CN105348354A - Chenodeoxycholic acid compound and preparation method and application thereof - Google Patents

Chenodeoxycholic acid compound and preparation method and application thereof Download PDF

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Publication number
CN105348354A
CN105348354A CN201510865138.2A CN201510865138A CN105348354A CN 105348354 A CN105348354 A CN 105348354A CN 201510865138 A CN201510865138 A CN 201510865138A CN 105348354 A CN105348354 A CN 105348354A
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compound
solvate
amino acid
acceptable salt
pharmacy acceptable
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朱义
王一茜
李�杰
何桂佳
刘威加
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Sichuan Baili Pharmaceutical Co Ltd
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Sichuan Baili Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/001—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class spiro-linked
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a compound with a structural formula (I) and a pharmaceutically-acceptable salt, solvate or amino acid conjugate thereof (shown in the description). Six substituent groups are respectively located at alpha or beta positions, the R1 represents COOH or OSO3H, and the R2 represents a halogen alkyl group, a naphthenic base, a naphthenic-alkyl group, a heterocyclic group, a heterocyclic-alkyl group, a heterocyclic aryl group, a heterocyclic aryl-alkyl group, an acyl group or an alkoxyalkyl group.

Description

One class CDCA acid compounds and its production and use
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to class CDCA acid compounds and its production and use.
Background technology
Method Buddhist nun ester X acceptor (fanesoidXreceptor) is that a class is by bile acide (bileacid, BA) nuclear receptor activated, this receptor can activate after activating and a series ofly transcribe network and signal cascade, thus affect the expression of a series of target gene, participate in regulating multiple physiological metabolism process in human body, comprise bile acide steady-state adjustment, fat and carbohydrate metabolism; In addition, some target genes also relate to inflammation generation, fibrosis and Carcinogenesis.The tissue that FXR acceptor great expression exists in BA, such as liver, small intestine, kidney, suprarenal gland and ileal epithelium, in enteron aisle, endogenic bile acide is absorbed in large quantities.FXR under physiological concentration, can comprise the taurate of Chenodiol (CDCA), Septochol (DCA), lithocholic acid (LCA) and these cholic acid by endogenic bile acide and glycine conjugates activated.
FXR has similar modular structure to other nuclear receptor superfamily, comprises a DNA binding domain (DBD) and a carbon teminal ligand binding domain (LBD) highly retained.The specific DNA sequence dna of DBD binding domain identification, namely response element, i.e. the enhanser region of target gene.FXR and 9-cis-retinoic acid acceptor (RXR) forms heterodimer and is combined with DNA.LBD and lipophilic ligand binding can be recruited and be transcribed receptor coactivator, produce corresponding biological effect.
Liver and gall relative disease has higher sickness rate in China, comprises hepatitis, hepatic fibrosis, liver cirrhosis, fatty liver, liver cancer etc.Wherein, non-alcoholic fatty liver disease (NAFLD) has developed into severe liver disease the most common, and in American-European countries, NAFLD morbidity is about 20-30%, and has 10-20% can develop into nonalcoholic fatty liver disease (NASH).In China, the morbidity of NAFLD is about 15-20%, and about 15% is NASH, and in adiposis patient, NASH morbidity then can up to 30%.And suffer from suffer from NAFLD in diabetes and adiposis patient ratio respectively up to 62% and 96%.And NAFLD there is no marketed drug, current treatment means mainly concentrates on and keeps on a diet, and change living habit, the symptoms such as symptomatic treatment diabetes, obesity and hyperlipidemia, the medicine therefore developing new improvement NASH patient tissue pathologic condition is imperative.
Current research shows, the performance of FXR receptor stimulant shows larger potentiality to liver and gall diseases.The medicine being expected to most at present go on the market is 6-ECDA (6 α-ethyl-chenodeoxycholicacid), is 6 ethyl substituted derivative of CDCA, is carrying out now the clinical three phases clinical experiment with primary biliary cirrhosis of three phases of NASH.Because 6-ECDCA can not optionally swash and FXR receptor subtype, create the multigentic effect not wishing to occur in therapeutic process, high, active good, that bioavailability the is high compound of exploitation selectivity is significant.On the basis of 6-ECDCA, be lead compound with CDCA, by modifying for chemical structure, structure distribution carried out in its 6-position and side chain, devises the derivative of a series of CDCA.The present invention meets the present situation that China's liver and gall diseases is occurred frequently and medicine extremely lacks, and has good market outlook.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, a class CDCA derivative and pharmacy acceptable salt, solvate or amino acid conjugates are provided.
Another object of the present invention is the preparation method disclosing such CDCA derivative and pharmacy acceptable salt thereof.
Another object of the present invention is to disclose such CDCA derivative and pharmacy acceptable salt, solvate or amino acid conjugates are preparing the purposes treated and/or prevented in various liver and gall relative disease medicine, include but not limited to cholestasis and liver metabolism disease, comprise the liver and gall diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
The compound of structural formula (I) and pharmacy acceptable salt, solvate or amino acid conjugates:
Wherein: 6 bit substituents can lay respectively at α position or β position;
R 1for COOH or OSO 3h;
R 2for alkylhalide group, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, heterocyclyl-alkyl, heteroaryl, heteroaryl-alkyl, acyl group or alkoxyalkyl.
As preferably, described alkylhalide group is monosubstituted or polysubstituted.
As preferably, described cycloalkyl is C3-7 carbocylic radical.
As preferably, described cycloalkyl-alkyl is-(CH 2) m-A, wherein m be 1 or 2, A be C 3-7carbocylic radical.
As preferably, described heterocyclic radical is the C replaced by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms 3-7carbocylic radical.
