JP3499595B2 - Method for producing 2-cyanoimidazole compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an imidazole compound useful as an active ingredient of agricultural chemicals or pharmaceuticals, and more particularly to a method for producing an intermediate 2-cyanoimidazole compound.

[0002]

2. Description of the Related Art A method for producing a 2-cyanoimidazole compound is described in JP-A-1-131163.

[Chemical 4]

[Chemical 5] However, in these descriptions, the point that the 2-dimethoxymethyl group is hydrolyzed with HCl is different from the present invention. Further, Japanese Patent Laid-Open No. 2-108670 discloses the following.

[Chemical 6]

[Chemical 7] However, these described starting materials differ from the present invention.

[0003]

Conventionally, as a method for obtaining a 2-cyanoimidazole compound, the method described in JP-A-2-
There was a method described in Japanese Patent No. 108670. However, in order to industrially produce the starting material, a compound in which the 2-position is formyl, an expensive reagent such as butyllithium and special equipment such as a cryogenic device were required.

On the other hand, according to the method described in JP-A-1-131163 described above, although an expensive reagent and special equipment are not required, since a reaction material is hydrolyzed with HCl, a reaction product is generated. Since the dehydration reaction cannot be carried out without isolation, purification and drying once, the reaction procedure is complicated, and the reaction step becomes long, so that the total yield is inevitably reduced.

[0005]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to establish an industrial production method for 2-cyanoimidazole compounds, as a starting material, 2-
In the oxime formation reaction in which the formyl imidazole compound was used, it was found that the reaction proceeded even when the 2-dialkoxymethyl imidazole compound was used, and the present invention was completed.

That is, the present invention is based on the formula (I)

[Chemical 8] A method for producing a 2-cyanoimidazole-based compound represented by the formula (wherein Z is a phenyl group which may be substituted), wherein the formula (II) is used in the presence of (1) a solvent.

[Chemical 9] (Wherein R is a lower alkyl group and Z is as described above) is reacted with hydroxylamine, and then the product obtained in (2) and (1) is reacted with a dehydrating agent. And a method for producing the 2-cyanoimidazole compound.

In formulas (I) and (II), any substituent of the optionally substituted phenyl group as Z can be substituted with a phenyl group as long as it does not adversely affect the reaction. It may be one. As these Z, specifically, a phenyl group substituted with a lower alkyl group, a phenyl group substituted with a trifluoromethyl group, a phenyl group substituted with a lower alkoxy group, a phenyl group substituted with a lower alkylthio group, Substituted phenyl groups and the like are included. The lower alkyl group as R, or the other lower alkyl group and lower alkyl moiety used in the present specification means alkyl having 1 to 6 carbon atoms. These R
Specific examples thereof include methyl, ethyl, propyl, butyl, pentyl and hexyl, which may be linear or branched alkyl, especially methyl,
Ethyl is preferred.

Specific examples of the compound of the above formula (II) include the following. 2- (diethoxymethyl) -4 (5)-(4-methylphenyl) imidazole 2- (dimethoxymethyl) -4 (5)-(4-methylphenyl) imidazole 2- (diethoxymethyl)- 4 (5)-(3-Trifluoromethylphenyl) imidazole 2- (diethoxymethyl) -4 (5)-(4-methoxyphenyl) imidazole 2- (dimethoxymethyl) -4 (5) -phenylimidazole 2- (diethoxymethyl) -4 (5)-(3-methylphenyl) imidazole 2- (diethoxymethyl) -4 (5)-(3,4-dimethylphenyl) imidazole 2- (diethoxy) Methyl) -4 (5)-(4-ethylphenyl) imidazole 2- (diethoxymethyl) -4 (5)-(3-methoxyphenyl) imidazole 2- (di Toxoxymethyl) -4 (5)-(4-isopropylphenyl) imidazole-2- (diethoxymethyl) -4 (5)-(4-methylthiophenyl) imidazole-2- (diethoxymethyl) -4 (5)- (2-Methylphenyl) imidazole 2- (dimethoxymethyl) -4 (5)-(4-ethylphenyl) imidazole

The method for producing a 2-cyanoimidazole-based compound of the present invention uses a compound of the formula (II) as a starting material,
It consists of two steps: (1) oxime formation reaction and (2) dehydration reaction.

