CN107129452A - A kind of preparation method of blood lipid-lowering medicine ezetimibe and its key intermediate - Google Patents
A kind of preparation method of blood lipid-lowering medicine ezetimibe and its key intermediate Download PDFInfo
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- CN107129452A CN107129452A CN201610104276.3A CN201610104276A CN107129452A CN 107129452 A CN107129452 A CN 107129452A CN 201610104276 A CN201610104276 A CN 201610104276A CN 107129452 A CN107129452 A CN 107129452A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention relates to a kind of blood lipid-lowering medicine ezetimibe and its preparation method of key intermediate suitable for industrialized production.
Description
Technical field
In the middle of a kind of preparation method of the ezetimibe of optimum conditions (Formulas I), and key
The preparation method of body.
Background technology
Ezetimibe is one kind by Merck (Merck) and Schering Plough (Schering-Plough) company joint development
The blood lipid-lowering medicine of new suppression cholesterol absorption.Its chemical entitled 1- (4- fluorophenyls) -3 (R)-[3- (4- fluorophenyls) -3
(S)-hydroxypropyl] -4 (S)-(4- hydroxyphenyls) -2- aza cyclo-butanones.Ezetimibe belongs to beta-lactam compounds of group, is into
First monobactams cholesterol absorption inhibitor of work(exploitation.
Ezetimibe is white crystalline powder, is highly soluble in ethanol, methanol and acetone, and water insoluble, fusing point is about
163 DEG C, stablize at normal temperatures.Ezetimibe can be absorbed by suppressing intestinal brush border TC and reduce blood TC, itself
With faint Lipid-regulating effect.After oral absorption, generation active material-ezetimibe-Portugal is combined with glucuronic acid
Grape uronic acid, through bile and renal excretion.Blood peak concentration of drug is reached after oral in 4 ~ 12h, Cmax is 3.4 ~ 5.8mg/ml, biological profit
Expenditure is between 35% ~ 60%, tl/2About 22h.Ezetimibe and ezetimibe-glucuronic acid are combined with plasma protein
Rate is higher than 90%.
Ezetimibe is in November, 2002 in German Initial Public Offering, and the same period is in the U.S., Switzerland, Britain, Sweden's listing.
World market main lipid-loweringing (norcholesterol) product market scale report in 2003 shows ezetimibe/Simvastatin 2003
Global marketing volume be 4.71 hundred million dollars.Inegy (ezetimibe/Simvastatin) obtained German Government approval use in 2004
In the treatment of hyperlipidemia.Inegy is also that first granted the having in the whole world blocks hepatic cholesterol synthesis and suppression small intestine courage to consolidate
Alcohol absorbs the fat-reducing medicament of double mechanism.Ezetimibe is due to good drug effect and relatively low side effect, increasingly by people
Concern, wide market.
Research confirms that ezetimibe is effective cholesterol absorption inhibitor, especially joins with stanin fat-reducing medicament
With better.Ezetimibe is that alone statins produces 8 times that norcholesterol is acted on Statins use in conjunction.According to
Pool there is no potential pharmacokinetics/pharmacodynamics for meter Bei and Statins and other conventional oral drugs in terms of interaction,
Ezetimibe is administered alone or good with statins administering drug combinations tolerance, adverse events incidence and placebo phase
Seemingly.The advantage that ezetimibe and statins are shared is to significantly increase Lipid-regulating effect, and it is higher to share security, and can
The risk of rhabdomyolysis and hepatotoxicity and myalgia caused by reducing high dose medication.This is to many due to not being resistant to
High dose Statins and can not reach expected blood fat target lipid disorders patient provide wish.
