Process for the preparation of chebulagic acid

Abstract

The application provides chebulinic acid and a preparation method thereof, and the method comprises the following steps: extracting medicinal materials of Terminalia chebula by using an extracting agent to obtain an extracting solution; extracting the extracting solution by using an extracting agent, collecting an organic phase, drying, and obtaining a solid; dissolving the solid in an alcohol solution, adding a saturated alcohol solution containing an alkaline substance, precipitating a solid, filtering, and collecting a filter residue; dissolving the filter residue in a first acid solution, filtering, and collecting a filtrate as a sample loading liquid; and performing chromatography on the sample loading liquid by using a macroporous resin, and collecting an eluent of a chebulinic acid enrichment part. The method provided by the application can obtain chebulinic acid with high purity and high transfer rate, and is simple to operate, low in cost, and suitable for industrialized production and application.

Description

Technical Field

[0001] This application relates to the field of traditional Chinese medicine, and specifically, to a method for preparing chebulic acid. Background Technology

[0002] Terminalia chebula ( Terminalia chebula (This refers to Terminalia chebula, a plant in the Combretaceae family) Terminalia chebula Retz. Or Terminalia chebula Terminalia chebula Retz. var. Kurt worries. The dried, ripe fruit of the plant is widely distributed in Tibet, Yunnan, Guangxi, and other regions. Known as the "King of Tibetan Medicine," it is a commonly used traditional Tibetan and Chinese medicine. It is neutral in nature, bitter, sour, and astringent in taste, and enters the lung and large intestine meridians. It has the effects of astringing the intestines to stop diarrhea, astringing the lungs to stop cough, reducing internal heat and relieving sore throat. Clinically, it is often used to treat chronic diarrhea and dysentery, hematochezia and rectal prolapse, lung deficiency and cough, persistent cough, sore throat, and hoarseness.

[0003] Terminalia chebula contains a rich variety of chemical components, mainly including tannins, phenolic acids, triterpenoids, flavonoids, volatile oils, amino acids, trace elements, and sugars. Among these, tannins account for 23.6%-37.4% of the total composition and form the basis of its main active substances. These tannins are primarily hydrolyzable, with representative components including chebulagic acid and chebulinic acid. Modern pharmacological studies have confirmed that Terminalia chebula extract possesses significant antioxidant, anti-aging, anti-inflammatory, anti-diabetic, and neuroprotective activities, largely attributed to its tannin content. Currently, Terminalia chebula extract is widely used in cosmetics and health foods, but most products on the market exist in the form of total extracts, and the underlying active substances require further clarification and refinement.

[0004] Chebulagic acid, chemical formula C 41 H 30 O 27 It is a white to beige crystalline powder. Its solubility is characterized by easy solubility in organic solvents such as methanol and ethanol, but low solubility in water. Currently, domestic research on the isolation and preparation of chebulic acid mainly focuses on chebulic myrobalan (Terminalia chebula). Terminalia chebula ) or Phyllanthus emblica ( Phyllanthus emblica ) are used as raw materials for development.

[0005] Currently, the main extraction methods for chebulic acid include reflux extraction, maceration, and ultrasonic extraction. However, chebulic acid is a type of chebulic tannin, which is unstable. During reflux extraction, chebulic tannin degrades into corilagin and chebulic acid at high temperatures, and corilagin further degrades into gallic acid and ellagic acid. Maceration is a static extraction method, lacking an effective concentration difference and dynamic exchange between the solvent and the medicinal material, resulting in low extraction efficiency. While ultrasonic extraction is more efficient, its industrial application relies on specialized power conversion devices, resulting in relatively complex equipment structures, high technical requirements, and high maintenance costs, which hinders large-scale production and cost control.

[0006] In the existing technology, there are few reports on the preparation methods of high-purity chebulic acid, and further research is needed. Summary of the Invention

[0007] This application aims to at least partially address the technical problems existing in the prior art. To this end, this application proposes chebulic acid and its preparation method. Using the method of this application, high-purity and high-transfer-rate chebulic acid can be obtained, and the operation is simple, low-cost, and suitable for industrial production applications.

[0008] In one aspect of this application, a method for preparing chebulic acid is provided. According to an embodiment of this application, the method includes: (1) The Terminalia chebula medicinal material was extracted using an extractant to obtain an extract; (2) The extract is extracted with an extractant, the organic phase is collected, dried, and a solid is obtained; (3) After dissolving the solid in alcohol, add it to a saturated alcohol solution containing alkaline substances to precipitate the solid, filter it, and collect the filter residue; (4) Dissolve the filter residue in the first acid solution, filter, and collect the filtrate as the sample loading solution; (5) The sample solution is subjected to chromatography using macroporous resin, and the eluent of the chebulic acid-enriched portion is collected.

