CN106279335A - A kind of prepare shellfish cholic acid difficult to understand and the method for intermediate thereof - Google Patents
A kind of prepare shellfish cholic acid difficult to understand and the method for intermediate thereof Download PDFInfo
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- CN106279335A CN106279335A CN201610660723.3A CN201610660723A CN106279335A CN 106279335 A CN106279335 A CN 106279335A CN 201610660723 A CN201610660723 A CN 201610660723A CN 106279335 A CN106279335 A CN 106279335A
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- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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Abstract
The invention belongs to technical field of medical chemistry, it is specifically related to a kind of prepare medicine Austria shellfish cholic acid and the new method of intermediate thereof, it obtains intermediate II and then preparation shellfish cholic acid difficult to understand by Catalytic hydrogenation of compound III, there is advantage easy and simple to handle, that reaction condition is gentle, reduce reaction temperature, reduce the generation of the side reactions such as hydroxyls dehydrate, improve yield, be suitable for large-scale production.
Description
Technical field
The invention belongs to technical field of medical chemistry, be specifically related to a kind of new side preparing shellfish cholic acid difficult to understand and intermediate thereof
Method.The method is easy and simple to handle, and reaction condition is gentle, reduces the generation of side reaction, improves yield, is suitable for large-scale production.
Background technology
Shellfish cholic acid (Obeticholic acid) difficult to understand, chemistry entitled 3 Alpha-hydroxy-6 α-ethyl-7 Alpha-hydroxy-5 β-cholanic acid,
There is the chemical constitution shown in Formulas I, be method Buddhist nun's ester derivant X receptor (FXR) specific agonist, be first research and development over 20 years
For treating the medicine of cholestatic liver disease.Shellfish cholic acid difficult to understand is developed by American I ntercept drugmaker, and in 2016
May in year is approved by the fda in the United States for and ursodesoxycholic acid (UDCA) therapeutic alliance primary biliary cirrhosis (PBC).
Patent WO02072598 report with 3-Alpha-hydroxy-7-ketone group-5 β-cholanic acid as raw material, through dihydropyran hydroxyl protection,
Ethyl esterified, ethylize, reduce and hydrolyze both get Ao Bei cholic acid, this technique comprises less synthesis step, but total recovery extremely low (<
3.5%) the hexa-methylene phosphonic acid amide with carcinogenecity is used, and in technique.
Patent US20090062526 reports the improvement technique based on patent WO02072598 preparation technology, with goose
Deoxycholic acid is raw material, obtains shellfish cholic acid difficult to understand through PCC oxidation, dihydropyran hydroxyl protection, ethylization, reduction reaction, and former
Technique is compared total recovery and is improved to about 20%, but respectively step intermediate remains a need for chromatography, it is difficult to realize industrialized production.
Patent CN200680017025 is with 3-Alpha-hydroxy-7-ketone group-5 β-cholanic acid as raw material, through esterification, monosilane
The intermediate that base, acetaldehyde condensation obtain obtains shellfish cholic acid difficult to understand through hydrolysis, hydro-reduction and sodium borohydride reduction again.This technique
Produce although can realize amplifying, but compound VII palladium carbon hydrogenating reduction under strongly alkaline conditions and strong basicity high-temperature process system
During standby compound Ⅸ, there is the side reactions such as hydroxyls dehydrate, cause this technique separation yield relatively low.
Summary of the invention
Present invention aim at providing the shellfish cholic acid difficult to understand of a kind of improvement and the preparation method of intermediate thereof, reacted by reduction
Temperature and alkalescence condition, reduce the generation of the side reactions such as hydroxyls dehydrate, improve yield, and answer mild condition, easy to operate, suitable
The technique closing large-scale production.
First aspect present invention provides the preparation method of a kind of shellfish cholic acid intermediate II difficult to understand, and the method is by by compound
III carries out catalytic hydrogenation and obtains intermediate II.
