Preparation method of resveratrol, resveratrol and application of resveratrol

Abstract

The invention provides a resveratrol preparation method, which comprises: mixing a compound 1 and an acylation reagent in an organic solvent, carrying out a reaction to obtain a compound 2, adding chlorobenzene and a catalyst, and carrying out a Friedel-Crafts reaction on the compound 2 and chlorobenzene under the ultraviolet light condition to obtain a compound 3, oxidizing the compound 3 to obtain 1-(4-phenol)-2-(3, 5-dihydroxyphenyl) ethanone; the preparation method comprises the following steps: reducing 1-(4-phenol)-2-(3, 5-dihydroxyphenyl) ethanone to obtain 1-(4-phenol)-2-(3, 5-dihydroxyphenyl) ethanol; and removing an alcoholic hydroxyl group in the 1-(4-phenol)-2-(3, 5-dihydroxyphenyl) ethanol to obtain the resveratrol.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing resveratrol. Background Art

[0002] Resveratrol is a non-flavonoid stilbene compound with the chemical formula C 14 H 12 O3. It has a variety of biological activities, can scavenge free radicals, reduce oxidative stress, and thus slow down cell aging and damage; has significant anti-inflammatory effects, can inhibit the production and release of various inflammatory factors; can reduce cholesterol levels in the blood, inhibit platelet aggregation, and thus prevent the occurrence and development of cardiovascular diseases; can activate acetylase, increase the lifespan and vitality of cells, and thus play an anti-aging role, etc. Resveratrol has been widely used in the fields of health foods, cosmetics, and drug research and development due to its various biological activities.

[0003] Resveratrol has two main stereoisomers, trans-resveratrol and cis-resveratrol, among which the trans isomer is more stable and has higher biological activity. It is easily absorbed in the human body and excreted through urine and feces metabolism. Therefore, the present invention mainly focuses on the synthesis of trans-resveratrol.

[0004] Specifically, the structural formula of trans-resveratrol is as follows: .

[0005] There are various methods for synthesizing resveratrol in the prior art.

[0006] Among them, Liu Changhui et al. synthesized resveratrol by total synthesis using the Grignard reaction. First, 4-methoxybenzyl alcohol was chlorinated with SOCl2, and then reacted with Mg to prepare an intermediate. Then, it was reacted with 3,5-dimethoxybenzaldehyde to obtain an ethanol derivative. Then, an elimination reaction occurred on the alcohol hydroxyl group under the catalysis of KHSO4 to form a double bond to prepare an intermediate. Finally, demethylation was carried out under the catalysis of AlCl3 to obtain resveratrol. The specific synthesis route is as follows: . Summary of the Invention

[0007] The first object of the present invention is to provide a method for preparing resveratrol with few side reactions, high yield, and a relatively simple reaction process.

[0008] The second object of the present invention is to provide resveratrol prepared by the above method.

[0009] The third object of the present invention is to provide an application of the above resveratrol.

[0010] The present invention is achieved through the following technical solutions: A preparation method of resveratrol, comprising the following steps: Mix compound 1 with an acylating agent in an organic solvent and then react to obtain compound 2, and then add chlorobenzene and a catalyst, and under the condition of ultraviolet light, make compound 2 undergo a Friedel-Crafts reaction with chlorobenzene to obtain compound 3; Oxidize compound 3 to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone; Reduce 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol; Eliminate the alcohol hydroxyl group in 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol to obtain resveratrol.

[0011] Among them, the structure of compound 1 is as follows: The structure of compound 2 is as follows: The structure of compound 3 is as follows: Among them, R represents an alkyl group or a halogen;

[0012] The alkyl group is selected from methyl, ethyl, and propyl; The halogen is selected from chlorine or bromine.

[0013] The molar ratio of 3,5-dichlorophenylacetic acid to the acylating agent and chlorobenzene is 1.0:1.5:1.3.

[0014] The catalyst includes aluminum chloride; or The catalyst includes Beta zeolite doped with anhydrous AlCl3; The wavelength of the ultraviolet light is 280-350 nm; The acylating agent includes SOCl2; The oxidizing agent used for the oxidation is a FENTON reagent; The pH value used for the oxidation is 3-4; The temperature used for the oxidation is 20-40 °C.

[0015] The catalyst used for the oxidation is a titanium dioxide-silver composite metal catalyst.

[0016] The loading amount of titanium dioxide in the catalyst is 2-8 wt%.

[0017] The reducing agent used in the reduction includes sodium borohydride or potassium borohydride; The dehydrating agent used in the elimination includes aluminum chloride or p-toluenesulfonic acid.

[0018] Resveratrol prepared by a method for preparing the resveratrol as described above.

