CN113461639B - Piperazine-containing ferulic acid derivative, and preparation method and application thereof - Google Patents
Piperazine-containing ferulic acid derivative, and preparation method and application thereof Download PDFInfo
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- CN113461639B CN113461639B CN202110775583.5A CN202110775583A CN113461639B CN 113461639 B CN113461639 B CN 113461639B CN 202110775583 A CN202110775583 A CN 202110775583A CN 113461639 B CN113461639 B CN 113461639B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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Abstract
The invention discloses a piperazine-containing ferulic acid derivative, a preparation method and application thereof, belonging to the technical field of drug synthesis and agricultural disease control, and the structural general formula (1216) of the piperazine-containing ferulic acid derivative is shown as follows, wherein R is represented by the following formula1Is ethyl, allyl, isopropyl, propynyl, benzyl, o-methylbenzyl, m-methylbenzyl, o-fluorobenzyl; r2Is ethylsulfonyl, 4-methylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-fluorobenzenesulfonyl, 2, 5-dichlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-bromo-3-trifluoromethylbenzenesulfonyl, 3-trifluoromethylbenzoyl, 4-fluorobenzoyl, 2-fluorobenzoyl, 4-methoxybenzoyl, 5-chloropentanoyl, 4-chlorobutyryl, 4-fluorobenzyl, 2-methoxybenzyl, 3, 4-trifluorobut-3-en-1-yl, 2-methoxy-2-oxyethyl, 2-oxo-2-phenylethyl. The drug molecule has strong activity, obvious inhibition activity on TMV and CMV, environment-friendly and easy metabolism, and the structure of the drug molecule is derived from natural productsDegradation, simple preparation process, safety and relatively stable physical and chemical properties.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis and agricultural protection, and particularly relates to a piperazine-containing ferulic acid derivative, a preparation method of the piperazine-containing ferulic acid derivative, and application of the piperazine-containing ferulic acid derivative in resisting plant viruses.
Background
Plant viral diseases are second only to fungal plant diseases in agricultural production. In recent years, the prevalence and outbreak of plant viral diseases have posed a serious threat to crop yield and quality. The common plant viruses in agricultural production include Tobacco Mosaic Virus (TMV), cucumber Mosaic Virus (CMV), pepper mild mottle virus (PMMoV), etc., and the economic loss caused by plant virus diseases is as high as $ 200 billion per year. Since the virus has absolute parasitism in plants, the control of plant virus diseases is difficult. At present, the main mode for preventing and treating plant virus diseases is mainly chemical agent prevention and treatment, the main chemical agents comprise ningnanmycin and ribavirin, but the ningnanmycin has the unstable properties of easy decomposition by visible light, easy moisture absorption and the like; ribavirin has the problems of poor control effect and the like. Therefore, the development of green, efficient and stable plant virus resistant medicaments is urgently needed.
The natural product is also called secondary metabolite, has the advantages of high drug effect, unique action mechanism, environmental protection and the like, and plays an important role in the development of new drugs. Thus. The natural product is modified on the basis of structural modification, and the modified natural product becomes one of approaches for researchers to research green pesticides. Ferulic acid is a typical natural phenolic acid, and is one of the effective components of Chinese medicinal materials such as asafetida, angelica sinensis, ligusticum chuanxiong hort and the like. Pharmacological activity researches show that the ferulic acid has broad-spectrum biological activity, such as bacteriostasis, inflammation diminishing, virus resisting and the like.
The inventor of Wang Qingmin, wang Kai Liang, wangzzhen, chinese patent publication No. CN102090412A discloses application of ferulic acid and derivatives thereof in pesticides on 2011, 06 and 15, and the application of ferulic acid and derivatives thereof in inhibiting plant viruses can well inhibit the plant viruses when being used as a novel plant virus resisting agent and has a good inhibiting effect on tobacco mosaic viruses. At the concentration of 500 mu g/mL, the inhibition rate of ferulic acid on tobacco mosaic virus is up to more than 80 percent, which is higher than that of virus A, ribavirin, DADHT and DHT (the inhibition rate is lower than 50 percent).
The inventor of Wang Qingmin, wu Meng, wangzzhen, menglong pine, wang Keliang, huyanna, wanli Bell, chinese patent publication No. CN103626652A disclosed the application of 3-aryl acrylic acid and its derivatives in the aspect of pesticides in 2014 03 and 12. The Wanqingmin topic group widens the parent structure of ferulic acid into 3-aryl acrylic acid derivatives, and designs and synthesizes a series of 3-aryl acrylic acid derivatives by taking different aromatic aldehydes as raw materials. The biological activity test result shows that the series of compounds have higher inhibition rate on tobacco mosaic virus.
In 2015, angrag Khatkar et al (Res Chem Intermed.,2015, 41. The results of the MBC/MFC studies show that the activity of the synthesized compounds ranges between 0.14 and 0.24mM, and therefore they have better antibacterial and antifungal effects.
