Aryl isoxazole arecoline derivative or aryl isoxazoline arecoline derivative and application thereof

Abstract

The invention discloses an aryl isoxazole (line) arecoline derivative and its application, and relates to the technical field of chemical pesticides. The aryl isoxazole (line) arecoline derivative has a general formula shown in formula (I): wherein the definitions of the groups in the formula are as shown in the specification. The present invention adopts the above-mentioned aryl isoxazole (line) arecoline derivative and its application, has a brand-new molecular structure, can significantly enhance the antibacterial activity of the arecoline parent, has a good inhibitory effect on plant fungal diseases such as pepper phytophthora, pitaya black spot fungus, mango stem rot fungus, banana anthracnose fungus, phomopsis, wheat fusarium, rice sheath blight fungus, rice blast fungus, rapeseed sclerotinia fungus, apple ring rot fungus, banana wilt fungus, etc., and can be used for the development and use of effective ingredients for preparing agricultural fungicides or adjuvants.

Description

Technical Field

[0001] The invention relates to the technical field of chemical pesticides, in particular to an arylisoxazole arecoline derivative or an arylisoxazoline arecoline derivative and application thereof. Background Art

[0002] As an important component of natural products, alkaloids are widely present in organisms. Due to their environmentally friendly natural advantages and significant biological activities, they have become a hot topic in the fields of medicine and pesticides. In the agricultural field, the main research content is the research that uses alkaloids as lead compounds to carry out structural modification, enhance their biological activity or weaken their disadvantages. Using natural alkaloids as precursors, creating environmentally friendly, efficient, low-toxic green pesticides under human influence can increase the selectivity of agricultural agents and better solve the increasingly severe "3R" problem in agriculture. my country has a vast territory and rich biological resources, and has great advantages in the research of natural products as lead compounds.

[0003] Arecoline, as the most representative alkaloid in betel nut, exhibits extremely obvious pharmacological characteristics. The research related to it mainly focuses on the fields of nervous system, treatment of cardiovascular diseases, anti-parasite and anti-pathogenic microorganisms. Existing studies have confirmed that arecoline can effectively inhibit the uptake of γ-aminobutyric acid (GABA) and β-alanine (PLOSONE, 2015, 10 (10)); at the same time, arecoline can significantly reduce the oxygen consumption rate and ammonia excretion rate of organisms and inhibit acetylcholinesterase (AChE). In addition, arecoline has inhibitory effects on Staphylococcus aureus, Bacillus subtilis, Bacillus cereus and Escherichia coli. The minimum inhibitory concentrations for Staphylococcus aureus and Bacillus subtilis are 12.50 and 6.25 mg / L respectively (Agricultural Products Processing (Innovation Edition), 2010 (09): 47-50). In comparison, there are not many reports on agricultural chemicals led by arecoline.

[0004] Isoxazole and isoxazoline structures are widely present in natural products and are the active groups of many drugs. Isoxazole and isoxazoline can interact with a variety of protein targets and show high physiological and pharmacological activities, so they are widely used in drug design and synthesis. In the field of agriculture, pesticides containing isoxazole and isoxazoline have also been reported one after another. Isocycloseram is a new insecticide created by Syngenta. It has high insecticidal activity against many types of pests such as Lepidoptera, Hemiptera, Thysanoptera, and Coleoptera, and has high ecological safety for mammals, crops and the environment; Pyroxasulfonw is a new herbicide jointly developed by Kumizu Chemical Co., Ltd. and Ibara Chemical Industry Co., Ltd. It can be safely used in economic crops such as rice, and can also effectively control grass weeds such as Setaria and Echinochloa, as well as broad-leaved weeds such as Amaranthus and Datura. There are also related reports on the use of isoxazole (line) compounds in the domestic agricultural field, such as patents CN114539180A, CN112745312A, and CN117756735A, which disclose certain isoxazole (line) derivatives with agricultural activity. However, there are few reports on the derivation of natural product alkaloids. Summary of the invention

[0005] The present invention aims to provide an aromatic isoxazole (line) arecoline derivative and its application. The derivative has a brand-new molecular structure, can significantly enhance the antibacterial activity of the arecoline parent, has a good inhibitory effect on plant fungal diseases such as pepper phytophthora, pitaya black spot pathogen, mango stem rot pathogen, banana anthracnose pathogen, phomopsis, wheat fusarium, rice sheath blight pathogen, rice blast pathogen, rapeseed sclerotinia pathogen, apple ring rot pathogen, banana wilt pathogen, etc., and can be used for the development and use of effective ingredients for preparing agricultural fungicides or adjuvants.

[0006] To achieve the above object, the present invention provides an aryl isoxazole (line) arecoline derivative having the general formula (I):

[0007] ;

[0008] Wherein, X is NH or O;

[0009] A 1 , A 2 , A 3 , A 4are the same or different and are independently selected from hydrogen, a halogen atom, a cyano group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogenated C1-C6 alkylamino group, a C1-C6 alkylthio group, a halogenated C1-C6 alkylthio group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a di(C1-C6 alkyl)amino group, a halogenated di(C1-C6 alkyl)amino group, a C2-C6 alkenyl group, a halogenated C2-C6 alkenyl group, a halogenated C2-C6 alkenyloxy group, a C1-C6 alkenylthio group, a halogenated C1-C6 alkenylthio group, a C2-C6 alkynyl group, a halogenated C2-C6 alkynyl group alkyl, C2-C6 alkynyloxy, halogenated C2-C6 alkynyloxy, C1-C6 alkynylthio, halogenated C1-C6 alkynylthio, C1-C6 alkylcarbonyl, halogenated C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, halogenated C1-C6 alkylaminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, halogenated di(C1-C6 alkyl)aminocarbonyl, C1-C6 alkylsulfonyl, halogenated C1-C6 alkylsulfonyl, di(C1-C6 alkyl)aminosulfonyl, halogenated di(C1-C6 alkyl)aminosulfonyl, C1-C6 alkylsulfonyloxy, halogenated C1-C6 alkylsulfonyloxy;

[0010] Carbon atom C 1 and C 2 connected by single or double bonds;

[0011] R 1 is hydrogen, a halogen atom, a C1-C6 alkyl group or a halogenated C1-C6 alkyl group;

