RU2476428C1 - Method of producing 5-amino-3-aminomethyl-1,2,4-triazole dihydrochloride - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: described is an improved method of producing 5-amino-3-aminomethyl-1,2,4-triazole dihydrochloride, which can be used in producing medicinal and biologically active substances and chemicals. The described method involves successively mixing aminoguanidine bicarbonate, hydrochloric acid and phthalimidoglycine of formula (II)

in molar ratio 1.0:(1.0÷1.1):1.0 and the obtained mixture is heated with gradual distillation of water at atmospheric pressure and stirring until achieving temperature of 160-185°C; the reaction mixture is then heated at that temperature for 1-5 hours, after which a solution of sodium carbonate in water is added until achieving pH 10-11; the obtained solution is boiled and the compound of formula (III)

formed is separated and subjected to hydrolysis with hydrochloric acid.

EFFECT: improved method of producing 5-amino-3-aminomethyl-1,2,4-triazole dihydrochloride.

1 cl, 6 ex

Description

The invention relates to the field of production of organic substances, namely 5-amino-3-aminomethyl-1,2,4-triazole dihydrochloride of the formula (I)

and can be used in the production of medicinal and biologically active substances, chemical reagents. In particular, compound (I) is used as a reagent to produce potential antihypertensive drugs and cosmetic additives (Rudolf K. et al. Amino acid derivatives, pharmaceutical compositions containing these compounds and processes for preparing them. US Pat. 5807875 USA. IPC A61K 31 / 445. Declaration of December 11, 1996. Publish. September 15, 1998; Blanc-Ferras E. et al. Cosmetic composition containing a neuropeptide Y receptor antagonist. Pat. US Pat. 6313128. IPC A61K 8/99. 11/06/2001).

A known method for producing 3 (5) -pyridyl-substituted 5 (3) -amino-1,2,4-triazoles by the interaction of pyridinecarboxylic acids with aminoguanidine bicarbonate in the presence of hydrochloric acid with the gradual distillation of water at atmospheric pressure until the temperature of the reaction mixture reaches 165-180 ° C followed by heating at this temperature for 3-5 hours and processing the resulting reaction products with alkali (Tarasova E.V., Chernyshev V.M., Taranushich V.A. Method for producing 3 (5) -pyridyl-substituted 5 (3) -amino -1,2,4-triazoles Patent 2412180 of the Russian Federation. IPC C07D 401/04. publ. 20.02.2011. Bull. №5). The disadvantage of this method is the inability to obtain compound (I) due to the low reaction rate of aminoacetic acid with aminoguanidine and the formation of by-products.

A known method of producing 5-amino-3-aminomethyl-1,2,4-triazole dihydrochloride (I) by reaction of hippuric acid hydrazide with methylisothiourea sulfate in the presence of alkali, followed by hydrolysis of the resulting 5-amino-3-benzamidomethyl-1,2,4- triazole hydrochloric acid (Biemann K., Bretschneider N. // Monatshefte fur Chemie. 1959. Vol. 89. N. 4-5. P. 603-610). The disadvantage of this method is the high cost of the starting materials (hippuric acid hydrazide) and the release of toxic methyl mercaptan during the synthesis.

The closest in technical essence and the achieved result is a method for producing 5-amino-3-aminomethyl-1,2,4-triazole (I) dihydrochloride by reaction of phthalimidoglycine chloride with aminoguanidine hydrochloride in a melt at 170-180 ° C and a molar ratio of aminoganidine hydrochloride: phthalimidoglycine equal to 2: 1, followed by isolation of phthalimidoacetylaminoguanidine hydrochloride, cyclization of this compound to 3-phthalimidomethyl-5-amino-1,2,4-triazole (III) under the action of alkali, isolation of compound (III) and its subsequent hydrolysis to the target boiling product with boiling with hydrochloric acid (Bagal L.I., Pevzner M.S., Lopyrev V.A., Yurchak E.A. Synthesis of 3-aminomethyl-5-amino-1,2,4-triazole // Chemistry heterocyclic compounds. Collection 1. Riga: Zinatne, 1967. S.184-185). The disadvantage of this method is the high cost of phthalimidoglycine chloride and the cost overrun of expensive aminoguanidine hydrochloride. Due to the low selectivity of the reaction to prevent the formation of diacyl derivatives of aminoguanidine contaminating the target product, the method uses a 100% excess of aminoguanidine hydrochloride with respect to the stoichiometrically necessary amount. Excess aminoguanidine hydrochloride is lost in subsequent stages.

