RU2341525C1 - Substituted anilides of nicotinic acid with fungicidal activity - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: presented are anilides of nicotinic acid of general formula I

, where R means atom of hydrogen, halogen or benzyloxy-group, R' means atom of hydrogen or halogen, X means 2-furyl, 2-pyridyl, 3-pyridyl unsubstituted or substituted with phenyl halogen atom with fungicidal activity.

EFFECT: new compound are effective for hazardous fungi.

3 tbl, 6 ex

Description

The invention relates to the chemistry of heterocyclic compounds, namely to substituted nicotinic acid anilides of the general formula I, where R is a hydrogen, halogen or benzyloxy atom, R 'is a hydrogen or halogen atom, X is 2-furyl, 2-pyridyl, 3-pyridyl, phenyl unsubstituted or substituted by a halogen atom having fungicidal activity.

Substituted nicotinic acid anilides of the general formula I can be used to control harmful fungi in medicine, veterinary medicine, agriculture, and construction.

Nicotinamides of the general formula II are known, where R is alkyl, alkenyl, alkoxy, R 'is aryl, which are effective against powdery mildew of legumes [US Pat. US 4504484, 1982].

The closest to the structure of the compounds of formula I are anilides of the general formula III, where R is alkyl or cycloalkyl, R 'is a cyano, nitro or methoxycarbonyl group having fungicidal activity [US Pat. WO 95/25723, 1994].

However, compounds of structures II and III have a narrow spectrum of action and show fungicidal activity only against certain types of fungi. In addition, fungi often develop resistance to fungicides.

The technical problem solved by the present invention is to expand the range of fungicides for a more effective fight against harmful fungi.

The problem is solved by obtaining substituted nicotinic acid anilides of the general formula I having fungicidal activity.

Substituted nicotinic acid anilides of general formula I can be prepared by reacting substituted anilines of general formula IV, where R, R 'and X have the same meanings as in formula I, with nicotinic acid chloride:

Similar reactions are described in the literature [Weigand-Hilgetag. Experimental methods in organic chemistry. - M.: Chemistry, 1968 - 944 p.].

Compounds of general formula IV can be prepared by known methods from anilines of general formula V, where R and R 'have the same meanings as in formula I, by reductive condensation with aldehydes of general formula VI, where X has the same meanings as in the formula I, in the presence of sodium borohydride or formic acid, followed by hydrolysis of the obtained formamide, or the reduction of Schiff bases with sodium borohydride, lithium aluminum hydride or hydrogen using catalysts:

Similar reactions are described in the literature [Organikum: in 2 volumes, trans. with him. - M.: Mir, 1979].

The invention can be illustrated by the following examples.

Example 1. A solution of 4.28 g (0.04 mol) of 2-pyridinecarbaldehyde, 3.72 g (0.04 mol) of freshly distilled aniline and a catalytic amount of n-toluenesulfonic acid in 36 ml of toluene was boiled for 6 hours with a Dean-Stark nozzle, after wherein the solvent was distilled off in vacuo. 5.25 ml (0.13 mol) of 93% formic acid was added to the residue and refluxed for 15 hours, then 50 ml of 6N hydrochloric acid was added, boiling was continued for 1.5 hours. The reaction mixture was cooled, 50 was added. % aqueous sodium hydroxide solution to pH 12. The product was extracted with chloroform (3 × 20 ml), the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off in vacuo. The residue was distilled in vacuo, collecting the fraction with so Kip. 127-135 ° C (0.1 mmHg). After recrystallization from hexane-toluene (4: 1), 3.4 g (45%) of N- (pyrid-2-ylmethyl) aniline were obtained in the form of light yellow crystals with mp. 98-99 ° C. NMR ¹ H-spectrum (δ, ppm, J, Hz): 4.25 s (2Н, СН ₂ ), 6.07 s (1Н, NH), 6.50-6.65 m (3Н, СН phen.), 7.06 t ( 2H, CH phenol., J = 7.8). 7.30-7.40 m (1H, CH pyrid.), 7.45-7.53 m (1H, CH pyrid.), 7.75 d (1H, CH pyrid., J = 8.9), 8.45 d (1H, CH pyrid., J = 4.4 )

