CN102993077B - Preparation method for Ezetimibe - Google Patents
Preparation method for Ezetimibe Download PDFInfo
- Publication number
- CN102993077B CN102993077B CN201210549943.0A CN201210549943A CN102993077B CN 102993077 B CN102993077 B CN 102993077B CN 201210549943 A CN201210549943 A CN 201210549943A CN 102993077 B CN102993077 B CN 102993077B
- Authority
- CN
- China
- Prior art keywords
- preparation
- compound
- ezetimibe
- ezetimibes
- oxygenant
- 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.)
- Active
Links
- 0 CC(*)(O)O[C@](C(COC1OC(*)(*)OC)I)C1=O Chemical compound CC(*)(O)O[C@](C(COC1OC(*)(*)OC)I)C1=O 0.000 description 3
Abstract
The invention relates to the technical field of preparation methods for Ezetimibe. The preparation method for Ezetimibe disclosed by the invention comprises the following steps of: preparing via SHI oxidation reaction on the basis of an olefin compound to obtain a new intermediate, namely, an epoxy compound 1, and performing loop opening and hydrogenation on the compound 1 to prepare a high-chiral-selectivity Ezetimibe product. Via the preparation method, an expensive and unstable chiral catalyst is avoided, and replaced by a cheap and easily-gotten fructose derivative, so that the preparation method is economic, efficient, cost-saving, simple and practical in aftertreatment, and suitable for industrialized production.
Description
Technical field
The present invention relates to Ezetimibe preparation method technical field.
Background technology
Cardiovascular and cerebrovascular diseases is the most serious illness of current harm humans life and health, is common disease and the frequently-occurring disease of the elderly.In the first place that many countries are M & Ms.Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases, and a large amount of experiments and clinical data prove that atherosclerosis is closely related with the exception of blood lipid metabolism.Therefore, lipid lowering agent becomes the key areas of current new drug research.
By perspective, immediately with contrast clinical study, verified statinses can reduce the generation of atherosclerosis and coronary heart disease, reduce the mortality ratio caused by coronary heart disease, reduce the incidence of myocardial infarction, and the treatment proving to be down to medicine further can reduce the content of atherosclerotic plaque inner lipid.Reinforced fibers fat and stabilize plaque, reduce plaque rupture and myocardial infarction and cerebral infarction etc. the matters of aggravation that causes.In addition, lipid regulating agent also can recover the function of damaged blood vessels endotheliocyte, strengthens fibrinolytic and prevents thrombosis, and delaying the atherosclerotic progress of people and the established patch that disappears.Therefore, actively the treatment of use lipid lowering agent is the important measures of the generation alleviating atherosclerosis and reduce coronary heart disease.
The types of drugs of adjusting blood lipid clinical and conventional is at present more, such as HMG-CoA reductase inhibitor class, fibrate, ion exchange resin or cholic acid chelating agent, nicotinic acid class and other Adjust-blood lipid class medicines.Wherein Ezetimibe (structural formula is as follows) is as the novel serum regulating drug of Selective depression cholesterol absorption, shows good effect.
The method of synthesis Ezetimibe has a lot, but difficult point is the structure of chirality S-hydroxyl in molecule.Current most popular method is exactly first build latent chiral intermediate arone (referenced patent document: CN1131416, WO2006137080, WO2007119106, WO2007120824, WO2009067960 etc.) or arone derivative (referenced patent document: WO0034240, WO2005049592, WO200506120 etc.), build s-hydroxyl by asymmetric hydrogenation reduction.
The method of existing asymmetric hydrogenation and deficiency: 1. with the homogeneous catalyst containing transition metal Ru etc., reclaim difficulty, cause cost to increase, and heavy metal contamination can be caused (as patent documentation EP1953140, the disclosed method such as WO2007144780, WO2007/120824); 2. with (-)-diisopinocampheylchloroborane base chloroborane (disclosed in patent documentation WO2005049592 and WO2005066120 method) or R-2-methyl-CBS-oxazaborolidine (patent documentation WO2008/032338, the disclosed method such as WO2009067960) be chiral catalyst, although the de value of reduction is ideal, but there is catalyzer instability, expensive, severe reaction conditions, operation is loaded down with trivial details waits deficiency.
