CN110698523B - Method for chemically synthesizing beta-arbutin - Google Patents
Method for chemically synthesizing beta-arbutin Download PDFInfo
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Abstract
The invention provides a method for chemically synthesizing beta-arbutin. The synthesis method takes D-glucose and acetic anhydride as raw materials, and obtains a pentaacetylglucose anomer mixture through reaction under the catalysis of molecular iodine; the mixture reacts with p-methoxyphenol under the catalysis of boron trifluoride diethyl etherate without separation to obtain p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside; dissolving p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside in absolute methanol, and removing acetyl on a sugar ring and methyl of methoxy on a benzene ring under the conditions of sodium methoxide and cuprous oxide to obtain beta-arbutin. The method has the advantages of convenient operation, less discharge of three wastes, high yield and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of fine chemical engineering, relates to a synthesis method of beta-arbutin, and particularly relates to an improved chemical synthesis process of beta-arbutin.
Background
Arbutin, whose chemical name is 4-hydroxyphenyl-beta-D-glucopyranoside, is a natural bioactive substance extracted from medicinal plants such as folium Vaccinii Vitis-idaeae. Arbutin has various medical activities, and is mainly used as a green, safe and efficient skin whitening aid and widely used in whitening cosmetics. Besides the extraction preparation, the arbutin can also be prepared by a biological synthesis method and a chemical synthesis method. At present, beta-arbutin prepared by chemical synthesis has been widely used in the market. The structural formula of the beta-arbutin is as follows:
the synthesis of beta-arbutin takes D-glucose as a starting material, and firstly, the glucose is converted into beta-pentaacetylglucose. The early synthesis process needs to firstly react beta-pentaacetylglucosamine with hydrogen bromide solution of glacial acetic acid to prepare alpha-bromo-peracetylpyran-D-glucose, then the alpha-bromo-peracetylpyran-D-glucose reacts with hydroquinone or mono-protected hydroquinone to obtain tetraacetyl-beta-arbutin, and the sugar ring protecting group is removed to obtain the beta-arbutin. The disadvantages of this preparation method are: the raw materials are extremely toxic, the steps are frequent, and the bromo-sugar intermediate is unstable, so that the method is not suitable for industrial production. Therefore, the synthesis of beta-arbutin mainly takes beta-pentaacetylglucosamine as glycosyl as a donor and is synthesized with hydroquinone or mono-protected hydroquinone (USP 3201385; Synth. Commun. 1992, 22, 2121; J. chem. Soc. Perkin Trans. 1, 1994, 985). At present, the most common method is to react beta-pentaacetylglucose with hydroquinone (or 4-phenyl glycolate) under the catalysis of boron trifluoride ethyl ether to obtain tetraacetyl-beta-arbutin (pentaacetyl-beta-arbutin), and then remove acetyl protecting groups to obtain beta-arbutin. Hydroquinone is used as a glycosyl acceptor to react with beta-pentaacetylglucose to generate a diglycosidation by-product; phenyl 4-hydroxyacetate does not produce a diglycosidated by-product, but the acetyl protecting group reduces the nucleophilicity of the hydroxyl group of a benzene ring so as to reduce the glycosylation reaction yield, and under the optimal reaction condition, the yield of beta-arbutin is not more than 60 percent based on glucose. In addition, the preparation of beta-pentaacetylglucose requires a large excess of acetic anhydride (6-10 times the amount of glucose), thereby increasing the production cost; the prepared beta-pentaacetylglucosamine needs to be crystallized and purified, the purification yield is not more than 80%, and after the solvent is recovered from the crystallization mother liquor, the residue needs to be subjected to three-waste treatment.
