RU2300527C1 - Method for preparing n-substituted derivatives of 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of N-substituted derivatives of 4,5-dimethyl-3-cyanopyridyl-2-sulfonylamides that can be used as biologically active substances. Method involves preliminary synthesis of 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride by oxidative chlorination of 4,6-dimethyl-3-cyano-(1H)-pyridyl-2-thione without drying step that is subjected for interaction with amine. Interaction with amines is carried out by addition of amine solution in acetone to aqueous suspension of 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride at temperature 8-10°C. Invention provides synthesis of end substances with high yields - 69-74%. N-substituted derivatives of 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide show antidote activity with respect to herbicide 2,4-D in sunflower seedlings.

EFFECT: improved method of synthesis.

3 cl, 8 ex

Description

The invention relates to organic chemistry, specifically to a method for producing new chemical compounds of the pyridine series of the general formula:

IR ¹ = allyl; R ² = allyl; II R ¹ = H, R ² = cyclohexyl;

III R ¹ = H, R ² = 2-ethylphenyl; IV R ¹ = H, R ² = isopropyl;

which can find application in agriculture as biologically active substances.

A known method of producing aromatic and heterocyclic N-substituted sulfonylamides by reacting the corresponding sulfonyl chlorides with primary and secondary amines [1. Weigand Hilgetag. Experimental methods in organic chemistry. - M .: Chemistry. 1969. S.621-622].

In turn, aromatic and heterocyclic sulfonyl chlorides are conveniently obtained by oxidative chlorination of the corresponding mercapto derivatives [ibid., P.613].

For the synthesis of sulfonylamides, dried and purified sulfonyl chloride are introduced into the reaction with amines; the reaction is carried out in an anhydrous solvent, since sulfonyl chlorides are readily hydrolyzable substances. However, this method does not allow to obtain N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides.

Closest to the proposed method by technical essence is a method for producing N-substituted 1,2,4-triazolyl-3-sulfonylamides, which is selected as a prototype, which consists in the fact that obtained by oxidative chlorination and dried 1,2,4-triazolyl- 3-sulfonyl chloride is added to an aqueous solution of amines at 20 ° C and, after stirring at the same temperature, the desired products are isolated [2. Czechoslovak Patent No. 1789897 dated 03.15.79 “Herbicide - a means and method of obtaining the main component”]. The disadvantage of this method is that it also does not allow to obtain N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides.

The objective of the present invention is to develop a convenient and reliable method for producing N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides I-IV, which can be used in agriculture as biologically active substances.

The task is achieved by two-stage synthesis: the first stage is the synthesis of 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V, the second stage is the interaction of the latter with amines according to the scheme:

The synthesis of 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V was carried out by oxidative chlorination of 4,6-dimethyl-3-cyano (1H) pyridyl-2-thione VI in 2N HCl at a temperature of -2-0 ° С, similarly described in analogues [1, 2].

A feature of the sulfonyl chloride V obtained is that when it is dried under different conditions (room temperature, atmospheric pressure or 5-10 mm Hg, or drying of the extract followed by distillation of the solvent) in all cases, the SO ₂ group is eliminated from the molecule of the latter, and instead of the desired 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V, undesired 4,6-dimethyl-2-chloro nicotinonitrile is isolated. To avoid decomposition of 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride, crude product V, bypassing the drying step, was immediately used in reactions with amines. To this end, a solution of the corresponding amine in acetone was added dropwise to an aqueous suspension of V at a temperature of 8–10 ° C, and after 3-4 h of stirring, sulfonylamides I – IV were isolated in rather high yields of 69–74%.

In the case when sulfochloride V was added to a solution of amines in water at 20 ° С, as described in [2], the reaction mass was heated to 35–40 ° С and the yield of sulfonylamides I – IV sharply decreased to 42–46%, probably decomposition of sulfonyl chloride V.

Thus, the proposed method allows to obtain in high yields the desired N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides I-IV.

This result is achieved in that 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V, excluding the drying step, is reacted with amines, and an amine solution (and not vice versa) is added to the aqueous suspension of sulfonyl chloride V at a temperature of 8-10 ° C.

The initial 4,6-dimethyl-3-cyano- (1H) pyridin-2-thion was obtained in a known manner [3. E.A. Kaygorodova, L.D. Konyushkin and others // Izv. Academy of Sciences. Ser. chemical - 1994. - No. 12. - S.2215-2219.].

