CN111592533B - 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof - Google Patents
1,2, 4-oxadiazole bipyridyl substituted benzamide compound and preparation method and application thereof Download PDFInfo
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- -1 benzamide compound Chemical class 0.000 title claims abstract description 26
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003936 benzamides Chemical class 0.000 claims abstract description 5
- HUBANNPOLNYSAD-UHFFFAOYSA-N clopyralid Chemical compound OC(=O)C1=NC(Cl)=CC=C1Cl HUBANNPOLNYSAD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- RGLQGCVEXOWXEK-UHFFFAOYSA-N methyl 2-chloro-5-cyanobenzoate Chemical compound COC(=O)C1=CC(C#N)=CC=C1Cl RGLQGCVEXOWXEK-UHFFFAOYSA-N 0.000 claims description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- DLSYOOCTSGXXCP-UHFFFAOYSA-N methyl 2-chloro-5-iodobenzoate Chemical compound COC(=O)C1=CC(I)=CC=C1Cl DLSYOOCTSGXXCP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- 229930182821 L-proline Natural products 0.000 claims description 3
- 229960002429 proline Drugs 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 239000011737 fluorine Substances 0.000 claims 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000000855 fungicidal effect Effects 0.000 claims 1
- 239000000417 fungicide Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 240000008067 Cucumis sativus Species 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 235000006008 Brassica napus var napus Nutrition 0.000 abstract description 3
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 240000007594 Oryza sativa Species 0.000 abstract description 3
- 235000007164 Oryza sativa Nutrition 0.000 abstract description 3
- 241000221662 Sclerotinia Species 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 235000009566 rice Nutrition 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 240000000385 Brassica napus var. napus Species 0.000 abstract 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 abstract 1
- 229940095102 methyl benzoate Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000002390 rotary evaporation Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000000575 pesticide Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940054066 benzamide antipsychotics Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- 150000005071 1,2,4-oxadiazoles Chemical class 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000123650 Botrytis cinerea Species 0.000 description 2
- 240000002791 Brassica napus Species 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 241000221696 Sclerotinia sclerotiorum Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000009333 weeding Methods 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
- GEBYSTBEDVQOTK-UHFFFAOYSA-N 2-chloro-5-iodobenzoic acid Chemical compound OC(=O)C1=CC(I)=CC=C1Cl GEBYSTBEDVQOTK-UHFFFAOYSA-N 0.000 description 1
- 235000009849 Cucumis sativus Nutrition 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000315044 Passalora arachidicola Species 0.000 description 1
- 241000172199 Phyllospora Species 0.000 description 1
- 241000899394 Pseudocercospora Species 0.000 description 1
- 241000813090 Rhizoctonia solani Species 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the technical field of chemical synthesis and drug application, and particularly relates to a 1,2, 4-oxadiazole bipyridyl substituted benzamide compound and a preparation method and application thereof. The invention generates 5-iodine-2-chlorobenzoic acid methyl ester by 5-iodine-2-chlorobenzoic acid and methanol, the product reacts with cuprous cyanide to generate 2-chlorine-5-cyano methyl benzoate, the obtained product reacts with hydroxylamine hydrochloride and 3, 6-dichloropicolinic acid in sequence, and then hydrolyzes and condenses to obtain the 1,2, 4-oxadiazole bipyridyl substituted benzamide compounds, the preparation method is simple and the operation is convenient, the structure of the obtained product is confirmed by nuclear magnetic hydrogen spectrum, 14 obtained target products are tested for bactericidal activity, and the result shows that: the target product of the invention shows better inhibition to sclerotinia rot of colza, gray mold of cucumber and rice sheath blight disease under the concentration of 50ppm, and the inhibition rate of some compounds is up to more than 80%.
Description
Technical Field
The invention belongs to the fields of chemical synthesis and drug application, and particularly relates to a 1,2, 4-oxadiazole bipyridyl substituted benzamide compound as well as a preparation method and application thereof.
