CN109369749B - Preparation method of astilbin - Google Patents
Preparation method of astilbin Download PDFInfo
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- CN109369749B CN109369749B CN201811454062.4A CN201811454062A CN109369749B CN 109369749 B CN109369749 B CN 109369749B CN 201811454062 A CN201811454062 A CN 201811454062A CN 109369749 B CN109369749 B CN 109369749B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention relates to a method for synthesizing a raw material medicament, in particular to a method for preparing astilbin. In order to solve the problems that when the astilbin is extracted from plants in the prior art, the content of the astilbin is low, and a product with high yield is difficult to obtain by using the extraction method, the invention provides a synthesis method of astilbin, which takes myricitrin as a starting material, firstly hydrogenates to obtain dihydromyricitrin, then, hydrolysis reaction is carried out under certain alkaline conditions to generate hydroxyacetophenone intermediate (2- (3,4, 5-trihydroxy-6-methyltetrahydro-2-pyran) -1- (2,4, 6-trihydroxy phenyl) -acetyl), then the hydroxyacetophenone intermediate and 3, 4-dihydroxybenzaldehyde are catalyzed and cyclized to generate astilbin crude product, and finally the astilbin pure product with the mass content of more than 98 percent is obtained by refining. The astilbin prepared by the method has the advantages of easily obtained raw materials, simple operation and low cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing a raw material medicament, in particular to a method for preparing astilbin.
Background
Astilbin, named astilbin in English and also named (2R,3R) -taxifolin-3-O-alpha-L-rhamnopyranoside, is a compound extracted from plant astilbin in 1950 for the first time by Kozo Hayashi and Kazuhiko Ouchi, and is reported in documents to have various remarkable biological activities, including inhibition of coenzyme A reductase and inhibition of aldose reductase, and has the effects of protecting liver, relieving pain, resisting edema and the like. In recent years, astilbin has been reported to have a remarkable selective immunosuppressive effect, and the selective effect is remarkably superior to that of a general immunosuppressive agent, so that astilbin can be used as a novel immunosuppressive agent for treating immune-related diseases. Meanwhile, the astilbin-containing plants have homology of medicine and food, so the astilbin is also present in a plurality of functional foods.
The molecular formula of astilbin is C21H22O11Molecular weight is 450.408, CAS number is 29838-67-3. The structural formula of astilbin is as follows:
in recent years, astilbin has been found to be widely present in various plants in the natural world, such as Brazilian rue (Dimorphandramollis), grape, Smilax glabra, Smilax china, Engelhardtia chrysolepis (Rooho tea), Hypericum perforatum, Eucheuma glabra, and leaves of Madagana javanica (Harungana madagascariensis). Quantitative research shows that the content of astilbin in the glabrous greenbrier rhizome is between 1 and 2 percent, and the astilbin is the most main flavone component. In addition, the leaves of Engelhardtia chrysolepis similarly contain a certain amount of astilbin.
At present, astilbin is mainly prepared by extracting from plants. It is reported in the literature that when astilbin is extracted and prepared from smilax glabra and engelhardtia roxburghiana, because the content of astilbin in plants is low, a product with high yield is difficult to obtain by using an extraction method, and wastes of plant resources and solvents are large, a new preparation method needs to be developed to improve the yield so as to meet the market demand.
Disclosure of Invention
The invention provides a preparation method of astilbin, aiming at solving the technical problems that when the astilbin is extracted from plants in the prior art, because the content of the astilbin is low, a product with higher yield is difficult to obtain by using the extraction method, and the waste of plant resources and solvents is large.
The invention has the following inventive concept: selecting myricitrin as a starting material, carrying out three-step reactions of hydrogenation, hydrolysis and catalytic ring closure to obtain a crude astilbin product, and purifying and refining to obtain a qualified refined astilbin product. The specific synthetic route is as follows:
the main raw materials in the synthetic route are myricitrin and 3, 4-dihydroxy benzaldehyde. Wherein myricitrin is also named as pentahydroxyflavone-3-rhamnoside. It is a main chemical component of bark and leaf of Myrica rubra (oar.) of Myricaceae, also exists in natural plants such as onion, berry and tea, and is also one of the main flavonol components in red wine. At present, the method for extracting myricitrin from plants is mature, so that the raw materials for preparing astilbin from myricitrin are simple and easy to obtain. 3, 4-dihydroxy benzaldehyde is also named protocatechuic aldehyde, and has low price and sufficient market supply.