[0012] Ar is A 5 A substituted aromatic group, aliphatic heterocycle, oxygen heterocycle, nitrogen heterocycle, sulfur heterocycle, aromatic heterocycle, benzoheterocycle, or condensed ring; 5is selected from the group consisting of hydrogen, a halogen atom, a cyano group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogenated C1-C6 alkylamino group, a C1-C6 alkylthio group, a halogenated C1-C6 alkylthio group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a di(C1-C6 alkyl)amino group, a halogenated di(C1-C6 alkyl)amino group, a C2-C6 alkenyl group, a halogenated C2-C6 alkenyl group, a halogenated C2-C6 alkenyloxy group, a C1-C6 alkenylthio group, a halogenated C1-C6 alkenylthio group, a C2-C6 alkynyl group, a halogenated C2-C6 alkynyl group, a C2-C6 C1-C6 alkynyloxy, halogenated C2-C6 alkynyloxy, C1-C6 alkynylthio, halogenated C1-C6 alkynylthio, C1-C6 alkylcarbonyl, halogenated C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, halogenated C1-C6 alkylaminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, halogenated di(C1-C6 alkyl)aminocarbonyl, C1-C6 alkylsulfonyl, halogenated C1-C6 alkylsulfonyl, di(C1-C6 alkyl)aminosulfonyl, halogenated di(C1-C6 alkyl)aminosulfonyl, C1-C6 alkylsulfonyloxy, halogenated C1-C6 alkylsulfonyloxy.

[0013] Furthermore, in formula (I), A 1 , A 2 , A 3 , A 4 The same or different, are independently selected from hydrogen, a halogen atom, a cyano group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halo-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a halo-substituted C1-C6 alkoxy group, a C1-C6 alkylamino group, a halo-substituted C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a halo-substituted C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a halo-substituted C2-C6 alkenyl group, a C2-C6 alkynyl group, a halo-substituted C2-C6 alkynyl group, a C1-C6 alkylcarbonyl group, a halo-substituted C1-C6 alkylcarbonyl group, a C1-C6 alkylsulfonyl group, and a halo-substituted C1-C6 alkylsulfonyl group.

[0014] Furthermore, in formula (I), R 1 Selected from fluorine atom, chlorine atom, methyl group, ethyl group, isopropyl group, tert-butyl group, difluoromethyl group and trifluoromethyl group.

[0015] Further, in formula (I), Ar is selected from A 5 Substituted cyclopropane, A 5 Substituted cyclobutane, A 5 Substituted cyclopentane, A 5 Substituted cyclohexanes, A 5 Substituted tetrahydrofuran, A 5 Substituted tetrahydropyrrole, A 5Substituted tetrahydrothiophene, A 5 Substituted tetrahydrothiophene, A 5 Substituted piperidine, A 5 Substituted tetrahydrothiopyran, A 5 Substituted dioxane, A 5 Substituted piperazine, A 5 Substituted hexahydropyrazine, A 5 Substituted morpholine, A 5 Substituted dithianes, A 5 Substituted pyrrole, A 5 Substituted pyrazole, A 5 Substituted imidazole, A 5 Substituted triazole, A 5 Substituted tetrazolyl, A 5 Substituted furan, A 5 Substituted isoxazole (line), A 5 Substituted oxazole, A 5 Substituted oxadiazole, A 5 Substituted thiophene, A 5 Substituted isothiazole, A 5 Substituted thiazole, A 5 Substituted thiadiazoles, A 5 Substituted pyrans, A 5 Substituted pyridine, A 5 Substituted diazines, A 5 Substituted triazine, A 5 Substituted indole, A 5 Substituted quinoline, A 5 Substituted isoquinoline, A 5 Substituted purine, A 5 Substituted benzofuran, A 5 Substituted benzothiophene, A 5 Substituted purine, A 5 Substituted pyrone, A 5 Substituted pyrrolidone, A 5 Substituted benzene, A 5 Substituted naphthalene, A 5 Substituted anthracene, A 5 Replace phenanthrene; wherein A 5 It is monosubstituted or polysubstituted.

[0016] A method for preparing an aryl isoxazole (line) arecoline derivative. In formula (I), when X is O, the preparation method is as follows:

[0017] .

[0018] A method for preparing an aryl isoxazole (line) arecoline derivative. In formula (I), when X is NH, the preparation method is as follows:

[0019] ;

[0020] In the above reaction, the compound of formula II (Formula II-a, Formula II-b) and an aqueous solution of hydroxylamine hydrochloride are added to a round-bottom flask, and an alkaline solution is used to adjust the pH of the reaction solution to neutral. After the reaction is completed, recrystallization is performed to obtain a compound of formula III (Formula III-a, Formula III-b);

[0021] The compound of formula III, N-chlorosuccinimide and an organic solvent are mixed evenly, and a substance with an unsaturated bond and 1,8-diazabicyclo (5,4,0) undec-7-ene are added to react at -5°C to 50°C, and then extracted and concentrated to obtain a compound of formula IV (Formula IV-a, Formula IV-b);

[0022] Compound IV-b is dissolved in an organic solvent, reacted with glacial acetic acid solution and reducing metal atoms or ions at -5°C to 80°C, and then extracted, concentrated, and recrystallized to obtain a compound of formula VI;

[0023] The Ⅳ-a compound or Ⅵ compound, arecoline, a condensation reagent and an organic solvent are reacted at -5°C to 40°C, and then extracted and recrystallized to obtain aromatic isoxazole (line) type arecoline derivatives (Formula Ⅰ-a, Formula Ⅰ-b).

[0024] Preferably, the alkaline solution is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate solution or alkali metal alcoholate.

[0025] Preferably, the organic solvent is dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, acetonitrile, N , N - one or more of dimethylformamide, dimethyl sulfoxide, methanol, ethanol, petroleum ether (60-90°C), n-butanol, benzene, toluene, xylene, ether, tetrahydrofuran.

[0026] Preferably, the unsaturated bond substance is ethylene or acetylene.

[0027] Preferably, the reducing metal atoms or ions are iron powder, zinc powder, magnesium powder, aluminum powder, zinc powder, tin powder, Fe 2+ Sn 2+ One or more of.

[0028] Preferably, the condensation reagent is one or more of EDC hydrochloride, DMAP, DCC, HATU, PyBOP, TCFH, T3P, HOBt.