The preparation method of ezetimibe is first disclosed in United States Patent (USP) US 5767115, and its route is as follows：
The preparation method of the disclosure includes：Glutaric acid esterification by ring opening reaction occurs under methanol effect monomethyl glutarate is made,
With (4S) -4- phenyl-oxazolidone sour aminating reaction occurs for monomethyl glutarate, and (4S) -3- (4- formic acid formoxyls -1- are made
Oxo butyl) -4- phenyl -2- oxazolidones, it is under titanium tetrachloride, titanium tetraisopropylate and DIPEA collective effects and N- (4- fluorine
Phenyl) -4- benzyloxy benzene methylene amine it is counter occur condensation reaction generation (6), then by BSA/TBAF (tetrabutyl amine fluoride) effect close
Ring is obtained (7), then obtains (8) by LiOH hydrolysis, and (8) generate (9) through oxalyl chloride chloride, and (9) exist through flourophenyl magnesium bromide
ZnC12With Pd (PPh3)4(10) are obtained under effect, then through CBS/BH3Asymmetric reduction carbonyl, Pd/C removing benzyls are obtained according to pool
For rice shellfish, multiple key intermediates are required to purify using column chromatography in the method disclosed in the patent, add industrialized production
Difficulty and cost, and final step using palladium carbon when sloughing benzyl, and the fluorine on phenyl ring is easily divested, so as to produce miscellaneous
Matter.The risk for having residual heavy metal palladium in final product is reduced using palladium carbon.Shortcoming, therefore this route is not suitable for work in summary
Industry metaplasia produces
On process route basis of the present invention based on patent US5767115, make improvements, optimization has obtained a kind of suitable
The synthetic method of industrialized production is closed, with easy to operate, reaction condition is gentle, the selectivity of intermediate asymmetric reduction configuration
Higher, reactions steps are short, and middle weight is high, and production cost is low, and product quality meets the quality to bulk drug in ICH guides
It is required that the advantages of.
The content of the invention
It is an object of the invention to provide a kind of preparation method of the ezetimibe of optimum conditions, side of the invention
Closed in method there is provided a kind of short-cut method that high-purity midbody compound 2 is prepared by accurately controlling pH value there is provided one kind
Key midbody compound 4 is in suitable solvent by the preparation method of coupling reaction；By using bis-triphenylphosphipalladium palladium dichloride
As coupling catalyst, and the palladium remained using charcoal absorption, make the control of finished product ezetimibe palladium content 5ppm with
Under；During asymmetric reduction prepares midbody compound 5, we are in chiral catalyst and borane dimethylsulf iotade reducing agent
On the basis of cooperation, by the TFAA for adding catalytic amount, hence it is evident that reduce the content of its diastereomer.The conjunction of the present invention
It is as follows into route：
1. the present invention provides a kind of short-cut method of the preparation high-purity intermediate (compound 2) of optimization：
By accurately controlling solution ph, gradually it is acidified, because the alkalescence of compound 2 and compound 2 ' has differences, compound 2
Preferential separate out in acidization, impurity compound 2 ' is still remained in water with mono-sodium salt or double sodium salt, so as to reach removal
Impurity, the purpose for purifying midbody compound 2；The alkali of hydrolysis can be sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonic acid
One or more of mixtures in sodium, potassium carbonate, most preferably sodium hydroxide；The acid that neutralization mother liquor is selected can use inorganic
Acid, organic acid；Inorganic acid includes hydrochloric acid, and sulfuric acid, phosphoric acid, organic acid includes p-methyl benzenesulfonic acid, acetic acid, propionic acid
2. the present invention provides a kind of preparation method of Compound Compound 4：
Compound 2 is dissolved in atent solvent, and chloride compounds are obtained with chlorinating agent reaction under the DMF effects of catalytic amount,
Chlorinating agent can select oxalyl chloride, thionyl chloride etc.；Atent solvent is dichloromethane, chloroform, tetrahydrofuran, ether, acetic acid
Ethyl ester, toluene or dimethylbenzene；Chloride compounds again with RMgBr bromination p-fluorophenyl magnesium in atent solvent zinc chloride,
Coupling obtains midbody compound 4 in the presence of catalyst；Atent solvent be dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile,
One or more of mixtures in ethyl acetate, toluene, dimethylbenzene；Catalyst is palladium bichloride, palladium, tetra-triphenylphosphine palladium, double
Triphenylphosphine palladium, preferably bis-triphenylphosphipalladium palladium dichloride；When the catalyst of selection is bis-triphenylphosphipalladium palladium dichloride, urge
Agent consumption is the 0.5%-2%. of the weight of compound 2
3. the present invention provides a kind of compound 5（Ezetimibe）Preparation method：
Compound 4 and reducing agent borane dimethylsulf iotade are in the presence of the TFAA of catalytic amount to compound in atent solvent
Carbonyl carries out asymmetric reduction in 4, and high-purity compound ezetimibe is obtained with high selectivity；It is characterized in that reaction dissolvent
For tetrahydrofuran, dichloroethanes, chloroform, one or more of mixtures, preferably dichloro in dichloromethane, toluene or dimethylbenzene
Methane or tetrahydrofuran.
