Zingerone compound containing isopropanolamine substructure as well as preparation method and application of zingerone compound

Abstract

The invention discloses zingiberone compounds containing an isopropanolamine substructure as well as a preparation method and application of the zingiberone compounds. The compound has the effects on plant pathogenic bacteria such as Xanthomonas oryzae pv. Oryzae, Xanthomonas citri, Xanthomonas oryzae pv. Oryzae and Kiwi berry canker; the plant pathogenic fungi such as cucumber gray mold, pepper fusarium wilt, sclerotinia rot of colza, eggplant verticillium wilt, wheat scab, potato late blight, blueberry root rot, botryosphaeria dothidea, pitaya anthracnose or rice sheath blight disease have an excellent inhibition effect. Part of the compounds show excellent inhibitory activity on Xanthomonas oryzae pv. Oryzae, EC50 of the compounds is 3.55-9.96 mu g / mL, and the compounds show excellent inhibitory activity on Xanthomonas citri pv. Oryzae and Xanthomonas oryzae pv. Oryzae, and can be used for preparing pesticides for resisting plant pathogenic bacteria.

Description

Technical Field

[0001] The invention relates to the technical field of medicinal chemistry, and in particular to a ginger ketone compound containing an isopropanolamine substructure, a preparation method and an application thereof. Background Art

[0002] In recent years, the emergence and development of bacterial and fungal plant diseases have restricted global production and are a major challenge facing agriculture worldwide. These diseases are mainly caused and spread by invasive plant pathogenic bacteria and fungi, causing significant damage to a variety of economically important crops such as rice, citrus, and tobacco. At present, chemical control is still the main means of prevention and control of bacterial diseases because of its easy operation and low cost. However, the long-term irrational use of existing traditional chemical fungicides, such as chlorothalonil and thiophanate-methyl, has led to a significant decrease in their control effect and the development of drug-resistant pathogens. Therefore, there is an urgent need to develop new pesticides with high biological activity, unique mechanisms of action, and high efficiency to meet the severe challenges brought by drug resistance.

[0003] Natural products, with their rich and diverse sources, multi-structures and diverse functions, continue to bring new opportunities for the creation and research of new pesticides. At the same time, they show excellent biological activity and present good application prospects in the development of drugs and agricultural chemicals. Zingerone is a natural product extracted from ginger. It exists in large quantities in ginger, accounting for about 9.25%. It has attracted much attention because of its many pharmacological activities.

[0004] In order to find active compounds with high antibacterial properties, the present invention takes ginger ketone as a guide, introduces an isopropanolamine skeleton, designs and synthesizes a series of ginger ketone derivatives containing an isopropanolamine structure, tests their biological activities, and provides an important scientific basis for the research and development and creation of new pesticides.

[0005] The research progress of the biological activity of ginger ketone compounds is as follows

[0006] In 2019, the results of a study by Kung et al. showed that ginger ketone nanoparticles significantly inhibited Akt activity and NFκB expression, and activated the caspase cascade signaling pathway, participating in anti-proliferation, anti-tumor, interfering with cell cycle progression, inducing DNA damage and cell apoptosis. These findings are expected to provide a "nano-chemoprevention" strategy in future cancer treatment, medical and clinical applications.

[0007] In 2023, Kung et al. used two human endothelial cells, EA.hy293 and HUVECs, and two liver cancer cell lines, SK-Hep-1 and Huh7, as research objects to investigate the anti-tumor angiogenesis effect of ginger ketone nanoparticles. The results showed that ginger ketone NPs significantly inhibited the viability of human endothelial cells EA.hy296 cells and HUVECs. In addition, ginger ketone nanoparticles showed excellent inhibitory effects on cell invasion, in vitro lumen formation, and in vitro rat aortic ring angiogenesis.

[0008] In 2013, Kumar et al. found that the natural product gingerone can inhibit the formation of Pseudomonas aeruginosa biofilm and can effectively inhibit its movement. In the presence of sublethal concentrations of gingerone, the formation of Pseudomonas aeruginosa biofilm was significantly reduced. In the presence of gingerone, the swimming, swarming and gliding movements of Pseudomonas aeruginosa were observed to be inhibited. The combined treatment of gingerone and ciprofloxacin showed significantly high biofilm inhibition and biofilm removal activity.

