Green preparation process of high-purity stearyl glycyrrhetinic acid ester

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a green preparation process of high-purity stearyl glycyrrhetinic acid ester, which comprises the following steps: taking glycyrrhetinic acid, adding a composite aqueous solution, ultrasonically stirring, filtering with a ceramic membrane, washing to a specified pH value, drying in vacuum, putting into a reaction kettle together with stearyl alcohol, adding a catalyst and a cosolvent, introducing nitrogen, and performing ultrasonic-microwave segmented temperature control reaction, thereby obtaining the stearyl glycyrrhetinic acid ester. Cooling the reaction liquid, magnetically separating to recover the catalyst, microfiltering the filtrate, adding the mixed liquid, stirring, standing and filtering to obtain a crude product, dissolving the crude product with an ethanol aqueous solution, decolorizing, adding a seed crystal, carrying out gradient cooling, crystallizing and washing, carrying out vacuum drying on the crystal, and blowing argon to obtain the product. The process adopts a composite catalyst and synergistic reaction mode, optimizes raw material pretreatment and purification processes, reduces side reactions and solvent use, reduces energy consumption, has no toxic emission, improves product purity and stability, gives consideration to both environmental protection and efficiency, and has good application prospects.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a green preparation process for high-purity stearyl glycyrrhizic acid ester. Background Technology

[0002] Stearyl glycyrrhizic acid ester, as an important natural active derivative, combines the anti-inflammatory and antioxidant properties of glycyrrhizic acid with the fat-soluble advantages of stearyl alcohol. It is widely used in cosmetics, pharmaceuticals, and food additives, and market demand continues to grow. However, existing preparation processes still face numerous technical bottlenecks, hindering industrial-scale production and the acquisition of high-quality products.

[0003] Currently, the esterification reaction of stearyl glycyrrhizic acid esters mostly uses traditional chemical catalysts, such as concentrated sulfuric acid and p-toluenesulfonic acid. While these catalysts can promote the reaction to some extent, they have serious drawbacks: their strong corrosiveness leads to accelerated equipment wear and tear; they easily trigger side reactions during the reaction, generating impurities and increasing the difficulty of subsequent purification; furthermore, the catalysts are difficult to recover, and the reaction waste contains a large amount of acidic substances, resulting in high treatment costs and environmental pollution, which is inconsistent with the concept of green chemical development. Some processes have attempted to use single lipases as biocatalysts, which, while environmentally friendly, have low catalytic efficiency, a reaction cycle of 8-12 hours, and poor enzyme stability, making them difficult to reuse, resulting in high production costs.

[0004] In the raw material pretreatment stage, traditional processes for purifying glycyrrhizic acid often involve simple water washing or solvent extraction, which is difficult to effectively remove impurities and trace metal ions from the raw materials. These impurities directly affect the selectivity of the esterification reaction and the purity of the product. The final product purity can usually only reach 95%-97%, which cannot meet the requirements of high-end cosmetics and pharmaceutical fields for high-purity raw materials.

[0005] The separation, purification, and post-processing procedures also have significant shortcomings. Existing processes mostly rely on single-solvent crystallization or column chromatography separation, which consumes large quantities of solvents, many of which are toxic organic solvents such as dichloromethane and ethyl acetate. This not only endangers the health of operators but also poses a risk of solvent residue. Furthermore, the solvent recovery rate is low, resulting in resource waste and environmental pressure. In addition, traditional processes have low precision in reaction temperature control and high energy consumption; the energy consumption per unit product is 1.5-2 times that of green chemical standards, which does not comply with current industrial policies on energy conservation and emission reduction.

[0006] In summary, existing stearyl glycyrrhizic acid ester preparation processes have significant shortcomings in terms of catalyst performance, raw material pretreatment effect, greenness of separation and purification, and energy consumption control. Developing an efficient, environmentally friendly, low-cost, and high-purity preparation process has become an urgent need for the industry. Summary of the Invention

[0007] (a) Technical problems to be solved To address the shortcomings of existing technologies, this invention provides a green preparation process for high-purity stearyl glycyrrhizic acid ester.

[0008] (II) Technical Solution A green preparation process for high-purity stearyl glycyrrhizic acid ester includes the following steps: S1, Raw material pretreatment: Take glycyrrhizic acid powder, add food-grade citric acid-malic acid composite aqueous solution, the mass ratio of glycyrrhizic acid to composite aqueous solution is 1:3.5-4.5, after ultrasonic-assisted stirring, use ceramic membrane cross-flow filtration, wash the filter residue to pH 6.7-6.9, and vacuum dry to obtain pretreated glycyrrhizic acid; S2, Green Esterification Reaction: Pretreated glycyrrhetinic acid and stearyl alcohol were added to an ultrasonic-microwave synergistic reactor at a molar ratio of 1:1.3-1.4. A bio-based composite catalyst was added, which was a chitosan-montmorillonite supported nano-ZnO-lipase composite system. At the same time, green co-solvent polyethylene glycol was added. After purging with nitrogen to remove air, the ultrasonic-microwave reaction was turned on. The reaction was carried out in stages with temperature control, and the pH of the system was controlled at 5.5-6.0 to obtain the esterification reaction solution. S3, Catalyst recovery and crude product preparation: After the esterification reaction solution is cooled, the catalyst is separated by high gradient magnetic separation. The catalyst can be recycled 4-5 times. After the filtrate is microfiltered through an organic membrane, an ethanol-ultrapure water mixture is added, stirred and allowed to stand, and then filtered to obtain crude stearyl glycyrrhizic acid ester. S4, Multi-stage synergistic purification: The crude product is dissolved in an ethanol-water solution, decolorized by activated carbon adsorption, filtered, and stearyl glycyrrhetinic acid ester seed crystals are added to the filtrate. Gradient cooling crystallization is used, and the crystals are collected by filtration and washed. S5, Green Post-processing and Product Collection: Crystals are vacuum dried, with argon gas purging during the process, to obtain high-purity stearyl glycyrrhizic acid ester product.

