CN114409611A - Oxadiazole hydrazide compound and preparation method and application thereof - Google Patents

Oxadiazole hydrazide compound and preparation method and application thereof Download PDF

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CN114409611A
CN114409611A CN202210090460.2A CN202210090460A CN114409611A CN 114409611 A CN114409611 A CN 114409611A CN 202210090460 A CN202210090460 A CN 202210090460A CN 114409611 A CN114409611 A CN 114409611A
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unsubstituted
optionally substituted
canker
oxadiazole
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王培义
朱建军
龙周卿
黄星
杨松
薛伟
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • 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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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

The invention relates to an oxadiazole hydrazide compound and a preparation method and application thereof. The compound has a structure shown as a general formula (I):

Description

Oxadiazole hydrazide compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a substituted benzyl, phenoxy (sulfur) methylene and 1, 3, 4-oxadiazole hydrazide compound and a preparation method and application thereof.
Background
Fungal diseases not only seriously affect the yield of crops, but also threaten the health of human beings. Wheat scab, pepper wilt, potato late blight and rape sclerotinia are widely existed in crops such as wheat, pepper, potato and rape in agriculture. Currently, common chemical drugs are hymexazol, carbendazim and the like, but the conventional chemical drugs have the problems of poor control effect, enhanced resistance of pathogenic bacteria after long-term use, environmental pollution and the like, so that the development of novel pesticides with high activity and high selectivity is urgently needed.
Heterocyclic compounds have the characteristics of structural diversity and biological activity diversity, and attract extensive attention in the fields of medicinal chemistry, agrochemical chemistry and organic chemistry. The oxadiazole compound has broad-spectrum medical and pesticide biological activity, the typical structure of the oxadiazole compound is 1, 3, 4-oxadiazole, and the biological activity comprises insect killing, weeding, virus resisting, sterilization, malaria resisting, cancer resisting, inflammation resisting, oxidation resisting, AIDS resisting, tuberculosis resisting, tumor resisting and the like. On the other hand, molecules containing hydrazide (-CO-NH-) skeletons exhibit biological activities such as sterilization, disinsection, and weeding. The 1, 3, 4-oxadiazole structure with wide biological activity is combined with the hydrazide substructure to prepare the 1, 3, 4-oxadiazole hydrazide derivative, and a compound with higher biological activity is expected to be found from the 1, 3, 4-oxadiazole hydrazide derivative, so that an important scientific basis is provided for the research and development of new pesticides.
The research on the biological activity of 1, 3, 4-oxadiazole and hydrazide compounds has progressed as follows:
2017, Wang et al [ Wang, P.Y.; shao, w.b.; xue, h.t.; fang, h.s.; zhou, j.; wu, z.b.; song, b.a.; yang, S.Synthesis of novel 1, 3, 4-oxoderivative as modifying reagents and reagents [ J].Res.Chem.Intermediat.，2017，43，6115-6130.]A series of 1, 3, 4-oxadiazole derivatives are designed and synthesized, and the biological activity of the derivatives is researched. The result shows that the compound 9 has better activity of resisting citrus canker pathogen (Xac)Of which EC505.9 +/-0.1 mu g/mL, which is superior to the control drug of thiediazole copper (EC)50＝77.0±2.0μg/mL)。
In 2014, Li et al [ Li, P.; shi, l.; yang, x.; yang, L.; chen, x.w.; wu, f.; shi, q.c.; xu, w.m.; he, m.; hu, d.y.; song, B.A. design, synthesis, and antibacterial activity against bacteria leaf bright and leaf stream of 2, 5-substistuted-1, 3, 4-oxydiazole/thiodiazole leaf derivative [ J].Bioorg.Med.Chem.Lett.，2014，24，1677-1680.]A series of 2, 5-substituted-1, 3, 4 oxadiazole sulfone derivatives were synthesized, and their antibacterial activity against bacterial blight of rice (Xoo) was evaluated. The results show that the compound 13 has good antibacterial activity on rice bacterial blight bacteria, and the EC of the compound50The value is 1.07 +/-0.68 mu g/mL, which is superior to that of the control drug bismerthiazol (EC)50Values of 92.61. + -. 2.15. mu.g/mL) and Thiodiazole copper (EC)50The value was 121.82. + -. 3.59. mu.g/mL).
