CN110746407A - Amide derivative containing benzimidazole group, preparation method and application thereof - Google Patents

Amide derivative containing benzimidazole group, preparation method and application thereof Download PDF

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CN110746407A
CN110746407A CN201810830432.3A CN201810830432A CN110746407A CN 110746407 A CN110746407 A CN 110746407A CN 201810830432 A CN201810830432 A CN 201810830432A CN 110746407 A CN110746407 A CN 110746407A
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phenyl
methyl
benzimidazol
chloro
pyrazole
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杨春龙
司伟杰
王濛琪
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Nanjing Agricultural University
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Nanjing Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A01N43/52—1,3-Diazoles; Hydrogenated 1,3-diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention belongs to the field of pesticides, and discloses an amide derivative containing benzimidazole group, a preparation method and an application thereof, wherein the structure of the derivative is shown as the formula (I):

Description

Amide derivative containing benzimidazole group, preparation method and application thereof
Technical Field
The invention relates to the field of pesticides, in particular to an amide derivative containing benzimidazole groups, a preparation method of the derivative, and application of the derivative in preventing and treating plant fungal diseases.
Background
The crop diseases, especially fungal diseases, are various in types, wide in distribution, rapid in propagation and difficult to control, and some fungal diseases also have the characteristics of wide host range, long harm period, toxin generation and the like, so that the growth of crops is seriously influenced, and the quality and the safety of agricultural products are influenced. Currently, chemical control still occupies the main position in the comprehensive control of crop diseases, but the existing bactericides have relatively single action targets and are singly used or used in large quantities for a long time, so that the problem of drug resistance of fungi is increasingly prominent, and the use and development of the bactericides are limited. Therefore, the development of a new high-efficiency, low-toxicity and environment-friendly bactericide candidate drug has important significance for preventing and treating crop diseases and ensuring the safety of agricultural products.
Benzimidazole is an active group in the molecular structure of some bactericides, and bactericides containing benzimidazole frameworks, such as carbendazim (carbendazim), benomyl (benomyl) and the like, have good bactericidal activity and play a great role in the aspect of preventing and controlling crop diseases. Pyrazole and pyridine are common active heterocycles in pesticide molecular structures, and are also often introduced as key groups by people to synthesize and screen high-activity new compounds when new pesticide molecular structures are designed.
The invention applies an active substructure splicing method to organically combine benzimidazole groups and heterocycles such as pyrazole, pyridine and the like into the same molecular structure through amide bonds, designs and synthesizes a series of amide derivatives containing benzimidazole groups, wherein the derivatives have obvious fungicidal activity.
Disclosure of Invention
The invention aims to provide an amide derivative containing benzimidazole group.
The invention also aims to provide a preparation method of the amide derivative containing the benzimidazole group.
The 3 rd object of the present invention is to provide the use of the above derivatives.
The invention provides an amide derivative containing benzimidazole group, which has the structure shown in the general formula (I),
in formula (I), the various groups have the definitions set forth below:
R1selected from the following 1-4 groups: hydrogen, C1-6Alkyl, halogen;
r is selected from substituted pyrazole and substituted pyridine, and the substituted group is selected from 1 to 3 groups as follows: hydrogen, C1-6Alkyl, halogen, mercapto, methyl substituted with 1-3 halogens;
in formula (I), the respective groups have the preferred definitions as described below:
R1selected from hydrogen, C1-6Alkyl, halogen;
r is selected from 1-methyl-3-C1-6alkyl-5-halo-1H-pyrazol-4-yl, 1-methyl-3-trifluoromethyl-5-halo-1H-pyrazol-4-yl, 1-methyl-3-C1-6alkyl-1H-pyrazol-5-yl, pyridin-3-yl, 2-halopyridin-3-yl, mercaptopyridin-3-yl.
In formula (I), the respective groups have further preferred definitions as described below:
R1selected from H, 6-CH3、6-Cl；
R is selected from 1, 3-dimethyl-5-chloro-1H-pyrazol-4-yl, 1-methyl-3-trifluoromethyl-5-chloro-1H-pyrazol-4-yl, 1, 3-dimethyl-1H-pyrazol-5-yl, 1-methyl-3-isobutyl-1H-pyrazol-5-yl, pyridine-3-yl, 2-chloropyridine-3-yl and 2-mercaptopyridine-3-yl.