As preferably, described heterocyclyl-alkyl is-(CH2) m-B, wherein m be 1 or 2, B be the C replaced by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms 3-7carbocylic radical.
As preferably, described heteroaryl is the C replaced by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms 3-7cyclophane base.
As preferably, described heteroaryl-alkyl is-(CH2) m-D, m be 1 or 2, D be the C replaced by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms 3-7cyclophane base.
As preferably, described acyl group represents the monosubstituted or polysubstituted formyl radical of halogen or ethanoyl.
As preferably, described alkoxyalkyl is-(CH2) m-X-E, m be 1,2 or 3, X be heteroatoms O, S or N, E is hydrogen, C 1-C 6alkyl, C 3-7the C that carbocylic radical, one or more Sauerstoffatom, sulphur atom or nitrogen-atoms replace 3-7the C that carbocylic radical or one or more Sauerstoffatom, sulphur atom or nitrogen-atoms replace 3-7cyclophane base.
Comprise above-mentioned arbitrary described compound of logical formula I and the pharmaceutical composition of pharmacy acceptable salt, solvate or amino acid conjugates thereof.
The purposes in metabolic trouble, inflammation, hepatopathy, autoimmune disorder, heart trouble, ephrosis, cancer or gastrointestinal illness medicine is being prepared according to the compound of above-mentioned arbitrary described logical formula I and pharmacy acceptable salt, solvate or amino acid conjugates.
Noun:
DCM: methylene dichloride; DMAP:4-Dimethylamino pyridine; DME: glycol dimethyl ether;
LDA: lithium diisopropylamine; NBS:N-bromo-succinimide; PCC: pyridinium chlorochromate ester;
TBAF: tetrabutyl ammonium fluoride; THF: tetrahydrofuran (THF).
Embodiment
All features disclosed in this specification sheets, or the step in disclosed all methods or process, except mutually exclusive feature and/or step, all can combine by any way.
Embodiment 1: the preparation of compound 7 and its 6-beta isomer
Steps A
By 3 а, 7 а-two-hydroxyls-5 β ursodeoxycholic acid (2.0g, 5.1mmol), Sodium Bromide (30mg, 0.25mmol), Tetrabutyl amonium bromide (5.4g, 16.8mmol) and (methyl alcohol: glacial acetic acid: water: ethyl acetate=3:1:0.25:6.5) 43mL mixed solution join in reaction flask.Reaction mixture is down to 0 oc drips clorox (5%, 10mL, 5.6mmol), and 0 oc rises to room temperature reaction 6 hours after activating 30min.The sodium sulfite solution of 3.3% adds in reaction solution and becomes white suspension liquid from light yellow to solution, and water (50mL) to add in above-mentioned solution 15 oc stirs 5min, extraction into ethyl acetate reaction solution three times, and merge organic interdependent secondary sodium sulfite solution with 3.3% and wash, washing, anhydrous sodium sulfate drying, filters and be spin-dried for obtain crude product 2.0g.Column chromatography purification (methylene dichloride: methyl alcohol=100:1) obtains the compound 1 of 1.2g.Yield 60%.
Step B
By compound 1(1.17g, 3.0mmol) and ethanol (60mL) add in reaction flask, make reacting liquid temperature be down to 10 0below C, join in above-mentioned reaction solution successively by 2 furan carboxyaldehyde (576mg, 6.0mmol) and potassium hydroxide (7.5mL, in 40% ethanol), stirring reaction 0.5 hour, rises to room temperature reaction and spends the night.Add glacial acetic acid neutralization reaction liquid and pour in 300mL frozen water, filtering, dry after solid washing, ethyl alcohol recrystallization, obtains 0.84g compound 5.Yield 60%.
Step C
By compound 5(1.4g, 3.0mmol) and THF:MeOH(75mL, 4:1v/v) join in reaction flask, add cerous compounds (0.74g, 9.0mmol) and sodium borohydride (136mg, 3.6mmol) after stirring successively.Room temperature reaction added water and methyl alcohol after 3 hours, solvent evaporated, thin up, extraction into ethyl acetate solution three times.Wash with saturated common salt successively after merging organic phase, anhydrous sodium sulfate drying, filter, after solvent evaporated, obtain crude product, after column chromatography purification, obtain 1.27g compound 6.Yield 90%.
Step D
By compound 6(1.41g, 3.0mmol) and THF:MeOH(60mL, 1:1v/v) join in reaction flask, add palladium carbon (5wt%, 50mg) after nitrogen replacement three times, again replace nitrogen three times, rear substitution hydrogen three times, stir lower room temperature reaction 8 hours.Be spin-dried for obtain crude product after reaction solution filtering palladium carbon, after column chromatography purification, obtain 1.04g compound 7(yield 74%) and 0.23g compound 8(yield 16%).
embodiment 2: the preparation of compound 9 and its 6-beta isomer
According to the method for embodiment 1, compound 1 and 2 furan carboxyaldehyde are reacted, obtain compound 9 and and its 6-beta isomer.
embodiment 3: the preparation of compound 10 and its 6-beta isomer
According to the method for embodiment 1, compound 1 and 3-furtural are reacted, obtain compound 10 and its 6-beta isomer.
embodiment 4: the preparation of compound 11 and its 6-beta isomer
According to the method for embodiment 1, compound 1 and 2-imidazole formaldehyde are reacted, obtain compound 11 and its 6-beta isomer.
embodiment 5: the preparation of compound 12 and its 6-beta isomer
According to the method for embodiment 1, compound 1 and 3-imidazole formaldehyde are reacted, obtain compound 12 and its 6-beta isomer.
embodiment 6: the preparation of compound 13 and its 6-beta isomer
According to the method for embodiment 1, compound 1 and tetrahydrofuran (THF)-2-formaldehyde are reacted, obtain compound 13 and its 6-beta isomer.
embodiment 7: the preparation of compound 18 and 6-beta isomer thereof
Steps A
In 250mL there-necked flask, add CDCA7.85g, anhydrous methanol 150mL, stir clearly molten, add the vitriol oil of catalytic amount, back flow reaction 1 hour, it is complete that TLC detects raw material reaction.Be spin-dried for methyl alcohol, add ethyl acetate 300mL and dissolve resistates, use saturated sodium bicarbonate solution 100mLx2 successively, water 100mL, saturated brine 100mL washs, anhydrous sodium sulfate drying, filters, is spin-dried for, obtains 7.95g compound 2, yield 97.8%.
