CN108117579A - The preparation method of shellfish cholic acid and its intermediate difficult to understand - Google Patents
The preparation method of shellfish cholic acid and its intermediate difficult to understand Download PDFInfo
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- 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 present invention relates to the preparation method of a kind of shellfish cholic acid difficult to understand and its intermediate, the described method includes：Using 3 α hydroxyls, 6 methylene, 7 ketone group, 5 β cholanic acids as raw material, carbon-carbon double bond is reduced in protonic solvent using Pd/C catalytic transfer hydrogenation reduction systems, using aqueous slkali, carries out configuration reversal, it is reduced again with reducing agent, synthesizes to obtain shellfish cholic acid difficult to understand by three steps.Compared with prior art, reaction condition is mild for the method, is achieved that production at normal temperatures, and easy to operate, and safety does not use toxic reducing agent, can obtain the shellfish cholic acid difficult to understand of high-purity, reaction yield is high, and reaction time is short, is more suitable for industrialized production.
Description
Technical field
The invention belongs to drug fields, are related to a kind of preparation method of medical compounds, and in particular to a kind of Austria's shellfish cholic acid
The preparation method of intermediate and shellfish cholic acid difficult to understand.
Background technology
Shellfish cholic acid (Obeticholic acid) difficult to understand, chemical name：3 α, 7-6 α of alpha-dihydroxy-- 5 β of ethyl-cholanic acid, knot
Structure formula is as follows：
Shellfish cholic acid difficult to understand is a kind of method Buddhist nun ester X receptor stimulating agents, can inhibit cholic acid indirectly by activating farnesoid X receptor
The gene expression of rate-limiting enzyme cytochromes 7A (CYP7A1) in biosynthetic process, and then inhibit cholic acid synthesis, available for controlling
Treat primary biliary cirrhosis (PBC) and non-alcohol fatty liver (NASH).
In in by the end of May, 2016, shellfish cholic acid difficult to understand takes the lead in as the medicine for the treatment of primary biliary cirrhosis (PBC)
The U.S. ratifies, and clinical stage is being carried out to the indication of non-alcohol fatty liver (NASH).
At present, for the synthesis of shellfish cholic acid difficult to understand, two synthesis technologies are primarily present.
Patent WO02072598 is reacted by alkyl bromination and sodium borohydride reduction is reacted come synthesising target compound, should
Route uses carcinogen hexa-methylene phosphonic acid amide, and toxicity is larger as reducing agent, and in the later stage, removal is not easy, even across
Purifying also has micro toxic reducing agent in finished product and exists.And need to use chromatography in this synthetic method,
Amplifieroperation is not easy, realizes that industrialization is difficult, it is less efficient.Since this synthetic method needs chromatography, so final
Product yield is extremely low, only 12%-13%, causes production cost larger.
Preparation process disclosed in patent WO2006122977 is with 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid
(formula 1) is raw material, using hydrogen as reducing agent, the catalytic hydrogenation under the conditions of high temperature (100 DEG C), then through boron at 70-105 DEG C
Shellfish cholic acid difficult to understand is made in hydrogenation sodium reduction.Hydroprocessing in the preparation process is cumbersome, and high temperature and pressure catalysis hydrogen is carried out using hydrogen
Change reaction and industrially belong to highly dangerous reaction, there are the security risk of combustion explosion, and individually hydrogenation workshop need to be built,
Reaction time is longer, there are the risk of larger safety and energy consumption, is unfavorable for industrialization production, and the total recovery of entire route is also only
Have 63.25%.
For above synthetic method, it is necessary to use toxicity reducing agent, yield is low or needs reaction under high pressure, and it is hidden to there is safety
Suffer from, so in view of the pharmacy value of shellfish cholic acid difficult to understand, finds a kind of mode of production for being capable of safety, be easy to industrialization, reduce production
Originally, improving finished product purity will become very significant for life.
The content of the invention
Present inventor has carried out substantial amounts of experiment, from feasible process, cost rationally, reaction condition, height can be obtained
The various aspects such as purity product account for, and have invented a kind of new synthetic method, are reacting 2 chemical combination of production by 1 compound of formula
In the critical process of object, apply Pd/C catalytic transfer hydrogenations reduction system and reacted in protonic solvent, avoid danger
The high-temperature catalytic hydrogenation of danger, reaction condition is mild, and individual hydrogenation equipment and hydrogenation workshop is not required.Needed for reaction
Cycle is shorter, is suitble to industrialized production, does not use toxic solvent in synthesis, and yield improves, and production cost reduces, and is suitble to work
Industry metaplasia is produced.
