RU2292339C1 - Method for preparing 5-amino-1,2,4-triazol-3-ylcarboxylic acid amides - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel carboxylic acid amides of the general formula (I):

wherein R¹ represents hydrogen atom (H); R² represents a linear or branched (C₁-C₈)-alkyl possibly substituted with phenyl; or R¹ and R² in common with nitrogen atom (N) represent a 5-membered heterocyclic residue or a 6-membered heterocyclic residue comprising oxygen atom additionally; n = 0, 1. Method involves heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II):

wherein R³ represents (C₁-C₄)-alkyl group; n = 0, 1, amine of the general formula (III):

wherein R¹ and R² have value given above and tertiary aliphatic amine of the formula (IV) given in the invention description at temperature 70-130°C wherein components are taken in the ratio (II) : (III) : (IV) = 1.0:(1.1-2.5):(1.0-3.0), respectively. Method provides decreasing the cost of compounds of the formula (I) based on using the more inexpensive raw, reducing duration of the process and enhancing safety of the process. Synthesized compounds can be used in synthesis of biologically active substances and dyes.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 6 ex

Description

The invention relates to the field of production of organic substances and can be used in the production of biologically active compounds and dyes.

A known method of producing amides of 1,2,4-triazole-5-carboxylic acids by the interaction of thioamides and S-alkylisothioamides with oxamosides of the general formula NH ₂ NHCOCONR ¹ R ² (French Patent 1512421, MKI C 07 D. Published. 12/22/1966. Publ. 01/01/1968). The disadvantage of this method is the inaccessibility of oxamosides, due to the multi-stage synthesis, as well as the inability to obtain compounds of formula (I) in which n = 1.

Known methods for producing amides of 1,2,4-triazole-5-carboxylic acids by the interaction of monothiooxamides RNHCSCONR ¹ R ² with hydrazine and the subsequent reaction of the resulting amidrazones with acid chlorides (Thiel. W. // Z. Chem. 1990. Bd.30. S .365) or a one-step interaction of monothiooxamides RNHCSCONR ¹ R ² with hydrazides of carboxylic acids (Yarovenko V.N., Kosarev S.A., Shirokov A.V., Zavarzin I.V., Krajushkin M.M. // Izv. AN Ser. Chem. 2000. No. 8. S.1487-1488). The disadvantage of these methods is the inaccessibility and high cost of monothiooxamides, as well as the inability to obtain compounds of formula (I) in which n = 1.

A known method of producing 5-amino-1,2,4-triazol-3-yl-carboxylic acid amides by reacting oxamic esters of the general formula ROCOCONR ¹ R ² with aminoguanidine derivatives (US Patent 5021081, MKI C 07 D 249/14. Claim 15.03. 1989. Published 04.06.1991). The disadvantage of this method is the high cost of esters of oxamic acids, low yield of target products, as well as the inability to obtain compounds of formula (I) in which n = 1.

A known method for producing 5-amino-3-carboxamido-1,2,4-triazole by the interaction of methyl ester of 5-amino-1,2,4-triazol-3-ylcarboxylic acid with aqueous ammonia (Auth. Certificate. USSR 320497. MKI C 07 D 55/06, Declared on December 25, 69, Published on January 24, 72). The disadvantages of this method are the low yield and purity of the target product, due to the side reaction of hydrolysis of methyl ester of 5-amino-1,2,4-triazol-3-ylcarboxylic acid, the high duration of the process when using amines, sparingly soluble in water.

The closest to the technical result is a method for producing amides of 5-amino-1,2,4-triazol-3-ylcarboxylic acids by heating a mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid esters with amines in tetrahydrofuran at a temperature 200 ° C and a pressure of 20 bar (US Patent 5021081, MKI C 07 D 249/14. Declared March 15, 1989. Published 04.06.1991). The disadvantages of this method are the use of an expensive flammable organic solvent (tetrahydrofuran), the explosiveness of the process associated with the synthesis at high pressure, as well as the possibility of the formation of explosive peroxide compounds upon contact of tetrahydrofuran with air, low yield of the target product.

The objective of the invention is to increase the safety and cost of the method for producing amides of 5-amino-1,2,4-triazol-3-yl-carboxylic acid and 5-amino-1,2,4-triazol-3-yl-acetic acid of the general formula (I).

