Eugenol derivative as well as preparation method and application thereof

Abstract

The invention discloses an eugenol derivative as well as a preparation method and application thereof, and belongs to the technical field of insecticides. Firstly, eugenol and dibromoalkane are subjected to reflux under a weakly alkaline condition to prepare a brominated intermediate of a compound 1; and refluxing corresponding amines of the compound 1 and the compound 2 to obtain the eugenol derivative. Experimental results of the eugenol derivative show that compared with a parent compound eugenol, most of the derivatives show significantly enhanced cytotoxicity and show good killing activity of selaginella seseloides adults.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of insecticides, and particularly relates to a eugenol derivative, a preparation method and application thereof. BACKGROUND

[0002] Eugenol, as a natural phenylpropanoid compound, widely exists in clove, cinnamon and other plants, and has antibacterial, antioxidant and insecticidal activities. However, natural eugenol has problems such as strong volatility, poor stability, single target and limited insecticidal activity, and is difficult to be directly used as an efficient insecticide. In the prior art, the chemical modification of eugenol is mainly focused on simple reactions such as esterification and etherification. For example, Chinese invention patent (CN108191665B) eugenol ester analogues, a preparation method and an insecticide thereof; Chinese invention patent (CN119563631A) a hygienic insecticide composition containing pyroxyfop and its application.

[0003] At present, the insecticidal activity of eugenol derivatives is limitedly improved, and the mechanism is not clear. In addition, the long-term use of chemical pesticides leads to the increase of pest resistance, and it is urgent to develop new green insecticides with environmental friendliness, high efficiency and multi-target effect. SUMMARY

[0004] A first object of the present application is to provide a eugenol derivative,

[0005] The structural formula of the eugenol derivative is as follows:

[0006]

[0007] Among them,

[0008] R1 is selected from one of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, benzyl, aryl, pyridylmethyl, carbazylmethyl, indolylmethyl, piperidylmethyl, pyrrolidylmethyl, piperazylmethyl, sulfur-containing aryl and carbonyl substituents; R2 is selected from one of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, benzyl, aryl, pyridylmethyl, carbazylmethyl, indolylmethyl, piperidylmethyl, pyrrolidylmethyl, piperazylmethyl, sulfur-containing aryl and carbonyl substituents;

[0009] or R1 and R2 are combined to be selected from one of phenyl, benzyl, substituted phenyl, pyridyl, indolyl, carbazyl, piperidyl, piperazyl, morpholyl, tetrahydroquinolyl, bicyclic structure, pyrrolidyl, biphenyl and anthracene;

[0010] n is selected from 0, 1, 2, 3 or 4.

[0011] As a preferred, the eugenol derivative is one of the following A1-A18 structural formula:

[0012]

[0013] A second object of the present application is to provide a preparation method of eugenol derivatives, which is used for preparing the above-mentioned eugenol derivatives and comprises the following steps:

[0014] S1, refluxing eugenol and dibromoalkane under weak alkaline conditions to obtain compound 1 bromo intermediate, the reaction formula is,

[0015]

[0016] S2, refluxing compound 1 and the corresponding amine of compound 2 to obtain eugenol derivatives, the reaction formula is,

[0017]

[0018] As preferred, refluxing compound 1 and compound 2 under weak alkaline conditions such as potassium carbonate, sodium carbonate, sodium bicarbonate to obtain eugenol derivatives;

[0019] The structural formula of the compound 1 is:

[0020] The structural formula of the compound 2 is NH3,

[0021] As preferred, the weak alkaline condition is pH 7.3-9.0.

[0022] A third object of the present application is to provide an application of eugenol derivatives, which applies the above-mentioned eugenol derivatives to insecticide.

[0023] The present application has the following beneficial effects.

