CN112608307A - Heterocyclic ring substituted 1,3, 4-oxadiazole hydrazide compounds, and preparation method and application thereof - Google Patents

Heterocyclic ring substituted 1,3, 4-oxadiazole hydrazide compounds, and preparation method and application thereof Download PDF

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CN112608307A
CN112608307A CN202110139878.3A CN202110139878A CN112608307A CN 112608307 A CN112608307 A CN 112608307A CN 202110139878 A CN202110139878 A CN 202110139878A CN 112608307 A CN112608307 A CN 112608307A
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杨松
龙周卿
王培义
朱建军
柳立伟
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Guizhou University
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    • 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
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention relates to a heterocyclic ring substituted 1,3, 4-oxadiazole hydrazide compound, a preparation method and application thereof. The compound has a structure shown as a general formula (I):

Description

Heterocyclic ring substituted 1,3, 4-oxadiazole hydrazide compounds, and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a 1,3, 4-oxadiazole hydrazide compound substituted by N heterocyclic group or 1,3, 4-oxadiazole hydrazide group, a preparation method and application thereof.
Background
In recent years, plant fungi and bacteria seriously affect the yield and quality of crops all over the world, and plant fungal diseases directly cause the yield reduction and the quality reduction of the crops, thereby bringing huge economic loss to farmers. For example, gibberella zeae (fetch) is a filamentous ascomycete, a disease that occurs on wheat caused by infection with a variety of fusarium species. The germs can cause seedling rot, stem rot, stalk rot and ear rot of wheat, and bring about 10-20% of yield reduction to the wheat planting countries every year. In addition, rice leaf blight (Xanthomonas oryzae, Oryzae) is a rod-shaped gram-negative bacterium that causes withering and whitening of rice leaves, which causes at least 10-50% reduction in yield per year in rice-growing countries. Citrus canker pathogen (Xanthomonas axonopodis pv. citri) causes decay of citrus, affecting citrus yield on a global scale. In the agricultural production process, due to the long-term use of the traditional medicament, phytopathogens have certain resistance to the traditional medicament. Therefore, the creation of novel, efficient, low-toxicity and safe green pesticide has very important significance.
It is reported in the literature that 1,3, 4-oxadiazole derivatives exhibit a broad spectrum of biological activities, such as: antibacterial, antifungal, insecticidal, herbicidal, plant growth regulating, antitumor, and antiinflammatory etc. According to the previous work of the center, the 1,3, 4-oxadiazole compound shows better anti-phytopathogen activity. The nitrogen-containing heterocyclic compound has the characteristics of structural diversity and biological activity diversity, and draws wide attention in the fields of medicinal chemistry, pesticide chemistry and organic chemistry. The compound using pyrazole, pyrrole, indole, thiazole, oxazole and other nitrogen-containing heterocycles as parent bodies has broad-spectrum medical and agricultural biological activity reported in the literature, such as: sterilizing, antivirus, weeding, killing parasite, antioxidant, antiinflammatory, anticancer, antimalarial, antitumor, antituberculosis, anti-AIDS etc. biological activity. On the other hand, molecules containing a hydrazide (-CO-NH-) skeleton exhibit biological activities such as bactericidal, insecticidal, antiviral, etc.
Therefore, in order to search for an active compound with high-efficiency sterilization, the invention takes a 1,3, 4-oxadiazole hydrazide structure as a connecting chain, introduces a series of nitrogen-containing heterocyclic groups into the 1,3, 4-oxadiazole hydrazide structure, synthesizes a series of 1,3, 4-oxadiazole hydrazide compounds with nitrogen-containing heterocyclic groups with novel structures, tests the biological activity of the compounds, and provides an important scientific basis for the research and development of new pesticides.
The study of the biological activity of the compounds based on nitrogen-containing heterocyclic groups has progressed as follows:
2017, Gomha et al [ Gomha, s.; dawood, k. synthetic Utility of Pyridinium amide: a series of tri-substituted pyridine compounds are designed and synthesized by synthetic and antibacterial activities of Novel 2, 4, 6-Trisubstituted pyrimidines J. Journal of Heterocyclic Chemistry 2017, 54, 1943-1948. the bioactivity test result of staphylococcus aureus shows that when the measured concentration is 2.5 mug/ml, the sizes of the bacteriostatic rings of the compounds 4J and 4l are respectively 9mm and 10mm, and the size of the bacteriostatic ring is superior to that of a control medicament terbinafine (the size of the bacteriostatic ring is 6 mm).
