CN105566428B - A kind of method that hyocholic acid is removed from chenodeoxycholic acid - Google Patents
A kind of method that hyocholic acid is removed from chenodeoxycholic acid Download PDFInfo
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- CN105566428B CN105566428B CN201610036122.5A CN201610036122A CN105566428B CN 105566428 B CN105566428 B CN 105566428B CN 201610036122 A CN201610036122 A CN 201610036122A CN 105566428 B CN105566428 B CN 105566428B
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- acid
- butyl acetate
- chenodeoxycholic acid
- chenodeoxycholic
- cdca
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- 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 66
- 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 52
- 229960001091 chenodeoxycholic acid Drugs 0.000 title claims abstract description 52
- DKPMWHFRUGMUKF-UHFFFAOYSA-N (3alpha,5alpha,6alpha,7alpha)-3,6,7-Trihydroxycholan-24-oic acid Natural products OC1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DKPMWHFRUGMUKF-UHFFFAOYSA-N 0.000 title claims abstract description 16
- JOYGXTIHTHBSOA-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-thiophen-2-ylprop-2-en-1-one Chemical compound C1=CC(Cl)=CC=C1C(=O)C=CC1=CC=CS1 JOYGXTIHTHBSOA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 13
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims abstract description 32
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000005119 centrifugation Methods 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 15
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 10
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 8
- 239000003613 bile acid Substances 0.000 claims abstract description 8
- 238000004945 emulsification Methods 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 238000009835 boiling Methods 0.000 claims abstract description 7
- 239000002893 slag Substances 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 34
- 239000000047 product Substances 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- 239000002244 precipitate Substances 0.000 claims description 12
- 150000003863 ammonium salts Chemical class 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000006166 lysate Substances 0.000 claims description 10
- 239000012452 mother liquor Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 241000272814 Anser sp. Species 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- 210000000941 bile Anatomy 0.000 claims description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 230000011218 segmentation Effects 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 4
- 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 3
- 239000004380 Cholic acid Substances 0.000 claims description 3
- 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 3
- 229960002471 cholic acid Drugs 0.000 claims description 3
- 235000019416 cholic acid Nutrition 0.000 claims description 3
- 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 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 125000003907 chenodeoxycholic acid group Chemical group 0.000 claims description 2
- 230000000536 complexating effect Effects 0.000 claims description 2
- 230000008719 thickening Effects 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 8
- -1 dissolving Chemical compound 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 238000010668 complexation reaction Methods 0.000 abstract description 2
- 238000002955 isolation Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 230000008929 regeneration Effects 0.000 abstract description 2
- 238000011069 regeneration method Methods 0.000 abstract description 2
- 210000003298 dental enamel Anatomy 0.000 description 9
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 8
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic 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)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- DGABKXLVXPYZII-SIBKNCMHSA-N hyodeoxycholic acid Chemical compound C([C@H]1[C@@H](O)C2)[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 DGABKXLVXPYZII-SIBKNCMHSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229910001220 stainless steel Inorganic materials 0.000 description 6
- 239000010935 stainless steel Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 206010013786 Dry skin Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 238000011895 specific detection Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 238000010813 internal standard method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229940054870 urso Drugs 0.000 description 2
- 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 description 2
- 150000001412 amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000010812 external standard method Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a kind of method that hyocholic acid is removed from chenodeoxycholic acid, including dissolving, removing slag, be complexed, crystallization, centrifugation, emulsification, acidifying, drying, step etc. mother liquid disposal, it is solvent using higher boiling butyl acetate, reduce the volatilization of solvent, and using the butyl acetate stripping property unique to impurity, preferable separating effect is reached, the solvent is three class low toxicities danger category；Using the characteristic of sec-butylamine selective complexation bile acid, can higher degree separation hyocholic acid and other impurity.The disposable removal of impurities of isolation and purification method of the invention is qualified, and the chenodeoxycholic acid proportion of goods damageds are less than 5%, the active ingredient loss of conventional crystallization method 30%, and solvent energy regeneration are significantly less than, three wastes are produced, and are a kind of environmentally friendly, low expense, efficient separation method.
Description
Technical field
The present invention relates to chenodeoxycholic acid extractive technique field, and in particular to one kind removes hyocholic acid from chenodeoxycholic acid
Method.
