CN102993077A - Preparation method for Ezetimibe - Google Patents
Preparation method for Ezetimibe Download PDFInfo
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- CN102993077A CN102993077A CN2012105499430A CN201210549943A CN102993077A CN 102993077 A CN102993077 A CN 102993077A CN 2012105499430 A CN2012105499430 A CN 2012105499430A CN 201210549943 A CN201210549943 A CN 201210549943A CN 102993077 A CN102993077 A CN 102993077A
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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 the elderly's common disease and frequently-occurring disease.First places of M ﹠ M in many countries.Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases, and a large amount of experiments and clinical data prove the unusually closely related of atherosclerosis and blood lipid metabolism.Therefore, lipid lowering agent becomes the key areas of current new drug research.
By perspective, immediately with the contrast clinical study, verified statinses can reduce the generation of atherosclerosis and coronary heart disease, reduced the mortality ratio due to the coronary heart disease, reduced the incidence of myocardial infarction, and proved that further the treatment of being down to medicine can reduce the content of atherosclerotic plaque inner lipid.Reinforced fibers fat and stabilize plaque reduce plaque rupture and the myocardial infarction that causes and cerebral infarction etc. matters of aggravation.In addition, lipid regulating agent also can recover the function of damaged blood vessels endotheliocyte, strengthens fibrinolytic and prevents thrombosis, and delay people's atherosclerotic progress and the established patch that disappears.Therefore, actively using the lipid lowering agent treatment is the important measures that alleviate atherosclerosis and reduce the generation of coronary heart disease.
At present the types of drugs of adjusting blood fat clinical and commonly used is more, HMG-CoA reductase inhibitor class for example, fibrate, ion exchange resin or cholic acid chelating agent, nicotinic acid class and other accent blood-lipoids medicines.Wherein Ezetimibe (structural formula is as follows) shows good effect as the novel serum regulating drug of selectivity inhibition cholesterol absorption.
The method of synthetic Ezetimibe has a lot, but difficult point is the structure of chirality S-hydroxyl in the molecule.Present most popular method is exactly to make up first the chiral intermediate arone of diving (to refer to Patent Document: CN1131416, WO2006137080, WO2007119106, WO2007120824, WO2009067960 etc.) or the arone derivative (refer to Patent Document: WO0034240, WO2005049592, WO200506120 etc.), make up the s-hydroxyl by the asymmetric hydrogenation reduction.
The method of existing asymmetric hydrogenation and deficiency: 1. with the homogeneous catalyst that contains transition metal Ru etc., reclaim difficulty, cause cost to increase, and can cause heavy metal contamination (such as patent documentation EP1953140, WO2007144780, the disclosed method such as WO2007/120824); 2. with (-)-diisopinocampheylchloroborane base chloroborane (the disclosed method of patent documentation WO2005049592 and WO2005066120) 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 it is unstable to exist catalyzer, expensive, severe reaction conditions, the loaded down with trivial details deficiency that waits of operation.
The SHI oxidation is the new technology of in recent years asymmetric Epoxidation field appearance, and take the fructose derivative as chiral catalyst, economical and efficient is oxidized to optionally epoxide of high chirality with olefin(e) compound.In addition, the fructose wide material sources, low price, catalyzer is synthetic convenient, thereby causes more and more people's concern.
Summary of the invention
Purpose of the present invention is exactly the problems referred to above that solve prior art, and a kind of new Ezetimibe preparation method is provided, and compares with prior art, and 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 the solvent, compound 1 is added hydroboration an alkali metal salt and hexichol connection selenium reaction system, adds again alkali and oxidant reaction and get final product to get target product compound 4:
R
1Be silylation or the tetrahydrochysene-2H-pyranyl of hydrogen atom, arylmethyl, single replacement or polysubstituted arylmethyl, replacement, preferred benzyl.Wherein, the preferred benzyl of arylmethyl or trityl; Single replace or polysubstituted arylmethyl described in substituting group be halogen, nitro, contain C1-C6 alkyl substituent, contain the alkoxy substituent of C1-C6 or contain the aryl substituent of C6-C10, preferred chlorine atom, fluorine atom, nitro, methoxyl group or phenyl; Substituting group described in the silylation that replaces is the alkyl substituent that contains C1-C6, the aryl substituent that contains c6-c10.
