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WO2016045480A1 - Procédé de préparation d'acide obéticholique - Google Patents

Procédé de préparation d'acide obéticholique Download PDF

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Publication number
WO2016045480A1
WO2016045480A1 PCT/CN2015/088238 CN2015088238W WO2016045480A1 WO 2016045480 A1 WO2016045480 A1 WO 2016045480A1 CN 2015088238 W CN2015088238 W CN 2015088238W WO 2016045480 A1 WO2016045480 A1 WO 2016045480A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
protecting group
group
preparing
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.)
Ceased
Application number
PCT/CN2015/088238
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English (en)
Chinese (zh)
Inventor
张富尧
陈谦益
刘鹏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Unitris Biopharma Co Ltd
Original Assignee
Unitris Biopharma Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Unitris Biopharma Co Ltd filed Critical Unitris Biopharma Co Ltd
Priority to CN201580035031.3A priority Critical patent/CN106459136B/zh
Publication of WO2016045480A1 publication Critical patent/WO2016045480A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the invention relates to a preparation method of oleic acid.
  • Abecholic acid (as shown in Formula I) is a semi-synthetic chenodeoxycholic acid derivative for the treatment of portal hypertension and liver disease, including primary biliary cirrhosis, bile acid diarrhea, non-alcohol Sexual steatohepatitis.
  • Obecholic acid acts by activating FXR receptors, a nuclear receptor that is expressed primarily in the liver, intestines, and kidneys. It regulates the expression of genes involved in bile acids, fats, and glucose metabolism, and regulates immune response. Activation of FXR inhibits bile acid synthesis and prevents toxic reactions caused by excessive accumulation of bile acids.
  • WO2002072598 discloses for the first time the preparation method of oleic acid (as shown below), which is obtained by direct alkylation of compound VI with ethyl iodide under strong basic conditions to obtain compound VII, which is obtained by reduction and decarboxylation of compound VII.
  • Abecholic acid due to the poor selectivity and low yield of direct alkylation with iodoethane, it is difficult to achieve amplification synthesis in this synthesis process.
  • WO2006122977 has improved the above synthesis process (as shown below) by converting compound IX to a silicon-based protected enol compound X, which is condensed and dehydrated with acetaldehyde to give compound Vb, and compound Vb is subjected to basic conditions.
  • the lower palladium carbon is hydrogenated and reduced to obtain compound XI, and compound XI is reduced by carbonyl to obtain oleic acid.
  • choline acid provides a preparation method of oleic acid which is less suitable for large-scale production, has less by-products, is easy to operate, and has low synthesis cost.
  • the invention provides a new method for synthesizing oleic acid
  • R 1 is a hydroxy protecting group and R 2 is a carboxy protecting group.
  • the synthesis method includes the following steps:
  • Formula IV is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula III;
  • Formula II is deprotected by hydroxy groups under acidic conditions to produce oleic acid as shown in Formula I.
  • the compound V is synthesized according to the method described in WO2006122977.
  • the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is ethyl.
  • the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is methyl.
  • the present invention provides a synthetic route for oleic acid as follows:
  • the synthesis method includes the following steps:
  • Formula IVa is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula IIIa;
  • Formula IIa is hydrolyzed by hydrochloric acid to remove hydroxy group protection to obtain oleic acid as shown in Formula I.
  • the compound Va is synthesized according to the method described in WO2006122977.
  • the invention also provides a compound of formula IV,
  • R 1 is a hydroxy protecting group and R 2 is a carboxy protecting group.
  • the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is ethyl.
  • the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is methyl.
  • the invention further provides a process for the preparation of a compound of formula IV, which is prepared by hydroxy protecting a compound of formula V.
  • R 1 is a hydroxy protecting group and R 2 is a carboxy protecting group.
  • the invention also provides a compound of formula III,
  • R 1 is a hydroxy protecting group
  • the hydroxy protecting group R 1 is MOM.
  • the invention further provides a process for the preparation of a compound of formula III, which is prepared by catalytic hydrogenation of palladium on carbon under basic conditions by a compound of formula VI.
  • R 1 is a hydroxy protecting group
  • the hydroxy protecting group R 1 is MOM.
  • the invention also provides a compound of formula II,
  • R 1 is a hydroxy protecting group
  • the hydroxy protecting group R 1 is MOM.
  • the present invention further provides a process for the preparation of a compound of the formula II, which is obtained by subjecting a compound of the formula III to a reduction reaction.
  • R 1 is a hydroxy protecting group
  • the hydroxy protecting group R 1 is MOM.
  • the hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
  • the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl,
  • Carboxylic acid protecting group is a suitable group for carboxylic acid protection known in the art, see the carboxylic acid protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts), As an example, preferably, the carboxylic acid protecting group may be a substituted or unsubstituted C 1-10 linear or branched alkyl group, a substituted or unsubstituted C 2-10 linear or branched alkenyl group.
  • alkynyl substituted or unsubstituted C 3-8 cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl) 3 silane
  • a straight or branched alkyl group of C 1-6 is preferred, and a linear or branched alkyl group of C 1-4 is more preferred.
  • the compound IIa (584 g) was dissolved in 6 liters of tetrahydrofuran, cooled to 0 ° C, 5 liters of 4N aqueous hydrochloric acid was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours, and 10 liters of ethyl acetate was added thereto, and the extract was concentrated and analyzed. Crystallization, filtration and drying gave 497 g of oleic acid in a yield of 94%.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule (III) et un procédé de préparation associé, où R1 est un groupe de protection hydroxyle et est de préférence MOM; et l'invention concerne également un procédé de préparation d'acide obéticholique à l'aide dudit composé. Le procédé de préparation présente des conditions de réaction modérées, peu de sous-produits, ainsi qu'un fonctionnement simple et pratique, et il convient à une production à grande échelle.
PCT/CN2015/088238 2014-09-28 2015-08-27 Procédé de préparation d'acide obéticholique Ceased WO2016045480A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580035031.3A CN106459136B (zh) 2014-09-28 2015-08-27 一种奥贝胆酸的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410509597.2 2014-09-28
CN201410509597 2014-09-28