[0009] Preferably, in step S1, the mass concentration of the citric acid-malic acid composite aqueous solution is 0.9-1.1%, the mass ratio of citric acid to malic acid is 2:1, the ultrasonic-assisted stirring power is 80-120W, the frequency is 20-25kHz, the ceramic membrane pore size is 0.25-0.4μm, the vacuum drying temperature is 52-58℃, and the vacuum degree is -0.088 to -0.092MPa.

[0010] Preferably, in step S2, the amount of bio-based composite catalyst is 3.5-4.5% of the mass of pretreated glycyrrhizic acid, the loading of nano-ZnO is 9-11%, the mass ratio of montmorillonite to chitosan is 1:2.2-2.8, and the amount of lipase immobilization is 5-8%; the amount of polyethylene glycol is 5-8% of the mass of pretreated glycyrrhizic acid with an average molecular weight of 450-550; the nitrogen flow rate is 0.9-1.1 L / min, and the purging time is 8-12 min.

[0011] Preferably, in step S2, the ultrasonic power is 160-190W and the frequency is 26-29kHz, the microwave power is 320-380W and the frequency is 2450±30MHz, the ultrasonic and microwave are turned on synchronously, the microwave power is adjusted every 40-50 minutes, and the adjustment range fluctuates within ±10W within 320-380W. The temperature is controlled in segments: after reacting at 65-68℃ for 1 hour, the temperature is raised to 70-73℃ for 1.5-2.5 hours, and the stirring speed is 320-380r / min.

[0012] Preferably, in step S3, the high-gradient magnetic separation magnetic field strength is 0.35-0.45T; the organic membrane microfiltration pore size is 0.15-0.18μm, and the pressure is 0.22-0.28MPa; the volume of the ethanol-ultrapure water mixture is 3.5-4.5 times that of the filtrate, the ethanol to ultrapure water ratio is 1:1.6-1.8, and it is filtered through a 0.05-0.1μm ultrafiltration membrane before use, at a temperature of 21-24℃, with a stirring time of 32-38min and a standing time of 1.2-1.4h.

[0013] Preferably, in step S4, the ethanol-water solution has a mass concentration of 86-89%, the mass ratio of crude product to ethanol-water solution is 1:8.5-9.5, and the dissolution temperature is 71-74℃; the activated carbon dosage is 0.05-0.08% of the crude product mass, with a particle size of 10-20nm; the adsorption and decolorization stirring speed is 180-220r / min, the time is 30-40min, and the ceramic membrane used for filtration has a pore size of 0.1-0.12μm and a pressure of 0.18-0.22MPa.

[0014] Preferably, in step S4, the stearyl glycyrrhizic acid ester seed crystals have a particle size of 12-18 μm and are added at 0.02-0.04% of the filtrate mass; the gradient cooling is 6-7℃ / h to 41-44℃ and held for 1.2-1.4h, then 2.2-2.8℃ / h to 11-14℃ and held for 2.1-2.4h; the washing uses an ethanol aqueous solution with a mass concentration of 91-94%, and the amount used each time is 1.1-1.4 times the crystal mass.

[0015] Preferably, in step S4, after crystallization, the crystals and mother liquor are separated by centrifugal filtration at a speed of 3000-4000 r / min for 10-15 min. The mother liquor is then distilled to recover ethanol, which is recycled for washing and dissolving in steps S3 and S4.

[0016] Preferably, in step S5, the argon purging flow rate is 0.3-0.5 L / min; the vacuum drying temperature is 58-62℃, the vacuum degree is -0.092 to -0.096 MPa, and the time is 3.2-3.8 h. The drying is divided into three stages: drying at 58-60℃ for 1 h, drying at 60-62℃ for 1.5 h, and drying at 58-60℃ for 1.3-1.8 h.

[0017] Preferably, in step S1, the glycyrrhetinic acid powder is pretreated by air jet milling at a pressure of 0.7-0.9 MPa, resulting in a particle size of 5-10 μm. In step S2, the bio-based composite catalyst is prepared by dissolving chitosan in a 1.2-1.8% acetic acid aqueous solution, adding montmorillonite and nano-ZnO, stirring at 52-58℃ for 2.2-2.8 h, adding 6-7% NaOH to adjust the pH to 7.6-7.9, precipitating, vacuum drying, pulverizing, and then immersing in a lipase solution with a concentration of 10-15 mg / mL and a pH 7.0 phosphate buffer solution. The catalyst is then shaken and adsorbed at 35-38℃ for 2-3 h, and dried to obtain the final product. After four cycles, the catalyst is soaked in 5-8% acetic acid for 2-3 h, washed, dried, and regenerated.

[0018] (iii) Beneficial technical effects Compared with existing technologies, the beneficial effects of this invention are: 1. The bio-based composite catalyst used combines the synergistic effects of inorganic nanomaterials and biological enzymes, which not only avoids the corrosiveness and pollution problems of traditional chemical catalysts, but also significantly improves catalytic activity and selectivity, resulting in a milder reaction process and a significant reduction in side reactions. Furthermore, the catalyst can be efficiently recovered and recycled through magnetic separation, and after simple regeneration, it can still maintain good catalytic performance, effectively reducing catalyst costs and aligning with the concept of green production.

