CN108218943B - Method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall - Google Patents
Method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall Download PDFInfo
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- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 title claims abstract description 83
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 title claims abstract description 59
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 title claims abstract description 59
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 239000004380 Cholic acid Substances 0.000 title claims abstract description 58
- 229960002471 cholic acid Drugs 0.000 title claims abstract description 58
- 235000019416 cholic acid Nutrition 0.000 title claims abstract description 58
- 229960001661 ursodiol Drugs 0.000 title claims abstract description 51
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 title claims abstract description 49
- 229960001091 chenodeoxycholic acid Drugs 0.000 title claims abstract description 39
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 title claims abstract description 39
- 241000287828 Gallus gallus Species 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims abstract description 42
- 239000003613 bile acid Substances 0.000 claims abstract description 42
- 239000012043 crude product Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000013078 crystal Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 20
- -1 amine salt Chemical class 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- 230000020477 pH reduction Effects 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- RVGVSOKFBAOUCH-JDCDKZKASA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-12-oxo-1,2,3,4,5,6,7,8,9,11,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)C(=O)C2 RVGVSOKFBAOUCH-JDCDKZKASA-N 0.000 claims description 10
- KIQFUORWRVZTHT-PBDHEXIJSA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CC2CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 KIQFUORWRVZTHT-PBDHEXIJSA-N 0.000 claims description 10
- ZKGCEXPUCJDWMB-ZPMVHPDISA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-7-oxo-1,2,3,4,5,6,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CCCC2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)CC[C@@H]3[C@]21C ZKGCEXPUCJDWMB-ZPMVHPDISA-N 0.000 claims description 10
- 159000000000 sodium salts Chemical class 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- 101710088194 Dehydrogenase Proteins 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 6
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 6
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 claims description 5
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 claims description 5
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- 229950006238 nadide Drugs 0.000 claims description 5
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- 108010032887 7 beta-hydroxysteroid dehydrogenase Proteins 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 210000000232 gallbladder Anatomy 0.000 claims 2
- NEEIOMGUTSQVRZ-WNOQBHAASA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2,2-dihydroxypentanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CC(O)(O)C(O)=O)C)[C@@]1(C)CC2 NEEIOMGUTSQVRZ-WNOQBHAASA-N 0.000 claims 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 claims 1
- 239000002699 waste material Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000000047 product Substances 0.000 description 9
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 1
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960002997 dehydrocholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 235000021190 leftovers Nutrition 0.000 description 1
Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall. The method of the invention reduces the steps of extracting chenodeoxycholic acid from chicken bile acid, purifying and then synthesizing ursodesoxycholic acid in the prior art, greatly shortens the process links and saves the cost. The waste cholic acid discarded by the prior art is used as a widened raw material source and reacts with the chenodeoxycholic acid in the chicken bile acid at the same time to synthesize the ursodesoxycholic acid crude product, so that waste is changed into valuable, the utilization rate of the chenodeoxycholic acid is greatly improved, limited biological resources are developed and utilized to the maximum extent, and the technical problems of complex process, high cost, low yield and more waste in the prior art are solved.
Description
Technical Field
The invention relates to a preparation method of ursodeoxycholic acid, in particular to a preparation method for directly synthesizing crude ursodeoxycholic acid from two main components chenodeoxycholic acid and cholic acid in chicken bile acid.
Background
Chenodeoxycholic acid is a main raw material for producing ursodeoxycholic acid, and the demand of the ursodeoxycholic acid is rapidly increased, so that the supply of the chenodeoxycholic acid is short. Because two main components, namely chenodeoxycholic acid and cholic acid, exist in chicken bile acid (also called chicken cholic acid), the chicken bile acid becomes a main raw material source for extracting the chenodeoxycholic acid. However, in view of the utilization of the existing chicken bile acid, the cholic acid cannot be converted or can be fully converted into ursodeoxycholic acid due to the fact that the cholic acid is reduced by a chemical method in the existing process, so that when the chenodeoxycholic acid is extracted from the chicken bile acid, the main component chenodeoxycholic acid is extracted from the chicken bile acid firstly and then the ursodeoxycholic acid is synthesized, and the cholic acid serving as another main component in the chicken bile acid can only be removed as one impurity due to the limitation of the existing process in the industry. However, through detection, the chenodeoxycholic acid mixed in the removed cholic acid has more residues, and the chenodeoxycholic acid is discarded and then treated as leftovers, so that the utilization rate of the chenodeoxycholic acid is not high, and the limited biological resource of the cholic acid is not developed and utilized to the maximum extent, thereby causing serious waste. Therefore, how to widen the raw material source of chenodeoxycholic acid will be a necessary choice for the development of the industry.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall. The method for synthesizing ursodesoxycholic acid after discarding cholic acid and extracting chenodeoxycholic acid in the prior art is improved into the method for simultaneously synthesizing crude ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken bile acid, and the method has the advantages of simple process, low cost, high resource utilization rate and high yield, and is suitable for large-scale production.