[0029] Application of the above-mentioned aryl isoxazole (line) arecoline derivative or the aryl isoxazole (line) arecoline derivative obtained by the above-mentioned preparation method in the preparation of fungicides.

[0030] Further, pathogens that fungicides act on include:

[0031] ① Oomycetes: downy mildew, white rust, damping-off, cotton rot, phytophthora, and late blight;

[0032] ②Basidiomycetes: stripe rust, smut, sheath blight;

[0033] ③ Ascomycetes: powdery mildew, sclerotinia, black spot, fusarium;

[0034] ④ Ascomycetes: wilt pathogens, root rot pathogens, damping-off pathogens, anthracnose pathogens, verticillium wilt pathogens, gray mold pathogens, brown spot pathogens, black spot pathogens, black rot pathogens, stem rot pathogens, leaf blight pathogens, early blight pathogens, ring rot pathogens, leaf blight pathogens, and phomopsis pathogens.

[0035] Furthermore, the pathogens affected by the fungicide include pepper blight, pitaya black spot, mango stem rot, banana anthracnose, phomopsis, wheat fusarium, rice sheath blight, rice blast, rapeseed sclerotinia, apple ring rot, and banana wilt.

[0036] The advantages and positive effects of the aromatic isoxazole (line) arecoline derivative and its application described in the present invention are:

[0037] 1. The aromatic isoxazole (line) arecoline derivatives provided by the present invention have a brand-new molecular structure, can significantly enhance the antibacterial activity of the arecoline parent, and have a good inhibitory effect on plant fungal diseases such as pepper phytophthora, pitaya black spot pathogen, mango stem rot pathogen, banana anthracnose pathogen, phomopsis, wheat fusarium, rice sheath blight pathogen, rice blast pathogen, rapeseed sclerotinia pathogen, apple ring rot pathogen, banana wilt pathogen, etc., and can be used for the development and use of effective ingredients for the preparation of agricultural fungicides or adjuvants.

[0038] The technical solution of the present invention is further described in detail below through embodiments. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is further illustrated by the following examples.

[0040] Unless otherwise defined, technical or scientific terms used in the present invention shall have the common meanings understood by one having ordinary skills in the field to which the present invention belongs.

[0041] Example 1

[0042] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in 1a below:

[0043] ;

[0044] Its synthesis method is:

[0045] S1. Preparation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (arecaline):

[0046] Dissolve 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester-hydrobromide (arecoline hydrobromide) (2.35g, 10 mmol) in water (30 mL) and adjust the pH to 10-11 with 30% Na2CO3. Extract the mixed solution with CH2Cl2 (3×30 mL), combine the organic phases, wash with saturated brine, and dry over anhydrous magnesium sulfate. Filter and concentrate under reduced pressure to obtain a yellow oil, add water (30 mL) and reflux at high temperature for 24h. After the reaction is completed, concentrate under reduced pressure, wash the crude product with anhydrous ethanol, and obtain 1.212 g of white flaky crystals of arecoline with a yield of 86%.

[0047] S2. Preparation of p-hydroxybenzaldehyde oxime:

[0048] Take a 100 mL round-bottom flask, add p-hydroxybenzaldehyde (20 mmol, 2.492 g) and water (60 mL) in sequence, and stir to dissolve. Use a 25 mL beaker to weigh hydroxylamine hydrochloride (60 mmol, 6.348 g) and sodium hydroxide (60 mmol, 3.750 g), add 10 mL of water to each and stir to dissolve. Slowly add the sodium hydroxide solution to the hydroxylamine hydrochloride solution under ice bath conditions, and adjust the pH of the mixed solution to neutral; use a rubber-tipped dropper to slowly add the mixed solution to the round-bottom flask, and stir the reaction at room temperature overnight. Use ethyl acetate (2×30 mL) to extract, combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and add water to recrystallize to obtain 2.672 g of white solid with a yield of 97.5%.

[0049] S3. Preparation of intermediate 4-(5-(4-chlorophenyl)-5-methyl-isoxazoline-3-yl)phenol:

[0050] Take a 50 mL round-bottom flask, add p-hydroxybenzaldehyde oxime (2 mmol, 0.280 g) and N,N-dimethylformamide (DMF) (4 mL) in sequence; stir to dissolve, heat to 50 °C, and add N-chlorosuccinimide (NCS) (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add 4-chloro-α-methylstyrene (2.4 mmol, 0.364 g) and 1,8-diazabicyclo(5,4,0)undec-7-ene (DBU) (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir at room temperature for 3 h, and the reaction is completed. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, use ethyl acetate (3×20 The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and recrystallized by adding anhydrous ethanol to obtain 0.473 g of a brown solid with a yield of 82.5%.

[0051] S4. Preparation of compound 1a

[0052] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.288 g), 4-dimethylaminopyridine (DMAP) (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2 mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.325 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 7:1), with a yield of 79.5%.

[0053] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.7 Hz, 2H),7.41 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.28 – 7.24 (m, 1H), 7.13(d, J = 8.7 Hz, 2H), 3.45 (s, 2H), 3.26 (q, J = 2.5 Hz, 2H), 2.56 (t,J = 5.6Hz, 2H), 2.49 – 2.44 (m, 5H), 1.77 (s, 3H).

[0054] The substitution of compound 1a is shown in Ⅰ-1 in Table 1.

[0055] Example 2

[0056] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in 1b below:

[0057] ;

[0058] Its synthesis method is:

[0059] Step S1 is the same as step S1 in Example 1;

[0060] S2. Preparation of 3-(3,3-dimethylbutyl)-4-hydroxybenzaldehyde oxime:

[0061] Take a 100 mL round-bottom flask, add 3-(3,3-dimethylbutyl)-4-hydroxybenzaldehyde (20 mmol, 4.125 g) and water (60 mL) in sequence, and stir to dissolve. Use a 25 mL beaker to weigh hydroxylamine hydrochloride (60 mmol, 6.348 g) and sodium hydroxide (60 mmol, 3.750 g), add 10 mL of water to each and stir to dissolve. Slowly add the sodium hydroxide solution to the hydroxylamine hydrochloride solution under ice bath conditions to adjust the pH of the mixed solution to neutral; use a rubber-tipped dropper to slowly drop the mixed solution into the round-bottom flask, and stir the reaction at room temperature overnight. Use ethyl acetate (2×30 mL) to extract, combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and recrystallize from water to obtain 4.355 g of white crystals with a yield of 98.4%.

