CN110256517B - Method for producing high-purity chenodeoxycholic acid from pig bile or leftovers - Google Patents
Method for producing high-purity chenodeoxycholic acid from pig bile or leftovers Download PDFInfo
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Abstract
The invention belongs to the technical field of fine chemical engineering and medicine, and particularly relates to a method for producing chenodeoxycholic acid from pig bile or leftovers. The process comprises the production processes of saponification, crystallization and impurity removal, salt formation of crystallization mother liquor, extraction, crystallization and the like, and the whole process is environment-friendly, safe and nontoxic, has low cost, is easy for industrial large-scale production of chenodeoxycholic acid, and has the content of more than or equal to 99%.
Description
Technical Field
The invention belongs to the technical field of fine chemical engineering and medicine, and particularly relates to a method for producing high-purity chenodeoxycholic acid from pig bile or leftovers.
Background
Chenodeoxycholic Acid (CDCA), i.e., 3 α, 7 α -dihydroxy-5 β -cholanic acid. Chenodeoxycholic acid is natural primary bile acid, is a steroid compound consisting of 24 carbon atoms in total, namely 1 rigid steroid ring and 1 fatty side chain, wherein the A ring and the B ring of the steroid nucleus are fused in cis to form a concave cavity, alpha hydroxyl groups on the 3-position and the 7-position in the molecule respectively point to the concave surface and form a hydrophilic alpha surface together with carboxyl on the side chain, and 3 methyl groups point to the other surface to form a hydrophobic beta surface, and has the characteristic of lipid/water amphiphilicity.
Chenodeoxycholic acid is a biochemical substance in animal body bile, and is natural primary bile acid. It is widely found in human, livestock and poultry bile. The Chinese medicinal composition is clinically used as a medicament for dissolving gallstones and correcting saturated bile, and also has the obvious effects of relieving asthma, resisting inflammation, relieving cough, reducing blood fat and eliminating phlegm. The choleretic action is particularly remarkable, cholesterol in bile is reduced by reducing the absorption and synthesis of cholesterol, so that the formation of cholesterol calculus is simulated, the dissolution of the cholesterol calculus is promoted, and the cholesterol saturation can be effectively reduced.
Chenodeoxycholic acid is also used as an intermediate for preparing ursodeoxycholic acid, which is a main component contained in famous and precious Chinese medicine bear gall and is clinically used for treating various biliary diseases and digestive tract diseases. At present, bile of traditional rare medicinal animals is comprehensively developed and utilized. Therefore, the preparation of the chenodeoxycholic acid is of great significance for further preparing the ursodeoxycholic acid.
Chenodeoxycholic acid is mainly extracted from poultry bile or animal bile, because the poultry bile, particularly goose bile is less in amount and is not easy to collect, people turn to the extraction from pig bile, particularly bilirubin or leftovers after the extraction of hyodeoxycholic acid, the traditional extraction and preparation process is complex, the yield is low, particularly the purity is not high, the purity is not high (high performance liquid chromatography), other substances (hyodeoxycholic acid, hyocholic acid and hyoketodeoxycholic acid is higher), and a large amount of unsafe organic reagents are used.
The prior art for producing hyodeoxycholic acid mainly comprises the following steps:
1. although the silica gel column chromatography can obtain high-purity chenodeoxycholic acid (more than 98%), the product yield is low, the productivity is low, the solvent consumption is large, and the method is not suitable for industrial mass production;
2. the synthesis method generally uses high-purity cholic acid as a raw material, but the price of the cholic acid in China is higher than that of chenodeoxycholic acid at present, the synthesis route is complicated, and the industrial value is not high;
3. chenodeoxycholic acid prepared by methyl esterification and acetylation derivatization can obtain high-content CDCA, but the yield is low, toxic reagents such as acetic anhydride and hexane are used, industrialization can be realized, but the method is not particularly friendly to the environment.
Chinese patent application CN1775798A discloses a method for producing high-purity chenodeoxycholic acid from livestock bile by a macroporous resin method, and Chinese patent application CN1830996A discloses a method for preparing chenodeoxycholic acid by a barium salt method.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for producing high-purity chenodeoxycholic acid from pig bile or leftovers. The method has the advantages of simple process, low pollution, high product yield and high purity.