[0024] The present application modifies the structure of eugenol through a modular synthesis strategy, designs and synthesizes a series of novel eugenol derivatives, and the activity experiment results show that the contact killing activity (LD 50 =0.2505 μmol / head) of the third instar larvae of Spodoptera exigua is increased by 11.6 times compared with the parent eugenol, which interferes with mitochondrial energy metabolism by inhibiting succinate dehydrogenase (SDH activity is reduced by 47%), and enhances the binding affinity (binding energy-9.4 kcal / mol) with acetylcholinesterase (AChE), induces compensatory dysfunction of nerve signal transmission. In addition, the LD 50 of the adult of Oryzaephilus surinamensis is 1.724 nmol / head, and the activity is increased by 9.7 times, and the tertiary amine structure may enhance the target binding capacity through cation-π interaction. The present application provides an innovative solution for the development of plant source pesticides. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 The experimental results of scanning electron microscope observation of the body surface of Tribolium castaneum adults before and after treatment with compound A15 of the present application. DETAILED DESCRIPTION

[0026] In order to make the objectives, technical solutions and advantages of the present application clearer, further detailed description will be made to the present application in combination with the accompanying drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application.

[0027] The present application discloses a preparation method of eugenol derivatives, comprising the following steps:

[0028] S1, eugenol and dibromoalkane are refluxed under weak alkaline conditions to obtain compound 1 bromo intermediate, and the reaction formula is:

[0029]

[0030] The structural formula of compound 1 is:

[0031]

[0032] S2, compound 1 and the corresponding amine of compound 2 are refluxed to obtain eugenol derivatives, and the reaction formula is:

[0033]

[0034] The structural formula of compound 2 is:

[0035]

[0036] Preparation method of compound 1 2a:

[0037]

[0038] Eugenol (0.10-0.30 mol, 1.0 equiv.) and 1,2-dibromoethane (0.30-0.60 mol, 3.0 equiv.) are uniformly dispersed with 200 mL of acetonitrile, and then anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) is added, and refluxed at 60-80℃ for 12-36h, and concentrated under reduced pressure to obtain an oily residue. The crude residue is purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (40:1-70:1) to obtain a light yellow oily liquid product with a yield of 70%.

[0039] 1H NMR (400 MHz, Chloroform-d) δ 6.85 (d, J = 8.0 Hz, 1H), 6.74-6.70 (m, 2H), 6.01-5.90 (m, 1H), 5.11-5.05 (m, 2H), 4.31 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.64 (t, J = 6.8 Hz, 2H), 3.34 (d, J = 6.4 Hz, 2H).

[0040] Method for preparing compound 12b:

[0041]

[0042] Eugenol (0.10-0.30 mol, 1.0 equiv.) and 1,3-dibromopropane (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. Refluxing was performed at 60-80 °C for 12-36 h, and an oil was obtained after concentration under reduced pressure. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (40:1-70:1) to obtain a light yellow oily liquid product with a yield of 72%.

[0043] 1 H NMR (300 MHz, Chloroform-d) δ 6.85 (d, J = 8.7 Hz, 1H), 6.74-6.67 (m, 2H), 6.03-5.89 (m, 1H), 5.12-5.04 (m, 2H), 4.13 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.63 (t, J = 6.3 Hz, 2H), 3.34 (d, J = 6.6 Hz, 2H), 2.35 (p, J = 6.3 Hz, 2H).

[0044] Method for preparing compound 12c

[0045]

[0046] Eugenol (0.10-0.30 mol, 1.0 equiv.) and 1,4-dibromobutane (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. Refluxing was performed at 60-80 °C for 12-36 h, and an oil was obtained after concentration under reduced pressure. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (40:1-70:1) to obtain a light yellow oily liquid product with a yield of 73%.

[0047] 1H NMR (400 MHz, Chloroform-d) δ 6.81 (d, J = 8.4 Hz, 1H), 6.72-6.69 (m, 2H), 6.01-5.91 (m, 1H), 5.11-5.04 (m, 2H), 4.03 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.50 (t, J = 6.4 Hz, 2H), 3.33 (d, J = 6.8 Hz, 2H), 2.12-2.04 (m, 2H), 2.01-1.93 (m, 2H).

