CN108794558A - A kind of shellfish cholic acid preparation method difficult to understand that reaction condition is mild - Google Patents
A kind of shellfish cholic acid preparation method difficult to understand that reaction condition is mild Download PDFInfo
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- CN108794558A CN108794558A CN201810716607.8A CN201810716607A CN108794558A CN 108794558 A CN108794558 A CN 108794558A CN 201810716607 A CN201810716607 A CN 201810716607A CN 108794558 A CN108794558 A CN 108794558A
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- 0 C*(CCC(O)=O)C(CC1)[C@@](C)(CCC2[C@@](C)(CC*C3)C3C3)C1C2C3=O Chemical compound C*(CCC(O)=O)C(CC1)[C@@](C)(CCC2[C@@](C)(CC*C3)C3C3)C1C2C3=O 0.000 description 6
- GLXWZDSRWCURCP-PFZZMIQBSA-N CC(CCC(O)=O)C(CC1)[C@@](C)(CCC2[C@@](C)(CC3)C(C4)CC3=O)C1C2C41OC1 Chemical compound CC(CCC(O)=O)C(CC1)[C@@](C)(CCC2[C@@](C)(CC3)C(C4)CC3=O)C1C2C41OC1 GLXWZDSRWCURCP-PFZZMIQBSA-N 0.000 description 1
- ALRJMBWQUGBAGX-SESMEABUSA-N CC[C@@H](C1)C(CCCC2)[C@@]2(C)C(CC2)C1C(CC1)[C@@]2(C)C1C(C)CCC(O)=O Chemical compound CC[C@@H](C1)C(CCCC2)[C@@]2(C)C(CC2)C1C(CC1)[C@@]2(C)C1C(C)CCC(O)=O ALRJMBWQUGBAGX-SESMEABUSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the shellfish cholic acid preparation method difficult to understand that a kind of reaction condition is mild, synthetic route is
Description
Technical field
The present invention relates to a kind of preparation method of compound, more particularly to prepared by the mild shellfish cholic acid difficult to understand of a kind of reaction condition
Method.
Background technology
Shellfish cholic acid (Obeticholic Acid, CAS difficult to understand:459789-99-2), trade name Ocalive, chemical name 3 α, 7 α-
There is -6 α of dihydroxy--5 β of ethyl-cholanic acid specific stereochemical structure, structural formula to be shown below:
Shellfish cholic acid difficult to understand be the U.S. English spy Sept (Intercept) company develop a kind of to treat primary biliary liver hard
The newtype drug for changing (PBC), successively on May 27th, 2016 and 12 Huo Food and Drug Adminstration of the US December in 2016
(FDA) and European drug administration (EMA) ratifies listing.Primary biliary cirrhosis (PBC) is a kind of chronic, progressivity
Autoimmune disease, 90% betides women (be mostly 40-60 Sui women).Final conclusion is that hepatic sclerosis and liver function decline
It exhausts, at this moment will carry out liver transplant, be the second largest factor that women carries out liver transplant.The head of such indication is treated at present
Drug of choice is ursodesoxycholic acid (UDCA), however has 40% PBC patient will be dead to bad or even 10% patient of UCDA reactions
Or need liver transplant.And shellfish cholic acid (once authorizing express passway and Orphan drug by FDA) difficult to understand is then anti-for UDCA for treating
Insufficient or intolerance adult patient is answered, is last one of the barrier for coping with such indication.
In addition, (NASH, is authorized prominent at the clinical III phases other indications such as nonalcoholic fatty liver of shellfish cholic acid difficult to understand by FDA
Broken property drug), primary sclerotic cholangitis (clinical II phases, Orphan drug is authorized by FDA) is also actively developing clinical test, exhibition
Good market prospects are revealed.