First purpose of the invention is to provide a kind of preparation method of shellfish cholic acid intermediate difficult to understand, the technical solution used
For：With 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (formula 1) for starting material, reduced in Pd/C catalytic transfer hydrogenations
System carry out double bond reduction reaction, solvent for protonic solvent (such as methanol, ethyl alcohol, isopropanol, butanol etc. or its mixing
Object), it is filtered after the completion of reaction, filtrate decompression is concentrated to give-5 β-24- cholanic acids (formula 2) of 3-6 α of Alpha-hydroxy-ethyl-7- ketone groups.
Second object of the present invention is to provide a kind of preparation method of shellfish cholic acid difficult to understand, the technical solution used for：
(1) with 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (formula 1) for starting material, with Pd/C-NH4COOH
Reduction system or Pd/C-HCOOH reduction systems carry out the reduction reaction of double bond, and solvent is protonic solvent (such as methanol, second
Alcohol, isopropanol, butanol etc. or its mixture), it is filtered after the completion of reaction, filtrate decompression is concentrated to give 3-6 α of Alpha-hydroxy-ethyl-7-
- 5 β -24- cholanic acids (formula 2) of ketone group.
(2) by 2 compound of formula heating reflux reaction in sodium hydrate aqueous solution, reaction temperature is 20 DEG C -30 DEG C, reaction
Time 2-4h.It is acidity that dilute hydrochloric acid to system is added in after the completion of reaction, is then extracted with n-butyl acetate, is concentrated under reduced pressure to give 3
- 5 β -24- cholanic acids (formula 3) of -6 β of Alpha-hydroxy-ethyl -7- ketone groups.
(3) sodium hydrate aqueous solution of 3 compound of formula is carried out with metal hydride sodium borohydride at 75 DEG C -105 DEG C
Reduction reaction, reaction time 2-4h.It is acidity that dilute hydrochloric acid to system is added in after the completion of reaction, is then extracted with n-butyl acetate,
It is concentrated under reduced pressure, cooling stirring and crystallizing obtains the shellfish cholic acid (formula 4) difficult to understand of high-purity.
The application method is that one kind is markedly improved compared with method disclosed in the prior art：
(1) in terms of with regard to the security of technique, patent WO02072598 methods are reacted by alkyl bromination and sodium borohydride
Reduction reaction carrys out synthesising target compound, which uses carcinogen hexa-methylene phosphonic acid amide as reducing agent, and toxicity is non-
Chang great, and the solvent that the present invention uses is Conventional solvents, is not related to larger toxicity.
(2) patent WO2006122977 methods are with 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (compound 1)
Raw material, using hydrogen as reducing agent, the catalytic hydrogenation under the conditions of high temperature (100 DEG C), then through sodium borohydride at 70-105 DEG C
Shellfish cholic acid difficult to understand is made in reduction, and carrying out high temperature and pressure catalytic hydrogenation using hydrogen industrially belongs to highly dangerous reaction, deposits
In the security risk of combustion explosion.And this patent method is original with 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (formula 1)
Material, by Pd/C catalytic transfer hydrogenation reduction systems, normal-temperature reaction can obtain shellfish cholic acid intermediate difficult to understand in protonic solvent,
Technological operation is safe and simple, does not use the dangerous big processing step such as pressurization.
(3) in terms of with regard to the industrialization of technique, the method that patent WO02072598 is reported all is needed in entire technical process
Column chromatography is wanted to purify, and route total recovery only has 12%-13%, cost is higher, is not suitable for industrialization production.Patent
WO2006122977 methods need to build individually hydrogenation workshop, while hydrogenation equipment can also limit the development of production capacity, be unfavorable for
Industrialization production.And this patent method uses popular response condition, without using special installation, and whole process operation letter
Just, process overall yields greatly improve, and can reach 81%, greatly reduce cost.
(4) just in terms of shellfish cholic acid product quality difficult to understand, the more difficult purifying of patent WO02072598 methods, this method can finally reach
ELSD detects more than 99.5% high purity product, and great convenience is brought to industrialization.
Description of the drawings
Fig. 1 shows 2 compound of formula that is prepared in the embodiment of the present invention 121H NMR spectras.
Fig. 2 shows 3 compound of formula that is prepared in the embodiment of the present invention 121H NMR spectras.
Fig. 3 shows 4 compound of formula (i.e. difficult to understand shellfish cholic acid) that is prepared in the embodiment of the present invention 121H NMR spectras.
