A quinoline compound and its preparation method and application

Abstract

The present invention belongs to the technical field of pesticides and provides a quinoline compound and a preparation method and application thereof. The chemical structural formula of the quinoline compound is:. Using tobacco mosaic virus as a test object, it is found that the compound has a very obvious inhibitory activity against plant pathogenic viruses and can be used as a new type of effective ingredient for resisting plant viruses.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticides, and specifically relates to a quinoline compound and a preparation method and application thereof. Background Art

[0002] Quinoline and its derivatives are a class of nitrogen-containing heterocyclic compounds with important biological activities, which are widely used in the fields of medicinal chemistry, agricultural chemistry, metallurgy, materials, etc. In pharmacology, quinoline compounds have rich biological activities, such as antibacterial, antitumor, antimalarial, anti-HIV and antibiotic drugs. In agriculture, quinoline compounds have gradually become the mainstream of new pesticide research due to their low toxicity, high efficiency, environmental friendliness and diverse structural changes, and have shown a wide range of insecticidal, fungicidal and herbicidal activities. At present, there are already a number of pesticide products containing quinoline skeletons on the market, such as phenoxyquinoline and copper salts of 8-hydroxyquinoline, which have good fungicidal activity; quinoline hydrazone derivatives and quinoline ester compounds containing amino acid have shown good insecticidal activity.

[0003] In agricultural production, plant virus disease is one of the important pathogens that harm crops. Plant virus disease causes a 20-30% reduction in grain production and economic losses of more than $60 billion worldwide each year. There are more than 900 known plant viruses, which cause more than 1,000 diseases. It is the second largest plant disease after fungi. Because it is difficult to effectively prevent and control, it is known as "plant cancer."

[0004] In recent years, plant viral diseases have caused increasingly serious damage to vegetables, fruit trees, and flowers. Among them, tobacco mosaic virus (TMV) and potato virus Y (PVY) are the most common and most harmful viruses in the world. They are mainly transmitted through juice and can widely infect more than 350 plants such as tobacco, tomatoes, and peppers, causing plant leaf mosaics, growth deformities, plant stunting, dwarfing, and other symptoms, seriously reducing crop yields and quality. However, at present, only a few antiviral agents have entered the practical stage, and many antiviral agents can only reduce the severity of symptoms, far from achieving effective and satisfactory application effects. Therefore, the development of new antiviral active compounds is an extremely urgent task. Summary of the invention

[0005] In view of the problems in the prior art, the present invention provides a quinoline compound that can be applied to plants to exert an antiviral effect.

[0006] Another object of the present invention is to provide a method for preparing the above quinoline compounds.

[0007] To achieve the above purpose, the present invention adopts the following technical solution.

[0008] A quinoline compound, referred to as BBPQ6, has a chemical structure as shown in formula (I):

[0009]

[0010] Formula (I).

[0011] The preparation method of the above quinoline compound comprises the following steps:

[0012] (1) and diethyl carbonate in a solvent under strong alkaline conditions to obtain compound 1a: ;

[0013] (2) Compound 1a and triethyl orthoformate react in acetic anhydride to obtain compound 2a: ;

[0014] (3) Compound 2a and 3,4-(methylenedioxy)aniline react in a solvent to obtain compound 3a: ;

[0015] (4) Compound 3a reacts with diphenyl ether to obtain compound 4a: ;

[0016] (5) Compound 4a and 2-bromophenylethane react in a solvent under strong alkaline conditions to obtain compound 5a: ;

[0017] (6) Compound 5a reacts with acetic acid and hydrazine hydrate to obtain compound BBPQ6: .

[0018] In steps (1), (3) and (5), the solvent may be tetrahydrofuran, N,N-dimethylformamide or isopropanol.

[0019] An application of the quinoline compound in preventing and controlling plant viruses.

[0020] A composition comprising the above quinoline compound.

[0021] The mass percentage of the quinoline compound in the composition is 0.1%-99%.

[0022] In order to expand the control spectrum or enhance the efficacy of quinoline compounds, the composition may also contain other active ingredients; the active ingredients may be compounds, natural extracts or microorganisms with insecticidal, bactericidal and antiviral effects, such as organophosphorus, carbamate, pyrethroid, nicotinoid insecticides, copper preparations, morpholine guanidine, ene adenine, hydroxyene adenine, amino oligosaccharides, Ningnanmycin, chitosan, lentinan, etc.

[0023] The composition can be prepared into various forms suitable for use or attachment to an application object by adding inert auxiliary materials, such as powder, wettable powder, granule, emulsifiable concentrate, suspoemulsion, suspension, etc.

[0024] The present invention has the following advantages:

[0025] The novel quinoline derivative of the invention is modified by aromatic substitution on the nitrogen atom of the quinoline structure, has obvious inhibitory activity on tobacco mosaic virus and cucumber mosaic virus, and can be used as a novel effective component for resisting plant viruses. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the compound BBPQ6 1 H NMR spectrum;

[0027] Figure 2 is the compound BBPQ6 13 C NMR spectrum;

[0028] Figure 3 It is the HRMS spectrum of compound BBPQ6. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with embodiments and drawings, but the present invention is not limited by the following embodiments.

