CN113801022B

CN113801022B - Eugenol ferulate and isoeugenol hybrid and application thereof

Info

Publication number: CN113801022B
Application number: CN202110836762.5A
Authority: CN
Inventors: 甘秀海; 刘丹; 袁婷; 宋宝安; 胡德禹
Original assignee: Guizhou University
Current assignee: Guizhou University
Priority date: 2021-07-23
Filing date: 2021-07-23
Publication date: 2023-07-28
Anticipated expiration: 2041-07-23
Also published as: CN113801022A

Abstract

The invention discloses a ferulic acid eugenol and isoeugenol hybrid and application thereof, wherein the structural general formula (I) is shown as follows, and the structural general formula (I) is shown as follows: r1 is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, 2-chlorobenzyl, 3-methylbenzyl, 4-chlorobenzyl, eugenol and isoeugenol; r2 is methyl, ethynyl, 4-methylphenyl, eugenol and isoeugenol; x is an oxygen atom, an oxyacetyl group, an aminoethylene group, an ethylene group; y is a hydrogen atom, methylene, ethylene or oxyacetyl group. The invention has better treatment, protection and passivation activities on tobacco mosaic virus and cucumber mosaic virus, and has simple preparation process and low production cost.

Description

Eugenol ferulate and isoeugenol hybrid and application thereof

Technical Field

The invention relates to the fields of chemical industry and pesticides, in particular to a ferulic acid eugenol and isoeugenol hybrid, and also relates to application of the ferulic acid eugenol and isoeugenol hybrid in preparation of medicines for preventing and treating plant virus diseases such as tobacco mosaic virus diseases and cucumber mosaic virus diseases.

Background

Plant viral diseases accompany the whole growth cycle of plants and bring about a great influence on agricultural production. Due to the absolute parasitism of plant viruses, once a plant infects a plant virus, viral diseases are spread over a large area and are difficult to control, with an economic loss of up to $200 billion per year due to plant virus disease. In recent years, plant virus diseases have shown an outbreak trend, and among the plant viruses which are serious in hazard are mainly tobacco mosaic virus (Tobacco mosaic virus, TMV), cucumber mosaic virus (Cucumber mosaic virus, CMV) and the like. At present, chemical agents for preventing and treating plant virus diseases mainly comprise ningnanmycin and ribavirin, but the ningnanmycin is unstable and is difficult to apply in a large-area field, and the ribavirin has unsatisfactory prevention effect, so far, effective plant virus disease prevention and treatment agents are still lacking. Therefore, the creation of a novel, efficient and environmentally friendly anti-plant virus agent remains a key to the prevention and control of plant virus diseases.

Natural products are focused by pharmaceutical companies because of the advantages of high efficiency, unique action mechanism, environmental friendliness and the like, and are also an important source for the creation of new drugs. Ferulic acid is widely used in Chinese medicinal materials such as resina Ferulae, radix Angelicae sinensis, rhizoma Ligustici Chuanxiong, etc., and has antibacterial, antiinflammatory, and antiviral effects. In recent years, ferulic acid has been found to have a variety of agricultural activities, especially in terms of anti-plant virus activity.

The inventors Wang Qingmin, wang Kailiang, wang Ciwen, chinese patent publication No. CN102090412A, 2011, month 06, 15, disclose the use of ferulic acid and derivatives thereof in the treatment of plant viral diseases, wherein the in vitro inhibitory activity of ferulic acid and caffeic acid against tobacco mosaic virus is more than 90% at a concentration of 500 μg/mL, which is higher than that of virus a, ribavirin, DADHT and DHT.

The inventors Zhao Weiguang, cui Can, huang Anying, wang Lizhong, li Yongjiang, li Zhengming, chinese patent publication No. CN102503851A, in 2012, month 06 and 20, disclose the use of a ferulic acid phenethyl alcohol amine derivative in pesticides. The half leaf spot method is adopted to find that the ferulic acid phenethyl alcohol amine derivative has weaker treatment and protection activities on tobacco mosaic virus, and the activity is slightly higher than 30%.

The inventors Wang Qingmin, wu Meng, wang Ciwen, manchurian pine, wang Kailiang, huyanna, wang Lizhong, chinese patent publication No. CN103626652a, on 2014, 03, 12, disclose the use of 3-aryl acrylic acid and its derivatives in pesticides. The 3-aryl acrylic acid derivative is found to have better inhibition activity on tobacco mosaic virus.

The inventor Wang Qingmin, chinese patent publication No. CN104412972A, on 18 th 2015, discloses the application of trans-ferulic acid microemulsion in preventing and treating tobacco mosaic virus diseases, southern rice black-streaked dwarf virus diseases and tomato virus diseases. The field test result shows that the trans-ferulic acid microemulsion can well prevent and treat tobacco mosaic virus diseases, southern rice black-streaked dwarf virus diseases and tomato virus diseases, and is safe to crops.

The inventors Song Baoan, wu Zengxue, hu Deyu, xue Wei, lou, once pine, chinese patent publication No. CN105777654A disclosed the use of ferulic acid ester compounds containing quinazoline in plant virus resistance in the year 2016, month 07 and day 20. The ferulic acid ester compound containing quinazoline is found to have better treatment and protection activity on tobacco mosaic virus, which is equivalent to Ningnan mycin.

The inventors Xue Wei, zhang Cheng, chen Lijuan, guo Tao, xia Rongjiao, chen Ying, tang Xianfu, wang Lan, li Xiangyang, he Ming, chinese patent publication No. CN109369594a, in 2019, 02 and 22, disclose the use of a myricetin derivative containing ferulic acid amide in pesticides. The myricetin derivative containing ferulic acid amide is found to have certain treatment and protection activities on tobacco mosaic virus by adopting a half-leaf spot-drying method, and only Ningnanmycin is equivalent.

Eugenol and isoeugenol are widely used in various traditional Chinese medicinal materials containing essential oil, such as clove, laurel and the like, are mainly used in the fields of cosmetics, soap, eating and the like, and have biological activities such as antibiosis, disinsection and the like. Eugenol has also been found to have anti-plant virus activity in recent years. Chen Hao, et al (Jiangxi agricultural journal 2009, 21 (12): 112-113) found that eugenol had a control effect of 65% -73% on cucurbita pepo virus disease through field experiments. In addition, suzhou et al (agricultural journal, 2012, 14 (1): 24-29) found that 400 μg/mL eugenol had 65.82% and 62.14% protective and therapeutic effects, respectively, on tobacco mosaic virus by indoor potting test results.

In conclusion, the drug small molecules containing the ferulic acid structure have better anti-plant virus activity, but the structures of the drug small molecules are single, and the anti-plant virus activity only comprises the aspects of treatment and protection, and does not show better passivation of the virus activity. And isoeugenol, isoeugenol and isoeugenol

Disclosure of Invention

The invention aims to overcome the defects and provide the ferulic acid eugenol and isoeugenol hybrid which have better treatment, protection and passivation activities on tobacco mosaic virus and cucumber mosaic virus, simple preparation process and low production cost.

Another object of the invention is to provide the use of eugenol ferulate and isoeugenol hybrids for combating plant viruses.

The structural general formula (I) of the ferulic acid eugenol and isoeugenol hybrid is shown as follows:

wherein: r is R ₁ Is hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, 2-chlorobenzyl, 3-methylbenzyl, 4-chlorobenzyl, eugenol and isoeugenol; r is R ₂ Methyl, ethynyl, 4-methylphenyl, eugenol, isoeugenol; x is an oxygen atom, an oxyacetyl group, an aminoethylene group, an ethylene group; y is a hydrogen atom, methylene, ethylene or oxyacetyl group.