The domestic and foreign literature route for preparing shellfish cholic acid difficult to understand at present is mainly the following:
WO02072598A/US20090062526A discloses the synthesis step of shellfish cholic acid difficult to understand, such as formula 1-1 and formula 1-2 institutes
Show:
In route shown in formula 1-1 and formula 1-2, with chenodeoxycholic acid (CDCA) for raw material, protected through peroxidating, 3- hydroxyls
It protects, be alkylated and be esterified (bromoethane) or alkylation (iodoethane), sodium borohydride reduction simultaneously hydrolyze (bromoethane) or sodium borohydride
Reduction (iodoethane) amounts to 4 steps and obtains shellfish cholic acid difficult to understand.Wherein in route shown in formula 1-1, alkylation (bromoethane) step yield compared with
Low (12%), total recovery 3%;In route shown in formula 1-2, alkylation (iodoethane) step yield is slightly higher (37%), total recovery
It is 20%.This reaction step is few, but chromatography process is more to lead to hempa that is cumbersome and having used high poison
Acyl triamine, thus be not suitable for industrialized production.
US71390B2/CN101203526B/CN104781272A discloses the synthesis step of shellfish cholic acid difficult to understand, such as 2 institute of formula
Show:
In the patent with 7- ketone chenodeoxycholic acid (1) be starting material, through over-churning, two step silyl enol ethers, aldol condensation,
Hydrolysis, catalytic hydrogenation, totally 7 steps obtain shellfish cholic acid difficult to understand, total recovery 24% to sodium borohydride reduction.This reaction step avoids using high poison
Hexamethylphosphoramide and chromatography, be suitble to industrialized production.
Document Sepe V, Ummarino R, D ' Auria M V, et al.Conicasterol E, a small
heterodimer partner sparing farnesoid X receptor modulator endowed with a
pregnane X receptor agonistic activity,from the marine sponge Theonella
swinhoei[J].Journal of medicinal chemistry,2011,55(1):84-93. discloses shellfish cholic acid difficult to understand
Synthesis step, as shown in Equation 3:
With chenodeoxycholic acid (CDCA) for starting material in the document, through peroxidating, esterification, a step silyl enol ether, aldol
Condensation, sodium borohydride/cerous chloride reduction, totally 6 steps obtain shellfish cholic acid difficult to understand, total recovery 32% to catalytic hydrogenation.This reaction step is only
Can be obtained by compound 3 by a step silyl enol ether, at the same Pd/C catalytic hydrogenations can fast eliminating benzyl obtain
Shellfish cholic acid difficult to understand, enormously simplifies reaction step and operation difficulty, is suitble to industrialized production.BnBr strong stimulations have been used in this route
Material increases the difficulty for feeding intake and post-processing;And in sodium borohydride reduction step, in order to further increase the production of product
Rate reduces impurity level, has used catalysis specificity more preferable but same more expensive cerous chloride, has increased production cost.
Shellfish cholic acid intermediate difficult to understand how inexpensive, that low impurity content is efficiently prepared and shellfish cholic acid difficult to understand are to need to be solved
Certainly the problem of.
Invention content
The purpose of the present invention is to provide the shellfish cholic acid preparation methods difficult to understand that a kind of reaction condition is mild.
The technical solution used in the present invention is:
A kind of preparation method of Austria's shellfish cholic acid, synthetic route are as follows:
In formula, R is carboxyl-protecting group, is specifically comprised the following steps:
1) 1) intermediate 1 is dissolved in polar organic solvent A, using hydrogen be hydrogen source, 80 DEG C~100 DEG C, relative pressure
Catalytic hydrogenating reduction ethylene linkage is carried out under 0.5~1.0MPa, obtains intermediate 2;
2) by intermediate 2, boron hydrogen salt, alkali soluble are in polar organic solvent B, 50~100 DEG C of progress carbonyl reduction reactions, instead
Should reaction be quenched after the completion;
3) post-processing obtains shellfish cholic acid difficult to understand.
As being further improved for above-mentioned preparation method, linear or branched alkyl group, phenyl or benzyl that R is C1~C8 are appointed
The linear or branched alkyl group of C1~C8 of meaning substitution, the phenyl or benzyl arbitrarily replaced.
