CN105481925B - A kind of preparation method of Austria's shellfish cholic acid and its intermediate - Google Patents

A kind of preparation method of Austria's shellfish cholic acid and its intermediate Download PDF

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CN105481925B
CN105481925B CN201510954983.7A CN201510954983A CN105481925B CN 105481925 B CN105481925 B CN 105481925B CN 201510954983 A CN201510954983 A CN 201510954983A CN 105481925 B CN105481925 B CN 105481925B
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compound
reaction
cholic acid
acid
shellfish cholic
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CN105481925A (en
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杨建楠
李营
赵卿
霍立茹
李战
周静
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Fudan Zhangjiang Biological Medicine Co., Ltd., Shanghai
NANJING JIQUN PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO.,LIMITED
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FUDAN ZHANGJIANG BIOLOGICAL MEDICINE Co Ltd SHANGHAI
Nanjing Ji Medicine Polytron Technologies Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal 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
    • C07J9/005Normal 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

Abstract

The present invention relates to the preparation methods of a kind of shellfish cholic acid difficult to understand and its intermediate, 3 α hydroxyls, 6 α ethyls, 7 ketone group, 5 β cholanic acids are obtained by the reaction by 3 α hydroxyls, 6 ethylidene, 7 ketone group, 5 β cholane acid benzyl esters etc compound under catalyst and hydrogen donor effect;The catalyst is selected from Pd/C, PtO2Or Raney Ni, the hydrogen donor are selected from cyclohexene, cyclohexadiene or tetrahydronaphthalene.This method high income, stereoselectivity are high, safety is good, reaction condition is mild, are suitable for industrialized production.

Description

A kind of preparation method of Austria's shellfish cholic acid and its intermediate
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the preparation method of a kind of Austria's shellfish cholic acid and its intermediate.
Background technology
Shellfish cholic acid (Obeticholic Acid) difficult to understand also known as INT-747 are developed by Intercept drugmakers of the U.S. and opened Hair, indication are primary biliary cirrhosis (PBC) and non-alcohol fatty liver (NASH), are in clinical III at present Phase.Shellfish cholic acid difficult to understand is the specific agonist of a kind of semi-synthetic chenodeoxycholic acid and method Buddhist nun's ester derivant X receptors, animal Experiment is proved its effect for improving insulin resistance and mitigating hepatic fat content, be over 20 years first research and development for treating The drug of cholestatic liver disease, market potential are huge.
Shellfish cholic acid difficult to understand, chemical entitled-3 α of 6 α-ethyl, 7-5 β of alpha-dihydroxy-cholanic acid, structural formula are as follows:
CN101203526 and CN104781272A discloses the preparation method of shellfish cholic acid difficult to understand, is protected by esterification, hydroxyl Shield, ethylidene (aldol condensation), ester hydrolysis, catalytic hydrogenation obtain formula (I) compound, then obtain shellfish courage difficult to understand by carbonyl reduction Acid, but in above-mentioned patent route methyl esters hydrolytic process, if during pH < 12, temperature is less than at 49-53 DEG C, MeOH/NaOH solution In, ester hydrolysis is not thorough, but if under highly basic heating condition, ethylidene easily degradation again ultimately forms major impurity goose Deoxycholic aicd, while the yield of shellfish cholic acid preparation process difficult to understand can be reduced.Therefore a kind of new shellfish cholic acid important intermediate difficult to understand is developed The synthetic method of formula (I) is conducive to the industrialization of shellfish cholic acid difficult to understand.
J.Med.Chem.2012,55,84-93 discloses following reaction route:It is with chenodeoxycholic acid (compound 4) Beginning raw material obtains Austria through peroxidating, benzyl protection, hydroxyl protection, ethylidene (aldol condensation), carbonyl reduction and catalytic hydrogenation Shellfish cholic acid (i.e. compound 2).The route solves the problems, such as ester hydrolysis process, but 8 catalytic hydrogenation of compound In (reaction f steps), although the protection of benzyl derivative can be removed smoothly, due to the shadow of 7 hydroxyl richnesses ionizations of condensed ring It rings, 6 catalytic hydrogenation difficulties, obtains product as in -5 β -24- cholanic acids of 3,7-, bis- Alpha-hydroxy -6- ethylidene rather than document Compound 2, the reaction are not suitable for industrial production.