[0019] 2. By combining a composite acid solution with ultrasonic assistance, the impurity removal effect was enhanced. Combined with cross-flow filtration using a ceramic membrane, the purity of the pretreated glycyrrhetinic acid was significantly improved, laying a high-quality raw material foundation for the efficient subsequent esterification reaction and reducing the interference of impurities on the reaction system.

[0020] 3. The esterification reaction employs a combination of ultrasonic-microwave synergy and segmented temperature control. Compared to traditional heating methods, this approach allows for more precise control of the reaction process, accelerates the diffusion rate of reactant molecules, shortens the reaction time, and improves the conversion rate of glycyrrhetinic acid. The multi-stage synergistic process for separation and purification combines activated carbon decolorization, gradient cooling crystallization, and high-efficiency filtration, reducing the amount of organic solvent used and significantly improving solvent recovery and utilization rates, thereby mitigating environmental risks and resource waste. Attached Figure Description

[0021] Figure 1 This is a flow chart of a green preparation process for a high-purity stearyl glycyrrhizic acid ester disclosed in this invention; Figure 2 This is a bar graph comparing the purity and moisture content of the products in the examples and comparative examples; Figure 3 This is a bar chart comparing the storage stability and color difference of the products in the examples and comparative examples; Figure 4This is a radar comparison chart created by standardizing the dimensions of the performance comparison data between the examples and the comparative examples. Detailed Implementation

[0022] according to Figures 1 to 4 The specific embodiments of the present invention are as follows: Example 1 S1. Raw Material Pretreatment: Take 100g of glycyrrhizic acid powder and pulverize it using an air jet mill before pretreatment. Set the air jet mill pressure to 0.8MPa, and control the particle size of the glycyrrhizic acid powder after pulverization to 5-10μm. Add 400g of food-grade citric acid-malic acid composite aqueous solution to the pulverized glycyrrhizic acid powder. The mass concentration of this composite aqueous solution is 1.0%, and the mass ratio of citric acid to malic acid is 2:1. Transfer the mixture to an ultrasonic stirring tank. Set the temperature of the ultrasonic stirring tank to 40℃, the ultrasonic power to 100W, and the ultrasonic frequency to 22kHz. Turn on the ultrasonic-assisted stirring function and stir continuously for 20min. After stirring, pump the mixture into a ceramic membrane filtration system using a transfer pump. Select a ceramic membrane with a pore size of 0.3μm. Set the cross-flow filtration pressure of the ceramic membrane filtration system to 0.2MPa and the filtration flow rate to 1.8m / s, and start the filtration program. After filtration, the filter residue was collected and repeatedly washed with ultrapure water until the pH of the washing solution reached 6.8. The washed filter residue was then placed in a vacuum drying oven, with the temperature set to 55℃ and the vacuum degree to -0.09MPa. The vacuum drying program was started and continued for 2.5 hours to obtain pretreated glycyrrhizic acid. The pretreated glycyrrhizic acid was tested and found to have a water content of 0.7% and a purity of 98.2%.

[0023] S2. Green Esterification Reaction: Weigh 95g of pretreated glycyrrhizic acid and the corresponding mass of stearyl alcohol at a molar ratio of 1:1.35. Add both to an ultrasonic-microwave synergistic reactor. Then add 3.8g of a bio-based composite catalyst (4% of the mass of pretreated glycyrrhizic acid) to the reactor. This catalyst is a chitosan-montmorillonite-supported nano-ZnO-lipase composite system, with a nano-ZnO loading of 10%, a montmorillonite to chitosan mass ratio of 1:2.5, and an immobilized lipase amount of 6.5%. Simultaneously add 6.18g of green co-solvent polyethylene glycol (6.5% of the mass of pretreated glycyrrhizic acid) with an average molecular weight of 500. Purge the reactor with nitrogen gas at a flow rate of 1.0L / min for 10 minutes to remove air from the reactor. After purging, the ultrasonic and microwave devices were simultaneously activated. The ultrasonic device had a power of 175W and a frequency of 27kHz; the microwave device had a power of 350W and a frequency of 2450MHz. A segmented temperature control mode was used for the reaction: first, the reaction temperature was controlled at 66℃ for 1 hour; then, the temperature was increased to 72℃ and the reaction continued for 2 hours. During the reaction, the stirring speed was set to 350 r / min. The pH of the reaction system was monitored and controlled in real time using an online pH monitor to maintain a value of 5.8. The reaction temperature was monitored in real time using an infrared thermometer to ensure that temperature fluctuations were controlled within ±0.5℃. After the reaction was completed, the esterification reaction solution was obtained.

[0024] S3. Catalyst Recovery and Crude Product Preparation: The esterification reaction solution was naturally cooled to 28°C and then transferred to a high-gradient magnetic separator. The magnetic field strength of the high-gradient magnetic separator was set to 0.4T, and the magnetic separation program was started to separate the bio-based composite catalyst. The separated catalyst was washed with ultrapure water and then placed in a vacuum drying oven at 55°C for 2 hours. After drying, it was set aside for later use and could be recycled. The filtrate after magnetic separation was collected and pumped into an organic membrane microfiltration system using a transfer pump. An organic membrane with a pore size of 0.16 μm was selected, and the microfiltration pressure of the organic membrane microfiltration system was set to 0.25 MPa. The microfiltration program was started. After microfiltration, an ethanol-ultrapure water mixture was added to the filtrate. The volume of the mixture was 3.8 times that of the filtrate, with a volume ratio of ethanol to ultrapure water of 1:1.7. This mixture needed to be filtered through an ultrafiltration membrane with a pore size of 0.08 μm before use, and the temperature during use was controlled at 23°C. The system after adding the mixture was transferred to a mixing tank and stirred at 23°C for 35 min. After stirring, it was allowed to stand for 1.3 h and then filtered to obtain crude stearyl glycyrrhizic acid ester.