Specifically, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand comprises the following steps: compound III exist at catalyst and
React under certain pressure atmosphere of hydrogen, obtain intermediate II；
Wherein, the preferred palladium catalyst of described catalyst, more preferably palladium-carbon catalyst；The most described urge
Agent is 10wt% palladium carbon.
Preferably, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand is preferably carried out in reaction dissolvent I；Described reaction is molten
One or more in methanol, ethanol, isopropanol, oxolane of agent I, preferably one or both in methanol, ethanol, more
Preferably methanol.
Preferably, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand is carried out in atmosphere of hydrogen, described atmosphere of hydrogen
Pressure preferably 1～2Mpa.
Preferably, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand is carried out under room temperature or lower temperature, preferably reacts
Temperature is 20～50 DEG C or 20～40 DEG C, more preferably 20～30 DEG C.
Preferably, in the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand, the mass body of compound III and reaction dissolvent I
Long-pending ratio 1:2～10, preferably: 1:4～8, more preferably 1:4～6, unit: g/ml.
Preferably, in the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand, catalyst amount is conventional catalytic amount；?
In one technical scheme of the present invention, the mass ratio of compound III and catalyst is 1:0.01～0.20, preferably 1:0.05～
0.15, more preferably 1:0.10.
In of the present invention is embodied as, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand comprises the following steps:
Compound III is dissolved in methanol, adds palladium carbon (10wt%), in hydrogen 1～2Mpa pressure and 20～40 DEG C of reactions 2～6h, mistake
Filter, filtrate obtain intermediate II after concentrating.
Second aspect present invention provides a kind of method preparing compound III, and the method comprises the following steps:
Being dissolved in reaction dissolvent II by compound IV, add sodium borohydride, 20～40 DEG C of reactions 2～5h, decompression steams solvent, adds
Entering water and ethyl acetate extraction, separate organic facies, anhydrous sodium sulfate steams solvent after drying, obtains compound III；
Wherein, compound IV is 1:0.10～0.15, preferably 1:0.12 with the mass ratio of sodium borohydride.
Preferably, in the above-mentioned method preparing compound III, described reaction dissolvent II selected from methanol, ethanol, isopropanol,
One or both in one or more in oxolane, preferably methanol, ethanol, more preferably methanol.
Preferably, in the above-mentioned method preparing compound III, the mass volume ratio of compound IV and reaction dissolvent II is 1:
5～15, preferably 1:8～12, more preferably 1:10, unit: g/ml.
Third aspect present invention provides a kind of method preparing shellfish cholic acid difficult to understand, and the method comprises the following steps:
(1) being dissolved in reaction dissolvent III by compound IV, add sodium borohydride, 20～40 DEG C of reactions 2～5h, decompression steams molten
Agent, addition water and ethyl acetate extraction, separate organic facies, and anhydrous sodium sulfate steams solvent after drying, obtains compound III；
(2) compound III is dissolved in reaction dissolvent III, adds palladium carbon (10wt%), at hydrogen 1～2MPa pressure and 20～40
DEG C reaction 2～6h, filter, filtrate concentrate after obtain intermediate II；
(3) intermediate II is dissolved in reaction dissolvent III, adds sodium hydrate aqueous solution, 20～40 DEG C of reactions 0.5～3h, use
After pH value is adjusted to 7～8 by hydrochloric acid, adding ethyl acetate extraction, anhydrous sodium sulfate is dried, and body reason agent ammonium iyi decompression steams solvent
Decompression decompression steams solvent, obtains the shellfish cholic acid difficult to understand shown in Formulas I,
Wherein, reaction dissolvent III described in step (1)～(3) is independently selected from methanol, ethanol, isopropanol, oxolane
One or more, preferably one or both in methanol, ethanol, more preferably methanol.
