CN103772465A - Preparation method of high-purity hyodeoxycholic acid - Google Patents
Preparation method of high-purity hyodeoxycholic acid Download PDFInfo
- Publication number
- CN103772465A CN103772465A CN201410019946.2A CN201410019946A CN103772465A CN 103772465 A CN103772465 A CN 103772465A CN 201410019946 A CN201410019946 A CN 201410019946A CN 103772465 A CN103772465 A CN 103772465A
- Authority
- CN
- China
- Prior art keywords
- hyodeoxycholic acid
- preparation
- acid
- water
- high purity
- Prior art date
- 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.)
- Granted
Links
- DGABKXLVXPYZII-UHFFFAOYSA-N Hyodeoxycholic acid Natural products C1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DGABKXLVXPYZII-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 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 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 72
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000003756 stirring Methods 0.000 claims abstract description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 7
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- 239000006228 supernatant Substances 0.000 claims abstract description 6
- 238000012360 testing method Methods 0.000 claims abstract description 6
- 238000001291 vacuum drying Methods 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- -1 add highly basic Substances 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 20
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000001556 precipitation Methods 0.000 claims description 10
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- 238000007127 saponification reaction Methods 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- 238000013517 stratification Methods 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- 241001062009 Indigofera Species 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 210000000941 bile Anatomy 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 3
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 239000012530 fluid Substances 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 239000002244 precipitate Substances 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 239000008923 Qingkailing Substances 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002479 acid--base titration Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001663 anti-spastic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 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 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 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 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of high-purity hyodeoxycholic acid, which comprises the following steps: taking raw materials, adding strong base and water, saponifying at 95-100 ℃ for 16-24h, cooling to room temperature, standing, siphoning out supernatant fluid, discarding, adding water into lower-layer paste, stirring and dissolving, enhancing acid acidification until Congo red test paper turns blue, adding ethyl acetate, stirring and extracting for 20-50min, standing and layering, discarding water phase, adding ethyl acetate, washing until pH =6-7 of water phase, adding anhydrous sodium sulfate into ethyl acetate phase for dehydration, decolorizing with activated carbon, filtering, concentrating until precipitate is separated out, cooling, filtering or squeezing, and vacuum drying; adding alcohol solvent, stirring for dissolving, slowly adding alkaline organic solvent, stirring, cooling, precipitating, filtering, and drying; adding water and sodium hydroxide, stirring for dissolving, dropwise adding hydrochloric acid with the volume ratio of 1:1, stirring, filtering, and drying to obtain hyodeoxycholic acid. The invention aims to provide a preparation method of hyodeoxycholic acid, which is simple in process, high in product yield and high in purity.
Description
Technical field
The present invention relates to a kind of preparation method of high purity Hyodeoxycholic Acid.
Background technology
Hyodeoxycholic Acid (Hyodesoxycholic Acid, HDCA) is a kind of biochemical substances being extensively present in animal bile, and content is 0.1%～0.2%, and chemical name is 3 α, 6 alpha-dihydroxy--5 β-ursodeoxycholic acids, molecular formula C
24h
40o
4, molecular weight is 392.58, easily molten in ethanol, slightly soluble in acetone, and soluble,very slightly in ethyl acetate, chloroform or ether, almost insoluble in water.The effect that HDCA has reducing blood-fat, antispastic and eliminates the phlegm, is used for the treatment of hyperlipidemia, atherosclerosis, trachitis, child virus upper respiratory tract infection clinically, and the maldigestion being caused by liver and gall diseases; Bacillus pertussis, diphtheria corynebacterium, streptococcus aureus etc. are had to certain restraining effect; As the effective constituent in QINGKAILING ZHUSHEJI, through clinical observation, the treatment of acute leukemia is had to good action, experiment in vitro proves that HDCA has cell death inducing, suppresses the effect that cell proliferation is divided.
At present, the content of the Hyodeoxycholic Acid that " Chinese Pharmacopoeia " is written into is greater than 90%, is to adopt determination of acid-basetitration.The content that commercially available Hyodeoxycholic Acid indicates is 98%, fusing point 197-199 ℃, but, show by thin-layer chromatographic analysis, wherein contain the impurity of more amount, further analyze by high performance liquid chromatography, find except Hyodeoxycholic Acid, foreign matter content accounts for 9-15% left and right.
Produce at present Hyodeoxycholic Acid technology and mainly contain following three kinds:
1, ethyl acetate or acetone recrystallization method, though this technology main drawback is to produce the product of fusing point more than 195, product liquid phase purity is low, between Hyodeoxycholic Acid liquid phase purity 88-95%.
