A pterostilbene pyridine salt compound, intermediate compound, composition, medicine, preparation method and application

Abstract

The present invention provides a pterostilbene pyridine salt compound, an intermediate compound, a composition, a medicine, a preparation method and an application, and belongs to the field of pharmaceutical chemistry technology. The compound provided by the present invention has a structural formula as shown in formula I, wherein R is selected from one or more of hydrogen, deuterium, an arbitrarily substituted or unsubstituted alkyl, an arbitrarily substituted or unsubstituted alkenyl, an arbitrarily substituted or unsubstituted alkynyl, an arbitrarily substituted or unsubstituted alkoxy, an arbitrarily substituted or unsubstituted cycloalkyl, an arbitrarily substituted or unsubstituted aryl, and an arbitrarily substituted or unsubstituted heteroaryl; and X is selected from chlorine, bromine, fluorine or iodine. The compound provided by the present invention has a good inhibitory effect on plant pathogenic bacteria and fungi, and has a significant inhibitory effect on tobacco mosaic virus, cucumber mosaic virus, cauliflower mosaic virus and potato virus Y.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a pterostilbene pyridine salt compound, an intermediate compound, a composition, a medicine, a preparation method and an application. Background Art

[0002] Plant bacterial, fungal and viral diseases, such as rice bacterial blight, pepper bacterial wilt, cabbage leaf spot, tobacco bacterial wilt, citrus canker, kiwi canker, cucumber gray mold, pepper wilt, rapeseed sclerotinia, wheat scab, potato late blight, blueberry root rot, grape spore fungus, pitaya anthracnose, rice sheath blight, tobacco mosaic virus, cucumber mosaic virus, cauliflower mosaic virus and potato virus Y, are several important diseases caused by plant pathogenic bacteria, fungi and viruses that affect crop production, and are mainly manifested by symptoms such as necrosis, wilt, rot, etc. The use of traditional fungicides and antiviral agents not only increases the resistance of plant pathogenic microorganisms but also affects the environment and endangers crop safety.

[0003] Pterostilbene (PTE) is a trans-stilbene compound and a methylated derivative of resveratrol. According to literature reports: In 2018, Kolouchova et al. found that microbial adhesion to surfaces and subsequent biofilm formation may lead to food industry contamination and medical device infection, and may significantly affect postoperative care. Some plants produce substances with antioxidant and antibacterial properties that can inhibit the growth of foodborne pathogens and the formation of biofilms. Irena Kolouchova and Jan Masak further found that resveratrol and pterostilbene can inhibit the formation of initial biofilms of Candida albicans, Staphylococcus epidermidis and Escherichia coli in the food industry, and destroy the biofilms that have been formed. This shows that resveratrol and pterostilbene can effectively control the contamination of foodborne bacterial biofilms in the food industry.

[0004] In 2020, Vankova et al. reported the effect of pterostilbene (PTE) on biofilms of Staphylococcus aureus and Enterococcus faecalis. The results of MTT experiment, crystal violet staining experiment, and CLSM (laser confocal microscopy) observation showed that PTE significantly affected the formation of Gram-positive coccal biofilms and was able to remove mature biofilms. Therefore, PTE can treat diseases caused by biofilms of Staphylococcus aureus and Enterococcus faecalis.

[0005] Therefore, it is necessary to develop a new fungicide and antiviral agent based on pterostilbene that is environmentally safe and has high activity and selectivity. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a pterostilbene pyridinium salt compound, an intermediate compound, a composition, a medicine, a preparation method and an application. The compound provided by the present invention has a good inhibitory effect on plant pathogenic bacteria, has a significant inhibitory effect on pathogenic fungi, and has a significant inhibitory effect on tobacco mosaic virus, cucumber mosaic virus, cauliflower mosaic virus and potato virus Y.

[0007] In order to achieve the above-mentioned object, the present invention provides the following technical solution: a pterostilbene pyridine salt compound having a structural formula as shown in Formula I or its stereoisomers, salts, and solvates:

[0008]

[0009] 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; X is selected from chlorine, bromine, fluorine, or iodine.

[0010] Preferably, R is selected from one or more of hydrogen, deuterium, C1-C20 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl; wherein the substitution is substitution by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl.