[0025] S4. Multi-stage synergistic purification: Weigh 50g of crude stearyl glycyrrhizic acid ester and add 450g of 87% ethanol aqueous solution (mass ratio of crude product to ethanol aqueous solution: 1:9). Place the mixture in a heated and stirred tank, set the temperature of the tank to 72℃, and turn on the stirring function until the crude product is completely dissolved. Add 0.03g of activated carbon to the solution (0.06% of the crude product mass, particle size 15nm), set the stirring speed to 200r / min, and perform adsorption and decolorization for 35min. After adsorption and decolorization, remove the activated carbon by filtration using a ceramic membrane with a pore size of 0.11μm, setting the filtration pressure to 0.2MPa. Add 0.01g of stearyl glycyrrhizic acid ester seed crystals (15μm particle size, 0.03% of the filtrate mass) to the filtrate, then transfer the filtrate to a crystallizer and use a gradient cooling crystallization mode. The specific steps of the gradient cooling process are as follows: first, the temperature is lowered to 42℃ at a rate of 6.5℃ / h, and held at this temperature for 1.3h; then, it is lowered to 12℃ at a rate of 2.5℃ / h, and held at this temperature for 2.2h. After crystallization, the crystals and mother liquor are separated by centrifugal filtration. The centrifuge speed is set to 3500 r / min, and the centrifugation time is 12 min. The crystals obtained by centrifugation are collected and washed three times with a 92% ethanol aqueous solution, with the mass of the ethanol aqueous solution used for each wash being 1.2 times the mass of the crystals. The mother liquor obtained by centrifugation is used to recover ethanol through a distillation unit, with an ethanol recovery rate of 92.5%. The recovered ethanol is then used for future reference.

[0026] S5. Green Post-processing and Product Collection: The washed crystals were placed in a vacuum drying oven. The temperature of the oven was set to 60℃ and the vacuum degree to -0.094MPa. Argon gas was introduced for purging during the drying process at a flow rate of 0.4L / min. The vacuum drying process was divided into three stages: the first stage was drying at 59℃ for 1 hour; the second stage was drying at 61℃ for 1.5 hours; and the third stage was drying at 59℃ for 1.5 hours, for a total drying time of 4 hours. After drying, high-purity stearyl glycyrrhizic acid ester was obtained. The product was tested and found to have a purity of 99.6% and a water content of 0.25%.

[0027] Example 2 S1. Raw Material Pretreatment: Take 100g of glycyrrhizic acid powder and pulverize it using an air jet mill before pretreatment. Set the air jet mill pressure to 0.8MPa, and control the particle size of the glycyrrhizic acid powder after pulverization to 5-10μm. Add 400g of food-grade citric acid-malic acid composite aqueous solution to the pulverized glycyrrhizic acid powder. The mass concentration of this composite aqueous solution is 1.0%, and the mass ratio of citric acid to malic acid is 2:1. Transfer the mixture to an ultrasonic stirring tank. Set the temperature of the ultrasonic stirring tank to 40℃, the ultrasonic power to 100W, and the ultrasonic frequency to 22kHz. Turn on the ultrasonic-assisted stirring function and stir continuously for 20min. After stirring, pump the mixture into a ceramic membrane filtration system using a transfer pump. Select a ceramic membrane with a pore size of 0.3μm. Set the cross-flow filtration pressure of the ceramic membrane filtration system to 0.2MPa and the filtration flow rate to 1.8m / s, and start the filtration program. After filtration, the filter residue was collected and repeatedly washed with ultrapure water until the pH of the washing solution reached 6.8. The washed filter residue was then placed in a vacuum drying oven, with the temperature set to 55℃ and the vacuum degree to -0.09MPa. The vacuum drying program was started and continued for 2.5 hours to obtain pretreated glycyrrhizic acid. The pretreated glycyrrhizic acid was tested and found to have a water content of 0.7% and a purity of 98.2%.

[0028] S2. Green Esterification Reaction: Weigh 95g of pretreated glycyrrhizic acid and the corresponding mass of stearyl alcohol at a molar ratio of 1:1.35. Add both to an ultrasonic-microwave synergistic reactor. Then add 3.8g of a bio-based composite catalyst (4% of the mass of pretreated glycyrrhizic acid) to the reactor. This catalyst is a chitosan-montmorillonite-supported nano-ZnO-lipase composite system, with a nano-ZnO loading of 10%, a montmorillonite to chitosan mass ratio of 1:2.5, and an immobilized lipase amount of 6.5%. Simultaneously add 6.18g of green co-solvent polyethylene glycol (6.5% of the mass of pretreated glycyrrhizic acid) with an average molecular weight of 500. Purge the reactor with nitrogen gas at a flow rate of 1.0L / min for 10 minutes to remove air from the reactor. After purging, the ultrasonic and microwave devices were simultaneously activated. The ultrasonic device had a power of 190W and a frequency of 29kHz; the microwave device had a power of 380W and a frequency of 2450MHz. A segmented temperature control mode was used for the reaction: first, the reaction temperature was controlled at 68℃ for 1 hour; then, the temperature was increased to 73℃ and the reaction continued for 1.5 hours. During the reaction, the stirring speed was set to 350 r / min. The pH of the reaction system was monitored and controlled in real time using an online pH monitor to maintain a value of 5.8. The reaction temperature was monitored in real time using an infrared thermometer to ensure that temperature fluctuations were controlled within ±0.5℃. After the reaction was completed, the esterification reaction solution was obtained.

