CN108299538A - A method of removing different ursodesoxycholic acid in duck bile - Google Patents
A method of removing different ursodesoxycholic acid in duck bile Download PDFInfo
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- CN108299538A CN108299538A CN201810192425.5A CN201810192425A CN108299538A CN 108299538 A CN108299538 A CN 108299538A CN 201810192425 A CN201810192425 A CN 201810192425A CN 108299538 A CN108299538 A CN 108299538A
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- China
- Prior art keywords
- acid
- different
- ursodesoxycholic
- chenodeoxycholic acid
- crude product
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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 60
- 229960001661 ursodiol Drugs 0.000 title claims abstract description 60
- 238000000034 method Methods 0.000 title claims abstract description 37
- 241000272525 Anas platyrhynchos Species 0.000 title claims abstract description 31
- 210000000941 bile Anatomy 0.000 title claims abstract description 27
- 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 claims abstract description 60
- 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 claims abstract description 60
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims abstract description 60
- 239000012043 crude product Substances 0.000 claims abstract description 38
- 239000013078 crystal Substances 0.000 claims abstract description 38
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 238000012545 processing Methods 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 38
- 239000012074 organic phase Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 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 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- BHQCQFFYRZLCQQ-PGHAKIONSA-N allocholic 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-PGHAKIONSA-N 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 15
- 238000004064 recycling Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 239000012071 phase Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000012360 testing method Methods 0.000 claims description 6
- MXQYDMPSTCVFJC-UHFFFAOYSA-N C(C)(=O)OCCCC.[Mg] Chemical class C(C)(=O)OCCCC.[Mg] MXQYDMPSTCVFJC-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000005119 centrifugation Methods 0.000 claims description 4
- 235000019416 cholic acid Nutrition 0.000 claims description 4
- 239000004380 Cholic acid Substances 0.000 claims description 2
- 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 claims description 2
- 229960002471 cholic acid Drugs 0.000 claims description 2
- 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 claims description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 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 abstract description 9
- 239000003613 bile acid Substances 0.000 abstract description 9
- 238000000605 extraction Methods 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 description 8
- 238000007689 inspection Methods 0.000 description 7
- 229910001220 stainless steel Inorganic materials 0.000 description 6
- 241000272814 Anser sp. Species 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000010865 sewage Substances 0.000 description 4
- 150000007824 aliphatic compounds Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- -1 Cholic acids compound Chemical class 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000002812 cholic acid derivative Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- UYVVLXVBEQAATF-UHFFFAOYSA-N 4-(1,3,7,12-tetrahydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoic acid Chemical compound OC1CC2CC(O)CC(O)C2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 UYVVLXVBEQAATF-UHFFFAOYSA-N 0.000 description 1
- 206010012374 Depressed mood Diseases 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 150000001801 chenodeoxycholic acids Chemical class 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000007704 transition Effects 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
Abstract
The invention discloses a kind of methods of different ursodesoxycholic acid in removing duck bile, including chenodeoxycholic acid crude product preparation, the preparation of crystal solution, crystallization to obtain the processing steps such as the preparation of chenodeoxycholic acid crystal solution, chenodeoxycholic acid sterling.By the method for the invention, the chenodeoxycholic acid in duck bile can be purified and isolate the different ursodesoxycholic acid with pharmacy value, farthest improve the utilization rate of bile acid resource.And the leftover bits and pieces that the method for the present invention generates is few, can be utilized by extraction cycle, largely reduce the loss of bile acid resource.
Description
Technical field
The present invention relates to technical field of bioengineering, more particularly to a kind of side of different ursodesoxycholic acid in removing duck bile
Method.
Background technology
People have longer history to the research of Cholic acids compound, right under the promotion of biochemistry fast development
The research of Cholic acids compound is also constantly being goed deep into.Chenodeoxycholic acid is the current maximum treatment gall stone of dosage in the world
One of drug, but be synthesize ursodesoxycholic acid primary raw material, the market demand of chenodeoxycholic acid and ursodesoxycholic acid not
In the case of disconnected rapid growth, in order to widen the source of its raw material, people start to carry from the duck bile that low cost, raw material are easy to get
Chenodeoxycholic acid is taken, to obtain more raw materials for preparing ursodesoxycholic acid.