Background technology
Chenodeoxycholic acid is the primary raw material of urso synthesis, because the demand of urso is increased dramatically, is led
Supply falls short of demand to cause chenodeoxycholic acid.Pig's bile is a kind of biological not regenerated resources, and its TBA content is 10%, wherein containing
Chenodeoxycholic acid account for the 40% of TBA content, thus be a kind of very excellent chenodeoxycholic acid raw materials for production.But due to
It is also containing accounting for the hyocholic acid of TBA content 5% in pig's bile and close with CDCA Acidity, in chenodeoxycholic acid plus
During work extraction purification, easily crystallization, according to current conventional separation method --- the selective crystallization in mixed solvent,
Its inferior separating effect, efficiency is low, and mother liquor needs fractional crystallization repeatedly, causes technological process long, and solvent loss is big, in crystallization process also
Substantial amounts of chenodeoxycholic acid can be taken out of, cause to waste and improve production cost.
The content of the invention
Difficulty is big, effect is poor, efficiency is low, high cost problem when the present invention is removed for above-mentioned hyocholic acid impurity, there is provided
It is a kind of it is simple efficiently, low cost and the good method that hyocholic acid is removed from chenodeoxycholic acid of elimination effect.
Technical scheme：A kind of method that hyocholic acid is removed from chenodeoxycholic acid, it is characterised in that including such as
Lower step：
（1）Dissolve, remove slag：The chenodeoxycholic acid crude product extracted from pig's bile of rough segmentation de-oiling is taken, 4-5 times of goose is added
The butyl acetate of deoxycholic aicd crude product amount, is flowed back 1 hour after being heated to boiling, adds activated carbon, and the deal of activated carbon is gone for goose
The 8-10% of oxycholic acid crude product amount, is stirred at reflux 1 hour, is then incubated by titanium rod filter bank and filtered, and obtains chenodeoxycholic acid second
Acid butyl ester lysate；
（2）Complexing, crystallization：Chenodeoxycholic acid butyl acetate lysate is cooled to 40 DEG C, sec-butylamine is added, sec-butylamine
Deal is the 10-12% of chenodeoxycholic acid crude product amount, and insulated and stirred 1 hour is cooled to normal temperature, and crystallization 4 hours must mix suspended
Liquid；
（3）Centrifugation：Mixing suspension is centrifuged, CDCA acid ammonium salt is obtained after separation of solid and liquid and butyl acetate is female
Liquid, it is standby；
（4）Emulsify, be acidified, dry：CDCA acid ammonium salt is added water emulsification, the addition of water is chenodeoxycholic acid crude product
4-4.5 times of amount, stirring is warming up to 35 DEG C, adds the hydrochloric acid that concentration is 10%, after regulation pH value to 2-3, continues to stir 30 points
Clock, keeps pH value 2-3 during stirring, be then centrifuged for separating, and obtains chenodeoxycholic acid finished product wet product, centrifugation sour water, wherein goose deoxidation
Cholic acid finished product wet product enters drying shed, dry chenodeoxycholic acid finished product；The centrifugation sour water of collection is used for lower batch of chenodeoxycholic acid
Ammonium salt emulsification acidifying, recycles；
（5）Mother liquid disposal：It is 0.4 atmospheric pressure by butyl acetate mother liquor vacuum concentration, vacuum, thickening temperature is 80
DEG C, butyl acetate, concentration precipitate are obtained, wherein butyl acetate is acid treated, recycles, and concentrates precipitate through drying
Afterwards, it is used for foodstuff additive as mixing bile acid, takes out.
Compared with prior art, advantages of the present invention：1st, it is solvent using higher boiling butyl acetate, reduces waving for solvent
Hair, and using the butyl acetate stripping property unique to impurity, preferable separating effect has been reached, the solvent is dangerous three class low toxicities
Category.2nd, using the characteristic of sec-butylamine selective complexation bile acid, can higher degree separation hyocholic acid and other impurity.3rd, should
The disposable removal of impurities of isolation and purification method is qualified, and the chenodeoxycholic acid proportion of goods damageds are less than 5%, are significantly less than conventional crystallization method 30%
Active ingredient is lost, and solvent energy regeneration, and three wastes are produced, and are a kind of environmentally friendly, low expense, efficient separation method.
Specific embodiment
In conjunction with embodiment, the invention will be further elaborated.
Embodiment one
Take the chenodeoxycholic acid crude product extracted from pig's bile of 120 kg rough segmentation de-oiling（HPLC contents 61.3%, tool
Body Testing index sees attached list one）, in input 1000L enamel extraction kettles, 600 kilograms of butyl acetates are added, returned after being heated to boiling
Stream 1 hour, adds 12 kilograms of activated carbon, continues to be stirred at reflux 1 hour, is then incubated by titanium rod filter bank and filtered, and obtains goose
Deoxycholic aicd butyl acetate lysate.