As being further improved for above-mentioned preparation method, the substitution of the linear or branched alkyl group, phenyl or benzyl of C1~C8
Base is independently selected from electron-withdrawing group.Further, electron-withdrawing group in halogen, ester group, nitro, cyano at least one
Kind.
As being further improved for above-mentioned preparation method, boron hydrogen salt is lithium borohydride, sodium borohydride, potassium borohydride, boron hydrogen
Change or mixtures thereof calcium.
As being further improved for above-mentioned preparation method, polar organic solvent A is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropyl
Alcohol, tetrahydrofuran or its mixed solvent.
As being further improved for above-mentioned preparation method, polar organic solvent B is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropyl
The mixed solution of at least one of alcohol, tetrahydrofuran and water.
As being further improved for above-mentioned preparation method, the temperature of carbonyl reduction reaction is 50~80 DEG C.
As being further improved for above-mentioned preparation method, post-processing includes concentration, extraction and separation, acid-base neutralization purifying.
The beneficial effects of the invention are as follows:
The shellfish cholic acid preparation method difficult to understand of the present invention, reaction condition is mild, and reaction step is relatively fewer, during reaction
The intermediate 2 of high-purity has been obtained, and shellfish cholic acid difficult to understand can be directly carried out without specially carrying out configuration conversion to intermediate
Synthesis, greatlies simplify the synthesis flow of shellfish cholic acid difficult to understand, and the impurity being synthetically produced is less, reduce the synthesis of shellfish cholic acid difficult to understand at
This.
Compared to route shown in formula 2, this method uses single dicyandiamide solution, obtains the beta comfiguration intermediate 2 of high-purity, whole
A process can equally obtain the shellfish cholic acid product difficult to understand of purity qualification without carrying out configuration conversion.Simplify the same of reaction step
When, improve product yield.
Compared to route shown in formula 3, this method avoids expensive cerous chloride is used, greatly reduce raw material at
This;While simplifying intermediate rate-determining steps, product yield is improved.
Specific implementation mode
A kind of preparation method of Austria's shellfish cholic acid, synthetic route are as follows:
In formula, R is carboxyl-protecting group, is specifically comprised the following steps:
1) intermediate 1 is dissolved in polar organic solvent A, using hydrogen be hydrogen source, 80 DEG C~100 DEG C, relative pressure 0.5
Catalytic hydrogenating reduction ethylene linkage is carried out under~1.0MPa, obtains intermediate 2;
2) by intermediate 2, boron hydrogen salt, alkali soluble are in polar organic solvent B, 50~100 DEG C of progress carbonyl reduction reactions, instead
Should reaction be quenched after the completion;
3) post-processing obtains shellfish cholic acid difficult to understand.
R can be carboxyl-protecting group commonly used in the art, it is contemplated that specific reaction condition of the invention, R group preferably exist
The group that hydrogenation reaction will not occur under reaction condition avoids influencing reaction efficiency.To advantageously promote the conformation selection of reaction
Property, R group is more preferably electron-withdrawing group.As being further improved for the above method, R is the linear chain or branched chain of C1~C8
Alkyl, phenyl or benzyl, the linear or branched alkyl group of the C1~C8 arbitrarily replaced, the phenyl or benzyl that arbitrarily replace.Substitution was both
It can be monosubstituted, can also be more than one substitution.
The catalyst that catalytic hydrogenation uses is common catalytic hydrogenation catalyst, including but not limited to Pd/C, Raney's nickel, oxygen
Change transition metal and their compounds such as platinum, alumel, cobalt, triphenylphosphine radium chloride.From catalytic effect, safety, at
The consideration of this grade, preferably Pd/C etc..
As being further improved for the above method, the substituent group of the linear or branched alkyl group of C1~C8, phenyl or benzyl is only
It is vertical to be selected from least one of halogen, ester group, nitro, cyano.
