JPS6121472B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 1-substituted imidazole-5-carboxylic acids.

1-Substituted imidazole-5-carboxamide derivatives are useful substances as agricultural chemicals, medicines, dyes, curing agents, etc., but hitherto no method for practically producing them in high yield has been known. As a known method for producing 1-substituted imidazole-5-carboxamide derivatives, for example, 4,5-dicyanoimidazole is hydrolyzed to give imidazole-4,5-dicarboxylic acid, and this is heated under reflux in aniline. imidazole-4(5)-carboanilide,
This is hydrolyzed to give imidazole-4(5)-carboxylic acid, which is reacted with methanol under a hydrochloric acid catalyst to give methyl imidazole-4(5)-carboxylate, which is then reacted with dimethyl sulfate to give 1-methyl There is a method of obtaining 1-methylimidazole-5-carboxide derivatives by preparing methyl imidazole-5-carboxylate and reacting this with an amine, but the reaction route is long and the overall yield is extremely low.

Therefore, the inventor has determined that 1-substituted imidazole-5
-As a result of intensive research into a practical method for producing carboxamide derivatives with good yields, we have discovered a new and excellent method for producing 1-substituted imidazole-5-carboxamide derivatives via 1-substituted imidazole-5-carboxylic acid. I came to invent it.

According to the present invention, the general formula [] (wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms) is heated in acetic anhydride. General formula [] (wherein R ¹ is as defined above) A method for producing a 1-substituted imidazole-5-carboxylic acid is provided.

The above reaction involves stirring the 1-substituted imidazole-4,5-dicarboxylic acid of the formula [] in acetic anhydride at a temperature of, for example, about 80 to 140°C, more preferably about 100 to 110°C. The reaction proceeds easily by heating, and 1-substituted imidazole-5-carboxylic acid of the formula [] is produced in high yield. In the reaction, the larger the amount of acetic anhydride, the shorter the reaction time, and the higher the reaction temperature, the shorter the reaction time, but if it is too high, the yield will decrease.

The raw material compound of the formula [], 1-substituted imidazole-4,5-dicarboxylic acid, can be prepared, for example, from 1-substituted-4,5-dicyanoimidazole by a known method (for example, Bull.Chem.Soc.Jap., 41, 1237
(1968)), 1-substitution-
4,5-dicyanoimidazole can be prepared by a known method (for example, Bull.
Chem.Soc.Jap.41, 1237 (1968)). Various methods for synthesizing 4,5-dicyanoimidazole are known, including a method of synthesizing by reacting liquid hydrocyanic acid and liquid ammonia or alkali cyanide and ammonium chloride (for example, J.Org.
Chem.31, 2035 (1966) and Chem.33, 642 (1968)
) and the method of synthesis from diaminomaleonitrile and formic acid (for example, J.Org.Chem.41, 713
(1976), U.S. Patent No. 2534331, Special Publication No. 46-4373
Publication No. 47-20623, Japanese Patent Publication No. 49-2062
(Refer to Publication No. 108071 and Japanese Unexamined Patent Publication No. 1983-65268)
is typical.

The 1-substituted imidazole-5-carboxylic acid of the formula [] produced according to the method of the present invention is obtained by subjecting it to a heating reaction with thionyl chloride, and then distilling off excess thionyl chloride.
R ² R ³ NH (wherein R ² and R ³ are independently substituted with hydrogen; an alkyl group having 1 to 4 carbon atoms; a phenyl group; a halogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group) Indicates a phenyl group, and also
^The general formula ^[ ] (wherein R ¹ , R ² and R ³ are as defined above) A 1-substituted imidazole-5-carboxamide derivative can be produced.

The 1-substituted imidazole-5-carboxylic acid of the above formula [] preferably has a molecular weight of about 50 to
It is converted to 1-substituted imidazole-5-carboxylic acid chloride by reaction with thionyl chloride by heating to a temperature of about 76°C (reflux temperature). This generated acid chloride is hydrolyzed by moisture in the air,
Since it returns to the raw material carboxylic acid, it is not isolated, but after distilling off excess thionyl chloride, the above formula R ² R ³ NH
The 1-substituted imidazole-5-carboxamide derivative of the formula [] is produced by reacting with the amine of the formula []. This reaction between acid chloride and amine is usually
For example, it is carried out in a solvent such as methylene chloride or chloroform dimethylformamide at a temperature of 0 to 100°C, and an amine such as triethylamine can be present in order to collect hydrogen chloride produced as a by-product in the reaction. . 1-Substituted imidazole-5- of the above formula [] produced in this way
Carboxamide derivatives are useful substances that can be used as agricultural chemicals, medicines, dyes, hardeners, etc.

Examples of the present invention will be described below.