The objective of the invention is to reduce the cost of the method for producing 5-amino-3-aminomethyl-1,2,4-triazole (I) dihydrochloride by using cheaper starting materials and reducing the consumption of aminoguanidine salts.

The problem is achieved in the claimed method for producing 5-amino-3-aminomethyl-1,2,4-triazole (I) dihydrochloride, which consists in sequentially mixing aminoguanidine bicarbonate, hydrochloric acid and phthalimidoglycine of formula (II) in a molar ratio of aminoguanidine bicarbonate : hydrochloric acid: compound (II) = 1.0: 1.0 ÷ 1.1: 1.0 and the resulting mixture is heated with gradual distillation of water at atmospheric pressure and stirring until a temperature of 160-185 ° C is reached, then the reaction mixture is heated at this temperature for 1-5 h, last why add a solution of sodium carbonate in water to pH 10 ÷ 11, boil the resulting solution, then the resulting compound of formula (III) is separated and subjected to hydrolysis with hydrochloric acid.

The process is carried out according to reactions (1) - (4).

In the claimed method, instead of phthalimidoglycine chloride and aminoguanidine hydrochloride, substantially cheaper starting materials are used - phthalimidoglycine (II), aminoguanidine bicarbonate and hydrochloric acid. In addition, reaction (2) - acylation of aminoguanidine with phthalimidoglycine (II) - is more selective than acylation of phthalimidoglycine chloride. Therefore, the process is carried out at a stoichiometric ratio of aminoguanidine bicarbonate: compound (II), which allows to reduce the consumption of aminoguanidine salts, as well as to carry out the next step without isolation and purification of phthalimidoacetylaminaminoguanidine hydrochloride. In this case, the yield of the target product (I) calculated on amino guanidine is higher than in the prototype. The result is a reduction in the cost of the method for producing compound (I).

The molar ratio of aminoguanidine bicarbonate: hydrochloric acid: compound (II) = 1.0: 1.0 ÷ 1.1: 1.0 is optimal. A decrease in the amount of hydrochloric acid below the stoichiometric in the first stage of synthesis leads to a significant decrease in the reaction rate (2) and a decrease in the yield of the intermediate product (III). An increase in the amount of hydrochloric acid also leads to a decrease in yield due to partial hydrolysis of the phthalimide group and the occurrence of adverse reactions. The use of an excess of aminoguanidine or phthalimidoglycine (II) bicarbonate is impractical because it does not increase the yield.

Maintaining the temperature in the range of 160-185 ° C at the stage of the acylation of aminoguanidine allows for an acceptable reaction rate and to achieve a high degree of conversion of the reactants.

The pH range of 10–11 at the stage of cyclization of phthalimidoacetylaminoguanidine (reaction (3)) provides an acceptable rate of the target reaction and avoids partial hydrolysis of the phthalimide fragment of the molecule.

The method is as follows.

Aminoguanidine bicarbonate is mixed with concentrated hydrochloric acid, then phthalimidoglycine (II) is added, the resulting mixture is heated to boiling with stirring, and water is gradually distilled off, raising the temperature of the reaction mixture to 160-185 ° C. Then the reaction mixture is heated at this temperature for 1-5 hours, cooled, a solution of sodium carbonate in water is poured to pH 10 ÷ 11, and the resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water, dissolved in 20% hydrochloric acid and boiled for 6 hours. Then it is cooled to 0-5 ° С, the precipitated precipitate of phthalic acid is filtered off, the aqueous solution is evaporated to dryness. The residue was recrystallized from water-alcohol and dried.