2, esterification acetylate derivatization method, although this technology can be produced highly purified Hyodeoxycholic Acid, Hyodeoxycholic Acid purity more than 98%, is used the strong carcinogens such as benzene in technological process, technique is more loaded down with trivial details, is not suitable for suitability for industrialized production.
3, chromatography column method, this technology first goes pig cholic acid crude product to carry out esterification, then goes up silicagel column and separates, and the main drawback of this method is that the production cycle is long, and production efficiency is low.
So, in order to improve Hyodeoxycholic Acid product purity, overcome that existing HDCA purification process technique is loaded down with trivial details, not easy to operate, the production cycle is long, high in cost of production defect, is badly in need of a kind of technological method with advantages such as the large production of the technology of being easy to, cost are low, with short production cycle of exploitation.
Summary of the invention
The object of the invention is, in order to overcome weak point of the prior art, provides a kind of technique simple, and product yield is high, the preparation method of the Hyodeoxycholic Acid that purity is high.
In order to achieve the above object, the present invention adopts following scheme:
A preparation method for high purity Hyodeoxycholic Acid, is characterized in that comprising the following steps:
The preparation of A, Hyodeoxycholic Acid crude product
Get raw material, add highly basic, water, saponification 16-24h at 95-100 ℃, be chilled to room temperature, leave standstill, siphon goes out supernatant liquor and discards, lower floor's paste adds water stirring and dissolving, add strong acid and be acidified to congo-red test paper change indigo plant, add ethyl acetate to stir extraction 20-50min, stratification, water discards, ethyl acetate is added and is washed to water pH=6-7, and ethyl acetate is added to anhydrous sodium sulfate dehydration, activated carbon decolorizing, filter, be concentrated into Precipitation, be cooled to 0-5 ℃, filtered or squeezing, vacuum-drying, obtains Hyodeoxycholic Acid crude product; Wherein said raw material is fresh pig bile or bilirubin tankage;
The preparation of B, Hyodeoxycholic Acid amine salt
Hyodeoxycholic Acid crude product in steps A adds alcoholic solvent, and stirring and dissolving slowly adds alkali organic solvent to stir, and is cooled to 0-5 ℃, has a large amount of Precipitations, and filtration drying obtains Hyodeoxycholic Acid amine salt;
The preparation of C, high purity Hyodeoxycholic Acid
Hyodeoxycholic Acid amine salt in step B adds water, sodium hydroxide, and stirring and dissolving, drips volume ratio 1:1 hydrochloric acid, stirs, and filters, and is dried to obtain Hyodeoxycholic Acid.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, is characterized in that the tankage of bilirubin described in steps A, highly basic, and the mass ratio of water is bilirubin tankage: highly basic: water=1:0.1-0.5:0.1-0.3.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, is characterized in that the highly basic described in steps A is potassium hydroxide or potassium hydroxide.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, is characterized in that strong acid described in steps A is concentrated hydrochloric acid or 50% sulfuric acid.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, it is characterized in that ethyl acetate described in steps A with the volume mass of, gac than being ethyl acetate (ml): anhydrous sodium sulphate (g): gac (g)=60-100ml:1-3g:1g.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, it is characterized in that Hyodeoxycholic Acid crude product and alcoholic solvent in step B, the weightmeasurement ratio of alkali organic solvent is Hyodeoxycholic Acid crude product (g): alcoholic solvent (ml): alkali organic solvent (g)=1g:4-8ml:0.2-0.5g.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, it is characterized in that Hyodeoxycholic Acid amine salt and water in step C, sodium hydroxide, the mass volume ratio of hydrochloric acid is Hyodeoxycholic Acid amine salt (g): water (ml): sodium hydroxide (g): hydrochloric acid (ml)=1:8-12:0.05-0.15:0.4-0.8.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, is characterized in that described hydrochloric acid is the hydrochloric acid of 1:1 volumetric concentration.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, is characterized in that alcoholic solvent described in step B is one or more the mixture in ethanol, methyl alcohol, Virahol, the trimethyl carbinol, sec-butyl alcohol.
The preparation method of a kind of high purity Hyodeoxycholic Acid as above, is characterized in that the alkali organic solvent described in step B is one or more the mixture in triethylamine, methylamine, diethylamine, propylamine, TERTIARY BUTYL AMINE, aniline.