Example 1 Production of 1-methylimidazole-5-carboxylic acid 1-methyl-4,5-dicyanoimidazole
Add 13.2 g (0.1 mol) to a 300 ml flask equipped with a stirrer, thermometer, and reflux condenser, add 100 ml of 6N aqueous sodium hydroxide solution, and heat under reflux until the generation of ammonia stops (about 6 hours). Made it react. Next, concentrated hydrochloric acid was gradually added under cooling to make the reaction solution acidic. The formed precipitate was separated and recrystallized from dilute hydrochloric acid to obtain 15.5 g (90% yield) of white crystals of 1-methylimidazole-4,5-dicarboxylic acid having a melting point of 245° C. (decomposed).

5 g of 1-methylimidazole-4,5-dicarboxylic acid thus prepared were then suspended in 250 ml of acetic anhydride in a 500 ml flask equipped with a stirrer, a thermometer and a reflux condenser, and heated to 100°C. The mixture was heated while stirring. The raw material carboxylic acid gradually reacted and dissolved, and the reaction was completed in about 4 hours to obtain a colorless and transparent liquid. Next, acetic anhydride is distilled off from this liquid under reduced pressure (this recovered acetic anhydride can be used repeatedly), and the remaining solid content is recrystallized from ethanol.
3.6 g (yield 97%) of almost colorless needle-like crystals of 1-methylimidazole-5-carboxylic acid were obtained.
Melting point 256-257°C (decomposition). The elemental analysis values of the produced compound were as follows.

C H N Calculated value: 47.62 4.76 22.22 Actual value: 47.91 4.71 22.04 Example 2 Production of 1-methylimidazole-5-carboxylic acid 1-Methylimidazole-4,5 synthesized as described in the first part of Example 1 -5 g of dicarboxylic acid was suspended in 250 ml of acetic anhydride in a 500 ml flask equipped with a stirrer thermometer and a reflux condenser, and heated and stirred while refluxing. The reaction proceeded rapidly, turning into a brown, transparent solution in about 30 minutes. 1-methylimidazole was treated in the same manner as in Example 1 above.
2.6 g (yield 70%) of 5-carboxylic acid was obtained. melting point
256-257℃ (decomposition).

Example 3 Preparation of 1-methylimidazole-5-carboxylic acid 3.4 g of 1-methylimidazole-4,5-dicarboxylic acid are dissolved in 100 ml of acetic anhydride in a 200 ml flask equipped with a stirrer, thermometer and reflux condenser. The mixture was suspended in acetic anhydride and heated for about 1 hour while stirring at the reflux temperature of acetic anhydride. During this time, most of the suspended dicarboxylic acid was reacted and dissolved to obtain a clear liquid. This solution was treated as in Example 1 above to obtain 1.6 g of white crystals of 1-methylimidazole-5-carboxylic acid (yield:
63.5%). Melting point 256-257°C (decomposition).

Example 4 Production of 1-benzylimidazole-5-carboxylic acid 1 g of benzyl chloride and 5 g of triethylamine were dissolved in 50 ml of chloroform, and 5 g of 4,5-dicyanoimidazole was suspended therein and heated under reflux. After the reaction mixture became a homogeneous solution (approximately 1 hour), the reaction was stopped. Chloroform and unreacted benzyl chloride and triethylamine were distilled off from the reaction solution under reduced pressure, and the remaining solid was washed with hexane and then dissolved again in chloroform (or benzene). After washing with water, the organic layer was separated and dried. Let it harden,
Recrystallized from water to give 8.1 g of white needle-like crystals of 1-benzyl-4,5-dicyanoimidazole (yield: 92
%) was obtained. The melting point of the product was 120.5-121.5°C, and the elemental analysis values were as follows.

C H N Calculated value 69.23 3.85 26.92 Actual value 68.92 3.84 26.71 4 g of 1-benzyl-4,5-dicyanoimidazole obtained above was added to a 6N aqueous sodium hydroxide solution.
100 ml and the mixture was heated under reflux until ammonia evolution ceased (approximately 5 hours). Then, concentrated hydrochloric acid was added under cooling to make the reaction solution acidic, and a white precipitate was formed. This precipitate was separated and recrystallized from dilute hydrochloric acid to obtain 4 g of white crystals of 1-benzylimidazole-4,5-dicarboxylic acid (yield). rate of 85%). The melting point of the product was 223-225°C (decomposed), and the elemental analysis values were as follows.

C H N Calculated value 58.54 4.06 11.38 Actual value 58.41 3.89 11.31 1-Benzylimidazole-4,5- obtained above
3 g of dicarboxylic acid were suspended in 300 ml of acetic anhydride and heated to about 120° C. with stirring. As the reaction progresses, suspended dicarboxylic acid dissolves in acetic anhydride and dissolves for about 30 minutes.
It became a colorless and transparent solution in minutes. Acetic anhydride was distilled off from the reaction solution under reduced pressure, and the remaining solid was recrystallized from ethanol to obtain 2 g of white crystals of 1-benzylimidazole-5-carboxylic acid (yield: 82%). The melting point of the product was 220-222°C (decomposed), and the elemental analysis values were as follows.

