CN112358514A - Synthesis process of arbutin - Google Patents
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Abstract
The invention belongs to the technical field of fine chemical engineering, and particularly discloses a synthesis process of arbutin, wherein the arbutin adopts the following synthesis path: performing condensation reaction by using monoacetylhydroquinone and pentaacetylglucosamine as raw materials, dichloromethane as a solvent and boron trifluoride acetic acid as a catalyst to obtain pentaacetylarbutin; deacetylating pentaacetylarbutin with methanol and sodium methoxide to obtain arbutin; the specific process flow comprises a condensation section and an alcoholysis section, wherein the condensation section comprises condensation, washing and crystallization steps, the obtained pentaacetylarbutin enters the alcoholysis section for use, and the alcoholysis section comprises alcoholysis, neutralization, decolorization and recrystallization steps to obtain an arbutin finished product. The invention can effectively solve the problem of hydroquinone residue in the existing Helferich synthesis method, and the used catalyst is safe, environment-friendly and efficient; the method has the advantages of high arbutin yield and high product purity.
Description
Technical Field
The invention belongs to the technical field of fine chemical engineering, and particularly relates to a synthesis process of arbutin.
Background
Arbutin, also called arbutin, is chemically known as p-hydroxy-phenyl-beta-glucopyranoside, is initially applied to medicaments, has the effects of resisting bacteria and diminishing inflammation, is discovered to be capable of inhibiting the formation of melanin through research, has the effect of whitening, and has wide application in the aspect of skin care products.
The preparation method of arbutin mainly comprises the following steps: natural plant extraction, plant tissue culture, chemical synthesis and enzymatic conversion. The natural plant extraction method has the disadvantages of difficult raw material source, low arbutin content, multiple separation steps and low purity of the extracted product; the plant tissue culture method has overlong production cycle, low content of useful substances and difficult subsequent separation; the enzyme conversion method is difficult to find a proper enzyme source and needs long-time research; the chemical synthesis method has the advantages of easily available raw materials, relatively simple process and higher product purity, so at present, the chemical synthesis is still the preferred way.
The general steps of the chemical synthesis of arbutin are that glucose and hydroquinone are subjected to glycosylation reaction after being properly protected, and then protective groups are removed. The glycosylation reaction is the basis of arbutin synthesis, and can be divided into two methods according to the difference of glycosyl donors in the reaction: a Koenigs-Knorr synthetic method taking bromoglucoside as a donor and a Helferich synthetic method taking acyl as a donor.
The classical Koenigs-Knorr reaction is to acetylate glucose, obtain bromotetraacetyl glucose after bromine substitution, then condense with hydroquinone protected by a single side chain under the action of an alkaline catalyst to obtain pentaacetylglucose, and then deacetylate to obtain arbutin; the intermediate bromotetraacetylglucose in the method is unstable, has complex separation means, and is not suitable for large-scale production.
The synthesis method of Helferich comprises acetylating glucose to obtain pentaacetylglucosamine, condensing with hydroquinone under the action of catalyst to obtain pentaacetylarbutin, and deacetylating to obtain arbutin (such as patent application CN 105968149A); compared with the Koenigs-Knorr synthesis method, the method has more stable intermediates, is the main method for industrially producing arbutin at present, but has the following defects: the residual quantity of hydroquinone is large, the hydroquinone has stimulation to skin, and the content of the hydroquinone needs to be strictly controlled; secondly, the catalyst is boron trifluoride diethyl etherate and triethylamine generally, the boron trifluoride diethyl etherate has high toxicity, is inflammable and explosive and has potential safety hazard, and the triethylamine can generate ammonia nitrogen compounds, so that the difficulty and the cost of wastewater treatment are increased.
Disclosure of Invention
In order to solve the problems, the invention provides a synthesis process of arbutin, which can effectively solve the problem of hydroquinone residue in the existing Helferich synthesis method, and the used catalyst is safe and environment-friendly; the method has the advantages of high arbutin yield and high product purity.
