Heterocyclic alkaloid-oriented polysubstituted chain amide compound as well as preparation method and application thereof

Abstract

The invention provides a heterocyclic alkaloid-oriented polysubstituted chain amide compound as well as a preparation method and application thereof. The structural formula of the polysubstituted chain amide compound is as shown in (I): # imgabs0. The polysubstituted chain amide compound is designed and synthesized by applying a four-component Ugi reaction, putting formic acid, amine, formaldehyde and tert-butyl isonitrile containing different substituent groups into an organic solvent, heating, reacting, separating and purifying. The preparation method does not need a catalyst, and is simple to operate and relatively low in cost. Experiments prove that the compound has good bactericidal activity on various plant pathogenic fungi, and can be used as an active lead compound for development of amide fungicides.

Description

Technical Field

[0001] The present invention relates to the technical field of bio-organic and medicinal chemistry, and in particular to a heterocyclic alkaloid-directed multi-substituted chain amide compound and a preparation method and application thereof. Background Art

[0002] Natural products usually come from plants, animals or microorganisms. Due to the diversity of their structures and biological activities, they play a vital role in drug research and development. It is not only an important source of many existing drugs, but also an important lead compound in the development of new drugs. At present, many drugs on the market are derived from natural products, such as penicillin extracted from Penicillium, which is widely used as an important antibiotic; paclitaxel extracted from yew trees is widely used in anti-cancer drugs. There are also many drugs that are finally developed into drugs by structural modification of natural products, such as aspirin, a non-steroidal anti-inflammatory drug obtained by modifying salicylic acid, which has better efficacy and lower side effects and is widely used. Compared with synthetic chemicals, natural products have lower side effects and toxicity, and usually act on multiple biological targets at the same time, often with lower risk of drug resistance and better therapeutic effects. Therefore, the development of drug molecules based on natural products has unique advantages.

[0003] Plant fungal diseases pose a serious threat to agricultural production. They can lead to reduced or even complete crop failures, and pose a potential safety risk to food security. Although the use of chemical fungicides has become one of the important means of preventing and controlling diseases, the high-frequency use of fungicides has led to the generation of resistant strains and reduced efficacy, which is becoming increasingly serious. Therefore, it is inevitable to develop high-efficiency, low-toxic, highly safe, and environmentally friendly fungicide products based on natural products. Summary of the invention

[0004] In view of the above problems existing in the prior art, the purpose of the present invention is to provide a preparation and application of a polysubstituted chain amide compound based on heterocyclic alkaloids. In order to develop a greener and more efficient chemical fungicide, a one-pot four-component Ugi reaction is adopted, and natural heterocyclic aromatic acids, amines, formaldehyde and isonitriles containing different substituents are used as starting materials to design and synthesize the polysubstituted chain amide compound of the present invention.

[0005] The technical solution adopted by the present invention is as follows:

[0006] In a first aspect, the present invention provides a multi-substituted chain amide compound, wherein the structural formula of the multi-substituted chain amide compound is shown in (I):

[0007]

[0008] Among them, the R 1is any one of pyrrolyl, substituted pyridyl, substituted indolyl, substituted methylpyrazolyl, phenyl, and substituted phenyl;

[0009] The substituent on the substituted pyridyl group is 4-trifluoromethyl, 4-chloro, or 4-fluoro;

[0010] The substituted indolyl group is a substituted 2-indolyl group or a substituted 3-indolyl group;

[0011] The substituent on the substituted methylpyrazolyl group is one of 3-difluoromethyl and 3-trifluoromethyl;

[0012] The R 2 is any one of a straight chain or branched chain alkyl group, a saturated or unsaturated cycloalkyl group, a phenyl group, and a heteroaryl group;

[0013] The R 3 is any one of substituted phenyl, substituted aryl, and substituted heteroaryl, and the substituents on the phenyl, aryl, and heteroaryl are each independently selected from any one of fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, and methoxy;

[0014] R 4 It is any one of a straight chain or branched chain alkyl group, a saturated or unsaturated cycloalkyl group, a phenyl group, and a heteroaryl group.

[0015] Preferably, the R 2 Any one selected from n-butyl, cyclopropyl, and phenyl;

[0016] The R 4 Any one selected from tert-butyl and 4-methoxyphenyl.

[0017] Preferably, the multi-substituted chain amide compound is selected from any one of the following compounds 1 to 28;

[0018]

[0019]

[0020] In a second aspect, the present invention further provides a method for preparing the polysubstituted chain amide compound, comprising the following steps:

[0021] R 2 Substituted amine, R 3 Substituted formaldehyde is added to an organic solvent to react and generate imine;

[0022] Add R to the above reaction system 1 Substituted formic acid and R 4 Substitute the isonitrile to obtain a multi-substituted chain amide compound through reaction.

