CN108059608A - A kind of preparation method of Ezetimibe - Google Patents
A kind of preparation method of Ezetimibe Download PDFInfo
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- CN108059608A CN108059608A CN201610973998.2A CN201610973998A CN108059608A CN 108059608 A CN108059608 A CN 108059608A CN 201610973998 A CN201610973998 A CN 201610973998A CN 108059608 A CN108059608 A CN 108059608A
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to a kind of preparation method of Ezetimibe, which respectively walks high income, and process stabilizing, aftertreatment technology is simple, without the not easy-operating purification process such as column chromatography, is conducive to industrialized production.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to a kind of preparation method of Ezetimibe.
Background technology
Entitled 1- (4- fluorophenyls) -3 (R)-[- 3 (S)-hydroxypropyls of 3- (4- fluorophenyls)] -4 (S) of chemistry of Ezetimibe -
(4- hydroxyphenyls) -2- azetidines (azetidine) ketone, structural formula are as follows:
It is also unique cholesterol absorption inhibitor that Ezetimibe, which is first, is turned by selective depression small intestine cholesterol
Albumen is transported, enteron aisle inner cholesterol is effectively reduced and absorbs, reduce blood plasma cholesterol level and hepatic cholesterol reserves.
US5886171 discloses a kind of by 4- benzyloxies benzylidene -4- fluoroanilines and former for starting to fluoro acetophenone
Material, unsaturated phenyl ketone intermediate is obtained by multistep reaction, and final product is being obtained by reduction, debenzylation.But the conjunction
It needs to protect using Pd/C catalytic hydrogenation C-C unsaturated double-bonds and debenzylation under elevated pressure conditions into route.Pd/C is catalyzed hydrogen
Change, unsuitable industrialized production more demanding to consersion unit.In addition, the use of precious metals pd is not only increased and is produced into
This, also makes the control of heavy metal limit in product become difficult, and the operation of removing heavy metals need to be gone by adding final product.
CN1050830C discloses a kind of synthetic route using monomethyl succinate acyl chlorides as starting material.The synthetic route
It also needs to protect using Pd/C catalytic hydrogenations debenzylation under elevated pressure conditions, thus it is more demanding to consersion unit, and hydrogen
Gas is inflammable and explosive.It also needs using Pd catalyzing and condensings, the use of noble metal equally adds production cost and later stage quality control
Difficulty.In addition, the introducing for introducing p-fluorophenyl employs kumada coupling reactions, it is well known that the reaction requires absolute
Oxygen free operation technology, difficult and reaction substrate complicated for operation is inflammable and explosive, therefore the synthetic route is not suitable for industrialized production.
The step for although technique disclosed in CN1130342C is avoided using Pd/C catalytic hydrogenations, but the route is closing
Into early period begin to chiral reduction carbonyl, add reduction reaction difficulty, also increase the usage amount of chiral catalyst, produce
Cost greatly increases.There are 4 steps to be reacted to final product after reduction, add the risk of chiral hydroxyl group racemization, be difficult to guarantee chiral hydroxyl
The chiral purity of base.
The syntheti c route of existing Ezetimibe has respective advantage and disadvantage, and urgent need finds simple process and low cost, product
Purity is high again suitable for the preparation process of industrialized production.
The content of the invention
The object of the present invention is to it is simple to overcome the deficiencies of the prior art and provide a kind of synthetic operation, without using valuable gold
Belong to reagent, reaction routine, high income, synthetic method at low cost, suitable for industrial Ezetimibe.
The technical solution adopted in the present invention is a kind of preparation method of Ezetimibe, and process route is as follows:
Ezetimibe preparation method of the present invention comprises the following steps:
Step (1):Comprising step (a) and step (b),
(a) fluorobenzoyl butyric acid is reacted in the presence of a base with acyl chlorides;
(b) above-mentioned reaction product is reacted in the presence of a catalyst with (S) -4- oxazolyl phenyl alkane -2- ketone, obtains compound II;
The preferred lithium chloride of catalyst.