The raw material myricitrin is firstly hydrogenated to obtain dihydromyricitrin, then hydrolysis reaction is carried out under certain alkaline condition to generate 2- (3,4, 5-trihydroxy-6-methyltetrahydro-2-pyran) -1- (2,4, 6-trihydroxy phenyl) -acetyl (called as hydroxyacetophenone intermediate), the hydroxyacetophenone intermediate is catalyzed and cyclized with 3, 4-dihydroxybenzaldehyde to generate astilbin crude product, and finally, the pure product with the mass content of more than 98 percent is obtained by refining.
In order to achieve the above purpose, the technical solution provided by the present invention is as follows:
the preparation method of astilbin is characterized by comprising the following steps:
1) preparation of dihydromyricitrin by hydrogenation
Uniformly mixing myricitrin and an alkaline solution, adding a catalytic amount of palladium-carbon, introducing hydrogen, and carrying out hydrogenation reaction; after the reaction is finished, filtering, adjusting the pH of the filtrate to 3-4 by using an acid solution, standing, filtering after a solid is separated out, and drying a filter cake to obtain the dihydromyricitrin;
2) hydrolysis for preparing hydroxyacetophenone intermediate
2.1) uniformly mixing the dihydromyricitrin obtained in the step 1) with an alkaline solution, heating and refluxing, and carrying out hydrolysis reaction; after the reaction is finished, cooling to room temperature, filtering, adjusting the pH of the filtrate to 6-7 by using an acid solution, standing, and filtering to obtain a light yellow solid;
2.2) adding water into the light yellow solid obtained in the step 2.1) for refluxing, filtering while the light yellow solid is hot, standing the filtrate at 0-5 ℃, filtering again, washing the filter cake to be neutral and drying to obtain a hydroxyacetophenone intermediate (namely 2- (3,4, 5-trihydroxy-6-methyltetrahydro-2-pyran) -1- (2,4, 6-trihydroxy phenyl) -ethane);
3) catalytic closed-loop preparation of astilbin
3.1) adding an organic solvent into the hydroxyacetophenone intermediate obtained in the step 2.2) to dissolve the hydroxyacetophenone intermediate;
3.2) adding proline with a catalytic amount into the solution obtained in the step 3.1), heating and keeping the temperature unchanged, and slowly dropwise adding a 3, 4-dihydroxy benzaldehyde solution; after dripping, heating to reflux again to carry out catalytic ring-closing reaction; wherein the 3, 4-dihydroxy benzaldehyde solution is prepared from 3, 4-dihydroxy benzaldehyde and an organic solvent, and the organic solvent is the same as the organic solvent in the step 3.1);
3.3) after the catalytic ring-closure reaction is finished, recovering the solvent under reduced pressure until the solvent is dry, adding water for refluxing, cooling and filtering, and washing a filter cake to be neutral to obtain a crude astilbin product;
3.4) refining the astilbin crude product obtained in the step 3.3) to obtain an astilbin refined product.
Further, in the step 1), the myricitrin adopts myricitrin with the liquid phase content of more than 98%; the alkaline solution adopts sodium hydroxide or potassium hydroxide solution with the mass concentration of 5-10%, and the dosage of the sodium hydroxide or potassium hydroxide solution is 10-15 times of the mass of the myricitrin; the palladium carbon is 5 to 10 percent of palladium carbon, and the dosage of the palladium carbon is 5 to 15 percent of the mass of the myricitrin; the reaction pressure is 1.5-2.5 Mpa; the reaction temperature is 25-50 ℃.
Further, in the step 2.1), the alkaline solution is sodium hydroxide or potassium hydroxide solution with the mass concentration of 15-25%, and the dosage of the alkaline solution is 5-10 times of the mass of the myricitrin; the acid solution is hydrochloric acid solution or sulfuric acid solution.
Further, in the step 2.2), the amount of water for refluxing is 6-12 times of the mass of the light yellow solid.
Further, in step 3.1), the organic solvent is methanol, ethanol or N, N-dimethylformamide.
Further, in the step 3.2), the consumption of the proline is 10-20% of the mass of the hydroxyacetophenone intermediate;
the molar ratio of the 3, 4-dihydroxy benzaldehyde to the hydroxyacetophenone intermediate is 0.8-1.2: 1;
the dropping temperature of the 3, 4-dihydroxy benzaldehyde solution is 60-80 ℃; the temperature of the catalytic ring-closing reaction after the completion of the dropwise addition is 80-100 ℃.
