CN105481925A - Preparation method for obeticholic acid and intermediate thereof - Google Patents
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Abstract
The invention relates to a preparation method for obeticholic acid and an intermediate thereof. The intermediate 3alpha-hydroxy-6alpha-ethyl-7-keto-5beta-cholanic acid is obtained by subjecting 3alpha-hydroxy-6-ethylidene-7-keto-5beta-cholanic acid benzyl ester compounds to a reaction under the action of a catalyst and a hydrogen donor. The catalyst is selected from Pd/C or PtO2 or Raney Ni. The hydrogen donor is selected from cyclohexene or cyclohexadiene or tetrahydronaphthalene. According to the method, the yield is high, the stereoselectivity is high, safety is good, the reaction condition is mild, and the method is applicable to industrial production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of a kind of shellfish cholic acid difficult to understand and intermediate thereof.
Background technology
Shellfish cholic acid (ObeticholicAcid) difficult to understand, have another name called INT-747, developed by American I ntercept drugmaker, indication is primary biliary cirrhosis (PBC) and non-alcohol fatty liver (NASH), is in the clinical III phase at present.Shellfish cholic acid difficult to understand is a kind of semisynthetic Chenodiol, also be the specific agonist of method Buddhist nun ester derivative X acceptor, animal experiment has proved its effect improving insulin resistant and alleviate hepatic fat content, be the medicine that the first research and development of Two decades years are used for the treatment of cholestatic liver disease, market potential is huge.
Shellfish cholic acid difficult to understand, chemistry 6 α-ethyl-3 α by name, 7 alpha-dihydroxy--5 β-ursodeoxycholic acids, its structural formula is as follows:
CN101203526 and CN104781272A discloses the preparation method of shellfish cholic acid difficult to understand, through esterification, hydroxyl protection, ethylidene (aldol condensation), Ester hydrolysis, catalytic hydrogenation obtains formula (I) compound, shellfish cholic acid difficult to understand is obtained again by carbonyl reduction, but in above-mentioned patent route methyl esters hydrolytic process, if during pH < 12, temperature is lower than at 49-53 DEG C, in MeOH/NaOH solution, Ester hydrolysis is not thorough, if but under highly basic heating condition, ethylidene is easily degraded again, final formation major impurity Chenodiol, the yield of shellfish cholic acid preparation technology difficult to understand can be reduced simultaneously.Therefore the synthetic method developing a kind of shellfish cholic acid important intermediate formula (I) difficult to understand is newly conducive to the industrialization of shellfish cholic acid difficult to understand.
J.Med.Chem.2012; 55; 84-93 discloses following reaction scheme: with Chenodiol (compound 4) for starting raw material, obtains shellfish cholic acid difficult to understand (i.e. compound 2) through peroxidation, benzyl protection, hydroxyl protection, ethylidene (aldol condensation), carbonyl reduction and catalytic hydrogenation.This route solves Problems existing in Ester hydrolysis process; but in compound 8 catalytic hydrogenation (reaction f step); although the protection of benzyl derivative can be removed smoothly; but due to the rich Ionized impact of condensed ring 7 hydroxyls; 6 shortening difficulties, obtaining product is 3,7-bis-Alpha-hydroxy-6-ethylidene-5 β-24-ursodeoxycholic acid; but not the compound 2 in document, this reaction is not suitable for industrial production.
In order to solve the impact of hydroxyl in catalytic hydrogenation; compound 7 is first carried out catalytic transfer hydrogenation by the present invention; take off benzyl derivative protection while this step catalytic transfer hydrogenation and obtain key intermediate compound (I), then carry out carbonyl reduction and obtain shellfish cholic acid difficult to understand.
