RU2442784C1 - N,n-disubstituted nicotinamide-(z)-o-methyloximes characterized by fungicidal activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to the chemistry of N,N-disubstituted nicotinamide-(Z)-O-methyloximes with the general formula I

where if X denotes a methylene group, then R denotes phenyl, benzyl or 2-furyl, R' denotes methyl or n-chlorophenyl, if X denotes a carbonyl group, then R denotes styryl, n-chlorostyryl or benzyl, R' denotes methyl that is characterized by the fungicidal activity.

EFFECT: new compounds that can be efficient against maleficent fungi.

1 cl, 10 ex, 1 tbl

Description

The invention relates to the chemistry of heterocyclic compounds, namely to N, N-disubstituted nicotinamide- (Z) -O-methyloxy of the general formula I, where if X is a methylene group, then R is phenyl, benzyl or 2-furyl, R 'is methyl or n-chlorophenyl, if X is a carbonyl group, then R is styryl, n-chlorostyryl or benzyl, R 'is methyl having fungicidal activity

N, N - disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I can be used to combat harmful fungi in medicine, veterinary medicine, agriculture, and construction.

Compounds of the general formula II are known, where R is ortho-substituted phenyl [Patent EP 477631, 1990] having fungicidal activity

Known azadioxacycloalkenes of the General formula III

where E is a methylene group, A is a substituted aryl or hetaryl having fungicidal activity [US Pat. WO 95/04728, 1993].

Among the nicotinic acid derivatives, the nicotinamides of the general formula IV are closest in structure to the compounds of formula I

where X is 2-furyl, 2-pyridyl, 3-pyridyl, unsubstituted or substituted by a halogen atom, phenyl, Y is unsubstituted, substituted by a halogen atom or benzyloxy group phenyl, exhibiting fungitoxicity [US Pat. RF 2341525, 2008].

Despite the effectiveness of fungicidal preparations existing today, the search for new means of combating harmful fungi always remains relevant because of the emergence of resistant strains.

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 N, N-disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I, where if X is a methylene group, then R is phenyl, benzyl or 2-furyl, R 'is methyl or n-chlorophenyl, if X is a carbonyl group, then R is styryl, n-chlorostyryl or benzyl, R 'is methyl having fungicidal activity.

N, N are disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I, where X is a methylene group, R is phenyl, benzyl or 2-furyl, R 'is methyl or n-chlorophenyl, can be obtained by methylation of N, N -disubstituted (Z) -nicotinamidoximes of the general formula V, where X is a methylene group, R is phenyl, benzyl or 2-furyl, R 'is methyl or n-chlorophenyl, in the presence of bases, with various methylating agents, for example dimethyl sulfate, according to a known method [ Rubina K. O-Alkylation of pyridine aldoximes under phase-transfer conditions. / Rubina K., Goldberg Yu., Gaukhman A., Shymanska M. // Synth. Comm. - 1989. - P.3129-3138.]:

as well as the interaction of lithium salts of compounds of General formula VI, where X, R and R 'have the same meanings as in formula V, with O-methylnicotinhydroxamoyl chloride:

The reactions of O-substituted hydroxamoyl chlorides with bases are described in the literature [Andersen N.H. Reaction of O-Methylbenzohydroximoyl Chlorides with Sodium Methoxide. Inversion of Configuration at Trigonal Carbon during Nucleophilic Substitution. / Andersen N.H., Costin C.R., Syrdal D.D., Svedberg D.P. // J. Am. Chem. Soc. - 1973. - P. 2051-2051].

Compounds of general formula V can be prepared in a known manner from nicotine hydroxamoyl chloride and amines of general formula VI, where X, R and R 'have the same meanings as in formula V:

Similar reactions are described in the literature [Ex O. Configuration and conformation of amidoximes. N, N-dialkyl derivatives. / Exner 0., Motekov N. // Coll. Czech Chem. Comm. -1982. - Vol. 47. - P. 814-827].

N, N-disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I, where X is a carbonyl group, R is styryl, n-chlorostyryl or benzyl, R 'is methyl, can be obtained by acylation of acid chlorides VII, where R is styryl, n-chlorostyryl or benzyl, compounds of the general formula VIII, where R 'is methyl:

Compounds of general formula VIII, in turn, can be prepared analogously to compounds of general formula V from the corresponding amines. Nicotinhydroxamoyl chloride and O-methylnicotinhydroxamoyl chloride can be obtained by known methods from the corresponding aldoximes by direct chlorination, as well as from the corresponding N, N-unsubstituted amidoximes by the diazotization reaction. Such methods are presented in the literature [Chiang Y.H. Chlorination of oximes. I. Reaction and mechanism of the chlorination of oximes in commercial chloroform and methylene chloride. / Chiang Y.H. // J. Org. Chem. - 1971. - Vol. 36 - P. 2146-2155].