Example 2. To 1.91 g (15 mmol) of n-chloroaniline in a mixture of 75 ml of tetrahydrofuran and 25 ml of methanol was added at 0 ° C a solution of 3.17 g (17 mmol) of n-bromobenzaldehyde and 4.3 ml of 3N sulfuric acid in 15 ml of tetrahydrofuran. The mixture was stirred at 0 ° C. for 5 minutes, then 1 g (26 mmol) of sodium borohydride was added. The mixture was kept at room temperature for 10 minutes and 30 ml of water was added. Sodium hydroxide was added to pH 9 and extracted with chloroform (3 × 10 ml). The extract was dried over anhydrous sodium sulfate, the solvent was distilled off in vacuo. The residue was recrystallized from 50% ethanol. 2.64 g (60%) of N- (4-bromobenzyl) -4-chloroaniline were obtained in the form of yellow crystals with mp. 83-85 ° C. NMR ¹ H-spectrum (δ, ppm, J, Hz): 4.21 s (2Н, СН ₂ ), 5.62 s (1Н, NH) 6.82-7.14 А ₂ В ₂ system (4Н, С ₆ Н ₄ , J = 9.5), 7.15-7.33 A ₂ B ₂ system (4H, C ₆ H ₄ , J = 8.9).

Example 3. To 0.68 g (3.8 mmol) of nicotinic acid chloride hydrochloride in 15 ml of methylene chloride was added 1.06 ml (7.6 mmol) of dry triethylamine and 0.64 g (3.2 mmol) of N- ( pyrid-3-ylmethyl) -4-fluoroaniline. The mixture was stirred for 4 hours, the solvent was distilled off in vacuo, 15 ml of water was added to the residue, and extracted with chloroform (3 × 10 ml). The extract was washed with 15 ml of 10% potassium carbonate solution, water, dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by column chromatography (eluent-chloroform). 0.66 g (68%) of N- (pyrid-3-ylmethyl) -4'-fluoro-nicotinanilide (compound 6) was obtained in the form of white crystals with mp. 109-110 ° C. NMR ¹ H-spectrum (δ, ppm, J, Hz): 5.12 s (2Н, СН ₂ ), 7.05 t (2Н, СН phen., J = 8.9), 7.12-7.25 m (2Н, СН phen .). 7.25-7.32 m (1H, CH pyrid.), 7.32-7.38 m (1H, CH pyrid.), 7.68-7.75 m (2H, CH pyrid.), 8.44-8.52 m (4H, CH pyrid.).

Example 4. To 0.677 g (3.8 mmol) of nicotinic acid chloride hydrochloride in 15 ml of methylene chloride were added 1.06 ml (7.6 mmol) of dry triethylamine and 0.84 g (3.2 mmol) of N- (pyrid- 2-ylmethyl) -4-bromaniline. The mixture was stirred for 4 hours. The solvent was distilled off in vacuo, 15 ml of water was added to the residue, and extracted with chloroform (3 × 10 ml). The extract was washed with 15 ml of 10% potassium carbonate solution, water, dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by column chromatography (eluent-chloroform). 0.51 g (43%) of N- (pyrid-2-ylmethyl) -4'-bromonicotinanilide (compound 11) was obtained as yellow crystals with mp. 108-109 ° C. NMR ¹ H-spectrum (δ ppm, J, Hz): 5.15 s (2Н, СН ₂ ), 7.20-7.42 А ₂ В ₂ system (4Н, С ₅ Н ₄ , J = 8.9), 7.24 -7.35 m (2H, CH pyrid.), 7.47 m (1H, CH pyrid.), 7.68-7.82 m (2H, CH pyrid.), 8.45-8.55 m (3H, CH pyrid.).

Example 5. To 0.54 g (3 mmol) of nicotinic acid chloride hydrochloride in 10 ml of methylene chloride was added 0.84 ml (6 mmol) of dry triethylamine and 0.73 g (2.6 mmol) of N- (fur-2- ylmethyl) -4- (benzyloxy) aniline. The mixture was stirred for 4 hours. The solvent was distilled off in vacuo, 10 ml of water was added to the residue, and extracted with chloroform (3 × 10 ml). The extract was washed with 10 ml of a 10% solution of potassium carbonate, water, dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by column chromatography (eluent — chloroform). 0.68 g (68%) of N- (fur-2-ylmethyl) -4 '- (benzyloxy) nicotinanilide (compound 16) was obtained as a yellow oil. ¹ H-NMR spectrum (δ, ppm, J, Hz): 5.05 s (2H, _CH2), 5.35 s (2H, OCH _2), 6.30 s (1H, CH Fur.), 6.37 s (1 H (CHF), 7.08-7.45 A ₂ V ₂ -system (4H, C ₆ H ₄ , J = 11.0), 7.11-7.20 m (5H, CH phen.), 7.22-7.35 m (1H, CH pyrid. ), 7.60 s (1H, CH fur.), 7.65-7.73 m (1H, pyrid.), 8.40-8.50 m (2H, CH pyrid.).