[0009] According to the preparation method of this application, the target component is first efficiently obtained using an extractant and a chelating agent to achieve preliminary impurity removal. Then, taking advantage of the high solubility of chebulic acid in alcohol and its significantly decreased solubility after salt formation, a saturated alkaline alcohol solution is added to the solid residue after alcohol dissolution, promoting the selective precipitation of chebulic acid as a salt. This process not only effectively removes non-tannin phenolic acid impurities, achieving further enrichment, but also results in almost no loss of the target product. The filter residue is dissolved in acidic water to neutralize excess alkali and restore the target product to its free state. Next, macroporous resin chromatography is used for further impurity removal, yielding an eluent rich in chebulic acid. This process avoids the use of repeated column chromatography or preparative chromatography in traditional methods, and is characterized by its simple operation and ease of industrial production, enabling the stable acquisition of high-purity and high-conversion chebulic acid.

[0010] According to the embodiments of this application, the above-mentioned method for preparing chebulic acid may also have the following additional technical features: According to an embodiment of this application, in step (3), the pH value of the saturated alcohol solution containing alkaline substances is 10-12. In this alkaline environment, chebulic acid can precipitate as salt in the saturated alcohol solution, thereby improving the transfer rate and purity of chebulic acid. The amount of saturated alcohol solution containing alkaline substances added can be reasonably selected according to the content of the target chebulic acid to ensure that the target chebulic acid is fully precipitated in the saturated alcohol solution.

[0011] According to embodiments of this application, the alcohol solution comprises at least one of methanol and a 95-100 vol% ethanol solution. In some embodiments, the concentration of the ethanol solution is 95 vol%, 96 vol%, 97 vol%, 98 vol%, 99 vol%, or 100 vol%. This allows for sufficient dissolution of chebulic acid, minimizing loss.

[0012] According to embodiments of this application, the saturated alcohol solution comprises ethanol. Therefore, chebulic acid can precipitate as a salt in the saturated ethanol solution, thereby improving the transfer rate and purity of chebulic acid.

[0013] According to embodiments of this application, the alkaline substance includes at least one of sodium hydroxide, potassium hydroxide, ammonia, and organic amines.

[0014] According to an embodiment of this application, in step (1), the extractant includes an acetone solution or an ethanol solution. This allows for the sufficient extraction of chebulic acid from the Terminalia chebula herb, achieving the purpose of impurity removal and increasing the yield of chebulic acid.

[0015] According to embodiments of this application, the concentration of the acetone solution is 50-90% by volume, for example, 50%, 60%, 70%, 80%, or 90% by volume. This allows for the efficient extraction of chebulic acid from the Terminalia chebula herb, achieving the purpose of impurity removal and increasing the yield of chebulic acid.

[0016] According to embodiments of this application, the mass-to-volume ratio of the extractant to the Terminalia chebula herb is (4-8):1, for example, 4:1, 5:1, 6:1, 7:1, or 8:1, in g / mL. This allows for the efficient extraction of chebulic acid from the Terminalia chebula herb, achieving the purpose of impurity removal and increasing the yield of chebulic acid.

[0017] According to embodiments of this application, the extraction process includes percolation. Percolation is used to extract chebulic acid. As a dynamic extraction process, the solvent flows from top to bottom within the herb layer, creating a concentration gradient, resulting in significantly higher extraction efficiency than static maceration. Compared to reflux extraction, it is conducted at room temperature or low temperature, effectively avoiding the damage to heat-sensitive components caused by continuous heating. At the industrial level, compared to ultrasonic extraction, which requires special power conversion devices, percolation equipment has a simpler structure, lower technical requirements, is easier to scale up for production, and has lower equipment investment and maintenance costs. Therefore, it helps to improve the purity and transfer rate of chebulic acid.

[0018] According to embodiments of this application, the percolation rate is 5-10 mL / min·kg, for example, 5 mL / min·kg, 6 mL / min·kg, 7 mL / min·kg, 8 mL / min·kg, 9 mL / min·kg, or 10 mL / min·kg. This further improves the purity and transfer rate of chebulic acid.

