CN103044305A - Preparation method of ezetimibe intermediate - Google Patents

Preparation method of ezetimibe intermediate Download PDF

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CN103044305A
CN103044305A CN2013100277109A CN201310027710A CN103044305A CN 103044305 A CN103044305 A CN 103044305A CN 2013100277109 A CN2013100277109 A CN 2013100277109A CN 201310027710 A CN201310027710 A CN 201310027710A CN 103044305 A CN103044305 A CN 103044305A
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compound
preparation
phenyl
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ether
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于振鹏
魏宝康
王国平
刘石
侯建
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Shanghai Shyndec Pharmaceutical Co Ltd
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Shanghai Modern Pharmaceutical Co Ltd
Shanghai Shyndec Pharmaceutical Co Ltd
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Abstract

The invention relates to the technical field of a preparation method of an ezetimibe intermediate compound. The preparation method of the compound I comprises the steps of: preparing a ternary complex system by using a chiral catalyst, titanate and a p-fluorophenylmagnesium bromide solution, and then reacting the ternary complex system with a compound a in a formula shown in the specification to obtain the target compound I. The preparation method of the key ezetimibe intermediate has the advantages that operation is simple, consumption is low, cost is saved, aftertreatment is simple, convenient and practical, the product with a high de (dextrose equivalent) value can be prepared, and the preparation method is suitable for industrial production. The raw material compound a used in the method is prepared by synthesizing a compound C with the same method in the prior art, then obtaining a compound b through reduction reaction and finally carrying out oxidation reaction; and the key ezetimibe intermediate compound 1 is simply and conveniently synthesized through asymmetrical Grignard reaction in the end; the compound I is used for preparing the ezetimibe through deprotection; the whole process is environment-friendly and economical; operation is easy and practicable; and the de value can reach above 99 percent.