In formula (I), the various groups have the particularly preferred definitions as set forth in table 1 below:
numbering and corresponding Structure of Compounds (I1-I19) of Table 1
Figure BSA0000167796530000031
Figure BSA0000167796530000041
In a second aspect of the present invention, there is provided a process for producing a benzimidazole group-containing amide derivative of the formula (I), which comprises reacting a compound of the formula (II) with an acid of the formula (III) to produce a benzimidazole group-containing amide derivative of the formula (I), wherein the reaction formula is represented by the following general formula (A):
Figure BSA0000167796530000042
wherein in each of the above structural formulae:
R1and R have the definitions of the corresponding groups as described above.
The third aspect of the invention relates to application of the amide derivative containing the benzimidazole group in the formula (I), which is characterized in that the amide derivative is applied to the aspects of inhibiting plant pathogenic fungi and preventing and treating plant fungal diseases, can be applied to the field of pesticides and can be used as a bactericide.
The derivative of the formula (I) can be used for inhibiting plant pathogenic fungi, such as botrytis cinerea, rhizoctonia solani, fusarium graminearum and early blight of tomato.
The derivative of the formula (I) can be used for preventing and treating various crop fungal diseases, such as gray mold, banded sclerotial blight, gibberellic disease, early blight and anthracnose.
The application of the derivative of the formula (I) is characterized in that the derivative is suitable for preventing and treating tomato gray mold, rice sheath blight, wheat scab and tomato early blight.
Has the advantages that:
1. the amide derivative containing benzimidazole group in the formula (I) has a novel molecular structure, and a chemical structural formula of the amide derivative has a distinct characteristic, wherein the structural formula contains benzimidazole-2-yl phenyl and pyrazole (or pyridine) heterocycle, and the phenyl and the heterocycle are connected through amido bond.
2. The preparation method of the derivative shown in the formula (I) has the advantages of easily obtained raw materials, easily controlled reaction conditions, simple and convenient operation and high yield.
3. The derivative of the formula (I) shows obvious effects of inhibiting the activity of plant pathogenic fungi and preventing and treating agricultural fungal diseases, and has application as a pesticide bactericide.
Detailed Description
The essential features of the invention can be seen from the following examples, which should not be construed as limiting the invention in any way.
Preparation examples
Example 1: n- (2- (1H-benzimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide (I1) Preparation of
Slowly adding 5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxylic acid (0.52g, 3mmol) into 10mL thionyl chloride, refluxing for 6H, evaporating the thionyl chloride under reduced pressure, adding 20mL dichloromethane, cooling to-5 ℃, slowly adding 2- (1H-benzimidazole-2-yl) aniline (0.63g, 3mmol) in batches, adding triethylamine (0.60g, 6mmol), stirring for reacting for 1H, naturally heating to room temperature, and continuously stirring for 4H. The reaction solution is washed by water, washed by saturated saline, washed by water, dried, pressurized to evaporate the solvent, and purified by column chromatography to obtain the N- (2- (1H-benzimidazole-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-formamide (I1).
Example 2: n- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H- Preparation of pyrazole-4-carboxamide (I8)
Slowly adding 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.68g and 3mmol) into 10mL of thionyl chloride, refluxing for 6H, evaporating the thionyl chloride under reduced pressure, adding 20mL of dichloromethane, cooling to-5 ℃, slowly adding 2- (6-chloro-1H-benzimidazol-2-yl) aniline (0.73g and 3mmol) in batches, adding triethylamine (0.60g and 6mmol), stirring for reacting for 1H, naturally heating to room temperature, and continuously stirring for 6H. The reaction solution is washed by water, washed by saturated saline, washed by water, dried, pressurized to evaporate the solvent, and purified by column chromatography to obtain the N- (2- (5-chloro-1H-benzimidazole-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-formamide (I8).
Example 3: preparation of N- (2- (6-chloro-1H-benzimidazol-2-yl) phenylnicotinic acid amide (I11)
Dissolving nicotinic acid (0.37g and 3mmol) and TBTU (1.15g and 3.6mmol) in dichloromethane, adding triethylamine (0.60g and 6mmol), stirring for 30min, adding 2- (6-chloro-1H-benzimidazol-2-yl) aniline (0.63g and 3mmol), continuing stirring for 10H, generating a large amount of solid in the reaction mixed solution, filtering, washing with water, and drying to obtain N- (2- (6-chloro-1H-benzimidazol-2-yl) phenylnicotinic acid amide (I11).
