A preparation method of trans-resveratrol

Abstract

The invention belongs to the technical field of resveratrol preparation, and specifically relates to a method for preparing trans-resveratrol, comprising the following steps: S1, dissolving tribenzyloxy-resveratrol in an organic solvent A under a hydrogen atmosphere, and purifying the mixture through a hydrogenation reaction under the action of a catalyst to obtain dihydro-resveratrol; S2, dissolving the dihydro-resveratrol prepared by S1 and a halogenation reagent in an organic solvent B under a protective gas atmosphere, and preparing a crude halogenated intermediate I through a halogenation reaction; S3, dissolving the crude halogenated intermediate I prepared by S2 in an organic solvent C under a protective gas atmosphere, and performing a dehalogenation olefination reaction with a base, and purifying the mixture to obtain a product, trans-resveratrol. The method has multiple sources of raw materials and obvious cost advantages, and the preparation method is more convenient and environmentally friendly, has a high total yield, less three wastes, and higher purity, and is conducive to industrialization.

Description

Technical Field

[0001] The invention belongs to the technical field of resveratrol preparation, and particularly relates to a method for preparing trans-resveratrol. Background Art

[0002] Resveratrol was discovered as early as 1924. In 1974, it was found in grape plants and was first identified as a substance that can produce stress resistance. It is widely found in many plants and has important biological activities such as anti-tumor and anti-viral. At present, resveratrol plant extracts have been made into capsules with lipid-regulating and anti-cancer effects.

[0003] There are two methods for preparing resveratrol: plant extraction and synthesis. The plant extraction method has been gradually abandoned due to the environmental pollution caused by the use of a large amount of Class A solvents. The organic synthesis method has been widely studied. In these methods, different groups are usually used to protect the hydroxyl group, such as methyl, benzyl, etc., but Lewis acids such as aluminum trichloride and boron tribromide are usually introduced during the deprotection process, which produces a large amount of three wastes and greatly increases the treatment cost. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a method for preparing trans-resveratrol.

[0005] The present invention is specifically achieved through the following technical solutions.

[0006] A method for preparing trans-resveratrol comprises the following steps:

[0007] S1. Dissolving tribenzyl resveratrol in an organic solvent A under a hydrogen atmosphere, causing a hydrogenation reaction under the action of a catalyst, and obtaining dihydro-resveratrol after purification;

[0008] S2. Under a protective gas atmosphere, dissolving the dihydro-resveratrol prepared in S1 and a halogenation reagent in an organic solvent B to undergo a halogenation reaction, and preparing a crude halogenated intermediate I after purification;

[0009] S3, under a protective gas atmosphere, dissolving the crude halogenated intermediate I prepared in S2 in an organic solvent C, and subjecting it to a dehalogenation olefination reaction with a base, and obtaining the product trans-resveratrol after purification;

[0010] Its synthetic route is as follows:

[0011]

[0012] Preferably, in S1, the catalyst is any one of palladium carbon, Raney nickel, ruthenium carbon, rhodium carbon, or a mixture of two of them, and the molar ratio of tribenzyl resveratrol to the catalyst is 100:1-10.

[0013] Preferably, in S1, the hydrogen pressure is 0.1-5 MPa.

[0014] Preferably, in S2, the halogenating agent is any one of NBS, bromine, hydrogen peroxide + hydrobromic acid, NCS, NIS, I2, Cl2, cyanuric chloride, dibromohydantoin, dichlorohydantoin, or a mixture of two thereof, and the molar ratio of dihydro-resveratrol to the halogenating agent is 1:1-5.

[0015] Preferably, in S3, the base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof, and the molar ratio of the halogenated intermediate I to the base is 1:1-5.

[0016] Preferably, organic solvent A, organic solvent B, and organic solvent C are any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents, alcohol solvents, and highly polar solvents containing heteroatoms;

[0017] The molar ratio of organic solvent A to tribenzyloxy-resveratrol is 1-10:1; the molar ratio of organic solvent B to dihydro-resveratrol is 1-10:1; and the molar ratio of organic solvent C to halogenated intermediate I is 1-10:1.

[0018] More preferably, the halogenated hydrocarbon solvents include dichloromethane and dichloroethane; the aromatic solvents include toluene and xylene; the ether solvents include tetrahydrofuran; the ester solvents include methyl acetate and ethyl acetate; the alcohol solvents include methanol, ethanol and ethylene glycol; the highly polar solvents containing heteroatoms include DMF, DMA, DMSO, NMP, sulfolane and DMI.