Specific embodiment
It to make the object, technical solutions and advantages of the present invention clearer, in the following, will be to the specific embodiment of the present invention
It is described in detail.Obviously, described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.
Based on the embodiments of the present invention, the institute that those of ordinary skill in the art are obtained on the premise of creative work is not made
There is other embodiment, belong to the scope of protection of the invention.
Detecting instrument
Nuclear magnetic resonance：Under fixed frequency 298.4K, 300.3K or 299.6K, Bruker is usedTMDPX400 or AV400 instrument
Device obtains NMR spectra, with CDCl3Or DMSO weak solutions operation.All NMR spectras refer to tetramethylsilane (TMS δH0、δC0).Institute
There is coupling constant to be recorded with hertz (Hz), multiplicity is labeled as s (unimodal) and m (multiplet).
Embodiment 1：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 55mL ethyl alcohol add in the wet Pd/C of palladium content 10%
(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with ethyl alcohol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains white
2 compound of formula of solid, 5.48g, yield 99.1%.
Embodiment 2：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then formic acid (3.04g, 66.00mmol) and 55mL ethyl alcohol add in the wet Pd/C (0.55g) of palladium content 10%.
Normal-temperature reaction 6h.By reacting liquid filtering, filter cake is washed with ethyl alcohol, and filtrate is concentrated under reduced pressure at 50 DEG C, and obtained solid carries out column layer
Analysis purifying, eluent is concentrated under reduced pressure, obtains 2 compound of formula of white solid, 4.35g, yield 78.6%.
Embodiment 3：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 55mL methanol add in the wet Pd/C of palladium content 15%
(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with methanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains white
2 compound of formula of solid, 5.47g, yield 98.9%.
Embodiment 4：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 55mL ethyl alcohol add in the wet Pd/C of palladium content 20%
(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with methanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains white
2 compound of formula of solid, 5.36g, yield 96.9%.
Embodiment 5：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 55mL ethyl alcohol add in the wet Pd/C of palladium content 12%
(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with methanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains white
2 compound of formula of solid, 5.40g, yield 97.6%.
Embodiment 6：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 55mL ethyl alcohol add in the wet Pd/C of palladium content 8%
(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with methanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains white
2 compound of formula of solid, 5.16g, yield 93.3%.
Embodiment 7：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 55mL butanol add in the wet Pd/C of palladium content 25%
(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with butanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains white
2 compound of formula of solid, 5.39g, yield 97.5%.
Embodiment 8：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then formic acid (3.04g, 66.00mmol) and 55mL ethyl alcohol add in the wet Pd/C (0.55g) of palladium content 5%.
Normal-temperature reaction 6h.By reacting liquid filtering, filter cake is washed with ethyl alcohol, and filtrate is concentrated under reduced pressure at 50 DEG C, by obtained solid through column layer
Analysis purifying, eluent are concentrated under reduced pressure, and obtain 2 compound of formula of white solid, 4.15g, yield 75.0%.
Embodiment 9：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 25mL methanol and 25mL ethyl alcohol add in the wet of palladium content 10%
Pd/C(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with ethyl alcohol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains
2 compound of formula of white solid, 5.30g, yield 95.8%.
Embodiment 10：The synthesis of the shellfish cholic acid midbody compound difficult to understand of formula 2
Added in the there-necked flask of 100mL 3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (5.50g,
13.20mmol), then ammonium formate (1.66g, 26.40mmol) and 25mL ethyl alcohol and 25mL butanol add in the wet of palladium content 10%
Pd/C(0.55g).Normal-temperature reaction 3h.By reacting liquid filtering, filter cake is washed with butanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains
2 compound of formula of white solid, 5.32g, yield 96.2%.
Embodiment 11：The synthesis of the shellfish cholic acid difficult to understand of formula 4
3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (110.05g, 0.26mol) is added in the there-necked flask of 2L,
Then ammonium formate (32.79g, 0.52mol) and 1.10L methanol add in the wet Pd/C (11.01g) of palladium content 10%.Normal-temperature reaction
3h.By reacting liquid filtering, filter cake is washed with methanol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains 2 compound of formula of white solid,
107.75g yield 99.0%.