SHI oxidation is the new technology of asymmetric Epoxidation field appearance in recent years, and take fructose derivatives as chiral catalyst, olefin(e) compound is oxidized to high chiral optionally epoxide by economical and efficient.In addition, sources of fructose is extensive, low price, and catalyzer synthesis is convenient, thus causes the concern of more and more people.
Summary of the invention
Object of the present invention is exactly the problems referred to above solving prior art, and provide a kind of new Ezetimibe preparation method, compare with prior art, the inventive method is simple and convenient, and selectivity is high, and toxicity is low, is suitable for suitability for industrialized production.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The preparation method of Ezetimibe, comprises the steps:
1), in solvent, compound 1 is added hydroboration an alkali metal salt and hexichol connection selenium reaction system, then add alkali and oxidant reaction target product compound 4:
R
1for silylation or the tetrahydrochysene-2H-pyranyl of hydrogen atom, arylmethyl, monosubstituted or polysubstituted arylmethyl, replacement, preferred benzyl.Wherein, the preferred benzyl of arylmethyl or trityl; Substituting group described in monosubstituted or polysubstituted arylmethyl is halogen, nitro, the alkyl substituent containing C1-C6, the alkoxy substituent containing C1-C6 or the aryl substituent containing C6-C10, preferred chlorine atom, fluorine atom, nitro, methoxyl group or phenyl; The substituting group described in silylation replaced is containing the alkyl substituent of C1-C6, the aryl substituent containing c6-c10.
2) compound 4 hydro-reduction is obtained Ezetimibe:
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in step 1), preferred technical scheme is, starting compound 1 adds in latter 24 hours and adds alkali and oxygenant again, reacts completely.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in step 1), the preferred C of described solvent
1-C
4alcoholic solvent.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in step 1), the preferred sodium borohydride of hydroboration an alkali metal salt, and the mol ratio that sodium borohydride and hexichol join selenium is 0.5-1:1, preferred 0.55:1.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in step 1), the alkali reacting used is an alkali metal salts such as sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide or the alkaloid containing C1-C10, as pyridine, pyrroles, triethylamine, diethylamine, dipropyl amine or diisopropylethylamine etc.; Be preferably sodium bicarbonate or pyridine.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in step 1), oxygenant is preferably sodium periodate or hydrogen peroxide.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in step 1), after adding alkali and oxygenant, temperature of reaction is preferably 0 DEG C-78 DEG C, more preferably at 20-60 DEG C.
The preparation method of above-mentioned Ezetimibe, step 2) the existing various mature technology method of hydro-reduction.
Further, the preparation method of above-mentioned Ezetimibe, following method is selected in the preparation of compound 1:
The preparation method of formula 1 compound, the method is: in a solvent, and compound 2 reacts and generates target compound 1 under the effect of oxygenant:
The preparation method of above-mentioned formula 1 compound, described oxygenant can select the superoxide such as metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide, hydrogen peroxide, ammonium persulfate-sodium bisulfate (trade(brand)name OXONE), preferred metachloroperbenzoic acid.When oxygenant selects ammonium persulfate-sodium bisulfate (trade(brand)name OXONE), mol ratio OXONE: compound 2=1-5:1 preferred 2 times of molar weights.When oxygenant selects metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide or hydrogen peroxide, consumption is 1-3 times of molar weight of compound 2, preferably 1.3 times of molar weights.
The preparation method of formula 1 compound, solvent is can promote to react the suitable solvent that carries out, as halohydrocarbon, the aliphatic hydrocarbon of C1-C10, the buffered soln of the hydro carbons that the itrile group of C1-C10 replaces, ethers, water, water or arbitrarily mixed solvent etc.The mixed solvent of the buffered soln of preferred methylene dichloride, water, acetonitrile, dimethyl ether, dimethyl ether and acetonitrile.When selecting the mixed solvent of dimethyl ether and acetonitrile, the mol ratio of dimethyl ether and acetonitrile is 0.01-10:1, preferred 1:2.
