CN110698392A - Bisamide compound and preparation method and application thereof - Google Patents
Bisamide compound and preparation method and application thereof Download PDFInfo
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- CN110698392A CN110698392A CN201910846201.6A CN201910846201A CN110698392A CN 110698392 A CN110698392 A CN 110698392A CN 201910846201 A CN201910846201 A CN 201910846201A CN 110698392 A CN110698392 A CN 110698392A
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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Abstract
The invention relates to a bisamide compound and a preparation method and application thereof, and the bisamide compound has a structural formula (I) or a compound shown in a formula (II), wherein the formula (I) is CAUZX-A, the formula (II) is CAUZX-B, or pharmaceutically acceptable salts thereof; r in the formula (I)1Is trifluoromethyl, n-propyl, isopropyl, n-butyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, p-methoxyphenyl, o-bromophenyl, p-bromophenyl, o-trifluoromethylbenzenePhenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, p-phenylphenyl, 2, 4-dichloro-phenyl, p-methoxyphenethyl, 4-chloro-3-trifluoromethylphenyl, 2-furan, 2-pyridine, 4-pyridine; r in the formula (II)2Is methyl, phenyl, p-methylphenyl. The compound has high pesticide research value.
Description
Technical Field
The invention relates to the technical field of organic compound synthesis, in particular to a bisamide compound, a preparation method thereof and application of the bisamide compound as a nematicide and a bactericide.
Background
Amide compounds are widely concerned chemical structures in the research fields of medicines, pesticides, veterinary drugs and the like, and often have unique activities of killing insects, killing mites, killing bacteria, weeding, regulating plant growth and the like. The amide compounds have the history of about 50 years and occupy a large proportion in the bactericide, and varieties with novel structures are reported all the time, the amide compounds are full of the bactericide, the amide compounds account for about one fourth of the total number of the existing bactericidal active pesticide compounds, the Bayer company obtains the bactericide fluopyram (fluopicolide) on the basis of the derivation of 2, 3-dichloro-5-trifluoromethylpyridine, and further optimizes the bactericide to obtain the fluopyram, and the fluopyram has bactericidal and nematicidal activities.
Due to the development of pesticide resistance, new pesticides with independent intellectual property rights are required to be developed to guarantee the food safety of China, the inventor develops molecular design and activity research of novel amide compounds according to the splicing principle of active substructures, deeply explores the influence of molecules which are different from the protective amide structures of the existing patents and contain characteristic bisamide structures on the pesticide activity, and further guides the research of high-activity novel pesticide candidate compounds. A series of compounds containing bisamide structures with brand-new structures are designed and synthesized, and the compounds are subjected to extensive bactericidal activity determination and structure-activity relationship research to find out good structures of the bactericidal and nematicidal active compounds.
Disclosure of Invention
In view of the defects in the prior art, the invention aims to provide a bisamide compound or a pharmaceutically acceptable salt thereof.
In order to achieve the above purposes, the technical scheme adopted by the invention is as follows:
a bisamide compound is a compound shown as a formula (I) or a formula (II), wherein the formula (I) is recorded as CAUZX-A, the formula (II) is recorded as CAUZX-B, or a pharmaceutically acceptable salt thereof;
r in the formula (I)1Is one of trifluoromethyl, n-propyl, isopropyl, n-butyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, p-methoxyphenyl, o-bromophenyl, p-bromophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, p-phenylphenyl, 2, 4-dichloro-phenyl, p-methoxyphenethyl, 4-chloro-3-trifluoromethylphenyl, 2-furan, 2-pyridine and 4-pyridine;
r in the formula (II)2Is one of methyl, phenyl and p-methylphenyl.
