Resveratrol and its preparation method and application

Abstract

The invention provides a method for preparing resveratrol, comprising the following steps: mixing 3,5-dichlorophenylacetic acid and an acylating agent in an organic solvent and reacting the mixture to obtain 3,5-dichlorophenylacetyl chloride; then adding chlorobenzene and a catalyst to react 3,5-dichlorophenylacetyl chloride with chlorobenzene under ultraviolet light to obtain 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone; replacing chlorine in 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone; reducing 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol; and eliminating alcoholic hydroxyl groups in 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol to obtain resveratrol.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to resveratrol and a preparation method and application thereof. Background Art

[0002] Resveratrol is a non-flavonoid stilbene compound with the chemical formula C 14 H 12 O3 has multiple biological activities, can remove 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 multiple inflammatory factors; can reduce blood cholesterol levels, inhibit platelet aggregation, and thus prevent the occurrence and development of cardiovascular diseases; can activate acetylase, increase cell life and vitality, and thus play an anti-aging role, etc. Resveratrol is widely used in health foods, cosmetics, and drug research and development due to its multiple biological activities.

[0003] Resveratrol has two main stereoisomers, trans-resveratrol and cis-resveratrol, of 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. Therefore, the present invention is mainly aimed at 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. used the Grignard reaction to fully synthesize resveratrol. First, 4-methoxybenzyl alcohol was chlorinated with SOCl2, then reacted with Mg to obtain an intermediate by Grignard reaction, then reacted with 3,5-dimethoxybenzaldehyde to obtain an ethanol derivative, then the alcohol hydroxyl group under the catalysis of KHSO4 underwent elimination reaction to form a double bond to obtain an intermediate, and finally demethylated 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 less side reactions, high yield and relatively simple reaction process.

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

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

[0010] A method for preparing resveratrol comprises the following steps: 3,5-dichlorophenylacetic acid and an acylating agent are mixed in an organic solvent and reacted to obtain 3,5-dichlorophenylacetyl chloride, and then chlorobenzene and a catalyst are added to cause 3,5-dichlorophenylacetyl chloride to react with chlorobenzene under ultraviolet light to obtain 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone; Substituting the chlorine in 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone; Reducing 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol; Resveratrol is obtained by eliminating the alcoholic hydroxyl group in 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol.

[0011] The organic solvent includes one of toluene, ethylbenzene, dichloromethane or dichloroethane.

[0012] The molar ratio of the 3,5-dichlorophenylacetic acid to the acylating agent and chlorobenzene is 1.0:1.5:1.3.

[0013] The catalyst comprises aluminum chloride; or The catalyst comprises a Beta molecular sieve doped with anhydrous AlCl3; The wavelength of the ultraviolet light is 280-350nm; The acylating agent includes SOCl2; The base used in the substitution includes sodium hydroxide; The reducing agent used in the reduction comprises sodium borohydride; The dehydrating agent used in the elimination includes aluminum chloride.

[0014] The resveratrol prepared by the resveratrol preparation method.

[0015] The application of resveratrol is used to prepare a drug for activating acetylase; or Used in the preparation of drugs for scavenging free radicals; or Used in the preparation of drugs for inhibiting the production and release of inflammatory factors; or Used in the preparation of drugs for lowering blood cholesterol.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The invention adopts a one-pot reaction, adopts 3,5-dichlorophenylacetic acid and chlorobenzene to synthesize 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone, simplifies the preparation method of resveratrol, and reduces the preparation cost thereof.

[0017] The method provided by the invention uses ultraviolet light to assist the Friedel-Crafts reaction, thereby reducing the content of by-products in the product of the Friedel-Crafts reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 A chromatogram of the product of Example 1 is shown; Figure 2 The chromatogram of the product of Comparative Example 1 is shown; Figure 3 The chromatogram of the product of Example 3 is shown; Figure 4 The chromatogram of the product of Example 4 is shown; Figure 5 The chromatogram of the product of Example 5 is shown; Figure 6 The NMR spectrum of the product of Example 1 is shown; Figure 7 The NMR spectrum of the product of Comparative Example 1 is shown; Figure 8 The NMR spectrum of the product of Example 3 is shown; Fig. 9 The NMR spectrum of the product of Example 4 is shown; Fig.10 The NMR spectrum of the product of Example 5 is shown. DETAILED DESCRIPTION