[0062] S3. Preparation of intermediate 4-(5-(4-chloro-3,5-difluorophenyl)isoxazol-3-yl)-2-(3,3-dimethylbutyl)phenol:

[0063] Take a 50 mL round-bottom flask, add 3-bromo-4-hydroxy-5-methylbenzaldehyde oxime (2 mmol, 0.443 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add 2-chloro-5-ethynyl-1,3-difluorobenzene (2.4 mmol, 0.414 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.599 g of brown powder with a yield of 76.5%.

[0064] S4. Preparation of compound 1b:

[0065] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.392 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.403 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 5:1), with a yield of 78.3%.

[0066] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 8.9, 2.1 Hz,1H), 7.46–7.43 (m, 1H), 7.34 (d, J = 9.0 Hz,1H), 7.26 (d, J = 1.0 Hz,1H), 7.24(d, J = 1.0 Hz, 1H), 7.13 (s, 1H), 6.91 (tq, J = 4.4, 0.9 Hz, 1H), 3.62 (q, J = 0.9 Hz, 2H), 2.86 (dd, J= 5.8,0.9 Hz,2H), 2.69 (td, J = 7.4, 1.0 Hz,2H),2.43 – 2.25 (m, 5H), 1.56 (d, J = 14.8 Hz, 2H), 0.83 (s, 9H).

[0067] The substitution of compound 1b is shown in Ⅰ-13 in Table 1.

[0068] Example 3

[0069] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in 1c below:

[0070] ;

[0071] Its synthesis method is:

[0072] Step S1 is the same as step S1 in Example 1;

[0073] S2. Preparation of 3-bromo-4-hydroxy-5-methylbenzaldehyde oxime:

[0074] Take a 100 mL round-bottom flask, add 3-bromo-4-hydroxy-5-methylbenzaldehyde (20 mmol, 4.301g) and water (60 mL) in sequence, and stir to dissolve. Use a 25 mL beaker to weigh hydroxylamine hydrochloride (60 mmol, 6.348 g) and sodium hydroxide (60 mmol, 3.750 g), add 10 mL of water to each and stir to dissolve. Slowly add the sodium hydroxide solution to the hydroxylamine hydrochloride solution under ice bath conditions to adjust the pH of the mixed solution to neutral; use a rubber-tipped dropper to slowly add the mixed solution to the round-bottom flask, and stir the reaction at room temperature overnight. Use ethyl acetate (2×30 mL) to extract, combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and add water to recrystallize to obtain 4.278 g of white crystals with a yield of 93.0%.

[0075] S3. Preparation of intermediate 4-(5-(1H-imidazol-1-yl)isoxazol-3-yl)-2-bromo-6-methylphenol:

[0076] Take a 50 mL round-bottom flask, add 3-bromo-4-hydroxy-5-methylbenzaldehyde oxime (2 mmol, 0.460 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add nitrogen-ethynyl imidazole (2.4 mmol, 0.221 g) and DBU (2mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.528 g of brown powder with a yield of 81.9%.

[0077] S4. Preparation of compound 1c:

[0078] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.322 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.286 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 5:1), with a yield of 64.3%.

[0079] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.48 (dt, J = 2.1, 1.1 Hz,1H), 7.26 (s, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.94 (dd, J = 1.7, 0.7 Hz, 1H),6.89 (dd, J = 4.0, 1.6 Hz, 1H), 6.65 (tq, J = 4.3, 0.9 Hz, 1H), 6.23 – 6.18(m, 1H), 3.89 (dd, J = 15.1, 3.6 Hz, 1H), 3.64 (dd, J= 15.1, 3.6 Hz, 1H),3.36 (q, J = 1.0 Hz, 2H), 2.60 (ddd, J = 5.8, 3.6, 0.9 Hz, 2H), 2.13 (s, 3H), 2.10–1.98 (m, 5H).

[0080] The substitution of compound 1c is shown in Ⅰ-51 in Table 1.

[0081] Example 4

[0082] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in 1d below:

[0083] ;

[0084] Its synthesis method is:

[0085] Steps S1 to S2 are the same as steps S1 to S2 in Example 1;

[0086] S3. Preparation of intermediate 4-(5-(thiophen-2-yl)isoxazol-3-yl)phenol:

[0087] Take a 50 mL round-bottom flask, add p-hydroxybenzaldehyde oxime (2 mmol, 0.280 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add 2-ethynylthiophene (2.4 mmol, 0.259 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.387 g of a yellow solid with a yield of 79.8%.

[0088] S4. Preparation of compound 1d:

[0089] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.243 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.244 g of light yellow solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 8:1), with a yield of 66.8%.

[0090] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.90 – 7.83 (m, 2H), 7.55(dd, J = 3.7, 1.2 Hz, 1H), 7.46 (dd, J = 5.0, 1.2 Hz, 1H), 7.28 (tt, J = 3.9,1.9 Hz, 1H), 7.25 – 7.19 (m, 2H), 7.13 (dd, J = 5.0, 3.7 Hz, 1H), 6.67 (s,1H), 3.29 (q, J = 2.7 Hz, 2H), 2.59 (t, J = 5.6 Hz, 2H), 2.52 – 2.47 (m, 2H), 2.46 (s, 3H).

[0091] The substitution of compound 1d is shown in Ⅰ-23 in Table 1.

[0092] Example 5

[0093] The structural formula of the aromatic isoxazole (line) arecoline derivative of this embodiment is shown in 1e below:

[0094] ;

[0095] Its synthesis method is:

[0096] Step S1 is the same as step S1 in Example 1;

[0097] S2. Preparation of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde oxime:

[0098] Take a 100 mL round-bottom flask, add 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (20 mmol, 4.403 g) and water (60 mL) in sequence, and stir to dissolve. Use a 25 mL beaker to weigh hydroxylamine hydrochloride (60 mmol, 6.348 g) and sodium hydroxide (60 mmol, 3.750 g), add 10 mL of water to each and stir to dissolve. Slowly add the sodium hydroxide solution to the hydroxylamine hydrochloride solution under ice bath conditions to adjust the pH of the mixed solution to neutral; use a rubber-tipped dropper to slowly drop the mixed solution into the round-bottom flask, and stir the reaction at room temperature overnight. Use ethyl acetate (2×30 mL) to extract, combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and recrystallize from water to obtain 4.044 g of white crystals with a yield of 86.0%.

