JP2003267955A - Method for fixing tautomer of imidazoles and fixing agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for fixing tautomers of imidazoles comprising the tautomers present therein with which only one of the tautomers of the imidazoles is fixed. <P>SOLUTION: The method for fixing the tautomers of the imidazoles having a structure represented by general formula (I) and comprising the tautomers present therein comprises including and crystallizing the imidazoles by using a host compound. Thereby, the only one of the tautomers is fixed in the included crystal. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to crystallization of imidazoles having tautomers with a host compound to fix only one of the tautomers in the inclusion crystals. The present invention relates to an immobilization method and an immobilizing agent.

[0002]

2. Description of the Related Art It has been reported that some chemical substances include a compound which exhibits a tautomerism when the substance is in a liquid state or when the substance is dissolved in a solvent, that is, a tautomer exists. I have (HETEROCYCLES, Vo
l. 32, No. 2, p. 329, 1991). When a compound showing such tautomerism is chemically reacted in a solvent using this compound as a raw material, various by-products are generated due to the presence of tautomers, and the chemical reaction rate (yield or yield Phenomena such as poor selectivity occur. For this reason, the yield of the target compound is deteriorated, and a separation and purification step for purifying the target compound is required, and further, a disposal treatment step of by-products is required. As described above, since there are various problems due to tautomers in the synthesis using tautomeric compounds as raw materials, it is necessary to separate the tautomers in the raw materials before the synthesis. Is desired.

Conventionally, research on compounds exhibiting such tautomerism has been carried out by NMR spectrum analysis and the like. In the past, however, only one of tautomers of imidazoles was extracted and its structure and physical properties were taken out. No case has been reported. Further, it has been reported in JP-A-5-194711 that imidazoles are clathrated by various multimolecular host compounds, but one isomer of the imidazoles showing tautomerism is selectively selected. Immobilization has not been revealed.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above conventional circumstances, and is an immobilization method for immobilizing only one tautomer of an imidazole having a tautomer. And to provide an immobilizing agent.

[0005]

The method for immobilizing a tautomer of an imidazole of the present invention is a method of immobilizing an imidazole having a structure represented by the following general formula (I) and having a tautomer, By inclusion crystallization using a host compound,
It is characterized in that only one of the tautomers is immobilized in the inclusion crystal.

The imidazole tautomer-immobilizing agent of the present invention has a structure represented by the following general formula (I), and encloses an imidazole having a tautomer with a host compound. It is characterized by immobilizing only one of the tautomers in the crystal by inclusion in the crystal.

[0007]

[Chemical 3] (In the general formula (I), R ¹ , R ² and R ³ are each independently a hydrogen atom; a linear or branched alkyl group having 1 to 20 carbon atoms, which may have a substituent. Group; cycloalkyl group having 3 to 20 carbon atoms, which may have a substituent;
A linear or branched alkoxy group having 1 to 20 carbon atoms, which may have a substituent; a cycloalkoxy group having 3 to 20 carbon atoms, which may have a substituent; a carboxyl group;
Thiocarboxyl group; phenyl group which may have a substituent group; naphthyl group which may have a substituent group; anthranyl group which may have a substituent group; benzyl group which may have a substituent group Represents a group, and R ² and R ³ are different substituents. )

Has a structure represented by the above general formula (I),
It has been reported that imidazoles having different substituents R ² and R ³ coexist in solution with the following compounds [A] and [B] in an equilibrium state (HETEROCYCLE).
S, Vol. 32, No. 2, p. 329,199
1).

[0009]

[Chemical 4]

In the present invention, only one tautomer of an imidazole having such a tautomer as a guest compound can be immobilized by being included in a host compound and crystallized. it can.

