A method for separating hyodeoxycholic acid and chenodeoxycholic acid

Abstract

The present invention provides a method for separating hyodeoxycholic acid and chenodeoxycholic acid. The method of the present invention comprises fractionating and extracting a raw material liquid containing hyodeoxycholic acid and chenodeoxycholic acid using an extractant containing an ionic liquid and / or a polar solvent. The method has good stability and high separation selectivity, and is simple in process, easy to scale up, safe and environmentally friendly, and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical separation, and in particular to a method for separating hyodeoxycholic acid and chenodeoxycholic acid. Background Art

[0002] Chenodeoxycholic acid, also known as 3α,7α-dihydroxy-5β cholanoic acid, is a white needle-shaped crystal. It is the main bile acid contained in animal bile. It is the same as bile acid in the human body. It has the functions of dissolving cholesterol gallstones in the human body, relieving cough and asthma, and antibacterial and anti-inflammatory. It can also be used as a precursor to synthesize another important drug precursor-ursodeoxycholic acid; hyodeoxycholic acid is a bile acid extracted from pig bile. It can inhibit the formation of bile acid and dissolve fat, and reduce cholesterol in the blood. It can be taken directly as a drug, hyodeoxycholic acid tablets. It is also the main ingredient of traditional Chinese patent medicines such as Qingkailing and Huodan tablets. In vitro experiments have shown that hyodeoxycholic acid can exert pharmacological activities such as inducing cell apoptosis. In addition to its medical effects, hyodeoxycholic acid can also be used as a raw material to obtain chenodeoxycholic acid and ursodeoxycholic acid through catalytic stereosynthesis. Therefore, hyodeoxycholic acid and chenodeoxycholic acid have broad application prospects.

[0003]

[0004] The main components of pig bile are hyodeoxycholic acid and chenodeoxycholic acid, of which hyodeoxycholic acid contains about 40% and chenodeoxycholic acid contains about 25%. Compared with the chemical synthesis method, the method of separating and purifying hyodeoxycholic acid and chenodeoxycholic acid from pig bile extract has the advantages of cheap raw materials, easy availability and high economic benefits. However, hyodeoxycholic acid and chenodeoxycholic acid are isomers, and their structural difference lies only in the different positions of the hydroxyl groups on the steroid nucleus. Their physical and chemical properties are extremely similar, so the separation of hyodeoxycholic acid and chenodeoxycholic acid is extremely challenging.

[0005] Most of the existing methods for separating hyodeoxycholic acid and chenodeoxycholic acid are precipitation methods. Canadian patent P1041479 uses a methylation-complexation precipitation method to separate hyodeoxycholic acid and chenodeoxycholic acid: first, the mixed pig bile acid is methylated under sulfuric acid catalysis, and then the complex formed by hyodeoxycholic acid methyl ester and benzene is insoluble in benzene to precipitate it and separate it from chenodeoxycholic acid methyl ester, and finally the mother liquor and the complex precipitate are demethylated and crystallized to obtain chenodeoxycholic acid and hyodeoxycholic acid products. However, this method requires the use of benzene, which is highly toxic, and is prone to environmental pollution and human health problems, and the process is complicated. There are also related reports on the direct precipitation method for extracting chenodeoxycholic acid. Some studies (Wang Youtong, Wu Wenjun. Preparation of chenodeoxycholic acid. Jiangsu Agricultural Science, 1986 (08): 39-40) use the principle that chenodeoxycholic acid is easier to precipitate with barium salt than hyodeoxycholic acid. After adding barium chloride to the chenodeoxycholic acid paste solution, the chenodeoxycholic acid product is obtained by recrystallization with ethyl acetate; however, barium salt is a heavy metal that is harmful to health and is not suitable for large-scale production of chenodeoxycholic acid. There are also studies (Pan Xianjun, Zhang Xiaomei. New process for separating and purifying chenodeoxycholic acid from hyodeoxycholic acid paste. Hebei Medicine, 2006 (02): 147-148.) using calcium chloride instead of barium chloride to separate and purify chenodeoxycholic acid by calcium salt precipitation. Although this method solves the toxicity problem, the yield of the entire process is only 2.6%, and the economic benefit is low. It can be seen that there is an urgent need to develop an economical and efficient method for separating hyodeoxycholic acid and chenodeoxycholic acid. Summary of the invention