Fourth aspect present invention provides the method for a kind of one kettle way preparation shellfish cholic acid difficult to understand, and the method comprises the following steps:
(1) being dissolved in reaction dissolvent IV by compound IV, add sodium borohydride, 20～40 DEG C of reactions 2～5h, decompression steams molten
Agent, addition water and ethyl acetate extraction, separate organic facies, adds anhydrous sodium sulfate and is dried；
(2) by step (1) gained organic facies add palladium carbon (10wt%), hydrogen 1～2MPa pressure and 20～40 DEG C reaction 2～
6h, filters；
(3) will add sodium hydrate aqueous solution in step (2) gained filtrate, 20～40 DEG C of reactions 0.5～3h, with hydrochloric acid by pH
After value is adjusted to 7～8, adding ethyl acetate extraction, organic facies adds the reason agent ammonium iyi decompression of anhydrous sodium sulfate dried body and steams molten
Agent decompression decompression steams solvent, obtains the shellfish cholic acid difficult to understand shown in Formulas I;
Wherein, one or more in methanol, ethanol, isopropanol, the oxolane of described reaction dissolvent IV, preferably methanol,
One or both in ethanol, more preferably methanol.
Fifth aspect present invention provides a kind of method preparing shellfish cholic acid difficult to understand, and the method comprises the following steps:
Compound V, Feldalat NM are added in methanol, are warming up to 50～65 DEG C, after insulation reaction 1～3h, are cooled to 25～45 DEG C,
Add sodium borohydride, after insulation reaction 2～6h, add water, after pH value being adjusted to 2～3 with hydrochloric acid, add ethyl acetate extraction,
Organic facies anhydrous sodium sulfate is dried, and steams solvent and obtains the shellfish cholic acid difficult to understand shown in Formulas I.
In the present invention, if not otherwise specified, described solvent is Conventional solvents, and reaction is typically entered at ambient temperature
OK, the consumption of reaction dissolvent is the conventional amount used of reaction, and the consumption of catalyst is conventional catalytic amount, and organic facies is dried all adopts
It is dried with anhydrous sodium sulfate.Although the present invention to partial reaction thing and the consumption of reaction dissolvent or ingredient proportion (in the middle of preparation
Body II) carry out suitable restriction, but these restriction scopes still fall within the conventional amount used of this area, limit amount ranges and not say
Consumption outside bright scope can not realize the present invention or carry out chemical preparation reaction, but inventor combined reaction condition,
Post-processing operation, specify that, after the factor such as reaction cost, the use being more suitable for the present invention or this reaction in the range of conventional amount used
Weight range.The reactant that skilled person still can record in the present invention according to the basic principles of chemistry of general knowledge known in this field
With determine consumption outside reaction dissolvent amount ranges in right amount.Reagent used in the present invention or raw material all can pass through existing document
Or prior art prepares, or can be commercially available.
The beneficial effects of the present invention is: the present invention obtains intermediate II by compound III catalytic hydrogenation, and then passes through
Hydrolysis prepares shellfish cholic acid difficult to understand, it is to avoid the use of strong reductant, substantially increases the safety of reaction, and preparation method operates
Easier, reaction condition is gentleer, reduces the generation of the side reactions such as hydroxyls dehydrate, improves yield, is suitable for extensive raw
Produce；In the method for the one kettle way preparation shellfish cholic acid difficult to understand that the present invention provides, often after step reaction, directly carry out lower step without post processing
Reaction, has saved the energy, has reduced production cost, and decrease waste water and waste liquid produces the pollution to environment.
Detailed description of the invention
Below by way of specific embodiment, the foregoing of the present invention is described in further detail, but should be by
This is interpreted as any restriction to subject matter of the present invention.All technical schemes realized based on foregoing of the present invention belong to
The scope of the present invention.It will be apparent to those skilled in the art that hereinafter, if not specified, the operation that the present invention is carried out is
Carrying out under the room temperature condition that this area is conventional, described room temperature has art-recognized meanings well known in the art, generally refers to 10～30 DEG C,
Preferably 15～25 DEG C, more preferably 20～25 DEG C.Raw materials used in the present invention all can be bought by market or according to existing literary composition
Offer and prepare, as the compounds of this invention IV can be commercially available from Nanjing Youjie Pharmaceutical Technology Co., Ltd..