Further, the sum of the mass of the organic solvent in the step 3.1) and the mass of the organic solvent in the step 3.2) is 5-12 times of the mass of the hydroxyacetophenone intermediate.
Further, in the step 3.3), the amount of water for refluxing is 3-5 times of the mass of the hydroxyacetophenone intermediate.
Further, in the step 3.4), the refining of the astilbin crude product comprises the specific steps of adding purified water into the astilbin crude product obtained in the step 3.3), heating and refluxing, filtering, cooling the filtrate to room temperature, filtering again, and drying the filter cake to obtain a refined astilbin product.
Further, in order to better control the reaction progress, the hydrogenation reaction in the step 1), the hydrolysis reaction in the step 2.1) and the catalytic ring-closing reaction in the step 3.2) are monitored by high performance liquid chromatography, and the end point is that products are not increased any more.
Compared with the prior art, the invention has the following beneficial effects:
1) compared with the method for extracting and preparing astilbin from plants, the semisynthetic method adopted by the invention can obtain a product with higher yield;
2) the semisynthesis method adopted by the invention can greatly save plant resources and solvents;
3) the semisynthesis method adopted by the invention has simple process steps and easy operation;
4) the semi-synthesis method adopted by the invention has the advantages that the main raw materials of myricitrin and 3, 4-dihydroxy benzaldehyde are easy to obtain, the price is low, the market supply is sufficient, the production cost is greatly reduced, and the method is suitable for industrial production;
5) the semisynthesis method adopted by the invention has the advantages of environment-friendly production process and less pollution.
Detailed Description
First, the process of preparing dihydromyricitrin from myricitrin in the preparation method of the present invention is described as follows:
example 1:
1) preparation of dihydromyricitrin by hydrogenation
Putting 50g of myricitrin with the content of more than 98 percent and 550g of sodium hydroxide solution with the mass concentration of 5 percent into a high-pressure reaction container, and stirring to uniformly mix the myricitrin and the alkaline solution; adding 7.5g of 5% palladium carbon, replacing nitrogen, introducing hydrogen, maintaining the pressure at 2MPa and the temperature at about 40 ℃, carrying out hydrogenation reaction, monitoring by high performance liquid chromatography, taking the condition that no dihydromyricitrin is increased as a reaction control end point, and stopping the reaction after about 28 hours. And filtering the reaction solution to obtain a filtrate, adjusting the pH of the filtrate to 3-4 by using concentrated hydrochloric acid, stirring for about 2 hours, filtering, washing a filter cake with water to be neutral, and drying to obtain 43.6g of a light yellow solid (namely dihydromyricitrin).
2) Hydrolysis for preparing hydroxyacetophenone intermediate
2.1) putting 43.6g of dihydromyricitrin obtained in the step 1) into a reactor, adding 440g of sodium hydroxide solution with the mass concentration of 15%, stirring to completely dissolve the dihydromyricitrin, heating to reflux, carrying out hydrolysis reaction, monitoring by high performance liquid chromatography, taking the condition that the hydroxyacetophenone intermediate is not increased any more as a reaction control end point, and stopping the reaction after about 1 hour. Cooling to 30 ℃, slowly dropwise adding 50% hydrochloric acid solution into the reaction solution, adjusting the pH to 6.2, stirring for 2 hours, standing for 1 hour, and filtering to obtain a light yellow solid;
2.2) adding 350g of water into the light yellow solid obtained in the step 2.1), heating to reflux, filtering while hot after 1h, standing the filtrate at 0-5 ℃ overnight, filtering again, washing the filter cake to be neutral and drying to obtain 26.3g of off-white solid (namely intermediate hydroxyacetophenone).