[0006] In order to solve the above technical problems existing in the prior art, the present invention provides a method for separating high-purity hyodeoxycholic acid and chenodeoxycholic acid from a mixture containing hyodeoxycholic acid and chenodeoxycholic acid by multi-stage fractionation extraction using a polar solvent, an ionic liquid or an ionic liquid-polar solvent mixture as an extractant. Compared with the reported precipitation separation method, the extraction method adopted by the present invention has better stability and higher separation selectivity, has the characteristics of simple process, safe process, easy scale-up, environmental protection, etc., and is suitable for industrial production.

[0007] In order to achieve the above object, the present invention provides a method for separating hyodeoxycholic acid and chenodeoxycholic acid, comprising fractionating and extracting a raw material solution containing hyodeoxycholic acid and chenodeoxycholic acid using an extractant containing an ionic liquid and / or a polar solvent.

[0008] Hyodeoxycholic acid and chenodeoxycholic acid are a pair of isomers, and the structural difference lies only in the different positions of the hydroxyl groups of the steroid nucleus. Hyodeoxycholic acid has a hydroxyl group at the C-6 position, while the hydroxyl group of chenodeoxycholic acid is located at the C-7 position, which will lead to differences in the sites and strengths of interaction between hyodeoxycholic acid / chenodeoxycholic acid molecules, and between the separation medium and the molecules of hyodeoxycholic acid and chenodeoxycholic acid. The inventors have found that the use of an extractant with a certain hydrogen bond interaction ability can improve the separation selectivity by the difference in the sites and strengths of the interaction forces between the extract and the two. In the present invention, it is preferred to use an ionic liquid or a mixture of an ionic liquid and a polar solvent as an extractant.

[0009] In some preferred embodiments, the extractant comprises an ionic liquid and a polar solvent.

[0010] In some preferred embodiments, the extractant is a mixture of an ionic liquid and a polar solvent.

[0011] In some embodiments, the molar fraction of the ionic liquid in the extractant is 0.1%-100%, such as 0.1%, 0.5%, 1%, 5%, 10%, 20%, 25%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or any value therebetween, preferably 1-50%, more preferably 5-25%. Adding ionic liquid to the polar solvent can make hyodeoxycholic acid and chenodeoxycholic acid have an appropriate distribution coefficient and higher separation selectivity.

[0012] In some embodiments, the polar solvent includes at least one of water, alcohol, sulfone, sulfoxide, nitrile, ketone, and amide. Preferably, the polar solvent includes at least one of water, methanol, ethanol, ethylene glycol, 1,3-propylene glycol, polyethylene glycol, dimethyl sulfoxide, sulfolane, acetonitrile, N-methylpyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0013] In some more preferred embodiments, the extractant is a mixture of ionic liquid and water.

[0014] In some embodiments, the ionic liquid is composed of a cation and an anion, wherein the cation is selected from at least one of an imidazolium cation, a pyridinium cation, a quinolinium cation, an isoquinolinium cation, a benzimidazolium cation, a piperidinium cation, and a pyrrolidinium cation.

[0015] Optionally, the cation is substituted by one or more substituents selected from C1-C10 alkyl, C1-C10 alkenyl, C6-C20 aryl, hydroxyl, cyano, thiocyano, hydroxyethyl, sulfone, amino, carboxyl and carbonyl. Preferably, the substituent is selected from at least one of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and phenyl.

[0016] When there are plural substituents, the plural substituents may be the same as or different from each other.

[0017] In the present invention, the cation of the ionic liquid preferably contains one or more substituents.

[0018] In some embodiments, the anion is selected from at least one of p-toluenesulfonate, thiocyanate, dicyanamide, tricyanomethane, tetracyanoborate, trifluoromethanesulfonate, sulfate, bisulfate, nitrate, tetrafluoroborate, acetate, glycine, chloride, bromide, and iodide.

