CN106459136A - Method for preparing obeticholic acid - Google Patents
Method for preparing obeticholic acid Download PDFInfo
- Publication number
- CN106459136A CN106459136A CN201580035031.3A CN201580035031A CN106459136A CN 106459136 A CN106459136 A CN 106459136A CN 201580035031 A CN201580035031 A CN 201580035031A CN 106459136 A CN106459136 A CN 106459136A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- protecting group
- cholic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Vascular Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
Provided are a compound represented by formula (III) and a preparation method therefor, wherein R1 is a hydroxyl protective group and preferably is MOM; and also provided is a method for preparing obeticholic acid by using the compound. The preparation method has moderate reaction conditions, few by-products and simple and convenient operation, and is suitable for large-scale production.
Description
The present invention relates to a kind of preparation method of shellfish cholic acid difficult to understand.
Shellfish cholic acid (shown in formula I) difficult to understand is a kind of semi-synthetic chenodeoxycholic acid derivatives, and for treating, portal blood pressure is too high and liver diseases, including PBC, bile acid diarrhoea, nonalcoholic fatty liver disease.Shellfish cholic acid difficult to understand is played a role by activating FXR acceptors, and FXR is a kind of nuclear receptor, is mainly expressed in liver, intestines, kidney, and it can be adjusted and bile acid, the expression of fat and sugar metabolism related gene, moreover it is possible to adjust immune response.Activation FXR can suppress bile acid biosynthesis, and prevention bile acid builds up caused toxic reaction.
WO2002072598 makes public for the first time the preparation method (as follows) of shellfish cholic acid difficult to understand; this method obtains compound VII with iodoethane direct alkylation under strongly alkaline conditions by compound VI, and shellfish cholic acid difficult to understand is made by reduction and carboxyl deprotection in compound VII.But due to, the building-up process difficult to realize amplification synthesis too low with the poor selectivity and yield of iodoethane direct alkylation.
Shellfish cholic acid synthetic method (WO2002072598) difficult to understand
WO2006122977 is improved (as follows) above synthesis technique; compound IX by being converted into the enolization compound X that silicon substrate is protected by this method; compound X after acetaldehyde condensation dehydration with obtaining compound Vb; compound Vb obtains compound XI by palladium carbon hydrogenating reduction in the basic conditions, and Austria's shellfish cholic acid is made in compound XI after carbonyl reduction.
Shellfish cholic acid synthetic method (WO2006122977) difficult to understand
Although the synthesis technique can realize amplification synthesis; but; substantial amounts of accessory substance is produced during compound Vb under strongly alkaline conditions palladium carbon hydrogenating reduction and strong basicity high-temperature process prepare compound XI; so as to which the separation yield for causing the step to be reacted is relatively low (about 60%), the low yield of step reaction is probably to be caused because the side reactions such as dehydration occur under the conditions of strong basicity (30%NaOH) and high temperature (95-105 DEG C) for the unprotected hydroxyl in compound Vb and XI.
The content of the invention
Shortcoming present in synthetic method for existing shellfish cholic acid difficult to understand; inventor is by discovery of concentrating on studies; protected by the hydroxyl to compound V; it can avoid that the side reactions such as dehydration occur under strong basicity and hot conditions; the combined coefficient of shellfish cholic acid difficult to understand is substantially increased, thus it is few there is provided a kind of accessory substance, it is easy to operate; synthesize with low cost, the shellfish cholic acid preparation method difficult to understand suitable for large-scale production.
The invention provides a kind of new method for synthesizing shellfish cholic acid difficult to understand,
Wherein, R1For hydroxyl protecting group, R2For carboxyl-protecting group.
Specifically, the synthetic method comprises the following steps：
1) Formula V compound obtains the compound as shown in formula IV by hydroxyl protection；
2) compound as shown in formula III is made by palladium carbon catalytic hydrogenation reaction in the basic conditions in formula IV；
3) compound as shown in Formula II is made by reduction for formula III；
4) eliminating hydroxide protects the shellfish cholic acid difficult to understand being made shown in formula I to Formula II in acid condition.
Wherein, method synthesis of the compound V according to described in WO2006122977 is obtained.
In yet other embodiments, hydroxyl protecting group R1For MOM, carboxyl-protecting group R2For ethyl.
In presently preferred embodiment, hydroxyl protecting group R1For MOM, carboxyl-protecting group R2For methyl.