[0019] According to an embodiment of this application, before the extraction process, the Terminalia chebula herb is pulverized and sieved. The particle size of the sieved Terminalia chebula herb is 20-80 mesh, for example, 20 mesh, 30 mesh, 40 mesh, 50 mesh, 60 mesh, 70 mesh, or 80 mesh. This facilitates the full interaction of the Terminalia chebula herb with the extractant, thereby increasing the yield of chebulic acid.

[0020] According to an embodiment of this application, in step (2), the extractant includes ethyl acetate. This allows for the complete extraction of chebulic acid and the removal of some water-soluble impurities.

[0021] According to an embodiment of this application, before performing the extraction process, the method further includes: (2-1) recovering the extractant from the extract to obtain a concentrated solution; (2-2) mixing the concentrated solution with a second acid solution, filtering, and collecting the filtrate for the extraction process. The pH value of the environment has a significant impact on the extraction rate during the extraction process. Chebulic acid exists in molecular form under acidic conditions, and compared to its dissociated state, its partition coefficient in the ethyl acetate phase is increased, which is beneficial for improving the extraction transfer rate and reducing losses. By using acidic water (the second acid solution) for dilution, a high transfer rate of the target product, chebulic acid, is ensured while achieving impurity removal. After mixing the acid solution, filtration is performed to further remove a small amount of medicinal powder introduced during the percolation process.

[0022] According to embodiments of this application, the second acid solution comprises at least one of an aqueous phosphoric acid solution and an aqueous acetic acid solution. This further improves the extraction and transfer rate of chebulic acid.

[0023] According to embodiments of this application, the recovery includes heating at a temperature of 40-60°C, with a concentration factor of 1-2 times. In some embodiments, the temperature for recovering the extractant is 40°C, 45°C, 50°C, 55°C, or 60°C, with concentration factors of 1, 1.2, 1.5, 1.8, or 2 times, respectively. This effectively removes the extractant, preventing it from interfering with subsequent separation and extraction. Furthermore, it avoids the denaturation and loss of chebulic acid caused by high temperatures.

[0024] According to embodiments of this application, the amount of the second acid solution added is 10 to 15 times the volume of the concentrated solution, for example, 10, 11, 12, 13, 14, or 15 times. This facilitates subsequent macroporous resin separation and extraction, reducing reagent usage.

[0025] According to embodiments of this application, the total amount of the extractant is 2 to 5 times the volume of the filtrate in step (2-2), for example, 2, 3, 4, or 5 times. This ensures the complete extraction of chebulic acid.

[0026] According to embodiments of this application, the extraction process is performed 2 to 5 times, for example, 2, 3, 4, or 5 times. This ensures that chebulic acid is fully extracted.

[0027] According to an embodiment of this application, in step (4), the first acid solution comprises an aqueous solution of phosphoric acid or an aqueous solution of acetic acid. Dissolving in acidic water is to neutralize excess alkali and restore the target product to its free state.

[0028] According to embodiments of this application, the pH value of the loading solution is 1-2. This facilitates separation and purification using macroporous resin, improving the purity and transfer rate of chebulic acid.

[0029] According to the embodiments of this application, in step (5), the macroporous resin is selected from D101 or HP-20. This allows for the separation and extraction of chebulic acid, achieving the purpose of impurity removal, and resulting in high purity and transfer rate of chebulic acid.

[0030] According to embodiments of this application, the column diameter-to-height ratio in the chromatographic treatment is 1:3 to 1:7, for example, 1:3, 1:4, 1:5, 1:6, or 1:7. This allows for the thorough separation and extraction of chebulic acid, achieving the purpose of impurity removal, and resulting in high purity and transfer rate of chebulic acid.

[0031] According to embodiments of this application, the elution solvent for the chromatography process is an acidic ethanol solution. This facilitates the elution of chebulic acid from the resin column.

[0032] According to embodiments of this application, the elution method for the chromatography process is gradient elution. This further improves the purity and transfer rate of chebulic acid.

[0033] According to embodiments of this application, the gradient elution includes eluting with a first ethanol solution followed by eluting with a second ethanol solution, wherein the concentration of the first ethanol solution is less than the concentration of the second ethanol solution. In some embodiments, the concentration of the first ethanol solution is 10-20% by volume, the concentration of the second ethanol solution is 10-30%, and the ethanol solution contains 0.5-1.5‰ acetic acid or phosphoric acid. This facilitates the elution of chebulic acid from the chromatography column.

[0034] According to an embodiment of this application, step (5) further includes: concentrating and drying the eluent of the enriched portion of chebulic acid to obtain crude chebulic acid. In some embodiments, step (5) further includes: heating and dissolving the crude chebulic acid in a recrystallization solvent, then cooling to crystallize, filtering the crystals and drying to obtain chebulic acid. This facilitates further separation and purification of chebulic acid.