As being further improved for the above method, polar organic solvent A is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, four
Hydrogen furans or its mixed solvent.As being further improved for the above method, the reaction temperature of double bond reduction reaction is 80~100
℃。
As being further improved for the above method, polar organic solvent B is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, four
The mixed solution of at least one of hydrogen furans and water.
Further experiment show polar organic solvent be selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran or its
When mixed solvent (mixed liquor of wherein organic solvent B contains aqueous solvent), there is no the influence of essence, this field to reaction result
Technical staff can select solvability of reactant etc. accordingly according to solvent.
As being further improved for the above method, the reaction temperature of hydrolysis and carbonyl reduction reaction is 50~100 DEG C.Temperature
Too low then reaction speed is slow, and reaction is incomplete.Temperature is excessively high, is also easy to produce excessive impurity.
As being further improved for the above method, alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia
Water, methylamine, ethamine, propylamine, dimethylamine, diethylamine, di-n-propylamine, trimethylamine, triethylamine, tripropyl amine (TPA), n,N-diisopropylethylamine,
Or mixtures thereof sodium acetate.It is preferred that sodium hydroxide or potassium hydroxide one of which, the amount of alkali is worked as the 3~5 of compound intermediate 1
Amount measured few then reaction not exclusively, can determine the best type and additive amount of alkali by detecting the degree of reaction.
The time of reaction can be determined by detecting at least one of the degree of reaction and the amount of impurity, according to detection
As a result suitably the reaction time is adjusted.As being further improved for the above method, the time of hydro-reduction reaction is 3~5 hours.Hydrogen
The change time is too short, and hydrogenation will be caused incomplete.Hydrogenation time is long, impurity content can be caused to increase.Hydrolysis of ester group and carbonyl are also
The former time is 2~4 hours.Hydrolysis and recovery time are too short, then reaction is incomplete.
With reference to embodiment, the technical solution that further illustrates the present invention.
In following embodiments, unless otherwise indicated, the experimental method actual conditions usually according to normal condition or system
Make the implementation condition of quotient's suggestion;The raw material and reagent are purchased from commercially available product;Ratio, ratio, percentage or the number, such as
Without special instruction, calculated according to weight.
Embodiment 1:
The synthesis of shellfish cholic acid intermediate 4 difficult to understand
1) by 9.51g intermediates 3, the 10%Pd/C of 2.0g, 100mL absolute methanols are placed in hydrogenation reaction cauldron;It will hydrogenation
N is used after kettle is closed successively2And H2Air in displacement system, temperature control is at 80~90 DEG C, H2Pressure is 0.5-0.6MPa, item
4h is reacted under part;
2) reaction is terminated, uses N successively2With air displacement system H2;
3) after mixture being separated by filtration Pd/C, solution is evaporated under reduced pressure under the conditions of 55~60 DEG C and removes solvent, obtains intermediate
Body 28.74g, yield 92%;
Intermediate 4 can direct plunge into subsequent reactions without being further processed.
The synthesis of shellfish cholic acid difficult to understand
4) intermediate 415.6g (31mmol) is dissolved in methanol 150ml, is then added and contains 12.0g NaBH420%
NaOH solution 105ml, solution react 4 hours at 60~65 DEG C;
5) it is cooled to room temperature, after removing methanol solvate under reduced pressure, reaction solution modulates pH=2 with 2mol/L dilute hydrochloric acid, there is white
Solid is precipitated;
6) it filters, filter cake makes to be washed with distilled water to neutrality, and crude white solid is obtained after oven drying
7) white solid 12.1g, yield 94.1% are obtained after using n-butyl acetate recrystallization.
HPLC purity 99.5%, MS (m/z):[M+H]+=421.3.1H NMR (400MHz, CD3OD)(ppm):3.62 (m,
1H), 3.28 (m, 1H), 2.30-2.33 (m, 1H), 1.97-1.99 (m, 1H), 0.97 (d, J=6.4,3H), 0.91 (s, 3H),
0.90 (t, J=8.2,3H), 0.69 (s, 3H).
