RU2287275C1 - USING 3-[(SUBSTITUTED PHENYL)CARBOXAMIDO]-1,4,6-TRIMETHYL-5-R-PYRAZOLO[4,5-b]PYRIDINES AS ANTIDOTE OF 2,4-D - Google Patents

Abstract

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention describes using 3-[(substituted phenyl)carboxamido]-1,4,6-trimethyl-5-R-pyrazolo[4,5-b]pyridines of the formula (1-4):

wherein in (1) R means hydrogen atom (H); in (2) R means H; X means 2-methoxyphenyl; in (3) R means chlorine atom (Cl); X means 2-methoxyphenyl; in (4) R means Cl; X means ethyl as an antidote against 2,4-dichlorophenoxyacetic acid (2,4-D) in sunflower. Invention provides expanding assortment of biologically active substances prepared by synthetic method for their using in agriculture as an antidote of herbicide 2,4-D. Method involves treatment of sunflower seedlings damaged with herbicide by proposed 3-[(substituted phenyl)carboxamido]-1,4,6-trimethyl-5-R-pyrazolo[4,5-b]pyridines.

EFFECT: valuable biological properties of antidotes.

1 tbl, 6 ex

Description

The invention relates to synthetic, chemical biologically active substances from a number of heterocyclic compounds of the formula 1-4:

1 - R = H, X = 4-methylphenyl;

2 - R = H, X = 2-methoxyphenyl;

3 - R = Cl, X = 2-methoxyphenyl;

4 - R = Cl, X = ethyl,

as a means of protecting plants from the phytotoxic effect of the herbicide 2,4-dichloro-phenoxyacetic acid (antidotes). The claimed compounds are previously known (Chemical Blok Stok Library Catalog, Cas Registry No. 728887-44-3, 08/10/2004; No. 728888-08-2, 08/10/2004; No. 727667-16-5, 08/10/2004 and No. 728887-48 -7, 08/10/2004 compounds 1-4, respectively), however, their antidote properties were detected for the first time.

As you know, sunflower is an extremely sensitive crop to 2,4-D group herbicides, and in case of unintentional exposure of the herbicide to its crops, losses can be up to 100% depending on the dose [D.I. Chkanikov, M.S. Sokolov. The herbicidal effect of 2,4-D and other halo phenoxy acids. M .: Nauka, 1973].

Until now, the protection of vegetative sunflower plants from the damaging effects of 2,4-D remains relevant and unresolved.

The closest analogs in terms of the structure of the claimed compounds include 3-amino-4,6-dimethyl-1H-pyrazolo [4,5-b] pyridine 5 [Lacan M., Tabakovic K. Synthesis of pirazolo-, and tetrazolopyridines. / Croat. cem. Acta / 1975, 47, No. 2, s.127-133].

As an analogue in properties, Sulfalen is known ["Antidote of the hormonal action herbicides of 2,4-dichlorophenoxyacetic acid and 4-amino-3,5,6-trichlorpi-colinic acid" US Pat. RF №2043021 from 09/10/95, application No. 5042089 from 05/14/92] 6

Sulfalen of formula 6 is used as a means of reducing the negative effect of the 2,4-D herbicide; it is used at a dose of 200 g / ha for damaged vegetative plants. At the same time, Sulfalen is widely used as an antibacterial agent in medical practice, its synthesis is described in the literature [V. G. Belikov. Pharmaceutical Chemistry. - M .: Higher school. 1985. S. 383, 768.] However, the antidote activity of Sulfalene is not high enough.

The objective of the present invention is to expand the arsenal of biologically active substances obtained synthetically for use in agriculture as antidotes.

This is achieved by using 3 - [(substituted phenyl) carboxamido] -1,4,6-trimethyl-5-R-pyrazolo [4,5-b] pyridines 1-4 on sunflower seedlings.

Moreover, the claimed compounds are obtained by a known method - acylation of 3-amino-1,4,6-trimethyl-5-R-pyrazolo [4,5-b] pyridines with chlorides of aromatic and aliphatic carboxylic acids at a temperature of 10-12 ° C in anhydrous medium benzene in the presence of triethylamine as an acceptor of hydrogen chloride [see Weigand Hilgetag. Methods of experiment in organic chemistry. - M .: Chemistry. 1969. p. 431].