In process, in order to make the DNA purity higher of chenodeoxycholic acid, people use a variety of method removal duck courages
Allocholic acid impurity in juice, however effect is not notable.By for many years the study found that there is also one kind being called different bear in duck bile
The impurity of deoxycholic aicd, the content of the impurity are only second to the content of allocholic acid impurity in duck bile, equally generally between 7-8%
Belong to the impurity of most bad removing when purification chenodeoxycholic acid, this will influence to turn when chenodeoxycholic acid prepares ursodesoxycholic acid
Rate.
In addition, different ursodesoxycholic acid is the epimer of ursodesoxycholic acid, the metabolism of biochemical analysis and detection body's cholesterol
When index, the different ursodesoxycholic acid of high-purity need to be used as standard substance, thus different ursodesoxycholic acid has important biology
Utility value.Thus different ursodesoxycholic acid is removed from the chenodeoxycholic acid from duck bile raw material, is not only purification goose
The another important step of deoxycholic aicd, while the different ursodesoxycholic acid as obtained from removing can be also used for production bile acid
Downstream product.
Invention content
In view of the above-mentioned problems, the present invention provide it is a kind of removing duck bile in different ursodesoxycholic acid method, the purpose is to for
Extract chenodeoxycholic acid time-division divorced ursodesoxycholic acid impurity in duck bile raw material, this method be using chenodeoxycholic acid and
Different ursodesoxycholic acid is in esters, the in the mixed solvent of polyalcohol and aliphatic compound three's special ratios, existing dissolving
It spends difference and crystallizes and different ursodesoxycholic acid is precipitated, to realize the refined extraction of chenodeoxycholic acid.
Technical scheme of the present invention：A method of removing different ursodesoxycholic acid in duck bile, which is characterized in that technique walks
It is rapid as follows：
（1）It is prepared by chenodeoxycholic acid crude product：Using duck bile raw material, it is thick that chenodeoxycholic acid is obtained by butyl acetate magnesium salts legal system
The weight in wet base of product, crude product is less than 0.6%, and the content of allocholic acid is less than 1.0%, and the content of different ursodesoxycholic acid is more than 7%.
（2）The preparation of crystal solution：In step（1）In the chenodeoxycholic acid crude product of preparation, 6 times of amounts of crude product are added and moisture content is small
0.5 times of ethyl acetate and crude product in 1% are measured and purity is 99.5% ethylene glycol, are heated with stirring to boiling, it is small to protect boil-off solution 1
It is completely dissolved up to crude product.It stands 1 hour and separates lower layer's water phase, the water of upper organic phase is adjusted by reaction kettle reflux water-dividing device
Point, so that the moisture of upper organic phase is less than 1.0%；Then upper organic phase is concentrated using normal pressure, in the organic phase of concentration
The ethyl acetate and ethylene glycol mixed solvent that middle metering recycling is added, yield is the half of mixed solvent addition；It has recycled
Finish, the moisture for measuring and adjusting organic phase again is 1.0% hereinafter, being cooled to 29-30 DEG C, spare.
Step is added into above-mentioned organic phase（1）The 120# gasoline of the glacial acetic acid and 0.15 times of amount of 0.003 times of amount of middle crude product,
It is stirred to clarify under 28-30 DEG C of temperature condition, measure and adjusts the pH value of organic phase between 3.5-4, moisture
For 1.2-1.5%.Be added glacial acetic acid be in order to increase the solubility of bile acid, be added aliphatic compound 120# gasoline be for
Water suction and the solubility for reducing different ursodesoxycholic acid.
（3）Crystallization：By step（2）The crystal solution of preparation is stirred by the frequency conversion of 12-15HZ, is cooled to 23-25 DEG C, continuously
It is stirred to react 10-12 hours, crystal solution gradually becomes muddy by clarifying, and by embedded plate and frame filter press press filtration, obtains different bear
The filter residue and chenodeoxycholic acid crystal solution of deoxycholic aicd.Wherein, the filter residue of different ursodesoxycholic acid is in ash gray floccule, through inspection
It is 29-31%, purity 89-91% to survey its weight in wet base.