The invention can be illustrated by the following examples.

Example 1. A solution of 1.65 g (8.55 mmol) of nicotine hydroxamoyl chloride hydrochloride in 10 ml of MeOH was added dropwise to 4 ml of a 7 M solution of MeNH ₂ in MeOH at 0-5 ° C and stirred at the indicated temperature for 8 hours. The solvent was distilled off in in vacuo, 15 ml of water was added to the residue and extracted with CHCl ₃ (3 × 10 ml). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, the residue was chromatographed on a silica gel column (eluent CHCl ₃ -MeOH 10: 1). Received 1.05 g (79%) of (Z) -N-methylnicotinamidoxime in the form of a white powder with a mp of 108-110 ° C. ¹ H NMR spectrum ((CD ₃ ) ₂ SO, δ, ppm, J, Hz): 2.59 (d, 3 N, CH ₃ , J = 6.6); 5.91 (q, 1 H, NH, J = 6.6); 7.41-7.49 (m, 1H, 5-CH ru); 7.83 (d, 1 H, 4-CH ru, J = 8.3); 8.61 (d, 1 H, 6-CH ru, J = 4.2); 8.62 (s, 1 H, 2-CH ru); 9.81 (s, 1 H, OH).

Example 2. A solution of 1.30 g (6.7 mmol) of nicotinhydroxamoyl chloride hydrochloride in 25 ml of MeOH was added dropwise to 2.42 g (20 mmol) of N-methyl-N-benzylamine in 30 ml of MeOH at 0-5 ° C and stirred at the indicated temperature for 8 hours. The solvent was distilled off in vacuo, 15 ml of water was added to the residue, and extracted with CHCl ₃ (3 × 10 ml). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, the residue was chromatographed on a silica gel column (eluent CHCl ₃ -MeOH 10: 1). Received 1.29 g (80%) of (Z) -N-methyl-N-benzylnicotinamidoxime in the form of a white powder with so pl. 126-128 ° C. ¹ H NMR Spectrum ((CD ₃ ) ₂ SO, δ, ppm, J, Hz): 2.60 (s, 3 N, CH ₃ ); 4.07 (s, 2 N, CH ₂ ); 7.18-7.28 (m, 3 N, CH Ph); 7.29-7.37 (m, 2 H, CH Ph); 7.43-7.51 (m, 1 H, 5-CH ru); 7.81 (d, 1 H, 4-CH ru, J = 9.4); 8.56 (s, 1 H, 2-CH ru); 8.58 (d, 1 N, 6-CH ru, J = 6.2); 9.39 (s, 1 H, OH).

Example 3. A mixture of 0.37 g (6.8 mmol) of MeONa sodium methylate, 15 ml of dry DMF and 1.03 g (6.8 mmol) of N-methylnicotinamidoxime was cooled to 0 ° C and 0.65 ml (6.8 mmol) of dimethyl sulfate was added dropwise to it, maintaining the temperature at 0 -5 ° C. The reaction mass was stirred for 6 hours at the same temperature. Then DMF was removed in vacuo, and the residue was dissolved in 30 ml of cold water and extracted with ether (3 × 15 ml). The extract was dried over anhydrous magnesium sulfate. The ether was removed in vacuo. The residue was recrystallized from isopropanol. Received 0.54 g (48%) of N-methylnicotinamide- (Z) -O-methyloxy in the form of white crystals with so pl. 83-85 ° C. ¹ H NMR spectrum (CDCl ₃ , δ, ppm, J, Hz): 2.72 (d, 3 H, NCHH ₃ , J = 5.6); 3.85 (s, 3 N, OCH ₃ ); 5.21 (br s, 1 H, NH); 7.29-7.36 (m, 1 H, 5-CH ru); 7.76 (d, 1 H, 4-CH ru, J = 10.0); 8.62 (d, 1 H, 6-CH ru, J = 4.8); 8.71 (s, 1 H, 2-CH ru).