Background
With the improvement of living standard, people have more and more urgent requirements on low-degree, environment-friendly and pollution-free pesticides, so that the development of pesticides with low toxicity, high efficiency, low residue and environmental friendliness is a necessary trend for the development of new pesticides. Heterocyclic compounds are important in the research and development of new pesticides. Both natural and synthetic heterocyclic compounds play important roles in medicines and pesticides. In the heterocyclic compound, the 1,2, 4-oxadiazole derivative containing nitrogen and oxygen atoms is important, and the 1,2, 4-oxadiazole derivative has biological activities such as insect killing, mite killing, sterilization, weeding and the like due to the unique structure. In addition, the amide compound is widely applied to the fields of pesticides and medicines, shows good biological activities such as bacteriostasis, weeding, disinsection, antivirus and the like, and is one of hot spots for creating new pesticides through synthesis and activity research.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method and application of a 1,2, 4-oxadiazole bipyridyl substituted benzamide compound.
The 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that the structural formula is shown as a formula (7):
in the formula (7), H on a benzene ring is mono-substituted or multi-substituted by substituent groups, and the mono-substituted or multi-substituted substituent groups R are respectively and independently selected from H, alkyl, substituted alkyl and halogen.
The 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that substituents are H, C independently1～C4Alkyl of (C)1～C4F, Cl or Br.
The 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that R in the formula (7) is H, 2-methyl, 3-methyl, 4-tert-butyl, 2, 4-dimethyl, 3-trifluoromethyl, 2-fluoro, 3-fluoro, 4-fluoro, 2-chloro, 3-chloro, 4-chloro or 4-bromo.
The preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized by comprising the following steps:
1) adding 5-iodine-2-chlorobenzoic acid shown in a formula (1) into methanol, and carrying out esterification reaction under the catalysis of concentrated sulfuric acid to generate 5-iodine-2-chlorobenzoic acid methyl ester shown in a formula (2);
2) using DMF as a solvent, and reacting the 5-iodo-2-chlorobenzoic acid methyl ester obtained in the step 1) with cuprous cyanide under the catalysis of L-proline to generate 2-chloro-5-cyanobenzoic acid methyl ester shown in a formula (3);
3) using ethanol as a solvent, and reacting the methyl 2-chloro-5-cyanobenzoate obtained in the step 2) with hydroxylamine hydrochloride to generate a compound 4 shown in a formula (4);
4) cyclizing the compound 4 obtained in the step 3) and 3, 6-dichloropicolinic acid by taking toluene as a solvent to generate a compound 5 shown in a formula (5);
5) hydrolyzing the compound 5 obtained in the step 4) under an alkaline condition to generate a compound 6 shown in a formula (6), and carrying out a condensation reaction on the compound 6 and substituted aniline by using EDC & HCl as a condensing agent to obtain a 1,2, 4-oxadiazole bipyridyl substituted benzamide compound shown in the formula (I);
the reaction process is as follows:
the preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that in the step 2), the molar ratio of the 5-iodine-2-methyl chlorobenzoate to the cuprous cyanide is 1: 1.5.
The preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that in the step 2), the reaction is carried out in two stages, the stirring is carried out for 1-3 hours at 70-80 ℃, and then the temperature is raised to 100 ℃ for reaction for 7-8 hours.
The preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that in the step 3), the molar ratio of the 2-chloro-5-cyanobenzoic acid methyl ester to the hydroxylamine hydrochloride is 1: 1.1.
The preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is characterized in that in the step 5), the compound 6 is dissolved in dichloromethane at normal temperature, the temperature is reduced to 4-6 ℃, substituted aniline and EDC & HCl are added, and ice bath reaction is continued for 7-9 hours.
The 1,2, 4-oxadiazole bipyridyl substituted benzamide compound is applied as a bactericide.