[0023] Preferably, the structural formula of the multi-substituted chain amide compound is:

[0024]

[0025] The preparation method of the multi-substituted chain amide compound comprises the following steps:

[0026] R 2 Substituted amine, R 3 Substituted formaldehyde is added to an organic solvent to react and generate imine;

[0027] Add R to the above reaction system 1 Substituted formic acid and R 4 Substitute isonitrile to obtain multi-substituted chain amide compounds after reaction;

[0028] Among them, R 2 The structural formula of substituted amines is R2-NH2;

[0029] R 3 The structural formula of substituted formaldehyde is R3-CHO;

[0030] R 1 The structural formula of substituted formic acid is R1-COOH;

[0031] R 4 The substituted isonitrile is tert-butyl isonitrile.

[0032] Preferably, the organic solvent comprises N,N-dimethylformamide and methanol, and the volume ratio of N,N-dimethylformamide to methanol is 1:(2-5);

[0033] and / or, the R 1 Substituted formic acid, R 2 Substituted amine, R 3 The molar ratio of substituted formaldehyde to tert-butyl isonitrile is 1:(1-1.2):(1-1.2):(1-1.2);

[0034] and / or, the R 1 The molar volume ratio of the substituted formic acid to the organic solvent is 1 mmol: (3-6) mL.

[0035] Preferably, R 2 Substituting amine, R3 substituting formaldehyde is added to an organic solvent, and reacted at 20-25°C with stirring for 1-2 hours to generate an imine;

[0036] Add R to the above reaction system 1 Substituted formic acid and R 4 In the step of replacing isonitrile, the reaction temperature is 70-100° C. and the reaction time is 2-24 hours.

[0037] In a third aspect, the present invention also provides a bactericidal composition comprising the multi-substituted chain amide compound.

[0038] In a fourth aspect, the present invention also provides a use of the polysubstituted chain amide compound or the fungicide composition in the preparation of drugs for killing plant diseases.

[0039] Preferably, in the application, the plant diseases include at least one of rapeseed sclerotinia, rapeseed black shank, grape gray mold, wheat fusarium wilt, wheat glumes blight, cotton verticillium wilt, cotton wilt, rice sheath blight, rice blast, and banana Panama disease.

[0040] The multi-substituted chain amide compounds and the preparation method and application thereof provided by the present invention have the following beneficial effects compared with the prior art:

[0041] 1. The preparation method of the polysubstituted chain amide compounds of the present invention uses simple basic chemical raw materials to realize a one-pot four-component reaction to prepare the polysubstituted chain amide compounds. Compared with the traditional preparation method of amide compounds, the preparation method has cheap and easy-to-obtain raw materials, a one-pot four-component reaction without the use of a catalyst, simple operation, good reaction atom economy, easy separation of products, low production cost, and is easy to scale up production;

[0042] 2. The structures of the novel multi-substituted chain amide compounds of the present invention were confirmed by H-NMR, C-NMR and MS, and the 28 target products obtained were tested for their fungicidal activity. The results showed that some compounds showed obvious fungicidal activity against crop pathogens such as rapeseed sclerotinia, grape gray mold, rapeseed black shank, cotton verticillium wilt, rice sheath blight and rice blast. They can be used as lead compounds for the development of novel amide fungicides, and can also be used as fungicides or their active ingredients for the green prevention and control of agricultural pathogenic fungal diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0044] Figure 1 is the H NMR spectrum of compound 11;

[0045] Figure 2The treatment effects of compound 1, compound 3, compound 4, compound 6, compound 9, compound 16, compound 17, compound 19, compound 22 and the control group on four pathogenic fungi, namely, rice sheath blight, Botrytis cinerea, rapeseed sclerotinia and rapeseed black leg pathogen;

[0046] Figure 3 This is a graph showing the inhibitory effects of compound 9 and compound 16 on Sclerotinia sclerotiorum at different concentrations;

[0047] Figure 4 The inhibition rates of compounds 9 and 16 on Sclerotinia sclerotiorum of rapeseed at different concentrations. DETAILED DESCRIPTION

[0048] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0049] The present invention provides a multi-substituted chain amide compound, the structural formula of which is shown as (I):

[0050]

[0051] Among them, R 1 is any one of pyrrolyl, substituted pyridyl, substituted indolyl, substituted methylpyrazolyl, phenyl, and substituted phenyl;

[0052] The substituents on the substituted pyridyl group are 4-trifluoromethyl, 4-chloro, 4-fluoro;

[0053] The substituted indolyl group is a substituted 2-indolyl group or a substituted 3-indolyl group;

[0054] The substituent on the substituted methylpyrazolyl group is one of 3-difluoromethyl and 3-trifluoromethyl;

[0055] R 2 is any one of a straight chain or branched chain alkyl group, a saturated or unsaturated cycloalkyl group, a phenyl group, and a heteroaryl group;

[0056] R 3 is any one of substituted phenyl, substituted aryl, and substituted heteroaryl, and the substituents on the phenyl, aryl, and heteroaryl are each independently selected from any one of fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, and methoxy;

[0057] R 4 It is any one of a straight chain or branched chain alkyl group, a saturated or unsaturated cycloalkyl group, a phenyl group, and a heteroaryl group.

[0058] In some embodiments, R 2 Any one selected from n-butyl, cyclopropyl, and phenyl;

[0059] R 4 Any one selected from tert-butyl and 4-methoxyphenyl.