In an especially preferred embodiment, the synthetic route of present invention offer shellfish cholic acid difficult to understand is as follows：
Specifically, the synthetic method comprises the following steps：
1) Formula V a compounds react the compound obtained as shown in formula IV a with MOMCl；
2) compound as shown in formula III a is made by palladium carbon catalytic hydrogenation reaction in the basic conditions in formula IV a；
3) compound as shown in Formula II a is made by sodium borohydride reduction by formula III a；
4) Formula II a protects the shellfish cholic acid difficult to understand being made shown in formula I by hydrochloric acid water solution eliminating hydroxide.
Wherein, method synthesis of the compound Va according to described in WO2006122977 is obtained.
The present invention also provides a kind of compound as shown in formula IV,
Wherein, R1For hydroxyl protecting group, R2For carboxyl-protecting group.
In yet other embodiments, hydroxyl protecting group R1For MOM, carboxyl-protecting group R2For ethyl.
In presently preferred embodiment, hydroxyl protecting group R1For MOM, carboxyl-protecting group R2For methyl.
The present invention further provides a kind of preparation method of the compound as shown in formula IV, compound IV carries out being made after hydroxyl protection by compound shown as a formula V.
Wherein, R1For hydroxyl protecting group, R2For carboxyl-protecting group.
The present invention also provides a kind of compound as shown in formula III,
Wherein, R1For hydroxyl protecting group.
In yet other embodiments, hydroxyl protecting group R1For MOM.
The present invention further provides a kind of preparation method of the compound as shown in formula III, compound III is made by palladium carbon catalytic hydrogenation reaction in the basic conditions by the compound as shown in Formula IV,
Wherein, R1For hydroxyl protecting group.
In yet other embodiments, hydroxyl protecting group R1For MOM.
The present invention also provides a kind of compound as shown in Formula II,
Wherein, R1For hydroxyl protecting group.
In yet other embodiments, hydroxyl protecting group R1For MOM.
The present invention further provides a kind of preparation method of the compound as shown in Formula II, compound II is made by the compound as shown in formula III after reduction reaction,
Wherein, R1For hydroxyl protecting group.
In yet other embodiments, hydroxyl protecting group R1For MOM.
Term used in the present invention, in addition to having opposite statement, with following implication：
The hydroxyl protecting group of the present invention is the appropriate group for hydroxyl protection known in the art, referring to document (" Protective Groups in Organic Synthesis ", 5ThEd.T.W.Greene＆P.G.M.Wuts the hydroxy-protective group in).As an example, preferably, described hydroxyl protecting group can be (C1-10Alkyl or aryl)3Silylation, for example：Triethyl group silicon substrate, triisopropylsilyl, t-Butyldimethylsilyl, tert-butyl diphenyl silicon substrate etc.；Can be C1-10Alkyl or substitution alkyl, preferably alkoxy or the alkyl of aryl substitution, more preferably C1-6The C of alkoxy substitution1-6The C of alkyl or phenyl substitution1-6Alkyl, most preferably C1-4The C of alkoxy substitution1-4Alkyl, for example：Methyl, the tert-butyl group, pi-allyl, benzyl, methoxy, ethoxyethyl group, 2- THP trtrahydropyranyls (THP) etc.；Can be (C1-10Alkyl or aromatic radical) acyl group, for example：Formoxyl, acetyl group, benzoyl etc.；Can be (C1-6Alkyl or C6-10Aryl) sulfonyl；Can also be (C1-6Alkoxy or C6-10Aryloxy) carbonyl.
" carboxylic acid protecting group " be it is known in the art it is appropriate be used for the group that carboxylic acid is protected, referring to document (" Protective Groups in Organic Synthesis ", 5Th Ed.T.W.Greene&P.G.M.Wuts)
In carboxylic acid protective group, as an example, preferably, described carboxylic acid protecting group can be substituted or non-substituted C1-10Straight or branched alkyl, substituted or non-substituted C2-10Straight or branched alkenyl or alkynyl, substituted or non-substituted C3-8Cyclic alkyl, substituted or non-substituted C5-10Aryl or heteroaryl or (C1-8Alkyl or aryl)3Silylation；It is preferred that C1-6Straight or branched alkyl, more preferably C1-4Straight or branched alkyl.
