2022015617A - Triazinedione compound - Google Patents

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

The present invention relates to novel triazinedione compounds. The present invention also relates to a dehydration condensing agent comprising the above triazinedione compound for efficiently producing an ester or amide from various carboxylic acids and alcohols or amines.

Carboxylic acid derivatives such as esters and amides are important compounds that form the basic skeleton of various organic compounds such as pharmaceuticals, pesticides and polymer compounds. Therefore, a method for producing a carboxylic acid derivative has 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 industrially available. It is also the most versatile. However, since many carbodiimide-based condensing agents cause problems such as rashes, care must be taken in handling them, and when used in a condensation reaction in a protonic organic solvent, the reaction yield decreases. Had the problem of.
Further, a pyridinium oxide compound was reported by Mukaiyama et al. As a condensing agent for producing an ester compound under mild reaction conditions (Non-Patent Document 1), but carcinogenicity is observed when the pyridinium oxide compound is produced. Since it is necessary to use methyl iodide, which has been pointed out, there are problems such as having to pay close attention to the working environment.

On the other hand, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) reported by Kaminsky et al. And the present inventor at about the same time as a condensing agent for synthesizing an amide compound that does not cause irritation or the like. ) -4-Methylmorpholinium chloride (Non-Patent Documents 2 and 3) has been attracting attention in recent years. However, in the method for producing an amide compound by Kaminsky et al., The carboxylic acid compound and the condensing agent are subjected to an equimolar reaction to once generate a reactive derivative as an intermediate, and then the reactive derivative and the amine compound are reacted. Since the amide compound was obtained by allowing the amide compound to be obtained, the yield of the amide compound varied widely from 17 to 73%, which was not satisfactory.

The present inventor has 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (hereinafter, may be abbreviated as "DMT-MM"). We have reported a method for esterifying and amidating a carboxylic acid using a dimethoxytriazine-type quaternary ammonium salt as a dehydration condensing agent (Non-Patent Documents 4 and 5, Patent Document 1). These are effective methods for producing esters and amides, but in certain solvents, DMT-MM is decomposed and condensed by the demethyl reaction of the counter anion chloride ion by the nucleophilic attack. It was found that it was converted to 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) morpholine (DMTM), which is inactive as an agent (Non-Patent Documents 4, 5). In addition, the present inventor, as another dehydration condensing agent for esterification of carboxylic acid, 1- (4,6-dimethoxy-1,3,5-triazine-2-yl) -3,5-lutidinium chloride. (Hereinafter, it may be abbreviated as "DMT-3,5-LUT".) However, in the esterification reaction using DMT-3,5-LUT, carboxylic acid anhydride is also competitively produced. It was confirmed that this was done (Non-Patent Document 6). In addition, Non-Patent Document 6 describes 4- (N, N'-dimethylamino) -1- (4,6-dimethoxy-1,3,5 as a condensing agent similar to DMT-3,5-LUT. -Triazine-2-yl) pyridinium chloride (hereinafter, also abbreviated as "DMT-DMAP") is also described, but the activity of DMT-DMAP as a condensing agent due to the influence of the high electron donating property of DMAP. Is significantly lower than that of DMT-3,5-LUT, and it has been confirmed that the ester can be obtained only in a low yield even after a long period of time (24 hours).

On the other hand, the present inventor conducted research and development on a condensing agent obtained by converting the above-mentioned triazine-type condensing agent DMT-MM into a more active tautomeric structure, and found that the triazine-dione type condensing agent is considered to have the highest activity. Since the condensing agent was too active to decompose and could not be prepared, the following formula, which is considered to be the next highest activity:

(In the formula, R indicates methoxy, ethoxy, isopropoxy or N, N-dimethylamino) that the triazineone-type condensing agent is useful as a dehydration condensing agent in esterification and amidation reactions. Reported (Non-Patent Document 7, Patent Document 2).

International Publication No. 2000/53544 Japanese Unexamined Patent Publication No. 2017-149690

Mukaiyama, T. et al., Bull. Chem. Soc. Jpn., 1977, 50, 1863-1866. Kaminski, Z. J. et al., J. Org. Chem., 1998, 63, 4248-4255. Kunishima, M. et al., Tetrahedron Lett., 1999, 40, 5327-5330. Kunishima, M. et al., Tetrahedron, 1999, 55, 13159-13170. Kunishima, M. et al., Chem. Eur. J., 2012, 18, 15856-15867. Yamada, K. et al., Org. Biomol. Chem., 2018, 16, 6569-6575. Yamada, K. et al., J. Org. Chem., 2019, 84, 15042-15051.

An object of the present invention is to obtain a novel compound which has a different chemical structure from the conventional triazine-type quaternary ammonium salt or triazinone-type quaternary ammonium salt, has high activity, can suppress side reactions, and is useful as a dehydration condensing agent. To provide.

As a result of diligent studies under such circumstances, the present inventor has converted the triazine skeleton (that is, the triazine ring or the triazineone ring) of the conventional triazine-type quaternary ammonium salt or triazine-type quaternary ammonium salt into a triazinedione ring. In addition, by using a 4- (N, N-dialkylamino) pyridine derivative with high electron donating property as the amine for forming the quaternary salt, the desorption ability in the dehydration condensation reaction is improved, and it is derived from the counter anion. We have found a novel compound useful as a dehydration condensing agent capable of completely suppressing the side reaction of the above, and have completed the present invention.