[0019] In some specific embodiments, the ionic liquid is selected from at least one of 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium chloride, 1-ethyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium acetate, ethylpyridinium bromide, 1-ethyl-1-methylpyrrole hydrogen sulfate, and 1-ethyl-3-benzylimidazolium glycine.

[0020] In some embodiments, the method further comprises: concentrating and drying the raffinate of the fractionation extraction to obtain chenodeoxycholic acid. In some specific embodiments, the raffinate of the fractionation extraction is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid.

[0021] In some embodiments, the method further comprises: stripping the extract of the fractional extraction and concentrating and drying the stripping phase to obtain hyodeoxycholic acid. In some specific embodiments, stripping the extract of the fractional extraction, vacuum concentrating, washing and drying the stripping phase to obtain hyodeoxycholic acid.

[0022] In some embodiments, taking into account factors such as product quality and production cost, in the fractional extraction, the flow ratio of the extractant, the detergent and the raw material liquid is preferably (0.1-15):(1-10):1, and more preferably (0.5-10):(1-10):1.

[0023] In some embodiments, the total concentration of hyodeoxycholic acid and chenodeoxycholic acid in the raw material solution is 0.5 g / L-20.0 g / L, for example, 0.5 g / L, 1 g / L, 5 g / L, 10 g / L, 15 g / L, 20 g / L or any value therebetween. If the concentration of the raw material solution is too high, it is not conducive to the effective separation of hyodeoxycholic acid and chenodeoxycholic acid; if the concentration of the raw material solution is too low, the raw material processing volume is small, the solvent loss is large, and it is not conducive to the economy of the process.

[0024] In some embodiments, the raw material solution further includes a raw material solvent. Preferably, the raw material solution consists of the raw material to be separated containing hyodeoxycholic acid and chenodeoxycholic acid and a raw material solvent.

[0025] Preferably, in the raw material, the total weight percentage of hyodeoxycholic acid and chenodeoxycholic acid is more than 60%. The raw material to be separated can be purchased directly from the market, or can be obtained from pig bile or other poultry bile dissolution, extraction, precipitation and other steps to obtain a raw material with a total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid of more than 60%. The raw material is mainly composed of hyodeoxycholic acid and chenodeoxycholic acid, and also contains hyodeoxycholic acid, chenodeoxycholic acid, bile acid, ursodeoxycholic acid, etc.

[0026] Preferably, the raw material solvent is selected from C2-C10 ester solvents, C1-C10 alcohol solvents or C3-C10 ketone solvents. More preferably, the raw material solvent is selected from C2-C10 ester solvents.

[0027] The C2-C10 ester solvents of the present invention include but are not limited to methyl acetate, ethyl acetate, butyl acetate and the like.

[0028] The C1-C10 alcohol solvents described in the present invention include but are not limited to n-butanol, isobutanol, n-pentanol, isopentanol, n-hexanol, 2-hexanol, n-heptanol, isooctyl alcohol, and the like.

[0029] The C3-C10 ketone solvents of the present invention include but are not limited to hexanone, cyclohexanone and the like.

[0030] In some preferred embodiments, the raw material solvent includes ethyl acetate, and the extractant includes an ionic liquid and a polar solvent.

[0031] In some more preferred embodiments, the feed solvent comprises ethyl acetate, and the extractant comprises an ionic liquid and water.

[0032] In some preferred embodiments, the raw material solvent comprises methyl acetate, and the extractant comprises a polar solvent.

[0033] In some more preferred embodiments, the raw material solvent comprises methyl acetate, and the extractant comprises water.

[0034] In some embodiments, in the fractionation extraction, the detergent is selected from C2-C10 ester solvents, C2-C10 alcohol solvents or C2-C10 ketone solvents, preferably at least one of methyl acetate, ethyl acetate, butyl acetate, n-butanol, isobutanol, n-pentanol, isopentanol, n-hexanol, 2-hexanol, n-heptanol, isooctyl alcohol, hexanone and cyclohexanone.

