RU2786234C1 - 2-{ [3-CYANO-4-R-5,6,7,8-TETRAHYDROQUINOLINE-2-YL]THIO} -N[(2Z)-3-Ar-4-PHENYL-1,3-THIAZOLE-2(3H)-YLIDENE]ACETAMIDES, METHOD FOR THEIR PREPARATION AND USE AS ANTIDOTES 2,4-D BASED ON SUNFLOWER - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions relates to the field of organic chemistry and agriculture, namely to new synthetic, biologically active substances from a number of heterocyclic compounds used to protect sunflower plants from the phytotoxic action of the herbicide of 2,4-dichlorophenoxyacetic acid. 2-{[3-cyano-4-R-5,6,7,8-tetrahydroquinoline-2-yl]thio}-N[(2Z)-3-Ar-4-phenyl-1,3-thiazole-2(3H)-ylidene]acetamides of formula 1-3 were disclosed, where 1) Ar=PhMe, R=4-Cl-Ph, 2) Ar=PhMe, R=Tp, 3) Ar=4-Cl-Ph, R=Tp, exhibiting antidote activity. In addition, a method for obtaining the above compounds and the use of these compounds as an antidote after sunflower treatment with an herbicide is disclosed.

EFFECT: group of inventions provides effective protection of vegetating sunflower plants from the phytotoxic effect of the herbicide.

3 cl, 1 tbl, 4 ex

Description

The invention relates to the production of synthetic, biologically active substances from a number of heterocyclic compounds, and their use in agriculture to protect sunflower plants from the phytotoxic effect of the herbicide-2,4-dichlorophenoxyacetic acid.

As you know, sunflower is an extremely sensitive crop to hormonal herbicides of the 2,4-D group and, in cases of unintentional contact with herbicide on its crops, losses can be, depending on the dose, up to 100% [Chkanikov, D.I., Sokolov, M.S. Herbicidal action of 2,4-D and other halophenoxy acids. M.: Nauka, 1973. S. 95]. Despite intensive research to find new antidotes for the protection of vegetative sunflower plants from the damaging effects of 2,4-D, it remains relevant and unresolved [Strelkov V.D., Dyadyuchenko L.V., Dmitriev I.G. Synthesis of new herbicidal antidotes for sunflower. Krasnodar: Enlightenment-South, 2014. S. 79].

Known are 2-R-3-amino-4,6-dimethyl-5-X-thieno[2,3-b]pyridines with the structure

which are used as an effective antidote for hormonally acting herbicides [RF patent No. 2232762, IPC C07D 495/02 (2000.01), C07D 213/82 (2000.01), A01N 43/90 (2000.01), A01N 43/40 (2000.01), A01N 25/32 (2000.01) Thioalkylpyridines and thieno[2,3-b]pyridines - antidotes of hormonal herbicides 2,4-dichlorophenoxyacetic acid. / E.A. Kaigorodova, V.K. Vasilin, V.A. Tymorin, N.I. Nenko, G.D. Krapivin, L.V. Dyadyuchenko, L.I. Isakova, V.D. Strelkov. BI No. 20, 2004]. This compound has only been tested in laboratory conditions on sunflower seedlings, and it is not at all obvious that high biological activity will be preserved when it is tested in the field. Very often, compounds of a complex chemical structure do not withstand the action of solar UV radiation and lose their activity.

The closest analogue in structure and properties to the claimed compounds is 2-N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno-[2,3-b]-pyridine formula:

[RF patent No. 2276845, IPC A01N 43/90 (2006.01), C07D 495/04 (2006.01), A01P 21/00 (2006.01). Application of 2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno-[2,3-b]-pyridine as a seed germination stimulator. - No. 2005104358; dec. 02/17/2005; publ. May 27, 2006]. However, this compound has a low antidote activity.

2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno-[2,3-b]-pyridine compounds are obtained by a known two-stage method - the interaction of the corresponding 3-cyano-4,6-dimethyl -1 (H) pyridine-2-thiones with an equimolar amount of KOH and 2-iodophenylamide chloroacetic acid at a temperature of 20-25 ° C, followed by cyclization [Synthesis of substituted 2-alkyl (aryl) thio-3-cyanopyridines and 3-aminothieno-[ 2,3-b]pyridines / E.A. Kaigorodova, L.D. Konyushkin, S.N. Mikhailichenko. VK. Vasilin, V.G. Kulnevich // - KhGS, 1996, No. 10, p. 1432-1437].