Example 4: preparation of N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl-2-chloronicotinic acid amide (I19)
Dissolving 2-chloronicotinic acid (0.47g, 3mmol) and TBTU (1.15g, 3.6mmol) in dichloromethane, adding triethylamine (0.60g, 6mmol), stirring for 30min, adding 2- (6-methyl-1H-benzimidazole-2-yl) aniline (0.67g, 3mmol), continuing stirring for 10H, generating a large amount of solid in the reaction mixed solution, filtering, washing with water, and drying to obtain N- (2- (6-methyl-1H-benzimidazole-2-yl) phenyl-2-chloronicotinic acid amide (I19).
By the method of the above examples 1 to 4, an amide derivative containing a benzimidazole group I1-I19 of the formula (I):
n- (2- (1H-benzoimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide (I1): white solid, yield 70.6%, mp 240-;1H NMR(400MHz，DMSO-d6)δ：13.32(s，1H)，13.22(s，1H)，8.78(d，J＝8.4Hz，1H)，8.25-8.11(m，1H)，7.64(dd，J＝15.7，7.2Hz，2H)，7.54(t，J＝7.8Hz，1H)，7.32(t，J＝7.6Hz，3H)，3.87(s，3H)，2.48(s，3H).13C NMR(101MHz，DMSO-d6)δ：160.69，151.05，148.26，142.44，138.64，134.03，131.01，127.85，127.56，123.88，123.59，122.78，121.24，118.84，116.32，113.60，111.99，36.66，14.24.HRMS(ESI)Calcd forC19H17ClN5O[M+H]+：366.11161，found：366.11169.
n- (2- (1H-benzoimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide (I2): light yellow solid, yield 58.4%, mp 254-;1H NMR(400MHz，DMSO-d6)δ：13.92(s，1H)，13.30(s，1H)，8.80(d，J＝8.3Hz，1H)，8.30-8.14(m，1H)，7.66(s，2H)，7.61-7.53(m，1H)，7.42-7.34(m，1H)，7.30(s，2H)，4.07(s，3H).13C NMR(101MHz，DMSO-d6)δ：157.93，150.88，139.20(q，J＝38.38Hz)138.16，131.20，129.09，127.80，124.25，122.19，120.91，119.51，116.36，115.24，38.07.HRMS(ESI)Calcd for C19H14ClF3N5O[M+H]+：420.08335，found：420.08344.
n- (2- (1H-benzoimidazol-2-yl) phenyl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide (I3): white solid, yield 53.5%, mp245-247 deg.C;1H NMR(400MHz，DMSO-d6)δ：13.90(s，1H)，13.29(s，1H)，8.80(d，J＝8.3Hz，1H)，8.18(d，J＝7.4Hz，1H)，7.75(dd，J＝5.6，2.7Hz，1H)，7.63(dd，J＝5.6，2.6Hz，1H)，7.54(t，J＝7.6Hz，1H)，7.34(m，3H)，7.07(s，1H)，4.09(s，3H)，2.33(s，3H).13CNMR(101MHz，DMSO-d6)δ：158.25，151.22，146.32，142.25，138.53，136.63，133.84，131.16，127.66，124.00，123.57，122.91，120.17，118.41，115.82，112.06，107.14，39.13，13.57.HRMS(ESI)Calcd for C19H18N5O[M+H]+：332.15059，found：332.15085.
n- (2- (1H-benzoimidazol-2-yl) phenyl) -1-methyl-3-isobutyl-1H-pyrazole-5-carboxamide (I4): white solid, yield 51.4%, mp 213-;1H NMR(400MHz，DMSO-d6)δ：13.88(s，1H)，13.45(s，1H)，8.82(d，J＝7.8Hz，1H)，8.22(t，J＝13.6Hz，1H)，7.71-7.61(m，2H)，7.54(dd，J＝11.5，4.2Hz，1H)，7.32(dd，J＝8.8，6.5Hz，3H)，7.07(s，1H)，4.11(s，3H)，2.56(d，J＝7.0Hz，2H)，1.99(m，1H)，1.01(s，3H)，0.99(s，3H).13C NMR(101MHz，DMSO-d6)δ：158.38，151.31，150.00，142.28，138.50，136.51，133.96，131.19，127.93，123.98，123.65，122.84，120.21，118.15，115.93，112.24，106.82，39.25，37.18，28.94，22.82.HRMS(ESI)Calcd forC22H24N5O[M+H]+：374.19754，found：.374.19775.