2015, Shi et al [ Shi, L; li, P.; wang, w.l; gao, m.n.; wu, z.x.; song, x.p.; hu, D.Y.antibacterial activity and mechanism of action of sulfone derivatives stabilizing 1, 3, 4-oxadiazine moieties on edge bacterial leaf bright [ J].Molecules，2015，20，11660-11675.]A series of derivatives containing 1, 3, 4-oxadiazole sulfone are designed and synthesized, and the antibacterial activity of the derivatives is researched. The results show that the compounds all show effective antibacterial activity, EC, on rice bacterial blight (Xoo)50Value-average ratio of bismerthiazol (EC)5092.61 ± 2.15 μ g/mL) and thiediazole copper (EC)50121.82 ± 3.59 μ g/mL) low. Wherein the compound 12 has good activity of resisting rice bacterial blight disease EC50The value was 9.89. + -. 1.52 ug/mL.
2016, Khalilullah et al [ Khalilullah, h.; khan, s.; nomani, m.s.; a series of differently substituted 1, 3, 4-oxadiazole derivatives were synthesized and screened for their antibacterial activity by using Ahmed, B.Synthesis, catalysis and antibacterial activity of benzodioxan ring derivatives [ J ]. Arab.J.chem., 2016, 9, 1029-. The results of the biological activity tests show that the Minimum Inhibitory Concentration (MIC) of the compound 3 on Aspergillus niger (A.niger) is 1 mug/mL, which is better than that of the control drug fluconazole (16 mug/mL). The minimum inhibitory concentration of the compound 4 to aspergillus niger and aspergillus flavus (A.flavu) is 8 mug/mL, and compared with the control drug fluconazole (16 and 8 mug/mL respectively), the antibacterial activity is more obvious.
2019, Wang et al [ Wang, X.B.; fu, x.c.; chen, m.; wang, a.; yan, j.h.; mei, y.d.; wang, m.q.; yang, C.L. novel 1, 3, 5-thiadiazine-2-thionation relating ahydazidie: design, synthesis and biological evaluation against phytopathogenic fusion in vitro and in vivo [ J].Bio.Med.Chen.，2019，10，953-961.]A series of 1, 3, 5-thiadiazine-2-thioketone derivatives containing hydrazine groups are designed and synthesized, and biological activity of the derivatives is tested. The results show that the synthesized compound 16 has EC for in vitro activity test on rice sheath blight50The value is 0.24 mu g/mL, and is 2 times more effective than a commercial bactericide carbendazim (0.55 mu g/mL), the in vivo effect of the compound 16 on resisting rice sheath blight bacteria is further evaluated, and the prevention and control effects of the rice leaves are 98.58% and 61.27% respectively under the control of 200mg/mL and 100 mg/mL.
Disclosure of Invention
The invention provides a substituted benzyl, phenoxy (sulfur) methylene, 1, 3, 4-oxadiazole hydrazide compound or a salt or solvate thereof.
Another object of the present invention is to provide an intermediate compound for preparing the above compound or a salt thereof or a solvate thereof, and a preparation method thereof.
It is a further object of the present invention to provide a composition comprising the above compound or a salt or solvate thereof.
It is also an object of the present invention to provide the above compound or a salt thereof or a solvate thereof, or use of the composition.
Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or a salt thereof or a solvate thereof, or the composition.
In order to realize the purpose, the invention adopts the following technical scheme:
a substituted benzyl, phenoxy (thio) methylene, 1, 3, 4-oxadiazole hydrazide compound or a salt or solvate thereof, which has the structure shown in the general formula (I):
Figure BSA0000264733490000031
wherein
R is selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;
R1one or more selected from the group consisting of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;
preferably, R is selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl; preferably, R is selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl and substituted or unsubstituted C6-C10 heteroaryl, wherein the substituted refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl; more preferably, R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, wherein said substitution refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; most preferably, R is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-chlorophenyl, 2, 4-dichlorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, phenylthio, 2, 4-dichlorophenoxy, 4-fluorophenoxy, 4-methoxyphenoxy.
Preferably, R1One or more selected from the group consisting of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl; preferably, R1One or more selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl and substituted or unsubstituted C6-C10 heteroaryl, wherein the substituted refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl; more preferably, R1Selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenylOr unsubstituted benzyl, wherein substituted refers to substitution with one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; most preferably, R1Selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-fluorophenyl, 3-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl.