[0060] In some embodiments, the multi-substituted chain amide compound is selected from any one of the following compounds 1 to 28;

[0061]

[0062]

[0063] Based on the same inventive concept, the present invention also provides a method for preparing the above-mentioned multi-substituted chain amide compounds, comprising the following steps:

[0064] S1, R 2 Substituted amine, R 3 Substituted formaldehyde is added to an organic solvent to react and generate imine;

[0065] S2, add R to the above reaction system 1 Substituted formic acid and R 4 Substitute the isonitrile to obtain a multi-substituted chain amide compound through reaction.

[0066] In some embodiments, the structural formula of the multi-substituted chain amide compound is:

[0067]

[0068] The preparation method of a multi-substituted chain amide compound comprises the following steps:

[0069] R 2 Substituted amine, R3 substitutes formaldehyde and adds it to an organic solvent to react and form an imine;

[0070] Add R to the above reaction system 1 Substituted formic acid and R 4 Substitute isonitrile to obtain multi-substituted chain amide compounds after reaction;

[0071] Among them, R 2 The structural formula of substituted amines is R2-NH2;

[0072] R 3 The structural formula of substituted formaldehyde is R3-CHO;

[0073] R 1 The structural formula of substituted formic acid is R1-COOH;

[0074] R 4 The substituted isonitrile is tert-butyl isonitrile.

[0075] Specifically, the preparation method of the multi-substituted chain amide compound has the following reaction principle:

[0076]

[0077] ;in, That is, it means tert-butyl isocyanide.

[0078] The present invention uses a four-component Ugi reaction (i.e., Ugi reaction), places formic acid, amine, formaldehyde and tert-butyl isonitrile containing different substituents in an organic solvent for heating reaction and separation and purification, and designs and synthesizes the multi-substituted chain amide compounds of the present invention. The preparation method does not require the use of a catalyst, is simple to operate, and has low cost. Through experimental verification, the compounds have good fungicidal activity against a variety of plant pathogenic fungi and can be used as active lead compounds for the development of amide fungicides.

[0079] In some embodiments, the organic solvent includes N,N-dimethylformamide and methanol, and the volume ratio of N,N-dimethylformamide to methanol is 1:(2-5); preferably, the volume ratio of N,N-dimethylformamide to methanol is 1:2.

[0080] In some embodiments, R 1 Substituted formic acid, R 2 Substituted amine, R 3 The molar ratio of substituted formaldehyde to tert-butyl isocyanide is 1:(1-1.2):(1-1.2):(1-1.2); preferably, R 1 Substituted formic acid, R 2 Substituted amine, R 3 The molar ratio of substituted formaldehyde to tert-butyl isocyanide is 1:1:1:1.

[0081] In some embodiments, R 1 The molar volume ratio of the substituted formic acid to the organic solvent is 1 mmol: (3-6) mL, preferably, the molar volume ratio is 1 mmol: 3 mL.

[0082] In some embodiments, R 2 Substituted amine, R 3 Substitute formaldehyde into an organic solvent and stir to react at 20-25°C for 1-2 hours to generate imine;

[0083] Add R to the above reaction system 1 Substituted formic acid and R 4In the step of replacing isonitrile, the reaction temperature is 70-100° C. and the reaction time is 2-24 h. Preferably, the preferred reaction temperature is 70° C. and the reaction time is 2 h.

[0084] Based on the same inventive concept, the present invention also provides a bactericidal composition, comprising the multi-substituted chain amide compound.

[0085] Based on the same inventive concept, the present invention also provides an application of the multi-substituted chain amide compound or the fungicide composition in the preparation of drugs for killing plant diseases.

[0086] In some embodiments, the plant diseases include at least one of rapeseed sclerotinia, rapeseed blackleg, grape gray mold, wheat fusarium wilt, wheat glumen blight, cotton verticillium wilt, cotton wilt, rice sheath blight, rice blast, and banana Panama disease.

[0087] The preparation method of the polysubstituted chain amide compounds of the present invention uses simple basic chemical raw materials to realize a one-pot four-component reaction to prepare the polysubstituted chain amide compounds. Compared with the traditional preparation method of bisamide compounds, the preparation method has cheap and easy-to-obtain raw materials, a one-pot four-component reaction without the use of a catalyst, simple operation, good atomic economy of the reaction, easy separation of products, low production cost and convenient for scale-up production; the new structure of the polysubstituted chain amide compounds of the present invention was structurally confirmed by nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum, and the 28 target products obtained were tested for fungicidal activity. The results showed that some compounds showed obvious fungicidal activity against crop pathogens such as rapeseed sclerotinia, grape gray mold, rapeseed black shank, cotton wilt, rice sheath blight, and rice blast, and can be used as a lead for the development of new amide fungicides, and can also be used as fungicides or their active ingredients for green prevention and control of agricultural pathogenic fungal diseases.