Disclosure of Invention
Aiming at the defects of the technology, the invention aims to provide a method for chemically synthesizing beta-arbutin, which has the advantages of high yield, convenient operation, less three-waste discharge and low cost. The synthetic route of the invention is as follows:
the synthesis method of the beta-arbutin comprises the following steps:
step 1: reacting acetic anhydride and D-glucose serving as raw materials at 20-30 ℃ for 1-3 hours by using molecular iodine as a catalyst to obtain a pentaacetylglucose anomer mixture (alpha and beta isomer mixture); the molar ratio of acetic anhydride to D-glucose is 5-6: 1 (because D-glucose molecules contain 5 hydroxyl groups), and the optimal molar ratio of acetic anhydride to D-glucose is 5.5: 1; the dosage of the molecular iodine is 4 percent of the dosage (mass) of the D-glucose;
step 2: the pentaacetylglucose anomer mixture obtained in the step 1 is not separated, anhydrous dichloromethane is added for dilution, p-methoxyphenol and boron trifluoride diethyl etherate are added as catalysts, the mixture reacts for 1.5 to 3 hours at the temperature of 0 to 30 ℃, and p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside is obtained through a one-pot reaction; the molar ratio of the p-methoxyphenol to the pentaacetylglucose anomer mixture is 1.2-1: 1, and the molar ratio of the boron trifluoride diethyl etherate to the pentaacetylglucose anomer mixture is 1.1-1: 1;
and step 3: dissolving the p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside obtained in the step 2 in absolute methanol, adding sodium methoxide and cuprous oxide, reacting for 4 hours at 0-80 ℃, and removing acetyl on a sugar ring and methyl of methoxy on a benzene ring to obtain beta-arbutin; the dosage of the anhydrous methanol is 10 ml/g of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside, the dosage of the sodium methoxide is 2-5% (wt%) of the dosage of the p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside, and the dosage of the cuprous oxide is 5-8% (wt%) of the dosage of the p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside.
The invention has the advantages that: reacting D-glucose with stoichiometric acetic anhydride under the catalysis of molecular iodine to obtain a pentaacetylglucose anomer mixture almost quantitatively, directly reacting the obtained pentaacetylglucose anomer mixture with p-methoxyphenol under the catalysis of boron trifluoride ethyl ether in a one-pot method without separation to obtain p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside (the yield is over 90 percent), and removing acetyl on a sugar ring and methyl of methoxy on a benzene ring in sodium methoxide, cuprous oxide and methanol to obtain beta-arbutin (the reaction yield in the step is over 92 percent), so the total yield of the beta-arbutin synthesized by the method is over 85 percent. Therefore, the method has the advantages of convenient operation, less three-waste discharge, high yield and low cost.
Detailed Description
Example 1
D-glucose (18g, 0.1 mol) and acetic anhydride (51 g, 0.5 mol) are mixed, molecular iodine of 0.72 g is added, the mixture is stirred and reacted for 2.5 hours at the temperature of 20 ℃, the system is brown transparent liquid (indicating that the total acetylation reaction is finished), and the mixture of the end isomers of the pentaacetylglucose is obtained quantitatively. Without separation, adding 180 mL of anhydrous dichloromethane, adding p-methoxyphenol (12.4 g, 0.1 mol), dropwise adding boron trifluoride diethyl etherate (0.1 mol, 12.6 mL) at 0 ℃ under ice bath, after 30 minutes of dropwise addition, removing the ice bath, and reacting at 23-26 ℃ for 2.5 hours. The brown reaction mixture is washed with 200 ml of water for 2 times, a dichloromethane layer is separated, 10 ml of saturated sodium thiosulfate solution is used for washing to remove iodine, a colorless dichloromethane layer is obtained, 300 ml of saturated sodium bicarbonate solution and 300 ml of saturated sodium chloride solution are sequentially used for washing the dichloromethane layer, anhydrous sodium sulfate is dried, filtering is carried out, filtrate (the dichloromethane layer) is concentrated and dried, 46 g of light yellow solid is obtained, 200 ml of anhydrous ethanol is used for recrystallization, and 41.3 g of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside (white solid) is obtained, and the yield is 91%. m.p. 102-103.5 ℃.
