AR074752A1 - METHOD FOR PREPARING EZETIMIBA AND INTERMEDIARIES USED IN THE SAME - Google Patents
METHOD FOR PREPARING EZETIMIBA AND INTERMEDIARIES USED IN THE SAMEInfo
- Publication number
- AR074752A1 AR074752A1 ARP090104870A ARP090104870A AR074752A1 AR 074752 A1 AR074752 A1 AR 074752A1 AR P090104870 A ARP090104870 A AR P090104870A AR P090104870 A ARP090104870 A AR P090104870A AR 074752 A1 AR074752 A1 AR 074752A1
- Authority
- AR
- Argentina
- Prior art keywords
- formula
- compound
- piv
- preparing
- defined according
- Prior art date
Links
- 238000000034 method Methods 0.000 title abstract 6
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 abstract 12
- 229960000815 ezetimibe Drugs 0.000 abstract 3
- -1 borane compound Chemical class 0.000 abstract 2
- 206010003210 Arteriosclerosis Diseases 0.000 abstract 1
- 239000002841 Lewis acid Substances 0.000 abstract 1
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract 1
- 229910000085 borane Inorganic materials 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 150000002466 imines Chemical class 0.000 abstract 1
- 150000007517 lewis acids Chemical class 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 abstract 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Se revela un método para preparar ezetimiba que es efectiva para prevenir o tratar arteriosclerosis, e intermediarios usados en la misma. De acuerdo con el método que no usa reactivos costosos, los diastereoisómeros no deseados se pueden extraer con facilidad mediante un procedimiento de cristalización paso a paso, y la ezetimiba de fórmula (1) se puede preparar en alto rendimiento sin el uso de un procedimiento de hidrogenación bajo presión alta. Reivindicación 1: Un método para preparar ezetimiba de fórmula (1), caracterizado porque comprende: someter el compuesto de fórmula (2) a una reacción de copulación con la imina de fórmula (6) en presencia de un ácido Lewis y una base para preparar el compuesto de fórmula (3); realizar una reacción de ciclización del compuesto de fórmula (3) en presencia de una base para preparar el compuesto de fórmula (4); llevar a cabo una reducción asimétrica del compuesto de fórmula (4) en presencia de un compuesto borano y un catalizador quiral para preparar el compuesto de fórmula (5); y extraer el grupo protector de hidroxilo del compuesto de fórmula (5) en presencia de una base, en donde, Ph es fenilo; TMS es trimetilsililo; y Piv es trimetilacetilo. Reivindicación 13: El compuesto caracterizado porque es de fórmula (2), en donde Ph y TMS tienen los mismos significados que se definen de acuerdo con la reivindicación 1. Reivindicación 14: El compuesto caracterizado porque es de fórmula (3), en donde Ph, TMS, y Piv tienen los mismos significados que los definidos de acuerdo con la reivindicación 1. Reivindicación 15: El compuesto caracterizado porque es de fórmula (4), en donde Piv tiene el mismo significado que el definido de acuerdo con la reivindicación 1. Reivindicación 16: El compuesto caracterizado porque es de fórmula (5), en donde Piv tiene el mismo significado que el definido de acuerdo con la reivindicación. Reivindicación 17: El compuesto caracterizado porque es de fórmula (6), en donde Piv tiene el mismo significado que el definido de acuerdo con la reivindicación 1.A method for preparing ezetimibe is revealed that is effective in preventing or treating arteriosclerosis, and intermediaries used therein. According to the method that does not use expensive reagents, unwanted diastereoisomers can be easily extracted by a step-by-step crystallization process, and the ezetimibe of formula (1) can be prepared in high yield without the use of a process of hydrogenation under high pressure. Claim 1: A method for preparing ezetimibe of formula (1), characterized in that it comprises: subjecting the compound of formula (2) to a coupling reaction with the imine of formula (6) in the presence of a Lewis acid and a base for preparing the compound of formula (3); performing a