NMR ¹ H-spectra were recorded on a Bruker AM300 instrument in DMSO-d ₆ .

The yields and melting points of substituted nicotinic acid anilides of the general formula I are given in Table 1, NMR ¹ H-spectra are shown in Table 2.

Table 1.
Yields and melting points of substituted nicotinic acid anilides of the general formula I Compound R R ' X Exit, % Mp, ° C one N H 2-furyl 89 oil 2 N H 2-pyridyl 79 102-103 3 N H 3-pyridyl 74 126-127 four F H 2-furyl 70 oil 5 F H 2-pyridyl 83 88-89 6 F H 3-pyridyl 68 109-110 7 Cl H 2-furyl 76 107-109 8 Cl H 2-pyridyl 74 115-117 9 Cl H 3-pyridyl 81 95-96 10 Br H 2-furyl 64 92-93 eleven Br H 2-pyridyl 43 108-109 12 Br H 3-pyridyl 40 144-145 13 F F 2-furyl 81 oil fourteen F F 2-pyridyl 56 98-100 fifteen F F 3-pyridyl 63 111-112 16 OCH ₂ Ph H 2-furyl 68 oil 17 OCH ₂ Ph H 2-pyridyl 77 75-76 eighteen OCH ₂ Ph H 3-pyridyl 89 oil 19 H H phenyl 40 92-94 twenty F H phenyl 44 78-79 21 Cl H phenyl 49 128-129 22 Br H phenyl 44 142-143 23 Cl H 4-bromophenyl 89 136-138

