CN113801022A

CN113801022A - Ferulic acid eugenol and isoeugenol heterozygote and application thereof

Info

Publication number: CN113801022A
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: 2021-12-17
Anticipated expiration: 2041-07-23
Also published as: CN113801022B

Abstract

The invention discloses a ferulic acid eugenol and isoeugenol heterozygote and application thereof, wherein the structural general formula (Ӏ) is shown as follows, wherein: r1 is 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, isoeugenol; x is oxygen atom, oxyacetyl, amine ethylene, ethylene; y is hydrogen atom, methylene, ethylene or oxyacetyl. The invention has excellent treatment, protection and passivation activities on tobacco mosaic virus and cucumber mosaic virus, and has simple preparation process and low production cost.

Description

Ferulic acid eugenol and isoeugenol heterozygote and application thereof

Technical Field

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

Background

Plant viral diseases bring great influence on agricultural production along with the whole growth cycle of plants. Due to the absolute parasitism of plant viruses, once plants are infected with the plant viruses, the virus diseases are spread in a large area and are difficult to control, and the economic loss caused by the plant virus diseases is up to $ 200 billion each year. In recent years, plant virus diseases have a tendency to outbreak, and among them, the more harmful plant viruses mainly include Tobacco Mosaic Virus (TMV), Cucumber Mosaic Virus (CMV), and the like. At present, chemical agents are mainly used for preventing and treating plant virus diseases, and mainly comprise ningnanmycin and ribavirin, but the ningnanmycin is unstable and is difficult to apply in a large-area field, and the effect of preventing and treating the ribavirin is not ideal, so far, an effective plant virus disease prevention and treatment agent is still lacked. Therefore, the creation of novel, efficient and environment-friendly plant virus resistant medicaments is still the key for preventing and controlling plant virus diseases.

The natural product is always a focus of attention of pharmacologists and is an important source for creating new medicines due to the advantages of high efficiency, unique action mechanism, environmental friendliness and the like. Ferulic acid is widely contained in various traditional Chinese medicinal materials such as asafetida, angelica sinensis, ligusticum chuanxiong hort and the like, and has various biological activities such as bacteriostasis, inflammation diminishing, virus resisting and the like. In recent years, ferulic acid has been found to have various agricultural activities, particularly in terms of anti-plant viral activity.

The inventor's Wang Qingmin, Wang Kai Liang, Wangzzhen, Chinese patent publication No. CN102090412A discloses the application of ferulic acid and derivatives thereof in resisting plant virus diseases in 2011, 06 and 15, wherein the in vitro inhibitory activity of ferulic acid and caffeic acid on tobacco mosaic virus is more than 90% at the concentration of 500 mu g/mL, which is higher than that of virus A, ribavirin, DADHT and DHT.

The inventor discloses the application of ferulic acid phenylethanolamine derivatives in pesticides by Zhaowei, Zuo, Huangguangying, Wang Li Shi, Li Nengqiang and Li Ming, and Chinese patent publication No. CN102503851A in 2012 and 20.06.20. The half-leaf withered spot method is adopted to find that the ferulic acid phenylethanolamine derivative has weak treatment and protection activity on tobacco mosaic virus, which is slightly higher than 30%.

The inventor of Wang Qingmin, Wu Meng, Wangzzhen, Menglong pine, Wang Keliang, Huyanna, Wanli Bell, Chinese patent publication No. CN103626652A discloses the application of 3-aryl acrylic acid and derivatives thereof in the aspect of pesticides in 12 months 03 2014. It was found that the 3-arylacrylic acid derivatives exhibit a good inhibitory activity against tobacco mosaic virus.

The inventor's Wang Qingmin, Chinese patent publication No. CN104412972A, on 18/03/2015, discloses the use of trans-ferulic acid microemulsion in the control of tobacco mosaic virus, southern rice black-streaked dwarf virus and tomato virus. The field test result shows that the trans-ferulic acid microemulsion can well prevent and treat tobacco mosaic virus disease, southern rice black-streaked dwarf virus disease and tomato virus disease, and is safe to crops.

The inventor of Songbean, Wuzengxue, Hudeo Yu, Xue Wei, Shulu, Zeng Song, Chinese patent publication No. CN105777654A discloses the use of quinazoline-containing ferulic acid ester compounds in resisting plant viruses in 2016, 20.07. The ferulic acid ester compound containing quinazoline shows better treatment and protection activity on tobacco mosaic virus, and is equivalent to ningnanmycin.

The inventor Schuwei, Zhang Chen Li Juan, Guo, Xiyanjiao, Chenying, Tang Yifu, Wanglan, Li Zhang Yang and Heming, and the Chinese patent publication No. CN109369594A disclose the application of the myricetin derivative containing the ferulic acid amide in the aspect of pesticides in 2019, 02 and 22. The semi-leaf cumic spot method is adopted to find that the myricetin derivative containing the ferulic acid amide has certain treatment and protection activity on tobacco mosaic virus, and only the ningnanmycin is equivalent.

Eugenol and isoeugenol widely exist in various essential oil-containing Chinese medicinal materials such as flos Caryophylli and laurel, are mainly used in the fields of cosmetics, soaps, edibles and the like, and have biological activities such as antibiosis and disinsection. Eugenol has also been found to have anti-plant virus activity in recent years. Chenhao et al (Jiangxi agriculture bulletin, 2009, 21 (12): 112-. In addition, Suzhong et al (Proc. Nongo, 2012, 14 (1): 24-29) found that the protective and therapeutic effects of eugenol 400. mu.g/mL on tobacco mosaic virus were 65.82% and 62.14%, respectively, as a result of an indoor potting test.

In summary, the drug small molecules containing ferulic acid structures 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 treatment and protection aspects, and does not show better virus inactivation activity. And isoeugenol

Disclosure of Invention

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

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

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

wherein: r₁Is hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, 2-chlorobenzyl, 3-methylbenzyl, 4-chlorobenzyl, eugenol group, and isoeugenol group; r₂Is methyl, ethynyl, 4-methylphenyl, eugenol group, isoeugenol group; x is oxygen atom, oxyacetyl, amine ethylene, ethylene; y is hydrogen atom, methylene, ethylene or oxyacetyl.