[0011] Preferably, the compound is selected from one of the following structures A to R:

[0012]

[0013] The present invention also provides an intermediate compound for preparing the pterostilbene pyridine salt compound or its stereoisomers, salts, and solvates, which has a structural formula as shown in Formula II:

[0014]

[0015] The present invention also provides a method for preparing the pterostilbene pyridine salt compound or its stereoisomers, salts, and solvates, comprising the following steps:

[0016]

[0017] The present invention also provides a composition containing the pterostilbene pyridinium salt compound or its stereoisomer, salt or solvate.

[0018] The present invention also provides a medicine containing the pterostilbene pyridine salt compound or its stereoisomer, salt, solvate or the composition; and a diluent or auxiliary material.

[0019] Preferably, the diluent or adjuvant is suitable for emulsifiable concentrate, dust, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion or water-dispersible granule.

[0020] The present invention also provides the use of the pterostilbene pyridinium salt compound or its stereoisomer, salt, solvate, the composition or the medicine in preventing and controlling agricultural pests and diseases.

[0021] Preferably, the agricultural pests and diseases are plant bacterial diseases, plant fungal diseases or viral diseases.

[0022] Beneficial technical effects:

[0023] The pterostilbene pyridine salt compound provided by the invention has good inhibitory effect on plant pathogenic bacteria and fungi; it has good inhibitory effect on pathogenic bacteria, such as Xanthomonas oryzae pv.oryzae (Xoo) or Xanthomonas axonopodis pv.citri (Xac), etc., has significant inhibitory effect on pathogenic fungi, such as Botryosphaeria dothidea (Bd), Colletotrichungloeosporioides (Cg) or Rhizoctonia solani (Rs), etc., and has significant inhibitory effect on tobacco mosaic virus, cucumber mosaic virus, cauliflower mosaic virus and potato virus Y.

[0024] (2) The preparation method of the pterostilbene pyridine salt compound provided by the present invention is simple and the reaction conditions are mild. DETAILED DESCRIPTION

[0025] The following will be described clearly and completely in conjunction with the technical solutions in the embodiments of the present invention. Obviously, the embodiments are for better illustrating the present invention, but the content of the present invention is not limited to the embodiments. Therefore, those skilled in the art who make non-essential improvements and adjustments to the implementation scheme according to the above invention content still fall within the scope of protection of the present invention.

[0026] The terms used herein are only used to describe specific embodiments and are not intended to limit the present disclosure. Unless the context has a significantly different meaning, expressions in the singular include expressions in the plural. As used herein, it should be understood that terms such as "include", "have", "include" are intended to indicate the presence of features, numbers, operations, components, parts, elements, materials or combinations. The terms of the present invention are disclosed in the specification, and are not intended to exclude the possibility that one or more other features, numbers, operations, components, parts, elements, materials or combinations thereof may exist or may be added. As used herein, " / " may be interpreted as "and" or "or", depending on the circumstances.

[0027] The term "alkyl" as used in the present invention includes branched and straight chain saturated hydrocarbon groups having a specific number of carbon atoms. 1-20 "alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C14, C16, C18, C20 alkyl. In addition, for example, "C 1-20 The term "alkyl" refers to an alkyl group having 1 to 20 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), n-heptyl, n-octyl, decanyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, and the like.

[0028] The term "alkenyl" as used herein refers to hydrocarbons including straight or branched structures, and having one or more carbon-carbon double bonds appearing at any stable point in the chain. 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.

[0029] The term "alkynyl" as used herein refers to hydrocarbons that include straight or branched chains and have one or more carbon-carbon triple bonds that appear 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.

[0030] The term "substituted" as used herein refers to the substitution 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 substituent is 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. The ring double bond used herein is a double bond formed between two adjacent ring atoms (such as C=C, C=N or N=N). When substitution is mentioned, 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, 1,4-dichlorophenyl and 2,4-dichlorophenyl. Combinations of substituents and or variables are allowed only when these combinations produce 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 presently described compounds do not contain N-halogen, S(O)2H or S(O)H groups.

[0031] The term "aryl" used in the present invention 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.

[0032] The term "halogen" or "halogen atom" used in the present invention refers to chlorine, bromine, fluorine and iodine.