（4）To step（3）In the chenodeoxycholic acid crystal solution of preparation, the sodium carbonate liquor of crystal solution deal 0.5% is added,
The pure water of crystal solution deal 25%, normal pressure concentration is added, control kettle internal solvent vapor (steam) temperature is 65-68 DEG C, is recycled in crystal solution
Solution stirring is cooled to 30 DEG C after recycling completely, continuously adds crystal solution part by the mixed solvent of ethyl acetate and 120# gasoline
The pure water of amount 50%, it is 3.5 to be neutralized to pH value with a concentration of 10% dilute hydrochloric acid, and centrifugation obtains chenodeoxycholic acid sterling, then lead to
Air-flow boiled bed drying is crossed, obtains weight in wet base less than the granular chenodeoxycholic acid drying of off-white color that 1.2%, content is 96%-98%
Sterling.After testing, the content of different ursodesoxycholic acid is less than 0.1% in chenodeoxycholic acid sterling, and allocholic acid content is less than or equal to
0.5%。
The advantage of the invention is that：
1, in current laboratory for how removing the theoretical research of different ursodesoxycholic acid, be using conventional resin upper prop method,
Solvent acquisition dosage when this method operates is big, the production cycle is long, the resin replacement frequency is more, production efficiency is not high, unsuitable work
Sparetime university's large-scale production.The extraction separation that the present invention uses substitutes the tree used when progress theoretical research in current laboratory
Fat upper prop method, make to extract in duck bile different ursodesoxycholic acid this new issue realize it is extensive from laboratory research to industrialization
The fast transition of production.
2, by the method for the invention, the chenodeoxycholic acid in duck bile can be purified and isolated with pharmacy value
Different ursodesoxycholic acid, farthest improve the utilization rate of bile acid resource.
3, the different ursodesoxycholic acid for detaching generation by the method for the invention can be used for producing the downstream product of bile acid, such as
Food additives etc..It, can also be directly by different ursodeoxycholic since different ursodesoxycholic acid and ursodesoxycholic acid are epimers
Acid is used for being converted to ursodesoxycholic acid, has effectively widened the raw material sources of processing ursodesoxycholic acid.
4, the sewage that entire technical process generates is controllable, and COD can reach the discharge mark of local environmental protection administration
It is accurate.
5, the leftover bits and pieces that the method for the present invention generates is few, and can be utilized by extraction cycle, largely reduces courage
The loss of juice acid resource.Auxiliary material used in the step of detaching different ursodesoxycholic acid, especially solvent are conventional chemical industry
Solvent is not belonging to easily make malicious class, substantially without environmental hazard and security risk.
6, the process conditions that the method for the present invention is related to are of less demanding, and such as pH value and moisture standards are very fine, though it adjusts
Space is little, but in the case of auxiliary facility perfect in shape and function, has controllability.
7, the present invention in crystallization technique it is apparent to different ursodesoxycholic acid elimination effect, and to content interval 1.0% with
Under allocholic acid there is also certain scavenging effects.Verified through the present invention, allocholic acid and chenodeoxycholic acid esters, polyalcohol and
The in the mixed solvent of aliphatic compound three's special ratios, there is also certain dissolubility differences, though its diversity factor is too late
Different ursodesoxycholic acid, but can also remove a certain proportion of allocholic acid.Therefore while removing different ursodesoxycholic acid, allocholic acid etc. is miscellaneous
Matter can also obtain different degrees of removing.
Specific implementation mode
To make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, to present invention side
Method is further described.
Embodiment one
A method of different ursodesoxycholic acid in duck bile being removed, processing step is as follows：
（1）It is prepared by chenodeoxycholic acid crude product：Goose is made by butyl acetate magnesium salts method in 500 kilograms of bile acid starting material for taking duck courage
The weight in wet base of deoxycholic aicd crude product, crude product is 0.48%, and crude product weighs 75.6 kilograms, and the content of allocholic acid is 0.8% in crude product, different
The content of ursodesoxycholic acid is 7.2%.