2) compound 4 hydro-reductions are got Ezetimibe:
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in the step 1), preferred technical scheme are that starting compound 1 adds in rear 24 hours and adds alkali and oxygenant again, reacts completely.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in the 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 the step 1), the preferred sodium borohydride of hydroboration an alkali metal salt, and the mol ratio of sodium borohydride and hexichol connection selenium is 0.5-1:1, preferred 0.55:1.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in the step 1), the alkali that reacts used is an alkali metal salts such as sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide or the alkaloid that contains C1-C10, such 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 the step 1), oxygenant is preferably sodium periodate or hydrogen peroxide.
The preparation method of above-mentioned Ezetimibe, the preparation method of compound 4 in the step 1), temperature of reaction is preferably 0 ℃-78 ℃ after adding alkali and the oxygenant, more preferably at 20-60 ℃.
The preparation method of above-mentioned Ezetimibe, step 2) hydro-reduction all can with existing various mature technology methods.
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 solvent, compound 2 reacts under the effect of oxygenant and generates target compound 1:
The preparation method of above-mentioned formula 1 compound, described oxygenant can be selected the superoxide such as metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide, hydrogen peroxide, potassium hydrogen persulfate composite salt (trade(brand)name OXONE), preferred metachloroperbenzoic acid.When oxygenant is selected potassium hydrogen persulfate composite salt (trade(brand)name OXONE), mol ratio OXONE: the preferred 2 times of molar weights of compound 2=1-5:1.When oxygenant was selected metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide or hydrogen peroxide, consumption was 1-3 times of molar weight of compound 2, preferred 1.3 times of molar weights.
The preparation method of formula 1 compound, solvent gets final product for promoting to react the suitable solvent carry out, such as halohydrocarbon, the aliphatic hydrocarbon of C1-C10, the buffered soln of the hydro carbons of the itrile group of C1-C10 replacement, ethers, water, water or mixed solvent etc. arbitrarily.The mixed solvent of buffered soln, acetonitrile, dipropylene glycol dme, dipropylene glycol dme and the acetonitrile of preferred methylene dichloride, water.When selecting the mixed solvent of dipropylene glycol dme and acetonitrile, the mol ratio of dipropylene glycol dme 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 compounds to obtain target compound 1.Its concrete steps comprise: formula 1 compound dissolution in solvent, is added phase-transfer catalyst and chiral catalyst, add simultaneously oxygenant and alkali, reacting completely gets final product.
When adopting the method for SHI oxidation technology preparation formula 1 compound, employed chiral catalyst is that consumption is formula 1 compound 0.1-2 molar weight doubly, preferred 0.3 times molar weight shown in the following general formula 7,8,9:
R
2, R
3, R
4, R
5Be the alkyl of C1-C6, preferable methyl; R
6Be alkyl or substituted alkyl, acyl group or substituted acyl group, alkoxyl group or the substituted alkoxyl group that contains C1-C10, preferred tertiary butoxy carbonyl; R
7, R
8Be acyl group or the substituted acyl group of C1-C6, preferred ethanoyl.
When adopting the method for SHI oxidation technology preparation formula 1 compound, oxygenant preferably uses potassium hydrogen persulfate composite salt (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, hydro carbons, ethers or the mixed solvent that the C1-C10 itrile group replaces, and preferred (the 0.05M Sodium Tetraborate is dissolved in 10
-4M Na2 (EDTA) aqueous solution) mixing solutions of sodium borate buffer solution and acetonitrile-dipropylene glycol dme (1:2).
