RU2292340C1 - Method for preparing r-methyl-derivatives of 3,5-diamino-1,2,4-triazole - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C₁-C₄)-alkyl, -O-(C₁-C₄)-alkyl, -N-[(C₁-C₄)-alkyl]₂, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

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

2 cl, 13 ex

Description

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

A known method of producing alkyl derivatives of 3,5-diamino-1,2,4-triazole by heating 3,5-dichloro-1,2,4-triazole with an excess of aliphatic amine in a closed vessel at a temperature of 100-270 ° C (Becker H., Eisenschmidt V., Wehner K. Patent GDR 59288. MKI C 07 D). The disadvantage of this method is the use of expensive and inaccessible 3,5-dichloro-1,2,4-triazole, the need for synthesis at high pressure and the associated explosion hazard of the process.

A known method of producing alkyl derivatives of 3,5-diamino-1,2,4-triazole by the interaction of the hydrobromide of N-alkyl-S-ethylisothiourea with alkyl isothiocyanates, the alkylation of the resulting alkyl derivatives of isothiobioureth with ethyl iodide with the formation of alkyl derivatives of diisodithiobiouret, and followed by boiling Application No. 1946315 for the patent of Germany. Chem. Abstr. 1970. Vol.73. 25482d). The disadvantage of this method is the use of expensive N-alkyl-S-ethylisothioureas and toxic alkyl isothiocyanates.

A known method for producing 3-amino-5-alkylamino-1,2,4-triazoles by alkaline cyclization of 3-isopropylideneaminoamidino-1-alkylthioureas (Blank B., Nichols DM, Vaidya PD Synthesis of 1,2,4-triazoles as potential hypoglycemic agents // J. Med. Chem. 1972. Vol.15. No. 6. P.694-696). The disadvantage of this method is the use of hard-to-reach and expensive 3-isopropylideneaminoamidino-1-alkylthioureas obtained by condensation of isopropylideneaminoguanidine with toxic and expensive alkyl isothiocyanates.

A known method of producing 5-amino-3- (2-mercaptoethylamino) -1,2,4-triazole by the interaction of 2-cyanoiminothiazolidine with hydrazine (US Patent 5028716, MKI C 07 D 249/08). The disadvantage of this method is the possibility of obtaining only mercaptoethylamino derivatives of 3,5-diamino-1,2,4-triazole, namely, compounds of formula (I) in which the substituent R can be only a CH ₂ SH group.

The closest in technical result is a method for producing alkyl derivatives of 3,5-diamino-1,2,4-triazole by the interaction of dimethyl ether of cyanocarbioimidodithioic acid (dimethyl cyanodithioimidocarbonate) with arylidenehydrazines, reaction of the obtained methyl esters of N-cyano-1-methyl-2-aryl oxybide amide amide and subsequent cyclization of the formed intermediates in the presence of hydrochloric acid or by the reaction of dimethyl ether of cyanocarboimidodithioic acid (dimethylcyanodithioimidocarbonate a) with aliphatic amines, followed by the interaction of the formed N-cyano-N'-alkyl-S-methylisothioureas with hydrazine (US Patent 4764612, MKI C 07 D 295/012). The disadvantage of this method is the use of expensive cyanocarboimidodithioic acid dimethyl ether (dimethylcyanodithioimidocarbonate), the complexity of the isolation and purification of intermediate products, and the isolation of toxic methyl mercaptan during the synthesis.

The objective of the invention is to reduce the cost of the method of producing alkyl derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I) and increase its safety through the use of cheaper raw materials and the exclusion from the process of operations that require the use of high pressure or associated with the allocation toxic gaseous products.

The problem is achieved in that an aqueous solution of sodium hydroxide is poured into a suspension of 1-acetyl-3,5-diamino-1,2,4-triazole (II) in lower aliphatic alcohol, the reaction mixture is heated with stirring at a temperature of 50-100 ° C until complete homogenization, then neutralize with acetic acid to pH 7-9 and add aldehyde (III), where R has the above values, mix at a temperature of 50-100 ° C, then add sodium borohydride in portions and continue stirring at a temperature of 50-100 ° C, and the process is carried out at the next molar ratio Ocean reagents: (II): sodium hydroxide: (III): with sodium borohydride 1: (1.0-1.2) :( 0.9-1.0) :( 1.2-2.0).