n- (2- (1H-benzoimidazol-2-yl) phenyl) -2-chloronicotinic acid amide (I5): white solid, yield 80.5%, mp203-205 deg.C;1H NMR(400MHz，DMSO-d6)δ：13.87(s，1H)，13.28(s，1H)，8.82(d，J＝8.3Hz，1H)，8.70-8.63(m，1H)，8.38-8.30(m，1H)，8.21(d，J＝7.8Hz，1H)，7.71(dd，J＝7.5，4.9Hz，1H)，7.66-7.56(m，2H)，7.46-7.35(m，2H)，7.30(t，J＝7.5Hz，1H)，7.23(t，J＝7.5Hz，1H).13CNMR(101MHz，DMSO-d6)δ：163.84，151.73，151.06，147.27，142.16，139.00，138.24，133.83，133.01，131.32，127.85，124.35，124.02，123.89，122.83，120.62，118.73，116.50，112.06.HRMS(ESI)Calcd for C19H14ClN4O[M+H]+：349.08507，found：349.08511.
n- (2- (1H-benzoimidazol-2-yl) phenyl) -2-mercaptonicotinic acid amide (I6): yellow solid, yield 42.0%, mp 207-;1H NMR(400MHz，DMSO-d6)δ：13.89(s，1H)，13.33(s，1H)，13.12(s，1H)，8.70(d，J＝8.1Hz，1H)，8.08(d，J＝7.6Hz，1H)，7.99(d，J＝6.8Hz，1H)，7.88(d，J＝5.4Hz，1H)，7.62-7.45(m，3H)，7.31(dd，J＝14.9，7.4Hz，1H)，7.23(d，J＝8.7Hz，2H)，6.94(t，J＝6.6Hz，1H).13C NMR(101MHz，DMSO-d6)δ：174.89，165.09，150.72，140.71，139.06，138.85，138.21，130.91，128.54，123.99，121.59，118.06，113.10.HRMS(ESI)Calcd for C19H15N4OS[M+H]+：347.09611，found：347.09616.
n- (2- (6-chloro-1H-benzoimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide (I7): white solid, yield 59.6%, mp 231-;1H NMR(400MHz，DMSO-d6)δ：13.38(s，1H)，13.04(s，1H)，8.75(d，J＝8.3Hz，1H)，8.20-8.04(m，1H)，7.77-7.59(m，2H)，7.55(t，J＝7.8Hz，1H)，7.32(t，J＝7.6Hz，2H)，3.87(s，3H)，2.45(s，3H).13C NMR(101MHz，DMSO-d6)δ：160.65，152.34，148.40，138.65，131.32，128.02，127.48，123.61，121.36，116.02，113.41，36.69，14.25.HRMS(ESI)Calcd for C19H16Cl2N5O[M+H]+：400.07264，found：400.07245.
n- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trisfluoromethyl-1H-pyrazole-4-carboxamide (I8): white solid, yield 41.5%, mp 225-;1H NMR(400MHz，DMSO-d6)δ：13.62(s，1H)，13.44(s，1H)，8.78(d，J＝7.8Hz，1H)，8.19(dd，J＝7.9，1.0Hz，1H)，7.71(s，1H)，7.65(d，J＝8.5Hz，1H)，7.62-7.55(m，1H)，7.37(dd，J＝11.2，4.1Hz，1H)，7.31(dd，J＝8.5，1.3Hz，1H)，4.06(s，3H).13C NMR(101MHz，DMSO-d6)δ：157.92，152.17，139.20(q，J＝38.38Hz)，138.18，131.55，129.14，127.97，124.29，122.17，121.01，119.50，116.05，115.08，38.12.HRMS(ESI)Calcd for C19H13Cl2F3N5O[M+H]+：454.04438，found：454.04425.
n- (2- (6-chloro-1H-benzoimidazol-2-yl) phenyl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide (I9): white solid, yield 41.3%, mp 254-;1H NMR(400MHz，DMSO-d6)δ：13.61，13.52(s，s，1H)，13.44(s，1H)，8.77(d，J＝8.3Hz，1H)，8.14(d，J＝7.8Hz，1H)，7.79-7.47(m，3H)，7.32(dd，J＝16.1，8.4Hz，2H)，6.98(s，1H)，4.07(s，3H)，2.31(s，3H).13C NMR(101MHz，DMSO-d6)δ：158.09，146.18，138.55，136.41，131.29，127.65，123.36，120.10，115.29，107.01，39.11，13.55.HRMS(ESI)Calcd for C19H17ClN5O[M+H]+：366.11161，found：366.11182.