In order to solve the influence of hydroxyl in catalytic hydrogenation, compound 7 is first carried out catalytic transfer hydrogenation by the present invention, should Benzyl derivative is taken off while step catalytic transfer hydrogenation to protect to obtain key intermediate compound (I), then carry out carbonyl also Original obtains shellfish cholic acid difficult to understand.
Invention content
In order to solve the problems such as ester hydrolysis is not thorough, catalytic hydrogenation is difficult in existing shellfish cholic acid synthesis technology difficult to understand, further The yield and quality of shellfish cholic acid difficult to understand are improved, the present invention provides a kind of 3 Alpha-hydroxy -6- ethyl -7- ketone groups -5 of shellfish cholic acid intermediate difficult to understand The preparation method of β-cholane acid (I), the preparation method avoid the influence of hydroxyl in catalytic hydrogenation, and there is no ester hydrolysis Step.The intermediate formula (I) obtains shellfish cholic acid difficult to understand after carbonyl reduction, and the method for the present invention can improve shellfish cholic acid yield difficult to understand, Production cost is reduced, improves purity, reduces impurity content.
The present invention relates to the preparation method of shellfish cholic acid intermediate difficult to understand shown in a kind of formula (I),
Method is as follows:Catalytic transfer hydrogenation reacts, compound (VI) being obtained by the reaction under catalyst and hydrogen donor effect Close object (I);The catalyst is selected from Pd/C, PtO2Or Raney Ni, preferably 5-20%Pd/C, the hydrogen donor be selected from cyclohexene, Cyclohexadiene or tetrahydronaphthalene.Reaction equation is as follows:
Ar is phenyl, 4- aminomethyl phenyls or 4- methoxyphenyls in compound (VI), and preferably Ar is phenyl.The above method It is further as follows:Solvent is selected from methanol, ethyl alcohol, tetrahydrofuran or the one or more mixed systems of water, and reaction temperature is 20~65 DEG C, compound VI:Hydrogen donor molar ratio is 1:0.2~1:10, compound VI:The molar ratio of catalyst is 1:0.01~1: 0.2。
Second purpose of the present invention provides one kind and prepares shellfish cholic acid method difficult to understand by formula (I) intermediate, and method is as follows:
The metallic reducing agents such as sodium borohydride, potassium borohydride reducing compound (I) carbonyl obtains shellfish cholic acid difficult to understand, the chemical combination Object (I) is prepared by the above method or preferred method.
Preferred embodiment of the present invention, the carbonyl reduction react the metallic reducing agent for potassium borohydride or sodium borohydride, Coordinative solvent is methanol, ethyl alcohol, tetrahydrofuran or methanol/water, the mixed solution of ethanol/water, tetrahydrofuran/water.
Another object of the present invention provides a kind of shellfish cholic acid preparation method difficult to understand:
S1. oxidation reaction, compound (II) in the presence of an oxidizer, occur oxidation reaction and obtain compound (III);
S2. substituted benzyl is protected, and compound (IV) is obtained by the reaction under the effect of benzyl halogenated aromatic in compound (III);
S3. hydroxyl protection reacts, and compound (IV) is protected with silanes and tried in the presence of highly basic such as lithium diisopropylamine Compound (V) is obtained by the reaction under agent effect;
S4. ethylidene aldol reacts, and chemical combination is obtained by the reaction with electrophilic reagent acetaldehyde in acid condition in compound (V) Object (VI);
S5. catalytic transfer hydrogenation reacts, and compound is obtained by the reaction using method in first goal of the invention in compound (VI) (I);
S6. carbonyl reduction reacts, and shellfish courage difficult to understand is obtained using the metallic reducing agents reducing carbonyl such as sodium borohydride, potassium borohydride Acid.
Ar is phenyl, 4- aminomethyl phenyls or 4- methoxyphenyls.
