CN109810038A - A kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe - Google Patents
A kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of azetidinone class blood lipid-lowering medicine ezetimibe; it, as starting material, is prepared by grignard reaction, asymmetric reduction reaction, substitution reaction, addition reaction and deprotection reaction using (S) -5- oxo -5- (4- oxazolyl phenyl alkanone -3- base) valerate.The invention has the advantages that sources of initial raw materials is extensive, cheap, preparation cost is thereby reduced, and yield is higher, 90% or more, benefit is further improved, preparation process step is brief, easy to operate, intermediate weight easy purification is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical preparation fields, and in particular to a kind of system of azetidinone class blood lipid-lowering medicine ezetimibe
Preparation Method.
Background technique
Ezetimibe (Ezetimibe) is used to treat hyperlipidemia by what Schering Plough and Merck & Co., Inc. researched and developed jointly
Medicine, in 2002 through U.S. FDA ratify list, trade name Zetia.Its chemical name is: 1- (4- fluorophenyl)-(3R)-
[3- (4- fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4- hydroxy phenyl) -2- azetidinone.
Hyperlipidemia is the important risk factor for causing the cardiovascular diseases such as atherosclerosis to occur, and it is solid to reduce total gallbladder in blood plasma
Alcohol level can reduce the risk of cardiovascular disease.The drug of clinical treatment hyperlipidemia mainly includes cholesterol biosynthesis at present
Inhibitor, fibric acid and bile acid sequestrant etc..
Ezetimibe inhibits the cholesterol absorption in biliary tract and food by acting on the brush borders of small intestine cells, alternative
Without influencing the absorption to liposoluble vitamin, triglycerides and cholic acid.The action character of ezetimibe is: after oral absorption
Into hepato-enteric circulation, enter the site of action of enteron aisle repeatedly, glucuronidation metabolite also has pharmaceutical activity, further prevents
The absorption of cholesterol.
The technology of preparing route of existing ezetimibe is as follows: using chloroformyl methyl butyrate as starting material, through auxiliary with chirality
After agent reaction, azepine four membered ring intermediate is obtained with Schiff base intermediate Michael's addition, cyclization, then through hydrolysis, acylation, format
Ezetimibe is prepared in reaction, asymmetric reduction reaction.That there are preparation steps is complicated for the route, yield is low and at high cost etc.
Drawback is not suitable for large-scale industrial production.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of systems of azetidinone class blood lipid-lowering medicine ezetimibe
Preparation Method, the preparation method step is brief, high income, and raw material is easy to get.
The technical solution adopted by the present invention is that:
A kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe, with (S) -5- oxo -5- (4- oxazolyl phenyl
Alkanone -3- base) valerate is starting material, by grignard reaction, asymmetric reduction reaction, substitution reaction, addition reaction and de-
Protection reaction is prepared.
Further, the specific steps are as follows:
A, the preparation of intermediate E M1-1: being that starting is former with (S) -5- oxo -5- (4- oxazolyl phenyl alkanone -3- base) valerate
Material occurs grignard reaction with Grignard Reagent, intermediate E M1-1 is prepared；
B, the preparation of intermediate E M1-2: for intermediate E M1-1 under the action of chiral catalyst, carbonyl is under the action of reducing agent
Occur that intermediate E M1-2 is prepared not to chiral alcoholic extract hydroxyl group is reduced to after reduction reaction；
C, the preparation of intermediate E M1-3: intermediate E M1-2 is reacted under the action of inorganic base with halogenated benzyl, by alcoholic extract hydroxyl group
It is changed into benzyl oxide, intermediate E M1-3 is prepared；
D, the preparation of intermediate E I-1: (E)-N- (4- benzyloxy benzylidene) -4- fluoroaniline and intermediate E M1-3 are in catalyst
With substitution reaction is carried out under the action of lewis acid titanium tetrachloride, intermediate E I-1 is prepared；
E, the preparation of intermediate E I-2: intermediate E I-1 under the catalytic action of tertiary fourth ammonium salt with N, the bis- trimethyl silicon substrate acetyl of O-
Amine reaction, is prepared intermediate E I-2；
F, the preparation of finished product EZ: intermediate E I-2 sloughs benzyl protecting group under the catalytic action of metallic catalyst, obtains end
Product E Z, i.e. ezetimibe.