Conventionally, an example in which only one tautomer of an imidazole showing tautomerism is immobilized has not been reported so far, but according to the present invention, inclusion of this by using a host compound. It becomes possible to immobilize by crystallization, and by directly reacting the clathrate compound in which only one tautomer is immobilized in this way in the crystalline state, selective chemistry with few byproducts is obtained. Run the reaction,
It is expected to improve the reaction rate in the synthesis using imidazoles as raw materials.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the method for immobilizing a tautomer of an imidazole and the immobilizing agent of the present invention will be described in detail below.

In the present invention, the imidazoles showing the tautomerism to be immobilized have a structure represented by the following general formula.

[0014]

[Chemical 5] (In the general formula (I), R ¹ , R ² and R ³ are each independently a hydrogen atom; a linear or branched alkyl group having 1 to 20 carbon atoms, which may have a substituent. Group; cycloalkyl group having 3 to 20 carbon atoms, which may have a substituent;
A linear or branched alkoxy group having 1 to 20 carbon atoms, which may have a substituent; a cycloalkoxy group having 3 to 20 carbon atoms, which may have a substituent; a carboxyl group;
Thiocarboxyl group; phenyl group which may have a substituent group; naphthyl group which may have a substituent group; anthranyl group which may have a substituent group; benzyl group which may have a substituent group Represents a group, and R ² and R ³ are different substituents. )

Substituents R ¹ and R in the above general formula (I)
² , R ³ is a linear or branched alkyl group having 1 to 20 carbon atoms, a cycloalkyl group having 3 to 20 carbon atoms, and 1 carbon atom.
~ 20 straight or branched chain alkoxy groups, 3 carbon atoms
Examples of the substituent that the cycloalkoxy group of to 20 may have include a hydroxyl group, a carboxyl group, an amino group, an amide group, a formyl group, a cyano group, a halogen atom, a nitro group, and the like. May have been
Further, it may be substituted with two or more of the same or different substituents.

Further, the substituent R in the above general formula (I) is
^The substituent which the phenyl group, naphthyl group, anthranyl group and benzyl group of ¹ , R ² and R ³ may have is 1 carbon atom.
To straight or branched chain alkyl group having 3 to 20 carbon atoms
Cycloalkyl group, linear or branched alkoxy group having 1 to 20 carbon atoms, cycloalkoxy group having 3 to 20 carbon atoms, hydroxyl group, carboxyl group, amino group, amide group, formyl group, cyano group, halogen atom , A nitro group and the like, which may be substituted with one of these substituents,
Further, it may be substituted with two or more of the same or different substituents. Incidentally, a phenyl group, a naphthyl group, an anthranyl group, an alkyl group substituted with a benzyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group is further a hydroxyl group, a carboxyl group, an amino group, an amide group, a formyl group, a cyano group, It may be substituted with a halogen atom, a nitro group or the like.

In the present invention, the imidazoles exhibiting tautomerism to be immobilized are specifically 4-
Methylimidazole, 4-ethylimidazole, 2-methyl-4-methylimidazole, 2-ethyl-4-methylimidazole, 2-isopropyl-4-methylimidazole, 2-undecyl-4-methylimidazole, 2
-Heptadecyl-4-methylimidazole, 2-cyclohexyl-4-methylimidazole, 2-phenyl-4
-Methylimidazole, 2-naphthyl-4-methylimidazole, 2-benzyl-4-methylimidazole, 2
-Phenyl-4-methyl-5-hydroxymethylimidazole, 4-carboxylimidazole, 4-thiocarboxylimidazole, 2-methyl-4-methyl-5-
Carboxyimidazole, 2-methyl-4-methyl-
5-dithiocarboxylimidazole, 2-aminoethyl-4-methylimidazole, 2-methylimidazole-4-carboxylic acid, 2-methyl-4-formylimidazole, 2-phenyl-4-formylimidazole,
2-Ethyl-4-methyl-5-formylimidazole, 2-cyanoethyl-4-methylimidazole, 2-
Chloromethyl-4-methylimidazole, 2- (4'-
Hydroxy) cyclohexyl-4-methylimidazole, 2- (4'-methylphenyl) -4-methylimidazole, 2- (4'-hydroxyphenyl) -4-methylimidazole, 2- (4'-aminophenyl) -4 −
Methylimidazole, 2- (4'-nitrophenyl)-
Examples thereof include 4-methylimidazole, but are not limited thereto.