A preparation method of a compound CAUZX-A shown as a formula (I) comprises the following steps:
1) reacting a compound shown in a formula (III) with a reagent ethyl cyanoacetate in a solvent under an alkaline condition to obtain a compound shown in a formula (IV); the molar ratio of the compound shown in the formula (III) to ethyl cyanoacetate is 1: 1.01-10, adding an inorganic base in the step 1), wherein the molar ratio of the compound shown in the formula (III) to the inorganic base is 1: 1.5-10, wherein the inorganic base is anhydrous potassium carbonate or anhydrous sodium carbonate; the reaction temperature is 60-70 ℃, the reaction time is 4-8 h, and the solvent is dimethyl sulfoxide;
2) decarboxylating the compound shown in the formula (IV) in a solvent under an acidic condition to obtain a compound shown in the formula (V); in the step 2), inorganic acid is adopted to adjust the pH value to be less than or equal to 2, and the inorganic acid is hydrochloric acid or sulfuric acid; the reaction temperature is 120-130 ℃, the reaction time is 4-8 h, and the solvent is N, N-Dimethylformamide (DMF);
3) in a solvent, a compound shown as a formula (V) is catalyzed by Pd/C to obtain a compound shown as a formula (VI); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (V); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 4-7 h, and the solvent is methanol;
4) carrying out condensation reaction on the compound shown in the formula (VI) and a reagent o-nitrobenzoic acid to obtain a compound shown in a formula (VII); the mol ratio of the compound shown in the formula (VI) to the o-nitrobenzoic acid is 1: 1.01-10, adding a condensing agent in the condensation reaction, wherein the molar ratio of the compound shown as the formula (VI) to the condensing agent is 1: 1.01-10, wherein the condensing agent is EDCI or Dicyclohexylcarbodiimide (DCC), organic base is added in the step 4), the organic base is DMAP, and the amount of the organic base is 3% of that of the compound shown in the formula (VI) in terms of molar ratio; the reaction time is 5-12 h, and the reaction temperature is room temperature;
5) in a solvent, a compound shown as a formula (VII) is subjected to Pd/C catalysis to obtain a compound shown as a formula (VIII); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (VII); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 1-3 h, and the solvent is methanol;
6) in an anhydrous solvent, carrying out a condensation reaction on a compound shown as a formula (VIII) and a compound shown as a formula VIIII under an alkaline condition to obtain a compound shown as a formula (I), wherein a reagent used under the alkaline condition is 4-Dimethylaminopyridine (DMAP), the using amount of the DMAP is 3% of that of the compound shown as the formula (VIII), the PH under the alkaline condition is 8-9, a condensing agent is added in the condensation reaction, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI) or DCC, and the molar ratio of the compound shown as the formula (VIII) to the condensing agent is 1: 1.01-10, the temperature of the condensation reaction is room temperature, specifically 25 ℃, the time of the condensation reaction is 4-12 hours, specifically 12 hours, 4-12 hours and 7-12 hours, the anhydrous solvent is anhydrous dichloromethane, and the preparation method further comprises the steps of extraction, drying and column chromatography.
A preparation method of a compound CAUZX-B shown as a formula (II) comprises the following steps:
1) reacting a compound shown in a formula (III) with a reagent ethyl cyanoacetate in a solvent under an alkaline condition to obtain a compound shown in a formula (IV); the molar ratio of the compound shown in the formula (III) to ethyl cyanoacetate is 1: 1.01-10, adding an inorganic base in the step 1), wherein the molar ratio of the compound shown in the formula (III) to the inorganic base is 1: 1.5-10, wherein the inorganic base is anhydrous potassium carbonate or anhydrous sodium carbonate; the reaction temperature is 60-70 ℃, the reaction time is 4-8 h, and the solvent is dimethyl sulfoxide;
2) decarboxylating the compound shown in the formula (IV) in a solvent under an acidic condition to obtain a compound shown in the formula (V); in the step 2), inorganic acid is adopted to adjust the pH value to be less than or equal to 2, and the inorganic acid is hydrochloric acid or sulfuric acid; the reaction temperature is 120-130 ℃, the reaction time is 4-8 h, and the solvent is DMF;
3) in a solvent, a compound shown as a formula (V) is catalyzed by Pd/C to obtain a compound shown as a formula (VI); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (V); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 4-7 h, and the solvent is methanol;
4) carrying out condensation reaction on the compound shown in the formula (VI) and a reagent o-nitrobenzoic acid to obtain a compound shown in a formula (VII); the mol ratio of the compound shown in the formula (VI) to the o-nitrobenzoic acid is 1: 1.01-10, adding a condensing agent in the condensation reaction, wherein the molar ratio of the compound shown as the formula (VI) to the condensing agent is 1: 1.01-10, the condensing agent is EDCI or DCC, organic base is added in the step 4), the organic base is DMAP, and the amount of the organic base is 3% of that of the compound shown in the formula (VI) in terms of molar ratio; the reaction time is 5-12 h, and the reaction temperature is room temperature;
5) in a solvent, a compound shown as a formula (VII) is subjected to Pd/C catalysis to obtain a compound shown as a formula (VIII); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (VII); the reaction temperature is room temperature, specifically 25 ℃, the reaction time is 1-3 h, and the solvent is methanol;
6) in an anhydrous solvent, carrying out a condensation reaction on a compound shown in a formula (VIII) and a compound shown in a formula X to obtain a compound shown in a formula (II), adding an alkaline reagent into the condensation reaction, wherein the alkaline reagent is triethylamine, the dosage of the triethylamine is 1.5-2 times of that of the compound shown in the formula (VIII) in terms of molar ratio, the temperature of the condensation reaction is 0 ℃, the time of the condensation reaction is 2-3 h, specifically 2h or 3h, and the anhydrous solvent is anhydrous dichloromethane.
