CN116375784A - Method for separating hyodeoxycholic acid and chenodeoxycholic acid - Google Patents

Method for separating hyodeoxycholic acid and chenodeoxycholic acid Download PDF

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CN116375784A
CN116375784A CN202310267180.9A CN202310267180A CN116375784A CN 116375784 A CN116375784 A CN 116375784A CN 202310267180 A CN202310267180 A CN 202310267180A CN 116375784 A CN116375784 A CN 116375784A
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acid
extraction
extractant
chenodeoxycholic acid
raw material
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鲍宗必
丁泽相
曹义风
陈俐吭
杨启炜
刘宝鉴
张治国
任其龙
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Zhejiang University ZJU
Quzhou Research Institute of Zhejiang University
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Zhejiang University ZJU
Quzhou Research Institute of Zhejiang University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

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Abstract

The invention provides a method for separating hyodeoxycholic acid and chenodeoxycholic acid. The method comprises the step of fractional extraction of raw material liquid containing hyodeoxycholic acid and chenodeoxycholic acid by using an extractant containing ionic liquid and/or polar solvent. The method has the advantages of good stability, high separation selectivity, simple process, easy amplification, safety and environmental protection, and is suitable for industrial production.

Description

Method for separating hyodeoxycholic acid and chenodeoxycholic acid
Technical Field
The invention relates to the technical field of chemical separation, in particular to a method for separating hyodeoxycholic acid and chenodeoxycholic acid.
Background
Chenodeoxycholic acid, also called 3 alpha, 7 alpha-dihydroxyl-5 beta cholanic acid, is white needle-like crystal, is the main bile acid contained in animal bile, belongs to primary bile acid with cholic acid in human body, has the effects of dissolving cholesterol gall-stone in human body, relieving cough and asthma, resisting bacteria and inflammation, and the like, and can also be used as a precursor for synthesizing another important prodrug-ursodeoxycholic acid; hyodeoxycholic acid is a cholanic acid extracted from pig bile, can inhibit the formation of cholic acid, dissolve fat, reduce cholesterol in blood, and can be directly taken as hyodeoxycholic acid tablet, and is also the main component of traditional Chinese patent medicines such as qingkailing and Huochan tablet. In vitro experiments prove that the hyodeoxycholic acid can exert pharmacological activities such as inducing apoptosis and the like. Besides the medical effect, the hyodeoxycholic acid can also be used as a raw material, and chenodeoxycholic acid and ursodeoxycholic acid can be obtained through catalytic stereo synthesis. Therefore, the hyodeoxycholic acid and the chenodeoxycholic acid have wide application prospect.
Figure BDA0004133642040000011
The main components of pig bile are hyodeoxycholic acid and chenodeoxycholic acid, wherein the hyodeoxycholic acid contains about 40% and the chenodeoxycholic acid contains about 25%. Compared with chemical synthesis methods, the method for separating and purifying the hyodeoxycholic acid and the chenodeoxycholic acid from the pig bile extract has the advantages of low cost and high economic benefit, and the like. However, hyodeoxycholic acid and chenodeoxycholic acid are isomers, and the structural difference is only that the positions of hydroxyl groups on steroid cores are different, and the physical and chemical properties are very similar, so that the separation of the hyodeoxycholic acid and the chenodeoxycholic acid is very challenging.