In order to achieve the above purpose, the invention provides the following technical scheme:
a method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking bilirubin leftovers or pig bile, adding alkali and water, performing saponification reaction, cooling, standing for layering, siphoning out supernatant, discarding, taking out lower-layer paste, adding water for dissolving, acidifying until Congo red test paper turns blue, adding ethyl acetate, stirring for extraction, and standing for layering; washing ethyl acetate phase with water until pH of water phase is 6-7, adding anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing, filtering, concentrating, precipitating, cooling, filtering or squeezing, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholic acid amine salt: adding a solvent into the filtrate obtained after filtration in the step (1), slowly adding an organic alkali reagent, stirring, cooling, precipitating a large amount of precipitate, filtering, and drying to obtain a chenodeoxycholic acid amine salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking a chenodeoxycholic acid amine salt crude product, adding ethyl acetate, dropwise adding hydrochloric acid while stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) and (3) concentrating the ethyl acetate phase in vacuum, adding dichloromethane, cooling, stirring, crystallizing, filtering and drying to obtain a chenodeoxycholic acid final product.
Preferably, in step (1), the base is sodium hydroxide or potassium hydroxide;
preferably, in the step (1), the using amount of the alkali is 3% -50% of that of the bilirubin leftovers or the pig bile;
preferably, in the step (1), the dosage of the water added in the saponification reaction is 0.2-3 times of the dosage of the bilirubin leftovers or the pig bile;
preferably, in the step (1), the saponification temperature is 95-100 ℃;
preferably, in the step (1), the saponification time is 16-24 h;
preferably, in the step (1), the amount of water used for dissolving by adding water is the same as the amount of water added in the saponification reaction;
preferably, in the step (1), the reagent for acidification is concentrated hydrochloric acid or 30-60% sulfuric acid;
preferably, the sulfuric acid is 50% sulfuric acid.
Preferably, in the step (1), the amount of the ethyl acetate is 3-5 times of the added water amount of the lower-layer paste;
preferably, in the step (1), the extraction time is 20min-1 h;
preferably, in step (1), the concentrated volume is 1/10-1/3 of ethyl acetate added volume;
preferably, in the step (1), the temperature is reduced to 0-5 ℃;
preferably, in step (2), the solvent is an alkane or an alcohol;
preferably, in the step (2), the solvent is at least one of dichloromethane, dichloroethane, methanol, tert-butyl alcohol, ethanol and sec-butyl alcohol;
preferably, in the step (2), the solvent is used in an amount required to completely dissolve the crude hyodeoxycholic acid;
preferably, in the step (2), the stirring time is 1-3 h;
preferably, in the step (2), the temperature is reduced to 0-5 ℃;
preferably, in the step (2), the organic base reagent is at least one of triethylamine, methylamine, diethylamine, propylamine, tert-butylamine or sec-butylamine, aniline;
preferably, in the step (2), the amount of the organic alkali reagent is 1.1-1.5 times of the weight of the crude hyodeoxycholic acid product.
Preferably, in step (4), the ethyl acetate phase is concentrated to its added volume of 1/4-3/4;
preferably, in the step (4), the volume ratio of the dichloromethane to the ethyl acetate phase is 1: 1-3, preferably 1: 1.
compared with the prior art, the invention has the following technical advantages:
(1) the method utilizes an amine salt method to remove hyocholic acid, hyoketodeoxycholic acid, hyodeoxycholic acid, non-cholic acid impurities and the like in the chenodeoxycholic acid to obtain the high-purity chenodeoxycholic acid amine salt, wherein the yield of the prepared chenodeoxycholic acid product is higher than 85%, and the purity is higher than 99%; the product quality is better;
(2) the solvent used in the method is mainly alkane or alcohol solvent, and compared with the prior art, the yield and purity of the chenodeoxycholic acid product can be effectively improved;
(3) the production process is simple to operate and easy for industrial mass production.