3) Catalytic closed-loop preparation of astilbin
3.1) putting 26.3g of the hydroxyacetophenone intermediate obtained in the step 2.2) into a reaction bottle, adding 140g of DMF, and stirring to completely dissolve the hydroxyacetophenone intermediate;
3.2) adding 2.8g of proline into the solution of the step 3.1), heating to 60 ℃ and keeping the temperature unchanged, dissolving 8.9g of 3, 4-dihydroxy benzaldehyde by 15g of DMF, and slowly dropwise adding into a reaction bottle for about 2 hours. After dripping, raising the temperature to 80 ℃, preserving the temperature, carrying out catalytic ring-closure reaction, monitoring by high performance liquid chromatography, and finishing the reaction after 4 hours, wherein astilbin is not increased any more as a reaction control terminal point;
3.3) after the catalytic ring-closure reaction is finished, recovering the solvent to be dry under reduced pressure, adding 90g of water into a reaction bottle, heating, refluxing, pulping, cooling, filtering, washing a filter cake to be neutral, and obtaining a crude astilbin product;
3.4) adding 120g of purified water into the astilbin crude product obtained in the step 3.3), heating and refluxing, filtering, cooling the filtrate to room temperature, filtering again, and drying a filter cake to obtain 27.9g of astilbin refined product with the content of more than 98 percent (HPLC).
Example 2:
putting 50g of myricitrin with the content of more than 98% and 500g of sodium hydroxide solution with the mass concentration of 7.5% into a high-pressure reaction container, and stirring to uniformly mix the myricitrin and the alkaline solution; adding 5% palladium carbon 5g, replacing nitrogen, introducing hydrogen, maintaining pressure at 2.5MPa and temperature at about 35 deg.C, performing hydrogenation reaction, monitoring with high performance liquid chromatography, controlling the end point of reaction with no increase of dihydromyricitrin, and stopping reaction after about 24 hr. And filtering the reaction solution to obtain a filtrate, adjusting the pH of the filtrate to 3-4 by using concentrated hydrochloric acid, stirring for about 2 hours, filtering, washing a filter cake with water to be neutral, and drying to obtain 42.7g of a light yellow solid (namely dihydromyricitrin).
2) Hydrolysis for preparing hydroxyacetophenone intermediate
2.1) putting 42.7g of dihydromyricitrin obtained in the step 1) into a reactor, adding 350g of sodium hydroxide solution with the mass concentration of 17.5%, stirring to completely dissolve the dihydromyricitrin, heating to reflux, carrying out hydrolysis reaction, monitoring by high performance liquid chromatography, taking the condition that the hydroxyacetophenone intermediate is not increased any more as a reaction control end point, and stopping the reaction after about 1.5 hours. Cooling to 30 ℃, slowly dropwise adding 50% hydrochloric acid solution into the reaction solution, adjusting the pH to about 6.4, stirring for 2 hours, standing for 1 hour, and filtering to obtain a light yellow solid;
2.2) adding 400g of water into the light yellow solid obtained in the step 2.1), heating to reflux, filtering while hot after 1h, standing the filtrate at 0-5 ℃ overnight, filtering again, washing the filter cake to be neutral and drying to obtain 25.6g of off-white solid (namely the intermediate hydroxyacetophenone).
3) Catalytic closed-loop preparation of astilbin
3.1) putting 25.6g of the hydroxyacetophenone intermediate obtained in the step 2.2) into a reaction bottle, adding 205g of DMF, and stirring to completely dissolve the hydroxyacetophenone;
3.2) adding 3.8g of proline into the solution of the step 3.1), heating to 75 ℃ and keeping the temperature unchanged, dissolving 12.8g of 3, 4-dihydroxy benzaldehyde by 15g of DMF, and slowly dropwise adding into a reaction bottle for about 2 hours. After the dripping is finished, raising the temperature to 85 ℃, preserving the temperature, carrying out catalytic ring-closing reaction, monitoring by high performance liquid chromatography, taking the fact that astilbin is not increased any more as a reaction control end point, and finishing the reaction after about 6 hours;
3.3) after the catalytic ring-closure reaction is finished, recovering the solvent to be dry under reduced pressure, adding 120g of water into a reaction bottle, heating, refluxing, pulping, cooling, filtering, washing a filter cake to be neutral, and obtaining a crude astilbin product;
3.4) adding 120g of purified water into the astilbin crude product obtained in the step 3.3), heating and refluxing, filtering, cooling the filtrate to room temperature, filtering again, and drying a filter cake to obtain 28.39g of astilbin refined product with the content of more than 98 percent (HPLC).