Embodiment
1. the preparation of compound 2：
A methods：100ml dichloromethane is added into 1000ml reaction bulbs, 100.0g (0.259mol) compound 1 is put into, stirs
Mix, keep 0~5 DEG C of reaction temperature, sodium hydroxide solution (21.79g (0.545mol) sodium hydroxide -300ml water), control is added dropwise
Rate of addition processed keeps reacting liquid temperature at 0-5 DEG C, drips off within about 3 hours, completion of dropwise addition, keeps 0~5 DEG C of timing of reaction temperature anti-
Answer 4 hours, TLC detects that compound 1 clear is converted completely.250ml water, 500ml ethyl acetate, stirring are added into reaction solution
10~15 minutes, stratification, water layer was extracted with 250ml ethyl acetate, stratification, and point water intaking layer, organic phase is discarded, to
1N HCl solutions are slowly added dropwise in water layer, control ph 7~8 is stirred 30 minutes, successively with 1000ml, 250ml ethyl acetate
Extract, stratification, divide and take organic phase, organic phase TLC detections show the colour developing spot of free from admixture compound 2 ', water layer discarded.
Organic layer anhydrous sodium sulfate drying, suction filtration, mother liquor is concentrated under reduced pressure into dry, obtains off-white powder 81.2g, yield：95.0%.
B methods：100 methanol dichloromethanes are added into 1000ml reaction bulbs, 100.0g (0.259mol) compound 1 is put into,
Stirring, keeps 0~5 DEG C of reaction temperature, and potassium hydroxide solution (30.57g (0.545mol) potassium hydroxide -300ml water) is added dropwise,
Control rate of addition to keep reacting liquid temperature at 0-5 DEG C, drip off within about 3 hours, completion of dropwise addition, keep 0~5 DEG C of timing of reaction temperature
Reaction 4 hours, TLC detections show that compound 1 is converted completely.250ml water, 500ml ethyl acetate are added into reaction solution,
Stirring 10~15 minutes, stratification, water layer is extracted with 250ml ethyl acetate, stratification, and point water intaking layer, organic phase is abandoned
Go, 1N sulfuric acid solutions are slowly added dropwise into water layer, control ph 8~9 is stirred 30 minutes, successively with 1000ml, 250ml second
Acetoacetic ester is extracted, stratification, is divided and is taken organic phase, and organic phase TLC detections show the colour developing spot of free from admixture compound 2 ', water layer
Discard.Organic layer anhydrous sodium sulfate drying, suction filtration, mother liquor is concentrated under reduced pressure into dry, obtains off-white powder 75g, yield：87.8%.
