JPH0253435B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 1-substituted imidazole-5-carboxamide derivatives. [Prior Art] 1-Substituted imidazole-5-carboxamide derivatives are useful substances as agricultural chemicals, medicines, dyes, curing agents, etc., but until now there is no known method for practically producing them in high yields. . A known method for producing 1-substituted imidazole-5-carboxamide derivatives includes, for example, hydrolyzing 4,5-dicyanoimidazole to give imidazole-4,5-dicarboxylic acid, and heating this in aniline under reflux. imidazole-4(5)-carboanilide,
This is hydrolyzed to give imidazole-4(5)-carboxylic acid, which is reacted with methanol under 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-carboxamide 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. [Problems to be Solved by the Invention] Therefore, the present inventors solved the problem by solving the following problem: 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. [Means for solving the problem] According to the present invention, the general formula [] (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms) is heated to react with thionyl chloride, and then excess thionyl chloride is reacted with thionyl chloride. After distilling off, the product has the general formula R ² R ³ NH, where R ² and R ³
each independently represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a halogen, or a halogen group having 1 to 4 carbon atoms.
a phenyl group substituted with an alkyl group or an alkoxy group, and further R ² R ³ NH may represent hydrazine, semicarbazide or thiosemicarbazide). (wherein R ¹ , R ² and R ³ are as defined above)
-Processes for making substituted imidazole-5-carboxamide derivatives are provided. [Description of the Invention] The compound of the general formula [] is, for example, a compound of the general formula [] It can be produced by heating 1-substituted imidazole-4,5-dicarboxylic acid (wherein R ¹ is as defined above) in acetic anhydride. The above reaction involves stirring the 1-substituted imidazole-4,5-carboxylic 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 compound of formula [], 1-substituted imidazole-4,5-dicarboxylic acid, is, for example, 1-substituted imidazole-4,5-dicarboxylic acid.
Substituted-4,5-dicyanoimidazole by known methods (e.g. Bull.Chem.Soc.Jap., 41 , 1237
(1968)), 1-substituted-4,
5-Dicyanoimidazole is prepared from 4,5-dicyanoimidazole by known methods (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 33 , 642 (1968)) and a method of synthesis from diaminomaleonitrile and formic acid (for example, J.Org.Chem. 41 , 713 (1976),
U.S. Patent No. 2534331, Japanese Patent Publication No. 46-4373,
(Refer to Japanese Patent Publication No. 47-20623, Japanese Patent Application Laid-Open No. 108071-1982, and Japanese Patent Application Laid-open No. 65268-1982) are representative. The 1-substituted imidazole-5-carboxylic acid of the above formula [], which is the raw material compound of the method of the present invention, is heated to react with thionyl chloride, and after distilling off excess thionyl chloride, the product is converted into a product with the general formula
The desired 1-substituted imidazole-5-carboxamide derivative of general formula [ ] is prepared by thermal reaction with R ² R ³ NH (where R ² and R ³ are amines as defined above). The 1-substituted imidazole-5-carboxylic acid of the formula [] is preferably about 50 to
It is converted to the 1-substituted imidazole-5-carboxylic acid chloride by reaction with thionyl chloride by heating to a temperature of about 76°C (reflux temperature). The acid chloride produced in this way is hydrolyzed by moisture in the air and returns to the raw material carboxylic acid, so in the present invention, it is not isolated, but after distilling off excess thionyl chloride, it is directly represented by the formula R A 1-substituted imidazole-5-carboxamide derivative of the above formula [] is produced by reacting with an amine of ² R ³ NH. This reaction between acid chloride and amine is usually preferably carried out in a solvent such as methylene chloride or chloroform dimethylformamide at a temperature of 0 to 100°C, and hydrogen chloride produced as a by-product in the reaction is collected. Therefore, for example, an amine such as triethylamine can be present. 1-substituted imidazole of the above formula [] produced in this way
5-Carboxamide derivatives are used in concentrated drugs, pharmaceuticals, dyes,
It is a useful substance that can be used as a hardening agent. [Example] Examples of the present invention will be described below. Reference 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. Separate the formed precipitate and recrystallize it from dilute hydrochloric acid to obtain a
15.5 g (yield: 90%) of white crystals of -methylimidazole-4,5-dicarboxylic acid were obtained. Next, 5 g of 1-methylimidazole 4,5-dicarboxylic acid produced in this way was added using a stirrer,
Suspended in 250 ml of acetic anhydride in a 500 ml flask equipped with a thermometer and reflux condenser and heated to 100° C. with 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),
The residual solid content was recrystallized from ethanol to obtain 3.6 g (97% yield) of almost colorless needle-like crystals of 1-methylimidazole-5-carboxylic acid. Melting point 256~
257℃ (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 Reference example 2 Production of 1-methylimidazole-5-carboxylic acid 1-methylimidazole-4,5 synthesized as described in the first part of Reference example 1 - 5 g of dicarboxylic acid were 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 at reflux. The reaction proceeded rapidly, turning into a brown, transparent solution in about 30 minutes. Treated in the same manner as in Reference Example 1 above, 1-methylimidazole-
2.6 g (yield 70%) of 5-carboxylic acid was obtained. melting point 256
~257℃ (decomposition). Reference Example 3 Production of 1-methylimidazole-5-carboxylic acid 3.4 g of 1-methylimidazole-4,5-dicarboxylic acid was 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 liquid was treated as in Reference Example 1 above to obtain 1.6 g of white crystals of 1-methylimidazole-5-carboxylic acid (yield 63.5).