Oxidant described in preferred embodiment of the present invention, the wherein first step is selected from sodium hypochlorite or pyridinium chloro-chromate, preferably Sodium hypochlorite.
Esterification described in preferred embodiment of the present invention, wherein second step, benzyl halogenated aromatic are benzyl bromine, to methyl benzyl Bromine or to methoxy benzyl chloride, preferably benzyl bromine, alkali is cesium carbonate, potassium carbonate or sodium hydrogen, preferably cesium carbonate, and reaction dissolvent is tetrahydrochysene furan It mutters, acetonitrile or dimethylformamide.
The hydroxyl protection reaction of preferred embodiment of the present invention, wherein third step, silanes protection reagent are selected from trimethyl Chlorosilane, tert-butyl chloro-silicane, hexamethyldisilazane or tert-butyl diphenyl chlorosilane, preferably trimethylchloro-silicane Alkane, alkali are selected from lithium diisopropylamine or n-BuLi, preferably lithium diisopropylamine.
Preferred embodiment of the present invention, wherein the ethylidene aldol reactions described in the 4th step, electrophilic reagent are selected from acetaldehyde, road Lewis acid is boron trifluoride ether, and solvent is anhydrous methylene chloride.
Preferred embodiment of the present invention, wherein the carbonyl reduction reaction described in the 6th step, reducing agent are potassium borohydride or hydroboration Sodium, coordinative solvent is methanol, ethyl alcohol, tetrahydrofuran or methanol/water, the mixed solution of ethanol/water, tetrahydrofuran/water.
Advantageous effect:
The protection of benzyl ester in this route limited can avoid ethylidene drop caused by basic hydrolysis methyl esters in the prior art Solution, so as to which chenodeoxycholic acid is reduced to 0.1% hereinafter, far below 1% in patent CN101203526A.It can pass through simultaneously Catalytic transfer hydrogenation smoothly removes benzyl, synthesizes shellfish cholic acid six-step process total recovery difficult to understand and reaches 35%~40%, stereoselectivity It is high, without using hydrogen as hydrogen donor, safety is good, reaction condition is mild, obviates the column purification step in document report, suitable Together in industrialized production.
Specific embodiment
Following embodiments are specific preferred embodiments in order to demonstrate the invention, are not intended to limit this hair Bright protection domain.In all embodiments, TLC is silica gel H SGF254 plates, and 10% phosphomolybdic acid ethanol solution develops the color, and mass spectrum uses Finnigan LCQ ESI-MS mass spectrographs,1H-NMR uses BRUKER AVANCE AV-500 type Nuclear Magnetic Resonance, and HPLC is used 1260 high performance liquid chromatographs of Agilent.
The preparation of raw material chenodeoxycholic acid (CDCA) can according to patent CN102964416A, CN20060609C, Prepared by the prior arts conditions such as CN102827234B reports, also can directly purchase commercially available high-purity C DCA.
The preparation of 3-5 β of Alpha-hydroxy-7- ketone groups of embodiment 1a-cholanic acid (III)
Sequentially added into reaction bulb chenodeoxycholic acid (II) (113g, 0.288mol), sodium bromide (1.78g, 0.0173mol), acetic acid (30mL) and methanol (600mL), are stirred at room temperature to whole dissolvings, -10 DEG C ± 2 DEG C are cooled to, to reaction Be slowly added dropwise 13% liquor natrii hypochloritis (225mL, 0.39mol) in system, in control temperature be stirred to react at -10~0 DEG C to HPLC detection raw material chenodeoxycholic acid (II) contents are less than 1%.After the completion of reaction, ice bath is removed, reaction solution is warmed to room temperature naturally, 5% solution of sodium bisulfite (25mL) is added dropwise into reaction system, stirs 30 minutes, filters, is dried to obtain 3 Alpha-hydroxy -7- - 5 β of ketone group-cholanic acid (III) crude product (115.83g).Crude product and methanol (1L) are added in reaction bulb, are heated to 65 DEG C, is returned It stream reaction half an hour, filters while hot, filtrate is reheated into reflux half an hour, reaction solution natural cooling crystallization filters, is dry To 3-5 β of Alpha-hydroxy-7- ketone groups-cholanic acid (III) (91g, yield 80.9%, HPLC of white powder:99.64%).
