WO2009140932A3 - Method of producing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone - Google Patents

Method of producing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone Download PDF

Info

Publication number
WO2009140932A3
WO2009140932A3 PCT/CZ2009/000070 CZ2009000070W WO2009140932A3 WO 2009140932 A3 WO2009140932 A3 WO 2009140932A3 CZ 2009000070 W CZ2009000070 W CZ 2009000070W WO 2009140932 A3 WO2009140932 A3 WO 2009140932A3
Authority
WO
WIPO (PCT)
Prior art keywords
fluorophenyl
azetidinone
organic solvent
general formula
inert organic
Prior art date
Application number
PCT/CZ2009/000070
Other languages
French (fr)
Other versions
WO2009140932A2 (en
Inventor
Marketa Slavikova
Hana Stepankova
Josef Zezula
Josef Hajlcek
Original Assignee
Zentiva, K.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, K.S. filed Critical Zentiva, K.S.
Publication of WO2009140932A2 publication Critical patent/WO2009140932A2/en
Publication of WO2009140932A3 publication Critical patent/WO2009140932A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • 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
    • 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

Method of producing (3R,4S)1 -(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) of formula 1, in which alcohol-oxazolidide of general formula II, wherein PG is a phenol protecting group, is silylated by silylation agents in an inert organic solvent in the temperature range of -10°C to the boiling temperature of the mixture; the obtained silylether-oxazolidide of general formula III, wherein PG is as defined above and X is a silyl group is cyclized by action of bis(trimethyIsilyl)acetamide and a base in an inert organic solvent in the temperature range of, -20 to 40°C; and, finally, the obtained protected azetidinone of general formula IV is deprotected by action of deprotecting hydrogenolytic agents and/or acidic agents in an inert organic solvent.
PCT/CZ2009/000070 2008-05-21 2009-05-15 Method of producing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone WO2009140932A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2008-317 2008-05-21
CZ20080317A CZ2008317A3 (en) 2008-05-21 2008-05-21 Process for preparing (3R,4S)-1-(4-fluorphenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone

Publications (2)

Publication Number Publication Date
WO2009140932A2 WO2009140932A2 (en) 2009-11-26
WO2009140932A3 true WO2009140932A3 (en) 2010-01-14

Family

ID=40999788

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2009/000070 WO2009140932A2 (en) 2008-05-21 2009-05-15 Method of producing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone

Country Status (2)

Country Link
CZ (1) CZ2008317A3 (en)
WO (1) WO2009140932A2 (en)

Families Citing this family (8)

* 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
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited 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
CN101845010B (en) * 2010-02-10 2012-07-25 浙江大学 Method for preparing ezetimble
ES2372460B1 (en) * 2010-07-09 2012-11-16 Moehs Ibérica S.L. NEW METHOD FOR THE PREPARATION OF EZETIMIBA.
US8952000B2 (en) * 2011-02-16 2015-02-10 Pivotal Therapeutics Inc. Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events
CN102850390B (en) * 2011-07-01 2017-02-08 江苏豪森药业集团有限公司 Intermediate of ezetimibe and its preparation method
CN103864708A (en) * 2012-12-12 2014-06-18 天津市医药集团技术发展有限公司 Preparation method of ezetimibe intermediate
CN105985275B (en) * 2015-02-15 2018-12-14 和鼎（南京）医药技术有限公司 A kind of preparation method of ezetimibe and its intermediate