n- (2- (6-chloro-1H-benzoimidazol-2-yl) phenyl) -1-methyl-3-isobutyl-1H-pyrazole-5-carboxamide (I10): white solid, yield 52.4%, mp 194-195 deg.C;1H NMR(400MHz，DMSO-d6)δ：13.58(s，1H)，13.40(s，1H)，8.76(d，J＝8.3Hz，1H)，8.17-8.05(m，1H)，7.65-7.57(m，2H)，7.58-7.47(m，1H)，7.40-7.18(m，2H)，6.95(s，1H)，4.08(s，3H)，2.53(d，J＝3.8Hz，2H)，1.97(td，J＝13.3，6.6Hz，1H)，1.01(s，3H)，0.99(s，3H).13C NMR(101MHz，DMSO-d6)δ：158.22，152.63，149.94，138.55，136.40，131.37，127.77，127.51，123.48，120.20，115.53，106.64，39.17，37.13，28.88，22.83.HRMS(ESI)Calcd for C22H23ClN5O[M+H]+：408.15856，found：408.15866.
n- (2- (6-chloro-1H-benzimidazol-2-yl) phenylnicotinic acid amide (I11) as a white solid in 65.3% yield, mp300-302 deg.C;1H NMR(400MHz，DMSO-d6)δ：13.88(s，1H)，13.46(s，1H)，9.34(d，J＝1.7Hz，1H)，8.87(dd，J＝4.6，3.6Hz，2H)，8.51(d，J＝8.0Hz，1H)，8.15(d，J＝7.9Hz，1H)，7.75(dt，J＝14.5，7.3Hz，1H)，7.66(s，2H)，7.57(t，J＝7.8Hz，1H)，7.32(t，J＝7.2Hz，2H).13C NMR(101MHz，DMSO-d6)δ：163.68，152.83，152.52，148.97，138.60，135.38，131.52，130.67，127.76，124.40，123.76，120.42，115.69.HRMS(ESI)Calcd for C19H14ClN4O[M+H]+：349.08507，found：349.08527.
n- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl-2-chloronicotinicamide (I12) as a white solid in 49.1% yield, mp 228-;1H NMR(400MHz，DMSO-d6)δ：13.54，13.46(s，s，1H)，13.45，13.43(s，s，1H)，8.78(d，J＝8.3Hz，1H)，8.65(d，J＝4.6Hz，1H)，8.31(d，J＝7.6Hz，1H)，8.17(d，J＝7.9Hz，1H)，7.71(td，J＝8.3，5.0Hz，1H)，7.61(t，J＝8.0Hz，2H)，7.50-7.35(m，2H)，7.28(dd，J＝29.8，8.5Hz，1H).13C NMR(101MHz，DMSO-d6)δ：163.81，151.75，147.23，138.96，138.21，132.88，131.65，128.05，124.39123.93，120.77，118.05，116.29.HRMS(ESI)Calcdfor C19H13Cl2N4O[M+H]+：383.04609，found：383.04617.
n- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl-2-mercaptonicotinic acid amide (I13) as a yellow solid in 43.8% yield at 217 ℃ under mp 215-;1H NMR(400MHz，DMSO-d6)δ：13.93(s，1H)，13.26(s，1H)，13.18(s，1H)，8.67(d，J＝8.2Hz，1H)，8.11-7.99(m，2H)，7.90(d，J＝5.3Hz，1H)，7.56(d，J＝9.4Hz，3H)，7.32(dd，J＝15.5，8.0Hz，1H)，7.26(s，1H)，6.96(t，J＝6.7Hz，1H).13C NMR(101MHz，DMSO-d6)δ：174.69，164.80，141.01，139.70，138.16，138.07，131.22，128.92，124.14，121.93，118.39，113.29.HRMS(ESI)Calcd for C19H14ClN4OS[M+H]+：381.05714，found：381.05685.
n- (2- (6-methyl-1H-benzoimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide (I14): white solid, yield 53.0%, mp 220-;1H NMR(400MHz，DMSO-d6)δ：13.32(s，1H)，13.09，13.05(s，s，1H)，8.81-8.71(m，1H)，8.13(d，J＝7.9Hz，1H)，7.49(dd，J＝16.1，8.6Hz，2H)，7.40(d，J＝19.1Hz，1H)，7.30(t，J＝7.6Hz，1H)，7.13(d，J＝8.0Hz，1H)，7.08(d，J＝8.1Hz，1H)，3.86(s，3H)，2.46(t，J＝7.2Hz，6H).13C NMR(101MHz，DMSO-d6)δ：160.68，150.91，150.55，148.15(d，J＝10.7Hz)，142.82，140.62，138.53，134.30，133.37，132.06，131.87，130.76，127.64(d，J＝12.8Hz)，125.34，124.32，123.52，121.20，118.42(d，J＝7.4Hz)，116.46，113.65，111.58(d，J＝14.2Hz)，36.64，21.74(d，J＝17.4Hz)，14.24.HRMS(ESI)Calcd for C20H19ClN5O[M+H]+：380.12726，found：380.12711.