Most of the existing methods for separating hyodeoxycholic acid from chenodeoxycholic acid are precipitation methods. Canadian patent P1041479 adopts a methyl esterification-complexation precipitation method to separate hyodeoxycholic acid and chenodeoxycholic acid: firstly, methyl esterifying mixed pig bile acid under the catalysis of sulfuric acid, then precipitating and separating the mixed pig bile acid from chenodeoxycholic acid methyl ester by utilizing the property that a complex formed by the chenodeoxycholic acid methyl ester and benzene is insoluble in benzene, and finally, crystallizing after respectively carrying out demethylation on mother liquor and complex precipitate to obtain chenodeoxycholic acid and a chenodeoxycholic acid product. However, this method requires benzene with high toxicity, which is liable to cause environmental pollution and human health problems, and the process is complicated. Direct precipitation to extract chenodeoxycholic acid is also reported. Research (Wang Youtong, wu Wenjun. Preparation of chenodeoxycholic acid. Jiangsu agricultural science, 1986 (08): 39-40) utilizes the principle that chenodeoxycholic acid is easier to form a precipitate with barium salt than hyodeoxycholic acid, and after adding barium chloride into the amanita solution for precipitation, ethyl acetate is used for recrystallization to obtain chenodeoxycholic acid product; however, barium salt is a heavy metal which is harmful to health and is not suitable for the large-scale production process of chenodeoxycholic acid. There is also a study (Pan Xianjun, zhang Xiaomei. Novel process for separating and purifying chenodeoxycholic acid from pig gall paste. Hebei medicine, 2006 (02): 147-148.) uses calcium chloride instead of barium chloride, and chenodeoxycholic acid is separated and purified by calcium salt precipitation, which solves the toxicity problem, but the whole process yield is only 2.6%, and the economic benefit is low. It can be seen that there is a need to develop a method for economically and efficiently separating hyodeoxycholic acid from chenodeoxycholic acid.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a method for separating high-purity hyodeoxycholic acid and chenodeoxycholic acid from a mixture containing hyodeoxycholic acid and chenodeoxycholic acid by using a polar solvent, an ionic liquid or an ionic liquid-polar solvent mixed solution as an extracting agent through multistage fractional extraction. Compared with the reported precipitation separation method, the extraction method adopted by the invention has better stability and higher separation selectivity, has the characteristics of simple process, safe process, easy amplification, environmental protection and the like, and is suitable for industrial production.
In order to achieve the above object, the present invention provides a method for separating hyodeoxycholic acid from chenodeoxycholic acid, comprising fractional extraction of a raw material liquid containing hyodeoxycholic acid and chenodeoxycholic acid with an extractant containing an ionic liquid and/or a polar solvent.
Hyodeoxycholic acid and chenodeoxycholic acid are a pair of isomers, and the structural difference is only the difference of the positions of the steroid nucleus hydroxyl groups. Hyodeoxycholic acid has a hydroxyl group at the C-6 position and chenodeoxycholic acid has a hydroxyl group at the C-7 position, which results in intermolecular differences in swine/chenodeoxycholic acid, intermolecular sites of action of separation medium with hyodeoxycholic acid and chenodeoxycholic acid, and intensity. The inventor researches and discovers that the separation selectivity can be improved by adopting an extractant with a certain hydrogen bond interaction capability and through the interaction force site and strength difference of the extractant and the extractant. In the present invention, an ionic liquid or a mixed liquid of an ionic liquid and a polar solvent is preferably used as the extractant.
In some preferred embodiments, the extractant includes an ionic liquid and a polar solvent.
In some preferred embodiments, the extractant is a mixture of an ionic liquid and a polar solvent.
In some embodiments, the molar fraction of ionic liquid in the extractant is 0.1% -100%, e.g., 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%. The ionic liquid is added into the polar solvent, so that the hyodeoxycholic acid and the chenodeoxycholic acid have proper partition coefficients and higher separation selectivity.
In some embodiments, the polar solvent comprises at least one of water, an alcohol, a sulfone, a sulfoxide, a nitrile, a ketone, an amide. Preferably, the polar solvent comprises at least one of water, methanol, ethanol, ethylene glycol, 1, 3-propylene glycol, polyethylene glycol, dimethyl sulfoxide, sulfolane, acetonitrile, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide.
In some more preferred embodiments, the extractant is a mixture of an ionic liquid and water.
In some embodiments, the ionic liquid consists of a cation and an anion, wherein the cation is selected from at least one of an imidazole cation, a pyridine cation, a quinoline cation, an isoquinoline cation, a benzimidazole cation, a piperidine cation, a pyrrolidine cation.
Optionally, the cation is substituted with one or more substituents selected from the group consisting of C1-C10 alkyl, C1-C10 alkenyl, C6-C20 aryl, hydroxy, 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.
When the number of the substituents is plural, the plural substituents may be the same or different.
In the present invention, the cation of the ionic liquid preferably contains one or more substituents.
In some embodiments, the anion is selected from at least one of p-toluenesulfonate, thiocyanate, dicyandiamide, tricyanomethane, tetracyanoborate, trifluoromethanesulfonate, sulfate, hydrogen sulfate, nitrate, tetrafluoroborate, acetate, glycinate, chloride, bromide, iodide.
