RU2290398C2 - Method for preparing 5-amino-3-n-r1-amino-1-r-1,2,4-triazole - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a novel method for synthesis of 1,2,4-triazole derivatives of the general formula (I):

wherein R means radicals phenyl, benzyl, 4-phenylthiazole-2-yl or 4-methyl-5-carbethoxythiazole-2-yl; R¹ means radicals acetyl, trifluoroacetyl, succinoyl, benzoyl, methylbenzoyl or toluenesulfonyl. Method involves addition of an acylating agent of the general formula (IV): R¹X wherein R¹ means abovementioned values; X means chlorine atom (Cl) or group OR¹ wherein R¹ means abovementioned values to a mixture of 3,5-diamino-1-R-1,2,4-triazole of the general formula (II):

wherein R means abovementioned values, aprotonic solvent, for example acetonitrile or dimethylformamide, and an organic base (III) that represents triethylamine or pyridine. The interaction is carried out at temperature (-10)-(+120)°C and stirring in the mole ratio II : III : IV = 1.00:(1.15-1.40):(1.05-1.35), respectively. The proposed method provides preparing the end compound with high purity degree and without over consumption of reagents.

EFFECT: improved method of synthesis.

2 cl, 11 ex

Description

The invention relates to the field of producing organic substances and can be used in the manufacture of medicinal or biologically active compounds.

A known method for producing 3-amino-5-acetamido-1,2,4-triazole by heating 1-acetyl-3,5-diamino-1,2,4-triazole at a temperature of 187-190 ° C (Pevzner M.S., Gladkova N.V., Kravchenko T.A. 5-amino-3-nitro-1,2,4-triazole and 5-nitramino-3-nitro-1,2,4-triazole // ZhORKh. 1996. T .32. Issue 8. S.1230-1233). The disadvantage of this method is the possibility of obtaining only 5-amino-3-N-acetamido-1,2,4-triazole.

A known method for producing acyl derivatives of 3,5-diamino-1,2,4-triazole by acylation of 3,5-diamino-1,2,4-triazole (guanazole) by boiling with anhydrides or chloran hydrides of carboxylic acids in benzene or toluene (Selassie C .D., Lien EJ, Khwaja T.A. // J. Pharm. Sci. 1981. V.70. No. 11. P.1281-1283). The disadvantage of this method is the possibility of obtaining only 5-amino-3-N-acylamino-1-R-1,2,4-triazoles, in which R represents hydrogen, as well as the formation of by-products - 3,5-diacylamino-1, 2,4-triazoles.

The closest in technical essence and the achieved result is a method for producing 3-acetylamino-5-amino-1-phenyl-1,2,4-triazole by acylation of 3,5-diamino-1-phenyl-1,2,4-triazole in acetic anhydride (Pellizzari, Rongagloloi // Gazz. chim. Ital. 1893. V.31, I. P.478. / Belstein 1903. Bd IV. S.980). The main disadvantage of this method is the formation of difficult to separate mixtures of compounds when using other acylating agents, in addition to acetic anhydride. This makes the process unsuitable for the preparation of 5-amino-3-N-acylamino-1-R-1,2,4-triazoles in which the acyl group is different from the acetyl group.

The objective of the invention is to develop a method for producing 5-amino-3-N-acylamino-1-R-1,2,4-triazoles and 5-amino-3-N-sulfonylamino-1-R-1,2,4-triazoles formula (I), with high purity of the target products, without the formation of side compounds and excessive reagents.

The problem is achieved due to the fact that in the proposed method for producing 5-amino-3-N-acylamino-1-R-1,2,4-triazoles and 5-amino-3-N-sulfonylamino-1-R-1, 2,4-triazoles of general formula (I), including the acylation of 3,5-diamino-1-R-1,2,4-triazoles (II), to a mixture of 3,5-diamino-1-R-1,2, 4-triazole of formula (II), an aprotic solvent and an organic base (III), which is triethylamine or another tertiary aliphatic amine or pyridine or substituted pyridine, an acylating agent of general formula (IV) is added in a molar ratio of (II) :( III ) :( IV) = 1.00: 1.15-1.40: 1.05-1.35 , the reaction mixture is stirred at a temperature of -10 ÷ + 120 ° C.

Studies have shown that various aprotic solvents can be used in the proposed method, however, the best results were obtained using acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and acetone.

As organic bases, tertiary aliphatic amines or pyridine compounds can be used, but triethylamine or pyridine is most appropriate, since these compounds are the cheapest.