Most preferably, the compound or salt or solvate thereof is selected from the following specific compounds:
Figure BSA0000264733490000051
the invention also provides an intermediate compound for preparing the substituted benzyl, phenoxy (sulfur) methylene and 1, 3, 4-oxadiazole hydrazide compound or salt or solvate thereof, which is characterized by comprising the following components in percentage by weight:
Figure BSA0000264733490000052
the invention also provides a preparation method of the substituted benzyl, phenoxy (sulfur) methylene, 1, 3, 4-oxadiazole hydrazide compound or salt or solvate thereof, which is characterized by comprising the following steps:
Figure BSA0000264733490000061
r, R therein1As described above.
The invention also provides a composition containing the compound or the salt or the solvate thereof, and an agriculturally acceptable auxiliary agent or bactericide, pesticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
The compound or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably bacterial or fungal diseases of plants; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogenic bacteria, sclerotinia rot pathogenic bacteria of colza, wheat scab pathogenic bacteria, potato late blight pathogenic bacteria, blueberry root rot pathogenic bacteria and diamond back moth.
The invention also provides a method for controlling agricultural pests, which comprises the step of enabling the compound or the salt or the solvate thereof or the composition to act on pests or living environments thereof; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogen, sclerotinia rot of colza, wheat fusarium graminearum, potato late blight, blueberry root rot pathogen and plutella xylostella.
The invention also provides a method for protecting a plant from an agricultural pest comprising the method step wherein the plant is contacted with the compound or salt or solvate thereof, or the composition.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
"alkynyl" is intended to include both straight and branched chain hydrocarbons having one or more carbon-carbon triple bonds at any stable point in the chain. E.g. "C2-6Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N). When referring to substitution, especially polysubstitution, it is meant that the various substituents are substituted at various positions on the indicated group, e.g. dichlorophenyl means 1, 2-dichlorophenyl, 1, 3-dichlorophenyl and 1, 4-dichlorophenyl.
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O)2H or S (O) H group.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even if the halo in a haloalkyl group is specified as fluoro, chloro, bromo, iodo, the same refers to a substituted alkyl group having one or more fluoro, chloro, bromo, iodo substituents.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with ═ O (oxygen), as valency permits.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention.
Preferably, C1-C10Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; c1-C10Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomers thereof; c2-C5Alkenyl means BAlkenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.
When reference is made to substituents being alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino as specified, one to three of the above substituents are meant. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.
By adopting the technical scheme, a series of substituted benzyl, phenoxy (thio) methylene and 1, 3, 4-oxadiazole hydrazide compounds are synthesized on the basis of 1, 3, 4-oxadiazole and hydrazide fragments, and the compounds are found to have good inhibition effect on pathogenic fungi, have good inhibition effect on pathogenic fungi [ such as Gibberella zeae (G.z.), Sclerotinia sclerotiorum (S.s), and the like ], and provide important scientific basis for research, development and creation of new pesticides.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.
Example 1: preparation of intermediate 5- (4-trifluoromethylbenzyl) -1, 3, 4-oxadiazole-2-carboxylic acid methyl ester
3.84g of 4-trifluoromethylphenylacethydrazide (17.60mmol) was placed in a 150mL round-bottom flask, and 25.0mL of OCL was added3Then adding 2.43mL (26.39mmol) of the mixture, and heating to 75 ℃ for reaction; 5hTLC to monitor the reaction progress, the reaction is complete, and the POCl is removed partially by distillation and desolventization under reduced pressure3200mL of EA-dissolved system, washing with 100mL of water for 3 times, drying the organic phase with anhydrous sodium sulfate, suction-filtering, vacuum-distilling for desolventizing, and subjecting to column chromatography (PE/EA: 10/1) to obtain intermediate, which is 1.72g of pale yellow solid with high yieldIt was 34.2%. The nuclear magnetic data are:1H NMR(400MHz，DMSO)δ7.75(d，J＝8.1Hz，2H，Ph-H)，7.60(d，J＝8.0Hz，2H，Ph-H)，4.54(s，2H，-CH2-)，3.93(s，3H，-CH3-).13C NMR(101MHz，DMSO)δ167.42，157.37，154.91，139.15，130.51，128.52(dd，2JC-F＝57.2，38.4Hz)，126.13(dd，3JC-F＝9.3，5.6Hz)，124.66(dd，1JC-F＝543.9，271.5Hz)，53.97，30.92.19F NMR(376MHz，DMSO)δ-61.01.