In some embodiments, the ionic liquid is selected from at least one of 1-ethyl-3-methylimidazole acetate, 1-butyl-3-methylimidazole chloride, 1-ethyl-3-methylimidazole chloride, 1-butyl-3-methylimidazole acetate, ethylpyridine bromide, 1-ethyl-1-methylpyrrolidine bisulfate, 1-ethyl-3-benzylimidazole glycinate.
In some embodiments, the method further comprises: concentrating and drying the raffinate obtained by fractional extraction to obtain chenodeoxycholic acid. In some embodiments, the fractionated extracted raffinate is concentrated in vacuo, washed with water, and dried to yield chenodeoxycholic acid.
In some embodiments, the method further comprises: and (3) back-extracting the extract liquid of the fractional extraction, and concentrating and drying the back-extracted phase to obtain hyodeoxycholic acid. In some embodiments, the extractive solution of the fractional extraction is back-extracted, and the back-extracted phase is vacuum concentrated, water washed and dried to obtain hyodeoxycholic acid.
In some embodiments, the flow ratio of extractant, detergent, and feed solution in the fractional extraction is preferably (0.1-15): 1-10): 1, more preferably (0.5-10): 1, taking into account factors such as product quality, production cost, etc.
In some embodiments, the total concentration of hyodeoxycholic acid and chenodeoxycholic acid in the feedstock is from 0.5g/L to 20.0g/L, such as 0.5g/L, 1g/L, 5g/L, 10g/L, 15g/L, 20g/L, or any value therebetween. If the concentration of the raw material liquid is too high, the effective separation of hyodeoxycholic acid and chenodeoxycholic acid is not facilitated; if the concentration of the raw material liquid is too low, the raw material treatment capacity is small, the solvent loss is large, and the process economy is not facilitated.
In some embodiments, the raw material liquid further comprises a raw material solvent, preferably, the raw material liquid is composed of raw materials to be separated and the raw material solvent containing hyodeoxycholic acid and chenodeoxycholic acid.
Preferably, the total weight percentage of hyodeoxycholic acid and chenodeoxycholic acid in the raw materials is more than 60%. The raw materials to be separated can be purchased directly from the market, and can also be obtained from the steps of dissolving, extracting, precipitating and the like of pig bile or other poultry bile, so as to obtain the raw materials with the total mass percent of hyodeoxycholic acid and chenodeoxycholic acid of more than 60%. The raw materials mainly comprise hyodeoxycholic acid and chenodeoxycholic acid, and further comprise hyodeoxycholic acid, chenodeoxycholic acid, cholic acid, ursodeoxycholic acid and the like.
Preferably, the raw material solvent is selected from the group consisting of C2-C10 ester solvents, C1-C10 alcohol solvents, and C3-C10 ketone solvents. More preferably, the raw material solvent is selected from the group consisting of C2-C10 ester solvents.
The C2-C10 ester solvents of the present invention include, but are not limited to, methyl acetate, ethyl acetate, butyl acetate, and the like.
The C1-C10 alcohol solvents of the present invention include, but are not limited to, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, n-hexanol, 2-hexanol, n-heptanol, isooctanol, and the like.
The C3-C10 ketone solvents of the present invention include, but are not limited to, hexanone, cyclohexanone, and the like.
In some preferred embodiments, the feed solvent comprises ethyl acetate and the extractant comprises an ionic liquid and a polar solvent.
In some more preferred embodiments, the feed solvent comprises ethyl acetate and the extractant comprises an ionic liquid and water.
In some preferred embodiments, the feed solvent comprises methyl acetate and the extractant comprises a polar solvent.
In some more preferred embodiments, the feed solvent comprises methyl acetate and the extractant comprises water.
In some embodiments, the washing agent is selected from at least one of a C2-C10 ester solvent, a C2-C10 alcohol solvent, or a C2-C10 ketone solvent, preferably methyl acetate, ethyl acetate, butyl acetate, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, n-hexanol, 2-hexanol, n-heptanol, isooctanol, hexanone, cyclohexanone.
In some preferred embodiments, the detergent is the same as the raw material solvent. In the invention, the solvents in the detergent and the raw material liquid are the same solvents, so that the detergent and the raw material liquid have better dissolving capacity to the raw materials, and can form a liquid-liquid two-phase system with smaller mutual solubility with the extractant, thereby realizing better separation effect.
In some embodiments, the fractionation extraction is operated at a temperature of 20 ℃ to 70 ℃, such as 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, or any value therebetween. If the temperature is too low, the viscosity of the extractant is larger, the mass transfer rate is reduced, the treatment capacity is small, and the production operation is not facilitated; if the temperature is too high, the solvent is severely volatilized, which may reduce the partition ratio and selectivity of the fractional extraction.