The technical scheme of the invention is as follows:
the method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall is characterized by comprising the following preparation processes:
(1) and (3) extraction: taking 50-100kg of chicken bile acid, adding 250-500kg of ester solvent, adjusting the pH value to 2-3 under stirring, extracting the total cholic acid into the ester solvent, standing, layering, and removing the lower-layer water phase to obtain the total cholic acid extract.
(2) Salifying and crystallizing: and (2) adding 5-10kg of amine solvent into the extract liquor prepared in the step (1) to crystallize total cholic acid amine salt, and separating to obtain the total cholic acid amine salt crystal. Adding 50-100kg of water and 2-4kg of sodium hydroxide into the amine salt crystal, heating for alkaline hydrolysis, adjusting the pH value to 2-3 with dilute hydrochloric acid under stirring, and precipitating cholic acid crystal to obtain total bile acid acidification matter.
(3) And (3) oxidation: dissolving the total bile acid acidification substance obtained in the step (2) by 50-100kg of methanol, adding 25-50kg of calcium hypochlorite, adjusting the pH value to 3-4 by acetic acid, oxidizing chenodeoxycholic acid in the acidification substance and cholic acid, after the reaction is finished, adding 200kg of 100-ketone-containing water while stirring to separate out and crystallize the oxide of the total bile acid, and separating to obtain the oxide of the total bile acid, wherein the oxide comprises 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid.
(4) Reduction, namely adding 20-50mmol/L of 200-plus-2 kg of sodium dihydrogen phosphate aqueous solution into the oxide of total bile acid containing 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid obtained in the step (3), adjusting the pH value to 7.5-8.0 by 10mol/L of sodium hydroxide aqueous solution, heating and stirring the mixture to dissolve the mixture, adding 5-20kg of glucose, 2-8kg of 3 a-hydroxysteroid dehydrogenase, 3.5-14kg of 7 β -hydroxysteroid dehydrogenase, 4-16kg of glucose dehydrogenase, 4.5-18g of nicotinamide adenine dinucleotide and 7.5-30g of nicotinamide adenine dinucleotide phosphate, reacting the mixture at the temperature of 26-30 ℃ and the pH value of 7.5-8.0 for 4-8 hours, adjusting the pH value to 2-3 by using dilute hydrochloric acid after the reaction is completed, and crystallizing the mixture containing 3- α, 367-dihydroxy- β - α, 7-395-4612-5-5912 ketocholanic acid.
(5) Adding 30-60kg of diethylene glycol into the mixture obtained in the step (4) for dissolving, adding sodium hydroxide for adjusting the pH value to be more than 12, recovering water in vacuum to the temperature of more than 130 ℃, adding 1-2kg of hydrazine hydrate, carrying out heating reflux reaction for 2-4 hours, recovering the water of a solution system to be less than 0.1%, boiling for 2-4 hours, till the water of 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid is completely converted into 3 α,7 β -dihydroxy-5 β -cholanic acid, namely ursodeoxycholic acid, adding 10-20kg of sodium hydroxide and 10-20kg of water into the system, separating the ursodeoxycholic acid into a sodium salt under strong alkali, separating out the diethylene glycol, adding 100kg of water into the sodium salt of the ursodeoxycholic acid, reducing the pressure, recovering the residual diethylene glycol completely, adjusting the pH value to be 2-3 by using hydrochloric acid, separating out ursodeoxycholic acid crystallization, separating, drying to obtain a crude ursodeoxycholic acid product, and purifying the finished product according to the effective cholic acid conversion rate of the finished product, wherein the finished product is more than 0.96%.