The use of the compound 2-[N-(2'-iodophenyl)carboxamido]-3-amino-4,6-dimethylthieno-[2,3-b]-pyridine as a growth stimulant in a field experiment at a dose of 200 g/ha increases the yield sunflower seeds by 2.4 q/ha or 16%.

It should be noted that the main disadvantage of using this compound is the large dosage of its application, namely the dose of 200 g/ha. This is a very high dose for a growth promoter, which will certainly cause corresponding environmental problems, and, therefore, is an obstacle to the introduction of this drug into the crop production system.

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

The technical result is achieved by the synthesis of 2-{[3-cyano-4-R-5,6,7,8-tetrahydroquinolin-2-yl]thio}-N[(2Z)-3-Ar-4-phenyl-1,3 -thiazol-2(3H)-ylidene]acetamides of formula 1-3:

where 1 Ar=PhMe, R=4-Cl-Ph,

2 Ar=PhMe, R=Tp,

3 Ar=4-Cl-Ph, R=Tp,

and using them on herbicide-damaged vegetative sunflower plants in order to reduce the negative effect of 2,4-D as an antidote 3 days after herbicide treatment in the form of an aqueous solution at a dose of 30 g/ha with a working fluid consumption rate of 300 l/ha.

The claimed compounds are obtained by the interaction of N-(3-(aryl)-4-phenyl-1,3-thiazol-2-ylidene)-2-chloroacetamides with 4-(aryl)-2-thioxo-1,2,5,6, 7,8-hexahydroquinoline-3-carbonitriles in the presence of an equivalent of KOH in EtOH solution, according to the following scheme:

Compounds 1-3 were synthesized for the first time.

Known starting compounds used in the synthesis of target derivatives. So 4-aryl-2-thioxo-1,2,5,6,7,8-hexahydroquinolines are obtained according to the method described in [V.P. Litvinov. Chemistry of thienopyridines and related systems // Litvinov V.P., Dotsenko V.V., Krivokolisko S.G. - M.: Science. - 2006. - 407 p. ISBN 5-02-033674-2] according to the scheme:

N-(3-aryl-4-phenyl-1,3-thiazol-2-ylidene)-2-chloroacetamide are new and undescribed compounds, they are obtained by acelation of the corresponding 3-aryl-4-phenyl-1,3-thiazole-2 -imines. Methods for the synthesis of starting 3-aryl-4-phenyl-1,3-thiazol-2-imines are well known and described in [Sondhi, S.M. Synthesis and anti-inflammatory activity evaluation of some sulfonamide and amidine derivatives of 4-aryl-3-(2 or 4-picolyl)-2-imino-4-thiazolines / S.M. Sondhi, A.D. Dwivedi, J. Singh, P.P. Gupta // Indian Journal of Chemistry Sect. B. - 2010. - No. 49. - P. 1076-1081]. Synthesis is carried out according to the scheme:

Thus, the use of known starting materials during their interaction made it possible for the first time to synthesize compounds 1-3 according to the claimed method and develop a method for their use to protect vegetative sunflower plants from the phytotoxic effect of 2,4-D.

Example 1 2-{[4-(4-chlorophenyl)-3-cyano-1,2,5,6,7,8-hexahydroquinolin-2-yl]thio}-N-[(2Z)-3-( 2-methylphenyl)-4-diphenyl-l,3-thiazol-2(3H)-ylidene]acetaamide (compound 1).

4-(4-chlorophenyl)-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile in an amount of 0.002 mol was dissolved by stirring in 5 ml of ethanol, and 1 ml of 10% potassium hydroxide was added (0.002 mol), as a result, the color of the solution changed from yellow to light orange due to the formation of potassium salts. To the resulting solution was added 0.0022 mol of N-(3-(2-methylphenyl)-4-phenyl-1,3-thiazol-2-ylidene)-2-chloroacetamide. Stirring was continued for 30 minutes at room temperature.