The molar ratio (II) :( III) :( IV) = 1.00: 1.15-1.40: 1.05-1.35 is optimal. A change in the molar ratio leads either to the formation of side compounds and the low purity of the target products (I), or to an excessive consumption of reagents, which is not economically feasible.

Acylation should be carried out in the indicated temperature range. At temperatures below -10 ° C, the reaction rate decreases significantly and the duration of the process increases, which is technologically impractical. At temperatures above 120 ° C, the yield of the target compounds (I) decreases due to the occurrence of adverse reactions.

The method is as follows.

To a mixture of 3,5-diamino-1-R-1,2,4-triazole (II), an aprotic solvent and an organic base (III), an acylating agent of the general formula (IV) is added in a molar ratio (II) :( III): (IV) = 1.00: 1.15-1.40: 1.05-1.35, the reaction mixture is stirred at a temperature of -10 ÷ + 120 ° C for 10-30 minutes, the precipitate of the target product (I) is filtered off and recrystallized.

Example 1

To a mixture of 1 g (5.7 mmol) of 3,5-diamino-1-phenyl-1,2,4-triazole, 0.64 g (8.0 mmol) of pyridine and 5 ml of acetonitrile, 0.69 g (6.8 mmol) of acetic anhydride are added with stirring. The reaction mixture is stirred for 10 min at a temperature of 81-83 ° C, cooled to 20 ° C, the precipitate is filtered off. 1.1 g (90%) of 5-amino-3-acetylamino-1-phenyl-1,2,4-triazole are obtained. t _PL = 239-241 ° C (from water).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.05 s (3H, CH ₃ ), 6.38 s (2H, NH ₂ ), 7.30-7.55 m (5H, arom.), 9.92 s (1H, NH).

Found (%): C 55.30; H 5.12; N 32.21.

C ₁₀ H ₁₁ N ₅ O

Calculated (%): C 55.29; H 5.10; N 32.24.

Example 2

To a mixture of 1 g (5.7 mmol) of 3,5-diamino-1-phenyl-1,2,4-triazole, 0.64 g (8.0 mmol) of pyridine and 5 ml of acetonitrile are added dropwise with stirring at a temperature of minus 10-0 ° C. a solution of 0.82 g (7.2 mmol) of trifluoroacetic anhydride in 3 ml of acetonitrile. The reaction mixture is stirred at a temperature of minus 10-0 ° C for 20 minutes, the precipitate formed is filtered off. 0.94 g (61%) of 5-amino-3-trifluoroacetylamino-1-phenyl-1,2,4-triazole is obtained. _mp = 213-214 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 6.4 s (2H, NH ₂ ), 7.25-7.40, 8.0 m (5H, arom.), 12.5 s (1H, NH).

Found (%): C 44.30; H 2.95; N, 25.86.

C ₁₀ H ₈ F ₃ N ₅ O

Calculated (%): C 44.29; H 2.97; N, 25.82.

Example 3

To a mixture of 1 g (5.7 mmol) of 3,5-diamino-1-phenyl-1,2,4-triazole, 0.64 g (8.0 mmol) of pyridine and 5 ml of acetonitrile, a solution of 0.73 g (7.3 mol) of succinic anhydride is added in 3 ml acetonitrile. The reaction mixture is stirred for 15 min at a temperature of 81-83 ° C, cooled to 20 ° C, acidified with 1 N. HCl to pH 4-5, the precipitate is filtered off. 1.1 g (63%) of 5-amino-3-succinoylamino-1-phenyl-1,2,4-triazole are obtained. t _pl = 206 ° C with decomp. (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.45 m (4H, 2 CH ₂ ), 6.47 s (2H, NH ₂ ), 7.3-7.55 m (5H, arom.), 10.12 br. s (1H, NH), 12.5 broad. s (1H, BUT).

Found (%): C 52.38; H 4.75; N, 25.46.

C ₁₂ H ₁₃ N ₅ O ₃

Calculated (%): C 52.36; H 4.76; N, 25.44.

Example 4

1.1 g (7 mmol) of para-methylbenzoyl chloride are added dropwise to a mixture of 1 g (5.7 mmol) of 3,5-diamino-1-phenyl-1,2,4-triazole, 0.8 g (8.0 mmol) of triethylamine and 5 ml of acetonitrile. The reaction mixture is stirred for 10 min at a temperature of 81-83 ° C, the precipitate formed is filtered off. Obtain 1.31 g (71%) of 5-amino-3-para-methylbenzoylamino-1-phenyl-1,2,4-triazole. t _PL = 231-232 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.4 s (3H, CH ₃ ), 6.35 s (2H, NH ₂ ), 7.21-7.88 m (9H, arom.), 10.27 br.s (1H, NH).

