Synthesis and transformation in the series of 2-((5-(2,4- and 3,4-dimethoxyphenyl)-3H-1,2,4-triazole-3-yl)thio)acetic acids

Materials and methods. Compounds were synthesized using reagents and solvents qualified as “ch.p.”. The IUPAC nomenclature as supplemented was used during the preparation. The melting temperature was determined with the capillary method according to HFC (2.2.14) on the device PTP (M). Elemental analysis was determined with the ELEMENTAR vario EL cube analyzer (manufactured in Germany) (standard – sulfonamide). IR spectra were recorded using spectrophotometer Specord M-80 (manufactured in Germany) within the range of 4000–500 cm-1 (scanning was performed under the following conditions: slot program 3.0, time constant – τ = 3 s, scanning time 34 min, samples were analyzed in the form of tablets with potassium bromide). 1H NMR spectra were recorded using Varian VXR-300 spectrophotometer (manufactured in the USA), dimethyl sulfoxide-D6 solvent, and tetramethylsilane was used as an internal standard. The spectra were decoded using the computer program ADVASP 1.43. Thin layer chromatography was performed using Sorbfil plates (analytical, size 10 × 15 cm, base: polymer substrate, sorbent: silica gel STX-1A, grain: 5–17 μm, layer thickness: 110 m combination – silicazole).

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Aim
The purpose of the work is to develop preparative methods for the synthesis of 2-((5-(2,4-and 3,4-dimethoxyphenyl)-3H-1,2,4-triazole-3-yl)thio)acetic acids, to study the esterification reaction in this regard, to study physical and chemical properties of the obtained substances, and to predict their toxicity.
Acid esters have high biological activity and can also be intermediates for the synthesis of amides, hydrazides, ylidene hydrazides, and bicyclic structures -derivatives of 1,2,4-triazole.
In order to achieve better yields of products and their higher purity, another method was used to obtain esters of 2-((5-(2,4and 3,4-dimethoxyphenyl)-3H-1,2,4-triazole-3-yl)thio)acetic acids (compounds 2.6, 2.7, 2.9, 2.10, Fig. 2), which involves the esterification of the above mentioned acids (compounds 2.5, 2.8) with methyl and ethyl alcohols in the presence of a catalytic amount of concentrated sulfuric acid. After the reaction, the excess alcohol was evaporated, the residue was first thoroughly washed with sodium bicarbonate solution (to pH 7-8), then with water (to pH 7), the precipitate was filtered off, further washed with water and dried.
The individuality of the synthesized compounds was proved by thin layer chromatography. The acetone : hexane : propanol 2 : 1 : 1 system was used as the mobile medium.
Method B. 1 mole of the corresponding 5-(2,4-or 3,4-dimethoxyphenyl)-3H-1,2,4-triazole-3-thione (compound 2.1), dissolved in 20 ml of dimethylformamide, was put into a 250 ml round bottom flask, equipped with a reflux condenser. 1 mole of NaOH (pre-dissolved in 20 ml of water) and 1 mole of monochloroacetic acid were added. It was heated to the pH of the solution in a slightly acidic medium, after which the resulting solution was evaporated.
As a result of the reactions, the following compounds were obtained: yellow (2.5) and orange (2.8) crystalline substances insoluble in water, soluble in solutions of alkalis and alkali metal carbonates, as well as in organic solvents and solutions of mineral acids. For analysis, substances were recrystallized from a mixture of dimethylformamide-water 2 : 1.  2.6, 2.7, 2.9, 2.10).

Results
As predicted by GUSAR-online for tested 2-((5-(2,4-and 3,4-dimethoxyphenyl)-3H-1,2,4-triazole-3-yl)thio)acetic acids (compounds 2.5, 2.8) and their esters (compounds 2.6, 2.7, 2.9, 2.10), the average lethal dose of LD 50 for the corresponding acetic acids was when administered: intraperitoneally -from 455.4 to 480.1 mg/kg, intravenously -from According to the results of the prediction of the toxicity index, it should be noted that all compounds belong to low-toxic and practically non-toxic substances, which corresponds to the 4 th and 5 th toxicity class according to the classification of K. K. Sidorov and according to the OECD classification [8].

Discussion
New 2-((5-(2,4-and 3,4-dimethoxyphenyl)-3H-1,2,4-triazole-3-yl)thio)acetic acids were synthesized, becoming the basis for the production of a number of suitable esters. The structure of the obtained substances was confirmed by elemental analysis, the obtained results confirm the data on the percentage of elements (C, H, N, S) in the samples of the obtained compounds, IR-spectroscopy, in the IR-spectra of acids (compounds 2.5, 2.8) CH 2 absorption bands -COOH groups at 1760 cm -1 [6]. Besides, the IR spectra of esters (compounds 2.6, 2.7, 2.9, 2.10) were additionally characterized by absorption bands of CO-C groups in the range of 1283-1227 cm -1 [6] and 1 H NMR-spectrometry. In acetic acids, characteristic singlet signals of carboxyl groups were present at 12.32-12.34 ppm, and in esters of acetic acids there were signals of protons of the methyl group of the alcohol residue at 1.23-3.87 ppm, and their individuality was established by thin layer chromatography. According to the results of computer GUSAR-online prediction of toxicity indicators, it should be noted that all compounds were low-toxic and virtually non-toxic substances, which corresponds to 4 and 5 toxicity class according to the classification of K. K. Sidorov and the OECD classification [8].
2. The structure of the obtained compounds was confirmed by elemental analysis of IR-spectroscopy, 1 H NMR-spectra, and their individuality was justified by thin layer chromatography.
3. Computerized prediction of acute toxicity was performed for the synthesized compounds, which showed the possibility of searching for potential drugs based on them.