As a result of the reaction, precipitation of a light yellow precipitate, the product of direct S-alkylation, was observed. The purity of the product was checked by TLC: a 1:1 mixture of ethyl acetate and petroleum ether was used as the eluent. The yield of the obtained compound was 89%.

1H NMR spectrum (400 MHz, DMSO-d6), δ, ^ppm , 1.55-1.1.74 m (4H, CH ₂ ), 1.98 s (3H, CH ₃ ), 2.05-2.07 m (2H, CH ₂ ), 2.30-2.33 t (1H, CH ₂ ), 2.72-2.78 m (2H, CH ₂ ), 4.09 d (1H, C(O)-CH ₂ , ³ J 6 Hz), 4.19 d (1H, C (O)-CH ₂ , ³ J 6 Hz), 7.14-7.29 m (10H, H Ar), 7.37-7.41 m (2H, H Ar), 7.59-7.62 m (2H, H Ar).

Found, %: С 67.32; H 4.46; N 9.13. C ₃₄ H ₂₇ ClN ₄ OS ₂ .

Calculated, %: 67.26; H 4.48; N 9.23. M 607.19.

Example 2 2-{[3-cyano-4-(2-thienyl)-1,2,5,6,7,8-hexahydroquinolin-2-yl]thio}-N-[(2Z)-3-( 2-methylphenyl)-4-phenyl-l,3-thiazol-2(3H)-ylidene]acetaamide (compound 2)

4-(2-thienyl)-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile in an amount of 0.002 mol was dissolved by stirring in 5 ml of ethanol, and 1 ml of 10% potassium hydroxide was added (0.002 mol), as a result, the color of the solution changed from yellow to light orange due to the formation of potassium salts. To the resulting solution was added 0.0022 mol of N-(3-(2-methylphenyl)-4-phenyl-1,3-thiazol-2-ylidene)-2-chloroacetamide. Stirring was continued for 30 minutes at room temperature.

As a result of the reaction, precipitation of a light yellow precipitate, the product of direct S-alkylation, was observed. The purity of the product was checked by TLC: a 1:1 mixture of acetone and petroleum ether was used as the eluent. The yield of the obtained compound was 91%.

1H NMR spectrum (400 MHz, DMSO-d6), δ, ^ppm , 1.58–1.72 m (5H, CH ₂ ), 1.97 d (3H, CH ₃ , ² J 16), 2.25–2.28 m (1H , CH ₂ ), 2.73-2.79 m (2H, CH ₂ ), 4.10 d (1H, C(O)-CH ₂ , ² J 12 Hz), 4.20 d (1H, C(O)-CH ₂ , ² J 4 Hz), 7.15–7.30 m (13H, H Ar), 7.88 d (1H, H Ar, ^3J 5.6 Hz), 14.05 s (1H, NH).

Found, %: С 66.35; H 4.58; No. 9.67. C ₃₂ H ₂₆ N ₄ OS ₃ .

Calculated, %: 66.41; H 4.53; No. 9.68. M 578.13.

Example 3 N-[(2Z)-3-(4-chlorophenyl)-4-phenyl-l,3-thiazol-2(3H)-ylidene]-2-{[3-cyano-4-(2-thienyl )-5,6,7,8-tetrahydroquinolin-2-yl]thio}-acetamide (compound 3)

4-(2-thienyl)-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile in an amount of 0.002 mol was dissolved by stirring in 5 ml of ethanol and 1 ml of 10% potassium hydroxide was added ( 0.002 mol), as a result, the color of the solution changed from yellow to light orange due to the formation of potassium salts. To the resulting solution was added 0.0022 mol of N-(3-(4-chlorophenyl)-4-phenyl-1,3-thiazol-2-ylidene)-2-chloroacetamide. Stirring was continued for 30 minutes at room temperature.

As a result of the reaction, precipitation of a light yellow precipitate, the product of direct S-alkylation, was observed. The purity of the product was checked by TLC: a 1:1 mixture of acetone and petroleum ether was used as the eluent. The yield of the obtained compound was 77%.

