JP2002371068A - Method for producing 4(5)-cyanoimidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 4(5)-cyanoimidazole derivative, capable of expanding a range of an organic solvent to be practically usable, and therefore capable of smoothly producing the 4(5)-cyanoimidazole derivative in a high yield even when produced even in an organic solvent more ordinary than ever. SOLUTION: This method for producing the 4(5)-cyanoimidazole derivative expressed by formula (I) (A is H, a 1-20C hydrocarbon group, or the like; and B is H, a straight chain or branched chain 1-6C hydrocarbon group, or the like) comprises heating a compound expressed by formula (II) in an organic solvent in the presence of a catalyst so as to conduct decarboxylation reaction. At least one kind of compound selected from a phosphonium salt and a quaternary ammonium salt is preferably used as the catalyst. Further, the decarboxylation reaction is preferably conducted in the presence of an alkali metal salt or an alkaline earth metal salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 4 (5) -cyanoimidazole derivative which is an intermediate of a pharmaceutical and a pesticide.

[0002]

2. Description of the Related Art A method for producing a 4 (5) -cyanoimidazole derivative is described in, for example, J. Am. Heterocycl. Chem. ,
(1983), 20 (4), p1103-54,
A method for synthesizing 4 (5) -cyanoimidazole in which 4 (5) -cyano-5 (4) -imidazolecarboxylic acid is heated and refluxed in a nitrobenzene solvent for 20 hours to decarboxylate is described.

[0003]

With respect to the organic solvent used for producing the 4 (5) -cyanoimidazole derivative by decarboxylation of the 5 (4) -imidazolecarboxylic acid derivative, only one example of nitrobenzene described in the above document is used. is there.
However, nitrobenzene has never been a satisfactory reaction solvent in terms of physical properties, such as being relatively toxic, having a unique odor, and having a high melting point and boiling point. Further, the rate of the decarboxylation reaction largely depends on the properties of the organic solvent used, and for this reason, the organic solvents that can be practically used are limited to only a small part. The present invention broadens the range of organic solvents that can be used practically, and provides a method for producing a 4 (5) -cyanoimidazole derivative smoothly in a good yield even in more general organic solvents. The purpose is to.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a solvent having a low reaction rate has been used in the presence or absence of an alkali metal salt or an alkaline earth metal salt. Under the present invention, it has been found that the reaction rate is increased by adding a catalyst such as a phosphonium salt or an ammonium salt, thereby completing the present invention.

That is, the present invention provides a method of formula (I)

Embedded image (Where A represents a hydrogen atom or a C1-C20 hydrocarbon group or an RX group (R represents a C1-C20 hydrocarbon group or a heterocyclic group, and X represents an oxygen atom, a sulfur atom, or a nitrogen atom. ), And B represents a hydrogen atom and a linear or branched C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, aralkyl group,
Represents an acyl group, an alkoxycarbonyl group, an N-unsubstituted or substituted carbamoyl group, an arylsulfonyl group, an alkylsulfonyl group, or a substituted aminosulfonyl group. The method for producing a 4 (5) -cyanoimidazole derivative represented by the formula (II):

Embedded image (Wherein A and B have the same meanings as described above), wherein a compound represented by the formula (2) is heated in an organic solvent in the presence of a catalyst to cause a decarboxylation reaction. (3) The method according to (1), wherein the catalyst is at least one selected from the group consisting of phosphonium salts and quaternary ammonium salts, and (3) the presence of an alkali metal salt or an alkaline earth metal salt. Below, the production method according to (1) or (2), wherein a decarboxylation reaction is performed;
About.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the compound represented by the formula (I), A
Is a hydrogen atom, a C1-C20 hydrocarbon group, a heterocyclic group,
Or an RX group (R represents a C1 to C20 hydrocarbon group or a heterocyclic group, X represents an oxygen atom, a sulfur atom, or a nitrogen atom), and B represents a hydrogen atom, a linear or branched chain. C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, aralkyl, trityl, acyl, arylsulfonyl, alkylsulfonyl, and substituted aminosulfonyl.