In 2020, maria
Et al (processes, 2020,8 1401) synthesized a series of novel nitrogen-containing azetidin-2-one ferulic acid derivatives whose in vivo anti-inflammatory activity was assessed using acute and chronic models of inflammation. The research result shows that in an acute inflammation model, the tested compounds show obvious anti-inflammatory activity after 24 hours of administration, and the ferulic acid derivative can be classified as a long-acting compound from the pharmacokinetic point of view. In the chronic inflammation model, the compounds reduced the formation of granulation tissue compared to the control group.
In the research on piperazine drugs, piperazine-containing N-substituted compounds are found to exhibit a wide range of biological activities, such as antiviral and anti-inflammatory activities.
In 2018, daniel c.batista et al (inflamopharmacol, 2018, 217-226) assessed the anti-inflammatory activity of the novel piperazine derivatives by using a carrageenan-induced paw edema model. The experimental results show that the piperazine derivative reduced edema at a dose of 100mg/kg over all hours, with indomethacin as the positive control agent.
In 2020, vadabingi Nagaliakshmamma et al (Bioorganic chemistry, 2020, 104084) synthesized a series of urea/thiourea containing piperazine derivatives. The activity evaluation of the piperazine derivatives against TMV was performed by using the leaf-half-withered spot method. The results of the preliminary study show that: at a concentration of 500mg/mL, the therapeutic, protective and inactivating activity of some compounds was comparable to that of the positive control agent ningnanmycin.
In summary, the small drug molecules containing ferulic acid and piperazine structures have broad-spectrum biological activity, and through the investigation of the prior literature, no research report on the activity of introducing piperazine active groups into ferulic acid structures and resisting plant viruses exists at present.
Disclosure of Invention
The invention aims to overcome the defects and provide the piperazine-containing ferulic acid derivative anti-plant virus agent which has strong activity, obvious inhibitory activity on TMV and CMV, environment-friendly structure, easy metabolism and degradation, simple and safe preparation process and relatively stable physicochemical property, and the structure of the piperazine-containing ferulic acid derivative anti-plant virus agent is derived from natural products.
The invention also aims to provide a preparation method of the piperazine-containing ferulic acid derivative.
Still another object of the present invention is to provide the use of the piperazine-containing ferulic acid derivative in the preparation of anti-plant virus (tobacco mosaic virus (TMV), cucumber Mosaic Virus (CMV) drugs.
The structural general formula (I) of the piperazine-containing ferulic acid derivative is shown as follows:
in the formula R1Is ethyl, allyl, isopropyl, propynyl, benzyl, o-methylbenzyl, m-methylbenzyl or o-fluorobenzyl;
R2is ethylsulfonyl, 4-methylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-fluorobenzenesulfonyl, 2, 5-dichlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-bromo-3-trifluoromethylbenzenesulfonyl, 3-trifluoromethylbenzoyl, 4-fluorobenzoyl, 2-fluorobenzoyl, 4-methoxybenzoyl, 5-chloropentanoyl, 4-chlorobutyryl, 4-fluorobenzyl, 2-methoxybenzyl, 3, 4-trifluorobut-3-en-1-yl, 2-methoxy-2-oxyethyl, 2-oxo-2-phenylethyl.
Preferred compounds are as follows:
compound C1 (E) -1- (4-benzylpiperazin-1-yl) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one;
the compound C2 (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (4- (2-oxo-2-phenylethyl) piperazin-1-yl) prop-2-en-1-one;
compound C3 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (2-methoxybenzyl) piperazin-1-yl) prop-2-en-1-one;
compound C4 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (2- (2-methoxyphenyl) -2-oxoethyl) piperazin-1-yl) prop-2-en-1-one;
compound C5 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (3, 4-trifluorobut-3-en-1-yl) piperazin-1-yl) prop-2-en-1-one;
compound C6 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (4-fluorobenzyl) piperazin-1-yl) prop-2-en-1-one;
compound D1 (E) -1- (4- (4-fluorobenzoyl) piperazin-1-yl) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one;
compound D2 (E) -4-chloro-1- (4- (3- (4-ethoxy-3-methoxyphenyl) acryloyl) piperazin-1-yl) butan-1-one;
compound D3 (E) -3- (3-methoxy-4- (3-methylbenzyloxy) phenyl) -1- (4- (4-methoxybenzoyl) piperazin-1-yl) prop-2-en-1-one;
compound D4 (E) -1- (4- (3- (4- (allyloxy) -3-methoxyphenyl) acryloyl) piperazin-1-yl) -5-chloropentan-1-one;
compound D5 (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (4- (2-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one;
compound D6 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (4-methoxybenzoyl) piperazin-1-yl) prop-2-en-1-one;
compound D7 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) prop-2-en-1-one;
compound E1 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4-tosylpiperazin-1-yl) prop-2-en-1-one;
compound E2 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-fluorophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E3 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E4 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E5 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E6 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((2, 5-dichlorophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E7 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-bromo-3- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E8 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E9 (E) -1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one;
compound E10 (E) -1- (4- ((2, 5-dichlorophenyl) sulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one;
compound E11 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E12 (E) -1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) prop-2-en-1-one;
compound E13 (E) -1- (4- ((4-fluorophenyl) sulfonyl) piperazin-1-yl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) prop-2-en-1-one;
compound E14 (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E15 (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E16 (E) -3- (3-methoxy-4- (2-methylbenzyloxy) phenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E17 (E) -3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E18 (E) -3- (4- (benzyloxy) -3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E19 (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (4- (ethylsulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E20 (E) -1- (4- (ethylsulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one;
the compound E21 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (ethylsulfonyl) piperazin-1-yl) prop-2-en-1-one.