1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm, 1.55-1.78 m (5H, CH ₂ ), 2.23-2.26 m (1H, CH ² ), _2.74-2.78 m (2H, CH ₂ ), 4.12 s (1H, CH ₂ -C(O)), 4.21 s (1H, CH ₂ -C(O)), 6.80 s (1H, Ar H ⁵ ), 7.15 d (2H, Ph H), 7.21-7.25 m (2H, Ph H), 7.27-7.31 m (4H, H Ph), 7.33-7.36 m (2H, H Ph), 7.39-7.47 m (3H, H Tp, H Ph), 7.65 d ( 1H, H Tp ³ J 7 Hz) (1H, NH), 7.86 d (1H, H Tp ³ J 5 Hz).

Found, %: С 62.16; H 3.84; No. 9.41. C ₃₁ H ₂₃ ClN ₄ OS ₃ .

Calculated, %: 62.14; H 3.87; N 9.35. M 599.18.

Example 4. Evaluation of the antidote activity of compounds 1-3 and their prototype on sunflower plants in a field experiment.

Evaluation of the antidote activity of the claimed compounds of formula 1-3, taken as a prototype compound of formula 4:

and sulfalene, taken as a reference, were carried out on the experimental field of the Federal Scientific Center for Biological Plant Protection. Sulfalen is a pharmaceutical antibacterial drug that exhibits antidote (with respect to 2,4-D) properties [RF patent No. 2043021, IPC A01N 25/32 (1995.01) / Antidote for hormonal herbicides 2,4-dichlorophenoxyacetic and 4-amino-3,5, 6-trichloropicolinic acids. - No. 5042089/04, Appl. May 14, 1992; publ. 09/10/1995].

The tests were carried out according to the following procedure.

Under field conditions, flagman sunflower plants in the phase of 10-16 leaves were treated with an aqueous solution of 2,4-dichlorophenoxyacetic acid at a dose of 18 g/ha, and after 3 days each of the plots was worked out with solutions of compounds of formula 1-3, a compound of formula 4 and a standard in water as antidotes, at a dose of 30 g/ha with a working fluid consumption rate of 300 l/ha using a knapsack sprayer. The flow rate of the working fluid of 300 l/ha is due to the passport data of the serial spraying equipment, which is currently used in the plant protection system.

Experience has the following options:

- control - untreated plants;

- "herbicide" - plants treated with a herbicide;

- 2,4-dichlorophenoxyacetic acid;

- "herbicide + antidote" - plants treated with a herbicide, and then with an antidote, which were used as the claimed compounds of general formula 1-3;

- standard - plants treated after the herbicide with sulfalene.

The experiments were carried out on plots with an area of 2.8 m ² , repeated five times. Sunflower harvesting was carried out at the time of full ripening of seeds.

The antidote effect was determined by the absolute value of the yield increase to the herbicidal variant and as a percentage according to the formula:

And _x - antidote effect,%;

A - crop in the variant herbicide + antidote;

E - crop in the herbicide version.

The obtained data were statistically processed using Student's t-test.

The test results are presented in the table.

As can be seen from the table, the use of the claimed 2-{[3-cyano-4-R-5,6,7,8-tetrahydroquinolin-2-yl]thio}-N[(2Z)-3-Ar-4-phenyl- 1,3-thiazol-2(3H)-ylidene]acetamides (compounds 1-3) as antidotes provides an antidote effect at the level of 50.4-70.9% versus 32.3% for the prototype and 29.9% for standard, which allows us to conclude that their use as antidotes is promising.

Claims (8)

1. 2-{[3-cyano-4-R-5,6,7,8-tetrahydroquinolin-2-yl]thio}-N[(2Z)-3-Ar-4-phenyl-1,3-thiazole -2(3H)-ylidene]acetamides

where 1) Ar=PhMe, R=4-Cl-Ph, 2) Ar=PhMe, R=Tp, 3) Ar=4-Cl-Ph, R=Tp, showing antidote activity. 2. A method for preparing compounds according to claim 1, characterized in that N-(3-(aryl)-4-phenyl-1,3-thiazol-2-ylidene)-2-chloroacetamides are reacted with 4-(aryl)- 2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles in the presence of an equivalent of KOH in ethanol solution. 3. The use of the compounds according to claim 1 as an antidote 3 days after sunflower treatment with a herbicide at a consumption rate of 30 g/ha and a working fluid consumption of 300 l/ha.