2 compound of formula (110.00g, 0.26mol), sodium hydroxide (31.20g, 0.78mol) are added in the there-necked flask of 2L
With 1.32L water.2h is heated to reflux, reaction solution is cooled down, adds in 1.10L ethyl acetate, then adds in dilute hydrochloric acid (6N) to system
PH=3-4, extraction, organic phase through saturated sodium-chloride is washed, anhydrous sodium sulfate is dried, and is filtered, and filter cake is washed with ethyl acetate
It washs, filtrate is concentrated under reduced pressure at 50 DEG C, obtains 3 compound of formula of white solid, 104.50g, yield 95.0%.
3 compound of formula (100.00g, 0.24mol), sodium hydroxide (33.60g, 0.84mol) are added in the there-necked flask of 2L
With 1.05L water, sodium borohydride (9.08g, 0.24mol) is added with stirring.2h is heated to reflux, reaction solution is cooled down, adds in 1.00L
Then n-butyl acetate adds in dilute hydrochloric acid (6N) to system PH=4-5, extraction washs organic phase with saturated sodium-chloride, through nothing
Aqueous sodium persulfate is dried, and filtering, filter cake is washed with n-butyl acetate, and filtrate is concentrated under reduced pressure into 300ml, cooling stirring analysis at 50 DEG C
Brilliant 2h is filtered, and filter cake is washed with n-butyl acetate, and gained white solid is dried under reduced pressure at 60 DEG C, obtains the formula 4 of white solid
Shellfish cholic acid difficult to understand, 85.61g, yield 85.0%, evaporative light detection HPLC purity 99.101%.
Three step total recovery of shellfish cholic acid finished product production technology difficult to understand is about 79%.
Embodiment 12：The synthesis of the shellfish cholic acid difficult to understand of formula 4
3-5 β of Alpha-hydroxy-6- methylene-7- ketone groups-cholanic acid (150.35g, 0.36mol) is added in the there-necked flask of 2L,
Then ammonium formate (45.40g, 0.72mol) and 1.50L ethyl alcohol add in the wet Pd/C (15.04g) of palladium content 10%.Normal-temperature reaction
3h.By reacting liquid filtering, filter cake is washed with ethyl alcohol, and filtrate is concentrated under reduced pressure at 50 DEG C, obtains 2 compound of formula of white solid,
149.04g yield 98.9%.
1H NMR(400MHz,DMSO)δppm：0.67 (s, 3H), 0.74~0.77 (m, 3H), 0.88~0.90 (m, 4H),
1.06~1.12 (m, 5H), 1.17~1.24 (m, 5H), 1.36~1.38 (m, 4H), 1.40~1.48 (m, 2H), 1.59~
1.72 (m, 5H), 1.82~1.85 (m, 3H), 1.91~1.99 (m, 2H), 2.02~2.20 (m, 2H), 2.21~2.29 (m,
1H), 2.51~2.60 (m, 1H), 4.40~4.48 (m, 1H), 11.95 (s, 1H).
MS(ESI)m/z:835.94[2M-H]-
2 compound of formula (145.00g, 0.35mol), sodium hydroxide (42.00g, 1.05mol) are added in the there-necked flask of 2L
With 1.74L water.2h is heated to reflux, reaction solution is cooled down, adds in 1.45L ethyl acetate, then adds in dilute hydrochloric acid (6N) to system
PH=3-4, extraction, organic phase through saturated sodium-chloride is washed, is dried over anhydrous sodium sulfate, and is filtered, and filter cake is washed with ethyl acetate
It washs, filtrate is concentrated under reduced pressure at 50 DEG C, obtains 3 compound of formula of white solid, 138.62g, yield 95.6%.
1H NMR(400MHz,CDCl3)δppm：0.68 (S, 3H), 0.81~0.85 (m, 3H), 0.88~0.96 (m, 6H),
1.11~1.16 (m, 4H), 1.19~1.24 (m, 5H), 1.46~1.52 (m, 5H), 1.71~1.87 (m, 6H), 1.98~
1.99 (m, 2H), 2.02~2.42 (m, 4H), 2.71~2.72 (m, 1H), 3.56~3.60 (m, 1H).
MS(ESI)m/z:835.52[2M-H]-
3 compound of formula (135.00g, 0.32mol), sodium hydroxide (44.80g, 1.12mol) are added in the there-necked flask of 2L
With 1.35L water, sodium borohydride (12.11g, 0.32mol) is added with stirring.2h is heated to reflux, reaction solution is cooled down, is added in
Then 1.35L n-butyl acetates add in dilute hydrochloric acid (6N) to system PH=4-5, extraction washes organic phase through saturated sodium-chloride
It washs, is dried over anhydrous sodium sulfate, filter, filter cake is washed with n-butyl acetate, and filtrate is concentrated under reduced pressure into 400ml at 50 DEG C, drop
Warm stirring and crystallizing 2h is filtered, and filter cake is washed with n-butyl acetate, and gained white solid is dried under reduced pressure at 60 DEG C, obtains white
The shellfish cholic acid difficult to understand of formula 4 of solid, 115.89g, yield 86.1%, evaporative light detection HPLC purity 99.923%.