English abbreviation has following meaning employed in the present invention：
| Abbreviation | Full name |
| MOMCl | Chloromethyl methyl ether |
| MOM | Methoxy |
| TMS | Trimethyl silicon substrate |
Following table is the structural formula of involved compound in embodiment
The present invention is explained in detail below with reference to instantiation so that the present invention is more fully understood in those skilled in the art, instantiation is merely to illustrate technical scheme, the present invention is not limited in any way.
Embodiment 1：Prepare compound IVa
Compound Va (646 grams, the method in WO2006122977 is made) is dissolved in 7 liters of dichloromethane, 762 milliliters of diisopropylethylamines are added, it is cooled to 0 DEG C, 166 milliliters of MOMCl are added, reaction system is warming up to 20 DEG C, reacts 16 hours, add water and reaction is quenched, 10 liters of ethyl acetate extractions are added, organic phase, organic phase anhydrous sodium sulfate drying is separated, 696 g of compound IVa, yield 98% are obtained after filtering and concentrating.
1H NMR(400MHz,CDCl3)δ6.16(q,1H),4.76–4.59(m,2H),4.28–4.01(m,2H),3.70–3.48(m,1H),3.42–3.29(m,3H),2.56(dd,1H),2.46–2.14(m,4H),2.07–1.87(m,4H),1.87–1.68(m,5H),1.55–1.04(m,16H),1.00(s,3H),0.92(t,3H),0.78–0.62(m,3H).
Embodiment 2：Prepare compound IIIa
Compound IVa (696g) is dissolved in ethanol (7 liters), palladium carbon (76g, 10wt%) and 500 gram of 30% sodium hydrate aqueous solution is added, 16h is reacted at hydrogen (1.5 atmospheric pressure) and 20 DEG C, 95 DEG C are then warming up to, stirred 16 hours, it is cooled to after 20 DEG C, filters, the mother liquor after concentration is neutralized with 2N hydrochloric acid, plus 10 liters of ethyl acetate extractions, after extract is concentrated, crystallization, filtering, 606 g of compound IIIa, yield 92% are obtained after drying.
1H NMR(400MHz,CDCl3)δ4.74–4.55(m,2H),3.52–3.39(m,1H),3.38–3.30(m,3H),2.68(dd,1H),2.49–2.13(m,4H),2.02–1.65(m,9H),1.58–1.02(m,15H),0.95(dd,4H),0.86–0.77(m,3H),0.67(d,3H).
Embodiment 3：Prepare compound IIa
Compound IIIa (606 grams) is dissolved in 7 liters of ethanol, 0 DEG C is cooled to, 50 grams of sodium borohydrides is added, is warming up to 20 DEG C, reaction 8 hours, is slowly added dropwise phosphoric acid until pH=6, solid precipitation, filtering, solid is washed with water, and 584 g of compound IVa, yield 96% are obtained after drying.
1HNMR(400MHz,CDCl3)δ4.66(s,2H),3.72(m,2H),3.35(m,4H),2.25-1.07(m,28H),0.90(m,8H),0.65(s,3H).
Embodiment 4：Prepare shellfish cholic acid difficult to understand
Compound IIa (584 grams) is dissolved in 6 liters of tetrahydrofurans, 0 DEG C is cooled to, 5 liters of 4N aqueous hydrochloric acid solutions is added, is warming up to 20 DEG C, reaction 8 hours, plus 10 liters of ethyl acetate extractions, after extract is concentrated, crystallization, filtering, is dried to obtain 497 Ke Aobei cholic acid, yield 94%.
1HNMR(400MHz,CD3OD)δ3.65(m,1H),3.30(m,1H),2.32(m,1H),2.20(m,1H),2.03-1.65(m,8H),1.60-1.06(m,18H),0.90(m,9H),0.67(s,3H).
Embodiment 5：Prepare compound IVb
Compound Vb (500 grams, the method in WO2006122977 is made) is dissolved in 5 liters of dichloromethane, 650 milliliters of diisopropylethylamines are added, it is cooled to 0 DEG C, 147 milliliters of MOMCl are added, reaction system is gradually raised to 20 DEG C, reacts 16 hours, add water and reaction is quenched, 10 liters of ethyl acetate extractions are added, organic phase, organic phase anhydrous sodium sulfate drying is separated, 524 g of compound IVb, yield 95% are obtained after filtering and concentrating.