[0035] In some preferred embodiments, the detergent is the same as the raw material solvent. In the present invention, the detergent and the solvent in the raw material solution are selected from the same solvent, which not only has a good solubility for the raw material, but also can form a liquid-liquid two-phase system with a small mutual solubility with the extractant, thereby achieving a better separation effect.

[0036] In some embodiments, the operating temperature of the fractional extraction is 20°C-70°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C or any value therebetween. If the temperature is too low, the viscosity of the extractant is high, the mass transfer rate is reduced, the processing volume is small, and it is not conducive to production operation; if the temperature is too high, the solvent evaporates seriously, which will reduce the distribution ratio and selectivity of the fractional extraction.

[0037] The fractionation extraction described in the present invention can be carried out by using existing fractionation extraction equipment.

[0038] In some embodiments, the fractionation extraction is multi-stage fractionation extraction.

[0039] In some embodiments, the fractional extraction includes an extraction section and a washing section. The extractant enters the fractional extraction system from the first stage of the extraction section, the raw material liquid enters the fractional extraction system from the last stage of the extraction section, the detergent enters the fractional extraction system from the first stage of the washing section, the raw material liquids are combined at the last stage of the extraction section and enter the extraction section together, after multi-stage countercurrent contact, the raffinate enriched in chenodeoxycholic acid flows out from the first stage of the extraction section, the raffinate is collected, and the chenodeoxycholic acid product is obtained through vacuum concentration-water washing-drying. The extract enriched in hyodeoxycholic acid flows out from the first stage of the washing section, and the hyodeoxycholic acid product is obtained through vacuum concentration-water washing-drying.

[0040] In some embodiments, the method comprises the following steps:

[0041] (1) preparing a mixture containing hyodeoxycholic acid and chenodeoxycholic acid with a raw material solvent to form a raw material liquid, using an ionic liquid and / or a polar solvent as an extractant and the raw material solvent as a detergent, and performing fractional extraction; the fractional extraction is divided into an extraction section and a washing section, the extractant enters the extraction system from the first stage of the extraction section, the raw material liquid enters the extraction system from the last stage of the extraction section, the detergent enters the extraction system from the first stage of the washing section, the feed liquid is combined at the last stage of the extraction section and enters the extraction section together, the extraction phase and the washing phase are subjected to multi-stage countercurrent contact, a raffinate enriched in chenodeoxycholic acid flows out from the first stage of the extraction section, and an extract enriched in hyodeoxycholic acid flows out from the first stage of the washing section;

[0042] (2) vacuum concentrating, washing and drying the raffinate in step (1) to obtain chenodeoxycholic acid; back-extracting the extract in step (1) with an ester or alcohol solvent, and vacuum concentrating, washing and drying the extract phase to obtain hyodeoxycholic acid.

[0043] In some preferred embodiments, the raw material solvent and the detergent are both hydrophobic organic solvents, the ionic liquid is a hydrophilic ionic liquid, and the polar solvent is water or a hydrophilic solvent.

[0044] The advantages of the present invention are:

[0045] 1. The present invention adopts a fractionation extraction method and selects a suitable extractant, which has a high selective separation ability for hyodeoxycholic acid and chenodeoxycholic acid system. At the same time, the extractant used can not only be recycled and reused to reduce production costs, but also is green and environmentally friendly, with less pollution to the environment, and has broad application prospects.

[0046] 2. The present invention adopts fractionation extraction technology, which has low consumption of chemical raw materials, high production capacity and low cost.

[0047] 3. The method of the present invention optimizes the fractionation extraction conditions, and the purity of the hyodeoxycholic acid and chenodeoxycholic acid obtained after separation can reach more than 95%, and the recovery rate can reach more than 70%. DETAILED DESCRIPTION

[0048] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation to the present invention.

[0049] The object of the present invention is to provide an environmentally friendly, simple process and efficient method for separating hyodeoxycholic acid and chenodeoxycholic acid. The method uses an ionic liquid, a polar solvent or a mixture of an ionic liquid and a polar solvent as an extractant, and has a good separation effect on hyodeoxycholic acid and chenodeoxycholic acid.