1H NMR(400MHz,CDCl3)δppm：0.68 (S, 3H), 0.90~1.03 (m, 10H), 1.15~1.22 (m,
4H), 1.31~1.53 (m, 11H), 1.61~1.71 (m, 4H), 1.81~2.00 (m, 7H), 2.25~2.32 (m, 1H), 2.38
~2.46 (m, 1H), 3.41~3.48 (m, 1H), 3.73 (s, 1H).
MS(ESI)m/z:419.36[M-H]-
Three step total recovery of shellfish cholic acid finished product production technology difficult to understand is about 81%.
Above-described specific embodiment is only used for illustrating the spirit of the present invention, and protection scope of the present invention is not
This is confined to, to those of ordinary skill in the art, can be led to certainly according to technology contents disclosed in this specification
The mode for crossing change, displacement or modification makes other embodiments easily, and these other embodiments should all cover at this
Within the protection domain of invention.
Claims (15)
1. the preparation method of the shellfish cholic acid intermediate difficult to understand of formula 2, the described method includes 1 compound of formula in Pd/C catalytic transfer hydrogenations
Under reduction system, reduction carbon-carbon double bond obtains 2 compound of formula in protonic solvent
2. preparation method according to claim 1, wherein the Pd/C catalytic transfer hydrogenations reduction system is Pd/C-
NH4COOH catalytic transfer hydrogenations reduction system or Pd/C-HCOOH catalytic transfer hydrogenation reduction systems.
3. preparation method according to claim 1 or 2, wherein the protonic solvent is selected from：Methanol, ethyl alcohol, isopropanol,
Butanol or the mixture being wherein combined.
4. preparation method according to claim 3, wherein the protonic solvent is methanol or ethyl alcohol.
5. preparation method according to claim 4, wherein the protonic solvent is ethyl alcohol.
6. preparation method according to any one of claim 1 to 5, wherein the content of palladium is in the reduction system
5%-25%.
7. preparation method according to claim 6, wherein the content of palladium is 8%-15% in the reduction system.
8. preparation method according to claim 6, wherein the content of palladium is 10% in the reduction system.
9. the preparation method of shellfish cholic acid difficult to understand, the described method comprises the following steps：(1) side as claimed in one of claims 1-8
The shellfish cholic acid intermediate difficult to understand of method formula 2；(2) by 3 compound of shellfish cholic acid intermediate reaction production difficult to understand of formula 2；(3) by formula 3
Compound reacts the shellfish cholic acid difficult to understand of production 4,
10. preparation method according to claim 9, wherein in step (2), 2 compound of formula adds in sodium hydrate aqueous solution
Hot back flow reaction, it is acidity, 3 compound of production that dilute hydrochloric acid to system is added in after the completion of reaction.
11. preparation method according to claim 9 or 10, wherein in step (3), the sodium hydroxide of 3 compound of formula is water-soluble
Liquid metal hydride sodium borohydride reduction, the shellfish cholic acid difficult to understand of production 4.
12. preparation method according to claim 9, it is characterised in that：Wherein described protonic solvent is methanol, ethyl alcohol, isopropyl
The mixture of alcohol, butanol or its any combination.
13. preparation method according to claim 10, it is characterised in that：Wherein described protonic solvent is methanol or ethyl alcohol.
14. preparation method according to claim 9, it is characterised in that：The content of palladium is 5%- in wherein described reduction system
25%.
15. preparation method according to claim 13, it is characterised in that：The content of palladium is 10%- in wherein described reduction system
15%.
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| CN105481925A (en) * | 2015-12-17 | 2016-04-13 | 南京济群医药科技有限公司 | Preparation method for obeticholic acid and intermediate thereof |
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| CN109485686A (en) * | 2018-12-27 | 2019-03-19 | 重庆华邦胜凯制药有限公司 | A method of improving 6 β content of key intermediate in the synthesis of Methylprednisolone succinate impurity |
| CN109485686B (en) * | 2018-12-27 | 2021-08-27 | 重庆华邦胜凯制药有限公司 | Method for improving content of key intermediate 6 beta in methylprednisolone succinate impurity synthesis |
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