2. the preparation of compound 4：
A methods：Add 100ml dichloromethane into 500ml reaction bulbs, and 20g (60.7mmol) compound 2 and 0.1ml
DMF, stirring is lower to be added dropwise the chloro- dichloromethane solution of oxalyl（The chloro- 50ml dichloromethane of 11.5g (91.1mmol) oxalyl), control
Rate of addition is with maintenance reaction liquid temperature degree at 0~5 DEG C, and completion of dropwise addition, 15~20 DEG C of room temperature is reacted 6 hours.Reaction terminates, decompression
Concentration of reaction solution obtains grease to dry, and 100ml ether, stirring and dissolving are added into grease.To another 500ml reaction bulbs
Middle addition 180ml dichloromethane, 2.2g (91.4mmol) magnesium and 0.1g iodine, nitrogen protection, are heated with stirring to reacting liquid temperature
30~40 DEG C, 16g (91.4mmol) fluorobromobenzene is added dropwise, control rate of addition keeps 20~25 DEG C of reaction temperature, completion of dropwise addition
20~25 DEG C are incubated afterwards reacts 1 hour to magnesium disappearance.Stirring is cooled to 0~5 DEG C, puts into 25g zinc chloride, is kept for 0~5 DEG C instead
Answer 3 hours；0.1g bis-triphenylphosphipalladium palladium dichlorides are added, stirs 30 minutes, above-mentioned acyl chlorides ether is added dropwise into reaction solution
Solution, is incubated 0~5 DEG C and reacts 2 hours after completion of dropwise addition.Reaction terminates, and suction filtration, filter cake is washed with dichloromethane, and filter cake is abandoned
Go, merging filtrate, anhydrous sodium sulfate and activated carbon are dried, suction filtration, mother liquor is concentrated under reduced pressure into dry grease, is induced by crystal seed
Refined in isopropanol, and vacuum drying obtains off-white powder 15.6g, yield：62%, palladium content 4ppm.
B methods：Add 100ml tetrahydrofurans into 500ml reaction bulbs, and 20g (60.7mmol) compound 2 and 0.1ml
DMF, stirring is lower to be added dropwise the chloro- tetrahydrofuran solution of oxalyl（The chloro- 50ml tetrahydrofurans of 11.5g (91.1mmol) oxalyl), control
Rate of addition is with maintenance reaction liquid temperature degree at 0~5 DEG C, and completion of dropwise addition, 15~20 DEG C of room temperature is reacted 6 hours.Reaction terminates, decompression
Concentration of reaction solution obtains grease to dry, and 100ml tetrahydrofurans, stirring and dissolving are added into grease.It is anti-to another 500ml
Addition 180ml tetrahydrofurans, 2.2g (91.4mmol) magnesium and 0.1g iodine in bottle are answered, nitrogen protection is heated with stirring to reaction solution
30~40 DEG C of temperature, is added dropwise 16g (91.4mmol) fluorobromobenzene, and control rate of addition keeps 20~25 DEG C of reaction temperature, is added dropwise
20~25 DEG C are incubated after end and reacts 1 hour to magnesium disappearance.Stirring is cooled to 0~5 DEG C, puts into 25g zinc chloride, keeps 0~5
DEG C reaction 3 hours；0.1g bis-triphenylphosphipalladium palladium dichlorides are added, stirs 30 minutes, above-mentioned acyl chlorides is added dropwise into reaction solution
Tetrahydrofuran solution, is incubated 0~5 DEG C and reacts 2 hours after completion of dropwise addition.Reaction terminates, and suction filtration, filter cake is washed with tetrahydrofuran,
Filter cake is discarded, merging filtrate, and anhydrous sodium sulfate and activated carbon are dried, suction filtration, and mother liquor is concentrated under reduced pressure into dry grease, passes through crystalline substance
Induction is planted to refine in isopropanol, and vacuum drying obtains off-white powder 17.1g, yield：68%, palladium content 3ppm.