[0030] Example 1 Synthesis of quinoline derivatives

[0031] (1) Synthesis of 1a

[0032]

[0033] Take a centrifuge tube and add dry THF (15 mL), add 3,4-(methylenedioxy)acetophenone (S0, 30 mmol), and stir and dissolve at 0 °C to obtain S0 solution;

[0034] Take another clean 100 mL flask and add NaH (60% mineral oil, 4.8 g, 120 mmol), anhydrous THF (25 mL), and diethyl carbonate (19.4 mL, 120 mmol) in sequence;

[0035] Under nitrogen protection, the S0 solution was slowly added dropwise to the above flask within 5 min, and the mixture was heated to reflux at 70 °C for reaction. The reaction progress was monitored by thin layer chromatography (TLC) using petroleum ether:ethyl acetate (PE:EA=1:5, v / v) as the developing solvent. After reflux for 6 h, 1 mol / L HCl (30 mL) was added to the reaction mixture to remove excess NaH and terminate the reaction.

[0036] Water (20 mL) was added to the above system, and the mixture was extracted with ethyl acetate for three times, 20 mL each time. The organic layer was then extracted with saturated NaCl solution. The organic layer was dried over Na2SO4, and the solvent was dried by rotary evaporation at 48 °C and pumped dry with an oil pump to obtain a yellow-brown oil 1a with a yield of 72.2%.

[0037] (2) Synthesis of 2a

[0038]

[0039] Take a 50 ml round-bottom flask, add compound 1a (5.1 g, 21.6 mmol), CH(OEt)3 (18 mL, 108 mmol), Ac2O (11 mL, 108 mmol), and reflux at 140 °C for 16 h; add 25 mL of water to the reactant, extract with EA, dry the organic layer with anhydrous Na2SO4, and then purify by column chromatography (PE: EA=3: 1, v / v) to obtain compound 2a with a yield of 62.9%.

[0040] (3) Synthesis of 3a

[0041]

[0042] Compound 2a (4.0 g, 13.59 mmol) and 25 mL isopropanol were added to a 50 mL round-bottom flask, followed by 3,4-(methylenedioxy)aniline (1.12 g, 8.15 mmol). The reaction progress was monitored by TLC after half an hour (EA:PE=2:1, v / v). The reaction was complete after 4 h. The reaction system was filtered under reduced pressure, and the filter cake was washed with ethanol and dried with an oil pump. The product was purified by column chromatography (PE:EA=3:1, v / v) to obtain a white precipitate 3a with a yield of 47.8%.

[0043] (4) Synthesis of 4a

[0044]

[0045] 5 mL of diphenyl ether and 0.3 g of compound 3a were added to each of 5 10 mL high-temperature reaction tubes. The reaction was refluxed at 260 °C and monitored by TLC petroleum ether: ethyl acetate (PE: EA=1: 5, v / v). The reaction was complete after 5 h. PE was added to the reaction system for extraction 3 times, 20 mL each time, to precipitate a black solid. The solid was filtered and washed with ethyl acetate to obtain a black solid 4a with a yield of 63.9%.

[0046] (5) Synthesis of 5a

[0047]

[0048] Compound 4a (300 mg) was added to a 50 mL round-bottom flask, followed by NaH (42.73 mg, 1.07 mmol), DMF (20 mL), and 2-bromophenylethane (105 μL, 1.07 mol), and the mixture was refluxed at 80 °C. The reaction was monitored by TLC using methanol: dichloromethane (MeOH: DCM=1: 10, v / v) as the developing solvent. After 8 h, the reaction was complete, and 1 mol / L HCl (30 mL) was added to remove NaH. The reaction solution was dried by rotary evaporation, and DCM (20 mL) was added for extraction. The organic layer was washed with NaHCO3, and the organic layer was dried and passed through a chromatography column (MeOH: DCM=1: 20, v / v) to obtain a brown solid 5a. 1 H NMR (600 MHz, DMSO-d6) δ8.50 (s, 1H), 7.51 (s, 1H), 7.45-7.18 (m, 8H), 6.99 (d, J = 8.1 Hz, 1H), 6.14(d, J = 9.8 Hz, 4H), 5.62 (d, J = 15.9 Hz, 2H). MS (ESI) for C 25 H 17 O6N [M+H] + ,calculated 428.1134, found 428.1032, yield 60%.