Preferred compounds are as follows:

compound A1: (E) -methyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound A2: (E) -methyl-3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound A3: (E) -ethyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound A4: (E) -ethyl-3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

Compound A5: (E) -propyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound A6: (E) -propyl-3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound A7: (E) -isopropyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound A8: (E) -isopropyl-3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound A9: (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylic acid;

compound a10: (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylic acid;

compound a11: benzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a12: benzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a13: 2-chlorobenzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

Compound a14: 2-chlorobenzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a15: 3-methylbenzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a16: 3-methylbenzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a17: 4-chlorobenzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a18: 4-chlorobenzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound B1: 4-allyl-2-methoxyphenyl (E) -3- (4-hydroxy-3-methoxyphenyl) acrylate;

compound B2: 2-methoxy-4- ((E) -1-allyl) phenyl (E) -3- (4-hydroxy-3-methoxyphenyl) acrylate;

compound B3: 4-allyl-2-methoxyphenyl (E) -3- (4-ethoxy-3-methoxyphenyl) acrylate;

compound B4: 2-methoxy-4- ((E) -1-allyl) phenyl (E) -3- (4-ethoxy-3-methoxyphenyl) acrylate;

compound B5: 4-allyl-2-methoxyphenyl (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) acrylate;

Compound B6: 2-methoxy-4- ((E) -1-allyl) phenyl (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) acrylate;

compound B7: 4-allyl-2-methoxyphenyl (E) -3- (3-methoxy-4- (4-methylbenzyloxy) phenyl) acrylate;

compound B8: 2-methoxy-4- ((E) -1-allyl) phenyl (E) -3- (4-methylbenzyloxy) phenyl) acrylate;

compound C1: (E) -N- (2- (4-allyl-2-methoxyphenoxy) ethyl) -3- (3-methoxy-4- (4-methylbenzyloxy) phenyl) acrylate;

compound C2: (E) -3- (3-methoxy-4- (4-methylbenzyloxy) phenyl) -N- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) ethyl) acrylate;

compound C3: (E) -N- (2- (4-allyl-2-methoxyphenoxy) ethyl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) acrylate;

compound C4: (E) -N- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) ethyl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) acrylate;

compound C5: (E) -N- (2- (4-allyl-2-methoxyphenoxy) ethyl) -3- (4-ethoxy-3-methoxyphenyl) acrylate;

compound C6: (E) -3- (4-ethoxy-3-methoxyphenyl) -N- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) ethyl) acrylate;

Compound D1: (E) -methyl 3- (4- (2- (4-allyl-2-methoxyphenoxy) -2-oxoethoxy) -3-methoxyphenyl) acrylate;

compound D2: (E) -methyl 3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethoxy) phenyl) acrylate;

compound D3: (E) -n-propyl 3- (4- (2- (4-allyl-2-methoxyphenoxy) -2-oxoethoxy) -3-methoxyphenyl) acrylate;

compound D4: (E) -n-propyl 3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethoxy) phenyl) acrylate;

compound D5: (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) -2-oxoethoxy) -3-methoxyphenyl) acrylic acid n-butyl ester;

compound D6: (E) -n-butyl 3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethoxy) phenyl) acrylate.

Compound E1:2- (4-allyl-2-methoxyphenoxy) -2-oxoethyl (E) -3- (3-methoxy-4- (4-methylbenzyloxy) phenyl) acrylate;

compound E2:2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethyl (E) -3- (3-methoxy-4- (4-methylbenzyloxy) phenyl) acrylate;

compound E3:2- (4-allyl-2-methoxyphenoxy) -2-oxoethyl (E) -3- (4-ethoxy-3-methoxyphenyl) acrylate;

Compound E4:2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethyl (E) -3- (4-ethoxy-3-methoxyphenyl) acrylate;

compound E5:2- (4-allyl-2-methoxyphenoxy) -2-oxoethyl (E) -3- (3-methoxy-4-prop-2-ynyloxyphenyl) acrylate;

compound E6:2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethyl (E) -3- (3-methoxy-4-prop-2-ynyloxyphenyl) acrylate.

The preparation method of the eugenol ferulate and isoeugenol hybrid A1-A18 comprises the following steps:

(1) Preparation of ferulic acid ester:

taking ferulic acid in a three-necked bottle, adding 10 times of alcohol, stirring for 10 minutes, dripping 1 equivalent of 98% concentrated sulfuric acid, reacting for about 8 hours at the temperature of 80 ℃, recovering the solvent under reduced pressure, adding 10mL of water into the system, regulating the pH value to 8 by using saturated sodium bicarbonate solution, then adding ethyl acetate for extraction for three times, drying by using anhydrous sodium sulfate, and recovering the solvent under reduced pressure to obtain a ferulate intermediate;

(2) Preparation of bromoethyl ferulate:

placing ferulic acid ester intermediate in a three-necked bottle, adding 10 times of n-butanone and 1.2 equivalent of anhydrous potassium carbonate, stirring at room temperature for 1 hour, adding 1.5 equivalent of 1, 2-dibromoethane at one time, reacting at 80 ℃ for about 4 hours, filtering, concentrating the filtrate under reduced pressure, and separating residues by column chromatography to obtain bromoethyl ferulic acid ester intermediate; (3) preparation of target Compounds A1 to A8:

Taking eugenol or isoeugenol in a three-necked bottle, adding 10 times of acetonitrile and 1.2 equivalent of anhydrous potassium carbonate, stirring for 1 hour at room temperature, adding 1 equivalent of bromoethyl ferulate intermediate, reacting for about 4 hours at 80 ℃, filtering, concentrating the filtrate under reduced pressure, and recrystallizing the residual ethyl acetate to obtain the target compounds A1-A8.

(4) Preparation of the target Compounds A9-A10:

taking A1 or A2, adding 10 times of ethanol into a three-necked flask, stirring at room temperature for 30 minutes, then dropwise adding 1 equivalent of 40% sodium hydroxide solution, reacting at 80 ℃ for about 2 hours, recovering the solvent under reduced pressure, adding a small amount of water, adjusting the pH to about 3 by using dilute hydrochloric acid, filtering, and drying to obtain the target compound A9-A10.

(5) Preparation of the target Compounds A11-A18:

taking A9 or A10 in a three-necked flask, adding 20 times of acetonitrile and 1.1 equivalent of anhydrous potassium carbonate, stirring for 30 minutes at room temperature, then adding 1.1 equivalent of benzyl halide, reacting at 80 ℃ for about 4 hours, recovering the solvent under reduced pressure, adding a small amount of water into the system, filtering and drying to obtain the target compound A11-A18.

The preparation method of the eugenol ferulate and isoeugenol hybrid B1-B8 comprises the following steps:

(1) Preparation of methyl ferulate:

taking ferulic acid in a three-necked bottle, adding 10 times of methanol, stirring for 10 minutes, dripping 1 equivalent of 98% concentrated sulfuric acid, reacting for about 8 hours at the temperature of 80 ℃, recovering the solvent under reduced pressure, adding water into the system, regulating the pH value to 8 by using saturated sodium bicarbonate solution, adding ethyl acetate for extraction for three times, drying by using anhydrous sodium sulfate, and recovering the solvent under reduced pressure to obtain the ferulate intermediate.

(2) Preparation of oxygen-substituted methyl ferulate:

taking methyl ferulate, adding 10 times of n-butanone into a three-necked flask, stirring for 10 minutes, adding 1.2 equivalents of anhydrous potassium carbonate, stirring for 30 minutes, dripping 1.1 equivalents of halogenated hydrocarbon, reacting for about 6 hours at 80 ℃, recovering the solvent under reduced pressure, adding water into the system, filtering, and recrystallizing the solid with ethyl acetate to obtain the methyl ferulate intermediate.

(3) Preparation of oxygen-substituted ferulic acid:

taking oxygen-substituted ferulic acid methyl ester, adding 10 times of ethanol into a three-necked bottle, stirring for 1 hour, dripping 1 equivalent of 2M sodium hydroxide solution, reacting at 80 ℃ for about 4 hours, recovering solvent under reduced pressure, adding a small amount of water into the system, regulating the pH value to 3 by using 5% dilute hydrochloric acid, precipitating a large amount of solid, filtering, and drying to obtain the oxygen-substituted ferulic acid intermediate.

(4) Preparation of the target Compounds B1 to B8:

taking ferulic acid or oxygen substituted ferulic acid in a three-necked bottle, adding 10 times of dichloromethane, stirring for 10 minutes, adding 1 equivalent of N, N' -carbonyldiimidazole, reacting for 10 minutes in an ice bath, then adding 1 equivalent of eugenol (or isoeugenol) at room temperature, continuing for 1 hour, recovering the solvent under reduced pressure, pouring residues into ice water, separating out solids, recrystallizing with ethanol, pumping filtration, and drying to obtain the target compounds B1-B8.