The starting 3-amino-1,4,6-trimethyl-5R-pyrazolo [4,5-b] pyridines are also prepared by a known method [see Z.A. Bomika, M.B. Andaburskaya, Yu.E. Pelcher, G.Ya.Dubur. Some nucleophilic substitution reactions in the series of 2-chloro-3-cyanopyridines. - HGS, 1976, No. 8, s. 1085-1088].

Used benzene and acetone are absolute in a known manner [see A. Weissberger, E. Proskauer, J. Riddick, E. Tups. Organic solvents. M .: Foreign literature, 1958, p. 518].

The invention is illustrated by the following examples:

Example 1. 3 [- (4-methylphenyl) -carboxamido] -1,4,6-trimethyl-pyrazolo [4,5-b] pyridine (compound 1)

To a suspension of 0.7 g (0.00370 mol) of 3-amino-1,4,6-trimethylpyrazolo [4,5-b] pyridine and 0.38 (0.00370 mol) of triethylamine in 20 ml of absolute benzene is added dropwise within 40-50 minutes, a solution of 0.69 g (0.00440 mol) of 4-methylbenzoyl chloride in 10 ml of absolute benzene, maintaining the temperature of the reaction mixture in the range of 10-12 ° C. Upon completion of the addition, they are stirred at the same temperature for another 10-20 minutes, then at room temperature for 3 hours. From the reaction mass, the precipitate was separated by filtration, washed with warm water (3 × 20 ml), and dried. The mother liquor is evaporated to dryness, the residue is taken up in 15 ml of sulfuric ether and dried. Both precipitates are combined, recrystallized from ethanol, to obtain 1.1 g (72%) of the desired product 1 in the form of white crystals with so pl. 236-237 ° C.

Found,%: C 69.61; H, 6.27; N, 18.54. C ₁₇ H ₁₈ N ₄ O

Calculated,%: C 69.35; H, 6.18; N18.36.

1 H NMR, δ, ppm (group): 2.35 (3H, s, CH ₃ Ph); 2.55 (3H, s, 4-CH ₃ Ru); 2.65 (3H, s, 6-CH ₃ Ru); 3.98 (3H, s, N-CH ₃ ); 6.88 (1H, s, 5-N Ru); 7.35 ... 7.93 (4H, m, CH-Ph); 10.45 (1H, s, NH).

Mass spectrum; m / z (relative intensity): 294 M ⁺ (28); 134 (3); 119 (100); 104 (5); 91 (30); 65 (12).

Example 2. 3 - [(2-Methoxyphenyl) -carboxamido] -1,4,6-trimethyl-pyrazolo [4,5-b] pyridine (compound 2)

To a suspension of 0.6 g (0.00320 mol) of 3-amino-1,4,6-trimethylpyrazolo [4,5-b] pyridine and 0.32 (0.00320 mol) of triethylamine in 18 ml of absolute benzene are added dropwise within 40 minutes, a solution of 0.52 g (0.00380 mol) of 2-methoxybenzoyl chloride in 10 ml of absolute benzene, maintaining the temperature of the reaction mixture in the range of 10-12 ° C. Upon completion of the addition, the mixture is stirred at the same temperature for another 10-20 minutes, then at room temperature for 2 hours.

The reaction mixture is separated from the precipitate (triethylamine hydrochloride), evaporated to dryness, the residue is taken up in 10 ml of Et ₂ O. After recrystallization from ethyl acetate, 0.66 g (68%) of target compound 2 are obtained in the form of white crystals with mp 158-159 ° C.

Found%: C 65.51; H 5.72; N, 18.28; C ₁₇ H ₁₈ N ₄ O;

Calculated,%: C 65.78; H 5.86; N, 18.05.

1 H NMR, δ, ppm (group): 2.58 (3H, s, 4-CH ₃ Ru); 2.68 (3H, s, 6-CH ₃ Ru); 3.90 (3H, s, N-CH ₃ ); 4.05 (3H, s, OCH ₃ ); 6.90 (1H, s, 5H Py); 7.09 ... 7.85 (4H, m, CH Ph); 10.12 (1H, s. NH).

Mass spectrum, m / z (relative intensity): 310 M ⁺ (16); 135 (100); 104 (4); 92 (12); 77 (22)

Example 3. 3 - [(2-methoxyphenyl) -carboxamido] -1,4,6-trimethyl-5-chloropyrazolo [4,5-b] pyridine (compound 3).

