JPH0361669B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides 1,2,4-triazole-3-
This invention relates to a new and simple method for producing carboxylic acid amides.

Latvijas PSR Zinatnu Akad. Vestis, Khim.
Ser., (2), 204-208 (1965) contains 1, 2, 4-
It is described that triazole-3-carboxylic acid amide can be obtained from acetyl chloride through the following six reaction steps.

Ciechoslovakia National Patent No. 175118 discloses that formylhydrazine is added to ethyl thioxamate from 50 to 50%.
React at 60℃ to form (2-formylhydrazino)
Obtain ethyl iminoacetate, heat it to 160°C,
By dehydration and ring closure, 1,2,4-triazole-3
- A method for producing ethyl carboxylate is disclosed. Ethyl thioxamate is synthesized by reacting ethyl oxamate obtained by reacting ethyl oxalate with ammonia with phosphorus pentasulfide, so it is a 1,2,4-triazole-3-carboxylic acid amide. is produced from oxalic acid ester through the following five reaction steps. In this case, hydrogen sulfide is produced as a by-product, and its deodorization requires complicated equipment.

An object of the present invention is to provide a new method for producing 1,2,4-triazole-3-carboxylic acid amides. Another object of the present invention is to provide a method for efficiently producing 1,2,4-triazole-3-carboxylic acid amides without producing by-products that require complicated reaction equipment such as odor control. It's about doing.

This invention is based on the formula (In the formula, R ¹ and R ² are each a hydrogen atom,
It represents an alkyl group or an aryl group, and R ³ represents a lower alkyl group. ) is reacted with ammonia or ammonium carboxylate.

formula 1,2,4- represented by (wherein R ¹ and R ² each have the same meaning as above)
This is a method for producing triazole-3-carboxylic acid amides.

According to the present invention, it is possible to obtain 1,2,4-triazole-3-carboxylic acid amides in fewer steps than in the known method, without using a bad-smelling compound as in the known method, and without producing by-products. I can do it.

The 1,2,4-triazole-3-carboxylic acid amides obtained by the present invention are useful as medicines, agricultural chemicals, and intermediates thereof. For example, 1,2,4-triazole-3-carboxylic acid amide can be prepared by reacting with the enzyme nucleoside phosphorylase in the presence of ribose phosphate.
It can be a triazole-3-carboxylic acid amide, which is effective against influenza virus infections.

Specific examples of R ¹ and R ² in the above formula are:
In addition to hydrogen atoms, carbon atoms with 1 to 10 carbon atoms such as methyl, ethyl, propyl, butyl, and hexyl groups
Examples include an alkyl group having 6 to 10 carbon atoms, a phenyl group, an alkyl group having 1 to 4 carbon atoms, or an aryl group having 6 to 10 carbon atoms, such as a phenyl group substituted with a halogen atom. Specific examples of R ² include methyl, ethyl, propyl, and butyl groups with a carbon number of 1.
-4 alkyl groups are mentioned.

Oxamidic acid (alkoxyalkylidene hydrazide) represented by the formula [] is obtained by reacting an oxalic acid ester with an amine and then reacting it with hydrazine. It can be obtained in good yield by reacting with an ester.