cyclization reaction of the compound of formula (3) in the presence of a base to prepare the compound of formula (4); carrying out an asymmetric reduction of the compound of formula (4) in the presence of a borane compound and a chiral catalyst to prepare the compound of formula (5); and extracting the hydroxyl protecting group of the compound of formula (5) in the presence of a base, wherein, Ph is phenyl; TMS is trimethylsilyl; and Piv is trimethylacetyl. Claim 13: The compound characterized in that it is of formula (2), wherein Ph and TMS have the same meanings as defined in accordance with claim 1. Claim 14: The compound characterized in that it is of formula (3), wherein Ph , TMS, and Piv have the same meanings as those defined according to claim 1. Claim 15: The compound characterized in that it is of formula (4), wherein Piv has the same meaning as defined according to claim 1. Claim 16: The compound characterized in that it is of formula (5), wherein Piv has the same meaning as defined according to claim. Claim 17: The compound characterized in that it is of formula (6), wherein Piv has the same meaning as defined according to claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20080128457 | 2008-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AR074752A1 true AR074752A1 (en) | 2011-02-09 |
Family
ID=42269242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ARP090104870A AR074752A1 (en) | 2008-12-17 | 2009-12-15 | METHOD FOR PREPARING EZETIMIBA AND INTERMEDIARIES USED IN THE SAME |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR101156588B1 (en) |
| AR (1) | AR074752A1 (en) |
| TW (1) | TW201028374A (en) |
| WO (1) | WO2010071358A2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2012076030A1 (en) | 2010-12-10 | 2012-06-14 | Pharmathen S.A. | Process for the preparation of intermediate compounds useful in the preparation of ezetimibe |
| CN103086938A (en) * | 2011-10-28 | 2013-05-08 | 沈阳药科大学 | Ezetimibe synthesis method |
| CN103204795B (en) * | 2012-01-11 | 2016-12-14 | 重庆华邦胜凯制药有限公司 | A kind of preparation method of chirality azetidinones |
| CN103373970A (en) * | 2012-04-16 | 2013-10-30 | 重庆圣华曦药业股份有限公司 | Synthetic method for Ezetimibe intermediate |
| CN106831522B (en) * | 2015-12-03 | 2021-06-08 | 中国科学院上海有机化学研究所 | Lactam compound and preparation method thereof |
| CN106967106B (en) * | 2017-04-24 | 2018-08-10 | 上海华源医药科技发展有限公司 | A kind of production method of Ezetimibe intermediate |
| KR102078158B1 (en) | 2018-02-21 | 2020-02-17 | 강원대학교산학협력단 | Process for preparing Ezetimibe and intermediate thereof |
| US11110444B2 (en) | 2019-12-30 | 2021-09-07 | Industrial Technology Research Institute | Chiral catalyst and heterogeneous chiral catalyst comprising the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5886171A (en) * | 1996-05-31 | 1999-03-23 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
| AR025144A1 (en) * | 1998-12-07 | 2002-11-13 | Schering Corp | PROCESS TO PREPARE AZETIDINONES, PROCESS TO PREPARE INTERMEDIATE COMPOUNDS AS WELL AS SUCH INTERMEDIATE COMPOUNDS |
| US6207822B1 (en) * | 1998-12-07 | 2001-03-27 | Schering Corporation | Process for the synthesis of azetidinones |
| EP1922304A2 (en) * | 2005-09-08 | 2008-05-21 | 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 |
| HUP0501164A2 (en) * | 2005-12-20 | 2007-07-30 | Richter Gedeon Nyrt | New industrial process for the production of ezetimibe |
-
2009
- 2009-12-15 AR ARP090104870A patent/AR074752A1/en not_active Application Discontinuation
- 2009-12-16 WO PCT/KR2009/007535 patent/WO2010071358A2/en not_active Ceased
- 2009-12-16 TW TW098143111A patent/TW201028374A/en unknown
- 2009-12-16 KR KR1020090125646A patent/KR101156588B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| KR101156588B1 (en) | 2012-06-20 |
| WO2010071358A2 (en) | 2010-06-24 |
| TW201028374A (en) | 2010-08-01 |
| WO2010071358A3 (en) | 2010-09-10 |
| KR20100070305A (en) | 2010-06-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FA | Abandonment or withdrawal |