To a suspension of 0.8 g (0.00380 mol) of 3-amino-1,4,6-trimethyl-5-chloropyrazolo [4,5-b] pyridine and 0.38 (0.00380 mol) of triethylamine in 25 over a period of 40-50 minutes, a solution of 0.78 g (0.00456 mol) of 2-methoxybenzoyl chloride in 10 ml of absolute benzene is added dropwise in absolute benzene, maintaining the temperature of the reaction mixture in the range of 10-12 ° C. Upon completion of the addition, they are stirred at the same temperature for another 10-20 minutes, then at room temperature for 3 hours.

The reaction mixture is separated from the precipitate (triethylamine hydrochloride), evaporated to dryness, the residue is taken up with 10 ml Et ₂ O. After recrystallization from ethyl acetate, 0.84 g (64%) of target compound 3 are obtained in the form of white crystals with mp 173-174 ° C.

Found,%: C 59.44; H 4.79; N, 16.41; C ₁₇ H ₁₇ ClN ₄ O

Calculated,%: C 59.20; H 4.98; N, 16.25.

PMR, δ, ppm (group): 2.58 (3H, s, 4-CH ₃ Ru); 2.68 (3H, s, 6-CH ₃ Ru); 3.90 (3H, s, N-CH ₃ ); 4.00 (3H, s, OCH ₃ ); 7.09 ... 7.35 (4H, m, CH Ph); 10.15 (1H, cN-H).

Mass spectrum, m / z (relative intensity): 344 M ⁺ (7); 135 (100); 92 (11); 77 (24).

Example 4. 3- (ethylcarboxamido) -1,4,6-trimethyl-5-chloropyrazolo [4,5-b] pyridine (compound 4)

To a suspension of 0.8 g (0.00380 mol) of 3-amino-1,4,6-trimethyl-5-chloropyrazolo [4,5-b] pyridine and 0.38 (0.00380 mol) of triethylamine in 25 over a period of 40-50 minutes, a solution of 0.33 g (0.0043 mol) of propionyl chloride in 10 ml of absolute benzene is added dropwise in absolute benzene, maintaining the temperature of the reaction mixture in the range of 10-12 ° C. Upon completion of the addition, they are stirred at the same temperature for another 10-20 minutes, then at room temperature for 3 hours.

The reaction mixture is separated from the precipitate (triethylamine hydrochloride), evaporated to dryness, the residue is taken up in 10 ml of Et ₂ O. After recrystallization from ethanol, 0.67 g (71%) of target compound 4 are obtained in the form of white crystals with mp 194-195 ° C.

Found,%: C 54.30; H 5.52; N, 21.18; C ₁₂ H ₁₅ ClN ₄ O

Calculated,%: C 54.03; H 5.68; N, 21.01.

PMR, δ, ppm (group): 1.12 (3H, t, CH ₂ CH ₃ ); 2.35 (2H, q, CH ₂ CH ₃ ); 2.55 (3H, s, 4-CH ₃ Ru); 2.65 (3H, s, 6-CH ₃ Ru); 3.91 (3H, s, N-CH ₃ ); 10.08 (1H, s, N-n).

Mass spectrum, m / z (relative intensity): 266 M ⁺ (5); 210 (35); 77 (6); 44 (100).

Example 5. 3-amino-1,4,6-trimethylpyrazolo [4,5-b] pyridine (compound 5)

A mixture of 1.0 g (0.0061 mol) of 2-chloro-3-cyano 4,6-dimethylpyridine, 1.22 g (0.0244 mol) of hydrazine hydrate and 25 ml of anhydrous ethanol is boiled for 9 hours. After cooling the reaction mass, the precipitate was filtered off, washed on the filter with alcohol, recrystallized from methanol, and 0.72 g (73%) of target compound 5 were obtained in the form of light yellow crystals with mp. 239-240 ° C

Found%: C 59.39; H, 6.12; N, 34.40; C ₈ H ₁₀ N ₄

Calculated,%: C 59.22; H, 6.23; N, 34.55.

PMR, δ, ppm (group): 2.40 (3H, s, 4-CH ₃ Ru); 2.55 (3H, s, 6-CH ₃ Ru); 5.08 (2H s, NH ₂ ); 6.58 (1H, s, 5HPu); 11.71 (1H, s, NH).

Mass spectrum, m / z (relative intensity): 162 M ⁺ (100); 133 (24); 107 (40); 105 (32); 92 (5); 84 (12).