Preferred compounds are as follows:

compound a 1: (E) -methyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

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

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

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

compound a 5: (E) -propyl-3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 6: (E) -propyl-3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 7: (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 a 9: (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylic acid;

compound a 10: (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylic acid;

compound a 11: benzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 12: benzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 13: 2-chlorobenzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 14: 2-chlorobenzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 15: 3-methylbenzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 16: 3-methylbenzyl (E) -3- (3-methoxy-4- (2- (2-methoxy-4- ((E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 17: 4-chlorobenzyl (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 18: 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-oxy) phenyl) acrylate;

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

compound C4: (E) -N- (2- (2-methoxy-4- ((E) -1-propenyl) phenoxy) ethyl) -3- (3-methoxy-4- (prop-2-yn-1-oxy) 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) -n-butyl 3- (4- (2- (4-allyl-2-methoxyphenoxy) -2-oxoethoxy) -3-methoxyphenyl) acrylate;

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 ferulic acid eugenol and isoeugenol hybrid A1-A18 comprises the following steps:

(1) preparing ferulic acid ester:

adding ferulic acid into a three-necked bottle, adding 10 times of alcohol, stirring for 10 minutes, dropwise adding 1 equivalent of 98% concentrated sulfuric acid, reacting at 80 ℃ for about 8 hours, recovering the solvent under reduced pressure, adding 10mL of water into the system, adjusting the pH to 8 with a saturated sodium bicarbonate solution, adding ethyl acetate, extracting for three times, drying with anhydrous sodium sulfate, and recovering the solvent under reduced pressure to obtain a ferulic acid ester intermediate;

(2) preparation of bromoethyl ferulate:

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

and (2) putting eugenol or isoeugenol into a three-necked bottle, adding 10 times of acetonitrile and 1.2 equivalents of anhydrous potassium carbonate, stirring for 1 hour at room temperature, adding 1 equivalent of bromoethyl ferulic acid ester intermediate, reacting for about 4 hours at the temperature of 80 ℃, filtering, concentrating the filtrate under reduced pressure, and recrystallizing the residue ethyl acetate to obtain the target compound A1-A8.

(4) Preparation of target compound a 9-a 10:

adding 10 times of ethanol into A1 or A2 in a three-necked flask, stirring at room temperature for 30 minutes, 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 value to about 3 with dilute hydrochloric acid, filtering, and drying to obtain the target compound A9-A10.

(5) Preparation of target compound a 11-a 18:

a9 or A10 is taken in a three-necked bottle, 20 times of acetonitrile and 1.1 equivalent of anhydrous potassium carbonate are added, the mixture is stirred for 30 minutes at room temperature, 1.1 equivalent of benzyl halide is added, the mixture reacts 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, and the mixture is filtered and dried to obtain the target compound A11-A18.

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

(1) preparing ferulic acid methyl ester:

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

(2) Preparation of oxygen-substituted ferulic acid methyl ester:

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

(3) Preparation of oxygen-substituted ferulic acid:

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

(4) Preparation of target compound B1-B8:

taking ferulic acid or oxygen to replace 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 a solid, recrystallizing with ethanol, carrying out suction filtration, and drying to obtain a target compound B1-B8.

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

(1) preparing bromoethoxy eugenol and isoeugenol:

and (2) putting eugenol and isoeugenol into a three-necked bottle, adding 10 times of n-butyl ketone, 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 the temperature of 80 ℃, recovering the solvent under reduced pressure, and purifying by column chromatography to obtain bromoethoxy eugenol and isoeugenol intermediates.

(2) Preparing o-phthalamide ethyl eugenol and isoeugenol:

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

(3) Preparation of aminoethyl eugenol and isoeugenol:

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

(4) Preparation of target compound C1-C6:

taking ferulic acid or oxygen substituted ferulic acid into 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 residues into ice water, separating out solids, recrystallizing with ethanol, carrying out suction filtration, and drying to obtain a target compound C1-C6.

The preparation method of the ferulic acid eugenol and isoeugenol heterozygote D1-D6 and E1-E6 comprises the following steps:

(1) preparation of chloracetyl eugenol and isoeugenol:

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

(2) Preparation of target Compounds D1-D6:

and (2) putting the ferulic acid ester intermediate into a three-necked bottle, adding 10 times of DMF (dimethyl formamide) and 1.1 equivalent of anhydrous potassium carbonate, stirring at room temperature for 1 hour, adding 1 equivalent of chloracetyl eugenol and isoeugenol, reacting at 40 ℃ for about 4 hours, filtering, concentrating the filtrate under reduced pressure, and recrystallizing the residue with ethyl acetate to obtain the target compound D1-D6.

(3) Preparation of target compound E1-E6:

and (2) placing the oxygen-substituted ferulic acid intermediate into a three-necked bottle, adding 10 times of DMF (dimethyl formamide) and 1.2 equivalents of anhydrous sodium bicarbonate, stirring at room temperature for 1 hour, adding 1 equivalent of chloracetyl eugenol and isoeugenol, reacting at 40 ℃ for about 4 hours, filtering, concentrating the filtrate under reduced pressure, and recrystallizing the residue with ethyl acetate to obtain the target compound E1-E6.

The invention relates to an application of a ferulic acid eugenol and isoeugenol heterozygote in preparing a medicament 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 show that: based on the principle of active substructure splicing, the invention prepares the ferulic acid eugenol and isoeugenol heterozygote with structural diversity through a plurality of linking modes, tests prove that the ferulic acid eugenol and isoeugenol heterozygote has better treatment, protection and passivation activities on tobacco mosaic virus and cucumber mosaic virus, is obviously superior to a contrast medicament ningnanmycin and a lead compound ferulic acid, and has simple preparation process, low production cost and wide application prospect.

Detailed Description

Example 1

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

(1) preparing ferulic acid methyl ester:

adding ferulic acid (10g,51.50mmol) into a three-necked bottle, adding 50mL of methanol, stirring for 10 minutes, dropwise adding 98% concentrated sulfuric acid (5.06g, 51.50mmol) to react at 80 ℃ for about 8 hours, recovering the solvent under reduced pressure, adding 10mL of water into the system, adjusting the pH to 8 with saturated sodium bicarbonate solution, adding ethyl acetate to extract for three times (100 mL each time), combining the extracts, drying with anhydrous sodium sulfate, recovering the solvent under reduced pressure to obtain a ferulic acid methyl ester intermediate 9.85g, and obtaining the yield of 91.7%.

