A method for synthesizing dihydromyricetin

Abstract

The application provides a high-efficiency and green synthesis method of dihydromyricetin, which takes myricetin and a Pd-PEG2000 catalyst as main raw materials, and finally obtains a dihydromyricetin product with high purity and high content through chemical reduction and hydrogenation reactions.The method is not only simple in operation, but also mild in reaction conditions; meanwhile, the prepared Pd-PEG2000 catalyst can be recycled and recovered easily, and is suitable for industrial production of dihydromyricetin.

Description

TECHNICAL FIELD

[0001] The present application relates to a chemical synthesis method of a cosmetic raw material, in particular to a method for synthesizing dihydromyricetin by one-step hydrogenation of myricetin using Pd-polyethylene glycol. BACKGROUND

[0002] Dihydromyricetin (DMY for short) is a natural flavonoid compound, which generally exists in plants such as rattan, and has significant antioxidant, anti-inflammatory, alcoholism prevention, liver protection, immunity enhancement, blood lipid regulation and other effects. However, the traditional extraction and purification method is to crush the rattan tea, then dissolve and filter with a solvent, and purify by crystallization, but there are a series of problems such as low efficiency, high cost and the like. SUMMARY

[0003] The present application aims to overcome the above-mentioned defects, and develop a method for one-step hydrogenation of myricetin using a high-efficiency catalyst, which has important industrial application value. Specifically, the present application uses a Pd-polyethylene glycol catalyst to prepare dihydromyricetin by one-step hydrogenation of myricetin.

[0004] The specific equation is as follows:

[0005]

[0006] The method realizes high-efficiency hydrogenation reaction under mild conditions, and prepares high-purity dihydromyricetin, which is simple to operate and suitable for large-scale production.

[0007] The present application provides a method for synthesizing dihydromyricetin, specifically: using myricetin as a substrate, using Pd-polyethylene glycol as a catalyst, and catalyzing hydrogenation under a hydrogen atmosphere to synthesize dihydromyricetin (polyethylene glycol is abbreviated as PEG, and the catalyst is named Pd-PEG, and the PEG grafted macromolecule is selected from PEG 200-6000).

[0008] Further, the method for synthesizing dihydromyricetin provided by the present application further has the following characteristics: the polyethylene glycol in the Pd-polyethylene glycol is selected from one kind of polyethylene glycol with an average molecular weight greater than 1000.

[0009] Further, the application provides a method for synthesizing dihydromyricetin, which has the following characteristics: the preparation method of the Pd-polyethylene glycol is as follows: step 1, preparation of a palladium source solution: dissolving Na2[PdCl4] or PdCl2 in deionized water to obtain a palladium ion solution; step 2, preparation of a polyethylene glycol solution: dissolving polyethylene glycol in deionized water to obtain a polyethylene glycol solution; step 3, reduction of palladium: slowly adding the dissolved palladium source solution into the polyethylene glycol solution while stirring, and gradually adding a NaBH4 solution into the reaction system at room temperature to reduce the palladium ions and form metallic palladium; and step 4, reaction, separation and drying: continuing to stir the reaction mixture for 1-2 hours to ensure that the palladium is completely reduced and loaded on the polyethylene glycol, and then performing post-treatment to obtain the Pd-polyethylene glycol.

[0010] Further, the application provides a method for synthesizing dihydromyricetin, which has the following characteristics: the reaction temperature is 25-55°C, the pressure is 1-5 MPa, and the reaction time is 1-5 hours.

[0011] Further, the application provides a method for synthesizing dihydromyricetin, which has the following characteristics: the amount of the catalyst is 1-5% of the mass of myricetin.

[0012] Further, the application provides a method for synthesizing dihydromyricetin, which has the following characteristics: the flow rate of hydrogen is 0.1-1.0 L / min.