Chenodeoxycholic acid butyl acetate lysate is pumped into 1000L enamel stillpots, 40 DEG C are cooled to, sec-butylamine is added
12 kilograms, insulated and stirred 1 hour is cooled to 25 DEG C of normal temperature, and crystallization 4 hours obtains mixing suspension.
Mixing suspension is put into D800 cleaning closed type stainless steel centrifuges and is centrifuged, CDCA is obtained after separation of solid and liquid
Amine acid salt and butyl acetate mother liquor, wherein 95.1 kilograms of CDCA acid ammonium salt net weight.
By in 95.1 kilograms of CDCA amine acid salts input 1000L enamel souring tanks, the emulsification of 500L pure water, stirring is added to rise
Temperature is slowly added to the hydrochloric acid that concentration is 10% to 35 DEG C, after regulation solution ph to 2-3, continues to stir 30 minutes, and period keeps
PH value 2-3, is then discharged to centrifugation in D800 type common stainless steel centrifuges, obtains chenodeoxycholic acid finished product wet product, centrifugation sour water,
During wherein drying shed is sent in the pack of chenodeoxycholic acid finished product wet product, dried using 4 × 0.25 air-flow boiling-bed dryings, obtain CDCA
75.96 kilograms of sour finished product, after testing, its chromatographic content 92.1%, conversion ratio（75.96×92.1%）÷（120×61.3）×
100/100=95.2%, pig gall acid content 0.85%, specific testing result sees attached list two；And the centrifugation sour water collected is to glue tank
In keep in, for the emulsification acidifying of the lower batch of ammonium salt, recycle.
Butyl acetate mother liquor is pumped into 1000L vacuum concentration pots, and the atmospheric pressure of vacuum 0.4,80 DEG C of temperature is concentrated to give butyl acetate
558 kilograms, 33 kilograms of concentration precipitate dry weight, wherein butyl acetate is acid treated, recycles；And precipitate is concentrated through dry
It is used for foodstuff additive as mixing bile acid after dry, takes out.After testing, pig gall acid content 21.09%, goose in concentration precipitate
Deoxycholic aicd content 6.5%, hyodesoxycholic acid, lithocholic acid and fat content amount to 11%, and specific detection sees attached list three.
Embodiment two
Take 110 kilograms of chenodeoxycholic acid crude products extracted from pig's bile of rough segmentation de-oiling（HPLC contents 59.7%, tool
Body Testing index sees attached list one）Input 1000L enamel is extracted in kettle, adds 540 kilograms of butyl acetates, is flowed back after being heated to boiling
1 hour, 10 kilograms of activated carbon is added, continue to be stirred at reflux 1 hour, be then incubated by titanium rod filter bank and filtered, obtained goose and go
Oxycholic acid butyl acetate lysate.
Chenodeoxycholic acid butyl acetate lysate is pumped into 1000L enamel stillpots, 40 DEG C are cooled to, sec-butylamine is added
11 kilograms, insulated and stirred 1 hour is cooled to 25 DEG C of normal temperature, and crystallization 4 hours obtains mixing suspension.
Mixing suspension is put into D800 cleaning closed type stainless steel centrifuges, is centrifuged, obtain CDCA
Amine acid salt and butyl acetate mother liquor, wherein 86.8 kilograms of CDCA acid ammonium salt net weight.
By in 86.8 kilograms of CDCA amine acid salts input 1000L enamel souring tanks, the emulsification of 450L pure water, stirring is added to rise
Temperature is slowly added to the hydrochloric acid that concentration is 10% to 35 DEG C, after regulation pH value to 2-3, continues to stir 30 minutes, is kept during stirring
PH value 2-3, is then discharged to centrifugation in D800 type common stainless steel centrifuges, obtains chenodeoxycholic acid finished product wet product, centrifugation
Drying shed is sent in the pack of sour water, wherein chenodeoxycholic acid finished product wet product, is dried using 4 × 0.25 air-flow boiling-bed dryings, obtains goose and goes
67.38 kilograms of oxycholic acid finished product, after testing, its chromatographic content 92.4%, conversion ratio（67.38×92.4%）÷（110×59.7%）
× 100/100=94.8%, pig gall acid content is 0.89%, and specific testing result sees attached list two；And the centrifugation sour water being collected into
For lower batch of CDCA acid ammonium salt emulsified acid, recycle.