[0019] Preferably, the reaction temperatures in S1 and S2 are 0-100°C respectively; in S3, the reaction temperature is -50-150°C.

[0020] More preferably, the reaction temperatures in S1 and S2 are 50-80°C respectively; in S3, the reaction temperature is -30-10°C.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] In order to solve the problem of large amount of wastewater generated due to the use of Lewis acid in the synthesis of trans-resveratrol in the prior art, a new synthesis route is proposed. Specifically, in the present invention, tribenzyloxy-resveratrol is used as a raw material in an organic solvent at a certain temperature to obtain the product trans-resveratrol through three steps of hydrogenation, halogenation and olefination. The raw material sources are multiple and the cost advantage is obvious. The use of Lewis acid is avoided in the preparation process. The preparation method is more convenient and environmentally friendly, with a high total yield, less three wastes and higher purity, which is conducive to industrialization. DETAILED DESCRIPTION

[0023] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below in conjunction with specific examples and data, but the examples are not intended to limit the present invention.

[0024] The experimental methods and detection methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0025] The present invention provides a method for preparing trans-resveratrol, comprising the following steps:

[0026] S1. Dissolving tribenzyl resveratrol in an organic solvent A under a hydrogen atmosphere, causing a hydrogenation reaction under the action of a catalyst, and obtaining dihydro-resveratrol after purification;

[0027] S2. Under a protective gas atmosphere, dissolving the dihydro-resveratrol prepared in S1 and a halogenation reagent in an organic solvent B to undergo a halogenation reaction, and preparing a crude halogenated intermediate I after purification;

[0028] S3, under a protective gas atmosphere, dissolving the crude halogenated intermediate I prepared in S2 in an organic solvent C, and subjecting it to a dehalogenation olefination reaction with a base, and obtaining the product trans-resveratrol after purification;

[0029] Its synthetic route is as follows:

[0030]

[0031] Wherein, organic solvent A, organic solvent B, and organic solvent C are any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents or alcohol solvents, and highly polar solvents containing heteroatoms; the halogenated hydrocarbon solvents include dichloromethane and dichloroethane; the aromatic solvents include toluene and xylene; the ether solvents include tetrahydrofuran; the ester solvents include methyl acetate and ethyl acetate; the alcohol solvents include methanol, ethanol, and ethylene glycol; the highly polar solvents containing heteroatoms include DMF, DMA, DMSO, NMP, sulfolane, and DMI. The base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, and potassium tert-butoxide, or a mixture of two of them. The halogenating agent is any one of NBS, bromine, hydrogen peroxide + hydrobromic acid, NCS, NIS, I2, Cl2, cyanuric chloride, dibromohydantoin, and dichlorohydantoin, or a mixture of two of them. The catalyst A is any one of palladium carbon, Raney nickel, ruthenium carbon, and rhodium carbon, or a mixture of two of them.

[0032] The above contents are specifically described below through the following embodiments.

[0033] First, dihydro-resveratrol is synthesized. The synthesis formula is as follows:

[0034]

[0035] The above synthesis is specifically described below through the following examples.

[0036] Example 1

[0037] In a 500mL high-pressure reactor, 49.8g (0.10mol) of tribenzyloxy-resveratrol, 100mL of methanol, and 1g of 3% ruthenium carbon solid were added. The atmosphere was replaced with nitrogen three times and hydrogen three times, and the pressure was set to 1MPa. The mixture was heated to 50 degrees and stirred for reaction for 12h. The temperature was lowered and the pressure was released. The catalyst was recovered by pressure filtration, and methanol was recovered by atmospheric distillation (directly applied to the next batch of reactions). The recovery rate was 90%. 50mL of water was added, and the mixture was extracted with ethyl acetate and desolventized to obtain >98% of dihydro-resveratrol. The product weight was 20.7g, and the yield was 90%.

[0038] Example 2

[0039] In a 500mL high-pressure reactor, 49.8g (0.10mol) of tribenzyloxy-resveratrol, 100mL of methanol, and 1g of 5% palladium-carbon solid were added. The atmosphere was replaced with nitrogen three times and hydrogen three times, and the pressure was set to 1MPa. The mixture was heated to 50°C and stirred for 12h. The temperature was lowered and the pressure was released. The catalyst was recovered by pressure filtration, and methanol was recovered by atmospheric distillation (directly applied to the next batch of reactions). The recovery rate was 90%. 50mL of water was added, and the mixture was extracted with ethyl acetate and desolventized to obtain >98% of dihydro-resveratrol. The product weight was 21.85g, and the yield was 95%.