[0088] The following further illustrates the polysubstituted chain amide compounds of the present application and their preparation methods and applications with specific examples. This section further illustrates the content of the present invention in conjunction with specific examples, but should not be construed as limiting the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0089] Example 1

[0090] This example provides the preparation of compound 1. The following is the chemical reaction equation for preparing compound 1:

[0091]

[0092] The specific preparation method of compound 1 is as follows: 3 mmol of n-butylamine and 3 mmol of benzaldehyde are dissolved in 12 mL of an organic solvent (the organic solvent is N, N-dimethylformamide and methanol, and the volume ratio of N, N-dimethylformamide and methanol is 1:2), and after stirring at room temperature (25°C) for 1 hour, 3 mmol of 2-pyrrolcarboxylic acid and 3 mmol of tert-butyl isonitrile are added to obtain a reaction solution; the above reaction solution is stirred at 70°C in a reactor equipped with a magnetic stirrer for 12 hours. After the reaction is completed, the reaction solution is slowly dripped into ice water to quench, extracted three times with ethyl acetate, and the organic phases are combined and separated by column chromatography (the eluent is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 99:1), and 532 mg of compound 1 is purified, and the separation yield is 49.88%.

[0093] The spectral data of the obtained compound 1 are as follows: 1 HNMR(600MHz, CDCl3)δ9.64(s,1H),7.42–7.31(m,4H),6.93(s,1H),6.58(s,1H),6.28(s,1H) ,5.82(s,1H),3.63(d,J=27.6Hz,2H),1.35(s,9H),1.25–1.05(m,4H),0.78(t,J=7.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ169.36,162.86,135.89,129.22,128.81,128.36,124.8 1,121.39,112.39,110.47,65.54,51.67,47.99,31.14,28.77,20.06,13.73.

[0094] Example 2

[0095] This example provides the preparation of compound 11. The following is the chemical reaction equation for preparing compound 11:

[0096]

[0097] The specific preparation method of compound 11 is as follows: 3 mmol of cyclopropylamine and 3 mmol of 4-trifluoromethylbenzaldehyde are dissolved in 12 mL of an organic solvent (the organic solvent is N, N-dimethylformamide and methanol, and the volume ratio of N, N-dimethylformamide and methanol is 1:2), and after stirring at room temperature for 1 hour, 3 mmol of 2-indolecarboxylic acid and 3 mmol of tert-butyl isonitrile are added to obtain a reaction solution; the above reaction solution is stirred at 70°C in a reactor equipped with a magnetic stirrer for 2 hours. After the reaction is completed, the reaction solution is slowly dripped into ice water to quench, extracted three times with ethyl acetate, and the organic phases are combined and separated by column chromatography (the eluent is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 98:2), and the compound 11 is purified to obtain 589 mg, and the separation yield is 42.91%.

[0098] The H NMR spectrum of the obtained compound 11 is as follows: Figure 1 shown.

[0099] The spectral data of the obtained compound 11 are as follows: 1 H NMR (600MHz, CDCl3) δ9.37(s,1H),7.68(d,J=8.4Hz,1H),7.63(d,J=7.8Hz,2H),7.57(d,J=7.8Hz,2H),7.38(d,J=8.4Hz,1H),7.30(t,J=8 .4Hz,1H),7.22(s,1H),7.15(t,J=7.8Hz,1H),6.57(s,1H),5.68(s,1H),2.98(s,1H),1.36(s,9H),1.14–0.95(m,2H),0.94–0.81(m,2H). 13 C NMR (151MHz, CDCl3) δ169.00,165.52,139.88,135.87,130.41,129.58,129.26,127.93,12 5.62,125.33,122.57,120.83,111.86,108.46,68.86,51.69,32.77,28.68,12.08,11.80.

[0100] Example 3

[0101] This example provides the preparation of compound 15. The following is the chemical reaction formula for preparing compound 15:

[0102]

[0103] The specific preparation method of compound 15 is as follows: 3 mmol of aniline and 3 mmol of benzaldehyde are dissolved in 12 mL of an organic solvent (the organic solvent is N, N-dimethylformamide and methanol, and the volume ratio of N, N-dimethylformamide and methanol is 1:2), and after stirring at room temperature for 1 hour, 3 mmol of 4-trifluoromethyl-3-pyridinecarboxylic acid and 3 mmol of tert-butyl isonitrile are added to obtain a reaction solution; the above reaction solution is stirred at 70°C in a reactor equipped with a magnetic stirrer for 2 hours. After the reaction is completed, the reaction solution is slowly dripped into ice water to quench, extracted three times with ethyl acetate, and the organic phases are combined and separated by column chromatography (the eluent is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 98:2), and 510 mg of compound 15 is obtained by purification, and the separation yield is 37.32%.

[0104] The spectral data of the obtained compound 15 are as follows: 1 H NMR (600MHz, CDCl3) δ8.59(s,1H),8.52(d,J=4.8Hz,1H),7.36(d,J=5.4Hz,1H),7.25–6.91(m,10H),6.13(s,1H),5.72(s,1H),1.39(s,9H). 13 C NMR (151MHz, CDCl3) δ168.09,166.45,150.26,139.14,134.81,134.09,130.64,130.44, 129.45,128.85,128.77,128.65,128.23,123.54,121.71,119.86,66.39,51.99,28.75.