example 2: preparation of 5- (4-trifluoromethylbenzyl) -N' -phenyl-1, 3, 4-oxadiazole-2-carbohydrazide
Adding 0.3g (1.05mmol) of 5- (4-trifluoromethylbenzyl) -1, 3, 4-oxadiazole-2-carboxylic acid methyl ester into a 15mL pressure-resistant bottle, adding 0.23g (2.1mmol) of phenylhydrazine and 2g of (1-butyl-3-methylimidazole) chloride, introducing argon, heating to 100 ℃ for reaction for about 2 hours, monitoring the reaction process by TLC, and stopping the reaction after the reaction is finished; 150mL of EA dissolves a compound in the system, 50mL of EA washes for 3 times, the organic phase is added with anhydrous sodium sulfate for drying, suction filtration and decompression distillation for desolventizing to obtain a light yellow solid, the anhydrous ethanol is added for recrystallization to separate out the light yellow solid, the suction filtration and a small amount of anhydrous ethanol washing are carried out, the compound is placed under an infrared lamp for drying, and then 0.19g is weighed, and the yield is 47.7%.
Other target compounds were synthesized by following the procedures of the above examples using the corresponding starting materials or substituents.
The structures, nuclear magnetic resonance hydrogen spectra and carbon spectra data of the synthesized substituted benzyl, phenoxy (sulfur) methylene and 1, 3, 4-oxadiazole hydrazide partial compounds are shown in table 1, and the physicochemical properties are shown in table 2.
TABLE 1 NMR Hydrogen and carbon spectra data for compounds of the present application
Figure BSA0000264733490000091
Figure BSA0000264733490000101
Figure BSA0000264733490000111
Figure BSA0000264733490000121
Figure BSA0000264733490000131
Figure BSA0000264733490000141
Figure BSA0000264733490000151
Figure BSA0000264733490000161
Figure BSA0000264733490000171
Figure BSA0000264733490000181
Table 2 physicochemical properties of the compounds of the present application
Figure BSA0000264733490000182
Figure BSA0000264733490000191
Pharmacological example 1:
EC50(mean effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to compounds, and is also an important parameter for setting the concentration of compounds when researching the action mechanism of target compounds. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, finally the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated50。
Testing the effective medium concentration EC of target compound on plant pathogenic bacteria by adopting a growth rate method50The test subjects were gibberella zeae (G.z), botryococcus (b.d), sclerotinia sclerotiorum (S.s), colza anthracnose (C.h), capsicum wilt (F.o), and potato late blight (P.i). DMSO was dissolved in the medium as a blank control. Weighing a compound to be detected by a ten-thousandth balance, adding 1mLDMSO to dissolve the compound, transferring the compound to a 15mL sterilized centrifuge tube in a sterile operating platform, adding 9mL of water (Tween-20) for constant volume to 10mL, pouring the water into a melted culture medium, uniformly mixing, and then uniformly subpackaging the mixture into 9 culture dishes for cooling for later use; in an aseptic operation table, a puncher (5mm) is burnt and sterilized, bacterial colonies are made into bacterial cakes, the bacterial cakes are connected to a middle clamp of a culture medium by a bacterial ring, the bacterial cakes are cultured for about 5 days at the temperature of 25-28 ℃, when the bacterial colonies of a blank control grow to about 6cm, the bacterial colonies are measured for 2 times by a ruler according to a cross method, and the average value is taken as the diameter of the bacterial colonies. The hypha growth inhibition rate of each concentration is calculated according to a calculation formula, and a linear regression equation is made according to the concentration and the corresponding inhibition rate, so that EC is obtained50Values, hymexazol, carbendazim were tested together as a drug control.
Inhibition ratio (%) - (N1-N2)/(N1-0.5) × 100
0.5-diameter of mother fungus cake.
N1 — control colony diameter, i.e. colony diameter of control group;
n2 — diameter of treated colonies, i.e. colonies treated with the compound of interest;
the examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 3.
TABLE 3 EC of the Compounds of the present application against phytopathogenic fungi50
Figure BSA0000264733490000201
Figure BSA0000264733490000211
Figure BSA0000264733490000221
As can be seen from Table 3, the compound of interest showed good inhibitory activity against phytopathogenic fungi in vitro. Wherein 18 the compound has anti-Gibberella tritici EC50Lower than the control drug carbendazim (EC)500.95 μ g/mL). 4, 15, 16 anti-Proteus Vitis-vinifera EC in these 3 compounds50The value is lower than 1 mu g/mL, the activity of most compounds is superior to that of hymexazol, and the hymexazol can be used for preparing pesticides for resisting plant pathogenic fungi.