[0033] The term "haloalkyl" used in the present invention 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 the haloalkyl group is specifically defined as fluorine, chlorine, bromine or iodine, it also refers to a substituted alkyl group having one or more fluorine, chlorine, bromine or iodine substituents.

[0034] The term "heteroaryl" as used in the present invention 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 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 of any ring. When valence permits, if the other ring is a cycloalkyl or heterocycle, it is optionally substituted with =O (oxygen). Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromone, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolyl and the like.

[0035] The term "X" used in the present invention, if not otherwise specified, indicates that X is selected from chlorine, bromine, fluorine and iodine.

[0036] The term "compound" used in the present invention is understood to include the free state and its salts if there is no other explanation. "Salt" means acidic and / or basic salts formed with inorganic and / or organic acids and bases; in addition, "salts 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.

[0037] In the present invention, C1-C10 alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; C1-C10 alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyl, octyloxy, nonyloxy, decyl and isomers thereof; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.

[0038] In the present invention, when it is mentioned that the substituent is 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.

[0039] In one aspect, the present invention provides a pterostilbene pyridine salt compound having a structural formula as shown in Formula I or a stereoisomer, salt, or solvate thereof:

[0040]

[0041] 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; X is selected from chlorine, bromine, fluorine, or iodine.

[0042] The pterostilbene pyridinium salt compounds of the present invention are natural products of plant origin with biological activity. Most plant-derived pesticides have low toxicity or even no toxicity to mammals and are relatively safe for humans and animals during use. They are important resources for the creation and development of new pesticides.

[0043] In some embodiments, R is selected from one or more of hydrogen, deuterium, C1-C20 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, substituted or unsubstituted C6-C15 aryl, substituted or unsubstituted C6-C10 heteroaryl; wherein the substitution is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl.

[0044] In some embodiments, R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, n-heptyl, n-octyl, dodecyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, 1,1-diethanol, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl; wherein the substitution is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, amino, hydroxyl, halogen, nitro and trifluoromethyl.

[0045] In some embodiments, R is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethyl, 1,5-dimethylhexyl, n-heptyl, n-octyl, dodecyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, 1,1-diethanolyl, propenyl, allyl, methoxy, ethoxy, propoxy, butoxy, phenyl, benzyl, phenethyl, 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-methoxyphenethyl, 3-methoxyphenethyl, 4-methoxyphenethyl, 2-methylphenethyl, 3-methylphenethyl, 4-methylphenethyl, 2-chlorophenethyl, 3-chlorophenethyl, 4-chlorophenethyl, 2-fluorophenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2-bromophenethyl, 3-bromophenethyl, 4-bromophenethyl, 2-aminophenethyl, 3-aminophenethyl, 4-aminophenethyl, 2-hydroxyphenethyl, 3-hydroxyphenethyl, 4-hydroxyphenethyl, 2-nitrophenethyl, 3-nitrophenethyl, 4-nitrophenethyl, 2-trifluoromethylphenethyl, 3-trifluoromethylphenethyl, 4-trifluoromethylphenethyl.

[0046] In some embodiments, the compound is selected from one of the following structures A to R:

[0047]

[0048] The present invention also provides an intermediate compound for preparing the pterostilbene pyridine salt compound or its stereoisomers, salts, and solvates, which has a structural formula as shown in Formula II:

[0049]

[0050] In some embodiments, the method for preparing the intermediate compound of the structural formula shown in Formula II comprises the following steps:

[0051]

[0052] The present invention also provides a method for preparing the pterostilbene pyridine salt compound or its stereoisomers, salts, and solvates, comprising the following steps:

[0053]

[0054] In some embodiments, the preparation method comprises the following steps:

[0055]

[0056] The present invention also provides a composition containing the pterostilbene pyridinium salt compound or its stereoisomer, salt or solvate.

[0057] The present invention also provides a medicine containing the pterostilbene pyridine salt compound or its stereoisomer, salt, solvate or the composition; and a diluent or auxiliary material.

[0058] Preferably, the diluent or adjuvant is suitable for emulsifiable concentrate, dust, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion or water-dispersible granule.

[0059] The present invention also provides the use of the pterostilbene pyridinium salt compound or its stereoisomer, salt, solvate, the composition or the medicine in preventing and controlling agricultural pests and diseases.