Summary of the invention
In order to solve the problems such as Ester hydrolysis is thorough, catalytic hydrogenation is difficult in existing shellfish cholic acid synthesis technique difficult to understand, the productive rate of further raising shellfish cholic acid difficult to understand and quality, the invention provides a kind of preparation method of shellfish cholic acid intermediate 3 Alpha-hydroxy-6-ethyl-7-ketone group-5 β-cholane acid (I) difficult to understand, this preparation method avoids the impact of hydroxyl in catalytic hydrogenation, there is not Ester hydrolysis step.This intermediate formula (I) obtains shellfish cholic acid difficult to understand after carbonyl reduction, and the inventive method can improve shellfish cholic acid productive rate difficult to understand, reduces production cost, improves purity, reduces foreign matter 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, and compound (VI) is obtained by reacting compound (I) under catalyzer and hydrogen donor effect; Described catalyzer is selected from Pd/C, PtO
2or Raney Ni, preferred 5-20%Pd/C, described hydrogen donor is selected from tetrahydrobenzene, cyclohexadiene or tetraline.Reaction equation is as follows:
In compound (VI), Ar is phenyl, 4-aminomethyl phenyl or 4-p-methoxy-phenyl, and preferred Ar is phenyl.Aforesaid method is as follows further: one or more mixed systems of solvent selected from methanol, ethanol, tetrahydrofuran (THF) or water, temperature of reaction is 20 ~ 65 DEG C, compound VI: hydrogen donor mol ratio is 1:0.2 ~ 1:10, compound VI: molecular proportion of catalyst is 1:0.01 ~ 1:0.2.
The present invention's second object provides a kind of through type (I) Intermediate Preparation shellfish cholic acid difficult to understand method, and method is as follows:
The metallic reducing agent such as sodium borohydride, POTASSIUM BOROHYDRIDE reducing compound (I) carbonyl obtains shellfish cholic acid difficult to understand, and described compound (I) is prepared by aforesaid method or preferred method.
Preferred version of the present invention, it is POTASSIUM BOROHYDRIDE or sodium borohydride that described carbonyl reduction reacts described metallic reducing agent, and coordinative solvent is the mixing solutions of methyl alcohol, ethanol, tetrahydrofuran (THF) or methanol/water, ethanol/water, tetrahydrofuran (THF)/water.
Another object of the present invention provides a kind of shellfish cholic acid preparation method difficult to understand:
S1. oxidizing reaction, in the presence of an oxidizer, there is oxidizing reaction and obtain compound (III) in compound (II);
S2. substituted benzyl protection, compound (III) is obtained by reacting compound (IV) under the effect of benzyl halogenated aromatic;
S3. hydroxyl protection reaction, compound (IV) as under lithium diisopropylamine existence, is obtained by reacting compound (V) at highly basic with silicane under protecting reagent effect;
S4. ethylidene aldol reacts, and compound (V) is obtained by reacting compound (VI) with electrophilic reagent acetaldehyde in acid condition;
S5. catalytic transfer hydrogenation reaction, compound (VI) uses method in first goal of the invention to be obtained by reacting compound (I);
S6. carbonyl reduction reaction, adopts the metallic reducing agent such as sodium borohydride, POTASSIUM BOROHYDRIDE reducing carbonyl to obtain shellfish cholic acid difficult to understand.
Ar is phenyl, 4-aminomethyl phenyl or 4-p-methoxy-phenyl.
Preferred version of the present invention, the oxygenant wherein described in the first step is selected from clorox or pyridinium chloro-chromate, preferred clorox.
Preferred version of the present invention, the esterification wherein described in second step, benzyl halogenated aromatic is benzyl bromine, to methyl benzyl bromine or to methoxy benzyl chlorine, preferred benzyl bromine, alkali is cesium carbonate, salt of wormwood or sodium hydrogen, preferred cesium carbonate, and reaction solvent is tetrahydrofuran (THF), acetonitrile or dimethyl formamide.
Preferred version of the present invention; hydroxyl protection reaction wherein described in the 3rd step; silicane protection reagent is selected from trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, hexamethyldisilazane or tert-butyl diphenyl chlorosilane; preferred trimethylchlorosilane; alkali is selected from lithium diisopropylamine or n-Butyl Lithium, preferred lithium diisopropylamine.
Preferred version of the present invention, the ethylidene aldol wherein described in the 4th step reacts, and electrophilic reagent is selected from acetaldehyde, and Lewis acid is boron trifluoride diethyl etherate, and solvent is anhydrous methylene chloride.