In sum, beneficial effect of the present invention:
1, technological operation of the present invention is simple, is easy to industrialized production.
2, solvent environment close friend in the present invention.
3, product yield is high, and product purity is high.
Embodiment
Below in conjunction with embodiment, the present invention is described further:
Embodiment 1
1, the preparation of Hyodeoxycholic Acid crude product
Get bilirubin tankage 100g, add sodium hydroxide or potassium hydroxide 30g, water 200ml, 98 ℃ of saponification 20h, be chilled to room temperature, leave standstill, siphon goes out supernatant liquor and discards, lower floor's paste adds water 200ml, stirring and dissolving, adds concentrated hydrochloric acid and is acidified to congo-red test paper change indigo plant, adds ethyl acetate 800ml to stir extraction 30min, stratification, water discards.Ethyl acetate is added to 800ml and is washed to water pH=6, and ethyl acetate is added to anhydrous sodium sulphate 20g dehydration, 10g activated carbon decolorizing 30min, filter, be concentrated into 160ml left and right, have Precipitation, be cooled to 3 ℃, filter or squeezing vacuum drying Hyodeoxycholic Acid crude product 35g.
2, Hyodeoxycholic Acid amine salt preparation
Hyodeoxycholic Acid crude product 35g, adds dehydrated alcohol 200ml, stirring and dissolving, and slowly stream adds triethylamine 10.5g, stirs 2h, is cooled to 2 degree, has a large amount of Precipitations.Filtration drying obtains Hyodeoxycholic Acid amine salt 20g.
3, the preparation of high purity hdca
Hyodeoxycholic Acid amine salt 20g, adds water 200ml, sodium hydroxide 2g, and stirring and dissolving, to drip volumetric concentration be 1:1 hydrochloric acid 12ml, stirs 1h, filters, the dry Hyodeoxycholic Acid 15g that to obtain, liquid content is more than 99%, fusing point 200-201 ℃.
Embodiment 2
1, the preparation of Hyodeoxycholic Acid crude product
Get bilirubin tankage 100g, add sodium hydroxide or potassium hydroxide 10g, water 10g, 95 ℃ of saponification 16h, be chilled to room temperature, leave standstill, siphon goes out supernatant liquor and discards, lower floor's paste adds water 200ml, stirring and dissolving, adds 50% sulfuric acid acidation to congo-red test paper and becomes blue, adds ethyl acetate 600ml to stir extraction 30min, stratification, water discards.Ethyl acetate is added to 800ml and is washed to water pH=6, and ethyl acetate is added to anhydrous sodium sulphate 10g dehydration, 10g activated carbon decolorizing 30min, filter, be concentrated into 160ml left and right, have Precipitation, be cooled to 0 ℃, filter or squeezing vacuum drying Hyodeoxycholic Acid crude product 34.8g.
2, Hyodeoxycholic Acid amine salt preparation
Hyodeoxycholic Acid crude product 34.8g, adds dehydrated alcohol 200ml, stirring and dissolving, and slowly stream adds triethylamine 10.5g, stirs 2h, is cooled to 0 ℃, has a large amount of Precipitations.Filtration drying obtains Hyodeoxycholic Acid amine salt 19g.
3, the preparation of high purity hdca
Hyodeoxycholic Acid amine salt 19g, adds water 160ml, sodium hydroxide 1g, and stirring and dissolving, to drip volumetric concentration be 1:1 hydrochloric acid 8ml, stirs 1h, filters, the dry Hyodeoxycholic Acid 14.5g that to obtain, liquid content is more than 99%, fusing point 200-201 ℃.
Embodiment 3
1, the preparation of Hyodeoxycholic Acid crude product
Get fresh pig bile 1000ml, add sodium hydroxide or potassium hydroxide 50g, water 300ml, 100 ℃ of saponification 24h, be chilled to room temperature, leave standstill, siphon goes out supernatant liquor and discards, lower floor's paste adds water 200ml, stirring and dissolving, adds concentrated hydrochloric acid and is acidified to congo-red test paper change indigo plant, adds ethyl acetate 1000ml to stir extraction 30min, stratification, water discards.Ethyl acetate is added to 1000ml and is washed to water pH=7, and ethyl acetate is added to anhydrous sodium sulphate 19.5g dehydration, 10g activated carbon decolorizing 30min, filter, be concentrated into 160ml left and right, have Precipitation, be cooled to 5 ℃, filter or squeezing vacuum drying Hyodeoxycholic Acid crude product 34.2g.