Example 3:
1) preparation of dihydromyricitrin by hydrogenation
Putting 50g of myricitrin with the content of more than 98 percent and 600g of sodium hydroxide solution with the mass content of 8 percent into a high-pressure reaction container, and stirring to uniformly mix the myricitrin and the alkaline solution; adding 10% palladium carbon 5g, replacing nitrogen, introducing hydrogen, maintaining pressure at 1.5MPa and temperature at about 25 deg.C, performing hydrogenation reaction, monitoring with high performance liquid chromatography, controlling the end point of reaction with no increase of dihydromyricitrin, and stopping reaction after about 28 hr. And filtering the reaction solution to obtain a filtrate, adjusting the pH of the filtrate to 3-4 by using concentrated hydrochloric acid, stirring for about 2 hours, filtering, washing a filter cake with water to be neutral, and drying to obtain 39.8g of a light yellow solid (namely the dihydromyricitrin).
2) Hydrolysis for preparing hydroxyacetophenone intermediate
2.1) putting 39.8g of dihydromyricitrin obtained in the step 1) into a reactor, adding 200g of sodium hydroxide solution with the mass concentration of 17.5%, stirring to completely dissolve the dihydromyricitrin, heating to reflux, carrying out hydrolysis reaction, monitoring by high performance liquid chromatography, taking the condition that the hydroxyacetophenone intermediate is not increased any more as a reaction control end point, and stopping the reaction after about 1.5 hours. Cooling to 30 ℃, slowly dropping a hydrochloric acid solution with the mass content of 50%, adjusting the pH to 6.4, stirring for 2 hours, standing for 1 hour, and filtering to obtain a light yellow solid;
2.2) adding 450g of water into the light yellow solid obtained in the step 2.1), heating to reflux, filtering while hot after 1h, standing the filtrate at 0-5 ℃ overnight, filtering again, washing the filter cake to be neutral and drying to obtain 24.8g of off-white solid (namely intermediate hydroxyacetophenone).
3) Catalytic closed-loop preparation of astilbin
3.1) putting 24.8g of the hydroxyacetophenone intermediate obtained in the step 2.2) into a reaction bottle, adding 120g of methanol, and stirring to completely dissolve the hydroxyacetophenone intermediate;
3.2) adding 4.3g of proline into the solution of the step 3.1), heating to 80 ℃ and keeping the temperature unchanged, dissolving 10.7g of 3, 4-dihydroxy benzaldehyde by 20g of DMF, and slowly dropwise adding into a reaction bottle for about 2 hours. After the dripping is finished, raising the temperature to 85 ℃, preserving the temperature, carrying out catalytic ring-closing reaction, monitoring by high performance liquid chromatography, taking the fact that astilbin is not increased any more as a reaction control end point, and finishing the reaction after about 5 hours;
3.3) after the catalytic ring-closure reaction is finished, recovering the solvent to be dry under reduced pressure, adding 100g of water into a reaction bottle, heating, refluxing, pulping, cooling, filtering, washing a filter cake to be neutral, and obtaining a crude astilbin product;
3.4) adding 120g of purified water into the astilbin crude product obtained in the step 3.3), heating and refluxing, filtering, cooling the filtrate to room temperature, filtering again, and drying a filter cake to obtain 25.7g of astilbin refined product with the content of more than 98 percent (HPLC).
Example 4:
putting 50g of myricitrin with the content of more than 98 percent and 750g of sodium hydroxide solution with the mass concentration of 10 percent into a high-pressure reaction container, and stirring to uniformly mix the myricitrin and the alkaline solution; adding 10% palladium carbon 5g, replacing nitrogen, introducing hydrogen, maintaining pressure at 2MPa and temperature at about 45 deg.C, performing hydrogenation reaction, monitoring with high performance liquid chromatography, and stopping reaction after about 28 hr. And filtering the reaction solution to obtain a filtrate, adjusting the pH of the filtrate to 3-4 by using concentrated hydrochloric acid, stirring for about 2 hours, filtering, washing a filter cake with water to be neutral, and drying to obtain 42.3g of a light yellow solid (namely dihydromyricitrin).
