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 PDFInfo
- 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
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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.
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU0501164D0 (en) * | 2005-12-20 | 2006-02-28 | Richter Gedeon Vegyeszet | 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)
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 |
-
2008
- 2008-05-21 CZ CZ20080317A patent/CZ2008317A3/en unknown
-
2009
- 2009-05-15 WO PCT/CZ2009/000070 patent/WO2009140932A2/en active Application Filing
Patent Citations (8)
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)
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 |
---|---|
WO2009140932A2 (en) | 2009-11-26 |
CZ2008317A3 (en) | 2009-12-02 |
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 | |
ES2354728T3 (en) | PROCEDURE FOR THE PRODUCTION OF EZETIMIBA AND INTERMEDIATES USED IN THIS PROCEDURE. | |
UA103020C2 (en) | Intermediates for the preparation of (3r, 4s)-1-(4-fluorophenyl)-3-[(3s)-3- (4-fluorophenyl)-3-hydroxypropyl)]-4- (4-hydroxyphenyl)-2-azetidinone | |
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 | |
TW200745215A (en) | Low VOC epoxy silane oligomer and compositions containing same | |
WO2008032338A3 (en) | Improved process for the preparation of ezetimibe and its intermediates | |
NO20055688L (en) | Organic compounds | |
TW200641076A (en) | Coating composition containing a low VOC-producing silane | |
NZ593052A (en) | Asphalt-mineral compositions containing a cationic organosilicon compound | |
WO2009025839A3 (en) | Phosphodiesterase 10 inhibitors | |
EP2495245A3 (en) | Gram-positive carbapenem antibacterials and processes for their preparation | |
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 |
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 |