The oximation reaction is carried out by the reaction of the formula (I
The compound of I) is reacted with hydroxylamine. As the solvent used in this reaction, for example, methanol,
Alcohols such as ethanol and isopropanol, ethers such as monoglyme, diglyme, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and diethylene glycol, halogenated hydrocarbons such as dichloroethane, chloroform and tetrachloroethane, benzene, monochlorobenzene, nitrobenzene, toluene Examples thereof include aromatic hydrocarbons, nitriles such as acetonitrile, dimethylsulfoxide, dimethylformamide, pyridine and the like, and among them, dimethylformamide is preferable. Furthermore, a mixed solvent in which solvents selected from these are combined may be used. When the two-phase reaction is carried out using a mixed solvent, a phase transfer catalyst such as triethylbenzylammonium chloride or trioctylmethylammonium chloride can be used. The solvent is usually used in an amount of 6 times or more the volume of the compound of the formula (II), and in the case of less than 6 times the volume, the smaller the amount used, the lower the yield. On the other hand, the upper limit is preferably 10 times or less. The use of a solvent in an amount exceeding 10 times the volume does not lead to a decrease in yield except in an extreme case, but no advantage is recognized. Hydroxylamine may be used by itself or may be used as a mineral acid salt such as a hydrochloride or a sulfate thereof, but it is preferable to use the mineral acid salt. When using the mineral acid salt, it is desirable to add a base to the reaction system. The base may be any as long as it has the ability to convert the mineral acid salt back to hydroxylamine. As the base, specifically, an inorganic base or an organic base can be used. For example, as the inorganic base, carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate and sodium hydrogen carbonate. , And alkali metal or alkaline earth metal hydroxides or hydrides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydride and the like. Examples of the organic base include diethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and the like, and among them, pyridine is preferable. Hydroxylamine is theoretically consumed in an amount of 1 equivalent to the compound of formula (II), but it is usually 1.2 to 1.
It is desirable to use 3 equivalents. The amount of the base used is the same as that of hydroxylamine. The reaction temperature of this reaction is usually 50 to 150 ° C, preferably 70 to 90 ° C, and the reaction is usually completed in 0.1 to 24 hours. By this reaction, the formula (III)

[Chemical 10] A compound represented by the formula (in the formula, Z is as described above) is produced.

Specific examples of the compound of the formula (III) include the following. -2- (hydroxyiminomethyl) -4 (5)-(4-
Methylphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(3-
Trifluoromethylphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(4-
Methoxyphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5) -phenylimidazole 2- (hydroxyiminomethyl) -4 (5)-(3-
Methylphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(3
4-Dimethylphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(4-
Ethylphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(3-
Methoxyphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(4-
Isopropylphenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(4-
Methylthiophenyl) imidazole 2- (hydroxyiminomethyl) -4 (5)-(2-
Methylphenyl) imidazole

In the dehydration reaction, the product obtained in the oxime-forming reaction is reacted with a dehydrating agent. The product obtained by the oximation reaction may be subjected to a dehydration reaction after being isolated and purified, but this dehydration reaction does not require isolation and purification of the product after the oximation reaction. Alternatively, it can be carried out continuously as it is, and it can be expected that such a continuous reaction will bring advantageous results. As the dehydrating agent, for example, acetic anhydride, trichloroacetic anhydride, trichloroacetonitrile, trichloroacetyl chloride, oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride,
Phosphorus pentoxide, phosphonitrilic chloride, phosgene (dimer), cyanuric chloride, titanium tetrachloride, formic acid and the like can be used, and acetic anhydride is preferable. The dehydrating agent is usually used in an amount of 1.5 to 2.5 equivalents, preferably 1.5 to 2 equivalents, relative to the compound of formula (II). The reaction temperature of this reaction is usually 50 to 150 ° C., preferably 8
The reaction temperature is 0 to 100 ° C., and the reaction is usually completed in 1 to 24 hours. After completion of the reaction, a usual post-treatment operation, for example, the reaction mixture is put into water, the precipitated solid is collected by filtration and washed to obtain a highly pure 2-cyanoimidazole compound represented by the formula (I). can do.

The compound represented by the formula (II) as the starting material can be produced by the following method.

[Chemical 11] (In the formula, Z and R are as described above, and A is a lower alkyl group.)

Mineral salts of formula (II) include hydrochlorides and sulfates. The stoichiometric ratio between the compound of formula (IV) and the compound of formula (V) is 1: 1, but without isolating the compound of formula (V) synthesized by a known method. When used in the above reaction, the compound of the formula (V) may be used in an amount of 1 equivalent or more with respect to the compound of the formula (IV).

The above reaction is carried out in the presence of a solvent and an acid acceptor. The amount of the acid acceptor used may be 1 equivalent or more with respect to the compound of the formula (IV). The reaction temperature for this reaction is usually 2
The temperature is 0 to 150 ° C, preferably 50 to 120 ° C, and the reaction time is usually 1 to 24 hours. A production example of the compound represented by the above formula (II) will be described as a reference example.