Step (2):Compound ii is reacted with ethylene glycol, trimethyl orthoformate, N- bromo-succinimides (NBS), is obtained
Compound III.
Step (3):4- [[(4- fluorophenyls) imines] methyl]-phenol and tert-butyl chloro-silicane are anti-in the presence of a base
Should, obtain compounds Ⅳ.
Step (4):Compound III and compounds Ⅳ react in the presence of a catalyst, obtain compound V;The catalyst is excellent
Select tiron.
Step (5):Compound V and double (trimethyl silicon substrate) acetamides of N, O- react, and obtain compound VI, it is preferred to use
Tetrabutyl ammonium fluoride is as catalyst.
Step (6):Compound VI is deprotected group in acid condition, obtains compound VII.
Step (7):Compound VII and pivaloyl chloride react in the presence of a base, obtain compound VIII.
Step (8):Compound VIII reduces, and obtains compound Ⅸ;It is preferred that (R) -2- methyl-CBS- oxazaborolidines, borine two
It is reacted in the presence of dimethylsulfide complex.
Step (9):Compound Ⅸ hydrolyzes in alkaline conditions, obtains compound X.
As example, the preparation method concrete operation step of Ezetimibe of the present invention is as follows:
Step (1):
Comprising step (a) and step (b),
Step (a) will suspend to fluorobenzoyl butyric acid in organic solvent, and add in organic base, be slowly added dropwise at room temperature
Acyl chlorides, when reaction 1-6 is small;
Step (b), above-mentioned reaction solution add in organic solvent after being concentrated to dryness, and add (S) -4- oxazolyl phenyl alkane -2- ketone
With catalytic amount anhydrous lithium chloride, when reaction 1-10 is small, compound II is obtained after separation;Further preferably, gained compound II is used
Alcohols solvent recrystallizes, and obtains purified product.The structural formula of compound ii is:
In step (a), the organic solvent is aprotic solvent, for dichloromethane, tetrahydrofuran, N, N- dimethyl formyls
Amine or acetonitrile, preferably dichloromethane;The organic base is triethylamine, DBU, pyridine or DMAP, preferably triethylamine;The acyl chlorides is
Pivaloyl chloride, methylchloroformate, ethyl chloroformate or isopropyl chlorocarbonate, preferably pivaloyl chloride.
In step (b), the organic solvent is dichloromethane, chloroform, tetrahydrofuran, n,N-Dimethylformamide or second
Nitrile, preferably tetrahydrofuran;The alcohols solvent for recrystallization is methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol, preferably isopropyl
Alcohol.
Step (2):
Compound ii is suspended in ethylene glycol, sequentially adds trimethyl orthoformate, N- bromo-succinimides (NBS),
80~120 DEG C are heated to, reacts 1-10h, reaction solution natural cooling is precipitated solid, compound III is obtained by filtration.Compound III
Structure is:
Purification step is further further included, compound III adds in isopropanol and 2h is stirred at room temperature, and filters, isopropanol elution filter
Cake, the dry compound III that must be purified.
Step (3):
4- [[(4- fluorophenyls) imines] methyl]-phenol is dissolved in organic solvent, be cooled at 0 DEG C sequentially add it is organic
Alkali and tert-butyl chloro-silicane are stirred at room temperature lower reaction 1-10h, compounds Ⅳ are obtained after separation.The structure of compounds Ⅳ
For:
Wherein, organic solvent described in step (3) is aprotic solvent, for dichloromethane, tetrahydrofuran, N, N- dimethyl
Formamide, acetonitrile, preferably dichloromethane;The organic base is triethylamine, DBU, pyridine, DMAP, preferably imidazoles, imidazoles.