n- (2- (6-methyl-1H-benzoimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide (I15): white solid, yield 65.1%, mp 160-;1H NMR(400MHz，DMSO-d6)δ：13.90(s，1H)，13.13，13.09(s，s，1H)，8.81-8.73(m，1H)，8.17(dd，J＝7.9，1.1Hz，1H)，7.61-7.31(m，4H)，7.11(dd，J＝22.5，8.2Hz，1H)，4.06(d，J＝5.9Hz，3H)，2.45(d，J＝11.7Hz，3H).13C NMR(101MHz，DMSO-d6)δ：157.91，150.73，150.37，142.63，140.44，139.13(dd，J＝38.1Hz，5.4Hz)138.03(d，J＝2.2Hz)，134.19，133.51，131.92(d，J＝5.1Hz)，131.00(d，J＝6.1Hz)，129.11(d，J＝9.0Hz)，127.62，125.47，124.28(d，J＝13.9Hz)，122.18，120.89(d，J＝5.9Hz)，119.50，118.73(d，J＝3.2Hz)，116.49，115.26，111.55(d，J＝11.8Hz)，38.09(d，J＝4.8Hz)，21.82，21.63.HRMS(ESI)Calcd for C20H16ClF3N5O[M+H]+：434.09900，found：434.09889.
n- (2- (6-methyl-1H-benzoimidazol-2-yl) phenyl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide (I16): white solid, yield 66.1%, mp 256-;1H NMR(400MHz，DMSO-d6)δ：13.90(s，1H)，13.15，13.11(s，s，1H)，8.79(d，J＝8.4Hz，1H)，8.15(d，J＝7.9Hz，1H)，7.64-7.37(m，3H)，7.30(t，J＝7.5Hz，1H)，7.15(t，J＝8.2Hz，1H)，7.05(s，1H)，4.09(s，3H)，2.48(s，3H)，2.32(d，J＝3.8Hz，3H).13C NMR(101MHz，DMSO-d6)δ：158.25，151.04，150.70，146.28，142.60，140.42，138.44(d，J＝4.8Hz)，136.66，134.10，133.48，131.90(d，J＝5.4Hz)，130.91(d，J＝5.4Hz)，127.50，125.42，124.45，123.49，120.13，118.00(d，J＝12.4Hz)，115.96，111.61(d，J＝15.5Hz)，107.14，21.82(d，J＝10.0Hz)，13.58.HRMS(ESI)Calcd for C20H20N5O[M+H]+：346.16624，found：346.16632.
n- (2- (6-methyl-1H-benzoimidazol-2-yl) phenyl) -1-methyl-3-isobutyl-1H-pyrazole-5-carboxamide (I17): white solid, yield 51.7%, mp 180-;1H NMR(400MHz，DMSO-d6)δ：13.96，13.87(s，s，1H)，13.17，13.13(s，s，1H)，8.80(dd，J＝8.2，3.5Hz，1H)，8.15(d，J＝8.0Hz，1H)，7.59-7.48(m，2H)，7.43(d，J＝23.1Hz，1H)，7.31(t，J＝7.6Hz，1H)，7.16(t，J＝8.0Hz，1H)，7.06(d，J＝10.7Hz，1H)，4.10(s，3H)，2.58-2.53(m，2H)，2.47(d，J＝9.7Hz，3H)，2.08-1.92(m，1H)，1.01(dd，J＝10.9，6.6Hz，6H).13C NMR(101MHz，DMSO-d6)δ：158.32(d，J＝4.2Hz)，151.12，150.76，149.99(d，J＝6.0Hz)，142.59，140.46，138.43(d，J＝8.6Hz)，136.55(d，J＝7.7Hz)，134.14，133.52，131.85(d，J＝11.4Hz)，130.96(d，J＝5.9Hz)，127.56，125.35，124.42，123.53，120.19，117.96，117.73，116.01(d，J＝3.3Hz)，111.69(d，J＝15.1Hz)，106.74(d，J＝9.7Hz)，37.18，28.95(d，J＝5.4Hz)，22.83(d，J＝2.7Hz)，21.74(d，J＝16.3Hz).HRMS(ESI)Calcd for C23H26N5O[M+H]+：388.21319，found：388.21304.
