CN102531986A - Preparation method for ezetimibe - Google Patents
Preparation method for ezetimibe Download PDFInfo
- Publication number
- CN102531986A CN102531986A CN2012100420422A CN201210042042A CN102531986A CN 102531986 A CN102531986 A CN 102531986A CN 2012100420422 A CN2012100420422 A CN 2012100420422A CN 201210042042 A CN201210042042 A CN 201210042042A CN 102531986 A CN102531986 A CN 102531986A
- Authority
- CN
- China
- Prior art keywords
- methylene dichloride
- formula
- rany
- preparation
- solvent
- 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.)
- Pending
Links
- 0 *c1ccc([C@@](C(CC[C@@](c(cc2)ccc2F)O)C2=O)N2c(cc2)ccc2F)cc1 Chemical compound *c1ccc([C@@](C(CC[C@@](c(cc2)ccc2F)O)C2=O)N2c(cc2)ccc2F)cc1 0.000 description 1
- OLNTVTPDXPETLC-ATTQYFOMSA-N O[C@@H](CCC([C@@H](c(cc1)ccc1O)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound O[C@@H](CCC([C@@H](c(cc1)ccc1O)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F OLNTVTPDXPETLC-ATTQYFOMSA-N 0.000 description 1
- KEYVFYMGVLFXQK-YHCMTOLSSA-N O[C@@H](CCC([C@@H](c(cc1)ccc1OCc1ccccc1)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound O[C@@H](CCC([C@@H](c(cc1)ccc1OCc1ccccc1)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F KEYVFYMGVLFXQK-YHCMTOLSSA-N 0.000 description 1
Abstract
The invention discloses a preparation method and aims to provide a preparation method for ezetimibe (shown as a formula I), which is different from the known method.
Description
Technical field
The present invention relates to the method that the production of a kind of enantio-selectivity ground can be used as the substituted lactan of hydroxyl-alkyl (being formula one) that reduces blood cholesterol reagent.
Background technology
Zetia is the novel cholesterol absorption inhibitor of being developed jointly by U.S. Schering Plough company and Merck & Co., Inc..In November, 2002, went on the market in the U.S. same period in German Initial Public Offering.
Document reports its compound method, but the mode of the high-pressure hydrogenation that all reports all are to use the deprotection of benzyl accomplish, the present invention has avoided the mode of high-pressure hydrogenation fully, under normal pressure, accomplishes reaction.
Summary of the invention
The invention discloses the novel method of a preparation Zetia, this method reaction conditions is simple, can avoid the mode of high-pressure hydrogenation fully, under normal pressure, can accomplish reaction, and raw material cheaply is easy to get, and can obtain high-purity product simultaneously.
The invention provides a kind of preparation method of Zetia, this method comprises the following steps:
A, formula A asymmetry catalysis reduction under the chiral catalyst condition obtains formula B, and chiral catalyst is (R)-methyl-CBS-oxazolidone.
B, formula B obtain formula one through catalytic reduction reaction.The deprotection mode is: non-hydrogenating reduction mode comprises the Pd/C+ ammonium formiate; Rany Ni+ ammonium formiate; Rany Ni+ Hydrazine Hydrate 80; Reduced iron powder+hydrochloric acid.Non-hydrogenating reduction mode Pd/C+ ammonium formiate solvent is the pure and mild THF of C1-C5, methylene dichloride, and MTBE, wherein preferred methylene dichloride, MTBE more selects methylene dichloride; Reduction mode Rany Ni+ ammonium formiate solvent is the pure and mild THF of C1-C5, methylene dichloride, and MTBE, wherein preferred methylene dichloride, MTBE more selects methylene dichloride; Reduction mode Rany Ni+ Hydrazine Hydrate 80 solvent is the pure and mild THF of C1-C5, methylene dichloride, and MTBE, wherein preferred methylene dichloride, MTBE more selects methylene dichloride; Reduction mode reduced iron powder+hydrochloric acid solvent is a Hydrogen chloride, wherein preferred 1M Hydrogen chloride.
Preparing method of the present invention does not see bibliographical information, and raw material used in the present invention all can conveniently be buied through commercially available, is suitable for suitability for industrialized production.Preparing method's raw material of the present invention is easy to get, and low price is easy and simple to handle, and reaction yield is high, is suitable for suitability for industrialized production.
Embodiment
Through following examples the present invention is done further elaboration.