[0099] S3. Preparation of intermediate 2-methoxy-4-(5-methyl-5-(pyrimidin-4-yl)-4,5-isoxazoline-3-yl)-6-trifluoromethylphenol:

[0100] Take a 50 mL round-bottom flask, add 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde oxime (2 mmol, 0.470 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add α-methyl-4-vinylpyrimidine (2.4 mmol, 0.288 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir at room temperature for 3 h, and the reaction is completed. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.478 g of brown solid, with a yield of 67.7%.

[0101] S4. Preparation of compound 1e:

[0102] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.353 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.279 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 3:1), with a yield of 58.7%.

[0103] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 8.96 (t, J = 1.6 Hz, 1H),8.64 (dd, J = 4.2, 1.6 Hz, 1H), 7.46 (dq, J = 2.5, 1.3 Hz, 1H), 7.29 – 7.22(m, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.89 (tq, J = 4.4, 0.9 Hz, 1H), 4.01 (d, J = 18.1 Hz, 1H), 3.88 (s, 3H), 3.75 (d, J = 18.3 Hz, 1H), 3.60 (q, J = 1.0 Hz,2H), 2.84 (ddd, J = 5.7, 3.6, 0.9 Hz, 2H), 2.40–2.24 (m, 5H).

[0104] Among them, the substitution situation of compound 1e corresponds to that shown in Ⅰ-57 in Table 1.

[0105] Example 6

[0106] The structural formula of the aromatic isoxazole (line) arecoline derivative of this embodiment is shown in 1f below:

[0107] ;

[0108] Its synthesis method is:

[0109] Steps S1 to S2 are the same as steps S1 to S2 in Example 1;

[0110] S3, preparation of intermediate 4-(5-aryl-5-(trifluoromethyl)-isoxazoline-3-yl)phenol:

[0111] Take a 50 mL round-bottom flask, add p-hydroxybenzaldehyde oxime (2 mmol, 0.280 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add α-trifluoromethyl-styrene (2.4 mmol, 0.412 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.489 g of brown solid, with a yield of 79.8%.

[0112] S4. Preparation of compound 1f:

[0113] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.307 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.318 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 7:1), with a yield of 74.1%.

[0114] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.8 Hz, 2H),7.59 (d, J = 5.5 Hz, 2H), 7.42 (q, J = 5.6 Hz, 3H), 7.26 (dd, J = 7.0, 2.9Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 4.07 (d, J= 17.1 Hz, 1H), 3.74 (d, J =17.2 Hz, 1H), 3.26 (q, J = 2.6 Hz, 2H), 2.57 (t, J = 5.6 Hz, 2H), 2.50–2.41(m, 5H).

[0115] The substitution of compound 1f is shown in Ⅰ-4 in Table 1.

[0116] Example 7

[0117] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in the following 1g:

[0118] ;

[0119] Its synthesis method is:

[0120] Step S1 is the same as step S1 in Example 1;

[0121] S2. Preparation of 2-(cyclopropylmethoxy)-5-((dimethylamino)methyl)-4-hydroxybenzaldehyde oxime:

[0122] Take a 100 mL round-bottom flask, add 2-(cyclopropylmethoxy)-5-((dimethylamino)methyl)-4-hydroxybenzaldehyde (20 mmol, 4.986 g) and water (60 mL) in sequence, and stir to dissolve. Use a 25 mL beaker to weigh hydroxylamine hydrochloride (60mmol, 6.348 g) and sodium hydroxide (60 mmol, 3.750 g), add 10 mL of water to each and stir to dissolve. Slowly add the sodium hydroxide solution to the hydroxylamine hydrochloride solution under ice bath conditions to adjust the pH of the mixed solution to neutral; use a rubber-tipped dropper to slowly drop the mixed solution into the round-bottom flask, and stir the reaction at room temperature overnight. Use ethyl acetate (2×30 mL) to extract, combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and add water to recrystallize to obtain 4.456g of white crystals with a yield of 84.3%.

[0123] S3. Preparation of 5-(cyclopropylmethoxy)-2-((dimethylamino)methyl)-4-(5-(2,4-dimethylpiperidin-3-yl)isoxazol-3-yl)phenol:

[0124] Take a 50 mL round-bottom flask, add 2-(cyclopropylmethoxy)-5-((dimethylamino)methyl)-4-hydroxybenzaldehyde oxime (2 mmol, 0.799 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add 2,4-dimethyl-3-ethynylpiperidine (2.4 mmol, 0.329 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.447 g of a yellow-brown solid with a yield of 56.9%.

[0125] S4. Preparation of compound 1g:

[0126] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.399 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.417 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 4:1), with a yield of 79.8%.

[0127] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 1.8 Hz, 1H),6.60 (q, J = 4.4, 0.9 Hz, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 3.74 – 3.67 (m,4H), 3.45 – 3.35 (m, 1H), 3.32 (q, J = 0.9 Hz, 2H), 2.63 (dd, J= 13.2, 5.9,4.2, 3.1 Hz, 1H), 2.58 – 2.53 (m, 3H), 2.50 – 2.41 (m, 2H), 2.32 (s, 6H), 2.10 – 1.95 (m, 5H), 1.94 – 1.84 (m, 1H), 1.49 – 1.38 (m, 1H), 1.16 – 1.10 (m, 1H), 1.10 – 1.04 (m, 1H), 0.82 (dd, J = 4.7, 1.6 Hz, 3H), 0.57 (dd, J =5.7, 1.5 Hz, 3H), 0.47 – 0.35 (m, 2H), 0.20 – 0.05 (m, 2H).

[0128] The substitution of compound 1g is shown in Ⅰ-63 in Table 1.

[0129] Example 8

[0130] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in 1h below:

[0131] ;

[0132] Its synthesis method is:

[0133] Steps S1 to S2 are the same as steps S1 to S2 in Example 1;

[0134] S3, preparation of intermediate 1-(3-(4-hydroxyphenyl)-isoxazoline-5-yl)pyrrolidin-2-one:

[0135] Take a 50 mL round-bottom flask, add p-hydroxybenzaldehyde oxime (2 mmol, 0.280 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add nitrogen-vinyl pyrrolidone (2.4 mmol, 0.266 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.390 g of light yellow solid, with a yield of 79.3%.