[0009] In 2015, Kumar et al. further studied the anti-bacterial quorum sensing activity of gingerone. In addition to reducing the swimming, swarming and walking phenotypes of Pseudomonas aeruginosa PAO1, gingerone also reduced the biofilm formation ability of Pseudomonas aeruginosa PAO1 and the production of virulence factors including rhamnolipids, elastase, protease, pyocyanin, free hemolysin and cell-bound hemolysin.

[0010] In 2013, Su et al. found that curcumin, a ginger analog, showed good inhibitory activity against 10 strains of Staphylococcus aureus (MIC = 125-250 μg / ml). After being used in combination with a variety of antibiotics, the antibacterial activity was significantly enhanced. Summary of the invention

[0011] One of the purposes of the present invention is to provide a ginger ketone compound containing an isopropanolamine substructure and a preparation method and application thereof.

[0012] To achieve the above object, the present invention provides a capsaicinoid compound containing an isopropanolamine substructure, having a structure as shown in the general formula (I):

[0013]

[0014] in,

[0015] R1 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;

[0016] R2 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;

[0017] Preferably, R1 is selected from one or more of hydrogen, deuterium, alkyl, alkenyl, alkynyl, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocycle; More preferably, R1 is selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 10One or more of heteroaryl, wherein the substituted refers to being substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro, trifluoromethyl; most preferably, R1 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, butenyl, pentenyl, hexenyl, propynyl, butynyl, pentynyl, hexynyl, methoxy, ethoxy, propoxy, butoxy, phenyl, chlorophenyl, bromophenyl, Fluorophenyl, dichlorophenyl, dibromophenyl, difluorophenyl, tolyl, aminophenyl, hydroxyphenyl, benzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, methoxyphenyl, ethoxyphenyl, phenoxymethyl, phenoxyethyl, nitrophenyl, trifluoromethylphenyl, naphthyl, phenanthrenyl, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyranyl, pyrimidinyl, o-fluoropyridyl, m-fluoropyridyl, p-fluoropyridyl, o-bromopyridyl, m-bromopyridyl, p-bromopyridyl, o-chloropyridyl, m-chloropyridyl, p-chloropyridyl, o-fluoropyranyl, m-fluoropyranyl, p-fluoropyranyl, o-bromopyranyl, m-bromopyranyl, p-bromopyranyl, o-chloropyranyl, m-chloropyranyl, p-chloropyranyl, o-fluorofuranyl, m-fluorofuranyl, o-chlorofuranyl, m-chlorofuranyl, o-bromofuranyl, m-bromofuranyl, o-fluorothienyl, m-fluorothienyl, o-chlorothienyl, m-chlorothienyl, o-bromothienyl, m-bromothienyl, o-fluoropyrrolyl, m-fluoropyrrolyl, o-chloropyrrolyl, m-chloropyrrolyl, o-bromopyrrolyl, m-bromopyrrolyl, 2-fluoroimidazole oxazolyl, 4-fluoroimidazolyl, 5-fluoroimidazolyl, 2-chloroimidazolyl, 4-chloroimidazolyl, 5-chloroimidazolyl, 2-bromoimidazolyl, 4-bromoimidazolyl, 5-bromoimidazolyl, 2-fluorothiazolyl, 4-fluorothiazolyl, 5-fluorothiazolyl, 2-chlorothiazolyl, 4-chlorothiazolyl, 5-chlorothiazolyl, 2-bromothiazolyl, 4-bromothiazolyl, 5-bromothiazolyl, 2-fluoropyrimidinyl, 4-fluoropyrimidinyl, 5-fluoropyrimidinyl, 2-chloropyrimidinyl, 4-chloropyrimidinyl, 5-chloropyrimidinyl, 2-bromopyrimidinyl, 4-bromopyrimidinyl, 5-bromopyrimidinyl;

