LT4128B - Process for the preparation of 1,2,4-triazole sodium salt - Google Patents

Abstract

Herein is described the method of analytically pure 1, 2, 4 - triazole sodium salt production. This salt is used in the processes of synthesis of Na-substituted 1, 2, 4 - triazole derivatives of various biological effect, which are used in medicine and agriculture and which are characteristic by their antiallergenic, vegetation growth regulating, fungicidal and other properties.

Description

The present invention relates to a novel process for the preparation of an analytically pure 1,2,4-triazole sodium salt. Only the technical preparation of this salt is known in the literature, but so far analytically pure product has not been isolated.

A number of patents are known which state that the 1,2,4-triazole sodium salt is a widely used and important compound in the synthesis of N-substituted 1,2,4-triazole derivatives of various biological effects widely used in medicine, agriculture, which are characterized by growth-regulating, anti-allergic and fungicidal activity and are proposed for the treatment of fungal diseases of warm-blooded animals and humans.

For the synthesis of all of the above derivatives, the Na salt of 1,2,4-triazole is obtained, which is obtained by the action of 1,2,4-triazole sodium-containing organic and inorganic reagents.

1,2,4-Triazole is a heterocyclic aromatic system characterized by electrophilic substitution reactions for the formation of 1H and 4H 1,2,4-triazole derivatives. One of the isomers may be expected to form reaction conditions, but mixtures of isomers, usually dominated by 1H-1,2,4-triazole derivatives, are expected to form. However, the preparation of an analytically pure isomer by purification of a reaction mixture containing both isomers by conventional methods is a complex and difficult process, usually due to the similar solubility of the isomers. Therefore, only methods for preparing the crude 1,2,4-triazole Na salt by direct use in the synthesis of biologically active compounds are known in patent and scientific sources. The reaction mixtures thus obtained are hygroscopic, unstable and, even after short storage, are unsuitable for further synthesis. The preparation of the analytically pure 1H-substituted 1,2,4-triazole Na salt is problematic and has not yet been described. In the literature, the known methods are based on the fact that 1,2,4-triazole, in addition to the electrophilic substitution properties of aromatic compounds, has weak acidic properties due to the presence of nitrogen atoms in the ring. It has been found that weaker solvation solvents such as e.g. in the presence of liquid ammonia, the triazoles have weak acidic properties and can react with more electro-positive elements such as Li, Na, K, Cu, Ag and their organic derivatives to form their corresponding salts.

These properties of the triazole ring determined the peculiarities of the crude 1H-1,2,4-triazole Na salt known in the literature. There are three ways to obtain this salt.

1. The interaction of 1,2,4-triazole with sodium methylate is described in European patents

No. 0053307, No. 0126430, Former. German Patent No. 284225 and Federal German Patent No. 4105538.

2. Replacement of 1,2,4-triazole with NaH is described in US patents

No. 4737508, No. 4518415, No. 4482564, European Patent No. 47594, Japanese Patent No. 02-15297, British Patent No. 2011414.

3. J.Am.Chem.Soc. 49, 1927 describes the action of 1,2,4-triazole on NaNH ₂ as a solvent using liquid ammonia.

According to method 1, European Patent Nos. 0126430 and 0053307 describe a synthesis in which a solution of Na methylate in methanol and 1,2,4-triazole is mixed in equivalent quantities, after which the solvent is removed by adding toluene to the residue and then evaporating the toluene. The resulting reaction mixture, a solid without purification and characterization, was further used to obtain the physiologically active 1H-1,2,4-triazole derivatives.

The German Democratic Patent No. 284225 states that the Na salt of 1 H-1,2,4-triazole is obtained analogously to Method 1, except that another ratio of Na methylate to 1,2,4-triazole is used (1: 2). The resulting product was not purified and characterized. The first German patent No. 4105538 modifies the first process by replacing the methanol solvent with a mixture of methanol and dimethylformamide, and the reaction is carried out at 80 ° C. After removal of the solvent in vacuo, the resulting reaction mixture is a solid crystalline material which has not been characterized and is further used to obtain fungicides by reaction with bis-4-fluoro-phenylmethylchlorosilane.