In 2015, Rajurkar et al [ Rajurkar, V.; lambe, s.; deshmukh, V.Synthesis of SomeN- (4- (Ary1) -2-Thixo-1, 3-Thiazol-3(2H) -yl) Pyridine-4-Carboxamide as Antimicrobial and Anti-inflammatory-inhibiting Agents [ J ] Med. chem., 2015, 5, 285. times.289 ] reported some thiocarbonylthiazole pyridines, and the results of the bioactivity tests showed that the minimum inhibitory concentrations of compound IIj to pneumococci and Staphylococcus aureus were 36 and 28. mu.g/ml, respectively, comparable to the control agent norfloxacin (29 and 24. mu.g/ml), and that the compound also showed good Anti-inflammatory activity at a concentration of 100. mu.g/ml, an inhibition rate of 75.8%, comparable to the control agent ibuprofen (an inhibition rate of 80.4%).
The study of the biological activity of 1,3, 4-oxadiazole derivatives has progressed as follows:
2017, Li et al [ Li, P.; tian, p.y.; chen, y.z.; song, x.p.; xue, w.; jin, l.h.; the total mass of the Hu and the Hu,D.Y.；Yang，S.；Song，B.A.Novel bisthioether derivatives containing a 1，3，4-oxadiazole moiety：design，synthesis，antibacterial and nematocidal activities[J].Pest Manag.Sci.2018，74，844-852.]a series of 1,3, 4-oxadiazole-containing dithioether derivatives were reported and tested for biological activity. Wherein the compound 4f has the best activity against rice bacterial blight, rice bacterial streak germ and citrus canker germ, and the EC thereof is50The values are 4.82, 11.15 and 16.57 mu g/mL respectively, which are superior to the control medicaments of the thiabendazole and the thiacumidine. Meanwhile, the compound 4f has the best activity against caenorhabditis elegans within 48h, and LC thereof50The value is 2.89 mu g/mL, which is superior to the control agents ethoprophos and fosthiazate. The analysis of structure-activity relationship shows that the activity of the 5-position phenyl ring thioether is better than that of benzyl thioether, and the activity of the 4-Cl substituent group on the phenyl ring is better than that of 4-F; when the 5-position group is fixed, the activity of the sulfydryl-connected small group is better than that of the large group.
2016, Zhao et al [ Zhao, j.j.; wang, x.f.; li, b.l.; zhang, r.l.; li, B.; liu, y.m.; li, c.w.; liu, j.b.; synthesis and in vitro inactivation evaluation of novel nonphysiological disorders bearing 1,3, 4-oxomolar moiety [ J].Bioorg.Med.Chem.Lett.，2016，26，4414-4416.]A series of asymmetric novel 1,3, 4-oxadiazole derivatives containing disulfide bonds are reported, and biological activity test results show that the compounds have different inhibition effects on different cancer cells, wherein the compound 7j has the best inhibition activity on human liver cancer cells (SMMC-7721), and the IC of the compound is IC50The value was 3.40. mu.M, and the inhibitory activity of Compound 7a against human cervical cancer cells (Hela) was the best, its IC50The value is 3.40 μ M, the inhibitory activity of compound 7g to human lung adenocarcinoma cell line (A549) is best, and IC thereof50The value was 6.26. mu.M.
The research on the biological activity based on hydrazide compounds has progressed as follows:
2017, Wang et al [ Wang, X.; dai, z.c.; chen, y.f.; cao, l.l.; yan, w.; li, s.k.; wang, j.x.; zhang, z.g.; ye, Y.H., Synthesis of 1, 2, 3-triazole hydrazide derivatives inhibiting i-phytopathogenic activity.Eur.J.Med.Chem.2017, 126, 171. cozac.182 ] the triazole hydrazide derivatives were designed and synthesized, preliminary bioactivity tests show that the compound 14 has good antibacterial activity on rice sheath blight (R.solani) and wheat scab (F.graminearum), EC50 is 0.18 + -0.01 and 0.37 + -0.020 μ g/mL respectively, and the antibacterial activity is superior to that of commercial bactericide carbendazim (EC50 is 1.32 + -0.18 and 0.60 + -0.050 μ g/mL respectively).