[0060] In some embodiments, the pterostilbene pyridinium salt compound can be used alone to eliminate pests, or can be used in combination with other insecticidal active ingredients to form a composition to eliminate pests.

[0061] In some embodiments, the pterostilbene pyridinium salt compound can be added with diluents or excipients to prepare various dosage forms for use in different usage environments.

[0062] In some embodiments, the agricultural pests and diseases are plant bacterial diseases, plant fungal diseases or viral diseases; the agricultural pests and diseases may be plant leaf blight and plant canker.

[0063] In some embodiments, the agricultural pests and diseases are one or more of rice bacterial blight, cucumber bacterial blight, konjac bacterial blight, citrus canker, tobacco bacterial wilt, grape canker, tomato canker, kiwi canker, apple canker, cucumber gray mold, pepper wilt pathogen, rapeseed sclerotinia, wheat fusarium, potato infestation, blueberry root rot, grape syringa, pitaya anthracnose, rice sheath blight, tobacco mosaic virus, cucumber mosaic virus, cauliflower mosaic virus and potato virus Y.

[0064] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with the examples, but the content of the present invention is not limited to the following examples. All raw materials and solvents used in the examples are commercially available products.

[0065] Example 1

[0066]

[0067] Step 1. Preparation of the intermediate compound (E)-1-(3-oxy)pyridinyl-3-(4-(3,5-dimethoxyphenyl)phenoxy)isopropyl-2-ol

[0068] 0.20 g, 0.66 mmol of pterostilbene and 0.18 g, 1.2 mmol of potassium carbonate were added to a 15 mL reaction tube, and the air in the tube was removed by multiple argon replacements; 0.10 g, 0.73 mmol of epibromopropane and 5 mL of anhydrous DMF were continued to be added dropwise using a syringe, and an argon balloon was installed on the reaction tube for inert gas protection, and then stirred at 40 ° C for 8 hours until the reaction was complete; the reaction was stopped, 30 mL of ethyl acetate was added, and the organic layer was washed three times with 45 mL of saturated ammonium chloride water, washed with saturated brine, dried over anhydrous sodium sulfate, desolventized, and column chromatography to obtain a colorless oily liquid with a yield of 71.7%.

[0069] Its NMR data are:

[0070] 1 HNMR(500MHz,CDCl3)δ5.76(s,1H,isopropyl-C=C H ),5.44–5.25(t,J=15.0,1H,C=C H ),4.37(ddd,J=23.5,12.0,3.0,1H,1 / 2COOC H2 ),3.90(ddd,J=18.0,12.5,6.0,1H,1 / 2COOC H2 ),3.17(td,J=6.5,3.0,1H,epoxy-OC H),2.82(td,J=5.0,1.0,1H,1 / 2epoxy-OC H2 ),2.61(td,J=4.5,2.5,1H,1 / 2epoxy-OC H2 ),2.20(ddd,J=20.5,13.5,6.5,1H,CH),2.09–2.02(m,4H),1.95–1.93(d,J=10.0,1H,CH),1. 88–1.86(d,J=10.0,1H,CH),1.81–1.76(m,2H,CH2),1.64–1.55(m,4H,CH2+CH2),1.27(s,3H,C H3 CCOO),1.24–1.13(m,2H,CH2),1.00(dd,J=6.5,4.0,6H,2CH3),0.82(s,3H,CH3); 13 CNMR(126MHz, CDCl3)δ178.28,145.42,135.62,122.47,120.58,64.92,50.98,49.54,49.52,46.82,46.81, 45.20,44.70,38.35,37.26,37.24,34.97,34.65,27.53,25.74,22.55,21.48,20.92,18.17,17.10,14.13.

[0071] Take a clean 100mL round-bottom flask, add a magnetic stirrer, a colorless oily liquid (1.6mmol) and anhydrous potassium carbonate (1.92mmol) into the round-bottom flask, then use a 10mL sterile syringe to add 30mL of anhydrous isopropanol into the flask three times and stir until the intermediate is completely dissolved, then add 3-hydroxypyridine (3.2mmol) into the round-bottom flask, finally add a straight drying tube and heat the reaction system to 60℃ for reaction. The reaction was monitored by TLC for 6 hours and the reaction was basically completed. The post-treatment was direct desolventization and wet column loading (dichloromethane / methanol, CH2Cl2:MeOH, V / V, 100:1-30:1) with gradient elution. Desolventization and purification gave 5.7 g of white solid pterostilbene hydroxypyridine intermediate ((E)-1-(3-oxy)pyridinyl-3-(4-(3,5-dimethoxyphenyl)phenoxy)isopropyl-2-ol) with a yield of 87.3%.