The host compound which includes only one of the tautomers of these imidazoles may be any compound which can include only one of the tautomers of these imidazoles, and is not particularly limited. Not done.

As the host compound, a monomolecular system, a multimolecular system, a polymer system, an inorganic system host and the like are known.

As the monomolecular host, cyclodextrins, crown ethers, cryptands, cyclophanes, azacyclophanes, calixarenes,
Examples include cyclotriperatrilenes, spherands, cyclic oligopeptides and the like.

Examples of the polymolecular host include ureas, thioureas, deoxycholic acids, perhydrotriphenylenes, tri-o-thymotides, bianthrils, spirobifluorenes, cyclophosphazenes, acetylene alcohols. , Phenols, bisphenols, trisphenols, tetrakisphenols, naphthols, diphenylmethanols, carboxylic acid amides, carboxylic acids, imidazoles, hydroquinones and the like.

As the polymer host, celluloses,
Examples thereof include starches, chitins, chitosans, polyvinyl alcohols and the like.

Examples of the inorganic host include graphites, clay minerals, montmorillonites, zeolites and the like.

Of these, a multi-molecular host whose inclusion ability is less likely to be affected by the molecular size of the imidazole guest compound is more effective. Specific examples of the multimolecular host include 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol and bis-β-
Naphthol, 1,1-bis (4-hydroxyphenyl)
Examples thereof include cyclohexane, diphenic acid bisdicyclohexylamide, and fumaric acid bisdicyclohexylamide.

As a method for obtaining an inclusion compound by inclusion clathrate crystallization of one tautomer of the above imidazole using such a host compound, both the imidazoles of the host compound and the guest compound are dissolved. Recrystallization method in which it is mixed with a solvent to be dissolved or heated and dissolved and left to stand; direct mixing method in which imidazoles of a host compound and a guest compound are directly mixed without using a solvent and the like, but are not limited thereto. Absent.

The ratio of the imidazoles forming the clathrate compound to the host compound varies depending on the type of the imidazole and the host compound used, but generally, imidazoles: host compound = 1: 0.2 to 5
Since it is (molar ratio), when producing an inclusion compound,
It is preferable to react the imidazoles and the host compound so that such a molar ratio is obtained.

Which of the tautomers is included in the clathrate thus obtained can be determined by conducting X-ray crystal structure analysis of the clathrate thus obtained. . In addition, the molecular structure (interatomic bond distance, bond angle, etc.) of one tautomer can be confirmed from the obtained crystal structure analysis result of the clathrate compound.

In the present invention, as a method for immobilizing only one tautomer of an imidazole which exhibits tautomerism,
Although it is revealed that inclusion crystallization technology can be used,
In this way, the clathrate compound having one tautomer immobilized thereon is subjected to a chemical reaction in the solid state as it is, whereby a selective chemical reaction is performed, and the industrial utility thereof is extremely large.

[0029]

EXAMPLES The present invention will be described in more detail with reference to the following examples.

Example 1 Bis-β-naphthol (hereinafter abbreviated as "BNO")
0.286 mg (1 mmol) and 10 ml of methanol were put in a sample bottle and dissolved by heating. 2-phenyl-
4-Methylimidazole (hereinafter abbreviated as "2P4MI") 0.158 mg (1 mmol) was added, dissolved by heating again, and allowed to stand at room temperature. As a result, BNO / 2P4MI = 1
A clathrate compound of / 1 (molar ratio) was obtained as crystals. As a result of X-ray crystal structure analysis of this clathrate compound, as shown in FIG. 1, it was revealed that 2P4MI was immobilized in the state of 2-phenyl-5-methylimidazole in the clathrate compound crystal. Became.