Example 1

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 6.1 g (0.055 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 185 ° C. The reaction mixture is heated at this temperature for 1 h, then it is cooled to 40-50 ° С and a 15% sodium carbonate solution is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 5.73 g (62%), mp. 270-272 ° C. Found by potentiometric titration M = 186.

Found (%): C 19.65; H 4.60; N 38.01

C ₃ H ₉ Cl ₂ N ₅ .

Calculated (%): C 19.37; H 4.88; N 37.64

Example 2

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 5.53 g (0.05 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 185 ° C. The reaction mixture is heated at this temperature for 5 hours, then cooled to 40-50 ° C and a 15% solution of sodium carbonate is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 5.58 g (60%), the properties of the obtained product are identical to those described in example 1.

Example 3

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 6.1 g (0.055 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 160 ° C. The reaction mixture is heated at this temperature for 5 hours, then cooled to 40-50 ° C and a 15% solution of sodium carbonate is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 5.30 g (57%), the properties of the obtained product are identical to those described in example 1.

Example 4

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 7.1 g (0.065 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 160 ° C. The reaction mixture is heated at this temperature for 5 hours, then cooled to 40-50 ° C and a 15% solution of sodium carbonate is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 3.72 g (40%), the properties of the obtained product are identical to those described in example 1.

Example 5

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 4.4 g (0.04 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 160 ° C. The reaction mixture is heated at this temperature for 5 hours, then cooled to 40-50 ° C and a 15% solution of sodium carbonate is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 3.68 g (43%), the properties of the obtained product are identical to those described in example 1.

Example 6

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 5.53 g (0.05 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 200 ° C. The reaction mixture is heated at this temperature for 5 hours, then cooled to 40-50 ° C and a 15% solution of sodium carbonate is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 4.19 g (45%), the properties of the obtained product are identical to those described in example 1.

Example 7

6.8 g (0.05 mol) of aminoguanidine bicarbonate and 6.1 g (0.055 mol) of 33% hydrochloric acid are mixed. Then add 10.25 g (0.05 mol) of phthalimidoglycine (II) and the resulting mixture is heated with stirring with the gradual distillation of water at atmospheric pressure to a temperature of 150 ° C. The reaction mixture is heated at this temperature for 5 hours, then cooled to 40-50 ° C and a 15% solution of sodium carbonate is added with stirring until the pH of the resulting solution reaches 10 ÷ 11. The resulting solution is boiled for 20-30 minutes, then cooled to 10-15 ° C. The precipitated precipitate of compound (III) is filtered off, washed with a small amount of cold water and dissolved in 100 ml of 20% hydrochloric acid. The resulting solution was boiled for 6 hours, then cooled to 0-5 ° C, the precipitated phthalic acid precipitate was filtered off, and the aqueous solution was evaporated to dryness. The residue is dissolved in a minimum amount of hot water (~ 80 ° C), ethanol is added to the resulting solution (in a 4-5-fold amount of the volume of the resulting solution), and the resulting mixture is cooled to 3-5 ° C. The precipitate formed is filtered off and dried at 100 ° C. Yield 3.81 g (41%), the properties of the obtained product are identical to those described in example 1.

Claims (1)

A method of obtaining a 5-amino-3-aminomethyl-1,2,4-triazole dihydrochloride of the formula (I)

consisting in the fact that sequentially mixed aminoguanidine bicarbonate, hydrochloric acid and phthalimidoglycine of the formula (II)

in a molar ratio of aminoguanidine bicarbonate: hydrochloric acid: compound (II) = 1.0: 1.0 ÷ 1.1: 1.0 and the resulting mixture is heated with gradual distillation of water at atmospheric pressure and stirring until a temperature of 160-185 ° C is reached, then the reaction mixture is heated at this temperature for 1-5 hours, after which a solution of sodium carbonate in water is added to pH 10 ÷ 11, the resulting solution is boiled, then the resulting compound of formula (III)

separated and hydrolyzed with hydrochloric acid.