[0013] Further, the application provides a method for synthesizing dihydromyricetin, which has the following characteristics: the reaction is carried out in a solvent environment, and the solvent is selected from alcohols. DETAILED DESCRIPTION

[0014] Example 1. Preparation of a catalyst

[0015] Example 1.1. Pd-PEG2000 catalyst

[0016] (1) Preparation of a palladium solution

[0017] Dissolving a palladium source: dissolving a certain amount of Na2[PdCl4] or PdCl2 in deionized water to obtain a palladium ion solution 1.0 mmol.

[0018] (2) Preparation of a polyethylene glycol 2000 (PEG2000) solution

[0019] Taking 1.0 g of PEG2000, dissolving in 10 ml of deionized water to obtain a PEG2000 solution.

[0020] (3) Reduction of palladium

[0021] The dissolved palladium source solution is slowly added to the PEG 2000 solution while stirring. A solution of NaBH4 (e.g., 0.01 M, typically 2-3 times the amount of the palladium source) is added to the reaction mixture at room temperature to reduce the palladium ions to metallic palladium.

[0022] (4) Reaction separation from precipitate and drying

[0023] The reaction mixture is stirred for an additional 1 to 2 hours to ensure complete reduction of the palladium and loading onto the PEG 2000. If a precipitate forms, the insoluble material can be removed by centrifugation or filtration, and then the unreacted reducing agent and solvent can be removed by washing. The excess solvent is removed by rotary evaporation or low temperature vacuum drying to give the final Pd-PEG 2000 catalyst.

[0024] Example 1.2. Pd-PEG 200 catalyst

[0025] (1) Preparation of palladium solution

[0026] Dissolve a quantity of Na2[PdCl4] or PdCl2 in deionized water to give a solution of palladium ions, 1.0 mmol.

[0027] (2) Preparation of polyethylene glycol 200 (PEG 200) solution

[0028] Take 1.0 g of PEG 200 and dissolve in 10 ml of deionized water to give a solution of PEG 200.

[0029] (3) Reduction of palladium

[0030] The dissolved palladium source solution is slowly added to the PEG 200 solution while stirring. A solution of NaBH4 (e.g., 0.01 M, typically 2-3 times the amount of the palladium source) is added to the reaction mixture at room temperature to reduce the palladium ions to metallic palladium.

[0031] (4) Reaction separation from precipitate and drying

[0032] The reaction mixture is stirred for an additional 1 to 2 hours to ensure complete reduction of the palladium and loading onto the PEG 200. If a precipitate forms, the insoluble material can be removed by centrifugation or filtration, and then the unreacted reducing agent and solvent can be removed by washing. The excess solvent is removed by rotary evaporation or low temperature vacuum drying to give the final Pd-PEG 200 catalyst.

[0033] Example 1.3. Pd-PEG 1000 catalyst

[0034] (1) Preparation of palladium solution

[0035] Dissolve the palladium source: dissolve a certain amount of Na2[PdCl4] or PdCl2 in deionized water to obtain 1.0 mmol of palladium ion solution.

[0036] (2) Preparation of polyethylene glycol 1000 (PEG1000) solution

[0037] Take 1.0 g of PEG1000 and dissolve it in 10 ml of deionized water to obtain a PEG1000 solution.

[0038] (3) Reduction of palladium

[0039] The dissolved palladium source solution is slowly added dropwise to the PEG1000 solution while stirring. At room temperature, a NaBH4 solution (e.g., 0.01 M, usually 2-3 times the amount of the palladium source) is gradually added to the reaction system to reduce the palladium ions to form metallic palladium.

[0040] (4) Reaction, precipitation, separation and drying

[0041] Continue stirring the reaction mixture for 1 to 2 hours to ensure complete reduction and loading of the palladium onto the PEG1000. If precipitation occurs, remove the insoluble material by centrifugation or filtration, then wash to remove any unreacted reducing agent and solvent. Remove excess solvent by rotary evaporation or low-temperature vacuum drying to yield the final Pd-PEG1000 catalyst.