[0018] Preferably, R2 is selected from one or more of hydrogen, deuterium, alkyl, alkenyl, alkynyl, alkoxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocycle; More preferably, R2 is selected from hydrogen, deuterium, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkoxy, C1-C5 alkyl substituted or unsubstituted amino, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 10One or more of the heteroaryl groups, wherein the substitution refers to the substitution of C1-C 10 Alkyl, C1-C 10 Preferably, R is substituted by one or more of alkoxy, amino, hydroxy, halogen, nitro, trifluoromethyl; Most 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, butenyl, pentenyl, hexenyl, propynyl, butynyl, pentynyl, hexynyl, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, propylamino, dipropylamino, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyranyl , substituted or unsubstituted pyrimidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted piperazinyl, wherein the substitution refers to substitution with one or more of C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, trifluoromethyl, nitro, amino, hydroxyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl.

[0019] Most preferably, it is selected from the following compounds:

[0020]

[0021] The present invention also provides an intermediate compound for preparing the compound of general formula (I), as shown in the following compound of formula (II):

[0022]

[0023] The present invention also provides a method for preparing the ginger ketone compound containing the isopropanolamine substructure, and the synthesis route is as follows:

[0024]

[0025] R1 and R2 are 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;

[0026] The present invention also provides a composition, which contains the compound or its stereoisomer, or its salt or solvate, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide; preferably, the composition is in the form of emulsifiable concentrate (EC), dust (DP), wettable powder (WP), granule (GR), aqueous solution (AS), suspension (SC), ultra low volume spray (ULV), soluble powder (SP), microcapsule (MC), smoke agent (FU), emulsion in water (EW), water dispersible granule (WG).

[0027] The use of the compound or its stereoisomer, or its salt or solvate, or the composition in preventing and controlling agricultural pests and diseases, preferably, the agricultural pests and diseases are plant bacterial or fungal diseases; more preferably, the agricultural pests and diseases are plant leaf blight and plant canker; most preferably, the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium, potato late blight, pepper wilt, blueberry root rot, wheat fusarium, potato late blight, rapeseed sclerotinia and pitaya anthracnose.

[0028] The present invention also provides a method for preventing and controlling agricultural pests and diseases: allowing the compound or its stereoisomer, or its salt or solvate, or the composition to act on a harmful substance or its living environment; preferably, the agricultural pests and diseases are plant bacterial or fungal diseases; more preferably, the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium head blight, potato late blight, pepper wilt, blueberry root rot, wheat fusarium head blight, potato late blight, rapeseed sclerotinia and pitaya anthracnose.

[0029] The present invention also provides a method for protecting plants from agricultural pests and diseases, which comprises a method step in which the plant is contacted with the compound or its stereoisomer, or its salt or solvate, or the composition.

[0030] The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having a specified number of carbon atoms. 1-10 "alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C 1-6"Alkyl" means an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like. Also, when hexyl, heptyl, octyl are mentioned, in addition to n-hexyl, n-heptyl, n-octyl, all isomers thereof are included.

[0031] "Alkenyl" is a hydrocarbon group that includes both straight and branched structures and has one or more carbon-carbon double bonds occurring at any stable point in the chain. For example, "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-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.

[0032] "Alkynyl" is a hydrocarbon group that includes both straight and branched structures and has one or more carbon-carbon triple bonds occurring at any stable point in the chain. 2-6 "Alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0033] The term "substituted" as used herein refers to the replacement of any one or more hydrogen atoms on a designated atom or group with a selected designated group, provided that the general valence of the designated atom is not exceeded. If not otherwise specified, the 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 portion. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (such as C=C, C=N or N=N). When referring to substitution, especially polysubstitution, it means that multiple substituents are substituted at various positions on the designated group, such as dichlorophenyl refers to 1,2-dichlorophenyl, 1,3-dichlorophenyl and 1,4-dichlorophenyl.

[0034] Combinations of substituents and or variables are permitted only when these combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable when isolated from a reaction mixture in a useful purity, and then formulated to form an effective therapeutic agent. Preferably, the compound does not contain N-halogen, S(O)2H or S(O)H groups.

[0035] The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

[0036] The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.

[0037] The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di- and trifluoromethyl groups; even if the halo in haloalkyl is specified as fluorine, chlorine, bromine, or iodine, it also refers to a substituted alkyl group having one or more fluorine, chlorine, bromine, or iodine substituents.