[0035] According to embodiments of this application, the recrystallization solvent includes water. Using water as a recrystallization solvent allows for the effective purification of chebulic acid, and it is readily available and inexpensive, reducing preparation costs.

[0036] According to embodiments of this application, the heating and dissolving temperature is 50-90°C. In some embodiments, the heating and dissolving temperature is 50°C, 60°C, 70°C, 80°C, or 90°C, heated until completely dissolved. This ensures thorough dissolution of the crude chebulic acid.

[0037] According to embodiments of this application, the cooling temperature is 10~25°C. In some embodiments, the cooling temperature is 10°C, 12°C, 15°C, 18°C, 20°C, 22°C, or 25°C. This facilitates the rapid and complete extraction of chebulic acid.

[0038] According to an embodiment of this application, the method includes: (1) Weigh the Terminalia chebula medicinal material, crush it, sieve it, and percolate it with acetone to obtain chebulic acid extract; (2) Take the extract obtained in step (1), recover the acetone, add the second acid solution, mix well, filter, and collect the filtrate; (3) Extract the filtrate from step (2) with ethyl acetate, concentrate and dry the organic phase to obtain a solid. (4) Take the solid obtained in step (3), dissolve it in alcohol, add it to a saturated alcohol solution containing alkaline substances, precipitate the solid, filter it, and collect the filter residue; (5) Take the filter residue obtained in step (4), dissolve it in the first acid solution, filter it, and collect the filtrate as the sample loading solution; (6) Pack the column with macroporous resin, take the sample solution obtained in step (5) for sample loading, use different concentrations of ethanol solution for gradient elution and collect the eluent of the chebulic acid enrichment part; (7) Take the eluent obtained in step (6), concentrate and dry it to obtain crude chebulic acid; (8) Take the crude chebulic acid obtained in step (7) and dissolve it in water by heating. After cooling and precipitation, filter and dry to obtain chebulic acid.

[0039] In another aspect of this application, a chebulic acid is proposed. According to an embodiment of this application, the chebulic acid is obtained by the aforementioned method for preparing chebulic acid. Therefore, the chebulic acid of this application has high purity.

[0040] The beneficial effects of this invention are as follows: 1. This application uses percolation to extract chebulic acid. As a dynamic extraction process, the solvent flows from top to bottom in the herb layer, forming a concentration difference, and the extraction efficiency is significantly higher than that of static maceration. Compared with reflux extraction, it is carried out at room temperature or low temperature, which can effectively avoid the damage of heat-sensitive components caused by continuous heating. At the industrial level, compared with ultrasonic extraction, which requires special power conversion devices, percolation equipment has a simple structure, low technical requirements, is easier to scale up, and has a greater advantage in equipment investment and maintenance costs.

[0041] 2. Based on the molecular structure characteristics of chebulic acid, this application removes some water-soluble impurities through ethyl acetate extraction. In the ethyl acetate extraction process, the pH of the solution directly affects the extraction rate. Chebulic acid exists in molecular form under acidic conditions, and compared to its dissociated state, its partition coefficient in the ethyl acetate phase is increased, which is beneficial for improving the extraction transfer rate and reducing losses. By using acidic water dilution, the high transfer rate of the target product, chebulic acid, is ensured while achieving the desired impurity removal effect.

[0042] 3. Based on the acidity and alkalinity of chebulic acid, this application addresses the issue that chebulic acid is easily soluble in alcohol solutions and its solubility decreases significantly after salt formation. By precipitating chebulic acid after salt formation in an alkali-alcohol mixture, this step results in almost no loss of chebulic acid. While removing non-tannin phenolic acid impurities, it further purifies and enriches chebulic acid.

[0043] 4. Based on the physicochemical characteristics of the target product, this application employs a "gradual impurity removal-recrystallization" method. Through multiple simple impurity removal steps, the crude chalcedony acid, purified and enriched using macroporous resin, is recrystallized with pure water to obtain chalcedony acid monomer with a content of over 95% as detected by HPLC normalization. This method does not rely on reversed-phase column preparation and purification; the equipment is simple, the operation is easy, and it is suitable for large-scale industrial production.

[0044] Therefore, this application has great feasibility for industrial production, and the resulting economic benefits are obvious.