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

[During the ceremony,
The two Rs independently represent a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
The two R'independently indicate a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl group, and R ³ and R ⁴ independently represent a C _1-4 alkyl group or R ¹ respectively. And R ³ , R ³ and R ⁴ , and / or R ² and R ⁴ , respectively, independently, together with the carbon and / or nitrogen atoms to which they bind, and further select from oxygen and sulfur atoms. It may contain a heteroatom to be added, may form a substituted 5-8 membered ring; and X ^- is a non-nucleophilic or poorly nucleophilic pair. Indicates an anion. ]
Compounds represented by (hereinafter, also referred to as "compound (I)" or "compound of the present invention"; hereinafter, compounds represented by formulas (I') and formulas (II) to (IV). May use similar abbreviations),
[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 combined with the nitrogen atom to which they are attached. The compound according to the above [1], which further forms a 5- or 6-membered ring which may further contain a hetero atom selected from an oxygen atom and a sulfur atom.
[3] The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups.
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are both methyl or ethyl groups, or R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form a pyrrolidinyl or piperidyl group, ^and X- Fluolid ion, chloride ion, bromide ion, iodide ion, optionally substituted alkyl sulfonate ion, optionally substituted aryl sulfonate ion, perchlorate ion, tetrafluoroborate ion, hexafluorophosphate ion, The compound according to the above [1], which is a counter anion selected from the group consisting of a hexafluoroantimonate ion, a tetraphenylborate ion and an alsenato ion.
[4] R and R'are all hydrogen atoms, and
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are both methyl or ethyl groups, and X ^- is fluoride ion, chloride ion, bromide ion, iodine ion, C _1-4 alkyl sulfonate ion, halo C _1-4 alkyl sulfonate. The compound according to the above [1], which is a counter anion selected from the group consisting of an ion, a phenylsulfonate ion which may be substituted, and a perchlorate ion.
[5] A dehydration condensing agent comprising the compound according to any one of the above [1] to [4].
[6] A method for dehydrating and condensing a nucleophile selected from the group consisting of alcohol, amine, aniline and phenol, and a carboxylic acid, which comprises using the dehydration condensing agent according to the above [5] and a base. ,
[7] Equation (IV):

[During the ceremony,
The two Rs independently represent a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
The two R'independently indicate a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group; and
Y indicates a leaving group. ]
By heating the compound represented by the above in the presence of a divalent palladium catalyst, the formula (III):

[Each symbol in the formula has the same meaning as described above. ]
The step of converting to the compound represented by the above formula (III) and the compound represented by the above formula (III) are expressed in the formula (II) :.

[During the ceremony,
R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl group, and R ³ and R ⁴ independently represent a C _1-4 alkyl group or R ¹ respectively. And R ³ , R ³ and R ⁴ , and / or R ² and R ⁴ , respectively, independently, together with the carbon and / or nitrogen atoms to which they bind, and further select from oxygen and sulfur atoms. It may contain a heteroatom to be substituted, and may form a 5- to 8-membered ring which may be substituted. ]
By reacting with the compound represented by, the formula (I'):

[During the ceremony,
Y ⁻ indicates a counter anion derived from a leaving group, and other symbols indicate the same meanings as described above. ]
Formula (I), which comprises the step of converting to the compound represented by.

[During the ceremony,
X ^- indicates a non-nucleophilic or low nucleophilic counter anion, and the other symbols are synonymous with the above. ]
Method for producing a compound represented by
[8] The production method according to the above [7], wherein Y ⁻ is the same as X ⁻ .
[9] The present invention relates to the production method and the like according to the above [7], further comprising a counter-anion exchange reaction step from the compound of the formula (I') to the compound of the formula (I).

According to the present invention, it is possible to provide a novel dehydration condensing agent having the most excellent condensing ability among the dehydration condensing agents having a triazine skeleton developed so far. Specifically, according to the present invention, in the condensation reaction of a carboxylic acid with a nucleophilic compound selected from the group consisting of alcohol, amine, aniline and phenol, the purpose is to achieve a short time and a high yield under mild conditions. It is possible to provide a compound useful as a practical dehydration condensing agent capable of producing a carboxylic acid derivative (ester, amide, etc.), and a method for producing the same.

Hereinafter, the present invention will be described in detail.
(Definition)

As used herein, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the "alkyl group" means a linear or branched alkyl group having 1 or more carbon atoms, and is preferably C _1- when the carbon number range is not particularly limited. It is a ₁₂ alkyl group, with a C _1-6 alkyl group being more preferred and a C _1-4 alkyl group being particularly preferred.

Preferred specific examples of the "C _1-6 alkyl group" in the present specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. In addition, suitable specific examples of the "C _1-4 alkyl group" include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Of these, methyl or ethyl is particularly preferable.

As used herein, the term "halo C _1-6 alkyl group" means a group in which one or more hydrogen atoms of a C _1-6 alkyl group are substituted with a halogen atom. Specific examples of the "halo C _1-6 alkyl group" include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoro. Ethyl, 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, 6,6,6-trifluorohexyl and the like can be mentioned. Of these, "halo C _1-4 alkyl group" is preferable.

As used herein, the term "halo C _1-4 alkyl group" means a group in which one or more hydrogen atoms of a C _1-4 alkyl group are substituted with a halogen atom. Specific examples of the "halo C _1-4 alkyl group" include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, chloromethyl, bromomethyl, 2,2. Examples include 2-trichloromethyl and the like. Of these, trifluoromethyl or 2,2,2-trifluoroethyl is preferable, and trifluoromethyl is more preferable.

In the present specification, the “alkoxy group” means an alkoxy group having 1 or more carbon atoms in a linear or branched chain, and is preferably C _1-12 alkoxy when the carbon number range is not particularly limited. It is a group, and a C _1-6 alkoxy group is more preferable.

In the present specification, the "C _1-6 alkoxy group" means an alkoxy group having 1 to 6 carbon atoms in a linear or branched chain, and for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and the like. Examples thereof include sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Among them, C _1-4 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy are preferable, and methoxy or ethoxy is more preferable.

As used herein, the term "halo C _1-6 alkoxy group" means a group in which one or more hydrogen atoms of the C _1-6 alkoxy group are substituted with a halogen atom. Specific examples of the "halo C _1-6 alkoxy group" include, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, trichloromethoxy, 2-chloroethoxy, bromomethoxy, 2-bromoethoxy, and 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, 6,6,6-trifluorohexyloxy and the like. Of these, the halo C _1-4 alkoxy group is preferable, and trifluoromethoxy or 2,2,2-trifluoroethoxy is more preferable.

As used herein, the term "C _3-8 cycloalkyl group" means a cyclic alkyl group having 3 to 8 carbon atoms. Specific examples of the "C _3-8 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, the C _3-6 cycloalkyl group is preferable.

In the present specification, the "C _2-6 alkenyl group" is a linear or branched monovalent hydrocarbon having one or more carbon-carbon double bonds and having 2 to 6 carbon atoms. Group means, for example, ethenyl, 1-propenyl (allyl), 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1- Examples thereof include pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like. Of these, the C _2-4 alkenyl group is particularly preferable.

In the present specification, the "C _2-6 alkynyl group" is a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having 2 to 6 carbon atoms. Means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- Examples thereof include hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl. Of these, ethynyl is preferred.