[0019] The present invention provides a method for preparing resveratrol, and the preparation process is as follows: As is known, according to the records in the prior art Catalytic Friedel-Crafts Acylation of Benzene, Chlorobenzene, and Fluorobenzene Using a Novel Catalyst System, HafniumTriflate and Trifluoromethanesulfonic Acid, in the presence of Hf(OTf)4 and TfOH, unactivated benzene series, such as chlorobenzene and fluorobenzene, can react smoothly to obtain corresponding aromatic ketones. However, there are many reaction sites in chlorobenzene, and the reaction impurities are relatively large. This is because the chlorine on the benzene ring has an electron-withdrawing effect and also has a slight electron-donating conjugation effect. In general, 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 conjugation effect makes the electron cloud density of the ortho-para position of the benzene ring higher than that of the meta position, so the chlorine atom is a kind of ortho-para position positioning substituent that slightly passivates the benzene ring. In other words, using chlorobenzene as the raw material of the Friedel-Crafts reaction, the difficulty of the reaction increases first, and a variety of by-products are also produced.

[0020] Specifically in the present invention, when preparing resveratrol, if 3,5-dichlorophenylacetyl chloride and chlorobenzene are used to carry out Friedel-Crafts reaction to prepare the intermediate product 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone, multiple by-products may be produced, such as 1-(3-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone and 1-(2-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone. How to specifically make the reaction occur on the hydrogen at the fourth position of chlorobenzene is a problem that needs to be solved.

[0021] In order to reduce side reactions and increase the reactivity of chlorobenzene, the present invention improves the preparation method of resveratrol, adopts ultraviolet light catalysis to achieve a one-pot preparation of the intermediate product 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone, and also reduces the occurrence of side reactions.

[0022] Specifically, 3,5-dichlorophenylacetic acid and an acylating agent are mixed in an organic solvent in the same container, and 3,5-dichlorophenylacetic acid reacts with an acylating agent to generate 3,5-dichlorophenylacetyl chloride, and then chlorobenzene is added, and with the aid of ultraviolet light and a catalyst, a Friedel-Crafts reaction can occur to achieve a one-pot reaction. In the above steps, the nucleophilic agent is chlorobenzene. Under ultraviolet light, the hydrogen at the 4-position of chlorobenzene is activated to form an isochlorobenzene complex (the isochlorobenzene complex is disclosed in the article Charge-Separated Reactive Intermediates from the UV Photodissociation of Chlorobenzene in Solution).

[0023] The structure of the isochlorobenzene complex is as follows: .

[0024] The electron cloud schematic diagram of the isochlorobenzene complex is as follows: The 4-position hydrogen 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, while the vacant 4-position of the chlorobenzene complex has a strong attraction to the positively charged group. Therefore, the positively charged 3,5-dichlorophenylacetyl group is attracted and specifically generates the chlorobenzene 4-position substitution 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone, thereby reducing the generation of by-products 1-(3-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone and 1-(2-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone.

[0025] 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 electron at the adjacent position. Therefore, chlorobenzene is activated and its nucleophilic ability is further enhanced.

[0026] Then, the chlorine in 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone is replaced to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone; then 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone is reduced to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol; finally, the alcoholic hydroxyl group in 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol is eliminated to obtain resveratrol.

[0027] Specifically, in a specific embodiment of the present invention, the catalyst is aluminum trichloride. The acyl chloride group in 3,5-dichlorobenzene acyl 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.

[0028] Specifically, the organic solvent includes common organic solvents such as toluene, ethylbenzene, dichloromethane or dichloroethane.

[0029] Specifically, the molar ratio of the 3,5-dichlorophenylacetic acid to the acylating agent and chlorobenzene is 0.8-1.2:1.2-1.8:1.1-1.5.

[0030] Specifically, in a specific embodiment of the present invention, the catalyst is a Beta molecular sieve doped with anhydrous AlCl3. There are many advantages in doping anhydrous AlCl3 in a Beta molecular sieve as a catalyst. First, the molecular sieve can provide additional acid sites to enhance the catalytic activity of AlCl3. At the same time, the pores of the molecular sieve can control the entry and exit of reactants and products, which is conducive to improving the selectivity and yield of the reaction. AlCl3 can be filled in the pores of the molecular sieve to form a composite catalyst, which can more effectively promote the acylation reaction, especially for substrates with large steric hindrance. At the same time, the pores in the molecular sieve can also absorb the gas generated in the process, and the molecular sieve can be reused by subsequent heating and other treatments, and the whole process has a high conversion rate and clean production. Specifically, by impregnation, AlCl3 can be loaded in the pores of Beta molecular sieve (pore size is 0.55-0.65nm), forming a Beta molecular sieve catalyst loaded with AlCl3 with AlCl3 accounting for 5%-20% of the total weight of the Beta molecular sieve.

