CN103012383B - A kind of Ezetimibe intermediate and its preparation method and application - Google Patents
A kind of Ezetimibe intermediate and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to Ezetimibe intermediate and preparation method's technical field.The present invention, based on olefin(e) compound, prepares new intermediate epoxy compounds 1 by SHI oxidizing reaction.Compound 1 is by open loop, and hydrogenation can prepare the Ezetimibe product of high chiral selection.Synthesizing epoxy compound 1 preparation method of the present invention is simple, avoids and uses costliness and the chiral catalyst of instability, economical and efficient, cost-saving, and aftertreatment is simple and easy to do, is applicable to suitability for industrialized production.Follow-up prepare Ezetimibe time, same reaction scheme is short, and working method is simple, consumes few, cost-saving, can prepare high de value product, be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to Ezetimibe intermediate and preparation method's 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 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, WO 2006137080, WO2007119106, WO 2007120824, WO 2009067960 etc.) or arone derivative (referenced patent document: WO 0034240, WO 2005049592, WO 200506120 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 EP 1953140, method disclosed in WO 2007144780, WO 2007/120824 grade); 2. with (-)-diisopinocampheylchloroborane base chloroborane (disclosed in patent documentation WO 2005049592 and WO 2005066120 method) or R-2-methyl-CBS-oxazaborolidine (patent documentation WO 2008/032338, method disclosed in WO 2009067960 grade) 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, provides a kind of new Ezetimibe intermediate and preparation method thereof, by the intermediate that this is new, can synthesize Ezetimibe simply and easily.And the preparation method of this intermediate itself compares with prior art, simple to operate, consume few, be suitable for suitability for industrialized production.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The compound 1 of following formula:
R
1for hydrogen atom or arylmethyl is monosubstituted or the silylation of polysubstituted arylmethyl or replacement or tetrahydrochysene-2H-pyranyl, preferred benzyl.Wherein, the preferred benzyl of arylmethyl, trityl; Substituting group described in monosubstituted or polysubstituted arylmethyl is halogen, nitro, alkyl substituent containing C1-C6, the alkoxy substituent containing C1-C6, the aryl substituent containing C6-C10, preferred chlorine atom, fluorine atom, nitro, methoxyl group, phenyl; The substituting group described in silylation replaced is containing the alkyl substituent of C1-C6, the aryl substituent containing c6-c10.
The preparation method of above-mentioned 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), OXONE: compound 2 mol ratios=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, 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 times of molar weight, preferably 0.3 times of molar weight:
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 times of molar weight, most preferably 0.4 times of molar weight.
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.
The application of formula 1 compound when preparing Ezetimibe.
Following compound 4 is the back intermediates preparing Ezetimibe in prior art.The method utilizing formula 1 compound to prepare compound 4 is: in solvent, compound 1 is added hydroboration an alkali metal salt and hexichol connection selenium reaction system, then add alkali and oxidant reaction can target product compound 4:
The preparation method of above-claimed cpd 4, preferred technical scheme is, starting compound 1 adds in latter 24 hours and adds alkali and oxygenant again, reacts completely.
In the preparation method of above-claimed cpd 4, the preferred C of described solvent
1-C
4alcoholic solvent.
In the preparation method of above-claimed cpd 4, 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.
In the preparation method of above-claimed cpd 4, 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.
In the preparation method of above-claimed cpd 4, oxygenant is preferably sodium periodate or hydrogen peroxide.
In the preparation method of above-claimed cpd 4, after adding alkali and oxygenant, temperature of reaction is preferably 0 DEG C-78 DEG C, more preferably at 20-60 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.
Synthesizing epoxy compound 1 method of the present invention is simple to operate, 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.Follow-up prepare Ezetimibe time, same reaction scheme is short, and working method is simple, consumes few, cost-saving, can prepare high de value product, be applicable to suitability for industrialized production.The synthesis of new intermediate 1 of the present invention, provide one and prepare Ezetimibe method with prior art is diverse, selectivity is high.
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); Finnign-MAT212 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, rises to room temperature naturally, 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, stirring is spent the night, ethyl acetate: sherwood oil=1:3 column chromatography, obtain 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 (32)
1. the compound 1 of following formula:
R
1for silylation or the tetrahydrochysene-2H-pyranyl of hydrogen, arylmethyl, monosubstituted or polysubstituted arylmethyl, replacement.
2. compound 1 as claimed in claim 1, is characterized in that: said arylmethyl is benzyl or trityl.
3. compound 1 as claimed in claim 1 or 2, is characterized in that: R
1by arylmethyl that halogen, nitro, the alkyl containing C1-C6 or the alkoxyl group containing C1-C6 replace on aromatic ring.
4. compound 1 as claimed in claim 1, is characterized in that: R
1for the silylation that the alkyl of C1-C6 or the aryl of C6-C10 replace.
5. compound 1 as claimed in claim 1, is characterized in that: R
1for tert-butyldimethylsilane base.
6. compound 1 as claimed in claim 1, is characterized in that: R
1for tetrahydrochysene-2H-pyranyl.