The preparation method of the ferulic acid eugenol and isoeugenol hybrid C1-C6 comprises the following steps:

(1) Preparation of bromoethoxy eugenol and isoeugenol:

taking eugenol and isoeugenol in a three-necked flask, adding 10 times of n-butanone, stirring for 10 minutes, adding 1.2 equivalents of anhydrous potassium carbonate, stirring for 1 hour at room temperature, adding 1.5 equivalents of 1, 2-dibromoethane, reacting for about 6 hours at 80 ℃, recovering the solvent under reduced pressure, and purifying by column chromatography to obtain bromoethoxyeugenol and isoeugenol intermediates.

(2) Preparation of phthalamide ethyl eugenol and isoeugenol:

taking phthalic acid diamide in a three-necked bottle, adding 10 times of D MF and 1.2 equivalent of anhydrous potassium carbonate, stirring for 1 hour at room temperature, adding 1 equivalent of bromoethoxy eugenol and isoeugenol, reacting for about 2 hours at 80 ℃, filtering, concentrating the filtrate under reduced pressure, and separating residues by column chromatography to obtain phthalic acid diamide ethyl eugenol and isoeugenol intermediates.

(3) Preparation of aminoethyl eugenol and isoeugenol:

taking phthalamide ethyl eugenol and isoeugenol intermediate in a three-necked bottle, adding 10 times of methanol, dissolving, adding 1.1 equivalent of hydrazine hydrate, stirring at room temperature for 2 hours, filtering, concentrating the filtrate under reduced pressure, and separating residues by column chromatography to obtain the aminoethyl eugenol and isoeugenol intermediate.

(4) Preparation of the target compounds C1-C6:

taking ferulic acid or oxygen substituted ferulic acid in a three-necked bottle, adding 10 times of dichloromethane, stirring for 10 minutes, adding 1 equivalent of N, N' -carbonyldiimidazole, reacting for 10 minutes in an ice bath, then adding 1 equivalent of aminoethyl eugenol and isoeugenol intermediate at room temperature, continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, separating out solid, recrystallizing with ethanol, carrying out suction filtration, and drying to obtain the target compound C1-C6.

The preparation method of the eugenol ferulate and isoeugenol heterozygotes D1-D6 and E1-E6 comprises the following steps:

(1) Preparation of chloroacetyl eugenol and isoeugenol:

taking eugenol and isoeugenol in a three-necked bottle, adding 10 times of dichloromethane, dropwise adding 1 equivalent of triethylamine, stirring for 10 minutes, dropwise adding 1 equivalent of chloroacetyl chloride, reacting at room temperature for about 2 hours, recovering solvent under reduced pressure, and recrystallizing ethyl acetate to obtain chloroacetyl eugenol and isoeugenol intermediates.

(2) Preparation of the target Compounds D1 to D6:

taking ferulic acid ester intermediate in a three-necked bottle, adding 10 times of DMF and 1.1 equivalent of anhydrous potassium carbonate, stirring for 1 hour at room temperature, adding 1 equivalent of chloracetyl eugenol and isoeugenol, reacting for about 4 hours at 40 ℃, filtering, concentrating the filtrate under reduced pressure, and recrystallizing the residue by ethyl acetate to obtain the target compound D1-D6.

(3) Preparation of the target Compounds E1 to E6:

taking oxygen to replace ferulic acid intermediate, adding 10 times of DMF and 1.2 equivalent of anhydrous sodium bicarbonate into the three-necked bottle, stirring the mixture for 1 hour at room temperature, adding 1 equivalent of chloracetyl eugenol and isoeugenol, reacting the mixture for about 4 hours at the temperature of 40 ℃, filtering the mixture, concentrating the filtrate under reduced pressure, and recrystallizing the residue by ethyl acetate to obtain the target compounds E1-E6.

The invention relates to application of ferulic acid eugenol and isoeugenol heterozygote in preparing medicines for preventing and treating tobacco mosaic virus and cucumber mosaic virus.

Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can be adopted as follows: based on the principle of splicing active substructures, the invention prepares ferulic acid eugenol and isoeugenol heterozygote with various structures through various linking modes, and experiments prove that the ferulic acid eugenol and isoeugenol heterozygote has better treatment, protection and passivation activities on tobacco mosaic virus and cucumber mosaic virus, and is obviously superior to that of a contrast medicament Ningnan mycin and a lead compound ferulic acid, and the preparation process is simple, the production cost is low, and the application prospect is wide.

Detailed Description

Example 1

The preparation method of the ferulic acid eugenol hybrid A1 comprises the following steps:

(1) Preparation of methyl ferulate:

ferulic acid (10 g,51.50 mmol) was taken in a three-necked flask, 50mL of methanol was added thereto, stirring was carried out for 10 minutes, 98% concentrated sulfuric acid (5.06 g,51.50 mmol) was added dropwise thereto for reaction at 80℃for about 8 hours, the solvent was recovered under reduced pressure, 10mL of water was added to the system, and the pH was adjusted to 8 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times (100 mL each time), the extracts were combined, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to give 9.85g of a ferulic acid methyl ester intermediate in 91.7% yield.

(2) Preparation of bromoethyl ferulic acid methyl ester:

methyl ferulate (5.0 g,24.01 mmol) was taken in a three-necked flask, 50mL of n-butanone and anhydrous potassium carbonate (3.98 g,28.82 mmol) were then added, stirring was carried out at room temperature for 1 hour, 1, 2-dibromoethane (6.77 g,36.02 mmol) was then added in one portion, and reacted at 80℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give methyl bromoethyl ferulate intermediate 6.10g, yield 80.6%.

(3) Preparation of the target compound A1:

eugenol (1.5 g,9.13 mmol) was taken in a three-necked flask, followed by addition of 20mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol), stirring at room temperature for 1 hour, followed by addition of bromoethyl ferulic acid methyl ester (2.88 g,9.13 mmol), and reaction at 80℃for about 4 hours, filtration, concentration of the filtrate under reduced pressure, and recrystallization of the residue from ethyl acetate gave the objective compound A1,2.86g, yield 78.5%.

Example 2

The preparation method of the isoeugenol ferulate hybrid A2 comprises the following steps:

steps (1) - (2) are as in example 1

(3) Preparation of target compound A2:

isoeugenol (1.5 g,9.13 mmol) was taken in a three-necked flask, then 20mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol) were added, stirring was carried out at room temperature for 1 hour, then methyl bromoethyl ferulate (2.88 g,9.13 mmol) was added, and reacted at 80℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound A2,2.95g, yield 81.2%.

Example 3

The preparation method of the ferulic acid eugenol hybrid A3 comprises the following steps:

(1) Preparation of ethyl ferulate:

ferulic acid (10 g,51.50 mmol) was taken in a three-necked flask, 50mL of ethanol was added, stirring was performed for 10 minutes, 98% concentrated sulfuric acid (5.06 g,51.50 mol) was added dropwise, the reaction was performed at 80℃for about 8 hours, the solvent was recovered under reduced pressure, water was added to the system, the pH was adjusted to 8 with saturated sodium bicarbonate solution, ethyl acetate was added for three extractions (100 mL each time), the extracts were combined, anhydrous sodium sulfate was dried, and the solvent was recovered under reduced pressure to obtain ethyl ferulate intermediate, 10.50g, yield 91.7%.

(2) Preparation of bromoethyl ferulate:

Ethyl ferulate (5.0 g,22.50 mmol) was taken in a three-necked flask, 50mL of n-butanone and anhydrous potassium carbonate (3.73 g,27.00 mmol) were then added, stirring was carried out at room temperature for 1 hour, 1, 2-dibromoethane (6.34 g,33.75 mmol) was then added in one portion, and reacted at 80℃for about 4 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give ethyl bromoethyl ferulate intermediate 5.82g, yield 75.6%.

(3) Preparation of target compound A3:

eugenol (1.0 g,6.09 mmol) was taken in a three-necked flask, followed by 15mL of acetonitrile and anhydrous potassium carbonate (1.01 g,7.31 mmol), stirred at room temperature for 1 hour, followed by bromoethyl ferulate (2.0 g,6.09 mmol) and reacted at 80℃for about 4 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound A3,1.91g, yield 76.1%.

Example 4

The preparation method of the isoeugenol ferulate hybrid A4 comprises the following steps:

steps (1) - (2) are as in example 3

(3) Preparation of target compound A4: isoeugenol (1.0 g,6.09 mmol) was taken in a three-necked flask, followed by 15mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol), stirred at room temperature for 1 hour, followed by bromoethyl ferulate (2.0 g,6.09 mmol), and reacted at 80℃for about 4 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound A4,2.15g, yield 85.8%.