Preferred version of the present invention, the carbonyl reduction reaction wherein described in the 6th step, reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride, and coordinative solvent is the mixing solutions of methyl alcohol, ethanol, tetrahydrofuran (THF) or methanol/water, ethanol/water, tetrahydrofuran (THF)/water.
Beneficial effect:
The protection of benzyl ester in this route, limitedly can avoid the ethylidene degraded that prior art neutral and alkali hydrolysis methyl esters causes, thus Chenodiol is reduced to less than 0.1%, far below 1% in patent CN101203526A.Benzyl can be removed smoothly by catalytic transfer hydrogenation simultaneously, synthesize that shellfish cholic acid six-step process total recovery difficult to understand arrives 35% ~ 40%, stereoselectivity is high, do not use hydrogen as hydrogen donor, security is good, reaction conditions is gentle, obviate the column purification step in bibliographical information, be suitable for suitability for industrialized production.
Embodiment
Following embodiment is specific preferred embodiment in order to demonstrate the invention, the protection domain be not meant to limit the present invention.In all embodiments, TLC is silica gel H SGF254 plate, 10% phosphomolybdic acid ethanol solution colour developing, and mass spectrum adopts FinniganLCQESI-MS mass spectrograph,
1h-NMR adopts BRUKERAVANCEAV-500 type nuclear magnetic resonance analyser, and HPLC adopts Agilent1260 high performance liquid chromatograph.
The preparation of raw material Chenodiol (CDCA) according to prior art condition preparations such as patent CN102964416A, CN20060609C, CN102827234B reports, also can directly can purchase commercially available high-purity C DCA.
The preparation of embodiment 1a3 Alpha-hydroxy-7-ketone group-5 β-ursodeoxycholic acid (III)
Chenodiol (II) (113g is added successively in reaction flask, 0.288mol), Sodium Bromide (1.78g, 0.0173mol), acetic acid (30mL) and methyl alcohol (600mL), stirring at room temperature is to all dissolving, be cooled to-10 DEG C ± 2 DEG C, chlorine bleach liquor (the 225mL of 13% is slowly dripped in reaction system, 0.39mol), control interior temperature and detect raw material Chenodiol (II) content lower than 1% at-10 ~ 0 DEG C of stirring reaction to HPLC.After having reacted, remove ice bath, reaction solution rises to room temperature naturally, drips the sodium sulfite solution (25mL) of 5% in reaction system, stir 30 minutes, suction filtration, drying obtain 3 Alpha-hydroxy-7-ketone groups-5 β-ursodeoxycholic acid (III) crude product (115.83g).Crude product and methyl alcohol (1L) are joined in reaction flask, be heated to 65 DEG C, back flow reaction half an hour, filtered while hot, filtrate is reheated half an hour of refluxing, reaction solution naturally cooling crystallization, suction filtration, drying obtain 3 Alpha-hydroxy-7-ketone group-5 β-ursodeoxycholic acid (III) (91g of white powder, yield 80.9%, HPLC:99.64%).
The preparation of embodiment 1b3 Alpha-hydroxy-7-ketone group-5 β-ursodeoxycholic acid (III)
Chenodiol (II) (100g is added successively in reaction flask, 0.255mol), anhydrous magnesium sulfate (200g), chloroform (300mL), stirring at room temperature, pyridinium chloro-chromate dichloromethane solution (61g pyridinium chloro-chromate is dissolved in 2.5L methylene dichloride) is added, reaction solution stirring at room temperature 30min in reaction system is dripped.Filtering solids insolubles, filtrate uses water and saturated common salt water washing successively, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, (73g, yield 73.3%, HPLC detects: 97.7%) to obtain 3 Alpha-hydroxy-7-ketone groups-5 β-ursodeoxycholic acid (III).