2, Hyodeoxycholic Acid amine salt preparation
Hyodeoxycholic Acid crude product 34.2g, adds dehydrated alcohol 250ml, stirring and dissolving, and slowly stream adds triethylamine 15g, stirs 2h, is cooled to 5 degree, has a large amount of Precipitations.Filtration drying obtains Hyodeoxycholic Acid amine salt 19.3g.
3, the preparation of high purity hdca
Hyodeoxycholic Acid amine salt 19.3g, adds water 230ml, sodium hydroxide 2.5g, and stirring and dissolving, to drip volumetric concentration be 1:1 hydrochloric acid 15ml, stirs 1h, filters, the dry Hyodeoxycholic Acid 14.8g that to obtain, liquid content is more than 99%, fusing point 200-201 ℃.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that in above-described embodiment and specification sheets, describes just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (10)
1. a preparation method for high purity Hyodeoxycholic Acid, is characterized in that comprising the following steps:
The preparation of A, Hyodeoxycholic Acid crude product
Get raw material, add highly basic, water, saponification 16-24h at 95-100 ℃, be chilled to room temperature, leave standstill, siphon goes out supernatant liquor and discards, lower floor's paste adds water stirring and dissolving, add strong acid and be acidified to congo-red test paper change indigo plant, add ethyl acetate to stir extraction 20-50min, stratification, water discards, ethyl acetate is added and is washed to water pH=6-7, and ethyl acetate is added to anhydrous sodium sulfate dehydration, activated carbon decolorizing, filter, be concentrated into Precipitation, be cooled to 0-5 ℃, filtered or squeezing, vacuum-drying, obtains Hyodeoxycholic Acid crude product; Wherein said raw material is fresh pig bile or bilirubin tankage;
The preparation of B, Hyodeoxycholic Acid amine salt
Hyodeoxycholic Acid crude product in steps A adds alcoholic solvent, and stirring and dissolving slowly adds alkali organic solvent to stir, and is cooled to 0-5 ℃, has a large amount of Precipitations, and filtration drying obtains Hyodeoxycholic Acid amine salt;
The preparation of C, high purity Hyodeoxycholic Acid
Hyodeoxycholic Acid amine salt in step B adds water, sodium hydroxide, and stirring and dissolving, drips volume ratio 1:1 hydrochloric acid, stirs, and filters, and is dried to obtain Hyodeoxycholic Acid.
2. the preparation method of a kind of high purity Hyodeoxycholic Acid according to claim 1, is characterized in that the tankage of bilirubin described in steps A, highly basic, and the mass ratio of water is bilirubin tankage: highly basic: water=1:0.1-0.5:0.1-0.3.
3. the preparation method of a kind of high purity Hyodeoxycholic Acid according to claim 1, is characterized in that the highly basic described in steps A is potassium hydroxide or potassium hydroxide.
4. the preparation method of a kind of high purity Hyodeoxycholic Acid according to claim 1, is characterized in that strong acid described in steps A is concentrated hydrochloric acid or 50% sulfuric acid.
5. the preparation method of a kind of high purity Hyodeoxycholic Acid according to claim 1, it is characterized in that ethyl acetate described in steps A with the volume mass of, gac than being ethyl acetate (ml): anhydrous sodium sulphate (g): gac (g)=60-100ml:1-3g:1g.
6. the preparation method of a kind of high purity Hyodeoxycholic Acid according to claim 1, it is characterized in that Hyodeoxycholic Acid crude product and alcoholic solvent in step B, the weightmeasurement ratio of alkali organic solvent is Hyodeoxycholic Acid crude product (g): alcoholic solvent (ml): alkali organic solvent (g)=1g:4-8ml:0.2-0.5g.
7. the preparation method of a kind of high purity Hyodeoxycholic Acid according to claim 1, it is characterized in that Hyodeoxycholic Acid amine salt and water in step C, sodium hydroxide, the mass volume ratio of hydrochloric acid is Hyodeoxycholic Acid amine salt (g): water (ml): sodium hydroxide (g): hydrochloric acid (ml)=1:8-12:0.05-0.15:0.4-0.8.
8. according to the preparation method of a kind of high purity Hyodeoxycholic Acid described in claim 1 or 7, it is characterized in that described hydrochloric acid is the hydrochloric acid of 1:1 volumetric concentration.
9. according to the preparation method of a kind of high purity Hyodeoxycholic Acid described in claim 1 or 6, it is characterized in that alcoholic solvent described in step B is one or more the mixture in ethanol, methyl alcohol, Virahol, the trimethyl carbinol, sec-butyl alcohol.