The preparation method of the ferulic acid derivative containing piperazine comprises the following steps:
(1) The method for preparing the ferulic acid methyl ester (intermediate 1) by using trans-ferulic acid as a raw material, concentrated sulfuric acid as a catalyst and methanol as a solvent comprises the following steps:
(2) The intermediate 1 and the different substituted halogenated hydrocarbons are used as raw materials, potassium carbonate and potassium iodide are used as catalysts, and acetonitrile is used as a solvent to prepare the (E) -methyl 3- (4-substituted oxy-3-methoxyphenyl) acrylate (intermediate 2) as follows:
(3) The prepared intermediate 2 is hydrolyzed under alkaline conditions, and the acidity is adjusted to about 3-4 to obtain (E) -3- (4-substituted oxy-3-methoxyphenyl) acrylic acid (intermediate 3), which is shown as follows:
(4) The intermediate 3 and 1-Boc-piperazine were used as raw materials, CDI was used as a condensing agent, and methylene chloride was used as a solvent to perform amide condensation to obtain (E) -4- (3- (4- (4-substituted oxy-3-methoxyphenyl) acryloyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 4), as follows:
(5) Deprotection in the presence of trifluoroacetic acid (TFA) starting from intermediate 4 gives (E) -3- (4-substituted oxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (intermediate 5) as follows:
(6) The intermediate 5, substituted benzene sulfonyl chloride or substituted acyl chloride or halogenated hydrocarbon are used as raw materials, methylene dichloride is used as a solvent to prepare the ferulic acid derivative (target compounds C, D and E) containing piperazine, which is shown as follows:
the invention relates to application of ferulic acid derivatives containing piperazine in preparing anti-plant virus (TMV and CMV) medicaments.
Compared with the prior art, the invention has obvious beneficial effects, and the technical scheme can show that: according to the invention, piperazine structural unit bridging is adopted, and the easily obtained natural product ferulic acid and substituted benzene sulfonyl chloride or substituted acyl chloride or halogenated hydrocarbon are subjected to active splicing to prepare a series of ferulic acid derivatives containing piperazine with a novel structure, wherein piperazine has a good nitrogen balance symmetric structure and is introduced into drug molecules, so that the pharmacokinetic property of the drug can be effectively improved, and the lipid-water distribution coefficient and the acid-base equilibrium constant of the drug can be adjusted; effectively increases the alkalinity and water solubility of ferulic acid derivative molecules, thereby enhancing the activity of drug molecules. The invention takes natural products of trans-ferulic acid, halohydrocarbon, substituted acyl chloride and substituted sulfonyl chloride as raw materials, and synthesizes target compounds through esterification, substitution, hydrolysis, condensation and the like respectively. The ferulic acid derivative containing piperazine has obvious inhibitory activity on TMV and CMV and is obviously superior to positive control medicaments of ningnanmycin and ribavirin.
The specific implementation mode is as follows:
example 1: (E) A process for the preparation of (E) -1- (4-benzylpiperazin-1-yl) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one (compound No. C1), comprising the steps of:
(1) Preparation of trans-ferulic acid methyl ester
Adding trans-ferulic acid (20.00g, 102.99mmoL) and 100mL of anhydrous methanol solution into a 250mL three-neck flask, stirring at normal temperature for 5min, and slowly dropwise adding concentrated H2SO4(10.10 g, 102.99mmoL), and the temperature was raised to 50 ℃. After the reaction was completed, the methanol solution was removed under reduced pressure, and then 40mL of water was added to the system, and the system was adjusted to be free from bubble generation with a saturated sodium bicarbonate solution. Finally, extraction was carried out three times with dichloromethane, the organic phases were combined and concentrated under reduced pressure to give 19.08g of a viscous liquid with a yield of 88.97%.
(2) Preparation of methyl (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) acrylate
To a 50mL three-necked flask, trans-ferulic acid methyl ester (1.00g, 4.80mmoL), crystalline potassium carbonate (1.00g, 4.80mmoL) and 10mL acetonitrile solution were added, and after stirring at room temperature for 1 hour, o-fluorobenzyl chloride (0.69g, 4.80mmoL) and KI (0.079g, 0.48mmoL) were added to the system and the temperature was raised to 80 ℃. After the reaction, filtration was carried out, and the solvent was recovered under reduced pressure to obtain 1.35g of a crystalline solid with a yield of 88.86%.