Embodiment 2:
The synthesis of shellfish cholic acid intermediate 6 difficult to understand
1) in 500ml hydriding reactors, ethyl alcohol 280ml, compound 515.0g (27.9mmol), 10%Pd/C are sequentially added
1.5g, sodium hydroxide 0.75g and 25mL water, after object to be mixed stirs evenly, by hydriding reactor it is closed after successively use N2And H2Displacement
Air in system, control temperature is at 85~90 DEG C, H2Pressure is controlled in 0.5-0.6MPa, and mixture system is anti-under agitation
It answers 4 hours;
2) reaction is terminated, uses N successively2With air displacement system H2;
3) after mixture being separated by filtration Pd/C, solution is evaporated under reduced pressure under the conditions of 40~50 DEG C and removes solvent, obtains intermediate
Body 414.0g, yield 93.0%.
Intermediate 5 can direct plunge into subsequent reactions without being further processed;
The synthesis of shellfish cholic acid difficult to understand
4) intermediate 615.6g (28.9mmol) is dissolved in methanol 150ml, is then added and contains 12.2g NaBH4
20%NaOH solution 105mL, solution react 4 hours at 60~65 DEG C;
5) it is cooled to room temperature, after removing methanol solvate under reduced pressure, reaction solution modulates pH=2 with 2mol/L dilute hydrochloric acid, there is white
Solid is precipitated;
6) it filters, filter cake makes to be washed with distilled water to neutrality, and crude white solid is obtained after oven drying;
7) white solid 11.6g, yield 95.1% are obtained after using n-butyl acetate recrystallization.
HPLC purity 99.4%, MS (m/z):[M+H]+=421.3.1H NMR (400MHz, CD3OD)(ppm):3.62 (m,
1H), 3.28 (m, 1H), 2.30-2.33 (m, 1H), 1.97-1.99 (m, 1H), 0.97 (d, J=6.4,3H), 0.91 (s, 3H),
0.90 (t, J=8.2,3H), 0.69 (s, 3H).
Embodiment 3:
The synthesis of shellfish cholic acid intermediate 8 difficult to understand
1) by 6.50g (14.2mmol) intermediate 7, the 10%Pd/C of 1.30g, 100mL isopropanols are placed in hydrogenation reaction cauldron
It is interior;By hydriding reactor it is closed after successively use N2And H2Air in displacement system, temperature control is at 80~90 DEG C, H2Pressure is 0.5-
4h is reacted under the conditions of 0.6MPa;
2) reaction is terminated, uses N successively2With air displacement system H2;
3) after mixture being separated by filtration Pd/C, solution is evaporated under reduced pressure under the conditions of 55~60 DEG C and removes solvent, obtains intermediate
Body 86.23g, yield 95.4%;
Intermediate 8 can direct plunge into subsequent reactions without being further processed.
The synthesis of shellfish cholic acid difficult to understand
4) intermediate 86.23g (13.5mmol) is dissolved in methanol 150ml, is then added and contains 5.13g NaBH4
20%NaOH solution 105ml, solution react 4 hours at 60~65 DEG C;Filtering, filter cake make to be washed with distilled water to neutrality, through drying
Crude white solid is obtained after case drying;
5) it is cooled to room temperature, after removing methanol solvate under reduced pressure, reaction solution modulates pH=2 with 2mol/L dilute hydrochloric acid, there is white
Solid is precipitated;
6) it filters, filter cake makes to be washed with distilled water to neutrality, and crude white solid is obtained after oven drying
7) white solid 5.44g, yield 95.8% are obtained after using n-butyl acetate recrystallization.