Step (4):
It is dissolved in organic solvent after compound III and compounds Ⅳ are mixed, tiron is slowly added at -60~0 DEG C,
Insulation reaction 1-5h, is quenched, and compound V is obtained after separation;Further preferably, gained compound V adds in ethyl acetate, stirring
Purified product is obtained by filtration in 0.5-5h.The structure of compound V is:
Wherein, the organic solvent for dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, n,N-Dimethylformamide,
Acetonitrile, preferably dichloromethane;The tiron is one or two kinds of combination, preferably four in titanium tetrachloride or tetraisopropyl titanate
Two kinds of combinations of titanium chloride and tetraisopropyl titanate;It is highly preferred that the tiron is molten by titanium tetrachloride and tetraisopropyl titanate
In dichloromethane, stirred at 0-5 DEG C obtained by 30min preparations.
Further, ethyl acetate whipping temp is preferably 50~60 DEG C, and the amount that every gram of crude product adds in ethyl acetate is preferred
For 1-10mL, ethyl acetate can remove crude product stirring V optical isomer of compound of the overwhelming majority.
Step (5):
Compound V is added in into organic solvent, adds in N at room temperature, double (trimethyl silicon substrate) acetamides (BSA) of O- stir
Reaction 1-5h is mixed, tetrabutyl ammonium fluoride hydrate is added in and continues to be stirred to react 1-10h.It is quenched, isolated compound VI.Chemical combination
The structural formula of object VI is as follows:
Wherein, organic solvent described in step (5) for dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N, N- diformazans
The combination of base formamide, acetonitrile one or more, preferably acetonitrile;Further, the reagent of reaction is quenched as water or alcohols, alcohol
Class solvent is methanol, ethyl alcohol, isopropanol or n-butanol.
Step (6):
Compound VI is dissolved in organic solvent, then add in acid and reaction system is heated to 50~100 DEG C of reactions.It stirs
Isolated compound VII after reaction 1-10h is mixed, the structural formula of compound VII is as follows:
Wherein, organic solvent described in step (6) for chloroform, carbon tetrachloride, tetrahydrofuran, n,N-Dimethylformamide or
Alcohols solvent, the alcohols solvent are methanol, ethyl alcohol, isopropanol or n-butanol, preferably isopropanol;It is described acid for hydrochloric acid, sulfuric acid,
Glacial acetic acid or p-methyl benzenesulfonic acid, preferably sulfuric acid.
Step (7):
Compound VII is dissolved in organic solvent, organic base and pivaloyl chloride is added dropwise to above-mentioned reaction system, is added dropwise
After react 2-10h, be quenched after the reaction was complete with dilute hydrochloric acid, isolated compound VIII;Further preferably, gained compound
VIII is recrystallized to give refined product;The structural formula of compound VIII is as follows:
Wherein, in step (7), the organic solvent is aprotic solvent, for dichloromethane, tetrahydrofuran, N, N- diformazans
Base formamide, acetonitrile, preferably dichloromethane;The organic base is triethylamine, DBU, preferably pyridine, triethylamine.
Further, the concentration that reaction dilute hydrochloric acid used is quenched in step (7) is 1mol/L, and reaction is collected after being quenched to be had
Machine phase, organic phase are respectively washed once with saturated sodium bicarbonate and saturation NaCl, anhydrous Na2SO4Crude product is concentrated to give after drying.
Further, described in step (7) in crude product with recrystallizing methanol, the dosage of methanol 5ml is added in for every gram of crude product
Methanol.
Step (8):
(R) -2- methyl-CBS- oxazaborolidines, borane dimethylsulfide ether complexes are added in organic solvent, at -30~-5 DEG C
The tetrahydrofuran solution of compound VIII is slowly added dropwise.After completion of the reaction, alcohols and diluted acid, stirring, isolatedization are added dropwise successively
Object Ⅸ is closed, the chemical formula of compound Ⅸ is as follows:
Wherein, in step (8), the organic solvent is one kind or more in dichloromethane, tetrahydrofuran or dioxane
Kind, preferably tetrahydrofuran;The alcohols is methanol, ethyl alcohol, isopropanol or n-butanol, preferably methanol;The diluted acid for dilute hydrochloric acid,
Dilute sulfuric acid or spirit of vinegar, preferably dilute hydrochloric acid.