The synthesis of embodiment 2a3 Alpha-hydroxy-7-ketone group-5 β-cholane-24 acid benzyl ester (IVa)
In reaction flask, add compound III (20g, 51mmol), anhydrous tetrahydro furan (450ml), stirs, add salt of wormwood (10.5g, 76mmol), be warming up to backflow, add cylite (30ml), back flow reaction, 12h monitoring reaction (TLC condition: acetone: methylene dichloride: acetic acid=1:15:1).Reaction terminates, and adds triethylamine (30ml), continues reaction and removes excessive cylite to form quaternary ammonium salt, be cooled to room temperature, diatomite aided filter solid insoluble, filtrate reduced in volume, adds water (200ml), extract by ethyl acetate (200ml*3), merge organic phase, successively purified water, saturated sodium-chloride washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound (IVa) 20.3g, yield 82.8%.
The acid of embodiment 2b3 Alpha-hydroxy-7-ketone group-5 β-cholane-24 is to the synthesis of methoxy benzyl ester (IVb)
In reaction flask, add compound III (20g, 51mmol), anhydrous acetonitrile (450ml), stir, add cesium carbonate (25g), be warming up to backflow, add methoxyl group cylite (30ml), backflow 10h monitoring reaction (TLC condition: acetone: methylene dichloride: acetic acid=1:15:1).Reaction terminates, add triethylamine (25ml), continue reaction and remove excessive cylite to form quaternary ammonium salt, be cooled to room temperature, diatomite aided filter solid insoluble, filtrate reduced in volume, adds ethyl acetate (250ml*3) extraction, merges organic phase, purified water, saturated sodium-chloride washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains compound (IVb) 21.7g, yield 86%.
Embodiment 33 α, the preparation of 7 α-two-trimethylsiloxy-6-alkene-5 β-cholane acid benzyl esters (Va)
Anhydrous tetrahydro furan (300mL) is added in nitrogen protection downhill reaction bottle; dry ice ethanol bath drips the tetrahydrofuran solution (C=2mol/L of lithium diisopropylamine at being cooled to-78 DEG C; 140mL; 0.28mol); dropwise rear stirring 30 minutes; trimethylchlorosilane (63mL is dripped at-65 DEG C; 0.5mol); after stirring; by 3 Alpha-hydroxy-7-ketone group-5 β-cholane acid benzyl ester (IVa) (18.0g; tetrahydrofuran (THF) (100mL) solution 0.037mol) drops in reaction soln, reacts 1 hour at-75 DEG C.After reaction terminates, remove ice bath, be warming up to-10 DEG C, drip saturated sodium bicarbonate solution (250mL), control temperature is no more than 20 DEG C, leave standstill separatory, be extracted with ethyl acetate (200mL × 2), merge organic phase, use saturated sodium bicarbonate (200mL) successively, saturated aqueous common salt (400mL) washs, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure obtains 3 α of yellow oily, 7 α-two-trimethylsiloxy-6-alkene-5 β-cholane acid benzyl ester (Va) crude products (23.8g), oil pump underpressure distillation 30min, inflated with nitrogen is protected, be directly used in the next step.
The preparation of embodiment 43 Alpha-hydroxy-6-ethylidene-7-ketone group-5 β-cholane acid benzyl ester (VIa)
Under nitrogen protection; 3 α are added in reaction flask; 7 α-two-trimethylsiloxy-6-alkene-5 β-cholane acid benzyl ester (Va) (17g) and methylene dichloride (300mL); at dry ice/ethanol bath is cooled to-65 DEG C; acetaldehyde (3.3mL) is added in reaction flask; stir in backward reaction solution and add boron trifluoride ether solution (37mL), after dropwising, reaction 5 hours at-60 DEG C, rises to room temperature reaction 2 hours.After reaction terminates; ice-water bath drips saturated sodium bicarbonate solution (300mL) at being cooled to 0-5 DEG C, leave standstill separatory, with dichloromethane extraction (200mL × 3); merge organic phase; with saturated common salt water washing (250mL), anhydrous sodium sulfate drying, filters; concentrating under reduced pressure obtains 3 Alpha-hydroxy-6-ethylidene-7-ketone group-5 β-cholane acid benzyl esters (VIa) of brown yellow oil; oil pump underpressure distillation 30min, inflated with nitrogen is protected, and is directly used in the next step.