The fractional extraction of the invention is carried out by adopting the existing fractional extraction equipment.
In some embodiments, the fractional extraction is a multi-stage fractional extraction.
In some embodiments, the fractional extraction comprises an extraction section and a washing section. The extraction agent enters a fractionation extraction system from the first stage of the extraction section, the raw material liquid enters the fractionation extraction system from the last stage of the extraction section, the washing agent enters the fractionation extraction system from the first stage of the washing section, the raw material liquid is combined at the last stage of the extraction section and enters the extraction section together, the raffinate which is enriched in chenodeoxycholic acid flows out of the first stage of the extraction section through multi-stage countercurrent contact, the raffinate is collected, and the chenodeoxycholic acid product is obtained through vacuum concentration, water washing and drying. And (3) flowing out an extract enriched in hyodeoxycholic acid from the first stage of the washing section, and carrying out vacuum concentration, water washing and drying to obtain a hyodeoxycholic acid product.
In some embodiments, the method comprises the steps of:
(1) Preparing a raw material liquid from a mixture containing hyodeoxycholic acid and chenodeoxycholic acid and a raw material solvent, and performing fractional extraction by taking ionic liquid and/or polar solvent as an extractant and taking the raw material solvent as a detergent; the fractionation extraction is divided into an extraction section and a washing section, wherein an extracting agent enters an extraction system from the first stage of the extraction section, a raw material liquid enters the extraction system from the last stage of the extraction section, a washing agent enters the extraction system from the first stage of the washing section, a 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 multistage countercurrent contact, a raffinate enriched in chenodeoxycholic acid flows out of the first stage of the extraction section, and an extract enriched in hyodeoxycholic acid flows out of the first stage of the washing section;
(2) Concentrating, washing and drying the raffinate obtained in the step (1) in vacuum to obtain chenodeoxycholic acid; and (3) carrying out back extraction on the extract liquid obtained in the step (1) by using an ester or alcohol solvent, and carrying out vacuum concentration, water washing and drying on an extract phase to obtain the hyodeoxycholic acid.
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.
The invention has the advantages that:
1. the method adopts a fractional extraction method, selects a proper extractant, has higher selective separation capability on the hyodeoxycholic acid and chenodeoxycholic acid system, and simultaneously the adopted extractant not only can be recycled, reduces the production cost, but also is more environment-friendly, has less pollution to the environment and has wide application prospect.
2. The invention adopts the fractional extraction technology, and has the advantages of low consumption of chemical raw materials, high productivity and low cost.
3. The purity of the hyodeoxycholic acid and the chenodeoxycholic acid obtained after separation can reach more than 95% and the recovery rate can reach more than 70% through optimizing the fractionation extraction conditions.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way.
The invention aims to provide a method for separating hyodeoxycholic acid from chenodeoxycholic acid, which is environment-friendly, simple in process and high in efficiency. The method adopts ionic liquid, polar solvent or mixed liquid of ionic liquid and polar solvent as extractant, and has good separation effect on hyodeoxycholic acid and chenodeoxycholic acid.
The polar solvent in the invention can be water, dimethyl sulfoxide, sulfolane and other solvents, and has separation effect on hyodeoxycholic acid and chenodeoxycholic acid. If pure ionic liquid is used as an extractant, the ionic liquid has the defects of high viscosity, high dosage, solid even some ionic liquids at normal temperature and the like, so that a third solvent is required to be added. The added third solvent has good mutual solubility with the ionic liquid, can form a two-phase system with the raw material solvent, and can accurately adjust the property of the extractant so as to achieve the purposes of improving the mass transfer rate and improving the separation effect.
The invention preferably adopts a hydrophobic organic solvent as a hyodeoxycholic acid-chenodeoxycholic acid raw material solvent and a detergent.
For raw materials of hyodeoxycholic acid and chenodeoxycholic acid, ethyl acetate is used as a solvent, aqueous solution of 1-ethyl-3-methylimidazole acetate with the mole percentage of 10% is used as an extractant, single-stage extraction is carried out at the temperature of 30 ℃, and the partition coefficients of the hyodeoxycholic acid and the chenodeoxycholic acid are respectively 2.417 and 0.742, and the selectivity is 3.26. Single-stage extraction experiments show that ionic liquid molecules with hydrogen bond alkalinity have stronger interaction with hyodeoxycholic acid, and can achieve higher selectivity for separating isomers.