2) Hydrolysis for preparing hydroxyacetophenone intermediate
2.1) putting 42.3g of dihydromyricitrin obtained in the step 1) into a reactor, adding 360g of sodium hydroxide solution with the mass concentration of 25%, stirring to completely dissolve the dihydromyricitrin, heating to reflux, carrying out hydrolysis reaction, monitoring by high performance liquid chromatography, taking the condition that the hydroxyacetophenone intermediate is not increased any more as a reaction control end point, and stopping the reaction after about 1 hour. Cooling to 30 ℃, slowly dropwise adding 50% hydrochloric acid solution into the reaction solution, adjusting the pH to 6.4, stirring for 2 hours, standing for 1 hour, and filtering to obtain a light yellow solid;
2.2) adding 500g of water into the light yellow solid obtained in the step 2.1), heating to reflux, filtering while hot after 1h, standing the filtrate at 0-5 ℃ overnight, filtering again, washing the filter cake to be neutral and drying to obtain 28.6g of off-white solid (namely intermediate hydroxyacetophenone).
3) Catalytic closed-loop preparation of astilbin
3.1) putting 28.6g of the hydroxyacetophenone intermediate obtained in the step 2.2) into a reaction bottle, adding 310g of DMF, and stirring to completely dissolve the hydroxyacetophenone intermediate;
3.2) adding 5.6g of proline into the solution of the step 3.1), heating to 80 ℃ and keeping the temperature unchanged, dissolving 14.3g of 3, 4-dihydroxy benzaldehyde by 30g of DMF, and slowly dropwise adding into a reaction bottle for about 2 hours. After dripping, raising the temperature to about 100 ℃, preserving the temperature, carrying out catalytic ring-closure reaction, monitoring by high performance liquid chromatography, and finishing the reaction after about 3 hours by taking the fact that astilbin is not increased any more as a reaction control terminal point;
3.3) after the catalytic ring-closure reaction is finished, recovering the solvent to be dry under reduced pressure, adding 140g of water into a reaction bottle, heating, refluxing, pulping, cooling, filtering, washing a filter cake to be neutral, and obtaining a crude astilbin product;
3.4) adding 120g of purified water into the astilbin crude product obtained in the step 3.3), heating and refluxing, filtering, cooling the filtrate to room temperature, filtering again, and drying a filter cake to obtain 28.9g of astilbin refined product with the content of more than 98 percent (HPLC).
In the above embodiments, the hydrogenation reaction in step 1), the hydrolysis reaction in step 2.1) and the catalytic ring-closing reaction in step 3.2) are all monitored by high performance liquid chromatography, and the end point of the reaction is that the products are not increased any more; the detection instrument and conditions adopted by the high performance liquid chromatography monitoring are as follows:
the instrument comprises the following steps: shimadzu CTO-15C;
a chromatographic column: LunaC18,4.6mm × 250mm,5 μm;
mobile phase: water: methanol is 30: 80;
column temperature: 25 ℃;
flow rate: 1.0 mL/min;
detection wavelength: 320 nm.
Finally, it should be noted that: the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same, and it is obvious for a person skilled in the art to modify the specific technical solutions described in the foregoing embodiments or to substitute part of the technical features, and these modifications or substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions protected by the present invention.
Claims (10)
1. A preparation method of astilbin is characterized by comprising the following steps:
1) preparation of dihydromyricitrin by hydrogenation
Uniformly mixing myricitrin and an alkaline solution, adding a catalytic amount of palladium-carbon, introducing hydrogen, and carrying out hydrogenation reaction; after the reaction is finished, filtering, adjusting the pH of the filtrate to 3-4 by using an acid solution, standing, filtering after a solid is separated out, and drying a filter cake to obtain the dihydromyricitrin; the alkaline solution is sodium hydroxide or potassium hydroxide solution with the mass concentration of 5-10%, and the dosage of the alkaline solution is 10-15 times of the mass of the myricitrin;
2) hydrolysis for preparing hydroxyacetophenone intermediate
2.1) uniformly mixing the dihydromyricitrin obtained in the step 1) with an alkaline solution, heating and refluxing, and carrying out hydrolysis reaction; after the reaction is finished, cooling to room temperature, filtering, adjusting the pH of the filtrate to 6-7 by using an acid solution, standing, and filtering to obtain a light yellow solid; the alkaline solution is sodium hydroxide or potassium hydroxide solution with the mass concentration of 15-25%, and the dosage of the alkaline solution is 5-10 times of the mass of the dihydromyricitrin;
2.2) adding water into the light yellow solid obtained in the step 2.1) for refluxing, filtering while the light yellow solid is hot, standing the filtrate at 0-5 ℃, filtering again, washing the filter cake to be neutral and drying to obtain a hydroxyacetophenone intermediate;
3) catalytic closed-loop preparation of astilbin
3.1) adding an organic solvent into the hydroxyacetophenone intermediate obtained in the step 2.2) to dissolve the hydroxyacetophenone intermediate;
3.2) adding proline with a catalytic amount into the solution obtained in the step 3.1), heating and keeping the temperature unchanged, and slowly dropwise adding a 3, 4-dihydroxy benzaldehyde solution; after dripping, heating to reflux again to carry out catalytic ring-closing reaction; wherein the 3, 4-dihydroxy benzaldehyde solution is prepared from 3, 4-dihydroxy benzaldehyde and an organic solvent, and the organic solvent is the same as the organic solvent in the step 3.1);
3.3) after the catalytic ring-closure reaction is finished, recovering the solvent under reduced pressure until the solvent is dry, adding water for refluxing, cooling and filtering, and washing a filter cake to be neutral to obtain a crude astilbin product;
3.4) refining the astilbin crude product obtained in the step 3.3) to obtain an astilbin refined product.