Butyl acetate mother liquor is pumped into 1000L vacuum concentration pots, the atmospheric pressure of vacuum 0.4,80 DEG C of temperature is concentrated to give acetic acid fourth
501 kilograms of ester, 30.1 kilograms of concentration precipitate thing dry weight, wherein butyl acetate is acid treated, recycles, and concentrates and separate out
Thing is used for foodstuff additive as mixing bile acid after drying, takes out.After testing, pig gall acid content in concentration precipitate
23.2%, CDCA acid content 5.7%, hyodesoxycholic acid, lithocholic acid and fat content amount to 10.9%, and specific detection sees attached list
Three.
Embodiment three
Take 125 kilograms of chenodeoxycholic acid crude products extracted from pig's bile of rough segmentation de-oiling（HPLC contents 63.3%, tool
Body Testing index sees attached list one）Input 1000L enamel is extracted in kettle, adds 625 kilograms of butyl acetates, is flowed back after being heated to boiling
1 hour, 12.5 kilograms of activated carbon is added, continue to be stirred at reflux 1 hour, be then incubated by titanium rod filter bank and filtered, obtain goose
Deoxycholic aicd butyl acetate lysate.
Chenodeoxycholic acid butyl acetate lysate is pumped into 1000L enamel stillpots, 40 DEG C are cooled to, sec-butylamine is added
12.5 kilograms, insulated and stirred 1 hour is cooled to 25 DEG C of normal temperature, and crystallization 4 hours obtains mixing suspension.
Mixing suspension is put into D800 cleaning closed type stainless steel centrifuges, is centrifuged, obtain CDCA
Amine acid salt and butyl acetate mother liquor, wherein 100.6 kilograms of CDCA acid ammonium salt net weight.
By in 100.6 kilograms of CDCA amine acid salts input 1000L enamel souring tanks, the emulsification of 500L pure water, stirring are added
35 DEG C are warming up to, the hydrochloric acid that concentration is 10% is slowly added to, after regulation solution ph to 2-3, continue to stir 30 minutes, stir the phase
Between keep pH value 2-3, be then discharged to centrifugation in D800 type common stainless steel centrifuges, obtain chenodeoxycholic acid finished product wet
Product, centrifugation sour water, wherein chenodeoxycholic acid finished product wet product pack are sent drying shed, are dried using 4 × 0.25 air-flow boiling-bed dryings,
Obtain 80.73 kilograms of chenodeoxycholic acid finished product, after testing, its chromatographic content 93.8%, conversion ratio（80.7×93.8%）÷（125×
63.3%）× 100/100=95.7%, pig gall acid content is 0.66%, and specific testing result sees attached list two；And the centrifugation collected
Sour water is kept in delivering to glue tank, for lower batch of CDCA acid ammonium salt emulsified acid, is recycled.
Butyl acetate mother liquor is pumped into 1000L vacuum concentration pots, the atmospheric pressure of vacuum 0.4,80 DEG C of temperature is concentrated to give acetic acid fourth
558 kilograms of ester, 35.7 kilograms of concentration precipitate dry weight, wherein butyl acetate is acid treated, recycles, and concentrates precipitate
It is used for foodstuff additive as mixing bile acid after drying, takes out.After testing, pig gall acid content 20.8% in concentration precipitate,
CDCA acid content 6.1%, hyodesoxycholic acid, lithocholic acid and fat content amount to 13.2%, and specific detection sees attached list three.
Detection chenodeoxycholic acid crude product, finished product and its leftover bits and pieces mixing bile acid, its index parameter such as subordinate list one, subordinate list
2nd, shown in subordinate list three.