Disclosure of Invention
The invention provides a heterocyclic substituted 1,3, 4-oxadiazole hydrazide compound or a stereoisomer thereof, or a salt or a solvate thereof.
Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.
It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.
It is a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.
Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition.
In order to realize the purpose, the invention adopts the following technical scheme:
a1, 3, 4-oxadiazole thioether compound or a stereoisomer thereof, or a salt or solvate thereof, having a structure shown in the general formula (I):
Figure BSA0000232466910000041
wherein the content of the first and second substances,
R1selected from hydrogen, deuterium, nitro, halogen, hydroxyl, amino, mercapto, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substitutedOr one or more of unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl;
R3selected from hydrogen, deuterium, hydroxy,
Figure BSA0000232466910000051
One or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, or optionally substituted or unsubstituted heteroaryl;
wherein R is2One or more selected from deuterium, amino, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.
Further, the compound has a structure represented by general formula (II):
Figure BSA0000232466910000052
preferably, R1Selected from hydrogen, deuterium, nitro, halogen, hydroxy, amino, mercapto, C1-C6Alkyl radical, C1-C6Alkenyl, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C10One or more of heteroaryl;
R3selected from hydrogen, deuterium, hydroxy,
Figure BSA0000232466910000053
One or more of;
R2selected from deuterium, amino, C1-C6Alkyl radical, C1-C6Alkenyl, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C10One or more of heteroaryl groups；
Preferably, R1And R2Each independently selected from hydrogen, deuterium, nitro, halogen, hydroxy, amino, mercapto, methyl, ethyl, N-propyl, sec-propyl, N-butyl, sec-butyl, isobutyl, phenyl, benzyl, pyridyl, pyrazolyl, pyrrolyl, furyl, thienyl, N-methylpyrrolyl, thiazolyl, benzopyrrole, nitro, amino, methyl, phenyl, benzyl, pyridyl, pyrazolyl, pyrrolyl, furyl, thienyl, N-methylpyrrole, thiazolyl, pyrrolyl, pyridyl,
Figure BSA0000232466910000054
Figure BSA0000232466910000061
Figure BSA0000232466910000071
Figure BSA0000232466910000081
Figure BSA0000232466910000091
Most preferably, the compound is selected from the following specific compounds:
Figure BSA0000232466910000092
Figure BSA0000232466910000101
an intermediate compound for preparing the compound or a stereoisomer thereof, or a salt or solvate thereof, as shown below:
Figure BSA0000232466910000102
wherein R is1As described above.
The compound or a stereoisomer thereof, or a salt or a solution thereofA process for preparing an agent comprising: compound (I)
Figure BSA0000232466910000103
A step of producing a compound represented by the general formula (I) in the presence of a halogen compound.
The preparation method also comprises the following specific steps:
Figure BSA0000232466910000111
wherein R is1、R2And R3As described above.
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.
The term "cycloalkyl" refers to cycloalkyl groups, including mono-, bi-or polycyclic ring systems. C3-7Cycloalkyl groups are intended to include C3, C4, C5, C6 and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylAlkyl, norbornyl and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3,4, 5, 6 or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bi-or tricyclic ring which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]Bicyclo-octane, [4.3.0]Bicyclo nonane, [4.4.0]Bicyclo decane, [2.2.2]Bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As mentioned above, bridged rings are also included in carbocyclic rings (e.g. [2.2.2 ]]Bicyclooctane). Preferred carbocycles, if not otherwise stated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connects two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is pointed out that the bridge always converts a single ring into a double ring. When the rings are bridged, substituents of the rings are also present on the bridge.
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 fluorine, chlorine, bromine and iodine.
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.