Reference Example 1 2- (diethoxymethyl) -4
Synthesis of (5)-(4-methylphenyl) imidazole To 12 ml of methanol was added 0.77 g of 28% sodium methylate methanol solution, and 2.58 g (0.02 mol) of diethoxyacetonitrile was added dropwise at room temperature. After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour to obtain a methanol solution of methyldiethoxyacetimidate.
Methylphenacylamine hydrochloride 1.85 g (0.01 mol) was added in small portions. Next, 1.93 g of 28% sodium methylate methanol solution was added dropwise, and further 18 ml of methanol was added. The reaction mixture was reacted at room temperature for 1 hour and then heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled and the solvent was distilled off under reduced pressure. The residue was extracted with methylene chloride, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was washed with hexane, the solid was collected by filtration, and 1.65 g of the desired product having a melting point of 103 to 105 ° C.
(Yield 64%) was obtained.

Reference Example 2 2- (dimethoxymethyl) -4
2.05 g (0.02 mol) of dimethoxyacetonitrile instead of 2.58 g of diethoxyacetonitrile as a starting material for the synthesis of (5)-(4-methylphenyl) imidazole.
The reaction and post-treatment were carried out in the same manner as in Reference Example 1 except that was used to obtain 1.42 g (yield 61%) of the desired product having a melting point of 127 to 129 ° C. Next, examples of the present invention will be described in which the compound represented by the formula (II) obtained by the above-mentioned reference example is used as a starting material, but the present invention is not limited thereto.

[0018]

【Example】

Example 1 Preparation of 2-cyano-4 (5)-(4-methylphenyl) imidazole 2- (diethoxymethyl) -4
0.5 g of (5)-(4-methylphenyl) imidazole
(0.00192 mol) of dimethylformamide 5m
dissolved in 1, 0.16 g of hydroxylamine hydrochloride
(0.0023 mol) and pyridine 0.183 g (0.
And 0023 mol) were added, and the mixture was reacted at 80 ° C. for 1 hour. Then, acetic anhydride 0.393 g (0.00384 mo
1) was added dropwise, and after completion of the addition, the mixture was reacted at 90 ° C. for 3 hours.
After completion of the reaction, the reaction product cooled to room temperature was poured into 30 ml of water, and the precipitated solid was collected by filtration and washed with water and hexane to obtain 0.306 g of the desired product (0.00167 mol, yield 87%). .

Example 2 2-Cyano-4 (5)-(4-
2- (diethoxymethyl) -4 (5)-(4 as a raw material for producing methylphenyl) imidazole
Instead of 0.5 g of -methylphenyl) imidazole,
2- (dimethoxymethyl) -4 (5)-(4-methylphenyl) imidazole 0.446 g (0.00192 m)
ol) was used and the reaction was carried out in the same manner as in Example 1 and post-treatment was carried out to obtain 0.27 g of the desired product.

Claims (11)

(57) [Claims] 1. A compound represented by the formula (I): (In the formula, Z is a lower alkyl group, a trifluoromethyl group,
A phenyl group which may be substituted with a lower alkoxy group or a lower alkylthio group), and a method for producing a 2-cyanoimidazole compound, which comprises (1)
Formula (II) in the presence of a solvent (Wherein R is a lower alkyl group and Z is as described above) is reacted with hydroxylamine, and then the product obtained in (2) and (1) is reacted with a dehydrating agent. The method for producing a 2-cyanoimidazole-based compound described above. 2. In the compound of formula (I) and the compound of formula (II), Z is a phenyl group substituted with a lower alkyl group,
The manufacturing method according to claim 1. 3. The production method according to claim 1, wherein the solvent is dimethylformamide. 4. The process according to claim 1, wherein the mineral acid salt thereof is used as hydroxylamine and a base is used. 5. The production method according to claim 4, wherein the base is pyridine. 6. The reaction of (1) comprises reacting a compound of formula (II) with a compound of formula (II) in the presence of a solvent in an amount of 6 to 10 times that of the compound of formula (II). The production method according to claim 1, which is achieved by mixing 1.2 to 1.3 equivalents of a hydroxylamine mineral acid salt and its salt with an equivalent amount of a base in a temperature range of 50 to 150 ° C. 7. The product obtained in (1) has the formula (III): The production method according to claim 1, which is a compound represented by the formula (wherein Z is as described above). 8. The production method according to claim 1, wherein the dehydrating agent is acetic anhydride. 9. The production method according to claim 1, wherein the reaction (2) is continuously performed after the reaction (1). 10. The reaction of (2) is carried out by adding the product obtained in (1) and 1.5 to 2.5 equivalents of acetic anhydride to the compound of formula (II) at a temperature of 50 to 150 ° C. The manufacturing method according to claim 1, which is achieved by mixing within the range. 11. A compound of the formula (II) in the presence of a solvent: (In the formula, R is a lower alkyl group and Z is a lower alkyl group.
Group, trifluoromethyl group, lower alkoxy group or
Phenyl group optionally substituted by lower alkylthio group
Expression, wherein the compound and reacting the hydroxylamine represented by the a) (III) embedded image (Wherein Z is as described above) .