1HNMR(400MHz,CDCl3) δ 6.16 (m, 1H), 4.65 (s, 2H), 3.66 (s, 3H), 3.55 (m, 1H), 3.34 (s, 3H), 3.08 (m, 1H), 2.55 (m, 2H), 2.53 (m, 2H), 2.22 (m, 2H), 1.96 (m, 6H), 1.80 (m, 2H), 1.69 (m, 4H), 1.56-1.01 (m, 14H), 0.93 (m, 3H), 0.62 (s, 3H)
Embodiment 6：Prepare compound IIIa
Compound IVb (70g) is dissolved in ethanol (750 persons of outstanding talent rise), palladium carbon (8g, 10wt%) and 50 gram of 30% sodium hydrate aqueous solution is added, 10h is reacted at hydrogen (1.5 atmospheric pressure) and 20 DEG C, 100 DEG C are then warming up to, stirred 10 hours, it is cooled to after 20 DEG C, filters, the mother liquor after concentration is neutralized with 2N hydrochloric acid, plus 1 liter of ethyl acetate extraction, after extract is concentrated, crystallization, filtering, 65 g of compound IIIa, yield 95% are obtained after drying.
1H NMR(400MHz,CDCl3)δ4.62(m,2H),3.43(m,1H),3.34(m,3H),2.68(m,1H),2.25(m,4H),1.82(m,9H),1.58–1.02(m,15H),0.95(m,4H),0.80(m,3H),0.66(s,3H).
Due to describing the present invention according to its specific embodiment, some modifications and equivalent variations are obvious for those skilled in this art and are included within the scope of the invention.
Claims (11)
- A kind of compound as shown in formula III,Wherein, R1For hydroxyl protecting group, preferably MOM.
- A kind of preparation method of compound as shown in formula III; it is characterized in that compound IV is made by protection of the compound shown as a formula V through perhydroxyl radical; compound III is made by hydrogenation reaction in compound IV, is preferably to pass through palladium carbon catalytic hydrogenation reaction in the basic conditionsWherein, R1For hydroxyl protecting group, preferably MOM；R2For carboxyl-protecting group, preferably C1-10Straight or branched alkyl, more preferably ethyl or methyl.
- The preparation method of a kind of compound as shown in formula III a, it is characterised in that comprise the following steps,1) Formula V a compounds react the compound obtained as shown in formula IV a with MOMCl；2) compound as shown in formula III a is made by palladium carbon catalytic hydrogenation reaction in the basic conditions in formula IV a.
- A kind of compound as shown in formula IV,Wherein, R1And R2As defined in claim 2.
- The preparation method of a kind of compound as shown in formula IV, it is characterised in that be made by compound shown as a formula V after hydroxyl protection,Wherein, R1And R2As defined in claim 2.
- A kind of compound as shown in Formula II,Wherein, R1As defined in claim 1.
- The preparation method of a kind of compound as shown in Formula II, it is characterised in that be made by the compound as shown in formula III after carbonyl reduction, preferably use sodium borohydride reduction,Wherein, R1As defined in claim 1.
- The preparation method of a kind of compound as shown in Formula II a, it is characterised in that comprise the following steps,1) Formula V a compounds react the compound obtained as shown in formula IV a with MOMCl；2) compound as shown in formula III a is made by palladium carbon catalytic hydrogenation reaction in the basic conditions in formula IV a；3) compound as shown in Formula II a is made by sodium borohydride reduction by formula III a.
- A kind of preparation method of shellfish cholic acid difficult to understand, it is characterised in that the step of preparing shellfish cholic acid difficult to understand by hydroxyl protecting group removing including compound shown in Formula II,Wherein, R1As defined in claim 1.
- The preparation method of shellfish cholic acid difficult to understand according to claim 9, it is characterised in that also including the compound shown in the formula II described in claim 7 the step of.