By adopting the technical scheme, the invention introduces the nitrogen heterocyclic group capable of improving the biological activity of the target compound into the system on the basis of the 1,3, 4-oxadiazole hydrazide compound, synthesizing a series of 1,3, 4-oxadiazole hydrazide compounds containing nitrogen heterocyclic groups, the compound is found to have good inhibitory action on pathogenic fungi and bacteria, has good scientific inhibitory effect on pathogenic fungi [ such as botrytis cinerea (B.cinerea), phytophthora capsici leoniana (F.oxysporum), sclerotinia sclerotiorum (S.sclerotiorum), fusarium graminearum (G.zeae), potato late blight (P.infestans), blueberry root rot (P.cinmamomi) and the like ] and pathogenic bacteria such as rice leaf blight (Xanthomonas oryzae pv. oryzae, Xoo), tobacco bacterial wilt (Ralstonia solanaceum, R.solanaceum), citrus canker (Xanthomonas axonopo pv. citri, Xac) and the like ], and provides an important basis for research and development 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 starting materials and solvents used in the examples are commercially available products of the corresponding purity.
Example 1: preparation of methyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate
10.0g (56.8mmol) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid was dissolved in 100mL of methanol, concentrated sulfuric acid (8.0mL, 85.2mmol) was added thereto, the reaction was stopped at 75 ℃ for 8 hours, 200mL of ethyl acetate was added after the precipitation, 50mL × 3 times of water washing was carried out, dried over anhydrous sodium sulfate was added, and the precipitation gave 10.5g of a colorless oily substance in a yield of 97.2%.
Other ester intermediate compounds were synthesized by following the procedure of example 1 using the corresponding starting materials or substituents.
Example 2: preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid hydrazide
10.5g (55.2mmol) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid methyl ester are dissolved in 50mL of anhydrous methanol, hydrazine hydrate (6.0mL, 82.8mmol) is added, the reaction is stopped at 0 ℃ for 10H, petroleum ether is added after the precipitation, the filtration is carried out again, and the solid is dried to obtain 8.7g of white solid with the yield of 82.9%.
Other hydrazide intermediate compounds were synthesized by following the procedure of example 2 using the corresponding starting materials or substituents.
Example 3: preparation of methyl 5- (3- (difluoromethyl) -1-methyl-1H-pyrazolyl) -1, 3, 4-oxadiazole-2-carboxylate
5.0g (26.3mmol) of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid hydrazide is dissolved in 20mL of phosphorus oxychloride, methyloxalyl chloride (3.6mL, 39.4mmol) is added, the reaction is stopped at 85 ℃ for 4H, 200mL of ethyl acetate is added after desolventization, 50mL of X3 times of water washing is carried out, drying is carried out on anhydrous sodium sulfate, desolventization is carried out to obtain a brown solid, and recrystallization is carried out by adding ethanol to obtain a white solid with the yield of 51.5 g and the yield of 51.5%. Melting point 112.2-113.7 ℃.
Other ester intermediate compounds were synthesized by following the procedure of example 3 using the corresponding starting materials or substituents.
Example 4: preparation of 5- (3- (difluoromethyl) -1-methyl-1H-pyrazolyl) -N' -phenyl-1, 3, 4-oxadiazole-2-carbohydrazide
0.3g (2.3mmol) of methyl 5- (3- (difluoromethyl) -1-methyl-1H-pyrazolyl) -1, 3, 4-oxadiazole-2-carboxylate was placed in a 15mL pressure-resistant bottle, and then (1-butyl-3-methylimidazole) (1.0g, 5.81mmol) chloride and phenylhydrazine (248.9 μ L, 2.32mmol) were added thereto, and after 6 hours of reaction at 85 ℃, the reaction was stopped, 80mL of ethyl acetate was added, and 20mL × 3 times of water washing were performed, and drying over anhydrous sodium sulfate, desolventization and column chromatography (petroleum ether: ethyl acetate ═ 6: 1) were performed to obtain a yellow solid, the yield was 15.4%, and the melting point was 178.8 to 179.7 ℃.
The hydrazide target compound was synthesized by the procedure of example 4 using the corresponding starting materials or substituents.
The structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized partial nitrogen heterocyclic radical 1,3, 4-oxadiazole hydrazide compound 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 BSA0000232466910000141
Figure BSA0000232466910000151
Figure BSA0000232466910000161
Figure BSA0000232466910000171
Figure BSA0000232466910000181
Figure BSA0000232466910000191
Figure BSA0000232466910000201
Table 2 physicochemical properties of the compounds of the present application
Figure BSA0000232466910000202
Figure BSA0000232466910000211
Pharmacological example 1:
the inhibition rate of the target compound on plant pathogenic bacteria is tested by a turbidity method, and the test objects are rice bacterial blight (Xoo), tobacco bacterial wilt and citrus canker pathogenic bacteria (Xac). DMSO was dissolved in the medium as a blank control. Placing rice bacterial leaf blight bacteria (in M210 solid culture medium) in NB culture medium, and shake culturing in constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for use; placing ralstonia solanacearum (on M210 solid culture medium) into NB culture medium, and performing shake culture in a constant temperature shaking table at 28 deg.C and 180rpm to logarithmic phase for later use; 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 culture medium prepared into different concentrations (e.g., 100, 50. mu.g/mL) of the medicament (compound) is added into a test tube, 40. mu.L of NB liquid culture medium containing plant-borne bacteria is respectively added, shaking is carried out in a constant-temperature shaking table at 28-30 ℃ and 180rpm, and the bacterial blight of rice is cultured for 36h, and the bacterial wilt of tobacco and citrus canker are 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.
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 some experimental results of the target compounds are shown in table 3.
TABLE 3 inhibitory Activity of the Compounds of the present application against plant pathogenic bacteria
Figure BSA0000232466910000221
As can be seen from Table 3, the target compounds showed good inhibitory activity against plant pathogenic bacteria (e.g., bacterial blight of rice, citrus canker, and kiwi canker) in the in vitro test. Wherein, the compounds 4, 5 and 9 are applied to the white leaves of the riceThe fungus blight (Xanthomonas oryzae pv. oryzae, Xoo) shows excellent inhibitory activity, EC thereof508.43-13.4 mug/mL; compounds 4-6, 9, 19 and 27 showed excellent inhibitory activity against Xanthomonas (pv. citri) with EC of the same503.98-9.60 mu g/mL; can be used for preparing pesticide for resisting plant pathogenic bacteria.
Pharmacological example 1: the application of the nitrogen heterocyclic group-containing 1,3, 4-oxadiazole hydrazide compound in resisting pathogenic fungi is used for the anti-test methods of wheat scab (G.zeae), potato late blight (P.infestans), blueberry root rot (P.cinnamomi), pepper blight (F.oxysporum), sclerotinia sclerotiorum (S.sclerotiorum), colletotrichum (C.higginsianum), botrytis cinerea (B.dothidea) and rice sheath blight (R.solani Kuhn).
As can be seen from Table 4, the series of compounds are tested for biological activity by a growth rate method by taking Hymexazol (HM), Carbendazim (CB), imizamide (PC), Fluopyram (FP), Boscalid (BS) and Azoxystrobin (AZX) as reference medicaments and selecting 7 pathogenic fungi as test objects, and the test results show that the series of compounds have excellent antifungal activity, wherein the compounds 2 and 3 have excellent inhibitory activity on wheat scab (G.zeae) and EC thereof has excellent inhibitory activity500.47-0.56 μ g/mL; compounds 2 and 3 showed excellent inhibitory activity against Fusarium oxysporum (F. oxysporum) capsici with EC thereof50Is 1.05 to 1.81 mu g/mL. The compound can be used for preparing pesticides for resisting plant pathogenic fungi.
TABLE 4 inhibitory Activity of the Compounds of the present application against phytopathogenic fungi
Figure BSA0000232466910000231
Figure BSA0000232466910000241

Claims (10)

1. A heterocycle substituted 1,3, 4-oxadiazole hydrazide compound or a stereoisomer thereof, or a salt or a solvate thereof, which is characterized in that the compound has a structure shown as a general formula (I):
Figure FSA0000232466900000011
wherein the content of the first and second substances,
R1one or more selected from the group consisting of hydrogen, deuterium, nitro, halogen, hydroxy, amino, mercapto, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;
R3selected from hydrogen, deuterium, hydroxy,
Figure FSA0000232466900000012
One or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, or optionally substituted or unsubstituted heteroaryl;
wherein R is2One or more selected from deuterium, amino, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.
