Method for producing high-purity grabrizin using melt crystallization

Abstract

To provide a method for producing grabridin that is easy to operate, does not require solvents, has high product purity, is environmentally friendly, and has low energy.SOLUTION: A method for producing grabridin using melt crystallization includes the steps of :dissolving crude grabrizin in a solvent, adsorbing it with a macroporous adsorption resin AB-8, washing with ethanol, and recrystallizing to obtain a crude material; adding the crude material to a melt crystallization apparatus and heating and melting it to a liquid state; cooling the crude material at a temperature falling rate of 10-30°C / h to a final temperature of 155-160°C, maintaining the temperature to crystallize grabrizin, and using mother liquor as a raw material for the next batch; after discharging the mother liquor, sweating the crystals, heating them at a temperature rising rate of 1-15°C / h to 160-168°C, maintaining the temperature to discharge the sweating liquid, and using it as a raw material for the next batch; after discharging the sweating liquid, melting at 175°C or higher, and using the molten liquid as a supply material for the next stage; and repeating the steps to perform multistage crystallization, collecting the molten liquid, and cooling and crystallizing it to obtain ultra-high purity grabrizin.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the technical field of chemical purification, specifically to a method for producing high purity glabridin using melt crystallization. [Background technology]

[0002] Licorice is mainly distributed in the western regions of China and is a traditional Chinese medicinal material that has been used in China since ancient times. In traditional Chinese medicine, it is believed that licorice has the effects of tonicizing the spleen, replenishing qi, clearing heat, detoxifying, clearing phlegm and relieving coughs, relieving acute illnesses and relieving pain, and adjusting various medicines. In Western countries, licorice is mainly used as a flavoring agent, tobacco additive, and expectorant. There are three kinds of raw plants for licorice herbal medicine recognized by the "Pharmacopoeia of the People's Republic of China", namely, Glycyrrhiza uralensis, Glycyrrhiza inflata, and dried roots and rhizomes of Glycyrrhiza glabra, of which Glycyrrhiza glabra has a salt tolerance limit of less than 10% and poor drought resistance, so it is distributed scatteredly, has the lowest yield, and is only produced in Xinjiang.

[0003] Glabridin is a unique isoflavone component found in Spanish licorice. It has multiple whitening effects and is highly safe, and is currently widely used in the cosmetics industry as the "gold of whitening." Continuing research in recent years has revealed that glabridin has anti-blood lipid, anti-breast cancer, and anti-atherosclerosis effects in addition to antioxidant and melanin-suppressing effects. The chemical structure of glabridin is as follows: [ka]

[0004] Glabridin cannot currently be chemically or biosynthesized, and can only be extracted from the roots of liquorice. The amount of glabridin in liquorice is only about 2 / 1000, so the procedure for extracting high-purity glabridin is very complicated and expensive. The main standards of glabridin available on the market are 40% and 90% glabridin content, and while it is easy to achieve a purity of 40% by crude extraction, 40% glabridin products are yellow, which affects the color of makeup when mixed into cosmetics, so high-end customers inevitably require colorless and high-purity glabridin. 90% glabridin is white, but multiple recrystallizations are required to achieve a purity of 90% or more. The more recrystallizations, the higher the purity, which can reach 98% or more, but the production costs are accordingly higher.

[0005] High-purity glabridin is in short supply, and glabridin with a purity of 95% (measured by high-performance liquid chromatography HPLC) is commercially available at a high price of 400,000 RMB per kg. However, it is difficult to achieve this purity in the current domestic production process in China, and toxic organic solvents such as chloroform and methanol are often used during production. Melt crystallization technology has the advantages of not using solvents, low energy consumption, small equipment, and high purity products, and is widely used in the field of separation and purification of organic compounds. Its principle is to use the difference in freezing points of each component of the substance to be separated to control the supply and discharge of heat, crystallize the components to be separated from the molten liquid, and separate and purify the target components through operations such as washing and sweating. Statistics show that hundreds of thousands of tons of organic compounds are currently separated and purified by melt crystallization. For example, the production scale of 99.99% paradichlorobenzene is 17,000 tons / year, that of 99.95% paraxylene is 70,000 tons / year, and that of bisphenol A is 15,000 tons / year.