Subordinate list one：Chenodeoxycholic acid crude product assay（This content is the detection of HPLC internal standard methods, and lithocholic acid uses thin layer
Chromatography）
| Lot number | Chenodeoxycholic acid | Hyocholic acid | Hyodesoxycholic acid | Lithocholic acid | Loss on drying |
| Example one（20150501） | 61.3% | 5.8% | 0.37% | ≤1.0% | 2.5% |
| Example two（20150502） | 59.7% | 5.1% | 0.47% | ≤1.0% | 2.8% |
| Example three（20150503） | 63.3% | 4.9% | 0.35% | ≤1.0% | 2.1% |
Subordinate list two：Chenodeoxycholic acid product inspection result（This content is the detection of HPLC internal standard methods, and lithocholic acid uses thin layer
Chromatography）
| Lot number | Chenodeoxycholic acid | Hyocholic acid | Hyodesoxycholic acid | Lithocholic acid | Loss on drying |
| Example one（20150501） | 92.1% | 0.85% | 0.34% | ≤0.2% | 1.3% |
| Example two（20150502） | 92.4% | 0.89% | 0.41% | ≤0.2% | 0.9% |
| Example three（20150503） | 93.8% | 0.66% | 0.27% | ≤0.2% | 0.77% |
Subordinate list three：Leftover bits and pieces assay（This content is the detection of HPLC external standard methods）
| Lot number | Chenodeoxycholic acid | Hyocholic acid | Other TBAs |
| Example one（20150501） | 6.5% | 21.09% | 11% |
| Example two（20150502） | 5.7% | 23.2% | 10.9% |
| Example three（20150503） | 6.1% | 20.8% | 13.2% |
Can be illustrated according to above assay, by method of the present invention chenodeoxycholic acid after purification, through efficient liquid
Phase chromatogram detect, CDCA acid content in 92-94%, its major impurity：Hyodesoxycholic acid is less than 0.5%, and hyocholic acid is less than 1%,
Lithocholic acid is less than 0.2%, the miscellaneous control of hyocholic acid list within 1%, other it is single it is miscellaneous be completely below 0.5%, reached the deoxidation of processing bear
The quality standard of cholic acid EP7.0 and CP2010.
Claims (1)
1. it is a kind of from chenodeoxycholic acid remove hyocholic acid method, it is characterised in that comprise the following steps：
（1）Dissolve, remove slag：The chenodeoxycholic acid crude product extracted from pig's bile of rough segmentation de-oiling is taken, 4-5 times of goose deoxidation is added
The butyl acetate of cholic acid crude product amount, flows back 1 hour after being heated to boiling, adds activated carbon, and the deal of activated carbon is CDCA
The 8-10% of acid crude amount, is stirred at reflux 1 hour, is then incubated by titanium rod filter bank and filtered, and obtains chenodeoxycholic acid acetic acid fourth
Ester lysate；
（2）Complexing, crystallization：Chenodeoxycholic acid butyl acetate lysate is cooled to 40 DEG C, sec-butylamine, the deal of sec-butylamine is added
It is the 10-12% of chenodeoxycholic acid crude product amount, insulated and stirred 1 hour is cooled to normal temperature, and crystallization 4 hours obtains mixing suspension；
（3）Centrifugation：Mixing suspension is centrifuged, CDCA acid ammonium salt and butyl acetate mother liquor are obtained after separation of solid and liquid, it is standby
With；
（4）Emulsify, be acidified, dry：CDCA acid ammonium salt is added water emulsification, the addition of water is chenodeoxycholic acid crude product amount
4-4.5 times, stirring is warming up to 35 DEG C, adds the hydrochloric acid that concentration is 10%, after regulation pH value to 2-3, continues to stir 30 minutes, stirs
PH value 2-3 is kept during mixing, is then centrifuged for separating, obtain chenodeoxycholic acid finished product wet product, centrifugation sour water, wherein chenodeoxycholic acid into
Product wet product enters drying shed, dry chenodeoxycholic acid finished product；The centrifugation sour water of collection is used for lower batch of CDCA acid ammonium salt breast
Change acidifying, recycle；
（5）Mother liquid disposal：By butyl acetate mother liquor vacuum concentration, vacuum is 0.4 atmospheric pressure, and thickening temperature is 80 DEG C, is obtained
Butyl acetate, concentration precipitate, wherein butyl acetate are acid treated, recycle, and concentrate precipitate after drying, as
Mixing bile acid is used for foodstuff additive, takes out.
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| CN109810159B (en) * | 2019-01-22 | 2021-05-11 | 常德云港生物科技有限公司 | Method for improving yield of allopholic acid from duck bile |
| CN112062802A (en) * | 2019-06-11 | 2020-12-11 | 四川澄华生物科技有限公司 | Chenodeoxycholic acid butyl acetate extracting solution and preparation method thereof, and chenodeoxycholic acid ammonium salt and chenodeoxycholic acid preparation method |
| CN110256517B (en) * | 2019-07-19 | 2021-03-09 | 中山百灵生物技术股份有限公司 | Method for producing high-purity chenodeoxycholic acid from pig bile or leftovers |
| CN110790805B (en) * | 2019-11-14 | 2022-08-30 | 湖南九典制药股份有限公司 | Method for extracting chenodeoxycholic acid from pig bile paste |
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