C methods：Add 100ml dichloromethane into 500ml reaction bulbs, and 20g (60.7mmol) compound 2 and 0.1ml
DMF, stirring is lower to be added dropwise the chloro- dichloromethane solution of oxalyl（The chloro- 50ml dichloromethane of 11.5g (91.1mmol) oxalyl), control
Rate of addition is with maintenance reaction liquid temperature degree at 0~5 DEG C, and completion of dropwise addition, 15~20 DEG C of room temperature is reacted 6 hours.Reaction terminates, decompression
Concentration of reaction solution obtains grease to dry, and 100ml ether, stirring and dissolving are added into grease.To another 500ml reaction bulbs
Middle addition 180ml dichloromethane, 2.2g (91.4mmol) magnesium and 0.1g iodine, nitrogen protection, are heated with stirring to reacting liquid temperature
30~40 DEG C, 16g (91.4mmol) fluorobromobenzene is added dropwise, control rate of addition keeps 20~25 DEG C of reaction temperature, completion of dropwise addition
20~25 DEG C are incubated afterwards reacts 1 hour to magnesium disappearance.Stirring is cooled to 0~5 DEG C, puts into 25g zinc chloride, is kept for 0~5 DEG C instead
Answer 3 hours；1g tetra-triphenylphosphine palladiums are added, stirs 30 minutes, above-mentioned acyl chlorides diethyl ether solution is added dropwise into reaction solution, are dripped
Plus 0~5 DEG C of insulation is reacted 2 hours after terminating.Reaction terminates, and suction filtration, filter cake is washed with dichloromethane, and filter cake is discarded, and merges filter
Liquid, anhydrous sodium sulfate drying, suction filtration, mother liquor is concentrated under reduced pressure into dry grease, is refined by crystal seed induction in isopropanol, and
Vacuum drying obtains off-white powder 12.6g, yield：50%, palladium content 12ppm.
3. the preparation of compound 5
A methods：100ml dichloromethane, 10.0g (24.5mmol) compound 4,0.05g trifluoros are added into 500ml reaction bulbs
Acetic anhydride, nitrogen protection, stirring is cooled to -20~-25 DEG C, adds 6.6ml (R-Methyl CBS) toluene solution (6.8g
(R-Methyl CBS) -35ml toluene).4ml borane dimethylsulf iotades are added dropwise into reaction solution, control rate of addition keeps reaction
Liquid temperature degree is incubated -20~-25 DEG C at -20~-25 DEG C, after completion of dropwise addition and reacted 3 hours, and TLC detections, which are shown in reaction solution, to be changed
Compound 4 reacts complete.Reaction terminates, and 15ml ethanol is added dropwise into reaction solution, and control rate of addition keeps reacting liquid temperature -20
~-25 DEG C, completion of dropwise addition is warming up to 0~5 DEG C and stirred 1 hour.Continue that 18ml 1N HCl solution, keeping temperature 5~10 is added dropwise
DEG C stirring 1 hour.Reaction solution is extracted with the ethyl acetate of 60ml × 2, merges organic phase, saturated nacl aqueous solution is used successively
(80ml × 2), purified water (80ml × 2) are washed, anhydrous sodium sulfate drying, suction filtration, and mother liquor is concentrated under reduced pressure into dry solid, very
Empty dry white solid 9g, yield：90%.
B methods：100ml tetrahydrofurans, 10.0g (24.5mmol) compound 4,0.05g trifluoros are added into 500ml reaction bulbs
Acetic anhydride, nitrogen protection, stirring is cooled to -20~-25 DEG C, adds 6.6ml (R-Methyl CBS) toluene solution (6.8g
(R-Methyl CBS) -35ml toluene).4ml borane dimethylsulf iotades are added dropwise into reaction solution, control rate of addition keeps reaction
Liquid temperature degree is incubated -20~-25 DEG C at -20~-25 DEG C, after completion of dropwise addition and reacted 3 hours, and TLC detections, which are shown in reaction solution, to be changed
Compound 4 reacts complete.Reaction terminates, and 15ml ethanol is added dropwise into reaction solution, and control rate of addition keeps reacting liquid temperature -20
~-25 DEG C, completion of dropwise addition is warming up to 0~5 DEG C and stirred 1 hour.Continue that 18ml 1N HCl solution, keeping temperature 5~10 is added dropwise
DEG C stirring 1 hour.Reaction solution is extracted with the ethyl acetate of 60ml × 2, merges organic phase, saturated nacl aqueous solution is used successively
(80ml × 2), purified water (80ml × 2) are washed, anhydrous sodium sulfate drying, suction filtration, and mother liquor is concentrated under reduced pressure into dry solid, very
Empty dry white solid 8.8g, yield：88%.