[0048] Method for preparing compound 12d:

[0049]

[0050] Syringaldehyde (0.10-0.30 mol, 1.0 equiv.) and 1,5-dibromopentane (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The mixture was refluxed at 60-80 °C for 12-36 h, and concentrated under reduced pressure to obtain an oily substance. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (40:1-70:1) to obtain a light yellow oily liquid product with a yield of 67%.

[0051] 1 H NMR (400 MHz, Chloroform-d) δ 6.81 (d, J = 8.4 Hz, 1H), 6.72-6.69 (m, 2H), 6.01-5.91 (m, 1H), 5.11-5.04 (m, 2H), 4.00 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.43 (t, J = 6.8 Hz, 2H), 3.33 (d, J = 6.8 Hz, 2H), 1.98-1.89 (m, 2H), 1.88-1.82 (m, 2H), 1.66-1.58 (m, 2H).

[0052] Method for preparing compound 12e:

[0053]

[0054] Eugenol (0.10-0.30 mol, 1.0 equiv.) and 1,6-dibromohexane (0.30-0.60 mol, 3.0 equiv.) were homogenously dispersed with 200 mL of acetonitrile, followed by the addition of anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.). The mixture was refluxed at 60-80 °C for 12-36 h, and concentrated under reduced pressure to give an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (40:1-70:1) to give the product as a light yellow oily liquid with a yield of 68%.

[0055] 1 H NMR (400 MHz, Chloroform-d) δ 6.81 (d, J = 8.4 Hz, 1H), 6.74-6.69 (m, 2H), 6.01-5.91 (m, 1H), 5.11-5.04 (m, 2H), 3.99 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.42 (t, J = 6.8 Hz, 2H), 3.33 (d, J = 6.8 Hz, 2H), 1.93-1.82 (m, 4H), 1.52-1.48 (m, 4H).

[0056] Example 1

[0057] Preparation of eugenol derivative A1

[0058]

[0059] Compound 2b (0.10-0.30 mol, 1.0 equiv.) was dissolved in methanol (100 mL), followed by the addition of 7.0 M aqueous ammonia (in methanol, 40 mL). The mixture was stirred and refluxed at 65 °C for 24 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (20:1-15:1) as the eluent to give compound A1 with a yield of 79%.

[0060] 1 H NMR (400 MHz, Chloroform-d) δ 6.80 (d, J = 7.6 Hz, 1H), 6.72-6.68 (m, 2H), 6.01-5.92 (m, 1H), 5.90 (s, 1H), 5.11-5.04 (m, 2H), 4.11 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 3.37 (t, J = 6.0 Hz, 2H), 3.33 (d, J = 6.8 Hz, 2H), 2.09 (p, J = 6.0 Hz, 2H).

[0061] Example 2

[0062] Preparation of eugenol derivative A2

[0063]

[0064] A mixture of eugenol (0.7 mmol) and epichlorohydrin (1 mL) was added dropwise with vigorous stirring at 85 °C an aqueous solution of sodium hydroxide (0.7 mmol) in water (1 mL). The reaction was maintained at this temperature until the complete consumption of eugenol, then the mixture was diluted with ethyl acetate (10 mL), washed with brine (2 x 5 mL), dried over anhydrous Na2S04and filtered. The organic solvent was removed under reduced pressure to obtain the crude intermediate. Subsequently, the crude intermediate was dissolved in a saturated aqueous solution of K2C03and 1,3-propanediamine (2 mmol) was added at room temperature. The mixture was stirred vigorously until the reaction was complete. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (20:1 to 15:1) as eluent to obtain compound A2 in 79% yield.

[0065] 1 H NMR (400 MHz, Chloroform-d) δ 6.81 (d, J = 8.4 Hz, 1H), 6.71-6.68 (m, 2H), 5.99-5.88 (m, 1H), 5.10-5.04 (m, 2H), 4.77 (s, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.85 (s, 3H), 3.32 (d, J = 6.8 Hz, 2H), 3.09 (t, J = 6.0 Hz, 2H), 2.09 (p, J = 6.0 Hz, 2H).