Further, the reaction temperature in the step a is preferably -15 ~ -20 DEG C, the throwing of the Grignard Reagent and starting material
Expect ratio are as follows: 2.0:1.0 ~ 2.5:1.0, the Grignard Reagent are p-fluorophenyl magnesium chloride or p-fluorophenyl magnesium bromide.
Further, the chiral catalyst in the step b is (S) -2- methyl-CBS- oxazaborolidine or R- diphenyl (pyrroles
Alkane -2- base) methanol, the feed ratio of the chiral catalyst and intermediate E M1-1 are 0.05:1.0 ~ 0.1:1.0, the step b
In reducing agent be borane dimethylsulf iotade, sodium borohydride or lithium borohydride, the feed ratio of the reducing agent and intermediate E M1-1 is
1.05:1.0~2.0:1.0。
Further, the halogenated benzyl in the step c is benzyl chloride or bromobenzyl, the feed ratio of the halogenated benzyl and intermediate E M1-2
For 1.3:1.0 ~ 1.5:1.0, the inorganic base is potassium carbonate, sodium acetate or sodium carbonate.
Further, the catalyst in the step d is tetraisopropyl titanate, the throwing of the titanium tetrachloride and intermediate E M1-3
Material proportion are as follows: 1.05:1.0 ~ 1.5:1.0, (E)-N- (4- benzyloxy the benzylidene) -4- fluoroaniline and intermediate E M1-3
Charge ratio are as follows: 1.2:1.0 ~ 1.5:1.0.
Further, the tertiary fourth ammonium salt in the step e is tetrabutyl ammonium fluoride or tetrabutylammonium bromide, the bis- front threes of the N, O-
The charge ratio of base silicon substrate acetamide and intermediate E I-1 are as follows: 1.2:1.0 ~ 1.8:1.0.
Further, the metallic catalyst in the step f is palladium charcoal, palladium dydroxide or hydroxide carbon, the metallic catalyst
Inventory is the 5-15% of intermediate E I-2 mass.
The beneficial effects of the present invention are: sources of initial raw materials is extensive, cheap, thereby reduce preparation cost, and yield compared with
Height further improves benefit 90% or more, and preparation process step is brief, easy to operate, intermediate weight easy purification, is applicable in
In large-scale industrial production.
Specific embodiment
In order to deepen the understanding of the present invention, the present invention will be described in further detail with reference to the examples below, the embodiment
For explaining only the invention, it does not restrict the protection scope of the present invention.
Embodiment 1
A kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe, the specific steps are as follows:
A, under the conditions of anhydrous and oxygen-free, 150mL 2N p-fluorophenyl magnesium chloride the preparation of intermediate E M1-1: is added into reaction flask
Tetrahydrofuran solution (0.3mol, 2.0eq) and 200mL tetrahydrofuran, stirring, are cooled to -15~-20 DEG C, then to above-mentioned anti-
Answer the tetrahydrofuran solution that 150mL (S) -5- oxo -5- (4- oxazolyl phenyl alkanone -3- base) methyl valerate is added dropwise in liquid
(45g, 0.15mol, 1.0eq), drop finish, react 30 minutes under -15 ~ -20 DEG C of reaction temperature, then heat to 0~5 DEG C
Reaction, TLC monitoring reaction；
End of reaction is added dropwise 300mL 1N concentrated hydrochloric acid solution and carries out quenching reaction, removes tetrahydrofuran under reduced pressure, be then added
200mL methyl tertiary butyl ether(MTBE), stirring stand liquid separation, and water layer is extracted with methyl tertiary butyl ether(MTBE) (200mL × 2), merge organic phase,
It is washed with saturated sodium bicarbonate solution (200mL × 1) and saturated sodium chloride solution (200mL × 1), anhydrous sodium sulfate is dry, takes out
Filter is concentrated under reduced pressure, and obtains 54.3g intermediate E M1-1 grease crude product, which directly carries out anti-in next step without polishing purification
It answers；
B, under the conditions of anhydrous and oxygen-free, 54.3g intermediate E M1-1 the preparation of intermediate E M1-2: is added into reaction flask
Then (0.15mol, 1.0eq) and 300mL tetrahydrofuran, stirring and dissolving are cooled to -20~-25 DEG C, add 2.3g (S) -
2- methyl-CBS- oxazaborolidine (0.01mol, 0.05eq), stirring, and 32mL 5N borane dimethylsulfide is added dropwise in backward reaction solution
Ether tetrahydrofuran solution (0.16mol, 1.05eq).Drop finishes, and reacts at -20~-25 DEG C, TLC monitoring reaction.