Example 5

The preparation method of the ferulic acid eugenol hybrid A5 comprises the following steps:

(1) Preparation of n-propyl ferulate:

ferulic acid (10 g,51.50 mmol) was taken in a three-necked flask, 50mL of n-propanol was added, stirring was performed for 10 minutes, 98% concentrated sulfuric acid (5.06 g,51.50 mol) was added dropwise, the reaction was performed at 80℃for about 8 hours, the solvent was recovered under reduced pressure, water was added to the system, the pH was adjusted to 8 with saturated sodium bicarbonate solution, ethyl acetate was added for extraction three times (100 mL each time), the extract was combined, anhydrous sodium sulfate was dried, and the solvent was recovered under reduced pressure to obtain 9.8g of ferulic acid methyl ester intermediate, the yield was 80.5%.

(2) Preparation of bromoethyl ferulic acid n-propyl ester:

n-propyl ferulate (5.0 g,21.16 mmol) was taken in a three-necked flask, 50mL of n-butanone and anhydrous potassium carbonate (3.51 g,25.39 mmol) were then added, stirring was performed at room temperature for 1 hour, 1, 2-dibromoethane (5.96 g,31.74 mol) was then added at one time, and reacted at 80℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give methyl bromoethyl ferulate intermediate 5.66g, yield 84.8%.

(3) Preparation of target compound A5:

eugenol (1.5 g,9.13 mmol) was taken in a three-necked flask, followed by addition of 20mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol), stirring at room temperature for 1 hour, followed by addition of bromoethyl n-propyl ferulate (3.14 g,9.13 mmol), and reaction at 80℃for about 4 hours, filtration, concentration of the filtrate under reduced pressure, and recrystallization of the residue from ethyl acetate gave the objective compound A5,3.25g in 89.4% yield.

Example 6

The preparation method of the isoeugenol ferulate hybrid A6 comprises the following steps:

steps (1) - (2) are as in example 5

(3) Preparation of the target compound A6:

isoeugenol (1.5 g,9.13 mmol) was taken in a three-necked flask, then 20mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol) were added, stirring was carried out at room temperature for 1 hour, then bromoethyl n-propyl ferulate (3.14 g,9.13 mmol) was added, and reacted at 80℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound A6,2.61g, yield 71.8%.

Example 7

The preparation method of the ferulic acid eugenol hybrid A7 comprises the following steps:

(1) Preparation of isopropyl ferulate:

ferulic acid (10 g,51.50 mmol) was taken in a three-necked flask, 50mL of isopropanol was added, stirring was performed for 10 minutes, 98% concentrated sulfuric acid (5.06 g,51.50 mol) was added dropwise, the reaction was performed at 80℃for about 8 hours, the solvent was recovered under reduced pressure, water was added to the system, the pH was adjusted to 8 with saturated sodium bicarbonate solution, ethyl acetate was added for extraction three times (100 mL each time), the extracts were combined, anhydrous sodium sulfate was dried, and the solvent was recovered under reduced pressure to obtain 9.8g of a ferulic acid methyl ester intermediate with a yield of 80.5%.

(2) Preparation of bromoethyl ferulic acid isopropyl ester:

Isopropyl ferulate (5.0 g,21.16 mmol) was taken in a three-necked flask, 50mL of n-butanone and anhydrous potassium carbonate (3.51 g,25.39 mmol) were then added, stirring was performed at room temperature for 1 hour, 1, 2-dibromoethane (5.96 g,31.74 mol) was then added in one portion, and reacted at 80℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give methyl bromoethyl ferulate intermediate 5.66g, yield 84.8%.

(3) Preparation of the target compound A7:

eugenol (1.5 g,9.13 mmol) was taken in a three-necked flask, followed by addition of 20mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol), stirring at room temperature for 1 hour, followed by addition of bromoethyl ferulic acid isopropyl ester (3.14 g,9.13 mmol), and reaction at 80℃for about 4 hours, filtration, concentration of the filtrate under reduced pressure, and recrystallization of the residue from ethyl acetate gave the objective compound A5,3.04g, yield 83.5%.

Example 8

The preparation method of the isoeugenol ferulate hybrid A8 comprises the following steps:

steps (1) - (2) are as in example 7

(3) Preparation of the target compound A8:

isoeugenol (1.5 g,9.13 mmol) was taken in a three-necked flask, then 20mL of acetonitrile and anhydrous potassium carbonate (1.51 g,10.96 mmol) were added, stirring was carried out at room temperature for 1 hour, then bromoethyl ferulic acid isopropyl ester (3.14 g,9.13 mmol) was added, and reacted at 80℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound A8,3.1g, yield 85.2%.

Example 9

The preparation method of the isoeugenol ferulate hybrid A9 comprises the following steps:

the compound A1 (2.0 g,5.02 mmol) obtained in example 1 was taken in a three-necked flask, 20mL of ethanol was added and stirred at room temperature for 30 minutes, then 40% sodium hydroxide solution (containing 0.24g,6.02mmol of sodium hydroxide) was added dropwise and reacted at 80℃for about 2 hours, the solvent was recovered under reduced pressure, a small amount of water was added, and pH was adjusted to about 3 with dilute hydrochloric acid, and filtration and drying were carried out to obtain the objective compound A9,1.31g, yield 68.8%.

Example 10

The preparation method of the isoeugenol ferulate hybrid A10 comprises the following steps:

the compound A2 (2.0 g,5.02 mmol) obtained in example 2 was taken in a three-necked flask, 20mL of ethanol was added and stirred at room temperature for 30 minutes, then 40% sodium hydroxide solution (containing 0.24g,6.02mmol of sodium hydroxide) was added dropwise and reacted at 80℃for about 2 hours, the solvent was recovered under reduced pressure, a small amount of water was added, and pH was adjusted to about 3 with dilute hydrochloric acid, and filtration and drying were carried out to obtain the objective compound A10,1.25g, yield 65.2%.

Example 11

The preparation method of the isoeugenol ferulate hybrid A11 comprises the following steps:

the compound A9 (0.2 g,0.52 mmol) obtained in example 9 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added and stirred at room temperature for 30 minutes, followed by addition of benzyl chloride (0.072 g,0.57 mmol) and reaction at 80℃for about 4 hours, recovery of the solvent under reduced pressure, and addition of a small amount of water to the system, filtration and drying gave the objective compound A11,0.20g,80.5%.

Example 12

The preparation method of the isoeugenol ferulate hybrid A12 comprises the following steps:

the compound A10 (0.2 g,0.52 mmol) obtained in example 10 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added and stirred at room temperature for 30 minutes, followed by addition of benzyl chloride (0.072 g,0.57 mmol) and reaction at 80℃for about 4 hours, recovery of the solvent under reduced pressure, and addition of a small amount of water to the system, filtration and drying gave the objective compound A12,0.20g,79.5%.

Example 13

The preparation method of the isoeugenol ferulate hybrid A13 comprises the following steps:

the compound A9 (0.2 g,0.52 mmol) obtained in example 9 was taken in a three-necked flask, 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added, stirring was carried out at room temperature for 30 minutes, then 2-chlorobenzyl chloride (0.092 g,0.57 mmol) was added, and reacted at 80℃for about 4 hours, the solvent was recovered under reduced pressure, and a small amount of water was added to the system, filtered and dried to obtain the objective compound A13,0.23g,75.5%.

Example 14

The preparation method of the isoeugenol ferulate hybrid A14 comprises the following steps:

the compound A10 (0.2 g,0.52 mmol) obtained in example 10 was taken in a three-necked flask, 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added, stirring was carried out at room temperature for 30 minutes, then 2-chlorobenzyl chloride (0.092 g,0.57 mmol) was added and reacted at 80℃for about 4 hours, the solvent was recovered under reduced pressure, and a small amount of water was added to the system, filtered and dried to obtain the objective compound A14,0.19g,71.9%.

Example 15

The preparation method of the isoeugenol ferulate hybrid A15 comprises the following steps:

the compound A9 (0.2 g,0.52 mmol) obtained in example 9 was taken in a three-necked flask, 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added, stirring was carried out at room temperature for 30 minutes, then 3-methylbenzyl chloride (0.080 g,0.57 mmol) was added, and the reaction was carried out at 80℃for about 4 hours, the solvent was recovered under reduced pressure, and a small amount of water was added to the system, and filtration and drying were carried out to obtain the objective compound A15,0.20g,81.6%.