The synthesized N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides I-IV were tested for antidote activity on sunflower seedlings with respect to the herbicide 2,4-dichlorophenoxyacetic acid under laboratory conditions. Compounds I-IV reduced the negative effect of 2,4-D on the hypocotyl of sunflower seedlings by 20-31%, on the roots by 25-33%.

Obviously, a number of N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides I-IV are promising in terms of searching for new plant protection products from the undesirable effect of herbicides and, if this series of compounds is expanded, more effective ones can be found antidotes. The invention is illustrated by the following examples:

Example 1. N, N-diallyl-4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide (compound I).

Stage 1. In a suspension of 2.0 g (10 mmol) of 4,6-dimethyl-3-cyano (1H) pyridyl-2-thione in 20 ml of 2 N HCl with stirring for 1 h, they bubbler Cl ₂ , maintaining the temperature of the reaction mixture in the range 0 ...- 2 ° C. After turning off the chlorine current, stirring is continued at the same temperature for another 20 minutes. The precipitate of the resulting 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V is filtered off, washed on the filter with ice water and immediately used in stage 2.

Stage 2. A portion of 1.5 g (6.5 mmol) of wet 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V is suspended in 6 ml of water at a temperature of 8-10 ° C, and solution 1 is added dropwise with stirring. 26 g (13 mmol) of diallylamine in 2 ml of acetone, keeping the temperature of the reaction mixture constant. After the addition is complete, stirring is continued at the same temperature for 1.5-2 hours, then the temperature is gradually raised to room temperature and stirred for another 1.5-2 hours. The reaction mixture is acidified with conc. HCl to pH = 3-4, the precipitate is filtered off, washed with water, dried. After recrystallization from hexane, 1.33 g (70%) of the desired product I are obtained, mp = 52-53 ° C.

Found,%: C = 57.58; H = 5.69; N = 14.57; S = 11.11; C ₁₄ H ₁₇ N ₃ O ₂ S;

Calculated,%: C = 57.71; H = 5.88; N = 14.42, S = 11.00.

¹ H NMR Spectrum (DMSO-D ₆ ): 7.69 (1H, s, H-5), 5.77 (2H, m, CH ₂ CH = CH ₂ ), 5.20 (4H, m, CH ₂ CH = CH ₂ ), 3.93 (4H, d, CH ₂ CH = CH ₂ ), 2.62 (3H, s, 6-CH ₃ Ru), 2.57 (3H, s, 4-CH ₃ Ru )

Mass spectrum (m / z, relative intensity,%): 186 [M-SO ₂ , - CH ₂ CH = CH ₂ ] ⁺ (8), 171 [186-CH ₃ ] ⁺ (5), 131 [M- SO ₂ N (CH ₂ CH = CH ₂ ) ₂ ] ⁺ (23), 96 [N (CH ₂ CH = CH ₂ ) ₂ ] ⁺ (100).

Example 2. N-cyclohexyl-4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide (compound II).

Stage 1. The same as in example 1.

Stage 2. 1.5 g (6.5 mmol) of wet 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V is suspended in 6 ml of water at a temperature of 8-10 ° C, and a solution of 1.29 is added dropwise with stirring g (13 mmol) of cyclohexylamine in 2 ml of acetone. After the addition is complete, stirring is continued at the same temperature for 1.5-2 hours, then the temperature is gradually raised to room temperature and stirred for another 1.5-2 hours. The reaction mixture is acidified with conc. HCl to pH = 3-4, the precipitate is filtered off, washed with water, dried. After recrystallization from hexane: ethyl acetate = 1: 3, 1.41 g (74%) of the desired product II are obtained, mp = 151-152 ° C.

Found,%: C = 57.12; H = 6.41; N = 14.17; S = 11.08; C ₁₄ H ₁₉ N ₃ O ₂ S;

Calculated,%: C = 57.31; H = 6.53; N = 14.32, S = 10.93.

¹ H NMR spectrum (DMSO-D ₆ ): 8.30 (1H, br.s. NH), 7.65 (1H, s, H-5), cyclohexane ring: 3.18 (m), 1.81 (m), 1.75 (m), 1.48 (m), 1.21 (m), 1.10 (m), 2.62 (3H, s, 6-CH ₃ Ru), 2.55 (3H, s, 4-CH ₃ Ru).