Example 6. Evaluation of compounds 1-6 for antidote activity on sunflower seedlings

Sprouted sunflower seeds with a germinal root length of 2-4 mm were placed for 1 h 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 herbicidal action, the seedlings were washed with water and placed in solutions of substances tested for antidote activity at concentrations of 10 ^-2 , 10 ^-3 , 10 ^-4 , 10 ^-5 (variant herbicide + antidote). After 1 h, the seeds were washed with water and laid out on strips of filter paper (size 10 × 75 cm) of 20 pieces, which were rolled up and placed in glasses with 50 ml of water. Further seed germination was carried out in a thermostat for 3 days at a temperature of 28 ° C. The temperature of solutions and wash water is 28 ° C.

The seeds of the herbicide variant (reference standard) were kept for 1 h in a 2,4-D solution at a concentration of 10 ^-3 and 1 h in water.

The seeds of the control variant were kept in water for 2 hours.

The experiment was repeated three times. In each repetition, 20 seeds were used.

The protective (antidote) effect was determined by increasing the length of the hypocotyl and root in the herbicide + antidote variant relative to the named values in the “herbicide” variant (standard).

Statistical processing of experimental data was carried out using Student's t-test at P = 0.95.

The research results are shown in the table.

As can be seen from the table, the use of 3- (substituted phenylcarboxamido) -1,4,6-trimethyl-1-R-pyrazolo [4,5-b] pyridines 1-4 sharply reduces the toxic effect against the background of the action of the herbicide herbicide.

Compounds 1-4 reduced the negative effect of 2,4-D on the hypocotyl of sunflower seedlings by 28-41% when used mainly in three or more concentrations, while compound 5 (structurally analogous) did not show a protective effect, and the antidote value the effect of Sulfalen (prototype) was 12-20%.

Compounds 1-4 reduced the inhibitory effect of 2,4-D on the roots of seedlings by 29-55% also when used in three or more concentrations, compound 5 did not increase the length of the root of the seedlings, and Sulfalen (prototype) showed an antidote effect at the level of 18-28 %

Thus, the use of the claimed 3- (substituted phenylcarboxamido) -1,4,6-trimethyl-1-R-pyrazolo [4,5-b] pyridines as antidotes can effectively protect sunflower from the negative effects of 2,4-D, and also expand the range of well-known antidotes.

Table.
Antidote activity of compounds 1-6 to 2,4-D on seedlings of sunflower cultivar VNIIMK-8883. A drug Concentration,% Hypocotyl Length Root length mm K 2,4-D,% mm K 2,4-D,% The control 0 68 119 2,4-D 10 ^-3 36 35 2,4-D + compound 1 10 ^-2 51 141 * 54 153 * 10 ^-3 43 120 48 138 * 10 ^-4 48 134 * 49 140 * 10 ^-5 48 134 * 53 151 * 2,4-D + compound 2 10 ^-2 44 122 46 131 * 10 ^-3 49 136 * 48 136 * 10 ^-4 46 128 * 41 116 10 ^-5 45 124 * 45 129 * 2,4-D + compound 3 10 ^-2 48 133 * fifty 142 * 10 ^-3 49 136 * fifty 142 * 10 ^-4 45 124 45 129 10 ^-5 46 128 * 52 148 * 2.4-D + compound 4 10 ^-2 49 236 * 55 155 * 10 ^-3 47 132 * 49 140 * 10 ^-4 46 128 * 49 140 * 10 ^-5 46 128 * 53 151 * 2,4-D + compound 5 10 ^-2 32 89 39 111 * 10 ^-3 38 106 * 33 93 10 ^-4 37 103 35 one hundred 10 ^-5 38 106 * thirty 86 2,4-D + Sulfalen (6) (prototype) 10 ^-2 40 112 45 128 * 10 ^-3 42 118 * 45 128 * 10 ^-4 45 124 * 40 114 10 ^-5 43 120 * 41 118 * * The differences between the options are significant at P = 0.95.

Claims (4)

The use of 3 - [(substituted phenyl) carboxamido] -1,4,6-trimethyl-5-R-pyrazolo [4,5-b] pyridines of the formula 1-4

where 1. R = H, X = 4-methylphenyl; 2. R = H, X = 2-methoxyphenyl; 3. R = Cl, X = 2-methoxyphenyl; 4. R = Cl, X-ethyl, as an antidote to 2,4-dichlorophenoxyacetic acid in sunflower.