Step B
Compound 2(4.06g is added in 500mL there-necked flask, 10mmol) and DCM125mL, stir clearly molten, silica gel 20g (200-300 order) is added again in reaction solution, the DCM solution (2.4gPCC is dissolved in 125mLDCM) containing PCC is dripped under ice-water bath, rise to room temperature reaction after dripping off, TLC detection reaction is complete to raw material reaction, filters, filter residue DCM washs, merge washing lotion and filtrate, use water (100mLx2) successively, saturated brine (100mL) washs, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 3.0g compound 3.Yield: 74.1%.
Step C
Compound 3 (2.02g, 5mmol) is added, ethyl acetate 40mL in 100mL there-necked flask, stir clearly molten, then add DMAP50mg successively, triethylamine 1.01g, diacetyl oxide 1.02g, room temperature reaction 4 hours, TLC detection reaction is complete, use 0.5M dilute hydrochloric acid (10mLx2) successively, water (10mL), saturated aqueous common salt (10mL) washs, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 2.1g compound 4.Yield: 94.0%.
Step D
By compound 4(5.60g, 12.54mmol) be dissolved in acetic acid (100mL), add the acetic acid solution (10mL) of bromine (2.8g), and add the hydrobromic acid solution (0.74mL) of 48% immediately thereupon.Reaction solution, in stirred overnight at room temperature, is then poured in 300mL water, and filter, solid column chromatography purification, obtains 5.9g compound 14.Yield 90%.
Step e
By azetidine (0.27mL, 4mmol) be dissolved in DCM(30mL) in, add triethylamine (1.26mL), reaction solution is down to 0 DEG C and is stirred 0.5h, then compound 14(2.36g is dripped, DCM solution (20mL) 4.5mmol), rises to stirred overnight at room temperature, concentration of reaction solution, be dissolved in 100mL ethyl acetate, use water (20mL) successively, saturated aqueous common salt (20mL) washs, anhydrous sodium sulfate drying, filter, be spin-dried for, crude product column chromatography purification, obtain 0.93g compound 15(yield 41%) and 0.41g compound 16(yield 18%).
Step F
By compound 15(3.00g, 6mmol) be dissolved in 30mL methyl alcohol and 10mLTHF, stir clearly molten, add 1MNaOH solution 24mL, room temperature reaction, it is complete that TLC detects raw material reaction, add 1M hydrochloric acid and adjust PH to 3, spin off solvent, add ethyl acetate (30mL × 3) extraction, merge organic phase, use water (30mL × 2) successively, saturated brine (30mL) washs, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 2.74g compound 17.Yield: 91%.
Step G
By compound 17(1.78g, 4mmol) be dissolved in 100mL anhydrous methanol, be cooled to 0 DEG C, by NaBH 4(1.06g, 28mmol) adds reaction solution, room temperature reaction 3 hours, slowly add water 100mL, steam half solvent, add ethyl acetate (60mL × 3) extraction, merge organic phase, with water (40mL × 2), saturated brine (40mL) washs, anhydrous sodium sulfate drying, filters, be spin-dried for, obtain 1.54g compound 18.Yield: 86%.
The 6-beta isomer of compound 18 can be prepared by the method compound 20 of step F, G.
embodiment 8: the preparation of compound 21 and its 6-beta isomer
Copper powder (0.03g is added in reaction flask, 0.53mmol), compound 14(2.78g, 5.30mmol), azetidinone (0.45g, 6.36mmol) with salt of wormwood (1.10g, 7.95mmol), after nitrogen replacement, add N, N '-dimethyl quadrol (0.09g, 1.06mmol) with toluene (20mL), rise to 135 DEG C of stirring reaction 6h.Reaction solution is down to room temperature, filters, ethyl acetate is washed, and filtrate concentrates, and gained crude product column chromatography purification, obtains 1.34g compound 19(yield 49%) and 0.36g compound 20(yield 13%).
According to the method for embodiment 7 step F, G, compound 21 and its 6-beta isomer can be prepared with compound 19 and compound 20
。
embodiment 9: the preparation of compound 25 and its 6-beta isomer
Steps A
By the method for embodiment 7 step e, compound and glycine ethyl ester are reacted, obtain compound 22 and 23.
Step B
To compound 22(1.31g, DCM(30mL 2.4mmol)) in solution, add ethyl isocyanate (0.34g, 4.8mmol), after air in nitrogen replacement reaction flask, reaction solution is risen to 80 DEG C of reactions, it is complete that TLC detects raw material reaction, reaction solution is concentrated, column chromatography purification, obtain 0.96g compound 24.Yield: 70%.
According to the method for embodiment 7 step F, G, compound 25 can be prepared by compound 24.