Specific examples of oxamic acid (alkoxyalkylidene hydrazide) include oxamic acid (methoxymethylidene hydrazide), oxamic acid (ethoxymethylidene hydrazide), oxamic acid (propoxymethylidene hydrazide), oxamic acid (butoxymethylidene hydrazide), N - methyloxamidic acid (methoxymethylidene hydrazide),
N-Methyloxamidic acid (ethoxymethylidene hydrazide), N-ethyloxamidic acid (methoxymethylidene hydrazide), N-ethyloxamidic acid (ethoxymethylidene hydrazide), N-propyloxamidic acid (methoxymethylidene hydrazide) ), N-propyl oxamidic acid (ethoxymethylidene hydrazide), N-butyl (methoxymethylidene hydrazide), N-butyl (ethoxymethylidene hydrazide), N-hexyl (methoxymethylidene hydrazide), N-hexyl (ethoxy Methylidene hydrazide), N-phenyloxamidic acid (methoxymethylidene hydrazide), N-phenyloxamidic acid (ethoxymethylidene hydrazide), N-chlorophenyloxamidic acid (methoxymethylidene hydrazide), N-chlorophenyloxamidic acid (methoxymethylidene hydrazide), Enyloxamidic acid (ethoxymethylidene hydrazide), N-dichlorophenyloxamidic acid (methoxymethylidene hydrazide), N-dichlorophenyloxamidic acid (ethoxymethylidene hydrazide), N-tolyloxamidic acid (methoxymethylidene hydrazide) ), N-tolyloxamic acid (ethoxymethylidene hydrazide), N-chlorotolyloxamic acid (methoxymethylidene hydrazide), N-chlorotolyloxamic acid (ethoxymethylidene hydrazide), oxamic acid (1-methoxyethylidene hydrazide) , oxamidic acid (1-ethoxyethylidene hydrazide), N-methyloxamidic acid (1-methoxyethylidene hydrazide), N-methyloxamidic acid (1-ethoxyethylidene hydrazide), N-phenyloxamidic acid (1-methoxyethylidene hydrazide), ethylidene hydrazide), oxamic acid (1-methoxypropylidene hydrazide), oxamic acid (1-ethoxypropylidene hydrazide), N-methyloxamic acid (1-methoxypropylidene hydrazide), N-phenyloxamic acid (1-methoxypropylidene hydrazide), -Methoxypropylidene hydrazide, oxamic acid (1-methoxybutylidene hydrazide), oxamic acid (1-ethoxybutylidene hydrazide), N-methyloxamic acid (1-methoxybutylidene hydrazide),
-methoxybutylidene hydrazide), N-phenyloxamidic acid (1-methoxybutylidene hydrazide), oxamidic acid (1-methoxyhexylidene hydrazide), N-methyloxamidic acid (1-
methoxyhexylidene hydrazide), N-phenyloxamidic acid (1-methoxyhexylidene hydrazide), oxamidic acid (α-methoxybenzylidene hydrazide), oxamic acid (α-ethoxybenzylidene hydrazide), N-methyloxamidic acid (α-methoxybenzylidene hydrazide),
N-phenyloxamidic acid (α-methoxybenzylidene hydrazide), oxamidic acid [α-(methoxy)chlorobenzylidene hydrazide], N-methyloxamidic acid [α-(methoxy)chlorobenzylidene hydrazide], N-phenyloxamate Midic acid [α-(methoxy)chlorobenzylidene hydrazide], Oxamidic acid [α-(methoxy)methylbenzylidene hydrazide], N-methyloxamidic acid [α-(methoxy)methylbenzylidene hydrazide], N-phenyloxamidic acid [α-(methoxy)methylbenzylidene hydrazide], oxamidic acid [α-(methoxy)methylchlorobenzylidene hydrazide], N-methyloxamidic acid [α-
(methoxy)methylchlorobenzylidene hydrazide] and N-phenyloxamidic acid [α-(methoxy)methylchlorobenzylidene hydrazide].

As the ammonium carboxylate, any ammonium salt of carboxylic acid can be used in the reaction, but ammonium salts of lower aliphatic carboxylic acids such as formic acid, acetic acid, and propionic acid are usually used.

The amount of ammonia and ammonium carboxylate used is preferably 1 mol or more per 1 mol of oxamidic acid (alkoxyalkylidene hydrazide).

The reaction is carried out in the presence of a solvent, such as carboxylic acids such as acetic acid and propionic acid,
Amides such as formamide, N,N-dimethylformamide and water are used.

The reaction temperature is generally in the range of 80 to 200°C, and the reaction is completed in 1 to 2 hours.

1,2,4- of formula [] produced by reaction
Triazole-3-carboxylic acid amides are solid at around room temperature, and can be isolated from the reaction product mixture by a known isolation method by utilizing the difference in solubility.