[0105] Example 4

[0106] This example provides the preparation of compound 20. The following is the chemical reaction formula for preparing compound 20:

[0107]

[0108] The specific preparation method of compound 20 is as follows: 3 mmol of cyclopropylamine and 3 mmol of benzaldehyde are dissolved in 12 mL of an organic solvent (the organic solvent is N, N-dimethylformamide and methanol, and the volume ratio of N, N-dimethylformamide and methanol is 1:2), and after stirring at room temperature for 1 hour, 3 mmol of 3-indolecarboxylic acid and 3 mmol of tert-butyl isonitrile are added to obtain a reaction solution; the above reaction solution is stirred at 70°C in a reactor equipped with a magnetic stirrer for 24 hours. After the reaction is completed, the reaction solution is slowly dripped into ice water to quench, extracted three times with ethyl acetate, and the organic phases are combined and separated by column chromatography (the eluent is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol is 99:1), and purified to obtain 340 mg of compound 20, with an isolated yield of 29.10%.

[0109] The spectral data of the obtained compound 20 are as follows: 1 H NMR (600MHz, CDCl3) δ8.91(s,1H),8.06(d,J=7.8Hz,1H),7.59(d,J=2.4Hz,1H),7.53(d,J=7.8Hz,2H),7.37(t ,J=7.2Hz,3H),7.31(t,J=7.8Hz,1H),7.24–7.17(m,2H),6.68(s,1H),5.69(s,1H),1.37(s,9H),1.25(s,4H). 13 C NMR (151MHz, CDCl3) δ170.48,169.17,136.29,135.53,129.55,128.59,128.18,128.0 2,123.03,121.77,121.49,111.44,68.16,51.43,32.44,29.84,28.75,11.58,10.81.

[0110] Example 5

[0111] Referring to the above examples, different basic chemical starting materials such as pyrrole carboxylic acid, cyclopropylamine, benzaldehyde and tert-butyl isonitrile are selected, and other compounds in the general formula (I) of the present invention can be prepared by a one-pot four-component reaction preparation method. All the reaction raw materials disclosed in the present invention can be purchased commercially, and the purity is preferably analytical grade. The prepared compounds can be used as precursor molecules or key intermediates for further preparation or construction of new amide drug molecular building blocks. The spectral data of some representative compounds are as follows:

[0112] The spectral data of compound 2 are as follows: 1H NMR (600MHz, CDCl3) δ9.48(s,1H),7.39(d,J=7.8Hz,2H),7.35(t,J=7.2Hz,2H),7.30(t,J=7.2Hz,1H),6.93(d,J=16.2 Hz,2H),6.29(s,1H),5.59(s,1H),2.82(s,1H),1.36(s,9H),1.15–1.03(m,1H),0.97–0.83(m,2H),0.80–0.70(m,1H). 13 CNMR (151MHz, CDCl3) δ169.89,136.16,129.04,128.60,127.99,125.53,121.62,114.89,110.27,68.91,51.43,32.16,28.73,12.04,11.48.

[0113] The spectral data of compound 3 are as follows: 1 H NMR (600MHz, CDCl3) δ9.58(s,1H),7.29(t,J=7.8Hz,1H),7.24–7.11(m,8H),6.81(s,1H),6.04(s,1H),5.87(s,2H),4.70(s,1H),1.34(s,9H). 13 CNMR(151MHz,CDCl3)δ169.03,161.75,140.40,134.82,131.31,130.38,129.07 ,128.65,128.45,128.42,125.01,121.29,114.38,110.03,67.03,51.67,28.79.

[0114] The spectral data of compound 4 are as follows: 1 H NMR(600MHz, CDCl3)δ9.85(s,1H),7.60(d,J=7.8Hz,2H),7.49(d,J=7.8Hz,2H),6.90(s,1H),6.62(s,1H), 6.30(s,1H),5.73(s,1H),3.68(s,2H),1.71(s,1H),1.34(s,9H),1.29–1.20(m,3H),0.84(t,J=7.2Hz,3H). 13C NMR (151MHz, CDCl3) δ168.79,163.07,140.13,130.39,128.82,125.61,124.98,12 4.32,123.18,121.99,112.79,110.62,65.89,51.70,31.16,28.67,20.02,13.73.

[0115] The spectral data of compound 5 are as follows: 1 H NMR (600MHz, CDCl3) δ9.51 (s, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.4Hz, 2H), 6. 95(s,2H),6.31(s,1H),5.62(s,1H),2.89(s,1H),1.36(s,9H),1.11–0.76(m,4H). 13 C NMR (151MHz, CDCl3) δ169.44,164.61,140.22,129.05,127.60,125.47,12 5.16,123.24,122.13,115.30,110.56,68.74,51.53,32.65,28.70,11.71.

[0116] The spectral data of compound 6 are as follows: 1 H NMR (600MHz, CDCl3) δ9.53 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.4Hz, 2H), 7.35–7. 26(m,4H),6.83(s,1H),6.17(s,1H),6.07(s,1H),5.89(s,1H),4.77(s,1H),1.36(s,9H). 13 C NMR (151MHz, CDCl3) δ168.39,161.94,140.23,138.85,131.00,130.59,129.42,129 .10,125.30,124.93,124.70,123.12,121.67,114.77,110.29,66.64,51.83,28.79.

