RU2794339C1 - 2-alkylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles, method for their preparation and fungicidal compositions based on them - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to 2-alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles of general formula I

where R is an aryloxyalkyl group of the general formula X_nC₆H_5-nO(СН₂)_m, where X, the same or different, denote a hydrogen or halogen atom, an alkyl group with 1 to 4 carbon atoms, an alkyloxy group with the number of atoms carbon from 1 to 4, a nitro group, where n is an integer from 0 to 5, m is an integer from 1 to 2. The invention also relates to a process for the preparation of compounds of formula I and to a fungicidal composition containing them.

EFFECT: compounds of general formula I with fungicidal activity.

3 cl, 3 tbl, 10 ex

Description

The invention relates to the chemistry of heterocyclic compounds, namely to 2-alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles with the general formula I:

where R denotes an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, denotes a hydrogen or halogen atom, an alkyl group with 1 to 4 carbon atoms, an alkyloxy group with the number carbon atoms from 1 to 4, a nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, except for 2-(2-(3-methylphenoxy)ethylthio)-5-(1,2 ,4-triazol-1-ylmethyl)-1,3,4-oxadiazole and 2-(2-(2-fluorophenoxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3 ,4-oxadiazole, to their agrochemically as well as pharmaceutically acceptable salts.

Compounds of general formula I may find use as agricultural, industrial, medical or veterinary fungicides.

The invention also relates to methods for the preparation of compounds of general formula I, and the use of these compounds in compositions with other active and auxiliary compounds for the control of fungal diseases of crops, animals and humans.

One close in biological activity to the claimed 2-alkylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles of general formula I is the series 2-alkylthio-5-(benzimidazol- 1-methyl)-1,3,4-oxadiazoles II, where R₁ is represented by a halogen, an alkyl group, an alkyloxy group, a nitro group, a nitrile group, or an aminoacetyl group, and R₂ is represented by a halogen, an alkyl group, an alkyloxy group, a nitro group, or a nitrile group. Compounds II have moderate fungicidal activity against pathogens of plant and human fungal diseases and inhibit the development of fungi at MICs up to 100 μg/disk. [Patel R.V. et. al. Synthesis of benzimidazolyl-l,3,4-oxadiazol-2-ylthio-N-phenyl-(benzothiazolyl)acetamides as antibacterial, antifungal and antituberculosis agents // Eur. J. Med. Chem. - 2012. - Vol. 53. - P. 41-51].

The closest in terms of the method of preparation and biological activity of compounds of general formula I is the method of obtaining substances of general formula III, where R ₃ is represented by a halogen, an alkyl group, an alkyloxy group, a nitro group or a nitrile group, which are obtained by alkylation of 5-(1H-1,2 ,4-triazol-1-yl)methyl-1,3,4-oxadiazol-2-thiol IV with α-haloacetophenones in acetone in the presence of triethylamine at reflux for 4 h [Xu L. et. al. Structure and biological activities of novel triazole compounds containing 1, 3, 4-oxadiazole ring // Chem. Res. Chin. Univ. - 2008. - Vol. 24, no.3. - P. 299-302]. Also, the authors present the results of fungicidal activity against Gibberella zeae, Alternaria solani, Phoma asparagi, Physalospora pircola and Cercospora arachidicola at conc. 50 mg/l, however, the compounds show low fungicidal activity and are inferior to the standard difenoconazole.

The problem solved by this invention is to increase the effectiveness of the fight against harmful fungi and expand the range of fungicidal preparations.

The problem is solved by obtaining compounds of general formula I, where R means an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, means a hydrogen or halogen atom, an alkyl group with the number of carbon atoms from 1 to 4, an alkyloxy group with a number of carbon atoms from 1 to 4, a nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, having fungicidal activity, as well as increasing the effectiveness of fungicidal preparations due to the use of 2-alkylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles of general formula I and the expansion of the range of fungicides.