Reaction terminates, and 100mL methanol is added dropwise into reaction solution and is quenched.End is quenched, is warming up to 0~5 DEG C, is stirred to react 30
Minute, 500mL water and 300mL ethyl acetate is then added, stirring stands liquid separation.Aqueous layer with ethyl acetate extraction (300mL ×
3), merge organic phase, successively washed with saturated sodium chloride solution (300mL × 1) and water (300mL × 1), it is dry with anhydrous sodium sulfate
Dry, filtrate decompression obtains 53.3g EM1-2 crude product, and crude product is placed in 200mL ethyl acetate and 400mL n-hexane, stirs, and rises
Temperature is cooled to 10~15 DEG C to back flow reaction after 1h, stand crystallization, filters, and drying obtains 50.2g EM1-2 solid product, receives
Rate 92%；
C, the preparation of intermediate E M1-3: into reaction flask, be added 50.2g EM1-2(0.14mol, 1.0eq), 30.6g cylite
(0.18mol, 1.3eq), 38.6g potassium carbonate (0.28mol, 2.0eq) and 500mL toluene, stirring, are warming up to 70 DEG C of reactions, TLC
Monitoring reaction；End of reaction is cooled to room temperature, and is filtered, is washed filter cake with a small amount of toluene, mother liquor is concentrated to dryness, and obtains 61.1g
Solid product, yield: 91%；
D, the preparation of intermediate E I-1: under the conditions of anhydrous and oxygen-free, in reaction flask, by 26.6g titanium tetrachloride (0.14mol,
It 1.05eq) is placed in 50mL methylene chloride with 2.8g tetraisopropyl titanate (0.01mol, 0.1eq), stirs, be cooled to -15 DEG C,
Then 400mL EM1-3(61.1g, 0.13mol, 1.0eq is added dropwise) dichloromethane solution, then 26.3g triethylamine is added dropwise
(0.26mol, 2.0eq)；Drop finishes, and stirs 30 minutes, 300mL (E)-N- (4- benzyloxy benzylidene) -4- fluorobenzene is then added dropwise
The dichloromethane solution of amine (48.8g, 0.16mol, 1.2eq)；Drop finishes, and reacts at -15 DEG C, TLC monitoring reaction；It has reacted
Finish, 20mL glacial acetic acid is added dropwise and is quenched, reaction is then warmed to room temperature, stirs, reaction solution 500mL saturated sodium bicarbonate solution
Washing, anhydrous sodium sulfate is dry, and evaporated under reduced pressure obtains 74.5g crude product.The crude product is beaten with 400mL isopropanol, obtains 69.4g white
Solid product, i.e. intermediate E I-1, yield 72%.
E, in reaction flask, 69.4g EI-1(0.09mol, 1.0eq the preparation of intermediate E I-2: are sequentially added), 22.3g N,
The bis- trimethyl silicane yl acetamides (0.11mol, 1.2eq) of O- and 600mL tetrahydrofuran, stirring, are warming up to 50 DEG C of reactions；Reaction 1
After hour, it is added 2.3g tetrabutyl ammonium fluoride (0.009mol, 0.1eq), is stirred to react, TLC monitoring reaction；End of reaction, it is cold
But to room temperature, methanol is added and is quenched, 500mL ethyl acetate is added in solvent evaporated, and stirring is organic with 150mL water washing
Phase, anhydrous sodium sulfate is dry, evaporated under reduced pressure, obtains 55.6g oily product EI-2, which directly carries out in next step；
F, 55.6g EI-2(0.09mol, 1.0eq the preparation of finished product EZ: are added in reaction flask), 450mL methanol and 2.8g
Palladium charcoal, stirring, nitrogen displacement, then it is passed through hydrogen, it is warming up to 30 DEG C~35 DEG C reactions, TLC monitoring reaction；
End of reaction is cooled to room temperature, emptying, and nitrogen displacement filters, and filter cake methanol rinse, filtrate decompression is evaporated to obtain
38.5g EZ crude product, which is placed in 300mL toluene, is warming up to reflux, is stirred to react, then is cooled to room temperature crystallization, is taken out
Filter, it is dry, obtain 36.9g white solid product, i.e. final product ezetimibe, yield 96%.