Description

A kind of preparation method of Ezetimibe intermediate
Technical field
The present invention relates to a kind of preparation method's technical field of Ezetimibe key intermediate compound.
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 clinical study of contrast, verified statinses can reduce the generation of atherosclerosis and coronary heart disease, have reduced the mortality ratio due to the coronary heart disease, have reduced the incidence of myocardial infarction.And prove 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 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 (CN1131416 that dives, WO2006137080WO2007119106, WO2007120824, WO2009067960 etc.) or arone derivative (WO0034240, WO2005049592, WO200506120 etc.), make up the s-hydroxyl by the asymmetric hydrogenation reduction.
Figure BDA00002770552600011
The method of existing asymmetric hydrogenation and deficiency: 1. with the homogeneous catalyst that contains transition metal Ru etc., the problem that exists is the catalyst recovery difficulty, causes cost to increase, and can cause heavy metal contamination (EP1953140, WO2007144780, WO2007/120824 etc.).2. with (-)-diisopinocampheylchloroborane base chloroborane (WO2005049592, WO2005066120) or R-2-methyl-CBS-oxazaborolidine (WO2008/032338, WO2009067960 etc.) be chiral catalyst, although the de value of reduction is ideal, but it is unstable to be accompanied by catalyzer, expensive, severe reaction conditions, the loaded down with trivial details deficiency that waits of operation.
The former CN94193466.7 of Schering Corp of company that grinds of Ezetimibe discloses a route for preparing Ezetimibe, and is as follows,
Dinaphthol/titanic acid ester system is the novel method that occurs of asymmetric grignard reaction field in recent years, with dinaphthol and titanic acid ester complex system asymmetry catalysis grignard reaction, economical and efficient generates optionally alcohol compound of high chirality, and dinaphthol can be by the alkalization washing, the method that acidifying is filtered reclaims, and is simple and easy to do.
Summary of the invention
Purpose of the present invention solves above-mentioned prior art problem with regard to being, provides a kind of and the preparation method diverse Ezetimibe important intermediate of prior art compound 1.Preparation method of the present invention is simple to operate, consumes to lack, and save cost, and aftertreatment is simple and easy to do, can prepare high de value product, is applicable to suitability for industrialized production.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The preparation method of following formula: compound 1, the method is: make together the ternary complex system with chiral catalyst, titanic acid ester with to the fluorophenyl magnesium halide, then the compound a reaction with following formula can obtain target compound 1:
Figure BDA00002770552600021
R is silylation or the tetrahydrochysene-2H-pyranyl of hydrogen atom, benzyl, 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 aryl substituent that contains the alkyl substituent of C1-C6 or contain c6-c10; X is halogen, preferred bromine.
The preparation method of above-claimed cpd 1, chiral catalyst is optional from glycols chipal compounds shown in following R-(+)-1,1 '-union-2-naphthol, the formula 2,3,4,5,6, wherein, R 1-R 12Be the alkyl substituent of hydrogen or C1-C6, preferred hydrogen atom; R 13Substituted-phenyl for phenyl or C6-C10; R 14Be the substituting group phenyl of phenyl or C6-C10, preferred phenyl; R-(+)-1,1 '-union-2-naphthol most preferably.The preferred titanium isopropylate of titanic acid ester.
Figure BDA00002770552600031
The preparation method of above-claimed cpd 1, operation steps specifically can be according to two kinds of methods: 1, in the solvent, chiral catalyst and titanic acid ester are mixed, add the fluorophenyl magnesium bromide is prepared the ternary complex system, add at last compound a, obtain compound 1 and get final product; 2, also can first compound a be dissolved in the solvent, drip above-mentioned ternary complex system.Method 1, preferred working method is, in ether solvent,-5-5 ℃ adds titanium isopropylate and R-(+)-1,1 '-union-2-naphthol, stirs, be cooled to-10 ℃ or following adding the fluorophenyl magnesium bromide was stirred 1 hour, add at last compound a, TLC monitoring reaction terminal point.
The preparation method of above-claimed cpd 1, ether solvent is C 4-C 10Ether solvent, preferred ether, tetrahydrofuran (THF), methyl tertiary butyl ether.
The preparation method of above-claimed cpd 1, titanium isopropylate: R-(+)-1,1 '-union-2-naphthol=1~10: 1.
The preparation method of above-claimed cpd 1, compound a: to fluorophenyl magnesium bromide=1: 1~20.
The preparation method of above-claimed cpd 1, R-(+)-1, when 1'-union-2-naphthol and titanium isopropylate mixed, temperature was-30~50 ℃.
The preparation method of above-claimed cpd 1, when adding Grignard reagent, temperature is-30 ℃~50.
The preparation method of above-claimed cpd 1, when Grignard reagent and compound a reaction, temperature is-78~50 ℃.