[0136] S4. Preparation of compound 1h:

[0137] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.246 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.252 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 5:1), with a yield of 68.4%.

[0138] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.73 – 7.65 (m, 2H), 7.30 –7.22 (m, 1H), 7.20 – 7.12 (m, 2H), 6.64 (dd, J = 9.9, 3.4 Hz, 1H), 3.53 (dd, J = 17.6, 9.9 Hz, 1H), 3.37 – 3.27 (m, 1H), 3.24 (q, J = 2.5 Hz, 2H), 3.17(dd, J = 8.8, 5.1 Hz, 1H), 3.11 (dd, J = 17.6, 3.4 Hz, 1H), 2.54 (t, J = 5.5Hz, 2H), 2.50 – 2.44 (m, 2H), 2.43 (s, 3H), 2.42 – 2.37 (m, 2H), 2.08 –1.95(m, 2H).

[0139] The substitution of compound 1h is shown in Ⅰ-29 in Table 1.

[0140] Example 9

[0141] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in the following 1i:

[0142] ;

[0143] Its synthesis method is:

[0144] Steps S1 to S2 are the same as steps S1 to S2 in Example 1;

[0145] S3, preparation of intermediate 4-(5-(pyridin-3-yl)isoxazol-3-yl)phenol:

[0146] Take a 50 mL round-bottom flask, add p-hydroxybenzaldehyde oxime (2 mmol, 0.280 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add 3-ethynylpyridine (2.4 mmol, 0.247 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.416 g of a yellow solid with a yield of 87.6%.

[0147] S4. Preparation of compound 1i:

[0148] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.238 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate by silica gel column chromatography (eluent: ethyl acetate: methanol = 5:1) to obtain 0.236 g of yellow solid, with a yield of 65.4%.

[0149] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.66 (d, J =4.8 Hz, 1H), 8.12 – 8.07 (m, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.40 (dd, J =8.0, 4.9 Hz, 1H), 7.28 – 7.25 (m, 1H), 7.21 (d, J= 8.7 Hz, 2H), 6.89 (s,1H), 3.26 (q, J = 2.5 Hz, 2H), 2.56 (t, J = 5.6 Hz, 2H), 2.48 – 2.42 (m, 5H).

[0150] The substitution of compound 1i is shown in Ⅰ-35 in Table 1.

[0151] Example 10

[0152] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in the following figure:

[0153] ;

[0154] Its synthesis method is:

[0155] Steps S1 to S2 are the same as steps S1 to S2 in Example 1;

[0156] S3, preparation of intermediate 4-(5-(naphthalene-2-yl)isoxazol-3-yl)phenol:

[0157] Take a 50 mL round-bottom flask, add p-hydroxybenzaldehyde oxime (2 mmol, 0.280 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (2.4 mmol, 0.327 g) to react for 1 h. After the reaction is completed, stop heating, add 2-ethynylnaphthalene (2.4 mmol, 0.364 g) and DBU (2 mmol, 0.309 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.452 g of brown solid, with a yield of 78.9%.

[0158] S4. Preparation of compound 1j:

[0159] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S3 (1 mmol, 0.287 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate 0.280 g of white solid by silica gel column chromatography (eluent: ethyl acetate: methanol = 9:1), with a yield of 68.5%.

[0160] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 1.7 Hz, 1H),7.97 – 7.90 (m, 4H), 7.90 – 7.81 (m, 2H), 7.56 (dt, J = 6.3, 3.4 Hz, 2H),7.32 – 7.28 (m, 1H), 7.27 – 7.23 (m, 2H), 6.92 (s, 1H), 3.31 (q, J = 2.5 Hz,2H), 2.60 (t, J = 5.6 Hz, 2H), 2.48 (d, J = 6.2 Hz, 5H).

[0161] The substitution of compound 1j is shown in Ⅰ-43 in Table 1.

[0162] Embodiment 11

[0163] The structural formula of the aryl isoxazole (line) arecoline derivative of this embodiment is shown in Figure 1k:

[0164] ;

[0165] Its synthesis method is:

[0166] Step S1 is the same as step S1 in Example 1;

[0167] S2. Preparation of p-nitrobenzaldehyde oxime:

[0168] Take a 100 mL round-bottom flask, add p-nitrobenzaldehyde (20 mmol, 3.020 g) and water (60 mL) in sequence, and stir to dissolve. Use a 25 mL beaker to weigh hydroxylamine hydrochloride (60 mmol, 6.348 g) and sodium hydroxide (60 mmol, 3.750 g), add 10 mL of water to each and stir to dissolve. Slowly add the sodium hydroxide solution to the hydroxylamine hydrochloride solution under ice bath conditions, and adjust the pH of the mixed solution to neutral; use a rubber-tipped dropper to slowly add the mixed solution to the round-bottom flask, and stir the reaction at room temperature overnight. Use ethyl acetate (2×30 mL) to extract, combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, and add water to recrystallize to obtain 3.087 g of yellow crystals with a yield of 93.0%.

[0169] S3, preparation of intermediate 5-(4-bromophenyl)-3-(4-nitrophenyl)-isoxazoline:

[0170] Take a 50 mL round-bottom flask, add p-nitrobenzaldehyde oxime (5 mmol, 0.848 g) and DMF (4 mL) in sequence; stir to dissolve, heat to 50 ° C, and add NCS (6 mmol, 0.813 g) to react for 1 h. After the reaction is completed, stop heating, add 4-bromo-styrene (6 mmol, 1.144 g) and DBU (5 mmol, 0.769 g) in sequence under ice bath conditions, remove the ice bath, stir and react at room temperature for 3 h. After the reaction is completed, add water (20 mL) to quench the reaction, pour the reaction solution into a separatory funnel, extract with ethyl acetate (3×20 mL), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add anhydrous ethanol for recrystallization to obtain 0.895 g of brown solid, with a yield of 51.6%.