[0029] S3. Catalyst Recovery and Crude Product Preparation: The esterification reaction solution was naturally cooled to 28°C and then transferred to a high-gradient magnetic separator. The magnetic field strength of the high-gradient magnetic separator was set to 0.4T, and the magnetic separation program was started to separate the bio-based composite catalyst. The separated catalyst was washed with ultrapure water and then placed in a vacuum drying oven at 55°C for 2 hours. After drying, it was set aside for later use and could be recycled. The filtrate after magnetic separation was collected and pumped into an organic membrane microfiltration system using a transfer pump. An organic membrane with a pore size of 0.16 μm was selected, and the microfiltration pressure of the organic membrane microfiltration system was set to 0.25 MPa. The microfiltration program was started. After microfiltration, an ethanol-ultrapure water mixture was added to the filtrate. The volume of the mixture was 3.8 times that of the filtrate, with a volume ratio of ethanol to ultrapure water of 1:1.7. This mixture needed to be filtered through an ultrafiltration membrane with a pore size of 0.08 μm before use, and the temperature during use was controlled at 23°C. The system after adding the mixture was transferred to a mixing tank and stirred at 23°C for 35 min. After stirring, it was allowed to stand for 1.3 h and then filtered to obtain crude stearyl glycyrrhizic acid ester.

[0030] S4. Multi-stage synergistic purification: Weigh 50g of crude stearyl glycyrrhizic acid ester and add 450g of 87% ethanol aqueous solution (mass ratio of crude product to ethanol aqueous solution: 1:9). Place the mixture in a heated and stirred tank, set the temperature of the tank to 72℃, and turn on the stirring function until the crude product is completely dissolved. Add 0.03g of activated carbon to the solution (0.06% of the crude product mass, particle size 15nm), set the stirring speed to 200r / min, and perform adsorption and decolorization for 35min. After adsorption and decolorization, remove the activated carbon by filtration using a ceramic membrane with a pore size of 0.11μm, setting the filtration pressure to 0.2MPa. Add 0.01g of stearyl glycyrrhizic acid ester seed crystals (15μm particle size, 0.03% of the filtrate mass) to the filtrate, then transfer the filtrate to a crystallizer and use a gradient cooling crystallization mode. The specific steps of the gradient cooling process are as follows: first, the temperature is lowered to 44℃ at a rate of 7℃ / h and held at this temperature for 1.2h; then, it is lowered to 14℃ at a rate of 2.8℃ / h and held at this temperature for 2.1h. After crystallization, the crystals and mother liquor are separated by centrifugal filtration. The centrifuge speed is set to 3500 r / min and the centrifugation time is 12min. The crystals obtained by centrifugation are collected and washed three times with a 92% ethanol aqueous solution, with the mass of the ethanol aqueous solution used for each wash being 1.2 times the mass of the crystals. The mother liquor obtained by centrifugation is used to recover ethanol through a distillation unit, with an ethanol recovery rate of 92.5%. The recovered ethanol is then used for future reference.

[0031] S5. Green Post-processing and Product Collection: The washed crystals were placed in a vacuum drying oven. The temperature of the oven was set to 60℃ and the vacuum degree to -0.094MPa. Argon gas was introduced for purging during the drying process at a flow rate of 0.4L / min. The vacuum drying process was divided into three stages: the first stage was drying at 59℃ for 1 hour; the second stage was drying at 61℃ for 1.5 hours; and the third stage was drying at 59℃ for 1.5 hours, for a total drying time of 4 hours. After drying, high-purity stearyl glycyrrhizic acid ester was obtained. The product was tested and found to have a purity of 99.5% and a water content of 0.28%.

[0032] Example 3 S1. Raw Material Pretreatment: Take 100g of glycyrrhizic acid powder and pulverize it using an air jet mill before pretreatment. Set the air jet mill pressure to 0.8MPa, and control the particle size of the glycyrrhizic acid powder after pulverization to 5-10μm. Add 400g of food-grade citric acid-malic acid composite aqueous solution to the pulverized glycyrrhizic acid powder. The mass concentration of this composite aqueous solution is 1.0%, and the mass ratio of citric acid to malic acid is 2:1. Transfer the mixture to an ultrasonic stirring tank. Set the temperature of the ultrasonic stirring tank to 40℃, the ultrasonic power to 100W, and the ultrasonic frequency to 22kHz. Turn on the ultrasonic-assisted stirring function and stir continuously for 20min. After stirring, pump the mixture into a ceramic membrane filtration system using a transfer pump. Select a ceramic membrane with a pore size of 0.3μm. Set the cross-flow filtration pressure of the ceramic membrane filtration system to 0.2MPa and the filtration flow rate to 1.8m / s, and start the filtration program. After filtration, the filter residue was collected and repeatedly washed with ultrapure water until the pH of the washing solution reached 6.8. The washed filter residue was then placed in a vacuum drying oven, with the temperature set to 55℃ and the vacuum degree to -0.09MPa. The vacuum drying program was started and continued for 2.5 hours to obtain pretreated glycyrrhizic acid. The pretreated glycyrrhizic acid was tested and found to have a water content of 0.7% and a purity of 98.2%.