In the inventive method, instead of expensive cyanocarboimidodithioic acid dimethyl ether, cheap raw materials are used - 1-acetyl-3,5-diamino-1,2,4-triazole (II), which can be obtained by a known method (Russian Patent 2148579. MKI C 07 V 249 /fourteen). This allows you to reduce the cost of the target products. All technological operations are carried out at atmospheric pressure, during the synthesis toxic gaseous products are not released, which increases the safety of the process. The temperature range of 50-100 ° C. indicated in the invention is optimal. At lower temperatures, the process is too slow, and at higher temperatures, a decrease in yield occurs due to the occurrence of adverse reactions. The molar ratio (II): NaOH: (III): NaBH ₄ = 1: (1.0-1.2) :( 0.9-1.0) :( 1.2-2.0) is optimal, its change leads either to a decrease in the yield of the target product, or to an incomplete the consumption of one of the reagents and is not economically feasible.

The method is as follows:

1-Acetyl-3,5-diamino-1,2,4-triazole (II) is suspended in aliphatic alcohol (methanol, ethanol, isopropanol or others) and an aqueous solution of sodium hydroxide is added to the suspension at a rate of 1-1.2 mol NaOH per 1 mol of compound (II), the reaction mixture is stirred at a temperature of 50-100 ° C (depending on the boiling point of alcohol) until complete dissolution (II). In this case, the hydrolysis of compound (II) occurs with the formation of a water-alcohol solution of 3,5-diamino-1,2,4-triazole and sodium acetate. Then the mixture is neutralized with acetic acid, aldehyde (III) is added at a rate of 0.9-1.0 mol of aldehyde per 1 mol of starting compound (II) and stirred at a temperature of 50-100 ° C (depending on the boiling point of alcohol) for 10-20 minutes. At this stage, 3,5-diamino-1,2,4-triazole is condensed with the aldehyde and a solution or suspension of the corresponding Schiff base is formed. Then, sodium borohydride is gradually added to the reaction mixture with stirring and a temperature of 50-100 ° C over 10-20 minutes at the rate of 1.2-2.0 mol of NaBH ₄ per 1 mol (II), then stirred at this temperature for another 20 minutes. In this case, the Schiff base is hydrogenated and the R-methyl derivative of 3,5-diamino-1,2,4-triazole is formed. The reaction mixture was evaporated, diluted with water, the precipitate formed was filtered off and recrystallized. Get the compound of General formula (I).

Example 1

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 50 ml of ethanol is added, with stirring, a solution of 4.8 g (0.12 mol) of NaOH in 10 ml of H ₂ O. The reaction mixture is stirred at a temperature of 65-75 ° C until complete homogenization (10-15 min), then neutralized with acetic acid to a pH of 7-9 and 10.1 g (0.09 mol) of thiophene-2-carboxaldehyde are added dropwise with stirring. The reaction mixture was stirred at 65-75 ° C for 10 minutes, then 4.56 g (0.12 mol) of sodium borohydride was added portionwise over 10 minutes, stirred at 75 ° C for 20 minutes and then evaporated to a small volume. 30 ml of water are added to the residue and the resulting solution is evaporated twice, cooled, the precipitate formed is filtered off. 9.8 g (50%) of 5-amino-3-thiophen-2-ylmethylamino-1,2,4-triazole are obtained. _Mp = 138-139 ° C (from water).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.35 d (2H, CH ₂ , J = 5.8), 5.63 broad. s (2H, NH ₂ ), 5.81 broad. s (1H, NH), 6.91 m (2H, CH), 7.30 m (1H, CH), 10.7 s (1H, NH).

Found (%): C 43.13; H 4.62; N 36.00.

C ₇ H ₉ N ₅ S.

Calculated (%): C 43.06; H 4.65; N 35.87.

Example 2

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 50 ml of ethanol is added, with stirring, a solution of 4.8 g (0.12 mol) of NaOH in 10 ml of H ₂ O. The reaction mixture is stirred at a temperature of 65-75 ° C until complete homogenization (10-15 min), then neutralized with acetic acid to pH 7-9 and a solution of 13.6 g (0.1 mol) of 4-methoxybenzaldehyde in 10 ml of ethanol is added dropwise with stirring. The reaction mixture was stirred at 65-75 ° C for 15 minutes, then 7.60 g (0.2 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at 75 ° C for 20 minutes and then 30 ml of water was added and the reaction mixture was evaporated to a small volume . An additional 30 ml of water was added to the residue, and the precipitate formed was filtered off. 16.7 g (76%) of 5-amino-3-para-methoxybenzylamino-1,2,4-triazole are obtained. _Mp = 194-196 ° C (from ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 3.69 s (3H, OCH ₃ ), 4.11 d (2H, CH ₂ , J = 6.5), 5.37 broad. s (2H, NH ₂ ), 5.85 broad. s (1H, NH), 6.82 d (2H, arom., J = 8.6), 7.21 d (2H, arom., J = 8.6), 10.68 s (1H, NH).