In order to achieve the purpose, the invention adopts the following specific technical scheme:
a synthesis process of arbutin comprises the steps of carrying out condensation reaction on raw materials of monoacetylhydroquinone and pentaacetylglucose, dichloromethane serving as a solvent and boron trifluoride acetic acid serving as a catalyst to obtain pentaacetylarbutin; the pentaacetyl arbutin is deacetylated by methanol and sodium methoxide to obtain arbutin.
The invention uses the monoacetylhydroquinone to replace the traditional hydroquinone, avoids the residue of the hydroquinone in the final product and improves the application safety of the arbutin; boron trifluoride acetic acid is used for replacing the traditional boron trifluoride diethyl etherate and triethylamine, so that the safety of the reaction is improved, ammonia nitrogen is not generated, the environment is protected, and the control and wastewater treatment cost is effectively reduced; and boron trifluoride acetic acid catalyzes the condensation reaction of monoacetylhydroquinone and pentaacetylglucose and has high catalytic efficiency, stable reaction and high yield of the condensation product pentaacetylarbutin, thereby laying a good foundation for the subsequent alcoholysis reaction.
Preferably, the synthesis process of arbutin specifically comprises the following steps:
s1, condensation: putting 1200-1500 kg of dichloromethane into a reaction kettle, adding 200-230 kg of monoacetylhydroquinone and 510-540 kg of pentaacetylglucose, covering and sealing, cooling to 5-10 ℃, dropwise adding a boron trifluoride acetic acid solution for one hour, stopping cooling after dropwise adding, raising the temperature of a jacket to 40-50 ℃, and carrying out heating reflux reaction for 5-7 hours;
s2, washing: after the condensation reaction is finished and the temperature is reduced to be below 20 ℃, 550-650 kg of purified water is added into the reaction product for washing; separating, removing a water layer, adding 350-450 kg of NaOH aqueous solution with the concentration of 1-3% into the organic layer for alkali washing, and controlling the pH value of the water layer to be 7-8; separating, removing the water layer, and distilling the organic layer to recover dichloromethane;
s3, crystallization: adding 800-1200 kg of absolute ethyl alcohol into the organic layer, stirring for 1.5-2.5 hours at 45-55 ℃, and then cooling and crystallizing; centrifuging when the temperature is reduced to 5-10 ℃, distilling the centrifuged mother liquor to recover ethanol, mechanically applying the recovered ethanol to crystals, and drying the centrifuged solid penta-acetyl arbutin by a double cone for later use;
s4, alcoholysis: adding 1900-2200 kg of methanol into a reaction kettle, adding 560-600 kg of pentaacetyl arbutin, heating, adding 2-5 kg of sodium methoxide when the temperature in the kettle reaches 45-55 ℃, heating to 60-70 ℃ for heating reflux reaction, and reacting for 3-4 hours;
s5, neutralization and decoloration: cooling the alcoholysis reaction product to 23-28 ℃, adjusting the pH value to 6-7 by using acetic acid, adding 0.5-1.5 kg of activated carbon for decolorization, and stirring for 0.5-1.5 hours; then filtering, and distilling the filtrate to remove methanol and methyl acetate;
s6, recrystallization: adding 800-1200 kg of methyl acetate into the filtrate, heating to 45-55 ℃, pulping for 1.5-2.5 hours, then stirring, cooling to 5-10 ℃, and centrifuging to obtain a filter cake which is an arbutin crude product; adding 800-1200 g of purified water into the arbutin crude product, heating to 60-70 ℃ for dissolving, filtering, cooling for crystallization, and stirring in the crystallization process; and when the temperature is reduced to 5-10 ℃, centrifuging, and drying the centrifuged solid to obtain an arbutin finished product.