[0019] An application of the resveratrol as described above, which is applied to the preparation of a drug for activating acetylase; or applied to the preparation of a drug for scavenging free radicals; or applied to the preparation of a drug for inhibiting the production and release of inflammatory factors; or applied to the preparation of a drug for reducing cholesterol in blood.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention adopts a one-pot reaction and uses and chlorobenzene to synthesize , which simplifies the preparation method of resveratrol and reduces its preparation cost.

[0021] The method provided by the present invention uses ultraviolet light to assist the progress of the Friedel-Crafts reaction, thereby reducing the content of by-products in the product of the Friedel-Crafts reaction. Detailed implementation manners

[0022] As is well known, according to the record in the prior art Catalytic Friedel-Crafts Acylation of Benzene, Chlorobenzene, and Fluorobenzene Using a Novel Catalyst System, Hafnium Triflate and Trifluoromethanesulfonic Acid, in the presence of Hf(OTf)4 and TfOH, unactivated benzene series compounds, such as chlorobenzene and fluorobenzene, can react smoothly to obtain corresponding aromatic ketones. However, there are many reaction sites in chlorobenzene and there are many impurities in this reaction. This is because the chlorine on the benzene ring has an electron-withdrawing effect and also has a slight electron-donating conjugate effect. Generally speaking, the chlorine atom reduces the electron cloud density on the benzene ring. Therefore, compared with benzene, chlorobenzene is more difficult to undergo electrophilic substitution reaction than benzene. Moreover, the electron conjugate effect makes the electron cloud density at the ortho and para positions of the benzene ring higher than that at the meta position, so the chlorine atom is an ortho and para positioning substituent that slightly deactivates the benzene ring. That is to say, using chlorobenzene as the raw material for the Friedel-Crafts reaction, firstly, the reaction difficulty increases, and at the same time, various by-products will be generated.

[0023] Specifically in the present invention, when preparing resveratrol, if and chlorobenzene are used for Friedel-Crafts reaction to prepare the intermediate , it is possible to produce various by-products, such as and . How to specifically make the reaction occur on the hydrogen at the 4-position of chlorobenzene is a problem to be solved.

[0024] In order to reduce side reactions and improve the reaction activity of chlorobenzene, the present invention improves the preparation method of resveratrol. By adopting the way of ultraviolet photocatalysis, the one-pot preparation of the intermediate is realized, and at the same time, the generation of side reactions is reduced.

[0025] Specifically, is mixed with an acylating reagent in an organic solvent in the same container, so that reacts with the acyl chloride reagent to generate , and then chlorobenzene is added. With the assistance of ultraviolet light and a catalyst, the Friedel-Crafts reaction can occur, thus realizing the one-pot reaction. In the above steps, the nucleophile is chlorobenzene. Under ultraviolet light irradiation, the hydrogen at the 4-position of chlorobenzene will be activated into an isochlorobenzene complex (the isochlorobenzene complex is disclosed in the article Charge-Separated Reactive Intermediates from the UV Photodissociation of Chlorobenzene in Solution).

[0026] The structure of the isochlorobenzene complex is as follows: .

[0027] The electron cloud schematic diagram of the isochlorobenzene complex is as follows: The hydrogen at the 4-position coordinated with chlorine in the isochlorobenzene complex has strong activity and will accelerate the reaction with the chlorine on the acyl chloride to generate hydrochloric acid, and the vacant 4-position of the chlorobenzene complex has a strong attraction to the positively charged group. Therefore, the positively charged group is attracted and specifically generates the 4-position substituted product of chlorobenzene, thereby reducing the generation of by-products and .

[0028] At the same time, ultraviolet light can also increase the electron cloud density at the 4-position of chlorobenzene and form an electron cloud with an adjacent electron. Therefore, chlorobenzene is activated and its nucleophilic ability is further enhanced.

[0029] Then, Chlorine substitution and alkyl oxidation in [substance] yield 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanone; Moreover Due to greater steric hindrance than 3,5-dichlorophenylacetyl chloride, therefore, The site for the Friedel-Crafts acylation reaction is more definite, and thus the product purity is higher.

[0030] Then 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanone is reduced to obtain 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanol; finally, the alcoholic hydroxyl group in 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanol is eliminated to obtain resveratrol.

[0031] Specifically, in the specific embodiments of the present invention, the catalyst is aluminum trichloride. The acyl chloride group in 3,5-dichlorobenzoyl chloride forms an aluminum trichloride complex with the assistance of aluminum trichloride. The carbon on the acyl chloride has a positive charge, which has a strong attraction to the 4-position of chlorobenzene, further enhancing the selectivity of the 4-position of chlorobenzene.