In the present specification, the "C _6-10 aryl group" means a monocyclic or bicyclic (condensed) hydrocarbon group exhibiting aromaticity, and specific examples thereof include phenyl and 1-. Examples include naphthyl and 2-naphthyl. Of these, phenyl is preferred.

In the present specification, the "aralkyl group" means a group in which the "aryl group" is substituted with the "aryl group", and preferably the "C _1-4 alkyl group" is replaced with the "C _6-10 ". It is a "C _7-14 aralkyl group" substituted with an "aryl group".

Specific examples of the "C _7-14 aralkyl group" include, for example, benzyl, 1-phenylethyl, 2-phenylethyl, (naphthyl-1-yl) methyl, (naphthyl-2-yl) methyl, 1- (naphthyl). Examples thereof include -1-yl) ethyl, 1- (naphthyl-2-yl) ethyl, 2- (naphthyl-1-yl) ethyl, 2- (naphthyl-2-yl) ethyl and the like, and among them, benzyl is preferable. Is.

In the present specification, the "aralkyloxy group" means a group in which the "aralkyl group" is bonded to an oxygen atom. Examples of the "aralkyloxy group" include _C7-14 aralkyloxy groups such as benzyloxy, 1-naphthylmethyloxy and 2-naphthylmethyloxy, and among them, the benzyloxy group is preferable.

In the present specification, the "acyl group" means an alkanoyl or an aloyl, and the carbon number range is not particularly limited, but a C _1-7 alkanoyl group or a C _7-11 aloyl is preferable.

In the present specification, the "C _1-7 alkanoyl group" is a linear or branched formyl or alkylcarbonyl (that is, C _1-6 alkyl-carbonyl) having 1 to 7 carbon atoms, for example. , Formyl, Acetyl, Propionyl, Butyryl, Isobutyryl, Pentanoyl, Hexanoyl, Heptanoyl and the like.

In the present specification, the "C _7-11 aloyl group" is an arylcarbonyl having 7 to 11 carbon atoms (that is, C _6-10 aryl-carbonyl), and examples thereof include benzoyl and the like.

As used herein, the term "haloacyl group" means a group in which one or more hydrogen atoms of the acyl group are substituted with halogen atoms. Specific examples of the "haloacyl group" include trifluoroacetyl, trichloroacetyl, 4-chlorobenzoyl and the like.

In the present specification, the "acyloxy group" means a group in which the alkanoyl group or the alloyl group is bonded to an oxygen atom, and the carbon number range is not particularly limited, but C _1-7 alkanoyloxy group or C is preferable. _7-11 Aloyloxy group.

In the present specification, the "C _1-7 alkanoyloxy group" includes, for example, formyloxy, acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, and the like. Examples thereof include tert-butylcarbonyloxy (pivaloyloxy), pentylcarbonyloxy, isopentylcarbonyloxy, neopentylcarbonyloxy, hexylcarbonyloxy and the like, preferably acetoxy or pivaloyloxy.

In the present specification, examples of the "C _7-11 aloyloxy group" include benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy and the like.

As used herein, the term "haloacyloxy group" means a group in which one or more hydrogen atoms of the acyloxy group are substituted with a halogen atom. Specific examples of the "haloacyloxy group" include trifluoroacetoxy, trichloroacetoxy, 4-chlorobenzoyloxy and the like.

In the present specification, "R ¹ and R ³ , R ³ and R ⁴ , and R ² and R ⁴ are formed independently of each other, together with a carbon atom and / or a nitrogen atom to which they are bonded". The compound containing "a 5- to 8-membered ring which may further contain a hetero atom selected from an oxygen atom and a sulfur atom and may be substituted" is not particularly limited, but is not particularly limited, and for example, the 5th. The 8-membered ring may be further substituted, the following equation:

[Each symbol in the formula has the same meaning as described above. ]
The compound (II) represented by the above compound (II) and the compound (I) prepared from the compound (II) can be mentioned.

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

In the present specification, the "alkylsulfonyloxy group" in the "optionally substituted alkylsulfonyloxy group" is a group in which the "alkyl group" is bonded to the sulfur atom of —S (O) ₂ -O—. Means, for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, Examples thereof include C _1-6 alkyl sulfonyl oxy groups such as neopentyl sulfonyl oxy and hexyl sulfonyl oxy. Of these, the C _1-4 alkylsulfonyloxy group is preferable. As the "optionally substituted alkylsulfonyloxy group", a methylsulfonyloxy group optionally substituted with a halogen atom (eg, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group) is particularly preferable.

In the present specification, the "optionally substituted arylsulfonyloxy group" means a group in which an "aryl group" is bonded to a sulfur atom of —S (O) ₂ -O—, for example, phenylsulfonyloxy. , 1-naphthylsulfonyloxy, 2-naphthylsulfonyloxy and the like. Of these, the phenylsulfonyloxy group is preferable. The "optionally substituted arylsulfonyloxy group" includes a phenylsulfonyloxy group optionally substituted with a methyl group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group, o-nitrobenzenesulfonyloxy, p. -Nitrobenzenesulfonyloxy, 2,4-dinitrobenzenesulfonyloxy) is particularly preferred.

In the present specification, the "alkyl sulfonate ion" in the "optionally substituted alkyl sulfonate ion" means an anion in which an "alkyl group" is bonded to -SO _3- ^, and for example, a methyl sulfonate ion. , Ethyl sulfonate ion, propyl sulfonate ion, isopropyl sulfonate ion, butyl sulfonate ion, isobutyl sulfonate ion, sec-butyl sulfonate ion, tert-butyl sulfonate ion, pentyl sulfonate ion, isopentyl sulfonate ion , Neopentyl sulfonate ion, hexyl sulfonate ion and the like. Of these, C _1-4 alkyl sulphonate ion (eg, methane sulphonate ion) or halo C _1-4 alkyl sulphonate ion (eg, trifluoromethane sulphonate ion) is preferable.

In the present specification, the "aryl sulfonate ion" in the "optionally substituted aryl sulfonate ion" means an anion in which an "aryl group" is bonded to -SO _3- ^, for example, a phenyl sulfonate ion. , 1-naphthylsulfonate ion, 2-naphthylsulfonate ion and the like, _C6-10 arylsulfonate ion and the like. Of these, phenylsulfonate ion is preferable. The "aryl sulfonate ion" in the "optionally substituted aryl sulfonate ion" is a phenyl sulfonate ion that may be substituted with a methyl group (eg, benzene sulfonate ion, p-toluene sulfonate ion, etc. O-nitrobenzene sulfonate ion, p-nitrobenzene sulfonate ion, 2,4-dinitrobenzene sulfonate ion) are particularly preferable.