The preparation method of above-claimed cpd 1, also can add and contain nitrogen compound is catalyzer, such as dimethylaminoethyl ether (BDMAEE), morpholine, triethylamine, pyrroles etc., preferred dimethylaminoethyl ether.
The starting compound a that the preparation of above-claimed cpd 1 is used can prepare in the following method: in the solvent, compound b and oxygenant effect generation compound a are got final product:
Figure BDA00002770552600041
R is silylation or the tetrahydrochysene-2H-pyranyl of hydrogen atom, benzyl, 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 aryl substituent that contains the alkyl substituent of C1-C6 or contain c6-c10.
In the preparation of compound a, the halogenated hydrocarbon solvent of the C1-C6 that described solvent is, preferred methylene dichloride; Oxygenant is clorox/2,2,6,6-tetramethyl piperidine oxide compound (TEMPO) or pyridinium chlorochromate drone salt (PCC) or activated manganese dioxide etc., preferred clorox/2,2,6,6-tetramethyl piperidine oxide compound (TEMPO); Temperature of reaction is-20-40 ℃;
It is clorox/2,2,6 that above-mentioned oxidizing reaction is selected oxygenant, and 6-tetramethyl piperidine oxide compound (TEMPO) also can comprise the steps: aqueous sodium hypochlorite solution for subsequent use with the molten accent of saturated sodium bicarbonate water pH=9-10; Compound b is dissolved in methylene dichloride: in the mixed solvent of water=100: 1, add the 1mol% Sodium Bromide, in the ice-water bath, above-mentioned stand-by solution slowly splashed into, drip complete, TLC monitoring reaction terminal point.
Can adopt following method in the preparation of above-claimed cpd b, the method is: in the solvent, compound c generates compound b under the effect of reductive agent:
Figure BDA00002770552600042
R is silylation or the tetrahydrochysene-2H-pyranyl of hydrogen atom, benzyl, 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 aryl substituent that contains the alkyl substituent of C1-C6 or contain c6-c10.
In the preparation process of above-claimed cpd b, described reductive agent can be selected red aluminium, hydroboration an alkali metal salt, diisobutyl aluminium hydride etc.
In the preparation process of above-claimed cpd b, solvent is the ethers of C4-C10, aromatic hydrocarbon; Temperature-78-40 ℃.
Beneficial effect of the present invention:
The preparation method of Ezetimibe key intermediate compound 1 of the present invention is simple to operate, consumes to lack, and save cost, and aftertreatment is simple and easy to do, can prepare high de value product, is applicable to suitability for industrialized production.
The starting compound a that the inventive method is used; available with identical method synthetic compound C in the prior art; then obtain compound b by reduction reaction; obtain compound a through peroxidation again; last asymmetric grignard reaction is easy has synthesized Ezetimibe key intermediate-compound 1, and compound 1 prepares Ezetimibe, whole piece route environmental protection and economy by deprotection; operation is row easily, and the de value can reach more than 99%.
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); Finnign-MAT212 type mass spectrograph.
Substituent R all adopts phenmethyl among the embodiment 1-12.
The preparation of embodiment 1 compound b
Add 5g(11.5mmol in the 100mL three-necked bottle) compound c, toluene 50mL, magnetic agitation,-20 ℃ of red aluminium toluene solution 3.32g(70%W/W of lower adding), TLC judges that reaction finishes, and adds 1mol/L aqueous hydrochloric acid 50ml, the organic layer washing, dry, filter evaporate to dryness, ethyl alcohol recrystallization, obtain compound b 3.72g, yield 80%.
The preparation of embodiment 2 compound b
Add 5g(11.5mmol in the 100mL three-necked bottle) compound c, tetrahydrofuran (THF) 50mL, magnetic agitation,-20 ℃ of lower Lithium Aluminium Hydride 500mg that add, TLC judges that reaction finishes, and adds 1mol/L aqueous hydrochloric acid 50ml, the organic layer washing, dry, filter evaporate to dryness, ethyl alcohol recrystallization, obtain compound b 3.49g, yield 75%.
The preparation of embodiment 3 compound as
In the 100ml three-necked bottle, add methylene dichloride 30ml, compound b 2g(4.96mmol), add PCC1.6g, TLC monitoring reaction terminal point filters, evaporate to dryness, the sherwood oil making beating obtains compound a 1.9g, yield 95%.
The preparation of embodiment 4 compound as
In the 100ml three-necked bottle, add methylene dichloride 50ml, water 5ml, compound b 2g(4.96mmol), Sodium Bromide 5mg, it is molten that aqueous sodium hypochlorite solution adds saturated sodium bicarbonate water, transfer pH=9-10, slowly splash into TLC monitoring reaction terminal point, add entry 50ml, organic layer is dry, and is concentrated, the sherwood oil making beating, obtain compound a 1.92g, yield 96%.
The preparation of embodiment 5 compounds 1
In the 25ml three-necked bottle, under 0 ℃, add R-(+)-1,1'-union-2-naphthol 141mg, ether 5ml, titanium isopropylate 858mg stirred 30 minutes, under-10 ℃, adding was stirred 1 hour fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 3ml, slowly splashed into the tetrahydrofuran solution 0.5ml(1mol/L of compound a), TCL monitoring reaction terminal point adds 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating, obtain compound a 0.21g, yield 85%, de value 88.5%.