(3) Preparation of (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) acrylic acid
A50 mL three-necked flask was charged with (E) -methyl 3- (4- (((2-fluorobenzyl) oxy) -3-methoxybenzene) acrylate (1.35g, 4.27mmoL) and 40% aqueous NaOH (NaOH 0.35g, 8.54mmoL) and methanol, heated to 75 deg.C, after the reaction was completed, the solvent was recovered under reduced pressure, the concentrate was dissolved in 10mL of water, the system was adjusted to pH 3-4 with dilute hydrochloric acid, and finally, 0.85g of a white solid was obtained by filtration under reduced pressure, with a yield of 65.88%.
(4) Preparation of (E) -4- (3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) acryloyl) piperazine-1-carboxylic acid tert-butyl ester
A50 mL round-bottomed flask was charged with (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) acrylic acid (0.85g, 2.81mmoL), CDI (0.46g, 2.81mmoL) and a dried dichloromethane solution, and after stirring at normal temperature for 20min, 1-Boc-piperazine (0.53 g,2.81 mmoL) was added to the system, and stirring at normal temperature was continued. After the reaction, the reaction mixture was concentrated under reduced pressure and subjected to column chromatography to obtain 0.65g of tert-butyl intermediate (E) -4- (3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) acryloyl) piperazine-1-carboxylate, which was obtained in 49.13% yield.
(5) Preparation of (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one
A50 mL round bottom flask was charged with tert-butyl (E) -4- (3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) acryloyl) piperazine-1-carboxylate (0.65g, 1.38mmoL), CF3COOH (0.32 g, 2.76mmol) and dry dichloromethane solution, stirring at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added to the system until no air bubbles were generated, and the mixture was extracted with dichloromethane three times with 30mL each, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.41g of (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one in a yield of 78.17%.
(6) Preparation of (E) -1- (4-benzylpiperazin-1-yl) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one (compound No. C1)
A50 mL round-bottom flask was charged with a solution of (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.81mmoL) and methylene chloride, stirred at room temperature, and then benzyl chloride (0.10g, 0.81mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.22g of an oily compound with a yield of 58.98%.
Example 2: (E) A process for the preparation of (e) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (4- (2-oxo-2-phenylethyl) piperazin-1-yl) prop-2-en-1-one (compound No. C2) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round bottom flask was charged with a solution of (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.81mmoL) and dichloromethane, stirred at ambient temperature, and then α -bromoacetophenone (0.16g, 0.81mmoL) was slowly added to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.24g of an oily compound with a yield of 49.84%.
Example 3: (E) A method for preparing (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (2-methoxybenzyl) piperazin-1-yl) prop-2-en-1-one (compound No. C3), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then o-methylbenzyl chloride (0.14g, 0.99mmoL) was slowly added to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.23g of an oily compound in a yield of 57.12%.
Example 4: (E) A method for preparing (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (2- (2-methoxyphenyl) -2-oxyethyl) piperazin-1-yl) prop-2-en-1-one (compound No. C4), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, and stirred at room temperature, followed by slow addition of o-methoxy-2-bromoacetophenone (0.23g, 0.99mmoL) to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.21g of an oily compound in 47.08% yield.
Example 5: (E) A method for preparing (e) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (3, 4-trifluorobut-3-en-1-yl) piperazin-1-yl) prop-2-en-1-one (compound No. C5), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-bromo-1, 2-trifluorobutene (0.23g, 0.99mmoL) was slowly added to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.20g of an oily compound with a yield of 49.20%.
Example 6: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (4-fluorobenzyl) piperazin-1-yl) prop-2-en-1-one (compound No. C6) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, and stirred at room temperature, followed by slowly adding 4-fluorobenzyl chloride (0.23g, 0.99mmoL) to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.20g with a yield of 49.11%.
Example 7: (E) A process for the preparation of (e) -1- (4- (4-fluorobenzoyl) piperazin-1-yl) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one (compound No. D1) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.81mmoL) and methylene chloride, stirred at room temperature, and p-fluorobenzoyl chloride (0.13g, 0.81mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.19g of a white solid with a yield of 47.63%.
Example 8: (E) A method for producing (E) -4-chloro-1- (4- (3- (4-ethoxy-3-methoxyphenyl) acryloyl) piperazin-1-yl) butan-1-one (compound No. D2), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.03mmoL) and methylene chloride, and stirred at room temperature, followed by slowly adding 4-chlorobutyryl chloride (0.15g, 1.03mmoL) to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.20g of an oily compound with a yield of 49.02%.
Example 9: (E) A method for preparing (e) -3- (3-methoxy-4- (3-methylbenzyloxy) phenyl) -1- (4- (4-methoxybenzoyl) piperazin-1-yl) prop-2-en-1-one (compound No. D3), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (3-methoxy-4- (3-methylbenzyloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.81mmoL) and methylene chloride, stirred at room temperature, and p-methoxybenzoyl chloride (0.14g, 0.81mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.12g of a white solid with a yield of 37.12%.
Example 10: (E) A method for producing (E) -1- (4- (3- (4- (allyloxy) -3-methoxyphenyl) acryloyl) piperazin-1-yl) -5-chloropentan-1-one (compound No. D4), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 5-chloropentanoyl chloride (0.15g, 0.99mmoL) was slowly added to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.18g of an oily compound with a yield of 45.21%.