Based on the above, the invention provides a method for separating hyodeoxycholic acid and chenodeoxycholic acid with higher purity from hyodeoxycholic acid-chenodeoxycholic acid raw material liquid by using an extracting agent containing ionic liquid and/or polar solvent through multistage fractional extraction.
In the following examples of the present invention, the concentrations of hyodeoxycholic acid and chenodeoxycholic acid monomers were analyzed by high performance liquid chromatography, and the specific analysis conditions by HPLC were: c18 column (4.8 mm. Times.250 mm, particle size 5 μm, agilent), column temperature 30 ℃, mobile phase methanol: acetonitrile: 0.1vol% formic acid aqueous solution=63:17:20 (v/v/v), flow rate 0.8mL/min, detector was an electrospray detector (Thermo Fisher).
The method for calculating the yield and purity in the invention comprises the following steps:
hyodeoxycholic acid yield = weight of hyodeoxycholic acid in product/weight of hyodeoxycholic acid in raw material x 100%;
chenodeoxycholic acid yield = weight of chenodeoxycholic acid in product/weight of chenodeoxycholic acid in raw material x 100%;
absolute purity of hyodeoxycholic acid = mass of hyodeoxycholic acid in product/total mass of product x 100%;
absolute purity of chenodeoxycholic acid = mass of chenodeoxycholic acid in product/total mass of product x 100%.
Example 1
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in methyl acetate to prepare raw material liquid with the total concentration of 5 g/L. The method comprises the steps of taking water as an extractant, taking methyl acetate as a detergent, carrying out fractional extraction at 30 ℃ with the flow ratio of the extractant, the detergent and raw material liquid being 3:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 20 stages), the extractant enters a 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 extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of methyl acetate at 30deg.C for 3 times, mixing methyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 86.10%, the yield is 79.08%, the purity of chenodeoxycholic acid is 75.13%, and the yield is 83.57%.
Example 2
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking 1-ethyl-3-methylimidazole acetate as an extractant, taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ with the flow ratio of the extractant to the detergent to the raw material liquid being 0.5:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages in total, the washing section is 5 stages in total), the extractant enters a 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 extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extract with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 76.98%, the yield is 92.57%, the purity of chenodeoxycholic acid is 89.12%, and the yield is 83.56%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 3
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 10%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 0.5:3:1, enabling the fractional extraction to be divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), enabling the extractant to enter a fractional extraction system from the first stage of the extraction section, enabling the raw material liquid to enter the fractional extraction system from the last stage of the extraction section, enabling the detergent to enter the fractional extraction system from the first stage of the washing section, enabling the extract liquid rich in hyodeoxycholic acid to flow out from the first stage of the washing section, reserving the raffinate rich in chenodeoxycholic acid from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extract with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 96.66%, the yield is 99.74%, the purity of chenodeoxycholic acid is 99.73%, and the yield is 96.56%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 4
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in n-butyl alcohol to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 10%), taking n-butanol as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant to the detergent to the raw material liquid of 0.5:3:1, enabling the fractional extraction to be divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), enabling the extractant to enter a fractional extraction system from the first stage of the extraction section, enabling the raw material liquid to enter the fractional extraction system from the last stage of the extraction section, enabling the detergent to enter the fractional extraction system from the first stage of the washing section, enabling the extract liquid rich in hyodeoxycholic acid to flow out from the first stage of the washing section, reserving the raffinate rich in chenodeoxycholic acid from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extractive solution with 1/10 volume of n-butanol at 30deg.C for 3 times, mixing n-butanol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 83.24%, the yield is 73.46%, the purity of chenodeoxycholic acid is 93.73%, and the yield is 86.56%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 5
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a mixed solvent of 1-butyl-3-methylimidazole chloride and water as an extractant (the mole fraction of the 1-butyl-3-methylimidazole chloride is 10%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant to the detergent to the raw material liquid of 0.5:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extract with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 63.78%, the yield is 83.49%, the purity of chenodeoxycholic acid is 82.52%, and the yield is 76.18%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 6