Specific examples of A include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-
Butyl, t-butyl, s-butyl, isobutyl, n-pentyl, s-pentyl, isopentyl, neopentyl, n-hexyl, s-hexyl, 1,1-dimethyl-n- Hexyl group, n-heptyl group, n-decyl group, n-dodecyl group, C1-C20 alkyl group, vinyl group, allyl group, 2-butenyl group, 1-
C2 such as methyl-2-propenyl group and 4-octenyl group
C2 to C20 alkynyl, ethynyl, propargyl, 1-methyl-propynyl, C2-C20 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopentyl, 1-methylcyclohexyl, -Adamantyl group, 1-methyladamantyl group, 2-adamantyl group, 2-methyl-2-
An adamantyl group, a C3-C20 alicyclic hydrocarbon group such as a norbornyl group, a phenyl group, a 1-naphthyl group, a C6-C20 aromatic hydrocarbon group such as a 9-anthracenyl group,
2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2
-Furanyl group, 2-thienyl group, 3-thienyl group, 1-
A pyrrolo group, a 2-oxazolyl group, a 3-ioxazolyl group, a 2-thiazolyl group, a 3-iothiazolyl group, a 1-pyrazolyl group, a 4-pyrazolyl group, a 2-imidazolyl group,
1,3,4-oxadiazol-2-yl, 1,2,4
-Oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-5
Yl, 1,3,4-triazol-2-yl, 1,2,2
3-thiadiazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3,4-tetrazol-5
Yl, pyrimidin-2-yl, pyrimidin-4-yl,
Pyrazin-2-yl, pyridazin-3-yl, 1,2,
4-triazin-6-yl, 1,3,5-triazine-
2-yl, 1-pyrrolidinyl group, 1-piperidyl group, 4
-Morpholinyl group, 2-tetrahydrofuranyl group, 4-
A heterocyclic group such as a tetrahydropyranyl group, a methoxy group,
Ethoxy, n-propoxy, i-propoxy, n
Hydrocarbon oxy groups such as -butoxy group, t-butoxy group, phenoxy group and benzyloxy group; heterocyclic oxy groups such as 2-pyridyloxy group; hydrocarbon thio groups such as methylthio group, ethylthio group, phenylthio group and benzylthio group. And a heterocyclic thio group such as a 2-pyridylthio group; a hydrocarbon amino group such as a methylamino group, a dimethylamino group, a t-butylamino group and an anilino group; and a heterocyclic amino group such as a 2-pyridylamino group. be able to. Specific examples of B include a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, isoamyl group, n
-Hexyl group, vinyl group, propargyl group, allyl group,
Examples thereof include a benzyl group, a trityl group, an acetyl group, a t-butoxycarbonyl group, an N, N-dimethylcarbamoyl group, a phenylsulfonyl group, a methylsulfonyl group, an N, N-dimethylsulfamoyl group, and the like. In the compound represented by the formula (II), A and B have the same meanings as described above, and may be the same as those described above. Depending on the substitution position of B, the substitution position of the cyano group may be any of 4-position and 5-position.

As the phosphonium salt used in this reaction, for example, a compound represented by the formula (III) can be exemplified.

[0009]

Embedded image In the compound represented by the formula (III), R ₁ , R ₂ , R ₃ , and R ₄ each independently represent a hydrogen atom or a linear or branched C1 to C20 alkyl group or a C2 to C6 alkenyl group. , A C2-C6 alkynyl group or an aralkyl group;
Is halide ion, sulfate ion, hydrogen sulfate ion,
It represents an organic acid ion such as a nitrate ion or an acetate ion, and n represents an integer of 1 to 2. R ₁ , R ₂ , R ₃ , R ₄
Specifically, a hydrogen atom, a methyl group, an ethyl group, n
-Propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n- Examples include a dodecanoyl group, an n-tetradecyl group, an n-octadecyl group, a vinyl group, a propargyl group, an allyl group, and a benzyl group.
Specifically, X is a fluoride ion, a chloride ion,
Examples thereof include halide ions such as bromide ions and iodide ions, sulfate ions, hydrogen sulfate ions, nitrate ions, acetate ions, and hydroxide ions. n is X or 1 or 2 depending on the valence of the anion forming the pair.
Represents an integer.

Specific examples of the phosphonium salt include ethyltriphenylphosphonium acetate, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, tetraphenylphosphonium tetraphenyl volley, tetra-n-butylphosphonium hydroxide, Examples thereof include n-butylphosphonium bromide, tetraethylphosphonium chloride, tetraethylphosphonium bromide, tetraethylphosphonium iodide, tetraphenylphosphonium bromide, and triphenylbenzylphosphonium bromide.

As the quaternary ammonium salt used in this reaction, for example, a compound represented by the formula (II) can be exemplified.

[0012]

Embedded image

In the compound represented by the formula (IV), R ₁ , R ₂ ,
R ₃ , R ₄ and X have the same meaning as described above, and may be the same as those described above. n represents X, that is, an integer of 1 or 2, depending on the valence of the anion forming the pair.

Specific examples of the quaternary ammonium salt include tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide, tetramethylammonium bromide, tetraethylammonium bromide, and tetraethylammonium bromide. Butylammonium, triethylbenzylammonium bromide, trimethylphenylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium chloride, trimethylphenylammonium chloride, trioctylmethylammonium chloride, tributylbenzylammonium chloride, Trimethylbenzylammonium chloride, N-laurylpyridinium chloride, N chloride
-Benzylpicolinium, tricaprylmethylammonium chloride, tetramethylammonium iodide, tetrabutylammonium iodide, tetrabutylammonium sulfate and the like.