Embodiment 1: the preparation of compound III
In reaction bulb, add 10.0g compound IV and 100ml methanol, add 1.3g sodium borohydride, be incubated 20～40 DEG C of reactions
5h, is evaporated to do, and adds 100ml water and 100ml ethyl acetate, separatory, and anhydrous sodium sulfate is dried organic facies, filtering and concentrating
After obtain 9.8g compound III, yield 97.6%.
MS(ESI, m/z): 433.6([M+H]+)
H-NMR:5.556 (d, 1H), 4.483 (d, 1H), 4.138 (d, 1H), 3.736 (s, 1H), 3.573 (s, 3H),
(3.403 s, 1H), 2.290～2.401 (m, 2H), 2.177～2.237 (m, 1H), 0.839～1.945 (m, 27H),
0.699(s,3H), 0.585(s,3H)。
Embodiment 2: the preparation of intermediate II
5.0g compound III is dissolved in 40ml methanol, add 0.5g palladium carbon (10wt%), hydrogen 1～2MPa pressure and 20～
40 DEG C of reaction 5h, obtain 4.8g intermediate II, yield 95.6% after filtering and concentrating.
MS(ESI, m/z): 435.6([M+H]+)
H-NMR:4.028 (m, 2H), 3.573 (s, 3H), 3.493 (s, 1H), 3.126 (t, 1H), 2.299～2.342
(m, 1H), 2.191～2.232 (m, 1H), 1.902 (d, 1H), 1.670～1.815 (m, 7H), 0.875～1.527 (m,
17H), 0.845(d,3H), 0.821(d,6H), 0.602(s,3H)。
Embodiment 3: the preparation of shellfish cholic acid (compound I) difficult to understand
4.0 intermediate II are dissolved in 16ml methanol, add 8ml 10% sodium hydrate aqueous solution, 20～40 DEG C of reaction 1h, subtract
Pressure concentrates, and organic solvent is evaporated off, and adds 40ml purified water and 40ml dichloromethane, stirs 10～20min, and separatory, aqueous phase divides again
Do not wash twice with 40ml dichloromethane.After aqueous pH values being adjusted to 7～8 with 3mol/L hydrochloric acid, add 40ml ethyl acetate, continue
Continuing and adjust pH value to 2～3 with 3mol/L hydrochloric acid, separatory, organic facies is respectively by 40ml water, the washing of 40ml saturated sodium-chloride, organic facies
It is dried with anhydrous sodium sulfate.Body reason agent ammonium iyi sucking filtration, filtrate reduced in volume is the most dry, adds the refined shellfish gallbladder difficult to understand of 80ml dichloromethane
Acid fine work 2.2g, yield 56.8%.
MS(ESI, m/z): 443.3([M+Na]+)
H-NMR:11.945 (s, 1H), 4.293 (s, 1H), 4.044 (s, 1H), 3.495 (s, 1H), 3.124 (s, 1H),
2.079～2.242 (m, 2H), 1.685～1.921 (m, 7H), 1.088～1.532 (m, 16H), 0.875 (s, 3H),
0.829 (s,6H), 0.605(s,3H)。
Embodiment 4: the preparation of shellfish cholic acid (compound I) difficult to understand
In reaction bulb, add 28.5g compound V and 170ml methanol, 30ml methanol solution of sodium methylate (mass fraction 28%), rise
Temperature, to 55～65 DEG C, after insulation reaction 2h, is cooled to 35～45 DEG C, adds 3.6g sodium borohydride, is incubated 35～45 DEG C of reaction 5h
After, add 70ml water, be incubated 35～45 DEG C, after reaction 1h, concentrating under reduced pressure, organic solvent be evaporated off, add 130ml purified water with
130ml dichloromethane, stirs 10～20min, and separatory, aqueous phase washes twice with 130ml dichloromethane the most respectively.Use 3mol/L salt
After aqueous pH values is adjusted to 7～8 by acid, add 130ml ethyl acetate, continue with 3mol/L hydrochloric acid tune pH value to 2～3, separatory, have
Machine washs with 130ml water, 130ml saturated sodium-chloride the most respectively, and organic facies anhydrous sodium sulfate is dried.Body reason agent ammonium iyi sucking filtration,
Filtrate reduced in volume is the most dry, adds the refined shellfish cholic acid fine work 16.0g difficult to understand of 700ml dichloromethane, yield 57.8%.