Further, the ester solvent in the step (1) is one of ethyl acetate, butyl acetate and propyl acetate.
Further, the amine solvent in the step (2) is one of butylamine, triethylamine and triethanolamine.
Compared with the prior art, the invention has the following beneficial effects:
the method of the invention reduces the steps of extracting chenodeoxycholic acid from chicken bile acid, purifying and then synthesizing ursodesoxycholic acid in the prior art, greatly shortens the process links and saves the cost. The waste cholic acid discarded by the prior art is used as a widened raw material source and reacts with the chenodeoxycholic acid in the chicken bile acid at the same time to synthesize the ursodesoxycholic acid crude product, so that waste is changed into valuable, the utilization rate of the chenodeoxycholic acid is greatly improved, limited biological resources are developed and utilized to the maximum extent, and the technical problems of complex process, high cost, low yield and more waste in the prior art are solved.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the method of the present invention is further described in detail below with reference to specific examples.
Example one
The method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall comprises the following preparation processes:
(1) and (3) extraction: taking 50kg of chicken bile acid, adding 250kg of ethyl acetate solvent, adjusting the pH value to 2 under stirring, extracting the total cholic acid into the ethyl acetate solvent, standing, layering, and removing the lower water phase to obtain the total cholic acid extract.
(2) Salifying and crystallizing: and (2) adding 5kg of an butylamine solvent into the extract prepared in the step (1) to crystallize total cholic acid amine salt, and separating to obtain the total cholic acid amine salt crystal. Adding 50kg of water and 2kg of sodium hydroxide into the amine salt crystal, heating for alkaline hydrolysis, adjusting the pH value to 2 by using dilute hydrochloric acid under stirring, and separating out cholic acid crystal to obtain total bile acid acidification matter.
(3) And (3) oxidation: dissolving the total bile acid acidification substance obtained in the step (2) by 50kg of methanol, adding 25kg of calcium hypochlorite, adjusting the pH value to 3 by using acetic acid, oxidizing chenodeoxycholic acid in the acidification substance and cholic acid, after the reaction is finished, adding 100kg of water under stirring to separate out and crystallize the oxide of the total bile acid, and separating to obtain the oxide of the total bile acid, wherein the oxide contains 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid.
(4) And (3) reducing, namely adding 300kg of 20mmol/L sodium dihydrogen phosphate aqueous solution into the oxide of total bile acid containing 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid obtained in the step (3), adjusting the pH value to 7.8 by using 10mol/L sodium hydroxide aqueous solution, heating and stirring the mixture to dissolve the mixture, adding 6kg of glucose, 3 a-hydroxyl steroid dehydrogenase, 3.5kg of 7 β -hydroxyl steroid dehydrogenase, 4kg of glucose dehydrogenase, 4.5g of nicotinamide adenine dinucleotide and 7.5g of nicotinamide adenine dinucleotide phosphate, reacting the mixture at the temperature of 27 ℃ and the pH value of 7.7 for 5 hours, adjusting the pH value to 2 by using dilute hydrochloric acid after the reaction is completed, and precipitating crystals to obtain a mixture containing 3 α,7 β -dihydroxy-5 β -cholanic acid and 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid.
(5) And (3) performing Huang Minlon reaction, namely adding 30kg of diethylene glycol into the mixture obtained in the step (4) for dissolving, adding sodium hydroxide for regulating the pH value to be more than 12, recovering water in vacuum to 135 ℃, adding 1kg of hydrazine hydrate, heating and refluxing for 2 hours, recovering until the water content of a solution system is 0.08%, performing boiling-maintaining reaction for 2 hours, until the water content of 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid is completely converted into 3 α,7 β -dihydroxy-5 β -cholanic acid, namely ursodeoxycholic acid, adding 10kg of sodium hydroxide and 10kg of water into the system, separating the ursodeoxycholic acid into sodium salts under strong alkali, separating out diethylene glycol, adding 100kg of water into the sodium salts of the ursodeoxycholic acid, decompressing and completely recovering the residual diethylene glycol, then regulating the pH value to 2 by using dilute hydrochloric acid, separating out crystals of the ursodeoxycholic acid, separating out, drying to obtain 15.7kg of crude ursodeoxycholic acid, wherein the conversion rate is 98.46%, and finally refining according to the existing purification process to obtain the finished product.