(2) Preparation of methyl bromoethyl ferulate:

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

(3) Preparation of target compound a 1:

eugenol (1.5g,9.13mmol) was taken in a three-necked flask, then 20mL acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then methyl bromoethyl ferulate (2.88g,9.13mmol) was added 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 target compound A1, 2.86g, yield 78.5%.

Example 2

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

steps (1) to (2) were carried out in the same manner as in example 1

(3) Preparation of target compound a 2:

isobutyleugenol (1.5g,9.13mmol) was taken in a three-necked flask, then 20mL of acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then bromoethyl methyl ferulate (2.88g,9.13mmol) was added 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 target compound a2, 2.95g, yield 81.2%.

Example 3

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

(1) preparing ferulic acid ethyl ester:

adding ferulic acid (10g,51.50mmol) into a three-necked bottle, adding 50mL of ethanol, stirring for 10 minutes, dropwise adding 98% concentrated sulfuric acid (5.06g, 51.50mol) to react at 80 ℃ for about 8 hours, recovering the solvent under reduced pressure, adding water into the system, adjusting the pH to 8 with saturated sodium bicarbonate solution, adding ethyl acetate to extract for three times (100 mL each time), combining the extracts, drying with anhydrous sodium sulfate, recovering the solvent under reduced pressure to obtain 10.50g of ferulic acid ethyl ester intermediate, wherein the yield is 91.7%.

(2) Preparing bromoethyl ferulic acid ethyl ester:

ethyl ferulate (5.0g,22.50mmol) was taken in a three-necked flask, then 50mL of n-butanone and anhydrous potassium carbonate (3.73g,27.00mmol) were added, stirred at room temperature for 1 hour, then 1, 2-dibromoethane (6.34g,33.75mmol) was 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 5.82g of bromoethyl ferulate intermediate, with a yield of 75.6%.

(3) Preparation of target compound a 3:

eugenol (1.0g,6.09mmol) was taken in a three-necked flask, then 15mL acetonitrile and anhydrous potassium carbonate (1.01g,7.31mmol) were added, stirred at room temperature for 1 hour, then ethyl bromoethyl ferulate (2.0g,6.09mmol) was added 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 target compound A3, 1.91g, yield 76.1%.

Example 4

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

steps (1) to (2) were carried out in the same manner as in example 3

(3) Preparation of target compound a 4: isobutyleugenol (1.0g,6.09mmol) was put in a three-necked flask, then 15mL of acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then ethyl bromoethylferulate (2.0g,6.09mmol) was added 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) preparing n-propyl ferulate:

ferulic acid (10g,51.50mmol) is put into a three-necked bottle, 50mL of n-propanol is added, stirring is carried out for 10 minutes, 98% concentrated sulfuric acid (5.06g, 51.50mol) is added dropwise to react for about 8 hours at the temperature of 80 ℃, the solvent is recovered under reduced pressure, water is added into the system, the pH value is adjusted to 8 by saturated sodium bicarbonate solution, then ethyl acetate is added to extract for three times (100 mL each time), the extracts are combined, anhydrous sodium sulfate is used for drying, the solvent is recovered under reduced pressure, 9.8g of ferulic acid methyl ester intermediate is obtained, and the yield is 80.5%.

(2) Preparation of n-propyl bromoethyl ferulate:

taking ferulic acid n-propyl ester (5.0g,21.16mmol) in a three-necked bottle, adding 50mL of n-butanone and anhydrous potassium carbonate (3.51g,25.39mmol), stirring at room temperature for 1 hour, adding 1, 2-dibromoethane (5.96g,31.74mol) in one step, reacting at 80 ℃ for about 4 hours, filtering, concentrating the filtrate under reduced pressure, and separating the residue by column chromatography to obtain bromoethyl ferulic acid methyl ester intermediate 5.66g with yield of 84.8%.

(3) Preparation of target compound a 5:

eugenol (1.5g,9.13mmol) was taken in a three-necked flask, then 20mL of acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then n-propyl bromoethyl ferulate (3.14g,9.13mmol) was added 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 target compound A5, 3.25g, yield 89.4%.

Example 6

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

steps (1) to (2) were carried out in the same manner as in example 5

(3) Preparation of target compound a 6:

isoeugenol (1.5g,9.13mmol) was taken in a three-necked flask, then 20mL of acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then n-propyl bromoethyl ferulate (3.14g,9.13mmol) was added 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 target 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 (10g,51.50mmol) is put into a three-necked bottle, 50mL of isopropanol is added, stirring is carried out for 10 minutes, 98% concentrated sulfuric acid (5.06g, 51.50mol) is added dropwise to react at the temperature of 80 ℃ for about 8 hours, the solvent is recovered under reduced pressure, water is added into the system, the pH value is adjusted to 8 by saturated sodium bicarbonate solution, then ethyl acetate is added to extract for three times (100 mL each time), the extracts are combined, anhydrous sodium sulfate is used for drying, the solvent is recovered under reduced pressure, 9.8g of ferulic acid methyl ester intermediate is obtained, and the yield is 80.5%.

(2) Preparation of isopropyl bromoethyl ferulate:

taking isopropyl ferulate (5.0g,21.16mmol) and putting in a three-necked bottle, then adding 50mL of n-butanone and anhydrous potassium carbonate (3.51g,25.39mmol), stirring at room temperature for 1 hour, then adding 1, 2-dibromoethane (5.96g,31.74mol) in one step, reacting at 80 ℃ for about 4 hours, filtering, concentrating the filtrate under reduced pressure, and separating the residue by column chromatography to obtain 5.66g of methyl bromoethyl ferulate intermediate with yield of 84.8%.

(3) Preparation of target compound a 7:

eugenol (1.5g,9.13mmol) was taken in a three-necked flask, then 20mL acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then bromoethyl isopropyl ferulate (3.14g,9.13mmol) was added 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 target compound A5, 3.04g, 83.5% yield.

Example 8

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

steps (1) to (2) were carried out in the same manner as in example 7

(3) Preparation of target compound A8:

iso-eugenol (1.5g,9.13mmol) was taken in a three-necked flask, then 20mL acetonitrile and anhydrous potassium carbonate (1.51g,10.96mmol) were added, stirred at room temperature for 1 hour, then bromoethyl isopropyl ferulate (3.14g,9.13mmol) was added 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 target compound A8, 3.1g, yield 85.2%.