[0050] The polar solvent in the present invention can be water, dimethyl sulfoxide, sulfolane and other solvents, which have a separation effect on hyodeoxycholic acid and chenodeoxycholic acid. If pure ionic liquid is used as an extractant, there are disadvantages such as high viscosity and large dosage of ionic liquid, and even some ionic liquids are solid at room temperature, so a third solvent needs to be added. The added third solvent should have good mutual solubility with the ionic liquid, can form a two-phase system with the raw material solvent, and can also accurately adjust the properties of the extractant to achieve the purpose of increasing the mass transfer rate and improving the separation effect.

[0051] The present invention preferably uses a hydrophobic organic solvent as the hyodeoxycholic acid-chenodeoxycholic acid raw material solvent and detergent.

[0052] For the raw materials of hyodeoxycholic acid and chenodeoxycholic acid, ethyl acetate was used as solvent, 10% 1-ethyl-3-methylimidazolium acetate aqueous solution was used as extractant, and single-stage extraction was performed at 30°C. The distribution coefficients of hyodeoxycholic acid and chenodeoxycholic acid were 2.417 and 0.742, respectively, and the selectivity was 3.26. The single-stage extraction experiment showed that the use of ionic liquid molecules with hydrogen bond alkalinity has a stronger interaction with hyodeoxycholic acid, and a higher selectivity can also be achieved for the separation of isomers.

[0053] Based on this, the present invention provides a method for separating hyodeoxycholic acid and chenodeoxycholic acid with higher purity from a hyodeoxycholic acid-chenodeoxycholic acid raw material solution by using an extractant containing an ionic liquid and / or a polar solvent through multi-stage fractionation extraction.

[0054] In the following examples of the present invention, the concentrations of hyodeoxycholic acid and chenodeoxycholic acid monomers were analyzed by high performance liquid chromatography. The specific analysis conditions of HPLC were: C18 column (4.8 mm×250 mm, particle size 5 μm, Agilent), column temperature 30° C., mobile phase methanol:acetonitrile:0.1 vol% formic acid aqueous solution = 63:17:20 (v / v / v), flow rate 0.8 mL / min, and detector was a charged aerosol detector (Thermo Fisher).

[0055] The calculation method of yield and purity in the present invention is as follows:

[0056] Hyodeoxycholic acid yield = weight of hyodeoxycholic acid in the product / weight of hyodeoxycholic acid in the raw material × 100%;

[0057] Chenodeoxycholic acid yield = weight of Chenodeoxycholic acid in the product / weight of Chenodeoxycholic acid in the raw material × 100%;

[0058] Absolute purity of hyodeoxycholic acid = mass of hyodeoxycholic acid in the product / total mass of the product × 100%;

[0059] Absolute purity of chenodeoxycholic acid = mass of chenodeoxycholic acid in the product / total mass of the product × 100%.

[0060] Example 1

[0061] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in methyl acetate to prepare a raw material liquid with a total concentration of 5 g / L. Water is used as an extractant, methyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 3:3:1, and fractional distillation extraction is performed at 30°C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages and the washing section has 20 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is retained from the first stage of the extraction section, and the extract and the raffinate are collected.

[0062] The raffinate was vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract was diluted 10 times, back-extracted with 1 / 10 volume of methyl acetate at 30°C for 3 times, the methyl acetate phases were combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product was 86.10%, the yield was 79.08%, and the purity of chenodeoxycholic acid was 75.13%, the yield was 83.57%.

[0063] Example 2

[0064] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 2 g / L. 1-ethyl-3-methylimidazolium acetate is used as an extractant, ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30°C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is retained from the first stage of the extraction section, and the extract and the raffinate are collected.

[0065] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 76.98%, the yield is 92.57%, and the purity of chenodeoxycholic acid is 89.12%, the yield is 83.56%. The ionic liquid phase after back-extraction is concentrated and can be recycled.

[0066] Example 3

[0067] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 2 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 10%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0068] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 96.66%, the yield is 99.74%, and the purity of chenodeoxycholic acid is 99.73%, the yield is 96.56%. The ionic liquid phase after back-extraction is concentrated and can be recycled.