Claims (7)
1. a preparation method for shellfish cholic acid intermediate II difficult to understand, during the method by carrying out catalytic hydrogenation and obtaining by compound III
Mesosome II,
。
Preparation method the most according to claim 1, it is characterised in that said method comprising the steps of: compound III exists
Catalyst exists and reacts under certain pressure atmosphere of hydrogen, obtains intermediate II；
Wherein, the preferred palladium catalyst of described catalyst, more preferably palladium-carbon catalyst；The most described urge
Agent is 10wt% palladium carbon；
Preferably, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand is preferably carried out in reaction dissolvent I；Described reaction dissolvent I
One or both in one or more in methanol, ethanol, isopropanol, oxolane, preferably methanol, ethanol, more excellent
Select methanol；
Preferably, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand is carried out in atmosphere of hydrogen, the pressure of described atmosphere of hydrogen
Preferably 1～2Mpa；
Preferably, the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand is carried out under room temperature or lower temperature, preferable reaction temperature
It is 20～50 DEG C or 20～40 DEG C, more preferably 20～30 DEG C；
Preferably, in the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand, the mass volume ratio of compound III and reaction dissolvent I
1:2～10, preferably: 1:4～8, more preferably 1:4～6, unit: g/ml；
Preferably, in the preparation method of above-mentioned shellfish cholic acid intermediate II difficult to understand, catalyst amount is conventional catalytic amount；At this
In a bright technical scheme, compound III is 1:0.01～0.20 with the mass ratio of catalyst, preferably 1:0.05～0.15,
More preferably 1:0.10.
Preparation method the most according to claim 2, it is characterised in that said method comprising the steps of: by compound III
Being dissolved in methanol, add palladium carbon (10wt%), in hydrogen 1～2Mpa pressure and 20～40 DEG C of reactions 2～6h, filtration, filtrate concentrate
After obtain intermediate II.
Preparation method the most according to claim 1, it is characterised in that the method also includes preparing compound III's as follows
Step:
Being dissolved in reaction dissolvent II by compound IV, add sodium borohydride, 20～40 DEG C of reactions 2～5h, decompression steams solvent, adds
Entering water and ethyl acetate extraction, separate organic facies, anhydrous sodium sulfate steams solvent after drying, obtains compound III；
Wherein, compound IV is 1:0.10～0.15, preferably 1:0.12 with the mass ratio of sodium borohydride；
Preferably, in the above-mentioned method preparing compound III, described reaction dissolvent II is selected from methanol, ethanol, isopropanol, tetrahydrochysene
One or both in one or more in furan, preferably methanol, ethanol, more preferably methanol；
Preferably, in the above-mentioned method preparing compound III, the mass volume ratio of compound IV and reaction dissolvent II be 1:5～
15, preferably 1:8～12, more preferably 1:10, unit: g/ml.
5. the method preparing shellfish cholic acid difficult to understand, the method comprises the following steps:
(1) being dissolved in reaction dissolvent III by compound IV, add sodium borohydride, 20～40 DEG C of reactions 2～5h, decompression steams molten
Agent, addition water and ethyl acetate extraction, separate organic facies, and anhydrous sodium sulfate steams solvent after drying, obtains compound III；
(2) compound III is dissolved in reaction dissolvent III, adds palladium carbon (10wt%), at hydrogen 1～2MPa pressure and 20～40
DEG C reaction 2～6h, filter, filtrate concentrate after obtain intermediate II；
(3) intermediate II is dissolved in reaction dissolvent III, adds sodium hydrate aqueous solution, 20～40 DEG C of reactions 0.5～3h, use
After pH value is adjusted to 7～8 by hydrochloric acid, adding ethyl acetate extraction, anhydrous sodium sulfate is dried, and body reason agent ammonium iyi decompression steams solvent
Decompression decompression steams solvent, obtains the shellfish cholic acid difficult to understand shown in Formulas I,
Wherein, reaction dissolvent III described in step (1)～(3) is independently selected from methanol, ethanol, isopropanol, oxolane
One or more, preferably one or both in methanol, ethanol, more preferably methanol.