Found (%): C 54.70; H 5.99; N 32.00.

C ₁₀ H ₁₃ N ₅ O.

Calculated (%): C 54.78; H 5.98; N 31.94.

Example 3

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of methanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 65 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 13.6 g (0.09 mol) of 3-nitrobenzaldehyde in 30 ml of methanol is added dropwise with stirring. The reaction mixture was stirred at 65 ° C for 15 minutes, then 5.7 g (0.15 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at 65 ° C for 20 minutes, evaporated twice and 60 ml of water was added. The precipitate formed is filtered off and 14.5 g (62%) of 5-amino-3-meta-nitrobenzylamino-1,2,4-triazole are obtained. _Mp = 178-180 ° C (from ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.31 d (2H, CH ₂ , J = 5.9), 5.65 broad. s (2H, NH ₂ ), 6.16 broad. s (1H, NH), 7.57 m (1H, arom.), 7.76 m (1H, arom), 8.04 m (1H, arom), 8.17 s (1H, arom), 10.71 s (1H, NH).

Found (%): C 46.18; H 4.32; N 36.00.

C ₉ H ₁₀ N ₆ O ₂ .

Calculated (%): C 46.15; H 4.30; N, 35.88.

Example 4

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 16.6 g (0.09 mol) of meta-bromobenzaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture was stirred at a temperature of 75-80 ° C for 15 minutes, then 5.7 g (0.15 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water was added. The precipitate formed is filtered off and 16.73 g (78%) of 5-amino-3-meta-bromobenzylamino-1,2,4-triazole are obtained. _Mp = 207-208 ° C (from a mixture of DMF / ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.19 d (2H, CH ₂ , J = 6.4), 5.42 broad. s (2H, NH ₂ ), 6.15 broad. s (1H, NH), 7.25 m (2H, arom.), 7.37 m (1H, arom), 7.47 s (1H, arom), 10.73 br. s (1H, NH).

Found (%): C 40.3; H 3.9; N 26.00.

C ₉ H ₁₀ BrN ₅ .

Calculated (%): C 40.32; H 3.76; N 26.12.

Example 5

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 50 ml of ethanol is added, with stirring, a solution of 4.8 g (0.12 mol) of NaOH in 10 ml of H ₂ O. The reaction mixture is stirred at a temperature of 65-75 ° C until complete homogenization (10-15 min), then neutralized with acetic acid to pH 7-9 and a solution of 16.6 g (0.1 mol) of 3,4-dimethoxybenzaldehyde in 10 ml of ethanol is added dropwise with stirring. The reaction mixture was stirred at 65-75 ° C for 15 minutes, then 7.60 g (0.2 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at 75 ° C for 20 minutes, then 30 ml of water was added and the reaction mixture was evaporated to a small volume . An additional 30 ml of water was added to the residue, and the precipitate formed was filtered off. 17.5 g (70%) of 5-amino-3- (3,4-dimethoxybenzylamino) -1,2,4-triazole are obtained. _Mp = 238-240 ° C (from ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 3.69 s (3H, CH ₃ ), 3.70 s (3H, CH ₃ ), 4.11 d (2H, CH ₂ , J = 6.4), 5.50 broad. s (3H, NH + NH ₂ ), 6.82 m (2H, arom.), 6.92 s (1H, arom), 10.70 br. s (1H, NH).

Found (%): C 53.14; H 6.20; N, 27.99.

C ₁₁ H ₁₅ N ₅ O ₂ .

Calculated (%): C 53.00; H 6.07; N 28.09.