The problem is achieved in that in the claimed method for producing amides of 5-amino-1,2,4-triazol-3-ylcarboxylic acids of the general formula (I),

where R ¹ represents hydrogen;

R ² means straight or branched C _1-8 alkyl, possibly substituted by phenyl, or

R ¹ and R ² together with the N atom to which they are attached form a 5-membered heterocyclic residue or a 6-membered heterocyclic residue, optionally containing an oxygen atom, n = 0 or 1,

a mixture of 5-amino-1,2,4-triazol-3-yl-carboxylic acid ester of the general formula (II) is heated,

where R ³ means an alkyl group of C ₁ -C ₄ , n = 0, 1, an amine of the general formula (III)

where R ¹ and R ² have the above meanings, and a tertiary aliphatic amine (IV) at a temperature of 70-130 ° C and a molar ratio (II) :( III) :( IV) = 1.0: 1.1-2.5: 1.0-3.0.

In the inventive method, instead of the expensive and flammable tetrahydrofuran, a tertiary aliphatic amine (IV) is used, which acts as a solvent and catalyst. The use of amine (IV) leads to a significant increase in the reaction rate and yield of the target products, allows the process to be carried out at atmospheric pressure without the use of expensive flammable and explosive tetrahydrofuran, and, therefore, to increase the safety of the process and reduce the cost of the process for preparing compounds (I). As a tertiary aliphatic amine (IV), such available materials as triethylamine, tributylamine, tripropylamine and other tertiary aliphatic amines can be used. The temperature range of 70-130 ° C. indicated in the invention is optimal. At temperatures below 70 ° C, the process is too slow, and a temperature increase of more than 130 ° C leads to a decrease in yield due to adverse reactions. The molar ratio (II) :( III) :( IV) = 1.0: 1.1-2.5: 1.0-3.0 is optimal, its change leads either to a decrease in the yield of the target product, or to the incomplete consumption of one of the reagents and is not economically feasible.

The method is as follows:

The 5-amino-1,2,4-triazol-3-yl-carboxylic acid ester (n = 0) or 5-amino-1,2,4-triazol-3-yl-acetic acid (n = 1) of the general formula (II) is mixed , an amine of the general formula (III) and a tertiary aliphatic amine (IV) in a molar ratio (II) :( III) :( IV) = 1.0: 1.1-2.5: 1.0-3.0 and the resulting mixture is heated at a temperature of 70-130 ° C. for 40-120 minutes. Then the mixture is cooled, the precipitate formed is filtered off and crystallized. Get the compound of General formula (I).

Example 1

1.42 g (0.01 mol) of 5-amino-1,2,4-triazol-3-yl-carboxylic acid methyl ester, 0.96 g (0.011 mol) of morpholine, 3 g (0.03 mol) of triethylamine are mixed and the mixture is heated at a temperature of 85-90 ° C 60 min, then cooled. The precipitate formed is filtered off. 5-amino-1,2,4-triazol-3-yl-carboxylic acid morpholide is obtained. Yield 1.46 g (74%). _Mp = 222-224 ° C (from water).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 3.55 m (8H, 4CH ₂ ), 5.62 s (2H, NH ₂ ), 11.52 s (1H, NH).

Found (%): C, 42.4; H, 5.7; N, 35.8.

C ₇ H ₁₁ N ₅ O ₂ .

Calculated (%): C, 42.6; H, 5.6; N, 35.5.

Example 2

1.70 g (0.01 mol) of 5-amino-1,2,4-triazol-3-yl-acetic acid ethyl ester, 0.96 g (0.011 mol) of morpholine, 3 g (0.03 mol) of triethylamine are mixed and the resulting mixture is heated at a temperature of 85-90 ° C 60 min, then cooled. The precipitate formed is filtered off. 5-amino-1,2,4-triazol-3-yl-acetic acid morpholide is obtained. Yield 1.13 g (54%). _Mp = 239-240 ° C (from water).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 3.58 m (10H, 5CH ₂ ), 5.62 s (2H, NH ₂ ), 11.58 s (1H, NH)

Found (%): C, 45.8; H, 6.2; N, 33.1.

C ₈ H ₁₃ N ₅ O ₂ .

Calculated (%): C, 45.5; H, 6.2; N, 33.2.

Example 3

1.70 g (0.01 mol) of 5-amino-1,2,4-triazol-3-yl-acetic acid ethyl ester, 1.18 g (0.011 mol) of benzylamine, 1 g (0.01 mol) of triethylamine are mixed and the resulting mixture is heated at a temperature of 85-90 ° C 40 min, then cooled. The precipitate formed is filtered off. Get 5-amino-1,2,4-triazol-3-yl-acetic acid benzylamide. Yield 1.75 g (76%). _Mp = 172-175 ° C (DMF / EtOH).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 3.31 s (2H, CH ₂ ), 4.26 d (2H, CH ₂ , J = 5.9), 5.87 s (2H, NH ₂ ), 7.23 m (5H, arom.), 8.43 br. s (1H, NH), 11.58 broad. c (1H, NH).