[0045] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Detailed Implementation

[0046] The following will explain the solution of this application with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0047] Example 1 (1) Weigh 100g of Terminalia chebula medicinal material, crush it, sieve it to a particle size of 40 mesh, and percolate it with 600mL of 70% acetone solution at a percolation rate of 8mL / min·kg to obtain 355mL of Terminalia chebula acid extract with a content of 5.2%; (2) Take the percolate obtained in step (1), recover acetone at 45°C and concentrate it to 100mL, then add 1‰ phosphoric acid aqueous solution to a volume of 1300mL, mix thoroughly and filter to obtain 1270mL of filtrate. (3) Take the filtrate obtained in step (2), extract it with 3939 mL of ethyl acetate in 4 portions, concentrate and dry it to obtain 13.47 g of ethyl acetate solids, with a transfer rate of 84%; (4) Take 11.64 g of the solid obtained in step (3), add 70 mL of 95% ethanol to dissolve it, add a saturated ethanol solution of sodium hydroxide (pH 11) to precipitate the solid, and continue until the transfer of chebulic acid is complete as monitored by HPLC. Filter to obtain the filter residue with a transfer rate of 93%. (5) Take the filter residue obtained in step (4), add 140 mL of 1% phosphoric acid water to dissolve it and adjust the pH to 2, then filter to obtain 157 mL of filtrate; (6) Take 450 mL of HP-20 column with a diameter-to-height ratio of 1:5, take the filtrate obtained in step (5), load the sample, wash with 15% acidic ethanol (containing 1‰ phosphoric acid) for 8 BV, wash with 20% acidic ethanol (containing 1‰ phosphoric acid) for 10 BV, identify by high performance liquid chromatography, combine the eluent containing chebulic acid, and obtain the eluent of the chebulic acid-rich part; (7) The eluent obtained in step (6) was concentrated and dried to obtain 1.583 g of ethyl acetate solids; (8) The solid obtained in step (7) was recrystallized, 32 mL of water was added, and the mixture was heated to 60 °C to dissolve. The mixture was then slowly cooled to 17 °C in a water bath to precipitate the product, yielding 1.34 g of chebulic acid product with a content of 96.64%.

[0048] Example 2 (1) Weigh 200g of Terminalia chebula medicinal material, crush it, sieve it to a particle size of 40 mesh, and percolate it with 1200mL of 70% acetone solution at a percolation rate of 8mL / min·kg to obtain 758mL of Terminalia chebula acid extract with a content of 5.3%; (2) Take the percolate obtained in step (1), recover acetone at 45°C and concentrate to 360 mL, add 1‰ phosphoric acid aqueous solution to a volume of 2700 mL, mix thoroughly and filter to obtain 2710 mL of filtrate. (3) Take the filtrate obtained in step (2), extract it with 8965 mL of ethyl acetate in 4 portions, concentrate and dry it to obtain 26.17 g of ethyl acetate solids, with a transfer rate of 83%; (4) Take 23.17 g of the solid obtained in step (3), add 120 mL of 95% ethanol to dissolve it, add a saturated ethanol solution of sodium hydroxide (pH 11) to precipitate the solid, until the transfer of chebulic acid is complete as monitored by HPLC, filter, and obtain the filter residue; (5) Take the filter residue obtained in step (4), add 240 mL of 1% phosphoric acid water to dissolve it and adjust the pH to 2, then filter (ellagic acid) to obtain 260 mL of filtrate; the transfer rate is 98%; (6) Take 900 mL of HP-20 column with a diameter-to-height ratio of 1:5, take the filtrate obtained in step (5), load the sample, wash with 15% vol% acidic ethanol (containing 1‰ acetic acid) for 8 BV, wash with 20% vol% acidic ethanol (containing 1‰ acetic acid) for 10 BV, identify by high performance liquid chromatography, combine the eluent containing chebulic acid, and obtain the eluent of the chebulic acid-rich part; (7) The eluent obtained in step (6) was concentrated and dried to obtain 1.481 g of ethyl acetate solids; (8) The solid obtained in step (7) was recrystallized, 30 mL of water was added, and the mixture was heated to 60 °C to dissolve. The mixture was then slowly cooled to 17 °C in a water bath to precipitate the product, which contained 1.25 g of chebulic acid with a content of 97.61%.