%) was obtained. Melting point 256-257°C (decomposition). Reference Example 4 Production of 1-benzylimidazole-5-carboxylic acid 10 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 becomes a homogeneous solution (approximately 1 hour),
The reaction was stopped. Chloroform and unreacted benzyl chloride and triethylamine are distilled off from the reaction solution under reduced pressure, and the remaining solid is washed with hexane, and then chloroform (or benzene may be used) again.
After washing with water, the organic layer was separated, dried, and recrystallized from water to obtain 8.1 g of white needle-like crystals of 1-benzyl-4,5-dicyanoimidazole (yield: 92%). 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 100 g of 6N aqueous sodium hydroxide solution.
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). 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 11.39 Actual value 58.41 3.89 11.31 1-benzylimidazole-4,5- obtained above
Suspend 3 g of dicarboxylic acid in 300 ml of acetic anhydride,
The mixture was heated to about 120° C. while stirring. As the reaction progressed, the suspended dicarboxylic acid dissolved in acetic anhydride and became a colorless and transparent solution in about 30 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 Example 1 Production of 1-methylimidazole-5-carboanilide 2.5 g of 1-methylimidazole-5-carboxylic acid
200, equipped with a stirrer, thermometer and reflux condenser.
ml flask, 50 ml of thionyl chloride was added thereto, and the mixture was 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 thionyl 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 chloroform 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. −2.4 g of white crystals of carboanilide (yield: 60
%) was obtained. 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 Example 2 Production of 1-methylimidazole-5-carboxamide 1-methylimidazole-5-carboxylic acid 0.9g
300, equipped with a stirrer, thermometer and reflux condenser.
ml flask, 100 ml of thionyl chloride was added thereto, and the mixture was 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 an additional hour, excess thionyl chloride was distilled off from the reaction solution, and 100 ml of chloroform was immediately added to obtain a chloroform solution of acid chloride. Dry ammonia gas was passed through this to form a white precipitate. Apart from this,
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 Example 3 Production of N,N-diethyl-1-methylimidazole-5-carboxamide 1.0 g of 1-methylimidazole-5-carboxylic acid
200, equipped with a stirrer, thermometer and reflux condenser.
ml flask, 50 ml of thionyl chloride was added thereto, and the mixture was 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 chloroform 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 oily 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 Example 4 Production of N-(3,5-dichlorophenyl)-1-methylimidazole-5-carboxamide 1-methylimidazole-5-carvone acid 1.0g
200, equipped with a stirrer, thermometer and reflux condenser.
ml flask, 50 ml of thionyl chloride was added thereto, and the mixture was 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 1.3 g of 3,5-dichloroaniline was added.
and 2 ml of triethylamine and 500 ml of chloroform.
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.
0.9g of pale yellow crystals of (3,5-dichlorophenyl)-1-methylimidazole-5-carboxamide
(yield 42%). Melting point 139-140℃.

Claims (1)

[Claims] 1. General formula [] (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or an aralkyl group having 7 to 10 carbon atoms) is heated to react with thionyl chloride, and then excess thionyl chloride is reacted with thionyl chloride. After distilling off, the product has the general formula R ² R ³ NH, where R ² and R ³
each independently represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a phenyl group substituted with a halogen, an alkyl group having 1 to 4 carbon atoms, or ^{an alkoxy} group; , which may represent semicarbazide or thiosemicarbazide). (wherein R ¹ , R ² and R ³ are as defined above)
-Production method of substituted imidazole-5-carboxamide derivative. 2. The production method according to claim 1, wherein the reaction between the compound of the formula [] and thionyl chloride is carried out at 50 to 76°C. 3. The production method according to claim 1 or 2, wherein the reaction product of the compound of the formula [] and thionyl chloride and the amine of the formula R ² R ³ NH is reacted at 0 to 100°C. .