- The preparation method of shellfish cholic acid difficult to understand according to claim 10, it is characterised in that also including described in claim 2 the step of preparing compound as shown in formula III.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2014105095972 | 2014-09-28 | ||
| CN201410509597 | 2014-09-28 | ||
| PCT/CN2015/088238 WO2016045480A1 (en) | 2014-09-28 | 2015-08-27 | Method for preparing obeticholic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106459136A true CN106459136A (en) | 2017-02-22 |
| CN106459136B CN106459136B (en) | 2018-06-26 |
Family
ID=55580269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580035031.3A Active CN106459136B (en) | 2014-09-28 | 2015-08-27 | A kind of preparation method of Austria's shellfish cholic acid |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN106459136B (en) |
| WO (1) | WO2016045480A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112898369A (en) * | 2019-12-04 | 2021-06-04 | 博瑞生物医药（苏州）股份有限公司 | Process for the preparation of obeticholic acid |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9982008B2 (en) | 2012-06-19 | 2018-05-29 | Intercept Pharmaceuticals, Inc. | Preparation and uses of obeticholic acid |
| CN111574577A (en) * | 2015-04-29 | 2020-08-25 | 正大天晴药业集团股份有限公司 | Chenodeoxycholic acid derivatives |
| JP2018538331A (en) * | 2015-12-22 | 2018-12-27 | インターセプト ファーマシューティカルズ， インコーポレイテッド | Polymorphic crystal form of obeticholic acid |
| US11161871B2 (en) | 2016-03-31 | 2021-11-02 | Jiangsu Hengrui Medicine Co., Ltd. | Crystalline form of obeticholic acid and preparation method therefor |
| CN107400154A (en) * | 2016-05-18 | 2017-11-28 | 北京凯因科技股份有限公司 | One kind prepares 3 α, the method for the 7 α-α of bis-hydroxy-6-β of ethyl-5-cholanic 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 |
| CN108602850B (en) * | 2016-07-13 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | Preparation method of obeticholic acid and intermediate thereof |
| CN106279336A (en) * | 2016-08-18 | 2017-01-04 | 合肥诺瑞吉医药科技有限公司 | A kind of synthetic method of shellfish cholic acid difficult to understand |
| CN108264532B (en) * | 2016-12-30 | 2021-02-26 | 上海现代制药股份有限公司 | Preparation method and intermediate of obeticholic acid |
| CN108264533B (en) * | 2016-12-30 | 2020-12-04 | 上海现代制药股份有限公司 | Preparation method and intermediate of obeticholic acid |
| CN108659086A (en) * | 2017-03-29 | 2018-10-16 | 杭州源昶医药科技有限公司 | A kind of synthetic method of Austria's shellfish cholic acid |
| US11434256B2 (en) | 2018-01-25 | 2022-09-06 | Msn Laboratories Private Limited, R&D Center | Process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid |
| CN113264972B (en) * | 2020-02-14 | 2024-07-12 | 四川科伦药物研究院有限公司 | Method for preparing obeticholic acid |
| CN113493485A (en) * | 2020-04-08 | 2021-10-12 | 西安奥立泰医药科技有限公司 | Bile acid derivative salt, crystal form structure thereof, and preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| US20090062526A1 (en) * | 2007-08-28 | 2009-03-05 | Yu Donna D | novel method of synthesizing alkylated bile acid derivatives |
| CN101522703A (en) * | 2006-06-27 | 2009-09-02 | 英特塞普特医药品公司 | Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated deseases or conditions |
| WO2013192097A1 (en) * | 2012-06-19 | 2013-12-27 | Intercept Pharmaceuticals, Inc. | Preparation, uses and solid forms of obeticholic acid |
| CN104558086A (en) * | 2014-12-25 | 2015-04-29 | 康美（北京）药物研究院有限公司 | Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid |
| CN106661079A (en) * | 2014-05-29 | 2017-05-10 | 巴尔制药有限公司 | Cholane derivatives for use in the treatment and/or prevention of fxr and tgr5/gpbar1 mediated diseases |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104853758A (en) * | 2012-11-28 | 2015-08-19 | 英特赛普特医药品公司 | Treatment of pulmonary disease |
-
2015
- 2015-08-27 WO PCT/CN2015/088238 patent/WO2016045480A1/en active Application Filing
- 2015-08-27 CN CN201580035031.3A patent/CN106459136B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101203526A (en) * | 2005-05-19 | 2008-06-18 | 伊莱吉尔瑞公司 | Process for preparing 3alpha(beta)-7alpha(beta)-dihydroxy-6alpha(beta)-alkyl-5beta-cholanic acid |