As used herein, the term "tri-substituted silyl group" means a silyl group substituted with three identical or different substituents (eg, C _1-6 alkyl group, C _6-10 aryl group, etc.). Examples of the group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triphenylsilyl group and the like.

In the present specification, "may be substituted" means that it may have one or more substituents, unless otherwise specified, and the "substituent" is (1). 1) Halogen atom, (2) Nitro group, (3) Cyano group, (4) C _1-6 alkyl group, (5) Halo C _1-6 alkyl group, (6) C _1-6 alkoxy group, (7) ) Halo C _1-6 alkoxy group, (8) C _1-6 alkoxy-C _1-6 alkoxy group, (9) C _3-8 cycloalkyl group, (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 alkylene dioxy group, (15) acyl group, (16) haloacyl group , (17) Acyloxy group, (18) Haloacyloxy group, (19) C _1-6 alkoxy-carbonyl group, (20) Tri-substituted silyl group and the like. Among them, halogen atom, nitro, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxy, methylenedioxy, acetyl, trifluoroacetyl, acetoxy, trifluoroacetoxy, benzyl, benzyl. Oxy and the like are preferable. Further, when a plurality of substituents are present, each substituent may be the same or different.

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

(Compound of the present invention)
The compound of the present invention (compound (I)) has the following formula (I):

[During the ceremony,
The two Rs independently represent a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
The two R'independently indicate a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl group, and R ³ and R ⁴ independently represent a C _1-4 alkyl group or R ¹ respectively. And R ³ , R ³ and R ⁴ , and / or R ² and R ⁴ , respectively, independently, together with the carbon and / or nitrogen atoms to which they bind, and further select from oxygen and sulfur atoms. It may contain a heteroatom to be added, may form a substituted 5-8 membered ring; and X ^- is a non-nucleophilic or poorly nucleophilic pair. Indicates an anion. ]
It is a triazinedione compound represented by.

Hereinafter, each group of compound (I) will be described.

The two Rs independently represent a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group (eg, a phenyl group). ..

The two Rs are preferably both hydrogen atoms.

The two R's each independently have a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or a optionally substituted C _6-10 aryl group (eg, a phenyl group). show.

The two R's are preferably both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups, and more preferably both hydrogen atoms.

R ¹ and R ² each independently represent a hydrogen atom or a C _1-4 alkyl group.

Both R ¹ and R ² are preferably hydrogen atoms.

R ³ and R ⁴ each independently represent a C _1-4 alkyl group.

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

As another aspect of R ¹ , R ² , R ³ and R ⁴ , R ¹ and R ³ , R ³ and R ⁴ , and / or R ² and R ⁴ , respectively, are independently bonded carbon atoms. And / or together with the nitrogen atom, they may further form a 5- to 8-membered ring, which may further contain a heteroatom selected from an oxygen atom and a sulfur atom, which may be substituted.

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

R ³ and R ⁴ more preferably combine with the nitrogen atom to which they bind to form a pyrrolidinyl or piperidyl group, in which case R ¹ and R ² more preferably both have a hydrogen atom. Is.

R ¹ and R ³ and / or R ² and R ⁴ may be substituted, preferably independently, together with the carbon and nitrogen atoms to which they are bonded, 5 or 6 members, respectively. In the presence of R ¹ and R ³ , or R ² and R ⁴ , which form a partially unsaturated nitrogen-containing heterocycle and do not form a ring, R ¹ or R ² which does not form a ring is preferable. Is a hydrogen atom, and R ³ and R ⁴ which do not form a ring are preferably both a methyl group or an ethyl group.

R ¹ and R ³ and R ² and R ⁴ are more preferably both substituted with 6-membered partially unsaturated nitrogen atoms, together with the carbon and nitrogen atoms to which they are attached. Form a heterocycle.

X ^- indicates a non-nucleophilic or poorly nucleophilic counter anion.

X- is preferably a fluoride ion ^, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkyl sulfonate ion, an optionally substituted aryl sulfonate ion, a perchlorate ion, a tetrafluoroborate. It is a counter anion selected from the group consisting of an ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion and an alsenato ion.

More preferably, X ^- is a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a C _1-4 alkyl sulfonate ion which may be substituted with a halogen atom, a phenyl sulfonate ion which may be substituted, and a phenyl sulfonate ion which may be substituted. It is a counter anion selected from the group consisting of perchlorate ions.

X ^- is more preferably chloride ion, trifluoromethanesulfonate ion, methanesulfonate ion, benzenesulfonate ion, p-toluenesulfonate ion, o-nitrobenzenesulfonate ion, p-nitrobenzenesulfonate ion, 2, It is a counter anion selected from the group consisting of 4-dinitrobenzene sulfonate ion and a perchlorate ion.

As the compound (I), the following compounds are suitable.

[Compound (IA)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups.
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are both methyl or ethyl groups, and X ^- is a fluoride ion, a chloride ion, a bromide ion, an iodide ion, an optionally substituted alkyl sulfonate ion, and optionally substituted. A compound (a compound) which is a counter anion selected from the group consisting of an aryl sulfonate ion, a perchlorate ion, a tetrafluoroborate ion, a hexafluorophosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion and an alsenato ion. I).

[Compound (IB)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups.
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ together with the nitrogen atom to which they bind form a 5- or 6-membered ring, which may further contain a hetero atom selected from oxygen and sulfur atoms, and X. ^-Is fluoride ion, chloride ion, bromide ion, iodide ion, optionally substituted alkyl sulfonate ion, optionally substituted aryl sulfonate ion, perchlorate ion, tetrafluoroborate ion, hexafluoro Compound (I), which is a counter anion selected from the group consisting of a phosphate ion, a hexafluoroantimonate ion, a tetraphenylborate ion and an alsenato ion.

[Compound (IC)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms,
Both R ¹ and R ² are 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, a halogen atom, or a C _1-4 alkyl sulfonate. Compound (I), which is a counter anion selected from the group consisting of an ion, an optionally substituted phenylsulfonate ion, and a perchlorate ion.