The 6-beta isomer of compound 25 according to the step method of this embodiment, can be prepared by compound 23.
embodiment 10: the preparation of compound 26 and its 6-beta isomer
According to the method for step B in embodiment 9, compound 22 and ethyl mustard oil are reacted, then according to the method for embodiment 7 step e, F, obtain compound 26 and its 6-beta isomer.
embodiment 11: the preparation of compound 31 and its 6-beta isomer
Steps A
To compound 14(2.20g, 4.2mmol) fold silane (0.97g with trimethylammonium, THF(20mL 8.4mmol)) drip the THF solution (8.3mL of 1M tetrabutyl ammonium fluoride in solution, 8.3mmol), reaction solution is risen to 75 DEG C of stirring reaction 17h, be down to room temperature, column chromatography purification after concentrated solvent.Gained compound is dissolved in 80mL dehydrated alcohol, adds 5% palladium carbon (0.69g, 0.3mmol), pass into hydrogen, stirring reaction 2h under 20psi pressure.By reacting liquid filtering, filtrate concentrates, and with (ethyl acetate: methyl alcohol=7:1) recrystallization, obtains 1.55g compound 27, yield 80%.
Step B
Salt of wormwood (4.50g, 24mmol) and monobromethane (2.60g, 24mmol) is added, back flow reaction 24h in acetone (50mL) solution of methyl aceto acetate (2.60g, 20mmol).Reaction solution is down to room temperature, filters, after concentrated solvent, carry out column chromatography purification.By gained compound (1.90g, 12mmol) and NBS(2.56g, 14.4mmol) be placed in 100mL reaction flask, add p-methyl benzenesulfonic acid (0.23g, 1.2mmol), stirring at room temperature reaction 6h, by ether (100mL) extracted products, use 20mL water washing again, anhydrous sodium sulfate drying, filter, concentrated, crude product column chromatography purification, obtains 2.01g compound 28, yield 43%.
Step C
By compound 27(0.92g, 2mmol) be dissolved in THF(10mL) in, add compound 28(0.57g, 2.4mmol) and triethylamine (0.40g, 4mmol), stirring reaction 36h.By ethyl acetate (100mL × 3) extracted products after concentrated solvent, then use 20mL water washing, anhydrous sodium sulfate drying, filter, concentrated, crude product column chromatography purification, obtains 0.69g compound 29(yield 60%) and 0.16g compound 30(yield 14%).
According to the method for embodiment 7 step F, G, compound 31 can be prepared by compound 29.
The 6-beta isomer of compound 31 according to the step method of this embodiment, can be prepared by compound 30.
embodiment 12: following compounds is prepared according to the method for embodiment 9 and embodiment 10, and its chemical structural formula is as follows:
Wherein, when X is C, R 3and R 4listed by form 1, moiety combinations forms; When X is S, R 4for R listed in ethyl or cyclopentyl and form 1 3moiety combinations forms:
Form 1
R 1 R 2
H
embodiment 13: following compounds is prepared according to the method for embodiment 11, and its chemical structural formula is as follows:
Wherein, R 4for group listed in form 1.
embodiment 14: the preparation of compound 34
Steps A
At N 2under protection, by compound 4 (2.23g, 5mmol) be dissolved in the anhydrous THF of 100mL, be cooled to-78 DEG C, successively by n-Butyl Lithium 6mL(1.6M hexane solution) and LDA6mL(2.0M hexane solution) be added dropwise to reaction solution, stirring reaction 30 minutes, by 1, 3-dibromopropane 1.41g is added dropwise to reaction solution, then room temperature reaction is risen to, TLC detection reaction is complete, by reaction solution 1M dilute hydrochloric acid cancellation, add suitable quantity of water and ethyl acetate extraction separatory, collect organic phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain crude product, column chromatography purification, obtain 1.11g compound 32.Yield: 45.5%.
Step B
By compound 32(2.92g, 6mmol) be dissolved in 30mL methyl alcohol and 10mLTHF, stir clearly molten, add 1MNaOH solution 24mL, room temperature reaction, it is complete that TLC detects raw material reaction, add 1M hydrochloric acid and adjust PH to 3, spin off solvent, add ethyl acetate (30mL × 3) extraction, merge organic phase, use water (30mL × 2) successively, saturated brine (30mL) washs, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain 2.34g compound 33.Yield: 90.6%.
Step C
By 33(1.72g, 4mmol) be dissolved in 100mL anhydrous methanol, be cooled to 0 DEG C, by NaBH 4(1.06g, 28mmol) adds reaction solution, room temperature reaction 3 hours, slowly add water 100mL, steam half solvent, add ethyl acetate (60mL × 3) extraction, merge organic phase, with water (40mL × 2), saturated brine (40mL) washs, anhydrous sodium sulfate drying, filters, be spin-dried for, obtain 1.49g compound 34.Yield: 86.1%.
embodiment 15: the preparation of compound 35
According to the method for embodiment 14, compound 4 and 1,3-ethylene dibromide are reacted, obtains compound 35.
embodiment 16: the preparation of compound 38 and its 6-beta isomer
Steps A
At N 2under protection, by compound 4 (2.23g, 5mmol) be dissolved in the anhydrous THF of 100mL, be cooled to-78 DEG C, successively by n-Butyl Lithium 3mL(1.6M hexane solution), LDA3mL(2.0M hexane solution) be added dropwise to reaction solution, stirring reaction 30 minutes, add cyclopropane bromide 0.85g(7mmol), then room temperature reaction is risen to, TLC detection reaction is complete, by reaction solution 1M dilute hydrochloric acid cancellation, add suitable quantity of water and ethyl acetate extraction separatory, collect organic phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, filter, be spin-dried for, obtain crude product, column chromatography purification obtains 0.92g compound 36(yield 37.8%) and 0.20g compound 37(yield 8.2%).