The preparation of 3-5 β of Alpha-hydroxy-7- ketone groups of embodiment 1b-cholanic acid (III)
Chenodeoxycholic acid (II) (100g, 0.255mol), anhydrous magnesium sulfate (200g), chloroform are sequentially added into reaction bulb (300mL), is stirred at room temperature, and adding in pyridinium chloro-chromate dichloromethane solution into reaction system drop, (61g pyridinium chloro-chromates are molten In 2.5L dichloromethane), 30min is stirred at room temperature in reaction solution.Solid insoluble is filtered, filtrate is washed successively with water and saturated common salt It washs, the drying of organic phase anhydrous sodium sulfate is concentrated under reduced pressure, obtains 3-5 β of Alpha-hydroxy-7- ketone groups-cholanic acid (III) (73g, yield 73.3%, HPLC are detected:97.7%).
The synthesis of 3-5 β of Alpha-hydroxy-7- ketone groups of embodiment 2a-- 24 acid benzyl ester of cholane (IVa)
In reaction bulb, compound III (20g, 51mmol), anhydrous tetrahydro furan (450ml) are added in, stirring adds in carbon Sour potassium (10.5g, 76mmol) is warming up to reflux, adds in cylite (30ml), back flow reaction, 12h monitoring reaction (TLC conditions: Acetone:Dichloromethane:Acetic acid=1:15:1).Reaction terminates, and adds in triethylamine (30ml), the reaction was continued removes to form quaternary ammonium salt Excessive cylite to be removed, is cooled to room temperature, diatomite aided filter solid insoluble, filtrate decompression concentration adds in water (200ml), It is extracted with ethyl acetate (200ml*3), merges organic phase, successively purified water, saturated sodium-chloride washing, anhydrous sodium sulfate drying, It is concentrated under reduced pressure to give compound (IVa) 20.3g, yield 82.8%.
Synthesis of-24 acid of 3-5 β of Alpha-hydroxy-7- ketone groups of embodiment 2b-cholane to methoxy benzyl ester (IVb)
In reaction bulb, compound III (20g, 51mmol), anhydrous acetonitrile (450ml) are added in, stirring adds in cesium carbonate (25g) is warming up to reflux, adds in methoxyl group cylite (30ml), reflux 10h monitoring reaction (TLC conditions:Acetone:Dichloromethane Alkane:Acetic acid=1:15:1).Reaction terminates, and adds in triethylamine (25ml), and the reaction was continued removes excessive bromination to form quaternary ammonium salt Benzyl is cooled to room temperature, diatomite aided filter solid insoluble, and filtrate decompression concentration adds in ethyl acetate (250ml*3) and extracts It takes, merges organic phase, purified water, saturated sodium-chloride washing, anhydrous sodium sulfate drying successively is concentrated under reduced pressure to give compound (IVb) 21.7g, yield 86%.
The preparation of embodiment 33 α, 7 α-two--5 β of trimethylsiloxy -6- alkene-cholane acid benzyl ester (Va)
Anhydrous tetrahydro furan (300mL) is added in into reaction bulb under nitrogen protection, dry ice ethanol bath, which is cooled at -78 DEG C, drips Add the tetrahydrofuran solution (C=2mol/L, 140mL, 0.28mol) of lithium diisopropylamine, 30 points are stirred after being added dropwise Clock trim,ethylchlorosilane (63mL, 0.5mol) is added dropwise at-65 DEG C, after stirring evenly, by 3-5 β of Alpha-hydroxy-7- ketone groups-cholanic acid Tetrahydrofuran (100mL) solution of benzyl ester (IVa) (18.0g, 0.037mol) is added dropwise in reaction solution, and it is small that 1 is reacted at -75 DEG C When.After reaction, ice bath is removed, is warming up to -10 DEG C, saturated sodium bicarbonate solution (250mL) is added dropwise, control temperature is no more than 20 DEG C, stand liquid separation, be extracted with ethyl acetate (200mL × 2), merge organic phase, successively with saturated sodium bicarbonate (200mL), Saturated salt solution (400mL) washs, anhydrous sodium sulfate drying, filters, is concentrated under reduced pressure to give 3 α, 7 α-two-front three of yellow oily - 5 β of base siloxy -6- alkene-cholane acid benzyl ester (Va) crude product (23.8g), oil pump vacuum distillation 30min, nitrogen charging gas shielded, It is directly used in the next step.