In the invention, the room temperature is 10-30 ℃.
A bactericide, the active ingredient of which is a compound shown as a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof.
On the basis of the scheme, the bactericide is a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, suspending agent, powder, aqueous agent, smoke agent, granules and seed coating agent.
A nematicide, the active ingredient of which is a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof.
On the basis of the scheme, the nematicide is a pharmaceutically acceptable dosage form; the preparation formulation comprises at least one of wettable powder, soluble powder, water dispersible granules, missible oil, suspending agents, powder, aqueous agents, smoke agents, granules and seed coating agents.
A bactericide or nematicide emulsifiable concentrate comprises the following substances in percentage by mass: 1-10% of the bisamide compound or pharmaceutically acceptable salt thereof, 5-15% of an emulsifier, 0.1-1% of a penetrating agent and the balance of a solvent;
the emulsifier is a surfactant, and the surfactant comprises at least one of Nongru 0203B, Nongru 0208, Nongru GFC, OP-10 and Tween-60;
the penetrant comprises at least one of JFC-2, TX-10, FP-T, OX-408, OX-406, N-2 and UC-12A;
the solvent is toluene and/or xylene.
The wettable pesticide powder comprises the following substances in parts by mass: 15-50 parts of the bisamide compound or pharmaceutically acceptable salt thereof, 10-20 parts of a surfactant and 30-75 parts of white carbon black;
the surfactant comprises at least one of SP-408, APG-810, TA-15, AOS, NNO, MF, AEC, M4600, SP-2728, and VESTVACO.
The invention also provides the application of the bisamide compound or the pharmaceutically acceptable salt thereof in killing nematodes or preparing nematicides.
The invention also provides application of the bisamide compound or the pharmaceutically acceptable salt thereof in sterilization or preparation of a bactericide.
The invention has the beneficial effects that: the invention takes fluopyram with bactericidal activity and nematocidal activity as a lead compound to synthesize a series of novel bisamide compounds, the raw materials for preparing the compound CAUZX are cheap, the reaction route is simple, and the product has good activity. Most of the CAUZX compounds show excellent bactericidal and nematicidal activities, wherein the bactericidal activity and nematicidal activity of CAUZX-A-11 on apple canker, sclerotinia sclerotiorum and rhizoctonia solani exceed those of a lead compound, namely fluopyram. The compound has high pesticide research value.
Drawings
The invention has the following drawings:
FIG. 1 is the NMR spectrum of compound CAUZX-A-01.
FIG. 2 is the NMR carbon spectrum of the compound CAUZX-A-01.
FIG. 3 is the NMR spectrum of the compound CAUZX-B-01.
FIG. 4 is the NMR carbon spectrum of the compound CAUZX-B-01.
Detailed Description
The invention is described in further detail below with reference to figures 1-4.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1 Compound CAUZX-A-01, R1Is p-nitrophenyl and is prepared according to the following reaction route, and comprises the following specific steps:
in a 50mL round bottom flask was added the compound 2-amino-N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) benzamide (0.8g, 2.33mmol), p-nitrobenzoic acid (0.47g, 2.8mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (0.67g, 3.5mmol), 4-dimethylaminopyridine (0.06g, 0.466mmol), 15mL dry dichloromethane and TLC monitored for reaction completion. The filtrate was concentrated and subjected to column chromatography to obtain a pale yellow solid (0.95 g, 83% yield).