Step B
Compound 36 and compound 37 are reacted according to the method for step B and C in embodiment 14, obtains compound 38 and its 6-beta isomer respectively.
embodiment 17: the preparation of compound 39 and its 6-beta isomer
According to the method for embodiment 16, compound 4 and bromomethyl cyclopropane are reacted, obtain compound 39 and its 6-beta isomer.
embodiment 18: the preparation of compound 40 and its 6-beta isomer
According to the method for embodiment 16, compound 4 and bromo tetramethylene are reacted, obtain compound 40 and its 6-beta isomer.
embodiment 19: the preparation of compound 41 and its 6-beta isomer
According to the method for embodiment 16, compound 4 and Bromomethylcyclobutane are reacted, obtain compound 41 and its 6-beta isomer.
embodiment 20: the preparation of compound 42 and its 6-beta isomer
According to the method for embodiment 16, compound 4 and fluorine monobromethane are reacted, obtain compound 42 and its 6-beta isomer.
embodiment 21: the preparation of compound 45 and its 6-beta isomer
Steps A
At N 2under protection, by compound 1(3.91g, 10mmol) be dissolved in the anhydrous THF of 200mL, be cooled to-78 DEG C, by 25mLLDA(2.0M hexane solution) be added dropwise to reaction solution, stirring reaction 30 minutes, drip 1.99g Trifluoroacetic Acid Ethyl Ester again, by reaction solution in-78 DEG C of stirring reactions 30 minutes, then rise to room temperature to continue to stir, it is complete that TLC detects raw material reaction, by reaction solution 1M dilute hydrochloric acid cancellation, add suitable quantity of water and ethyl acetate extraction phase-splitting, collect organic phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography purification, obtain 1.98g compound 43(yield 40.7%) and 0.54g compound 44(yield 11.1%).
Step B
Compound 43 and compound 44 are reacted according to the method for step B in embodiment 14, obtains compound 45 and its 6-beta isomer respectively.
embodiment 22: the preparation of compound 51 and its 6-beta isomer
Steps A
By compound 9(2g, 4.09mmol) join in the mixed solution of 90% formic acid (30mL) and 70% perchloric acid (70uL), be warming up to 50 DEG C, be cooled to 40 DEG C (24mL) after stirring 1.5h, add acetic anhydride, stir 10min, be cooled to room temperature, be poured into water, vigorous stirring, filter disgorging, washing once, is dissolved in ether, anhydrous sodium sulfate drying, concentrate and obtain compound 46(2.13g, yield 97%), directly carry out next step reaction without the need to purifying.
Step B
By compound 46(2.13g at 5 DEG C, 3.91mmol) add trifluoroacetic acid (6.7mL) and trifluoroacetic anhydride (1.8mL, in mixing solutions 12.7mmol), add Sodium Nitrite (321mg in batches, 4.65mmol), and stirring reaction 1h at this temperature, then rise to 40 DEG C and stir 1.5h, again reaction solution is cooled to room temperature, add 2NNaOH(30mL), extracted with diethyl ether, organic phase 1NNaOH and water washing, anhydrous sodium sulfate drying, the crude product of concentrated compound 44, separation and purification is carried out with silica gel chromatographic column, namely sterling compound 47(1.6g is obtained with (normal hexane: ethyl acetate=8:2) wash-out, yield 80%).
Step C
By compound 47(1.66g, 3.13mmol) join in the mixing solutions of second alcohol and water (50mL, ethanol: water=1:1) of the KOH of 30%, reflux 48h, reaction solution concentrates, with extracted with diethyl ether, organic phase washed with water, anhydrous sodium sulfate drying, concentrate to obtain crude white solid, carry out separation and purification with silica gel chromatographic column, namely obtain sterling compound 48(1.15g, yield 78% with (methylene dichloride: methyl alcohol=9:1) wash-out).
Step D
By compound 48(1.15g, 2.42mmol) and p-methyl benzenesulfonic acid (1.2g, 6.22mmol) be dissolved in anhydrous methanol (50mL), room temperature for overnight.Add sodium bicarbonate cancellation reaction, concentrated solvent, add EA extraction, organic phase saturated common salt water washing, anhydrous slufuric acid is dry, obtains the methyl ester product of compound 45.Separation and purification is carried out, with methylene dichloride: namely methyl alcohol=95:5 wash-out obtains sterling with silica gel chromatographic column.
By above-mentioned products obtained therefrom and p-methyl benzene sulfonic chloride (2.4g, pyridine (15mL) solution 12.7mmol) joins in dry pyridine (15mL), and stirred at ambient temperature 4h, except desolventizing, residue is dissolved in methylene dichloride, with saturated sodium bicarbonate solution and water washing, anhydrous sodium sulfate drying, concentrate and obtain the crude product of compound 46, separation and purification is carried out with silica gel chromatographic column, with (normal hexane: ethyl acetate=1:1) wash-out, obtain the sterling (1.88g, yield 78%) of compound 49.
Step e
At 0 DEG C and under nitrogen protection by compound 49(1.88g; 2.36mmol) be dissolved in dry tetrahydrofuran (THF) (10mL); add anhydrous methanol (122ul); with the tetrahydrofuran solution (1.5mL) of 2M lithium borohydride; and stir 8h at this temperature; with 1NNaOH(4mL) cancellation reaction after; rise to room temperature, EA extracts, organic phase washed with water; anhydrous sodium sulfate drying; concentrate to obtain crude product, carry out separation and purification with silica gel chromatographic column, with (methylene dichloride: methyl alcohol=95:5) wash-out; obtain compound 50(1.24g, yield 69%).