[0038] 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, the heteroatom-containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms 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 nitrogen and other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom in any ring. If the other ring is a cycloalkyl or heterocycle, it is additionally optionally substituted with =0 (oxygen) when valence permits.

[0039] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0040] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothiophenyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0041] If not otherwise specified, the compounds of the present invention are understood to include free states and salts thereof. The term "salt" means acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (inner salts), such as when the compound of formula I contains a basic fragment such as an amine or a pyridine or imidazole ring, and an acidic fragment such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps used in the preparation process, and are therefore also included in the scope of the present invention.

[0042] Preferably, C1-C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; C1-C 10 Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomers thereof; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof. Similarly, C1-C5 alkyl refers to methyl, ethyl, propyl, butyl, pentyl and isomers thereof; C1-C5 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy and isomers thereof;

[0043] When referring to a substituent, such as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, phosphino, it refers to one to three of the above substituents. For example, methylphenyl refers to phenyl substituted with one to three methyl groups.

[0044] Compared with the prior art, the present invention has the following advantages and technical effects:

[0045] By adopting the above technical scheme, the present invention synthesizes a series of ginger ketone compounds containing isopropanolamine substructures based on ginger ketone compounds, and finds that the compounds have good inhibitory effects on pathogenic bacteria and fungi, and have good inhibitory effects on pathogenic bacteria [such as rice bacterial leaf blight fungus (Xanthomonas oryzae pv.oryzae, Xoo), citrus canker fungus (Xanthomonas axonopodis pv.citri, Xac), etc. In in vitro experiments, the target compounds show good inhibitory activity against plant pathogenic pathogens, such as rice bacterial leaf blight fungus, citrus canker fungus and rice bacterial leaf streak fungus. Compounds 9, 12, 14, 15, and 16 show excellent inhibitory activity against rice bacterial leaf blight fungus, and their EC50 The concentration of 5-amino-2-nitropropene in the mixture was 3.55-9.96 μg / mL, and it showed excellent inhibitory activity against citrus canker and rice bacterial leaf spot pathogen, and can be used to prepare pesticides against plant pathogenic bacteria, providing an important scientific basis for the research and development and creation of new pesticides. Specific implementation plan

[0046] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0047] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0048] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0049] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0050] Unless otherwise specified, the technical means used in the examples are conventional means known to those skilled in the art. All raw materials and solvents used in the examples are commercially available products.

[0051] The technical solution of the present invention is further illustrated by the following examples.

[0052] Example 1

[0053] Preparation of intermediate 1

[0054] Weigh (10.0 g, 51.49 mmol) ginger ketone analog, (14.23 g, 102.97 mmol) potassium carbonate and (8.45 mL, 102.97 mmol) epibromopropane in sequence and place them in a round-bottom flask containing 50 mL DMF. Stir the mixture at room temperature and monitor the reaction process using a TLC plate. After 24 hours of reaction, extract the mixture with 150 mL ethyl acetate, rinse the organic layer three times with a saturated sodium chloride solution, dry with anhydrous sodium sulfate, and distill under reduced pressure to remove the solvent. Finally, intermediate 1 (9.00 g) was purified by column chromatography using ethyl acetate: petroleum ether = 1:1 as eluent. White solid, yield 89.44%.

[0055] Other epoxy intermediate compounds were synthesized by using corresponding raw materials or substituents according to the steps of Example 1.

[0056] Example 2

[0057] Target compound 4-(4-(3-((2-fluorobenzyl)(methyl)amino)-2-hydroxypropoxy)-3-methoxyphenyl)butanone

[0058] Intermediate 1 (0.200 g, 0.8000 mmol), 2-fluorobenzylamine (0.2000 g, 1.600 mmol) and isopropanol (10.0 mL) were subjected to reductive amination reaction. The reaction mixture was stirred at 60 ° C until the intermediate 1 was completely reacted. The mixture was extracted with ethyl acetate to obtain an organic layer. The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to remove the solvent and any volatile impurities. Ethyl acetate was used as the mobile phase and column chromatography was used for purification. The target compound 1 was finally obtained as a yellow oily liquid with a yield of 74.64%.