10. according to the preparation method of a kind of high purity Hyodeoxycholic Acid described in claim 1 or 6, it is characterized in that the alkali organic solvent described in step B is one or more the mixture in triethylamine, methylamine, diethylamine, propylamine, TERTIARY BUTYL AMINE, aniline.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410019946.2A CN103772465B (en) | 2014-01-16 | 2014-01-16 | Preparation method of high-purity hyodeoxycholic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410019946.2A CN103772465B (en) | 2014-01-16 | 2014-01-16 | Preparation method of high-purity hyodeoxycholic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103772465A true CN103772465A (en) | 2014-05-07 |
| CN103772465B CN103772465B (en) | 2015-09-23 |
Family
ID=50565279
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410019946.2A Active CN103772465B (en) | 2014-01-16 | 2014-01-16 | Preparation method of high-purity hyodeoxycholic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103772465B (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104152387A (en) * | 2014-08-21 | 2014-11-19 | 曹国华 | Bile salt, preparation method thereof, and application of the bile salt in production of dry powder bacterium culture medium |
| CN105140490A (en) * | 2015-09-28 | 2015-12-09 | 中南大学 | Preparation method of lithium-sulfur battery flexible positive electrode |
| CN105175472A (en) * | 2015-08-19 | 2015-12-23 | 安徽科宝生物工程有限公司 | Refining method for high-content hyodeoxycholic acid |
| CN105541953A (en) * | 2016-03-15 | 2016-05-04 | 成都市新功生物科技有限公司 | Recrystallization purification method for high-purity obeticholic acid |
| CN106279008A (en) * | 2015-05-19 | 2017-01-04 | 浙江九洲药业股份有限公司 | A kind of purifying process of sulfasalazine |
| WO2017137931A1 (en) | 2016-02-10 | 2017-08-17 | Dr. Reddy’S Laboratories Limited | Amine salt of obeticholic acid |
| CN107549123A (en) * | 2017-10-18 | 2018-01-09 | 湖北聚注通用技术研究有限公司 | A kind of scorpion breeding method |
| CN110256517A (en) * | 2019-07-19 | 2019-09-20 | 中山百灵生物技术有限公司 | A method of producing high-purity chenodeoxy cholic acid from pig's bile or leftover bits and pieces |
| CN111961105A (en) * | 2020-09-23 | 2020-11-20 | 安徽科宝生物工程有限公司 | Method for separating hyodeoxycholic acid from pig bile paste by extraction method |
| CN112094883A (en) * | 2020-09-28 | 2020-12-18 | 常德云港生物科技有限公司 | Method for preparing beta-hyodeoxycholic acid by microbial transformation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617689A (en) * | 2012-03-14 | 2012-08-01 | 江苏正大清江制药有限公司 | Purification method of hyodeoxycholic acid |
| CN102863497A (en) * | 2012-09-29 | 2013-01-09 | 苏州天绿生物制药有限公司 | Hyodeoxycholic acid refining method |
| CN103012534A (en) * | 2012-12-19 | 2013-04-03 | 四川大熊生物技术有限公司 | Method for extracting hyodeoxycholic acid from pig bile |
-
2014
- 2014-01-16 CN CN201410019946.2A patent/CN103772465B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617689A (en) * | 2012-03-14 | 2012-08-01 | 江苏正大清江制药有限公司 | Purification method of hyodeoxycholic acid |
| CN102863497A (en) * | 2012-09-29 | 2013-01-09 | 苏州天绿生物制药有限公司 | Hyodeoxycholic acid refining method |
| CN103012534A (en) * | 2012-12-19 | 2013-04-03 | 四川大熊生物技术有限公司 | Method for extracting hyodeoxycholic acid from pig bile |
Non-Patent Citations (1)
| Title |
|---|
| 张文宝: "猪胆汁中猪去氧胆酸提取工艺条件的研究", 《农产品加工.学刊》, no. 2, 28 February 2010 (2010-02-28), pages 39 - 41 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104152387A (en) * | 2014-08-21 | 2014-11-19 | 曹国华 | Bile salt, preparation method thereof, and application of the bile salt in production of dry powder bacterium culture medium |
| CN106279008A (en) * | 2015-05-19 | 2017-01-04 | 浙江九洲药业股份有限公司 | A kind of purifying process of sulfasalazine |
| CN105175472A (en) * | 2015-08-19 | 2015-12-23 | 安徽科宝生物工程有限公司 | Refining method for high-content hyodeoxycholic acid |