Step F
By compound 50(1.24g; 1.61mmol) join pyridine. sulfur trioxide mixture (0.33g; in dry pyridine (16mL) solution 1.61mmol); nitrogen protection; stirred at ambient temperature 48h; removal of solvent under reduced pressure; residue is dissolved in methyl alcohol (6mL) solution of 5%NaOH; room temperature for overnight; be 2 ~ 3 with 1M salt acid for adjusting pH, concentrated solvent, is dissolved in the mixing solutions of (methyl alcohol: water=1:1) by residue; carry out separation and purification with reverse-phase chromatographic column (RP-18B type) and obtain compound 51(0.39g, yield 43%).
The 6-beta isomer of compound 51 according to the step method of this embodiment, can be prepared by the 6-beta isomer of compound 9.
embodiment 23: the synthesis of sulfonic group series compound, its chemical structural formula as follows listed by:
Wherein R 2group can lay respectively at α position or β position.
Be prepared according to the method for embodiment 22, the raw material of use is selected from the compound and 6-beta isomer thereof that describe in compound 7, compound 10, compound 12, compound 13, compound 18, compound 21, compound 25, compound 26, compound 31, compound 34, compound 35, compound 38, compound 39, compound 40, compound 41, compound 42, compound 45 or embodiment 12 and embodiment 13.
Embodiment 24: the preparation of compound 57 and its 6-beta isomer
Steps A
By compound 3(3.57g, 8.82mmol), 1 h-imidazoles (0.90g, 13.24mmol) and TBSCl(2.00g, 13.24mmol) be dissolved in dry methylene chloride (16mL), room temperature for overnight.Saturated NaHCO is added in reaction solution 3, water layer is with CH 2cl 2extraction (20mL × 3), merges organic layer and washes once with water and saturated NaCl successively, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 51.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate=30:1) wash-out, obtain the sterling of compound 51, be white solid (4.25g, 93%).
Step B
compound 51 is dissolved in dry THF (12mL), stirs borehole cooling to-78 DEG C, instillation LDA(2.0M hexane solution) (3.62mL, 7.25mmol), about 30min dropwises.Finish, slowly drip oxyethane (0.34mL, 6.79mmol), about 15min dropwises.Finish, be slowly warming up to nature stirring reaction and spend the night.Reaction is finished, and adds saturated NaHCO 3cancellation is reacted, and water layer, with EA extraction (20mL × 3), merges organic layer also successively with saturated NaHCO 3, H 2o and saturated NaCl respectively washes once, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 52 and 53.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate=20:1) wash-out, obtain the sterling of compound 52 and 53.Wherein, compound 52 is off-white color solid (0.99g, 39%), and compound 53 is light yellow solid (0.43g, 17%).
Step C
By compound 52(500mg, 0.89mmol) be dissolved in dry DME(3mL) in, add NaH(60%, 53mg, 1.33mmol under ice-water bath), after heat release stops, removing ice-water bath and be warming up to back flow reaction 2h.Reaction is finished, and is cooled to room temperature, drips the DME(2mL of methyl iodide (0.08mL, 1.33mmol)) solution, about 10min dropwises.Finish, be warming up to 40 DEG C of reaction 3h.Reaction is finished, and slowly drips shrend and to go out reaction.Water layer, with EA extraction (15mL × 3), merges organic layer also successively with 5% acetic acid, H 2o, saturated NaCl respectively wash once, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 54.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate=40:1) wash-out, obtain the sterling of compound 54, be pale yellow oil (317mg, 62%).
Step D
By compound 54(300mg, 0.52mmol) and TBAF(177mg, 0.68mmol) be dissolved in dry THF (6mL), stirred overnight at room temperature.Reaction is finished, and adds H 2o(20mL), water layer, with EA extraction (10mL × 3), merges organic layer and washes with saturated NaCl, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 55.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate=10:1) wash-out, obtain the sterling of compound 55, be white solid (175mg, 73%).
Step e
By compound 55(150mg, 0.32mmol) be dissolved in dry MeOH(5mL) in, add NaBH in batches 4(37mg, 0.97mmol), stirring at room temperature reaction 5h.Reaction is finished, and adds water (20mL) in reaction solution, and water layer, with EA extraction (10mL × 3), merges organic layer and washes with saturated NaCl, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 56.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate=15:1) wash-out, obtain the sterling of compound 56, be off-white color solid (102mg, 68%).
Step F
By compound 56(100mg, 0.22mmol) be dissolved in MeOH(2mL) and water (2mL) mixed solvent in, add LiOHH 2o(18mg, 0.43mmol) stirring at room temperature 8h afterwards.Reaction is finished, and most of methyl alcohol is removed in underpressure distillation.Add H 2o(10mL), water layer is washed (10mL × 2) with EA.Again water layer is adjusted pH to 3 with 10%HCl.Water layer, with EA extraction (10mL × 3), merges organic layer and washes with saturated NaCl, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 57.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate: acetic acid=15:1:2%) wash-out, obtain the sterling of compound 57, be white solid (82mg, 86%).
According to the method for step C-F in embodiment 24, with compound 53 for raw material, obtain the 6-beta isomer 58 of compound 57.
Embodiment 25: the preparation of compound 59 and its 6-beta isomer
According to the method for embodiment 24, compound 52 and 2-iodopropane are reacted, obtain compound 59 and its 6-beta isomer.
Embodiment 26: the preparation of compound 60 and its 6-beta isomer
According to the method for embodiment 24, compound 52 and cyclopropane bromide are reacted, obtain compound 60 and its 6-beta isomer.
Embodiment 27: the preparation of compound 61 and its 6-beta isomer
According to the method for embodiment 24, compound 52 and bromocyclohexane are reacted, obtain compound 61 and its 6-beta isomer.