An example of taking out and analyzing one tautomer of 2P4MI has not been reported so far, but from this result, one tautomer of the imidazoles is immobilized by inclusion crystallization. It became clear that it could be done.

Example 2 0.286 mg (1 mmol) of BNO and 1 of methanol
0 ml was placed in a sample bottle and dissolved by heating, and 4-methylimidazole (hereinafter abbreviated as “4MI”) 0.0
82 mg (1 mmol) was added, and it was dissolved again by heating and left at room temperature. As a result, BNO / 4MI = 1/1 (molar ratio)
The inclusion compound of was obtained as crystals. As a result of X-ray crystal structure analysis of this clathrate compound, as shown in FIGS.
It was revealed that 4MI was immobilized in the state of 4-methylimidazole in the crystal of the inclusion compound.

An example of taking out and analyzing one tautomer of 4MI has not been reported so far, but from this result, one tautomer of imidazoles is immobilized by inclusion crystallization. It became clear that it could be done.

[0034]

INDUSTRIAL APPLICABILITY As described in detail above, according to the method for immobilizing a tautomer of an imidazole and the immobilizing agent of the present invention, an imidazole having a tautomer is included with a host compound. By crystallization, only one of the tautomers can be immobilized in the inclusion crystal. Therefore, for example, by subjecting an inclusion compound in which only one tautomer is immobilized to a chemical reaction in the solid state as it is, it becomes possible to cause a selective chemical reaction with few byproducts. Efficient synthesis can be performed by reducing the steps of separating and purifying substances and the step of disposing of by-products.

[Brief description of drawings]

FIG. 1 is a view showing an X-ray crystal structure analysis result of a BNO / 2P4MI clathrate compound obtained in Example 1.

FIG. 2 is a diagram showing an X-ray crystal structure analysis result of a BNO / 4MI clathrate compound obtained in Example 2.

3 is a diagram showing the chemical formula of the clathrate compound obtained by X-ray crystal structure analysis of the clathrate compound of BNO / 4MI obtained in Example 2. FIG.

Claims (2)

[Claims] 1. An imidazole having a structure represented by the following general formula (I) and in which a tautomer is present, is subjected to inclusion crystallization with a host compound to give a tautomer of the tautomer. A method for immobilizing a tautomer of an imidazole, which comprises immobilizing only one of them in an inclusion crystal. [Chemical 1] (In the general formula (I), R ¹ , R ² and R ³ are each independently a hydrogen atom; optionally substituted C 1-20 carbon atoms.
A straight-chain or branched-chain alkyl group having 3 to 20 carbon atoms which may have a substituent; a straight-chain alkyl group having 1 to 20 carbon atoms which may have a substituent; Branched-chain alkoxy group; optionally substituted, C3-2
A cycloalkoxy group of 0; a carboxyl group; a thiocarboxyl group; a phenyl group which may have a substituent group; a naphthyl group which may have a substituent group; an anthranyl group which may have a substituent group; Represents a benzyl group which may have a group, and R ² and R ³ are different substituents. ) 2. A structure having a structure represented by the following general formula (I), wherein only one tautomer of an imidazole having a tautomer is included to immobilize it as a crystal. Immobilizing agent for tautomers of imidazoles. [Chemical 2] (In the general formula (I), R ¹ , R ² and R ³ are each independently a hydrogen atom; optionally substituted C 1-20 carbon atoms.
A straight-chain or branched-chain alkyl group having 3 to 20 carbon atoms which may have a substituent; a straight-chain alkyl group having 1 to 20 carbon atoms which may have a substituent; Branched-chain alkoxy group; optionally substituted, C3-2
A cycloalkoxy group of 0; a carboxyl group; a thiocarboxyl group; a phenyl group which may have a substituent group; a naphthyl group which may have a substituent group; an anthranyl group which may have a substituent group; Represents a benzyl group which may have a group, and R ² and R ³ are different substituents. )