[0042] Example 1.4. Pd-PEG5000 catalyst

[0043] (1) Preparation of palladium solution

[0044] Dissolve the palladium source: dissolve a certain amount of Na2[PdCl4] or PdCl2 in deionized water to obtain 1.0 mmol of palladium ion solution.

[0045] (2) Preparation of polyethylene glycol 5000 (PEG5000) solution

[0046] Take 1.0 g of PEG5000 and dissolve it in 10 ml of deionized water to obtain a PEG5000 solution.

[0047] (3) Reduction of palladium

[0048] The dissolved palladium source solution is slowly added dropwise to the PEG5000 solution while stirring. At room temperature, a NaBH4 solution (e.g., 0.01 M, usually 2-3 times the amount of the palladium source) is gradually added to the reaction system to reduce the palladium ions to form metallic palladium.

[0049] (4) Reaction, precipitation, separation and drying

[0050] The reaction mixture 1 is stirred for 1 to 2 hours to ensure complete reduction of palladium and loading on PEG 5000. If a precipitate appears, the insoluble material can be removed by centrifugation or filtration, and then the unreacted reducing agent and solvent are removed by washing. The excess solvent is removed by rotary evaporation or low-temperature vacuum drying to obtain the final Pd-PEG 5000 catalyst.

[0051] Example 2. Catalytic hydrogenation reaction

[0052] In this example, myricetin is used as the substrate, and the Pd-polyethylene glycol prepared in Example 1 is used as the catalyst to synthesize dihydromyricetin by catalytic hydrogenation under a hydrogen atmosphere. The reaction temperature is 25-55°C, the pressure is 1-5 MPa, the reaction time is 1-5 hours, and dihydromyricetin is synthesized. The amount of catalyst used is 1-5% of the mass of myricetin. The flow rate of hydrogen is 0.1-1.0 L / min. The reaction is carried out in an alcohol solvent environment.

[0053] Example 2.1. (Optimal conditions)

[0054] Into a 2L reactor, 80g (0.25mol) of myricetin, 400ml of ethanol, and 1.6g of Pd-PEG 2000 catalyst (2%) are added and stirred until dissolved. Hydrogen is introduced at a flow rate of 0.5L / min (0.4L / min, 0.6L / min, 0.7L / min result is similar). The reaction temperature is controlled at 45°C (50°C, 40°C result is similar), the reaction pressure is controlled at 2MPa (3MPa result is similar), and the reaction time is maintained for 3 hours (more than 3 hours result is similar). The catalyst is removed by cooling and filtration, and the solvent is evaporated to obtain crude dihydromyricetin with a yield of 76% and a purity of 91%. Liquid-liquid partitioning with ethyl acetate and water is performed to remove insoluble impurities, and then silica gel column chromatography is used for purification, finally obtaining dihydromyricetin with a purity of more than 98%.

[0055] 1 H-NMR (DMSO-d6, 500MHz) δ: 4.88 (1H, d, J=11Hz), 4.42 (1H, dd, J=11, 6.5Hz), 5.91 (1H, d, J=2.0Hz), 5.84 (1H, d, J=2.0Hz), 6.33 (1H, s), 6.38 (1H, s);

[0056] 13 C-NMR (DMSO-d6, 500MHz) δ: 83.2, 71.5, 197.8, 163.2, 95.8, 166.8, 94.7, 162.5, 100.4, 127.2, 106.9, 145.7, 133.1, 145.9, 106.9

[0057] m / z [M+H]+ :343.25

[0058] Example 2.2. (Lower catalyst amount)

[0059] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 1% 0.8g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 57%, purity 73%.

[0060] Example 2.3. (Very low catalyst amount)

[0061] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 0.5% 0.4g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 27%, purity 35%. Liquid-liquid distribution was performed using ethyl acetate and water to remove insoluble impurities, and then purified by silica gel column chromatography, the crude yield was again reduced by half.

[0062] Example 2.4. (Higher catalyst amount)

[0063] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 5% 4g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 53%, purity 79%.