[0049] Example 3 (1) Weigh 1.2 kg of Terminalia chebula medicinal material, crush it, sieve it to a particle size of 40 mesh, and percolate it with 7200 mL of 70% acetone solution at a percolation rate of 8 mL / min·kg to obtain 5250 mL of Terminalia chebula acid extract with a content of 4.9%; (2) Take the percolate obtained in step (1), recover acetone at 45°C and concentrate it to 1790mL, then add 1‰ phosphoric acid aqueous solution to a volume of 15L, mix thoroughly and filter to obtain 14.4L of filtrate; (3) Take the filtrate obtained in step (2), extract it with 45L of ethyl acetate in 4 fractions, concentrate and dry it to obtain 177.19g of ethyl acetate solids, with a transfer rate of 84%; (4) Take the solid obtained in step (3), add 1L of 95% ethanol to dissolve it, add a saturated ethanol solution of sodium hydroxide (pH value 11) to precipitate solid, until the transfer of chebulic acid is complete as monitored by HPLC, filter, and obtain filter residue; (5) Take the filter residue obtained in step (4), add 1800 mL of 1% phosphoric acid water to dissolve it and adjust the pH to 2, then filter (ellagic acid) to obtain 2420 mL of filtrate; the transfer rate is 92%; (6) Take 5.5L HP-20 to pack the column with a diameter-to-height ratio of 1:5. Take the filtrate obtained in step (5), load it onto the column, wash with 15% acidic ethanol (containing 1‰ phosphoric acid) for 8 BV, wash with 20% acidic ethanol (containing 1‰ phosphoric acid) for 10 BV, identify by high performance liquid chromatography, combine the eluent containing chebulic acid, and obtain the eluent of the chebulic acid-rich part; (7) The eluent obtained in step (6) was concentrated and dried to obtain 36.21 g of ethyl acetate solids; (8) The solid obtained in step (7) was recrystallized, 720 mL of water was added, and the mixture was heated to 60 °C to dissolve. The mixture was then slowly cooled to 15 °C in a water bath to precipitate the product, which contained 21.44 g of chebulic acid with a content of 97.57%.

[0050] Example 4 (1) Weigh 1.6 kg of Terminalia chebula medicinal material, crush it, sieve it to a particle size of 40 mesh, and percolate it with 9600 mL of 70% acetone solution at a percolation rate of 8 mL / min·kg to obtain 6610 mL of Terminalia chebula acid extract with a content of 5.2%; (2) Take the percolate obtained in step (1), recover acetone at 45°C and concentrate it to 2210 mL, then add 1‰ phosphoric acid aqueous solution to a volume of 20 L, mix thoroughly and filter to obtain 18.3 L of filtrate; (3) Take the filtrate obtained in step (2), extract it with 62L of ethyl acetate in 4 fractions, concentrate and dry it to obtain 326.51g of ethyl acetate solids, with a transfer rate of 85%; (4) Take the solid obtained in step (3), add 1.5L of 95% ethanol to dissolve it, add a saturated ethanol solution of sodium hydroxide (pH value 11) to precipitate solid, until the transfer of chebulic acid is complete as monitored by HPLC, filter and obtain filter residue; (5) Take the filter residue obtained in step (4), add 3300 mL of 1% phosphoric acid water to dissolve it and adjust the pH to 2, then filter (ellagic acid) to obtain 4600 mL of filtrate; the transfer rate is 98%; (6) Take 7.3L HP-20 to pack the column with a diameter-to-height ratio of 1:5. Take the filtrate obtained in step (5), load it onto the column, wash with 15% acidic ethanol (containing 1‰ phosphoric acid) for 8 BV, wash with 20% acidic ethanol (containing 1‰ phosphoric acid) for 10 BV, identify by high performance liquid chromatography, combine the eluent containing chebulic acid, and obtain the eluent of the chebulic acid-rich part; (7) The eluent obtained in step (6) was concentrated and dried to obtain 71.831 g of ethyl acetate solids; (8) The solid obtained in step (7) was recrystallized, 1.4L of water was added, and the mixture was heated to 60°C to dissolve. The mixture was then slowly cooled to 17°C in a water bath to precipitate the product, which contained 34.30g of chebulic acid with a content of 97.71%.

