JP6705111B2 - Triazinone compound - Google Patents

Description

The present invention relates to a novel triazinone compound. The present invention also relates to a dehydration condensing agent comprising the above triazinone compound for efficiently producing various carboxylic acid derivatives (eg, ester, amide) in water or a water-containing organic solvent.

Carboxylic acid derivatives such as esters and amides are important compounds that form the basic skeleton of various organic compounds such as pharmaceuticals, 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) capable of producing an amide compound under mild reaction conditions are commercially available. Most commonly used. However, carbodiimide-based condensing agents are often compounds that cause problems such as rash, so caution is required in handling, and when used in a condensation reaction in a protic organic solvent, the reaction yield decreases, etc. 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 when producing the pyridinium oxide compound, carcinogenicity However, there is a problem in that the work environment must be paid close attention because methyl iodide must be used.

On the other hand, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl) reported by Kaminsky et al. and the present inventor at about the same time as a condensing agent for amide compound synthesis that does not cause irritation and 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 of Kaminsky et al., a carboxylic acid compound and a condensing agent are reacted in equimolar amounts to once generate a reactive derivative as an intermediate, and then the reactive derivative is reacted with an amine compound. Since the amide compound was obtained by the above process, the yield of the amide compound varied widely from 17 to 73%, which was not satisfactory.

Further, the present inventor has 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (hereinafter sometimes abbreviated as DMT-MM). As a result of examining an amide production method using a dimethoxytriazine type quaternary ammonium salt, it was found that the quaternary ammonium salt exhibits high condensation activity even in the presence of an amine compound. This makes it possible to coexist three kinds of reaction reagents of a quaternary ammonium salt, a carboxylic acid compound and an amine compound, and succeeded in improving the reaction yield (Non-Patent Documents 3 and 4; Patent Document 1).

International Publication No. 2000/53544

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., Chem. Eur. J., 2012, 18, 15856-15867.

An object of the present invention is to provide a novel compound having a different chemical structure from the dimethoxytriazine type quaternary ammonium salt and useful as a dehydration condensation agent.

The present inventor, under such circumstances, as a result of extensive studies, by converting the triazine ring in the dimethoxytriazine type quaternary ammonium salt into a triazinone ring, the elimination ability in the dehydration condensation reaction is improved, and excellent condensation is achieved. The inventors have found that it can be used as an agent and completed the present invention.

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

[In the formula,
R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group;
R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, Represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted;
R ³ represents a C _1-4 alkyl group;
R ⁴ and R ⁵ each independently represent an optionally substituted alkyl group, or R ⁴ and R ⁵ are optionally substituted together with the nitrogen atom to which they are attached. Forming a secondary cyclic amino group, or
R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted tertiary cyclic amino group; and Y ⁻ is non-nucleophilic or Shows a counter anion with low nucleophilicity. ]
A compound represented by:
[2] R ¹ is a C _1-6 alkyl group or a C _2-6 alkenyl group,
R ² is a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or an optionally substituted 3 To a 8-membered cyclic amino group, or an optionally substituted C _6-10 aryl group,
R ³ is a methyl group;
R ⁴ and R ⁵ are each independently a C _1-6 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are substituted with 3 to 8 members. Optionally forms a secondary cyclic amino group, and Y ⁻ is a fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate. A compound according to the above [1], which is a counter anion selected from the group consisting of a salt, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate and arsenate;
[3] R ¹ is a methyl group or an allyl group;
R ² _{is, C 1-6 alkoxy, C 1-6} alkyl mono- or di-substituted amino group with a group, substituted with 5-6 membered cyclic amino group, or a halogen atom or a _{C 1-6} alkyl group Is a phenyl group which may be
R ³ is a methyl group;
R ⁴ and R ⁵ are each independently a C _1-4 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are bound are a 5-6 membered secondary ring. Forming an amino group, and Y ⁻ is composed of fluoride, chloride, bromide, iodide, C _1-4 alkyl sulfonate optionally substituted with a halogen atom, optionally substituted phenyl sulfonate, and perchlorate. The compound according to the above [1], which is a counter anion selected from the group;
[4] R ¹ is a methyl group or an allyl group;
R ² is a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group, or a C _1-4 alkyl group. A phenyl group which may be substituted,
R ³ is a methyl group;
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 4-morpholinyl, 1-pyrrolidinyl or 1-piperidyl group, and Y ⁻ is chloride, trifluoromethanesulfonate, methanesulfon. The compound according to [1] above, which is a counter anion selected from the group consisting of nato, benzene sulfonate, toluene sulfonate, 2-nitrobenzene sulfonate and perchlorate;
[5] A dehydration condensation agent comprising the compound according to any one of [1] to [4] above;
[6] Formula (II):

[In the formula,
R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group;
R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, Represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted; and Y'is a halogen atom, trifluoromethane A sulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group is shown. ]
A compound represented by:
[7] The compound described in [6] above and a compound of formula (III):

[In the formula,
R ³ represents a C _1-4 alkyl group; and R ⁴ and R ⁵ each independently represent an optionally substituted alkyl group, or R ⁴ and R ⁵ are bound to them. Forming a secondary cyclic amino group which may be substituted together with a nitrogen atom; or
R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted tertiary cyclic amino group. ]
A mixture of compounds represented by:
[8] A dehydration condensing agent comprising the mixture according to [7] above;
[9] Formula (IV):

[In the formula,
R ^2a is a halogen atom, an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or an optionally substituted. An alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and Y ^a is a halogen atom , A trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group. ]
A compound represented by the formula (IIa):

[In the formula, the definitions of R ^2a and Y ^a are as defined above. ]
A compound of formula (II′):

[In the formula, R ^2b represents an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or an optionally substituted group. A good alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and Y ^a is defined as follows. , Has the same meaning as above. ]
And the like.

According to the present invention, it can be stably used not only in a protic organic solvent such as methanol, but also in a wide range of solvents including aprotic organic solvents such as THF and water, and is stable and easy to handle, and has high yield. It is possible to provide a compound useful as a practical dehydration-condensation agent capable of producing a desired carboxylic acid derivative (ester, amide, etc.) in a short time.

Hereinafter, the present invention will be described in detail.

(Definition)

In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “alkyl group” in the “alkyl group which may be substituted” means a linear or branched alkyl group having 1 or more carbon atoms, and is particularly limited in the carbon number range. When it is not present, it is preferably a C _1-12 alkyl group, more preferably a C _1-6 alkyl group, and particularly preferably a C _1-4 alkyl group.

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

In the present specification, the "alkoxy group" in the "optionally substituted alkoxy group" means a linear or branched alkoxy group having 1 or more carbon atoms, and the carbon number range is not particularly limited. Preferably, it is a C _1-6 alkoxy group.

In the present specification, the “C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Examples include sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Of these, a C _1-4 alkoxy group is preferable.

In the present specification, the "alkenyl group" is preferably a linear or branched C _2-6 alkenyl group or the like, and among them, a 1-C _2-6 alkenyl group (C _2-6 alkene-1-yl). Groups) are preferred. Preferable specific examples of the 1-C _2-6 alkenyl group include, for example, vinyl, allyl (2-propenyl), 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 1-pentenyl, 2-pentenyl. , 1-hexenyl and the like, and an allyl group is particularly preferable.

In the present specification, the "alkynyl group" is preferably a C _2-6 alkynyl group or the like, and among them, a 1-C _2-6 alkynyl group (C _2-6 alkyn-1-yl group) is preferable. Preferable specific examples of the 1-C _2-6 alkynyl group include ethynyl, propargyl (2-propynyl), 1-propynyl, 1-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl and the like. Among them, an ethynyl group or a propargyl group is particularly preferable.

In the present specification, the “cycloalkyl group” means a cyclic alkyl group having 3 or more carbon atoms, and is preferably a C _3-10 cycloalkyl group unless the carbon number range is particularly limited. ..

In the present specification, examples of the “C _3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Among them, a C _3-8 cycloalkyl group is preferable, a C _3-6 cycloalkyl group is more preferable, and a cyclopentyl group or a cyclohexyl group is particularly preferable.

In the present specification, the “cycloalkenyl group” means a cyclic alkenyl group having 3 or more carbon atoms, and is preferably a C _3-10 cycloalkenyl group unless the carbon number range is particularly limited. ..

In the present specification, examples of the “C _3-10 cycloalkenyl group” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl. Etc. Especially, a _C3-6 cycloalkenyl group is preferable.

The above C _3-10 cycloalkyl group and C _3-10 cycloalkenyl group may each be condensed with a benzene ring to form a condensed ring group, and examples of such a condensed ring group include indanyl, Examples include dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.

Further, the above C _3-10 cycloalkyl group and C _3-10 cycloalkenyl group may be a C _7-10 bridged hydrocarbon group. Examples of the C _7-10 bridged hydrocarbon group include bicyclo[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3. 2.2] nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like.

Furthermore, _{C 3-10} cycloalkyl and _{C 3-10} cycloalkenyl groups mentioned may also form a _{C 3-10} cycloalkane or _{C 3-10} cycloalkene and spirocyclic groups, respectively. _Here, as the _{C 3-10} cycloalkane and _{C 3-10} cycloalkene, ring are exemplified corresponding to _{C 3-10} cycloalkyl group and _{C 3-10} cycloalkenyl groups described above. Examples of such a spiro ring group include spiro[4.5]decan-8-yl and the like.

In the present specification, the “aryl group” in the “aryl which may be substituted” and the “aryloxy group which may be substituted” means a monocyclic or polycyclic (condensed) aromatic group. It means a hydrocarbon group, specifically, a C _6-22 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, terphenyl, diphenylnaphthyl, 2-anthryl, phenanthryl and the like. Especially, a _C6-10 aryl group is preferable.

In the present specification, examples of the “C _6-10 aryl group” include phenyl, 1-naphthyl and 2-naphthyl, and phenyl is particularly preferable.

In the present specification, the “optionally substituted aryloxy group” means a group in which an “optionally substituted aryl group” is bonded to an oxygen atom. Examples of the “aryloxy group” include C _6-10 aryloxy groups such as phenoxy, 1-naphthyloxy and 2-naphthyloxy, and among them, a phenoxy group is preferable.

In the present specification, "aralkyl" means a group in which an "aryl group" is substituted on an "alkyl group", and preferably "C _7-14 aralkyl".

In the present specification, the "C _7-14 aralkyl" means a group in which a "C _1-4 alkyl group" is substituted with a "C _6-10 aryl group", and for example, 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, biphenylylmethyl and the like.

In the present specification, the “optionally substituted aralkyloxy group” means a group in which an “optionally substituted aralkyl group” is bonded to an oxygen atom. Examples of the “aralkyloxy group” include C _7-14 aralkyloxy groups such as benzyloxy, 1-naphthylmethyloxy and 2-naphthylmethyloxy, and among them, a benzyloxy group is preferable.