n- (2- (6-methyl-1H-benzimidazol-2-yl) phenylnicotinic acid amide (I18) as a white solid in a yield of 72.4%, mp 259-;1H NMR(400MHz，DMSO-d6)δ：14.24(s，1H)，13.20，13.15(s，s，1H)，9.46-9.35(m，1H)，8.98-8.80(m，2H)，8.56(d，J＝8.0Hz，1H)，8.19(d，J＝7.9Hz，1H)，7.76(dt，J＝8.0，5.1Hz，1H)，7.65-7.38(m，3H)，7.33(t，J＝7.3Hz，1H)，7.15(t，J＝9.3Hz，1H)，2.48(s，3H).13C NMR(101MHz，DMSO-d6)δ：163.76，152.88，151.13，150.79，149.11(d，J＝8.8Hz)，142.54，140.33，138.53(d，J＝4.4Hz)，135.40(d，J＝7.3Hz)，134.04，133.54，131.97，131.82，130.99(d，J＝6.9Hz)，130.82，127.48，125.50，124.42，124.32(d，J＝3.9Hz)，123.70，120.37，118.13(d，J＝8.7Hz)，116.24，111.69，111.54，21.86，21.70.HRMS(ESI)Calcd for C20H17N4O[M+H]+：329.13969，found：329.13992.
n- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl-2-chloronicotinicamide (I19) as a white solid in 70.3% yield, mp 150-;1H NMR(400MHz，DMSO-d6)δ：13.90(s，1H)，13.16，13.11(s，s，1H)，8.82(d，J＝8.1Hz，1H)，8.66(d，J＝3.0Hz，1H)，8.33(dd，J＝7.6，1.7Hz，1H)，8.18(d，J＝7.9Hz，1H)，7.71(dd，J＝12.1，6.1Hz，1H)，7.58(t，J＝7.8Hz，1H)，7.50-7.34(m，2H)，7.32-7.18(m，1H)，7.08(dd，J＝30.7，8.1Hz，1H)，2.42(d，J＝19.7Hz，3H).13C NMR(101MHz，DMSO-d6)δ：163.83，151.72，147.24，138.98，138.14，133.03，131.11，127.67，124.29，123.90，120.56，118.34，116.55，111.68，21.71(d，J＝21.2Hz).HRMS(ESI)Calcd for C20H16ClN4O[M+H]+：363.10072，found：363.10059.
examples of the use
Example 5: the invention relates to a bactericidal activity of amide derivatives I1-I19 containing benzimidazole group in formula (I) Sex determination
The bactericidal activity of amide derivatives I1-I19 containing benzimidazole group of formula (I) of the invention is measured by using Botrytis cinerea (Botrytis cinerea), Rhizoctonia solani (Rhizoctonia solani), Rhizoctonia cerealis (Fusarium graminearum) and early blight of tomato (Alternaria solani) as test fungi and adopting a hypha growth rate method.
The specific determination method is as follows:
weighing 18mg of original drug, dissolving in 0.8mL of DMSO (dimethylsulfoxide) to prepare a mother solution, adding 0.2mL of the mother solution into 45mL of sterile potato glucose agar culture medium (PDA culture medium), shaking uniformly to obtain 100mg/L of drug-containing culture medium, pouring the drug-containing culture medium into three sterile culture dishes in equal amount while the drug-containing culture medium is hot, cooling and solidifying, and inoculating a bacterial cake with the diameter of 0.5cm into the center of the culture medium. Blanks without test agent were set and each treatment was repeated 3 times. Culturing in 25 + -1 deg.C constant temperature incubator in dark, checking the inhibition of the agent on the growth of fungal hyphae after corresponding time (determined by the growth rate of different strains), and performing statistical analysis. Hypha growth inhibition rate: i (%) ═ C-T)/(C-0.5) × 100. C: blank control colony growth diameter (cm), T: agent treated colonies grew in diameter (cm).
The results of the bacteriostatic activity assay are shown in Table 2, and at a concentration of 100mg/L, the compounds I1-I19 showed significant bacteriostatic activity. The inhibition effect of the compounds I1, I2, I5, I7, I8, I10, I12, I14, I15, I16 and I19 on botrytis cinerea reaches more than 50%, and the inhibition effect of the compounds I2, I5, I14 and I15 reaches more than 80%. The inhibition rate of the compounds I1, I2, I5, I7, I8, I14, I15 and I19 on Rhizoctonia solani is higher than 60 percent. The inhibition rate of the compounds I2, I7 and I8 on wheat scab germ is higher than 50%. The inhibition rate of the compounds I7, I8, I14, I15, I16 and I19 on the early blight of tomato is higher than 50%, wherein the inhibition rate of the compounds I8, I14, I15, I16 and I19 is higher than 55.43% of that of a control medicament hymexazol. Among them, the compounds I7, I8, I14, I15 and I19 all showed good inhibitory activity against four tested fungi.