Example 11: (E) A method for preparing (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (4- (2-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one (compound No. D5), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.03mmoL) and methylene chloride, stirred at room temperature, and then o-fluorobenzoyl chloride (0.16g, 1.03mmoL) was slowly added to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.18g of an oily compound with a yield of 42.24%.
Example 12: (E) A method for producing (e) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (4-methoxybenzoyl) piperazin-1-yl) prop-2-en-1-one (compound No. D6), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-methoxybenzoyl chloride (0.16g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.17g of a white solid with a yield of 39.25%.
Example 13: (E) A method for preparing (e) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) prop-2-en-1-one (compound No. D7), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (isopropoxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, and stirred at room temperature, followed by slowly adding m-trifluoromethylbenzoyl chloride (0.21g, 0.99mmoL) to the system. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.22g of an oily compound with a yield of 51.14%.
Example 14: (E) A method for preparing (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4-tosylpiperazin-1-yl) prop-2-en-1-one (compound No. E1), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then p-methylbenzenesulfonyl chloride (0.19g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.16g of a white solid with a yield of 36.94%.
Example 15: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-fluorophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E2) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-fluorobenzenesulfonyl chloride (0.19g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.11g of a white solid with a yield of 25.40%.
Example 16: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E3) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-bromobenzenesulfonyl chloride (0.25g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, and the viscous substance was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, whereby 0.12g of a white solid was obtained in 23.20% yield.
Example 17: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E4) comprising the following steps:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-nitrobenzenesulfonyl chloride (0.22g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.12g of a yellow solid with a yield of 27.71%.
Example 18: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E5) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-trifluoromethylbenzenesulfonyl chloride (0.24g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, and the viscous substance was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.14g of a white solid with a yield of 32.33%.
Example 19: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((2, 5-dichlorophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E6) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 2, 5-dichlorobenzenesulfonyl chloride (0.22g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.15g of a white solid with a yield of 34.64%.
Example 20: (E) A process for the preparation of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-bromo-3- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E7) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-bromo-3-trifluoromethylbenzenesulfonyl chloride (0.32g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.18g of a white solid with a yield of 41.56%.
Example 21: (E) A process for the preparation of (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E8), comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (isopropoxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-nitrobenzenesulfonyl chloride (0.22g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance and purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.17g of a yellow solid with a yield of 39.33%.
Example 22: (E) -a process for the preparation of (1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one (compound No. E9) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (isopropoxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-bromobenzenesulfonyl chloride (0.25g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.15g of a white solid with a yield of 34.71%.
Example 23: (E) A process for the preparation of (E) -1- (4- ((2, 5-dichlorophenyl) sulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one (compound No. E10) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4- (isopropoxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 2, 5-dichlorobenzenesulfonyl chloride (0.24g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.21g of a white solid with a yield of 48.91%.
Example 24A process for the preparation of (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E11) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (isopropoxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then 4-trifluoromethylbenzenesulfonyl chloride (0.24g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.20g of a white solid with a yield of 46.27%.
Example 25 preparation of (E) -1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) prop-2-en-1-one (compound No. E12) comprising the following steps:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.00mmoL) and methylene chloride, stirred at room temperature, and then 4-bromobenzenesulfonyl chloride (0.26g, 1.00mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.19g of a white solid with a yield of 36.62%.
Example 26A preparation process for (E) -1- (4- ((4-fluorophenyl) sulfonyl) piperazin-1-yl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) prop-2-en-1-one (compound No. E13) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.00mmoL) and methylene chloride, stirred at room temperature, and then 4-fluorobenzenesulfonyl chloride (0.19g, 1.00mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.13g of a white solid with a yield of 25.06%.
Example 27A process for the preparation of (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E14) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.00mmoL) and methylene chloride, stirred at room temperature, and then 4-nitrobenzenesulfonyl chloride (0.22g, 1.00mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, and the viscous substance was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.18g of a white solid with a yield of 34.70%.
Example 28A process for the preparation of (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E15) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.00mmoL) and methylene chloride, stirred at room temperature, and then 4-trifluoromethylbenzenesulfonyl chloride (0.24g, 1.00mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.20g of a white solid with a yield of 37.56%.
Example 29 preparation of (E) -3- (3-methoxy-4- (2-methylbenzyloxy) phenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E16) comprising the following steps:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (3-methoxy-4- (2-methylbenzyloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.00mmoL) and methylene chloride, stirred at room temperature, and then 4-nitrobenzenesulfonyl chloride (0.18g, 1.00mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.25g of a white solid with a yield of 52.16%.
Example 30A process for the preparation of (E) -3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E17) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (3-methoxy-4- (2-methylbenzyloxy) phenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.82mmoL) and methylene chloride, stirred at ordinary temperature, and then 4-trifluoromethylbenzenesulfonyl chloride (0.20g, 0.82mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.24g of a white solid with a yield of 50.07%.
Example 31 a process for the preparation of (E) -3- (4- (benzyloxy) -3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E18) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (benzyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.85mmoL) and methylene chloride, stirred at room temperature, and then 4-nitrobenzenesulfonyl chloride (0.18g, 0.85mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance and purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.24g of a yellow solid with a yield of 48.12%.