Detailed Description
Example 1
A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking 200g of bilirubin leftovers, adding 60g of sodium hydroxide and 400ml of water, carrying out saponification reaction at 95 ℃ for 16h, cooling, standing, siphoning out supernatant, discarding, adding 400ml of water into lower-layer paste, stirring for dissolving, adding concentrated hydrochloric acid for acidification until Congo red test paper turns blue, adding 1600ml of ethyl acetate, stirring for extraction for 30min, standing and layering; washing ethyl acetate phase with water until pH of water phase is 6, adding 20g anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing for 30min 10g, filtering, concentrating to 320ml (1/5 volume), precipitating, cooling to 0 deg.C, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholic acid amine salt: taking the filtrate filtered in the step (1), adding 320ml of dichloromethane, slowly adding triethylamine with the weight being 1.3 times (calculated by the hyodeoxycholic acid crude product) in a flowing manner, stirring, cooling to 0 ℃, precipitating a large amount of precipitates, filtering, and drying to obtain a chenodeoxycholic acid amine salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking the chenodeoxycholic acid amine salt crude product, adding 400ml of ethyl acetate, dropwise adding 24ml of hydrochloric acid (1:1) under stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) and (3) concentrating the ethyl acetate phase in vacuum to 200ml (1/2 vol), adding dichloromethane with the same volume, cooling, stirring, crystallizing, filtering and drying to obtain a chenodeoxycholic acid final product with the yield of 86.7% and the purity of 99.5%.
Example 2
A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking 1000ml of pig bile, adding 30g of potassium hydroxide and 200ml of water, carrying out saponification reaction at 97 ℃ for 20h, cooling, standing, siphoning out supernatant, discarding, adding 200ml of water into lower-layer paste, stirring for dissolving, adding 50% sulfuric acid for acidification until Congo red test paper turns blue, adding 600ml of ethyl acetate, stirring for extraction for 1h, standing for layering; washing ethyl acetate phase with water until pH of water phase is 6.5, adding 20g anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing for 30min 10g, filtering, concentrating to 200ml (1/3 volume), precipitating, cooling to 5 deg.C, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholic acid amine salt: taking the filtrate filtered in the step (1), adding 300ml of tert-butyl alcohol, slowly adding 1.1 times of propylamine by weight, stirring, cooling to 5 ℃, precipitating a large amount of precipitate, filtering, and drying to obtain a chenodeoxycholic acid amine salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking the chenodeoxycholic acid amine salt crude product, adding 400ml of ethyl acetate, dropwise adding 24ml of hydrochloric acid (1:1) under stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) and (3) concentrating the ethyl acetate phase in vacuum to 300ml (3/4 vol), adding 1/2 vol of dichloromethane, cooling, stirring, crystallizing, filtering and drying to obtain the chenodeoxycholic acid final product, wherein the yield is 86.3 percent and the purity is 99.2 percent.
Example 3
A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking 200g of bilirubin leftovers, adding 100g of potassium hydroxide and 600ml of water, carrying out pressurized saponification reaction at 100 ℃ for 24h, cooling, standing, siphoning out supernatant, discarding, adding 600ml of water into lower-layer paste, stirring for dissolving, adding 50% sulfuric acid for acidification until Congo red test paper turns blue, adding 3000ml of ethyl acetate, stirring for extraction for 20min, standing and layering; washing ethyl acetate phase with water until pH of water phase is 7, adding 20g anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing for 30min 10g, filtering, concentrating to 300ml (1/10), precipitating, cooling to 3 deg.C, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholic acid amine salt: taking the filtrate filtered in the step (1), adding 400ml of ethanol, slowly adding 1.5 times of tert-butylamine by weight, stirring, cooling to 2 ℃, precipitating a large amount of precipitates, filtering, and drying to obtain a chenodeoxycholic acid amine salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking the chenodeoxycholic acid amine salt crude product, adding 400ml of ethyl acetate, dropwise adding 24ml of hydrochloric acid (1:1) under stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) and (3) concentrating the ethyl acetate phase in vacuum to 100ml (1/4 vol), adding 1/3 vol of dichloromethane, cooling, stirring, crystallizing, filtering and drying to obtain the chenodeoxycholic acid final product, wherein the yield is 85.6 percent and the purity is 99.4 percent.