Found (%): C 66.50, H 5.17, N 23.85.

C ₁₆ H ₁₅ N ₅ O

Calculated (%): C 66.52, H 5.15, N 23.88.

Example 5

To a mixture of 1 g (5.7 mmol) of 3,5-diamino-1-phenyl-1,2,4-triazole, 0.64 g (8.0 mmol) of pyridine and 5 ml of acetonitrile, a solution of 1.37 g (7.2 mmol) of para-toluenesulfonyl chloride is added dropwise. in 3 ml of acetonitrile. The reaction mixture is stirred 25 min at a temperature of 81-83 ° C, cooled to 20 ° C, the precipitate is filtered off. Obtain 1.51 g (73%) of 5-amino-3-para-toluenesulfonylamino-1-phenyl-1,2,4-triazole. _mp = 256-257 ° C (dimethylformamide).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.38 s (3H, CH ₃ ), 6.4 s (2H, NH ₂ ), 7.3-7.85 m (9H, arom.), 10.65 br.s (1H, NH).

Found (%): C 54.72; H 4.57; N, 21.25.

C ₁₅ H ₁₅ N ₅ O ₂ S

Calculated (%): C 54.70; H 4.59; N, 21.26.

Example 6

To a mixture of 1 g (5 mmol) of 3,5-diamino-1-benzyl-1,2,4-triazole, 0.64 g (8.0 mmol) of pyridine and 5 ml of acetonitrile was added dropwise a solution of 0.6 g (6.8 mmol) of acetic anhydride in 3 ml acetonitrile. The reaction mixture is stirred for 10 min at a temperature of 81-83 ° C, the precipitate formed is filtered off. 1 g (75%) of 5-amino-3-acetylamino-1-benzyl-1,2,4-triazole is obtained. _mp = 224-225 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.05 s (3H, CH ₃ ), 5.01 s (2H, CH ₂ ), 6.25 s (2H, NH ₂ ). 7.15-7.38 m (5H, arom.), 9.80 ears. s (1H, NH).

Found (%): C 57.15; H 5.68; N, 30.25.

C ₁₁ H ₁₃ N ₅ O

Calculated (%): C 57.13; H 5.67; N 30.28.

Example 7

To a mixture of 1 g (5 mmol) of 3,5-diamino-1-benzyl-1,2,4-triazole, 0.62 g (7.8 mmol) of pyridine and 5 ml of acetonitrile, a solution of 0.84 g (6.5 mmol) of benzoyl chloride in 3 is added dropwise. ml of acetonitrile. The reaction mixture is stirred for 10 min at a temperature of 81-83 ° C, cooled to 20 ° C, the precipitate is filtered off. Obtain 1.07 g (63%) of 5-amino-3-benzoylamino-1-benzyl-1,2,4-triazole. t _PL = 168-170 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 5.07 s (2H, CH ₂ ), 6.3 s (2H, NH ₂ ), 7.25-7.5, 7.92 m (10H, arom.), 10.15 br.s (1H, NH).

Found (%): C 65.53; H 5.16; N, 23.89.

C ₁₆ H ₁₅ N ₅ O

Calculated (%): C 65.52; H 5.15; N, 23.88.

Example 8

To a mixture of 1 g (5 mmol) of 3,5-diamino-1-benzyl-1,2,4-triazole, 0.65 g (8.2 mmol) of pyridine and 5 ml of acetonitrile was added dropwise a solution of 1.1 g (6.6 mmol) of para-toluenesulfonyl chloride in 3 ml of acetonitrile. The reaction mixture is stirred 25 min at a temperature of 81-83 ° C, cooled to 20 ° C, the precipitate is filtered off. Obtain 1.29 g (65%) of 5-amino-3-para-toluenesulfonylamino-1-benzyl-1,2,4-triazole. t _PL = 271-273 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.41 s (3H, CH ₃ ), 4.93 s (2H, CH ₂ ), 6.27 s (2H, NH ₂ ), 7.09-7.28, 7.73 m (9H, arom.), 10.40 br. s (1H, NH).

Found (%): C 55.94; H 4.97; N, 20.38.

C ₁₆ H ₁₇ N ₅ O ₂ S

Calculated (%): 55.96; H 4.99; N, 20.39.