[0072] Step 2. Preparation of the target compound (E)-1-(3-((4-chlorobenzyl)oxy))pyridinyl-3-(4-(3,5-dimethoxyphenyl)phenoxy)isopropyl-2-ol-chloride (E)

[0073] First, take a clean 15 mL pressure tube. Then, add the pterostilbene hydroxypyridine intermediate ((E)-1-(3-oxy)pyridinyl-3-(4-(3,5-dimethoxyphenyl)phenoxy)isopropyl-2-ol) (0.74 mmol) into the pressure tube and add 5 mL of dry anhydrous DMF to completely stir and dissolve the intermediate. Then, add 4-chlorobenzyl chloride (1.98 mmol). Finally, heat the reaction system to 75 °C for 24 hours and monitor by TLC at any time. Post-treatment: Directly wet-column (dichloromethane / methanol, CH2Cl2:MeOH, V / V, 100:1-20:1) with gradient elution and desolventization to obtain the target pterostilbene compound A ((E)-1-(3-((4-chlorobenzyl)oxy))pyridinyl-3-(4-(3,5-dimethoxyphenyl)phenoxy)isopropyl-2-ol-chloride (E)) containing an amino alcohol pyridine salt structure.

[0074] The following compounds were prepared by using steps similar to those in the above examples, except that the corresponding raw materials were replaced. The structures, hydrogen NMR spectra and carbon NMR spectra of the synthesized pterostilbene pyridine salt compounds containing amino alcohol structures are shown in Table 1, and the physicochemical properties are shown in Table 2.

[0075] Table 1 H NMR, C NMR, F NMR and high resolution mass spectrometry data of the compounds

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] Table 2. Physicochemical properties of target compound AR

[0096]

[0097] Test Example 1 Preliminary Screening of Plant Pathogenic Bacteria

[0098] EC 50 Median effective concentration (MEC) is an important indicator for evaluating the sensitivity of plant pathogens to compounds. It is also an important parameter for setting compound concentration when studying the mechanism of action of target compounds. 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 using SPSS software, and the EC was calculated. 50 .

[0099] The effective medium concentration EC of the target compound against plant pathogens was tested by turbidity method. 50The test subjects were Xanthoceras oryzae (Xoo), Xanthoceras citri citri (Xac) and Xanthoceras kiwifruit (Psa). DMSO was dissolved in the culture medium as a blank control. Xanthoceras oryzae (Xac) 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; Xac (Xac) was placed in NB culture medium; Xac (Psa) 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 poison (compound) with different concentrations (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 48 hours, the citrus canker pathogen was cultured for 48 hours, and the kiwi canker pathogen was cultured for 24 hours. The OD of the bacterial solution of each concentration was measured on an ELISA instrument. 595 The OD of the corresponding concentration of toxic sterile NB liquid culture medium was also measured. 595 value.

[0100] Among them, bacterial liquid culture medium: water: 1L, glucose: 10g, protein: 5g, beef extract: 3g, yeast powder: 1g, M210 solid culture medium: water: 1L, glucose: 10g, protein: 5g, beef extract: 3g, yeast powder: 1g.

[0101] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0102] 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

[0103] 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 the target compounds are shown in Table 3.

[0104] Table 3 Antimicrobial activity of target compound (AR) against four plant bacteria: Xanthoceras oryzae (Xoo), Xanthoceras citri (Xac), Xanthoceras kiwifruit (Psa) and Ralstonia spp. (Rs)

[0105]

[0106] Note: a EC50 is expressed as the mean ± SD (standard error) of three independent replicates; TC b As a positive control group.