[0066] Example 3

[0067] Preparation of eugenol derivative A3

[0068]

[0069] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and dimethylamine (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the completion of the reaction, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to obtain compound A3 in 78% yield.

[0070] 1H NMR (400 MHz, chloroform-d) δ 6.82 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 5.99-5.91 (m, 1H), 5.09-5.03 (m, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.84 (s, 3g), 3.32 (d, J = 6.4 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.39-2.35 (m, 4H), 1.99-1.92 (m, 2H), 1.49-1.39 (m, 4H), 0.86 (t, J = 7.2 Hz, 6H).

[0071] Example 4

[0072] Preparation of eugenol derivative A4

[0073]

[0074] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and dipropylamine (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The mixture was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A4 in a yield of 78%.

[0075] 1 H NMR (400 MHz, chloroform-d) δ 6.82 (d, J = 8.4 Hz, 1H), 6.70-6.68 (m, 2H), 5.99-5.91 (m, 1H), 5.09-5.03 (m, 2H), 4.04 (t, J = 6.4 Hz, 2H), 3.84 (s, 3g), 3.32 (d, J = 6.4 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.39-2.35 (m, 4H), 1.99-1.92 (m, 2H), 1.49-1.39 (m, 4H), 0.86 (t, J = 7.2 Hz, 6H).

[0076] Example 5

[0077] Preparation of eugenol derivative A5

[0078]

[0079] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and diisobutylamine (0.30-0.60 mol, 3.0 equiv.) were dispersed in 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The reaction was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A5 in 74% yield.

[0080] 1 H NMR (400 MHz, Chloroform-d) δ 6.83 (d, J = 8.0 Hz, 1H), 6.72-6.70 (m, 2H), 6.03-5.92 (m, 1H), 5.11-5.05 (m, 2H), 4.07 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.34 (d, J = 6.8 Hz, 2H), 2.52 (t, J = 6.8 Hz, 2H), 2.10-2.05 (m, 4H), 1.99-1.92 (m, 2H), 1.78-1.66 (m, 2H), 0.90-0.87 (m, 12H).

[0081] Example 6

[0082] Preparation of eugenol derivative A6

[0083]

[0084] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and pyrrolidine (0.30-0.60 mol, 3.0 equiv.) were dispersed in 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The reaction was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A6 in 81% yield.

[0085] 1H NMR (400 MHz, Chloroform-d) δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.66 (m, 2H), 5.99-5.88 (m, 1H), 5.08-5.02 (m, 2H), 4.03 (t, J = 6.8 Hz, 2H), 3.82 (s, 3H), 3.30 (d, J = 6.8 Hz, 2H), 2.82 (t, J = 12.4 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.00 (p, J = 6.8 Hz, 2H), 1.81 (t, J = 12.0 Hz, 1H), 1.69-1.49 (m, 5H), 0.84 (d, J = 6.0 Hz, 3H).

[0086] Example 7

[0087] Preparation of eugenol derivative A7

[0088]

[0089] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and 3-methylpiperidine (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A7 with a yield of 80%.

[0090] 1 H NMR (400 MHz, Chloroform-d) δ 6.82 (d, J = 8.0 Hz, 1H), 6.69-6.66 (m, 2H), 5.99-5.88 (m, 1H), 5.08-5.02 (m, 2H), 4.03 (t, J = 6.8 Hz, 2H), 3.82 (s, 3H), 3.30 (d, J = 6.8 Hz, 2H), 2.82 (t, J = 12.4 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.00 (p, J = 6.8 Hz, 2H), 1.81 (t, J = 12.0 Hz, 1H), 1.69-1.49 (m, 5H), 0.84 (d, J = 6.0 Hz, 3H).

[0091] Example 8

[0092] Preparation of eugenol derivative A8

[0093]

[0094] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and morpholine (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. Refluxing was performed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A8 with a yield of 68%.