Mass spectrum (m / z, relative intensity,%): 293 [M] ⁺ (2), 250 [M-C ₃ H ₇ ] ⁺ (57), 186 [250-SO ₂ ] ⁺ (28), 159 [186-HCN] ⁺ (38), 131 [M-SO ₂ NHC ₆ H ₁₁ ] ⁺ (49), 98 [NH C ₆ H ₁₁ ] ⁺ (100).

Example 3. N-ethylphenyl-4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide (compound III).

Stage 1. The same as in example 1.

Stage 2. 1.1 g (4.8 mmol) of wet 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V is suspended in 5 ml of water at a temperature of 8-10 ° C, and a solution of 0.58 is added dropwise with stirring g (4.8 mmol) of 2-ethylaniline and 1.48 g of triethylamine (4.8 mmol) in 2 ml of acetone. After the addition is complete, stirring is continued at the same temperature for 1.5-2 hours, then the temperature is gradually raised to room temperature and stirred for another 3.5-4 hours. The reaction mixture is acidified with conc. HCl to pH = 3-4, the precipitate is filtered off, washed with water, dried. After recrystallization from a mixture of hexane: ethyl acetate = 1: 1, 1.04 g (69%) of the target product of III t.pl. = 147-148 ° C.

Found,%: C = 61.17; H = 5.62; N = 13.18; S = 10.34; C ₁₆ H ₁₇ N ₃ O ₂ S;

Calculated,%: C = 60.93; H = 5.43; N = 13.32, S = 10.17.

¹ H NMR spectrum (DMSO-D ₆ ): 10.24 (1H, br s, NH), 7.70 (1H, s, H-5), 7.24 ... 7.05 (4H, m , Ar), 2.66 (2H, q, J = 5, CH ₂ CH ₃ ), 2.60 (3H, s, 6-CH ₃ Ru), 2.55 (3H, s, 4-CH ₃ Ru ), 1.08 (3H, t, J = 5, CH ₂ CH ₃ ).

Mass spectrum (m / z, relative intensity,%): 314 [M] ⁺ (23), 251 [M-SO ₂ ] ⁺ (16), 236 [251-CH ₃ ] ⁺ (23), 222 [251 -C ₂ H ₅ ] ⁺ (27), 131 [M-SO ₂ NH C ₆ H ₄ C ₂ H ₅ -2] ⁺ (11), 120 [NH C ₆ H ₄ C ₂ H ₅ -2] ⁺ ( one hundred).

Example 4. N-isopropyl-4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide (compound IV).

Stage 1. The same as in example 1.

Stage 2. 1.1 g (4.8 mmol) of wet 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V is suspended in 5 ml of water at a temperature of 8-10 ° C, and a solution of 0.57 is added dropwise with stirring g (9.6 mmol) of isopropylamine in 2 ml of acetone. After the addition is complete, stirring is continued at the same temperature for 1.5-2 hours, then the temperature is gradually raised to room temperature and stirred for another 1.5-2 hours. The reaction mixture is acidified with conc. HCl to pH = 3-4, the precipitate is filtered off, washed with water, dried. After recrystallization from hexane, 0.87 g (72%) of the expected product IV are obtained with mp = 98-99 ° C.

Found,%: C = 51.17; H = 5.64; N = 16.72; S = 12.43; C ₁₁ H ₁₅ N ₃ O ₂ S;

Calculated,%: C = 52.16; H = 5.97; N = 16.59, S = 12.66.

¹ H NMR Spectrum (DMSO-D ₆ ): 8.18 (1H, d, J =, NH), 7.66 (1H, s, H-5), 3.52 [1H, m, J =, CH (CH ₃ ) ₂ ], 2.60 (3H, s, 6-CH ₃ Ru), 2.55 (3H, s, 4-CH ₃ Ru), 1.12 [6H, d, J =, CH ( CH ₃ ) ₂ ] .

Mass spectrum (m / z, relative intensity,%): 238 [M-CH ₃ ] ⁺ (61), 174 [238-SO ₂ ] ⁺ (42), 131 [M-SO ₂ NHC ₃ H ₇ -i ] ⁺ (84), 104 [131-HCN] ⁺ (37), 58 [NHC ₃ H ₇ -i] ⁺ (100).