Example 6

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 50 ml of ethanol, a solution of 4.8 g (0.12 mol) of NaOH in 10 ml of H ₂ O is poured with stirring. The reaction mixture is stirred at a temperature of 65-75 ° С until complete homogenization (10-15 min), then it is neutralized with acetic acid to a pH of 7-9 and 9.9 g (0.09 mol) of 5-methylfuran-2-carboxaldehyde are added dropwise with stirring. The reaction mixture was stirred at 65-75 ° C for 10 minutes, then 4.56 g (0.12 mol) of sodium borohydride was added portionwise over 10 minutes, stirred at 75 ° C for 20 minutes and then evaporated to a small volume. 30 ml of water are added to the residue and the resulting solution is evaporated twice, cooled, the precipitate formed is filtered off. 10.4 g (60%) of 5-amino-3- (5-methylfuran-2-yl) methylamino-1,2,4-triazole are obtained. _Mp = 15-117 ° C (from water).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 2.28 s (3H, CH ₃ ), 4.35 d (2H, CH ₂ , J = 5.6), 5.60 broad. s (2H, NH ₂ ), 5.82 broad. s (1H, NH), 5.90 m (1H, arom.), 6.21 (1H, arom.), 10.5 s (1H, NH).

Found (%): C 48.01; H 5.80; N 36.00.

C ₈ H ₁₁ N ₅ O.

Calculated (%): C 49.73; H 5.74; N, 36.25.

Example 7

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to a pH of 7-9 and a solution of 14.0 g (0.09 mol) of 1-naphthaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C for 30 minutes, then 5.7 g (0.15 mol) of sodium borohydride are added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water are added. The precipitate formed is filtered off and 15.5 g (72%) of 5-amino-3- (1-naphthyl) methylamino-1,2,4-triazole are obtained. _Mp = 118-120 ° C (from a mixture of DMF / ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.28 d (2H, CH ₂ , J = 6.0), 5.38 broad. s (2H, NH ₂ ), 6.05 broad. s (1H, NH), 7.40-8.18 m (7H, arom.), 10.70 br. s (1H, NH).

Found (%): C 65.50; H 5.50; N 29.00.

C ₁₃ H ₁₃ N ₅ .

Calculated (%): C 65.26; H 5.48; N 29.27.

Example 8

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 10.8 g (0.09 mol) of meta-methylbenzaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture was stirred at a temperature of 75-80 ° C for 20 minutes, then 5.7 g (0.15 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water was added. The precipitate formed is filtered off and 15.0 g (82%) of 5-amino-3-meta-methylbenzylamino-1,2,4-triazole are obtained. T _pl = 175-176 ° C (from a mixture of DMF / ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 2.31 s (3H, CH ₃ ), 4.17 d (2H, CH ₂ , J = 6.4), 5.42 br. s (2H, NH ₂ ), 6.15 broad. s (1H, NH), 7.02-7.18 m (4H, arom.), 10.71 br. s (1H, NH).

Found (%): C 59.10; H 6.50; 34.41.

C ₁₀ H ₁₃ N ₅ .

Calculated (%): C 59.10; H 6.45; N 34.46.

Example 9

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 13.32 g (0.09 mol) of para-isopropylbenzaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C for 30 minutes, then 5.7 g (0.15 mol) of sodium borohydride are added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water are added. The precipitate formed is filtered off and 16.22 g (78%) of 5-amino-3-para-isopropylbenzylamino-1,2,4-triazole are obtained. _Mp = 125-127 ° C (from a mixture of DMF / ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 1.20 s (6H, 2CH ₃ ), 2.81 m (1H, CH), 4.20 d (2H, CH ₂ , J = 6.2), 5.42 br. s (2H, NH ₂ ), 6.15 broad. s (1H, NH), 7.13 d (2H, arom., J = 8.0), 7.31 d (2H, arom., J = 8.0), 10.80 broad. s (1H, NH).

Found (%): C 62.41; H 7.28; N 30.31.

C ₁₂ H ₁₇ N ₅ .

Calculated (%): C 62.31; H 7.41; N 30.28.

Example 10

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 13.41 g (0.09 mol) of para-dimethylaminobenzaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C for 30 minutes, then 5.7 g (0.15 mol) of sodium borohydride are added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water are added. The precipitate formed is filtered off and 14.82 g (71%) of 5-amino-3- (para-dimethylaminobenzyl) amino-1,2,4-triazole are obtained. _Mp = 174-176 ° C (from a mixture of DMF / ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 2.89 s (6H, 2CH ₃ ), 4.20 d (2H, CH ₂ , J = 6.4), 5.40 br. s (2H, NH ₂ ), 6.10 broad. s (1H, NH), 6.63 d (2H, arom., J = 8.0), 7.20 d (2H, arom., J = 8.0), 10.72 br. s (1H, NH).

Found (%): C 56.90; H 6.88; N 36.22.

C ₁₁ H ₁₆ N ₆ .

Calculated (%): C 56.88; H 6.94; N 36.18.