（2）Prepare crystal solution：By step（1）The 75.6 kilograms of chenodeoxycholic acid crude products prepared put into 2000L stainless steels
The ethyl acetate that 453.6 kg of water are divided into 0.2% is added in kettle, adds the ethylene glycol that 37.8 kilograms of purity are 99.5%, and stirring adds
Heat is protected boil-off solution and is completely dissolved to crude product for 1 hour to boiling.It stands 1 hour and separates lower layer's water phase, pass through reaction kettle reflux water-dividing device
The moisture for adjusting upper organic phase, it is 0.95% to make the moisture of upper organic phase.Then upper organic phase is dense using normal pressure
Contracting, the mixed solvent of metering recycling 245.7 kilograms of ethyl acetate and ethylene glycol, recycling finish, the moisture of repetition measurement organic phase
It is 0.65%, is cooled to 29 DEG C, it is spare.
0.23 kilogram of glacial acetic acid is added into above-mentioned organic phase, 11.3 kilograms of 120# gasoline are added, at a temperature of 29 DEG C
It stirs to clarify, the pH value for measuring and adjusting organic phase is 3.8, moisture 1.2%.
（3）Crystallization：By step（2）The crystal solution of preparation is stirred by the frequency conversion of 12HZ, is cooled to 25 DEG C, is then continuously stirred
Reaction 10 hours is mixed, crystal solution gradually becomes muddy by clarifying, by the embedded plate and frame filter press press filtration of 10 square meters, obtains different bear
324 kilograms of 8.5 kilograms of the filter residue of deoxycholic aicd and chenodeoxycholic acid crystal solution.Wherein, the filter residue of different ursodesoxycholic acid is in light ash
The floccule of color, its weight in wet base is 29.5% after testing, purity 90.3%.
（4）To step（3）In the 324 kilograms of chenodeoxycholic acid crystal solutions prepared, 1.62 kilograms of sodium carbonate liquors are added, add
Enter 81 kilograms of pure water, normal pressure concentration, control kettle internal solvent vapor (steam) temperature is 65 DEG C, recycles ethyl acetate and 120# in crystal solution
224 kilograms of the mixed solvent of gasoline.Solution in kettle is cooled to 30 DEG C after recycling completely, 162 kilograms of pure water is continuously added, stirs
After mixing uniformly, it is 3.5 to be neutralized to pH value with a concentration of 10% dilute hydrochloric acid, and with 1000 type stainless steel centrifuges, centrifugation sour water is logical
Sewage plant processing is crossed, centrifuges to obtain 91 kilograms of chenodeoxycholic acid wet product, then by air-flow boiled bed drying, obtain off-white color graininess
55 kilograms of chenodeoxycholic acid sterling.Quality inspection, dry weight in wet base are 1.0%, and the content of different ursodesoxycholic acid is 0.098%, allocholic acid
Content be 0.45%, the content of chenodeoxycholic acid is 96.9%.
Embodiment two
A method of different ursodesoxycholic acid in duck bile being removed, processing step is as follows：
（1）It is prepared by chenodeoxycholic acid crude product：Goose is made by butyl acetate magnesium salts method in 550 kilograms of bile acid starting material for taking duck courage
The weight in wet base of deoxycholic aicd crude product, crude product is 0.5%, and crude product weighs 85.2 kilograms, and the content of allocholic acid is 0.83% in crude product, different
The content of ursodesoxycholic acid is 7.5%.
（2）Prepare crystal solution：By step（1）The 85.2 kilograms of chenodeoxycholic acid crude products prepared put into 2000L stainless steels
The ethyl acetate that 511.2 kg of water are divided into 0.15% is added in kettle, adds the ethylene glycol that 42.6 kilograms of purity are 99.5%, stirring
It is heated to boiling, protects boil-off solution and be completely dissolved to crude product for 1 hour.It stands 1 hour and separates lower layer's water phase, pass through reaction kettle reflux water-dividing
Device adjusts the moisture of upper organic phase, and it is 0.9% to make the moisture of upper organic phase.Then upper organic phase is used into normal pressure
Concentration, the mixed solvent of metering recycling 276.9 kilograms of ethyl acetate and ethylene glycol, recycling finish, and the moisture of repetition measurement organic phase contains
Amount be 0.58%, be cooled to 29.5 DEG C it is spare.