[Compound (ID)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms,
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ together with the nitrogen atom to which they bind form a pyrrolidinyl or piperidyl group, and X ^- is substituted with a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a halogen atom. Compound (I), which is a counter anion selected from the group consisting of C _1-4 alkyl sulfonate ion which may be present, phenyl sulfonate ion which may be substituted, and perchlorate ion.

[Compound (IE)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms,
Both R ¹ and R ² are hydrogen atoms,
Both R ³ and R ⁴ are methyl groups, and X ^- is chloride ion, trifluoromethanesulfonate ion, methanesulfonate ion, benzenesulfonate ion, p-toluenesulfonate ion, o-nitrobenzenesulfonate. Compound (I), which is a counter anion (preferably chloride ion) selected from the group consisting of an ion, p-nitrobenzene sulfonate ion, 2,4-dinitrobenzene sulfonate ion, and perchlorate ion.

[Compound (IF)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups.
R ¹ and R ³ and / or R ² and R ⁴ may be substituted independently, together with the carbon and nitrogen atoms to which they are bonded, respectively, with a 5- or 6-membered partial defect. If a saturated nitrogen-containing heterocycle is formed (provided that a ring is not formed, ^R1 and R3 ^, or ^R2 and ^R4 are present, then ^R1 or ^R2 that does not form a ring is a hydrogen atom. R ³ and R ⁴ which do not form a ring are both methyl or ethyl groups), and X ^- is a fluoride ion, a chloride ion, a bromide ion, an iodide ion, or an alkyl which may be substituted. From the group consisting of sulfonate ions, optionally substituted aryl sulfonate ions, perchlorate ions, tetrafluoroborate ions, hexafluorophosphate ions, hexafluoroantimonate ions, tetraphenylborate ions and alsenato ions. Compound (I), which is the counterion of choice.

[Compound (IG)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms,
R ¹ and R ³ and R ² and R ⁴ together form a 6-membered partially unsaturated nitrogen-containing heterocycle that may be substituted together with the carbon and nitrogen atoms to which they are bonded. And X ^- is a C _1-4 alkyl sulfonate ion optionally substituted with a fluoride ion, a chloride ion, a bromide ion, an iodide ion, a halogen atom, a phenyl sulfonate ion optionally substituted, and a pel. Compound (I), which is a counter anion selected from the group consisting of chloride ions.

As the compound (II) used for producing the compound (I), the following compounds are suitable.

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

[Compound (II-B)]
Both R ¹ and R ² are hydrogen atoms,
A compound in which R ³ and R ⁴ 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. II).

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

[Compound (II-D)]
R ¹ and R ³ and / or R ² and R ⁴ may be substituted independently, together with the carbon and nitrogen atoms to which they are bonded, respectively, with 5 or 6 members. Forming a saturated nitrogen-containing heterocycle (however, if ^R1 and R3 ^, or ^R2 and ^R4 , which do not form a ring, are present, ^R1 or ^R2 which does not form a ring is a hydrogen atom. R ³ and R ⁴ which do not form a ring are both methyl or ethyl groups), compound (II).

[Compound (II-E)]
R ¹ and R ³ and R ² and R ⁴ together form a 6-membered partially unsaturated nitrogen-containing heterocycle that may be substituted together with the carbon and nitrogen atoms to which they are bonded. Compound (II).

Specific examples of the suitable compound (II) include, for example, N, N-dimethyl-4-aminopyridine (DMAP), N, N-diethyl-4-aminopyridine, and the following formula:

[Each symbol in the formula has the same meaning as described above. ]
Examples thereof include compounds represented by.

As the compound (III) used for producing the compound (I), the following compounds are suitable.

[Compound (III-A)]
The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups, and Y is a halogen atom, optionally substituted alkylsulfonyloxy group and substituted. Compound (III), which is a desorbing group selected from the group consisting of an arylsulfonyloxy group which may be present.

[Compound (III-B)]
The two Rs are both hydrogen atoms,
Two R's are both hydrogen atoms, and Y is from a halogen atom, a C _1-4 alkylsulfonyloxy group optionally substituted with a halogen atom, and a phenylsulfonyloxy group optionally substituted with a halogen atom. Compound (III), which is a desorbing group selected from the group consisting of.

When compound (I), compound (II) or compound (III) has isomers such as optical isomers, steric isomers and positional isomers, either one isomer or a mixture thereof is also a compound ( I), compound (II) or compound (III). For example, if an optical isomer is present in compound (I), compound (II) or compound (III), the optical isomer separated from the racemate is also compound (I), compound (II) or compound (III). ). Each of these isomers can be obtained as a single product by a synthetic method and a separation method known per se (eg, concentration, solvent extraction, column chromatography, recrystallization).

The compound (I), the compound (II) or the compound (III) may be a solvate or a non-solvate.

Compound (I), compound (II) or compound (III) may also be labeled with an isotope (eg, ^3H , ^14C , etc.) and the like.
Furthermore, compound (I), compound (II) or compound (III) may be a deuterium converter.

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

Unless otherwise specified, the starting compound can be easily obtained as a commercially available product, or can be produced according to a method known per se or a method similar thereto.

The compound obtained in each step in the following reaction formula can be used as it is in the reaction solution or as a crude product in the next reaction. Alternatively, the compound can be isolated from the reaction mixture according to conventional methods and can be easily purified by conventional separation means such as recrystallization, distillation, chromatography and the like.
(Production method)

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

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

The amount of compound (V) used is usually 2 to 5 mol, preferably 2.5 to 3.5 mol, relative to 1 mol of compound (VI). Examples of the suitable compound (V) include compounds corresponding to the respective definitions of R and R'in the above-mentioned compounds (III-A) and compound (III-B).

The base used is not particularly limited, but is, for example, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4]. .3.0] Organic bases such as -5-nonen (DBN), 2,6-lutidine, 2,6-di-tert-butylpyridine; inorganic bases such as sodium hydride, among others, N, N -Diisopropylethylamine is preferred.
The amount of the base used is usually 2 to 5 mol, preferably 2.5 to 3.5 mol, relative to 1 mol of compound (VI).

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-butylmethyl ether, diisopropyl ether, DME and diglyme. Hydrocarbons such as hexane, benzene and toluene; nitriles such as acetonitrile; mixed solvents thereof and the like are mentioned, among which dichloromethane, chloroform, THF and the like are preferable, and dichloromethane is particularly preferable.

The reaction temperature is usually −40 ° C. to 80 ° C., preferably −20 ° C. to room temperature.
The reaction time is usually 0.5 to 48 hours.