1HNMR (300 MHz, CDCl3): δ6.95～6.91 (m, 2H), 6.83～6.76 (m, 2H), 5.31～5.22 (m, 2H), 5.14 (t, J = 9.6 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H), 4.27(dd, J = 12.3, 5.2 Hz, 1H), 4.16 (dd, J = 12.3, 2.5 Hz, 1H), 3.81～3.77(m, 1H), 3.75(s, 3H), 2.07 (s, 3H), 2.05 (s,3H), 2.03 (s, 3H) 2.02 (s, 3H)。
The p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside (36g, 0.08 mol) obtained above is dissolved in 360 ml of anhydrous methanol, stirring is started, 0.72 g of sodium methoxide and 1.8 g of cuprous oxide are added, reaction is carried out for 1.5 hours at 0 ℃, and reaction is carried out for 2.5 hours at 80 ℃. Filtering the reaction mixed solution, recovering cuprous oxide, neutralizing the filtrate with Amberlite IR-120 (H +) resin until the pH is =7, filtering and recovering the resin, concentrating the filtrate in vacuum, drying to obtain 21.6 g of beta-arbutin white solid, recrystallizing ethyl acetate to obtain 19.8 g of white needle crystal, and obtaining the yield of 91%. M.p, 198.5-199.4 ℃.1H NMR (400 MHz, D2O): δ 7.04～7.01(m, 2H), 6.87～6.84 (m, 2H), 4.97 (d, J = 7.6 Hz, 1H), 3.91 (dd, J = 12.4, 2.2 Hz, 1H), 3.72 (dd, J = 12.5, 5.6 Hz, 1H), 3.59～3.51(m, 3H), 3.48 (dd, J = 9.7, 8.9 Hz, 1H)。
Example 2
D-glucose (36g, 0.2 mol) and acetic anhydride (112.2 g, 1.1 mol) are mixed, molecular iodine of 1.44 g is added, the mixture is stirred and reacted for 2 hours at the temperature of 24 ℃, the system is brown transparent liquid (indicating that the total acetylation reaction is finished), and the mixture of the end isomers of the pentaacetylglucose is obtained quantitatively. Adding 360 mL of anhydrous dichloromethane without separation, adding p-methoxyphenol (27.3 g, 0.22 mol), dropwise adding boron trifluoride diethyl etherate (0.22 mol, 27.7 mL) at 0 ℃ under ice bath for 30 minutes, removing the ice bath after the dropwise adding is finished, and reacting for 2 hours at 22-26 ℃. The brown reaction mixture was washed with 400 ml of water for 2 times to separate a dichloromethane layer, washed with 20 ml of saturated sodium thiosulfate solution to remove iodine to obtain a colorless dichloromethane layer, washed with 600 ml of saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated and dried in the filtrate (dichloromethane layer) to obtain 95 g of pale yellow solid, and recrystallized with 400 ml of anhydrous ethanol to obtain 84.4 g of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl- β -D-glucopyranoside (white solid) with a yield of 93%.
The p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside (72 g, 0.16 mol) obtained above is dissolved in 720 ml of anhydrous methanol, stirring is started, 2.16 g of sodium methoxide and 4.32 g of cuprous oxide are added, reaction is carried out at 0 ℃ for 1.2 hours, and reaction is carried out at 80 ℃ for 2.8 hours. Filtering the reaction mixed solution, recovering cuprous oxide, neutralizing the filtrate with Amberlite IR-120 (H +) resin until the pH is =7, filtering and recovering the resin, concentrating the filtrate in vacuum, drying to obtain 45.6 g of beta-arbutin white solid, recrystallizing ethyl acetate to obtain 41.3 g of white acicular crystal, and obtaining the yield of 95%.
Example 3
Mixing D-glucose (18g, 0.1 mol) and acetic anhydride (61.2 g, 0.6 mol), adding molecular iodine 0.72 g, stirring and reacting at 25 ℃ for 2 hours to obtain a brown transparent liquid (indicating that the total acetylation reaction is finished), and quantitatively obtaining a pentaacetylglucose anomer mixture. Without separation, adding 180 mL of anhydrous dichloromethane, adding p-methoxyphenol (13.9 g, 0.12 mol), dropwise adding boron trifluoride diethyl etherate (0.105 mol, 13.2 mL) at 0 ℃ under ice bath, after 30 minutes of dropwise addition, removing the ice bath, and reacting for 2 hours at 23-25 ℃. The brown reaction mixture was washed 2 times with 200 ml of water, the dichloromethane layer was separated, washed with 10 ml of saturated sodium thiosulfate solution to remove iodine to give a colorless dichloromethane layer, washed with 300 ml of saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate (dichloromethane layer) was concentrated and dried to give 45.8 g of pale yellow solid, and recrystallized with 200 ml of anhydrous ethanol to give 41.7 g of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl- β -D-glucopyranoside (white solid), with a yield of 91.8%.