Example 16

The preparation method of the isoeugenol ferulate hybrid A16 comprises the following steps:

the compound A10 (0.2 g,0.52 mmol) obtained in example 10 was taken in a three-necked flask, 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added, stirring was carried out at room temperature for 30 minutes, then 3-methylbenzyl chloride (0.080 g,0.57 mmol) was added, and the reaction was carried out at 80℃for about 4 hours, the solvent was recovered under reduced pressure, and a small amount of water was added to the system, and filtration and drying were carried out to obtain the objective compound A16,0.20g,90.5%.

Example 17

The preparation method of the isoeugenol ferulate hybrid A17 comprises the following steps:

the compound A9 (0.2 g,0.52 mmol) obtained in example 9 was taken in a three-necked flask, 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added, stirring was carried out at room temperature for 30 minutes, then 2-chlorobenzyl chloride (0.092 g,0.57 mmol) was added, and reacted at 80℃for about 4 hours, the solvent was recovered under reduced pressure, and a small amount of water was added to the system, filtered and dried to obtain the objective compound A17,0.20g,74.6%.

Example 18

The preparation method of the isoeugenol ferulate hybrid A18 comprises the following steps:

the compound A10 (0.2 g,0.52 mmol) obtained in example 10 was taken in a three-necked flask, 4mL of acetonitrile and anhydrous potassium carbonate (0.086 g,0.62 mmol) were added, stirred at room temperature for 30 minutes, then 2-chlorobenzyl chloride (0.092 g,0.57 mmol) was added and reacted at 80℃for about 4 hours, the solvent was recovered under reduced pressure, and a small amount of water was added to the system, filtered and dried to obtain the objective compound A18,0.19g,72.6%.

Example 19

The preparation method of the ferulic acid eugenol hybrid B1 comprises the following steps:

ferulic acid (0.5 g,2.57 mmol) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.41 g,2.57 mmol) was added and reacted under ice bath for 10 minutes, then eugenol (0.42 g,2.57 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtration was performed, and drying was performed to obtain the objective compound B1,0.39g, yield 45.2%.

Example 20

The preparation method of the isoeugenol ferulate hybrid B2 comprises the following steps:

ferulic acid (0.5 g,2.57 mmol) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.41 g,2.57 mmol) was added and reacted under ice bath for 10 minutes, isoeugenol (0.42 g,2.57 mmol) was then added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, the solid was precipitated, ethanol was recrystallized, suction filtration and drying were performed to obtain the objective compound B2,0.32g, yield 36.1%.

Example 21

The preparation method of the ferulic acid eugenol hybrid B3 comprises the following steps:

step (1) same as in example 1

(2) Preparation of ethyl substituted methyl ferulate

Taking the methyl ferulate (2.0 g,9.61 mmol) obtained in the step (1) in a three-necked bottle, adding 20mL of n-butanone, stirring for 10 minutes, adding anhydrous potassium carbonate (1.56 g,11.53 mmol), stirring for 30 minutes, dripping bromoethane (1.15 g,10.57 mmol), reacting at 80 ℃ for about 6 hours, recovering the solvent under reduced pressure, adding water into the system, recrystallizing the solid by ethyl acetate to obtain ethyl-substituted methyl ferulate (2.1 g) with the yield of 88.1 percent.

(3) Preparation of ethyl-substituted ferulic acid:

ethyl substituted ferulic acid methyl ester (2.0 g,8.46 mmol) is taken and placed in a three-necked bottle, 20mL of ethanol is added, stirring is carried out for 1 hour, 2M sodium hydroxide solution (0.34 g,8.46mmol of sodium hydroxide) is added dropwise, reaction is carried out for about 4 hours at the temperature of 80 ℃, the solvent is recovered under reduced pressure, a small amount of water is added into the system, the pH value is regulated to 3 by 5% of diluted hydrochloric acid, a large amount of solid is separated out, suction filtration and drying are carried out, and 1.6g of ethyl substituted ferulic acid is obtained, and the yield is 85.0%.

(4) Preparation of target compound B3:

ethyl-substituted ferulic acid (0.5 g,2.25 mmol) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.36 g,2.25 mmol) was added and reacted under ice bath for 10 minutes, then eugenol (0.37 g,2.25 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtration and drying were performed to obtain the objective compound B3,0.56g, yield 67.8%.

Example 22

The preparation method of the isoeugenol ferulate hybrid B4 comprises the following steps:

steps (1) - (3) are as in example 21

(4) Preparation of target compound B4:

ethyl-substituted ferulic acid (0.5 g,2.25 mmol) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.36 g,2.25 mmol) was added and reacted under ice bath for 10 minutes, isoeugenol (0.37 g,2.25 mmol) was then added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtration and drying gave the objective compound B4,0.65g, yield 78.5%.

Example 23

The preparation method of the ferulic acid eugenol hybrid B5 comprises the following steps:

step (1) same as in example 1

(2) Preparation of n-propyl substituted methyl ferulate

Taking the methyl ferulate (2.0 g,9.61 mmol) obtained in the step (1) in a three-necked bottle, adding 20mL of n-butanone, stirring for 10 minutes, adding anhydrous potassium carbonate (1.56 g,11.53 mmol), stirring for 30 minutes, dripping bromopropane (1.30 g,10.52 mmol), reacting at 80 ℃ for about 6 hours, recovering the solvent under reduced pressure, adding water into the system, and recrystallizing the solid with ethyl acetate to obtain 1.8g of n-propyl substituted methyl ferulate with the yield of 74.8%.

(3) Preparation of n-propyl substituted ferulic acid:

n-propyl substituted methyl ferulate (1.7 g,7.20 mmol) is taken and placed in a three-necked bottle, 20mL of ethanol is added, stirring is carried out for 1 hour, 2M sodium hydroxide solution (0.29 g,7.20mmol of sodium hydroxide) is added dropwise, reaction is carried out for about 4 hours at the temperature of 80 ℃, the solvent is recovered under reduced pressure, a small amount of water is added into the system, the pH value is regulated to 3 by 5% of diluted hydrochloric acid, a large amount of solid is separated out, suction filtration and drying are carried out, and 1.4g of ethyl substituted ferulic acid is obtained, and the yield is 87.5%.

(4) Preparation of target compound B5:

n-propyl substituted ferulic acid (0.6 g,2.54 mmol) was taken in a three-necked flask, 6mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.4 g,2.54 mmol) was added and reacted under ice bath for 10 minutes, then eugenol (0.42 g,2.54 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtration was performed, and drying was performed to obtain the objective compound B5,0.50g, yield 78.2%.

Example 24

The preparation method of the isoeugenol ferulate hybrid B6 comprises the following steps:

steps (1) - (3) are as in example 23

(4) Preparation of target compound B6:

n-propyl substituted ferulic acid (0.6 g,2.54 mmol) was taken in a three-necked flask, 6mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.4 g,2.54 mmol) was added and reacted under ice bath for 10 minutes, after which isoeugenol (0.42 g,2.54 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtered, and dried to obtain the objective compound B6,0.41g, yield 41.8%.

Example 25

The preparation method of the ferulic acid eugenol hybrid B7 comprises the following steps:

step (1) same as in example 1

(2) Preparation of 4-methylbenzyl-substituted methyl ferulate

Taking the methyl ferulate (2.0 g,9.61 mmol) obtained in the step (1) in a three-necked flask, adding 20mL of n-butanone, stirring for 10 minutes, adding anhydrous potassium carbonate (1.56 g,11.53 mmol), stirring for 30 minutes, dripping 4-methylbenzyl chloride (1.49 g,10.52 mmol), reacting for about 6 hours at 80 ℃, recovering the solvent under reduced pressure, adding water into the system, and recrystallizing the solid by ethyl acetate to obtain 2.2g of 4-methylbenzyl-substituted methyl ferulate with the yield of 73.3 percent.

(3) Preparation of 4-methylbenzyl substituted ferulic acid:

taking 4-methylbenzyl-substituted ferulic acid methyl ester (1.5 g,4.80 mmol) in a three-necked bottle, adding 15mL of ethanol, stirring for 1 hour, dripping 2M sodium hydroxide solution (0.19 g,4.80mmol of sodium hydroxide), reacting for about 4 hours at the temperature of 80 ℃, recovering the solvent under reduced pressure, adding a small amount of water into the system, regulating the pH value to 3 by using 5% of diluted hydrochloric acid, precipitating a large amount of solid, filtering, and drying to obtain 1.1g of 4-methylbenzyl-substituted ferulic acid with the yield of 76.7%.