[0051] Example 5 (1) Weigh 100g of Terminalia chebula medicinal material, crush it, sieve it to a particle size of 40 mesh, and percolate it with 600mL of 70% acetone solution at a percolation rate of 8mL / min·kg to obtain 356mL of Terminalia chebula acid extract with a content of 5.1%; (2) Take the percolate obtained in step (1), recover acetone at 45°C and concentrate it to 120mL, then add water to a volume of 1300mL, mix thoroughly and filter to obtain 1274mL of filtrate. (3) Take the filtrate obtained in step (2), extract it with 3939 mL of ethyl acetate in 4 portions, concentrate and dry it to obtain 10.90 g of ethyl acetate solids, with a transfer rate of 68%; (4) Take 9.35 g of the solid obtained in step (3), add 60 mL of 95% ethanol to dissolve it, add a saturated ethanol solution of sodium hydroxide (pH 11) to precipitate solid, and continue until the transfer of chebulic acid is complete as monitored by HPLC. Filter to obtain filter residue with a transfer rate of 92%. (5) Take the filter residue obtained in step (4), add 120 mL of 1% phosphoric acid water to dissolve it, adjust the pH to 2, filter it, and obtain 130 mL of filtrate. (6) Take 450 mL of HP-20 column with a diameter-to-height ratio of 1:5, take the filtrate obtained in step (5), load the sample, wash with 15% acidic ethanol (containing 1‰ phosphoric acid) for 8 BV, wash with 20% acidic ethanol (containing 1‰ phosphoric acid) for 10 BV, identify by high performance liquid chromatography, combine the eluent containing chebulic acid, and obtain the eluent of the chebulic acid-rich part; (7) The eluent obtained in step (6) was concentrated and dried to obtain 1.311 g of ethyl acetate solids; (8) The solid obtained in step (8) was recrystallized, 27 mL of water was added, and the mixture was heated to 60 °C to dissolve. The mixture was then slowly cooled to 17 °C in a water bath to precipitate the product, yielding 1.11 g of chebulic acid product with a content of 91.36%.

[0052] It can be seen that, compared with Example 1, in Example 5, after recovering and concentrating acetone, no acid solution is added, which will lead to a decrease in the transfer rate of chebulic acid after extraction treatment in step (3), resulting in low purity of chebulic acid and large extraction loss.

[0053] Example 6 (1) Weigh 200g of Terminalia chebula medicinal material, crush it, sieve it to a particle size of 40 mesh, and percolate it with 1200mL of 70% acetone solution at a percolation rate of 8mL / min·kg to obtain 720mL of Terminalia chebula acid extract with a content of 5.2%; (2) Take the percolate obtained in step (1), recover acetone at 45°C and concentrate it to 220mL, then add 1‰ phosphoric acid aqueous solution to a volume of 2600mL, mix thoroughly and filter to obtain 2530mL of filtrate. (3) Take the filtrate obtained in step (2), extract it with 7880 mL of ethyl acetate in 4 portions, concentrate and dry it to obtain 26.93 g of ethyl acetate solids, with a transfer rate of 84%; (4) Take the filter residue obtained in step (3), add 280 mL of 1% phosphoric acid water to dissolve it, adjust the pH to 2, filter it, and obtain 310 mL of filtrate. (5) Take 900 mL of HP-20 and pack it into a column with a diameter-to-height ratio of 1:5. Take the filtrate obtained in step (5), load it onto the column, wash with 15% acidic ethanol (containing 1‰ phosphoric acid) for 8 BV, wash with 20% acidic ethanol (containing 1‰ phosphoric acid) for 10 BV, identify it by high performance liquid chromatography, combine the eluent containing chebulic acid, and obtain the eluent of the chebulic acid-rich part. (6) The eluent obtained in step (5) was concentrated and dried to obtain 3.324 g of ethyl acetate solids; (7) The solid obtained in step (6) was recrystallized, 68 mL of water was added, and the mixture was heated to 60 °C to dissolve. The mixture was then slowly cooled to 16 °C in a water bath to precipitate the product, which contained 2.81 g of chebulic acid with a content of 88.72%.

[0054] It can be seen that, compared with Example 1, Example 6 does not contain the alkaline alcohol precipitation process (step (4) of Example 1). The impurity removal effect in the early stage is insufficient, which will cause cross-contamination in the subsequent macroporous resin purification. The purity of the crude chebulic acid is low, which leads to a corresponding decrease in the purity of the sample after recrystallization.

[0055] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0056] Although embodiments of this application have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting this application. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of this application.

Claims

1. A method for preparing chebulic acid, characterized in that, include: (1) The Terminalia chebula medicinal material was extracted using an extractant to obtain an extract; (2) The extract is extracted with an extractant, the organic phase is collected, dried, and a solid is obtained; (3) After dissolving the solid in alcohol, add it to a saturated alcohol solution containing alkaline substances to precipitate the solid, filter it, and collect the filter residue; (4) Dissolve the filter residue in the first acid solution, filter, and collect the filtrate as the sample loading solution; (5) The sample solution is subjected to chromatography using macroporous resin, and the eluent of the chebulic acid-enriched portion is collected.

