A benzamide compound, its preparation method and application

Abstract

The invention discloses a benzamide compound and a preparation method and application thereof. The structural formula of the benzamide compound is as shown in formula (I): in formula (I), when X is NH, the substituent R is an alkyl, a phenyl or a substituted phenyl, and the substituent of the substituted phenyl is selected from halogen, nitro, an alkyl or an alkoxy group; in formula (I), when X is O, R is a phenyl or a substituted phenyl, and the substituent of the substituted phenyl is selected from halogen. The N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compound provided by the invention is a novel bactericidal compound, which provides a basis for studying efficient and green bactericides.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and pharmaceutical application, and specifically relates to a benzamide compound and a preparation method and application thereof. Background Art

[0002] Pyridine and pyridine derivatives play an important role in the production of medicines, pesticides, dyes, fragrances, rubber additives, surfactants, feed additives, etc. Pyridine compounds are an important class of six-membered nitrogen-containing heterocyclic derivatives. Pyridine compounds have biological activities such as anti-cancer, bactericidal, insecticidal, herbicidal, and anti-neuropathic pain. Due to their high activity, high selectivity, low toxicity, and low residue, they have become a research hotspot in drug research in recent years.

[0003] The introduction of pyridine groups into pesticide molecules may make the resulting substances have higher biological activity, which provides a basis for the transformation and modification of drug structures. Summary of the invention

[0004] The object of the present invention is to provide a benzamide compound and a preparation method and application thereof. In order to study a greener and more efficient fungicide, fluopyram was used as a lead compound and its structure was modified to design and synthesize a novel N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compound, and the fungicidal activity was tested.

[0005] The benzamide compound has a structural formula as shown in formula (I):

[0006]

[0007] In formula (I), the substituent X is NH or O;

[0008] When the substituent X is NH, the substituent R is selected from alkyl, phenyl or substituted phenyl;

[0009] Preferably, the alkyl group is cyclopropyl and the substituent of the substituted phenyl group is 4-chloro, 2-chloro, 2-methyl, 2,3-dichloro, 4-tert-butyl, 3-methyl, 3-nitro, 3-fluoro or 3-methoxy;

[0010] When the substituent X is O, the substituent R is selected from phenyl or substituted phenyl;

[0011] Preferably, the substituent of the substituted phenyl group is 2-chloro or 3-chloro.

[0012] The preparation method of the benzamide compound comprises the following steps:

[0013] 1) using DMF as solvent and NaH to provide an alkaline environment, reacting the compound represented by formula (II) with 2,3-dichloro-5-trifluoromethylpyridine to generate a compound represented by formula (III);

[0014] 2) Using DCM as solvent, the compound of formula (III) obtained in step 1) is reacted with trifluoroacetic acid to obtain a compound of formula (IV).

[0015] 3) using DCM as solvent and triethylamine to provide an alkaline environment, reacting the compound of formula (IV) obtained in step 2) with the compound of formula (V) to obtain the N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compound of formula (I);

[0016]

[0017]

[0018] In formula (I), (II), (III) and (IV), the substituent X is NH or O;

[0019] In formula (I) and (V), when X is NH, R is alkyl, phenyl or substituted phenyl;

[0020] Preferably, the alkyl group is cyclopropyl and the substituent of the substituted phenyl group is 4-chloro, 2-chloro, 2-methyl, 2,3-dichloro, 4-tert-butyl, 3-methyl, 3-nitro, 3-fluoro or 3-methoxy;

[0021] In formula (I) and (V), when X is O, R is phenyl or substituted phenyl;

[0022] Preferably, the substituent of the substituted phenyl group is 2-chloro or 3-chloro.

[0023] The reaction process is as follows:

[0024]

[0025] Furthermore, when synthesizing the compound represented by formula (III) in step 1), the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to the compound represented by formula (II) is 1:1-1:1.5.

[0026] Furthermore, when synthesizing the compound represented by formula (IV) in step 2), the molar ratio of the compound represented by formula (III) to trifluoroacetic acid is 1:1-1:1.5.

[0027] Furthermore, in step 3), when synthesizing N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compounds, the molar ratio of the compound represented by formula (IV) to the compound represented by formula (V) is 1:1-1:1.5.

[0028] Application of the above-mentioned benzamide compounds in the preparation of fungicides.