(4) Preparation of target compound B7:

4-Methylbenzyl-substituted ferulic acid (0.6 g,2.01 mmol) was taken in a three-necked flask, 6mL of dichloromethane was further added thereto, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.32 g,2.01 mmol) was added thereto and reacted under ice bath for 10 minutes, then eugenol (0.33 g,2.01 mmol) was added thereto at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction-filtered, and dried to give the objective compound B7,0.37g, yield was 41.5%.

Example 26

The preparation method of the isoeugenol ferulate hybrid B8 comprises the following steps:

steps (1) - (3) are as in example 23

(4) Preparation of target compound B8:

4-Methylbenzyl-substituted ferulic acid (0.6 g,2.01 mmol) was taken in a three-necked flask, 6mL of dichloromethane was further added thereto, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.32 g,2.01 mmol) was added thereto and reacted under ice bath for 10 minutes, then isoeugenol (0.33 g,2.01 mmol) was added thereto at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water to precipitate a solid, ethanol was recrystallized, suction filtration was carried out, and drying was carried out to obtain the objective compound B8,0.33g, yield 36.8%.

Example 27

The preparation method of the ferulic acid eugenol hybrid C1 comprises the following steps:

(1) Preparation of bromoethoxy eugenol:

eugenol (5.0 g,30.45 mmol) was taken in a three-necked flask, 50mL of n-butanone was added thereto, stirring was carried out for 10 minutes, anhydrous potassium carbonate (5.1 g,36.54 mmol) was added thereto, stirring was carried out at room temperature for 1 hour, 1, 2-dibromoethane (8.58 g,45.67 mmol) was then added thereto, the reaction was carried out at 80℃for about 6 hours, the solvent was recovered under reduced pressure, and the bromoethoxyeugenol was obtained by column chromatography purification in a yield of 65.8%.

(2) Preparation of phthalamide ethyl eugenol:

Phthalic acid amide (2.17 g,14.75 mmol) was taken in a three-necked flask, followed by addition of 10mL of DMF and anhydrous potassium carbonate (2.45 g,17.70 mmol), stirring at room temperature for 1 hour, followed by addition of bromoethoxyeugenol (4.0 g,14.75 mmol), and reaction at 80℃for about 2 hours, filtration, concentration of the filtrate under reduced pressure, and isolation of the residue by column chromatography gave phthalic acid amide ethyleugenol intermediate 4.21g, yield 85.2%.

(3) Preparation of aminoethyl eugenol:

the phthalamide ethyl eugenol (3.5 g,10.37 mmol) intermediate was taken in a three-necked flask, 35mL of methanol was then added, hydrazine hydrate (0.57 g,11.41 mmol) was added after dissolution, stirring was carried out at room temperature for 2 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give 1.32g of the aminoethyl eugenol intermediate in a yield of 61.1%.

(4) Preparation of target compound C1:

the 4-methylbenzyl-substituted ferulic acid (0.43 g,1.45 mmol) obtained in example 25 (3) was taken in a three-necked flask, 5mL of methylene chloride was further added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.23 g,1.45 mmol) was added and reacted under ice bath for 10 minutes, then aminoethyl eugenol (0.3 g,1.45 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtration was carried out, and the title compound C1,0.33g was obtained by drying in 47.6% yield.

Example 28

The preparation method of the isoeugenol ferulate hybrid C2 comprises the following steps:

(1) Preparation of bromoethoxy isoeugenol:

isoeugenol (5.0 g,30.45 mmol) was taken in a three-necked flask, 50mL of n-butanone was added thereto, stirring was carried out for 10 minutes, anhydrous potassium carbonate (5.1 g,36.54 mmol) was added thereto, stirring was carried out at room temperature for 1 hour, 1, 2-dibromoethane (8.58 g,45.67 mmol) was then added thereto, the reaction was carried out at 80℃for about 6 hours, the solvent was recovered under reduced pressure, and bromoethoxyeugenol 6.41g was obtained by column chromatography purification in 78.5% yield.

(2) Preparation of phthalamide ethyl isoeugenol:

phthalic acid amide (2.17 g,14.75 mmol) was taken in a three-necked flask, followed by addition of 10mL of DMF and anhydrous potassium carbonate (2.45 g,17.70 mmol), stirring at room temperature for 1 hour, followed by addition of bromoethoxyisoeugenol (4.0 g,14.75 mmol), and reaction at 80℃for about 2 hours, filtration, concentration of the filtrate under reduced pressure, and isolation of the residue by column chromatography gave phthalic acid amide ethyl isoeugenol intermediate 4.52g, yield 89.9%.

(3) Preparation of aminoethyl isoeugenol:

the phthalamide ethyl isoeugenol (3.5 g,10.37 mmol) intermediate was taken in a three-necked flask, 35mL of methanol was then added, hydrazine hydrate (0.57 g,11.41 mmol) was added after dissolution, stirring was carried out at room temperature for 2 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give 1.51g of aminoethyl isoeugenol intermediate with a yield of 68.2%.

(4) Preparation of target compound C2:

the 4-methylbenzyl-substituted ferulic acid (0.43 g,1.45 mmol) obtained in example 25 (3) was taken in a three-necked flask, 5mL of methylene chloride was further added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.23 g,1.45 mmol) was added and reacted under ice bath for 10 minutes, then aminoethyl isoeugenol (0.3 g,1.45 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, a solid was precipitated, ethanol was recrystallized, suction filtration was carried out, and the yield of the objective compound C2,0.47g was obtained by drying.

Example 29

The preparation method of the ferulic acid eugenol hybrid C3 comprises the following steps:

steps (1) - (3) are as in example 27

(4) Preparation of eugenol ferulate hybrid C3

N-propyl-substituted ferulic acid (0.34 g,1.45 mmol) obtained in example 23 (3) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.23 g,1.45 mmol) was added and reacted under ice bath for 10 minutes, then aminoethyl eugenol (0.3 g,1.45 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction-filtered, and dried to obtain the objective compound C3,0.45g, yield 65.3%.

Example 30

The preparation method of the isoeugenol ferulate hybrid C4 comprises the following steps:

steps (1) - (3) are as in example 28

(4) Preparation of isoeugenol ferulate hybrid C4

N-propyl-substituted ferulic acid (0.34 g,1.45 mmol) obtained in example 23 (3) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.23 g,1.45 mmol) was added and reacted under ice bath for 10 minutes, then aminoethyl isoeugenol (0.3 g,1.45 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction-filtered, and dried to obtain the objective compound C4,0.26g, yield 42.8%.

Example 31

The preparation method of the ferulic acid eugenol hybrid C5 comprises the following steps:

steps (1) - (3) are as in example 27

(4) Preparation of eugenol ferulate hybrid C5

The ethyl-substituted ferulic acid (0.32 g,1.45 mmol) obtained in example 21 (3) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.23 g,1.45 mmol) was added and reacted under ice bath for 10 minutes, then aminoethyl eugenol (0.3 g,1.45 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtration and drying to obtain the objective compound C5,0.35g, yield 58.2%.

Example 32

The preparation method of the isoeugenol ferulate hybrid C6 comprises the following steps:

steps (1) - (3) are as in example 28

(4) Preparation of isoeugenol ferulate hybrid C6

The ethyl-substituted ferulic acid (0.32 g,1.45 mmol) obtained in example 21 (3) was taken in a three-necked flask, 5mL of dichloromethane was further added, stirring was performed for 10 minutes, N' -carbonyldiimidazole (0.23 g,1.45 mmol) was added and reacted under ice bath for 10 minutes, then aminoethyl isoeugenol (0.3 g,1.45 mmol) was added at room temperature and continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solid was precipitated, ethanol was recrystallized, suction filtered, and dried to obtain the objective compound C6,0.36g, yield 56.1%.