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 1%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 0.5:3:1, enabling the fractional extraction to be divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), enabling the extractant to enter a fractional extraction system from the first stage of the extraction section, enabling the raw material liquid to enter the fractional extraction system from the last stage of the extraction section, enabling the detergent to enter the fractional extraction system from the first stage of the washing section, enabling the extract liquid rich in hyodeoxycholic acid to flow out from the first stage of the washing section, reserving the raffinate rich in chenodeoxycholic acid from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extract with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 74.68%, the yield is 82.51%, the purity of chenodeoxycholic acid is 89.87%, and the yield is 81.06%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 7
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 5%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 0.5:3:1, enabling the fractional extraction to be divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), enabling the extractant to enter a fractional extraction system from the first stage of the extraction section, enabling the raw material liquid to enter the fractional extraction system from the last stage of the extraction section, enabling the detergent to enter the fractional extraction system from the first stage of the washing section, enabling the extract liquid rich in hyodeoxycholic acid to flow out from the first stage of the washing section, reserving the raffinate rich in chenodeoxycholic acid from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extract with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 89.70%, the yield is 89.38%, the purity of chenodeoxycholic acid is 85.67%, and the yield is 84.27%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 8
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 15%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 0.5:3:1, enabling the fractional extraction to be divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), enabling the extractant to enter a fractional extraction system from the first stage of the extraction section, enabling the raw material liquid to enter the fractional extraction system from the last stage of the extraction section, enabling the detergent to enter the fractional extraction system from the first stage of the washing section, enabling the extract liquid rich in hyodeoxycholic acid to flow out from the first stage of the washing section, reserving the raffinate rich in chenodeoxycholic acid from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; back-extracting the extract with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 94.83%, the yield is 92.40%, the purity of chenodeoxycholic acid is 96.73%, and the yield is 91.47%. The ion liquid phase after back extraction is concentrated and can be recycled.
Example 9
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 10 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 10%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 4:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (5 stages are added in the extraction section and 5 stages are added in the washing section), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 98.61%, the yield is 73.44%, the purity of chenodeoxycholic acid is 78.84%, and the yield is 98.97%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 10
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 10 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 5%), taking ethyl acetate as a detergent, carrying out fractional extraction at 30 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 4:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 94.60%, the yield is 78.07%, the purity of chenodeoxycholic acid is 81.34%, and the yield is 95.54%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 11
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in ethyl acetate to prepare raw material liquid with the total concentration of 10 g/L. The method comprises the steps of taking a 1-ethyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-3-methylimidazole acetate is 10%), taking ethyl acetate as a detergent, carrying out fractional extraction at 60 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 4:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of ethyl acetate at 30deg.C for 3 times, mixing ethyl acetate phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 90.05%, the yield is 86.19%, the purity of chenodeoxycholic acid is 70.23%, and the yield is 89.69%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 12
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in isoamyl alcohol to prepare raw material liquid with the total concentration of 15 g/L. The method comprises the steps of taking a chloridized 1-ethyl-3-methylimidazole-water mixed solvent as an extractant (the mole fraction of chloridized 1-ethyl-3-methylimidazole is 10%), taking isoamyl alcohol as a detergent, carrying out fractional extraction at 40 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 8:2.7:1, wherein the fractional extraction is divided into an extraction section and a washing section (4 extraction sections and 4 washing sections), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract liquid and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of isoamyl alcohol at 30deg.C for 3 times, mixing isoamyl alcohol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 97.38%, the yield is 83.57%, the purity of chenodeoxycholic acid is 96.86%, and the yield is 80.85%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 13
Raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 96%) are dissolved in n-hexanol to prepare raw material liquid with the total concentration of 2 g/L. The method comprises the steps of taking a 1-butyl-3-methylimidazole acetate-water mixed solvent as an extractant (the mole fraction of the 1-butyl-3-methylimidazole acetate is 5%), taking n-hexanol as a detergent, carrying out fractional extraction at 50 ℃ according to the flow ratio of the extractant to the detergent to the raw material liquid of 5:3.4:1, wherein the fractional extraction is divided into an extraction section and a washing section (6 stages are added in the extraction section and 4 stages are added in the washing section), the extractant enters a 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 extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of n-hexanol at 30deg.C for 3 times, mixing n-hexanol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 95.37%, the yield is 77.01%, the purity of chenodeoxycholic acid is 98.51%, and the yield is 79.72%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 14