Embodiment 28: the preparation of compound 66 and its 6-beta isomer
Steps A
At N 2by compound 52(600mg, 1.07mmol under atmosphere), 1 h(94mg, 1.39mmol and triphenyl phosphorus (335mg, 1.28mmol) are dissolved in dry chloroform (6mL)-imidazoles, and drip chloroform (6mL) solution of iodine (325mg, 1.28mmol) under ice-water bath, about 20min dropwises.Drip and finish, be naturally warming up to stirring at room temperature 5h.Reaction is finished, and underpressure distillation is except desolventizing, and residuum adopts silica gel column chromatography to carry out separation and purification, with (sherwood oil: ethyl acetate=25:1) wash-out, obtains the sterling of compound 62, is light brown oily matter (630mg, 88%).
Step B
Under nitrogen atmosphere by compound 62(600mg, 0.89mmol) and piperidines (0.41mL, 4.46mmol) be dissolved in dry acetonitrile (12mL), stirred overnight at room temperature.Reaction is finished, and removes solvent under reduced pressure, and residuum adopts silica gel column chromatography to carry out separation and purification, with (methylene dichloride: methyl alcohol=80:1) wash-out, obtains the sterling of compound 63, is yellow oil (420mg, 75%).
Step C
By compound 63(420mg, 0.67mmol) and TBAF(227mg, 0.87mmol) be dissolved in dry THF (6mL), stirred overnight at room temperature.Reaction is finished, and adds H 2o(20mL), water layer, with EA extraction (20mL × 3), merges organic layer and washes with saturated NaCl, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 64.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: acetone=3:1) wash-out, obtain the sterling of compound 64, be light yellow solid (230mg, 67%).
Step D
By compound 64(200mg, 0.39mmol) be dissolved in dry MeOH(6mL) in, add NaBH in batches 4(44mg, 1.16mmol), stirring at room temperature reaction 5h.Reaction is finished, and adds water (20mL) in reaction solution, and water layer, with EA extraction (20mL × 3), merges organic layer and washes with saturated NaCl, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 65.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: acetone=3:1) wash-out, obtain the sterling of compound 65, be off-white color solid (108mg, 54%).
Step e
By compound 65(108mg, 0.21mmol) be dissolved in MeOH(2mL) and water (2mL) mixed solvent in, add LiOHH 2o(18mg, 0.42mmol) stirring at room temperature 8h afterwards.Reaction is finished, and most of methyl alcohol is removed in underpressure distillation.Add H 2o(6mL), water layer is washed (10mL × 2) with EA.Again water layer is adjusted pH to 2 with 10%HCl.Separate out a large amount of white solid, suction filtration, filter cake, to be washed to neutrality, namely obtains the sterling of compound 66 with MeOH recrystallization, is white solid (80mg, 71%).
According to the method for embodiment 28, with compound 53 for raw material, obtain the 6-beta isomer 67 of compound 66.
Embodiment 29: the preparation of compound 70 and its 6-beta isomer
Steps A
By compound 52(500mg, 0.89mmol) and be dissolved in dry methylene chloride (10mL), add TEA(0.19mL, 1.33mmol), drip methylene dichloride (5mL) solution of methylsulfonyl chloride (0.1mL, 1.33mmol) under ice-water bath, about 10min dropwises.Naturally be warming up to room temperature reaction to spend the night.Reaction is finished, in reaction solution, add saturated NaHCO 3solution, water layer, with dichloromethane extraction (10mL × 3), merges organic layer also successively with saturated NaHCO 3, water, saturated NaCl respectively wash once, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 68.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: acetyl triethyl=80:1) wash-out, obtain the sterling of compound 68, be yellow oil (535mg, 94%).
Step B
By compound 68(500mg, 0.78mmol), succimide (93mg, 0.94mmol) and Anhydrous potassium carbonate (216mg, 1.56mmol) be dissolved in dry DMF(6mL) in, be warming up to 90 DEG C of reaction 40h.Reaction is finished, in reaction solution, add H 2o(15mL), water layer, with EA extraction (20mL × 3), merges organic layer to wash (20mL × 3), saturated NaCl washes (20mL × 1), anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 69.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: acetyl triethyl=10:1) wash-out, obtain the sterling of compound 69, be light yellow solid (160mg, 32%).
The method of compound 69 according to step D-F in embodiment 24 is reacted, obtains compound 70.
The method of compound 53 according to embodiment 29 is reacted, obtains the 6-beta isomer 71 of compound 70.
Embodiment 30: the preparation of compound and its 6-beta isomer
Steps A:
By compound 51(3g, 5.78mmol) be dissolved in dry THF (30mL), drip LDA(2.0M hexane solution at-78 DEG C) (5.78mL, 11.56mmol), about 30min dropwises.Drip and finish, drip ethyl formate (0.93mL, 11.56mmol) after reaction 2h, about 15min dropwises.Naturally room temperature reaction 12h is warming up to.Reaction is finished, and adds saturated NaHCO 3cancellation is reacted.Pressure reducing and steaming THF, water layer is with EA extraction (50mL × 3).Merge organic layer also successively with saturated NaHCO 3, water, saturated NaCl respectively wash once, anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 72.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: acetyl triethyl=20:1) wash-out, obtain the sterling of compound 72, be yellow oil (2.47g, 78%).
Step B:
By compound 72(2g, 2.66mmol), ammonium formiate (4.61g, 73.41mmol) and 10%Pd/C(200mg) be dissolved in methyl alcohol (20mL), return stirring reaction 3h.Reaction is finished, and underpressure distillation removing methyl alcohol, residuum dissolves, suction filtration with EA and water (each 30mL).Filtrate separates organic layer, and water layer, with EA extraction (30mL × 3), merges organic layer to wash (20mL × 3), saturated NaCl washes (20mL × 1), anhydrous Na 2sO 4dry.Filter and concentrate to obtain the crude product of compound 73 and 74.Adopt silica gel column chromatography to carry out separation and purification, with (sherwood oil: acetyl triethyl=60:1) wash-out, obtain the sterling of compound 73 and 74.Compound 73 is off-white color solid (1.30g, 64%); Compound 74 is light yellow solid (0.61g, 30%).