Preferably, in step S2, the organic layer is sequentially subjected to atmospheric distillation and vacuum distillation to remove dichloromethane, the temperature of the atmospheric distillation is controlled at 45 ℃, and the total time of the atmospheric distillation and the vacuum distillation is controlled at 6-8 hours.
Preferably, in step S5, the filtrate is subjected to atmospheric distillation and vacuum distillation in sequence to remove methanol and methyl acetate, and the atmospheric distillation temperature is controlled at 70 ℃.
Preferably, in step S5, the removed methanol and methyl acetate are recovered separately after rectification.
Preferably, in step S4, before adding the sodium methoxide, nitrogen is introduced into the reaction kettle, so that the sodium methoxide can be quickly and sufficiently dissolved in the methanol to facilitate the alcoholysis reaction.
Preferably, in step S6, the cooling crystallization process includes naturally cooling, and cooling the cold brine to 5-10 ℃.
Preferably, the cooling liquid is cold brine, and the temperature of the cold brine is below 0 ℃, which is faster than the cooling speed of the cooling water.
The invention has the following beneficial effects:
1. the invention provides a new arbutin synthesis path: performing condensation reaction by using monoacetylhydroquinone and pentaacetylglucosamine as raw materials, dichloromethane as a solvent and boron trifluoride acetic acid as a catalyst to obtain pentaacetylarbutin; the pentaacetyl arbutin is deacetylated by methanol and sodium methoxide to obtain arbutin. Compared with the existing Helferich synthesis method, the synthesis path has the advantages that the product does not have hydroquinone residue, and can be safely applied; the used catalyst is safe and efficient, does not produce ammonia nitrogen, and is more environment-friendly.
2. The synthesis of arbutin is carried out by adopting the synthesis route, the specific process flow comprises a condensation section and an alcoholysis section, the condensation section comprises condensation, washing and crystallization steps, the obtained pentaacetylarbutin enters the alcoholysis section for use, and the alcoholysis section comprises alcoholysis, neutralization and decolorization and recrystallization steps to obtain an arbutin finished product; the product yield of each section of the process flow is high (the yield of the pentaacetyl arbutin is more than 70 percent, the yield of the arbutin is more than 80 percent), and the purity of the arbutin finished product is high (more than 98 percent).
3. The invention adopts a mode of combining atmospheric distillation and reduced pressure distillation to recover organic solvents of dichloromethane, methanol and methyl acetate, can ensure that the organic solvents are completely removed, and simultaneously avoids excessive loss of pentaacetylarbutin and arbutin.
4. The anhydrous ethanol, the dichloromethane, the methanol and the methyl acetate recovered by the method can be used mechanically, so that the resource recycling is realized, the cost is reduced, the waste discharge is reduced, and the method is environment-friendly and energy-saving.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Example 1
A synthesis process of arbutin comprises the steps of carrying out condensation reaction on raw materials of monoacetylhydroquinone and pentaacetylglucose, dichloromethane serving as a solvent and boron trifluoride acetic acid serving as a catalyst to obtain pentaacetylarbutin; the method for obtaining arbutin from the pentaacetyl arbutin through methanol and sodium methoxide deacetylation comprises the following steps:
s1, condensation: pumping 1200-1500 kg of dichloromethane into a 3000L reaction kettle from a metering tank through a pump, adding 200-230 kg of monoacetylhydroquinone and 510-540 kg of pentaacetylglucose, covering and sealing, cooling to 5-10 ℃, dropwise adding a boron trifluoride acetic acid solution for one hour, stopping cooling brine after dropwise adding, raising the temperature of a jacket to 40-50 ℃, carrying out heating reflux reaction, and reacting for 5-7 hours;
