WO2009067960A3 - A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates - Google Patents

A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates Download PDF

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Publication number
WO2009067960A3
WO2009067960A3 PCT/CZ2008/000136 CZ2008000136W WO2009067960A3 WO 2009067960 A3 WO2009067960 A3 WO 2009067960A3 CZ 2008000136 W CZ2008000136 W CZ 2008000136W WO 2009067960 A3 WO2009067960 A3 WO 2009067960A3
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WO
WIPO (PCT)
Prior art keywords
fluorophenyl
azetidinone
hydroxyphenyl
hydroxypropyl
manufacturing
Prior art date
Application number
PCT/CZ2008/000136
Other languages
French (fr)
Other versions
WO2009067960A2 (en
Inventor
Hana Stepankova
Josef Hajicek
Marketa Slavikova
Josef Zezula
Original Assignee
Zentiva, A.S.
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 Zentiva, A.S. filed Critical Zentiva, A.S.
Publication of WO2009067960A2 publication Critical patent/WO2009067960A2/en
Publication of WO2009067960A3 publication Critical patent/WO2009067960A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Abstract

A method of manufacturing (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) of formula I, in which a protected ketone of general formula II, wherein R stands for a protective group, such as benzyloxycarbonyl, tert-butoxycarbonyl, benzhydryl or trityl, is reduced with asymmetrical borane agents in an inert organic solvent in the temperature range of -30 to +40 °C, and finally the obtained protected alcohol of general formula III, wherein R has the same meaning as above, is deprotected by the action of hydro genolytic or acidic agents in an inert organic solvent.
PCT/CZ2008/000136 2007-11-30 2008-11-05 A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates WO2009067960A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20070843A CZ2007843A3 (en) 2007-11-30 2007-11-30 Process for preparing (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and intermediates thereof
CZPV2007-843 2007-11-30

Publications (2)

Publication Number Publication Date
WO2009067960A2 WO2009067960A2 (en) 2009-06-04
WO2009067960A3 true WO2009067960A3 (en) 2009-09-24

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PCT/CZ2008/000136 WO2009067960A2 (en) 2007-11-30 2008-11-05 A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates

Country Status (2)

Country Link
CZ (1) CZ2007843A3 (en)
WO (1) WO2009067960A2 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0501164A2 (en) * 2005-12-20 2007-07-30 Richter Gedeon Nyrt New industrial process for the production of ezetimibe
CZ2008317A3 (en) * 2008-05-21 2009-12-02 Zentiva, A. S. Process for preparing (3R,4S)-1-(4-fluorphenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone
CA2757722C (en) 2009-04-01 2018-05-22 Matrix Laboratories Ltd. Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe
CN103086938A (en) * 2011-10-28 2013-05-08 沈阳药科大学 Ezetimibe synthesis method
CN103896700B (en) * 2012-12-25 2015-12-23 浙江九洲药物科技有限公司 The preparation method of ezetimibe chiral intermediate
CN104003921A (en) * 2014-05-06 2014-08-27 南通常佑药业科技有限公司 Preparation method of ezetimibe intermediate
JP6516576B2 (en) * 2015-06-15 2019-05-22 株式会社トクヤマ Process for the preparation of (3R, 4S) -1- (4-fluorophenyl)-[3 (S) -hydroxy-3- (4-fluorophenyl) propyl]-[4- (phenylmethoxy) phenyl] -2-azetidinone
CN105012244A (en) * 2015-08-03 2015-11-04 青岛蓝盛洋医药生物科技有限责任公司 Medicine ezetimibe composition granules for treating hyperlipidemia
CN114621126B (en) * 2020-12-12 2023-07-25 重庆圣华曦药业股份有限公司 Improved ezetimibe preparation method

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137080A1 (en) * 2005-06-22 2006-12-28 Manne Satyanarayana Reddy Improved process for the preparation of ezetimibe
WO2007030721A2 (en) * 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Processes for the preparation of (3r,4s)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((s)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
WO2007072088A1 (en) * 2005-12-20 2007-06-28 Richter Gedeon Nyrt. Process for the production of ezetimibe and intermediates used in this proces
WO2007119106A2 (en) * 2005-12-22 2007-10-25 Medichem, S.A. Processes for preparing intermediate compounds useful for the preparation of ezetimibe
WO2008089984A2 (en) * 2007-01-24 2008-07-31 Krka Process for the preparation of ezetimibe and derivatives thereof
EP1953140A1 (en) * 2007-01-24 2008-08-06 Krka Process for the preparation of ezetimibe and derivatives thereof
WO2008151324A1 (en) * 2007-06-07 2008-12-11 Teva Pharmaceutical Industries Ltd. Reduction processes for the preparation of ezetimibe

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137080A1 (en) * 2005-06-22 2006-12-28 Manne Satyanarayana Reddy Improved process for the preparation of ezetimibe
WO2007030721A2 (en) * 2005-09-08 2007-03-15 Teva Pharmaceutical Industries Ltd. Processes for the preparation of (3r,4s)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((s)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
WO2007072088A1 (en) * 2005-12-20 2007-06-28 Richter Gedeon Nyrt. Process for the production of ezetimibe and intermediates used in this proces
WO2007119106A2 (en) * 2005-12-22 2007-10-25 Medichem, S.A. Processes for preparing intermediate compounds useful for the preparation of ezetimibe
WO2008089984A2 (en) * 2007-01-24 2008-07-31 Krka Process for the preparation of ezetimibe and derivatives thereof
EP1953140A1 (en) * 2007-01-24 2008-08-06 Krka Process for the preparation of ezetimibe and derivatives thereof
WO2008151324A1 (en) * 2007-06-07 2008-12-11 Teva Pharmaceutical Industries Ltd. Reduction processes for the preparation of ezetimibe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THEODORA W. GREENE, PETER G.M. WUTS: "Protective Groups in Organic Chemistry", 1999, JOHN WILEY & SONS, XP002524747 *

Also Published As

Publication number Publication date
CZ2007843A3 (en) 2009-06-10
WO2009067960A2 (en) 2009-06-04

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