Example two
The method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall comprises the following preparation processes:
(1) and (3) extraction: adding 80kg of chicken bile acid into 400kg of butyl acetate solvent, adjusting the pH value to 2 under stirring, extracting the total cholic acid into the butyl acetate solvent, standing, layering, and removing the lower water phase to obtain the total cholic acid extract.
(2) Salifying and crystallizing: and (2) adding 8kg of triethylamine solvent into the extract liquid prepared in the step (1) to crystallize total cholic acid amine salt, and separating to obtain the total cholic acid amine salt crystal. Adding 80kg water and 3.2kg sodium hydroxide into the amine salt crystal, heating for alkaline hydrolysis, adjusting pH to 2 with dilute hydrochloric acid under stirring, and separating out cholic acid crystal to obtain total bile acid acidification substance.
(3) And (3) oxidation: dissolving the total bile acid acidification substance obtained in the step (2) by 80kg of methanol, adding 40kg of calcium hypochlorite, adjusting the pH value to 4 by using acetic acid, oxidizing chenodeoxycholic acid in the acidification substance and cholic acid, after the reaction is finished, adding 160kg of water under stirring to separate out and crystallize the oxide of the total bile acid, and separating to obtain the oxide of the total bile acid, wherein the oxide comprises 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid.
(4) And (2) reduction, namely adding 300kg of 30mmol/L sodium dihydrogen phosphate aqueous solution into the total bile acid oxide containing the 3-ketocholanic acid, the 7-ketocholanic acid and the 12-ketocholanic acid obtained in the step (3), adjusting the pH value to 8.0 by using 10mol/L sodium hydroxide aqueous solution, heating and stirring the mixture to dissolve the mixture, adding 15kg of glucose, 5kg of 3 a-hydroxyl steroid dehydrogenase, 8kg of 7 β -hydroxyl steroid dehydrogenase, 10kg of glucose dehydrogenase, 10g of nicotinamide adenine dinucleotide and 20g of nicotinamide adenine dinucleotide phosphate, reacting the mixture at the temperature of 28 ℃ and the pH value of 7.8 for 6 hours, adjusting the pH value to 3 by using dilute hydrochloric acid after the reaction is completed, and precipitating crystals to obtain a mixture containing the 3 α,7 β -dihydroxy-5 β -cholanic acid, the 3 α and 7 β -dihydroxy-12-keto-5 β -cholanic acid.
(5) Adding 48kg of diethylene glycol into the mixture obtained in the step (4) for dissolving, adding sodium hydroxide for adjusting the pH value to be more than 12, recovering water in vacuum to 132 ℃, adding 1.6kg of hydrazine hydrate, heating and refluxing for 3 hours, recovering until the water content of a solution system is 0.05%, boiling for 3 hours, until the water content of the solution system is 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid is completely converted into 3 α,7 β -dihydroxy-5 β -cholanic acid, namely ursodeoxycholic acid, adding 15kg of sodium hydroxide and 20kg of water into the system, separating out sodium salt of ursodeoxycholic acid under strong alkali, separating out diethylene glycol, adding 200kg of water into the sodium salt of ursodeoxycholic acid, decompressing and completely recovering the residual diethylene glycol, adjusting the pH value to 3 by using dilute hydrochloric acid, separating out deoxycholic acid crystals, separating, drying to obtain 24.6kg of crude ursodeoxycholic acid, wherein the conversion rate is 96.67%, and finally refining the finished product of ursodeoxycholic acid according to the existing purification process.
EXAMPLE III
The method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall comprises the following preparation processes:
(1) and (3) extraction: taking 100kg of chicken bile acid, adding 500kg of propyl acetate solvent, adjusting the pH value to 3 under stirring, extracting the total cholic acid into the propyl acetate solvent, standing, layering, and removing the lower water phase to obtain the total cholic acid extract.
(2) Salifying and crystallizing: and (2) adding 10kg of triethanolamine solvent into the extract liquid prepared in the step (1) to crystallize total cholic acid amine salt, and separating to obtain total cholic acid amine salt crystals. Adding 100kg water and 4kg sodium hydroxide into the amine salt crystal, heating for alkaline hydrolysis, adjusting pH to 3 with dilute hydrochloric acid under stirring, and separating out cholic acid crystal to obtain total bile acid acidification substance.