s2, washing: after the condensation reaction is finished and the temperature is reduced to be below 20 ℃, putting the reaction product into a washing kettle, and adding 550-650 kg of purified water into the reaction product for washing; separating, removing a water layer, putting an organic layer into a washing kettle, adding 350-450 kg of NaOH aqueous solution with the concentration of 1-3% into the organic layer for alkali washing, and controlling the pH value of the water layer to be 7-8; separating, removing a water layer, putting an organic layer into a desolventizing pulping kettle, controlling the external temperature at 45 ℃ and distilling at normal pressure to remove most of dichloromethane, then distilling under reduced pressure to remove the rest dichloromethane, controlling the total time at 6-8 hours, and recovering the dichloromethane;
s3, crystallization: adding 800-1200 kg of absolute ethyl alcohol into the organic layer, stirring for 1.5-2.5 hours at 45-55 ℃, and then cooling and crystallizing; centrifuging when the temperature is reduced to 5-10 ℃, distilling the centrifuged mother liquor to recover ethanol, recycling the recovered ethanol for crystallization, drying the centrifuged solid which is the penta-acetyl arbutin by bipyramid for later use, wherein the yield of the penta-acetyl arbutin is more than 70%;
s4, alcoholysis: pumping 1900-2200 kg of methanol from a metering tank into a 3000L reaction kettle by a pump, rapidly adding 560-600 kg of pentaacetyl arbutin, charging nitrogen, heating, adding 2-5 kg of sodium methoxide when the temperature in the kettle reaches 45-55 ℃, heating to 60-70 ℃ for heating reflux reaction, and reacting for 3-4 hours;
s5, neutralization and decoloration: feeding the alcoholysis reaction product into a neutralization and decoloration kettle, cooling to 23-28 ℃, adjusting the pH value to 6-7 by using acetic acid, adding 0.5-1.5 kg of activated carbon for decoloration, and stirring for 0.5-1.5 hours; then introducing a filter for filtration, pumping the filtrate into a distillation kettle, raising the temperature of a jacket to 70 ℃, desolventizing at normal pressure until most of the filtrate is removed, starting a vacuum pump to remove the residual solvent under reduced pressure, and respectively recovering the removed methanol and methyl acetate after rectification;
s6, recrystallization: adding 800-1200 kg of methyl acetate and the filtrate after desolventizing into a pulping kettle,
heating to 45-55 ℃, pulping for 1.5-2.5 hours, then stirring, cooling to 5-10 ℃, and centrifuging to obtain a filter cake which is an arbutin crude product; adding 800-1200 g of purified water into the arbutin crude product, heating to 60-70 ℃ for dissolving, filtering, cooling for crystallization (naturally cooling, slowly cooling by cold saline), and stirring in the crystallization process; and (3) when the temperature is reduced to 5-10 ℃, centrifuging, and drying the centrifuged solid to obtain an arbutin finished product, wherein the yield of the arbutin finished product is more than 80%, and the purity of the arbutin finished product is more than 98%.
Example 2
The embodiment provides a synthesis process of arbutin, which is further preferable in the scheme of embodiment 1, and specifically comprises the following steps:
s1, condensation: pumping 1300kg of dichloromethane into a 3000L reaction kettle from a metering tank through a pump, adding 220 kg of monoacetylhydroquinone and 530kg of pentaacetylglucose, covering and sealing, cooling to 5-10 ℃, dropwise adding a boron trifluoride acetic acid solution for one hour, stopping cooling brine after dropwise adding, heating to 45 ℃ by a jacket for reflux reaction, and reacting for 6 hours;
s2, washing: after the condensation reaction is finished and the temperature is reduced to be below 20 ℃, the reaction product is injected into a washing kettle, and 600kg of purified water is added into the reaction product for washing; separating, discarding a water layer, putting an organic layer into a washing kettle, adding 400kg of NaOH aqueous solution with the concentration of 2% into the organic layer for alkali washing, and controlling the pH value of the water layer to be 7-8; separating, removing water layer, placing organic layer in a desolventizing pulping kettle, distilling at 45 deg.C under normal pressure to remove most of dichloromethane, distilling under reduced pressure to remove the rest dichloromethane, controlling total time at 7 hr, and recovering dichloromethane;