Embodiment 2
A kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe, the specific steps are as follows:
A, under the conditions of anhydrous and oxygen-free, in reaction flask, 250mL 1N p-fluorophenyl bromination the preparation of intermediate E M1-1: is added
Magnesium tetrahydrofuran solution (0.25mol, 2.5eq) and 200mL ether, stirring, are cooled to -15 ~ -20 DEG C, then to above-mentioned reaction
In liquid be added dropwise 150mL (S) -5- oxo -5- (4- oxazolyl phenyl alkanone -3- base) ethyl valerate diethyl ether solution (32g,
0.1mol, 1.0eq), drop finishes, and reacts 30 minutes under -15~-20 DEG C of reaction temperatures, then heats to 0~5 DEG C of reaction, TLC
Monitoring reaction.
End of reaction is added dropwise 200mL 1N concentrated hydrochloric acid solution and carries out quenching reaction, then 200mL second is added in evaporating solvent under reduced pressure
Acetoacetic ester, stirring stand liquid separation, and aqueous layer with ethyl acetate (150mL × 2) extraction merges organic phase, molten with saturated sodium bicarbonate
Liquid (200mL × 1), saturated sodium chloride solution (200mL × 1) washing, anhydrous sodium sulfate is dry, filters, and is concentrated under reduced pressure, obtains
35.5g EM1-1 grease crude product, the product directly carry out next step reaction without polishing purification；
B, the preparation of intermediate E M1-2: under the conditions of anhydrous and oxygen-free, being added 35.5g EM1-1(0.1mol in reaction flask,
1.0eq) and then 180mL toluene, stirring and dissolving are cooled to -20~-25 DEG C, add 2.8g (S) -2- methyl-CBS- evil
Azoles borine (0.01mol, 0.1eq), stirring, is added portionwise 7.6g sodium borohydride (0.2mol, 2.0eq) into reaction solution, and drop finishes,
It is reacted at -20~-25 DEG C, TLC monitoring reaction.
Reaction terminates, and 80mL methanol is added dropwise into reaction solution and is quenched.End is quenched, is warming up to 0~5 DEG C, is stirred to react 30
Minute, 150mL water and 200mL toluene is then added, stirring stands liquid separation.Water layer extracts (100mL × 3) with toluene, is associated with
Machine phase is successively washed with saturated sodium chloride solution (200mL × 1), water (200mL × 1), and anhydrous sodium sulfate is dry, filtrate decompression
38.3g EM1-2 crude product is obtained, crude product is placed in 150mL ethyl acetate and 300mL n-hexane, is stirred, it is anti-to be warming up to reflux
It answers, 10~15 DEG C is cooled to after 1h, stand crystallization, filter, drying obtains 35.3g EM1-2 solid product, yield 93%；
C, the preparation of intermediate E M1-3: in reaction flask, be added 35.3g EM1-2(0.1mol, 1.0eq), 19g benzyl chloride
(0.15mol, 1.5eq), 16.4g sodium acetate (0.2mol, 2.0eq) and 400mL acetonitrile, stirring, are warming up to 70 DEG C of reactions, TLC
Monitoring reaction；End of reaction is cooled to room temperature, and is filtered, is washed filter cake with a small amount of acetonitrile, mother liquor is concentrated to dryness, and obtains 43.8g
Solid product EM1-3, yield: 93%.