0.26 kilogram of glacial acetic acid is added into above-mentioned organic phase, 12.78 kilograms of 120# gasoline are added, at a temperature of 28 DEG C
It stirs to clarify, the pH value for measuring and adjusting organic phase is 3.6, moisture 1.25%.
（3）Crystallization：By step（2）The crystal solution of preparation is stirred by the frequency conversion of 15HZ, is cooled to 24.5 DEG C, then continuously
It is stirred to react 10 hours, crystal solution gradually becomes muddy by clarifying, and by the embedded plate and frame filter press press filtration of 10 square meters, obtains different
365 kilograms of 9.4 kilograms of the filter residue of ursodesoxycholic acid and chenodeoxycholic acid crystal solution.Wherein, the filter residue of different ursodesoxycholic acid is in light
The floccule of grey, its weight in wet base is 30% after testing, purity 90%.
（4）To step（3）In the 365 kilograms of chenodeoxycholic acid crystal solutions prepared, 1.83 kilograms of sodium carbonate liquors are added, add
Enter 91.3 kilograms of pure water, normal pressure concentration, control kettle internal solvent vapor (steam) temperature is 65 DEG C, recycle in crystal solution ethyl acetate and
265 kilograms of the mixed solvent of 120# gasoline.Solution in kettle is cooled to 30 DEG C after recycling completely, continuously add 182.5 kilograms it is pure
Water purification, after stirring evenly, it is 3.5 to be neutralized to pH value with a concentration of 10% dilute hydrochloric acid, with 1000 type stainless steel centrifuges, from
Water of feeling sad is handled by sewage plant, centrifuges to obtain 100.5 kilograms of chenodeoxycholic acid wet product, then by air-flow boiled bed drying, obtain
63.3 kilograms of the granular chenodeoxycholic acid sterling of off-white color.Quality inspection, dry weight in wet base is 1.1%, and the content of different ursodesoxycholic acid is
0.099%, the content of allocholic acid is 0.5%, and the content of chenodeoxycholic acid is 96.4%.
Embodiment three
A method of different ursodesoxycholic acid in duck bile being removed, processing step is as follows：
（1）It is prepared by chenodeoxycholic acid crude product：Goose is made by butyl acetate magnesium salts method in 480 kilograms of bile acid starting material for taking duck courage
The weight in wet base of deoxycholic aicd crude product, crude product is 0.58%, and crude product weighs 73.2 kilograms, and the content of allocholic acid is 0.85% in crude product,
The content of different ursodesoxycholic acid is 7.3%.
（2）Prepare crystal solution：By step（1）The 73.2 kilograms of chenodeoxycholic acid crude products prepared put into 2000L stainless steels
The ethyl acetate that 439.2 kg of water are divided into 0.15% is added in kettle, adds the ethylene glycol that 36.6 kilograms of purity are 99.5%, stirring
It is heated to boiling, protects boil-off solution and be completely dissolved to crude product for 1 hour.It stands 1 hour and separates lower layer's water phase, pass through reaction kettle reflux water-dividing
Device adjusts the moisture of upper organic phase, and it is 0.87% to make the moisture of upper organic phase.Then upper organic phase is used into normal pressure
Concentration, the mixed solvent of metering recycling 237.9 kilograms of ethyl acetate and ethylene glycol, recycling finish, and the moisture of repetition measurement organic phase contains
Amount is 0.61%, is cooled to 29.5 DEG C.
0.22 kilogram of glacial acetic acid is added into above-mentioned organic phase, 10.98 kilograms of 120# gasoline are added, at a temperature of 30 DEG C
It stirs to clarify, the pH value for measuring and adjusting organic phase is 3.75, moisture 1.28%.