Example 33

The preparation method of the ferulic acid eugenol hybrid D1 comprises the following steps:

(1) Preparation of chloroacetyl eugenol:

eugenol (5.0 g,30.45 mmol) was taken in a three-necked flask, 50mL of dichloromethane was added thereto, triethylamine (3.08 g,30.45 mmol) was added dropwise thereto, and after stirring for 10 minutes, chloroacetyl chloride (3.44 g,30.45 mmol) was added dropwise thereto, the reaction was carried out at room temperature for about 2 hours, the solvent was recovered under reduced pressure, and ethyl acetate was recrystallized to give chloroacetyl eugenol intermediate 5.97g, yield 81.5%.

(2) Preparation of a ferulic acid eugenol hybrid D1:

Methyl ferulate (0.26 g,1.25 mmol) obtained in example 1 (1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added, and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound D1,0.30g, yield 58.6%.

Example 34

The preparation method of the isoeugenol ferulate hybrid D2 comprises the following steps:

(1) Preparation of chloroacetyl isoeugenol:

isoeugenol (5.0 g,30.45 mmol) was taken in a three-necked flask, 50mL of dichloromethane was further added thereto, triethylamine (3.08 g,30.45 mmol) was further added dropwise thereto, and after stirring for 10 minutes, chloroacetyl chloride (3.44 g,30.45 mmol) was added dropwise thereto, the reaction was carried out at room temperature for about 2 hours, the solvent was recovered under reduced pressure, and ethyl acetate was recrystallized to give chloroacetyl isoeugenol intermediate 6.25g, yield 85.2%.

(2) Preparation of isoeugenol ferulate hybrid D2:

methyl ferulate (0.26 g,1.25 mmol) obtained in example 1 (1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3 g,1.25 mmol) was added, and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound D2,0.34g, yield 65.4%.

Example 35

The preparation method of the ferulic acid eugenol hybrid D3 comprises the following steps:

step (1) as in example 33

(2) Preparation of a ferulic acid eugenol hybrid D3:

n-propyl ferulate (0.29 g,1.25 mmol) obtained in example 5 (1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19 g,1.37 mmol) were then added, stirring was performed at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added, and reacted at 40℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound D3,0.26g, yield 48.1%.

Example 36

The preparation method of the isoeugenol ferulate hybrid D4 comprises the following steps:

step (1) same as in example 34

(2) Preparation of isoeugenol ferulate hybrid D4:

n-propyl ferulate (0.29 g,1.25 mmol) obtained in example 5 (1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19 g,1.37 mmol) were then added, stirring was performed at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added, and reacted at 40℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound D4,0.31g, yield 56.8%.

Example 37

The preparation method of the ferulic acid eugenol hybrid D5 comprises the following steps:

step (1) as in example 33

(2) Preparation of butyl ferulate:

ferulic acid (5 g,25.75 mmol) was taken in a three-necked flask, 25mL of n-butanol was added, stirring was performed for 10 minutes, 98% concentrated sulfuric acid (2.53 g,25.75 mmol) was added dropwise, the reaction was performed at 80℃for about 8 hours, the solvent was recovered under reduced pressure, water was added to the system, the pH was adjusted to 8 with saturated sodium bicarbonate solution, ethyl acetate was added for extraction three times (50 mL each time), the extracts were combined, anhydrous sodium sulfate was dried, and the solvent was recovered under reduced pressure to obtain 4.8g of a ferulic acid methyl ester intermediate, yield was 74.5%.

(3) Preparation of a ferulic acid eugenol hybrid D5:

n-butyl ferulate (0.31 g,1.25 mmol) obtained in example 5 (1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3 g,1.25 mmol) was added, and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound D5,0.31g, yield 55.4%.

Example 38

The preparation method of the isoeugenol ferulate hybrid D6 comprises the following steps:

Step (1) same as in example 34

Step (2) as in example 37

(3) Preparation of the target compound D6:

n-propyl ferulate (0.31 g,1.25 mmol) obtained in example 5 (1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19 g,1.37 mmol) were then added, stirring was performed at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added, and reacted at 40℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound D6,0.36g, yield 63.8%.

Example 39

The preparation method of the ferulic acid eugenol hybrid E1 comprises the following steps:

step (1) as in example 33

(2) Preparation of a ferulic acid eugenol hybrid E1:

the ethyl-substituted ferulic acid (0.28 g,1.25 mmol) obtained in example 21 (3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3 g,1.25 mmol) was added, and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound E1,0.25g, yield 47.2%.

Example 40

The preparation method of the isoeugenol ferulate hybrid E2 comprises the following steps:

Step (1) same as in example 34

(2) Preparation of isoeugenol ferulate hybrid E2:

the ethyl-substituted ferulic acid (0.28 g,1.25 mmol) obtained in example 21 (3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3 g,1.25 mmol) was added, and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound E2,0.30g in 57.2% yield.

Example 41

The preparation method of the ferulic acid eugenol hybrid E3 comprises the following steps:

step (1) as in example 33

(2) Preparation of ferulic acid eugenol hybrid E3:

n-propyl-substituted ferulic acid (0.29 g,1.25 mmol) obtained in example 21 (3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12 g,1.37 mmol) were then added, stirring was performed at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added, and reacted at 40℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound E3,0.31g, yield 56.8%.

Example 42

The preparation method of the isoeugenol ferulate hybrid E4 comprises the following steps:

Step (1) same as in example 34

(2) Preparation of isoeugenol ferulate hybrid E4:

n-propyl-substituted ferulic acid (0.29 g,1.25 mmol) obtained in example 21 (3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12 g,1.37 mmol) were then added, stirring was performed at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added, and reacted at 40℃for about 4 hours, filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound E4,0.40g, yield 72.5%.

Example 43

The preparation method of the ferulic acid eugenol hybrid E5 comprises the following steps:

step (1) as in example 33

(2) Preparation of a ferulic acid eugenol hybrid E5:

the 4-methylbenzyl-substituted ferulic acid (0.37 g,1.25 mmol) obtained in example 21 (3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound E5,0.42g, yield 67.1%.

Example 44

The preparation method of the isoeugenol ferulate hybrid E6 comprises the following steps:

Step (1) same as in example 34

(2) Preparation of isoeugenol ferulate hybrid E6:

the 4-methylbenzyl-substituted ferulic acid (0.37 g,1.25 mmol) obtained in example 21 (3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12 g,1.37 mmol) were then added, stirring was carried out at room temperature for 1 hour, chloroacetyl eugenol (0.3 g,1.25 mmol) was then added and reacted at 40℃for about 4 hours, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound E6,0.44g, yield 70.6%. Eugenol group, isoeugenol group

The structural formula and molecular formula of the target compound prepared in the above example are shown in table 1, and physicochemical properties and spectrogram information of the target compound are shown in table 2.

Table 1 shows the structural formulae and molecular formulas of the target compounds obtained in the examples

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TABLE 2 physicochemical Properties and Spectrum data of the target Compounds prepared in examples

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Test example 1: examples test of anti-plant Virus Activity of the resulting Compounds

The experimental method comprises the following steps: a half leaf spot method;

virus: TMV, CMV, guizhou university fine chemical research and development center;

tobacco: core She Yan (TMV cumquat host), amaranth (CMV cumquat host);

control agent: ningnanmycin and ribavirin;

Phosphate buffer: phosphate Buffer (PBS) at pH 7.0, 0.2 mol/L; 0.01mol/L Phosphate Buffer (PBS) at pH 7.0; phosphate Buffer (PBS) at pH 7.5, 0.5mol/L

Reagent: ethylenediamine tetraacetic acid (EDTA): tianjin chemical reagent Co., ltd; tween 80: chengdu Jinshan chemical reagent Co., ltd., analytically pure; triton X-100: aclacin, biochemical reagent grade; mercaptoethanol: alatine, biotechnological grade

Purification of TMV

(a) Selecting common tobacco leaves which are infected with TMV for more than three weeks, cutting the tobacco leaves after removing veins, putting the tobacco leaves into a mortar, adding a proper amount of liquid nitrogen for grinding, and ensuring that tissues are ground so as to improve the virus extraction rate;

(b) Twice the volume of pre-chilled 0.2mol/L Phosphate Buffer (PBS) at pH 7.0 (containing 0.1% mercaptoethanol) was added, homogenized for several minutes, and 10% chloroform was added: n-butanol (V: v=1:1), filtered with double layer nylon gauze;

(c) Pouring the filtrate into a centrifuge tube (ice bath), and centrifuging at a temperature of at least 8000rmp for 20min;