The preparation method of above-mentioned formula 1 compound, other method is: adopt SHI oxidation technology oxidation-type 2 compound to obtain target compound 1.Its concrete steps comprise: by formula 1 compound dissolution in solvent, add phase-transfer catalyst and chiral catalyst, add oxygenant and alkali simultaneously, react completely.
When adopting the method for SHI oxidation technology preparation formula 1 compound, the chiral catalyst used is for shown in following general formula 7,8,9, and consumption is formula 1 compound 0.1-2 molar weight doubly, the preferably molar weight of 0.3 times:
R
2, R
3, R
4, R
5for the alkyl of C1-C6, preferable methyl; R
6for the alkyl containing C1-C10 or the alkyl be substituted, acyl group or the acyl group be substituted, alkoxyl group or the alkoxyl group that is substituted, preferred tertiary butoxy carbonyl; R
7, R
8for acyl group or the acyl group that is substituted of C1-C6, preferred ethanoyl.
When adopting the method for SHI oxidation technology preparation formula 1 compound, oxygenant preferably uses ammonium persulfate-sodium bisulfate (trade(brand)name OXONE), and OXONE can be made into 10 of 0.05-0.4g/ml
-4m Na2 (EDTA) aqueous solution, preferred 0.15g/ml.
When adopting the method for SHI oxidation technology preparation formula 1 compound, solvent is selected from the buffered soln of water or water, C1-C10 itrile group replaces hydro carbons, ethers or mixed solvent, preferably (0.05M Sodium Tetraborate is dissolved in 10
-4m Na2 (EDTA) aqueous solution) mixing solutions of sodium borate buffer solution and acetonitrile-dimethyl ether (1:2).
When adopting the method for SHI oxidation technology preparation formula 1 compound, alkaline solution and buffered soln maintenance reaction system pH=7-14, more preferably pH=10-12 in solvent, to be added.Alkali is selected from an alkali metal salt such as carbonate, bicarbonate radical, preferred salt of wormwood.The aqueous solution being made into 0.04-04g/ml uses, preferred 0.14g/ml.
When adopting the method for SHI oxidation technology preparation formula 1 compound, phase-transfer catalyst is the quaternary ammonium salt that crown ether or tetraalkyl replace, preferred 4-butyl ammonium hydrogen sulfate.4-butyl ammonium hydrogen sulfate is preferably 0.04-2 molar weight doubly, the most preferably molar weight of 0.4 times.
When adopting the method for SHI oxidation technology preparation formula 1 compound, temperature of reaction at-30-50 DEG C, preferably-20-20 DEG C, most preferably 0 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material as being not particularly illustrated, all commercially.
Beneficial effect of the present invention:
The present invention, based on olefin(e) compound, prepares new intermediate epoxy compounds 1 by SHI oxidizing reaction, and compound 1 is by open loop, and the Ezetimibe product of high chiral selection is prepared in hydrogenation.SHI oxidation is the new technology of asymmetric Epoxidation field appearance in recent years, and be chiral catalyst with fructose derivatives (such as compound 7 disclosed in the present invention, 8,9), olefin(e) compound is oxidized to high chiral optionally epoxide by economical and efficient; Meanwhile, sources of fructose is extensive, low price, and catalyzer synthesis is convenient, avoids and uses costliness and the chiral catalyst of instability, substitutes, economical and efficient with fructose derivatives cheap and easy to get, cost-saving, and aftertreatment is simple and easy to do, is applicable to suitability for industrialized production.
The invention provides one and prepare Ezetimibe method with prior art is diverse, selectivity is high, after utilizing epoxy compounds 1 to obtain compound 4 as intermediate, follow-up prepare Ezetimibe time, same reaction scheme is short, and working method is simple, consume few, cost-saving, high de value product can be prepared, be applicable to suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Use instrument: Varian Inova type nuclear magnetic resonance analyser (interior mark TMS, solvent C DCl
3); FinnignMAT212 type mass spectrograph.