HPLC purity 99.6%, MS (m/z):[M+H]+=421.3.1H NMR (400MHz, CD3OD)(ppm):3.62 (m,
1H), 3.28 (m, 1H), 2.30-2.33 (m, 1H), 1.97-1.99 (m, 1H), 0.97 (d, J=6.4,3H), 0.91 (s, 3H),
0.90 (t, J=8.2,3H), 0.69 (s, 3H).
Route described in document and patent is repeated, its yield and purity data is obtained, is compared with data of the present invention:
Comparative example 1:Method disclosed in CN101203526B prepares shellfish cholic acid difficult to understand
Comparative example 2:Document J.Med.Chem., 2012,55:84-93 methods prepare shellfish cholic acid difficult to understand
The comparable situation of different Austria's shellfish cholic acid preparation methods is as follows:
From the data in the table:
Comparative example 1 is compared:Embodiment 1,2 and 3 differences reside in reduced reaction step, and intermediate Part need not carry out list
Only configuration conversion operation, and hydrolysis is merged with carbonyl reduction in a step, simplifying step reduces Material Cost.And
And yield is significantly increased.
Compared with comparative example 2:Embodiment 1,2 and 3 does not use CeCl by the optimization of reaction condition3, and without making
Double bond is restored under high pressure with special Pd/C and takes off benzyl, reduces Material Cost, while improving the receipts of product
Rate.
In conclusion the synthesis difficulty of shellfish cholic acid difficult to understand, reaction can be simplified by implementing reaction using the technological parameter of the present invention
Mild condition, operating procedure is simple, reduces the synthesis cost of shellfish cholic acid difficult to understand.
Claims (10)
1. a kind of preparation method of Austria's shellfish cholic acid, synthetic route are as follows:
In formula, R is carboxyl-protecting group, is specifically comprised the following steps:
1) intermediate 1 is dissolved in polar organic solvent A, using hydrogen be hydrogen source, 80 DEG C~100 DEG C, relative pressure 0.5~
Catalytic hydrogenating reduction ethylene linkage is carried out under 1.0MPa, obtains intermediate 2;
2) by intermediate 2, in polar organic solvent B, 50~100 DEG C of progress carbonyl reduction reactions have been reacted for boron hydrogen salt, alkali soluble
Reaction is quenched after;
3) post-processing obtains shellfish cholic acid difficult to understand.
2. preparation method according to claim 1, it is characterised in that:R be the linear or branched alkyl group of C1~C8, phenyl or
Benzyl, the linear or branched alkyl group of the C1~C8 arbitrarily replaced, the phenyl or benzyl that arbitrarily replace.
3. preparation method according to claim 1, it is characterised in that:Boron hydrogen salt is lithium borohydride, sodium borohydride, hydroboration
Or mixtures thereof potassium, calcium borohydride.
4. according to claims 1 to 3 any one of them preparation method, it is characterised in that:Alkali be lithium hydroxide, sodium hydroxide,
Potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylamine, ethamine, propylamine, dimethylamine, diethylamine, di-n-propylamine, trimethylamine, triethylamine, 3 third
Or mixtures thereof amine, n,N-diisopropylethylamine, sodium acetate.
5. preparation method according to claim 1, it is characterised in that:Linear or branched alkyl group, phenyl or the benzyl of C1~C8
The substituent group of base is independently selected from electron-withdrawing group.
6. preparation method according to claim 5, it is characterised in that:Electron-withdrawing group is selected from halogen, ester group, nitro, cyanogen
At least one of base.
7. according to any one of them preparation method of claims 1 to 3,5 or 6, it is characterised in that:Polar organic solvent A is selected from
Methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran or its mixed solvent.
8. according to any one of them preparation method of claims 1 to 3,5 or 6, it is characterised in that:Polar organic solvent B is selected from
The mixed solution of at least one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran and water.
9. preparation method according to claim 1, it is characterised in that:The temperature of carbonyl reduction reaction is 50~80 DEG C.
10. preparation method according to claim 1, it is characterised in that:Post-processing includes in concentration, extraction and separation, soda acid
With purifying.
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