The organic solvent used in this reaction includes triethylene glycol dimethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran (THF),
Ethers such as dioxane, benzene, toluene, chlorobenzene, orthodichlorobenzene, o-xylene,
Examples thereof include aromatic solvents such as m-xylene, p-xylene, benzonitrile, and nitrobenzene; hydrocarbon solvents such as tetralin and decalin; and dimethylformamide (DMF). These can be used in combination. Although the amount of the solvent used is not particularly limited, it is preferable to use 300 ml or more based on 100 g of the compound represented by the formula (II) in consideration of thermal efficiency and reaction safety.

The reaction is preferably carried out in an organic solvent while heating, and the temperature ranges from room temperature to the reflux temperature of the organic solvent used. In addition, the reflux temperature is preferably in the range of 130 to 220 ° C. in consideration of the reaction time and the like. The heating method is not particularly limited, and any method such as a method of heating while gradually increasing the temperature from room temperature, a method of heating at a stretch with a heat source at the solvent reflux temperature, a method of heating stepwise to a predetermined temperature, and the like are employed. be able to. The reaction is usually performed under normal pressure, but the reaction can be performed under pressure.

In the present reaction, at least one salt selected from the group consisting of phosphonium salts and ammonium salts is preferably used as a catalyst. The amount used is preferably in the range of 1 to 50 mol% based on the compound represented by the formula (II).

The alkali metal salt used in this reaction is specifically sodium chloride, potassium chloride, lithium chloride,
Examples thereof include alkali metal halides such as sodium bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide, lithium iodide, sodium sulfate, and sodium hydrogen sulfate. In addition, examples of the alkaline earth metal include an alkaline earth metal halide such as calcium chloride and magnesium chloride, calcium sulfate, and magnesium sulfate. The amount of the alkali metal salt or alkaline earth metal salt used is
Although not particularly limited, it is preferable to use the compound represented by the formula (II) in a range of 1 to 200 g / mol.

The reaction is usually carried out in the atmosphere, but the reaction can be carried out while blowing an inert gas such as nitrogen into the reaction vessel or the reaction solution in order to drive out the generated carbon dioxide gas out of the reaction system. Hereinafter, the present invention will be described in detail with reference to examples, but the scope of the present invention is not limited to the examples.

[0020]

EXAMPLE 1 1.36 g (10 mmol) of 4 (5) -cyano-5 (4) -imidazolecarboxylic acid (CIMC) was suspended in 20 ml of o-dichlorobenzene, and tetrabutylphosphonium bromide was added thereto. .68 g (2 mmol) and 0.5 g (12 mmol) of lithium chloride were added, and the mixture was heated to reflux for 4 hours. After cooling, the reaction solution was analyzed by high performance liquid chromatography to determine the yield of 4 (5) -cyanoimidazole (CIM). 4 (5) -cyanoimidazole: 89% yield

Examples 2 to 3 The reaction was carried out in the same manner as in Example 1, and the results, including the results of Example 1, are summarized in Table 1.

Comparative Example 1 A reaction was carried out in the same manner as in Example 1 except that tetrabutylphosphonium bromide was not used. The results are summarized in Table 1.

[0023]

[Table 1] a) o-dichlorobenzene b) tetra-n-butylammonium bromide c) tetra-n-butylphosphonium bromide d) 20 mol% based on CIMC. e) 50 g / mol was used for CIMC. g) 4 (5) -cyanoimidazole f) 4 (5) -cyano-5 (4) -imidazolecarboxylic acid

4 (5) -cyano-5 (4) -imidazole carboxylic acid can be prepared by the method described in JP-A-50-29560.
J. Heterocycl. Chem. , (1983), 20 (4),
The compound was synthesized by the method described in p.

[0025]

As described above, by using the method of the present invention, the selection range of the reaction solvent that can be used practically is widened, and an environment that is problematic when industrially manufactured using nitrobenzene is used. Can be suppressed, and is useful as an industrial production method.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Shiro Tsubokura 950, Fujisawa, Nakasato-mura, Nakakubijo-gun, Niigata Japan F-term in Nihon Soda Co., Ltd. Nihongi Plant Production Technology Research Laboratory 4H039 CA42 CG40

Claims (3)

[Claims] (1) Formula (I) (Where A represents a hydrogen atom or a C1-C20 hydrocarbon group or an RX group (R represents a C1-C20 hydrocarbon group or a heterocyclic group, and X represents an oxygen atom, a sulfur atom, or a nitrogen atom. B represents a hydrogen atom and a linear or branched C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, aralkyl group, acyl group, alkoxycarbonyl group, N-unsubstituted Or a substituted carbamoyl group, an arylsulfonyl group, an alkylsulfonyl group, or a substituted aminosulfonyl group) in the method for producing a 4 (5) -cyanoimidazole derivative represented by the formula (II): (Wherein A and B have the same meanings as described above), wherein the compound is heated in an organic solvent in the presence of a catalyst to cause a decarboxylation reaction. 2. The method according to claim 1, wherein the catalyst is at least one selected from the group consisting of a phosphonium salt and a quaternary ammonium salt. 3. The process according to claim 1, wherein the decarboxylation reaction is carried out in the presence of an alkali metal salt or an alkaline earth metal salt.