RU2831200C1 - 3-AMINO-4,6-DIMETHYL-N-(4-CYANO-3-(CYANOMETHYL)-1H-PYRAZOL-5-YL) THIENO[2,3-b]PYRIDINE-2-CARBOXAMIDES AS ANTIDOTES 2,4-D ON SUNFLOWER - Google Patents

Abstract

FIELD: agricultural chemistry.

SUBSTANCE: invention relates to agricultural chemistry and specifically to compounds of a number of heterocyclic compounds used to protect sunflower plants from phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide (antidotes). Disclosed is 3-amino-4,6-dimethyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide 2a and 3-amino-4,6-dimethyl-5-pentyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)-thieno[2,3-b]pyridine-2-carboxamide 2b as antidotes of 2,4-dichlorophenoxyacetic acid on sunflower. .

EFFECT: disclosed is a compound for protecting sunflower plants from phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide.

1 cl, 1 tbl, 1 ex

Description

The invention relates to new synthetic, biologically active substances from a series of heterocyclic compounds used to protect sunflower plants from the phytotoxic action of the herbicide 2,4-dichlorophenoxyacetic acid (antidotes).

As is known, sunflower is an extremely sensitive crop to hormonal herbicides of the 2,4-D group, and in cases of unintentional contact of the herbicide with its crops, losses can amount to, depending on the dose, up to 100% [Chkanikov D. I., Sokolov M. S. Herbicidal action of 2,4-D and other halogen-phenoxy acids, Moscow: Nauka, 1973, 95 p.].

Despite intensive research to find new antidotes, the protection of vegetative sunflower plants from the damaging effects of 2,4-D remains relevant and unresolved [Strelkov V.D., Dyaduchenko L.V., Dmitriev I.G. Synthesis of new herbicide antidotes for sunflower. Krasnodar: Prosveshchenie-Yug, 2014. P. 79].

The closest analogue in structure and properties to the claimed compound is 3-amino-N-(4-fluorophenyl)-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide of formula 1 [patent No. 2277333 RF, IPC A01N 25/32 (2006.01) A01P 15/00 (2006.01)]

Compound 1 (prototype) in field conditions at a dose of 200 g/ha on vegetative sunflower plants exhibits an antidote effect in relation to 2,4-D at a level of 22-24% and can be used as a means of protecting sunflower. However, its antidote activity is not high enough, while the dose of 200 g/ha is quite high and can cause negative environmental problems.

The technical result of the claimed invention is the expansion of the arsenal of biologically active substances obtained synthetically for their use in agriculture as antidotes.

This is achieved by using 3-amino-4,6-dimethyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide 2a and 3-amino-4,6-dimethyl-5-pentyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide 2b :

Compounds 2a and 2b exhibit antidote activity against 2,4-dichlorophenoxyacetic acid on sunflower seedlings under laboratory conditions.

Compounds 2a and 2b were synthesized in two steps – by the reaction of available 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile 3 [Sato T. Reaction of hydrazine hydrate and phenylhydrazine with malononitrile // Journal of Organic Chemistry. 1959. Vol. 24. No. 7. P. 963-966; Taylor EC, Hartke KS The Reaction of Malononitrile with Hydrazine // Journal of the American Chemical Society. 1959. Vol. 81. No. 10. P. 2452-2455; patents WO2004/58781 (2004); CN104024246 (2016); WO2009/111028 (2009)] with chloroacetyl chloride in a mixture of acetic acid and toluene under reflux. The resulting chloroacetamide 4 was reacted with available substituted 3-cyanopyridine-2(1H)-thiones 5a,b [Gallagher, T., Hirschhäuser, C. (2001). 1,2-Dihydro-4,6-dimethyl-2-thioxo-3-pyridinecarbonitrile. Encyclopedia of Reagents for Organic Synthesis, https://doi.org/10.1002/047084289X.rd226.pub2; DS Buryi, VV Dotsenko, NA Aksenov, IV Aksenova, SG Krivokolysko, LV Dyadyuchenko. Synthesis and properties of 4,6-dimethyl-5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile and 3-amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridines // Russian Journal of General Chemistry, 2019, Vol. 89, P. 1575–1585. https://doi.org/10.1134/S1070363219080061] in the presence of a twofold excess of KOH in N,N-dimethylformamide. The reaction proceeds as a tandem S-alkylation/Thorpe-Ziegler cyclization process and leads to the target thienopyridines 2a,b :