(Step 2)
This step is a step of producing compound (III) by heating and refluxing compound (IV) in the presence of a divalent palladium catalyst, in a solvent that does not affect the reaction, and in the presence of a base, if necessary. Is.

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 diglime. Etc., and among them, chloroform or THF is preferable.

Examples of the divalent palladium catalyst include bis (benzonitrile) palladium (II) dichloride, palladium (II) chloride, palladium (II) acetate and the like, and among them, bis (benzonitrile) palladium (II) dichloride is preferable.
The amount of the divalent palladium catalyst used is usually 0.001 to 0.2 mol, preferably 0.01 to 0.01 mol, relative to 1 mol of compound (IV).

Examples of the base when a base is used 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 colidine. , 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, based on 1 mol of compound (IV).

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.

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

The amount of compound (II) used is usually 1 to 2 mol, preferably 1 to 1.5 mol, relative to 1 mol of compound (III). Examples of the suitable compound (II) include compounds corresponding to the above-mentioned compounds (II-A) to (II-E).

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-butylmethyl ether, diisopropyl ether, DME, and diglyme. Hydrocarbons such as hexane, benzene and toluene; nitriles such as acetonitrile; mixed solvents thereof and the like can be mentioned, with THF being preferred.

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

(Step 4)
In this step, the compound (I') obtained in the above step 3 is mixed with MX in a solvent that does not affect the reaction, thereby converting Y ⁻ , which is a counter anion, to another counter anion X ⁻ . This is a step of synthesizing compound (I). In addition, this step can be omitted when Y is the same group as X.

M in the reactant represented by MX represents a metal atom or a quaternary ammonium group, and specifically, for example, an alkali metal such as lithium, potassium, sodium or cesium; an alkaline earth metal such as magnesium or calcium. , Noble metals such as gold and silver, heavy metals such as tarium, tetramethylammonium groups and the like, and among them, lithium, sodium or silver are preferable.

In the reactant represented by MX, X is a halogen atom (eg, a chlorine atom), an optionally substituted alkylsulfonyloxy group and a substituted group corresponding to Y ⁻ of the compound (I'). It exhibits a group that has no or low nucleophilicity other than a group that can be Y, such as a good arylsulfonyloxy group, and specifically, for example, perchlorate, tetrafluoroborate, hexafluorophosphate, etc. Hexafluoroantimonate, tetraphenylborate, arsenate and the like can be mentioned.

The amount of the MX used is usually 1 to 10 mol, preferably 1 to 3 mol, relative to 1 mol of compound (I').

Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and trichloroethylene; nitriles such as acetonitrile; 1,4-dioxane, THF, diethyl ether, tert-butylmethyl ether, diisopropyl ether and DME. , Ethers such as diglime; 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 Examples thereof include a mixed solvent thereof (eg, a mixed organic solvent, a two-layer system of water and an organic solvent, etc.), and dichloromethane or acetonitrile are particularly preferable.

The reaction temperature is usually −30 to 100 ° C., preferably 0 to 40 ° C.
The reaction time is usually 0.1 to 30 hours.

(Method for producing an amide compound or an ester compound using the compound (I) of the present invention as a dehydration condensing agent)
The compound (I) of the present invention is an ester 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 alcohol, amine, aniline and phenol. It can be suitably used as a dehydration condensing agent in producing a compound or an amide compound.

In the method for producing an ester compound or an amide compound using the compound (I) of the present invention as a condensing agent, the type of the compound (I) and the amount thereof used are not particularly limited, but are preferably with respect to 1 mol of the carboxylic acid. It is usually 0.9 to 1.5 mol, preferably 1.1 to 1.2 mol.

As the carboxylic acid compound used in the method for producing an ester compound or an amide compound, any compound having a carboxy group can be used without any limitation.

(Method for producing amide compound)
As the amine compound used in the method for producing an amide compound, any compound having a primary amino group or a secondary amino group can be used without any limitation.

The dehydration condensation reaction (amidization reaction) in the method for producing an amide compound is preferably carried out in a solvent that does not affect the reaction.

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

The reaction temperature is usually room temperature.

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

The operating procedure of the amidation reaction using the compound (I) as a condensing agent (the order in which the reaction substrate and the compound (I) are added, etc.) is not particularly limited, but the three types of reaction reagents (that is, the compound (I) and the carboxylic acid) are not particularly limited. It is preferable to mix (acid compound and amine compound) in a solvent and react. The mixing method of the above three types of reaction reagents is not particularly limited, and each reaction reagent may be added and mixed in the reaction system at the same time, or each reaction reagent may be added and mixed in sequence in the reaction system. From the viewpoint of operability and reaction yield, it is particularly preferable to add and mix each reaction reagent sequentially and in a short time in the reaction solvent at room temperature.

The amide compound obtained by the above amidation reaction can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means such as recrystallization, distillation and chromatography.

(Manufacturing method of ester compound)
As the alcohol compound used in the method for producing an ester compound, any primary alcohol, secondary alcohol or phenol can be used without any limitation.

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

As the solvent, the same solvent as in the amidation reaction can be used.

The reaction temperature in the esterification reaction is usually room temperature.

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. be.
The amount of the base used is not particularly limited, but is preferably 1 to 1.5 mol, preferably 1.2 mol, per 1 mol of the carboxylic acid compound.

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.

Since the compound (I) of the present invention has extremely high activity as a dehydration condensing agent, as shown in the experimental examples described later, a dehydration condensing agent (DMT-MM, DMT-DMAP) having a similar triazine skeleton known conventionally is known. , DMT-3,5-LUT) takes a lot of time, the yield is low, and a side reaction is observed. It has the advantage that it can be completed within a good yield.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited thereto, and may be changed without departing from the scope of the present invention.
The reaction was monitored by thin layer chromatography using a Merck 60 F254 silica gel plate (thickness 0.25 mm).
^The 1H and ¹³ C-NMR spectra were measured using JEOL ECS400 and deuterated chloroform as a solvent. The data for ¹ H-NMR are chemical shift (δppm), multiplicity (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 spectrum analysis (HRMS) was performed using JEOL JMS-T100TD (DART).
The melting point (mp) was measured using a Yanagimoto trace melting point measuring instrument.
Elemental analysis was performed using Yanaco CHN Coder MT-5.
Preparative thin layer chromatography was performed using a Merck 60 F254 silica gel plate (thickness 0.5 mm). Flash chromatography was performed using silica gel 60N from Kanto Chemical Co., Inc. (Japan, Tokyo).
As used herein, "room temperature" usually means about 10 ° C to about 30 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates weight% unless otherwise specified.