C H N Calculated value 65.35 4.95 13.86 Actual value 65.17 4.72 13.89 Reference example 1 Production of 1-methylimidazole-5-carboanilide 1-methylimidazole-5-carboxylic acid 2.5
g equipped with a stirrer, thermometer and reflux condenser.
Add 50ml of thionyl chloride to the 200ml flask.
was added and heated under reflux for about 6 hours. As time passed, the raw material carboxylic acid gradually reacted and dissolved to become a red homogeneous solution. Excess thionine chloride was distilled off from this reaction solution, and a solution of 1.86 g of aniline and 20 ml of triethylamine dissolved in 50 ml of 700 form was immediately added thereto.

The mixture was heated under reflux for 1 hour, then cooled, washed with water to remove triethylamine hydrochloride, the chloroform layer was separated to dryness, and the remaining solid was recrystallized from benzene to form 1-methylimidazole-5. -2.4g of white crystals of carboanilide (yield
60%). The melting point of the product was 184-186°C, and the elemental analysis values were as follows.

C H N Calculated value 65.67 5.47 20.90 Actual value 65.52 5.31 20.65 Reference example 2 Production of 1-methylimidazole-5-carboxamide 1-methylimidazole-5-carboxylic acid 0.9
g equipped with a stirrer, thermometer and reflux condenser.
Add 100ml of thionyl chloride to the 300ml flask.
was added and heated under reflux. As time passed, the raw material carboxylic acid gradually reacted and dissolved, becoming a transparent solution in about 20 minutes. After continuing heating for another hour,
Excess thionyl chloride was distilled off from this reaction solution, and 100 ml of 700 form was immediately added to remove 700 ml of acid chloride.
A white precipitate was produced when dry ammonia gas was passed through the form-dissolved acid. This was separated, the chloroform layer was dried, and the remaining solid content was recrystallized from benzene to obtain 0.5 g of white crystals of 1-methylimidazole-5-carboxamide (yield: 55%). The melting point of the product was 165°C, and the elemental analysis values were as follows.

C H N Calculated value 48.00 5.60 33.60 Actual value 47.84 5.38 33.38 Reference example 3 N,N-diethyl-1-methylimidazole-
Production of 5-carboxamide 1-methylimidazole-5-carboxylic acid 1.0
g equipped with a stirrer, thermometer and reflux condenser.
Add 50ml of thionyl chloride to the 200ml flask.
was added and heated under reflux for about 2 hours. As time passed, the raw material carboxylic acid gradually reacted and dissolved to become a transparent solution. Excess thionyl chloride was distilled off from the reaction solution, and a solution of 2 g of diethylamine in 100 ml of 700 form was immediately added.

This mixture was heated under reflux for 1 hour, then cooled, washed with water to remove diethylamine hydrochloride, the chloroform layer was dried, low-boiling substances were distilled off under reduced pressure, and the remaining oil was distilled under vacuum. Yellow oil-colored N,N-diethyl-1-methylimidazole-5
-0.4 g (yield 28%) of carboxamide was obtained. Boiling point 110-115℃/0.5mmHg.

Elemental analysis value: C H N Calculated value 59.67 8.29 23.20 Actual value 59.23 7.98 22.82 Reference example 4 Production of N-(3,5-dichlorophenyl)-1-methylimidazole-5-carboxamide 1-methylimidazole-5-carvone acid 1.0
g equipped with a stirrer, thermometer and reflux condenser.
Add 50ml of thionyl chloride to the 200ml flask.
was added and heated under reflux for about 2 hours. As time passed, the raw material carboxylic acid gradually reacted and dissolved to become a transparent solution. Excess thionyl chloride was distilled off from this reaction solution, and immediately 3,5-dichloroaniline
1.3g and 20ml of triethylamine in chloroform
A solution of 50 ml was added.

The mixture was heated under reflux for 1 hour, then cooled, washed with water to remove triethylamine hydrochloride, the chloroform layer was separated to dryness, and the remaining solid was recrystallized from a water-ethanol mixed solvent.
Pale yellow crystals of (3,5-dichlorophenyl)-1-methylimidazole-5-carboxamide 0.9
g (yield 42%) was obtained. Melting point 139-140℃.

Claims (1)

[Claims] 1. General formula [] (wherein R ¹ represents an alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms) is heated in acetic anhydride. General formula [] (wherein R ¹ is as defined above) A method for producing a 1-substituted imidazole-5-carboxylic acid. 2. The manufacturing method according to claim 1, wherein the heating is performed at a temperature of 80 to 140°C.