Embodiment 1
(10g 20mmol) is dissolved among the exsiccant THF100ml compd A, adds R-MeCBS (4ml, 1mol/l toluene solution); Ice bath is cooled to 3-5 ℃, drips borine-dimethyl sulphide (20ml, 40mmol, 2M in THF); Dripped complete insulated and stirred 4 hours, ice bath slowly drips methyl alcohol 30ml (heat release is obvious) down, drips 1N hydrochloric acid 50ml again, the ethyl acetate extraction reaction solution; Organic layer washing, the salt washing, drying, concentrate oily matter; Stir with isopropyl ether 15ml, filter, dry to such an extent that white powder 6 restrains yield 60%.
Embodiment 2
With intermediate B (7.1g, 13.8mmol), 10%Pd-C (0.4g) adds among the ethanol 70ml ammonium formiate (3.3g; 41.4mmol), in about 6 hours of 60 ℃ of reactions, it is complete that TLC detects the raw material total overall reaction; Filter, concentrate, use the isopropanol recrystallization; Filter, once get white solid 4.5g with the isopropanol recrystallization again.
Embodiment 3
With intermediate B (7.1g, 13.8mmol), 10%Pd-C (0.4g) adds among the methylene dichloride 70ml ammonium formiate (3.3g; 41.4mmol), about 6 hours of back flow reaction, it is complete that TLC detects the raw material total overall reaction; Filter, concentrate, use the isopropanol recrystallization; Filter, once get white solid 4.0g with the isopropanol recrystallization again.
Embodiment 4
The 15g intermediate B, 150ml ethanol, 1.5g Raney's nickel; 10g one Hydrazine Hydrate 80 joins in the 500ml there-necked flask, and 70 degrees centigrade were reacted 2 hours down, are cooled to room temperature; It is complete that TLC detects the raw material total overall reaction, filters, and concentrates; Use the isopropanol recrystallization, filter, once get white solid 9.1g with the isopropanol recrystallization again.
Embodiment 5
The 15g intermediate B, 150ml methylene dichloride, 1.5g Raney's nickel; 10g one Hydrazine Hydrate 80 joins in the 500ml there-necked flask, and back flow reaction 2 hours is cooled to room temperature; It is complete that TLC detects the raw material total overall reaction, filters, and concentrates; Use the isopropanol recrystallization, filter, once get white solid 9.0g with the isopropanol recrystallization again.
Claims (3)
1. the preparation method of a Zetia (formula one), structural formula is following:
Formula one
It is characterized in that this method comprises the following steps:
A, formula A asymmetry catalysis reduction under the chiral catalyst condition obtains formula B;
B, formula B obtain formula one through catalytic reduction reaction;
。
2. the preparation method of a kind of Zetia according to claim 1 (formula one) is characterized in that, the deprotection mode is in the said step (b): non-hydrogenating reduction mode comprises the Pd/C+ ammonium formiate; Rany Ni+ ammonium formiate; Rany Ni+ Hydrazine Hydrate 80; Reduced iron powder+hydrochloric acid.
3. the preparation method of a kind of Zetia according to claim 2 (formula one); It is characterized in that non-hydrogenating reduction mode Pd/C+ ammonium formiate solvent is the pure and mild THF of C1-C5 in the said step (b), methylene dichloride; MTBE; Wherein preferred methylene dichloride, ethanol more selects methylene dichloride; Reduction mode Rany Ni+ ammonium formiate solvent is the pure and mild THF of C1-C5, methylene dichloride, ethanol, wherein preferred methylene dichloride, MTBE, more preferably methylene dichloride; Reduction mode Rany Ni+ Hydrazine Hydrate 80 solvent is the pure and mild THF of C1-C5, methylene dichloride, MTBE, wherein preferred methylene dichloride, ethanol, more preferably methylene dichloride; Reduction mode reduced iron powder+hydrochloric acid solvent is a Hydrogen chloride, preferred 1M Hydrogen chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100420422A CN102531986A (en) | 2012-02-23 | 2012-02-23 | Preparation method for ezetimibe |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100420422A CN102531986A (en) | 2012-02-23 | 2012-02-23 | Preparation method for ezetimibe |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102531986A true CN102531986A (en) | 2012-07-04 |
Family
ID=46340166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100420422A Pending CN102531986A (en) | 2012-02-23 | 2012-02-23 | Preparation method for ezetimibe |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102531986A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044305A (en) * | 2013-01-24 | 2013-04-17 | 上海现代制药股份有限公司 | Preparation method of ezetimibe intermediate |