The problem is solved by developing a method for obtaining 2-alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles of the general formula I, where R denotes an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, denotes a hydrogen or halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkyloxy group of 1 to 4 carbon atoms, a nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, which are obtained by reacting 5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazol-2-thiol IV with various alkyl halides V, where R denotes an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, denotes a hydrogen or halogen atom, an alkyl group with a number of carbon atoms from 1 to 8, an alkyloxy group of 1 to 8 carbon atoms, a nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, in the presence of tertiary amines in polar aprotic solvents.

1,2,4-Triazol-1-ylacethydrazide VI is obtained according to the method described in the literature [Popkov S.V., Alekseenko A.L., Tikhomirov D.S. Synthesis, structure and fungicidal activity of substituted N ² -phenylalkyliden-2-(azol-1-yl)acethydrazides // Izv. universities. Chemistry and chem. technology. - 2007. - T. 50, V. 6. - S. 98-101]. Next, the obtained hydrazide VI is reacted with carbon disulfide in the presence of a potassium hydroxide base at boiling for 24 hours. obtaining 5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazol-2-thiol IV [Xu L. et. al. Structure and biological activities of novel triazole compounds containing 1, 3, 4-oxadiazole ring // Chem. Res. Chin. Univ. - 2008. - Vol.24, No.3. - P. 299-302].

The effectiveness of pesticides directly depends on the preparative form of the drug and the conditions under which the active substance comes into contact with pests and pathogens of plants. The most effective and economical preparative form is determined based on the physicochemical properties of the drug, its purpose and method of application. These may be, for example, dusts, granules, microencapsulated preparations, wettable powders, emulsion concentrates, ointments, water-dispersible granules, suspension concentrates. Also, in addition to the active substance, the composition of the preparative form may include excipients: fillers, solvents, surfactants, water softeners, synergistic additives, etc. The drug triadimefon is known, which is used in the form of a 5.25% wettable powder, 10% emulsifying concentrate for combating diseases of wheat, rye, barley, sugar beets, apple trees, cucumbers during the growing season, as well as a seed disinfectant. [Pesticides and plant growth regulators: Ref, ed. / N.N. Melnikov, K.V. Novozhilov, S.R. Belan. - M.: Chemistry, 1995, p. 24, p. 287.]

The problem is solved by the development of fungicidal compositions consisting of 2-alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles with the general formula I, where R denotes an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, denotes a hydrogen or halogen atom, an alkyl group of 1 to 4 carbon atoms, an alkyloxy group of 1 to 4 carbon atoms, nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, agrochemically, as well as their pharmaceutically acceptable salts, at a concentration of 0.3-25% of the mass. and excipients that can be successfully used to combat harmful fungal diseases of crops, animals or humans.

The invention can be illustrated by the following examples:

Example 1 Preparation of (5-(1,2,4-triazole-1-methyl)-1,3,4-oxadiazole-2-thiol (1).

To a solution of 1.41 g (0.01 mol) of 2-(1H-1,2,4-triazol-1-yl) acetohydrazide and 0.659 g (0.01 mol) of 85% potassium hydroxide in 80 ml of abs. ethanol is added dropwise 0.87 g (0.01 mol) of carbon disulfide, the reaction mass is boiled for 20 h, 100 ml of water is added and acidified with conc. hydrochloric acid to pH=7. The precipitate is filtered off, washed with 50 ml of cold water and recrystallized from 1 ml of anhydrous ethanol. 2.1 g (40%) of 5-(1,2,4-triazol-1-methyl)-1,3,4-oxadiazole-2-thiol, m.p. 190-190°C.

¹ H NMR spectrum (δ, ppm, J, Hz): 5.69 s (2H, CH ₂ ), 8.08 s (1H, C ⁵ H _Trz ), 8.72 s (1H, C ³ H _Trz ), 14.69 br.s.(1H, NH).

Mass spectrum, m/z: 183 [M+H] ⁺ .

Example 2 Preparation of 2-methylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole (2).