Example 9

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

compound a1(2.0g, 5.02mmol) obtained in example 1 was put in a three-necked flask, 20mL of ethanol was added, and stirred at room temperature for 30 minutes, after which a 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 the pH was adjusted to about 3 with dilute hydrochloric acid, filtered, and dried to obtain the objective compound a9, 1.31g, and the yield was 68.8%.

Example 10

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

compound a2(2.0g, 5.02mmol) obtained in example 2 was put in a three-necked flask, 20mL of ethanol was added, and stirred at room temperature for 30 minutes, after which a 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 the pH was adjusted to about 3 with dilute hydrochloric acid, filtered, and dried to obtain the objective compound a10, 1.25g, and the yield was 65.2%.

Example 11

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

compound a9(0.2g, 0.52mmol) from example 9 was taken in a three-necked flask and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added and stirred at room temperature for 30 minutes, after which benzyl chloride (0.072g, 0.57mmol) 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 give the title compound a11, 0.20g, 80.5%.

Example 12

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

compound a10(0.2g, 0.52mmol) from example 10 was taken in a three-necked flask and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added and stirred at room temperature for 30 minutes, after which benzyl chloride (0.072g, 0.57mmol) 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 give the title compound a12, 0.20g, 79.5%.

Example 13

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

compound a9(0.2g, 0.52mmol) obtained in example 9 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added, stirred at room temperature for 30 minutes, after which 2-chlorobenzyl chloride (0.092g, 0.57mmol) 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 heterozygote A14 comprises the following steps:

compound a10(0.2g, 0.52mmol) obtained in example 10 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added, stirred at room temperature for 30 minutes, after which 2-chlorobenzyl chloride (0.092g, 0.57mmol) 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 heterozygote A15 comprises the following steps:

compound a9(0.2g, 0.52mmol) obtained in example 9 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added, and stirred at room temperature for 30 minutes, after which 3-methylbenzyl chloride (0.080g, 0.57mmol) was added and reacted at 80 ℃ for about 4 hours, and 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 a15, 0.20g, 81.6%.

Example 16

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

compound a10(0.2g, 0.52mmol) obtained in example 10 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added, and stirred at room temperature for 30 minutes, after which 3-methylbenzyl chloride (0.080g, 0.57mmol) was added and reacted at 80 ℃ for about 4 hours, and 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 a16, 0.20g, 90.5%.

Example 17

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

compound a9(0.2g, 0.52mmol) obtained in example 9 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added, stirred at room temperature for 30 minutes, after which 2-chlorobenzyl chloride (0.092g, 0.57mmol) 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 heterozygote A18 comprises the following steps:

compound a10(0.2g, 0.52mmol) obtained in example 10 was taken in a three-necked flask, and 4mL of acetonitrile and anhydrous potassium carbonate (0.086g, 0.62mmol) were added, stirred at room temperature for 30 minutes, after which 2-chlorobenzyl chloride (0.092g, 0.57mmol) 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 (0.5g, 2.57mmol) was taken in a three-necked flask, 5mL of dichloromethane was added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.41g, 2.57mmol) was added and the reaction was carried out in an ice bath for 10 minutes, eugenol (0.42g, 2.57mmol) was added at room temperature and the reaction was 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 B1, 0.39g, yield 45.2%.

Example 20

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

ferulic acid (0.5g, 2.57mmol) was taken in a three-necked flask, 5mL of dichloromethane was added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.41g, 2.57mmol) was added and the reaction was carried out in an ice bath for 10 minutes, then isoeugenol (0.42g, 2.57mmol) was added at room temperature and the reaction was 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 and drying were carried out to obtain the target 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 example 1

(2) Preparation of ethyl substituted ferulic acid methyl ester

And (2) putting the ferulic acid methyl ester (2.0g, 9.61mmol) obtained in the step (1) into a three-necked bottle, adding 20mL of n-butanone, stirring for 10 minutes, adding anhydrous potassium carbonate (1.56g, 11.53mmol), stirring for 30 minutes, adding bromoethane (1.15g, 10.57mmol) dropwise, reacting at the temperature of 80 ℃ for about 6 hours, recovering the solvent under reduced pressure, adding water into the system, recrystallizing the solid with ethyl acetate to obtain 2.1g of ethyl-substituted ferulic acid methyl ester, wherein the yield is 88.1%.

(3) Preparation of ethyl substituted ferulic acid:

taking ethyl substituted ferulic acid methyl ester (2.0g, 8.46mmol) to a three-necked bottle, adding 20mL ethanol, stirring for 1 hour, dropwise adding 2M sodium hydroxide solution (0.34g, 8.46mmol) again, reacting at 80 ℃ for about 4 hours, recovering the solvent under reduced pressure, adding a small amount of water into the system, adjusting the pH value to 3 by using 5% dilute hydrochloric acid, precipitating a large amount of solid, performing suction filtration, and drying to obtain 1.6g of ethyl substituted ferulic acid, wherein the yield is 85.0%.

(4) Preparation of target compound B3:

ethyl-substituted ferulic acid (0.5g, 2.25mmol) was taken in a three-necked flask, 5mL of dichloromethane was added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.36g, 2.25mmol) was added and the reaction was carried out in an ice bath for 10 minutes, eugenol (0.37g, 2.25mmol) was added at room temperature and the reaction was 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 and drying were carried out to obtain the target compound B3, 0.56g, yield 67.8%.

Example 22

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

steps (1) to (3) were carried out in the same manner as in example 21

(4) Preparation of target compound B4:

ethyl substituted ferulic acid (0.5g, 2.25mmol) was taken in a three-necked flask, 5mL dichloromethane was added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.36g, 2.25mmol) was added and the reaction was carried out in an ice bath for 10 minutes, then isoeugenol (0.37g, 2.25mmol) was added at room temperature and the reaction was continued for 1 hour, the solvent was recovered under reduced pressure, the residue was poured into ice water, solids were precipitated, ethanol was recrystallized, suction filtration and drying were carried out to obtain the target 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 example 1

(2) Preparation of n-propyl substituted ferulic acid methyl ester

And (2) putting the ferulic acid methyl ester (2.0g, 9.61mmol) obtained in the step (1) into a three-necked bottle, adding 20mL of n-butanone, stirring for 10 minutes, adding anhydrous potassium carbonate (1.56g, 11.53mmol), stirring for 30 minutes, adding bromopropane (1.30g, 10.52mmol) dropwise, reacting at the temperature of 80 ℃ for about 6 hours, recovering the solvent under reduced pressure, adding water into the system, recrystallizing the solid with ethyl acetate to obtain n-propyl substituted ferulic acid methyl ester (1.8 g), wherein the yield is 74.8%.