[0095] 1 H NMR (400 MHz, Chloroform-d) δ 6.83 (d, J = 8.8 Hz, 1H), 6.70-6.68 (m, 2H), 6.00-5.89 (m, 1H), 5.09-5.03 (m, 2H), 4.05 (t, J = 6.8 Hz, 2H), 3.84 (s, 3H), 3.70 (t, J = 4.8 Hz, 4H), 3.32 (d, J = 6.8 Hz, 2H), 2.53-2.43 (m, 6H), 2.00 (p, J = 6.8 Hz, 2H).

[0096] Example 9

[0097] Preparation of eugenol derivative A9

[0098]

[0099] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and thiomorpholine (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. Refluxing was performed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A9 with a yield of 72%.

[0100] 1H NMR (400 MHz, Chloroform-d) δ 6.78 (d, J = 8.0 Hz, 1H), 6.67-6.64 (m, 2H), 5.96-5.86 (m, 1H), 5.06-5.00 (m, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 3.28 (d, J = 6.4 Hz, 2H), 2.68-2.59 (m, 8H), 2.49 (t, J = 7.2 Hz, 2H), 1.93 (p, J = 6.8 Hz, 2H).

[0101] Example 10

[0102] Preparation of eugenol derivative A10

[0103]

[0104] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and 4h (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A10 with a yield of 62%.

[0105] 1 H NMR (400 MHz, Chloroform-d) δ 7.24-7.19 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.73-6.62 (m, 5H), 6.02-5.91 (m, 1H), 5.12-5.04 (m, 2H), 4.08 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.39 (t, J = 7.2 Hz, 2H), 3.34 (d, J = 6.8 Hz, 2H), 2.92 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.01 (p, J = 6.4 Hz, 2H), 1.78 (p, J = 7.2 Hz, 2H).

[0106] Example 11

[0107] Preparation of eugenol derivative A11

[0108]

[0109] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and 4i (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A11 with a yield of 77%.

[0110] 1 H NMR (400 MHz, chloroform-d) δ 6.99 (t, J = 8.0 Hz, 1H), 6.73-6.61 (m, 3H), 6.49 (d, J = 7.6 Hz, 1H), 6.44 (s, 1H), 6.32 (d, J = 8.0 Hz, 1H), 5.91-5.82 (m, 1H), 5.02-4.96 (m, 2H), 4.35 (s, 1H) 4.03 (t, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.26-3.22 (m, 4H), 2.35 (s, 3H), 2.06-1.99 (m, 2H).

[0111] Example 12

[0112] Preparation of eugenol derivative A12

[0113]

[0114] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and 4j (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A12 with a yield of 80%.

[0115] 1H NMR (400 MHz, Chloroform-d) δ 8.02 (dd, J = 7.6, 1.6 Hz, 1H), 7.84 (dd, J = 7.6, 2.0 Hz, 1H), 7.52 - 7.39 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.80 - 6.76 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.09 - 5.98 (m, 1H), 5.21 (s, 1H), 5.18 - 5.12 (m, 2H), 4.24 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.56 (t, J = 6.0 Hz, 2H), 3.41 (d, J = 6.8 Hz, 2H), 2.33 (p, J = 6.0 Hz, 2H).

[0116] Example 13

[0117] Preparation of eugenol derivative A13

[0118]

[0119] Compound 2a (0.10-0.30 mol, 1.0 equiv.) and 4k (0.30-0.60 mol, 3.0 equiv.) were uniformly dispersed with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A13 with a yield of 77%.

[0120] 1 H NMR (400 MHz, Chloroform-d) δ 6.84 (d, J = 8.4 Hz, 1H), 6.72 - 6.70 (m, 2H), 6.01 - 5.90 (m, 1H), 5.10 - 5.05 (m, 2H), 4.10 (t, J = 5.0 Hz, 2H), 3.84 (s, 3H), 3.45 - 3.24 (m, 4H), 3.11 (t, J = 5.0 Hz, 2H), 1.97 (s, 1H).