2. The heterocyclic substituted 1,3, 4-oxadiazole hydrazide compound or a stereoisomer thereof, or a salt or solvate thereof according to claim 1, wherein the compound has a structure represented by the general formula (II):
Figure FSA0000232466900000013
3. a heterocycle substituted 1,3, 4-oxadiazole hydrazide compound or a stereoisomer thereof, or a salt or solvate thereof according to claim 1 or 2, wherein:
R1selected from hydrogen, deuterium, nitro, halogen, hydroxy, amino, mercapto, C1-C6Alkyl radical, C1-C6Alkenyl, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C10One or more of heteroaryl;
R3selected from hydrogen, deuterium, hydroxy,
Figure FSA0000232466900000021
One or more of;
R2selected from deuterium, amino, C1-C6Alkyl radical, C1-C6Alkenyl, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C10One or more of heteroaryl;
preferably, R1And R2Each independently selected from hydrogen, deuterium, nitro, halogen, hydroxy, amino, mercapto, methyl, ethyl, N-propyl, sec-propyl, N-butyl, sec-butyl, isobutyl, phenyl, benzyl, pyridyl, pyrazolyl, pyrrolyl, furyl, thienyl, N-methylpyrrolyl, thiazolyl, benzopyrrole, nitro, amino, methyl, phenyl, benzyl, pyridyl, pyrazolyl, pyrrolyl, furyl, thienyl, N-methylpyrrole, thiazolyl, pyrrolyl, pyridyl,
Figure FSA0000232466900000022
Figure FSA0000232466900000023
Figure FSA0000232466900000031
Figure FSA0000232466900000041
Figure FSA0000232466900000051
4. The heterocycle-substituted 1,3, 4-oxadiazole hydrazide compound according to claim 3, or a stereoisomer thereof, or a salt or solvate thereof, wherein: the compound is selected from the following specific compounds:
Figure FSA0000232466900000052
Figure FSA0000232466900000061
5. an intermediate compound for preparing the compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, characterized by the following:
Figure FSA0000232466900000062
wherein R is1And R3As claimed in the preceding claims.
6. A process for preparing a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, which comprises:
Figure FSA0000232466900000071
preferably, further comprising:
Figure FSA0000232466900000072
more preferably comprises:
Figure FSA0000232466900000073
wherein R is1、R2And R3As claimed in claim 1.
7. A composition characterized by comprising a compound of any one of claims 1 to 4 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).
8. Use of a compound according to any one of claims 1 to 4 or a stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 5, for controlling an agricultural pest, preferably a fungal or bacterial disease of a plant; more preferably, the agricultural pests are plant scab and plant leaf blight; most preferably, the agricultural pests are fusarium graminearum, potato late blight, blueberry root rot, pepper wilt, sclerotinia sclerotiorum, colletotrichum colza, botrytis cinerea, rhizoctonia solani, fusarium solani, tobacco ralstonia solani, citrus canker, kiwi canker, cucumber leaf blight, konjac leaf blight, grape canker, tomato canker and apple canker.
9. A method for controlling agricultural pests is characterized in that: allowing the compound according to claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or the composition according to claim 5 to act on harmful substances or their living environments; preferably, the agricultural pest is a fungal or bacterial disease of a plant; more preferably, the agricultural pests and diseases are fusarium graminearum, potato late blight, blueberry root rot, pepper wilt, sclerotinia sclerotiorum, colletotrichum colza, botrytis cinerea, rhizoctonia solani, rice leaf blight, tobacco ralstonia solani, citrus canker, kiwi canker, cucumber leaf blight, konjac leaf blight, grape canker, tomato canker and apple canker.
10. A method for protecting a plant from an agricultural pest comprising a method step wherein the plant is contacted with a compound of any one of claims 1-4 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 5.
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CN115490647A (en) * 2022-08-26 2022-12-20 贵州大学 Malonate compound containing chiral isoxazole benzene sulfonamide group, preparation method and application
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