[0107] As can be seen from Table 3, in the in vitro test, the target compounds showed good antibacterial activity against plant pathogenic bacteria (such as Xanthoceras oryzae, Xanthoceras oryzae, Xanthoceras citri citri and Xanthoceras kiwifruit) :

[0108] Compound AR showed good antibacterial activity against Xoo, and its EC 50 0.28-24.8 μg / mL;

[0109] Compound AR showed good antibacterial activity against Xoc. 50 0.84-11.6 μg / mL;

[0110] Compound AR showed good antibacterial activity against Xac, and its EC 50 1.24-26.9 μg / mL;

[0111] Compound AR showed good antibacterial activity against Psa. 50 5.41-159 μg / mL;

[0112] Therefore, compounds A to R can be used to prepare pesticides against plant pathogenic bacteria.

[0113] Test Example 2: Preliminary screening of plant pathogenic fungi

[0114] The antibacterial activity of the compounds against plant pathogenic fungi and oomycetes such as Botryosphaeria dothidea (Bd), Gibberella zeae (Gz), Fusarium oxysporum (Fo), Verticillium dahliae (Vd), and Rhizoctonia solani (Rs) was determined on PDA culture medium using the mycelium growth rate inhibition method. All the strains were activated in advance. Weigh the compound to be tested with a 1 / 10,000 balance, add 1 mL DMSO to dissolve, transfer to a 15 mL sterilized centrifuge tube in a sterile operating table, add 9 mL Tween-20 to dissolve 10 mL, pour into the culture medium, mix well, and evenly distribute to 9 culture dishes for cooling; in a sterile operating table, use a sterilized hole puncher (5 mm) to make a bacterial cake from the normal growing colony, use a bacterial ring to turn the bacterial cake upside down in the center of the culture medium, and culture at 28 ° C for 3 to 5 days. When the control colony grows to 2 / 3 of the diameter of the entire plate, use a ruler to measure twice according to the cross method, and calculate the colony diameter size with the average value. We selected some compounds with higher antibacterial activity. When the initial screening concentration is 25 μg / mL, the growth inhibition rate of the compound on fungi is calculated according to the following formula. Boscalid was used as a control agent to participate in the test.

[0115] The calculation formula is as follows: Inhibition rate (%) = (C1-C2) / (C1-0.5)×100

[0116] In the formula: C1-control colony diameter is the diameter of DMSO-treated colonies;

[0117] C2-treated colony diameter is the diameter of the colony treated with the drug;

[0118] 0.5- is the diameter of the mother fungus cake.

[0119] 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 the target compounds are shown in Table 4.

[0120] Table 4 Preliminary screening results of amino alcohol-containing pterostilbene pyridine salt compounds against plant pathogenic fungi

[0121]

[0122]

[0123] As can be seen from Table 4, in the in vitro activity test, at a concentration of 25 μg / mL, the target compounds G, H, J, K, and O showed good antibacterial activity against plant pathogenic fungi (wheat fusarium and pepper wilt fungi), with the initial screening results of 21.73-67.38%, which was 12.02-16.67% higher than the control drug boscalid. At the same time, they showed certain antibacterial activity against Botrytis cinerea, with the best activity of 41.74%, which was almost equivalent to the inhibition rate of 40.19% of the control drug boscalid. They can be used to prepare pesticides against plant pathogenic fungi.

[0124] Test Example 3: Preliminary screening of plant viruses

[0125] The half-leaf spot method was used to test the inhibition rate of tripterygium wilfordii on plant viruses, and the test object was tobacco mosaic virus. Select heart-leaf tobacco with relatively consistent growth, mark the sample number on the side of the pot with an oil-based marker, and place the heart-leaf tobacco neatly on the test bench; dilute the TMV crude extract to an appropriate concentration with phosphate buffer in advance for later use.

[0126] 1) Therapeutic activity:

[0127] First, select the heart-leaf tobacco with relatively consistent growth, and use a brush to rub the TMV diluted to an appropriate concentration in advance on the leaves of the appropriate age sprinkled with corundum. The whole leaf is inoculated with the virus, and each leaf is manually and gently smeared with the virus once. The strength of the left and right half leaves should be as uniform as possible, and then the inoculated leaves are rinsed with sterile water. After the rinsing is completed, the plant is placed in a dark and ventilated place outdoors for about 1 hour. After the water droplets on the surface of the leaves are completely dry, the compound solution that has been prepared in advance is applied to the right half of the leaf, and the solvent of the corresponding dose is applied to the left half of the leaf as a control. The plants are placed in a light incubator with a temperature of 23±1℃, a light of 10000Lux, a light of 16h, and a dark of 8h. After 3-4d, the number of dead spots produced is observed and recorded. Three plants are set up for each agent treatment, and each plant has 3-4 leaves. Repeat 3 times for each agent according to the above method.