The p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside (36g, 0.08 mol) obtained above is dissolved in 360 ml of anhydrous methanol, stirring is started, 1.8 g of sodium methoxide and 2.88 g of cuprous oxide are added, reaction is carried out for 1 hour at 0 ℃, and reaction is carried out for 3 hours at 80 ℃. Filtering the reaction mixed solution, recovering cuprous oxide, neutralizing the filtrate with Amberlite IR-120 (H +) resin until the pH is =7, filtering and recovering the resin, concentrating the filtrate in vacuum, drying to obtain 21.8 g of beta-arbutin white solid, and recrystallizing ethyl acetate to obtain 20.2 g of white needle crystals with the yield of 93%.
Claims (6)
1. A method for chemically synthesizing beta-arbutin comprises the following steps:
step 1: reacting acetic anhydride and D-glucose serving as raw materials with molecular iodine serving as a catalyst at the temperature of 20-30 ℃ for 1-3 hours to obtain a mixture of pentaacetylglucose end group alpha and beta isomers;
step 2: the pentaacetylglucose anomer mixture obtained in the step 1 is not separated, anhydrous dichloromethane is added for dilution, p-methoxyphenol and boron trifluoride diethyl etherate are added as catalysts, the mixture reacts for 1.5 to 3 hours at the temperature of 0 to 30 ℃, and p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside is obtained through a one-pot reaction;
and step 3: and (3) dissolving the p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl-beta-D-glucopyranoside obtained in the step (2) in absolute methanol, adding sodium methoxide and cuprous oxide, reacting for 4 hours at 0-80 ℃, and removing acetyl on a sugar ring and methyl of methoxy on a benzene ring to obtain the beta-arbutin.
2. The method according to claim 1, wherein the molar ratio of acetic anhydride to D-glucose in step 1 is 5.5: 1.
3. The method according to claim 1, wherein the molecular iodine is used in an amount of 4% by mass based on the mass of D-glucose in step 1.
4. The method according to claim 1, wherein the molar ratio of p-methoxyphenol to the mixture of pentaacetylglucose anomers in step 2 is 1.2 to 1:1, and the molar ratio of boron trifluoride diethyl ether to the mixture of pentaacetylglucose anomers is 1.1 to 1: 1.
5. The method according to claim 1, wherein the amount of the anhydrous dichloromethane used in the step 2 is 15 ml of dichloromethane/g of p-methoxyphenol.
6. The method according to claim 1, wherein the amount of the absolute methanol in the step 3 is 10 ml of absolute methanol per gram of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl- β -D-glucopyranoside, the amount of sodium methoxide is 2 to 5 wt% of the amount of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl- β -D-glucopyranoside, and the amount of cuprous oxide is 5 to 8 wt% of the amount of p-methoxyphenyl-2, 3,4, 6-tetra-O-acetyl- β -D-glucopyranoside.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1043321A1 (en) * | 1999-03-29 | 2000-10-11 | Nisshin Flour Milling Co., Ltd. | Process for the preparation of tetrahydropyran derivatives |
| CN104163806A (en) * | 2013-05-20 | 2014-11-26 | 重庆圣华曦药业股份有限公司 | Preparation method of triacetylglucal |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1043321A1 (en) * | 1999-03-29 | 2000-10-11 | Nisshin Flour Milling Co., Ltd. | Process for the preparation of tetrahydropyran derivatives |
| CN104163806A (en) * | 2013-05-20 | 2014-11-26 | 重庆圣华曦药业股份有限公司 | Preparation method of triacetylglucal |
Non-Patent Citations (5)
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| A convenient method for the synthesis of radioactively labelled aryl glycosides;Simon D.J. Griffin，等;《Journal of Labelled Compounds and Radiopharmacuticals》;19931231(第6期);557-562 * |
| Efficient dealkylation of aryl alkyl ethers catalyzed by Cu2O;Lingxian Liu，等;《Tetrahedron》;20180330;第74卷;2447-2453 * |
| O-Aryl-Glycoside ice recrystallization inhibitors as novel cryoprotectants –A structure-function study;Chantelle J. Capicciotti，等;《ACS Omega》;20161024;第1卷(第4期);656-662 * |
| β-熊果苷合成新方法;陈方达，等;《浙江化工》;20161231;第47卷(第9期);29-31 * |
| β-熊果苷的合成;宗飞，等;《浙江化工》;20131231;第44卷(第8期);10-14 * |
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