s3, crystallization: adding 1000kg of absolute ethyl alcohol into the organic layer, stirring for 2 hours at 45-55 ℃, and then cooling and crystallizing; centrifuging when the temperature is reduced to 5 ℃, distilling the centrifuged mother liquor to recover ethanol, recycling the recovered ethanol for crystallization, wherein the centrifuged solid is penta-acetyl arbutin, drying by double cones for later use, and the yield of the penta-acetyl arbutin is 88.5%;
s4, alcoholysis: pumping 2000kg of methanol into a 3000L reaction kettle from a metering tank through a pump, rapidly adding 580kg of pentaacetyl arbutin, charging nitrogen, heating, adding 3kg of sodium methoxide when the temperature in the kettle reaches 50 ℃, heating to 65 ℃ for heating reflux reaction, and reacting for 3.5 hours;
s5, neutralization and decoloration: adding the alcoholysis reaction product into a neutralization and decoloration kettle, cooling to 25 ℃, adjusting the pH value to 6.5 by using acetic acid, adding 1kg of activated carbon for decoloration, and stirring for 1 hour; then introducing a filter for filtration, pumping the filtrate into a distillation kettle, raising the temperature of a jacket to 70 ℃, desolventizing at normal pressure until most of the filtrate is removed, starting a vacuum pump to remove the residual solvent under reduced pressure, and respectively recovering the removed methanol and methyl acetate after rectification;
s6, recrystallization: adding 1000kg of methyl acetate and the filtrate after desolventizing into a pulping kettle, heating to 50 ℃, pulping for 2 hours, then stirring, cooling to 5 ℃, and centrifuging to obtain a filter cake which is an arbutin crude product; adding 1000g purified water into the crude product of arbutin, heating to 65 deg.C for dissolving, filtering, cooling for crystallization (naturally cooling, and slowly cooling with cold saline water), and stirring during crystallization; centrifuging when the temperature is reduced to 5 deg.C, drying the centrifuged solid to obtain arbutin product with yield of 89.0%, and purity of 99.5% as determined by high performance liquid chromatography.
Comparative example 1
A synthesis process of arbutin, which is basically the same as example 1, and only differs from the following process: in step S1, boron trifluoride diethyl etherate and triethylamine are used as catalysts. The yield of the pentaacetyl arbutin is less than 65 percent; the yield of arbutin is above 80%, the purity of arbutin is less than 95%, and boron trifluoride acetic acid as a catalyst has obvious advantages compared with boron trifluoride diethyl etherate and triethylamine.
Comparative example 2
A synthesis process of arbutin is basically the same as that of example 2, and only differs from the following processes: in step S4, nitrogen is not purged before adding sodium methoxide to methanol. The yield of arbutin is 78.9%, the purity is 99.3%, and the nitrogen filling is helpful for the full performance of alcoholysis reaction.
Comparative example 3
A synthesis process of arbutin is basically the same as that of example 2, and only differs from the following processes: in step S2, the organic layer was subjected to distillation under reduced pressure to recover methylene chloride, and in step S5, the filtrate was subjected to distillation under reduced pressure to remove methanol and methyl acetate. The yield of the pentaacetyl arbutin is 73.4 percent; the yield of arbutin is 75.6%, the purity of arbutin is 98.1%, and thus the product loss can be effectively reduced by combining atmospheric distillation with reduced pressure distillation for desolventizing.
This detailed description is to be construed as illustrative only and is not to be taken as limiting the invention, as any changes that may be made by a person skilled in the art after reading the present specification will be protected by the patent laws within the scope of the appended claims.
Claims (8)
1. A synthesis process of arbutin is characterized by comprising the following steps: the arbutin adopts the following synthetic route: performing condensation reaction by using monoacetylhydroquinone and pentaacetylglucosamine as raw materials, dichloromethane as a solvent and boron trifluoride acetic acid as a catalyst to obtain pentaacetylarbutin; the pentaacetyl arbutin is deacetylated by methanol and sodium methoxide to obtain arbutin.