When adopting the method for SHI oxidation technology preparation formula 1 compound, to add alkaline solution in the solvent and buffered soln is kept reaction system pH=7-14, more preferably pH=10-12.Alkali is selected from an alkali metal salts such as carbonate, bicarbonate radical, preferred salt of wormwood.The aqueous solution that is 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, most preferably 0.4 times molar weight.
When adopting the method for SHI oxidation technology preparation formula 1 compound, temperature of reaction is at-30-50 ℃, and preferred-20-20 ℃, most preferably 0 ℃.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be not as having special instruction, all commercially available getting.
Beneficial effect of the present invention:
The present invention prepares new intermediate epoxy compounds 1 take olefin(e) compound as the basis by the SHI oxidizing reaction, and compound 1 is by open loop, and the Ezetimibe product that high chirality is selected is prepared in hydrogenation.The SHI oxidation is the new technology of in recent years asymmetric Epoxidation field appearance, is chiral catalyst with fructose derivative (for example disclosed compound 7,8,9 among the present invention), and economical and efficient is oxidized to optionally epoxide of high chirality with olefin(e) compound; Simultaneously, the fructose wide material sources, low price, catalyzer is synthetic convenient, has avoided using expensive and unsettled chiral catalyst, substitutes with fructose derivative cheap and easy to get, and economical and efficient save cost, and aftertreatment is simple and easy to do, is applicable to suitability for industrialized production.
The invention provides a kind of and the diverse preparation Ezetimibe of prior art method, selectivity is high, after utilizing epoxy compounds 1 to make compound 4 as intermediate, when follow-up preparation Ezetimibe, same reaction scheme is short, and working method is simple, consume few, save cost, can prepare high de value product, be applicable to suitability for industrialized production.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected 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
1Be tetrahydrochysene-2H-pyranyl)
Add 5g compound 2 in the 100mL three-necked bottle, methylene dichloride 50mL adds metachloroperbenzoic acid 2.74g under the magnetic agitation ice-water bath, TLC judges that reaction finishes, adding the 1mol/L wet chemical washes twice, drying is filtered evaporate to dryness, ethyl alcohol recrystallization, obtain compound c 1.41g, yield 27.3%, de value 95%.
Embodiment 2: the preparation (R of compound 1
1Be the tert-butyldimethylsilane base)
Add 5g(10.4mmol in the 100mL three-necked bottle) compound 2, methylene dichloride 50mL adds metachloroperbenzoic acid 2.74g under the magnetic agitation ice-water bath, TLC judges that reaction finishes, adding the 1mol/L wet chemical washes twice, drying is filtered evaporate to dryness, ethyl alcohol recrystallization, obtain compound c 1.55g, yield 30%, de value 95.5%.
Substituent R among the embodiment 3-9
1All adopt benzyl.
Embodiment 3: the preparation of compound 1
Add 5g(10.4mmol in the 100mL three-necked bottle) compound 2, methylene dichloride 50mL adds metachloroperbenzoic acid 2.74g under the magnetic agitation ice-water bath, TLC judges that reaction finishes, adding the 1mol/L wet chemical washes twice, drying is filtered evaporate to dryness, ethyl alcohol recrystallization, obtain compound c 1.45g, 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
Add 1.5g(10.4mmol in the 100mL three-necked bottle) compound 2, the 50mL of acetonitrile-DMM(1:2), (the 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
5Be methyl) 225mg, under 20 ℃ of the magnetic agitation, 1.5 synchronized OXONE and each 19ml of salt of wormwood respective concentration solution of splashing into of while dropwises in hour, TLC judges that reaction finishes, ethyl acetate extraction, 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
Add 1.5g(10.4mmol in the 100mL three-necked bottle) compound 2, acetonitrile DMM(1:2) 50mL, (the 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
3Be methyl, R
6Be tertbutyloxycarbonyl) 225mg, under 0 ℃ of the magnetic agitation, 1.5 synchronized OXONE and each 19ml of salt of wormwood respective concentration solution of splashing into of while dropwises in hour, TLC judges that reaction finishes, ethyl acetate extraction, anhydrous sodium sulfate drying, ethyl alcohol recrystallization obtains compound 836mg, yield 55.8%, de value 95.3%.
Embodiment 6: the preparation of compound 1
Add 1.5g(10.4mmol in the 100mL three-necked bottle) compound 2, the 50mL of acetonitrile-DMM(1:2), (the 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
5Be methyl, R
7, R
8Be ethanoyl) 225mg; under the magnetic agitation-20 ℃; 1.5 synchronized OXONE and each 19ml of salt of wormwood respective concentration solution of splashing into of while dropwises in hour, TLC judges that reaction finishes; ethyl acetate extraction; 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 the 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 entry 5ml, be cooled to 0 ℃, add sodium bicarbonate 438mg, sodium periodate 964mg rises to 20 ℃, 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 the 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 ℃, stirred 4 hours, ethyl acetate: sherwood oil=1:3 column chromatography obtains compound a 143mg, yield 35.8%.
Embodiment 9: the preparation of Ezetimibe
In the 250ml hydriding reactor, ethanol 15ml, compound 4150mg, (moisture 68.3%) 10% wet palladium carbon 60mg, hydrogen pressure 7atm reacted 4 hours, filters, 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 (28)
1. the preparation method of Ezetimibe comprises the steps:
1) in the solvent, compound 1 is added hydroboration an alkali metal salt and hexichol connection selenium reaction system, adds again alkali and oxidant reaction and get final product to get target product compound 4:
R
1Silylation or tetrahydrochysene-2H-pyranyl for hydrogen atom, arylmethyl, single replacement or polysubstituted arylmethyl, replacement;
2) compound 4 hydro-reductions are got Ezetimibe:
2. the preparation method of Ezetimibe as claimed in claim 1, it is characterized in that: said arylmethyl is benzyl or trityl.
3. the preparation method of Ezetimibe as claimed in claim 1 or 2 is characterized in that: R
1For on the aromatic ring by halogen, nitro, contain the alkyl of C1-C6 or contain the arylmethyl that the C1-C6 alkoxyl group replaces.
4. the preparation method of Ezetimibe as claimed in claim 1 is characterized in that: R
1The silylation that replaces for the aryl of the alkyl of C1-C6 or C6-C10.
5. the preparation method of Ezetimibe as claimed in claim 1 is characterized in that: R
1Be the tert-butyldimethylsilane base.
6. the preparation method of Ezetimibe as claimed in claim 1 is characterized in that: step 1) Raw compound 1 adds in rear 24 hours and adds alkali and oxygenant again.
7. the preparation method of Ezetimibe as claimed in claim 1, it is characterized in that: the hydroboration an alkali metal salt is sodium borohydride in the step 1), and the mol ratio of sodium borohydride and hexichol connection selenium is 0.5-1:1.
8. the preparation method of Ezetimibe as claimed in claim 7 is characterized in that: the mol ratio of sodium borohydride and hexichol connection selenium is 0.55:1.
9. the preparation method of Ezetimibe as claimed in claim 1 is characterized in that: the used alkali of step 1) reaction is sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide or the alkaloid that contains C1-C10.
10. the preparation method of Ezetimibe as claimed in claim 9, it is characterized in that: the alkaloid of said C1-C10 refers to pyridine, pyrroles, triethylamine, diethylamine, dipropyl amine or diisopropylethylamine.
11. the preparation method of Ezetimibe as claimed in claim 9 is characterized in that: the used alkali of step 1) reaction is sodium bicarbonate or pyridine.
12. the preparation method of Ezetimibe as claimed in claim 1 is characterized in that: the oxygenant of step 1) is sodium periodate or hydrogen peroxide.