Example 11

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 9.54 g (0.09 mol) of benzaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture was stirred at a temperature of 75-80 ° C for 20 minutes, then 5.7 g (0.15 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water was added. The precipitate formed is filtered off and 9.4 g (55%) of 5-amino-3-benzylamino-1,2,4-triazole are obtained. _Mp = 147-148 ° C (from ethanol).

¹ H NMR spectrum, δ 5, ppm (DMSO-d ₆ ): 4.20 d (2H, CH ₂ , J = 6.2), 5.32 broad. s (2H, NH ₂ ), 6.09 broad. s (1H, NH), 7.17-7.28 m (5H, Ph), 10.72 s (1H, NH).

Found (%): C 57.21; H 5.90; N 36.89.

C ₉ H ₁₁ N ₅ .

Calculated (%): C 57.13; H 5.86; N 37.01.

Example 12

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 12.65 g (0.09 mol) of para-chlorobenzaldehyde in 30 ml of ethanol is added dropwise with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C for 30 minutes, then 5.7 g (0.15 mol) of sodium borohydride are added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water are added. The precipitate formed is filtered off and 13.1 g (65%) of 5-amino-3-para-chlorobenzylamino-1,2,4-triazole are obtained. _Mp = 193-194 ° C (from a mixture of DMF / ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.18 d (2H, CH ₂ , J = 6.3), 5.50 broad. s (2H, NH ₂ ), 6.0 broad. s (1H, NH), 7.26-7.35 m (4H, arom.), 10.7 br. s (1H, NH).

Found (%): C 48.41; H 4.58; N 31.37.

C ₉ H ₁₀ N ₅ Cl.

Calculated (%): C 48.33; H 4.51; N 31.31.

Example 13

To a suspension of 14.1 g (0.1 mol) of 1-acetyl-3,5-diamino-1,2,4-triazole in 60 ml of ethanol, a solution of 4.4 g (0.11 mol) of NaOH in 10 ml of H ₂ O is added with stirring. The reaction mixture is stirred at a temperature of 75-80 ° C until complete homogenization, then neutralized with acetic acid to pH 7-9 and a solution of 11.2 g (0.09 mol) of para-fluorobenzaldehyde in 20 ml of ethanol is added dropwise with stirring. The reaction mixture was stirred at a temperature of 75-80 ° C for 20 minutes, then 5.7 g (0.15 mol) of sodium borohydride was added portionwise over 20 minutes, stirred at a temperature of 50-65 ° C for 20 minutes, evaporated to a small volume and 60 ml of water was added. The precipitate formed is filtered off and 11.2 g (60%) of 5-amino-3-para-fluorobenzylamino-1,2,4-triazole are obtained. _Mp = 164-166 ° C (from ethanol).

¹ H NMR spectrum, δ, ppm (DMSO-d ₆ ): 4.22 d (2H, CH ₂ , J = 6.0), 5.62 broad. s (2H, NH ₂ ), 6.0 broad. s (1H, NH), 6.98 m (2H, arom.), 7.33 m (2H, arom.), 10.6 br. c (1H, NH).

Found (%): C 52.09; H 4.88; N, 33.60.

C ₉ H ₁₀ N ₅ F.

Calculated (%): C 52.17; H 4.86; N 33.80.

Claims (1)

The method of obtaining R-methyl derivatives of 3,5-diamino-1,2,4-triazole of General formula (I),

where R means a benzene ring, possibly substituted by one or more substituents, such as branched or unbranched (C ₁ -C ₄ ) -alkyl, O- (C ₁ -C ₄ ) -alkyl, N ((C ₁ -C ₄ ) - alkyl) ₂ , halogen, nitro or R means naphthalene or a heterocycle from the thiophene series, furan optionally substituted with a methyl group, characterized in that to the suspension of 1-acetyl-3,5-diamino-1,2,4-triazole (II)

an aqueous solution of sodium hydroxide is poured into lower aliphatic alcohol, the reaction mixture is heated with stirring at a temperature of 50-100 ° C until complete homogenization, then it is neutralized with acetic acid to pH 7-9 and aldehyde (III) is added,

where R has the above meanings, mix at a temperature of 50-100 ° C, then sodium borohydride is added portionwise and stirring is continued at a temperature of 50-100 ° C, and the process is carried out at the following molar ratio of reactants: (II): sodium hydroxide: (III): sodium borohydride 1: (1.0-1.2): (0.9-1.0): (1.2-2.0).