Embodiment 1: the preparation (R of compound 1
1for tetrahydrochysene-2H-pyranyl)
5g compound 2 is added in 100mL three-necked bottle, methylene dichloride 50mL, adds metachloroperbenzoic acid 2.74g under magnetic agitation ice-water bath, TLC judges that reaction terminates, add 1mol/L wet chemical and wash twice, drying, filters, evaporate to dryness, ethyl alcohol recrystallization, obtain compound c1.41g, yield 27.3%, de value 95%.
Embodiment 2: the preparation (R of compound 1
1for tert-butyldimethylsilane base)
5g(10.4mmol is added in 100mL three-necked bottle) compound 2, methylene dichloride 50mL, adds metachloroperbenzoic acid 2.74g under magnetic agitation ice-water bath, TLC judges that reaction terminates, add 1mol/L wet chemical and wash twice, drying, filters, evaporate to dryness, ethyl alcohol recrystallization, obtain compound c1.55g, yield 30%, de value 95.5%.
Substituent R in embodiment 3-9
1all adopt benzyl.
Embodiment 3: the preparation of compound 1
5g(10.4mmol is added in 100mL three-necked bottle) compound 2, methylene dichloride 50mL, adds metachloroperbenzoic acid 2.74g under magnetic agitation ice-water bath, TLC judges that reaction terminates, add 1mol/L wet chemical and wash twice, drying, filters, evaporate to dryness, ethyl alcohol recrystallization, obtain compound c1.45g, yield 28%, de value 95.3%.
MS（ESI）：500（M+H
+）
1H?NMR(400MHz,DMSO)δ(ppm)：1.645-1.799（m，2H）；3.126-3.157（m，1H）;3.366-3.407(m,1H);4.170-4.180(d,1H);4.804-4.809(d,1H),5.061(s,2H);6.993-7.424(m,17H)。
Embodiment 4: the preparation of compound 1
1.5g(10.4mmol is added in 100mL three-necked bottle) compound 2, acetonitrile-DMM(1:2) 50mL, (0.05M Sodium Tetraborate is dissolved in 10
-4m Na2 (EDTA) aqueous solution) sodium borate buffer solution 31ml, 4-butyl ammonium hydrogen sulfate 427mg, part 7(R
2, R
3, R
4, R
5for methyl) 225mg, at magnetic agitation 20 DEG C, synchronized instillation OXONE and salt of wormwood respective concentration solution each 19ml while of in 1.5 hours, dropwises, and TLC judges that reaction terminates, ethyl acetate is extracted, anhydrous sodium sulfate drying, ethyl alcohol recrystallization, obtains compound 829mg, yield 55.3%, de value 96.7%.
MS（ESI）：500（M+H
+）
1H?NMR(400MHz,DMSO)δ(ppm)：1.662-1.842（m，2H）；3.165-3.199（m，1H）;3.403-3.445(m,1H);4.192-4.203(d,1H);4.832-4.838(d,1H),5.087(s,2H);7.012-7.446(m,17H)。
Embodiment 5: the preparation of compound 1
1.5g(10.4mmol is added in 100mL three-necked bottle) compound 2, acetonitrile DMM(1:2) 50mL, (0.05M Sodium Tetraborate is dissolved in 10
-4m Na2 (EDTA) aqueous solution) sodium borate buffer solution 31ml, 4-butyl ammonium hydrogen sulfate 427mg, part 8(R
2, R
3for methyl, R
6for tertbutyloxycarbonyl) 225mg, at magnetic agitation 0 DEG C, synchronized instillation OXONE and salt of wormwood respective concentration solution each 19ml while of in 1.5 hours, dropwises, and TLC judges that reaction terminates, ethyl acetate is extracted, anhydrous sodium sulfate drying, ethyl alcohol recrystallization, obtains compound 836mg, yield 55.8%, de value 95.3%.