Example 5. N-cyclohexyl-4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide (compound II).

Stage 1. The same as in example 1.

Stage 2. To a solution of 1.29 g (13 mmol) of cyclohexylamine in 5 ml of water at a temperature of 8-10 ° C, 1.5 g (6.6 mmol) of wet 4,6-dimethyl-3-cyanopyridyl-2- are added sulfonyl chloride (the temperature of the reaction mixture rises to 38 ° C), stirred for 30-40 minutes, acidified with conc. HCl to pH = 3-4, the precipitate is filtered off, dried. After reprecipitation from a 5% KOH solution, 0.79 g (42%) of the desired product II is obtained with mp = 151-152 ° C.

Elemental analysis and spectral characteristics are identical to those in example 2.

Example 6. N-cyclohexyl-4,6-dimethyl-3-cyanopyridyl-2-sulfonylamide (compound II).

Stage 1. The same as in example 1.

Stage 2. 1.5 g (6.5 mmol) of wet 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride V is suspended in 6 ml of water at room temperature, and a solution of 1.29 g (13 mmol) is added dropwise with stirring. ) cyclohexylamine in 2 ml of acetone. After the addition is complete, stirring is continued at the same temperature for 1.5-2 hours, then the temperature is gradually raised to room temperature and stirred for another 1.5-2 hours. The reaction mixture is acidified with conc. HCl to pH = 3-4, the precipitate is filtered off, washed with water, dried. After recrystallization from a mixture of hexane: ethyl acetate = 1: 3, 0.9 g (47%) of the desired product II are obtained, mp = 151-152 ° C.

Elemental analysis and spectral characteristics are identical to those in example 2.

Example 7. 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride (compound V).

In a suspension of 2.0 g (10 mmol) of 4,6-dimethyl-3-cyano (H) pyridyl-2-thione in 20 ml of 2N HCl, Cl _{2 was} bubbled under stirring for 1 h, keeping the temperature of the reaction mixture at 0. ..- 2 ° C. After switching off the chlorine current, stirring is continued at the same temperature for another 20 minutes. The precipitate is filtered off, washed on the filter with ice water and immediately reacted with an amine.

The structure of product V is indirectly confirmed by compounds I-IV synthesized on its basis.

Example 6. 4,6-dimethyl-2-chloronicotinonitrile

Method A. Product V (Example 5), after washing with ice-cold water, is dried in a vacuum desiccator at 5-10 mmHg, and 2-chloronicotinonitrile by-product is obtained in 81% yield.

Method B. Product V (Example 5), after washing with ice-cold water, was extracted with benzene, the extract was dried with anhydrous Na ₂ SO ₄ , the solvent was distilled off using a rotary evaporator, and 2-chloronicotinonitrile by-product was obtained in 73% yield.

Found,%: C = 57.82; H = 4.38; N = 17.02; C ₈ H ₇ ClN ₂ ;

Calculated,%: C = 57.67; H = 4.23; N = 16.81.

¹ H NMR Spectrum (DMSO-D ₆ ): 7.45 (1H, s, 5H), 2.62 (3H, s, CH ₃ -6), 2.55 (3H, s, CH ₃ -4).

Mass spectrum (m / z, relative intensity,%): 166 [M] ⁺ (100), 130 [M-CN] ⁺ (30), 104 [130-CN] ⁺ (24), 103 [130-HCN ] ⁺ (26).

Claims (3)

1. The method of obtaining N-substituted 4,6-dimethyl-3-cyanopyridyl-2-sulfonylamides of the formula

IR ¹ = allyl; R ² = allyl; II R ¹ = H, R ² = cyclohexyl; III R ¹ = H, R ² = 2-ethylphenyl; IV R ¹ = H, R ² = isopropyl, characterized in that 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride formed by the oxidative chlorination of 4,6-dimethyl-3-cyano (1H) pyridyl-2-thione bypassing the drying stage, is subjected to interaction with an amine. 2. The method according to claim 1, characterized in that the interaction with amines is carried out by adding to the aqueous suspension of 4,6-dimethyl-3-cyanopyridyl-2-sulfonyl chloride a solution of the amine in acetone. 3. The method according to claim 1, characterized in that the interaction with amines is carried out at a temperature of 8-10 ° C.