Example 4. To a solution of 0.45 g (2.17 mmol) of N- (n-chlorophenyl) -N- (2-furylmethyl) amine in 10 ml of THF at a temperature of -10 - -5 ° C in an argon atmosphere was added 1, 36 ml of 1.6 N (2.17 mmol) butyl lithium solution. Then, without removing cooling, the mixture was stirred for 20 minutes and a solution of 0.37 g (2.17 mmol) of O-methylnicotinhydroxamoyl chloride in 5 ml of THF was added. The reaction mass was boiled for 10 hours, poured into water and extracted with ether (3 × 5 ml). The extract was dried over anhydrous magnesium sulfate. The ether was removed in vacuo. The residue was chromatographed on a silica gel column (eluent hexane-EtOAc 5: 1). Received 0.15 g (20%) of N- (n-chlorophenyl) -N- (2-furylmethyl) nicotinamide- (Z) -O-methyloxy in the form of light brown crystals with so pl. 73-75 ° C. NMR ¹ H-spectrum ((CD ₃ ) ₂ SO, δ, ppm, J, Hz): 3.94 (s, 3 N, OCH ₃ ), 4.93 (s, 2 N, CH ₂ ); 6.38-6.42 (m, 2H, 3, 4-CH furyl); 6.85-7.20 (A ₂ B ₂ system, 4 N, C ₆ H ⁴ , J = 10.2); 7.30-7.35 (m, 1 H, 5-CH ru); 7.60 (s, 1H, 5-CH furyl); 7.65-7.70 (d, 1 H, 4-CH ru, J = 7.2); 8.45-8.55 (m, 2 H, 2, 6-CH ru).

Example 5. A mixture of 224 mg (4.1 mmol) of sodium methylate, 15 ml of dry DMF and 1 g (4.1 mmol) of N-benzyl-N-methylnicotinamidoxime was cooled to 0 ° C. and 0.4 ml was added dropwise to it. (4.1 mmol) of dimethyl sulfate, maintaining a temperature of 0-5 ° C. The mixture was stirred for 6 hours at the same temperature. Then, DMF was removed in vacuo, and the residue was dissolved in 60 ml of cold water and extracted with ether (3 × 20 ml). The extract was dried over anhydrous magnesium sulfate. The ether was removed in vacuo. The residue was chromatographed on a silica gel column (eluent CHCl ₃ -MeOH 10: 1). 190 mg (18%) of N-benzyl-N-methylnicotinamide- (Z) -O-methyloxy were obtained. 1 H NMR spectrum ((CO ₃ ) ₂ SO, δ, ppm, J, Hz): 2.65 (s, 3 H, NCH ₃ ); 3.53 (s, 3 N, OCH ₃ ); 4.11 (s, 2 N, CH ₂ ); 7.20 (d, 2 N, CH Ph, J = 6.9); 7.25-7.37 (m, 3 N, CH Ph); 7.45-7.51 (m, 1 H, 5-CH ru); 7.74 (d, 1 H, 4-CH ru, J = 7.8); 8.50 (s, 1 H, 2-CH ru); 8.59 (d, 1 H, 6-CH ru, J = 4.7).

Example 6. A solution of 1.3 g (6.7 mmol) of nicotine hydroxamoyl chloride hydrochloride in 25 ml of MeOH was added dropwise to 2.7 g (20 mmol) of N-methyl-N- (2-phenylethyl) amine in 30 ml of MeOH at 0 -5 ° C and stirred at the indicated temperature for 8 hours. The solvent was distilled off in vacuo, 15 ml of water was added to the residue, and extracted with CHCl ₃ (3 × 10 ml). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, the residue was chromatographed on a silica gel column (eluent CHCl ₃ -MeOH 10: 1). 1.4 g (82%) of (g) -N-methyl-N- (2-phenylethyl) nicotinamidoxime were obtained as a yellow oil. ¹ H NMR spectrum ((CD ₂ ) ₂ SO, δ, ppm, J, Hz): 2.68 (t, 2H, CH ₂ CH ₂ Ph, J = 5.7); 2.75 (s, 3H, NCH ₃ ); 3.06 (t, 2 H, CH ₂ CH ₂ Ph, J = 5.7); 6.98 (d, 2 N, CH Ph, J = 8.6); 7.10-7.27 (m, 3 H, 2CH Ph, 5-CH ru); 7.35-7.47 (m, 2 CH, CH Ph, 4-CH ru); 8.30 (s, 1 H, 2-CH ru); 8.32 (d, 1 H, 6-CH ru, J = 5.7); 9.55 (s, 1 H, OH).

Example 7. To a solution of 0.138 g (0.84 mmol) of N-methylnicotinamide-O-methyloxime and 0.122 g (1 mmol) of DMAP in 25 ml of CHCl _{3 was} added a solution of 0.168 g (1 mmol) of cinnamoyl chloride in 5 ml of CHCl ₃ . The mixture was boiled for 6 hours, cooled, washed with 20 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, the residue was chromatographed on a silica gel column (eluent EtOAc-hexane 5: 1). 0.051 g (24%) of N-methyl-N- (E) -cinnamoylonicotinamide- (Z) -O-methyloxy was obtained as an oil. ¹ H NMR spectrum ((CD ₃ ) ₂ SO, δ, ppm, J, Hz): 3.14 (s, 3 H, NCH ₃ ); 3.95 (s, 3 N, OCH ₃ ); 6.52 (d, 1 H, PhCH = CH, J = 19.0); 6.91 (d, 1 H, PhCH = CH , J = 19.0); 7.25-7.35 (m, 3 N, CH Ph); 7.52-7.65 (m, 2 H, CH Ph); 7.66-7.72 (m, 1 H, 5-CH ru), 8.28 (d, 1 H, 4-CH ru, J = 9.3); 8.79 (d, 1 H, 6-CH ru, J = 5.0); 9.04 (s, 1 H, 2-CH ru).