The preparation of embodiment 6 compounds 1
In the 25ml three-necked bottle, under 0 ℃, add R-(+)-1,1'-union-2-naphthol 141mg, tetrahydrofuran (THF) 5ml, titanium isopropylate 858mg stirred 30 minutes, under-10 ℃, adding is to fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 2.5ml, stirred 1 hour, and slowly splashed into the tetrahydrofuran solution 0.5ml(1mol/L of compound a), TCL monitoring reaction terminal point, add 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating, obtain compound a 0.22g, yield 89%, de value 88.7%.
The preparation of embodiment 7 compounds 1
In the 5ml single port bottle, under 0 ℃, add R-(+)-1,1'-union-2-naphthol 282mg, methyl tertiary butyl ether 5ml, titanium isopropylate 715mg stirred 30 minutes, under-10 ℃, adding was stirred 1 hour fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 3.5ml, and is for subsequent use.In the 25ml three-necked bottle, compound a 0.2g is dissolved in the 1ml tetrahydrofuran (THF), splashes into above-mentioned stock solution, TCL monitoring reaction terminal point, add 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating obtains compound a 0.206g, yield 83%, de value 89%.
The preparation of embodiment 8 compounds 1
In the 5ml single port bottle, under 0 ℃, add compound 3(R 13Be phenyl) 376mg, methyl tertiary butyl ether 5ml, titanium isopropylate 715mg stirred 30 minutes, under-10 ℃, added fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 3.5ml, stirred 1 hour, and is for subsequent use.In the 25ml three-necked bottle, compound a 0.2g is dissolved in the 1ml tetrahydrofuran (THF), splashes into above-mentioned stock solution, TCL monitoring reaction terminal point, add 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating obtains compound a 0.19g, yield 76.6%, de value 82%.
The preparation of embodiment 9 compounds 1
In the 5ml single port bottle, under 0 ℃, add compound 4490mg, methyl tertiary butyl ether 5ml, titanium isopropylate 715mg stirred 30 minutes, and under-10 ℃, adding was stirred 1 hour fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 3.5ml, and is for subsequent use.In the 25ml three-necked bottle, compound a 0.2g is dissolved in the 1ml tetrahydrofuran (THF), splashes into above-mentioned stock solution, TCL monitoring reaction terminal point, add 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating obtains compound a 0.2g, yield 81%, de value 83.4%.
The preparation of embodiment 10 compounds 1
In the 5ml single port bottle, under 0 ℃, add compound 5(R 14Be phenyl) 400mg, methyl tertiary butyl ether 5ml, titanium isopropylate 715mg, stirred 30 minutes, and under-10 ℃, added fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 3.5ml, stirred 1 hour, and slowly splashed into the tetrahydrofuran solution 0.5ml(1mol/L of compound a) TCL monitoring reaction terminal point, add 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating, obtain compound a 0.193g, yield 78%, de value 79%.
The preparation of embodiment 11 compounds 1
In the 5ml single port bottle, under 0 ℃, add compound 6298mg(R 1-R 12=H), and methyl tertiary butyl ether 5ml, titanium isopropylate 715mg stirred 30 minutes, and is for subsequent use.In the 5ml single port bottle, BDMAEE0.56g joins fluorophenyl magnesium bromide tetrahydrofuran solution (1mol/L) 3.5ml, stirs 1 hour, and the solution that the front is for subsequent use splashes into, and stirs 1 hour.In the 25ml three-necked bottle, slowly splash into the tetrahydrofuran solution 0.5ml(1mol/L of compound a), TCL monitoring reaction terminal point adds 1mol/L hydrochloric acid 5ml, the organic layer washing, drying, concentrated, the ethanol making beating obtains compound a 0.209g, yield 84%, de value 87%.
The preparation of embodiment 12 Ezetimibes
In the 250ml hydriding reactor, ethanol 15ml, compound 1150mg, (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 99.2%.
The preparation of embodiment 13 Ezetimibes
Same with the working method of embodiment 1, embodiment 5, it is the tert-butyldimethylsilane base that starting raw material adopts compound c (R is the tert-butyldimethylsilane base) to prepare compound 1(R)
In the 50ml four-hole bottle, THF15ml, compound 1(R are the tert-butyldimethylsilane base) 150mg, tetra-n-butyl Neutral ammonium fluoride 75mg reacted 1 hour, evaporate to dryness, isopropanol-water system crystallization obtains Ezetimibe 103mg, yield 88%, de value 99.1%.
The preparation of embodiment 14 Ezetimibes
Same with the working method of embodiment 1, embodiment 5, it is tetrahydrochysene-2H-pyranyl that starting raw material adopts compound c (R is tetrahydrochysene-2H-pyranyl) to prepare compound 1(R)
In the 50ml four-hole bottle, acetone 15ml, concentrated hydrochloric acid is transferred pH=1-2, adding compound 1(R is tetrahydrochysene-2H-pyranyl) 150mg, and reacted 1 hour, evaporate to dryness, isopropanol-water system crystallization obtains Ezetimibe 113mg, yield 97%, de value 99%.