C methods：100ml toluene, 10.0g (24.5mmol) compound 4,0.05g trifluoroacetic acids are added into 500ml reaction bulbs
Acid anhydride, nitrogen protection, stirring is cooled to -20~-25 DEG C, adds 6.6ml (R-Methyl CBS) toluene solutions (6.8g (R-
Methyl CBS) -35ml toluene).4ml borane dimethylsulf iotades are added dropwise into reaction solution, control rate of addition keeps reaction liquid temperature
Degree is incubated -20~-25 DEG C at -20~-25 DEG C, after completion of dropwise addition and reacted 3 hours, and TLC detections show compound 4 in reaction solution
Reaction is complete.Reaction terminates, and 15ml ethanol is added dropwise into reaction solution, and control rate of addition keeps reacting liquid temperature -20~-25
DEG C, completion of dropwise addition is warming up to 0~5 DEG C and stirred 1 hour.Continue that 18ml 1N HCl solution is added dropwise, 5~10 DEG C of keeping temperature is stirred
Mix 1 hour.Reaction solution is extracted with the ethyl acetate of 60ml × 2, merges organic phase, successively with saturated nacl aqueous solution (80ml ×
2), purified water (80ml × 2) is washed, anhydrous sodium sulfate drying, suction filtration, and mother liquor is concentrated under reduced pressure into dry solid, is dried in vacuo
White solid 7g, yield：70%.
Claims (14)
1. a kind of preparation method of compound 2, is primarily characterized in that the alkali using compound 2 and 2 ' (lactams open loop impurity)
Sex differernce, by accurately controlling mother liquor pH value to purify product compound 2, makes the residual mother liquor in a salt form of impurity compound 2 '
In.
2. the preparation method of the compound 2 as described in claim 1, it is characterised in that the alkali of selection is inorganic base, hydroxide
One or more of mixtures in sodium, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, most preferably sodium hydroxide.
3. the preparation method of the compound 2 as described in claim 1, it is characterised in that the pH value for controlling mother liquor is 7~10, most
Preferably pH value 7~8.
4. a kind of preparation method of compound 4, be primarily characterized in that first by compound 2 under the DMF effects of catalytic amount with
Thionyl chloride or oxalyl chloride are acylated, and obtain compound 3, then by compound 3 in the presence of zinc chloride and catalyst lazy
Property solvent in and bromination p-fluorophenyl magnesium coupling obtain compound 4.
5.
The preparation method of compound 4 as described in claim 4, it is characterised in that compound 3 is by chemical combination without isolation
The mother liquor of thing 3 carries out direct coupling reaction.
6. the preparation method of the compound 4 as described in claim 4, it is characterised in that the acylated examination selected during prepare compound 3
Agent is thionyl chloride or oxalyl chloride, preferably oxalyl chloride.
7. the preparation method of the compound 4 as described in claim 4, it is characterised in that be acylated during prepare compound 3 temperature be 0 ~
50 DEG C, preferably 0 ~ 5 DEG C.
8. the preparation method of the compound 4 as described in claim 4, it is characterised in that it is lazy that solvent is selected during prepare compound 3
Property methylene chloride, chloroform, tetrahydrofuran, ether, acetonitrile, ethyl acetate, toluene, dimethylbenzene and its mixture, preferably four
Hydrogen furans.