The invention provides a 1,2, 4-oxadiazole bipyridyl substituted benzamide compound, which has the advantages of simple preparation method and convenient operation, the structure is confirmed by nuclear magnetic hydrogen spectrum, 14 obtained target products are tested for bactericidal activity, and the result shows that: the target product of the invention shows better inhibition to sclerotinia rot of colza, gray mold of cucumber and rice sheath blight disease under the concentration of 50ppm, and the inhibition rate of some compounds is up to more than 80%.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1 preparation of methyl 5-iodo-2-chlorobenzoate represented by formula (2):
50mL of methanol, 2.8g (0.01mol) of 5-iodo-2-chlorobenzoic acid and 0.2mL of concentrated sulfuric acid are respectively added into a 100mL three-neck flask, reflux reaction is carried out, TLC (thin layer chromatography) is used for tracking and monitoring an experiment, the reaction is finished for about 8h, when a reaction solution is cooled to room temperature, rotary evaporation is carried out for desolventizing, ethyl acetate is added, the pH value of the system is adjusted to 7-8 by using a sodium carbonate aqueous solution, an organic layer is taken, and drying and desolventizing are carried out to obtain 2.7g of beige solid, wherein the: 92.1 percent and m.p.40-42 ℃;
1H NMR(500MHz,Chloroform-d)δ8.14(d,J＝2.0Hz,1H),7.72(dd,J＝8.5,2.5Hz,1H),7.19(d,J＝8.0Hz,1H),3.94(s,3H).
example 2 preparation of methyl 2-chloro-5-cyanobenzoate represented by formula (3):
adding (1.3mmol) of methyl 5-iodo-2-chlorobenzoate obtained in example 1, (2.0mmol) cuprous cyanide, (1.3mmol) L-proline and 15mL DMF into a 100mL three-necked flask, dissolving, heating to 75 ℃, reacting for two hours, heating to 100 ℃, continuing to react, monitoring the reaction by a TLC method, cooling the reaction solution after about 8 hours of reaction is finished, filtering to remove filter residues, adding 100mL of water and 100mL of ethyl acetate into the filtrate respectively, extracting the organic phase by anhydrous magnesium sulfate, and removing the ethyl acetate by rotary evaporation to obtain 0.2g of yellow solid, wherein the yield is as follows: 79.3 percent and m.p.102-105 ℃;
1H NMR(500MHz,Chloroform-d)δ8.15(d,J＝2.0Hz,1H),7.70(dd,J＝8.5,2.5Hz,1H),7.60(d,J＝8.5Hz,1H),3.98(s,3H).
example 3 preparation of compound 4 represented by formula (4):
1.4g (7.2mmol) of methyl 2-chloro-5-cyanobenzoate obtained in example 2 was weighed into a three-necked flask, 0.55g of hydroxylamine hydrochloride was added and dissolved in 45mL of ethanol, mechanical stirring was turned on at room temperature, then 1.1g of triethylamine was added dropwise, the reaction was completed in 10min, the reaction was started, the progress of the reaction was monitored by Thin Layer Chromatography (TLC), the reaction was allowed to proceed for 2 hours, the solution was removed by rotary evaporation, the residue was dissolved in ethyl acetate and saturated saline, and the mixture was poured into a separatory funnel and allowed to stand for separation, and the organic layer was retained. Adding anhydrous sodium sulfate into the organic phase to remove water, performing rotary evaporation to remove the solvent, and purifying by column chromatography to obtain a light yellow solid with the weight of 1.5g and the yield: 90.4 percent, m.p.108-111 ℃;
1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.13(d,J＝2.0Hz,1H),7.85(dd,J＝8.5,2.0Hz,1H),7.59(d,J＝8.5Hz,1H),5.98(s,2H),3.87(s,3H).
example 4 preparation of compound 5 represented by formula (5):
into a 100mL three-necked flask, 1.1g (5mmol) of 3, 6-dichloropicolinic acid was added followed by 20mL of SOCl2Dissolving, refluxing and stirring at 100 ℃ for 2h, monitoring by TLC that the raw material point basically disappears, and removing thionyl chloride by rotary evaporation to obtain the 3, 6-dichloropicolinic formyl chloride.