(d) Taking supernatant; then, 6% (V/W) PEG-6000 and NaCl were added to the supernatant, stirred at 4℃for 4 hours, and centrifuged at 8000rmp for 20 minutes. After removal of the supernatant, the pellet was suspended in 0.01mol/L PBS from 1/5 of the crude extract, transferred to a clean Erlenmeyer flask, and stirred for 2h. Then transferring into a centrifuge tube, and centrifuging for 20min at the temperature of 4 ℃ at the temperature of 800rmp;

(e) Taking supernatant, weighing PEG-6000 and NaCl with the volume (V/W) of the supernatant being 6%, stirring for 4 hours under the ice bath condition, and centrifuging for 20 minutes at 8000 rmp. Suspending the precipitate with 0.01mol/L pH=7.0, and obtaining supernatant as purified virus stock;

(f) After dilution with the buffer, the absorbance at 260nm was measured, and the TMV concentration was calculated according to the following formula (extinction coefficient of TMV: 3.1)

Virus stock concentration (mg/mL) =a260×dilution/3.1

Purification of CMV

(a) Selecting common tobacco leaves which are infected with CMV for more than three weeks, cutting the tobacco leaves after removing leaf veins, putting the tobacco leaves into a mortar, adding a proper amount of liquid nitrogen for grinding, and ensuring that tissues are ground so as to improve the virus extraction rate;

(b) Twice the volume of pre-chilled 0.5mol/L Phosphate Buffer (PBS) pH 7.5 (0.01 mol/L EDTA,0.1% mercaptoethanol, 2% Triton-x-100) was added, homogenized for several minutes, and 10% chloroform was added: n-butanol (V: v=1:1), filtered with double layer nylon gauze;

(d) Taking supernatant, namely the crude virus liquid, adding (V/W) 6% PEG-6000 and NaCl, stirring for 4 hours at 4 ℃, and centrifuging at 8000rpm for 20 minutes;

(e) The precipitate was retained, suspended in 0.01mol/L PBS at pH=7.0, and centrifuged at 800rmp for 20min at 4deg.C;

(f) Removing the supernatant, suspending the precipitate, repeating the process twice, and combining the supernatant to obtain purified virus stock solution;

(g) After dilution with the buffer, the absorbance at 260nm was measured, and the CMV concentration (extinction coefficient of CMV: 5.0) was calculated according to the following formula.

Virus stock concentration (mg/mL) =a260×dilution/5.0

Formulation of compound concentrations

Accurately weighing 2mg of the compound in a centrifuge tube, adding 30 mu L of an organic solvent DMSO to fully dissolve the compound, adding 4mL of secondary water containing 1% Tween 80, and preparing a medicament with the concentration of 500 mu g/mL.

(1) Test method

The compounds were tested for antiviral activity against TMV/CMV by the following procedure:

(a) Therapeutic effects of the agent on TMV/CMV in vivo

Selecting core leaf cigarettes or amaranth with consistent growth vigor in 5-6 leaf periods, uniformly scattering silicon carbide on each leaf, dipping a gang pen with prepared virus juice, manually rubbing and inoculating the virus juice on Quan She leaves, inoculating the virus for 30min, and washing with clear water. After the leaves were dried, the brush pen dip (500. Mu.g/mL) was applied to the right half of the leaf, and the left half She Tushi of the same dose of solvent was used as a control. And (5) after airing, transferring the mixture to a greenhouse for moisture preservation and culture. After 2-3d, the leaf showed obvious dead spots, and the number of dead spots of left and right half leaves was recorded. Each compound was replicated 3 times.

(b) Protection of TMV/CMV living bodies by agents

The tobacco leaf with 5-6 leaf periods or amaranth with consistent growth vigor is selected, and a writing brush dip drug (500 mug/mL) is applied to the right half leaf and the left half She Tushi with the same dosage of solvent is used as a control. After being dried, the seeds are moved into a greenhouse, after 12 to 24 hours, silicon carbide is uniformly scattered on the leaves, a gang pen dips in virus juice prepared in advance, the virus juice is rubbed and inoculated on Quan She leaves, and after 30 minutes of inoculation, the virus juice is washed by clean water. After the leaves are dried, the leaves are transferred to a greenhouse for moisture preservation and culture. After 2-3d, the leaf showed obvious dead spots, and the number of dead spots of left and right half leaves was recorded. Each compound was replicated 3 times.

(c) In vivo inactivation of TMV/CMV by agents

Selecting tobacco leaf with consistent growth vigor and in 5-6 leaf period or amaranth, and mixing the medicine with the virus liquid in the same volume for 30 min. The mixed liquid is dipped by a volleyball pen and rubbed and inoculated on the core leaf tobacco or the right half leaf of the amaranth, the mixed liquid of the solvent with corresponding dosage and the virus juice is rubbed and inoculated on the left half leaf, and the virus is inoculated for 30min and then washed by clean water. After natural air drying, the mixture is transferred to a greenhouse for moisture preservation and culture. After 2-3d, the leaf showed obvious dead spots, and the number of dead spots of left and right half leaves was recorded. Each compound was replicated 3 times and the inhibition was calculated as follows:

Inhibition ratio (%) = [ (number of plaques in blank control-number of plaques in drug treatment)/number of plaques in blank control ] ×100

The target compound was subjected to 5 corresponding concentration gradients, and its EC against TMV and CMV was determined ₅₀ Values.

(2) Results of anti-plant Virus Activity test

The anti-plant virus activity and EC of the compounds obtained in the examples were determined as described above ₅₀ The values and results are shown in tables 3 to 4.

TABLE 3 anti-TMV and CMV Activity of the example Compounds (500 μg mL) ^–1 )

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As can be seen from Table 3, the eugenol ferulate and isoeugenol hybrids have excellent anti-plant virus activity, wherein the compounds A7, A9, A10, E1, E2, E4 and E6 are at a concentration of 500. Mu.g/mLThe compound A9, A10, D5, E1, E2, E4 and E6 have better therapeutic, protective and passivation activities on TMV, and are better than the control medicament Ningnanmycin and the lead compound ferulic acid. anti-TMV and CMV protective Activity EC ₅₀ The value measurement results show that the compounds A9, A10, E1 and E4 have better protection activity on TMV and CMV, and the EC thereof ₅₀ Values 180.5, 169.5, 211.4, 165.2 and 210.5, 239.1, 218.4, 178.6. Mu.g/mL, respectively, are superior to Ningnanmycin (EC) ₅₀ =246.5 and 286.6 μg/mL) and the lead compound ferulic acid (EC ₅₀ = 571.5 and 589.2 μg/mL).

TABLE 4 anti-TMV and CMV protective Activity of example Compounds EC ₅₀ Value of

In conclusion, the eugenol ferulate and isoeugenol hybrid have excellent antibacterial activity, and in particular, the compounds A9, a10, E1 and E4 show excellent anti-plant virus activity on TMV and CMV. Can be used for preparing anti-plant virus medicines.

The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the invention in any way, and any simple modification, equivalent variation and variation of the above embodiment according to the technical matter of the present invention still fall within the scope of the technical scheme of the present invention.

Claims

1. A hybrid of eugenol ferulate and isoeugenol has a structural general formula (I) as follows:

wherein:

R ₁ is hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, 2-chlorobenzyl, 3-methylbenzyl,4-chlorobenzyl group, R ₂ Is eugenol and isoeugenol, X is oxygen atom, Y is ethylene and acetyl.

2. A hybrid of eugenol ferulate and isoeugenol has a structural general formula (I) as follows:

wherein:

R ₁ is eugenol, isoeugenol, R ₂ Is methyl, ethynyl or 4-methylphenyl, X is oxygen atom, amine ethylene or oxyacetyl, Y is methylene.

3. A hybrid of eugenol ferulate and isoeugenol is disclosed, which is prepared from the following compounds:

compound A7: (E) -isopropyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate; compound A8: (E) -isopropyl-3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound C5: (E) -N- (2- (4-allyl-2-methoxyphenoxy) ethyl) -3- (4-ethoxy-3-methoxyphenyl) acrylate; compound C6: (E) -3- (4-ethoxy-3-methoxyphenyl) -N- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) ethyl) acrylate;

compound D6: (E) -n-butyl 3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) -2-oxoethoxy) phenyl) acrylate;

4. Use of a hybrid of eugenol ferulate according to any one of claims 1-3 for the preparation of a medicament for the control of tobacco mosaic virus, cucumber mosaic virus.