13. the preparation method of Ezetimibe as claimed in claim 1 is characterized in that: temperature of reaction is 0 ℃-78 ℃ after step 1) adding alkali and the oxygenant.
14. the preparation method of Ezetimibe as claimed in claim 13 is characterized in that: temperature of reaction is 20 ℃-60 ℃ after step 1) adding alkali and the oxygenant.
15. the preparation method such as any described Ezetimibe of claim 1-14 is characterized in that: compound 1 adopts following method preparation: in solvent, compound 2 reacts under the effect of oxygenant and generates target compound 1
16. the preparation method of Ezetimibe as claimed in claim 15 is characterized in that: oxygenant is selected from metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide, hydrogen peroxide and potassium hydrogen persulfate composite salt.
17. the preparation method of Ezetimibe as claimed in claim 16 is characterized in that: oxygenant is metachloroperbenzoic acid.
18. the preparation method of Ezetimibe as claimed in claim 16 is characterized in that: when oxygenant is selected the potassium hydrogen persulfate composite salt, potassium hydrogen persulfate composite salt: compound 2 mol ratios=1-5:1; When oxygenant was selected metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide or hydrogen peroxide, consumption was 1-3 times of molar weight of compound 2.
19. the preparation method such as any described Ezetimibe of claim 1-14 is characterized in that: compound 1 adopts SHI oxidation technology oxidation-type 2 compounds to obtain.
20. the preparation method of Ezetimibe as claimed in claim 19 is characterized in that: concrete operation step be with formula 1 compound dissolution in solvent, add phase-transfer catalyst and chiral catalyst, add simultaneously oxygenant and alkali, react completely.
21. the preparation method of Ezetimibe as claimed in claim 20 is characterized in that: employed chiral catalyst is shown in the 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
5Alkyl for C1-C6; R
6Be alkyl or substituted alkyl, acyl group or substituted acyl group, alkoxyl group or the substituted alkoxyl group that contains C1-C10; R
7, R
8Acyl group or substituted acyl group for C1-C6.
22. the preparation method of Ezetimibe as claimed in claim 21 is characterized in that: R
2, R
3, R
4, R
5Be methyl, R
6Be tertbutyloxycarbonyl, R
7, R
8Be ethanoyl.
23. the preparation method of Ezetimibe as claimed in claim 20 is characterized in that: oxygenant is the potassium hydrogen persulfate composite salt.
24. the preparation method of Ezetimibe as claimed in claim 23 is characterized in that: oxygenant is 10 of 0.05-0.4g/ml
-4MNa2 (EDTA) the potassium hydrogen persulfate composite salt aqueous solution.
25. the preparation method of Ezetimibe as claimed in claim 20 is characterized in that: reaction system pH=7-14.
26. the preparation method of Ezetimibe as claimed in claim 20 is characterized in that: phase-transfer catalyst is the quaternary ammonium salt that crown ether or tetraalkyl replace.
27. the preparation method of Ezetimibe as claimed in claim 26 is characterized in that: phase-transfer catalyst is 4-butyl ammonium hydrogen sulfate.
28. the preparation method of Ezetimibe as claimed in claim 20 is characterized in that: the temperature of reaction of preparation formula 1 compound is-20-20 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022262768A1 (en) * | 2021-06-17 | 2022-12-22 | 浙江海正药业股份有限公司 | 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 |
|---|
| GUANGZHONG WU ET AL: "A Novel One-Step Diastereo- and Enantioselective Formation of trans-Azetidinones and Its Application to the Total Synthesis of Cholesterol Absorption Inhibitors", 《JOURNAL OF ORGANIC CHEMISTRY》, vol. 64, no. 10, 21 April 1999 (1999-04-21), pages 3714 - 3718 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022262768A1 (en) * | 2021-06-17 | 2022-12-22 | 浙江海正药业股份有限公司 | Hybutimibe intermediate and preparation method therefor |
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