[0069] Example 4

[0070] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in n-butanol to prepare a raw material liquid with a total concentration of 2 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 10%), n-butanol is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0071] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of n-butanol at 30°C, the n-butanol phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 83.24%, the yield is 73.46%, and the purity of chenodeoxycholic acid is 93.73%, the yield is 86.56%. The ionic liquid phase after back-extraction is concentrated and can be recycled.

[0072] Example 5

[0073] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 2 g / L. A 1-butyl-3-methylimidazole chloride-water mixed solvent is used as an extractant (the molar fraction of 1-butyl-3-methylimidazole chloride is 10%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0074] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 63.78%, the yield is 83.49%, and the purity of chenodeoxycholic acid is 82.52%, the yield is 76.18%. The ionic liquid phase after back extraction is concentrated and can be recycled.

[0075] Example 6

[0076] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 2 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 1%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0077] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 74.68%, the yield is 82.51%, and the purity of chenodeoxycholic acid is 89.87%, the yield is 81.06%. The ionic liquid phase after back-extraction is concentrated and can be recycled.

[0078] Example 7

[0079] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 2 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 5%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0080] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 89.70%, the yield is 89.38%, and the purity of chenodeoxycholic acid is 85.67%, the yield is 84.27%. The ionic liquid phase after back-extraction is concentrated and can be recycled.

[0081] Example 8

[0082] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 2 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 15%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 0.5:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0083] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is back-extracted three times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 94.83%, the yield is 92.40%, and the purity of chenodeoxycholic acid is 96.73%, the yield is 91.47%. The ionic liquid phase after back-extraction is concentrated and can be recycled.

[0084] Example 9

[0085] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 10 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 10%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 4:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0086] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 98.61%, the yield is 73.44%, and the purity of chenodeoxycholic acid is 78.84%, and the yield is 98.97%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0087] Example 10

[0088] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 10 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 5%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 4:3:1, and fractional distillation extraction is performed at 30° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0089] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 94.60%, the yield is 78.07%, and the purity of chenodeoxycholic acid is 81.34%, the yield is 95.54%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0090] Embodiment 11

[0091] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in ethyl acetate to prepare a raw material liquid with a total concentration of 10 g / L. A 1-ethyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazolium acetate is 10%), ethyl acetate is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 4:3:1, and fractional distillation extraction is performed at 60° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is retained from the first stage of the extraction section, and the extract and the raffinate are collected.

[0092] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of ethyl acetate at 30°C, the ethyl acetate phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 90.05%, the yield is 86.19%, and the purity of chenodeoxycholic acid is 70.23%, the yield is 89.69%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0093] Example 12

[0094] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in isoamyl alcohol to prepare a raw material liquid with a total concentration of 15 g / L. A 1-ethyl-3-methylimidazole chloride-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-3-methylimidazole chloride is 10%), isoamyl alcohol is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 8:2.7:1, and fractional distillation extraction is carried out at 40° C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 4 stages, and the washing section has 4 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0095] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of isoamyl alcohol at 30°C, the isoamyl alcohol phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 97.38%, the yield is 83.57%, and the purity of chenodeoxycholic acid is 96.86%, the yield is 80.85%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0096] Embodiment 13

[0097] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 96%) is dissolved in n-hexanol to prepare a raw material liquid with a total concentration of 2 g / L. A 1-butyl-3-methylimidazolium acetate-water mixed solvent is used as an extractant (the molar fraction of 1-butyl-3-methylimidazolium acetate is 5%), n-hexanol is used as a detergent, and the flow ratio of the extractant, the detergent and the raw material liquid is 5:3.4:1. Fractional extraction is carried out at 50° C. The fractional extraction is divided into an extraction section and a washing section (the extraction section has 6 stages and the washing section has 4 stages). The extractant enters the fractional extraction system from the first stage of the extraction section, the raw material liquid enters the fractional extraction system from the last stage of the extraction section, the detergent enters the fractional extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0098] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of n-hexanol at 30°C, the n-hexanol phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 95.37%, the yield is 77.01%, and the purity of chenodeoxycholic acid is 98.51%, the yield is 79.72%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0099] Embodiment 14