[0064] Example 2.5. (Very high catalyst amount)

[0065] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 10% 8g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 50%, purity 64%. Liquid-liquid distribution was performed using ethyl acetate and water to remove insoluble impurities, and then purified by silica gel column chromatography, the crude yield was again reduced by one third.

[0066] Example 2.6 (solvent selection)

[0067] Into a 2L reactor was added myricetin 80g (0.25mol), methanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 68%, purity 86%.

[0068] Example 2.7 (solvent selection)

[0069] Into a 2L reactor was added myricetin 80g (0.25mol), water 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. No product was produced.

[0070] Example 2.8 (solvent selection)

[0071] Into a 2L reactor was added myricetin 80g (0.25mol), DMSO 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated under reduced pressure to obtain crude dihydro myricetin, yield 28%, purity 16%. Liquid-liquid partitioning with ethyl acetate and water was performed to remove insoluble impurities, and then purified by silica gel column chromatography.

[0072] Example 2.9 (temperature too high)

[0073] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 55°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 25%, purity 72%.

[0074] Example 2.10 (temperature too low)

[0075] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 25°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 12%, purity 44%. Liquid-liquid partitioning with ethyl acetate and water was used to remove insoluble impurities, and then purified by silica gel column chromatography, the yield was reduced by half again.

[0076] Example 2.11 (hydrogen flow rate is too low)

[0077] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 25°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 12%, purity 44%. Liquid-liquid partitioning with ethyl acetate and water was used to remove insoluble impurities, and then purified by silica gel column chromatography, the yield was reduced by half again.

[0078] Example 2.12 (hydrogen flow rate is too high)

[0079] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 25°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 12%, purity 44%. Liquid-liquid partitioning with ethyl acetate and water was used to remove insoluble impurities, and then purified by silica gel column chromatography, the yield was reduced by half again.

[0080] Example 2.13 (reaction pressure is too low)

[0081] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, control flow rate 0.5L / min. The reaction temperature was controlled at 25°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydro myricetin, yield 12%, purity 44%. Liquid-liquid partitioning with ethyl acetate and water was used to remove insoluble impurities, and then purified by silica gel column chromatography, the yield was reduced by half again.

[0082] Example 2.14 (reaction pressure is too high)

[0083] Into a 2L reactor, add myricetin 80g (0.25mol), ethanol 400ml, stir to dissolve, introduce Pd-PEG2000 catalyst 2% 1.6g, and introduce hydrogen, control flow rate 0.5L / min. Control reaction temperature at 45°C, control reaction pressure at 2MPa, maintain reaction time 3 hours. Cool, filter to remove catalyst, evaporate solvent to obtain crude dihydromyricetin, yield 57%, purity 81%.

[0084] Example 2.15 (reaction time is too short)

[0085] Into a 2L reactor, add myricetin 80g (0.25mol), ethanol 400ml, stir to dissolve, introduce Pd-PEG2000 catalyst 2% 1.6g, and introduce hydrogen, control flow rate 0.5L / min. Control reaction temperature at 45°C, control reaction pressure at 2MPa, maintain reaction time 1 hour. Cool, filter to remove catalyst, evaporate solvent to obtain crude dihydromyricetin, yield 45%, purity 84%. Use ethyl acetate and water to perform liquid-liquid partitioning, remove insoluble impurities, and then purify by silica gel column chromatography, yield is reduced by one-third again.

[0086] Example 2.16 (reaction time is too long)

[0087] Into a 2L reactor, add myricetin 80g (0.25mol), ethanol 400ml, stir to dissolve, introduce Pd-PEG2000 catalyst 2% 1.6g, and introduce hydrogen, control flow rate 0.5L / min. Control reaction temperature at 45°C, control reaction pressure at 2MPa, maintain reaction time 5 hours. Cool, filter to remove catalyst, evaporate solvent to obtain crude dihydromyricetin, yield 70%, purity 89%.