Example 32A method for preparing (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (4- (ethylsulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E19) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.85mmoL) and methylene chloride, stirred at room temperature, and then ethylsulfonyl chloride (0.13g, 0.85mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.24g of a white solid with a yield of 49.13%.
Example 33A preparation process for (E) -1- (4- (ethylsulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one (compound No. E20) comprising the steps of:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottomed flask was charged with a solution of (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 1.00mmoL) and methylene chloride, stirred at room temperature, and then ethylsulfonyl chloride (0.13g, 1.00mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.23g of a yellow solid in a yield of 46.25%.
Example 34A preparation method of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (ethylsulfonyl) piperazin-1-yl) prop-2-en-1-one (compound No. E21) comprising the following steps:
steps (1) to (5) were the same as in example 1
(6) A50 mL round-bottom flask was charged with a solution of (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (piperazin-1-yl) prop-2-en-1-one (0.30g, 0.99mmoL) and methylene chloride, stirred at room temperature, and then ethylsulfonyl chloride (0.13g, 0.99mmoL) was slowly added to the system. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a viscous substance, which was purified by silica gel column chromatography using petroleum ether/ethyl acetate =1 (V/V) as an eluent, to obtain 0.25g of a white solid with a yield of 48.32%.
The physical and chemical properties of the compounds of the above examples are shown in Table 1, and the data of nuclear magnetic resonance spectra thereof are shown in Table 2.
TABLE 1 physicochemical Properties of the example Compounds C1-C6, D1-D7, E1-E21
TABLE 2 NMR spectra data for the example compounds C1-C6, D1-D7, E1-E21
Test example: examples test methods for testing the anti-plant viral activity of the compounds C1-C6, D1-D7, E1-E21: 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 caltrop (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 Solution (PBS) at pH 7.5
Reagent: ethylenediaminetetraacetic acid (EDTA): tianjin Kemi European chemical reagent, inc.; 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: V = 1), filtered with double-layer nylon gauze;
(c) Pouring the filtrate into a centrifuge tube (ice bath), and centrifuging at 8000rmp and 4 ℃ for 20min;
(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 20min. After removing the supernatant, the pellet was suspended in 1/5 of the crude extract in 0.01mol/L PBS, transferred to a clean Erlenmeyer flask and stirred for 2h. 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)
Virus mother liquor concentration (mg/mL) = a260X dilution 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) Add two volumes of pre-chilled 0.5mol/L Phosphate Buffered Saline (PBS) pH 7.5 (0.01 mol/LEDTA,0.1% mercaptoethanol, 2%: n-butanol (V: V = 1), filtered with double-layer nylon gauze;
(c) Pouring the filtrate into a centrifuge tube (ice bath), and centrifuging at 8000rmp and 4 ℃ for 20min;
(d) Collecting supernatant, which is crude extracted virus solution, adding (V/W) 6% PEG-6000 and NaCl, stirring at 4 deg.C for 4h, and centrifuging at 8000rpm for 20min;
(e) The pellet was retained, suspended in 0.01mol/L PBS at pH =7.0, and centrifuged at 8000rmp for 20min at 4 ℃;
(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) = A260X dilution factor/5.0
Preparation of the Compound concentration
2mg of the compound was accurately weighed out into a centrifuge tube, 30. Mu.L of DMSO, an organic solvent was added thereto to dissolve the compound sufficiently, and 4mL of secondary water containing 1% Tween 80 was added to prepare a 500. Mu.g/mL drug.
(1) Test method
The compounds C1-C6, D1-D7, E1-E21 were tested for their antiviral activity against TMV/CMV by the following specific procedures:
(a) In vitro action
Selecting core leaf tobacco with consistent growth vigor at 5-6 leaf stage, uniformly spreading carborundum on each leaf, dipping a row of pens with prepared virus juice, manually rubbing and inoculating on the whole leaf, inoculating virus for 30min, and washing with clear water. After the leaves are dry, the leaves are cut along the veins, the left half leaf is soaked in 1% Tween water, the right half leaf is soaked in the medicament, and the leaves are taken out after 30min and are subjected to moisture preservation culture at a proper illumination temperature. After 2-3d, the leaves appeared clear with blotches, and the number of blotches on the left and right halves was recorded. Each compound was repeated 3 times.
(b) Therapeutic effect of pharmaceutical agent on TMV/CMV living body
Selecting leaf tobacco or amaranth gooseberry with consistent growth vigor at 5-6 leaf stages, uniformly spreading carborundum on each leaf, dipping a pen in prepared virus juice, manually rubbing and inoculating on the whole leaf, inoculating 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. 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.
(c) 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.
(d) Inactivation of TMV/CMV living body by medicament
Selecting the tobacco or amaranth gooseberry with consistent growth vigor and 5-6 leaf stages, 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 scorched spots-number of drug-treated scorched spots)/number of blank control scorched spots ] × 100
A portion of the target compounds was subjected to 5 corresponding concentration gradients, and their EC for TMV and CMV was determined50The value is obtained.