Pharmacological example 2:
EC50(mean effective concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to compounds, and is also an important parameter for setting the concentration of compounds when researching the action mechanism of target compounds. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, finally the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated50。
Testing the effective medium concentration EC of target compound on plant pathogenic bacteria by adopting turbidity method50The test subjects were rice bacterial blight (Xoo) and citrus canker (Xac). DMSO was dissolved in the medium as a blank control. The bacterial blight of rice (bacterial blight of rice)The strain is in M210 solid culture medium) is put into NB culture medium, and is shake-cultured in a constant temperature shaking table at 28 ℃ and 180rpm to logarithmic phase for standby; the citrus canker pathogen (on M210 solid medium) was placed in NB medium and shake-cultured in a constant temperature shaker at 28 ℃ and 180rpm until logarithmic phase for use. 5mL of toxic NB-containing liquid medium prepared by the drug (compound) into different concentrations (e.g., 100, 50, 25, 12.5, 6.25. mu.g/mL) was added into a test tube, 40. mu.L of NB liquid medium containing plant-pathogenic bacteria was added, and shaking was carried out in a constant temperature shaker at 28-30 ℃ and 180rpm, wherein the bacterial blight of rice was cultured for 36h and the bacterial canker of citrus was cultured for 48 h. The OD was measured on a spectrophotometer using the bacterial solutions of the respective concentrations595Value, and additionally determining the OD of the corresponding concentration of the sterilized NB-containing liquid medium595The value is obtained.
Corrected OD value-bacteria-containing medium OD value-sterile medium OD value
Percent inhibition is [ (OD value of control medium liquid OD value after correction-OD value of medium containing toxin corrected)/OD value of control medium liquid OD value after correction ] × 100
The examples of the present invention are given to illustrate the technical solutions of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 4.
TABLE 4 EC of the Compounds of the present application against phytopathogenic bacteria50
Figure BSA0000264733490000231
Figure BSA0000264733490000241
As can be seen from Table 4, the target compounds showed good inhibitory activity against plant pathogenic bacteria such as rice bacterial blight and citrus canker in the in vitro test. Compounds 8 and 9 showed good inhibitory activity against Xanthomonas oryzae pv. oryzae, Xoo, with EC thereof5011.4-17.7 mug/mL; compounds 9, 11 and 15 against Leptospira citrea (Xanthomonas axonopodis)Cv. citi, Xac) showed excellent inhibitory activity, EC thereof503.79-7.98 mu g/mL; can be used for preparing pesticide for resisting plant pathogenic bacteria.
Pharmacological example 3:
and carrying out a cabbage moth poisoning activity test on the designed synthetic target compound by adopting a leaf soaking feeding method. Firstly, fresh cabbage leaves which are cultivated and available are picked, cleaned by clear water and dried for standby. Preparing a culture dish, cutting circular filter paper with the same size as the inner diameter of the culture dish, putting the circular filter paper into the bottom of the culture dish for standby, and sucking new prepared secondary water by using a disposable rubber head dropper to wet the filter paper placed at the bottom of the culture dish for standby. Then dispensing medicines, calculating and weighing, preparing 500 mu g/mL and 200 mu g/mL liquid medicine to be detected (40 mu L DMSO is added after the medicine to be detected is weighed, then 1% Tween-80 aqueous solution prepared by secondary water is diluted to a required concentration), cutting cabbage leaves prepared in advance into small pieces with basically consistent sizes and shapes, putting the small pieces into the liquid medicine to be detected, soaking the small pieces into the liquid medicine to be detected for about ten seconds, taking the small pieces out of a culture dish, taking the three medicines in parallel, taking Tween water as a blank control, picking 10 diamondback moth larvae with the same size in each parallel, covering the culture dish, putting the culture dish into an artificial intelligent climate box (temperature: 28 ℃, humidity 80%), appropriately supplementing water in the culture dish every day, taking the culture dish out after 72 hours, counting the death number of the diamondback moths, recording data, and calculating the inhibition rate. The insecticidal activity calculation formula is as follows:
the inhibition rate is (drug-containing death rate-drug-free death rate)/the total number of diamondback moths put in the solution is multiplied by 100 percent
The examples of the present invention are given to illustrate the technical means of the present invention, but the contents of the examples are not limited thereto, and the experimental results of the target compounds are shown in table 5.