Table 2.
NMR ¹ H-spectra of substituted nicotinic acid anilides of the general formula I. Compound δ, ppm, J, Hz one 5.07 s (2H, CH ₂ ), 6.27, 6.37 both s (1H each, CH lump), 7.05-7.30 m (6H, C ₆ H ₅ , CH pyrid.), 7.57 s (1H, CH lumens), 7.60-7.70 m (1H, CH pyrid.), 8.40-8.47 m (2H, CH pyrid.) 2 5.13 s (2H, CH ₂ ), 7.12-7.37 m (5H, C ₆ H ₅ ), 7.24-7.35 m (2H, CH pyrid.), 7.47 m (1H, CH pyrid.), 7.69-7.80 m (2H , CH pyrid.), 8.44-8.55 m (3H, CH pyrid.) 3 5.15 s (2H, CH ₂ ), 7.10-7.18 m (3H, CH phen.), 7.18-7.28 m (3H, 2CH phen., 1CH pyrid.), 7.30-7.38 m (1H, CH pyrid.). 7.68-7.75 m (2H, CH pyrid.), 8.40-8.50 m (4H, CH pyrid.) four 5.05 s (2H, CH ₂ ), 6.27, 6.37 both s (1H each, CH fu.), 7.02-7.20 m (4H, CH phen.), 7.22-7.30 m (1H, CH pyrid.), 7.57 s (1H, CH fur.), 7.63-7.70 m (1H, CH pyrid.), 8.40-8.50 m (2H, CH pyrid.) 5 5.15 s (2H, CH ₂ ), 7.05 t (2H, CH phen., J = 8.9), 7.24-7.35 m (4H, 2CH phen., 2CH pyrid.), 7.47 m (1H, CH pyrid., J = 9.6), 7.68-7.82 m (2H, CH pyrid.). 8.45-8.55 m (3H, CH pyrid.) 6 5.12 s (2H, CH ₂ phenol., J = 8.9), 7.12-7.25 m (2H, CH phen.), 7.25-7.32 m (1H, CH pyrid.), 7.32-7.38 m (1H, CH pyrid.), 7.68-7.75 m (2H, CH pyrid). 8.44-8.52 m (4H, CH pyrid.) 7 5.08 s (2H, СН ₂ ), 6.27, 6.37 both s (1Н, СН фур.), 7.05-7.48 А ₂ В ₂ -system (4Н, С ₆ Н ₄ , J = 12.5), 7.22-7.33 m ( 1H, CH pyrid.), 7.58 s (1H, CH fur.), 7.60-7.72 m (1H, CH pyrid.), 8.40-8.50 m (2H, CH pyrid.) 8 5.16 s (2Н, СН ₂ ), 7.23-7.46 А ₂ В ₂ system (4Н, С ₆ Н ₄ , J = 8.9), 7.25-7.33 m (2Н, СН pyrid.), 7.45 m (1Н, СН pyrid .), 7.70-7.82 m (2Н, СН pyrid), 8.46-8.57 m (3Н, СН pyrid) 9 5.13 s (2H, CH ₂ ), 7.10-7.38 A ₂ B ₂ system (4H, C ₆ H ₄ , J = 9.5); 7.27-7.39 m (2H, CH pyrid.), 7.80 d (2H, CH pyrid., J = 6.3), 8.45-8.56 m (4H, CH pyrid.) 10 5.07 s (2H, CH ₂ ), 6.29, 6.37 both s (1H each, CH lt.), 7.08-7.45 A ₂ B ₂ -system (4H, C ₆ H ₄ , J = 12.0), 7.22-7.35 m (1H, CH pyrid.), 7.58 s (1H, CH fur.), 7.65-7.73 m (1H, CH pyrid.), 8.40-8.50 m (2H, CH pyrid.) eleven 5.15 s (2Н, СН ₂ ), 7.20-7.42 А ₂ В ₂ system (4Н, С ₆ Н ₄ J = 8.9), 7.24-7.35 m (2Н, СН pyrid.), 7.47 m (1Н, СН pyrid.), 7.68-7.82 m (2H, CH pyrid.), 8.45-8.55 m (3H, CH pyrid.) 12 5.15 s (2Н, СН ₂ ), 7.12-7 42 А ₂ В ₂ system (4Н, С ₆ Н ₄ , J = 8.9), 7.25-7.40 m (2Н, СН pyrid.), 7.75 d (2Н, СН pyrid., J = 5.5), 8.42-8.55 m (4H, CH pyrid.) 13 5.06 s (2H, CH ₂ ), 6.30, 6.38 both s (1H each, CH fu.), 7.05-7.18 m (2H, CH phen.), 7.22-7.35 m (1H, CH pyrid.), 7.46 m ( 1H, CH phen.), 7.60 s (1H, CH fur.), 7.65-7.73 m (1H, CH pyrid.), 8.41-8.49 m (2H, CH pyrid.) fourteen 5.16 s (2H, CH ₂ ), 7.05-7.18 m (2H, CH phen), 7.20-7.35 m (2 H, CH pyrid.), 7.43 m (1 H, CH phen.), 7.45 m (1 H, CH pyrid ., J = 9.6), 7.70-7.83 m (2Н, СН pyrid.), 8.45-8.55 m (3Н, СН pyrid.) fifteen 5.14 s (2Н, СН ₂ ), 7.00-7.15 m (2Н, СН phen.), 7.25-7,40 m (2Н, СН pyrid.), 7.45 m (1Н, СН phen.), 7.75 d (2Н, CH pyrid., J = 5.5), 8.42-8.55 m (4H, CH pyrid.) 16 5.05 s (2H, CH ₂ ), 5.35 s (2H, OCH ₂ ), 6.30, 6.37 both (1H, CH lance), 7.08-7.45 A ₂ V ₂ -system (4H, C ₆ H ₄ , J = 11.0), 7.11-7.20 m (5Н, С ₆ Н ₅ ), 7.22-7.35 m (1Н, СН pyrid.), 7.60 s (1Н, СН fur.), 7.65-7.73 m (1Н, СН pyrid.) 8.40-8.50 m (2H, CH pyrid.) 17 5.15 s (2Н, СН ₂ ), 5.35 s (2Н, ОСН ₂ ), 7.11-7.42 А ₂ В ₂ -system (4Н, С ₆ Н ₄ , J = 10.0), 7.13-7.20 m (5Н, С ₆ Н ₅ ), 7.23-7.36 m (2H. CH pyrid.), 7.50 m (1H. CH pyrid.), 7.67-7.82 m (2H, CH pyrid.), 8.43-8.52 m (3H, CH pyrid.) eighteen 5.15 s (2Н, СН ₂ ), 5.36 s (2Н, ОСН ₂ ), 7.10-7.39 А ₂ В ₂ -system (4Н, С ₆ Н ₄ , J = 9.5), 7.13-7.21 m (5Н, С ₆ Н ₅ ), 7.25-7.40 m (2Н, СН pyrid.), 7.75 d (2Н, СН pyrid., J = 5.5), 8.42-8.55 m (4Н, СН pyrid.) 19 5.15 s (2H. CH ₂ ), 7.10-7.18 m (3H. CH phen.), 7.18-7.38 m (7H, 2CH + 5CH phen.), 7.43-7.45 m (1H, CH pyrid.), 7.67 d ( 1H, CH pyrid., J = 6.5), 8.43-8.52 m (2H, CH pyrid.) twenty 5.10 s (2H, СН ₂ ), 7.05 t (2Н, СН phen., J = 8.9), 7.12-7.25 m (2Н, СН phen.), 7.30-7.40 m (5Н, С ₆ Н ₅ ), 7.43- 7.46 m (1H, CH pyrid.), 7.65 d (1H. CH pyrid., J = 6.8), 8.43-8.52 m (2H, CH pyrid.) 21 5.10 s (2Н, СН ₂ ), 6.84-7.16 А ₂ В ₂ -system (4Н, C ₆ H ₄ , J = 9.5), 7.35-7.39 m (5Н, С ₆ Н ₅ ), 7.40-7.45 m (1Н , CH pyrid.), 7.62 d (1Н, CH pyrid., J = 6.8), 8.40-8.51 m (2Н, CH pyrid.) 22 5.10 s (2Н, СН ₂ ), 7.12-7.42 А ₂ В ₂ system (4Н, С ₆ Н ₄ , J = 9.0), 7.32-7.39 m (5Н, С ₆ Н ₅ ), 7.40-7.45 m (1Н , CH pyrid.), 7.62 d (1Н, CH pyrid, J = 6.8), 8.40-8.51 m (2Н, CH pyrid.) 23 5.08 s (2H, CH ₂ ), 6.84-7.16 А ₂ В ₂ -system (4Н, С ₆ Н ₄ , J = 9.5), 7.18-7.35 А ₂ В ₂ -system (4Н, С ₆ Н ₄ , J = 8.9), 7.41-7.46 m (1Н, СН pyrid.), 7.62 d (1Н, СН pyrid., J = 6.8), 8.43-8.51 m (2Н, СН pyrid.)