Specific examples of 1,2,4-triazole-3-carboxylic acid amides represented by formula [] include:
1,2,4-triazole-3-carboxylic acid amide, 1,2,4-triazole-3-carboxylic acid methylamide, 1,2,4-triazole-3-
Carboxylic acid ethylamide, 1,2,4-triazole-3-carboxylic acid propylamide, 1,2,
4-triazole-3-carboxylic acid butyramide, 1,2,4-triazole-3-carboxylic acid hexylamide, 1,2,4-triazole-3
-Carboxylic acid anilide, 1,2,4-triazole-3-carboxylic acid chloroanilide, 1,2,4
-triazole-3-carboxylic acid dichloroanilide, 1,2,4-triazole-3-carboxylic acid toluide, 1,2,4-triazole-3-carboxylic acid chlorotoluide, 5-methyl-1,2,4
-triazole-3-carboxylic acid amide, 5-methyl-1,2,4-triazole-3-carboxylic acid methylamide, 5-methyl-1,2,4-triazole-3-carboxylic acid anilide, 5-ethyl-1 , 2,4-triazole-3-carboxylic acid amide, 5-ethyl-1,2,4-triazole-
3-carboxylic acid methylamide, 5-ethyl-1,
2,4-triazole-3-carboxylic acid anilide, 5-propyl-1,2,4-triazole-
3-carboxylic acid amide, 5-propyl-1,2,
4-triazole-3-carboxylic acid methylamide, 5-propyl-1,2,4-triazole-
3-carboxylic acid anilide, 5-pentyl-1,
2,4-triazole-3-carboxylic acid amide,
5-pentyl-1,2,4-triazole-3-
Carboxylic acid methylamide, 5-pentyl-1,
2,4-triazole-3-carboxylic acid anilide, 5-phenyl-1,2,4-triazole-
3-carboxylic acid amide, 5-phenyl-1,2,
4-triazole-3-carboxylic acid methylamide, 5-phenyl-1,2,4-triazole-
3-carboxylic acid anilide, 5-chlorophenyl-
1,2,4-triazole-3-carboxylic acid amide, 5-chlorophenyl-1,2,4-triazole-3-carboxylic acid methylamide, 5-chlorophenyl-1,2,4-triazole-3-carboxylic acid anilide, 5-tolyl-1,2,4-triazole-3-carboxylic acid amide, 5-tolyl-
1,2,4-triazole-3-carboxylic acid methylamide, 5-tolyl-1,2,4-triazole-3-carboxylic acid anilide, 5-chlorotolyl-1,2,4-triazole-3-carboxylic acid amide, Examples include 5-chlorotolyl-1,2,4-triazole-3-carboxylic acid methylamide and 5-chlorotolyl-1,2,4-triazole-3-carboxylic acid anilide.

Next, examples will be shown. In the example, 1,
The yield of 2,4-triazole-3-carboxylic acid amide is the yield based on the oxamic acid (alkoxyalkylidene hydrazide) used.

Example 1 1.59 g of oxamidic acid (ethoxymethylidene hydrazide) was added to 10 ml of concentrated aqueous ammonia, and the mixture was heated and reacted under reflux for 20 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered, and 0.33 g of the resulting crystals were added to 20 ml of water.
Recrystallized with 1,2,4-triazole-3-
Colorless needle crystals of carboxylic acid amide 0.2g (18%)
I got it.

The liquid obtained by filtering the reaction product mixture was concentrated under reduced pressure, 10 ml of water was added to the obtained residue, filtered, and 0.14 g of crystals of 1,2,4-triazole-3-carboxylic acid amide ( 12%).

Example 2 While heating a mixture of 1.7 g of oxamic acid (ethoxymethylidene hydrazide) and 15 ml of formamide on an oil bath at 110°C, 30% ammonia was added to the mixture.
It lasted for a minute. After bubbling the ammonia, the mixture was continued to be heated and allowed to react for an additional 30 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered. The obtained crystals are dissolved in ethanol.
Wash twice with 10 ml and add 1,2,4-triazole-
Mixture of 3-carboxylic acid amide and oxamide 0.43
I got g. Mix this mixture with 2 ml of concentrated ammonia water and water.
Add to 15 ml of the mixture and strain the oxamide crystals.
0.09g was obtained, and the liquid was concentrated under reduced pressure to give 1,2,4
-Triazole-3-carboxylic acid amide crystals
0.32g (27%) was obtained.

The liquid from which the mixture of 1,2,4-triazole-3-carboxylic acid amide and oxamide was obtained and the washing liquid were combined and concentrated under reduced pressure. 10 ml of water was added to the resulting residue, filtered, and 1,2,4-
Triazole-3-carboxylic acid amide crystal 0.28
g (24%) was obtained.

Example 3 A mixture of 1.59 g of oxamidic acid (ethoxymethylidene hydrazide), 1.16 g of ammonium acetate and 30 ml of water was heated and reacted under reflux for 10 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered. The obtained crystals were added to a mixture of 5 ml of concentrated aqueous ammonia and 20 ml of water, and the mixture was stirred at room temperature for 1 hour and then filtered to obtain 0.26 g of oxamic acid hydrazide crystals. Concentrated hydrochloric acid in liquid 6.5
1,2,4-triazole-
0.42 g (38%) of 3-carboxylic acid amide crystals were obtained.

Example 4 Oxamidic acid (ethoxymethylidene hydrazide) 1.59g, ammonium acetate 1.16g and acetic acid 20ml
The mixture was heated and reacted under reflux for 20 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered to obtain 0.2 g (18%) of crystals of 1,2,4-triazole-3-carboxylic acid amide.