D, the preparation of intermediate E I-1: under the conditions of anhydrous and oxygen-free, in reaction flask, by 20.9g titanium tetrachloride (0.11mol,
It 1.2eq) is placed in 50mL tetrahydrofuran with 2.6g tetraisopropyl titanate (0.009mol, 0.1eq), stirs, be cooled to -15 DEG C,
Then 400mL EM1-3(43.8g, 0.09mol, 1.0eq is added dropwise) tetrahydrofuran solution, then 18.2g triethylamine is added dropwise
(0.18mol, 2.0eq)；Drop finishes, and stirs 30 minutes, 300mL (E)-N- (4- benzyloxy benzylidene) -4- fluorobenzene is then added dropwise
The tetrahydrofuran solution of amine (42.7g, 0.14mol, 1.5eq)；Drop finishes, and reacts at -15 DEG C, TLC monitoring reaction；It has reacted
Finish, 15mL glacial acetic acid is added dropwise and is quenched, is then warmed to room temperature reaction, 500mL is added in gained residue in evaporating solvent under reduced pressure
Ethyl acetate, stirring, is washed with 200mL saturated sodium bicarbonate solution, and anhydrous sodium sulfate is dry, and it is thick to obtain 54.5g for evaporated under reduced pressure
Product, the crude product are beaten with 300mL isopropanol, obtain 51.8g white solid product E I-1, yield 75%；
E, in reaction flask, 51.8gEI-1(0.07mol, 1.0eq the preparation of intermediate E I-2: are sequentially added), 20.3g N, O-
Double trimethyl silicane yl acetamides (0.1mol, 1.5eq) and 500mL acetonitrile, stirring, are warming up to 50 DEG C of reactions；After reaction 1 hour,
It is added 2.2g tetrabutylammonium bromide (0.007mol, 0.1eq), is stirred to react, TLC monitoring reaction；End of reaction is cooled to room
Temperature is added methanol and is quenched, solvent evaporated, and 300mL ethyl acetate is added, and stirring is anhydrous with 100mL water washing organic phase
Sodium sulphate is dry, evaporated under reduced pressure, obtains 39.7g oily product EI-2, which directly carries out in next step；
F, 39.7g EI-2(0.07mol, 1.0eq the preparation of finished product EZ: are added in reaction flask), 300mL ethyl alcohol and 4g hydrogen
Palladium oxide, stirring, nitrogen displacement, then it is passed through hydrogen, it is warming up to 30 DEG C~35 DEG C reactions, TLC monitoring reaction.
End of reaction is cooled to room temperature, emptying, and nitrogen displacement filters, and filter cake is rinsed with ethyl alcohol, and filtrate decompression is evaporated to obtain
28.2g EZ crude product.The crude product is placed in 250mL toluene, reflux is warming up to, is stirred to react, then is cooled to room temperature crystallization, is taken out
Filter, it is dry, obtain 26.7g white solid product ezetimibe, yield 97%.
Embodiment 3
A kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe, the specific steps are as follows:
A, under the conditions of anhydrous and oxygen-free, in reaction flask, 140mL 2N p-fluorophenyl chlorination the preparation of intermediate E M1-1: is added
Magnesium tetrahydrofuran solution (0.28mol, 2.5eq) and 300mL tetrahydrofuran, stirring, are cooled to -15~-20 DEG C, then upwards
The tetrahydrofuran for stating dropwise addition 150mL (S) -5- oxo -5- (4- oxazolyl phenyl alkanone -3- base) isopropyl isovalerate in reaction solution is molten
Liquid (35g, 0.11mol, 1.0eq), drop finish, and 30 minutes under -15 ~ -20 DEG C of reactions, then heat to 0~5 DEG C of reaction, TLC
Monitoring reaction.