Preparation of 3-amino-4,6-dimethyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide 2a

A. Preparation of 2-chloro-N-(4-cyano-3-cyanomethyl-1H-pyrazol-5-yl)acetamide 4. In a 50 ml round-bottomed flask equipped with a reflux condenser, 2.0 g (0.014 mol) of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile 3 , 2.0 ml (0.015 mol) of chloroacetyl chloride (ρ = 1.420 g/cm ³ ), 10 ml of glacial acetic acid and 5.5 ml of absolute toluene are mixed. The reaction mixture is boiled for 7 h, cooled, kept at 25 °C for 48 h, and the precipitate is filtered off. Compound 4 is obtained as a light beige powder weighing 2.51 g, yield 81%. IR spectrum, ν, cm ^-1 : 3236 br (N–H), 2233 s, 2264 s (C≡N), 1691 s (C=O). ^1H NMR (400 MHz, DMSO- _d6 ), _δH , ppm: 4.12 s (2H, _CH2 ), 4.27 s (2H, _CH2Cl ), 11.33 s (1H, CONH), 13.45 s (1H, NH). NMR ^13C DEPTQ (101 MHz, DMSO-d ₆ ), _δC , ppm: 41.5 (CH ₂ ), 42.5 (CH ₂ ), 112.5 (C≡N), 116.7 (C≡N), 143.3 (C _pyrazole ), 143.8 (C _pyrazole ), 169.1 (CONH).

B. 0.300 g (0.002 mol) of 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile 5a and 10 ml of DMF are placed in a 50 ml beaker, 1.5 ml of 10% aqueous KOH solution are added. After 7 min, 0.449 g (0.002 mol) of 2-chloro-N-(4-cyano-3-cyanomethyl-1H-pyrazol-5-yl)acetamide 4 is added. The reaction mixture is stirred at room temperature for 2 h, another 1.5 ml of 10% aqueous KOH solution is added and stirred for another 2 h. The precipitate is filtered off and purified by recrystallization from ethyl acetate. The compound is obtained as a light green powder weighing 0.47 g, yield 67%. IR spectrum, ν, cm ^-1 : 3452 m, 3296 m (NH ₂ ), 3147 br (N–H), 2208 s (C≡N), 1695 s (C=O). NMR ¹ H (400 MHz, DMSO-d ₆ ), δ _H , ppm: 2.13 s (3H, CH ₃ -4), 2.23 s (3H, CH ₃ -6), 6.60 s (1H, H-5), 7.21 br s (2H, NH ₂ ), 10.41 br s (1H, CONH), 13.48 br s (1H, NH).

Preparation of 3-amino-4,6-dimethyl-5-pentyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide 2b

In a 50 ml beaker, 0.412 g (0.002 mol) of 4,6-dimethyl-5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile 5b and 10 ml of DMF are placed, 1.5 ml of 10% aqueous KOH solution are added. After 7 min, 0.449 g (0.002 mol) of 2-chloro-N-(4-cyano-3-cyanomethyl-1H-pyrazol-5-yl)acetamide are added. The reaction mixture is stirred at room temperature for 3 h, then another 1.5 ml of 10% aqueous KOH solution is added and stirred for another 2 h. The precipitate is filtered off and purified by recrystallization from ethyl acetate. The product is obtained as a sand-colored powder weighing 0.44 g, yield 52%. IR spectrum, ν, cm ^-1 : 3454 m, 3297 m (NH ₂ ), 3184 w (NH), 2206 m (C≡N), 1699 s (C=O). NMR ¹ H (400 MHz, DMSO-d ₆ ), δ _H , ppm: 0.91 t (3H, CH ₃ , ³ J = 6.3 Hz), 1.34-1.37 m (4H, CH ₂ CH ₂ ), 2.13 s (3H, CH ₃ -4), 2.40 s (3H, CH ₃ -6), 2.44-2.49 m (4H, CH ₂ CH ₂ ), 7.25 br.s (2H, NH ₂ ), 10.41 br. s (1H, CONH), 13.39 br.s (1H, NH). NMR ¹³ C DEPTQ (101 MHz, DMSO-d ₆ ), δ _C , ppm: 13.8* (CH ₃ ), 16.5* (CH ₃ ), 16.9* (CH ₃ ), 22.3 (CH ₂ ), 22.5 (CH ₂ ), 27.0 (CH ₂ ), 30.9 (CH ₂ ), 40.1 (CH ₂ CN), 80.7 (C _pyrazole ), 100.2 (C ² ), 116.3 (CN), 124.6 (C ^3a ), 137.7 (C ⁵ ), 145.7 (C _pyrazole ), 146.4 (C _pyrazole ), 156.2 (C ⁴ ), 160.2 (C ⁶ ), 171.2 (C ^7a ), 172.8 (CONH). *Signal in antiphase.