In the present specification, examples of the “heterocyclic group” include an aromatic heterocyclic group and a non-aromatic heterocyclic group.

Here, the aromatic heterocyclic group is, for example, a 4- to 7-membered (preferably 5 or 7-membered) containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring-constituting atoms. 6-membered) monocyclic aromatic heterocyclic groups and condensed aromatic heterocyclic groups. Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms. (Eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a ring formed by fusion of 1 or 2 selected from a benzene ring. Examples include groups that are derived.

Suitable examples of the aromatic heterocyclic group include:
A monocyclic aromatic heterocyclic group such as furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl;
Quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzpyrazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridyl, thienopyridyl, imidazopyridyl A condensed aromatic heterocyclic group such as razinyl, pyrazolopyridyl, pyrazolothienyl, pyrazolotriazinyl and pyridopyridyl;
Etc.

When the aromatic heterocyclic group is bonded to a carbon atom forming the triazine ring, it may form a bond with either a hetero atom or a carbon atom forming the aromatic heterocyclic group, and the aromatic heterocyclic group is A quaternary salt (eg, 1-pyridinio group) may be formed when a bond is formed with the constituting hetero atom (particularly nitrogen atom).

In the present specification, the “nitrogen-containing aromatic heterocyclic group” means at least one nitrogen atom as a ring-constituting atom in the “aromatic heterocyclic group” exemplified as the above “aromatic heterocyclic group”. It means a monocyclic aromatic heterocyclic group or a condensed aromatic heterocyclic group which may further contain 1 or 2 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom.

Preferable examples of the nitrogen-containing aromatic heterocyclic group include
A monocyclic nitrogen-containing aromatic heterocyclic group such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl;
Quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzpyrazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridyl, thienopyridyl, imidazopyrazinyl, pyrazolo. A condensed nitrogen-containing aromatic heterocyclic group such as pyridyl, pyrazolothienyl, pyrazolotriazinyl, pyridopyridyl;
Etc.

Examples of the non-aromatic heterocyclic group include 3 to 7-membered (preferably 4 to 7-membered) containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in addition to carbon atoms as ring-constituting atoms. , And more preferably 5 or 6-membered) monocyclic non-aromatic heterocyclic groups and condensed non-aromatic heterocyclic groups. Examples of the fused non-aromatic heterocyclic group include a ring corresponding to the 3- to 7-membered monocyclic non-aromatic heterocyclic group and a 5- or 6-membered aromatic group containing 1 or 2 nitrogen atoms. 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring Examples thereof include a group derived from a condensed ring, a group obtained by partial saturation of the group, and the like.

Suitable examples of the non-aromatic heterocyclic group include:
Azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, dioxolyl, pyranyl, tetrahydro, pyranyl, tetrahydro, pyrazolyl , Tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl, and other monocyclic non-aromatic heterocyclic groups;
Dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, dihydrobenzodioxynyl, dihydrobenzodioxepinyl, tetrahydrobenzofuranyl, chromenil, dihydrochromenil, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl A condensed non-aromatic heterocyclic group such as tetrahydroisoquinolyl, dihydrophthalazinyl, hexahydrofuropyrrolyl, etc.;
Etc.

The non-aromatic heterocyclic group may be crosslinked. Preferable examples of the bridged non-aromatic heterocyclic group include (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl and the like.

In the present specification, the “heterocyclic group” may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.

In the present specification, the “substituted amino group” means a group in which at least one of the two hydrogen atoms of the amino group is substituted with a group other than a hydrogen atom, and both of the two hydrogen atoms are When substituted with a substituent, the substituents may be the same or different.

In the present specification, as the substituent constituting the “substituted amino group”, for example, the amino-protecting group described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980) and the like can be used, and C _{1 -6} alkyl group, C _1-6 alkoxy group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _6-10 aryl group, heterocyclic group, C _7-14 aralkyl group, benzhydryl group, trityl group, Acyl group (eg, formyl group, C _1-6 alkyl-carbonyl group, C _1-6 alkoxy-carbonyl group, C _2-6 alkenyloxycarbonyl group, C _6-10 aryl-carbonyl group, C _7-14 aralkyl - carbonyl _{group, C 6-10} aryloxy - carbonyl _{group, C 7 - 14} aralkyloxy - carbonyl _{group, C 1-6} alkylsulfonyl _{group, C 6-10} arylsulfonyl group, a mono- or di _{-C 1-6} alkyl - Examples thereof include a carbamoyl group, a 9-fluorenylmethyloxycarbonyl group, a phthaloyl group, etc.) and a tri-substituted silyl group. The above substituents may each be further substituted with a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-carbonyl group, a cyano group, a nitro group or the like. Specific examples of the substituent of the substituted amino group are, independently, methyl, ethyl, isopropyl, benzyl, phenyl, pyridyl, methoxy, acetyl, trifluoroacetyl, pivaloyl, benzoyl, naphthoyl, tert-butoxycarbonyl, 2 , 2,2-Trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzhydryl, trityl, phthaloyl, allyloxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, trimethylsilyl. Ethoxycarbonyl, dimethylcarbamoyl and the like can be mentioned, and preferably methyl, phenyl, which may be substituted with a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy-carbonyl group, a cyano group or a nitro group, Examples include methoxy, acetyl, benzoyl, methanesulfonyl, benzenesulfonyl and the like.

Other preferable examples of the “substituted amino group” include an amino group mono- or di-substituted with a C _1-6 alkyl group, an optionally substituted secondary cyclic amino group and the like.

In the present specification, the "mono- or di-substituted amino group with a C _1-6 alkyl group" means a one or two C _1-6 alkyl group is bonded group to the nitrogen atom of the amino group Examples include methylamino, dimethylamino, ethylamino, diethylamino and the like. Preferred is an amino group (eg, dimethylamino etc.) di-substituted with a C _1-6 alkyl group.

In the present specification, the “cyclic amino group” means a secondary or tertiary saturated or partially unsaturated nitrogen-containing non-aromatic heterocyclic group formed together with the nitrogen atom of the amino group. The “cyclic amino group” may have a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the carbon atom as another ring-constituting atom of the nitrogen atom of the amino group, and may have 3 to 8 members ( Preferred are 5- or 6-membered) monocyclic nitrogen-containing non-aromatic heterocyclic groups and condensed nitrogen-containing non-aromatic heterocyclic groups. Examples of "cyclic amino group", for example, azetidinyl, pyrrolidinyl, pyrrolinyl, piperidyl, azepanyl, morpholinyl, thiomorpholinyl, piperazinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, dihydropyridyl, tetrahydropyridyl, 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group such as tetrahydropyrimidinyl, dihydrotriazolyl, tetrahydrotriazolyl, etc., the monocyclic nitrogen-containing non-aromatic heterocycle and 1 or 2 carbon rings A secondary cyclic amino group such as a condensed cyclic group, and a tertiary cyclic amino group such as a quinuclidinyl group.

Preferable examples of “optionally substituted (secondary) cyclic amino group” include, for example, optionally substituted azetidinyl, pyrrolidinyl, pyrrolinyl, piperidyl, azepanyl, morpholinyl, thiomorpholinyl, 2,5 -Dioxopyrrolidin-1-yl (succinimide group), 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl (phthalimido group), 2,5-dioxo-3-pyrroline- 1-yl (maleinimide group), 2-piperidone-1-yl, 1,2-dihydro-2-oxopyridin-1-yl, 1,4-dihydro-4-oxopyridin-1-yl, 9H-carbazole -9-yl, 1,3-dioxo-1,3,3a,4,7,7a-hexahydro-4,7-methano-2H-isoindol-2-yl(5-norbornene-2,3-dicarboxy Imido), 2-oxoimidazolin-1-yl and other secondary cyclic amino groups, and preferably 4-morpholinyl, 1-pyrrolidinyl (pyrrolidin-1-yl) or 1-piperidyl (piperidin-1-yl). ).

Preferable examples of the “optionally substituted tertiary cyclic amino group” include, for example, optionally substituted quinuclidinyl (eg, quinuclidinyl, 3-aminoquinuclidinyl, 3-hydroxyquinuclidinyl). Etc.), 1,4-diazabicyclo[2.2.2]octyl (DABCO), a tertiary amino group derived from strychnine, brun, quinine, quinidine, mequitazine and the like, and the like, and preferably quinuclidinyl.

In the present specification, examples of the “substituted mercapto group” include, for example, a C _1-20 alkyl group, a C _2-20 alkenyl group, a C _3-10 cycloalkyl group and a C _3-10 cyclo which may each be substituted. Alkenyl group, C _6-10 aryl group, C _7-14 aralkyl group, acyl group (eg, C _1-20 alkyl-carbonyl group, C _6-10 aryl-carbonyl group, C _1-20 alkylsulfonyl group, C _{6 -10} arylsulfonyl group, etc.), an optionally substituted silyl group (eg, triC _1-4 alkylsilyl group etc.), a mercapto group substituted with a substituent selected from a heterocyclic group and the like.

Preferable examples of the “substituted mercapto group” include, for example, a group derived from an odorless thiol from the viewpoint of easy handling during production. Specifically, for example, Node, M. et al., Tetrahedron Lett., 2001, 42, 9207 described in dodecylthio group, 4-dodecylphenylthio group and the like are preferable, and dodecylthio group derivable from a commercial product is particularly preferable. preferable.

In the present specification, the “acyl group” in the “acyl group which may be substituted” is, for example, formyl group, C _1-20 alkyl-carbonyl group, C _1-20 alkoxy-carbonyl group, C _3-10. Cycloalkyl-carbonyl group, C _3-10 cycloalkyloxy-carbonyl group, C _7-14 aralkyl-carbonyl group, C _7-14 aralkyloxy-carbonyl group, C _6-10 aryl-carbonyl group, C _6-10 aryl oxy - carbonyl group, a carbamoyl group (-CONH _2), a mono- or di _{-C 1-6} alkyl - carbamoyl group, a mono- or di _{-C 3-10} cycloalkyl - carbamoyl group, mono- or di - heterocyclic carbamoyl groups, C _1-20 alkylsulfonyl _{group, C 6-10} arylsulfonyl group, a cyclic aminocarbonyl group, a heterocyclic carbonyl group, a thiocarbamoyl group (-CSNH _2), mono- or di _{-C 1-6} alkylthiocarbamoyl group, mono- or di - C _3-10 cycloalkylthio carbamoyl group, cyclic aminocarbonyl group, a heterocyclic carbonyl group, a sulfamoyl group _{(-S (O) 2 NH 2} ), mono- or di _{-C 1-6} alkylsulfamoyl group, a mono- or di - It means a group including a C _3-10 cycloalkylsulfamoyl group, a cyclic aminosulfonyl group, a heterocyclic sulfonyl group and the like.