The preparation of 4 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups of embodiment-cholane acid benzyl ester (VIa)
Under nitrogen protection, 3 α, 7 α-two--5 β of trimethylsiloxy -6- alkene-cholane acid benzyl ester are added in into reaction bulb (Va) (17g) and dichloromethane (300mL), dry ice/ethanol bath are cooled at -65 DEG C, and acetaldehyde is added in into reaction bulb (3.3mL) is stirred evenly and boron trifluoride ether solution (37mL) is added in backward reaction solution, react 5 at -60 DEG C after being added dropwise Hour, it is warmed to room temperature reaction 2 hours.After reaction, ice-water bath is cooled at 0-5 DEG C and saturated sodium bicarbonate solution is added dropwise (300mL) stands liquid separation, is extracted (200mL × 3) with dichloromethane, merge organic phase, with saturated common salt water washing (250mL), Anhydrous sodium sulfate is dried, filtering, is concentrated under reduced pressure to give 3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholanic acid of brown yellow oil Benzyl ester (VIa), oil pump vacuum distillation 30min, nitrogen charging gas shielded are directly used in the next step.
The preparation of -5 β cholanic acids (I) of 3 Alpha-hydroxy -6- ethyl -7- ketone groups of embodiment 5a
3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholane acid benzyl ester (VIa) (15g) is dissolved in ethyl alcohol (300ml), is added in Sodium acetate 4.5g, stirring and dissolving are put into reaction bulb, add in cyclohexene (4.5ml), 10%Pd/C catalyst (0.8g), heating To back flow reaction.Reaction terminates, and filtration catalytic agent, filtrate decompression is concentrated into 120ml, is added dropwise in 900ml water, is precipitated a large amount of solid Body filters to obtain -5 β cholanic acids (I) of white 3 Alpha-hydroxy -6- ethyl -7- ketone groups.HPLC detection configurations:Chemical purity 98.5%, isomer proportion α/β=100:1.
The preparation of -5 β cholanic acids (I) of 3 Alpha-hydroxy -6- ethyl -7- ketone groups of embodiment 5b
3-5 β of Alpha-hydroxy-6- ethylidene-7- ketone groups-cholane acid benzyl ester (VIa) (15g) is dissolved in methanol (300ml), is stirred Dissolving adds in cyclohexadiene (4.5ml), puts into reaction bulb, 10%Pd/C catalyst (1.5g) is warming up to back flow reaction.Instead It should terminate, filtration catalytic agent, filtrate decompression is concentrated into 50ml, is added dropwise in 800ml water, and a large amount of solids are precipitated, and filters to obtain - 5 β cholanic acids (I) of white 3 Alpha-hydroxy -6- ethyl -7- ketone groups.HPLC detection configurations:Chemical purity 98.8%, isomer proportion α/β=98:1.
63 α of embodiment, the preparation of-5 β cholanic acids of 7-6 α of alpha-dihydroxy-ethyl (shellfish cholic acid difficult to understand)
- 5 β cholanic acids (I) (24.0g) of 3 Alpha-hydroxy -6- ethyl -7- ketone groups, tetrahydrofuran are added in into reaction bulb (480ml), purified water (120ml), stirring and dissolving, be cooled to 10 DEG C hereinafter, in batches add in sodium borohydride (6.5g), add, 1~2h is reacted in 20~30 DEG C.Reaction terminates, and concentrated solvent obtains pale yellow oil.Add water (200ml) and ethyl acetate (240ml), under ice bath cooling, with 2M salt acid for adjusting pH to 3.0, water phase is extracted again with ethyl acetate (240ml), is merged organic Phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate decompression are concentrated to dryness to obtain off-white powder (20.6g), Recrystallize with dichloromethane obtains shellfish cholic acid difficult to understand.