| CN105140490A (en) * | 2015-09-28 | 2015-12-09 | 中南大学 | Preparation method of lithium-sulfur battery flexible positive electrode |
| WO2017137931A1 (en) | 2016-02-10 | 2017-08-17 | Dr. Reddy’S Laboratories Limited | Amine salt of obeticholic acid |
| EP3414256B1 (en) | 2016-02-10 | 2022-01-19 | Dr. Reddy's Laboratories Limited | Purification process involving amine salt of obeticholic acid |
| CN105541953A (en) * | 2016-03-15 | 2016-05-04 | 成都市新功生物科技有限公司 | Recrystallization purification method for high-purity obeticholic acid |
| CN107549123A (en) * | 2017-10-18 | 2018-01-09 | 湖北聚注通用技术研究有限公司 | A kind of scorpion breeding method |
| CN110256517A (en) * | 2019-07-19 | 2019-09-20 | 中山百灵生物技术有限公司 | A method of producing high-purity chenodeoxy cholic acid from pig's bile or leftover bits and pieces |
| CN110256517B (en) * | 2019-07-19 | 2021-03-09 | 中山百灵生物技术股份有限公司 | A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers |
| CN111961105A (en) * | 2020-09-23 | 2020-11-20 | 安徽科宝生物工程有限公司 | Method for separating hyodeoxycholic acid from pig bile paste by extraction method |
| CN112094883A (en) * | 2020-09-28 | 2020-12-18 | 常德云港生物科技有限公司 | Method for preparing beta-hyodeoxycholic acid by microbial transformation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103772465B (en) | 2015-09-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103772465B (en) | Preparation method of high-purity hyodeoxycholic acid | |
| CN110256517B (en) | A method for producing high-purity chenodeoxycholic acid from pig bile or leftovers | |
| CN102766185B (en) | Method for respectively recovering ursodesoxycholic acid and chenodeoxycholic acid from ursodesoxycholic acid waste mother liquor | |
| CN102093456B (en) | Method for extracting astragaloside IV from astragalus | |
| CN103553908B (en) | Preparation method of o-ethoxybenzoic acid | |
| CN102351735B (en) | Preparation method of Iopromide | |
| CN104045669A (en) | Separation method suitable for chemical synthesis of salidroside for industrial production | |
| CN103819326A (en) | Method for separating and purifying coenzyme Q10 from microorganism | |
| CN102317256B (en) | Preparation method for racecadotril | |
| CN103397184A (en) | Method for separating uranium and iron from tertiary amine organic phase by back extraction | |
| CN101289439B (en) | Process for preparing arabglycal | |
| CN104447244A (en) | Roflumilast intermediates and preparation method of roflumilast | |
| CN102617461A (en) | Novel method for refining aripiprazole | |
| CN106631745B (en) | A method of purifying phloretin from Hubei Chinese flowering crabapple leaf | |
| CN101050214A (en) | New method for extracting Swainsonine from locoweed | |
| CN102093272B (en) | Racecadotril compound and novel preparation method thereof | |
| CN102675106B (en) | Method for preparing high-purity chlorogenic acid by aluminum salt precipitation | |
| CN103467428B (en) | A kind of preparation method of naringenin | |
| CN102775459B (en) | Process for preparing hyodeoxycholic acid | |
| CN105732547A (en) | Preparation method of dehydrated andrographolide diacid half ester basic salt | |
| CN101434522A (en) | Method for preparing high-purity gossypol from cottonseed dephenolizing solution | |
| CN104910153A (en) | 6-chloro-8-acetonitrile oxy imidazo [1,2-a] pyridine-3-carbonitrile preparation method | |
| CN103553909B (en) | The method of o-ethoxybenzoic acid is synthesized with Whitfield's ointment and acetone | |
| CN102432465A (en) | Method for preparing methyl methacrylate | |
| CN103570618A (en) | Preparation method of montelukast sodium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: No. 28, Jiuzhou Avenue, Torch Development Zone, Zhongshan City, Guangdong Province Patentee after: Zhongshan bailing Biotechnology Co.,Ltd. Address before: No.28 Jiuzhou Avenue, Torch Development Zone, Zhongshan City, Guangdong Province 528437 Patentee before: ZHONGSHAN BELLING BIOTECHNOLOGY Co.,Ltd. |
|
| CP03 | Change of name, title or address |