The structure validation data is as follows:1H NMR(300MHz,CDCl3)δ12.67(s,1H, NH),8.78(d,J＝8.5Hz,2H,Py-H),8.39–8.31(m,2H,Ar-H),8.24– 8.16(m,2H,Ar-H),7.94(d,J＝1.7Hz,1H,Ar-H),7.60–7.48(m,3H, Ar-H),7.19–7.10(m,1H,NH),4.07–3.97(m,2H,CH2),3.35(t,J＝5.9Hz,2H,CH2).
other series of compounds with the general formula of CAUZX-A are prepared according to the method. The number, substituent group and physical and chemical data of part of compounds are shown in table 1, and the nuclear magnetic resonance hydrogen spectrum and mass spectrum data of structure identification are shown in table 2.
EXAMPLE 2 Compound CAUZX-A-02, R1The p-chlorophenyl is prepared according to the following reaction route, and comprises the following specific steps:
in a 50mL round bottom flask was added the compound 2-amino-N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) benzamide (0.8g, 2.33mmol), p-chlorobenzoic acid (0.44g, 2.8mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.67g, 3.5mmol), 4-dimethylaminopyridine (0.06g, 0.466mmol), 15mL dry dichloromethane and TLC monitored for reaction completion. The filtrate was concentrated and subjected to column chromatography to obtain a pale yellow solid (0.96 g) in 87% yield.
The structure validation data is as follows:1H NMR(300MHz,CDCl3)δ12.32(s,1H, NH),8.75(dd,J＝4.2,3.3Hz,2H,Py-H),8.01–7.95(m,2H,Ar-H), 7.92(d,J＝1.7Hz,1H,Ar-H),7.50(t,J＝8.5Hz,5H,Ar-H),7.11–7.03 (m,1H,NH),4.00(q,J＝5.9Hz,2H,CH2),3.34(t,J＝5.9Hz,2H,CH2).
example 3 the Compound CAUZX-B-01, R2The method is the preparation and the structural identification of methyl.
A50 mL round-bottomed flask was charged with 2-amino-N- (2- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) ethyl) benzamide (1g, 2.91mmol), 15mL anhydrous dichloromethane, and triethylamine (0.44g, 4.37mmol), and 5mL anhydrous dichloromethane solution of methanesulfonyl chloride (0.4g, 3.5mmol) was added dropwise under ice bath conditions, reacted at 0 ℃ for 3h, and the reaction was monitored by TLC for completion. Adding 1mL of methanol to neutralize unreacted methanesulfonyl chloride, adding dichloromethane and water for extraction, washing an organic phase with water, drying, removing an organic solvent by rotation, and purifying by column chromatography to obtain 1.08g of a white solid with the yield of 88%.
The structure validation data is as follows:1H NMR(300MHz,CDCl3)δ10.86(s,1H), 8.76(s,1H),7.96(d,J＝1.5Hz,1H),7.72(dd,J＝8.8,1.1Hz,1H),7.53 –7.44(m,2H),7.40(s,1H),7.13(td,J＝7.8,1.1Hz,1H),3.98(dd,J＝ 11.9,5.9Hz,2H),3.33(t,J＝5.8Hz,2H),3.04(s,3H).
other series compounds with the general formula of CAUZX-B are prepared according to the method. The number, substituent group and physical and chemical data of part of the compounds are shown in table 3, and the nuclear magnetic resonance hydrogen spectrum and mass spectrum data of the structure identification are shown in table 4.
EXAMPLE 4 formulation of CAUZX-A-01 emulsifiable concentrate
Adding 5-15 g of compound CAUZX-A-011, 5-15 g of emulsifier and 0.1-1 g of penetrant into a 100mL volumetric flask, and then carrying out constant volume by using solvents such as toluene, xylene and the like to obtain 1-10% emulsifiable solution.
Other missible oil with the general formula of CAUZX-A and CAUZX-B compounds can be prepared according to the method.
EXAMPLE 5 preparation of the Compound CAUZX-A-01 wettable powder
Taking 5-50 g of compound CAUZX-A-011, 10-20 g of surfactant and 30-75 g of white carbon black, and mixing and crushing to obtain 15-50% of wettable powder.