A250 mL three-necked flask was charged with 41.1 g (5mmol) of the compound prepared in example 3, 1.2g (5mmol) of triethylamine, and 100mL of anhydrous toluene. Controlling the temperature to be 0 ℃, stirring for reaction for 2 hours, then dropwise adding the prepared 3, 6-dichloropicolinic acid formyl chloride (dissolved in 30mL of anhydrous toluene), continuing stirring for reaction for 3 hours at the temperature of 0 ℃, then heating for reflux reaction, monitoring by TLC, and ending the reaction for about 2 hours. The reaction solution was washed with 150mL of water, then with a saturated sodium chloride solution, the organic phase was added with anhydrous sodium sulfate to remove water, rotary evaporation was performed to remove the solvent, and drying was performed to obtain 1.5g of a product, yield: 78.3 percent and m.p.148-152 ℃;
1H NMR(500MHz,Chloroform-d)δ8.65(d,J＝2.0Hz,1H),8.32–8.15(m,1H),7.92(d,J＝8.5Hz,1H),7.61(d,J＝8.3Hz,1H),7.54(d,J＝8.4Hz,1H),3.98(s,3H).
example 5 preparation of compound 6 represented by formula (6):
in a 100mL three-necked flask, the compound obtained in example 5 (2.0mmol) and 40mL of THF were initially charged, and after dissolution, an aqueous solution of sodium hydroxide (5mL) was added, the reaction was refluxed and monitored by TLC, and the reaction was completed in about 2 hours. Removing THF through rotary evaporation, adding 50mL of water for dissolving, adjusting the pH value to 2-3, precipitating a white solid, performing suction filtration and drying to obtain a product compound 6, wherein the yield is as follows: 93.6 percent.1H NMR(500MHz,Chloroform-d)δ13.64(s,1H),8.45(d,J＝2.1Hz,1H),8.34(d,J＝8.5Hz,1H),8.25–8.17(m,1H),7.91(d,J＝8.6Hz,1H),7.80(d,J＝8.3Hz,1H).
Examples 6-19 preparation of the target product I:
after dissolving compound 6 (3.3mmol) obtained in example 5 and 15mL of dichloromethane in a 50mL three-neck flask, cooling to 5 ℃ in an ice bath, adding (2.3mmol) of EDC · HCl, dropwise adding substituted aniline (2.1mmol) while stirring, continuing the reaction in the ice bath after the dropwise addition, and monitoring the reaction by TLC method (the ratio of developing solvent is Ea: Pe ═ 1:3, two drops of triethylamine are added dropwise to 4mL of developing solvent), and the reaction is completed for about 8 hours. Removing dichloromethane by rotary evaporation to obtain brown viscous solid, dissolving with 10mL anhydrous ethanol under stirring, adding prepared 3% diluted hydrochloric acid solution under ice bath condition, adjusting pH to 7-8, adding anhydrous ethanol in ice water bath, stirring for 30min until the system is just clear, continuously precipitating cement color solid, and washing with ethanol-water mixed solution (V)Ethanol：VWater (W)1) and filtering, drying to obtain cement-colored solids, namely target products I-1 to I-14, wherein the specific data are shown in tables 1 and 2.
TABLE 11, 2, 4-oxadiazole bipyridyl substituted benzamides data
TABLE 21, 2, 4-oxadiazole bipyridyl substituted benzamides data of hydrogen spectra
Example 20 bactericidal Activity test
1 test sample:
the test subjects include Botrytis cinerea (Botrytis cinerea), Sclerotinia sclerotiorum (Sclerotinia sclerotiorum), Rhizoctonia solani (Thanatephora cupricis), Cucumis sativus (Fusarium oxysporum), Pseudocercospora arachidicola (Cercospora arachidicola), and Phyllospora malorum (Borgyposea berengiana).