Based on a combination of spectral analysis methods, it was established that the structures of the synthesized compounds2a,bcorrespond to the structures of 2,4-D 3-amino-4,6-dimethyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide claimed as antidotes2aAnd 3-amino-4,6-dimethyl-5-pentyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)-thieno[2,3-b]pyridine-2-carboxamide2b.

Example 1. Evaluation of compounds 2a,b for antidote activity on sunflower seedlings

Sprouted seeds of sunflower variety Master with the length of the embryonic root of 2-4 mm are placed for 1 hour in a solution of 2,4-dichlorophenoxyacetic acid (2,4-D) at a concentration of 10 ^-3 % in the calculation of obtaining 40-60% inhibition of hypocotyl growth. After the herbicide effect, the sprouts are washed with water and placed in solutions of substances tested for antidote activity at concentrations of 10 ^-2 , 10 ^-3 , 10 ^-4 , 10 ^-5 % (herbicide + antidote option). After 1 hour, the seeds are washed with water and laid out on strips of filter paper (size 10 × 75 cm), 20 pieces each, which are rolled into rolls and placed in glasses with 50 ml of water. Further germination of seeds is carried out in a thermostat for 3 days at a temperature of 28 ° C. The temperature of the solutions and wash water is 28 ° C. The seeds of the “herbicide” variant (the comparison standard) are kept in a 2,4-D solution at a concentration of ^10–3 % for 1 hour and in water for 1 hour. The seeds of the control variant are kept in water for 2 hours. The experiment is repeated three times. 20 seeds are used in each repetition. The protective (antidote) effect is determined by the increase in the length of the hypocotyl and root in the herbicide+antidote variant relative to the above values in the “herbicide” variant (the standard) as a percentage. Statistical processing of the experimental data was performed using Student’s t- criterion at P=0.95. The research results are presented in Table 1.

Table 1

Antidote activity of the compound1(prototype) and thienopyridines2a,bto the herbicide 2,4-D on sunflower seedlings of the Master variety

Preparation Concentration,
% Hypocotyl length Root length mm K 2,4-D,% mm K 2,4-D,% Control 0 76 - 162 - 2,4-D 10 ^-3 56 - 67 - 2,4-D+
compound 2a 10 ^-2
10 ^-3
10 ^-4
10 ^-5 72
76
75
76 129*
136*
134*
136* 83
90
94
92 124*
134*
140*
137* 2,4-D+
compound 2b 10 ^-2
10 ^-3
10 ^-4
10 ^-5 72
74
78
73 129*
132*
139*
130* 80
86
91
89 119*
128*
136*
133* 2,4-D+
connection 1 (prototype) 10 ^-2
10 ^-3
10 ^-4
10 ^-5 63
72
65.5
62 113*
129*
117*
111* 80.5
80.5
82.5
82.5 120*
120*
123*
123*

*Differences between variants are significant at P=0.95.

As can be seen from the data in Table 1, the use of 3-amino-4,6-dimethyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide, proposed as antidotes, against the background of the herbicide effect2aAnd 3-amino-4,6-dimethyl-5-pentyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)-thieno[2,3-b]pyridine-2-carboxamide2bsignificantly weakens the toxic effect of the herbicide. Thus, the compounds2aAnd2breduce the negative effect of 2,4-D on sunflower seedling hypocotyls by 28-36% and 28-39%, respectively, when used mainly in three or more concentrations, while the compound1(analogous in structure) exhibits an antidote effect at the level of 11-29%.

Compounds 2a and 2b reduce the inhibitory effect of 2,4-D on the effect of 2,4-D on the roots of seedlings by 24-40% and 19-36% also when used in three or more concentrations, whereas compound 1 (prototype) exhibits an antidote effect at the level of 20-23%.

Claims (3)

3-Amino-4,6-dimethyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)thieno[2,3-b]pyridine-2-carboxamide 2a and 3-amino-4,6-dimethyl-5-pentyl-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)-thieno[2,3-b]pyridine-2-carboxamide 2b of the formula: as antidotes for 2,4-dichlorophenoxyacetic acid on sunflower.