(3) And (3) oxidation: dissolving the total bile acid acidification substance obtained in the step (2) by 100kg of methanol, adding 50kg of calcium hypochlorite, adjusting the pH value to 4 by using acetic acid, oxidizing chenodeoxycholic acid in the acidification substance and cholic acid, after the reaction is finished, adding 200kg of water under stirring to separate out and crystallize the oxide of the total bile acid, and separating to obtain the oxide of the total bile acid, wherein the oxide contains 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid.
(4) And (2) reduction, namely adding 400kg of 50mmol/L sodium dihydrogen phosphate aqueous solution into the oxide of total bile acid containing 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid obtained in the step (3), adjusting the pH value to 8.0 by using 10mol/L sodium hydroxide aqueous solution, heating and stirring the mixture to dissolve the mixture, adding 20kg of glucose, 8kg of 3 a-hydroxysteroid dehydrogenase, 14kg of 7 β -hydroxysteroid dehydrogenase, 16kg of glucose dehydrogenase, 18g of nicotinamide adenine dinucleotide and 30g of nicotinamide adenine dinucleotide phosphate, reacting the mixture at the temperature of 30 ℃ and the pH value of 8.0 for 8 hours, adjusting the pH value to 3 by using dilute hydrochloric acid after the reaction is completed, and precipitating crystals to obtain a mixture containing 3 α,7 β -dihydroxy-5 β -cholanic acid, 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid.
(5) Adding 80kg of diethylene glycol into the mixture obtained in the step (4) for dissolving, adding sodium hydroxide for adjusting the pH value to be more than 12, recovering water in vacuum to 135 ℃, adding 2kg of hydrazine hydrate, heating and refluxing for 4 hours, recovering until the water content of a solution system is 0.06%, boiling for 4 hours, reacting until the water content of the solution system is 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid is completely converted into 3 α,7 β -dihydroxy-5 β -cholanic acid, namely ursodeoxycholic acid, adding 20kg of sodium hydroxide and 20kg of water into the system, separating out sodium salt of ursodeoxycholic acid under strong alkali, separating out diethylene glycol, adding 200kg of water into sodium salt of ursodeoxycholic acid, decompressing and completely recovering residual diethylene glycol, adjusting the pH value to 3 by using dilute hydrochloric acid, separating out crystals of ursodeoxycholic acid, separating, drying to obtain 30.2kg of crude ursodeoxycholic acid, wherein the conversion rate is 97.63%, and finally refining according to the existing purification process to obtain the finished product of ursodeoxycholic acid.
The raw materials adopted in the three embodiments, and the finally synthesized ursodeoxycholic acid crude product and finished product are detected, and the detected data are shown in the following table:
as can be seen from the data shown in the table, the overall conversion of chenodeoxycholic acid and cholic acid in the crude ursodeoxycholic acid synthesized by the method of the present invention is high, and the residues of chenodeoxycholic acid and cholic acid are low. Compared with the quality of the crude product obtained by the chemical method, the residual content of the chenodeoxycholic acid is reduced by about 80%, the residual content of the cholic acid is reduced by more than 60%, and the overall conversion rate is improved by more than 10%. The quality of the product is verified by the prior subsequent purification process to completely meet the standard of European pharmacopoeia EP8.0 commonly used in the industry.