Example 5 A mixture of 1.59 g of oxamic acid (ethoxymethylidene hydrazide), 0.77 g of ammonium acetate and 10 ml of formamide was heated on an oil bath at 110°C.
The reaction was allowed to proceed for 1 hour.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered. After washing the obtained crystals twice with 10 ml of 2-propanol, 5 ml of concentrated ammonia water was added.
ml and 20 ml of water. Mixture at room temperature
After stirring for an hour, the oxamide crystals
0.09g was obtained. Concentrate the liquid under reduced pressure to obtain 1,
0.56 g (47%) of crystals of 2,4-triazole-3-carboxylic acid amide was obtained.

Example 6 A mixture of 1.59 g of oxamic acid (ethoxymethylidene hydrazide), 0.94 g of ammonium formate and 10 ml of formamide was heated on an oil bath at 100°C to give 1.
Allowed time to react.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered. The obtained crystals are dissolved in ethanol.
After washing twice with 10ml, add 2ml of concentrated ammonia water and water.
Added to 15ml of the mixture. The mixture was stirred at room temperature for 1 hour and then filtered to obtain 0.04 g of oxamide crystals. The liquid was concentrated under reduced pressure to obtain 0.52 g of crystals of 1,2,4-triazole-3-carboxylic acid amide.
(46%).

Example 7 In a mixture of 7.26 g of oxamic acid (methoxymethylidene hydrazide) and formamide, 107 to 110
Ammonia was passed through for 1 hour at . After passing in the ammonia, the mixture was continued to heat and react for an additional 30 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered. After washing the obtained crystals twice with 10 ml of 2-propanol, 10 ml of concentrated ammonia water was added.
ml and 50 ml of water. Mixture at room temperature
After stirring for an hour and filtering, the oxamide crystals
0.79g was obtained. Concentrate the liquid under reduced pressure to obtain 1,
2.32 g (41%) of crystals of 2,4-triazole-3-carboxylic acid amide were obtained.

Example 8 Ammonia was passed through a mixture of 3.46 g of N-methyloxamidic acid (ethoxymethylidene hydrazide) and 30 ml of formamide at 108-114° C. for 1 hour. After passing in the ammonia, the mixture was continued to heat and react for an additional 30 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered to obtain 0.06 g of N-methyloxamide crystals. The liquid was concentrated under reduced pressure, and the residue was filtered by adding 10 ml of 2-propanol.
1.53 g (61%) of crystals of 4-triazole-3-carboxylic acid methylamide were obtained.

Example 9 Ammonia was passed through a mixture of 2.35 g of N-phenyloxamidic acid (ethoxymethylidene hydrazide) and 30 ml of formamide at 110° C. for 1 hour. After passing ammonia through, the reaction was continued at the same temperature for an additional 30 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered to obtain 0.08 g of N-phenyloxamide crystals. The liquid was concentrated under reduced pressure, and 10 ml of water was added to the residue and filtered to obtain a mixture of 1,2,4-triazole-3-carboxylic acid anilide and N-phenyloxamide. This mixture was added to a mixture of 2 ml of concentrated aqueous ammonia and 20 ml of water, and the mixture was stirred at room temperature for 1 hour and then filtered to obtain 0.52 g of N-phenyl oxamide crystals. The liquid was concentrated under reduced pressure to obtain 0.68 g (36%) of crystals of 1,2,4-triazole-3-carboxylic acid anilide.

Example 10 In a mixture of 4.77 g of oxamic acid (methoxymethylidene hydrazide) and 30 ml of formamide, 108
Ammonia was bubbled through for 1 hour at ~118°C. After ammonia was aerated, the reaction was further continued at the same temperature for 30 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered to obtain 0.41 g of oxamide crystals. The liquid was concentrated under reduced pressure, and 10 ml of 2-propanol was added to the residue and filtered. The obtained crystals were added to 60 ml of ethanol, the insoluble matter was removed by filtration, and the solution was concentrated under reduced pressure to give 5-methyl-1,2,4
-Triazole-3-carboxylic acid amide crystals
1.99g (53%) was obtained.

Claims (1)

[Claims] 1 formula (In the formula, R ¹ and R ² are each a hydrogen atom,
It represents an alkyl group or an aryl group, and R ³ represents a lower alkyl group. ) is characterized by reacting oxamidic acid (alkoxyalkylidene hydrazide) with ammonia or ammonia carboxylic acid. 1,2,4- represented by (wherein R ¹ and R ² each have the same meaning as above)
Method for producing triazole-3-carboxylic acid amides.