[0029] The beneficial effects of the present invention are:

[0030] The preparation method of the present invention is simple, does not require metal catalysts, is green and environmentally friendly, and the structure of the obtained product is 1 H NMR and HRMS were used to confirm the identity of the 14 new compounds. The fungicidal activity of the compounds was tested. At a concentration of 50 ppm, all the compounds showed certain fungicidal activity, which provided a basis for the study of fungicides containing pyridine rings. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0032] The reaction equation is:

[0033]

[0034] Example 1-2 Preparation of Compounds III-1 to III-2

[0035] In a 100mL round-bottom bottle, add 2,3-dichloro-5-trifluoromethylpyridine (10.8g, 0.05mol), 0.06mol of the compound shown in formula (II) (the substituent X is NH or O), and DMF (30mL) as solvent. At room temperature, add sodium hydride (1.2g, 0.05mol) in batches and stir to dissolve. Heat to reflux, TLC (V EV / V PE =1 / 4) to track the reaction, and the reaction was completed in about 4 hours. After the reaction was completed, it was cooled to room temperature, 60 mL of water was added, extracted with ethyl acetate (30 mL×2), and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by rotary evaporation, and purified by column chromatography to obtain compounds III-1 to III-2.

[0036] Example 3-4 Preparation of Compounds IV-1 to IV-2

[0037] In a 50 mL round-bottom flask, compound III-1 or compound III-2 (0.37 g, 1.1 mmol) and dichloromethane (15 mL) were added, stirred evenly, and trifluoroacetic acid (0.171 g, 1.5 mmol) was added, and the mixture was reacted at room temperature for 4 h. TLC (V EV / VPE =4 / 1) to track the reaction. After the reaction, dichloromethane and trifluoromethylacetic acid were removed by rotary evaporation to obtain compounds shown in IV-1 to IV-2.

[0038] Example 5-18 Preparation of N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compounds

[0039] Compound IV-1 or IV-2 (0.96 mmol), triethylamine (0.5 mmol) and DCM (5 mL) were added to a 50 mL round-bottom flask in sequence. After stirring at room temperature for half an hour, 1.06 mmol of the compound represented by formula (V) was added. When the substituent X is NH, the substituent R is selected from cyclopropyl, phenyl or substituted phenyl, and the substituent of the substituted phenyl is 4-chloro, 2-chloro, 2-methyl, 2,3-dichloro, 4-tert-butyl, 3-methyl, 3-nitro, 3-fluoro or 3-methoxy; when the substituent X is O, the substituent R is selected from phenyl or substituted phenyl, and the substituent of the substituted phenyl is 2-chloro or 3-chloro), stirring was continued, and TLC (V EA / V PE =1 / 1) to track the reaction progress. After the reaction is completed, transfer to a separatory funnel, add water (15 mL), extract with ethyl acetate (5 mL×3), combine the organic phases, wash with saturated brine (5 mL×3), dry over anhydrous sodium sulfate, filter, spin dry the solvent, and purify by column chromatography to obtain the target compounds I-1 to I-14.

[0040] Table 1 Physical properties of benzamide compounds

[0041] Target compound Substituent Group X Substituent group R Appearance Melting point℃ Yield % Ⅰ-1 NH Ph White solid 136.7～136.9 57.9 Ⅰ-2 NH 4-ClPh White solid 221.9～223.6 57.9 Ⅰ-3 NH 2-ClPh White solid 136.2～137.6 57.9 Ⅰ-4 NH 2-MePh White solid 167.8～168.2 66.7 Ⅰ-5 NH 2,3-diClPh White solid 252.3～252.7 61.7 Ⅰ-6 NH cyclopropyl White solid 170.5～170.5 58.5 Ⅰ-7 NH 4-t-BuPh White solid 156.0～156.2 63.8 Ⅰ-8 NH 3-MePh White solid 131.5～132.0 62.7 Ⅰ-9 NH <![CDATA[3-NO2Ph]]> White solid 150.9～151.7 62.4 Ⅰ-10 NH 3-FPh White solid 121.0～121.5 62.4 Ⅰ-11 NH 3-MeOPh White solid 100.1～100.3 61.3 Ⅰ-12 O Ph White solid 142.4～143.2 62.4 Ⅰ-13 O 2-ClPh White solid 130.1～130.8 65.3 Ⅰ-14 O 3-ClPh White solid 138.8～139.1 59.5

[0042] Table 2 Benzamide compounds 1 H NMR and HRMS data

[0043]

[0044]

[0045]

[0046]