[0171] S4, preparation of intermediate 4-(5-(4-bromophenyl)-4,5-isoxazoline-3-yl)aniline:

[0172] Take a 50 mL round-bottom flask, add the compound obtained in step S3 (2.5 mmol, 0.868 g) and ethyl acetate (5 mL) in sequence, stir to dissolve; then add glacial acetic acid (15 mmol, 0.908 g) and iron powder (5 mmol, 0.279 g) in sequence, heat to 80 ° C and react for 2 h; after the reaction is completed, filter while hot, pour the filtrate into a separatory funnel, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in sequence, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate by silica gel column chromatography (eluent is n-hexane: ethyl acetate = 1:1) to obtain 0.394 g of yellow powder, with a yield of 51.7%.

[0173] S5. Preparation of compound 1k:

[0174] Take a 50 mL round-bottom flask, add arecaline (1.1 mmol, 0.155 g), the compound obtained in step S4 (1 mmol, 0.317 g), DMAP (0.5 mmol, 0.061 g) and 5 mL DMF in turn, stir evenly, and then add EDCI (2mmol, 0.383 g). Stir the reaction at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash with water, saturated sodium bicarbonate and saturated brine in turn, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and separate by silica gel column chromatography (eluent: ethyl acetate: methanol = 7:1) to obtain 0.313 g of yellow solid, with a yield of 71.5%.

[0175] The results of H NMR spectrum are: 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 0.8 Hz, 1H),7.65 (d, J = 4.5 Hz, 2H), 7.62 (d, J = 9.2 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H),7.30 – 7.27 (m, 2H), 6.74 – 6.61 (m, 1H), 5.70 (dd, J = 10.9, 8.1 Hz, 1H),3.78 (dd, J = 16.6, 11.0 Hz, 1H), 3.38 – 3.20 (m, 3H), 2.59 (t, J = 5.7 Hz, 2H), 2.47 (s, 3H), 2.45 – 2.40 (m, 2H).

[0176] The substitution of compound 1k is shown in Ⅰ-81 in Table 1.

[0177] The above method can also be used to prepare other compounds described in the present invention.

[0178] Table 1 is a structural description of some compounds (Ⅰ-1 to Ⅰ-118) after the general formula (Ⅰ) structure is replaced by substituents.

[0179] General formula (Ⅰ):

[0180] ;

[0181] Table 1

[0182] ;

[0183] ;

[0184] ;

[0185] ;

[0186] Application Examples

[0187] Antibacterial biological activity assay:

[0188] The experimental method adopts the poisonous medium method:

[0189] The tested bacteria were rice blast pathogen ( M. oryzae )、Rhizoctonia solani( R.solani ) Mango stem rot B.theobromae )、Pitaya black spot pathogen ( B. cactivora )、Tea polytrichomoniasis ( P.theae )、Phomopsis fasciatus( P.sp )、Apple ring rot fungus( P.piricola )、Sclerotinia sclerotiorum( S. sclerotiorum ), wheat stem rot fungus ( F. verticillioides ), provided by the College of Tropical Agriculture and Forestry, Hainan University.

[0190] The aryl isoxazole (line) arecoline derivative test agent of the present invention is prepared into a liquid with a mass concentration of 100 mg / L. A 5 mm diameter puncher is used to take a bacterial cake, and it is inoculated on a potato dextrose agar medium containing the test agent, and a medium without the drug but with the same solvent and auxiliary agent is used as a control, and each test sample is repeated three times; the colony growth is observed, and when the colony diameter of the control group grows to 2 / 3 of the culture dish, the colony diameter of the treatment group is measured.

[0191] Result treatment: Inhibition rate (%) = [(average colony diameter of the control group - average colony diameter of the treatment group) / (average colony diameter of the control group - diameter of the bacterial cake)] × 100%.

[0192] According to the inhibition rate of plant pathogenic fungi, the compounds are divided into five levels: 90≤A≤100%; 80≤B<90%; 70≤C<80%; 60≤D<70%; E<60%. The antibacterial activity test results of some compounds are shown in Table 2.

[0193] Table 2 Antibacterial activity test results of some compounds

[0194] ;

[0195] ;

[0196] ;

[0197] ;

[0198] It can be seen from the bioassay results in Table 2 that at a concentration of 100 mg / L, the aromatic isoxazole (line) arecoline derivatives provided by the present invention have excellent antibacterial activity against plant pathogenic fungi, and can be used as active ingredients of chemical pesticides in the prevention and control of plant pathogenic fungi, and can be mixed with other carriers or adjuvants permitted in plant protection to prepare various dosage forms that can be used in agriculture.

[0199] Therefore, the present invention adopts the above-mentioned aromatic isoxazole (line) arecoline derivative and its application, which has a brand-new molecular structure, can significantly enhance the antibacterial activity of the arecoline parent, and has a good inhibitory effect on plant fungal diseases such as pepper phytophthora, pitaya black spot pathogen, mango stem rot pathogen, banana anthracnose pathogen, phomopsis, wheat fusarium, rice sheath blight pathogen, rice blast pathogen, rapeseed sclerotinia pathogen, apple ring rot pathogen, banana wilt pathogen, etc., and can be used for the development and use of effective ingredients for preparing agricultural fungicides or adjuvants.