[0049] (6) Synthesis of BBPQ6

[0050]

[0051] Take a high temperature reaction tube and add 200 mg of compound 5a, 5 mL of acetic acid, 18 μL of hydrazine hydrate, reflux at 80°C, monitor the reaction progress by TLC (MeOH: DCM=1:10), after the reaction is complete, spin dry the reaction solution, add 1 mol / L HCl (30 mL) to remove hydrazine hydrate, add DCM (20 mL) for extraction, wash the organic layer with NaHCO3, spin dry the organic layer and column chromatography (MeOH:DCM=1:20, v / v) to obtain a yellow solid BBPQ6, i.e., the target compound. 1 H NMR (600 MHz, DMSO-d6) δ7.99 (s, 1H), 7.72 - 7.67 (m, 3H), 7.39 - 7.25 (m, 6H), 7.15 (d, J = 8.2 Hz,1H), 6.33 (s, 2H), 6.20 (s, 2H), 6.15 (s, 2H). MS (ESI) for C 25 H 17 O4N3 13 C NMR(151 MHz, DMSO) δ 150.45, 149.90, 148.29, 147.76, 143.56, 135.97, 129.98,129.39, 128.51, 127.77, 126.90, 121.20, 115.97, 113.61, 109.20, 107.52,103.43, 101.66, 100.44, 98.80, 58.89, 40.52. [M+H] + , calculated 424.1297, found 424.1202, yield 58%; 1 H NMR, 13 C NMR and HRMS were Figure 1-3 shown.

[0052] Example 2 Antiviral activity of compound BBPQ6

[0053] (1) Preparation of compound solution

[0054] After accurately weighing compound BBPQ6, dissolve it in DMSO solution and prepare 5×10 5 μg / mL stock solution, and then diluted to the required concentration with an aqueous solution containing 1‰ Tween 80; the virazole preparation is directly diluted with water for use.

[0055] (2) In vivo passivation

[0056] Select 4-6 leaf-stage Sansi tobacco with uniform growth. Mix compound BBPQ6 with an equal volume of tobacco mosaic virus (TMV) virus particle solution and incubate for 30 min before friction inoculation. The virus concentration is 20 μg / mL. The half-leaf method is used for determination. The right side of the same leaf is inoculated with a mixture of compound and virus, and the left side is inoculated with the same concentration of virus and 1‰ Tween 80 aqueous solution as a control. After inoculation, rinse with running water, and repeat 3 times for each treatment. After 4-5 days, the number of leaf spots is counted and the inhibition rate is calculated.

[0057] (3) In vivo protection

[0058] Select Sanxi tobacco plants with uniform growth at the 4-6 leaf stage. The half-leaf method was used for determination. The right side of the same leaf was sprayed with the pesticide, and the right side was sprayed with 1‰ Tween 80 aqueous solution as a blank control. After 24 hours, diamond dust (500 mesh) was sprinkled on the leaf surface, and the virus solution was dipped with a brush. The whole leaf was rubbed with TMV virus at a virus concentration of 10 μg / mL, and rinsed with running water after inoculation. Each treatment was repeated 3 times. After 4-5 days, the number of leaf spots was counted and the inhibition rate was calculated.

[0059] (4) In vivo therapeutic effect

[0060] Select 4-6 leaf-stage Sansi tobacco plants with uniform growth, and use a brush to rub the whole leaf to inoculate TMV virus at a virus concentration of 10μg / mL. Rinse with running water 2 hours after inoculation. After the leaf surface is dried, the half-leaf method is used for determination. The right side of the same leaf is sprayed with the agent, and the right side is sprayed with 1‰ Tween 80 aqueous solution as a control. Each treatment is repeated 3 times. After 4-5 days, the number of leaf spots is counted and the inhibition rate is calculated.

[0061] Inhibition rate (%) = [(number of control necrosis spots - number of treated necrosis spots) / number of control necrosis spots] × 100%

[0062] Table 1 Anti-TMV activity results of quinoline derivative BBPQ6

[0063]

[0064] As can be seen from Table 1, compound BBPQ6 has good inhibitory activity against TMV under three modes of action. Compound BBPQ6 has the strongest passivation activity against TMV, followed by therapeutic activity. Moreover, at the same concentration, the protective effect of compound BBPQ6 is better than that of the commercialized agent ribavirin. In summary, compound BBPQ6, as a novel structural virus inhibitor, has great development and application potential.

Claims

1. An application of a quinoline compound in preventing and controlling plant viruses, wherein the chemical structure of the quinoline compound is: 。 2. An agricultural composition comprising a quinoline compound, wherein the chemical structure of the quinoline compound is: 。 3. The agricultural composition according to claim 2, characterized in that The mass percentage of the quinoline compound in the composition is 0.1%-99%.

4. The agricultural composition according to claim 2, characterized in that The agricultural composition also contains other effective ingredients.

5. The agricultural composition according to claim 2, characterized in that The composition may also include inert auxiliary materials.

6. The agricultural composition according to claim 2, characterized in that The agricultural composition is in the form of powder, granule, emulsifiable concentrate, suspoemulsion or suspension.

7. The agricultural composition according to claim 2, characterized in that The agricultural composition is in the form of a wettable powder.

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