Wettable powder of other compounds with the general formulas of CAUZX-A and CAUZX-B can be prepared according to the method.
EXAMPLE 6 measurement of fungicidal Activity of Compounds of the general formulae CAUZX-A, CAUZX-B
Preparing a PDA culture medium: firstly, washing and peeling potatoes, weighing 1600g of potatoes, cutting the potatoes into small pieces, wrapping the small pieces with double-layer gauze, boiling the small pieces with deionized water, and adding the potatoes to boil for 30 minutes. The potatoes are fished out, 160 g of agar strips soaked in cold water are slowly added, and the agar strips are slowly dissolved by stirring. After the agar is completely dissolved in 30-40 minutes, 160 g of glucose is added, the mixture is stirred uniformly, water is added for dissolving until 8L, the mixture is subpackaged by conical flasks, the conical flasks are sealed and bound, and the mixture is taken out for standby after being sterilized at high temperature for 30 minutes.
Preparing a liquid medicine: and respectively weighing 20mg of the compound to be detected and fluopyram by using a ten-thousandth electronic balance, adding into a 10mL centrifuge tube, and dissolving by using 2mL of mixed solvent system (MSO) to prepare a mother solution of 1 mg/mL. Diluting the prepared mother liquor with culture medium to 50mg/L of toxic culture medium plate under ultraclean aseptic condition, testing blank without drug treatment, and repeating each treatment for 3 times.
The test method comprises the following steps: the test is carried out by adopting a hypha growth rate method according to the agricultural industry standard (NY/T1156.2-2006) of the people's republic of China. Punching the activated various pathogenic bacteria on an ultra-clean laboratory bench by using a 5 mm-diameter puncher under aseptic conditions, cutting off the bacterial cakes, inoculating the bacterial cakes to the center of the cooled drug-containing culture medium by using a scalpel, covering the center with a dish cover, inversely placing the cooled drug-containing culture medium in an incubator, culturing the three bacteria in parallel, and taking an average value when counting results. The fungicidal activity of the compounds of the general formula CAUZX-A and CAUZX-B is shown in Table 5.
The following test targets:
1. apple rot pathogen, pathogen [ Rhizoctonia solani Kuhn ] (Gaoyongchao-Shandong agricultural science 2006,6,44.)
2. Sclerotinia sclerotiorum, pathogen [ sclerotitiorum (Lib.) de Bary ] (Li, J.J.J.Agric.food.chem.2010,58,2659.)
3. Botrytis cinerea, pathogen [ Botrytis cinerea Pers. ] (Li, j.j.j.agric.food.chem.2010,58,2659.)
4. Apple ring rot pathogen, pathogen [ Botryosphaeria berengiana ] (Sun Sheng. northern agricultural science, 2019,47,83)
5. Rhizoctonia solani, pathogen of cotton [ Rhizoctonia solani Kuhn ] (high Yongchao. Shandong agricultural science 2006,6,44.)
The 5 pathogens mentioned above are available from the university of agriculture in China.
EXAMPLE 7 determination of nematicidal Activity of Compounds of the general formulae CAUZX-A, CAUZX-B
NGM nematode growth medium: 10g of agar, 1.5g of sodium chloride and 1.25g of peptone are weighed, 500mL of distilled water are added and autoclaved. Cooling to 60 deg.C, adding suction-filtered sterilized 1MCaCl25mg/mL cholesterol in ethanol and 1M MgSO4Each 500. mu.L, and 12.5mL of 1M KPO4And (4) a buffer solution. Pouring the culture medium into a flat plate on a super clean bench, and collecting the culture medium after solidification.
C, C.elegans preparation: preparing an autoclaved NGM culture medium, adding 150 mu L of escherichia coli OP50 on the surface of the culture medium, uniformly coating, airing, putting the insect body into a thermostat, and culturing at 22 ℃.
The synchronization method comprises the following steps: after 3 days, the plates were removed, washed with M9 buffer to remove the caenorhabditis elegans, the bodies were collected in 2mL centrifuge tubes, centrifuged to remove the supernatant, and the wash was repeated three times. Adding 2mL of worm lysate into a centrifuge tube, uniformly mixing, standing for 20min, centrifuging at 3000rpm, discarding supernatant, and washing 3 times with M9 buffer. Eggs were added to freshly OP 50-coated NGM plates and incubated in a 22 ℃ incubator for 3 days to obtain larvae. Washing larva with sterilized water, centrifuging at 3800, discarding most of the supernatant, collecting the lower solution, and combining to obtain a tube for use.