9. the preparation method of the compound 4 as described in claim 4, it is characterised in that the catalyst selected during prepare compound 4
For palladium bichloride, palladium, tetra-triphenylphosphine palladium, bis-triphenylphosphipalladium palladium dichloride, preferably bis-triphenylphosphipalladium palladium dichloride.
10. the preparation method of the compound 4 as described in claim 4, it is characterised in that the catalysis selected during prepare compound 4
Agent is bis-triphenylphosphipalladium palladium dichloride, and catalyst amount is the 0.5%-2% of the weight of compound 2.
11. the preparation method of the compound 4 as described in claim 4, it is characterised in that be from solvent during prepare compound 4
Atent solvent dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethyl acetate, toluene, dimethylbenzene and its mixture, preferably
Tetrahydrofuran.
12. the preparation method of the compound 4 as described in claim 4, it is characterised in that removed during prepare compound 4 micro
Residual palladium can select activated carbon, silica gel or alchlor and be adsorbed, preferably activated carbon.
13. a kind of method of the ezetimibe of prepare compound 5, is primarily characterized in that compound 4 and reducing agent borine diformazan
Thioether carries out asymmetric reduction, Gao Xuan in atent solvent in the presence of the TFAA of catalytic amount to carbonyl in compound 4
Obtain to selecting property high-purity compound ezetimibe.
14. the method as described in claim 12 prepares ezetimibe, it is characterised in that reaction dissolvent is tetrahydrofuran, two
One or more of mixtures, preferably dichloromethane or tetrahydrofuran in chloroethanes, chloroform, dichloromethane, toluene or dimethylbenzene.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610104276.3A CN107129452A (en) | 2016-02-26 | 2016-02-26 | A kind of preparation method of blood lipid-lowering medicine ezetimibe and its key intermediate |
| PCT/CN2016/075539 WO2017143628A1 (en) | 2016-02-26 | 2016-03-03 | Method for preparing hypolipidemic drug ezetimibe and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610104276.3A CN107129452A (en) | 2016-02-26 | 2016-02-26 | A kind of preparation method of blood lipid-lowering medicine ezetimibe and its key intermediate |
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| Publication Number | Publication Date |
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| CN107129452A true CN107129452A (en) | 2017-09-05 |
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| CN201610104276.3A Pending CN107129452A (en) | 2016-02-26 | 2016-02-26 | A kind of preparation method of blood lipid-lowering medicine ezetimibe and its key intermediate |
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| WO (1) | WO2017143628A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032338A2 (en) * | 2006-09-11 | 2008-03-20 | Manne Satyanarayana Reddy | Improved process for the preparation of ezetimibe and its intermediates |
| CN101423511A (en) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | Ezetimible intermediate and synthetic method of ezetimible |
| CN102675177A (en) * | 2011-06-28 | 2012-09-19 | 常州制药厂有限公司 | Preparation methods of blood fat lowering medicament and key intermediates of blood fat lowering medicament |
-
2016
- 2016-02-26 CN CN201610104276.3A patent/CN107129452A/en active Pending
- 2016-03-03 WO PCT/CN2016/075539 patent/WO2017143628A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008032338A2 (en) * | 2006-09-11 | 2008-03-20 | Manne Satyanarayana Reddy | Improved process for the preparation of ezetimibe and its intermediates |
| CN101423511A (en) * | 2007-11-05 | 2009-05-06 | 中山奕安泰医药科技有限公司 | Ezetimible intermediate and synthetic method of ezetimible |
| CN102675177A (en) * | 2011-06-28 | 2012-09-19 | 常州制药厂有限公司 | Preparation methods of blood fat lowering medicament and key intermediates of blood fat lowering medicament |
Non-Patent Citations (1)
| Title |
|---|
| 王积涛，等: "《有机化学 第三版 上册》", 31 December 2009, 南开大学出版社 * |
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| WO2017143628A1 (en) | 2017-08-31 |
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Application publication date: 20170905 |