（3）Crystallization：By step（2）The crystal solution of preparation is stirred by the frequency conversion of 15HZ, is cooled to 25 DEG C, is then continuously stirred
Reaction 10 hours is mixed, crystal solution gradually becomes muddy by clarifying, by the embedded plate and frame filter press press filtration of 10 square meters, obtains different bear
312 kilograms of 8.2 kilograms of the filter residue of deoxycholic aicd and chenodeoxycholic acid crystal solution.Wherein, the filter residue of different ursodesoxycholic acid is in light ash
The floccule of color, its weight in wet base is 30.3% after testing, purity 89.7%.
（4）To step（3）In the 312 kilograms of chenodeoxycholic acid crystal solutions prepared, 1.56 kilograms of sodium carbonate liquors are added, add
Enter 78 kilograms of pure water, normal pressure concentration, control kettle internal solvent vapor (steam) temperature is 68 DEG C, recycles ethyl acetate and 120# in crystal solution
212 kilograms of the mixed solvent of gasoline.Solution in kettle is cooled to 30 DEG C after recycling completely, 156 kilograms of pure water is continuously added, stirs
After mixing uniformly, it is 3.5 to be neutralized to pH value with a concentration of 10% dilute hydrochloric acid, and with 1000 type stainless steel centrifuges, centrifugation sour water is logical
Sewage plant processing is crossed, centrifuges to obtain 88.1 kilograms of chenodeoxycholic acid wet product, then by air-flow boiled bed drying, obtain off-white color particle
51.8 kilograms of the chenodeoxycholic acid sterling of shape.Quality inspection, dry weight in wet base are 0.9%, and the content of different ursodesoxycholic acid is 0.089%, not
The content of cholic acid is 0.38%, and the content of chenodeoxycholic acid is 97.58%.
The inspection result of chenodeoxycholic acid crude product is as follows in above three embodiments：
The inspection result of chenodeoxycholic acid finished product is as follows in above three embodiments：
It can be obtained by the inspection data in two above table：Using the method for the present invention, extraction goose goes from duck bile raw material
When oxycholic acid, the chenodeoxycholic acid of high-content can be obtained and isolate different ursodesoxycholic acid to greatest extent this is obstinate
Impurity, and other related impurities such as allocholic acid can also obtain different degrees of removing.
Claims (7)
1. a kind of method for removing different ursodesoxycholic acid in duck bile, which is characterized in that processing step is as follows：
（1）It is prepared by chenodeoxycholic acid crude product：Using duck bile raw material, it is thick that chenodeoxycholic acid is obtained by butyl acetate magnesium salts legal system
Product；
（2）The preparation of crystal solution：In step（1）In the chenodeoxycholic acid crude product of preparation, ethyl acetate and ethylene glycol, stirring is added
It is heated to boiling, protects boil-off solution and be completely dissolved to crude product for 1 hour；It stands 1 hour and separates lower layer's water phase, pass through reaction kettle reflux water-dividing
Device adjusts the moisture of upper organic phase, and the moisture of upper organic phase is made to be less than 1.0%；Then by upper organic phase using normal
Pressure concentration, the ethyl acetate and ethylene glycol mixed solvent that metering recycling is added in the organic phase of concentration；Recycling finishes, and surveys again
The moisture for determining and adjusting organic phase is 1.0% hereinafter, being cooled to 29-30 DEG C, spare；
Glacial acetic acid and 120# gasoline are added into above-mentioned organic phase, is stirred to clarify under 28-30 DEG C of temperature condition, measures
And the pH value for adjusting organic phase be 3.5-4 between, moisture 1.2-1.5%；
（3）Crystallization：By step（2）The crystal solution of preparation is stirred by the frequency conversion of 12-15HZ, is cooled to 23-25 DEG C, is continuously stirred
Reaction 10-12 hours, crystal solution gradually become muddy by clarifying, and by embedded plate and frame filter press press filtration, obtain different bear deoxidation
The filter residue and chenodeoxycholic acid crystal solution of cholic acid；Wherein, the filter residue of different ursodesoxycholic acid be in ash gray floccule, after testing its
Weight in wet base is 29-31%, purity 89-91%；
（4）To step（3）In the chenodeoxycholic acid crystal solution of preparation, the sodium carbonate liquor of crystal solution deal 0.5% is added, is added
The pure water of crystal solution deal 25%, normal pressure concentration, control kettle internal solvent vapor (steam) temperature are 65-68 DEG C, recycle acetic acid in crystal solution
Solution stirring is cooled to 30 DEG C after recycling completely, continuously adds crystal solution deal 50% by the mixed solvent of ethyl ester and 120# gasoline
Pure water, with a concentration of 10% dilute hydrochloric acid be neutralized to pH value be 3.5, centrifugation, obtain chenodeoxycholic acid sterling, then pass through gas
Boiled bed drying is flowed, weight in wet base is obtained and dries sterling less than the granular chenodeoxycholic acid of off-white color that 1.2%, purity is 96-98%；
After testing, the content of different ursodesoxycholic acid is less than 0.1% in chenodeoxycholic acid sterling, and allocholic acid content is less than or equal to 0.5%.