| CN101522703A (en) * | 2006-06-27 | 2009-09-02 | 英特塞普特医药品公司 | Bile acid derivatives as fxr ligands for the prevention or treatment of fxr-mediated deseases or conditions |
| US20090062526A1 (en) * | 2007-08-28 | 2009-03-05 | Yu Donna D | novel method of synthesizing alkylated bile acid derivatives |
| WO2013192097A1 (en) * | 2012-06-19 | 2013-12-27 | Intercept Pharmaceuticals, Inc. | Preparation, uses and solid forms of obeticholic acid |
| CN106661079A (en) * | 2014-05-29 | 2017-05-10 | 巴尔制药有限公司 | Cholane derivatives for use in the treatment and/or prevention of fxr and tgr5/gpbar1 mediated diseases |
| CN104558086A (en) * | 2014-12-25 | 2015-04-29 | 康美（北京）药物研究院有限公司 | Preparation method for 5 beta-3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-cholanic acid |
Non-Patent Citations (1)
| Title |
|---|
| CLAUDIO D’AMORE 等: "Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112898369A (en) * | 2019-12-04 | 2021-06-04 | 博瑞生物医药（苏州）股份有限公司 | Process for the preparation of obeticholic acid |
| CN112898369B (en) * | 2019-12-04 | 2024-09-17 | 博瑞生物医药（苏州）股份有限公司 | Method for preparing obeticholic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016045480A1 (en) | 2016-03-31 |
| CN106459136B (en) | 2018-06-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106459136A (en) | Method for preparing obeticholic acid | |
| JP2751385B2 (en) | Process for producing erythromycin A oxime and its salt | |
| CN105801419B (en) | Synthetic method of treprostinil diethanolamine and novel intermediate | |
| US11384116B2 (en) | Methods of making cholic acid derivatives and starting materials therefor | |
| CN108602850B (en) | Preparation method of obeticholic acid and intermediate thereof | |
| JP2015512381A5 (en) | ||
| CN101407459B (en) | Monohydroxy-2-acyl phenylacetate, and preparation and use thereof | |
| CN106243079A (en) | The Preparation Method And Their Intermediate compound of bicyclol | |
| CN101531660A (en) | Industrialization production process of entecavir-monohydrate | |
| CN107383137A (en) | A kind of synthetic method of chenodeoxycholic acid | |
| CN1093529C (en) | Preparation of 1,5-di-o-coffeic acyl quininic acid derivative | |
| WO2009023191A2 (en) | An improved process for the preparation of clarithromycin | |
| CN101525310B (en) | The synthetic method of 1- benzoyl -3- (2- hydroxyl -1,1- dimethyl ethyl) thiocarbamide | |
| CN107903161A (en) | A kind of synthetic method of cis 3 hydroxycyclobutyl formic acid | |
| CN105218397B (en) | Method for synthesizing 2-azidomethyl-4-nitrobenzoyl chloride | |
| CN114349631B (en) | Preparation method and application of 4-methoxy crotonic acid | |
| CN113999101B (en) | Synthesis method of anthraquinone derivative SZ-685C | |
| CN109096098A (en) | A kind of anti-form-1, the preparation method of 3- dihydroxy cyclobutane -1- carboxylic acid | |
| CN102850244A (en) | Preparation method for 3-(3-phenylsulfamoyl-phenyl)-acrylic acid | |
| CN111087436B (en) | Preparation method of obeticholic acid | |
| CN107759483B (en) | Preparation method of methylamino-substituted alkyl cyclopentanecarboxylate | |
| CN106957296A (en) | The formoxyl of 5 ((alkoxymethylene) amino) thienyl 2) L glutamic acid dialkyl esters and preparation method thereof | |
| CN110551114A (en) | Preparation method of raltitrexed | |
| JP2004217540A (en) | Method for producing gallic acid glycoside | |
| CN117917425A (en) | Synthesis method of plant source ursodeoxycholic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20170217 Address after: 222069 Golden Bridge in Jiangsu province Lianyungang City Economic and Technological Development Zone Dapu Industrial Zone, Road No. 22 Applicant after: Jiangsu Sheng Di Pharmaceutical Co., Ltd. Address before: China (Shanghai) free trade zone, No. 581 Shen Kuo Road, Tong Tong Building, the east side of the building on the third floor Applicant before: UniTris Biopharma Co., Ltd. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210108 Address after: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee after: JIANGSU HENGRUI MEDICINE Co.,Ltd. Address before: 222069 No.22, Jinqiao Road, Dapu Industrial Zone, Lianyungang Economic and Technological Development Zone, Jiangsu Province Patentee before: Jiangsu Shengdi Pharmaceutical Co.,Ltd. |
|
| TR01 | Transfer of patent right |