[0040] Example 3

[0041] In a 500mL high-pressure reactor, 49.8g (0.10mol) of tribenzyl-resveratrol, 100mL of methanol and 1g of Raney nickel were added. After nitrogen replacement three times and hydrogen replacement three times, the pressure was set to 1MPa, heated to 50 degrees and stirred for reaction for 12h, cooled and depressurized, the catalyst was recovered by pressure filtration, and methanol was recovered by atmospheric distillation (directly applied to the next batch of reactions), with a recovery rate of 90%. 50mL of water was added, and the mixture was extracted with ethyl acetate and desolvated to obtain >98% of dihydro-resveratrol, with a product weight of 18.86g and a yield of 82%.

[0042] Example 4

[0043] In a 500mL high-pressure reactor, 49.8g (0.10mol) of tribenzyloxy-resveratrol, 100mL of methanol, and 1g of 1% rhodium-carbon solid were added. After nitrogen replacement three times and hydrogen replacement three times, the pressure was set to 1MPa, heated to 50 degrees and stirred for reaction for 12h, cooled and depressurized, the catalyst was recovered by pressure filtration, and methanol was recovered by atmospheric distillation (directly applied to the next batch of reactions), with a recovery rate of 90%. 50mL of water was added, and ethyl acetate was extracted and desolvated to obtain >98% of dihydro-resveratrol, with a product weight of 20.24g and a yield of 88%.

[0044] Example 5

[0045] In a 500L high-pressure reactor, 49.8kg of benzyloxy-resveratrol, 200L of methanol, and 100g of a 5% palladium carbon solid catalyst were added. The atmosphere was replaced with nitrogen three times and hydrogen three times, and the pressure was set to 2MPa. The mixture was heated to 50 degrees and stirred for reaction for 12h. The temperature was lowered and the pressure was released. The catalyst was recovered by filter press, and methanol was recovered by atmospheric distillation (directly applied to the next batch of reactions). The recovery rate was 93%. 100L of water was added, and 200L of ethyl acetate was used for extraction and desolvation to obtain >98% of dihydro-resveratrol.

[0046] It can be seen from the above examples that dihydro-resveratrol is successfully synthesized in this step, and the post-treatment is simple during the reaction, no Lewis acid is used, and the amount of wastewater generated is small, which is suitable for industrial synthesis.

[0047] Second, synthesize the halogenated intermediate I. The synthesis equation is as follows:

[0048]

[0049] The above synthesis is specifically described below through the following examples.

[0050] Example 6

[0051] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane, and 17.8 g (0.1 mol) of NBS were added to a 500 mL reactor, slowly heated to 50 degrees and stirred for reaction for 24 hours, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, 100 ml of water was added to the solid to pulp to remove succinimide to obtain a wet brominated intermediate I, and dried to obtain 27.7 g of the finished product with a yield of 89.5%; the filtered filtrate was added with dichloroethane (directly applied to the next batch of reactions).

[0052] Example 7

[0053] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane and 0.1 mol of bromine were added into a 500 mL reactor, slowly heated to 50 degrees and stirred for 24 hours, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, and the solid was pulped with 100 ml of water to remove succinimide to obtain the wet product of brominated intermediate I with a yield of 12%; the filtered filtrate was dichloroethane (directly applied to the next batch of reactions).

[0054] Example 8

[0055] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane, and 0.1 mol of hydrogen peroxide + hydrobromic acid were added to a 500 mL reactor, and the mixture was slowly heated to 50 degrees and stirred for 24 hours. The mixture was cooled to room temperature and filtered to obtain brominated intermediate I and succinimide by-products. The solid was pulped with 100 ml of water to remove succinimide to obtain a wet product of brominated intermediate I with a yield of 28%. The filtered filtrate was dichloroethane (directly applied to the next batch of reactions).

[0056] Example 9

[0057] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane, and 0.1 mol of chlorine were added to a 500 mL reactor, slowly heated to 50 degrees and stirred for reaction for 24 hours, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, and the solid was pulped with 100 ml of water to remove succinimide to obtain a wet product of brominated intermediate I with a yield of 65%; the filtered filtrate was dichloroethane (directly applied to the next batch of reactions).

[0058] Example 10

[0059] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane and 0.1 mol of NCS were added into a 500 mL reactor, slowly heated to 50 degrees and stirred for reaction for 24 hours, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, and the solid was pulped with 100 ml of water to remove succinimide to obtain a wet product of brominated intermediate I with a yield of 59%; the filtered filtrate was dichloroethane (directly applied to the next batch of reactions).