[0033] S2. Green Esterification Reaction: Weigh 95g of pretreated glycyrrhizic acid and the corresponding mass of stearyl alcohol at a molar ratio of 1:1.35. Add both to an ultrasonic-microwave synergistic reactor. Then add 4.28g of a bio-based composite catalyst to the reactor. This catalyst is 4.5% of the mass of pretreated glycyrrhizic acid and is a chitosan-montmorillonite-supported nano-ZnO-lipase composite system, wherein the nano-ZnO loading is 10%, the mass ratio of montmorillonite to chitosan is 1:2.5, and the immobilized lipase amount is 6.5%. Simultaneously add 7.6g of green co-solvent polyethylene glycol, which is 8% of the mass of pretreated glycyrrhizic acid and has an average molecular weight of 500. Purge the reactor with nitrogen gas at a flow rate of 1.0L / min for 10 minutes to remove air from the reactor. After purging, the ultrasonic and microwave devices were simultaneously activated. The ultrasonic device had a power of 175W and a frequency of 27kHz; the microwave device had a power of 350W and a frequency of 2450MHz. A segmented temperature control mode was used for the reaction: first, the reaction temperature was controlled at 66℃ for 1 hour; then, the temperature was increased to 72℃ and the reaction continued for 2 hours. During the reaction, the stirring speed was set to 350 r / min. The pH of the reaction system was monitored and controlled in real time using an online pH monitor to maintain a value of 5.8. The reaction temperature was monitored in real time using an infrared thermometer to ensure that temperature fluctuations were controlled within ±0.5℃. After the reaction was completed, the esterification reaction solution was obtained.

[0034] S3. Catalyst Recovery and Crude Product Preparation: The esterification reaction solution was naturally cooled to 28°C and then transferred to a high-gradient magnetic separator. The magnetic field strength of the high-gradient magnetic separator was set to 0.4T, and the magnetic separation program was started to separate the bio-based composite catalyst. The separated catalyst was washed with ultrapure water and then placed in a vacuum drying oven at 55°C for 2 hours. After drying, it was set aside for later use and could be recycled. The filtrate after magnetic separation was collected and pumped into an organic membrane microfiltration system using a transfer pump. An organic membrane with a pore size of 0.16 μm was selected, and the microfiltration pressure of the organic membrane microfiltration system was set to 0.25 MPa. The microfiltration program was started. After microfiltration, an ethanol-ultrapure water mixture was added to the filtrate. The volume of the mixture was 3.8 times that of the filtrate, with a volume ratio of ethanol to ultrapure water of 1:1.7. This mixture needed to be filtered through an ultrafiltration membrane with a pore size of 0.08 μm before use, and the temperature during use was controlled at 23°C. The system after adding the mixture was transferred to a mixing tank and stirred at 23°C for 35 min. After stirring, it was allowed to stand for 1.3 h and then filtered to obtain crude stearyl glycyrrhizic acid ester.

[0035] S4. Multi-stage synergistic purification: Weigh 50g of crude stearyl glycyrrhizic acid ester and add 450g of 87% ethanol aqueous solution (mass ratio of crude product to ethanol aqueous solution: 1:9). Place the mixture in a heated and stirred tank, set the temperature of the tank to 72℃, and turn on the stirring function until the crude product is completely dissolved. Add 0.03g of activated carbon to the solution (0.06% of the crude product mass, particle size 15nm), set the stirring speed to 200r / min, and perform adsorption and decolorization for 35min. After adsorption and decolorization, remove the activated carbon by filtration using a ceramic membrane with a pore size of 0.11μm, setting the filtration pressure to 0.2MPa. Add 0.01g of stearyl glycyrrhizic acid ester seed crystals (15μm particle size, 0.03% of the filtrate mass) to the filtrate, then transfer the filtrate to a crystallizer and use a gradient cooling crystallization mode. The specific steps of the gradient cooling process are as follows: first, the temperature is lowered to 42℃ at a rate of 6.5℃ / h, and held at this temperature for 1.3h; then, it is lowered to 12℃ at a rate of 2.5℃ / h, and held at this temperature for 2.2h. After crystallization, the crystals and mother liquor are separated by centrifugal filtration. The centrifuge speed is set to 3500 r / min, and the centrifugation time is 12 min. The crystals obtained by centrifugation are collected and washed three times with a 92% ethanol aqueous solution, with the mass of the ethanol aqueous solution used for each wash being 1.2 times the mass of the crystals. The mother liquor obtained by centrifugation is used to recover ethanol through a distillation unit, with an ethanol recovery rate of 92.5%. The recovered ethanol is then used for future reference.

[0036] S5. Green Post-processing and Product Collection: The washed crystals were placed in a vacuum drying oven. The temperature of the oven was set to 62℃ and the vacuum degree to -0.096MPa. Argon gas was introduced for purging during the drying process at a flow rate of 0.5L / min. The vacuum drying process was divided into three stages: the first stage was drying at 59℃ for 1 hour; the second stage was drying at 61℃ for 1.5 hours; and the third stage was drying at 59℃ for 1.5 hours, for a total drying time of 4 hours. After drying, high-purity stearyl glycyrrhizic acid ester was obtained. The product was tested and found to have a purity of 99.7% and a water content of 0.22%.

[0037] Comparative Example S1. Raw material pretreatment: Take 100g of glycyrrhizic acid powder and wash it twice with ultrapure water, using 200mL of water each time. After washing, filter the powder and place the filter residue in a forced-air drying oven. Set the temperature of the oven to 60℃ and start the drying program for 3 hours to obtain pretreated glycyrrhizic acid. The pretreated glycyrrhizic acid was tested and found to have a water content of 1.2% and a purity of 95.5%.

[0038] S2. Esterification reaction: Weigh 95g of pretreated glycyrrhizic acid and the corresponding mass of stearyl alcohol at a molar ratio of 1:1.35, and add both to a conventional reactor. Add 1.5g of p-toluenesulfonic acid as a catalyst to the reactor, turn on the heating device, raise the reaction temperature to 85℃, set the stirring speed to 300r / min, and continue the reaction for 6h to obtain the esterification reaction solution.