Publications (1)

Publication Number Publication Date
WO2016045480A1 true WO2016045480A1 (fr) 2016-03-31

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PCT/CN2015/088238 Ceased WO2016045480A1 (fr) 2014-09-28 2015-08-27 Procédé de préparation d'acide obéticholique

Country Status (2)

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CN (1) CN106459136B (fr)
WO (1) WO2016045480A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016173524A1 (fr) * 2015-04-29 2016-11-03 正大天晴药业集团股份有限公司 Dérivé d'acide chénodésoxycholique
CN106279336A (zh) * 2016-08-18 2017-01-04 合肥诺瑞吉医药科技有限公司 一种奥贝胆酸的合成方法
WO2017111979A1 (fr) * 2015-12-22 2017-06-29 Intercept Pharmaceuticals, Inc. Formes cristallines polymorphes de l'acide obéticholique
CN107400154A (zh) * 2016-05-18 2017-11-28 北京凯因科技股份有限公司 一种制备3α,7α-二-羟基-6α-乙基-5β-胆烷酸的方法
WO2017207648A1 (fr) * 2016-05-31 2017-12-07 Bionice, S.L.U Procédés et intermédiaires pour la préparation d'acide obéticholique et de dérivés de celui-ci
WO2018010651A1 (fr) * 2016-07-13 2018-01-18 江苏恒瑞医药股份有限公司 Procédé de fabrication d'acide obéticholique et de ses intermédiaires
US9982008B2 (en) 2012-06-19 2018-05-29 Intercept Pharmaceuticals, Inc. Preparation and uses of obeticholic acid
CN108264533A (zh) * 2016-12-30 2018-07-10 上海现代制药股份有限公司 一种奥贝胆酸的制备方法及其中间体
CN108264532A (zh) * 2016-12-30 2018-07-10 上海现代制药股份有限公司 一种奥贝胆酸的制备方法及其中间体
CN108659086A (zh) * 2017-03-29 2018-10-16 杭州源昶医药科技有限公司 一种奥贝胆酸的合成方法
WO2019145977A1 (fr) * 2018-01-25 2019-08-01 Msn Laboratories Private Limited, R&D Center PROCÉDÉ DE PRÉPARATION DE L'ACIDE 3α,7α-DIHYDROXY6α-ÉTHYL-5β-CHOLAN-24-OÏQUE
CN112898369A (zh) * 2019-12-04 2021-06-04 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法
CN113264972A (zh) * 2020-02-14 2021-08-17 四川科伦药物研究院有限公司 一种制备奥贝胆酸的方法
WO2021204142A1 (fr) * 2020-04-08 2021-10-14 西安奥立泰医药科技有限公司 Sel de dérivé d'acide biliaire, structure cristalline de celui-ci, son procédé de préparation et son utilisation
US11161871B2 (en) 2016-03-31 2021-11-02 Jiangsu Hengrui Medicine Co., Ltd. Crystalline form of obeticholic acid and preparation method therefor

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CN104558086A (zh) * 2014-12-25 2015-04-29 康美（北京）药物研究院有限公司 一种5β-3α,7α-二羟基-6α-乙基-胆烷酸的制备方法

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WO2008002573A2 (fr) * 2006-06-27 2008-01-03 Intercept Pharmaceuticals, Inc. Dérivés de l'acide biliaire en tant que des ligands de fxr pour la prévention ou le traitement de maladies ou conditions médiées par le fxr
ES2822375T3 (es) * 2012-06-19 2021-04-30 Intercept Pharmaceuticals Inc Preparación de la forma no cristalina del ácido obeticólico
ES2938874T3 (es) * 2014-05-29 2023-04-17 Bar Pharmaceuticals S R L Derivados de colano para su uso en el tratamiento y/o prevención de enfermedades mediadas por FXR y TGR5/GPBAR1