Comparative example 1 (No dichloromethane in step (4) in comparison with example 1)
A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking 200g of bilirubin leftovers, adding 60g of sodium hydroxide and 400ml of water, carrying out saponification reaction at 95 ℃ for 16h, cooling, standing, siphoning out supernatant, discarding, adding 400ml of water into lower-layer paste, stirring for dissolving, adding concentrated hydrochloric acid for acidification until Congo red test paper turns blue, adding 1600ml of ethyl acetate, stirring for extraction for 30min, standing and layering; washing ethyl acetate phase with water until pH of the water phase is 6, adding 20g anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing for 30min 10g, filtering, concentrating to 320ml, precipitating, cooling to 0 deg.C, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholic acid amine salt: taking the filtrate filtered in the step (1), adding 320ml of dichloromethane, slowly adding 21.5g of triethylamine with the weight being 1.3 times that of the filtrate, stirring, cooling to 0 ℃, precipitating a large amount of precipitate, filtering, and drying to obtain a chenodeoxycholic acid amine salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking the chenodeoxycholic acid amine salt crude product, adding 400ml of ethyl acetate, dropwise adding 24ml of hydrochloric acid (1:1) under stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) and (3) concentrating the ethyl acetate phase to 200ml in vacuum, cooling, stirring, crystallizing, filtering and drying to obtain a chenodeoxycholic acid final product, wherein the yield is 80.3 percent and the purity is 93.2 percent.
Comparative example 2 (different temperature drop compared with example 1)
A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking 200g of bilirubin leftovers, adding 60g of sodium hydroxide and 400ml of water, carrying out saponification reaction at 95 ℃ for 16h, cooling, standing, siphoning out supernatant, discarding, adding 400ml of water into lower-layer paste, stirring for dissolving, adding concentrated hydrochloric acid for acidification until Congo red test paper turns blue, adding 1600ml of ethyl acetate, stirring for extraction for 30min, standing and layering; washing ethyl acetate phase with water until pH of the water phase is 6, adding 20g anhydrous sodium sulfate into ethyl acetate phase, dehydrating, decolorizing for 30min with 10g, filtering, concentrating to 320ml, precipitating, cooling to 10 deg.C, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholic acid amine salt: taking the filtrate filtered in the step (1), adding 320ml of dichloromethane, slowly adding 21.5g of triethylamine with the weight being 1.3 times that of the filtrate, stirring, cooling to 10 ℃, precipitating a large amount of precipitate, filtering, and drying to obtain a chenodeoxycholic acid amine salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking the chenodeoxycholic acid amine salt crude product, adding 400ml of ethyl acetate, dropwise adding 24ml of hydrochloric acid (1:1) under stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) concentrating ethyl acetate phase in vacuum to 200ml, adding equal volume of dichloromethane, cooling, stirring, crystallizing, filtering, and drying to obtain chenodeoxycholic acid final product with yield of 77.9% and purity of 94.4%.
Comparative example 3 (in comparison with example 1, the organic base is replaced by barium chloride)
A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: taking 200g of bilirubin leftovers, adding 60g of sodium hydroxide and 400ml of water, carrying out saponification reaction at 95 ℃ for 16h, cooling, standing, siphoning out supernatant, discarding, adding 400ml of water into lower-layer paste, stirring for dissolving, adding concentrated hydrochloric acid for acidification until Congo red test paper turns blue, adding 1600ml of ethyl acetate, stirring for extraction for 30min, standing and layering; washing ethyl acetate phase with water until pH of water phase is 6, adding 20g anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing for 30min 10g, filtering, concentrating to 320ml (1/5 volume), precipitating, cooling to 0 deg.C, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
(2) preparing chenodeoxycholate: taking the filtrate filtered in the step (1), adding 320ml of dichloromethane, slowly adding 1.3 times of barium chloride solution by weight, stirring, cooling to 0 ℃, precipitating a large amount of precipitate, filtering, and drying to obtain a chenodeoxycholic acid barium salt crude product;
(3) preparing high-purity chenodeoxycholic acid: taking the chenodeoxycholic acid amine salt crude product, adding 400ml of ethyl acetate, dropwise adding 24ml of hydrochloric acid (1:1) under stirring, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) and (3) concentrating the ethyl acetate phase in vacuum to 200ml (1/2 vol), adding dichloromethane with the same volume, cooling, stirring, crystallizing, filtering and drying to obtain a chenodeoxycholic acid final product with the yield of 86.7% and the purity of 99.5%.