To a solution of 0.1 g (0.000546 mol) 5-(1H-1,2,4-triazol-1-methyl)-1,3,4-oxadiazol-2-thiol and 0.055 g (0.000546 mol) triethylamine in 3 ml of acetone, add 0.078 g (0.000546 mol) of iodomethane and stir for 24 hours at 20°C. Then the solvent is distilled off on FIR in the vacuum of a water jet pump, 4 ml of water and 4 ml of chloroform are added to the residue. The organic phase is separated, the aqueous layer is washed with chloroform (2×5 ml). The organic phases are combined and dried over magnesium sulfate, the solvent is removed by FIR under water jet vacuum. To the residue add 3 ml of diethyl ether, cool, the precipitate is filtered off. 0.060 g (57%) of 2-methylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole, m.p. 129-132°C.

¹ H NMR spectrum (δ, ppm, J ³ , Hz): 2.51 s (3H, (CH ₃ S), 5.82 s (2H, CH ₂ N), 8.06 s (1H, C ⁵ H _Trz ) , 8.73 s (1H, C ³ H _Trz ).

Example 3 Preparation of 2-benzylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole (3).

To a solution of 0.1 g (0.000546 mol) 5-(1H-1,2,4-triazol-1-methyl)-1,3,4-oxadiazol-2-thiol and 0.0705 g (0.000546 mol) of diisopropylethylamine in 3 ml of acetone, add 0.093 g (0.000546 mol) of benzyl bromide, boil for 5 hours at 56°C. The excess solvent is removed by FIR under water jet vacuum, 5 ml of water and 5 ml of chloroform are added to the residue. The organic phase is separated, the aqueous layer is washed with chloroform (2×5 ml). The organic phases are combined and dried over magnesium sulfate, the chloroform is removed by FIR under water jet vacuum. 3 ml of diethyl ether are added to the residue, the precipitate is filtered off. 0.095 g (64%) of 2-benzylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole, m.p. 87-90°C.

¹ H NMR spectrum (δ, ppm, J, Hz): 4.48 s (2H, SCH ₂ C ₆ H ₅ ), 5.83 s (2H, CH ₂ N _Trz ), 7.31 m (3H, CH _Ar ) , 7.38 m (2Н, CH _Ar ), 8.08 s (1H, CH ⁵ _Trz ), 8.73 s (1Н, CH ³ _Trz ).

Example 4 Preparation of 2-((4-chlorophenyl)methyl)thio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole (4).

To a solution of 0.1 g (0.000546 mol) 5-(1H-1,2,4-triazol-1-methyl)-1,3,4-oxadiazol-2-thiol and 0.055 g (0.000546 mol) triethylamine in 3 ml of DMF and add 0.088 g (0.000546 mol) of p-chlorobenzyl chloride, boil for 5 hours at 153°C. Then the excess DMF is removed by FIR in the vacuum of a membrane pump, 4 ml of water and 4 ml of chloroform are added to the residue. The organic phase is separated, the aqueous layer is washed with chloroform (2×4 ml). The organic phases are combined and dried over magnesium sulfate, the solvent is removed by FIR under water jet vacuum. 8 ml of diethyl ether are added to the residue, the precipitate is filtered off. 0.070 g (42%) of 2-((4-chlorophenyl)methyl)thio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole, m.p. 97-100°C.

¹ H NMR spectrum (δ, ppm, J ³ , Hz): 4.47 s (2H, S CH ₂ C ₆ H ₄ ), 5.82 s (2H, CH ₂ N), 7.39 m (2H, 4CH _Ar ), 8.07 s (1H, C ⁵ H _Trz ), 8.72 s (1H, C ³ H _Trz ).

Mass spectrum, m/z: 308.18 [M+H] ⁺

Example 5 Preparation of 2-(2-(4-nitrophenoxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole (5).