[0031] The wavelength of the ultraviolet light is 280-350nm; The acylating agent includes SOCl2. Ultraviolet light can decompose SOCl2. As is known, SOCl2 can also react with chlorobenzene. If ultraviolet light is present, SOCl2 will decompose and will not participate in subsequent reactions.

[0032] The base used for the substitution includes sodium hydroxide, KOH or LiOH.

[0033] The reducing agent used in the reduction includes sodium borohydride and potassium borohydride.

[0034] The dehydrating agent used in the elimination includes aluminum chloride, p-toluenesulfonic acid, etc.

[0035] The present invention also provides resveratrol prepared by the resveratrol preparation method.

[0036] The present invention also provides the application of the resveratrol, which can be specifically applied to the preparation of a drug for activating acetylase; or Used in the preparation of drugs for scavenging free radicals; or Used in the preparation of drugs for inhibiting the production and release of inflammatory factors; or Used in the preparation of drugs for lowering blood cholesterol.

[0037] The present invention is further described below in conjunction with specific embodiments.

[0038] Example 1 205 g of 3,5-dichlorophenylacetic acid, 178 g of thionyl chloride, 146 g of monochlorobenzene (the molar ratio of 3,5-dichlorophenylacetic acid, thionyl chloride and chlorobenzene is 1.0:1.5:1.3) and 300 g of Beta molecular sieve doped with anhydrous AlCl3 (mass ratio is 1:6) are dissolved in 1000 g of toluene, reacted and stirred at a constant temperature of 20°C and irradiated with 300 nm ultraviolet light for 14 hours, filtered, washed with water to remove impurities, and distilled under reduced pressure at 80°C, filtered and dried to obtain 290 g of light yellow solid with a purity of 90% and a yield of 87%.

[0039] Figure 1 The chromatogram of the product prepared in Example 1 is shown, Figure 6 The NMR spectrum of the product prepared in Example 1 is shown. The NMR data of the product prepared in Example 1 are as follows: 1H NMR (300MHz, DMSO, δ, ppm): 8.03 (2H in benzene), 7.63 (2H in benzene), 7.61 (1H in benzene), 7.50 (2H in benzene), 4.14 (2H in CH2).

[0040] Comparative Example 1 205 g of 3,5-dichlorophenylacetic acid, 178 g of thionyl chloride, 146 g of monochlorobenzene (the molar ratio of 3,5-dichlorophenylacetic acid, thionyl chloride and chlorobenzene is 1.0:1.5:1.3) and 300 g of Beta molecular sieve doped with anhydrous AlCl3 (mass ratio is 1:6) are dissolved in 1000 g of toluene, reacted and stirred at a constant temperature of 20°C for 14 hours, filtered and washed with water to remove impurities, and vacuum distilled at 80°C, filtered and dried to obtain 284 g of light yellow solid with a purity of 65% and a yield of 62%.

[0041] Figure 2 The chromatogram of the product prepared in Comparative Example 1 is shown, Figure 7 The NMR spectrum of the product prepared in Comparative Example 1 is shown. The NMR data of the product prepared in Comparative Example 1 are as follows: 1H NMR (300MHz, DMSO, δ, ppm): 8.03 (2H in benzene), 7.88(2H in benzene), 7.69(1H in benzene), 7.62(2H in benzene), 7.61(1H in benzene), 7.50(2H in benzene), 4.10 (2H in CH2).

[0042] from Figure 6 and Figure 7 It can be seen that the chromatographic peaks of the product of Comparative Example 1 are more than those of Example 1. This indicates that the reaction provided in Comparative Example 1 has many side reactions.

[0043] Example 2 205 g of 3,5-dichlorophenylacetic acid, 178 g of thionyl chloride, 146 g of monochlorobenzene (the molar ratio of 3,5-dichlorophenylacetic acid, thionyl chloride and chlorobenzene is 1.0:1.5:1.3) and 120 g of anhydrous AlCl3 were dissolved in 1000 g of toluene, reacted and stirred at a constant temperature of 20°C and irradiated with 300 nm ultraviolet light for 14 hours, then filtered and washed with water to remove impurities, and vacuum distilled at 80°C, filtered and dried to obtain 290 g of light yellow solid with a purity of 89% and a yield of 87%.

[0044] The NMR data of the product prepared in Example 2 are as follows: 1H NMR (300MHz, DMSO, δ, ppm): 8.02 (2H in benzene), 7.63 (2H in benzene), 7.60 (1H in benzene), 7.50 (2H in benzene), 4.11 (2H in CH2).

[0045] Example 3 This reaction is a substitution reaction, which replaces three chlorine atoms with hydroxyl groups.