Claims (3)
1. The method for synthesizing ursodesoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gall is characterized by comprising the following preparation processes:
(1) and (3) extraction: taking 50-100kg of chicken bile acid, adding 250-500kg of ester solvent, adjusting the pH value to 2-3 under stirring, extracting the total cholic acid into the ester solvent, standing, layering, and removing a lower-layer water phase to obtain a total cholic acid extraction liquid;
(2) salifying and crystallizing: adding 5-10kg of amine solvent into the extract liquid prepared in the step (1) to crystallize total cholic acid into amine salt, and separating to obtain total cholic acid amine salt crystal;
adding 50-100kg of water and 2-4kg of sodium hydroxide into the amine salt crystals, heating for alkaline hydrolysis, adjusting the pH value to 2-3 with dilute hydrochloric acid under stirring, and precipitating cholic acid crystals to obtain total bile acid acidification matters;
(3) and (3) oxidation: dissolving the total bile acid acidification substance obtained in the step (2) by 50-100kg of methanol, adding 25-50kg of calcium hypochlorite, adjusting the pH value to 3-4 by acetic acid, oxidizing chenodeoxycholic acid in the acidification substance and cholic acid, after the reaction is finished, adding 200kg of 100-ketone-containing water while stirring to separate out and crystallize the oxide of the total bile acid, and separating to obtain the oxide of the total bile acid, wherein the oxide comprises 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid;
(4) reduction, namely adding 20-50mmol/L sodium dihydrogen phosphate aqueous solution 200-400kg into the total bile acid oxide containing 3-ketocholanic acid, 7-ketocholanic acid and 12-ketocholanic acid obtained in the step (3), adjusting the pH value to 7.5-8.0 by using 10mol/L sodium hydroxide aqueous solution, heating and stirring to dissolve the sodium dihydrogen phosphate aqueous solution, adding 5-20kg of glucose, 2-8kg of 3 a-hydroxysteroid dehydrogenase, 3.5-14kg of 7 β -hydroxysteroid dehydrogenase, 4-16kg of glucose dehydrogenase, 4.5-18g of nicotinamide adenine dinucleotide and 7.5-30g of nicotinamide adenine dinucleotide phosphate, reacting at the temperature of 26-30 ℃ and the pH value of 7.5-8.0 for 4-8 hours, adjusting the pH value to 2-3 by using dilute hydrochloric acid after the reaction is completed, and crystallizing to obtain a mixture containing 3- α, 367-dihydroxy- β - α, 7-395-4612-395-5912 g of dihydroxycholanic acid;
(5) adding 30-60kg of diethylene glycol into the mixture obtained in the step (4) for dissolving, adding sodium hydroxide for regulating the pH value to be more than 12, recovering water in vacuum until the temperature is more than 130 ℃, adding 1-2kg of hydrazine hydrate, heating and refluxing for 2-4 hours, recovering until the water content of a solution system is less than 0.1%, boiling for 2-4 hours until 3 α,7 β -dihydroxy-12-keto-5 β -cholanic acid is completely converted into 3 α,7 β -dihydroxy-5 β -cholanic acid, namely ursodeoxycholic acid;
adding 10-20kg of sodium hydroxide and 10-20kg of water into the system to ensure that ursodeoxycholic acid becomes sodium salt under strong alkali to be separated out, separating diethylene glycol, adding 100kg of water into the sodium salt of the ursodeoxycholic acid, reducing the pressure and completely recovering the residual diethylene glycol, adjusting the pH value to be 2-3 by using dilute hydrochloric acid to separate out ursodeoxycholic acid crystals, separating and drying to obtain a crude product of the ursodeoxycholic acid, wherein the conversion rate is more than 96 percent according to the effective content of chenodeoxycholic acid and cholic acid.
2. The method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gallbladder as claimed in claim 1, wherein the ester solvent in step (1) is one of ethyl acetate, butyl acetate and propyl acetate.
3. The method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid and cholic acid in chicken gallbladder according to claim 1, wherein the amine solvent in the step (2) is one of sec-butylamine, triethylamine and triethanolamine.
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| CN109722463A (en) * | 2019-03-18 | 2019-05-07 | 常德云港生物科技有限公司 | A method of hyocholic acid is synthesized by ursodesoxycholic acid by half enzyme process |
| CN109825547A (en) * | 2019-03-18 | 2019-05-31 | 常德云港生物科技有限公司 | A method of passing through half enzymatic clarification ursodesoxycholic acid by raw material of cholic acid |
| CN110669091A (en) * | 2019-10-18 | 2020-01-10 | 武汉大学 | Method for purifying ursodeoxycholic acid |
| CN110845564B (en) * | 2019-11-14 | 2022-09-16 | 湖南九典制药股份有限公司 | Method for extracting chenodeoxycholic acid from chicken gall paste |
| CN114317663B (en) * | 2022-01-19 | 2023-09-01 | 常德云港生物科技股份有限公司 | Method for synthesizing ursodeoxycholic acid by utilizing feed after bilirubin extraction of pig gall |
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