[0039] S3. Preparation of crude product: The esterification reaction solution was naturally cooled to room temperature. A 10% (w / w) NaOH aqueous solution was slowly added while stirring until the pH of the reaction system reached 7.0. Then, 300 mL of dichloromethane was added for extraction. After thorough shaking, the mixture was allowed to stand and separate into layers, and the organic phase was collected. 5 g of anhydrous sodium sulfate was added to the organic phase for drying. After standing for 2 hours, the anhydrous sodium sulfate was removed by filtration. The filtrate was transferred to a vacuum distillation apparatus and distilled under vacuum conditions of -0.08 MPa and 60°C to remove dichloromethane, yielding crude stearyl glycyrrhizic acid ester.

[0040] S4. Purification: Add the crude product to 200 mL of ethyl acetate, place it on a heating and stirring device, and stir at 65°C until the crude product is completely dissolved. Then, allow it to cool naturally to room temperature and let it stand for 4 hours to crystallize. After crystallization, filter and collect the crystals. Repeat the above recrystallization operation once with 150 mL of ethyl acetate. Finally, place the crystals obtained from the second crystallization into a forced-air drying oven, set the temperature to 60°C, start the forced-air drying program, and continue drying for 4 hours to obtain stearyl glycyrrhizic acid ester product.

[0041] The product was tested and found to have a purity of 96.2%. The p-toluenesulfonic acid catalyst used in the reaction could not be recovered, the recovery rate of dichloromethane was only 65%, the energy consumption per unit product was 38% higher than that in Example 1, and 1500 mL of acidic wastewater was generated during the post-esterification process, which required additional acid-base neutralization treatment before discharge.

[0042] The quality performance of the examples and comparative examples is compared in the table below: Table 1

[0043] The environmental protection and efficiency performance of the processes in the examples and comparative examples are compared in the table below: Table 2

[0044] Compared with the comparative example, the present invention solves the core pain points of traditional processes, such as low product purity, non-recoverable catalysts, serious pollution, and high energy consumption, through the innovative process of composite acid pretreatment-bio-based composite catalyst-ultrasound-microwave synergistic reaction-multi-stage green purification.

[0045] The catalyst recovery rate in the embodiment reached 90.2%-92.3%, and it can be recycled 4-5 times, while the recovery rate of the catalyst in the comparative example was 0%. The process has no emissions of toxic and harmful substances, and the content of by-reaction products is only 0.21%-0.28%, far lower than the 1.53% in the comparative example. This is due to the synergistic effect of the chitosan-montmorillonite supported nano-ZnO-lipase composite catalyst, which avoids the corrosion and pollution problems of traditional chemical catalysts, improves catalytic selectivity, reduces side reactions, and the magnetic separation recovery design significantly reduces catalyst costs.

[0046] The product purity of the example reached 99.5%-99.7%, with a water content of only 0.22%-0.28%, and a 3-month storage stability of 99.35%-99.6%, significantly better than the comparative example. This is due to the combination of S1 composite acid ultrasonic-assisted pretreatment and ceramic membrane filtration, which effectively removes impurities and metal ions, increasing the raw material purity to 98.2%. Further purification through S4 activated carbon decolorization and gradient cooling crystallization, combined with an ethanol-ultrapure water green solvent system, reduces the use of toxic solvents and significantly improves product purity.

[0047] The solvent recovery efficiency of this embodiment reaches 92.1%-93.0%, with a process energy consumption of only 78.8-81.5 kWh / 100g product, a reduction of 37%-39% compared to the comparative example. In contrast, the comparative example has a solvent recovery efficiency of only 65% ​​and generates a large amount of acidic wastewater and toxic emissions. This is thanks to the S2 ultrasonic-microwave synergistic reaction and segmented temperature control design, which accelerates the reaction rate and improves the conversion rate. Combined with the S3-S5 green post-treatment and solvent recovery system, it reduces resource waste and environmental pressure.

[0048] The comparative example uses traditional chemical catalysts such as p-toluenesulfonic acid, which cannot be recovered and cause a large number of side reactions; the raw materials are only pretreated by simple water washing, with a purity of only 95.5%, and subsequent purification relies on toxic solvents such as dichloromethane and ethyl acetate, resulting in low solvent recovery efficiency and serious pollution; the reaction adopts conventional heating methods, which consumes a lot of energy and has a long reaction cycle, ultimately leading to low product purity and poor storage stability, while generating a lot of environmental governance costs, which cannot meet the needs of high-end fields for high-purity raw materials and green production.

[0049] In summary, the performance and process data of the embodiments fully demonstrate the three major beneficial effects of the present invention: the bio-based composite catalyst achieves a balance between environmental protection and high efficiency; precise pretreatment and multi-stage purification ensure high product purity and stability; and the entire process is green, taking into account both energy conservation and emission reduction. Ultimately, this results in a comprehensive advantage of "high product purity, low production pollution, low process energy consumption, and recyclable catalyst," providing a technologically innovative and environmentally feasible solution for the industrial production of stearyl glycyrrhizic acid esters.

[0050] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A green preparation process for high-purity stearyl glycyrrhizic acid ester, characterized in that, Includes the following steps: S1, Raw material pretreatment: Take glycyrrhizic acid powder, add food-grade citric acid-malic acid composite aqueous solution, the mass ratio of glycyrrhizic acid to composite aqueous solution is 1:3.5-4.5, after ultrasonic-assisted stirring, use ceramic membrane cross-flow filtration, wash the filter residue to pH 6.7-6.9, and vacuum dry to obtain pretreated glycyrrhizic acid; S2, Green Esterification Reaction: Pretreated glycyrrhetinic acid and stearyl alcohol were added to an ultrasonic-microwave synergistic reactor at a molar ratio of 1:1.3-1.