[0121] Example 14

[0122] Preparation of eugenol derivative A14

[0123]

[0124] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and 4k (0.30-0.60 mol, 3.0 equiv.) were dispersed in 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The reaction was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A14 with a yield of 77%.

[0125] 1 H NMR (400 MHz, chloroform-d) δ 6.82 (d, J = 8.4 Hz, 1H), 6.72-6.70 (d, J = 7.3 Hz, 2H), 6.01-5.90 (m, 1H), 5.11-5.04 (m, 2H), 4.08 (t, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.34 (d, J = 6.8 Hz, 2H), 3.20 (q, J = 9.6 Hz, 2H), 2.94 (t, J = 6.4 Hz, 2H), 1.99 (p, J = 6.4 Hz, 2H), 1.76 (s, 1H).

[0126] Example 15

[0127] Preparation of eugenol derivative A15

[0128]

[0129] Compound 2c (0.10-0.30 mol, 1.0 equiv.) and 4k (0.30-0.60 mol, 3.0 equiv.) were dispersed in 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The reaction was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A15 with a yield of 78%.

[0130] 1H NMR (400 MHz, chloroform-d) δ 6.80 (d, J = 8.0 Hz, 1H), 6.71-6.69 (m, 2H), 6.00-5.88 (m, 1H), 5.14-5.01 (m, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.83 (s, 3g), 3.33 (d, J = 6.8 Hz, 2H), 3.16 (q, J = 9.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 1.90-1.82 (m, 2H), 1.72-1.59 (m, 2H).

[0131] Example 16

[0132] Preparation of eugenol derivative A16

[0133]

[0134] Compound 2d (0.10-0.30 mol, 1.0 equiv.) and 4k (0.30-0.60 mol, 3.0 equiv.) were dispersed uniformly with 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added, and refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC, and after the reaction was completed, the obtained mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by silica gel flash column chromatography, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A16 with a yield of 75%.

[0135] 1 H NMR (400 MHz, chloroform-d) δ 6.80 (d, J = 8.0 Hz, 1H), 6.71-6.69 (m, 2H), 6.00-5.88 (m, 1H), 5.14-5.01 (m, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.83 (s, 3g), 3.33 (d, J = 6.8 Hz, 2H), 3.16 (q, J = 9.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 1.90-1.82 (m, 2H), 1.72-1.59 (m, 2H).

[0136] Example 17

[0137] Preparation of eugenol derivative A17

[0138]

[0139] Compound 2e (0.10-0.30 mol, 1.0 equiv.) and 4k (0.30-0.60 mol, 3.0 equiv.) were dispersed in 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The reaction was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A17 with a yield of 74%.

[0140] 1 H NMR (400 MHz, Chloroform-d) δ 6.80 (d, J = 8.4 Hz, 1H), 6.71-6.68 (m, 2H), 6.01-5.90 (m, 1H), 5.110-5.03 (m, 2H), 3.98 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.33 (d, J = 6.8 Hz, 2H), 3.17 (q, J = 9.6 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 1.83 (p, J = 6.8 Hz, 2H), 1.55-1.36 (m, 6H).

[0141] Example 18

[0142] Preparation of eugenol derivative A18

[0143]

[0144] Compound 2b (0.10-0.30 mol, 1.0 equiv.) and 4l (0.30-0.60 mol, 3.0 equiv.) were dispersed in 200 mL of acetonitrile, and anhydrous potassium carbonate (0.30-0.60 mol, 3.0 equiv.) was added. The reaction was refluxed at 60-80 °C for 12-36 h. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (100 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain an oil. The crude residue was purified by flash column chromatography on silica gel, eluted with petroleum ether / ethyl acetate (10:1-3:1) to obtain compound A18 with a yield of 64%.

[0145] 1H NMR (400 MHz, Chloroform-d) δ 6.84 (d, J = 8.8 Hz, 1H), 6.71-6.68 (m, 2H), 5.98-5.90 (m, 1H), 5.09-5.04 (m, 2H), 4.10-3.96 (m, 3H), 3.83 (s, 3H), 3.32 (d, J = 6.8 Hz, 2H), 2.81-2.70 (m, 6H), 2.52 (s, 3H), 1.69-1.61 (m, 2H).