The anti-plant Virus Activity and EC of the Compounds of examples C1-C6, D1-D7, E1-E21 were determined as described above50The values and results are shown in tables 3 to 4.
(2) Test results for anti-plant Virus Activity
TABLE 3 test data for the inhibitory activity of the example compounds C1-C6, D1-D7, E1-E21 on TMV
The inhibitory activity of the compounds C1-C6, D1-D7 and E1-E21 of the examples on TMV was tested by using the leaf-half-blight method, using ningnanmycin and ribavirin as positive control agents, at a test concentration of 500. Mu.g/mL. As shown in table 3, most of the target compounds showed better ex vivo and in vivo therapeutic activities, wherein the ex vivo activities of the compounds D4, E2, E4, E6, E10 and E16 were 60.8%, 62.9%, 59.7%, 58.1%, 59.7% and 59.8%, respectively, better than that of ningnanmycin (52.3%) and ribavirin (38.2%); the in vivo therapeutic activity of compounds D4, E2, E4, E6, E8, E10 and E16 was 59.8%, 63.1%, 59.8%, 56.7%, 57.9%, 60.3% and 59.6%, respectively, higher than the control agents ningnanmycin and ribavirin (52.3% and 38.2%), and showed the same trend as the ex vivo therapeutic activity. In terms of protection and inactivation activities, the protection activity and inactivation activity of the compound E2 on TMV are respectively 70.1% and 89.9%, which are higher than those of a control medicament, namely ningnanmycin (66.7% and 88.6%), and the activities of the rest compounds are lower than those of the ningnanmycin. EC against TMV therapeutic, protective and inactivating activity of Compound E250189.0, 187.0 and 169.2. Mu.g/mL are superior to the control agents ningnanmycin (387.0, 268.1 and 328.4. Mu.g/mL) and ribavirin (542.1, 589.7 and 359.4. Mu.g/mL), respectively.
TABLE 4 test data for CMV inhibitory Activity of the example Compounds C1-C6, D1-D7, E1-E21
The anti-CMV activity of piperazine-containing ferulic acid derivatives was measured by living body half-leaf blight method using commercially available drugs of ningnanmycin and ribavirin as positive control drugs at a test concentration of 500. Mu.g/mL (see Table 4). As can be seen from table 4, the piperazine-containing ferulic acid derivatives have a certain anti-CMV activity, wherein the therapeutic activity of compounds D1, D2, E3, E4, E6, E8, E12, E13, E16, E18 and E20 is 47.7%, 48.9%, 56.9%, 51.9%, 52.8%, 47.4%, 55.5%, 56.7%, 50.1%, 50.3%, 51.1% and 49.7%, respectively, higher than the control drugs ningnanmycin and ribavirin (47.3% and 39.2%). In terms of protective activity, the protective activity of the compounds D6, E2, E12, E16 and E18 was 55.2%, 56.7%, 55.7%, 56.1% and 55.7%, respectively, higher than that of the control agent ningnanmycin (55.1%), and the remaining compounds were lower than that of ningnanmycin. In terms of inactivating activity, compound E2 had an inactivating activity of 87.6% on CMV. EC of compound E2 for CMV therapeutic and protective Activity therein50Values of 401.7. Mu.g/mL and 431.2. Mu.g/mL were superior to ningnanmycin (519.3. Mu.g/mL and 457.1. Mu.g/mL) and ribavirin (721.5. Mu.g/mL and 652.6. Mu.g/mL), respectively.
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 modifications, equivalent variations and modifications made on the above embodiment according to the technical spirit of the present invention are within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.
Claims (3)
1. Piperazine-containing ferulic acid derivative, which has the following structural formula (I):
in the formula R1Is ethyl, allyl, isopropyl, propynyl, benzyl, o-methylbenzyl, m-methylbenzyl or o-fluorobenzyl; r is2Is ethylsulfonyl, 4-methylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-fluorobenzenesulfonyl, 2, 5-dichlorobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-bromo-3-trifluoromethylbenzenesulfonyl, 3-trifluoromethylbenzoyl, 4-fluorobenzoyl, 2-fluorobenzoyl, 4-methoxybenzoyl, 5-chloropentanoyl, 4-chlorobutyryl, 4-fluorobenzyl, 2-methoxybenzyl, 3, 4-trifluorobut-3-en-1-yl, 2-oxo-2-phenylethyl.