According to a second method, U.S. Patent No. 4,737,508, European Patent No. 4,759,400, U.S. Patent No. 4,518,415, Japanese Patent No. 02-145576 disclose methods for preparing the 1,2,4-triazole Na salt by treating 1,2,4-triazole with equimolar NaH at room temperature. in dry dimethylformamide. The 1,2,4-triazole Na salt is not isolated and the resulting dimethylformamide solution is used for subsequent reactions.

U.S. Pat. No. 4,482,564 describes a similar preparation in which a small excess of 1,2,4-triazole is added to a 60% NaH / oil suspension in dimethylformamide at a temperature of 10-4 ° C. The 1,2,4-triazole Na salt is not isolated and the desired salt reaction mixture in solution is used for further synthesis of p-chloro -oc-1H-1,2,4-triazolylmethylstyrene. In British Patent No. 2011414, the method for the preparation of the Na salt of 1H-1,2,4-triazole using NaH differs from that of using a 50% NaH / oil slurry, replacing dimethylformamide with tetrahydrofuran and using a double excess of NaH. The reaction is carried out for 1 hour. at room temperature and then for another 2 hours. At 50 ° C. The resulting solution was used for the synthesis of di-N-substituted carbamoyltriazole derivatives.

In a third way (prototype), the Na salt of 1H-1,2,4-triazole is obtained by treating 1,2,4-triazole with an equimolar amount of NaNH ₂ in liquid ammonia. This method is also used by Aldrich, a commercial manufacturer of 90% pure (m.p. 295 ° C) technical salt of 1H-1,2,4-triazole Na. According to the process prototype and other methods described in the invention, the Na salt of 1,2,4-triazole is obtained by reacting 1,2,4-triazole with Na-containing reagents: NaOCH ₃ , NaNH ₂ , NaH to form reaction mixtures containing unidentified impurities which are difficult to are removed by conventional methods for purification of reaction mixtures. The aforesaid mixtures and 90% purity technical 1,2,4-triazole sodium salt (Aldrich Chemical Catalogy 1994-95) are hygroscopic and hydrolyze to 1,2,4-triazole and NaOH in the presence of moisture. Such crude 1,2,4-triazole Na salt products cannot be stored for long periods and must be used immediately after synthesis for their intended purpose for the production of biologically active triazole derivatives.

The essence of the invention is that the synthesis method uses water as the solvent and NaOH as the substitution reagent. The use of these materials results in the formation of analytically pure 1 H-1,2,4-triazole Na salt crystallohydrate during the reaction, the desired material being isolated from the reaction mixture by filtration of the crystals formed during the reaction. The resulting crystalline hydrate readily decomposes the water at 120-150 ° C to give a dry, analytically pure 1 H -1,2,4-triazole Na salt. The synthesis of the desired salt according to the invention simplifies the process, since the resulting product does not need to be isolated from the reaction mixture, nor does it need to be purified from the impurities formed during the reaction. The reaction does not involve the use of aggressive and expensive reagents and solvents such as dimethylformamide, tetrahydrofuran, liquid ammonia, sodium amine, sodium methylate, and the solvent used water to substitute the reagent, sodium hydroxide, to give the analytically pure 1 H-1,2,4-triazole Na salt, of which melt. is 325-327 ° C.

Analysis data:

Found,%: C 26.21; H, 2.41; N, 46.28; Well, 25.75.

Calculated,%: C, 26.38; H, 2.21; N, 46.15; Well, 25.25.

¹ H-NMR Spectrum data (solvent D-dimethylsulfoxide) md: 7.84 (2H, singlet).

C-NMR spectrum data (solvent D-dimethylsulfoxide), m.p .: 2C 149.298.

The resulting salt and its crystalline hydrate are stable, non-hygroscopic compounds can be stored indefinitely under normal conditions and, if necessary, used for their intended purpose of obtaining biologically active fungicidal plant growth regulators and synthesis of other substances used in medicine and agriculture. The use of analytically pure 1 H-1,2,4-triazole sodium for these purposes results in an increase in the yield of the final compounds.

The invention is illustrated by experimental examples of the production method:

An example. Method for the preparation of the Na salt of 1H-1,2,4-triazole.