Preferable examples of the “optionally substituted acyl group” include optionally substituted C _1-6 alkyl-carbonyl group (eg, acetyl, pivaloyl, etc.), optionally substituted C _1-6. Alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), optionally substituted C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, etc.), optionally substituted C _3-10 cyclo Alkyl-carbonyl group (eg, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), optionally substituted C _3-10 cycloalkyloxy-carbonyl group, optionally substituted C _6-10 aryl-carbonyl group (eg, benzoyl) , 1-naphthoyl, 2-naphthoyl etc.), an optionally substituted di(C _1-6 alkyl)carbamoyl group (eg, dimethylcarbamoyl etc.), an optionally substituted C _1-20 alkylsulfonyl group (eg , Methanesulfonyl, etc.), an optionally substituted C _6-10 arylsulfonyl group (eg, benzenesulfonyl, toluenesulfonyl etc.), an optionally substituted di(C _1-6 alkyl)sulfamoyl group (eg, dimethyl) Sulfamoyl), optionally substituted cyclic aminocarbonyl group (eg, pyrrolidylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl, etc.), optionally substituted cyclic aminosulfonyl group (eg, pyrrolidylsulfonyl, Piperidylsulfonyl, morpholinylsulfonyl, etc.), an optionally substituted heterocyclic carbonyl group (eg, pyridylcarbonyl, etc.) and the like can be mentioned. Among them, acyl groups such as acetyl, methoxycarbonyl, ethoxycarbonyl, benzoyl, methanesulfonyl, dodecylsulfonyl, dodecylsulfinyl, trifluoromethanesulfonyl, benzenesulfonyl, toluenesulfonyl and dimethylcarbamoyl are particularly preferable.

In the present specification, the “cyclic aminocarbonyl group” or the “cyclic aminosulfonyl group” is one in which carbonyl or sulfonyl is bonded to the ring-constituting nitrogen atom of the cyclic amino group, and examples thereof include pyrrolidinylcarbonyl group and piperidyl. A carbonyl group, a morpholinyl carbonyl group, a pyrrolidinyl sulfonyl group, a piperidyl sulfonyl group, a morpholinyl sulfonyl group, etc. are mentioned.

In the present specification, the heterocyclic ring of the “heterocyclic carbonyl group” or the “heterocyclic sulfonyl group” includes the “aromatic heterocyclic group” and the “non-aromatic heterocyclic group” exemplified as the above “heterocyclic group”. Can be mentioned.

“C _1-6 alkyl-carbonyl group” means a group in which “C _1-6 alkyl group” is bonded to —C(═O)—, and examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl. , Butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, hexylcarbonyl and the like. Among them, a C _1-4 alkyl-carbonyl group is preferable, and an acetyl group is particularly preferable.

In the present specification, the “C _6-10 aryl-carbonyl group” means a group in which a “C _6-10 aryl group” is bonded to —C(═O)—, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like can be mentioned. Of these, a benzoyl group is preferable.

In the present specification, the “C _1-6 alkoxy-carbonyl group” means a group in which a “C _1-6 alkoxy group” is bonded to —C(═O)—, for example, methoxycarbonyl, ethoxycarbonyl, Examples thereof include propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and hexyloxycarbonyl. Of these, a C _1-4 alkoxy-carbonyl group is preferable.

In the present specification, the “alkylsulfinyl group” means a group in which an “alkyl group” is bonded to —S(O)—, and examples thereof include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl and isobutyl. C _1-20 such as sulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, hexylsulfinyl, heptylsulfinyl, octylsulfinyl, nonylsulfinyl, decylsulfinyl, undecylsulfinyl and dodecylsulfinyl. An alkylsulfinyl group is mentioned. Of these, a dodecylsulfinyl group is preferable.

In the present specification, the “arylsulfinyl group” means a group in which an “aryl group” is bonded to —S(O)—, and examples thereof include C ₆ such as phenylsulfinyl, 1-naphthylsulfinyl, and 2-naphthylsulfinyl. _-10 arylsulfinyl group. Of these, a phenylsulfinyl group is preferable.

In the present specification, the “alkylsulfonyl group” means a group in which an “alkyl group” is bonded to —S(O) ₂ —, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, C _{1 -,} such as isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, nonylsulfonyl, decylsulfonyl, undecylsulfonyl, dodecylsulfonyl, etc. ₂₀ alkyl sulfonyl group is mentioned. Of these, a dodecylsulfonyl group is preferable.

In the present specification, the “arylsulfonyl group” means a group in which an “aryl group” is bonded to —S(O) ₂ — and, for example, C such as phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like. _6-10 aryl sulfonyl group is mentioned. Of these, a phenylsulfonyl group is preferable.

In the present specification, the “alkylsulfonyloxy group” in the “optionally substituted alkylsulfonyloxy group” means a group in which an “alkyl group” is bonded to the sulfur atom of —S(O) ₂ —O—. However, for example, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, isopentylsulfonyloxy, neo. Examples thereof include C _1-6 alkylsulfonyloxy groups such as pentylsulfonyloxy and hexylsulfonyloxy. Of these, a C _1-4 alkylsulfonyloxy group is preferable. As the "optionally substituted alkylsulfonyloxy group", a methylsulfonyloxy group optionally substituted by a halogen atom (eg, 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 group. , 1-naphthylsulfonyloxy, 2-naphthylsulfonyloxy and the like. Of these, a phenylsulfonyloxy group is preferable. As the "arylsulfonyloxy group which may be substituted", a phenylsulfonyloxy group which may be substituted by a methyl group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group) is particularly preferable.

In the present specification, the “alkyl sulfonate” in the “optionally substituted alkyl sulfonate” means a group in which an “alkyl group” is bonded to —SO ₃ ^— , and examples thereof include methyl sulfonate and ethyl sulfonate. Nato, propyl sulfonate, isopropyl sulfonate, butyl sulfonate, isobutyl sulfonate, sec-butyl sulfonate, tert-butyl sulfonate, pentyl sulfonate, isopentyl sulfonate, neopentyl sulfonate, hexyl sulfonate and the like. Be done. Of these, C _1-4 alkyl sulfonate is preferable. As the "optionally substituted alkyl sulfonate", methyl sulfonate optionally substituted by a halogen atom (eg, trifluoromethane sulfonate) is particularly preferable.

In the present specification, the “arylsulfonate” in the “optionally substituted arylsulfonate” means a group in which an “aryl group” is bonded to —SO ₃ ^— , for example, phenylsulfonate, 1- _C6-10 aryl sulfonates, such as naphthyl sulfonate and 2-naphthyl sulfonate, are mentioned. Of these, phenyl sulfonate is preferable. As the "aryl sulfonate" in the "optionally substituted aryl sulfonate", phenyl sulfonate optionally substituted with a methyl group (eg, benzene sulfonate, p-toluene sulfonate) is particularly preferable.

In the present specification, the “tri-substituted silyl group” means a silyl group substituted with the same or different three 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, and a triphenylsilyl group.

In the present specification, the "optionally substituted" means that, unless otherwise specified, the compound may have one or more substituents, and the "substituent" includes ( 1) halogen atom, (2) nitro group, (3) cyano group, (4) hydroxy group, (5) substituted amino group, (6) oxo group, (7) thioxo group, (8) substituted mercapto group, ( 9) C _1-6 alkyl group, (10) C _3-8 cycloalkyl group, (11) C _3-8 cycloalkenyl group, (12) C _2-6 alkenyl group, (13) C _2-6 alkynyl group , (14) C _1-6 alkoxy group, (15) C _1-6 alkoxy-C _1-6 alkoxy group, (16) C _1-6 alkylenedioxy group, (17) C _6-10 aryl group, ( 18) C _6-10 aryloxy group, (19) C _7-14 aralkyl group, (20) C _7-14 aralkyloxy group, (21) C _1-6 alkoxy-carbonyl group, (22) C _7-14 Aralkyloxy-carbonyl group, (23)C _1-6 alkyl-carbonyl group, (24)C _6-10 aryl-carbonyl group, (25)C _1-6 alkyl-carbonyloxy group, (26)C _6-10 Aryl-carbonyloxy group, (27)C _6-10 aryloxy-carbonyl group, (28)C _1-6 alkylsulfonyl group, (29)C _6-10 arylsulfonyl group, (30)formyl group, (31) Azido group, (32)C _1-20 alkylthio group, (33)C _6-10 arylthio group, (34)di(C _1-6 alkyl)carbamoyl group, (35)tri-substituted silyl group,(36)ureido group , (37) dialkylphosphono group, (38) amidinooxy group, (39) heterocyclic oxy group and the like. Among them, halogen atom, nitro, cyano, C _1-6 alkyl, C _1-6 alkoxy, methylenedioxy, C _1-6 alkoxy-carbonyl, benzyloxycarbonyl, acetyl, benzoyl, formyl, benzyl, trityl, phenyl, phenoxy. , Naphthyl, azide, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, dimethylamino, acetyl(methyl)amino, acetyl(phenyl)amino, tert-butoxycarbonylamino. Is preferred. Further, when a plurality of substituents are present, each substituent may be the same or different.

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

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

[In the formula,
R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group;
R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, Represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted;
R ³ represents a C _1-4 alkyl group;
R ⁴ and R ⁵ each independently represent an optionally substituted alkyl group, or R ⁴ and R ⁵ are optionally substituted together with the nitrogen atom to which they are attached. Forming a secondary cyclic amino group, or
R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted tertiary cyclic amino group; and Y ⁻ is non-nucleophilic or Shows a counter anion with low nucleophilicity. ]
It is a triazinone compound represented by (hereinafter sometimes referred to as compound (I)).

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

R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group.

R ¹ is preferably a C _1-6 alkyl group or a C _2-6 alkenyl group.

R ¹ is more preferably a methyl group or an allyl group.

R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, It represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted.

R ² is preferably a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or substituted. Is a 3- to 8-membered cyclic amino group which may be substituted or a C _6-10 aryl group which may be substituted.

R ² is more preferably a C _1-6 alkoxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, a 5- or 6-membered cyclic amino group, a halogen atom or a C _1-6 alkyl group. It is a phenyl group which may be substituted with.

R ² is more preferably a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group or C _1-4. It is a phenyl group which may be substituted with an alkyl group.

R ³ represents a C _1-4 alkyl group; and R ⁴ and R ⁵ each independently represent an optionally substituted alkyl group, or R ⁴ and R ⁵ are bonded to each other. Together with the nitrogen atom form an optionally substituted secondary cyclic amino group.
In another aspect, R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted tertiary cyclic amino group.

In a preferred embodiment of R ³ , R ⁴ and R ⁵ , R ³ is a methyl group, and R ⁴ and R ⁵ are each independently a C _1-6 alkyl group, or R ⁴ and R ⁵ taken together with the nitrogen atom to which they are attached form a secondary cyclic amino group having 3 to 8 membered optionally substituted.

In a more preferred embodiment of R ³ , R ⁴ and R ⁵ , R ³ is a methyl group, and R ⁴ and R ⁵ are each independently a C _1-4 alkyl group, or R ⁴ and R ^5, together with the nitrogen atom to which they are attached form a secondary cyclic amino group 5-6 membered.