To a solution of 0.1 g (0.000546 mol) 5-(1H-1,2,4-triazol-1-methyl)-1,3,4-oxadiazol-2-thiol and 0.044 ml (0.000546 mol) pyridine in 3 ml of acetone add 0.134 g (0.000546 mol) of 1-(2-bromoethoxy)-4-nitrobenzene), boil for 4 hours at 56°C. Excess acetone is removed at the FIR under water jet vacuum. Then 5 ml of water and 5 ml of chloroform are added to the residue. The organic phase is separated, the aqueous layer is washed with chloroform (2×5 ml). The organic phases are combined and dried over magnesium sulfate, the solvent is removed by FIR under water jet vacuum. 5 ml of diethyl ether are added to the residue, the precipitate is filtered off. 0.150 g (79%) of 2-(2-(4-nitrophenoxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole, m.p. 97-100°C.

¹ H NMR spectrum (δ, ppm, J ³ , Hz): 3.68 t (2H, S CH ₂ CH ₂ O), 4.47 t (3H, SCH ₂ CH ₂ O), 5.84 s (2H, CH ₂ N), 7.15 d (2Н, 2CH _Ar , J ³ =9.5), 8.07 s (1Н, C ⁵ H _Trz ), 8.21 d (2Н, 2CH _Ar , J ³ =9.5), 8.74 s (1Н, C ³ H _Trz ).

Example 6 Preparation of 2-(2-(4-chlorophenoxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole (6).

To a solution of 0.1 g (0.000546 mol) 5-(1H-1,2,4-triazol-1-methyl)-1,3,4-oxadiazol-2-thiol and 0.055 g (0.000546 mol) triethylamine in 3 ml of methylethylctone add 0.134 g (0.000546 mol) of 1-(2-bromoethoxy)-4-chlorobenzene, boil for 5 hours at 80°C. The excess solvent is removed by FIR under water jet vacuum, 4 ml of water and 4 ml of chloroform are added to the residue. The organic phase is separated, the aqueous layer is washed with chloroform (2×5 ml). The organic phases are combined and dried over magnesium sulfate, the solvent is removed by FIR under water jet vacuum. 3 ml of diethyl ether are added to the residue, the precipitate is filtered off. Tech. the product is recrystallized from isopropanol. 0.167 g (90%) of 2-(2-(4-chlorophenoxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole, m.p. 80-83°C.

¹ H NMR spectrum (δ, ppm, J ³ Hz): 3.64 t (2Н, S CH ₂ CH ₂ O), 4.3 t (2Н, SCH ₂ CH ₂ O), 5.83 s (1Н, CH ₂ N _Trz ), 6.95 m (2Н, 2CH _Ar ), 7.32 m (2Н, 2CH _Ar ), 8.05 s(1Н, C ⁵ H _Trz ), 8.73 s (1H, C ³ H _Trz ).

Example 7 Preparation of 2-(2-(4-chloro-2-methylphenyloxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole (7).

To a solution of 0.1 g (0.000546 mol) 5-(1H-1,2,4-triazol-1-methyl)-1,3,4-oxadiazol-2-thiol and 0.055 g (0.000546 mol) triethylamine in 3 ml of acetonitrile, add 0.128 g (0.000546 mol) of 1-(2-bromoethoxy)-4-chloro-2-methylbenzene, boil for 5 hours at 82°C. Excess acetonitrile is removed by FIR under water jet vacuum, 5 ml of water and 5 ml of chloroform are added to the residue. The organic phase is separated, the aqueous layer is washed with chloroform (2×4 ml). The organic phases are combined and dried over magnesium sulfate, the chloroform is removed by FIR under water jet vacuum. 5 ml of diethyl ether are added to the residue, the precipitate is filtered off. 0.061 g (32%) of 2-(2-(4-chloro-2-methylphenyloxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole, m.p. sq. 83-86°C.

¹ H NMR spectrum (δ, ppm, J ³ , Hz): 2.04 s (3Н, CH ₃ С ₆ Н ₃ ), 3.66 t (2Н, S CH ₂ CH ₂ O), 4.31 t (2Н, SCH ₂ CH ₂ O), 5.82 s (2Н, 2CH ₂ N _Trz ), 6.97 d (1Н, CH _Ar J ³ =8.1), 7.2 m (2Н, 2CH _Ar ), 8.06 s (1Н, C ⁵ H _Trz ) , 8.72 s (1Н, C ³ H _Trz ).