Embodiment 6: the preparation of compound 1
1.5g(10.4mmol is added in 100mL three-necked bottle) compound 2, acetonitrile-DMM(1:2) 50mL, (0.05M Sodium Tetraborate is dissolved in 10
-4m Na2 (EDTA) aqueous solution) sodium borate buffer solution 31ml, 4-butyl ammonium hydrogen sulfate 427mg, part 9(R
4, R
5for methyl, R
7, R
8for ethanoyl) 225mg; at magnetic agitation-20 DEG C; synchronized instillation OXONE and salt of wormwood respective concentration solution each 19ml while of in 1.5 hours, dropwises, and TLC judges that reaction terminates; ethyl acetate is extracted; anhydrous sodium sulfate drying, ethyl alcohol recrystallization, obtains compound 812mg; yield 54.2%, de value 96.5%.
Embodiment 7: the preparation of compound 4
In 100ml three-necked bottle, add ethanol 30ml, hexichol connection selenium 194mg, add sodium borohydride 51mg, after 15 minutes, add compound 1400mg, after 4 hours, add water 5ml, be cooled to 0 DEG C, add sodium bicarbonate 438mg, sodium periodate 964mg, rise to 20 DEG C, stirring is spent the night, ethyl acetate: sherwood oil=1:3 column chromatography, obtains compound a 152mg, yield 38%.
Embodiment 8: the preparation of compound 4
In 100ml three-necked bottle, add ethanol 30ml, hexichol connection selenium 194mg, add sodium borohydride 51mg, after 15 minutes, add compound 1400mg, after 4 hours, add pyridine 200mg, 30% hydrogen peroxide 600mg, is warming up to 60 DEG C, stir 4 hours, ethyl acetate: sherwood oil=1:3 column chromatography, obtains compound a 143mg, yield 35.8%.
Embodiment 9: the preparation of Ezetimibe
In 250ml hydriding reactor, ethanol 15ml, compound 4150mg, (moisture 68.3%) 10% wet palladium carbon 60mg, hydrogen pressure 7atm, react 4 hours, filtration, evaporate to dryness, isopropanol-water system crystallization, obtains Ezetimibe 109mg, yield 89%, de value 99.1%.
MS（ESI）：410（M+H
+）
1H?NMR(500MHz,DMSO)δ(ppm)：1.683-1.774(m,2H);1.796-1.854(m,2H);3.059-3.082(m,1H);
4.486-4.495(d,1H);4.795-4.800(d,1H);5.235-5.262(d,1H);6.744-6.761(d,2H);7.092-7.140(m,4H);7.200-7.224(m,4H);7.285-7.314(m,2H);9.499(s,1H)。
Claims (25)
1. the preparation method of Ezetimibe, comprises the steps:
1), in solvent, compound 1 is added hydroboration an alkali metal salt and hexichol connection selenium reaction system, then add alkali and oxidant reaction target product compound 4:
R
1for hydrogen atom, arylmethyl, monosubstituted or polysubstituted arylmethyl;
2) compound 4 hydro-reduction is obtained Ezetimibe:
2. the preparation method of Ezetimibe as claimed in claim 1, is characterized in that: said arylmethyl is benzyl or trityl.
3. the preparation method of Ezetimibe as claimed in claim 1, is characterized in that: R
1for on aromatic ring by halogen, nitro, containing C1 ?C6 alkyl or containing C1 ?C6 alkoxyl group replace arylmethyl.
4. the preparation method of Ezetimibe as claimed in claim 1, is characterized in that: step 1) Raw compound 1 adds in latter 24 hours and adds alkali and oxygenant again.
5. the preparation method of Ezetimibe as claimed in claim 1, is characterized in that: step 1) middle hydroboration an alkali metal salt is sodium borohydride, and the mol ratio that sodium borohydride and hexichol join selenium is 0.5-1:1.
6. the preparation method of Ezetimibe as claimed in claim 5, is characterized in that: the mol ratio that sodium borohydride and hexichol join selenium is 0.55:1.