2. The piperazine-containing ferulic acid derivative of claim 1, which is a compound of:
compound C1 (E) -1- (4-benzylpiperazin-1-yl) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one;
the compound C2 (E) -3- (4- ((2-fluorobenzyl) oxy) -3-methoxyphenyl) -1- (4- (2-oxo-2-phenylethyl) piperazin-1-yl) prop-2-en-1-one;
compound C3 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (2-methoxybenzyl) piperazin-1-yl) prop-2-en-1-one;
compound C4 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (2- (2-methoxyphenyl) -2-oxoethyl) piperazin-1-yl) prop-2-en-1-one;
compound C5 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (3, 4-trifluorobut-3-en-1-yl) piperazin-1-yl) prop-2-en-1-one;
the compound C6 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (4-fluorobenzyl) piperazin-1-yl) prop-2-en-1-one;
compound D1 (E) -1- (4- (4-fluorobenzoyl) piperazin-1-yl) -3- (4- (((2-fluorobenzyl) oxy) -3-methoxyphenyl) prop-2-en-1-one;
compound D2 (E) -4-chloro-1- (4- (3- (4-ethoxy-3-methoxyphenyl) acryloyl) piperazin-1-yl) butan-1-one;
compound D3 (E) -3- (3-methoxy-4- ((3-methylbenzyloxy) phenyl) -1- (4- (4-methoxybenzoyl) piperazin-1-yl) prop-2-en-1-one;
compound D4 (E) -1- (4- (3- (4- (4- (allyloxy) -3-methoxyphenyl) acryloyl) piperazin-1-yl) -5-chloropentan-1-one;
compound D5 (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (4- (2-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one;
compound D6 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (4-methoxybenzoyl) piperazin-1-yl) prop-2-en-1-one;
compound D7 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- (3- (trifluoromethyl) benzoyl) piperazin-1-yl) prop-2-en-1-one;
compound E1 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4-tosylpiperazin-1-yl) prop-2-en-1-one;
compound E2 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-fluorophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E3 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-bromophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E4 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E5 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E6 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (((2, 5-dichlorophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E7 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- ((4-bromo-3- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E8 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E9 (E) -1- (4- (((4-bromophenyl) sulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one;
compound E10 (E) -1- (4- (((2, 5-dichlorophenyl) sulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one;
compound E11 (E) -3- (4-isopropoxy-3-methoxyphenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) cyclohexyl) prop-2-en-1-one;
compound E12 (E) -1- (4- (((4-bromophenyl) sulfonyl) piperazin-1-yl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) prop-2-en-1-one;
compound E13 (E) -1- (4- (((4-fluorophenyl) sulfonyl) piperazin-1-yl) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) prop-2-en-1-one;
compound E14 (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E15 (E) -3- (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E16 (E) -3- (3-methoxy-4- ((2-methylbenzyloxy) phenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E17 (E) -3- (3-methoxy-4- ((2-methylbenzyl) oxy) phenyl) -1- (4- ((4- (trifluoromethyl) phenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E18 (E) -3- (4- (benzyloxy) -3-methoxyphenyl) -1- (4- ((4-nitrophenyl) sulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E19 (E) -3- (4-ethoxy-3-methoxyphenyl) -1- (4- (ethylsulfonyl) piperazin-1-yl) prop-2-en-1-one;
compound E20 (E) -1- (4- (ethylsulfonyl) piperazin-1-yl) -3- (4-isopropoxy-3-methoxyphenyl) prop-2-en-1-one;
the compound E21 (E) -3- (4- (allyloxy) -3-methoxyphenyl) -1- (4- (ethylsulfonyl) piperazin-1-yl) prop-2-en-1-one.
3. Use of piperazine-containing ferulic acid derivative according to claim 1 or 2 for the preparation of a medicament against tobacco mosaic virus and cucumber mosaic virus.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105777654A (en) * | 2016-03-28 | 2016-07-20 | 贵州大学 | Ferulic acid ester derivative containing quinazoline, as well as preparation method and purpose of ferulic acid ester derivative |
| CN109824756A (en) * | 2019-03-19 | 2019-05-31 | 山东大学 | Contain 4-(benzenesulfonyl) phenylalanine derivative and the preparation method and application thereof of piperazine -2- ketone |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503851A (en) * | 2011-09-28 | 2012-06-20 | 南开大学 | Ferulic acid phenethyl alcohol amine derivative and application thereof |
| CN105777654A (en) * | 2016-03-28 | 2016-07-20 | 贵州大学 | Ferulic acid ester derivative containing quinazoline, as well as preparation method and purpose of ferulic acid ester derivative |
| CN109824756A (en) * | 2019-03-19 | 2019-05-31 | 山东大学 | Contain 4-(benzenesulfonyl) phenylalanine derivative and the preparation method and application thereof of piperazine -2- ketone |
Non-Patent Citations (5)
| Title |
|---|
| Design, Synthesis, and Structure Activity Relationship Analysis of New Betulinic Acid Derivatives as Potent HIV Inhibitors;YuZhao，等;《European Journal of Medicinal Chemistry》;20210415;第215卷;第1-15页 * |
| 含哌嗪片段的噻吩查尔酮衍生物的合成及其抗菌活性;黎勇坤，等;《有机化学》;20200131;第40卷(第01期);第109页右栏第1-2段、图式2 * |
| 含哌嗪酰胺类杨梅素衍生物的合成及生物活性;阮祥辉，等;《高等学校化学学报》;20180610(第06期);第95-102页 * |
| 阿魏酸衍生物的合成及生物活性研究;王珍珍;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20180415(第04期);第21页第2-3段，第22页第1-2段、图2-2，第23页图2-3 * |
| 阿魏酸酰腙类化合物的合成及抗病毒活性;王珍珍，等;《化学研究与应用》;20200715(第07期);第125-131页 * |
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