[0006] Therefore, establishing a simple, low-cost, and relatively safe method for purifying glabridin using melt crystallization has extremely important social and economic significance. Summary of the Invention [Problem to be solved by the invention]

[0007] In response to the technical problems of the above-mentioned glabridin purification process, such as low purity of the produced product, large amount of solvent consumption, and high energy consumption, the present invention provides a method for purifying glabridin by melt crystallization technology, and can use two or more stages of crystallization according to the needs of the process, and the purity of the glabridin product obtained by the technical solution of the present invention is more than 99.9%. The method is characterized by easy operation, no need for solvent, high product purity, environmental friendliness, and low energy consumption, which is suitable for the high market demand for high purity glabridin and has strong market competitive advantages. [Means for solving the problem]

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] A method for producing high-purity glycyrrhizin using melt crystallization, comprising: 1) purification step of dissolving the crude glycyrrhizin with a glycyrrhizin content of 40% by mass or more in a solvent, then adsorbing it with macroporous adsorption resin AB-8, then washing with ethanol, and recrystallizing to obtain crude glycyrrhizin material; Step 2) of heating and melting the glycyrrhizin crude material produced above into a melt crystallizer and melting it at a melting temperature until it becomes liquid; Step 3) of crystallization by cooling the glycyrrhizin crude material of step 2) at a cooling rate of 10°C / h to 30°C / h and a final temperature of 155°C to 160°C, and keeping the temperature for 0.5 to 4 hours to crystallize the glycyrrhizin, and collecting the uncrystallized residual liquid and reusing it as the raw material for the next batch; 4) sweating step: after discharging the uncrystallized mother liquor, the crystals are sweated, the temperature is raised to 160-168°C at a heating rate of 1-15°C / h, the temperature is kept at 160-2h, the sweated liquid is discharged, and the sweated liquid is reused as the raw material for the next batch; 5) material melting step, in which the sweating liquid is discharged, the temperature is increased to 175°C or more to melt all the material, and the melt is collected as the feed material for the next stage of crystallization; and step 6) of repeating steps 3) to 5) to perform multi-stage crystallization, collecting the molten liquid, cooling and crystallizing it to obtain glycyrrhizin having a purity of more than 99.9% as ultra-high purity glycyrrhizin.

[0010] In some embodiments, in step 1), the solvent is one selected from butanediol, propylene glycol.

[0011] In some embodiments, in step 1), the recrystallization solvent is one selected from ethanol, methanol, isopropanol, propanol, butanediol, and propylene glycol.

[0012] In some embodiments, in step 1), the recrystallization solvent is propanol.

[0013] In some embodiments, in step 3), the temperature decreasing rate is 15° C. / h to 20° C. / h.

[0014] In some embodiments, in step 3), the final temperature is 156°C to 159°C.

[0015] In some embodiments, in step 3), the incubation time is 1 to 3 hours.

[0016] In some embodiments, in step 4), the heating rate is 5° C. / h to 10° C. / h.

[0017] In some embodiments, in step 4), the final sweat temperature is 162°C to 166°C.

[0018] In some embodiments, in step 4), the incubation time is 1 to 1.5 hours.

[0019] In some embodiments, a method for purifying glabridin using melt crystallization includes the steps of: putting a glabridin crude product with a glabridin content of more than 40% into a melt crystallization apparatus, heating the material until it is all melted into a liquid state, lowering the temperature at a rate of 10°C / h to 30°C / h, setting the final temperature at 155°C to 160°C, and keeping the temperature for 0.5h to 4h; discharging the mother liquor, then heating the material to 160°C to 168°C at a rate of 1°C / h to 15°C / h, and keeping the temperature for 0.5h to 2h to cause sweating; discharging the sweating liquid, heating the material to 175°C or higher, heating and melting the material, discharging the material, collecting the molten liquid, and performing two-stage crystallization; and finally collecting the molten liquid, cooling and crystallizing it to obtain ultra-high purity glabridin.

[0020] In some embodiments, in step 1), the crude glabridin is a commercially available product or a crude glycyrrhizin obtained by a separation method using extraction, silica gel column chromatography, recrystallization, liquid phase separation, or macroporous adsorption resin.

[0021] According to the process needs, two or more stages of crystallization may be used. When two-stage crystallization is used, the first-stage mother liquor enters the two-stage crystallizer, the first-stage sweating liquor returns to the first-stage crystallizer as raw material, the first-stage product is obtained from the first-stage crystallizer, the second-stage sweating liquor is mixed with the first-stage mother liquor and sent to the two-stage crystallizer again, and the second-stage product is mixed with the raw material and the first-stage sweating liquor and sent to the first-stage crystallizer again.