Example 8. To a solution of 300 mg (1.81 mmol) of N-methylnicotinamide-O-methyloxy and 244 mg (2.0 mmol) of DMAP in 20 ml of CHCl _{3 was} added a solution of 365 mg (2.18 mmol) of n-chlorocinnamol chloride in 20 ml CHCl ₃ . The mixture was boiled for 6 hours, cooled, washed with 20 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, the residue was chromatographed on a silica gel column (eluent EtOAc-hexane 5: 1).

Received 150 mg (25%) of N-methyl-N - ((En-chlorcininnamoyl) nicotinamide- (Z) - O- methyloxime in the form of white crystals with a melting point of 79-81 ° C. ¹ H NMR spectrum ((CD ₃ ) ₂ SO, δ, ppm, J, Hz): 3.06 (s, 3 N, NCH ₃ ); 3.80 (s, 3 N, OCH ₃ ); 6.55 (d, 1 N, PhCH = CH, J = 20.0); 6.91 (d, 1 H, PhCH = CH , J = 20.0); 7.50-7.68 (A ₂ B ₂ system, 4 N, C ₆ H ₄ , J = 7.8); 7.51-7.57 (m , 1 N, 5-CH ru); 8.12 (d, 1 H, 4-CH ru, J = 7.0); 8.67 (d, 1 H, 6-CH ru, J = 4.1); 8.93 (s, 1 N , 2-CH ru).

Example 9. To a solution of 300 mg (1.81 mmol) of N-methylnicotinamide-O-methyloxy and 244 mg (2.0 mmol) of DMAP in 20 ml of CHCl _{3 was} added a solution of 309 mg (2.0 mmol) of phenylacetyl chloride in 20 ml of CHCl ₃ . The mixture was boiled for 6 hours, cooled, washed with 20 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, the residue was chromatographed on a silica gel column (EtOAc eluent). 70 mg (17%) of N-methyl-N- (phenylacetyl) nicotinamide- (Z) -O-methyloxy were obtained as an oil. ¹ H NMR Spectrum ((CD ₃ ) ₂ SO, δ, ppm, J, Hz): 2.98 (s, 3 H, NCH ₃ ); 3.80 (s, 2 N, CH ₂ ); 3.92 (s, 3 N, OCH ₃ ); 7.17-7.22 (m, 2 H, CH Ph); 7.23 (m, 3 N, CH Ph); 7.45-7.49 (m, 1 H, 5-CH ru); 7.87 (d, 1 H, 4-CH ru, J = 7.4); 8.62 (d, 1 H, 6-CH ru, J = 3.9); 8.70 (s, 1 H, 2-CH ru).

¹ H NMR spectra were recorded on a Bruker AM300 instrument in (CD ₃ ) ₂ SO.

Example 10. A preliminary assessment of the fungicidal activity of some compounds was carried out in vitro against phytopathogenic fungi: Rhizoctonia solani Kühn (R.s.), Fusarium moniliforme Sheldon (F.m.) and Helminthosporium sativum Pammel, King et Bakke (H.s.). The concentration of the active component was 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.

The fungicidal activity of N, N-disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I is shown in the table.

According to preliminary estimates, the activity of N, N-disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I in some cases is comparable to or exceeds the activity of the standard.

Fungicidal activity of N, N-disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I Compound Suppression of radial growth of fungal mycelium in comparison with control,% No. X R R ' R.s. F.m. H.s. one CH ₂ 2-furyl n-ClC ₆ H ₄ - 65 52 52 2 CH ₂ Ph Me 37 17 48 3 CH ₂ Bn Me 39 66 86 four C = o PhCH = CH- Me 48 47 74 5 C = o n-СlС ₆ Н ₄ СН = СН- Me 62 62 81 6 C = o Bn Me 25 32 6 Reference* 70 60 69 * Standard is the commercial fungicide spiroxamine (8-tert-butyl-1,4-dioxaspiro [4.5] decan-2-ylmethyl (ethyl) (propyl) amine).

Claims (1)

N, N-disubstituted nicotinamide- (Z) -O-methyloximes of the general formula I, where if X is a methylene group, then R is phenyl, benzyl or 2-furyl, R 'is methyl or n-chlorophenyl, if X is a carbonyl group , then R means styryl, n-chlorostyryl or benzyl, R 'means methyl having fungicidal activity