6. the method preparing shellfish cholic acid difficult to understand, the method comprises the following steps:
(1) being dissolved in reaction dissolvent IV by compound IV, add sodium borohydride, 20～40 DEG C of reactions 2～5h, decompression steams molten
Agent, addition water and ethyl acetate extraction, separate organic facies, adds anhydrous sodium sulfate and is dried；
(2) by step (1) gained organic facies add palladium carbon (10wt%), hydrogen 1～2MPa pressure and 20～40 DEG C reaction 2～
6h, filters；
(3) will add sodium hydrate aqueous solution in step (2) gained filtrate, 20～40 DEG C of reactions 0.5～3h, with hydrochloric acid by pH
After value is adjusted to 7～8, adding ethyl acetate extraction, organic facies adds the reason agent ammonium iyi decompression of anhydrous sodium sulfate dried body and steams molten
Agent decompression decompression steams solvent, obtains the shellfish cholic acid difficult to understand shown in Formulas I;
Wherein, one or more in methanol, ethanol, isopropanol, the oxolane of described reaction dissolvent IV, preferably methanol,
One or both in ethanol, more preferably methanol.
7. the method preparing shellfish cholic acid difficult to understand, the method comprises the following steps:
Compound V, Feldalat NM are added in methanol, are warming up to 50～65 DEG C, after insulation reaction 1～3h, are cooled to 25～45 DEG C,
Add sodium borohydride, after insulation reaction 2～6h, add water, after pH value being adjusted to 2～3 with hydrochloric acid, add ethyl acetate extraction,
Organic facies anhydrous sodium sulfate is dried, and steams solvent and obtains the shellfish cholic acid difficult to understand shown in Formulas I.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191939A (en) * | 2017-12-08 | 2018-06-22 | 丽珠集团新北江制药股份有限公司 | A kind of method for preparing shellfish cholic acid intermediate difficult to understand and shellfish cholic acid difficult to understand |
| CN108250262A (en) * | 2018-01-12 | 2018-07-06 | 丽珠集团新北江制药股份有限公司 | A kind of method for preparing shellfish cholic acid difficult to understand |
| CN108440629A (en) * | 2018-03-16 | 2018-08-24 | 丽珠集团新北江制药股份有限公司 | A method of preparing shellfish cholic acid intermediate difficult to understand and shellfish cholic acid difficult to understand |
| CZ307944B6 (en) * | 2018-02-12 | 2019-09-04 | Farmak, A.S. | Process for preparing obeticholic acid |
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| CN105294801A (en) * | 2015-07-02 | 2016-02-03 | 扬子江药业集团南京海陵药业有限公司 | Method for synthesizing, separating and determining obeticholic acid (OCA) isomer |
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| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108191939A (en) * | 2017-12-08 | 2018-06-22 | 丽珠集团新北江制药股份有限公司 | A kind of method for preparing shellfish cholic acid intermediate difficult to understand and shellfish cholic acid difficult to understand |
| CN108250262A (en) * | 2018-01-12 | 2018-07-06 | 丽珠集团新北江制药股份有限公司 | A kind of method for preparing shellfish cholic acid difficult to understand |
| CZ307944B6 (en) * | 2018-02-12 | 2019-09-04 | Farmak, A.S. | Process for preparing obeticholic acid |
| CN108440629A (en) * | 2018-03-16 | 2018-08-24 | 丽珠集团新北江制药股份有限公司 | A method of preparing shellfish cholic acid intermediate difficult to understand and shellfish cholic acid difficult to understand |
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Application publication date: 20170104 |