[0088] Example 2.17 (catalyst selection Pd-PEG200)

[0089] Into a 2L reactor, add myricetin 80g (0.25mol), ethanol 400ml, stir to dissolve, introduce Pd-PEG200 catalyst 2% 1.6g, and introduce hydrogen, control flow rate 0.5L / min. Control reaction temperature at 45°C, control reaction pressure at 2MPa, maintain reaction time 3 hours. Cool, filter to remove catalyst, evaporate solvent to obtain crude dihydromyricetin, yield 16%, purity 46%.

[0090] Example 2.18 (catalyst selection Pd-PEG1000)

[0091] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG1000 catalyst 2% 1.6g, and hydrogen was introduced, the flow rate was controlled at 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydromyricetin, with a yield of 38% and a purity of 55%.

[0092] Example 2.19 (catalyst selection Pd-PEG5000)

[0093] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-PEG5000 catalyst 2% 1.6g, and hydrogen was introduced, the flow rate was controlled at 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydromyricetin, with a yield of 29% and a purity of 48%.

[0094] Example 2.20 (catalyst selection Pd-C)

[0095] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-C catalyst 2% 1.6g, and hydrogen was introduced, the flow rate was controlled at 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydromyricetin, with a yield of 0%.

[0096] Example 2.21 (catalyst selection Pd-C-PEG2000)

[0097] Into a 2L reactor was added myricetin 80g (0.25mol), ethanol 400ml, stirred to dissolve, introduced Pd-C-PEG2000 catalyst 2% 1.6g, and hydrogen was introduced, the flow rate was controlled at 0.5L / min. The reaction temperature was controlled at 45°C, the reaction pressure was controlled at 2MPa, and the reaction time was maintained for 3 hours. The catalyst was removed by cooling and filtration, and the solvent was evaporated to obtain crude dihydromyricetin, with a yield of 5% and a purity of 22%.

[0098] Effects and advantages of the present embodiment:

[0099] In this example, the efficient hydrogenation of myricetin was achieved by using Pd-PEG2000 as catalyst, which has the advantages of mild reaction conditions and reduced side reactions. The catalyst has good stability and recyclability, and can be reused multiple times without affecting the reaction effect. This method is simple to operate and easy to realize industrialization, and has high product purity and yield, effectively reducing the production cost and having wide application prospect.

Claims

1. A method for synthesizing dihydromyricetin, characterized in that: Dihydromyricetin was synthesized by catalytic hydrogenation using myricetin as substrate and Pd-polyethylene glycol as catalyst under hydrogen atmosphere. The polyethylene glycol in the Pd-polyethylene glycol is selected from polyethylene glycols having an average molecular weight greater than 1000. The preparation method of the Pd-polyethylene glycol comprises the following steps: Step 1. preparing a palladium source solution: dissolving Na2[PdCl4] or PdCl2 in deionized water to obtain a palladium ion solution; Step 2. Preparation of polyethylene glycol solution: dissolving polyethylene glycol in deionized water to obtain a polyethylene glycol solution; Step 3. Palladium reduction: The dissolved palladium source solution is slowly added dropwise to the polyethylene glycol solution while stirring. At room temperature, NaBH4 solution is gradually added to the reaction system to reduce the palladium ions to form metallic palladium. Step 4. Reaction and precipitate separation and drying: The reaction mixture is stirred for 1-2 hours to ensure that the palladium is completely reduced and loaded onto the polyethylene glycol, followed by post-treatment to obtain Pd-polyethylene glycol. The reaction temperature is 25-55°C, the pressure is 1-5 MPa, and the reaction time is 1-5 hours to synthesize dihydromyricetin; the amount of the catalyst used is 1-5% of the quality of myricetin; The reaction is carried out in a solvent environment, and the solvent is selected from alcohol.

2. A method for synthesizing dihydromyricetin as claimed in claim 1, characterized in that: The flow rate of hydrogen is 0.1-1.0 L / min.

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