As a further preferred embodiment of R ^{3, R 4} and ^{R 5, R 3} is methyl group, and ^{R 4} and ^{R 5,} together with the nitrogen atom to which they are attached, 4-morpholinyl group, 1 To form a pyrrolidinyl group or a 1-piperidyl group.

Y ⁻ represents a counter anion that is non-nucleophilic or has low nucleophilicity.

Y ⁻ is preferably fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate. , A counter anion selected from the group consisting of tetraphenylborate and arsenate.

Y ⁻ is more preferably selected from the group consisting of fluoride, chloride, bromide, iodide, C _1-4 alkyl sulfonate optionally substituted with a halogen atom, optionally substituted phenyl sulfonate, and perchlorate. Is a counter anion.

Y ⁻ is more preferably a counter anion selected from the group consisting of chloride, trifluoromethane sulfonate, methane sulfonate, benzene sulfonate, toluene sulfonate, 2-nitrobenzene sulfonate and perchlorate. The counter anion of choice.

The following compounds are suitable as the compound (I).

[Compound (IA)]
R ¹ is a C _1-6 alkyl group or a C _2-6 alkenyl group,
R ² is a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or an optionally substituted 3 To a 8-membered cyclic amino group, or an optionally substituted C _6-10 aryl group,
R ³ is a methyl group;
R ⁴ and R ⁵ are each independently a C _1-6 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are substituted with 3 to 8 members. Optionally forms a secondary cyclic amino group, and Y ⁻ is a fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate. Compound (I), which is a counter anion selected from the group consisting of acrylate, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate and arsenate.

[Compound (IB)]
R ¹ is a methyl group or an allyl group;
R ² _{is, C 1-6 alkoxy, C 1-6} alkyl mono- or di-substituted amino group with a group, substituted with 5-6 membered cyclic amino group, or a halogen atom or a _{C 1-6} alkyl group Is a phenyl group which may be
R ³ is a methyl group;
R ⁴ and R ⁵ are each independently a C _1-4 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are bound are a 5-6 membered secondary ring. Forming an amino group, and Y ⁻ is composed of fluoride, chloride, bromide, iodide, C _1-4 alkyl sulfonate optionally substituted with a halogen atom, optionally substituted phenyl sulfonate, and perchlorate. Compound (I) which is a counter anion selected from the group.

[Compound (IC)]
R ¹ is a methyl group or an allyl group;
R ² is a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group, or a C _1-4 alkyl group. A phenyl group which may be substituted,
R ³ is a methyl group;
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 4-morpholinyl, 1-pyrrolidinyl or 1-piperidyl group, and Y ⁻ is chloride, trifluoromethanesulfonate, methanesulfon. Compound (I), which is a counter anion selected from the group consisting of nato, benzene sulfonate, toluene sulfonate, 2-nitrobenzene sulfonate and perchlorate.

Specific examples of suitable compound (I) include compound (I-1) to compound (I-5) described in the examples below.

Further, in the present invention, the compound (I), which is a synthetic precursor of the above compound (I):

[In the formula,
R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group;
R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, Represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted; and Y'is a halogen atom, trifluoromethane A sulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group is shown. ]
Also included is a triazinone compound represented by (hereinafter sometimes referred to as compound (II)).

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

R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group.

R ¹ is preferably a C _1-6 alkyl group or a C _2-6 alkenyl group.

R ¹ is more preferably a methyl group or an allyl group.

R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, It represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted.

R ² is preferably a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or substituted. Is a 3- to 8-membered cyclic amino group which may be substituted or a C _6-10 aryl group which may be substituted.

R ² is more preferably a C _1-6 alkoxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, a 5- or 6-membered cyclic amino group, a halogen atom or a C _1-6 alkyl group. It is a phenyl group which may be substituted with.

R ² is more preferably a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group or C _1-4. It is a phenyl group which may be substituted with an alkyl group.

Y'represents a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group.

Y'is preferably a chlorine atom, a trifluoromethanesulfonyloxy group or a 2-nitrobenzenesulfonyloxy group.

Y'is more preferably a chlorine atom.

The following compounds are suitable as the compound (II).

[Compound (IIA)]
R ¹ is a C _1-6 alkyl group or a C _2-6 alkenyl group,
R ² is a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or an optionally substituted 3 To an 8-membered cyclic amino group, or an optionally substituted C _6-10 aryl group, and Y′ represents a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, Or compound (II) which is a toluenesulfonyloxy group.

[Compound (IIB)]
R ¹ is a methyl group or an allyl group;
R ² _{is, C 1-6 alkoxy, C 1-6} alkyl mono- or di-substituted amino group with a group, substituted with 5-6 membered cyclic amino group, or a halogen atom or a _{C 1-6} alkyl group A phenyl group which may be present, and Y′ is a chlorine atom, a trifluoromethanesulfonyloxy group or a 2-nitrobenzenesulfonyloxy group, (II).

[Compound (IIC)]
R ¹ is a methyl group or an allyl group;
R ² is a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group, or a C _1-4 alkyl group. A compound (II), which is an optionally substituted phenyl group, and Y′ is a chlorine atom.

Suitable compound (II) is specifically compound (II-1) to compound (II-6) described in Examples below.

In another aspect of the present invention, a compound (I') which is a synthetic precursor of the above compound (I):

[In the formula, R ^2b represents an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or an optionally substituted group. Represents a good alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and Y ^a is halogen. An atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group. ]
Also included is a triazinone compound represented by (hereinafter sometimes referred to as compound (II′)).

Hereinafter, each group of the compound (II') will be described.

R ^2b represents an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, It represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted.

R ^2b is preferably a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or substituted. Is a 3- to 8-membered cyclic amino group which may be substituted or a C _6-10 aryl group which may be substituted.

R ^2b is more preferably a C _1-6 alkoxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, a 5- or 6-membered cyclic amino group, a halogen atom or a C _1-6 alkyl group. It is a phenyl group which may be substituted with.

R ^2b is more preferably a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group or C _1-4. It is a phenyl group which may be substituted with an alkyl group.

Y ^a represents a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group.

Y ^a is preferably a halogen atom, a trifluoromethanesulfonyloxy group or a 2-nitrobenzenesulfonyloxy group.

Y ^a is more preferably a chlorine atom.

The following compounds are suitable as the compound (II′).

[Compound (II'A)]
R ^2b is a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or an optionally substituted 3 To a 8-membered cyclic amino group, or an optionally substituted C _6-10 aryl group, and Y ^a represents a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, Alternatively, the compound (II′) is a toluenesulfonyloxy group.

[Compound (II'B)]
R ^2b _{is, C 1-6 alkoxy, C 1-6} alkyl mono- or di-substituted amino group with a group, substituted with 5-6 membered cyclic amino group, or a halogen atom or a _{C 1-6} alkyl group A phenyl group which may be present, and Y ^a is a chlorine atom, a trifluoromethanesulfonyloxy group or a 2-nitrobenzenesulfonyloxy group, (II′).

[Compound (II'C)]
R ^2b is a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group, or a C _1-4 alkyl group. A compound (II′) which is an optionally substituted phenyl group, and Y ^a is a chlorine atom.

Specific examples of suitable compound (II′) include compound (II-1) to compound (II-4) and compound (II-6) described in Examples described later.

Further, in still another embodiment of the present invention, a compound (Ia) which is a synthetic precursor of the above compound (I):

[In the formula, R ^2a represents a halogen atom, an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or a substituted An optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and Y ^a Represents a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group. ]
Also included is a triazinone compound represented by (hereinafter sometimes referred to as compound (IIa)).

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

R ^2a is a halogen atom, an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or an optionally substituted. An alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group is shown.

R ^2a is preferably a halogen atom, a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, and a substituent. It is an optionally substituted 3- to 8-membered cyclic amino group or an optionally substituted C _6-10 aryl group.

R ^2a is more preferably a halogen atom, a C _1-6 alkoxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, a 5- or 6-membered cyclic amino group, or a halogen atom or C _1-. It is a phenyl group which may be substituted with a ₆ alkyl group.

R ^2a is more preferably a chlorine atom, a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group or C. It is a phenyl group which may be substituted with a _1-4 alkyl group.

Y ^a represents a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group.

Y ^a is preferably a halogen atom, a trifluoromethanesulfonyloxy group or a 2-nitrobenzenesulfonyloxy group.

Y ^a is more preferably a chlorine atom.

The following compounds are suitable as the compound (IIa).

[Compound (IIaA)]
R ^2a is a halogen atom, a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or substituted. A cyclic amino group having 3 to 8 members, or an optionally substituted C _6-10 aryl group, and Y ^a is a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, or 2-nitrobenzenesulfonyl. A compound (IIa) which is an oxy group or a toluenesulfonyloxy group.

[Compound (IIaB)]
R ^2a is a halogen atom, a C _1-6 alkoxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, a 5- or 6-membered cyclic amino group, or a halogen atom or a C _1-6 alkyl group. Compound (IIa) which is a phenyl group which may be substituted, and Y ^a is a chlorine atom, a trifluoromethanesulfonyloxy group or a 2-nitrobenzenesulfonyloxy group.

[Compound (IIaC)]
R ^2a is a chlorine atom, a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group, or C _1-4. A compound (IIa), which is ^a phenyl group optionally substituted with an alkyl group, and Y ^a is a chlorine atom.

When the compound (I), compound (II), compound (II′) or compound (IIa) of the present invention has an acidic group or a basic group, it is reacted with a base or an acid to form a basic salt or an acidic group. It can be salted. When compound (I), compound (II), compound (II′) or compound (IIa) can be in the form of such a salt, the salt is also compound (I), compound (II) of the present invention. , Compound (II′) or compound (IIa).

The "basic salt" of compound (I), compound (II), compound (II') or compound (IIa) is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; magnesium salt. , Alkaline earth metal salts such as calcium salt; N-methylmorpholine salt, triethylamine salt, tributylamine salt, tert-butylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidone Organic base salts such as dinopyridine salt and picoline salt, or amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and asparaginate, more preferably alkali metal salts.

The “acid salt” of compound (I), compound (II), compound (II′) or compound (IIa) is preferably hydrofluoric acid salt, hydrochloride, hydrobromide or hydrogen iodide. Inorganic acid salts such as hydrohalides, nitrates, perchlorates, sulfates, phosphates such as acid salts; lower alkanes such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate Sulfonates, benzenesulfonates, arylsulfonates such as p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, Organic acid salts such as oxalate and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and asparaginate, most preferably hydrohalide (Especially the hydrochloride salt).