Claims (15)

1. a kind of preparation method of Austria's shellfish cholic acid intermediate shown in formula (I), which is characterized in that
Compound (I) is obtained by the reaction under catalyst and hydrogen donor effect in compound (VI);The catalyst is selected from Pd/C, PtO2 Or Raney Ni, the hydrogen donor are selected from cyclohexene, cyclohexadiene or tetrahydronaphthalene, reaction equation is as follows:
Ar is phenyl, 4- methoxyphenyls, 4- aminomethyl phenyls;
Solvent is selected from methanol, ethyl alcohol, tetrahydrofuran or the one or more mixed systems of water, and reaction temperature is 20~65 DEG C, is changed Close object VI:Hydrogen donor molar ratio is 1:0.2~1:10, compound VI:The molar ratio of catalyst is 1:0.01~1:0.2.
2. preparation method according to claim 1, which is characterized in that catalyst is 5%~20%Pd/C.
3. preparation method according to claim 1, which is characterized in that Ar is phenyl.
4. a kind of preparation method of Austria's shellfish cholic acid, which is characterized in that the carbonyl of metallic reducing agent reducing compound (I) obtains Ao Bei Cholic acid;The compound (I) is prepared by claim 1-3 either method.
5. preparation method according to claim 4, which is characterized in that the metallic reducing agent is potassium borohydride or boron hydrogen Change sodium, solvent is methanol, ethyl alcohol, tetrahydrofuran or methanol/water, the mixed solution of ethanol/water, tetrahydrofuran/water.
6. a kind of preparation method of Austria's shellfish cholic acid, which is characterized in that
S1. oxidation reaction, compound (II) in the presence of an oxidizer, occur oxidation reaction and obtain compound (III);
S2. substituted benzyl is protected, and compound (IV) is obtained by the reaction under the effect of benzyl halogenated aromatic in compound (III);
S3. hydroxyl protection reacts, and compound (IV) is under nucleophilicity highly basic, with alkene is obtained by the reaction under silanes protection reagent effect Alcohol silica-ether compound (V);
S4. ethylideneization is reacted, and compound (V) occurs aldol with acetaldehyde in acid condition and compound (VI) is obtained by the reaction;
S5. catalytic transfer hydrogenation reacts, and compound (VI) obtains compound (I) using claim 1-3 either method;
S6. carbonyl reduction reacts, and shellfish cholic acid difficult to understand is obtained using the metallic reducing agents reducing carbonyl such as sodium borohydride, potassium borohydride;
Ar is phenyl, 4- methoxyphenyls, 4- aminomethyl phenyls.
7. preparation method according to claim 6, which is characterized in that the S1. steps oxidant be selected from sodium hypochlorite or Pyridinium chloro-chromate;S2. it is benzyl bromine, to methyl benzyl bromine or to methoxy benzyl chloride, reaction system to walk the benzyl halogenated aromatic In further include alkali, the alkali is selected from cesium carbonate, potassium carbonate or sodium hydrogen, and reaction dissolvent is tetrahydrofuran, acetonitrile or dimethyl formyl Amine.
8. preparation method according to claim 6, which is characterized in that the S3. steps silanes protection reagent is selected from three Methylchlorosilane, tert-butyl chloro-silicane, hexamethyldisilazane or tert-butyl diphenyl chlorosilane, alkali are selected from diisopropyl Base lithium amide or n-BuLi.
9. preparation method according to claim 6, which is characterized in that the S4. steps ethylidene step aldol reactions Middle electrophilic reagent is selected from acetaldehyde, and lewis acid is boron trifluoride ether, and solvent is anhydrous methylene chloride.
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US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
WO2017207648A1 (en) * 2016-05-31 2017-12-07 Bionice, S.L.U Process and intermediates for the preparation of obeticholic acid and derivatives thereof
CN108239134B (en) * 2016-12-23 2020-07-07 上海博邦医药科技有限公司 Obeticholic acid intermediate and preparation method and application thereof
CN108680696B (en) * 2018-05-15 2020-06-30 南京正大天晴制药有限公司 Detection method of obeticholic acid starting material

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