TABLE 2 fungicidal Activity measurement data (%) (I1-I19) of a benzimidazole group-containing amide derivative of the formula (I)
Those of ordinary skill in the art will understand that: the invention is not to be considered as limited to the specific embodiments thereof, but is to be understood as being modified in all respects, all changes and equivalents that come within the spirit and scope of the invention.

Claims (9)

1. Amide derivatives containing benzimidazole group of formula (I),
Figure FSA0000167796520000011
wherein the content of the first and second substances,
R1selected from the following 1-4 groups: hydrogen, C1-6Alkyl, halogen;
r is selected from substituted pyrazole and substituted pyridine, and the substituted group is selected from 1 to 3 groups as follows: hydrogen, C1-6Alkyl, halogen, mercapto, methyl substituted with 1-3 halogens.
2. The benzimidazole group-containing amide derivative of claim 1, wherein:
R1selected from hydrogen, C1-6Alkyl, halogen;
r is selected from 1-methyl-3-C1-6alkyl-5-halo-1H-pyrazol-4-yl, 1-methyl-3-trifluoromethyl-5-halo-1H-pyrazol-4-yl, 1-methyl-3-C1-6alkyl-1H-pyrazol-5-yl, pyridin-3-yl, 2-halopyridin-3-yl, mercaptopyridin-3-yl.
3. The benzimidazole group-containing amide derivative of claim 2, wherein:
R1selected from H, 6-CH3、6-Cl；
R is selected from 1, 3-dimethyl-5-chloro-1H-pyrazol-4-yl, 1-methyl-3-trifluoromethyl-5-chloro-1H-pyrazol-4-yl, 1, 3-dimethyl-1H-pyrazol-5-yl, 1-methyl-3-isobutyl-1H-pyrazol-5-yl, pyridine-3-yl, 2-chloropyridine-3-yl and 2-mercaptopyridine-3-yl.
4. The benzimidazole group-containing amide derivative of claim 3, which is one of the following compounds:
n- (2- (1H-benzimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide,
N- (2- (1H-benzimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide,
N- (2- (1H-benzimidazol-2-yl) phenyl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide,
N- (2- (1H-benzimidazol-2-yl) phenyl) -1-methyl-3-isobutyl-1H-pyrazole-5-carboxamide,
N- (2- (1H-benzimidazol-2-yl) phenyl) -2-chloronicotinicamide,
N- (2- (1H-benzimidazol-2-yl) phenyl) -2-mercaptonicotinic acid amide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl) -1-methyl-3-isobutyl-1H-pyrazole-5-carboxamide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenylnicotinic acid amide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl-2-chloronicotinicamide,
N- (2- (6-chloro-1H-benzimidazol-2-yl) phenyl-2-mercaptonicotinic acid amide,
N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl) -5-chloro-1, 3-dimethyl-1H-pyrazole-4-carboxamide,
N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl) -5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamide,
N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide,
N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl) -1-methyl-3-isobutyl-1H-pyrazole-5-carboxamide,
N- (2- (6-methyl-1H-benzimidazole-2-yl) phenyl nicotinic acid amide,
N- (2- (6-methyl-1H-benzimidazol-2-yl) phenyl-2-chloronicotinicamide.
5. A process for producing the benzimidazole group-containing amide derivative of any one of claims 1 to 4, which comprises the step of preparing a compound represented by the general formula (A):
Figure FSA0000167796520000021
wherein in each of the above structural formulae:
R1r both have the meaning as claimed in any of claims 1 to 4.
6. Use of the amide derivative containing a benzimidazole group according to any one of claims 1 to 4 for inhibiting phytopathogenic fungi.
7. Use of the amide derivative containing a benzimidazole group according to any one of claims 1 to 4 for controlling fungal diseases in plants.
8. The use according to claim 6, characterized in that the amide derivatives containing benzimidazole group of any one of claims 1-4 is used for inhibiting Botrytis cinerea, Rhizoctonia solani, Fusarium graminearum, and Phytophthora solani.
9. The use of claim 7, wherein the amide derivative containing benzimidazole group is used for preventing and treating tomato gray mold, rice sheath blight disease, wheat scab and tomato early blight, according to any one of claims 1 to 4.
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Application publication date: 20200204