[0117] The spectral data of compound 7 are as follows: 1H NMR (600MHz, CDCl3) δ9.58(s,1H),7.66(d,J=7.8Hz,1H),7.51–7.32(m,7H),7.28(t,J=8.4Hz,1H),7.13(t,J=7.8Hz,1H ),6.86(s,1H),6.01(d,J=121.2Hz,1H),3.73(d,J=63.6Hz,2H),1.35(s,9H),1.29–1.08(m,4H),0.79(t,J=7.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ169.07,135.70,135.56,129.60,129.50,129.36,129.30,128.93,128.59 ,128.02,126.65,124.79,122.27,120.64,111.83,105.34,51.78,31.25,28.74,20.09,13.70.

[0118] The spectral data of compound 8 are as follows: 1 H NMR (600MHz, CDCl3) δ9.49(s,1H),7.67(d,J=7.8Hz,1H),7.44(d,J=7.2Hz,2H),7.40–7.31(m,4H),7.28(t,J=7.2Hz,1H),7.19(s,1H),7.13(t, J=7.2Hz,1H),6.28(s,1H),5.67(s,1H),2.92(s,1H),1.34(s,9H),1.15 –1.07(m,1H),0.99–0.91(m,1H),0.91–0.83(m,1H),0.81–0.72(m,1H). 13 C NMR (151MHz, CDCl3) δ169.48,165.44,135.78,130.06,129.19,128.72,128.20,127.9 4,124.94,122.43,120.58,111.88,108.02,69.11,51.55,32.33,28.69,12.20,11.58.

[0119] The spectral data of compound 9 are as follows: 1H NMR (600MHz, CDCl3) δ9.91 (s, 1H), 7.43–7.26 (m, 3H), 7.26–7.20 (m, 3H), 7.01 (t, J = 7.2Hz, 1H), 6.28 (s, 1H), 6.01 (s, 1H), 5.16 (s, 1H), 1.33 (s, 9H). 13 C NMR (151MHz, CDCl3) δ168.76,162.60,140.13,135.61,134.58,131.26,130.47,129.45,129.04, 128.73,128.47,128.44,127.68,124.66,122.35,120.16,111.73,107.82,67.19,51.61,28.65.

[0120] The spectral data of compound 10 are as follows: 1 H NMR (600MHz, CDCl3) δ9.41(s,1H),7.68(d,J=7.8Hz,1H),7.64(d,J=7.2Hz,2H),7.55(s,2H),7.40(d,J=8.4Hz,1H),7.3 0(t,J=7.2Hz,1H),7.15(t,J=7.2Hz,1H),6.90(s,1H),5.80(s,1H),3.79(s,2H),1.43–1.23(m,13H),0.91–0.82(m,3H). 13 C NMR (151MHz, CDCl3) δ168.47,164.05,139.73,135.76,130.68,129.11,127.99,125.78,125.22,1 24.94,123.14,122.42,120.94,111.87,105.76,65.97,51.91,31.34,29.57,28.74,20.09,13.74.

[0121] The spectral data of compound 12 are as follows: 1 H NMR(600MHz, CDCl3)δ9.44(s,1H),7.49(d,J=8.4Hz,2H),7.42–7.28(m,8H),7.21(t,J= 7.2Hz,1H),7.00(t,J=7.8Hz,1H),6.16(s,1H),6.05(s,1H),5.12(s,1H),1.35(s,9H). 13C NMR (151MHz, CDCl3) δ168.10,162.69,139.92,138.55,135.58,131.00,130.76,129.49,129.29,129 .05,127.75,125.38,125.09,124.87,123.07,122.56,120.49,111.62,108.17,66.80,51.94,28.75.

[0122] The spectral data of compound 14 are as follows: 1 H NMR (600MHz, CDCl3) δ9.07–8.58(m,2H),7.78–7.30(m,6H),6.15–5.34(m,2H),2.48(s,1H),1.35(s,9H),0.92–0.15(m,4H).

[0123] The spectral data of compound 17 are as follows: 1 H NMR (600MHz, CDCl3) δ8.87–8.72(m,2H),7.74–7.47(m,5H),6.24–5.65(m,2H),2.49(s,1H),1.36(s,9H),0.90–0.21(m,4H). 13 C NMR (151MHz, CDCl3) δ169.27,151.13,148.94,139.08,130.65,130.03,126.70,125 .77,125.39,124.90,123.57,123.09,121.75,121.29,120.39,51.99,28.58,10.63.

[0124] The spectral data of compound 18 are as follows: 1 H NMR (600MHz, CDCl3) δ8.64–8.45(m,2H),7.48(d,J=7.8Hz,2H),7.39(d,J=5.4Hz,3H),7.02(s,5H),6.17(s,1H),5.89(s,1H),1.40(s,9H). 13 CNMR (151MHz, CDCl3) δ167.41,166.63,150.42,149.81,138.72,137.97,135.21,130.82,130 .44,129.19,128.70,125.51,124.77,123.49,122.97,121.67,120.04,65.76,52.21,28.72.