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

taking n-propyl substituted ferulic acid methyl ester (1.7g, 7.20mmol) to a three-necked bottle, adding 20mL ethanol, stirring for 1 hour, dropwise adding 2M sodium hydroxide solution (0.29g, 7.20mmol) again, reacting at 80 ℃ for about 4 hours, recovering the solvent under reduced pressure, adding a small amount of water into the system, adjusting the pH value to 3 by using 5% dilute hydrochloric acid, precipitating a large amount of solid, performing suction filtration, and drying to obtain 1.4g ethyl substituted ferulic acid, wherein the yield is 87.5%.

(4) Preparation of target compound B5:

taking N-propyl substituted ferulic acid (0.6g, 2.54mmol) and putting the N-propyl substituted ferulic acid into a three-necked bottle, adding 6mL of dichloromethane, stirring for 10 minutes, adding N, N' -carbonyldiimidazole (0.4g, 2.54mmol) and reacting for 10 minutes in an ice bath, then adding eugenol (0.42g, 2.54mmol) at room temperature and continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, precipitating solid, recrystallizing with ethanol, filtering and drying to obtain the target compound B5, 0.50g and the yield of 78.2%.

Example 24

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

steps (1) to (3) were carried out in the same manner as in example 23

(4) Preparation of target compound B6:

taking N-propyl substituted ferulic acid (0.6g, 2.54mmol) and putting the N-propyl substituted ferulic acid into a three-necked bottle, adding 6mL of dichloromethane, stirring for 10 minutes, adding N, N' -carbonyldiimidazole (0.4g, 2.54mmol) and reacting for 10 minutes in an ice bath, then adding isoeugenol (0.42g, 2.54mmol) at room temperature and continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, precipitating solid, recrystallizing ethanol, filtering and drying to obtain the target compound B6, 0.41g and the yield of 41.8%.

Example 25

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

step (1), same as example 1

(2) Preparation of 4-methylbenzyl substituted ferulic acid methyl ester

And (2) putting the ferulic acid methyl ester (2.0g, 9.61mmol) obtained in the step (1) into a three-necked bottle, adding 20mL of n-butanone, stirring for 10 minutes, adding anhydrous potassium carbonate (1.56g, 11.53mmol), stirring for 30 minutes, dropwise adding 4-methylbenzyl chloride (1.49g, 10.52mmol), reacting at the temperature of 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 2.2g of 4-methylbenzyl substituted ferulic acid methyl ester, wherein the yield is 73.3%.

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

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

(4) Preparation of target compound B7:

taking 4-methylbenzyl substituted ferulic acid (0.6g, 2.01mmol) in a three-necked bottle, adding 6mL of dichloromethane, stirring for 10 minutes, adding N, N' -carbonyldiimidazole (0.32g, 2.01mmol) and reacting for 10 minutes in an ice bath, then adding eugenol (0.33g, 2.01mmol) at room temperature and continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, precipitating a solid, recrystallizing ethanol, filtering, and drying to obtain the target compound B7, 0.37g and the yield of 41.5%.

Example 26

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

steps (1) to (3) were carried out in the same manner as in example 23

(4) Preparation of target compound B8:

taking 4-methylbenzyl substituted ferulic acid (0.6g, 2.01mmol) in a three-necked bottle, adding 6mL of dichloromethane, stirring for 10 minutes, adding N, N' -carbonyldiimidazole (0.32g, 2.01mmol), reacting for 10 minutes in an ice bath, adding isoeugenol (0.33g, 2.01mmol) at room temperature, continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, precipitating a solid, recrystallizing with ethanol, filtering, and drying to obtain the target compound B8, 0.33g and the yield of 36.8%.

Example 27

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

(1) preparation of bromoethoxy eugenol:

eugenol (5.0g, 30.45mmol) is taken out of a three-necked flask, 50mL of n-butyl ketone is added, stirring is carried out for 10 minutes, anhydrous potassium carbonate (5.1g, 36.54mmol) is added, stirring is carried out for 1 hour at room temperature, then 1, 2-dibromoethane (8.58g, 45.67mmol) is added, reaction is carried out for about 6 hours at the temperature of 80 ℃, the solvent is recovered under reduced pressure, and column chromatography purification is carried out to obtain 5.41g of bromoethoxy eugenol, wherein the yield is 65.8%.

(2) Preparation of phthalic acid amide ethyl eugenol:

phthalic acid amide (2.17g, 14.75mmol) is taken in a three-necked flask, then 10mL of DMF and anhydrous potassium carbonate (2.45g, 17.70mmol) are added, the mixture is stirred for 1 hour at room temperature, then bromoethoxy eugenol (4.0g, 14.75mmol) is added, the reaction is carried out for about 2 hours at the temperature of 80 ℃, the filtration is carried out, the filtrate is concentrated under reduced pressure, and the residue is separated by column chromatography to obtain phthalic acid amide ethyl eugenol intermediate 4.21g with the yield of 85.2%.

(3) Preparation of aminoethyl eugenol:

putting the intermediate of phthalic amide ethyl eugenol (3.5g, 10.37mmol) into a three-necked bottle, adding 35mL of methanol, dissolving, adding hydrazine hydrate (0.57g, 11.41mmol), stirring at room temperature for 2 hours, filtering, concentrating the filtrate under reduced pressure, and separating the residue by column chromatography to obtain 1.32g of the intermediate of aminoethyl eugenol with the yield of 61.1%.

(4) Preparation of target compound C1:

4-methylbenzyl-substituted ferulic acid (0.43g, 1.45mmol) obtained in example 25(3) was taken in a three-necked flask, 5mL of dichloromethane was added thereto, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.23g, 1.45mmol) was added thereto and reacted in an ice bath for 10 minutes, aminoethyl eugenol (0.3g, 1.45mmol) 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-filtered, and dried to obtain the objective compound C1, 0.33g, yield 47.6%.