Step (9):
Compound Ⅸ is dissolved in organic solvent, alkali is added in and reacts 0.5~10h, separation obtains compound X;It is further excellent
Choosing, gained compound X is through being recrystallized to give Ezetimibe finished product.Its structural formula is as follows:
Wherein in step (9), the organic solvent be methanol, ethyl alcohol, dichloromethane, tetrahydrofuran or dioxane, it is excellent
Select tetrahydrofuran;The alkali includes the alcoholic solution of organic base or metal hydroxides, preferably metal hydroxides be sodium hydroxide,
Potassium hydroxide, lithium hydroxide or cesium hydroxide, preferred alcoholic solution is methanol, ethyl alcohol;The recrystallization solvent for water, methanol,
One or more kinds of combinations of ethyl alcohol, isopropanol, the tert-butyl alcohol, preferred alcohol.
Beneficial effects of the present invention are as follows:
A) process route that the present invention designs avoids the reaction step of Pd/C catalysis, of less demanding to consersion unit, again
Hazardous agents and harsh operation control are not required, greatly reduce the danger of operation, it is simple for process, it is easy to operate, it is suitble to work
Industry application.
B) preparation method of the invention need not use precious metals pd, not only reduce production cost, also simplify finished product
Purifying process.
C) the Ezetimibe finished product purity obtained by preparation method of the invention is high, and chiral isomer content is low, and technique is reappeared
Property is good.
D) process route of the invention respectively walks high income, and process stabilizing, aftertreatment technology is simple, and no column chromatography etc. is not easy
The purification process of operation, is conducive to industrialized production.
Description of the drawings
Fig. 1 is Ezetimibe1H-NMR collection of illustrative plates.
Specific embodiment
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.Furthermore, it is to be understood that after recorded content of the invention has been read, this field skill
Art personnel can make various changes or modifications the present invention, and such equivalent forms equally fall within limited range of the present invention.
The preparation of 1. compound ii of embodiment
Fluorobenzoyl butyric acid (50g, 238mmol) will be suspended at room temperature in the dichloromethane of 500mL, temperature will be dropped
To -10 DEG C, triethylamine (28.9g, 285mmol) is added in, solution becomes clarification, pivaloyl chloride (34.4g, 285mmol) is slowly existed
It is added dropwise in 0.5h in reaction kettle, in holding within 5 DEG C of temperature.20-25 DEG C of reaction 3h is warming up to after being added dropwise.Reaction solution concentrates
The tetrahydrofuran of 300mL is added in after doing, is filtered, (S) -4- oxazolyl phenyl alkane -2- ketone (58.2g, 357mmol) is added in filtrate
With anhydrous lithium chloride (1.01g, 23.8mmol), when 20-25 DEG C of reaction 4 is small, TLC monitoring raw material reactions finish, and add in 500mL
Saturated ammonium chloride, when 20~25 DEG C of stirrings 0.5 are small.Liquid separation concentrates organic phase, successively with 5% citric acid, unsaturated carbonate hydrogen
Sodium, saturated sodium-chloride washing.Organic phase concentrates, and adds in isopropanol (200mL) and recrystallizes, filters, and drying obtains white compound
II (75.6g, yield 89.4%).
The preparation of 2. compound III of embodiment
N2Under protection, orthoformic acid is sequentially added into ethylene glycol (250mL) suspension of compound II (40g, 113mmol)
Trimethyl (12.0g, 113mmol), N- bromo-succinimides (20.0g, 113mmol), 100 are heated to by above-mentioned reaction system
~105 DEG C, when reaction 7 is small.Reaction solution is cooled to room temperature, and solid is precipitated, and product is collected in filtering, is added in isopropanol (150mL) and is obtained
2h is stirred at room temperature in suspension, filters, dry, obtains compound as white solid III (41.2g, yield 91.6%).