[0032] Specifically, in the specific embodiments of the present invention, the catalyst is Beta zeolite doped with anhydrous AlCl3. Doping anhydrous AlCl3 in Beta zeolite as a catalyst has many advantages. First, the zeolite can provide additional acidic sites to enhance the catalytic activity of AlCl3. At the same time, the pore channels of the zeolite can control the entry and exit of reactants and products, which is beneficial to improving the reaction selectivity and yield. AlCl3 can be filled in the pores of the zeolite to form a composite catalyst, and this composite can more effectively promote the acylation reaction, especially for substrates with large steric hindrance. At the same time, the pore channels in the zeolite can absorb the gases generated during the process, and subsequent treatment such as heating enables the zeolite to be reused. The whole process has a high conversion rate and clean production. Specifically, through the impregnation method, AlCl3 can be loaded into the pores of Beta zeolite (pore diameter 0.55 - 0.65 nm) to form a Beta zeolite catalyst loaded with AlCl3 with AlCl3 accounting for 5% - 20% of the total weight of Beta zeolite.

[0033] Specifically, the oxidant used in the oxidation includes Fenton reagent. Fenton reagent can effectively hydroxylate the alkyl group and halogen in [substance].

[0034] The present invention is further described below in conjunction with specific embodiments.

[0035] Comparative Example 1 205 g of , 178 g of thionyl chloride, 146 g of monochlorobenzene ( , the molar ratio of thionyl chloride, chlorobenzene is 1.0:1.5:1.3) and 300 g of Beta zeolite doped with anhydrous AlCl3 (mass ratio 1:6) were dissolved in 1000 g of toluene, stirred at a constant temperature of 20 °C for 14 h, filtered, washed with water for impurity removal, distilled under reduced pressure at 80 °C, then suction filtered and dried to obtain 284 g of a pale yellow solid, purity: 68%, yield 62%.

[0036] 1H NMR (300 MHz, DMSO, δ, ppm): 8.03 (2H in benzene), 7.88(2H in benzene), 7.69(1H in benzene), 7.62(2H in in benzene), 7.34(1H in in benzene), 7.25(2H in in benzene), 4.10 (2Hin CH2), 2.18 (6H in -CH3),. Example 1 205 g of , 178 g of thionyl chloride, 146 g of monochlorobenzene ( , the molar ratio of thionyl chloride, chlorobenzene is 1.0:1.5:1.3) and 300 g of Beta zeolite doped with anhydrous AlCl3 (mass ratio 1:6) were dissolved in 1000 g of toluene, reacted and stirred at a constant temperature of 20 °C under 300 nm ultraviolet light irradiation for 14 h, filtered, washed with water for impurity removal, distilled under reduced pressure at 80 °C, then suction filtered and dried to obtain 290 g of a pale yellow solid, purity: 90%, yield 87%.

[0037] The equation is as follows, where R is methyl.

[0038] The product data of Example 1 are as follows: 1H NMR (300 MHz, DMSO, δ, ppm): 8.03 (2H in benzene), 7.63 (2H in in benzene), 7.34(1H in inbenzene), 7.25(2H in in benzene), 4.14 (2H in -CH2-), 2.18 (6H in -CH3).

[0039] Example 2 258 g of 1-(4-chlorophenyl)-2-(3,5-dimethylphenyl)ethanone and an appropriate Fenton's reagent (with a concentration ratio of reactants of 1:10 - 50 (wt / wt)) were stirred well at 25 °C to obtain 207 g of a white solid, purity: 15%, yield 12%.

[0040] The equation is as follows: 1H NMR(300MHz, DMSO, δ, ppm): 9.68 (1H in alcohol), 9.45 (2H in alcohol), 7.74 (2H in benzene), 6.81 (2H in benzene), 6.54 (2H in benzene), 6.27 (1H in benzene), 4.14 (2H in methylene).

[0041] Example 3 258 g of 1-(4-chlorophenyl)-2-(3,5-dimethylphenyl)ethanone, an appropriate Fenton's reagent (with a concentration ratio of reactants of 1:10 - 50 (wt / wt)), and 50 g of a 5% loading titanium dioxide-silver composite metal catalyst were subjected to photocatalysis while being stirred well at 25 °C to obtain 210 g of a white solid, purity: 25%, yield 21%.

[0042] The equation is as follows: 1H NMR(300MHz, DMSO, δ, ppm): 9.68 (1H in alcohol), 9.45 (2H in alcohol), 7.74 (2H in benzene), 6.81 (2H in benzene), 6.54 (2H in benzene), 6.27 (1H in benzene), 4.14 (2H in methylene).