When compound (I), compound (II), compound (II′) or compound (IIa) has isomers such as optical isomers, stereoisomers and positional isomers, any one of the isomers The mixture is also included in compound (I), compound (II), compound (II′) or compound (IIa). For example, when the compound (I), the compound (II), the compound (II′) or the compound (IIa) has an optical isomer, the optical isomer resolved from the racemate is also the compound (I) or the compound (II). II), compound (II′) or compound (IIa). Each of these isomers can be obtained as a single product by a known synthesis method and separation method (eg, concentration, solvent extraction, column chromatography, recrystallization).

Compound (I), compound (II), compound (II') or compound (IIa) may be a solvate or a non-solvate.

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

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

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

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

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

Process 1
This step is a step of producing compound (I′) by reacting compound (II) with compound (III).
The reaction is carried out in a solvent that does not affect the reaction.
Further, as the compound (II), the compound (II′) or the compound (IIa) (provided that R ^2a of the compound (IIa) is other than a halogen atom) can also be used.

The usage-amount of a compound (III) is 1-4 mol normally with respect to 1 mol of a compound (II), Preferably it is 1-1.5 mol. The preferred compound (III) includes compounds corresponding to the respective definitions of R ³ , R ⁴ and R ⁵ in the compound (IA), compound (IB) and compound (IC) described above.

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, toluene; Nitriles such as acetonitrile; Alcohols such as methanol and ethanol; Esters such as ethyl acetate; Urea such as 1,3-dimethyl-2-imidazolidinone; Water; Alternatively, a buffer solution containing phosphate and the like; a mixed solvent thereof and the like can be mentioned, and among them, dichloromethane, chloroform, THF, acetonitrile and the like are particularly preferable.

The reaction temperature is generally 0°C to 120°C, preferably room temperature to 80°C.
The reaction time is usually 0.1 to 6 hours.

Process 2
In this step, the compound (I′) obtained in Step 1 is mixed with MY in a solvent that does not influence the reaction, thereby converting the counter anion Y′ ⁻ into another counter anion Y ⁻ . Then, the step of synthesizing the compound (I). Note that this step can be omitted when Y′ is the same group as Y.

M in the reactant represented by MY 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, tetramethylammonium groups, and the like, and among them, lithium, sodium, and silver are preferable.

Y in the reactive agent represented by MY is, for example, a chlorine atom, an optionally substituted alkylsulfonyloxy group, or an optionally substituted arylsulfonyloxy group among the groups corresponding to Y ^−. A group having no nucleophilicity or a low nucleophilicity other than the group capable of becoming Y′ is shown, and specific examples thereof include perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate and tetraphenylborate. Ratato, arsenate, etc. are mentioned.

The amount of MY used is usually 1 to 10 mol, preferably 1 to 3 mol, per 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-butyl methyl ether, diisopropyl ether, DME. , Ethers such as diglyme; hydrocarbons such as hexane, benzene, toluene; alcohols such as methanol and ethanol; esters such as ethyl acetate; ureas such as 1,3-dimethyl-2-imidazolidinone; water A mixed solvent thereof (eg, a mixed organic solvent, a two-layer system of water and an organic solvent, etc.) and the like, among which dichloromethane or acetonitrile is particularly preferable.

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

The compound (II) of the present invention is not particularly limited, but can be synthesized, for example, through the following reaction (Scheme 2 or 3).

[In the formula, X ¹ and X ² represent a leaving group (eg, a halogen atom, etc.), and other symbols have the same meanings as described above. ]

Process 1
This step is a step of producing a compound (4) by a nucleophilic substitution reaction of cyanuric chloride (1) and R ² H (2) or a Grignard reagent (R ² MgX ¹ ) (3). When the compound (2) is used as the nucleophile, it is carried out in the presence of a base, if necessary.
The reaction is carried out in a solvent that does not affect the reaction.

The amount of compound (2) or compound (3) used is usually 1 to 2 mol, preferably 1 to 1.2 mol, and more preferably 1 mol with respect to 1 mol of cyanuric chloride.

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. Nitriles such as acetonitrile; ketones such as acetone; mixed solvents thereof; and the like, among which THF, acetonitrile, acetone and the like are particularly preferable.

As the base, organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as sodium hydride can be preferably used.
The amount of the base used is usually 1 to 2 mol, preferably 1 to 1.2 mol, and more preferably 1 mol with respect to 1 mol of cyanuric chloride.

The reaction temperature is generally -40°C to 100°C, preferably -20°C to room temperature.
The reaction time is usually 0.5 to 6 hours.

Process 2
This step is a step of producing compound (5) by subjecting compound (4) to alkaline hydrolysis.
The reaction is carried out in a solvent that does not affect the reaction.

Examples of the solvent include ethers such as 1,4-dioxane, THF, diethyl ether, tert-butylmethyl ether, diisopropyl ether, DME, and diglyme; nitriles such as acetonitrile; ketones such as acetone; mixed solvents thereof. Etc., among which acetonitrile is particularly preferable.

The aqueous alkali solution used is not particularly limited, but examples thereof include aqueous solutions of alkali metal hydroxides such as aqueous sodium hydroxide solution and aqueous potassium hydroxide solution, and preferably aqueous sodium hydroxide solution.
The amount of the alkali metal hydroxide used is usually 1 to 4 mol, preferably 1.5 to 3 mol, and more preferably 2 mol with respect to 1 mol of the compound (4).

The reaction temperature is generally -40°C to 100°C, preferably -20°C to room temperature.
The reaction time is usually 0.2 to 6 hours.

Process 3
This step is a step for producing compound (IIa-1) by reacting the triazinone nitrogen atom of compound (5) with compound (6) in the presence of a base.
The reaction is carried out in a solvent that does not affect the reaction.

Examples of the solvent include ethers such as 1,4-dioxane, THF, diethyl ether, tert-butyl methyl ether, diisopropyl ether, DME, and diglyme; nitriles such as acetonitrile; ketones such as acetone; dimethylformamide, dimethyl. Examples thereof include amides such as acetamide; and mixed solvents thereof. Among them, acetonitrile, 1,4-dioxane, dimethylformamide or a mixed solvent of 1,4-dioxane and dimethylformamide is particularly preferable.

The base used is not particularly limited, and examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and cesium carbonate; and organic bases such as pyridine, trimethylamine, and diisopropylethylamine. Inorganic bases such as sodium hydroxide and cesium carbonate are preferred.
The amount of the base used is usually 1 to 4 mol, preferably 1.5 to 2 mol, per 1 mol of compound (5).

The usage-amount of a compound (6) is 1-10 mol normally with respect to 1 mol of a compound (5), Preferably it is 1-5 mol, More preferably, it is 2-4 mol.

The reaction temperature is generally 0°C to 100°C, preferably room temperature to 90°C.
The reaction time is usually 0.5 to 6 hours.

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

Process 1
This step is a step for producing compound (IV) by reacting compound (7) with allyl alcohol in the presence of a base.
The reaction is carried out in a solvent that does not affect the reaction.

The amount of allyl alcohol used is usually 1 to 2 mol, preferably 1 to 1.2 mol, and more preferably 1 mol with respect to 1 mol of the compound (7).

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. Nitriles such as acetonitrile; ketones such as acetone; mixed solvents thereof; and the like, and THF is particularly preferable.

As the base, organic bases such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as sodium hydride can be preferably used. Of these, sodium hydride and the like are preferable.
The amount of the base used is usually 1 to 2 mol, preferably 1 to 1.2 mol, and more preferably 1 mol with respect to 1 mol of the compound (7).

The reaction temperature is generally -40°C to 100°C, preferably -20°C to room temperature.
The reaction time is usually 0.5 to 6 hours.

Process 2
This step is a step of producing compound (IIa) from compound (IV) by reacting with a palladium catalyst in the presence of a base.
The reaction is carried out in a solvent that does not affect the reaction.

Examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and trichloroethylene; nitriles such as acetonitrile and the like, and among them, dichloromethane and chloroform are particularly preferable.

Examples of the palladium catalyst include bis(benzonitrile)palladium(II) dichloride, palladium(II) chloride, palladium(II) acetate, and palladium(0) tetrakistriphenylphosphine. Among them, bis(benzonitrile)palladium( II) Dichloride is preferred.
The amount of the palladium catalyst used is usually 0.001 to 0.5 mol, preferably 0.01 to 0.2 mol, per 1 mol of compound (IV).

Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium carbonate and cesium carbonate, organic bases such as triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine and collidine, among which sodium hydrogen carbonate or potassium carbonate is used. preferable.

The amount of the base used is determined as follows depending on the type of R ^{2a and} the type of compound (8) used in the next Step 3.
(1) When R ^2a is other than a halogen atom (for example, an alkoxy group, a morpholinyl group, an aryl group, etc.), the amount of the base used is usually 0.001 to 0.5 with respect to 1 mol of the compound (IV). It is mol, preferably 0.01 to 0.2 mol, and more preferably 0.01 to 0.05 mol.
(2) When R ^2a is a halogen atom (chlorine atom) and the compound (8) used in the next step 3 is an alcohol (eg, methanol, ethanol, isopropanol, etc.), the amount of the base used is It is usually 2 mol to 4 mol, preferably 3 mol, relative to 1 mol of compound (IV). If the amount of the base is too large, two molecules of alcohol may be introduced into the triazine ring in the next step 3, and if the amount of the base is too small, the efficiency of introducing the alcohol in the step 3 becomes poor.
(3) When R ^2a is a halogen atom (chlorine atom) and the compound (8) used in the next step 3 is an amine, the amount of the base used is 1 mol of the compound (IV), It is usually 0.001 to 0.5 mol, preferably 0.01 to 0.2 mol, and more preferably 0.01 to 0.05 mol.

The reaction temperature is generally 0°C to 100°C, preferably room temperature to 80°C.
The reaction time is usually 0.5 to 8 hours.

When R ^2a is a halogen atom (eg, chlorine atom) and R ^2b of the compound (8) is introduced onto the triazinone ring, the subsequent step is performed in one pot without post-treatment or purification after this step. Do 3.

Process 3
In this step, the reaction solution containing the compound (IIa) obtained in step 2 is slowly added dropwise to the compound (8) using a syringe pump while the temperature is kept low to react the compound (II′). This is the step of synthesizing. According to this reaction, R ^2b can be regioselectively introduced onto the triazinone ring (to the carbon atom adjacent to the nitrogen atom to which the allyl group of the triazinone ring is introduced).
Since the reaction is carried out using the reaction solution of step 2 as it is, the solvent, the base and the amount of the base used are as described in step 2.
This step can be omitted when R ^2a is not a halogen atom but the same group as R ^2b .

The amount of the compound (8) used is determined as follows depending on the kind of the compound (8).
(1) When the compound (8) is an alcohol (eg, methanol, ethanol, isopropanol, etc.), it is generally 10 to 40 mol, preferably 20 mol, relative to 1 mol of the compound (IV). When the compound (8) is alcohol, it is reacted with the compound (8) in the presence of the base (sodium hydrogen carbonate) added in step 2.
(2) When the compound (8) is an amine, it is generally 2 to 3 mol, preferably 2 mol, relative to 1 mol of the compound (IV). One of the two moles of amine is used to scavenge hydrogen chloride produced by the substitution reaction.