[0125] The spectral data of compound 19 are as follows: 1 H NMR (600MHz, CDCl3) δ9.46–9.12(m,1H),7.88–7.74(m,1H),7.48–7.26(m,7H),7.22–7.12(m ,2H),5.67(s,1H),3.61–3.39(m,2H),1.39(s,9H),1.22–0.94(m,4H),0.65(t,J=7.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ169.87,168.96,136.22,135.79,128.94,128.82,128.25,126.16,126.0 0,122.96,121.26,120.63,111.84,111.60,66.30,51.67,31.51,28.78,27.79,20.11,13.63.

[0126] The spectral data of compound 22 are as follows: 1 H NMR (600MHz, CDCl3) δ9.55–9.08(m,1H),7.82–7.77(m,1H),7.63–7.55(m,4H),7.36–7.27(m,2H),7.2 3–7.17(m,2H),5.58(s,1H),3.68–3.47(m,2H),1.41(s,9H),1.39–1.28(m,4H),0.69(t,J=7.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ169.41,169.03,140.38,135.83,130.06,128.70,126.42,126.02,125.65,1 25.02,123.21,121.56,120.53,111.91,66.53,51.72,31.62,31.05,29.03,28.73,20.02,13.60.

[0127] Example 6

[0128] This example provides a test for the bactericidal activity of some compounds.

[0129] Test objects: Rice sheath blight (Rhizoctonia solani), Botrytis cinerea (Botrytis cinerea), rapeseed sclerotinia (Sclerotinia sclerotiorum), rapeseed black leg fungus (Leptosphaeria maculans), wheat glumen blight near shell polyspora (Parastagonospora nodorum).

[0130] Test treatment: Each test compound was dissolved in DMSO to form a 1% EC stock solution for later use. The mycelium growth rate inhibition method was used to evaluate the indoor fungicidal activity of the test compound at a dose of 100 μg / mL against the test target, with DMSO as the blank control (CK).

[0131] Test method: Weigh a certain mass of the compound to be tested, dissolve it with 500 μL of dimethyl sulfoxide (DMSO), then prepare the calculated amount of the drug solution with PDA medium to a test concentration of 100 μg / mL at a final concentration, prepare the medium into a plate in a 9 cm culture dish, cut off the hyphae on the fungal block with a diameter of 2 mm and place it in the culture medium, and after inoculation, culture it in a culture room with the optimal growth temperature for the pathogen. When the colony diameter in the blank control culture dish is 7.5-8 cm, the colony diameter of each treatment and control is measured by the cross method, and the inhibition rate is calculated, with 3 replicates per group.

[0132] Mycelial growth inhibition rate (%) = [blank colony growth diameter (mm) - colony growth diameter on drug-containing medium (mm)] / control colony growth diameter (mm) × 100%. When testing the inhibition rate of the compound on pathogens at different concentrations, the test compound and PDA medium were prepared to a final concentration of 100 μg / mL, 50 μg / mL, 25 μg / mL, 12.5 μg / mL, 6.25 μg / mL, and 3.13 μg / mL, respectively, and then the inhibition rate of the compound on pathogens at different concentrations was tested.

[0133] Some of the multi-substituted chain amide compounds are compound 1, compound 3, compound 4, compound 6, compound 9, compound 16, compound 17, compound 19, and compound 22; the structural formula of compound 1 is The structural formula of compound 3 is The structural formula of compound 4 is The structural formula of compound 6 is The structural formula of compound 9 is The structural formula of compound 16 is The structural formula of compound 17 is

[0134] The structural formula of compound 19 is The structural formula of compound 22 is

[0135] At a concentration of 100 μg / mL, the activity results of some multi-substituted chain amide compounds against pathogens are shown in Table 1 below.

[0136] Table 1 - Inhibition rate of some polysubstituted chain amide compounds against different fungi at a concentration of 100 μg / mL (%)

[0137]

[0138] As can be seen from Table 1, the compounds in the table have different degrees of inhibition on the plant pathogenic fungi in the table. The inhibition rates of the compounds on Botrytis cinerea and Sclerotinia sclerotiorum are generally high, especially compounds 1 and 16, which have inhibition rates of 90.35% and 88.38% on Sclerotinia sclerotiorum, respectively. These compounds have obvious inhibitory effects on Botrytis cinerea, Sclerotinia sclerotiorum, and Black Leg Pathogen listed in the table, and have the potential to become new agricultural antifungal agents.

[0139] Figure 2 The graph shows the treatment effects of compound 1, compound 3, compound 4, compound 6, compound 9, compound 16, compound 17, compound 19, and compound 22 at a concentration of 100 μg / mL and DMSO as the blank control (CK) group on four pathogenic fungi, namely, rice sheath blight, Botrytis cinerea, rapeseed sclerotinia, and rapeseed black shank pathogen.

[0140] from Figure 2 It can be seen that the nine compounds have different degrees of inhibition on the four pathogens, among which compound 1, compound 3, compound 9 and compound 16 have significant inhibitory effects on rapeseed sclerotinia, and these four compounds have a good inhibitory effect and have the potential to become a new fungicide.