Example 9

Tests for fungicidal activity of compounds of General formula I, was carried out in experiments in vitro [guidelines for determining the fungicidal activity of new compounds. Cherkasy: NIITEKHIM. 1984. 34 p.]. The effect of drugs on the radial growth of mycelium was determined by dissolving the composition of the compound in acetone (0.3%) and introducing an aliquot into potato-sucrose agar at 50°C to a concentration of 30 mg/l for the active substance. The final concentration of acetone in control solutions with active ingredients was 1%. In Petri dishes containing 15 ml of agar medium, the fungus culture needle was applied to the agar surface. The samples were kept in an incubator at 25°C and the radial growth was measured after 3 days. The percentage of inhibition was calculated according to Abbott in relation to the untreated control. The commercial fungicide triadimefon at the same concentration was used as a reference. The test results are presented in table 3.

Example 10 Emulsion concentrate composition of Compound 11 (6% wt).

Active ingredient 5-(1H-1,2,4-triazol-1-ylmethyl)-2-[2-(2,4,6-trichlorophenoxy)ethylthio]-1,3,4-oxadiazole (11) - 6 g

Alkylbenzenesulfonic acid calcium salt (ABSA) - 2 g

Oxyethylated octylphenol (OP-7) - 8 g

Cyclohexanone - 29 g

o-Xylene - 16 g

Oil solvent - 39 g.

According to the results of in vitro fungicidal tests of 2-alkylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles I, selected from the group, compounds 5, 7, 10, 11, 12 outperform according to fungitoxicity, the standard, the well-known fungicide triadimefon (3,3-dimethyl-1-(1,2,4-triazol-1-yl)-1-(4-chlorophenoxy)-2-butanone) in relation to 3 types of phytopathogen fungi: Venturia inaequalis, Rhizoctonia solani, Bipolaris sorokiniana. These compounds are significantly superior to the results of the fungicidal activity of the compounds of General formula III, presented in the prototype. Substituted 2-phenacylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles inhibit the growth of mycelium of phytopathogens at a higher concentration of 50 mg/l by no more than 56%, which is significantly inferior to fungitoxicity of our 2-alkylthio-5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles I.

Claims (9)

1. 2-Alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazole of general formula I

where R denotes an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, denotes a hydrogen or halogen atom, an alkyl group with 1 to 4 carbon atoms, an alkyloxy group with the number of atoms carbon from 1 to 4, a nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, except for 2-(2-(3-methylphenoxy)ethylthio)-5-(1,2,4- triazol-1-ylmethyl)-1,3,4-oxadiazole and 2-(2-(2-fluorophenoxy)ethylthio)-5-(1,2,4-triazol-1-ylmethyl)-1,3,4- oxadiazole, or its agrochemically or pharmaceutically acceptable salts. 2. Method for the preparation of 2-alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazoles of general formula I according to claim 1

where R denotes an aryloxyalkyl group of the general formula X _n C ₆ H _5-n O(CH ₂ ) _m , where X, identical or different, denotes a hydrogen or halogen atom, an alkyl group with 1 to 4 carbon atoms, an alkyloxy group with the number of atoms carbon from 1 to 4, a nitro group, n is an integer from 0 to 5, m is an integer from 1 to 2, consisting in the fact that 5-(1,2,4-triazol-1-ylmethyl)-1,3,4-oxadiazol-2-thiol IV is reacted with alkyl halides V in the presence of tertiary amines in polar aprotic solvents at temperatures from 20 to 155°С:

3. Fungicide composition containing a fungicide at a concentration of 0.3-25 wt.% and excipients, characterized in that 2-alkylthio-5-(1H-1,2,4-triazol-1-ylmethyl)-1 is used as a fungicide ,3,4-oxadiazole of formula I according to claim 1.