2. The method for preparing astilbin according to claim 1, wherein: in the step 1), the palladium carbon is 5-10% of palladium carbon, and the dosage of the palladium carbon is 5-15% of the mass of the myricitrin; the reaction pressure is 1.5-2.5 Mpa; the reaction temperature is 25-50 ℃.
3. The method for preparing astilbin according to claim 2, wherein: in the step 2.1), the acidic solution is a hydrochloric acid solution or a sulfuric acid solution.
4. The method for preparing astilbin according to claim 3, wherein the step of: in the step 2.2), the amount of water for refluxing is 6-12 times of the mass of the faint yellow solid.
5. The method for preparing astilbin according to claim 4, wherein the step of: in the step 3.1), the organic solvent is methanol, ethanol or N, N-dimethylformamide.
6. The method for preparing astilbin according to claim 5, wherein the step of: in the step 3.2), the consumption of the proline is 10-20% of the mass of the hydroxyacetophenone intermediate;
the molar ratio of the 3, 4-dihydroxy benzaldehyde to the hydroxyacetophenone intermediate is 0.8-1.2: 1;
the dropping temperature of the 3, 4-dihydroxy benzaldehyde solution is 60-80 ℃; the reaction temperature after the dropwise addition is 80-100 ℃.
7. The method of preparing astilbin according to claim 6, wherein the step of: the sum of the mass of the organic solvent in the step 3.1) and the mass of the organic solvent in the step 3.2) is 5-12 times of the mass of the hydroxyacetophenone intermediate.
8. The method of preparing astilbin according to claim 7, wherein: in the step 3.3), the amount of the reflux water is 3-5 times of the mass of the hydroxyacetophenone intermediate.
9. The method of preparing astilbin according to claim 8, wherein the step of: in the step 3.4), the refining of the astilbin crude product comprises the specific steps of adding purified water into the astilbin crude product obtained in the step 3.3), heating and refluxing, filtering, cooling the filtrate to room temperature, filtering again, and drying the filter cake to obtain a refined astilbin product.
10. The method for preparing astilbin according to any one of claims 1 to 9, wherein: the hydrogenation reaction in step 1), the hydrolysis reaction in step 2.1) and the catalytic ring-closure reaction in step 3.2) are monitored by high performance liquid chromatography, and the end point is that the products are not increased any more.
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| WO2001064701A1 (en) * | 2000-03-03 | 2001-09-07 | Suntory Limited | Process for preparing flavonoids |
| CN1724552A (en) * | 2005-07-08 | 2006-01-25 | 南京大学 | Preparation method of astilbin |
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2018
- 2018-11-30 CN CN201811454062.4A patent/CN109369749B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001064701A1 (en) * | 2000-03-03 | 2001-09-07 | Suntory Limited | Process for preparing flavonoids |
| CN1724552A (en) * | 2005-07-08 | 2006-01-25 | 南京大学 | Preparation method of astilbin |
Non-Patent Citations (2)
| Title |
|---|
| Cationic zirconocene- or hafnocene-based Lewis acids in organic synthesis: glycoside-flavonoid analogy;Ken Ohmori et al.;《Tetrahedron》;20041231;第60卷;第1365-1373页 * |
| Synthesis and immunosuppressive activity of L-rhamnopyranosyl flavonoids;Xiaoliang Yang et al.;《Organic & Biomolecular Chemistry》;20060608;第4卷;第2483-2491页 * |
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