Example 28

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

(1) preparation of bromoethoxy isoeugenol:

isoeugenol (5.0g, 30.45mmol) was taken out and put in a three-necked flask, 50mL of n-butyl ketone was added thereto, and stirred for 10 minutes, and anhydrous potassium carbonate (5.1g, 36.54mmol) was added thereto, and stirred at room temperature for 1 hour, after which 1, 2-dibromoethane (8.58g, 45.67mmol) was added thereto, and reacted at 80 ℃ for about 6 hours, and the solvent was recovered under reduced pressure, and purified by column chromatography to obtain 6.41g of bromoethoxy eugenol, with a yield of 78.5%.

(2) Preparation of phthalic acid amide ethyl isoeugenol:

phthalic amide (2.17g, 14.75mmol) was taken in a three-necked flask, 10mL of DMF and anhydrous potassium carbonate (2.45g, 17.70mmol) were then added, the mixture was stirred at room temperature for 1 hour, bromoethoxyisoeugenol (4.0g, 14.75mmol) was then added, the mixture was reacted at 80 ℃ for about 2 hours, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give phthalic amide ethyl isoeugenol intermediate 4.52g, with a yield of 89.9%.

(3) Preparation of aminoethyl isoeugenol:

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

(4) Preparation of target compound C2:

4-methylbenzyl-substituted ferulic acid (0.43g, 1.45mmol) obtained in example 25(3) was placed in a three-necked flask, 5mL of dichloromethane was added thereto, the mixture was stirred for 10 minutes, N' -carbonyldiimidazole (0.23g, 1.45mmol) was added thereto and the mixture was reacted in an ice bath for 10 minutes, aminoethyl-isoeugenol (0.3g, 1.45mmol) was added thereto at room temperature and the reaction was 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-filtered, and dried to obtain the objective compound C2, 0.47g, and the yield was 72.4%.

Example 29

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

steps (1) to (3) were carried out in the same manner as in example 27

(4) Preparation of eugenol ferulate hybrid C3

Taking the N-propyl substituted ferulic acid (0.34g, 1.45mmol) obtained in example 23(3) into a three-necked flask, adding 5mL of dichloromethane, stirring for 10 minutes, adding N, N' -carbonyldiimidazole (0.23g, 1.45mmol) and reacting in ice bath for 10 minutes, then adding aminoethyl eugenol (0.3g, 1.45mmol) at room temperature and continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, precipitating a solid, recrystallizing with ethanol, performing suction filtration and drying to obtain the target compound C3, 0.45g, and the yield is 65.3%.

Example 30

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

steps (1) to (3) were carried out in the same manner as in example 28

(4) Preparation of Isoeugenol ferulate heterozygote C4

Taking the N-propyl substituted ferulic acid (0.34g, 1.45mmol) obtained in example 23(3) into a three-necked flask, adding 5mL of dichloromethane, stirring for 10 minutes, adding N, N' -carbonyldiimidazole (0.23g, 1.45mmol) and reacting in ice bath for 10 minutes, then adding aminoethyl isobutyrophenol (0.3g, 1.45mmol) at room temperature and continuing for 1 hour, recovering the solvent under reduced pressure, pouring the residue into ice water, precipitating a solid, recrystallizing with ethanol, performing suction filtration, and drying to obtain the target compound C4, 0.26g, and obtaining the yield of 42.8%.

Example 31

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

steps (1) to (3) were carried out in the same manner as in example 27

(4) Preparation of eugenol ferulate hybrid C5

Ethyl-substituted ferulic acid (0.32g, 1.45mmol) obtained in example 21(3) was taken in a three-necked flask, 5mL of dichloromethane was added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.23g, 1.45mmol) was added and the reaction was carried out in an ice bath for 10 minutes, aminoethyl eugenol (0.3g, 1.45mmol) was added at room temperature and the reaction was 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 filtered and dried to obtain the objective compound C5, 0.35g, yield 58.2%.

Example 32

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

steps (1) to (3) were carried out in the same manner as in example 28

(4) Preparation of Isoeugenol ferulate heterozygote C6

Ethyl-substituted ferulic acid (0.32g, 1.45mmol) obtained in example 21(3) was taken in a three-necked flask, 5mL of dichloromethane was added, stirring was carried out for 10 minutes, N' -carbonyldiimidazole (0.23g, 1.45mmol) was added and the reaction was carried out in an ice bath for 10 minutes, aminoethyl isobutyrophenol (0.3g, 1.45mmol) was added at room temperature and the reaction was 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 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 (5.0g, 30.45mmol) is taken out of a three-necked bottle, 50mL of dichloromethane is added, triethylamine (3.08g, 30.45mmol) is added dropwise, after stirring for 10 minutes, chloroacetyl chloride (3.44g, 30.45mmol) is added dropwise, reaction is carried out for about 2 hours at room temperature, the solvent is recovered under reduced pressure, and ethyl acetate is recrystallized to obtain 5.97g of chloroacetyl eugenol intermediate with the yield of 81.5%.

(2) Preparation of eugenol ferulate hybrid D1:

methyl ferulate (0.26g, 1.25mmol) obtained in example 1(1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 heterozygote D2 comprises the following steps:

(1) preparation of chloroacetyl isoeugenol:

the method comprises the steps of putting isoeugenol (5.0g, 30.45mmol) into a three-necked bottle, adding 50mL of dichloromethane, adding triethylamine (3.08g, 30.45mmol) dropwise, stirring for 10 minutes, adding chloroacetyl chloride (3.44g, 30.45mmol) dropwise, reacting for about 2 hours at room temperature, recovering the solvent under reduced pressure, and recrystallizing ethyl acetate to obtain 6.25g of chloroacetyl isoeugenol intermediate with the yield of 85.2%.

(2) Preparation of isoeugenol ferulate hybrid D2:

methyl ferulate (0.26g, 1.25mmol) obtained in example 1(1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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, 65.4% yield.

Example 35

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

step (1), same as in example 33

(2) Preparation of eugenol ferulate hybrid D3:

n-propyl ferulate (0.29g, 1.25mmol) obtained in example 5(1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 D3, 0.26g, yield 48.1%.

Example 36

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

step (1), same as example 34

(2) Preparation of isoeugenol ferulate hybrid D4:

n-propyl ferulate (0.29g, 1.25mmol) obtained in example 5(1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 D4, 0.31g, yield 56.8%.