In the following examples, 2,4,6-trichloro-1,3,5-triazine, which is a raw material compound used for the synthesis of compound (I), compound (I'), compound (III) or compound (IV). As (cyanuric chloride) (a compound in which Y is a chlorine atom in the formula (VI)), a commercially available product (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was used as it was. For other raw material compounds, commercially available products can be used as they are, or by methods known per se (eg, Recl. Trav. Chim. Pays-Bas. 2010, 79, 83-89; Eur. J. Org. Chem. 2019, 4436-4446; J. Org. Chem. 2019, 84, 15042-45054; Angelw. Chem. Int. Ed. 2004, 43, 5436-5441) or a method similar thereto can be produced.
Chloroform and ethyl acetate were used by distilling reagent grades. Dichloromethane, acetonitrile, N, N-dimethylformamide and tetrahydrofuran (THF) were purchased in anhydrous solvent grade and used as is. Other reagents were purified as needed before use.

Example 1
1- (1,5-diallyl-4,6-dioxo-1,4,5,6-tetrahydro-1,3,5-triazine-2-yl) -4- (N, N-dimethylamino) pyridine- Synthesis of 1-ium chloride (compound (I-1))

2,4-Diallyloxy-6-chloro-1,3,5 synthesized in a 200 mL twin-necked eggplant flask according to the method described in a method known per se (Eur. J. Org. Chem. 2019, 4436-4446). -Triazine (Compound (IV-1)) (1.0 g, 4.39 mmol) and THF (6 mL) were added. Bis (benzonitrile) palladium (II) dichloride (7.1 mg, 18.3 μmol) was added to this solution under a nitrogen atmosphere at room temperature, and the mixture was heated under reflux for 4 hours and then allowed to cool to room temperature. The reaction without isolating and purifying the product (1,3-diallyl-6-chloro-1,3,5-triazine-2,4 (1H, 3H) -dione (compound (III-1)). A solution of N, N-dimethyl-4-aminopyridine (DMAP) (446.9 mg, 3.66 mmol) in THF (6 mL) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours, and the precipitate was centrifuged. The compound (I-1) (1.19 g, yield 93%) was obtained as a white solid by filtering by separation and washing with THF.
¹ H NMR (400 MHz, CDCl ₃ ): 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, CDCl ₃ ): 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 H ₂₀ N ₅ O ₂ ⁺ ([M] ⁺ ): 314.1617; found: 314.1631.

Experimental Example 1
Method for producing ester compound of the present invention (esterification reaction) using compound (I-1) as a dehydration condensing agent.

(Experimental operation 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) in a 10 mL eggplant flask. (53 μL, 0.48 mmol) was added. Compound (I-1) (167.9 mg, 0.48 mmol) was added to the solution, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The obtained organic layer was dried over magnesium sulfate, magnesium sulfate was removed by filtration, and the mixture was 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, CDCl ₃ ): 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, CDCl ₃ ): 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 ₁₉ O ₂ ([M + H] ⁺ ): 255.1385; found: 255.1379.

Experimental Example 2
Examination of optimization of dehydration condensing agent and reaction conditions in the esterification reaction of Experimental Example 1 In the esterification reaction of Experimental Example 1 above, the results of the experiment in which the dehydration condensing agent, the base, and / or the solvent were replaced were shown. It is shown in Table 1.

According to Table 1, in the esterification reaction using compound (I-1), the addition of a base is essential to complete the reaction, but the reaction takes less than 10 minutes regardless of the type of base or solvent. Was completed, and it was found that the desired ester compound was obtained in high yield. On the other hand, when DMT-MM, DMT-DMAP or DMT-3,5-LUT having a similar triazine structure is used as the dehydration condensing agent instead of compound (I-1), Non-Patent Documents As described in No. 6, it was found that it took a long time to complete the reaction and the yield of the ester was significantly reduced.

Experimental Examples 3-9
Results obtained by conducting a condensation reaction between various carboxylic acid compounds and an alcohol compound (primary alcohol, secondary alcohol or phenol) using compound (I-1) according to the method of Experimental Example 1 above. Is shown in Table 2.

According to Table 2, in the esterification reaction using compound (I-1), the reaction was completed in 10 minutes regardless of the type of the carboxylic acid compound and the alcohol compound, regardless of which substrate was used. It was found that the desired ester compound was given in high yield. It was also confirmed that the esterification reaction proceeds in good yield even when phenol is used as the alcohol compound.

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), but instrumental analysis data are shown below.

Experimental Example 3: 3-phenylpropionic acid 1,3-diphenylpropane-2-yl
¹ H NMR (400 MHz, CDCl ₃ ): 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, CDCl ₃ ): 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 O ₂ ([M + H] ⁺ ): 345.1855; found: 345.1844.

Experimental Example 4: Phenethyl cyclohexanecarboxylate
¹ H NMR (400 MHz, CDCl ₃ ): 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, CDCl ₃ ): 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 O ₂ ([M + H] ⁺ ): 233.1542; found: 233.1538.

Experimental Example 5: Cyclohexanecarboxylic acid 1,3-diphenylpropane-2-yl
¹ H NMR (400 MHz, CDCl ₃ ): 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, CDCl ₃ ): 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 O ₂ ([M + H] ⁺ ): 323.2011; found: 323.2017.

Experimental Example 6: Phenyl 3-phenylpropionate
¹1 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);
¹³C 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 C₁₅H₁₅O₂ ([M + H]^{+ +}): 227.1072; found: 227.1078.

Experimental Example 7: Phenethyl benzoate
¹ H NMR (400 MHz, CDCl ₃ ): 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, CDCl ₃ ): 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 O ₂ ([M + H] ⁺ ): 227.1072; found: 227.1065.

Experimental Example 8: Benzyl (tert-butoxycarbonyl) -L-alaninate
¹ H NMR (400 MHz, CDCl ₃ ): 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, CDCl ₃ ): 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 NO ₄ ([M + H] ⁺ ): 280.1549; found: 280.1545.

Experimental Example 9: Benzyl ((benzyloxy) carbonyl) -L-phenylalaninate
¹ H NMR (400 MHz, CDCl ₃ ): 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);
¹³ C NMR (100 MHz, CDCl ₃ ): 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 NO ₄ ([M + H] ⁺ ): 390.1705; found: 390.1702.