The preparation of embodiment 5a3 Alpha-hydroxy-6-ethyl-7-ketone group-5 β ursodeoxycholic acid (I)
3 Alpha-hydroxy-6-ethylidene-7-ketone group-5 β-cholane acid benzyl ester (VIa) (15g) are dissolved in ethanol (300ml), add sodium acetate 4.5g, stirring and dissolving, drop in reaction flask, add tetrahydrobenzene (4.5ml), 10%Pd/C catalyzer (0.8g), be warming up to back flow reaction.Reaction terminates, and filtering catalyst, filtrate reduced in volume, to 120ml, drops in 900ml water, separates out a large amount of solid, filters obtain white 3 Alpha-hydroxy-6-ethyls-7-ketone group-5 β ursodeoxycholic acid (I).HPLC detection configuration: chemical purity 98.5%, isomer proportion α/β=100:1.
The preparation of embodiment 5b3 Alpha-hydroxy-6-ethyl-7-ketone group-5 β ursodeoxycholic acid (I)
3 Alpha-hydroxy-6-ethylidene-7-ketone group-5 β-cholane acid benzyl ester (VIa) (15g) are dissolved in methyl alcohol (300ml), stirring and dissolving, add cyclohexadiene (4.5ml), drop in reaction flask, 10%Pd/C catalyzer (1.5g), is warming up to back flow reaction.Reaction terminates, and filtering catalyst, filtrate reduced in volume, to 50ml, drops in 800ml water, separates out a large amount of solid, filters obtain white 3 Alpha-hydroxy-6-ethyls-7-ketone group-5 β ursodeoxycholic acid (I).HPLC detection configuration: chemical purity 98.8%, isomer proportion α/β=98:1.
Embodiment 63 α, the preparation of 7 alpha-dihydroxy--6 α-ethyl-5 β ursodeoxycholic acids (shellfish cholic acid difficult to understand)
3 Alpha-hydroxy-6-ethyl-7-ketone group-5 β ursodeoxycholic acid (I) (24.0g), tetrahydrofuran (THF) (480ml), purified water (120ml) is added in reaction flask, stirring and dissolving, be cooled to less than 10 DEG C, add sodium borohydride (6.5g) in batches, add, in 20 ~ 30 DEG C of reaction 1 ~ 2h.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, aqueous phase uses ethyl acetate (240ml) to extract again, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains off-white color solid (20.6g) to dry, and methylene dichloride recrystallization obtains shellfish cholic acid difficult to understand.
Claims (10)
1. a preparation method for shellfish cholic acid intermediate difficult to understand shown in formula (I), is characterized in that,
Compound (VI) is obtained by reacting compound (I) under catalyzer and hydrogen donor effect; Described catalyzer is selected from Pd/C, PtO
2or Raney Ni, described hydrogen donor is selected from tetrahydrobenzene, cyclohexadiene or tetraline, and reaction equation is as follows:
Ar is phenyl, 4-p-methoxy-phenyl, 4-aminomethyl phenyl.
2. preparation method according to claim 1, it is characterized in that, one or more mixed systems of solvent selected from methanol, ethanol, tetrahydrofuran (THF) or water, temperature of reaction is 20 ~ 65 DEG C, compound VI: hydrogen donor mol ratio is 1:0.2 ~ 1:10, compound VI: molecular proportion of catalyst is 1:0.01 ~ 1:0.2.
3. preparation method according to claim 1 and 2, is characterized in that, catalyzer is 5% ~ 20%Pd/C.
4. preparation method according to claim 1 and 2, is characterized in that, Ar is phenyl.
5. a preparation method for shellfish cholic acid difficult to understand, is characterized in that, the carbonyl of metallic reducing agent reducing compound (I) obtains shellfish cholic acid difficult to understand; Described compound (I) is prepared by claim 1-4 either method.
6. preparation method according to claim 5, is characterized in that, described metallic reducing agent is POTASSIUM BOROHYDRIDE or sodium borohydride, and solvent is the mixing solutions of methyl alcohol, ethanol, tetrahydrofuran (THF) or methanol/water, ethanol/water, tetrahydrofuran (THF)/water.