The method of compound 73 according to step C-F in embodiment 24 is reacted, obtains compound 75.
The method of compound 74 according to embodiment 29 is reacted, obtains the 6-beta isomer 76 of compound 75
。
The present invention is not limited to aforesaid embodiment.The present invention expands to any new feature of disclosing in this manual or any combination newly, and the step of the arbitrary new method disclosed or process or any combination newly.

Claims (12)

1. the compound of structural formula (I) and pharmacy acceptable salt, solvate or amino acid conjugates:
Wherein: 6 bit substituents can lay respectively at α position or β position;
R 1for COOH or OSO 3h;
R 2for alkylhalide group, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, heterocyclyl-alkyl, heteroaryl, heteroaryl-alkyl, acyl group or alkoxyalkyl.
2. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, is characterized in that: described alkylhalide group is monosubstituted or polysubstituted.
3. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, is characterized in that: described cycloalkyl is C3-7 carbocylic radical.
4. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, is characterized in that: described cycloalkyl-alkyl is-(CH 2) m-A, wherein m be 1 or 2, A be C 3-7carbocylic radical.
5. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, is characterized in that: described heterocyclic radical is the C replaced by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms 3-7carbocylic radical.
6. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, it is characterized in that: described heterocyclyl-alkyl is-(CH2) m-B, wherein m be 1 or 2, B be by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms replace C 3-7carbocylic radical.
7. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, is characterized in that: described heteroaryl is the C replaced by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms 3-7cyclophane base.
8. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, it is characterized in that: described heteroaryl-alkyl is-(CH2) m-D, m be 1 or 2, D be by one or more Sauerstoffatom, sulphur atom or nitrogen-atoms replace C 3-7cyclophane base.
9. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, is characterized in that: described acyl group represents the monosubstituted or polysubstituted formyl radical of halogen or ethanoyl.
10. the compound of a kind of logical formula I according to claim 1 and pharmacy acceptable salt, solvate or amino acid conjugates, it is characterized in that: described alkoxyalkyl is-(CH2) m-X-E, m be 1,2 or 3, X be heteroatoms O, S or N, E is hydrogen, C 1-C 6alkyl, C 3-7the C that carbocylic radical, one or more Sauerstoffatom, sulphur atom or nitrogen-atoms replace 3-7the C that carbocylic radical or one or more Sauerstoffatom, sulphur atom or nitrogen-atoms replace 3-7cyclophane base.
11. comprise the arbitrary described compound of logical formula I of claim 1-10 and the pharmaceutical composition of pharmacy acceptable salt, solvate or amino acid conjugates thereof.
12. are preparing the purposes in metabolic trouble, inflammation, hepatopathy, autoimmune disorder, heart trouble, ephrosis, cancer or gastrointestinal illness medicine according to the compound of the arbitrary described logical formula I of claim 1-10 and pharmacy acceptable salt, solvate or amino acid conjugates.
CN201510865138.2A 2014-12-03 2015-12-01 Chenodeoxycholic acid compound and preparation method and application thereof Pending CN105348354A (en)

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CN108137643A (en) * 2015-08-07 2018-06-08 英特塞普特医药品公司 The method for preparing bile acid and its derivative
CN109381679A (en) * 2017-08-07 2019-02-26 北京蕴汇医药科技有限公司 With prevention and treatment hepatic precancerosis and the Chinese medicine composition of liver cancer effect and preparation method thereof
CN111072746A (en) * 2019-12-26 2020-04-28 中山百灵生物技术有限公司 Preparation method of 6- α -ethyl-7-ketocholic acid
CN111072745A (en) * 2019-12-26 2020-04-28 中山百灵生物技术有限公司 Preparation method of 6-methylene-7-ketocholic acid
CN115806578A (en) * 2021-09-15 2023-03-17 成都百泉生物医药科技有限公司 Nor-UDCA intermediate, nor-UDCA and preparation method of Nor-UDCA intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108137643A (en) * 2015-08-07 2018-06-08 英特塞普特医药品公司 The method for preparing bile acid and its derivative
US20180222937A1 (en) * 2015-08-07 2018-08-09 Intercept Pharmaceuticals, Inc. Methods for preparation of bile acids and derivatives thereof
EP3331896A4 (en) * 2015-08-07 2019-08-14 Intercept Pharmaceuticals, Inc. Methods for preparation of bile acids and derivatives thereof
US10604544B2 (en) * 2015-08-07 2020-03-31 Intercept Pharmaceuticals, Inc. Methods for preparation of bile acids and derivatives thereof
CN109381679A (en) * 2017-08-07 2019-02-26 北京蕴汇医药科技有限公司 With prevention and treatment hepatic precancerosis and the Chinese medicine composition of liver cancer effect and preparation method thereof
CN111072746A (en) * 2019-12-26 2020-04-28 中山百灵生物技术有限公司 Preparation method of 6- α -ethyl-7-ketocholic acid
CN111072745A (en) * 2019-12-26 2020-04-28 中山百灵生物技术有限公司 Preparation method of 6-methylene-7-ketocholic acid
CN111072746B (en) * 2019-12-26 2021-04-06 中山百灵生物技术股份有限公司 Preparation method of 6-alpha-ethyl-7-ketocholic acid
CN115806578A (en) * 2021-09-15 2023-03-17 成都百泉生物医药科技有限公司 Nor-UDCA intermediate, nor-UDCA and preparation method of Nor-UDCA intermediate

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