Example 9

To a mixture of 1 g (3.8 mmol) of 3,5-diamino-1 - [- 4-methyl-5-carbethoxythiazolyl-2] -1,2,4-triazole, 0.7 g (7.0 mmol) of triethylamine and 3 ml of dimethylformamide are poured over dropwise a solution of 0.97 g (5.1 mmol) of para-toluenesulfonyl chloride in 2 ml of dimethylformamide. The reaction mixture is stirred for 15 minutes at a temperature of 115-120 ° C, cooled to 20 ° C, the precipitate is filtered off. Obtain 0.83 g (53%) of 5-amino-3-para-toluenesulfonylamino-1 - [- 4-methyl-5-carbethoxythiazolyl-2] -1,2,4-triazole. _mp = 288-290 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 1.38 m (3H, CH ₃ ), 2.47 s (3H, CH ₃ ), 2.59 s (3H, CH ₃ ), 4.31 m (2H, CH ₂ ), 7.29 m (2H, arom.), 7.66 s (2H, NH ₂ ), 7.85 m (2H, arom.), 11.16 br.s (1H, NH).

Found (%): C 45.48; H 4.27; N, 19.90.

C ₁₆ H ₁₈ N ₆ O ₄ S ₂

Calculated (%): 45.49; H 4.29; N, 19.89.

Example 10

To a mixture of 1 g (3.8 mmol) of 3,5-diamino-1 - [- 4-methyl-5-carbethoxythiazolyl-2] -1,2,4-triazole, 0.54 g (6.8 mmol) of pyridine and 5 ml of acetonitrile are added dropwise a solution of 0.63 g (5.1 mmol) of benzoyl chloride in 3 ml of acetonitrile. The reaction mixture is stirred for 10 min at a temperature of 115-120 ° C, cooled to 20 ° C, the precipitate is filtered off. 0.42 g (30%) of 5-amino-3-benzoylamino-1 - [- 4-methyl-5-carbethoxythiazolyl-2] -1,2,4-triazole is obtained. t _PL = 258-260 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 1.35 m (3H, CH ₃ ), 2.65 s (3H, CH ₃ ), 4.28 m (2H, CH ₂ ), 7.41-7.52 m (3H, arom.), 7.71 s (2H, NH ₂ ), 7.98 m (2H, arom.), 10.75 br.s (1H, NH).

Found (%): C 51.61; H 4.32; N, 22.56.

C ₁₆ H ₁₆ N ₆ OS

Calculated (%): C 51.60; H 4.33; N, 22.57.

Example 11

A solution of 0.53 g was added dropwise to a mixture of 1 g (3.9 mmol) of 3,5-diamino-1 - [- 4-phenylthiazolyl-2] -1,2,4-triazole, 0.47 g (6.0 mmol) of pyridine and 3 ml of dimethylformamide. (5.2 mmol) of acetic anhydride. The reaction mixture is stirred for 10 min at a temperature of 115-120 ° C, cooled to 20 ° C, the precipitate is filtered off. 0.92 g (65%) of 5-amino-3-acetylamino-1 - [- 4-phenylthiazolyl-2] -1,2,4-triazole is obtained. t _PL = 294 ° C (ethanol).

¹ H NMR spectrum, δ, ppm (DMSO d ₆ ) 2.05 s (3H, CH ₃ ), 7.42-7.61 m (3H, arom.), 7.72 s (2H, NH ₂ ), 7.84 s (1H, CH), 8.02 m (2H, arom.) 10.51 br s (1H, NH).

Found (%): C 51.98; H 4.02; N, 27.99.

C ₁₃ H ₁₂ N ₆ OS

Calculated (%): C 51.99; H 4.03; N, 27.98.

Claims (1)

The method of obtaining 5-amino-3-NR ¹ -amino-1-R-1,2,4-triazoles of the general formula I

where R is a phenyl, benzyl, 4-phenylthiazol-2-yl or 4-methyl-5-carbethoxythiazol-2-yl radical; R ¹ means acetyl, trifluoroacetyl, succinoyl, benzoyl, methylbenzoyl or toluenesulfonyl radical, consisting in the fact that to a mixture of 3,5-diamino-1-R-1,2,4-triazole of General formula II

where R has the above meanings, an aprotic solvent such as acetonitrile or dimethylformamide and an organic base (III), which is triethylamine or pyridine, an acylating agent of general formula IV is added

where R ¹ has the above meanings, and X means Cl or a group OR ¹ , where R ¹ has the above meanings, and the interaction is carried out at a temperature of -10 - + 120 ° C and stirring at a molar ratio of II: III: IV = 1.00: 1.15-1.40: 1.05-1.35.