[0146] The compounds of the present application are useful for insecticidal purposes.

[0147] 1. Spodoptera frugiperda ovarian epithelial cell toxicity test

[0148] The toxicity of the eugenol derivatives to Sf9 cells was determined by cell proliferation test (CCK-8 method). The Grace's Insect Medium complete medium without compound but containing 0.2% DMSO was used as negative control (OD negative), and the wells containing 0.2% DMSO of Grace's Insect Medium complete medium without cells were used as blank control (OD blank). The test compound was prepared into a 10 mM stock solution with DMSO. Before testing, the Grace's Insect Medium complete medium was used to prepare a preliminary screening test solution containing 4 mg / mL of the test drug (DMSO content 0.2%) to detect the cell viability of Sf9 cells after treatment with the above eugenol derivatives. The wells were repeated three times, and the basic steps were as follows:

[0149] (1) Inoculate 100 μL of cell (about 5 x 10 3 cells) suspension in a 96-well plate, and incubate at 28°C in a cell incubator with 100% air for 24 h. Note that cells are not laid in the periphery of the 96-well plate, and 200 μL of sterile PBS is added to each well as a moisture retention to alleviate evaporation and avoid edge effects.

[0150] (2) Add 100 μL of fresh Grace's Insect Medium complete medium containing different concentrations of test drug, and continue to incubate in the incubator for 24 h.

[0151] (3) Add 20 μL of CCK-8 to each well, and continue to incubate for 4 h.

[0152] (4) Use a microplate reader to measure the absorbance at 450 nm, and calculate the inhibition rate of each cell proliferation at different concentrations of drug according to formula (1).

[0153] Cell viability (%) = [(OD 样品 - OD 空白 ) / (OD 对照 - OD空白 )] x 100% (1)

[0154] The half maximal inhibitory concentration (IC 50 ) of Sf9 cells was tested (Table 1),

[0155] Compound A15 showed the strongest cytotoxicity IC 50 = 34.5 mM), which was 80.7-fold more potent than eugenol (IC 50 = 2.785 mM). 50 = 2.785 mM). Notably, compound A15 with a secondary amine structure substituted with a trifluoroethyl group showed the highest cytotoxicity (IC

[0156] The cytotoxicity of eugenol and its derivatives on Sf9 cells was evaluated using the CCK-8 assay. The experimental results showed that most of the derivatives exhibited significantly enhanced cytotoxicity (IC 50 = 2.785 mM) compared to the parent compound eugenol. Notably, compound A15 with a secondary amine structure substituted with a trifluoroethyl group showed the highest cytotoxicity (IC 50 = 34.5 mM), which was 80.7-fold more potent than eugenol (IC 50 = 50.0 mM). These findings clearly indicate that the substitution of the phenolic hydroxyl group of eugenol with various nitrogen-containing groups such as cyclic / acyclic tertiary amines, secondary amines, or primary amines can significantly enhance its cytotoxic activity, and the phenolic hydroxyl group is not essential for the insecticidal activity of eugenol. In addition, it was found that the length of the linker chain plays a crucial role in modulating cytotoxicity, with optimal activity observed when the chain length contains 3 to 4 atoms. The cytotoxicity decreased when the linker was shorter than 3 atoms or longer than 5 atoms.

[0157] 2. Mortality activity test on adult sawtoothed grain beetles

[0158] Eugenol and its derivatives were diluted with acetone to the same concentration of test solution, and the test insects were paralyzed with an ice bag. 0.5 μL of the diluted solution was dropped onto the dorsal plate of the prothorax of the insects. The test insects were transferred to empty glass bottles with a diameter of 2.5 cm, a height of 5.5 cm, and a volume of 25 mL. Each drug was repeated 5 times, and 50 test insects were used each time. After 24 h of incubation in a constant temperature incubator at (29 ± 1) °C, the number of dead test insects was recorded. Since the test insects were all false dead, the test insects were touched multiple times with a hairbrush during observation, and the test insects were considered dead if they did not respond. For compounds with high mortality and eugenol, the test solution was diluted with acetone to 5 concentrations, and the experimental method was the same as above. The half lethal dose LD 50 (nmol / insect) was calculated using SPSS statistical software.