7. a preparation method for shellfish cholic acid difficult to understand, is characterized in that,
S1. oxidizing reaction, in the presence of an oxidizer, there is oxidizing reaction and obtain compound (III) in compound (II);
S2. substituted benzyl protection, compound (III) is obtained by reacting compound (IV) under the effect of benzyl halogenated aromatic;
S3. hydroxyl protection reaction, compound (IV), under nucleophilicity highly basic, is obtained by reacting silyl enol ether compound (V) with silicane under protecting reagent effect;
S4. ethylideneization reaction, there is aldol in acid condition with acetaldehyde and be obtained by reacting compound (VI) in compound (V);
S5. catalytic transfer hydrogenation reaction, compound (VI) uses claim 1-4 either method to obtain compound (I);
S6. carbonyl reduction reaction, adopts the metallic reducing agent such as sodium borohydride, POTASSIUM BOROHYDRIDE reducing carbonyl to obtain shellfish cholic acid difficult to understand;
Ar is phenyl, 4-p-methoxy-phenyl, 4-aminomethyl phenyl.
8. preparation method according to claim 7, is characterized in that, the oxygenant described in S1. step is selected from clorox or pyridinium chloro-chromate; S2. walk described benzyl halogenated aromatic to be benzyl bromine, to methyl benzyl bromine or to methoxy benzyl chlorine, also to comprise alkali in reaction system, described alkali is selected from cesium carbonate, salt of wormwood or sodium hydrogen, and reaction solvent is tetrahydrofuran (THF), acetonitrile or dimethyl formamide.
9. preparation method according to claim 7; it is characterized in that; S3. walk described silicane protection reagent and be selected from trimethylchlorosilane, TERT-BUTYL DIMETHYL CHLORO SILANE, hexamethyldisilazane or tert-butyl diphenyl chlorosilane, alkali is selected from lithium diisopropylamine or n-Butyl Lithium.
10. preparation method according to claim 7, is characterized in that, during the ethylidene step aldol described in S4. step reacts, electrophilic reagent is selected from acetaldehyde, and Lewis acid is boron trifluoride diethyl etherate, and solvent is anhydrous methylene chloride.
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| CN107936078A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of new method for preparing shellfish cholic acid difficult to understand |
| US9982008B2 (en) | 2012-06-19 | 2018-05-29 | Intercept Pharmaceuticals, Inc. | Preparation and uses of obeticholic acid |
| CN108117579A (en) * | 2016-11-29 | 2018-06-05 | 昆明积大制药股份有限公司 | The preparation method of shellfish cholic acid and its intermediate difficult to understand |
| CN108239134A (en) * | 2016-12-23 | 2018-07-03 | 上海博邦医药科技有限公司 | Shellfish cholic acid intermediate difficult to understand and its preparation method and application |
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| CN110655548A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN112898368A (en) * | 2019-12-03 | 2021-06-04 | 中国科学院成都有机化学有限公司 | Preparation method of obeticholic acid intermediate |
| CN114181274A (en) * | 2021-12-22 | 2022-03-15 | 中山百灵生物技术股份有限公司 | Enolization and ethylization combined reaction method |
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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 |
| CN107936078A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of new method for preparing shellfish cholic acid difficult to understand |
| CN108117579A (en) * | 2016-11-29 | 2018-06-05 | 昆明积大制药股份有限公司 | The preparation method of shellfish cholic acid and its intermediate difficult to understand |
| 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 |
| CN108239134A (en) * | 2016-12-23 | 2018-07-03 | 上海博邦医药科技有限公司 | Shellfish cholic acid intermediate difficult to understand and its preparation method and application |
| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| 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 |
| CN110655548A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN110655548B (en) * | 2018-06-29 | 2022-05-17 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN112898368A (en) * | 2019-12-03 | 2021-06-04 | 中国科学院成都有机化学有限公司 | Preparation method of obeticholic acid intermediate |
| CN112898368B (en) * | 2019-12-03 | 2023-08-18 | 中国科学院成都有机化学有限公司 | Preparation method of obeticholic acid intermediate |
| CN114181274A (en) * | 2021-12-22 | 2022-03-15 | 中山百灵生物技术股份有限公司 | Enolization and ethylization combined reaction method |
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