The reaction temperature is determined as follows depending on the type of compound (8).
(1) When the compound (8) is an alcohol (eg, methanol, ethanol, isopropanol, etc.), the reaction solution of step 2 is cooled to −18° C., the compound (8) is dropped by a syringe pump, and then stepwise. It is preferable to raise the temperature to room temperature.
(2) When the compound (8) is an amine, it is preferable to cool the reaction solution of step 2 to −78° C., drop the compound (8) with a syringe pump, and then complete the reaction at the same temperature.
When the reaction temperature is higher than the above temperature and/or the dropping rate is increased, the following formula in which two molecules of compound (8) are introduced:

[Each symbol in the formula has the same meaning as described above. ]
The ratio of the compound represented by is increased.
The reaction time is usually 12 to 24 hours when the compound (8) is alcohol, and specifically, it is about 18 hours when the compound (8) is methanol. When the compound (8) is an amine, it usually takes about 1 hour.

(Method for producing carboxylic acid derivative using compound (I) of the present invention as dehydration condensation agent)
The compound (I) of the present invention is a compound having a carboxy group (hereinafter also referred to as a carboxylic acid compound) and a compound having a nucleophilic functional group (eg, alcohol compound, mercapto(thiol) compound, amine compound). Etc.) and a carboxylic acid derivative (eg, an ester compound, a thioester compound, an amide compound, etc.) can be suitably used as a dehydrating condensing agent in the production. Among them, the compound (I) of the present invention can be particularly preferably used as a dehydration condensing agent when producing an amide compound.

In the method for producing a carboxylic acid derivative using the compound (I) of the present invention as a condensing agent, the type of the compound (I) and the amount used are not particularly limited and may be appropriately determined depending on the reaction system. Regarding the amount of the compound (I) used, if the amount is too small, the condensation reaction may be incomplete, and if it is too large, a side reaction may occur. In the case of reaction, it is usually 0.9 to 1.3 mol, preferably 0.95 to 1.2 mol, relative to 1 mol of carboxylic acid, and in the case of esterification reaction, relative to 1 mol of carboxylic acid. It is usually 0.9 to 3 mol, preferably 0.95 to 2.5 mol.

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

In the method for producing a carboxylic acid derivative, 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.
In the method for producing an amide compound of the present invention, the amounts of the carboxylic acid compound and the amine compound used are not particularly limited, but since the reaction between the carboxy group and the amino group in the production method is a stoichiometric reaction, each group is a molecule. In the reaction between the compounds each having one of them, the amine compound is usually used in an amount of 0.8 to 1.2 mol, preferably 0.9 to 1.1 mol, per 1 mol of the carboxylic acid.

The dehydration condensation reaction (amidation reaction) in the method for producing an amide compound is preferably performed in a solvent. Usually, a condensation reaction involving dehydration such as an amidation reaction is generally carried out in a dehydrated aprotic solvent, but when the compound (I) of the present invention is used as a condensing agent, The condensation reaction can be carried out not only in an aprotic solvent, but also in a wide range of solvents such as water, a protic organic solvent, or a water-containing organic solvent. The dehydration condensation reaction (amidation reaction) in the method for producing an amide compound of the present invention is preferably performed in the presence of a base.

As the solvent for the amidation reaction, any industrially usable solvent can be used without any limitation. Specific examples of the solvent include, for example, water, tetrahydrofuran (THF), ethers such as 1,4-dioxane, diethyl ether, and tert-butyl methyl ether; esters such as ethyl acetate, propyl acetate, and butyl acetate; acetonitrile; Nitriles such as propionitrile, halogenated aliphatic hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, isopropanol and tert-butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone , Carbonates such as dimethyl carbonate; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene; amides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide and the like. .. Of these, ethers such as THF, 1,4-dioxane, diethyl ether, and tert-butyl methyl ether; esters such as ethyl acetate, propyl acetate, and butyl acetate; acetonitrile, propio Nitriles such as nitriles; halogenated aliphatic hydrocarbons such as dichloromethane and chloroform; alcohols such as methanol, ethanol, isopropanol, tert-butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; carbonates such as dimethyl carbonate Buffers containing aromatic hydrocarbons such as benzene, toluene, xylene; or water or phosphate are preferably used. These solvents may be used alone or in combination of two or more.
When using a buffer solution containing a phosphate or the like as a solvent, the pH is usually 2 to 12, and preferably 5 to 9.

The base used in the amidation reaction is not particularly limited, but N-methylmorpholine (NMM) or triethylamine is preferable.

The reaction temperature in the amidation reaction varies depending on the kinds of the carboxylic acid compound and the amine compound used, but is usually -30 to 60°C, preferably room temperature.

The reaction time in the amidation reaction varies depending on the kinds of the carboxylic acid compound and the amine compound used, but is usually 0.1 to 6 hours, preferably 0.2 to 2 hours. Further, the amidation reaction can be carried out at any of normal pressure, increased pressure, or reduced pressure.

The operating procedure of the amidation reaction using compound (I) as a condensing agent (the reaction substrate, the order of adding compound (I), etc.) is not particularly limited, but three kinds of reaction reagents (that is, compound (I) and carvone It is preferable to mix and react the acid compound and the amine compound. The method for mixing the above three types of reaction reagents is not particularly limited, and each reaction reagent may be added and mixed to the reaction system at the same time, or each reaction reagent may be sequentially added and mixed to the reaction system. From the viewpoints of operability and reaction yield, it is particularly preferable to add and mix the respective reaction reagents in a reaction solvent previously kept at a predetermined temperature sequentially and without time.

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 a usual separation means such as recrystallization, distillation, chromatography and the like.

Other carboxylic acid derivatives (ester compounds, thioester compounds, etc.) can also be produced by a method similar to or similar to the above amidation reaction.

(Method for producing carboxylic acid derivative using mixture of compound (II) (or compound (II′)) and compound (III) of the present invention) (Method for producing carboxylic acid derivative using compound (I) of the present invention) Law)
In the method for producing a carboxylic acid derivative using compound (I), a mixture of compound (II) (or compound (II′)) and compound (III) is used in place of compound (I) to prepare a compound in the reaction system. The method for producing a carboxylic acid derivative, which comprises producing the compound (I) in step (4), is also included in the method for producing a carboxylic acid derivative of the present invention. Also according to this production method, the carboxylic acid derivative can be obtained in a short time and in a high yield, as in the case of using the compound (I) as a condensing agent.

Of the reaction solvent (reaction temperature, reaction time, etc.) used in the method for producing a carboxylic acid derivative using a mixture of compound (II) and compound (III), and the reaction substrate (carboxylic acid compound, amine compound and alcohol compound) The amount used is the same as in the method for producing the carboxylic acid derivative using compound (I). The equivalent relationship between the compound (II) and the compound (III) is the same as the molar ratio of the both in the step 1 of the above-mentioned production method of the compound (I).

Examples of the method for producing the carboxylic acid derivative of the present invention include the above-mentioned two production methods, that is, a method using compound (I) and a method using a mixture of compound (II) and compound (III). Since the step of isolating and purifying the condensing agent (that is, the compound (I)) can be omitted, the latter is more excellent in terms of simplicity of the experimental operation. However, when the compound (I) can be easily isolated and purified, the former method is also suitable.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, 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 Merck 60 F254 silica gel plates (thickness 0.25 mm).
^{The 1} H and ¹³ C-NMR spectra were measured by using JEOL ECS400 or ECS600 with deuterated chloroform or deuterated methanol as a solvent. Data for ¹ H-NMR are chemical shift (δ ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=double doublet, dt=double triplet, brs. = Broad singlet, sep=septet), coupling constant (Hz), integral and assignment.
High resolution mass spectral analysis (HRMS) was performed using JEOL JMS-T100TD.
The melting point (mp) was measured using a Yanagimoto trace melting point measuring device.
Elemental analysis was performed using a Yanaco CHN Corder MT-5.
Preparative thin layer chromatography was performed using Merck 60 F254 silica gel plates (thickness 0.5 mm). Flash chromatography was performed using silica gel 60N manufactured by Kanto Chemical Co., Inc. (Tokyo, Japan).
"Room temperature" in the following examples usually indicates about 10°C to about 30°C. The ratios shown in the mixed solvent are volume ratios unless otherwise specified. Unless otherwise specified,% means% by weight.

In the following examples, 2,4,6-trichloro-1,3,5-triazine, which is a raw material compound used in the synthesis of compound (I), compound (II), compound (II′) or compound (IIa) As the (cyanuric chloride), a commercially available product (manufactured by Tokyo Chemical Industry Co., Ltd.) was used as it was. As other raw material compounds, commercially available products may be used as they are, or methods known per se (for example, Hintermann, L. et al., Angew. Chem. Int. Ed., 2008, Vol.47, 8246-8250; Tanaka). , H. et al., Heterocycles, 2009, 79, 609-616; Fujita, H. et al., J. Org. Chem. 2015, 80, 11200-11205) or a method analogous thereto. ..
Methanol, ethanol, isopropyl alcohol, chloroform and 1,4-dioxane were used after distilling reagent grade ones. Dichloromethane, acetonitrile, N,N-dimethylformamide and tetrahydrofuran were purchased as anhydrous solvent grade and used as they were. The other reagents were used after purification if necessary.

Example 1
Synthesis of 1-allyl-4-chloro-6-methoxy-1,3,5-triazin-2(1H)-one (compound (II-1))

2-Allyloxy-4-chloro-6-methoxy-1,3,5-triazine (85.3 mg, 0.42 mmol), potassium carbonate (2.9 mg, 0.21 mmol), chloroform (in a 10 mL two-necked eggplant flask. 2.1 mL) was added. Under a nitrogen atmosphere, bis(benzonitrile)palladium(II) dichloride (8.1 mg, 0.21 mmol) was added to this solution at room temperature, and the mixture was heated under reflux. After 1 hour, the mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain compound (II-1) (46.7 mg, yield 55%).