Experimental Example 10
A method for producing an amide compound of the present invention (amidization reaction) using compound (I-1) as a dehydration condensing agent.

(Experimental operation 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 the mixture was stirred at room temperature for 10 minutes. The reaction mixture was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The obtained organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the mixture was 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 obtained instrumental analysis data of N-phenethyl-3-phenylpropanamide showed good agreement with the instrumental analysis data described in the literature (Tetrahedron, 1999, 55, 13159-13170).

Experimental Examples 11 to 22
Condensation reaction of various carboxylic acid compounds and amine compounds was carried out using compound (I-1) according to the method of Experimental Example 10, and the obtained results are shown in Table 3. The table also shows the results of the reaction 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. It is shown together with 3.

According to Table 3, in the amidation reaction using the compound (I-1), regardless of the type of the carboxylic acid compound and the amine compound, no further addition of a base is required, and in each case, 10 minutes. It was found that the reaction was completed in 1 and the desired amide compound was given in high yield. It was also confirmed that even when aniline was used as the amine compound, it took some time to complete the reaction, but the amidation reaction proceeded in the same high yield. On the other hand, as shown in the comparative example, when DMT-3,5-LUT is used as a dehydration condensing agent, the yield of the target amide compound is obtained when no further base (for example, NMM) is added. It was confirmed that the rate was significantly reduced and that the compound in which the amine compound was introduced into the triazine ring derived from the dehydration condensing agent produced as much as 31% by-product.

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

As described above, as shown in Tables 1 to 3, by using the compound (I) of the present invention as a dehydration condensing agent, a reaction substrate and a solvent are used in the condensation reaction between various carboxylic acid compounds and an amine compound or an alcohol compound. And / or regardless of the type of base, it was confirmed that the corresponding amide compound or ester compound can be obtained in a short time (within 10 minutes) and in a high yield without causing a side reaction under mild reaction conditions. Was done.

According to the present invention, it is possible to provide a novel dehydration condensing agent having the most excellent condensing ability among the dehydration condensing agents having a triazine skeleton developed so far. Specifically, according to the present invention, in the condensation reaction of a carboxylic acid with a nucleophilic compound selected from the group consisting of alcohol, amine, aniline and phenol, the purpose is to achieve a short time and a high yield under mild conditions. It is possible to provide a compound useful as a practical dehydration condensing agent capable of producing a carboxylic acid derivative (ester, amide, etc.), and a method for producing the same.

Claims (9)

Equation (I):

[During the ceremony,
The two Rs independently represent a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
The two R'independently indicate a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl group, and R ³ and R ⁴ independently represent a C _1-4 alkyl group or R ¹ respectively. And R ³ , R ³ and R ⁴ , and / or R ² and R ⁴ , respectively, independently, together with the carbon and / or nitrogen atoms to which they bind, and further select from oxygen and sulfur atoms. It may contain a heteroatom to be added, may form a substituted 5-8 membered ring; and X ^- is a non-nucleophilic or poorly nucleophilic pair. Indicates an anion. ]
The compound represented by. 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 combined with the nitrogen atom to which they are attached. The compound according to claim 1, further forming a 5- or 6-membered ring which may further contain a heteroatom selected from an oxygen atom and a sulfur atom. The two Rs are both hydrogen atoms,
The two R's are both hydrogen atoms, C _1-4 alkyl groups, or halo C _1-4 alkyl groups.
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are both methyl or ethyl groups, or R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form a pyrrolidinyl or piperidyl group, ^and X- Fluoride ion, chloride ion, bromide ion, iodide ion, optionally substituted alkyl sulfonate ion, optionally substituted aryl sulfonate ion, perchlorate ion, tetrafluoroborate ion, hexafluorophosphate ion, The compound according to claim 1, which is a counter anion selected from the group consisting of a hexafluoroantimonate ion, a tetraphenylborate ion and an alsenato ion. R and R'are all hydrogen atoms,
Both R ¹ and R ² are hydrogen atoms,
R ³ and R ⁴ are both methyl or ethyl groups, and X ^- is fluoride ion, chloride ion, bromide ion, iodine ion, C _1-4 alkyl sulfonate ion, halo C _1-4 alkyl sulfonate. The compound according to claim 1, which is a counter anion selected from the group consisting of an ion, a optionally substituted phenylsulfonate ion, and a perchlorate ion. A dehydration condensing agent comprising the compound according to any one of claims 1 to 4. A method for dehydrating and condensing a nucleophile selected from the group consisting of alcohol, amine, aniline and phenol, and a carboxylic acid, which comprises using the dehydration condensing agent according to claim 5 and a base. Equation (IV):

[During the ceremony,
The two Rs independently represent a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group;
The two R'independently indicate a hydrogen atom, a C _1-6 alkyl group, a halo C _1-6 alkyl group, or an optionally substituted C _6-10 aryl group; and
Y indicates a leaving group. ]
By heating the compound represented by the above in the presence of a divalent palladium catalyst, the formula (III):

[Each symbol in the formula has the same meaning as described above. ]
The step of converting to the compound represented by the above formula (III) and the compound represented by the above formula (III) are expressed in the formula (II) :.

[During the ceremony,
R ¹ and R ² independently represent a hydrogen atom or a C _1-4 alkyl group, and R ³ and R ⁴ independently represent a C _1-4 alkyl group or R ¹ respectively. And R ³ , R ³ and R ⁴ , and / or R ² and R ⁴ , respectively, independently, together with the carbon and / or nitrogen atoms to which they bind, and further select from oxygen and sulfur atoms. It may contain a heteroatom to be substituted, and may form a 5- to 8-membered ring which may be substituted. ]
By reacting with the compound represented by, the formula (I'):

[During the ceremony,
Y ⁻ indicates a counter anion derived from a leaving group, and other symbols indicate the same meanings as described above. ]
Formula (I), which comprises the step of converting to the compound represented by.

[During the ceremony,
X ^- indicates a non-nucleophilic or low nucleophilic counter anion, and the other symbols are synonymous with the above. ]
A method for producing a compound represented by. The manufacturing method according to claim 7 ^, wherein Y ^- is the same as X-. The production method according to claim 7, further comprising a counter-anion exchange reaction step from the compound of the formula (I') to the compound of the formula (I).