End of reaction is added dropwise 200mL 1N concentrated hydrochloric acid solution and carries out quenching reaction, removes tetrahydrofuran under reduced pressure, be then added
200mL methyl tertiary butyl ether(MTBE), stirring stand liquid separation, and water layer is extracted with methyl tertiary butyl ether(MTBE) (100mL × 2), merge organic phase,
With saturated sodium bicarbonate solution (150mL × 1), saturated sodium chloride solution (150mL × 1) washing, anhydrous sodium sulfate is dry, takes out
Filter is concentrated under reduced pressure, and obtains 38.1g EM1-1 grease crude product EM1-1, which directly carries out anti-in next step without polishing purification
It answers；
B, the preparation of intermediate E M1-2: under the conditions of anhydrous and oxygen-free, being added 38.1g EM1-1(0.11mol in reaction flask,
1.0eq) -20~-25 DEG C are then cooled to, 5.6g R- diphenyl (pyrroles is added with 200mL tetrahydrofuran, stirring and dissolving
Alkane -2- base) methanol (0.022mol, 0.1eq), stirring, into reaction solution be added dropwise lithium borohydride tetrahydrofuran solution (3.7g,
0.17mol, 1.5eq, 100mL tetrahydrofuran), drop finishes, and reacts at -20~-25 DEG C, TLC monitoring reaction.
Reaction terminates, and 150mL methanol is added dropwise into reaction solution and is quenched.End is quenched, is warming up to 0~5 DEG C, is stirred to react 30
Minute, 400mL water and 200mL ethyl acetate is then added, stirring stands liquid separation.Aqueous layer with ethyl acetate extraction (150mL ×
3), merge organic phase, successively washed with saturated sodium chloride solution (200mL × 1) and water (200mL × 1), anhydrous sodium sulfate is dry
Dry, filtrate decompression obtains 36.6g EM1-2 crude product, and crude product is placed in 150mL ethyl acetate and 300mL n-hexane, stirs, and rises
Temperature is cooled to 10~15 DEG C to back flow reaction after 1h, stand crystallization, filters, and drying obtains 34.7g EM1-2 solid product
EM1-2, yield 94%；
C, the preparation of intermediate E M1-3: in reaction flask, be added 34.7g EM1-2(0.1mol, 1.0eq), 25.5g cylite
(0.15mol, 1.5eq), 21.6g sodium carbonate (0.2mol, 2.0eq) and 400mL toluene, stirring, are warming up to 70 DEG C of reactions, TLC
Monitoring reaction；End of reaction is cooled to room temperature, and is filtered, is washed filter cake with a small amount of toluene, mother liquor is concentrated to dryness, and obtains 42.6g
Solid product EM1-3, yield: 92%；
D, the preparation of intermediate E I-1: under the conditions of anhydrous and oxygen-free, in reaction flask, by 24.7g titanium tetrachloride (0.13mol,
It 1.5eq) is placed in 100mL methylene chloride with 2.8g tetraisopropyl titanate (0.01mol, 0.1eq), stirs, be cooled to -15 DEG C,
Then 300mL EM1-3(42.6g, 0.09mol, 1.0eq is added dropwise) dichloromethane solution, then 18.2g triethylamine is added dropwise
(0.18mol, 2.0eq)；Drop finishes, and stirs 30 minutes, 200mL (E)-N- (4- benzyloxy benzylidene) -4- fluorobenzene is then added dropwise
The dichloromethane solution of amine (33.6g, 0.11mol, 1.2eq)；Drop finishes, and reacts at -15 DEG C, TLC monitoring reaction；It has reacted
Finish, 20mL glacial acetic acid is added dropwise and is quenched, reaction is then warmed to room temperature, stirs, reaction solution 200mL saturated sodium bicarbonate solution
Washing, anhydrous sodium sulfate is dry, and evaporated under reduced pressure obtains 51.2g crude product, which is beaten with 250mL isopropanol, and it is solid to obtain 49g white
Body product E I-1, yield 73%；
E, in reaction flask, 49gEI-1(0.07mol, 1.0eq the preparation of intermediate E I-2: are sequentially added), 26.4g N, O- is bis-
Trimethyl silicane yl acetamide (0.13mol, 1.8eq) and 600mL tetrahydrofuran, stirring, are warming up to 50 DEG C of reactions；Reaction 1 hour
Afterwards, 2.2g tetrabutyl ammonium fluoride (0.007mol, 0.1eq) is added, is stirred to react, TLC monitoring reaction；End of reaction is cooled to
Room temperature is added methanol and is quenched, and 300mL ethyl acetate, stirring, with 100mL water washing organic phase, nothing is added in solvent evaporated
Aqueous sodium persulfate is dry, evaporated under reduced pressure, obtains 37.3g oily product EI-2, which directly carries out in next step；
F, 37.3g EI-2(0.06mol, 1.0eq the preparation of finished product EZ: are added in reaction flask), 350mL methanol and 5.6g
Palladium charcoal, stirring, nitrogen displacement, then it is passed through hydrogen, it is warming up to 30 DEG C~35 DEG C reactions, TLC monitoring reaction.