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WO2006122977A2 (fr) * 2005-05-19 2006-11-23 Erregierre S.P.A. Procede d'elaboration d'acide 3?(?)-7?(?)-dihydroxy-6?(?)-alkyle-5?-cholanique
US20090062526A1 (en) * 2007-08-28 2009-03-05 Yu Donna D novel method of synthesizing alkylated bile acid derivatives
WO2014085474A1 (fr) * 2012-11-28 2014-06-05 Intercept Pharmaceuticals, Inc. Traitement d'une maladie pulmonaire
CN104558086A (zh) * 2014-12-25 2015-04-29 康美（北京）药物研究院有限公司 一种5β-3α,7α-二羟基-6α-乙基-胆烷酸的制备方法

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CLAUDIO D'AMOREET ET AL.: "Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, 4 January 2014 (2014-01-04) *
VALENTINA SEPEET ET AL.: "Conicasterol E, a Small Heterodimer Partner Sparing Farnesoid X Receptor Modulator Endowed with a Pregnane X Receptor Agonistic Activity, from the Marine Sponge Theonella swinhoei", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, 29 November 2011 (2011-11-29) *

Cited By (26)

* Cited by examiner, † Cited by third party
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
CN107531743B (zh) * 2015-04-29 2020-05-05 正大天晴药业集团股份有限公司 鹅去氧胆酸衍生物
CN107531743A (zh) * 2015-04-29 2018-01-02 正大天晴药业集团股份有限公司 鹅去氧胆酸衍生物
WO2016173524A1 (fr) * 2015-04-29 2016-11-03 正大天晴药业集团股份有限公司 Dérivé d'acide chénodésoxycholique
WO2017111979A1 (fr) * 2015-12-22 2017-06-29 Intercept Pharmaceuticals, Inc. Formes cristallines polymorphes de l'acide obéticholique
US11161871B2 (en) 2016-03-31 2021-11-02 Jiangsu Hengrui Medicine Co., Ltd. Crystalline form of obeticholic acid and preparation method therefor
CN107400154A (zh) * 2016-05-18 2017-11-28 北京凯因科技股份有限公司 一种制备3α,7α-二-羟基-6α-乙基-5β-胆烷酸的方法
WO2017207648A1 (fr) * 2016-05-31 2017-12-07 Bionice, S.L.U Procédés et intermédiaires pour la préparation d'acide obéticholique et de dérivés de celui-ci
CN108602850A (zh) * 2016-07-13 2018-09-28 江苏恒瑞医药股份有限公司 一种奥贝胆酸及其中间体的制备方法
WO2018010651A1 (fr) * 2016-07-13 2018-01-18 江苏恒瑞医药股份有限公司 Procédé de fabrication d'acide obéticholique et de ses intermédiaires
CN106279336A (zh) * 2016-08-18 2017-01-04 合肥诺瑞吉医药科技有限公司 一种奥贝胆酸的合成方法
CN108264533A (zh) * 2016-12-30 2018-07-10 上海现代制药股份有限公司 一种奥贝胆酸的制备方法及其中间体
CN108264532A (zh) * 2016-12-30 2018-07-10 上海现代制药股份有限公司 一种奥贝胆酸的制备方法及其中间体
CN108264533B (zh) * 2016-12-30 2020-12-04 上海现代制药股份有限公司 一种奥贝胆酸的制备方法及其中间体
CN108264532B (zh) * 2016-12-30 2021-02-26 上海现代制药股份有限公司 一种奥贝胆酸的制备方法及其中间体
CN108659086A (zh) * 2017-03-29 2018-10-16 杭州源昶医药科技有限公司 一种奥贝胆酸的合成方法
WO2019145977A1 (fr) * 2018-01-25 2019-08-01 Msn Laboratories Private Limited, R&D Center PROCÉDÉ DE PRÉPARATION DE L'ACIDE 3α,7α-DIHYDROXY6α-ÉTHYL-5β-CHOLAN-24-OÏQUE
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
WO2021109883A1 (fr) * 2019-12-04 2021-06-10 博瑞生物医药（苏州）股份有限公司 Procédé destiné à être utilisé dans la préparation d'acide obéticholique
CN112898369A (zh) * 2019-12-04 2021-06-04 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法
CN112898369B (zh) * 2019-12-04 2024-09-17 博瑞生物医药（苏州）股份有限公司 用于制备奥贝胆酸的方法
CN113264972A (zh) * 2020-02-14 2021-08-17 四川科伦药物研究院有限公司 一种制备奥贝胆酸的方法
CN113264972B (zh) * 2020-02-14 2024-07-12 四川科伦药物研究院有限公司 一种制备奥贝胆酸的方法
WO2021204142A1 (fr) * 2020-04-08 2021-10-14 西安奥立泰医药科技有限公司 Sel de dérivé d'acide biliaire, structure cristalline de celui-ci, son procédé de préparation et son utilisation
JP2023504015A (ja) * 2020-04-08 2023-02-01 西安奥立泰医薬科技有限公司 胆汁酸誘導体塩、その結晶形構造及びそれらの製造方法と使用
US12331071B2 (en) 2020-04-08 2025-06-17 Xi'an Biocare Pharma Ltd. Bile acid derivative salt, crystal structure thereof, preparation method therefor and use thereof

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