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in 2-hexanol to prepare raw material liquid with the total concentration of 5 g/L. The method comprises the steps of taking an ethylpyridine bromide-water mixed solvent as an extractant (mole fraction of ethylpyridine bromide is 15%), taking 2-hexanol as a detergent, carrying out fractional extraction at 45 ℃ with the flow ratio of the extractant to the detergent to the raw material liquid being 3.6:2:1, fractionating the extract into an extraction section and a washing section (5 extraction sections and 3 washing sections), feeding the extractant into a fractional extraction system from the first extraction section, feeding the raw material liquid into the fractional extraction system from the last extraction section, feeding the detergent into the fractional extraction system from the first washing section, discharging the extract rich in hyodeoxycholic acid from the first washing section, leaving the raffinate rich in chenodeoxycholic acid from the first extraction section, and collecting the extract and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of 2-hexanol at 30deg.C for 3 times, mixing 2-hexanol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of the hyodeoxycholic acid in the product is 96.60%, the yield is 75.65%, the purity of the chenodeoxycholic acid is 99.13%, and the yield is 78.90%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 15
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in n-heptanol to prepare raw material liquid with the total concentration of 3 g/L. The method comprises the steps of taking a 1-ethyl-1-methylpyrrolidine bisulfate-water mixed solvent as an extractant (the mole fraction of the 1-ethyl-1-methylpyrrolidine bisulfate is 25%), taking n-heptanol as a detergent, carrying out fractional extraction at 50 ℃ according to the flow ratio of the extractant, the detergent and the raw material liquid of 4.3:5:1, wherein the fractional extraction is divided into an extraction section and a washing section (3 extraction sections and 3 washing sections), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract liquid and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extractive solution 10 times, back-extracting with 1/10 volume of n-heptanol at 30deg.C for 3 times, mixing n-heptanol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 96.80%, the yield is 94.60%, the purity of chenodeoxycholic acid is 95.72%, and the yield is 96.88%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Example 16
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in isooctanol to prepare raw material liquid with the total concentration of 5 g/L. The method comprises the steps of taking a 1-ethyl-3-phenylmethylimidazole glycinate-water mixed solvent as an extractant (the mole fraction of 1-ethyl-1-methylpyrrole bisulfate is 25%), taking isooctanol as a detergent, carrying out fractional extraction at 55 ℃ according to the flow ratio of the extractant to the detergent to the raw material liquid of 5:7.8:1, enabling the fractional extraction to be divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 5 stages), enabling the extractant to enter a fractional extraction system from the first stage of the extraction section, enabling the raw material liquid to enter the fractional extraction system from the last stage of the extraction section, enabling the detergent to enter the fractional extraction system from the first stage of the washing section, enabling the extract liquid rich in hyodeoxycholic acid to flow out from the first stage of the washing section, reserving raffinate rich in chenodeoxycholic acid from the first stage of the extraction section, and collecting the extract liquid and the raffinate.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of isooctanol at 30deg.C for 3 times, mixing isooctanol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 99.22%, the yield is 84.06%, the purity of chenodeoxycholic acid is 96.17%, and the yield is 89.34%. The ion liquid-water phase after back extraction is concentrated to improve the concentration of the ion liquid, and can be recycled.
Comparative example 1
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in n-butyl alcohol to prepare raw material liquid with the total concentration of 10 g/L. The method comprises the steps of taking water as an extractant, taking n-butanol as a detergent, carrying out fractional extraction at 30 ℃ with the flow ratio of the extractant, the detergent and raw material liquid being 5:3:1, wherein the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages, the washing section is 5 stages), the extractant enters a 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 extract rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extractive solution 10 times, back-extracting with 1/10 volume of n-butanol at 30deg.C for 3 times, mixing n-butanol phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of hyodeoxycholic acid in the product is 98.85%, the yield is 0.08%, the purity of chenodeoxycholic acid is 57.82%, and the yield is 97.53%.
Comparative example 2
The raw materials (the total mass percent of the hyodeoxycholic acid and the chenodeoxycholic acid is 99%) are dissolved in n-heptane to prepare raw material liquid with the 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, fractional extraction is carried out at 30 ℃, the fractional extraction is divided into an extraction section and a washing section (the extraction section is 5 stages and the washing section is 2 stages), the extractant enters a 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 extract liquid rich in hyodeoxycholic acid flows out from the first stage of the washing section, the raffinate rich in chenodeoxycholic acid is reserved from the first stage of the extraction section, and the extract liquid and the raffinate are collected.