[0200] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. An arylisoxazole arecoline derivative or an arylisoxazoline arecoline derivative, characterized in that: It has the general formula shown in formula (I): ； Wherein, X is NH or O; A 1 , A 2 , A 3 , A 4 wherein the alkyl groups are the same or different and are independently hydrogen, a halogen atom, a cyano group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halo-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a halo-substituted C1-C6 alkoxy group, a C1-C6 alkylamino group, a halo-substituted C1-C6 alkylamino group, a C1-C6 alkylthio group, a halo-substituted C1-C6 alkylthio group, a C3-C6 cycloalkyl group, a halo-substituted C3-C6 cycloalkyl group, a di(C1-C6 alkyl)amino group, a halo-substituted di(C1-C6 alkyl)amino group, a C2-C6 alkenyl group, a halo-substituted C2-C6 alkenyl group, a halo-substituted C2-C6 alkenyloxy group, a C1-C6 alkenylthio group, a halo-substituted C1-C6 alkenylthio group, a C2-C6 alkynyl group, a halo-substituted C2-C6 alkynyl group, a C one of 2-C6 alkynyloxy, halogenated C2-C6 alkynyloxy, C1-C6 alkynylthio, halogenated C1-C6 alkynylthio, C1-C6 alkylcarbonyl, halogenated C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, halogenated C1-C6 alkylaminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, halogenated di(C1-C6 alkyl)aminocarbonyl, C1-C6 alkylsulfonyl, halogenated C1-C6 alkylsulfonyl, di(C1-C6 alkyl)aminosulfonyl, halogenated di(C1-C6 alkyl)aminosulfonyl, C1-C6 alkylsulfonyloxy and halogenated C1-C6 alkylsulfonyloxy; Carbon atom C 1 and C 2 connected by single or double bonds; R 1 is hydrogen, a halogen atom, a C1-C6 alkyl group or a halogenated C1-C6 alkyl group; Ar is A 5 Substituted cyclopropane, A 5 Substituted cyclobutane, A 5 Substituted cyclopentane, A 5 Substituted cyclohexanes, A 5 Substituted tetrahydrofuran, A 5 Substituted tetrahydropyrrole, A 5 Substituted tetrahydrothiophene, A 5 Substituted tetrahydrothiophene, A 5 Substituted piperidine, A 5 Substituted tetrahydrothiopyran, A 5 Substituted dioxane, A 5 Substituted piperazine, A 5 Substituted hexahydropyrazine, A 5 Substituted morpholine, A 5 Substituted dithianes, A 5 Substituted pyrrole, A 5 Substituted pyrazole, A 5 Substituted imidazole, A 5 Substituted triazole, A 5 Substituted tetrazolyl, A 5 Substituted furan, A 5 Substituted isoxazole (line), A 5 Substituted oxazole, A 5 Substituted oxadiazole, A 5 Substituted thiophene, A 5 Substituted isothiazole, A 5 Substituted thiazole, A 5 Substituted thiadiazoles, A 5 Substituted pyrans, A 5 Substituted pyridine, A 5 Substituted diazines, A 5 Substituted triazine, A 5 Substituted indole, A 5 Substituted quinoline, A 5 Substituted isoquinoline, A 5 Substituted purine, A 5 Substituted benzofuran, A 5 Substituted benzothiophene, A 5 Substituted purine, A 5 Substituted pyrone, A 5 Substituted pyrrolidone, A 5 Substituted benzene, A 5 Substituted naphthalene, A 5 Substituted anthracene, A 5 Replace phenanthrene; wherein A 5 is monosubstituted or polysubstituted; A 5 is hydrogen, a halogen atom, a cyano group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogenated C1-C6 alkylamino group, a C1-C6 alkylthio group, a halogenated C1-C6 alkylthio group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a di(C1-C6 alkyl)amino group, a halogenated di(C1-C6 alkyl)amino group, a C2-C6 alkenyl group, a halogenated C2-C6 alkenyl group, a halogenated C2-C6 alkenyloxy group, a C1-C6 alkenylthio group, a halogenated C1-C6 alkenylthio group, a C2-C6 alkynyl group, a halogenated C2-C6 alkynyl group, a C2-C6 alkynyl group The invention can be selected from the group consisting of oxy, halogenated C2-C6 alkynyloxy, C1-C6 alkynylthio, halogenated C1-C6 alkynylthio, C1-C6 alkylcarbonyl, halogenated C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, halogenated C1-C6 alkylaminocarbonyl, di(C1-C6 alkyl)aminocarbonyl, halogenated di(C1-C6 alkyl)aminocarbonyl, C1-C6 alkylsulfonyl, halogenated C1-C6 alkylsulfonyl, di(C1-C6 alkyl)aminosulfonyl, halogenated di(C1-C6 alkyl)aminosulfonyl, C1-C6 alkylsulfonyloxy and halogenated C1-C6 alkylsulfonyloxy.

2. An arylisoxazole arecoline derivative or arylisoxazoline arecoline derivative according to claim 1, characterized in that: In formula (I), A 1 , A 2 , A 3 , A 4 The same or different, respectively and independently are one of hydrogen, a halogen atom, a cyano group, an amino group, a hydroxyl group, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a C1-C6 alkylamino group, a halogenated C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a halogenated C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a halogenated C2-C6 alkenyl group, a C2-C6 alkynyl group, a halogenated C2-C6 alkynyl group, a C1-C6 alkylcarbonyl group, a halogenated C1-C6 alkylcarbonyl group, a C1-C6 alkylsulfonyl group, and a halogenated C1-C6 alkylsulfonyl group.

3. An arylisoxazole arecoline derivative or arylisoxazoline arecoline derivative according to claim 1, characterized in that: In formula (I), R 1 It is one of a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a difluoromethyl group and a trifluoromethyl group.

4. A method for preparing an arylisoxazole arecoline derivative or an arylisoxazoline arecoline derivative as claimed in any one of claims 1 to 3, characterized in that: In formula (I), when X is O, the preparation method is as follows: 。 5. A method for preparing an arylisoxazole arecoline derivative or an arylisoxazoline arecoline derivative as claimed in any one of claims 1 to 3, characterized in that: In formula (I), when X is NH, the preparation method is as follows: 。 6. Use of the arylisoxazole arecoline derivative or arylisoxazoline arecoline derivative as claimed in any one of claims 1 to 3 or the arylisoxazole arecoline derivative or arylisoxazoline arecoline derivative obtained by the preparation method as claimed in any one of claims 4 to 5 in the preparation of a fungicide, characterized in that: Fungicides target plant pathogenic fungi.

7. The use according to claim 6, characterized in that: The pathogens that fungicides act on are: ① Oomycetes: downy mildew, white rust, damping-off, cotton rot, phytophthora, and late blight; ②Basidiomycetes: stripe rust, smut, sheath blight; ③ Ascomycetes: powdery mildew, sclerotinia, black spot, fusarium; ④ Ascomycetes: wilt pathogens, root rot pathogens, damping-off pathogens, anthracnose pathogens, verticillium wilt pathogens, gray mold pathogens, brown spot pathogens, black spot pathogens, black rot pathogens, stem rot pathogens, leaf blight pathogens, early blight pathogens, ring rot pathogens, leaf blight pathogens, and phomopsis pathogens.

8. The use according to claim 7, characterized in that: The pathogens affected by the fungicide are pepper blight, pitaya black spot, mango stem rot, banana anthracnose, phomopsis, wheat fusarium, rice sheath blight, rice blast, rapeseed sclerotinia, apple ring rot, and banana wilt.

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