[0047] Example 19 Bactericidal activity test

[0048] Test methods

[0049] (1) Test subjects: Fusarium oxysporum (FO), Cercospora arachidicola (CA), Botryosphaeria berengriana (BB), Alternaria solani (AI), Gibberella zeae (GZ), Sclerotinia sclerotiorum (SS), Botrytis cinerea (BC), Riziocotinia solani (RS), Pyricularia oryae (PI), and Phytophthora capsici (PC)

[0050] (2) Test treatment: Each test compound was dissolved in DMSO to form a 1% EC stock solution for later use. The inhibition zone method was used to evaluate the indoor bactericidal activity of the test compound against the test target at a dose of 50 ppm, and a clear water control (CK) was set up.

[0051] (3) Test method: Use a pipette to draw 150 microliters of the above-prepared EC mother solution, dissolve it in 2.85 mL of Tween water, and prepare a solution with an effective concentration of 500 ppm of the compound to be tested. Use a pipette to draw 1 ml of the solution into a sterilized culture dish, then put in 9 ml of PDA culture medium, shake well, and cool. Use a hole punch to punch out a round bacterial cake and use an inoculation needle to pick it to the center of the culture dish, then place the culture dish in an incubator at 27°C and culture it. After 48 hours, measure the colony diameter. The pure growth of the colony is the difference between the average diameter of the colony and the diameter of the bacterial cake. The method for calculating the antibacterial rate (%) refers to the following formula.

[0052]

[0053] The activity test results are shown in Table 3:

[0054] Table 3 Bactericidal activity of benzamide compounds

[0055]

[0056] The fungicidal activity results of N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compounds (14) showed (Table 3) that at a concentration of 50 ppm, compound I-2 had an inhibitory activity of 47.6% against cucumber wilt pathogen and 37.5% against peanut brown spot pathogen; compound I-13 had inhibition rates of 53.6% and 56.1% against apple ring rot pathogen and rapeseed sclerotinia pathogen, respectively; compounds I-2 and I-7 had inhibition rates of 33.3% against tomato early blight pathogen, and compound I-4 had an inhibition rate of 41.7% against wheat fusarium rust pathogen; compound I-7 had inhibition rates of 40.0%, 37.9% and 40.9% against cucumber gray mold pathogen, rice sheath blight pathogen and rice blast pathogen; compound I-12 had an inhibition rate of 48.4% against pepper phytophthora pathogen.

[0057] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept. The protection scope of the present invention should not be regarded as limited to the specific forms described in the embodiments. The protection scope of the present invention is also limited to the equivalent technical means that can be thought of by those skilled in the art based on the inventive concept.

Claims

1. Use of a benzamide compound in the preparation of a fungicide, characterized in that: The structural formula of the benzamide compound is shown in formula (I), When the colony is rice blast fungus or rice sheath blight fungus, X is NH and R is 4-tert-butylbenzene; when the colony is wheat fusarium, X is O and R is 3-chlorophenyl; when the colony is pepper phytophthora, X is O, R is phenyl.

2. A method for preparing a benzamide compound as claimed in claim 1, characterized in that: The steps include: 1) using DMF as solvent and NaH to provide an alkaline environment, reacting the compound represented by formula (II) with 2,3-dichloro-5-trifluoromethylpyridine to generate a compound represented by formula (III); 2) using DCM as solvent, reacting the compound of formula (III) obtained in step 1) with trifluoroacetic acid to obtain a compound of formula (IV); 3) using DCM as solvent and triethylamine to provide an alkaline environment, reacting the compound of formula (IV) obtained in step 2) with the compound of formula (V) to obtain the N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compound of formula (I); X is NH, and R is 4-tert-butylbenzene; X is O, and R is 3-chlorophenyl or phenyl.

3. The method for preparing a benzamide compound according to claim 2, characterized in that When synthesizing the compound represented by formula (III) in step 1), the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to the compound represented by formula (II) is 1:1-1:1.

5.

4. The method for preparing a benzamide compound according to claim 2, characterized in that When synthesizing the compound represented by formula (IV) in step 2), the molar ratio of the compound represented by formula (III) to trifluoroacetic acid is 1:1-1:1.

5.

5. The method for preparing a benzamide compound according to claim 2, characterized in that In step 3), when synthesizing N-(2-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)benzamide compounds, the molar ratio of the compound represented by formula (IV) to the compound represented by formula (V) is 1:1-1:1.5.

Images