Test treatment, namely dissolving the compound shown in the formula (I) into 1% EC by DMF for standby, evaluating the indoor bactericidal activity of the test compound on 6 test targets under the dosage of 50mg/L by adopting a hypha growth inhibition method, wherein the activity test result is shown in Table 3;
TABLE 31, 2, 4-oxadiazole bipyridyl substituted benzamides compound bactericidal activity
The bactericidal activity results of 14 bactericidal activity results containing 1,2, 4-oxadiazole bipyridyl substituted benzamide compounds (table 3) show that 14 samples have certain inhibitory activity to 6 targets under the dosage of 50ppm, especially the compound I-5, has the inhibition rate of more than 80% on sclerotinia rot of colza, gray mold of cucumber and rice sheath blight, is superior to that of a control medicament, and provides a thought for further optimization of the structure later.
The description is given for the sole purpose of illustrating embodiments of the inventive concept and should not be taken as limiting the scope of the invention to the particular forms set forth in the embodiments, but rather as being limited only to the equivalents thereof as may be contemplated by those skilled in the art based on the teachings herein.
Claims (7)
1,2, 4-oxadiazole bipyridyl substituted benzamide compounds, which are characterized in that the structural formula is shown as formula (7):
in the formula (7), H on the benzene ring at the rightmost end is mono-substituted or multi-substituted by substituent, and the mono-substituted or multi-substituted substituent R is H, 2-methyl, 3-methyl, 4-tertiary butyl, 2, 4-dimethyl, 3-trifluoromethyl, 2-fluorine, 3-fluorine, 4-fluorine, 2-chlorine, 3-chlorine, 4-chlorine or 4-bromine.
2. A method for producing a 1,2, 4-oxadiazole-bipyridyl-substituted benzamide compound according to claim 1, which comprises the steps of:
1) adding 5-iodine-2-chlorobenzoic acid shown in a formula (1) into methanol, and carrying out esterification reaction under the catalysis of concentrated sulfuric acid to generate 5-iodine-2-chlorobenzoic acid methyl ester shown in a formula (2);
2) using DMF as a solvent, and reacting the 5-iodo-2-chlorobenzoic acid methyl ester obtained in the step 1) with cuprous cyanide under the catalysis of L-proline to generate 2-chloro-5-cyanobenzoic acid methyl ester shown in a formula (3);
3) using ethanol as a solvent, and reacting the methyl 2-chloro-5-cyanobenzoate obtained in the step 2) with hydroxylamine hydrochloride to generate a compound 4 shown in a formula (4);
4) cyclizing the compound 4 obtained in the step 3) and 3, 6-dichloropicolinic acid by taking toluene as a solvent to generate a compound 5 shown in a formula (5);
5) hydrolyzing the compound 5 obtained in the step 4) under an alkaline condition to generate a compound 6 shown in a formula (6), and carrying out a condensation reaction on the compound 6 and substituted aniline by using EDC & HCl as a condensing agent to obtain a 1,2, 4-oxadiazole bipyridyl substituted benzamide compound shown in the formula (I);
the reaction process is as follows:
3. the preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound according to claim 2, wherein the molar ratio of methyl 5-iodo-2-chlorobenzoate to cuprous cyanide in step 2) is 1: 1.5.
4. The method for preparing the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound according to claim 2, wherein the reaction in step 2) is carried out in two stages, the mixture is stirred for 1-3 hours at 70-80 ℃, and then heated to 100 ℃ for reaction for 7-8 hours.
5. The method for preparing 1,2, 4-oxadiazole bipyridyl substituted benzamide compound according to claim 2, wherein the molar ratio of methyl 2-chloro-5-cyanobenzoate to hydroxylamine hydrochloride in step 3) is 1: 1.1.
6. The preparation method of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound according to claim 2, wherein in step 5), the compound 6 is dissolved in dichloromethane at normal temperature, the temperature is reduced to 4-6 ℃, substituted aniline and EDC & HCl are added, and ice bath reaction is continued for 7-9 h.
7. Use of the 1,2, 4-oxadiazole bipyridyl substituted benzamide compound according to claim 1 for preparing a fungicide.
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