The determination method comprises the following steps: the CAUZX-A and CAUZX-B compounds are weighed respectively to be 1mg, 50 microliter DMSO is added for dissolution, and then 10mL of 1% Tween 80 aqueous solution is added. Three replicates of 100. mu.g/mL of each 250. mu.L of the different compound in water were added to 48-well plates. Fluopyram was used as a control. And adding 10 mu L of the enriched meloidogyne incognita second-instar larva aqueous solution into each well, counting the number of live nematodes, recording an initial value, recording a survival value after 24 hours, and performing blank control. The number of nematodes needs to be kept at 100-200. The nematicidal activity data of the compounds are shown in table 6.
The following test targets:
caenorhabditis elegans (Caenorhabditis elegans), provided by the institute for plant protection, national academy of agricultural sciences.
TABLE 1 CAUZX-A series of partial compound number, substituent group, physicochemical data
TABLE 2 nuclear magnetic resonance hydrogen spectrum and mass spectrum data of CAUZX-A series of partial compounds
(Pos: positive ion mode for Mass Spectrometry; Neg: negative ion mode for Mass Spectrometry)
TABLE 3 CAUZX-B series part compound number, substituent group, physicochemical data
TABLE 4 nuclear magnetic resonance hydrogen spectrum and mass spectrum data of CAUZX-B series partial compounds
(Pos: positive ion mode for Mass Spectrometry; Neg: negative ion mode for Mass Spectrometry)
TABLE 5 growth inhibition rates (50mg/L,%) of the CAUZX-A, CAUZX-B series of partial compounds against five pathogenic bacteria
TABLE 6 nematicidal activity of CAUZX-A, CAUZX-B series partial compounds (100. mu.g/mL)
Those not described in detail in this specification are within the skill of the art.
Claims (10)
1. A bisamide compound is a compound shown as a formula (I) or a formula (II), or a pharmaceutically acceptable salt thereof;
r in the formula (I)1Is trifluoromethyl, n-propyl, isopropyl, n-butyl, phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methylphenyl, p-methoxyphenyl, o-bromophenyl, p-bromophenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-nitrophenyl, m-chlorophenyl, p-phenylphenyl, 2, 4-dichloro-phenyl, p-methoxyphenylethyl, 4-chloro-3-trifluoromethylphenyl, 2-furan, 2-pyridine, or a mixture thereof,One of 4-pyridine;
r in the formula (II)2Is one of methyl, phenyl and p-methylphenyl.
2. The process for producing the bisamide-based compound according to claim 1, wherein the process for producing the compound represented by the formula (I) comprises the steps of:
in an anhydrous solvent, carrying out a condensation reaction on a compound shown as a formula (VIII) and a compound shown as a formula VIIII under an alkaline condition to obtain a compound shown as a formula (I), wherein a reagent used under the alkaline condition is 4-dimethylaminopyridine, the using amount of the 4-dimethylaminopyridine is 3% of that of the compound shown as the formula (VIII) in terms of molar ratio, the PH under the alkaline condition is 8-9, a condensation agent is added in the condensation reaction, the condensation agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide, and the molar ratio of the compound shown as the formula (VIII) to the condensation agent is 1: 1.01-10, wherein the temperature of the condensation reaction is room temperature, the time of the condensation reaction is 4-12 h, and the anhydrous solvent is anhydrous dichloromethane;
a process for the preparation of a compound of formula (II) comprising the steps of:
in an anhydrous solvent, carrying out a condensation reaction on a compound shown as a formula (VIII) and a compound shown as a formula X to obtain a compound shown as a formula (II), adding an alkaline reagent into the condensation reaction, wherein the alkaline reagent is triethylamine, the dosage of the triethylamine is 1.5-2 times of that of the compound shown as the formula (VIII) in terms of molar ratio, the temperature of the condensation reaction is 0 ℃, the time of the condensation reaction is 2-3 h, and the anhydrous solvent is anhydrous dichloromethane;
a process for preparing a compound of formula (VIII) comprising the steps of:
1) reacting a compound shown in a formula (III) with a reagent ethyl cyanoacetate in a solvent under an alkaline condition to obtain a compound shown in a formula (IV); the molar ratio of the compound shown in the formula (III) to ethyl cyanoacetate is 1: 1.01-10, adding an inorganic base in the step 1), wherein the molar ratio of the compound shown in the formula (III) to the inorganic base is 1: 1.5-10, wherein the inorganic base is anhydrous potassium carbonate or anhydrous sodium carbonate; the reaction temperature is 60-70 ℃, the reaction time is 4-8 h, and the solvent is dimethyl sulfoxide;
2) decarboxylating the compound shown in the formula (IV) in a solvent under an acidic condition to obtain a compound shown in the formula (V); in the step 2), inorganic acid is adopted to adjust the pH value to be less than or equal to 2, and the inorganic acid is hydrochloric acid or sulfuric acid; the reaction temperature is 120-130 ℃, the reaction time is 4-8 h, and the solvent is N, N-dimethylformamide;
3) in a solvent, a compound shown as a formula (V) is catalyzed by Pd/C to obtain a compound shown as a formula (VI); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (V); the reaction temperature is room temperature, the reaction time is 4-7 h, and the solvent is methanol;
4) carrying out condensation reaction on the compound shown in the formula (VI) and a reagent o-nitrobenzoic acid to obtain a compound shown in a formula (VII); the mol ratio of the compound shown in the formula (VI) to the o-nitrobenzoic acid is 1: 1.01-10, adding a condensing agent in the condensation reaction, wherein the molar ratio of the compound shown as the formula (VI) to the condensing agent is 1: 1.01 to 10, wherein the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide, and the organic base is added in the step 4), the organic base is 4-dimethylaminopyridine, and the amount of the organic base is 3% of that of the compound shown in the formula (VI) in terms of molar ratio; the reaction time is 5-12 h, and the reaction temperature is room temperature;
5) in a solvent, a compound shown as a formula (VII) is subjected to Pd/C catalysis to obtain a compound shown as a formula (VIII); the dosage of the Pd/C is 10 percent of the mass of the compound shown in the formula (VII); the reaction temperature is room temperature, the reaction time is 1-3 h, and the solvent is methanol.
3. A bactericide, the active ingredient of which is a compound shown as a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof.
4. The bactericidal agent of claim 3, wherein the bactericidal agent is in a pharmaceutically acceptable dosage form; the formulation comprises at least one of missible oil, suspending agent, powder, aqueous agent, smoke agent, granules and seed coating agent.
5. A nematicide, the active ingredient of which is a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof.
6. The nematicide of claim 5, wherein the nematicide is in a pharmaceutically acceptable dosage form; the preparation formulation comprises at least one of wettable powder, soluble powder, water dispersible granules, missible oil, suspending agents, powder, aqueous agents, smoke agents, granules and seed coating agents.
7. The bactericide or nematicide emulsifiable concentrate is characterized by comprising the following substances in percentage by mass: 1-10% of the bisamide compound or the pharmaceutically acceptable salt thereof according to claim 1, 5-15% of an emulsifier, 0.1-1% of a penetrating agent, and the balance of a solvent; the emulsifier is a surfactant, and the surfactant comprises at least one of Nongru 0203B, Nongru 0208, Nongru GFC, OP-10 and Tween-60; the penetrant comprises at least one of JFC-2, TX-10, FP-T, OX-408, OX-406, N-2 and UC-12A; the solvent is toluene and/or xylene.
8. The wettable pesticide powder is characterized by comprising the following substances in parts by mass: 15-50 parts of bisamide compound or pharmaceutically acceptable salt thereof according to claim 1, 10-20 parts of surfactant and 30-75 parts of white carbon black; the surfactant comprises at least one of SP-408, APG-810, TA-15, AOS, NNO, MF, AEC, M4600, SP-2728, and VESTVACO.
9. Use of the bisamide compound according to claim 1 or a pharmaceutically acceptable salt thereof for nematicidal or nematicidal agents.
10. Use of the bisamide compound or a pharmaceutically acceptable salt thereof according to claim 1 for sterilization or preparation of a bactericide.
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Cited By (1)
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