[0100] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in 2-hexanol to prepare a raw material liquid with a total concentration of 5 g / L. An ethylpyridinium bromide-water mixed solvent is used as an extractant (the molar fraction of ethylpyridinium bromide is 15%), 2-hexanol is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 3.6:2:1, and fractional distillation extraction is performed at 45°C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages and the washing section has 3 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0101] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of 2-hexanol at 30°C, the 2-hexanol phase is combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 96.60%, the yield is 75.65%, and the purity of chenodeoxycholic acid is 99.13%, the yield is 78.90%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0102] Embodiment 15

[0103] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in n-heptanol to prepare a raw material liquid with a total concentration of 3 g / L. A 1-ethyl-1-methylpyrrole hydrogen sulfate-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-1-methylpyrrole hydrogen sulfate is 25%), n-heptanol is used as a detergent, and the flow ratio of the extractant, the detergent and the raw material liquid is 4.3:5:1. Fractional extraction is carried out at 50° C. The fractional extraction is divided into an extraction section and a washing section (the extraction section has 3 stages, and the washing section has 3 stages). The extractant enters the fractional extraction system from the first stage of the extraction section, the raw material liquid enters the fractional extraction system from the last stage of the extraction section, the detergent enters the fractional extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.

[0104] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of n-heptanol at 30°C, the n-heptanol phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 96.80%, the yield is 94.60%, and the purity of chenodeoxycholic acid is 95.72%, the yield is 96.88%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled and reused.

[0105] Example 16

[0106] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in isooctyl alcohol to prepare a raw material liquid with a total concentration of 5 g / L. A 1-ethyl-3-benzyl imidazole glycine salt-water mixed solvent is used as an extractant (the molar fraction of 1-ethyl-1-methylpyrrole hydrogen sulfate is 25%), and isooctyl alcohol is used as a detergent. The flow ratio of the extractant, the detergent and the raw material liquid is 5:7.8:1. Fractional extraction is carried out at 55° C. The fractional extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional extraction system from the first stage of the extraction section, the raw material liquid enters the fractional extraction system from the last stage of the extraction section, and the detergent enters the fractional extraction system from the first stage of the washing section. An extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, and a raffinate rich in chenodeoxycholic acid is retained from the first stage of the extraction section. The extract and the raffinate are collected.

[0107] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of isooctyl alcohol at 30°C, the isooctyl alcohol phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 99.22%, the yield is 84.06%, and the purity of chenodeoxycholic acid is 96.17%, the yield is 89.34%. The ionic liquid-water phase after back extraction is concentrated to increase the concentration of the ionic liquid, which can be recycled for reuse.

[0108] Comparative Example 1

[0109] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in n-butanol to prepare a raw material liquid with a total concentration of 10 g / L. Water is used as an extractant, n-butanol is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 5:3:1, and fractional distillation extraction is performed at 30°C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages, and the washing section has 5 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is retained from the first stage of the extraction section, and the extract and the raffinate are collected.

[0110] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted with 1 / 10 volume of n-butanol at 30°C for 3 times, the n-butanol phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 98.85%, the yield is 0.08%, and the purity of chenodeoxycholic acid is 57.82%, the yield is 97.53%.

[0111] Comparative Example 2

[0112] The raw material (the total mass percentage of hyodeoxycholic acid and chenodeoxycholic acid is 99%) is dissolved in n-heptane to prepare a raw material liquid with a total concentration of 0.5 g / L. Methanol is used as an extractant, n-heptane is used as a detergent, the flow ratio of the extractant, the detergent and the raw material liquid is 6:3:1, and fractional distillation extraction is performed at 30°C. The fractional distillation extraction is divided into an extraction section and a washing section (the extraction section has 5 stages and the washing section has 2 stages). The extractant enters the fractional distillation extraction system from the first stage of the extraction section, the raw material liquid enters the fractional distillation extraction system from the last stage of the extraction section, the detergent enters the fractional distillation extraction system from the first stage of the washing section, an extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, a raffinate rich in chenodeoxycholic acid is retained from the first stage of the extraction section, and the extract and the raffinate are collected.