Example 37

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

step (1), same as in example 33

(2) Preparing ferulic acid butyl ester:

adding ferulic acid (5g, 25.75mmol) into a three-necked bottle, adding 25mL of n-butanol, stirring for 10 minutes, adding 98% concentrated sulfuric acid (2.53g, 25.75mmol) dropwise, reacting at 80 ℃ for about 8 hours, recovering the solvent under reduced pressure, adding water into the system, adjusting the pH to 8 with saturated sodium bicarbonate solution, adding ethyl acetate, extracting for three times (50 mL each time), combining the extracts, drying with anhydrous sodium sulfate, recovering the solvent under reduced pressure to obtain a ferulic acid methyl ester intermediate (4.8 g), wherein the yield is 74.5%.

(3) Preparation of eugenol ferulate hybrid D5:

n-butyl ferulate (0.31g, 1.25mmol) obtained in example 5(1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 heterozygote D6 comprises the following steps:

step (1), same as example 34

Step (2), same as example 37

(3) Preparation of target compound D6:

n-propyl ferulate (0.31g, 1.25mmol) obtained in example 5(1) was taken in a three-necked flask, 3mL of DMF and anhydrous potassium carbonate (0.19g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 D6, 0.36g, yield 63.8%.

Example 39

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

step (1), same as in example 33

(2) Preparation of eugenol ferulate hybrid E1:

ethyl-substituted ferulic acid (0.28g, 1.25mmol) obtained in example 21(3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, chloroacetyl eugenol (0.3g, 1.25mmol) was then added, the reaction was carried out 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 E1, 0.25g, 47.2% yield.

Example 40

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

step (1), same as example 34

(2) Preparation of isoeugenol ferulate hybrid E2:

ethyl-substituted ferulic acid (0.28g, 1.25mmol) obtained in example 21(3) was taken in a three-necked flask, 3mL of DMF and anhydrous sodium bicarbonate (0.12g, 1.37mmol) were then added, stirring was carried out at room temperature for 1 hour, chloroacetyl eugenol (0.3g, 1.25mmol) was then added, the reaction was carried out 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, yield 57.2%.

EXAMPLE 41

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

step (1), same as in example 33

(2) Preparation of eugenol ferulate hybrid E3:

n-propyl substituted ferulic acid (0.29g, 1.25mmol) obtained in example 21(3) was taken in a three-necked flask, then 3mL of DMF and anhydrous sodium bicarbonate (0.12g, 1.37mmol) were added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 E3, 0.31g, with a yield of 56.8%.

Example 42

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

step (1), same as example 34

(2) Preparation of isoeugenol ferulate hybrid E4:

n-propyl substituted ferulic acid (0.29g, 1.25mmol) obtained in example 21(3) was taken in a three-necked flask, then 3mL of DMF and anhydrous sodium bicarbonate (0.12g, 1.37mmol) were added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 E4, 0.40g, yield 72.5%.

Example 43

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

step (1), same as in example 33

(2) Preparation of eugenol ferulate hybrid E5:

4-methylbenzyl-substituted ferulic acid (0.37g, 1.25mmol) obtained in example 21(3) was taken in a three-necked flask, then 3mL of DMF and anhydrous sodium bicarbonate (0.12g, 1.37mmol) were added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 E5, 0.42g, 67.1% yield.

Example 44

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

step (1), same as example 34

(2) Preparation of isoeugenol ferulate hybrid E6:

4-methylbenzyl-substituted ferulic acid (0.37g, 1.25mmol) obtained in example 21(3) was taken in a three-necked flask, then 3mL of DMF and anhydrous sodium bicarbonate (0.12g, 1.37mmol) were added, stirring was carried out at room temperature for 1 hour, then chloroacetyl eugenol (0.3g, 1.25mmol) was added and the reaction was carried out 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 E6, 0.44g, in 70.6% yield. Eugenol group, isoeugenol group

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

TABLE 1 structural formula and molecular formula of the target compound prepared in example

TABLE 2 physicochemical Properties and spectral data of the target Compounds obtained in the examples

Test example 1: EXAMPLES testing of the anti-plant Virus Activity of the prepared Compounds

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

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

tobacco: leaf tobacco (TMV cumulus host), amaranth (CMV cumulus host);

control agents: ningnanmycin, ribavirin;

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

Reagent: ethylenediaminetetraacetic acid (EDTA): tianjin Kemi European Chemicals Co., Ltd; tween 80: chengdu Jinshan chemical reagent, Inc., analytically pure; triton X-100: alatin, biochemical reagent grade; mercaptoethanol: aladdin, biotechnological grade

Purification of TMV

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

(b) two volumes of pre-cooled 0.2mol/L Phosphate Buffer (PBS) pH 7.0 (containing 0.1% mercaptoethanol) were added, homogenized for several minutes, and 10% chloroform: n-butanol (V: V1: 1), filtering with double-layer nylon gauze;

(c) pouring the filtrate into a centrifuge tube (ice bath), and centrifuging at 8000rmp and 4 ℃ for 20 min;

(d) taking a supernatant; 6% (V/W) PEG-6000 and NaCl were then added to the supernatant, stirred at 4 ℃ for 4h, and centrifuged at 8000rmp for 20 min. After removing the supernatant, the precipitate was suspended with 1/5 crude extract in 0.01mol/LPBS, transferred to a clean Erlenmeyer flask and stirred for 2 h. Then, transferring the mixture into a centrifugal tube, and centrifuging the mixture for 20min at 8000rmp and 4 ℃;

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

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

Concentration of virus mother liquor (mg/mL) ═ A260 Xdilution factor/3.1

Purification of CMV

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

(b) two volumes of pre-chilled 0.5mol/L Phosphate Buffered Saline (PBS) pH 7.5 (containing 0.01mol/L EDTA, 0.1% mercaptoethanol, 2% Trition-x-100) was added, homogenized for several minutes, and 10% chloroform was added: n-butanol (V: V1: 1), filtering with double-layer nylon gauze;

(d) taking supernatant, wherein the obtained supernatant is crude virus solution, adding (V/W) 6% PEG-6000 and NaCl, stirring at 4 deg.C for 4h, and centrifuging at 8000rpm for 20 min;

(e) the precipitate was retained, suspended in 0.01mol/L PBS at pH 7.0, and centrifuged at 8000rmp at 4 ℃ for 20 min;

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

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

Concentration of virus mother liquor (mg/mL) ═ A260 Xdilution factor/5.0

Preparation of the Compound concentration

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

(1) Test method

The compounds were tested for their antiviral activity against TMV/CMV by the following specific procedures:

(a) therapeutic effect of pharmaceutical agent on TMV/CMV living body

Selecting leaf tobacco or amaranth gooseberry with consistent growth vigor of 5-6 leaves, uniformly spreading carborundum on each leaf, dipping a row of pens with prepared virus juice, manually rubbing and inoculating on the whole leaf, inoculating the virus for 30min, and washing with clear water. After the leaves are dry, a brush pen dipping agent (500. mu.g/mL) is applied to the right half leaf and the same amount of solvent is applied to the left half leaf as a control. After air-drying, transferring to a small greenhouse for moisture preservation and culture. After 2-3d, the leaves appeared markedly withered, and the number of the withered spots was recorded for the left and right halves. Each compound was repeated 3 times.