[0043] Example 4 Synthesis of 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol This reaction is a reduction reaction that reduces the carbonyl group to a hydroxyl group; The specific implementation examples are as follows: 244 g of 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanone and 500 g of absolute ethanol were added to a reaction kettle and fully dissolved. Under a nitrogen atmosphere, 56 g of sodium borohydride (the molar ratio of 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanone to sodium borohydride was 1.0:1.5) was slowly added. The reaction mixture was stirred at a low temperature of 0 - 5 °C until the reaction was completed. Water was slowly added to quench the reaction, followed by filtration, concentration, crystallization, and drying to obtain 240 g of a white solid with a purity of 98% and a yield of 97%.

[0044] 1H NMR (300 MHz, DMSO, δ, ppm): 9.45 (2H in alcohol), 9.06 (1H in alcohol), 7.11 (2H in benzene), 6.71 (2H in ethylene), 6.30 (2H in ethylene), 6.17 (1H in benzene), 5.26 (1H in methine), 5.17 (1H in alcohol), 3.15 (1H in methylene), 2.90 (1H in methylene).

[0045] Example 5 Synthesis of Resveratrol This reaction is a dehydration reaction to prepare resveratrol by dehydrating the hydroxyl group; The specific examples are as follows: 246 g of 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanol, 267 g of anhydrous AlCl3, and 400 g of anhydrous acetonitrile solution (the molar ratio of 1-(4-hydroxyphenyl)-2-(3,5-dihydroxyphenyl)ethanol, AlCl3 to acetonitrile was 1.0:2.0:9.7) were refluxed and stirred for 4 h. After the reaction was completed, it was allowed to stand and cool. An appropriate amount of water was added to hydrolyze AlCl3, followed by filtration, evaporation under reduced pressure to dryness, and recrystallization with absolute ethanol to obtain 200 g of white needle-like crystals with a purity of 74% and a yield of 65%.

[0046] 1H NMR (300 MHz, DMSO, δ, ppm): 9.68 (1H in alcohol), 9.07 (2H in alcohol), 7.38 (2H in benzene), 6.92 (1H in ethylene), 6.82 (1H in ethylene), 6.75 (2H in benzene), 6.38 (2H in benzene), 6.12 (1H in benzene).

Claims

1. A method for preparing resveratrol, characterized in that: It comprises the following steps: Compound 1 is mixed with an acylating agent in an organic solvent and then reacted to obtain Compound 2. Then, chlorobenzene and a catalyst are added, and under the condition of ultraviolet light, Compound 2 reacts with chlorobenzene to undergo a Friedel-Crafts reaction to obtain Compound 3; Compound 3 is oxidized to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone; 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone is reduced to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol; The alcoholic hydroxyl group in 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol is eliminated to obtain resveratrol; Among them, the structure of Compound 1 is as follows: The structure of Compound 2 is as follows: The structure of Compound 3 is as follows: Among them, R represents an alkyl group or a halogen.

2. The method for preparing resveratrol according to claim 1, characterized in that: The alkyl group is selected from methyl, ethyl, and propyl; The halogen is selected from chlorine or bromine.

3. The method for preparing resveratrol according to claim 1, characterized in that: The molar ratio of 3,5-dichlorophenylacetic acid to the acylating agent and chlorobenzene is 1.0:1.5:1.

3. The catalyst includes aluminum chloride; or The catalyst includes Beta zeolite doped with anhydrous AlCl3.

4. The method for preparing resveratrol according to claim 1, characterized in that: The wavelength of the ultraviolet light is 280 - 350 nm; The acylating agent includes SOCl2.

5. The method for preparing resveratrol according to claim 1, characterized in that: The oxidant used in the oxidation is FENTON reagent; The pH value used in the oxidation is 3 - 4; The temperature used in the oxidation is 20 - 40 °C.

6. The method for preparing resveratrol according to claim 1, characterized in that: The catalyst used in the oxidation is a titanium dioxide-silver composite metal catalyst.

7. The method for preparing resveratrol according to claim 1, characterized in that: The loading amount of titanium dioxide in the catalyst is 2 - 8 wt%.

8. The method for preparing resveratrol according to claim 1, characterized in that: The reducing agent used in the reduction includes sodium borohydride or potassium borohydride; The dehydrating agent used in the elimination includes aluminum chloride or p-toluenesulfonic acid.

9. Resveratrol prepared by the method for preparing resveratrol according to claim 1.

10. The application of the resveratrol according to claim 9, characterized in that: It is applied to the preparation of a drug for activating acetylase; or It is applied to the preparation of a drug for scavenging free radicals; or It is applied to the preparation of a drug for inhibiting the production and release of inflammatory factors; or It is applied to the preparation of a drug for reducing cholesterol in the blood.

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