[0022] The separation and purification of glabridin by the method of the present invention can be applied to crude glabridin (having a glabridin content of 40% or more, preferably 80% or more). When the raw materials in the process of the present invention enter the separation process, all of the materials obtained in the other steps, except for the second-stage mother liquor obtained by recrystallization of the mother liquor, can be used as first-stage or second-stage raw materials. Effect of the Invention

[0023] The advantages and beneficial effects of the present invention are as follows: 1. In the present invention, the ultra-high purity product of 99.9% or more can be obtained by refining using melt crystallization. This method is easy to operate, does not require a large amount of solvent, has the characteristics of high product purity, is environmentally friendly, and consumes little energy. It is an environmentally friendly separation and purification process, which is suitable for the high market demand for high-purity glabridin, and has strong market competitive advantages. 2. The Glabridin of the present invention can be entirely recycled except for the second-stage mother liquor, so that the raw material utilization rate is high.

[0024] It should be noted that in the present description, the terms "first" and "second" are used for descriptive purposes only and are not to be understood as indicating or implying a relative importance or number of technical features depicted. Thus, a feature qualified as "first" or "second" may explicitly or implicitly include one or more of said features. In the present description, "plurality" means two or more, unless otherwise expressly and specifically limited.

[0025] In the present description, reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means that the particular feature, structure, material, or characteristic described with reference to the embodiment or example is included in at least one embodiment or example of the present invention. In the present description, general expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine or combine different embodiments or examples described herein and features of different embodiments or examples without mutual inconsistency. [Brief description of the drawings]

[0026] [Figure 1] 1 is a chromatogram of high-purity glabridin produced in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In order to allow those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to describe the present invention in more detail.

[0028] The reagents used in the present invention can be obtained commercially or can be prepared by the methods described in the present invention.

[0029] In the present invention, min stands for minute, h stands for hour, g stands for gram, mL stands for milliliter, and mg stands for milligram.

[0030] In the present invention, the content of glabridin is detected by using high performance liquid chromatography of "QBT4951-2016 Cosmetic Raw Material Licorice Root Extract". In the present invention, room temperature refers to a temperature of 10°C to 40°C.

[0031] In the present invention, the one-pass recovery rate refers to the quality of the high-purity product obtained by one-stage melt crystallization / the mass of the input crude product×100%.

[0032] Example 1 50g of glabridin crude product with a glabridin content of 40.5% was put into a 500ml melt crystallizer, dissolved in propylene glycol, then adsorbed with macroporous adsorption resin AB-8, then washed with 90% ethanol, collected the washing liquid, concentrated under reduced pressure to remove part of the solvent, and then recrystallized at room temperature using 50mL of propanol, collected the crystals by filtration, and dried to obtain glabridin crude material. The glabridin crude material was heated to 160°C until the material was all melted into a liquid state, cooled at a rate of 20°C / h, and the final temperature was 158°C, and kept warm for 2h. The mother liquor was discharged, and then the material was heated to 165°C at a rate of 10°C / h, and kept warm for 1h to sweat. The sweating liquid was drained, the temperature was raised to above 175℃, the material was heated and melted, the melt was collected and crystallized in two stages, and finally the melt was collected, cooled and crystallized to obtain ultra-high purity glabridin. The purity of the product was 99.94%, and the one-pass yield was 74.5%.

[0033] Example 2 20g of glabridin crude product with a glabridin content of 40.5% was put into a 500ml melt crystallizer, dissolved in propylene glycol, then adsorbed with macroporous adsorption resin AB-8, then washed with 95% ethanol, collected the washing liquid, concentrated under reduced pressure to remove a part of the solvent, and then recrystallized at room temperature using 20mL of propanol, collected the crystals by filtration, and dried to obtain glabridin crude material, which was heated to 160°C until the material was all melted into a liquid state, cooled at a rate of 10°C / h, and the final temperature was 158°C, and kept warm for 2h. The mother liquor was discharged, and then the material was heated to 165°C at a rate of 5°C / h, and kept warm for 1h to sweat. The sweating liquid was discharged, the temperature was raised to above 175°C, the material was heated and melted, and the material was discharged. The melt was collected and subjected to two-stage crystallization. Finally, the melt was collected, cooled, and crystallized to obtain ultra-high purity glabridin. The purity of the product was 99.96%, and the one-pass yield was 52.0%.