2. The process for synthesizing arbutin according to claim 1, wherein: the method specifically comprises the following steps:
s1, condensation: putting 1200-1500 kg of dichloromethane into a reaction kettle, adding 200-230 kg of monoacetylhydroquinone and 510-540 kg of pentaacetylglucose, covering and sealing, cooling to 5-10 ℃, dropwise adding a boron trifluoride acetic acid solution for one hour, stopping cooling after dropwise adding, raising the temperature of a jacket to 40-50 ℃, and carrying out heating reflux reaction for 5-7 hours;
s2, washing: after the condensation reaction is finished and the temperature is reduced to be below 20 ℃, 550-650 kg of purified water is added into the reaction product for washing; separating, removing a water layer, adding 350-450 kg of NaOH aqueous solution with the concentration of 1-3% into the organic layer for alkali washing, and controlling the pH value of the water layer to be 7-8; separating, removing the water layer, and distilling the organic layer to recover dichloromethane;
s3, crystallization: adding 800-1200 kg of absolute ethyl alcohol into the organic layer, stirring for 1.5-2.5 hours at 45-55 ℃, and then cooling and crystallizing; centrifuging when the temperature is reduced to 5-10 ℃, distilling the centrifuged mother liquor to recover ethanol, mechanically applying the recovered ethanol to crystals, and drying the centrifuged solid penta-acetyl arbutin by a double cone for later use;
s4, alcoholysis: adding 1900-2200 kg of methanol into a reaction kettle, adding 560-600 kg of pentaacetyl arbutin, heating, adding 2-5 kg of sodium methoxide when the temperature in the kettle reaches 45-55 ℃, heating to 60-70 ℃ for heating reflux reaction, and reacting for 3-4 hours;
s5, neutralization and decoloration: cooling the alcoholysis reaction product to 23-28 ℃, adjusting the pH value to 6-7 by using acetic acid, adding 0.5-1.5 kg of activated carbon for decolorization, and stirring for 0.5-1.5 hours; then filtering, and distilling the filtrate to remove methanol and methyl acetate;
s6, recrystallization: adding 800-1200 kg of methyl acetate into the filtrate, heating to 45-55 ℃, pulping for 1.5-2.5 hours, then stirring, cooling to 5-10 ℃, and centrifuging to obtain a filter cake which is an arbutin crude product; adding 800-1200 g of purified water into the arbutin crude product, heating to 60-70 ℃ for dissolving, filtering, cooling for crystallization, and stirring in the crystallization process; and when the temperature is reduced to 5-10 ℃, centrifuging, and drying the centrifuged solid to obtain an arbutin finished product.
3. The process for synthesizing arbutin according to claim 2, wherein: in the step S2, the organic layer is subjected to atmospheric distillation and reduced pressure distillation in sequence to remove dichloromethane, the temperature of the atmospheric distillation is controlled at 45 ℃, and the total time of the atmospheric distillation and the reduced pressure distillation is controlled at 6-8 hours.
4. The process for synthesizing arbutin according to claim 2, wherein: in step S5, the filtrate is subjected to atmospheric distillation and vacuum distillation in sequence to remove methanol and methyl acetate, and the atmospheric distillation temperature is controlled at 70 ℃.
5. The process for synthesizing arbutin according to claim 2 or 4, wherein: in step S5, the removed methanol and methyl acetate are recovered after rectification respectively.
6. The process for synthesizing arbutin according to claim 2, wherein: in step S4, nitrogen gas is introduced into the reaction kettle before sodium methoxide is added.
7. The process for synthesizing arbutin according to claim 2, wherein: in step S6, the cooling crystallization process is carried out by naturally cooling and cooling the cold brine to 5-10 ℃.
8. The process for synthesizing arbutin according to claim 2, wherein: in step S1, the coolant is cold brine.
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