Example 6. Tests for the fungicidal activity of the compounds were carried out in vitro on fungi Venturia inaequalis (Vi), Rhizoctonia solani (Rs), Fuzarium oxysporum (Fo), Sclerotinia sclerotiorum (Ss), Helminthosporium sativum (Hs), Fuzarium moniliforme (concentration) active component 30 mg / l. Sucrose-potato agar was used as a nutrient medium. Inoculated media were kept in a thermostat at 25 ° C for 3 days. The activity of the compounds was determined as the percentage of inhibition of fungal mycelium growth in relation to the control. As a reference, the commercial fungicide triadimefon was used. The fungicidal activity of substituted nicotinic acid anilides of the general formula I is given in table 3.

Table 3.
Fungicidal activity of substituted nicotinic acid anilides of the general formula I Compound Suppression of radial growth of fungal mycelium in comparison with control,% V.i. R.s. F.o. F.m. H.s. S.s. one 41 fifteen 23 46 53 16 2 16 12 21 35 13 twenty 3 33 21 13 29th thirty 21 four 41 eighteen 17 53 34 eighteen 5 fourteen eleven 16 26 16 17 6 33 27 12 24 26 eleven 7 40 25 19 55 thirty eighteen 8 12 fifteen 23 29th eighteen fifteen 9 37 33 12 35 21 24 10 41 33 22 51 28 twenty eleven fourteen eleven 17 37 eleven twenty 12 35 37 9 39 fifteen 33 13 39 eighteen 44 53 40 23 fourteen 33 25 48 59 49 fifteen fifteen 34 fifteen 35 55 38 17 16 48 51 45 59 49 thirty 17 51 56 49 61 49 28 eighteen 44 48 39 68 43 21 19 66 74 23 57 72 9 twenty 40 43 25 42 60 0 21 fifty 69 43 64 80 26 22 40 71 25 49 49 fifteen 23 40 74 47 62 77 19 Reference 54 55 72 85 58 67

Claims (1)

Substituted nicotinic acid anilides of the general formula I,

where R is a hydrogen, halogen or benzyloxy atom, R 'is a hydrogen or halogen atom, X is 2-furyl, 2-pyridyl, 3-pyridyl, unsubstituted or substituted with a halogen atom phenyl.