[0059] Table 1 H NMR and C NMR data of some compounds

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] Table 2 Physicochemical properties of some target compounds

[0073]

[0074]

[0075] Example 3

[0076] EC 50 (median effective concentration) is an important indicator for evaluating the sensitivity of plant pathogens to compounds. It is also an important parameter for setting the concentration of compounds when studying the mechanism of action of target compounds. In the initial screening, the concentrations selected were 100ppm and 50ppm. In the concentration gradient experiment, the two-fold dilution method was used to set 5 appropriate concentrations. Finally, the inhibition rate of the agent on plant pathogens and the concentration of the agent were converted into logarithmic values. The toxicity curve was obtained through regression analysis with SPSS software, and the EC was calculated. 50 .

[0077] The effective medium concentration EC of the target compound against plant pathogens was tested by turbidity method. 50, the test subjects are Xanthoceras oryzae (Xoo) and Xanthoceras citri odoratus (Xac). DMSO was dissolved in the culture medium as a blank control. Xanthoceras oryzae (Xoo) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180rpm until the logarithmic growth phase for later use; Tobacco bacterial wilt pathogen was streaked on NA solid culture medium and placed in a constant temperature incubator at 30°C until a single colony grew. A single colony was picked, and Tobacco bacterial wilt pathogen was placed in NB liquid culture medium, and cultured in a constant temperature shaker at 30°C and 180rpm until the logarithmic growth phase for later use; Citrus canker pathogen (on M210 solid culture medium) was placed in NB culture medium, and cultured in a constant temperature shaker at 28°C and 180rpm until the logarithmic growth phase for later use. 5 mL of NB liquid medium containing different concentrations of the drug (compound) (e.g., 100, 50, 25, 12.5, 6.25 μg / mL) was added to the test tube, and 40 μL of NB liquid medium containing plant pathogenic bacteria was added respectively. The mixture was shaken in a constant temperature shaker at 28-30°C and 180 rpm. The rice bacterial blight pathogen was cultured for 36 hours and the citrus canker pathogen was cultured for 48 hours. The OD of the bacterial solution of each concentration was measured on a spectrophotometer. 595 The OD of the corresponding concentration of toxic sterile NB liquid culture medium was also measured. 595 value.

[0078] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0079] Inhibition rate % = [(corrected control culture medium bacterial solution OD value - corrected toxic culture medium OD value) / corrected control culture medium bacterial solution OD value] × 100

[0080] The examples of the present invention are used to illustrate the technical solutions of the present invention, but the contents of the examples are not limited thereto. The experimental results of some target compounds are shown in Table 3.

[0081] Table 3 EC values ​​of ginger ketones containing isopropanolamine against plant pathogenic bacteria 50 (μg / mL)

[0082]

[0083]

[0084] As can be seen from Table 3, in the in vitro test, the target compounds showed good inhibitory activity against plant pathogens (such as Xanthoceras oryzae, Xanthoceras citri var. citri and Xanthoceras oryzae). Compounds 9, 12, 14, 15 and 16 showed excellent inhibitory activity against Xanthoceras oryzae, with EC values ​​of 50The concentration of the compound was 3.55-9.96 μg / mL, and it showed excellent inhibitory activity against citrus canker and rice bacterial leaf streak pathogen, and can be used to prepare pesticides against plant pathogenic bacteria.

[0085] Example 4

[0086] Inhibitory activity of compounds against plant pathogenic fungi (50 μg / mL)