7. the preparation method of Ezetimibe as claimed in claim 1, is characterized in that: step 1) to react used alkali be sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide or the alkaloid containing C1-C10.
8. the preparation method of Ezetimibe as claimed in claim 7, is characterized in that: the alkaloid of said C1-C10 refers to pyridine, pyrroles, triethylamine, diethylamine, dipropyl amine or diisopropylethylamine.
9. the preparation method of Ezetimibe as claimed in claim 7, is characterized in that: step 1) to react used alkali be sodium bicarbonate or pyridine.
10. the preparation method of Ezetimibe as claimed in claim 1, is characterized in that: step 1) oxygenant be sodium periodate or hydrogen peroxide.
The preparation method of 11. Ezetimibes as claimed in claim 1, is characterized in that: step 1) to add temperature of reaction after alkali and oxygenant be 0 DEG C-78 DEG C.
The preparation method of 12. Ezetimibes as claimed in claim 11, is characterized in that: step 1) to add temperature of reaction after alkali and oxygenant be 20 DEG C-60 DEG C.
13. as arbitrary in claim 1-12 as described in the preparation method of Ezetimibe, it is characterized in that: compound 1 adopts following method to prepare: in a solvent, compound 2 reacts and generates target compound 1 under the effect of oxygenant
The preparation method of 14. Ezetimibes as claimed in claim 13, is characterized in that: oxygenant is selected from metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide, hydrogen peroxide and ammonium persulfate-sodium bisulfate.
The preparation method of 15. Ezetimibes as claimed in claim 14, is characterized in that: oxygenant is metachloroperbenzoic acid.
The preparation method of 16. Ezetimibes as claimed in claim 14, is characterized in that: when ammonium persulfate-sodium bisulfate selected by oxygenant, ammonium persulfate-sodium bisulfate: compound 2 mol ratios=1-5:1; When oxygenant selects metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide or hydrogen peroxide, consumption is 1-3 times of molar weight of compound 2.
17. as arbitrary in claim 1-12 as described in the preparation method of Ezetimibe, it is characterized in that: compound 1 adopts following method to prepare: by formula 2 compound dissolution in solvent, add phase-transfer catalyst and chiral catalyst, add oxygenant and alkali simultaneously, react completely
The preparation method of 18. Ezetimibes as claimed in claim 17, is characterized in that: the chiral catalyst used is for shown in following general formula 7,8 or 9, and consumption is formula 1 compound 0.1-2 molar weight doubly
R
2, R
3, R
4, R
5for the alkyl of C1-C6; R
6for the alkyl containing C1-C10 or the alkyl be substituted, acyl group or the acyl group be substituted, alkoxyl group or the alkoxyl group that is substituted; R
7, R
8for acyl group or the acyl group that is substituted of C1-C6.
The preparation method of 19. Ezetimibes as claimed in claim 18, is characterized in that: R
2, R
3, R
4, R
5for methyl, R
6for tertbutyloxycarbonyl, R
7, R
8for ethanoyl.
The preparation method of 20. Ezetimibes as claimed in claim 17, is characterized in that: oxygenant is ammonium persulfate-sodium bisulfate.
The preparation method of 21. Ezetimibes as claimed in claim 20, is characterized in that: oxygenant is 10 of 0.05-0.4g/ml
-4mNa2 (EDTA) the ammonium persulfate-sodium bisulfate aqueous solution.
The preparation method of 22. Ezetimibes as claimed in claim 17, is characterized in that: reaction system pH=7-14.
The preparation method of 23. Ezetimibes as claimed in claim 17, is characterized in that: phase-transfer catalyst is the quaternary ammonium salt that crown ether or tetraalkyl replace.
The preparation method of 24. Ezetimibes as claimed in claim 23, is characterized in that: phase-transfer catalyst is 4-butyl ammonium hydrogen sulfate.