End of reaction is cooled to room temperature, emptying, and nitrogen displacement filters, and filter cake methanol rinse, filtrate decompression is evaporated to obtain
25.9g EZ crude product, which is placed in 200mL toluene, is warming up to reflux, is stirred to react, then is cooled to room temperature crystallization, is taken out
Filter, it is dry, obtain 24.6g white solid product ezetimibe, yield 95%.
Claims (8)
1. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe, which is characterized in that with (S) -5- oxo -
5- (4- oxazolyl phenyl alkanone -3- base) valerate be starting material, by grignard reaction, asymmetric reduction reaction, substitution reaction,
Addition reaction and deprotection reaction are prepared.
2. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 1, feature
It is, the specific steps are as follows:
A, the preparation of intermediate E M1-1: being that starting is former with (S) -5- oxo -5- (4- oxazolyl phenyl alkanone -3- base) valerate
Material occurs grignard reaction with Grignard Reagent, intermediate E M1-1 is prepared；
B, the preparation of intermediate E M1-2: for intermediate E M1-1 under the action of chiral catalyst, carbonyl is under the action of reducing agent
Occur that intermediate E M1-2 is prepared not to chiral alcoholic extract hydroxyl group is reduced to after reduction reaction；
C, the preparation of intermediate E M1-3: intermediate E M1-2 is reacted under the action of inorganic base with halogenated benzyl, by alcoholic extract hydroxyl group
It is changed into benzyl oxide, intermediate E M1-3 is prepared；
D, the preparation of intermediate E I-1: (E)-N- (4- benzyloxy benzylidene) -4- fluoroaniline and intermediate E M1-3 are in catalyst
With substitution reaction is carried out under the action of lewis acid titanium tetrachloride, intermediate E I-1 is prepared；
E, the preparation of intermediate E I-2: intermediate E I-1 under the catalytic action of tertiary fourth ammonium salt with N, the bis- trimethyl silicon substrate acetyl of O-
Amine reaction, is prepared intermediate E I-2；
F, the preparation of finished product EZ: intermediate E I-2 sloughs benzyl protecting group under the catalytic action of metallic catalyst, obtains end
Product E Z, i.e. ezetimibe.
3. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 2, feature
It is, the reaction temperature in the step a is preferably -15 ~ -20 DEG C, the feed ratio of the Grignard Reagent and starting material are as follows:
2.0:1.0 ~ 2.5:1.0, the Grignard Reagent are p-fluorophenyl magnesium chloride or p-fluorophenyl magnesium bromide.
4. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 2, feature
It is, the chiral catalyst in the step b is (S) -2- methyl-CBS- oxazaborolidine or R- diphenyl (pyrrolidin-2-yl)
The feed ratio of methanol, the chiral catalyst and intermediate E M1-1 are 0.05:1.0 ~ 0.1:1.0, the reduction in the step b
Agent is borane dimethylsulf iotade, sodium borohydride or lithium borohydride, and the feed ratio of the reducing agent and intermediate E M1-1 are 1.05:1.0
~2.0:1.0。
5. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 2, feature
It is, the halogenated benzyl in the step c is benzyl chloride or bromobenzyl, and the feed ratio of the halogenated benzyl and intermediate E M1-2 are 1.3:1.0
~ 1.5:1.0, the inorganic base are potassium carbonate, sodium acetate or sodium carbonate.
6. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 2, feature
It is, the catalyst in the step d is tetraisopropyl titanate, the charge ratio of the titanium tetrachloride and intermediate E M1-3 are as follows:
1.05:1.0 ~ 1.5:1.0, the charge ratio of (E)-N- (4- benzyloxy the benzylidene) -4- fluoroaniline and intermediate E M1-3
Are as follows: 1.2:1.0 ~ 1.5:1.0.
7. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 2, feature
It is, the tertiary fourth ammonium salt in the step e is tetrabutyl ammonium fluoride or tetrabutylammonium bromide, the bis- trimethyl silicon substrate second of the N, O-
The charge ratio of amide and intermediate E I-1 are as follows: 1.2:1.0 ~ 1.8:1.0.
8. a kind of preparation method of azetidinone class blood lipid-lowering medicine ezetimibe according to claim 2, feature
It is, the metallic catalyst in the step f is palladium charcoal, palladium dydroxide or hydroxide carbon, and the metallic catalyst inventory is
The 5-15% of intermediate E I-2 mass.
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| CN115960054A (en) * | 2022-12-15 | 2023-04-14 | 南通常佑药业科技有限公司 | Preparation method of ezetimibe intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931838A (en) * | 2006-10-20 | 2007-03-21 | 屠勇军 | Azetidinone derivative and synthetic method thereof |
| CN101679236A (en) * | 2007-01-24 | 2010-03-24 | 克尔克公司 | Process for the preparation of ezetimibe and derivatives thereof |
| WO2010114762A1 (en) * | 2009-03-30 | 2010-10-07 | Berry And Associates, Inc. | Colorimetric-oxycarbonyl protecting groups for use in organic syntheses |
| WO2010113175A2 (en) * | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
| CN102531985A (en) * | 2011-04-25 | 2012-07-04 | 开原亨泰制药股份有限公司 | Novel method for preparing ezetimibe key intermediate |
| CN103864708A (en) * | 2012-12-12 | 2014-06-18 | 天津市医药集团技术发展有限公司 | Preparation method of ezetimibe intermediate |
| CN104402790A (en) * | 2014-12-28 | 2015-03-11 | 严白双 | Improved method for preparing ezetimibe |
| WO2017168438A1 (en) * | 2016-03-31 | 2017-10-05 | Ind-Swift Laboratories Limited | Process for preparing pure allyl protected keto derivative |
-
2019
- 2019-01-18 CN CN201910048197.9A patent/CN109810038A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931838A (en) * | 2006-10-20 | 2007-03-21 | 屠勇军 | Azetidinone derivative and synthetic method thereof |
| CN101679236A (en) * | 2007-01-24 | 2010-03-24 | 克尔克公司 | Process for the preparation of ezetimibe and derivatives thereof |
| WO2010114762A1 (en) * | 2009-03-30 | 2010-10-07 | Berry And Associates, Inc. | Colorimetric-oxycarbonyl protecting groups for use in organic syntheses |
| WO2010113175A2 (en) * | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
| CN102531985A (en) * | 2011-04-25 | 2012-07-04 | 开原亨泰制药股份有限公司 | Novel method for preparing ezetimibe key intermediate |
| CN103864708A (en) * | 2012-12-12 | 2014-06-18 | 天津市医药集团技术发展有限公司 | Preparation method of ezetimibe intermediate |
| CN104402790A (en) * | 2014-12-28 | 2015-03-11 | 严白双 | Improved method for preparing ezetimibe |
| WO2017168438A1 (en) * | 2016-03-31 | 2017-10-05 | Ind-Swift Laboratories Limited | Process for preparing pure allyl protected keto derivative |
Non-Patent Citations (7)
| Title |
|---|
| C. H. V. A. SASIKALA等: "An Improved and Scalable Process for the Synthesis of Ezetimibe: An Antihypercholesterolemia Drug", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| G. V. SATYANARAYANA等: "Total synthesis of ezetimibe and their key stereoisomers", 《HETEROCYCLIC LETTERS》 * |
| 余长泉等: "依替米贝合成新工艺的研究", 《高校化学工程学报》 * |
| 卡拉瑟斯等: "《当代有机合成方法》", 31 March 2006, 华东理工大学出版社 * |
| 吴桂英: "降血脂药物依折麦布的合成工艺研究", 《郑州大学硕士学位论文》 * |
| 张付利: "《有机化学 第2版》", 31 December 2017, 河南大学出版社 * |
| 王建新: "《精细有机合成》", 30 June 2000, 中国轻工业出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115960054A (en) * | 2022-12-15 | 2023-04-14 | 南通常佑药业科技有限公司 | Preparation method of ezetimibe intermediate |
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