[0034] Example 3 10g of glabridin crude product with a glabridin content of 40.5% was put into a 500ml melt crystallizer, dissolved in butanediol, then adsorbed with macroporous adsorption resin AB-8, then washed with 95% ethanol, collected the washing liquid, concentrated under reduced pressure to remove part of the solvent, and then recrystallized at room temperature using 15mL of propanol, collected the crystals by filtration, and dried to obtain glabridin crude material, which was heated to 165°C until the material was all melted into a liquid state, cooled at a rate of 30°C / h, and the final temperature was 158°C, and kept warm for 2h. The mother liquor was discharged, and then the material was heated to 165°C at a rate of 2°C / h, and kept warm for 1h to sweat. The sweating liquid was discharged, the temperature was raised to above 175°C, the material was heated and melted, and the material was discharged. The melt was collected and subjected to two-stage crystallization. Finally, the melt was collected, cooled, and crystallized to obtain ultra-high purity glabridin. The purity of the product was 99.96%, and the one-pass yield was 52.0%.

[0035] Consideration of reaction conditions Example 4 According to the method of Example 1, 50g of glabridin crude product with a glabridin content of 40.5% was dissolved in propylene glycol, then adsorbed with macroporous adsorption resin AB-8, then washed with 95% ethanol, the washing liquid was collected and concentrated under reduced pressure to remove part of the solvent, and then recrystallized with 50mL of propanol at room temperature, filtered to collect the crystals, and dried to obtain glabridin crude material, which was melted and crystallized. The effects of process conditions on the purity of the product and the yield of one pass were investigated, and the results are shown in the following table.

[0036] [Table 1]

[0037] Comparative Example 1 50g of glabridin crude product with a glabridin content of 40.5% was put into a 500ml melt crystallizer, dissolved in propylene glycol, then adsorbed with macroporous adsorption resin AB-8, then washed with 95% ethanol, the washing liquid was collected and concentrated under reduced pressure to remove part of the solvent, and then recrystallized at room temperature using 50mL of propanol, filtered to collect the crystals, dried, and obtained glabridin crude material, the glabridin crude material was heated to 160°C until the material was all melted into a liquid state, cooled at a rate of 20°C / h, the final temperature was 158°C, and kept warm for 2h. The mother liquor was discharged, and then the material was heated to 165°C at a rate of 10°C / h and kept warm for 1h, thereby sweating. The sweating liquid was discharged, the temperature was raised to 175°C or higher, the material was heated and melted, and then cooled and crystallized to obtain ultra-high purity glabridin. The purity of the product was 99.1%, and the first-pass yield was 71.2%.

[0038] Comparative Example 2 50g of glabridin crude product with a glabridin content of 40.5% was put into a 500ml melt crystallizer, dissolved in propylene glycol, then adsorbed with macroporous adsorption resin AB-8, then washed with 95% ethanol, the washing liquid was collected and concentrated under reduced pressure to remove part of the solvent, and then recrystallized at room temperature using 50mL of propanol, filtered to collect the crystals, dried, and obtained glabridin crude material, the glabridin crude material was heated to 175°C until the material was all melted into a liquid state, cooled at a rate of 20°C / h, the final temperature was 155°C, and kept warm for 2h. The mother liquor was discharged, and then the material was heated to 170°C at a rate of 10°C / h and kept warm for 1h, thereby sweating. The sweating liquid was discharged, the temperature was raised to 175°C or higher, the material was heated and melted, and the material was discharged, cooled and crystallized, and ultra-high purity glabridin was obtained. The purity of the product was 95.3%, and the first-pass yield was 61.2%.