2. The method according to claim 1, characterized in that, In step (3), the pH value of the saturated alcohol solution containing alkaline substances is 10~12; Optionally, the alcohol solution includes at least one of methanol and a 95-100% ethanol solution; Optionally, the saturated alcohol solution includes ethanol; Optionally, the alkaline substance includes at least one of sodium hydroxide, potassium hydroxide, ammonia, and organic amines.

3. The method according to claim 1, characterized in that, In step (1), the extractant includes an acetone solution or an ethanol solution; Optionally, the concentration of the acetone solution is 50-90% by volume. Optionally, the mass-to-volume ratio of the extractant to the Terminalia chebula herb is (4~8):1, in g / mL; Optionally, the extraction process includes percolation; Optionally, the percolation rate is 5~10 mL / min·kg; Optionally, before performing the extraction process, the Terminalia chebula medicinal material is crushed and sieved, and the particle size of the sieved Terminalia chebula medicinal material is 20-80 mesh.

4. The method according to claim 1, characterized in that, In step (2), the extractant includes ethyl acetate; Prior to performing the extraction process, the procedure further includes: (2-1) The extractant in the extract is recovered to obtain a concentrated solution; (2-2) Mix the concentrated solution with the second acid solution, filter, and collect the filtrate for the extraction process.

5. The method according to claim 4, characterized in that, The second acid solution includes at least one of an aqueous solution of phosphoric acid and an aqueous solution of acetic acid; Optionally, the recovery includes heating at a temperature of 40-60°C and a concentration factor of 1-2 times; Optionally, the amount of the second acid solution added is 10 to 15 times the volume of the concentrate; Optionally, the total amount of the extractant is 2 to 5 times the volume of the filtrate in step (2-2); Optionally, the extraction process is performed 2 to 5 times.

6. The method according to claim 1, characterized in that, In step (4), the first acid solution includes an aqueous solution of phosphoric acid or an aqueous solution of acetic acid; Optionally, the pH of the loading solution is 1 to 2.

7. The method according to claim 1, characterized in that, In step (5), the macroporous resin is selected from D101 or HP-20; Optionally, the column diameter-to-height ratio of the chromatography process is 1:3 to 1:7; Optionally, the elution solvent for the chromatography process is an acidic ethanol solution; Optionally, the elution method of the chromatography process is gradient elution; Optionally, the gradient elution includes: eluting with a first ethanol solution followed by elution with a second ethanol solution, wherein the concentration of the first ethanol solution is less than the concentration of the second ethanol solution; Optionally, the concentration of the first ethanol solution is 10-20% by volume, the concentration of the second ethanol solution is 10-30%, and the ethanol solution contains 0.5-1.5‰ acetic acid or phosphoric acid.

8. The method according to claim 1, characterized in that, Step (5) further includes: The eluent of the enriched chebulic acid fraction was concentrated and dried to obtain crude chebulic acid. Optionally, the crude chebulic acid is dissolved by heating with a recrystallization solvent, then cooled to crystallize, the crystals are filtered and dried to obtain chebulic acid; Optionally, the recrystallization solvent includes water; Optionally, the heating and melting temperature is 50~90℃; Optionally, the cooling temperature is 10~25℃.

9. The method according to any one of claims 1-8, characterized in that, include: (1) Weigh the Terminalia chebula medicinal material, crush it, sieve it, and percolate it with acetone to obtain chebulic acid extract; (2) Take the extract obtained in step (1), recover the acetone, add the second acid solution, mix well, filter, and collect the filtrate; (3) Extract the filtrate from step (2) with ethyl acetate, concentrate and dry the organic phase to obtain a solid. (4) Take the solid obtained in step (3), dissolve it in alcohol, add it to a saturated alcohol solution containing alkaline substances, precipitate the solid, filter it, and collect the filter residue; (5) Take the filter residue obtained in step (4), dissolve it in the first acid solution, filter it, and collect the filtrate as the sample loading solution; (6) Pack the column with macroporous resin, take the sample solution obtained in step (5) for sample loading, use different concentrations of ethanol solution for gradient elution and collect the eluent of the chebulic acid enrichment part; (7) Take the eluent obtained in step (6), concentrate and dry it to obtain crude chebulic acid; (8) Take the crude chebulic acid obtained in step (7) and dissolve it in water by heating. After cooling and precipitation, filter and dry to obtain chebulic acid.

10. A type of chebulic acid, characterized in that, The chellinoic acid is obtained by the preparation method of chellinoic acid according to any one of claims 1-9.