[0046] The details are as follows: 299 g of 1-(4-chlorobenzene)-2-(3,5-dichlorophenyl)ethanone and 144 g of sodium hydroxide (the molar ratio of 1-(4-chlorobenzene)-2-(3,5-dichlorophenyl)ethanone: sodium hydroxide is 1.0:1.2) were added into 500 g of tetrahydrofuran, heated to 40°C and refluxed, then washed with water to remove impurities, and 240 g of white solid was obtained after desolventizing, crystallizing, filtering and drying, with a purity of 98% and a yield of 96%.

[0047] Figure 3 The chromatogram of the product prepared in Example 3 is shown, Figure 8The NMR spectrum of the product prepared in Example 3 is shown. The NMR data of the product prepared in Example 3 are 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).

[0048] Example 4 Synthesis of 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol. This reaction is a reduction reaction, which reduces the carbonyl group to a hydroxyl group.

[0049] The details are as follows: 244 g of 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone and 500 g of anhydrous ethanol were added to the reactor and fully dissolved. 56 g of sodium borohydride (the molar ratio of 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone:sodium borohydride was 1.0:1.5) was slowly added under nitrogen. The reaction mixture was stirred at a low temperature of 0-5°C until the reaction was completed. Water was slowly added to quench, filtered, concentrated, crystallized, and dried to obtain 240 g of a white solid with a purity of 99.8% and a yield of 97%.

[0050] Figure 4 The chromatogram of the product prepared in Example 4 is shown, Fig. 9 The NMR spectrum of the product prepared in Example 4 is shown. The NMR data of the product prepared in Example 4 are as follows: 1H NMR (300MHz, 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 (1Hin methine), 5.17(1H in alcohol), 3.15(1H in methylene), 2.90(1H inmethylene).

[0051] Example 5 Synthesis of resveratrol. This reaction is a dehydration reaction, which dehydrates the hydroxyl group to produce resveratrol; The details are as follows: 246g of 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol, 267g of anhydrous AlCl3, and 400g of anhydrous acetonitrile solution (the molar ratio of 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol, AlCl3 and acetonitrile is 1.0:2.0:9.7), reflux and stir for 4h, and let stand and cool after the reaction. Add appropriate amount of water to hydrolyze AlCl3, filter, evaporate to dryness under reduced pressure, and then recrystallize from anhydrous ethanol to obtain 200g of white needle crystals with a purity of 75% and a yield of 65%.

[0052] Figure 5 The chromatogram of the product prepared in Example 5 is shown, Fig.10 The NMR spectrum of the product prepared in Example 5 is shown. The NMR data of the product prepared in Example 5 are as follows: 1H NMR (300MHz, 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: The steps include: 3,5-dichlorophenylacetic acid and an acylating agent are mixed in an organic solvent and reacted to obtain 3,5-dichlorophenylacetyl chloride, and then chlorobenzene and a catalyst are added to cause 3,5-dichlorophenylacetyl chloride to react with chlorobenzene under ultraviolet light to obtain 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone; Substituting the chlorine in 1-(4-chlorophenyl)-2-(3,5-dichlorophenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone; Reducing 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanone to obtain 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol; Resveratrol is obtained by eliminating the alcoholic hydroxyl group in 1-(4-phenol)-2-(3,5-dihydroxyphenyl)ethanol.

2. The method for preparing resveratrol according to claim 1, characterized in that: The organic solvent includes one of toluene, ethylbenzene, dichloromethane or dichloroethane.

3. The method for preparing resveratrol according to claim 1, characterized in that: The molar ratio of the 3,5-dichlorophenylacetic acid to the acylating agent and chlorobenzene is 0.8-1.2:1.2-1.8:1.1-1.

5.

4. The method for preparing resveratrol according to claim 1, characterized in that: The catalyst comprises aluminum chloride; or The catalyst comprises a Beta molecular sieve doped with anhydrous AlCl3.

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

6. The method for preparing resveratrol according to claim 1, characterized in that: The base used for the substitution includes sodium hydroxide, KOH or LiOH.

7. The method for preparing resveratrol according to claim 1, characterized in that: The reducing agent used in the reduction includes sodium borohydride and potassium borohydride.

8. The method for preparing resveratrol according to claim 1, characterized in that: The dehydrating agent used for the elimination includes aluminum chloride and p-toluenesulfonic acid.

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

10. The use of resveratrol according to claim 9, characterized in that: Used in the preparation of drugs for activating acetyltransferase; or Used in the preparation of drugs for scavenging free radicals; or Used in the preparation of drugs for inhibiting the production and release of inflammatory factors; or Used in the preparation of drugs for lowering blood cholesterol.

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