| CN104447473A (en) * | 2014-11-06 | 2015-03-25 | 成都森科制药有限公司 | Preparation method of Ezetimibe intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997016424A1 (en) * | 1995-11-02 | 1997-05-09 | Schering Corporation | Process for preparing 1-(4-fluorophenyl)-3(r)-(3(s)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(s)-(4-hydroxyphenyl)-2-azetidinone |
| EP0906278B1 (en) * | 1996-05-31 | 2002-10-16 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
| WO2006137080A1 (en) * | 2005-06-22 | 2006-12-28 | Manne Satyanarayana Reddy | Improved process for the preparation of ezetimibe |
| CN1931838A (en) * | 2006-10-20 | 2007-03-21 | 屠勇军 | Azetidinone derivative and synthetic method thereof |
| CN102234246A (en) * | 2010-04-23 | 2011-11-09 | 浙江华海药业股份有限公司 | Novel ezetimibe synthesis method |
-
2012
- 2012-02-23 CN CN2012100420422A patent/CN102531986A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997016424A1 (en) * | 1995-11-02 | 1997-05-09 | Schering Corporation | Process for preparing 1-(4-fluorophenyl)-3(r)-(3(s)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(s)-(4-hydroxyphenyl)-2-azetidinone |
| EP0906278B1 (en) * | 1996-05-31 | 2002-10-16 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
| WO2006137080A1 (en) * | 2005-06-22 | 2006-12-28 | Manne Satyanarayana Reddy | Improved process for the preparation of ezetimibe |
| CN1931838A (en) * | 2006-10-20 | 2007-03-21 | 屠勇军 | Azetidinone derivative and synthetic method thereof |
| CN102234246A (en) * | 2010-04-23 | 2011-11-09 | 浙江华海药业股份有限公司 | Novel ezetimibe synthesis method |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044305A (en) * | 2013-01-24 | 2013-04-17 | 上海现代制药股份有限公司 | Preparation method of ezetimibe intermediate |
| CN104447473A (en) * | 2014-11-06 | 2015-03-25 | 成都森科制药有限公司 | Preparation method of Ezetimibe intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102276481B (en) | Calixarene derivative and metal complex thereof, and preparation method and application of calixarene derivative and metal complex thereof | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN103193714B (en) | 5-amino-benzimidazolone synthetic method | |
| CN104356092A (en) | Preparation method for vortioxetine | |
| CN103694176B (en) | Preparation method of nilotinib intermediate | |
| Tang et al. | Synthesis of a water-soluble cationic chiral diamine ligand bearing a diguanidinium and application in asymmetric transfer hydrogenation | |
| CN104860872A (en) | Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method | |
| Wen et al. | Rhodium (III)-catalyzed coupling of aromatic ketazines or oximes with 2-vinyloxirane via C–H activation | |
| CN102531986A (en) | Preparation method for ezetimibe | |
| CN111574380B (en) | Method for preparing 5,5 '-disubstituted-2, 2' -diaminobiphenyl and hydrochloride thereof by reduction coupling method | |
| CN102976961A (en) | Method for preparing methoxamine hydrochloride | |
| CN105367470A (en) | Method for preparing vildagliptin | |
| CN110511117B (en) | Method for synthesizing 4-n-butylresorcinol by microchannel reaction | |
| Elumalai et al. | Indium powder as the reducing agent in the synthesis of 2-amino-1, 1′-biphenyls | |
| CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
| CN105523985A (en) | Preparation method of vildagliptin | |
| CN104803846B (en) | The method for preparing bis- [4- (6- acryloyl-oxy hexyl) phenyl] hexamethylene -1,4- dicarboxylic esters | |
| CN104326927B (en) | A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate | |
| CN103787968A (en) | Preparation method of compound | |
| CN104945376B (en) | A kind of synthetic method of 3 aroyl benzazolyl compounds | |
| CN101348444B (en) | Preparation of 2-ethoxy-4-acetaminobenzoic acid methyl ester | |
| CN102603622B (en) | Synthetic method of 2-amino-4-bromopyridine | |
| CN102351726B (en) | Method for synthesizing hydrochloric acid baclofen | |
| CN102206159A (en) | Preparation method and synthesizing method of alpha-phenylethylamine acetate | |
| CN107556226B (en) | Preparation method of Latricinib intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120704 |
|
| WD01 | Invention patent application deemed withdrawn after publication |