[0087] The mycelium growth rate method is also called the toxic medium method, which is one of the conventional methods for determining the toxicity of fungicides. The main principle is to mix the test agent with the culture medium, and measure the toxicity of the agent by the growth rate of the colony on the toxic culture medium. In this embodiment, rice sheath blight (Thanatephorus cucumeris, Tc), wheat fusarium (Gibberella zeae, Gz), solanum chain spore (Alternaria solani, As), fruit thorn spore (Colletotrichum fructicola, Cf), gloeosporioides (Colletotrichum gloeosporioides, Cg) and sorghum thorn spore (Colletotrichum sublineol, Cs) are used as test objects, and DMSO is used as a blank control. The specific operation is as follows: 1) according to the test concentration, weigh an appropriate amount of drug, dissolve it with DMSO (the amount should not exceed 1% of the final poisonous medium), then add 0.1% Tween 20 solution to make the volume 10mL, pour into 90mL melted PDA medium, mix well and pour into 9 culture dishes for later use; 2) burn and sterilize the puncher (with an inner diameter of 5mm), after cooling, punch the hyphae at the edge of the pre-activated strain, and use an inoculation needle to stick its hyphae surface to the center of the poisonous medium, and after the treatment is completed, place it uniformly at 25°C for culture; 3) after the colony diameter of the control group grows to 5.5-6.6cm, the colony diameter of the control group and each drug treatment group is determined by the cross method; 4) the inhibition rate (%) is calculated using the following formula: inhibition rate % = (CT) / (C-0.5) × 100; wherein C is the colony diameter of the control group, T is the colony diameter of the drug treatment group, and 0.5 is the diameter of the inoculated cake. According to the above method, the experimental results of some target compounds in Table 1 are shown in Table 4.

[0088] Table 4: Inhibitory activity of compounds against plant pathogenic fungi (50 μg / mL)

[0089]

[0090] As can be seen from Table 4, at 50 μg / mL, compounds 9, 12, 14, 15, and 16 have certain biological activities against the six plant pathogenic fungi tested. In the future, it can be considered to introduce other active fragments to improve the antifungal activity of this series of compounds and broaden its broad spectrum.

[0091] The above are only preferred specific implementations of the present application, but the protection scope of the present application is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed in the present application should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A class of ginger ketone compounds containing isopropanolamine substructures, characterized in that: The compound has a structure as shown in the general formula (I): in, R1, R2 are 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.

2. The ginger ketone compound containing isopropanolamine substructure according to claim 1, characterized in that R2 and R3 are the same or different, and R2 and R3 are independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C 15 Aryl, substituted or unsubstituted C6-C 10 one or more of heteroaryl groups; The substitution refers to substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxy, halogen, nitro and trifluoromethyl.

3. The ginger ketone compound containing isopropanolamine substructure according to claim 2, characterized in that: R2 and R3 are the same or different, and R2 and R3 are independently selected from:

4. The ginger ketone compound containing isopropanolamine substructure according to claim 1, characterized in that: Selected from the following compounds:

5. A method for preparing a ginger ketone compound containing an isopropanolamine substructure according to any one of claims 1 to 4, characterized in that: The synthetic route is as follows: R1 and R2 are the same or different, and R2 and R1 are independently selected from one or more of hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, and any substituted or unsubstituted heteroaryl.

6. A composition characterized in that A composition comprising a ginger ketone compound containing an isopropanolamine substructure according to any one of claims 1 to 4 or a stereoisomer thereof, or a salt thereof or a solvate thereof, and an agriculturally usable adjuvant or fungicide, insecticide or herbicide; the composition is in the form of an emulsifiable concentrate, a dust, a wettable powder, a granule, an aqueous solution, a suspension, an ultra-low volume spray, a soluble powder, a microcapsule, a smoke agent, an aqueous emulsion, and a water-dispersible granule.

7. Use of the compound or its stereoisomer, or its salt or solvate according to any one of claims 1 to 4, or the composition according to claim 6 for preventing and controlling agricultural pests and diseases, wherein the agricultural pests and diseases are bacterial or fungal diseases of plants; the agricultural pests and diseases are plant leaf blight and plant canker; the agricultural pests and diseases are rice bacterial leaf blight, cucumber bacterial leaf blight, konjac bacterial leaf blight, citrus canker, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium rust, potato late blight, pepper wilt, blueberry root rot, wheat fusarium rust, potato late blight, rapeseed sclerotinia and pitaya anthracnose.

8. A method for preventing and controlling agricultural pests and diseases, characterized in that: The compound or stereoisomer thereof, or salt or solvate thereof according to any one of claims 1 to 4, or the composition according to claim 6 is allowed to act on harmful substances or their living environment.

9. A method for protecting plants from agricultural pests and diseases, comprising a method step in which the plant is contacted with a compound or stereoisomer thereof, or a salt or solvate thereof, or a composition according to claim 6.

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