(b) Protective effect of medicament on TMV/CMV living body

Selecting leaf tobacco or amaranth gooseberry with consistent growth vigor at 5-6 leaf stage, applying a brush pen dipping medicament (500 mug/mL) to the right half leaf, and applying the same dosage of solvent to the left half leaf as a control. Air drying, transferring to a small greenhouse, spreading emery uniformly on the leaves after 12-24 hr, dipping the virus juice prepared in advance in a row pen, rubbing and inoculating on the whole leaf leaves, inoculating for 30min, and washing with clear water. After the leaves are dry, the leaves are transferred to a small greenhouse for moisture preservation and culture. After 2-3d, the leaves appeared markedly withered, and the number of the withered spots was recorded for the left and right halves. Each compound was repeated 3 times.

(c) Inactivation of TMV/CMV living body by medicament

Selecting the leaf tobacco or amaranth gooseberry with consistent growth vigor at the 5-6 leaf stage, and mixing the medicament with virus liquid with the same volume for 30 minutes. Dipping the mixed solution with a pen, rubbing and inoculating to the right half leaf of the core leaf tobacco or amaranth quinoa, rubbing and inoculating the mixed solution of the solvent and the virus juice with the corresponding dosage to the left half leaf, and washing with clear water after 30min of virus inoculation. Naturally air-drying, and transferring to a small greenhouse for moisture preservation and culture. After 2-3d, the leaves appeared markedly withered, and the number of the withered spots was recorded for the left and right halves. Each compound was replicated 3 times and the inhibition was calculated as follows:

inhibition (%) [ (blank control number of scorched spots-number of scorched spots treated with drug)/blank control number of scorched spots ] × 100

The EC for TMV and CMV was determined by setting 5 corresponding concentration gradients for the target compound₅₀The value is obtained.

(2) Test results for anti-plant Virus Activity

The anti-plant Virus Activity and EC of the Compounds obtained in the examples were determined as described above₅₀The values and results are shown in tables 3 to 4.

TABLE 3 anti-TMV and CMV Activity of the Compounds of the examples (500. mu.g mL)^–1)

As can be seen from table 3, the hybrid of eugenol ferulate and isoeugenol ferulate has excellent anti-plant virus activity, wherein compounds a7, a9, a10, E1, E2, E4 and E6 show better therapeutic, protective and inactivating activity to TMV at a concentration of 500 μ g/mL, and compounds a9, a10, D5, E1, E2, E4 and E6 show better therapeutic, protective and inactivating activity to CMV, and are all superior to the control medicament ningnanmycin and the lead compound ferulic acid. Protective Activity against TMV and CMV EC₅₀The value measurement result shows that the compounds A9, A10, E1 and E4 show better protective activity on TMV and CMV and the EC thereof₅₀The values are respectively 180.5, 169.5, 211.4, 165.2 and 210.5, 239.1, 218.4 and 178.6 mu g/mL, which are all superior to ningnanmycin (EC)₅₀246.5 and 286.6 μ g/mL) and the lead compound ferulic acid (EC)₅₀571.5 and 589.2 μ g/mL).

TABLE 4 protective Activity EC of the Compounds of the examples against TMV and CMV₅₀Value of

In conclusion, the hybrid of the ferulic acid eugenol and the isoeugenol has excellent bacteriostatic activity, and particularly, 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 drugs.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.

Claims

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

wherein:

R₁is hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, 2-chlorobenzyl, 3-methylbenzyl, 4-chlorobenzyl, eugenol group, and isoeugenol group;

R₂is methyl, ethynyl, 4-methylphenyl, eugenol group, isoeugenol group; x is oxygen atom, oxyacetyl, amine ethylene, ethylene; y is hydrogen atom, methylene, ethylene or oxyacetyl.

2. The ferulic acid eugenol and isoeugenol hybrid of claim 1, which comprises the following compounds:

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

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

compound a 6: (E) -propyl-3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-enePropyl) phenoxy) ethoxy) phenyl) acrylate;

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

compound a 10: (E) -3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-allyl) phenoxy) ethoxy) phenyl) acrylic acid;

compound a 11: benzyl (A)E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 12: benzyl (A)E) -3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 13: 2-chlorobenzyl(s) ((s))E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 14: 2-chlorobenzyl(s) ((s))E) -3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 15: 3-methylbenzyl(s) ((s))E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 16: 3-methylbenzyl(s) ((s))E) -3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound a 17: 4-chlorobenzyl group (E) -3- (4- (2- (4-allyl-2-methoxyphenoxy) ethoxy) -3-methoxyphenyl) acrylate;

compound a 18: 4-chlorobenzyl group (E) -3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-allyl) phenoxy) ethoxy) phenyl) acrylate;

compound B1: 4-allyl-2-Methoxyphenyl group (a)E) -3- (4-hydroxy-3-methoxyphenyl) 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-oxy) phenyl) acrylate;

compound C4: (E)-N- (2- (2-methoxy-4- ()E) -1-propenyl) phenoxy) ethyl) -3- (3-methoxy-4- (prop-2-yn-1-oxy) 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 D2: (E) -3- (3-methoxy-4- (2- (2-methoxy-4- (()E) -1-propenyl) phenoxy) -2-oxoethoxy) phenyl) acrylic acid methyl ester;

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

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

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

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

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

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

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

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

3. An application of the heterozygote of eugenol ferulate and isoeugenol in preparing the medicines for preventing and treating tobacco mosaic virus and cucumber mosaic virus is disclosed.