Example 2
Synthesis of 1-allyl-4-chloro-6-methoxy-1,3,5-triazin-2(1H)-one (compound (II-1)) (another method)

2-Allyloxy-4,6-dichloro-1,3,5-triazine (2.02 g, 9.79 mmol), sodium hydrogen carbonate (2.47 g, 29.4 mmol), and chloroform (in a 200 mL two-necked eggplant flask. 50 mL) was added. Bis(benzonitrile)palladium(II) dichloride (113 mg, 0.29 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 4 hours to give 1-allyl-4,6-dichloro-1,3,5. -Triazin-2(1H)-one was obtained. The reaction solution was cooled to −18° C. without taking out the product, and methanol (7.9 mL, 196 mmol) was added dropwise using a syringe pump over 2 hours. After the dropping was completed, the temperature was raised to 0° C., and after 9 hours, the temperature was raised to room temperature. After 6 hours, the mixture was filtered through Celite, ethyl acetate (200 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (200 mL) and saturated brine (200 mL). Each aqueous solution was extracted twice with ethyl acetate (30 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give compound (II-1) (1.59 g, yield 81%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.85 (ddt, J=17, 11, 6.0 Hz, 1 H), 5.29 (ddt, J=17, 1.4, 1.4 Hz, 1 H) ), 5.29 (ddt, J=11, 1.4, 1.4 Hz, 1H), 4.55 (ddd, J=6.0, 1.4, 1.4 Hz, 2H), 4.16 ( 13C NMR (100 MHz, CDCl3): δ170.1, 162.8, 153.8, 129.4, 120.0, 57.9, 45.0;
HRMS (DART): Calculated _{(C 7 H 9 ClN 3 O} 2 ([M + H] +)): 202.0383; Found: 202.0400;
Anal. _{Calcd for C 7 H 8 ClN 3} O 2: C, 41.70; H, 4.00; N, 20.84. Found: C, 41.62; H, 4.01; N, 20.83.

Example 3
Synthesis of 1-allyl-4-chloro-6-isopropoxy-1,3,5-triazin-2(1H)-one (compound (II-2))

By the same method as in Example 2 above, 1-allyl-4,6-dichloro-1,3,5-triazin-2(1H)-one was obtained, and isopropanol was added thereto instead of methanol. , Compound (II-2) (yield 80%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.84 (ddt, J=17, 11, 6.0 Hz, 1 H), 5.48 (sep, J=6.4 Hz, 1 H), 5.28 ( ddt, J=16, 1.4, 1.4 Hz, 1H), 5.28 (ddt, J=11, 1.4, 1.4 Hz, 1H), 4.53 (ddd, J=6.0, 1.4, 1.4 Hz, 1H), 1.43 (d, J=6.4, 6H);
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 170.3, 161.8, 154.1, 129.7, 120.0, 77.0, 44.9, 21.8;
HRMS (DART): Calculated _{(C 9 H 13 ClN 3 O} 2 ([M + H] +)): 230.0696; Found: 230.0713;
Anal. _{Calcd for C 9 H 12 ClN 3} O 2: C, 47.07; H, 5.27; N, 18.30. Found: C, 46.97; H, 5.30; N, 18.50.

Example 4
Synthesis of 1-allyl-4-chloro-6-dimethylamino-1,3,5-triazin-2(1H)-one (compound (II-3))

Compound (II-3) was obtained in the same manner as in Example 2 above, to give 1-allyl-4,6-dichloro-1,3,5-triazin-2(1H)-one, which was replaced with methanol. Compound (II-3) (yield 62%) was obtained by adding dimethylamine to the mixture at -50°C.
¹ H-NMR (600 MHz, CDCl ₃ ): δ 6.02 (ddt, 17, 11, 5.2, 1H), 5.31-5.37 (m, 1H), 5.20-5.26( m, 1H), 4.51-4.55 (m, 2H), 3.17 (s, 6H);
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 168.9, 162.5, 156.2, 131.9, 118.3, 50.3, 41.5;
HRMS (DART): Calculated ^{_{(C 8 H 12 ClN 4 O}} ([M + H] +)): 215.0700; Found: 215.0703;
Anal. _{Calcd for C 8 H 11 N 4} OCl: C, 44.76; H, 5.17; N, 26.10. Found: C, 44.67; H, 5.15; N, 25.98.

Example 5
Synthesis of 1-allyl-4-chloro-6-morpholino-1,3,5-triazin-2(1H)-one (compound (II-4))

By the same method as in Example 2 above, 1-allyl-4,6-dichloro-1,3,5-triazin-2(1H)-one was obtained, and morpholine was added thereto at −50° C. instead of methanol. By doing so, compound (II-4) (yield 57%) was obtained.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.05 (ddt, J=17, 11, 5.0 Hz, 1 H), 5.36 (ddd, J= 11, 1.8, 1.8 Hz, 1 H) ), 5.22 (ddd, J=17, 1.8, 1.8 Hz, 1H), 4.44 (ddd, J=4.6, 1.8, 1.8 Hz, 1H), 3.79 ( t, J=5.0 Hz, 4H), 3.65 (t, J=5.0 Hz, 4H);
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 169.6, 162.6, 155.9, 131.4, 118.7, 66.4, 50.9, 49.5;
HRMS (DART): Calculated _{(C 10 H 14 ClN 4 O} 2 ([M + H] +)): 257.0805; Found: 257.0784;
Anal. _{Calcd for C 10 H 13 ClN 4} O 2: C, 46.79; H, 5.10; N, 21.83. Found: C, 46.74; H, 5.06; N, 21.78.

Example 6
Synthesis of 4-chloro-1-methyl-6-(o-tolyl)-1,3,5-triazin-2(1H)-one (compound (II-5))

(1) Synthesis of 6-chloro-4-(o-tolyl)-1,3,5-triazin-2(1H)-one

In a 200 mL two-necked eggplant flask, 2,4-dichloro-6-(o-tolyl)-1,3,5-triazine (2.8 g, 11.66 mmol) and acetonitrile (58 mL) were added. To this solution was added 1M sodium hydroxide (23.3 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was cooled to 0° C. and 1M hydrochloric acid was added until pH2. Cold water was added, and the precipitated solid was collected by filtration to obtain 6-chloro-4-(o-tolyl)-1,3,5-triazin-2(1H)-one (796 mg, yield 31%). It was
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.71-7.65 (m, 1H), 7.57-7.51 (m, 1H), 7.44-7.36 (m, 2H). , 2.60 (s, 3H).

(2) Synthesis of compound (II-5)

Methyl iodide (168 μL, 2.7 mmol), cesium carbonate (440 mg, 1.35 mmol), 1,4-dioxane (2.25 mL), N,N-dimethylformamide (2.25 mL) in a 20 mL two-necked eggplant flask. Was added. 6-Chloro-4-(o-tolyl)-1,3,5-triazin-2(1H)-one (200 mg, 0.90 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours. did. The reaction mixture was cooled to 0° C., dichloromethane (30 mL) was added, and the mixture was washed with water (30 mL) and saturated saline (60 mL). Each aqueous solution was extracted twice with dichloromethane (10 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give compound (II-5) (70 mg, yield 33%).
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.51-7.45 (m, 1H), 7.41-7.34 (m, 2H), 7.30-7.27 (m, 2H). , 3.35 (s, 3H), 2.30 (s, 3H).

Example 7
Synthesis of 4-chloro-1-allyl-6-(o-tolyl)-1,3,5-triazin-2(1H)-one (compound (II-6))

(1) Synthesis of 2-allyloxy-4-chloro-6-(o-tolyl)-1,3,5-triazine

Sodium hydride (504 mg, 12.6 mmol) and tetrahydrofuran (24 mL) were added to a 50 mL two-necked eggplant flask under a nitrogen atmosphere, cooled to 0° C., allyl alcohol (856 μL, 12.6 mmol) was added, and the mixture was returned to room temperature. It was stirred. To another 50 mL two-necked eggplant flask, under a nitrogen atmosphere, 2,4-dichloro-6-(o-tolyl)-1,3,5-triazine (2.02 g, 8.4 mmol) and tetrahydrofuran (12 mL) were added, The sodium allyl oxide/THF solution (16 mL, corresponding to 8.4 mmol) prepared above was added dropwise to this solution, and the mixture was stirred for 30 minutes. Further, a sodium allyl oxide/THF solution (4 mL, 2.1 mmol equivalent) was added, and the mixture was stirred for 30 minutes and then washed with water and saturated brine. The aqueous layer was extracted with dichloromethane three times, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=29:1) to give the title compound (1.21 g, yield 55%).

(2) Synthesis of compound (II-6)

2-Allyloxy-4-chloro-6-(o-tolyl)-1,3,5-triazine (100 mg, 0.38 mmol), potassium carbonate (11 mg, 0.076 mmol) and dichloromethane (in a 10 mL two-necked eggplant flask. 1.9 mL) was added. Bis(benzonitrile)palladium(II) dichloride (29 mg, 0.076 mmol) was added to this solution at room temperature under a nitrogen atmosphere, and the mixture was stirred for 7 hours. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give compound (II-6) (46.8 mg, yield 47%).

Example 8
4-(5-allyl-6-methoxy-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-4-methylmorpholine-4-ium chloride (Compound (I-1) ) Synthesis

1-allyl-4-chloro-6-methoxy-1,3,5-triazin-2(1H)-one (200 mg, 0.99 mmol) obtained in Example 1 or 2 and tetrahydrofuran in a 30 mL eggplant flask. (10 mL) was added. N-methylmorpholine (120 μL, 1.09 mmol) was added to this solution at 0° C. under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours. After completion of the reaction, the precipitate was collected by filtration to obtain the compound (I-1) (225 mg, yield 75%).
¹ H-NMR (400 MHz, CD ₃ OD): δ 5.92 (ddt, J=17, 11, 6.0 Hz, 1 H), 5.41 (ddt, J=17, 1.4, 1.4 Hz, 1H), 5.32 (ddt, J=11, 1.4, 1.4Hz, 1H), 4.62 (ddd, J=6.0, 1.4, 1.4Hz, 2H), 4.50 -4.40 (m, 2H), 4.26 (s, 3H), 4.10-4.01 (m, 2H), 3.95-3.86 (m, 2H), 3.86-3. .76 (m, 2H), 3.51 (s, 3H);
¹³ C-NMR (100 MHz, CD ₃ OD): δ 168.4, 167.4, 156.2, 130.7, 120.4, 63.3, 61.3, 59.6, 55.9, 47. .0;
HRMS (ESI): Calculated _{(C 12 H 19 N 4 O} 3 ([M-Cl] +)): 267.1457, Found: 267.14599.

Example 9
4-(5-allyl-6-isopropoxy-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (Compound (I-2 )) Synthesis

Compound (I-2) (yield 82%) was obtained by using the compound (II-2) obtained in Example 3 according to the method of Example 8 above.
¹ H-NMR (400 MHz, CD ₃ OD): δ 5.92 (ddt, J=17, 10, 6.0 Hz, 1 H), 5.52 (sep, J=6.4, 1 H), 5.40. (Dd, J=17, 1.4 Hz, 1H), 5.32 (dd, J=10, 1.4 Hz, 1H), 4.89 (s, 3H), 4.61 (ddd, J=6. 0, 1.4, 1.4 Hz, 2H), 4.47-4.38 (m, 2H), 4.11-4.01 (m, 2H), 3.96-3.86 (m, 2H). ), 3.86-3.76 (m, 2H), 3.51 (s, 3H), 1.48 (d, J=6.4Hz, 6H);
¹³ C-NMR (100 MHz, CD ₃ OD): δ 168.6, 166.2, 156.4, 130.8, 120.4, 80.4, 63.3, 61.2, 55.7, 46. .9, 21.9;
HRMS (ESI): Calculated _{(C 14 H 23 N 4 O} 3 ([M-Cl] +)): 295.1770, Found: 295.1792.