[0159] The structure selectivity was further verified by the contact experiment against O. mercatorum adults (treatment concentration 25 mg / mL, Table 1). Compound A15 showed good lethal effect at low concentration, and its LD50 was 1.724 nmol / adult, which was 9.7 times of that of eugenol. 50 The activity was about 9.7 times of that of eugenol.

[0160] In the present study, the damage effect of eugenol derivatives on the body surface structure of two insects was observed by scanning electron microscopy (SEM), and the results were compared with those of eugenol. Figure 1 Figures A-C are the negative control group, and the body surface hair of O. mercatorum adults is arranged in order, and the pores are clear; Figures D-F are the compound A15 treatment group, and most of the originally clear pores disappear or are unclear, and the hair is arranged in disorder or even broken, indicating that the drug A15 has a significant destructive effect on the body wall structure of O. mercatorum.

[0161] Table 1. Cytotoxicity of eugenol and eugenol derivatives on SF9 cells and insecticidal activity against O. mercatorum adults

[0162] SF9 cell toxicity / IC50 50 (mM) Sawtoothed grain beetle adults / mortality (%) Eugenol 2.7847 20.00 A1 0.1081 62.00 A2 0.6227 43.00 A3 0.1169 65.00 A4 0.2618 63.33 A5 0.5127 33.00 A6 0.1761 58.00 A7 0.1796 58.00 A8 0.2052 44.67 A9 0.3736 44.33 A10 0.4072 76.67 A11 0.2112 49.33 A12 0.4226 43.67 A13 0.1988 49.33 A14 0.2025 44.33 A15 0.0545 92.00 A16 0.0847 83.33 A17 0.1030 59.67 A18 0.5577 43.00

[0163] The above only describes the preferred embodiments of the present application and is not used to limit the present application, and any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A eugenol derivative, characterized by, The structural formula I is as follows: Wherein, R1 is selected from one of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, benzyl, aryl, pyridylmethyl, carbazylmethyl, indolylmethyl, piperidylmethyl, pyrrolidinylmethyl, piperazinylmethyl, sulfur-containing aryl and carbonyl substituents; R2 is selected from one of hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, benzyl, aryl, pyridylmethyl, carbazylmethyl, indolylmethyl, piperidylmethyl, pyrrolidinylmethyl, piperazinylmethyl, sulfur-containing aryl and carbonyl substituents; Or R1 and R2 are combined to be selected from one of phenyl, benzyl, substituted phenyl, pyridyl, indolyl, carbazyl, piperidyl, piperazinyl, morpholinyl, tetrahydroquinolyl, bicyclic structure, pyrrolidinyl, biphenyl and anthracene; n is selected from 0, 1, 2, 3 or 4.

2. The eugenol derivative according to claim 1, wherein The eugenol derivative is one of the following A1-A18 structural formulae: 。 3. A process for preparing eugenol derivatives according to claim 2, characterized by, The method comprises the following steps: S1, eugenol and dibromoalkane are refluxed under weak alkaline conditions to obtain compound 1 bromo intermediate, and the reaction formula is as follows, ； S2, compound 1 and the corresponding amine of compound 2 are refluxed to obtain an eugenol derivative, and the reaction formula is as follows, 。 4. The preparation method of claim 3, wherein, The structural formula of the compound 1 is: , , , or ; The structural formula of the compound 2 is: NH3, , , , , , , , , , , or .

5. The production method according to claim 4, wherein The weak alkaline condition is pH 7.3-9.

0.

6. Use of eugenol derivatives, characterized in that, The eugenol derivative of claim 2 is applied to insect killing.

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