[0141] Figure 3 This is a graph showing the inhibitory effects of compound 9 and compound 16 on Sclerotinia sclerotiorum at different concentrations.

[0142] from Figure 3 It can be seen that compounds 9 and 16 have inhibitory effects on the growth of Sclerotinia sclerotiorum at different concentrations, and the inhibitory effect gradually increases with the increase of concentration.

[0143] Figure 4 The inhibition rates (%) of compound 9 and compound 16 on Sclerotinia sclerotiorum of rapeseed at different concentrations.

[0144] It can be seen from the results of in vitro activity tests that the polysubstituted chain amide compounds of the present application have different degrees of inhibitory effects on the tested plant pathogenic fungi, among which compound 1 has an inhibition rate of more than 90% against rapeseed sclerotinia, and an inhibition rate of nearly 80% against Botrytis cinerea and rapeseed black leg pathogen. At low concentrations, compounds 9 and 16 also exhibited antifungal activity against rapeseed sclerotinia.

[0145] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A polysubstituted chain amide compound, characterized in that: The structural formula of the multi-substituted chain amide compound is shown in (I): Among them, the R 1 is any one of pyrrolyl, substituted pyridyl, substituted indolyl, substituted methylpyrazolyl, phenyl, and substituted phenyl; The substituent on the substituted pyridyl group is 4-trifluoromethyl, 4-chloro, or 4-fluoro; The substituted indolyl group is a substituted 2-indolyl group or a substituted 3-indolyl group; The substituent on the substituted methylpyrazolyl group is one of 3-difluoromethyl and 3-trifluoromethyl; The R 2 is any one of a straight chain or branched chain alkyl group, a saturated or unsaturated cycloalkyl group, a phenyl group, and a heteroaryl group; The R 3 is any one of substituted phenyl, substituted aryl, and substituted heteroaryl, and the substituents on the phenyl, aryl, and heteroaryl are each independently selected from any one of fluorine, chlorine, bromine, trifluoromethyl, cyano, methyl, and methoxy; R 4 It is any one of a straight chain or branched chain alkyl group, a saturated or unsaturated cycloalkyl group, a phenyl group, and a heteroaryl group.

2. The multi-substituted chain amide compound according to claim 1, characterized in that: The R 2 Any one selected from n-butyl, cyclopropyl, and phenyl; The R 4 Any one selected from tert-butyl and 4-methoxyphenyl.

3. The multi-substituted chain amide compound according to claim 1, characterized in that: The multi-substituted chain amide compound is selected from any one of the following compounds 1 to 28; 4. A method for preparing a multi-substituted chain amide compound as claimed in any one of claims 1 to 3, characterized in that: The following steps are involved: R 2 Substituted amine, R 3 Substituted formaldehyde is added to an organic solvent to react and generate imine; Add R to the above reaction system 1 Substituted formic acid and R 4 Substitute the isonitrile to obtain a multi-substituted chain amide compound through reaction.

5. The method for preparing a multi-substituted chain amide compound according to claim 4, characterized in that: The structural formula of the multi-substituted chain amide compound is: The preparation method of the multi-substituted chain amide compound comprises the following steps: R 2 Substituted amine, R 3 Substituted formaldehyde is added to an organic solvent to react and generate imine; Add R to the above reaction system 1 Substituted formic acid and R 4 Substitute isonitrile to obtain multi-substituted chain amide compounds after reaction; Wherein, the structural formula of the R2-substituted amine is R2-NH2; The structural formula of R3-substituted formaldehyde is R3-CHO; The structural formula of R1-substituted formic acid is R1-COOH; R 4 The substituted isonitrile is tert-butyl isonitrile.

6. The method for preparing a multi-substituted chain amide compound according to claim 5, characterized in that: The organic solvent includes N,N-dimethylformamide and methanol, and the volume ratio of N,N-dimethylformamide to methanol is 1:(2-5); and / or, the R 1 Substituted formic acid, R 2 Substituted amine, R 3 The molar ratio of substituted formaldehyde to tert-butyl isonitrile is 1:(1-1.2):(1-1.2):(1-1.2); and / or, the R 1 The molar volume ratio of the substituted formic acid to the organic solvent is 1 mmol:(3-6) mL.

7. The method for preparing a multi-substituted chain amide compound according to claim 5, characterized in that: R 2 Substituted amine, R 3 Substitute formaldehyde into an organic solvent and stir to react at 20-25°C for 1-2 hours to generate imine; Add R to the above reaction system 1 Substituted formic acid and R 4 In the step of replacing isonitrile, the reaction temperature is 70-100° C. and the reaction time is 2-24 hours.

8. A bactericidal composition, characterized in that: It includes the multi-substituted chain amide compounds described in any one of claims 1 to 3.

9. Use of the multi-substituted chain amide compound according to any one of claims 1 to 3 or the fungicide composition according to claim 8 in the preparation of a drug for killing plant diseases.

10. The use according to claim 9, wherein the plant diseases include at least one of rapeseed sclerotinia, rapeseed black shank, grape gray mold, wheat head blight, wheat glumes blight, cotton verticillium wilt, cotton wilt, rice sheath blight, rice blast, and banana Panama disease.

Images