7. the preparation method of compound 1 as claimed in claim 1, the method is: in a solvent, and compound 2 reacts and generates target compound 1 under the effect of oxygenant:
R
1for silylation or the tetrahydrochysene-2H-pyranyl of hydrogen, arylmethyl, monosubstituted or polysubstituted arylmethyl, replacement.
8. the preparation method of compound 1 as claimed in claim 7, is characterized in that: oxygenant is selected from metachloroperbenzoic acid, Peracetic Acid, tertbutanol peroxide, hydrogen peroxide and ammonium persulfate-sodium bisulfate.
9. the preparation method of compound 1 as claimed in claim 8, is characterized in that: oxygenant is metachloroperbenzoic acid.
10. the preparation method of compound 1 as claimed in claim 8, 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.
The preparation method of 11. compounds 1 as claimed in claim 1, the method is: compound 1 adopts SHI oxidation technology oxygenated compound 2 to obtain:
R
1for silylation or the tetrahydrochysene-2H-pyranyl of hydrogen, arylmethyl, monosubstituted or polysubstituted arylmethyl, replacement.
The preparation method of 12. compounds 1 as claimed in claim 11, is characterized in that: SHI oxidation technology operation steps is dissolved in solvent by compound 2, adds phase-transfer catalyst and chiral catalyst, adds oxygenant and alkali simultaneously, reacts to obtain target product.
The preparation method of 13. compounds 1 as claimed in claim 12, is characterized in that: the chiral catalyst used is for shown in following general formula 7,8 or 9
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 14. compounds 1 as claimed in claim 13, 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 15. compounds 1 as claimed in claim 13, is characterized in that: chiral catalyst consumption is the 0.1-2 molar weight doubly of compound 1.
The preparation method of 16. compounds 1 as claimed in claim 11, is characterized in that: oxygenant is ammonium persulfate-sodium bisulfate.
The preparation method of 17. compounds 1 as claimed in claim 16, 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 18. compounds 1 as claimed in claim 11, is characterized in that: reaction system pH=7-14.
The preparation method of 19. compounds 1 as claimed in claim 11, is characterized in that: phase-transfer catalyst is the quaternary ammonium salt that crown ether or tetraalkyl replace.
The preparation method of 20. compounds 1 as claimed in claim 19, is characterized in that: phase-transfer catalyst is 4-butyl ammonium hydrogen sulfate.
The preparation method of 21. compounds 1 as claimed in claim 11, is characterized in that: the temperature of reaction preparing compound 1 is-20 ~ 20 DEG C.
The application of compound 1 when preparing Ezetimibe that 22. claim 1-6 are described arbitrarily.
23. application of compound 1 as claimed in claim 22 when preparing Ezetimibe, it is characterized in that the midbody compound 4 preparing Ezetimibe in the following manner: in solvent, compound 1 is added hydroboration an alkali metal salt and hexichol connection selenium reaction system, then add alkali and oxidant reaction
24. application of compound 1 as claimed in claim 23 when preparing Ezetimibe, is characterized in that: starting compound 1 adds in latter 24 hours and adds alkali and oxygenant again, react to obtain target compound 4.
25. application of compound 1 as claimed in claim 23 when preparing Ezetimibe, is characterized in that: hydroboration an alkali metal salt is sodium borohydride, and the mol ratio that sodium borohydride and hexichol join selenium is 0.5-1:1.
26. application of compound 1 as claimed in claim 25 when preparing Ezetimibe, is characterized in that: the mol ratio that sodium borohydride and hexichol join selenium is 0.55:1.
27. application of compound 1 as claimed in claim 23 when preparing Ezetimibe, is characterized in that: the alkali reacting used is sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide or the alkaloid containing C1-C10.
28. application of compound 1 as claimed in claim 27 when preparing Ezetimibe, is characterized in that: the alkaloid of said C1-C10 refers to pyridine, pyrroles, triethylamine, diethylamine, dipropyl amine or diisopropylethylamine.
29. application of compound 1 as claimed in claim 27 when preparing Ezetimibe, is characterized in that: the alkali reacting used is sodium bicarbonate or pyridine.
The preparation method of 30. compounds 1 as claimed in claim 12, is characterized in that: oxygenant is sodium periodate or hydrogen peroxide.
The preparation method of 31. compounds 1 as claimed in claim 12, is characterized in that: adding temperature of reaction after alkali and oxygenant is 0 DEG C-78 DEG C.
The preparation method of 32. compounds 1 as claimed in claim 12, is characterized in that: adding temperature of reaction after alkali and oxygenant is 20 DEG C-60 DEG C.
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Citations (2)
| 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 |
| CN102112430A (en) * | 2008-07-30 | 2011-06-29 | 力奇制药公司 | Process for synthesis of ezetimibe and intermediates useful therefor |
-
2012
- 2012-12-17 CN CN201210548394.5A patent/CN103012383B/en active Active
Patent Citations (2)
| 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 |
| CN102112430A (en) * | 2008-07-30 | 2011-06-29 | 力奇制药公司 | Process for synthesis of ezetimibe and intermediates useful therefor |
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