Claims (15)

1. the preparation method of following formula: compound 1, the method is: make together the ternary complex system with chiral catalyst, titanic acid ester with to the fluorophenyl magnesium halide, then the compound a reaction with following formula can obtain target compound 1:
R is silylation or the tetrahydrochysene-2H-pyranyl of hydrogen atom, benzyl, single replacement or polysubstituted arylmethyl, replacement, and X is halogen.
2. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: R is benzyl.
3. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: X is bromine.
4. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: described arylmethyl is benzyl or trityl.
5. the preparation method of compound 1 as claimed in claim 1 is characterized in that: 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.
6. the preparation method of compound 1 as claimed in claim 5 is characterized in that: single replace or polysubstituted arylmethyl described in substituting group be chlorine atom, fluorine atom, nitro, methoxyl group or phenyl.
7. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: the substituting group described in the silylation of replacement is the aryl substituent that contains the alkyl substituent of C1-C6 or contain C6-C10.
8. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: chiral catalyst is selected from R-(+)-1, glycols chipal compounds shown in 1'-union-2-naphthol, the following formula 2,3,4,5 or 6, wherein, R 1-R 12Alkyl substituent for hydrogen or C1-C6; R 13Substituted-phenyl for phenyl or C6-C10; R 14Substituting group phenyl for phenyl or C6-C10
Figure FDA00002770552500021
9. the preparation method of compound 1 as claimed in claim 8 is characterized in that: R 1-R 12Be hydrogen, R 14Be phenyl.
10. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: ether solvent is ether, tetrahydrofuran (THF) or methyl tertiary butyl ether.
11. the preparation method of compound 1 is characterized in that: reaction adding dimethylaminoethyl ether, morpholine, triethylamine or pyrroles as claimed in claim 1.
12. the preparation method of compound 1 is characterized in that: reaction adding dimethylaminoethyl ether as claimed in claim 11.
13. the preparation method of compound 1 as claimed in claim 1, it is characterized in that: titanium isopropylate and R-(+)-1, the mol ratio of 1'-union-2-naphthol is 1~10: 1.
14. the preparation method of compound 1 as claimed in claim 1 is characterized in that: compound a is 1: 1~20 with mol ratio to the fluorophenyl magnesium bromide.
15. the preparation method of compound 1 as claimed in claim 1 is characterized in that: when R-(+)-1,1 '-union-2-naphthol and titanium isopropylate mixed, temperature was-30~50 ℃.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104744331A (en) * 2013-12-31 2015-07-01 浙江九洲药业股份有限公司 Synthetic process of ezetimibe intermediate

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN102531986A (en) * 2012-02-23 2012-07-04 苏州朗科生物技术有限公司 Preparation method for ezetimibe
WO2012155932A1 (en) * 2011-05-17 2012-11-22 Pharmathen S.A. Improved process for the preparation of ezetimibe

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2012155932A1 (en) * 2011-05-17 2012-11-22 Pharmathen S.A. Improved process for the preparation of ezetimibe
CN102531986A (en) * 2012-02-23 2012-07-04 苏州朗科生物技术有限公司 Preparation method for ezetimibe

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104744331A (en) * 2013-12-31 2015-07-01 浙江九洲药业股份有限公司 Synthetic process of ezetimibe intermediate
CN104744331B (en) * 2013-12-31 2018-05-15 浙江九洲药业股份有限公司 A kind of synthesis technique of Ezetimible intermediate

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Application publication date: 20130417