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006068990A1 (en) * 2004-12-20 2006-06-29 Schering Corporation Process for the synthesis of azetidinones
WO2006086562A2 (en) * 2005-02-09 2006-08-17 Microbia, Inc. Phenylazetidinone derivatives
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
WO2007059871A1 (en) * 2005-11-23 2007-05-31 Sanofi-Aventis Deutschland Gmbh Hydroxy-substituted diphenylazetidinones for the treatment of hyperlipidaemia
WO2007072088A1 (en) * 2005-12-20 2007-06-28 Richter Gedeon Nyrt. Process for the production of ezetimibe and intermediates used in this proces
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
WO2009067960A2 (en) * 2007-11-30 2009-06-04 Zentiva, A.S. A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006068990A1 (en) * 2004-12-20 2006-06-29 Schering Corporation Process for the synthesis of azetidinones
WO2006086562A2 (en) * 2005-02-09 2006-08-17 Microbia, Inc. Phenylazetidinone derivatives
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
WO2007059871A1 (en) * 2005-11-23 2007-05-31 Sanofi-Aventis Deutschland Gmbh Hydroxy-substituted diphenylazetidinones for the treatment of hyperlipidaemia
WO2007072088A1 (en) * 2005-12-20 2007-06-28 Richter Gedeon Nyrt. Process for the production of ezetimibe and intermediates used in this proces
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
WO2009067960A2 (en) * 2007-11-30 2009-06-04 Zentiva, A.S. A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
L KVAERNO ET AL: "Synthesis and in Vitro Evaluation of Inhibitors of Intestinal Cholesterol Absorption", JOURNAL OF MEDICINAL CHEMISTRY., vol. 48, no. 19, 2005, USAMERICAN CHEMICAL SOCIETY. WASHINGTON., pages 6035 - 6053, XP002550654 *

Also Published As

Publication number Publication date
CZ2008317A3 (en) 2009-12-02
WO2009140932A2 (en) 2009-11-26

Similar Documents

Publication Publication Date Title
WO2009140932A3 (en) Method of producing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone
WO2007030721A3 (en) 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
WO2007119106A3 (en) Processes for preparing intermediate compounds useful for the preparation of ezetimibe
WO2009067960A3 (en) A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates
WO2007120824A3 (en) Processes for the synthesis of azetidinone
NO20080416L (en) Improved processes for the production of Ezetimibe
UA103020C2 (en) Intermediates for the preparation of (3r, 4s)-1-(4-fluorophenyl)-3-[(3s)-3- (4-fluorophenyl)-3-hydroxypropyl)]-4- (4-hydroxyphenyl)-2-azetidinone
DE602006018063D1 (en) PROCESS FOR PREPARING EZETIMIBE AND INTERMEDIATES USED IN THIS METHOD
DK1756052T3 (en) Improved Process for Preparing 3-Hydroxy-4-Hydroxymethyl-Pyrrolidine Compounds
WO2008106900A8 (en) Method of manufacturing (3r, 4s) -1- (4-fluorophenyl) -3- [ (3s) -3- (4 -fluorophenyl) -3-hydroxypropyl) ] -4- (4-hyd roxyphenyl) -2-azetidinone
BRPI0519292A2 (en) organic compounds
TW200505920A (en) Organic compounds
TW200745215A (en) Low VOC epoxy silane oligomer and compositions containing same
NZ593052A (en) Asphalt-mineral compositions containing a cationic organosilicon compound
MXPA05013823A (en) Organic compounds.
Cainelli et al. Diastereofacial selectivity in the reaction of chiral N-trimethylsilyl imines with ester enolates: Preparation of trans-azetidin-2-ones in high stereocontrolled fashion.
RU2006139015A (en) METHOD FOR PRODUCING STRENGTHENED RUBBER MIXTURES BASED ON HALOBUTYL RUBBER
TW200628464A (en) Insecticidal bis(substituted phenyl)-1-((4-(saturated heterocyclyl-substituted)phenylmethyl)-(4-piperidyl))methane derivatives
JP2017502063A5 (en)
GB0428416D0 (en) Organic compounds
WO2012116349A3 (en) Novel cocrystals of ezetimibe
WO2008005851A3 (en) Compositions containing silanes
JPH03383B2 (en)
CN103974959B (en) Hydrolyzable silane
Mota et al. New Diastereoselective Route to 2‐Substituted cis‐(2S, 5S)‐and trans‐(2S, 5R)‐5‐Alkylpyrrolidines as Indolizidine and Pyrrolizidine Scaffolds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09749474

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09749474

Country of ref document: EP

Kind code of ref document: A2