2. the method for removing different ursodesoxycholic acid in duck bile as described in claim 1, which is characterized in that step（1）Middle system
The weight in wet base of standby chenodeoxycholic acid crude product is less than 0.6%, and the content of allocholic acid is less than 1.0%, and the content of different ursodesoxycholic acid is more than
7%。
3. the method for removing different ursodesoxycholic acid in duck bile as described in claim 1, which is characterized in that step（2）Middle second
The addition of acetoacetic ester is step（1）6 times of middle chenodeoxycholic acid crude product amount, and the moisture content for the ethyl acetate being added is less than 1%.
4. the method for removing different ursodesoxycholic acid in duck bile as described in claim 1, which is characterized in that step（2）Middle second
The addition of glycol is step（1）0.5 times of middle chenodeoxycholic acid crude product amount, and the purity for the ethylene glycol being added is 99.5%.
5. the method for removing different ursodesoxycholic acid in duck bile as described in claim 1, which is characterized in that step（2）In it is dense
After contracting organic phase, the yield of ethyl acetate and ethylene glycol mixed solvent is the half of the prior addition of mixed solvent.
6. the method for removing different ursodesoxycholic acid in duck bile as described in claim 1, which is characterized in that step（2）Have
The addition of glacial acetic acid is step in machine phase（1）0.003 times of middle chenodeoxycholic acid crude product amount.
7. the method for removing different ursodesoxycholic acid in duck bile as described in claim 1, which is characterized in that step（2）Have
The addition of 120# gasoline is step in machine phase（1）0.15 times of middle chenodeoxycholic acid crude product amount.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109810159A (en) * | 2019-01-22 | 2019-05-28 | 常德云港生物科技有限公司 | A kind of method that allocholic acid yield can be improved from duck bile |
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| CN105481928A (en) * | 2016-01-20 | 2016-04-13 | 常德云港生物科技有限公司 | Method for removing lithocholic acid from chenodeoxycholic acid |
| CN105566428A (en) * | 2016-01-20 | 2016-05-11 | 常德云港生物科技有限公司 | Method for removing hyocholic acid from chenodeoxycholic acid |
| CN106749473A (en) * | 2017-01-13 | 2017-05-31 | 常德云港生物科技有限公司 | A kind of method that chenodeoxycholic acid and allocholic acid are extracted in the bile from duck |
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| CN106749473A (en) * | 2017-01-13 | 2017-05-31 | 常德云港生物科技有限公司 | A kind of method that chenodeoxycholic acid and allocholic acid are extracted in the bile from duck |
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Denomination of invention: A method for removing isoursodeoxycholic acid from duck bile Effective date of registration: 20220210 Granted publication date: 20200602 Pledgee: Bank of Changsha Limited by Share Ltd. Changde science and Technology Branch Pledgor: CHANGDE YUNGANG BIOTECHNOLOGY Co.,Ltd. Registration number: Y2022980001452 |
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