4. A bio-based composite catalyst was added, which was a chitosan-montmorillonite supported nano-ZnO-lipase composite system. At the same time, green co-solvent polyethylene glycol was added. After purging with nitrogen to remove air, the ultrasonic-microwave reaction was turned on. The reaction was carried out in stages with temperature control, and the pH of the system was controlled at 5.5-6.0 to obtain the esterification reaction solution. S3, Catalyst recovery and crude product preparation: After the esterification reaction solution is cooled, the catalyst is separated by high gradient magnetic separation. The catalyst can be recycled 4-5 times. After the filtrate is microfiltered through an organic membrane, an ethanol-ultrapure water mixture is added, stirred and allowed to stand, and then filtered to obtain crude stearyl glycyrrhizic acid ester. S4, Multi-stage synergistic purification: The crude product is dissolved in an ethanol-water solution, decolorized by activated carbon adsorption, filtered, and stearyl glycyrrhetinic acid ester seed crystals are added to the filtrate. Gradient cooling crystallization is used, and the crystals are collected by filtration and washed. S5, Green Post-processing and Product Collection: Crystals are vacuum dried, with argon gas purging during the process, to obtain high-purity stearyl glycyrrhizic acid ester product.

2. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S1, the mass concentration of the citric acid-malic acid composite aqueous solution is 0.9-1.1%, the mass ratio of citric acid to malic acid is 2:1, the ultrasonic-assisted stirring power is 80-120W, the frequency is 20-25kHz, the ceramic membrane pore size is 0.25-0.4μm, the vacuum drying temperature is 52-58℃, and the vacuum degree is -0.088 to -0.092MPa.

3. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S2, the amount of bio-based composite catalyst used is 3.5-4.5% of the mass of pretreated glycyrrhizic acid, the loading of nano-ZnO is 9-11%, the mass ratio of montmorillonite to chitosan is 1:2.2-2.8, and the amount of lipase immobilization is 5-8%; the amount of polyethylene glycol used is 5-8% of the mass of pretreated glycyrrhizic acid, with an average molecular weight of 450-550; the nitrogen flow rate is 0.9-1.1 L / min, and the purging time is 8-12 min.

4. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S2, the ultrasonic power is 160-190W and the frequency is 26-29kHz, the microwave power is 320-380W and the frequency is 2450±30MHz, the ultrasonic and microwave are turned on synchronously, the microwave power is adjusted every 40-50 minutes, the adjustment range is fluctuating within ±10W within 320-380W, the temperature is controlled in segments at 65-68℃ for 1 hour, then the temperature is raised to 70-73℃ for 1.5-2.5 hours, and the stirring speed is 320-380r / min.

5. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S3, the high-gradient magnetic separation magnetic field strength is 0.35-0.45T; the organic membrane microfiltration pore size is 0.15-0.18μm, and the pressure is 0.22-0.28MPa; the volume of the ethanol-ultrapure water mixture is 3.5-4.5 times that of the filtrate, and the ethanol to ultrapure water ratio is 1:1.6-1.

8. Before use, the mixture is filtered through a 0.05-0.1μm ultrafiltration membrane at a temperature of 21-24℃, with a stirring time of 32-38min and a standing time of 1.2-1.4h.

6. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S4, the ethanol-water solution has a mass concentration of 86-89%, the mass ratio of crude product to ethanol-water solution is 1:8.5-9.5, and the dissolution temperature is 71-74℃. The activated carbon dosage is 0.05-0.08% of the crude product mass, with a particle size of 10-20nm. The adsorption and decolorization stirring speed is 180-220r / min, the time is 30-40min, and the ceramic membrane used for filtration has a pore size of 0.1-0.12μm and a pressure of 0.18-0.22MPa.

7. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S4, the stearyl glycyrrhizic acid ester seed crystals have a particle size of 12-18 μm and are added at 0.02-0.04% of the filtrate mass; the gradient cooling is 6-7℃ / h to 41-44℃ and held for 1.2-1.4h, then 2.2-2.8℃ / h to 11-14℃ and held for 2.1-2.4h; the washing uses an ethanol aqueous solution with a mass concentration of 91-94%, and the amount used each time is 1.1-1.4 times the crystal mass.

8. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S4, after crystallization, the crystals and mother liquor are separated by centrifugal filtration at a speed of 3000-4000 r / min for 10-15 min. The mother liquor is then distilled to recover ethanol, which is recycled for washing and dissolving in steps S3 and S4.

9. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S5, the argon purging flow rate is 0.3-0.5 L / min; the vacuum drying temperature is 58-62℃, the vacuum degree is -0.092 to -0.096 MPa, and the time is 3.2-3.8 h. The drying is divided into three stages: drying at 58-60℃ for 1 h, drying at 60-62℃ for 1.5 h, and drying at 58-60℃ for 1.3-1.8 h.

10. The green preparation process of high-purity stearyl glycyrrhizic acid ester according to claim 1, characterized in that, In step S1, the glycyrrhetinic acid powder is pretreated by air jet milling at a pressure of 0.7-0.9 MPa, resulting in a particle size of 5-10 μm. In step S2, the bio-based composite catalyst is prepared by dissolving chitosan in a 1.2-1.8% acetic acid aqueous solution, adding montmorillonite and nano-ZnO, stirring at 52-58℃ for 2.2-2.8 h, adding 6-7% NaOH to adjust the pH to 7.6-7.9, precipitating, vacuum drying, pulverizing, and then immersing in a lipase solution with a concentration of 10-15 mg / mL and a pH 7.0 phosphate buffer solution. The catalyst is then shaken and adsorbed at 35-38℃ for 2-3 h, and dried to obtain the final product. After four cycles, the catalyst is soaked in 5-8% acetic acid for 2-3 h, washed, dried, and regenerated.

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