THE synTHEsIs and pHysIcOcHEmIcal prOpErTIEs of 2-(5-methoxy-phenyl-1h-1,2,4-triazole-3-ylthio) acETOnITrIlEs and THEIr ImInOETHErs

With the purpose of further search of biologically active substances among 5-(2-, 3-, 4-methoxyphenyl, 3,4,5- trimethoxyphenyl)-3-thio-1,2,4-triazoles and their derivatives 10 new compounds have been obtained. Acetonit-rilothio-1,2,4-triazoles have been synthesized by alkylation of 5-(2-, 3-, 4-methoxyphenyl and 3,4,5-trimethoxy- phenyl)-3-thio-1,2,4-triazoles with halogenonitriles; the primary computer pharmacological screening has shown that the class of compounds mentioned can show such types of the pharmacological activity as antitumor, anti- inflammatory and antioxidant ones. Alkylation of 5-R-1,2,4-triazole-3-thiols has been carried out in the medium of anhydrous alcohol or aprotic solvents. It has been found that replacement of the alcoholic solvent by the aprotic one increases the quantitative yield of 5-R-1,2,4-triazol-3-thioacetonitrile; in aprotic solvents the presence of impurities of alkaline hydrolysis products is not practically observed. Iminoethers of 2-(5-(2-, 3-, 4-methoxyphe- nyl and 3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-ylthio)acetatic acids have been synthesized by saturation of 2-(5-(2-, 3-, 4-methoxyphenyl and 3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-ylthio)acetonitriles with the flow of dry in the alcoholic medium when constant cooling the reaction mixture to –5ºC. It has been found by the method of HPLC/DAD-MS that the qualitative yield of the target product depends on the maintenance of the temperature mode of the reaction mixture. The structure and individuality of the molecules of the substances synthesized have been proven by the method of 1 Н NMR-spectroscopy and HPLC/DAD-MS.

A considerable interest is caused by the synthesis of biologically active compounds; among them there are substances several times exceeding their out-of-date analogues by action and, in addition, having lower indexes of acute and chronic toxicity. One of the classes of such compounds are derivatives of triazoles [1][2][3][4][5][6] used as original drugs with the antibacterial, neuroleptic, hypotensive and spasmolytic activity, and they are cardiac stimulants. The certain interest is also caused by synthetic medicines containing the nitrile group such as letrozole, anastrozole [6] used in modern medical practice as antitumor agents.
Alkylation of 5-R-1,2,4-triazole-3-thiols was carried out in the medium of anhydrous alcohol or aprotic solvents with addition of Θ-chloroacetonitrile and the equimolar amount of alkali when heating the reaction mixture to the temperature of 60-65ºC; whereupon forming the precipitate of the expected reaction product was observed. After filtration the precipitate was washed with ether ( Fig. 2).
When studying the conditions of obtaining the target product the successful attempt of thiol alkylation without addition of an alkaline agent was made, and the corresponding hydrochloric salt was formed. The pure product was isolated with anhydrous sodium acetate. Thus, the samples of the compounds synthesized did not give the melting point depression.
Individuality of the corresponding substances has been proven by the method of HPLC/DAD-MS. Descriptions of 1 Н NMR-spectra of the compounds obtained, some of their physical and chemical properties and the elemental composition are presented in Table 1 and 2.
It has been found that replacement of the alcoholic solvent by the aprotic one increases the quantitative yield of 5-R-1,2,4-triazol-3-thioacetonitrile; in aprotic solvents the presence of impurities of alkaline hydrolysis products is not practically observed (in the case of obtaining the target substances with the equimolar amount of alkali).
It should be noted that the highest yield was observed for compounds contained the 4-methoxyphenyl and 3,4,5-trimethoxyphenyl substituent at C 5 atom of the triazole ring (Table 1, compounds 3, 4). The lowest yield was observed for compound 2 (Table 1) with the 2-methoxyphenyl substituent.
One-proton singlets of the NH-group of N 2 atom of the 1H-1,2,4-triazole cycle at 13.48-13.55 mp are also recorded. Proton signals of the aromatic ring of the compounds with the 4-methoxyphenyl radical are interpreted by multiplet signals in the range of 7.92-7.98 mp, unlike singlet signals of the aromatic ring of the compounds with 3,4,5-trimethoxyphenyl substituents, which are fixed at 6.83-6.84 mp. The 1 Н NMRspectra are also characterized by the presence of the signal of protons of the methylene group in the range of 4.01-4.7 mp. The multiplet signals in the range of 0.90-3.46 mp confirm the presence of alkyl (alcohol) residues in iminoethers.
The reaction proceeds in two stages [9] -at the first stage imine chlorides of acids are formed when affecting the corresponding 2-(5-R-1H-1,2,4-triazol-3-ylthio)acetonitrile with hydrogen chloride. Then at the second stage the substitution of the alcohol residue for chlorine with formation of hydrochloride of the corresponding iminoether takes place (Fig. 4).   acetonitrile to the reaction mixture, boil the mixture for 20 min (until the neutral pH). Filter the primary precipitate of sodium chloride formed (from the solution heated). After complete cooling filter the precipitate of 2-(5 (2-, 3-, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-ylthio)acetonitrile formed, wash with diethyl ether and dry. The yellowish crystalline substances obtained are soluble in alkaline solutions, as well as in organic solvents and solutions of mineral acids. For further analysis recrystallize these substances from ethanol.
The elemental composition of new compounds (Table 2) was determined using an ELEMENTAR vario EL cube elemental analyzer (sulfonamide as the standard). 1 Н NMR spectra were recorded on a Varian VXR-300 spectrophotometer of nuclear magnetic resonance (DMSO-D 6 as a solvent, tetramethylsilane as the internal standard); the data were decoded with the ADVASP 143 software.
2. For all compounds the preliminary biological screening has been carried out using the PASS ON-LINE software.
3. The optimal synthetic conditions have been selected with the help of modern physical and chemical methods of analysis.
4. Individuality of the compounds synthesized has been determined, and their structure has been proven.