Therefore, the method for producing high-purity chenodeoxycholic acid from the pig bile or the leftovers has better yield and purity effect, and is a simple and efficient method for producing the chenodeoxycholic acid.
The above detailed description is specific to one possible embodiment of the present invention, and the embodiment is not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention should be included in the technical scope of the present invention.
Claims (2)
1. A method for producing chenodeoxycholic acid from pig bile or leftovers comprises the following steps:
(1) removing impurities from hyodeoxycholic acid: adding alkali and water into bilirubin leftovers or pig bile, performing saponification reaction, standing for layering, taking out a lower-layer paste, dissolving in water, acidifying, adding ethyl acetate for extraction, and standing for layering; washing ethyl acetate phase with water until pH of water phase is 6-7, dehydrating ethyl acetate phase, decolorizing, concentrating, cooling, filtering, and vacuum drying to obtain hyodeoxycholic acid crude product;
wherein, the alkali is sodium hydroxide or potassium hydroxide; the dosage of the alkali is 3-50% of that of the bilirubin leftovers or the pig bile; the dosage of the water added in the saponification reaction is 0.2-3 times of the dosage of the bilirubin leftovers or the pig bile; the saponification temperature is 95-100 ℃; the saponification time is 16-24 h; the extraction time is 20min-1 h; the volume of the concentrated solution is 1/10-1/3 of the volume of the added ethyl acetate; the temperature is reduced to 0-5 ℃;
(2) preparing chenodeoxycholic acid amine salt: taking the filtrate filtered in the step (1), adding a solvent, adding an organic alkali reagent, stirring, and cooling to obtain a chenodeoxycholic acid amine salt crude product;
wherein the solvent is at least one of dichloromethane, dichloroethane, methanol, tert-butyl alcohol, ethanol and sec-butyl alcohol; the stirring time is 1-3 h; the temperature is reduced to 0-5 ℃; the organic base reagent is at least one of triethylamine, methylamine, diethylamine, propylamine, tert-butylamine or sec-butylamine and aniline;
(3) preparing chenodeoxycholic acid: taking a chenodeoxycholic acid amine salt crude product, adding ethyl acetate, dropwise adding hydrochloric acid, standing and layering; adding ethyl acetate phase into water, and washing to neutrality for later use;
(4) vacuum concentrating ethyl acetate phase, adding dichloromethane, cooling, and crystallizing to obtain chenodeoxycholic acid final product;
wherein the volume ratio of the dichloromethane to the ethyl acetate phase is 1: 1-3.
2. The method of chenodeoxycholic acid according to claim 1, wherein in step (4), the volume ratio of the volume of dichloromethane to the volume of ethyl acetate phase is 1: 1.
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| CN110724085B (en) * | 2019-11-06 | 2021-07-16 | 河南利伟生物药业股份有限公司 | Co-production method for extracting bilirubin, hyodeoxycholic acid and chenodeoxycholic acid from pig bile |
| CN115181149A (en) * | 2021-04-01 | 2022-10-14 | 苏州恩泰新材料科技有限公司 | Novel crystal form of chenodeoxycholic acid and preparation method |
| CN113912660A (en) * | 2021-10-29 | 2022-01-11 | 四川澄华生物科技有限公司 | Chenodeoxycholic acid phenethylamine salt, preparation method and refining method thereof, and chenodeoxycholic acid preparation method |
| CN114085263A (en) * | 2021-12-27 | 2022-02-25 | 安徽科宝生物工程有限公司 | Synthesis process of ursodeoxycholic acid |
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