[0113] The raffinate is vacuum concentrated, washed with water and dried to obtain chenodeoxycholic acid; the extract is diluted 10 times, back-extracted 3 times with 1 / 10 volume of n-heptane at 30°C, the n-heptane phases are combined, vacuum concentrated, washed with water and dried to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 55.32%, the yield is 98.65%, and the purity of chenodeoxycholic acid is 84.92%, the yield is 0.03%.

[0114] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. All technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A method for separating hyodeoxycholic acid and chenodeoxycholic acid, comprising fractionating and extracting a raw material solution containing hyodeoxycholic acid and chenodeoxycholic acid using an extractant containing an ionic liquid; The extractant is an ionic liquid or a mixture of an ionic liquid and a polar solvent; The molar fraction of the ionic liquid in the extractant is 1%-100%; The polar solvent is selected from at least one of water, methanol, ethanol, dimethyl sulfoxide, sulfolane, and N-methylpyrrolidone; The ionic liquid is composed of the following cations and anions freely combined: The cation of the ionic liquid is selected from at least one of imidazolium cation, pyridinium cation, quinolinium cation, isoquinolinium cation, benzimidazolium cation, piperidinium cation, and pyrrolidinium cation, and the cation is optionally substituted by one or more substituents selected from C1-C10 alkyl, C6-C20 aryl, hydroxyl, hydroxyethyl, amino, and carboxyl; The anion of the ionic liquid is selected from at least one of p-toluenesulfonate, thiocyanate, dicyanamide, tricyanomethane, tetracyanoborate, trifluoromethanesulfonate, sulfate, hydrogensulfate, nitrate, tetrafluoroborate, acetate, glycine, chloride, bromide, and iodide; In the fractional extraction, the flow ratio of the extractant, the detergent and the raw material liquid is (0.1-15):(1-10):1; The total concentration of hyodeoxycholic acid and chenodeoxycholic acid in the raw material solution is 0.5 g / L-20.0 g / L; The raw material liquid also includes a raw material solvent, and the raw material solvent is selected from C2-C10 ester solvents and C1-C10 alcohol solvents; in the fractional distillation extraction, the detergent is the same as the raw material solvent.

2. The method according to claim 1, characterized in that The molar fraction of the ionic liquid in the extractant is 1-90%.

3. The method according to claim 1, characterized in that The molar fraction of the ionic liquid in the extractant is 1-50%.

4. The method according to claim 1, characterized in that: The molar fraction of the ionic liquid in the extractant is 1-25%.

5. The method according to claim 1, characterized in that The molar fraction of the ionic liquid in the extractant is 5-25%.

6. The method according to claim 1, characterized in that The polar solvent is water.

7. The method according to claim 1, characterized in that The substituent is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and phenyl.

8. The method according to claim 1, characterized in that The ionic liquid is selected from at least one of 1-ethyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium chloride, 1-ethyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium acetate, ethylpyridinium bromide, 1-ethyl-1-methylpyrrole hydrogen sulfate, and 1-ethyl-3-benzylimidazolium glycinate.

9. The method according to any one of claims 1 to 8, characterized in that The method further comprises: Concentrating and drying the raffinate from the fractionation extraction to obtain chenodeoxycholic acid; and / or The extract obtained by the fractionation extraction is subjected to back extraction, and the back extraction phase is concentrated and dried to obtain hyodeoxycholic acid.

10. The method according to any one of claims 1 to 8, characterized in that The raw material solvent is selected from at least one of methyl acetate, ethyl acetate, butyl acetate, n-butanol, isobutanol, n-pentanol, isopentanol, n-hexanol, 2-hexanol, n-heptanol and isooctyl alcohol.

11. The method according to any one of claims 1 to 8, characterized in that The operating temperature of the fractional extraction is 20°C-70°C.

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