[0128] 2) Protective activity

[0129] First, select the heart-leaf tobacco with relatively consistent growth, apply the compound solution prepared in advance on the right half of the leaf, apply the corresponding dose of solvent on the left half of the leaf as a control, and place it in a light incubator with a temperature of 23±1℃ and a light of 10000Lux for 12h. Then, use a brush to manually rub the TMV diluted to an appropriate concentration in advance on the leaves of the appropriate age sprinkled with emery. The whole leaf is inoculated with the virus, and each leaf is manually and gently smeared with the virus once. The strength of the left and right half leaves should be as uniform as possible, and then the inoculated leaves are rinsed with sterile water. After rinsing, the plants are placed in a light incubator with a temperature of 23±1℃, a light of 10000Lux, a light of 16h, and a dark of 8h. After 3-4d, observe and record the number of dead spots. Set up 3 plants for each agent treatment, and each plant has 3-4 leaves. Repeat 3 times for each agent according to the above method.

[0130] 3) Experimental results statistics

[0131] Observe the plants and keep records. When obvious necrosis spots appear on half of the blank control leaf, an investigation can be conducted about 3-4 days after the experiment. Calculate and record the number of necrosis spots on the left and right halves of each leaf, and calculate the inhibition rate of the test compound on tobacco mosaic virus, i.e. the relative effect, according to the following formula.

[0132] Y=(CA) / C×100%

[0133] Where: Y is the inhibition rate of the compound on tobacco mosaic virus

[0134] C is the number of necrosis spots in the control group, unit: piece;

[0135] A is the number of necrotic spots in the compound treatment group, unit: piece.

[0136] The number of necrotic spots in the control group and the compound treatment group can refer to the average number of each group of repetitions or the total number of necrotic spots in each group of repetitions. Each treatment uses the other half of the leaf as a control, and a group of commercial Ningnanmycin treatment is set as a comparison.

[0137] 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 5.

[0138] Table 5 Test results of biological activity of pterostilbene pyridine salt compounds (500 μg / mL) against tobacco mosaic virus

[0139]

[0140]

[0141] As shown in Table 5, pterostilbene pyridinium salt compounds G, H, J, K, and O also exhibited excellent inhibitory activity against tobacco mosaic virus. Among them, at a drug concentration of 500 μg / mL, their therapeutic activities were 63.1%, 72.2%, 62.7%, 56.9%, and 74.2%, respectively, which were significantly better than the commercial drug Ningnanmycin (56.8%), and their protective activities were 74.1%, 76.6%, 64.5%, 78.1%, and 75.4%, respectively, which were almost equivalent to the commercial drug Ningnanmycin (76.1%).

[0142] In summary, pterostilbene pyridinium salt compounds have a good inhibitory effect on plant viruses, and this type of compound has extremely high research and development value in the discovery of new pesticides against plant pathogenic bacteria, fungi and plant viruses.

[0143] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pterostilbene pyridine salt compound or a salt thereof having a structural formula as shown in Formula 1: in, R is selected from the group consisting of 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. The pterostilbene pyridinium salt compound or its salt according to claim 1, characterized in that: The compound is selected from one of the following structures A to R:

3. A pterostilbene pyridine salt compound, characterized in that: It has the following structural formula:

4. The method for preparing the pterostilbene pyridine salt compound or its salt according to claim 1, characterized in that: The following steps are involved:

5. A composition comprising the pterostilbene pyridinium salt compound or a salt thereof according to claim 1.

6. A medicine comprising the pterostilbene pyridinium salt compound or its salt according to claim 1 or the composition according to claim 5; and a diluent or an excipient.

7. The drug according to claim 6, characterized in that The diluent or adjuvant is used for emulsifiable concentrate, powder, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion or water-dispersible granule.

8. Use of the pterostilbene pyridinium salt compound or its salt according to claim 1, the composition according to claim 5 or the drug according to claim 6 in preventing and controlling agricultural pests and diseases; The agricultural pests and diseases are plant bacterial diseases, plant fungal diseases or viral diseases.

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