To a solution of sodium hydroxide (1.2 g, 0.03 mol) in water (5 ml) at room temperature was added 1.03 g (0.015 mol) of 1H-1,2,4-triazole. The reaction mixture is kept at room temperature for several hours and then cooled to 4 ° C. The crystallized product is filtered off, washed with chilled methanol, ether. The dried 1H-1,2,4-triazole sodium salt is dissolved in dry methanol. The solution is filtered and the filtrate is evaporated to dryness. The residue is dried at 120-150 ° C. 0.9 g (67%) of 1H-1,2,4-triazole sodium salt is obtained. Melting point 325-327 ° C.

Found,%: C 26.21; H, 46.28; Well, 25.75.

Calculated,%: C, 26.38; H, 2.21; N, 46.15; Well, 25.25.

H-NMR Spectrum data (solvent D-dimethylsulfoxide), m.p .: 7.84 (2H, singlet).

C-NMR spectrum data (solvent D-dimethylsulfoxide), m.p .: 2C 149.298.

2. Comparative Example. Process for the preparation of the active ingredient of the known 'Flusilazole' fungicidal preparation - bis (4-fluorophenyl) methyl (1H-1,2,4-triazol-1-ylmethyl) silane using the 1,2,4 obtained according to the invention (Example 1). -triazole Na salt.

A mixture of 4.2 g (0.0149 mol) of bis (4-fluorophenyl) methyl (chloromethyl) methylsilane and 1.42 g (0.0156 mol) of 1H-1,2,4-triazole sodium salt obtained by the proposed method, 8 ml of dry dimethylformamide (DMF) are heated to 90 ° C and stirred at this temperature for 3 hours. The reaction mixture was diluted with 30 mL of water and extracted (3 x 30 mL). The ether extract was washed with a saturated aqueous sodium chloride solution (2 x 20 mL) and dried over magnesium sulfate. After the ether is distilled off, the residue is mixed with 100 ml of hexane and the solvent is completely distilled off under vacuum at a bath temperature of no more than 40 ° C. The residue is left to crystallize at room temperature for 12 hours. and the resulting crystalline mass is mixed with 100 ml of hexane. It is separated, washed on the filter with hexane (20 x 2 mL) and recrystallized from ether-hexane (1:10). 3.50 g are obtained. 75% of the material, m.p. 52-53 ° C. ¹ H NMR Spectrum (D-chloroform solvent) md: 0.7 (3H, s), 4.2 (2H, s), 7.1 (4H, trip., J 9Hz). , 7.5 (4H, doublet J16Hz, J2, J3 9Hz).

3. Comparative Example. A process for the preparation of bis (4-fluorophenyl) methyl (1H-1,2,4-triazol-1-ylmethyl) silane using a prototype 1,2,4-triazole Na salt (U.S. Patent No. 4,510,136).

4.2 g (0.015 mol) of bis- (4-fluorophenyl) methyl (chloromethyl) silane and 1.4 g (0.015 mol) of 1H-1,2,4-triazole sodium salt in 8 ml of dry DMF are stirred at 80 ° C. C for 2 hours. Add to water, extract with ether. After evaporation of the ether extract, the fraction was concentrated under high vacuum (0.05 mm Hg) at 120-125 ° C. 2.3 g (49%) of "Flusilazole", m.p. 52-53 ° C.

From the experimental data presented, it has been found that in the process according to the invention the production of 1H-1,2,4-triazole sodium salt uses cheap, non-aggressive reagents - H ₂ O, NaOH, simplifies the synthesis process by immediately isolating crystalline material which is stable, non-hygroscopic. while used for the synthesis of Fluzilazole increases the yield of this product by 26% compared to the prototype method.

Claims (2)

1. A process for the preparation of 1,2,4-triazole sodium salt by reacting 1,2,4-triazole sodium-containing reagents in solvation solvents, characterized in that 1,2,4-triazole is reacted with excess sodium hydroxide in the presence of a strong solvation solvent. - water to give crystalline hydrate, which, after filtration and easy heating, affords the analytically pure 1,2,4-triazole sodium salt. 2. A process according to claim 1, characterized in that it produces an analytically pure 1,2,4-triazole sodium salt having the following melting point: 325-327 ° C; ¹ H-NMR Spectrum Data (Ddimethylformamide) md: 7.84 (2K, s); Analysis Found:%: C 26.21; H, 2.41; N, 46.28; Well, 25.75.