The preparation method of 25. Ezetimibes as claimed in claim 17, is characterized in that: the temperature of reaction of preparation formula 1 compound is-20-20 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210549943.0A CN102993077B (en) | 2012-12-17 | 2012-12-17 | Preparation method for Ezetimibe |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210549943.0A CN102993077B (en) | 2012-12-17 | 2012-12-17 | Preparation method for Ezetimibe |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102993077A CN102993077A (en) | 2013-03-27 |
| CN102993077B true CN102993077B (en) | 2014-12-31 |
Family
ID=47922256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210549943.0A Active CN102993077B (en) | 2012-12-17 | 2012-12-17 | Preparation method for Ezetimibe |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102993077B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2022291920A1 (en) * | 2021-06-17 | 2023-12-21 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Hybutimibe intermediate and preparation method therefor |
Citations (1)
| 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 |
-
2012
- 2012-12-17 CN CN201210549943.0A patent/CN102993077B/en active Active
Patent Citations (2)
| 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 |
| US6096883A (en) * | 1996-05-31 | 2000-08-01 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
Non-Patent Citations (1)
| Title |
|---|
| A Novel One-Step Diastereo- and Enantioselective Formation of trans-Azetidinones and Its Application to the Total Synthesis of Cholesterol Absorption Inhibitors;Guangzhong Wu et al;《Journal of organic chemistry》;19990421;第64卷(第10期);3714-3718 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102993077A (en) | 2013-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mock et al. | Catalysis by cucurbituril. The significance of bound-substrate destabilization for induced triazole formation | |
| JP5945603B2 (en) | Process for preparing five-membered cyclic anion salts | |
| CN101613341B (en) | Synthetic method of key intermediate of rosuvastatin calcium side chain | |
| CN102989513B (en) | Acidic ionic liquid catalyst, synthesis method thereof, and method for catalyzing microcrystalline cellulose hydrolysis | |
| WO2008056776A1 (en) | Mesoionic compound, ionic liquid composed of mesoionic compound, and method for producing mesoionic compound | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| Kotake et al. | Bimodal inclusion of nitroxide radicals by. beta.-cyclodextrin in water as detected by electron spin resonance | |
| RU2010129950A (en) | METHOD FOR OBTAINING A RADIOACTIVE, FLUORIDE-labeled ORGANIC COMPOUND | |
| CN102786534A (en) | Preparation method of everolimus | |
| Sarkar et al. | Laterally non-symmetric aza-cryptands: synthesis, catalysis and derivatization to new receptors | |
| CN102993077B (en) | Preparation method for Ezetimibe | |
| CN103012383B (en) | A kind of Ezetimibe intermediate and its preparation method and application | |
| CN101671340A (en) | Carboxyl porphyrin and preparation method thereof | |
| CN115108963A (en) | Compound and preparation method and application thereof | |
| CN108147981B (en) | Method for preparing sulfimide compound by reverse phase transfer catalysis | |
| WO2008111521A1 (en) | Method for producing iodizing agent and method for producing aromatic iodine compound | |
| Tantrakarn et al. | Synthesis of redox-active biscalix [4] quinones and their electrochemical properties | |
| Mizuhata et al. | Generation of 9-stannaphenanthrene and its reactivities | |
| CN104877046A (en) | Preparation method of 3-site substituted benzoyl-beta-cyclodextrin | |
| KR100755171B1 (en) | A new composition containing tetrakis(2-alkoxyisobutylisonitrile)copper(I)tetrafluoroborate derivatives for labelling agent of radioactive materials | |
| CN103664653B (en) | Method for preparing 2-[(N-benzyl-N-phenyl)amino]ethanol | |
| CN110256215B (en) | Preparation method of nopinone | |
| CN108285414B (en) | Halogenated material and preparation method thereof, composition for preparing halogenated material, and method for preparing corresponding product by reacting halogenated material with material to be halogenated | |
| Little et al. | Chemiluminescence from organic reactions. Formation of diphenoyl peroxide as an intermediate | |
| CN117069557A (en) | Preparation method of deuterated 3-formylindole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |