JPS59206368A - Preparation of 1,2,4-triazole-3-carboxylic acid amides - Google Patents

Abstract

PURPOSE:To obtain efficiently the titled compound useful as a drug, agricultural chemical, or an intermediate of them without formation of a by-product which requires a complicated reactor for deodorization, by reacting oxamic acid with ammonia or ammonia carboxylate. CONSTITUTION:1mol compond shown by the formula I (R<1> and R<2> are H, alkyl, or aryl; R<3> is lower alkyl) is reacted with preferably >=1mol ammonia or ammonium carboxylate in the presence of a solvent generally at 80-200 deg.C for 1- 2hr, to give the desired compound shown by the formula II useful as an intermediate for a drug effective for infectious disease of influenza virus by fewer number of processes than a well-known method without using a compound to emit an offensive smell and preparing it as a by-product. The compound shown by the formula I is obtained in high yield by reacting an oxalic ester with an amine, reacting the reaction product with hydrazine, reacting the prepared compound with an orthocarboxylic acid.

Description

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

Latvijas PSRZinatnu Akad,
Vestis, Khim, Ser, (2)
.

204-208 (1965), 1. ．． It is described that 2,4-triazole-3-carboxylic acid amide can be obtained from acetyl chloride through the following 6 steps of reaction.

Czechoslovakia Patent No. 175.118 states:
Add formylhydrazine to ethyl thioxamidate from 50 to
React at 60'C to form (2-formylhydrazuno,)
Ethyl iminoacetate was obtained and heated to 160°C,
A method for producing ethyl 1,2,4-tria/'-ru-3-carboxylate through dehydration and ring closure is disclosed. Ethyl thioxamate is synthesized by reacting ethyl oxamate, obtained by reacting ethyl oxalate with ammonia, with phosphorus pentasulfide.
．． 4-) Riazole-3-carboxylic acid amide is produced from a 7-acetyl ester through the following five reaction steps. In this case, hydrogen sulfide is produced as a by-product, and its deodorization requires complicated equipment.

The object of this invention is %11'214-t! An object of the present invention is to provide a new method for producing J azole-3-carboxylic acid amides. Another object of this invention is to eliminate the production of by-products such as deodorization, which require complex reaction equipment.
4-) An object of the present invention is to provide a method for efficiently producing lyazole-3-carboxylic acid amides.

This invention is based on an oxamic acid (alkoxyalkylidene hydrazide) represented by (wherein R1 and R2 each represent a hydrogen atom, an alkyl group or an aryl group, and R3 represents a lower alkyl group), and ammonia or carbonyl hydrazide. 1,2. ．． There is a method for producing 4-1 lyazole-3-carboxylic acid amides ""C.

According to this invention, the number of steps is fewer than that of the known method.

It is possible to obtain 1,2,4-triazole-3-carboxylic acid amides without using malodorous compounds as in known methods and without producing by-products.

The 1,2,4-triazole-3-carboxylic acid amides obtained in this invention are useful as medicines, agricultural chemicals, and intermediates thereof. For example 1.2.4-)
Riazole-3-carboxylic acid amide is converted into l-β-D-ribofuranone-1.2.4-triazole-3-carboxylic acid amide by reacting with the enzyme nucleondophosphorylase in the presence of ribose phosphate. This is effective against influenza virus infection.

Specific examples of R1 and R2 in the above formula include, in addition to a hydrogen atom, an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, and a hexyl group;
Examples thereof include phenyl groups, alkyl groups having 1 to 4 carbon atoms, and aryl groups having 6 to 10 carbon atoms such as phenyl groups substituted with halogen atoms. Further, specific examples of R2 include alkyl groups having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, and butyl group.

The oxamidic acid (alkoxyalkylidene hydrazide) represented by formula [II] is, as shown in the following formula,
It can be obtained in good yield by reacting oxamic acid hydrazide, which is obtained by reacting an oxalic acid ester with an amine and then reacting it with hydrazine, with an orthocarboxylic acid ester.

Specific examples of oxamic acid (alkoxyalkylidene hydrazide) include oxamic acid (methoxymethylidene hydrazide), oxamic acid (ethoxymethylidene hydrazide), oxamic acid (proboxymethylidene hydrazide), and oxamic acid (butquin methylidene hydrazide). hydrazide)
, N-methyloxamidic acid (methylidene hydrazide), 'N-methyloxamidic acid (methylidene hydrazide).

Draft), N-ethyloxamidic acid (nodoquinteritin hydrazide), N-ethyloxamidic acid (ethoxymethylidene hydrazide), N-propyloxamidic acid (ethoxymethylidene hydrazide), N-propyloxamidic acid (ethoxy methylidene hydrazide), N-butyl (
ethoxymethylidene hydrazide), N-butyl (ethoxymethylidene hydrazide), N-hexyl (ethoxymethylidene hydrazide), N-hexyl (ethoxymethylidene hydrazide), N-phenyloxamidic acid (methquin methylidene hydrazide), N-phenyloxamidic acid (ethquin methylidene hydrazide), N-chlorophenyloxamidic acid (methoxymethylidene hydrazide), N
-Chlorophenyloxamidic acid (ethoxymethylidene hydrazide), N-dichlorophenyloxamidic acid (methoxymethylidene hydrazide), N-dichlorophenyloxamidic acid (ethoxymethylidene hydrazide), N-)
Riloxamidic acid (methquin methylidene hydrazide),
N-Tolyloxamic acid (methoxymethylidene hydrazide), N-chlorotolyloxamic acid (methoxymethylidene hydrazide), N-chlorotolyloxamic acid (ethoxymethylidene hydrazide), oxamic acid (1-methoxy ethylidene hydranide), oxamic acid (l-ethoxymethylidene hydrazide), N-methyloxamide [(1-methylidene hydranide), N-methyloxamic acid (1-ethoxymethylidene hydrazide)
, N-phenyloxamic acid (l-ethoxymethylidene hydrazide), oxamic acid (1-methoxybutylidene hydrazide), oxamic acid (1-ethoxybutylidene hydrazide F'), N-, (f/L= Oya-91), acid (
1-, ('l-ya'/7・l.

(ropylidenohydrazide), N-hue-luoxamy:
: 1 acid (1-methoxybutylidene hydrazide, O.

Xamidic acid (1-methquine butylidene hydrazide).

Oxamidic acid (1-ethquinbutylidene hydrazide)
), N-methyloxamidic acid (1-methoxybutylidene hydrazide), N-phenyloxamidic acid (1-methoxybutylidene hydrazide), Oxamide M (1-nodoxyhexylidene hydrazide), N-methyloxamate Midic acid (l-methoxyhexylidene hydrazide), N-phenyloxamidic acid (1-methoxyhexylidene hydrazide), oxamic acid (α-methoxybennlide/hydrazide), oxamic acid (α-ethoxy/bennyl υte/human land), N-methyloxamidic acid (α-methquinenlidene hydrand), N-phenyloxamidic acid (
α-Methquin penziritene hydrazide), oxamidic acid [α-(Methquin) chlorobenziritine hydrazide],
N-methyloxamidic acid [α-(methquin)chloroben/lithin hydrazide], N-phenyloxamidic acid [α
-(methoxy)chlorobenzylitine hydrazide], oxamidic acid [α-(methoxy)methylbenzylidene hydrazide], N-methyloxamidic acid [α-(methoxy)methylbenzylidene hydrazide], N-phenyloxamidic acid [α-(methoxy)methylbenzylidene hydrazide] α-(Methquin) methylbenzylidene hydrazide], oxamidic acid [α-(methoxy)methylchlorobenzylidene hydrazide], N-methyloxamidic acid [,-
α-(Methquin) methylchlorobenziritine hydrazide] and N-phenyloxamidic acid [α-(methoxy)methylchlorobenziritine 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
Oxamidic acid (alkoxyalkylidene hydrazide) 1
It is preferable that the amount is 9.1 mol or more per mol.

The reaction is carried out in the presence of a solvent, such as carboxylic acids such as acetic acid and propionic acid, formamide,
More amides of 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 [I] produced by the reaction
) Riazole-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.

1,2.4-) Riazole-3 represented by formula [■1]
- Specific examples of carboxylic acid amides include 1゜2, 4
-) 1) Azole-3-carboxylic acid amide, 1.2
．． 4-) Riazole-3-carboxylic acid methylamide, I
, 2.4-triazole-3-carboxylic acid ethylamide, 1. ．． 2.4-Triazole-3-carboxylic acid propylamide, l, 2.4-triazole-3-carboxylic acid butylamide, ■.

2,4-trifsol-3-carboxylic acid hequinlamide, 1.2.4-triazole-3-carboxylic acid anilide, 1.2.4-)J noazole-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-) Riazole-3-carboxylic acid amide, 5-methyl-1゜2, 4-)! JAzole-3-carboxylic acid methylamide, 5-methyl-1,2,4-)lyazole-3-carboxylic acid anilide, 5-ethyl-1,2゜4-
Triazole-3-carboxylic acid amide, 5-ethyl-1
, 2,4-) lyazole-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
−)! J Azole-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-)lyazole-3-carboxylic acid anilide, 5-phenyl-1゜2.4-triazole-
3-carboxylic acid amide.

5-phenyl-1,2,4-,) lyazole-3-carboxylic acid butyramide, 5-phenyl-1,2゜4-triazole-3-carboxylic acid anilide, 5-chlorophenyl-1,2,4-) lyazole -3-carphonic acid 7
M, 5-chlorophenyl-1゜2,4-triazole-3-carboxylic acid butyramide, 5-chlorophenyl-1,2,4-)lyazole-3-carboxylic acid anilide, 5-tolyl-1,2,4-triazole -3-carboxylic acid amide, 5-tolyl-1,2,4,-) lyazole-3-carboxylic acid butyramide, 5-tolyl-1,
2゜4-triazole-3-carboxylic acid anilide, 5-
Chlorotolyl-1,2,4-triazole-3-carboxylic acid amide, 5-chlorotolyl-1,2゜4-triazole-3-carboxylic acid methylamide, 5-chlorotolyl-1,2,4,-)riazole-3- Examples include carboxylic acid anilides.

Next, examples will be shown. In the Examples, the yield of (1), 2°4-triazole-3-carboxylic acid amide is the yield based on the oxamidic acid (alkoxy7 alkylide/hydrazide) used.

Example 1 Oxamidic acid (ethquin methylidene hydrazide) 1.5
9y was added to 10rR1 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 the resulting crystals were re-dissolved in 20 ml of water.
Crystallization gave 0.2 y (18%) of colorless needle-like crystals of 1.2.4-) lyazole-3-carboxylic acid amide.

The P solution obtained by filtering the reaction product mixture was concentrated under reduced pressure, 10 ml of water was added to the obtained residue, filtered, and 10 ml of water was added to the resulting residue.
, 0.14 F (12%) crystals of 2.4-1 riazole-3-carboxylic acid amide were obtained.

Example 2 Oxamidic acid (ethquin methylidene hydrazide) 1.7
y and formamide15. While heating the ilV mixture on an oil bath at 1-10°C, ammonia was passed through the mixture for 30 minutes. 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 were washed twice with 10 ml of ethanol to obtain 0.43 F of a mixture of 1.2.4-triazole-3-carboxylic acid amide and oxamide. This mixture was added to a mixture of 2 ml of concentrated aqueous ammonia and 15 ml of water and filtered to obtain 0.091 oxamide crystals, and the PM was concentrated under reduced pressure to produce 1.2.4-) lyazole-3-carboxylic acid amide. A crystal sail of 32y (27%) was obtained.

1. 2. 4-) The P solution and washing solution obtained when the mixture of lyazole-3-carboxylic acid amide and oxamide was obtained were combined and concentrated under reduced pressure. Water LO was added to the resulting residue.
ml was added and filtered to obtain further crystals of 1.2.4=triazole-3-carboxylic acid amide at 0.28 F (24 も).

Example 3 Oxamidic acid (ethoxymethylidene hydrazide) L59
A mixture of 1.161 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 resulting crystals were added to a mixture of 5 ml of concentrated ammonia water and 20 ml of water, the mixture was stirred at room temperature for 1 hour, and then filtered. Oxamidic acid hydrazide crystal sail 261
I got it. Add 6.51 nl of concentrated hydrochloric acid to P solution and filter it.
, 2.4-) Riazole-3-carboxylic acid amide crystals of 0.42 F (38 も) were obtained.

Example 4 Oxamidic acid (ethoxymethylidene hydrazide) 1.5
9y, ammonium acetate 1. ．． 16y 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 at room temperature and then filtered to obtain 0.29 (18%) of 1.2.4-triazole-3-carboxylic acid amide crystals.

Example 5 Oxamidic acid (ethoxymethylidene hydrazide) 1.5
97, a mixture of 0.77.5" ammonium acetate and 10" formamide was heated on an oil bath at 110'C and allowed to react for 1 hour.

After the reaction, the resulting reaction product mixture was cooled to room temperature and then filtered. The obtained crystals were treated with 2-propertool lQ++
After washing twice with +/', it was added to a mixed solution of 5 ml of aqueous ammonia and 20 ml of water. The mixture was stirred at room temperature for 1 hour and then filtered to obtain 0.099 crystals of oxamide. The F solution was condensed under reduced pressure to give 1°2,4'-)
1) Azole-3-carboxylic acid amide crystal sail 5 fi
fl (4,7chi) was obtained.

Example 6 Oxamidic acid (ethoxymethylidene hydrazide) 1.5
9P, ammonium formate 0094F and formamide 10
The mixture was heated on an oil bath at 100°C and allowed to react for 1 hour.

After the reaction, the resulting reaction product mixture was cooled to room temperature and then filtered. After washing the obtained crystals twice with 1Qml of ethanol, 2ml of concentrated ammonia water and 15ml of water were added. Added to the mixture of e. The mixture was stirred at room temperature for 1 hour and then filtered to obtain 0.041 oxamide crystals. The P solution was concentrated under reduced pressure to obtain crystals of 1.2.4-triazole-3-carboxylic acid amide at a concentration of 0.52! (Article 46).

Example 7 Oxamidic acid (methquin methylitene hydrazide) 7.2
61 and formamide, 107~1,1'0
Ammonia was passed through at '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.7. The obtained crystals were diluted with 2-propano/L/l.
After washing twice with Oml, it was added to a mixed solution of 10 ml of concentrated aqueous ammonia and 5 Q ml of water. The mixture was stirred at room temperature for 1 hour and then filtered to crystallize oxamide to obtain 79y. The P solution was concentrated under reduced pressure to give 2.32 y(4
1%).

Example 8 N-methyloxamidic acid (ethoxymethylidene acid/
C) 3.46 f! Ammonia was passed through a mixture of 30 m7 of formamide and 30 m7 of formamide for 1 hour at 108-114°C. After passing through the ammonia, continue to heat the mixture and
The reaction was allowed to proceed for 0 minutes.

After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered to obtain N-methyloxamide crystals of 0.06 y.
The obtained 11F solution was concentrated under reduced pressure, 2-propatool 10alf was added to the residue, and filtered.

2.4-) Crystals of lyazole-3-carboxylic acid notylamide 1°53y (61%) were obtained.

Example 9 Ammonia was passed through a mixture of 2°351 N-phenyloxamidic acid (ethoxymethylidene hydrazide) and 30 ml of formamide at 110°G for 1 hour.

After passing ammonia through, 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 0.08 N-phenyloxamide crystals.
1. Concentrate the P solution under reduced pressure to obtain y, and add 10II of water to the residue.
Add Il and filter, 1.2.4-triazole-3-
A mixture of carboxylic acid anilide and N-phenyloxamide was obtained. Mix this mixture with 2ml of concentrated acetate/monia water and 20ml of water.
ml of the mixed solution, and the mixture was stirred at room temperature for 1 hour and then filtered to obtain N-phenyloxamide crystal filter 52F.
I got it. Concentrate P solution under reduced pressure to obtain 1, 2, 4-
To'J azole-3-carboxylic acid anilide crystal 0.6
8 y (36%) obtained 1, Example 10 Oxamidic acid (methoxyethyritenohydrazide) 4.7
7 y and formamide 3 Q me, 108
Ammonia was bubbled through for 1 hour at ~118°C. After ammonia was aerated, the reaction was further carried out for 30 minutes at the same temperature. After the reaction, the resulting reaction product mixture was cooled to room temperature and filtered to obtain 0.41 crystals of oxamide. Concentrate the P solution under reduced pressure, and add 2-propatool 10alf to the residue.
In addition, it is filtered. The obtained crystals were mixed with 5 Q m of ethanol.
The insoluble matter was removed by filtration, and the solution was concentrated under reduced pressure to give 5-methyl-■.

2.4-triazole-3-carboxylic acid amide crystal 1
．． 99 P (53%) was obtained.

Patent applicant: Ube Industries Co., Ltd.

Claims (1)

[Scope of Claims] Oxamidic acid (alkoxyalkylidene hydrazide) represented by (wherein R1 and R2 each represent a hydrogen atom, an alkyl group, or an aryl group, and R3 represents a lower alkyl group); , ammonia or ammonium carboxylate, 1,2, 4- Method for producing to'J azole-3-carboxylic acid amides.