[0060] Embodiment 11

[0061] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane, and 0.1 mol of NIS were added to a 500 mL reactor, slowly heated to 50 degrees and stirred for reaction for 24 hours, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, and the solid was pulped with 100 ml of water to remove succinimide to obtain a wet product of brominated intermediate I with a yield of 74%; the filtered filtrate was dichloroethane (directly applied to the next batch of reactions).

[0062] Example 12

[0063] Under nitrogen protection, 23 g (0.10 mol) of dihydro-resveratrol, 200 mL of dichloroethane and 0.1 mol of I were added into a 500 mL reactor, slowly heated to 50 degrees and stirred for reaction for 24 hours, cooled to room temperature, filtered to obtain brominated intermediate I and succinimide by-product, and the solid was pulped with 100 ml of water to remove succinimide to obtain a wet product of brominated intermediate I with a yield of 5%; the filtered filtrate was dichloroethane (directly applied to the next batch of reactions).

[0064] It can be seen from the above examples that the present invention synthesizes the brominated intermediate I by changing the type of halogenating reagent, and the synthesis route is simple and has strong operability.

[0065] Third, resveratrol synthesis, the synthesis equation is as follows:

[0066]

[0067] The above synthesis is specifically described below by means of the following examples.

[0068] Example 13

[0069] Under nitrogen protection, 0.8 g (0.10 mol) of brominated intermediate I3, 100 mL of methanol and 100 mL of water were added to a 500 mL reactor. 0.12 mol (96 mL) of 5% sodium hydroxide solution was added dropwise at 0 degrees. The mixture was kept warm for 1 hour. After filtration, washing and drying, 20 g of resveratrol was obtained with a yield of 87.7% and a purity of 99.9%.

[0070] It can be seen that the present invention successfully synthesized resveratrol through simple olefination based on the synthesized halogenated intermediate I. The synthesis process is simple and has strong operability. The synthesized product has high purity and is suitable for industrial production and application.

[0071] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, they are also intended to be included.

Claims

1. A method for preparing trans-resveratrol, characterized in that: The following steps are involved: S1. Dissolving tribenzyl resveratrol in an organic solvent A under a hydrogen atmosphere, causing a hydrogenation reaction under the action of a catalyst, and obtaining dihydro-resveratrol after purification; S2, under a protective gas atmosphere, dissolving the dihydro-resveratrol prepared in S1 and a halogenation reagent in an organic solvent B to undergo a halogenation reaction, and preparing a halogenated intermediate I after purification; S3, under a protective gas atmosphere, dissolving the halogenated intermediate I prepared in S2 in an organic solvent C, and subjecting it to a dehalogenation olefination reaction with a base, and obtaining the product trans-resveratrol after purification; The molar ratio of the halogenated intermediate I and the base is 1:1-5, and in S3, the reaction temperature is 0°C; In S1, the catalyst is any one of palladium carbon, Raney nickel, ruthenium carbon, rhodium carbon, or a mixture of two of them, and the molar ratio of tribenzyloxy-resveratrol to the catalyst is 100: 1-10; In S1, the hydrogen pressure is 0.1-5MPa; The reaction temperatures in S1 and S2 are 50-80°C, respectively.

2. The method for preparing trans-resveratrol according to claim 1, characterized in that: In S2, the halogenating agent is any one of NBS, bromine, hydrogen peroxide + hydrobromic acid, NCS, NIS, I2, Cl2, cyanuric chloride, dibromohydantoin, and dichlorohydantoin, and the molar ratio of dihydro-resveratrol to the halogenating agent is 1: 1-5.

3. The method for preparing trans-resveratrol according to claim 1, characterized in that: In S3, the base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a mixture of two thereof.

4. The method for preparing trans-resveratrol according to claim 1, characterized in that: The organic solvent A, organic solvent B, and organic solvent C are any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents, alcohol solvents, and polar solvents containing heteroatoms; The molar ratio of organic solvent A to tribenzyl-resveratrol is 1-10:1; the molar ratio of organic solvent B to dihydro-resveratrol is 1-10:1; and the molar ratio of organic solvent C to halogenated intermediate I is 1-10:

1.

5. The method for preparing trans-resveratrol according to claim 4, characterized in that: The halogenated hydrocarbon solvents are dichloromethane and dichloroethane; the aromatic solvents are toluene and xylene; the ether solvents are tetrahydrofuran; the ester solvents are methyl acetate and ethyl acetate; the alcohol solvents are methanol, ethanol and ethylene glycol; and the polar solvents containing heteroatoms are DMF, DMA, DMSO, NMP, sulfolane and DMI.

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