TABLE 5 Activity results of the compounds of the present application against Plutella xylostella
Figure BSA0000264733490000251
Figure BSA0000264733490000261
As can be seen from table 5, at 500 μ g/mL, the insecticidal activity against plutella xylostella of compound 11 was 85.2% close to that of the control drug tebufenozide, and the insecticidal activities against plutella xylostella of compounds 31 and 32 were 74.1% and 63.0%, respectively, except that the insecticidal activities against plutella xylostella of the remaining compounds were much lower than that of the control drug. At 200 mu g/mL, the insecticidal activity of all target compounds on the diamondback moth is lower than that of a control medicament, and part of the compounds have no toxic or killing effect on the diamondback moth. The compounds have the potential to become insecticidal pesticides.

Claims (9)

1. An oxadiazole hydrazide compound or a stereoisomer thereof, or a salt or a solvate thereof, which is characterized in that: it has a structure shown in general formula (I):
Figure RE-FSB0000198630790000011
wherein
R is selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;
R1one or more selected from the group consisting of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.
2. A class of oxadiazole hydrazide compounds or a stereoisomer thereof, or a salt or solvate thereof according to claim 1, wherein:
r is selected from one or more of hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl and substituted or unsubstituted C6-C10 heteroaryl, wherein the substituted refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, S, O, amino, hydroxyl, halogen, nitro and trifluoromethyl;
R1one or more selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, and substituted or unsubstituted C6-C10 heteroaryl, wherein the substituted refers to substitution by one or more selected from C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl;
preferably, R is selected from phenyl, chlorophenyl, fluorophenyl, bromophenyl, phenylthio, o-methoxyphenoxy, m-methoxyphenoxy, p-methoxyphenoxy, o-fluorophenoxy, m-fluorophenoxy, p-fluorophenoxy, o-chlorophenoxy, m-chlorophenoxy, p-chlorophenoxy, o-bromophenoxy, m-bromophenoxy, p-bromophenoxy, 2, 3-dichlorophenoxy, 2, 4-dichlorophenoxy, 2, 5-dichlorophenoxy, 2, 6-dichlorophenoxy, 3, 4-dichlorophenoxy, 3, 5-dichlorophenoxy, 1, 2-dichlorophenyl, 1, 3-dichlorophenyl, 1, 4-dichlorophenyl, tolyl, ethylphenyl, propylphenyl, methoxyphenyl, ethoxyphenyl, trifluorophenyl;
R1is selected from phenyl, chlorophenyl, fluorophenyl, bromophenyl, trifluorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, ethylphenyl, propylphenyl.
3. A class of oxadiazole hydrazide compounds or stereoisomers thereof, or salts or solvates thereof according to claim 1, characterized by being selected from the group consisting of:
Figure RE-FSB0000198630790000021
4. an intermediate compound for preparing the oxadiazole hydrazide compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, which is characterized by the following formula:
Figure RE-FSB0000198630790000022
wherein R is as defined in claim 1.
5. A process for the preparation of a class of oxadiazole hydrazide compounds as claimed in any one of claims 1 to 3, comprising the steps of:
Figure RE-FSB0000198630790000031
preferably further comprising:
Figure RE-FSB0000198630790000032
more preferably also comprises
Figure RE-FSB0000198630790000033
R, R therein1As described above.
6. A composition characterized by: a composition comprising a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).
7. Use of a compound according to any one of claims 1 to 3 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 7, for controlling an agricultural pest, preferably a bacterial or fungal disease of a plant; more preferably, the agricultural pests are plant leaf blight and plant canker; most preferably, the agricultural pests are rice bacterial leaf blight, cucumber bacterial leaf blight, sclerotinia rot of colza, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, rape anthracnose, kiwi canker, apple canker, botrytis cinerea, pepper fusarium wilt pathogen, sclerotinia rot of colza, fusarium graminearum, potato late blight, blueberry root rot, botrytis cinerea and diamond back moth.
8. A method for controlling agricultural pests is characterized in that: allowing the compound according to any one of claims 1 to 3 or a salt thereof or a solvate thereof, or the composition according to claim 6 to act on harmful substances or their living environments; preferably, the agricultural pest is a bacterial or fungal disease of a plant; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, tobacco bacterial wilt, cucumber bacterial leaf blight, konjak bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber botrytis cinerea, pepper fusarium wilt pathogen, sclerotinia rot of colza, wheat fusarium graminearum, potato late blight, blueberry root rot pathogen and plutella xylostella.
9. A method for protecting a plant from an agricultural pest, characterized by: a method step comprising contacting a plant with a compound of any one of claims 1-3, or a salt or solvate thereof, or a composition of claim 6.
CN202210090460.2A 2022-01-25 2022-01-25 Oxadiazole hydrazide compound and preparation method and application thereof Pending CN114409611A (en)

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