Concentrating the raffinate in vacuum, washing with water and drying to obtain chenodeoxycholic acid; diluting the extract 10 times, back-extracting with 1/10 volume of n-heptane at 30deg.C for 3 times, mixing n-heptane phases, vacuum concentrating, washing with water, and drying to obtain hyodeoxycholic acid. The purity of the hyodeoxycholic acid in the product is 55.32%, the yield is 98.65%, the purity of the chenodeoxycholic acid is 84.92%, and the yield is 0.03%.
The technical scheme of the invention is not limited to the specific embodiment, and all technical modifications made according to the technical scheme of the invention fall within the protection scope of the invention.

Claims (10)

1. A method for separating hyodeoxycholic acid from chenodeoxycholic acid comprises fractional extraction of raw material liquid containing hyodeoxycholic acid and chenodeoxycholic acid with extractant containing ionic liquid and/or polar solvent.
2. The method of claim 1, wherein the extractant comprises an ionic liquid and a polar solvent;
preferably, the extractant is a mixed solution of ionic liquid and polar solvent;
preferably, the molar fraction of ionic liquid in the extractant is between 0.1% and 100%, preferably between 1 and 50%.
3. The method according to claim 1 or 2, wherein the polar solvent comprises at least one of water, alcohol, sulfone, sulfoxide, nitrile, ketone, amide, preferably at least one of water, methanol, ethanol, ethylene glycol, 1, 3-propanediol, polyethylene glycol, dimethyl sulfoxide, sulfolane, acetonitrile, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide.
4. A method according to any one of claims 1-3, wherein the cation of the ionic liquid is selected from at least one of an imidazole cation, a pyridine cation, a quinoline cation, an isoquinoline cation, a benzimidazole cation, a piperidine cation, a pyrrolidine cation, said cation being optionally substituted with one or more substituents, preferably said substituents are selected from C1-C10 alkyl, C1-C10 alkenyl, C6-C20 aryl, hydroxy, cyano, thiocyano, hydroxyethyl, sulfone, amino, carboxyl and carbonyl, more preferably said substituents are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and phenyl; and/or
The anion of the ionic liquid is selected from at least one of p-toluenesulfonate, thiocyanate, dicyandiamide, tricyanomethane, tetracyanoborate, trifluoromethanesulfonate, sulfate, hydrogen sulfate, nitrate, tetrafluoroborate, acetate, glycinate, chloride, bromide and iodide;
preferably, the ionic liquid is selected from at least one of 1-ethyl-3-methylimidazole acetate, 1-butyl-3-methylimidazole chloride, 1-ethyl-3-methylimidazole chloride, 1-butyl-3-methylimidazole acetate, ethylpyridine bromide, 1-ethyl-1-methylpyrole bisulfate and 1-ethyl-3-phenylmethylimidazole glycinate.
5. The method according to any one of claims 1-4, further comprising:
concentrating and drying the raffinate obtained by fractional extraction to obtain chenodeoxycholic acid; and/or
And (3) back-extracting the extract liquid of the fractional extraction, and concentrating and drying the back-extracted phase to obtain hyodeoxycholic acid.
6. The process according to any one of claims 1 to 5, wherein the fractional extraction has a flow ratio of extractant, detergent and feed solution of (0.1 to 15): 1 to 10): 1.
7. The method according to any one of claims 1 to 6, wherein the total concentration of hyodeoxycholic acid and chenodeoxycholic acid in the raw material liquid is 0.5g/L to 20.0g/L.
8. The method according to any one of claims 1 to 7, further comprising a raw material solvent, preferably selected from the group consisting of C2-C10 ester solvents, C1-C10 alcohol solvents and C3-C10 ketone solvents, preferably at least one of methyl acetate, ethyl acetate, butyl acetate, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, n-hexanol, 2-hexanol, n-heptanol, isooctanol, hexanol, cyclohexanone.
9. The process according to any one of claims 1 to 8, wherein in the fractional extraction, the detergent is selected from at least one of C2-C10 ester solvents, C1-C10 alcohol solvents or C3-C10 ketone solvents, preferably methyl acetate, ethyl acetate, butyl acetate, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, n-hexanol, 2-hexanol, n-heptanol, isooctanol, hexanol, cyclohexanone;
preferably, the detergent is the same as the raw material solvent.
10. The process according to any one of claims 1 to 9, wherein the fractional extraction is operated at a temperature of 20 ℃ to 70 ℃.
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