[0039] Comparative Example 3 50g of glabridin crude product with a glabridin content of 40.5% was put into a 500ml melt crystallizer, dissolved in propylene glycol, then adsorbed with macroporous adsorption resin AB-8, then washed with 95% ethanol, the washing liquid was collected and concentrated under reduced pressure to remove part of the solvent, and then recrystallized at room temperature using 50mL of propanol, filtered to collect the crystals, dried, and obtained glabridin crude material, the glabridin crude material was heated to 160°C until the material was all melted into a liquid state, cooled at a rate of 8°C / h, the final temperature of the temperature drop was 158°C, and kept warm for 2h. The mother liquor was then discharged, and the material was then heated to 165°C at a rate of 20°C / h and kept warm for 1h to perform sweating. The sweating liquid was discharged, the temperature was raised to 175°C or higher, the material was heated and melted, and the material was discharged, cooled, and crystallized to obtain ultra-high purity glabridin. The purity of the product was 89.4%, and the first-pass yield was 51.1%.

[0040] Although the method of the present invention has been described by a preferred embodiment, it is obvious that a person skilled in the art can change, appropriately modify, or combine the methods and uses described herein within the content, spirit, and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can appropriately improve and realize the process parameters by referring to the content of this application. In particular, all similar replacements and changes are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for producing high purity glabridin using melt crystallization, comprising: 1) a purification step in which the crude glabridin product having a glabridin content of 40% by mass or more is dissolved in a solvent, and then adsorbed by macroporous adsorption resin AB-8, and then washed with ethanol and recrystallized to obtain a crude glabridin material; Step 2) of heating and melting the above-prepared glabridin crude material in a melt crystallizer and melting it at a melting temperature until it becomes liquid; Step 3) of crystallization under reduced temperature, in which the temperature of the glabridin crude material of step 2) is reduced at a rate of 10°C / h to 30°C / h, the final temperature is reduced to 155°C to 160°C, and the material is kept at the same temperature for 0.5 to 4 hours to crystallize the glabridin, and the remaining liquid that has not been crystallized is collected and reused as the raw material for the next batch. 4) sweating step, in which the uncrystallized mother liquor is drained, the crystals are sweated, the temperature is increased at a rate of 1-15°C / h to a final temperature of 160°C-168°C, and the temperature is maintained for a time of 0.5-2h, and the sweated liquid is drained and reused as a raw material for the next batch; 5) material melting step, which includes discharging the sweating liquid, heating the material to a temperature of 175° C. or higher to melt all the material, and collecting the melt to be used as the feed material for the next stage of crystallization; and step 6) of repeating steps 3) to 5) to perform multi-stage crystallization, collecting the molten liquid, cooling and crystallizing it to obtain glabridin having a purity of more than 99.9% as ultra-high purity glabridin.

2. The method according to claim 1, characterized in that the crude glabridin preparation in step 1) is a commercially available product or a crude glabridin preparation obtained by a separation method using extraction, silica gel column chromatography, recrystallization, liquid phase separation, or macroporous adsorption resin.

3. 2. The method of claim 1, wherein the multi-stage in step 6) comprises two or more multi-stage crystallization stages.

4. 2. The method according to claim 1, wherein in step 3), the temperature decreasing rate is 15° C. / h to 20° C. / h.

5. The method according to claim 1, wherein in step 3), the final temperature drop is 156°C to 159°C.

6. The method according to claim 1, characterized in that in step 3), the incubation time is 1 to 3 h.

7. 2. The method according to claim 1, wherein in step 4), the heating rate is 5° C. / h to 10° C. / h.

8. 2. The method according to claim 1, wherein in step 4), the sweat end temperature is 162°C to 166°C.

9. The method according to claim 1, characterized in that in step 4), the incubation time is 1 to 1.5 h.

10. A method for producing high purity glabridin using melt crystallization, comprising: The crude glabridin product having a glabridin content of 40% by mass or more is dissolved in a solvent, and then adsorbed by macroporous adsorption resin AB-8, and then washed with ethanol and recrystallized to obtain a crude glabridin material; The above-prepared glabridin crude material is put into a melt crystallizer, the temperature is raised until the material is completely melted into a liquid state, the temperature is lowered at a rate of 10°C / h to 30°C / h, the final temperature is 155°C to 160°C, and the temperature is maintained for 0.5h to 4h; Discharge the mother liquor, then heat the material to 160°C-168°C at a heating rate of 1°C / h-15°C / h and keep it at that temperature for 0.5h-2h to cause sweating; and (c) removing the sweating liquid, heating to 175°C or higher, melting the material by heating and removing the material, collecting the molten liquid and carrying out two-stage crystallization, and finally collecting the molten liquid, cooling and crystallizing the liquid to obtain ultra-high purity glabridin.

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