Example 10
4-(5-allyl-6-dimethylamino-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (Compound (I-3 )) Synthesis

By using the compound (II-3) obtained in Example 4 according to the method of Example 8 above, compound (I-3) (yield 96%) was obtained.
¹ H-NMR (400 MHz, CD ₃ OD): δ 6.11 (ddt, J=17, 11, 5.0 Hz, 1 H), 5.28-5.41 (m, 2H), 4.56-4 .64 (m, 2H), 3.64-4.47 (m, 8H), 3.46 (s, 3H), 3.28 (s, 6H);
¹³ C-NMR (100 MHz, CD ₃ OD): δ 166.8, 164.8, 159.6, 133.8, 118.4, 63.5, 60.8, 56.1, 52.2, 42. .3;
HRMS (ESI): Calculated _{(C 13 H 22 N 5 O} 2 ([M-Cl] +)): 280.1774, Found: 280.1790.

Example 11
4-Methyl-4-(5-methyl-4-oxo-6-(o-tolyl)-4,5-dihydro-1,3,5-triazin-2-yl)morpholin-4-ium chloride (compound ( Synthesis of I-4))

Compound (I-4) (yield 80%) was obtained by using the compound (II-6) obtained in Example 7 according to the method of Example 8 above.
¹ H-NMR (400 MHz, CD ₃ OD): δ 7.60-7.53 (m, 1H), 7.50-7.40 (m, 3H), 4.51-4.43 (m, 2H). ), 4.13-4.04 (m, 2H), 3.99-3.89 (m, 2H), 3.89-3.79 (m, 2H), 3.54 (s, 3H), 3.47 (s, 3H), 2.36 (s, 3H);
HRMS (ESI): Calculated _{(C 16 H 21 N 4 O} 2 ([M-Cl] +)): 301.1665, Found: 301.1637.

Example 12
1-(5-allyl-6-dimethylamino-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)-1-methylpyrrolidin-4-ium chloride (compound (I-5 )) Synthesis

According to the method of Example 8 above, the compound (II-3) obtained in Example 4 was used, and N-methylpyrrolidine was used instead of N-methylmorpholine to give a compound (I-5) (yield 72 %) was obtained.
¹ H-NMR (400 MHz, CD ₃ OD): δ 6.09 (ddt, J=17.5, 10.5, 5.0 Hz, 1 H), 5.38-5.26 (m, 2H), 4 .61-4, 56 (m, 2H), 4.46-4.37 (m, 2H), 4.65-3.75 (m, 2H), 3.46 (s, 3H), 3.28. (S, 6H), 2.35-2.15 (m, 2H);
¹³ C-NMR (100 MHz, CD ₃ OD): δ 168.6, 164.6, 159.7, 133.8, 118.4, 65.8, 56, 7, 52.0, 42.1, 23. .3;
HRMS (ESI): Calculated ^{_{(C 13 H 22 N 5 O}} ([M-Cl] +)): 264.1842, Found: 264.1797.

Experimental example 1
Method for Producing Amide Compound of the Present Invention (Method 1) Using Compound (I) as Dehydrating Condensing Agent

(Experimental operation example 1) Methanol (solvent) (2 mL), 3-phenylpropionic acid (60.1 mg, 0.40 mmol), 2-phenethylamine (55 μL, 0.44 mmol) and N-methylmorpholine ( Base) (48 μL, 0.44 mmol) was added. Compound (I-1) (146 mg, 0.44 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. A 1M potassium hydrogen sulfate aqueous solution (4 mL) was added to terminate the reaction. After the solution was distilled off with an evaporator, dichloromethane was added to the residue for dilution, and the mixture was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution 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=2:1) to give N-phenethyl-3-phenylpropanamide (90.8 mg, yield 89%).

(Experimental operation example 2) THF (solvent) (2 mL), 3-phenylpropionic acid (60.1 mg, 0.40 mmol), 2-phenethylamine (55 μL, 0.44 mmol) and triethylamine (base) were added to a 20 mL eggplant flask. 61 μL, 0.44 mmol) was added. Compound (I-1) (146 mg, 0.44 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. A 1M potassium hydrogen sulfate aqueous solution (4 mL) was added to terminate the reaction. After the solution was distilled off with an evaporator, the residue was diluted with dichloromethane and washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution 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=2:1) to give N-phenethyl-3-phenylpropanamide (96.4 mg, yield 95%).

Experimental example 2
Method for producing amide compound of the present invention (method 2), which uses a dehydration condensing agent produced in a reaction system by adding compound (II) and N-methylmorpholine (NMM) (compound (III))

(Experimental operation example) Methanol (solvent) (2 mL), 3-phenylpropionic acid (60.1 mg, 0.40 mmol), 2-phenethylamine (55 μL, 0.44 mmol) and N-methylmorpholine (compound (III)) (53 μL, 0.48 mmol) was added. Compound (II-1) (0.44 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. A 1M potassium hydrogen sulfate aqueous solution (4 mL) was added to terminate the reaction. After the solution was distilled off with an evaporator, chloroform was added to the residue to dilute it, and the residue was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline. The obtained organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated. The residue was calibrated by NMR to obtain N-phenethyl-3-phenylpropanamide (85 mg, yield 84%).

Using various compounds (I) or compounds (II) and compounds (III), a condensation reaction of a carboxylic acid compound and an amine compound was carried out according to the method of Experimental Example 1 or 2 above, and the obtained results are shown. Shown in 1.

As shown in Table 1, various carboxylic acid compounds can be obtained by using a mixture of the compound (I) of the present invention or its precursor compound (II) and compound (III) (that is, NMM) as a condensing agent. In the condensation reaction of the amine compound, the corresponding amide compound was obtained in a short time and in good yield in any solvent such as a protic organic solvent such as methanol or an aprotic organic solvent such as THF.

The compound (I) of the present invention is a solid that can be stably isolated and is easy to handle, and can be used not only in a protic organic solvent such as methanol but also in an aprotic organic solvent such as THF and water. It can be used as a dehydration condensing agent without deactivating even in a reaction system containing a wide range of solvents. According to the present invention, it is possible to provide a practical dehydration condensing agent which has low toxicity, can be used safely, and can produce a desired carboxylic acid derivative in a high yield in a short time.

Claims (9)

Formula (I):

[In the formula,
R ¹ is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkynyl group Or an optionally substituted aryl group;
R ² is an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, an optionally substituted alkyl group, Represents a cycloalkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, or an aryl group which may be substituted;
R ³ represents a C _1-4 alkyl group;
R ⁴ and R ⁵ each independently represent an optionally substituted alkyl group, or R ⁴ and R ⁵ are optionally substituted together with the nitrogen atom to which they are attached. Forming a secondary cyclic amino group, or
R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted tertiary cyclic amino group; and Y ⁻ is a fluoride, chloride, bromide, iodide, A pair selected from the group consisting of an optionally substituted alkyl sulfonate, an optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate and arsenate . Indicates an anion. ]
The compound represented by. R ¹ is a C _1-6 alkyl group or a C _2-6 alkenyl group,
R ² is a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or an optionally substituted 3 To a 8-membered cyclic amino group, or an optionally substituted C _6-10 aryl group,
R ³ is a methyl group;
R ⁴ and R ⁵ are each independently a C _1-6 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are substituted with 3 to 8 members. Optionally forms a secondary cyclic amino group, and Y ⁻ is a fluoride, chloride, bromide, iodide, optionally substituted alkyl sulfonate, optionally substituted aryl sulfonate, perchlorate, tetrafluoroborate. A compound according to claim 1 which is a counter anion selected from the group consisting of phthalates, hexafluorophosphate, hexafluoroantimonate, tetraphenylborate and arsenate. R ¹ is a methyl group or an allyl group;
R ² _{is, C 1-6 alkoxy, C 1-6} alkyl mono- or di-substituted amino group with a group, substituted with 5-6 membered cyclic amino group, or a halogen atom or a _{C 1-6} alkyl group Is a phenyl group which may be
R ³ is a methyl group;
R ⁴ and R ⁵ are each independently a C _1-4 alkyl group, or R ⁴ and R ⁵ together with the nitrogen atom to which they are bound are a 5-6 membered secondary ring. Forming an amino group, and Y ⁻ is composed of fluoride, chloride, bromide, iodide, C _1-4 alkyl sulfonate optionally substituted with a halogen atom, optionally substituted phenyl sulfonate, and perchlorate. The compound of claim 1 which is a counter anion selected from the group. R ¹ is a methyl group or an allyl group;
R ² is a C _1-4 alkoxy group, an amino group mono- or di-substituted with a C _1-4 alkyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidyl group, or a C _1-4 alkyl group. A phenyl group which may be substituted,
R ³ is a methyl group;
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a 4-morpholinyl, 1-pyrrolidinyl or 1-piperidyl group, and Y ⁻ is chloride, trifluoromethanesulfonate, methanesulfon. The compound according to claim 1, which is a counter anion selected from the group consisting of nato, benzene sulfonate, toluene sulfonate, 2-nitrobenzene sulfonate and perchlorate. A dehydration condensing agent comprising the compound according to any one of claims 1 to 4. Formula (II):

[In the formula,
R ¹ represents a C _1-6 alkyl group or a C _2-6 alkenyl group ;
R ² is a C _1-6 alkoxy group, a C _7-14 aralkyloxy group, a C _6-10 aryloxy group, an amino group mono- or di-substituted with a C _1-6 alkyl group, or an optionally substituted 3 ~8-membered cyclic amino group, or an optionally substituted _C6-10 aryl group; and Y'is a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, Alternatively, it represents a toluenesulfonyloxy group. ]
The compound represented by. A compound of claim 6 and formula (III):

[In the formula,
R ³ represents a C _1-4 alkyl group; and R ⁴ and R ⁵ each independently represent an optionally substituted alkyl group, or R ⁴ and R ⁵ are bound to them. Forming a secondary cyclic amino group which may be substituted together with a nitrogen atom; or
R ³ , R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form an optionally substituted tertiary cyclic amino group. ]
A mixture of compounds represented by: A dehydration condensation agent comprising the mixture according to claim 7. Formula (IV):

[In the formula,
R ^2a is a halogen atom, an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or an optionally substituted. An alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and Y ^a is a halogen atom , A trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, or a toluenesulfonyloxy group. ]
A compound represented by the formula (IIa):

[In the formula, the definitions of R ^2a and Y ^a are as defined above. ]
A compound of formula (II′):

[In the formula, R ^2b represents an optionally substituted alkoxy group, an optionally substituted aralkyloxy group, an optionally substituted aryloxy group, a substituted amino group, a substituted mercapto group, or an optionally substituted group. A good alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or an optionally substituted aryl group; and Y ^a is defined as follows. , Has the same meaning as above. ]
The manufacturing method of the compound represented by.