Found (%): C, 56.9; H, 5.7; N, 30.6.

C ₁₁ H ₁₃ N ₅ O.

Calculated (%): C, 57.1; H, 5.7; N, 30.3.

Example 4

1.54 g (0.01 mol) of 5-amino-1,2,4-triazol-3-yl-carboxylic acid ethyl ester, 1.18 g (0.011 mol) of benzylamine, 1 g (0.01 mol) of triethylamine are mixed and the resulting mixture is heated at a temperature of 85-90 ° C 40 min, then cooled. The precipitate formed is filtered off. Get 5-amino-1,2,4-triazol-3-yl-carboxylic acid benzylamide. Yield 1.70 g (78%). _Mp = 235-238 ° C (DMF / EtOH).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.42 d (2H, CH ₂ , J = 6.3), 5.89 s (2H, NH ₂ ), 7.21 m (5H, arom.), 8.27 s (1H, NH), 12.33 br. s (1H, NH).

Found (%): C, 55.4; H, 5.2; N, 32.0.

C ₁₀ H ₁₁ N ₅ O.

Calculated (%): C, 55.3; H, 5.1; N, 32.2.

Example 5

1.42 g (0.01 mol) of 5-amino-1,2,4-triazol-3-yl-carboxylic acid methyl ester, 1.78 g (0.025 mol) of pyrrolidine, 1 g (0.01 mol) of triethylamine are mixed and the resulting mixture is heated at a temperature of 80-85 ° C 120 min, then cooled. The precipitate formed is filtered off. 5-amino-1,2,4-triazol-3-yl-carboxylic acid pyrrolidide is obtained. Yield 1.52 g (84%). _Mp = 284-286 ° C (DMF / EtOH).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 1.90 m (4H, 2CH ₂ ), 3.47 m (2H, CH ₂ ), 3.82 m (2H, CH ₂ ), 5.80 s (2H, NH ₂ ), 12.05 s (1H, NH ₂ )

Found (%): C, 45.4; H, 6.2; N, 38.4.

C ₇ H ₁₁ N ₅ O.

Calculated (%): C, 46.4; H, 6.1; N, 38.6.

Example 6

1.70 g (0.01 mol) of 5-amino-1,2,4-triazol-3-yl-acetic ethyl ester, 1.78 g (0.025 mol) of pyrrolidine, 1 g (0.01 mol) of triethylamine are mixed and the resulting mixture is heated at a temperature of 80-85 ° With 120 min, then cool. The precipitate formed is filtered off. 5-amino-1,2,4-triazol-3-yl-acetic acid pyrrolidide is obtained.

Yield 1.05 g (54%). _Mp = 261-263 ° C (DMF / EtOH).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 1.80 m (4H, 2CH ₂ ), 3.22 t (2H, CH ₂ , J = 6.8), 3.38 s (2H, CH ₂ ), 3.49 t (2H, CH ₂ , J = 6.5) 5.83 s (2H, NH ₂ ); 11.67 s (1H, NH).

Found (%): C, 49.0; H, 6.8; N, 36.0.

C ₈ H ₁₃ N ₅ O.

Calculated (%): C, 49.2; H, 6.7; N, 35.9.

Claims (1)

A method of producing amides of 5-amino-1,2,4-triazol-3-ylcarboxylic acids of the general formula (I)

where R ¹ represents hydrogen; R ² means straight or branched C _1-8 alkyl, possibly substituted by phenyl, or R ¹ and R ² together with the N atom to which they are attached form a 5-membered heterocyclic radical, or a 6-membered heterocyclic radical additionally containing an oxygen atom; n = 0 or 1, characterized in that the mixture of 5-amino-1,2,4-triazol-3-ylcarboxylic acid ester of the general formula (II) is heated

where R ³ means a C _1-4 alkyl group, n = 0 or 1, an amine of General formula (III)

where R ¹ and R ² have the above meanings, and a tertiary aliphatic amine (IV) at a temperature of 70-130 ° C and a molar ratio (II) :( III) :( IV) = 1.0: 1.1-2, 5: 1.0-3.0.