The preparation of 3. compounds Ⅳ of embodiment
4- [[(4- fluorophenyls) imines] methyl]-phenol (35.0g, 163mmol) is dissolved in dichloromethane (300mL)
In, 0 DEG C is cooled to, imidazoles (13.3g, 195mmol) and tert-butyldimethylsilyl chloride silicon (29.4g, 195mmol), drop are added dropwise successively
It adds and reacts 6h at room temperature after finishing.The reaction was complete for TLC monitorings raw material, adds in water and stirs 10min, liquid separation, organic phase saturation
Brine It, it is dry, it is concentrated to give compounds Ⅳ (42.3g, yield 79%).
The preparation of 4. compound V of embodiment
Titanium tetrachloride (11.9g, 62.6mmol) is added in dichloromethane (100mL), is cooled to 0-5 DEG C, adds in titanium
Sour tetra-isopropyl (17.8g, 62.6mmol) keeps for use after 0-5 DEG C of reaction 30min.
Compound III (30.0g, 75.1mmol) and compound IV (20.6g, 62.6mmol) are dissolved in dichloromethane
In (400mL), -40 DEG C are down to, the tiron prepared is slowly added in this reaction solution, is kept for Nei Wen -40 DEG C, in 30min
It is added dropwise.This thermotonus 3h is kept, keeps addition isopropanol at Nei Wen -40 DEG C that reaction is quenched.Reaction solution is poured into PH=7
In tartaric acid buffer, two-phase is separated after stirring.Water is mutually extracted once with dichloromethane, merges organic phase, is washed twice, saturation
Sodium chloride is washed and separates organic phase afterwards twice, and organic phase is evaporated under reduced pressure to dry.It adds in ethyl acetate and is heated to 55 DEG C of stirring 1h, mistake
Filter, with ethyl acetate filter wash cake.The solid being collected into is dried to obtain white compound V (38.2g, yield 84%) in an oven.
The preparation of 5. compound VI of embodiment
Compound V (40g, 54.9mmol) is suspended in acetonitrile (500mL), adds in N, the double (trimethyl silicanes of O- at room temperature
Base) acetamide (13.4g, 65.9mmol), stirs and controls temperature at 25 DEG C, react the tetrabutyl fluorination of addition catalytic amount after 3h
Ammonium (1.43g, 5.49mmol), at this time reaction solution clarification is gradually begun to change by white suspension, clarified completely after about 1h.Xiang Ti
Water (300mL) is added in system, reaction is quenched, and add in n-hexane (400mL) stirring liquid separation, the organic phase saturated common salt of collection
Washing, anhydrous Na2SO4Dry, filtering is concentrated to give faint yellow oily compound VI (26.0g, yield 84%).
The preparation of 6. compound VII of embodiment
Compound VI (30.0g, 53.0mmol) is dissolved in isopropanol (200mL), is slowly added into above-mentioned solution
H2SO4(2mol/L, 50mL) reacts 3h after reaction system is heated to 70 DEG C.Reaction system is cooled to room temperature, slowly successively
Saturated sodium bicarbonate aqueous solution (500mL) and dichloromethane (300mL) are added in, stirs liquid separation after 10min, water mutually uses dichloromethane
Back extraction once, merges organic phase, and organic phase is washed once with saturation NaCl, anhydrous Na2SO4It is concentrated after drying, obtains compound VII
(18.6g, yield 86%).
The preparation of 7. compound VIII of embodiment
Compound VII (18.0g, 44.2mmol) is dissolved in dichloromethane (150mL), three second are added dropwise at 25 DEG C successively
Amine (8.95g, 88.4mmol) and pivaloyl chloride (6.39g, 53.0mmol).5h is reacted after being added dropwise at room temperature.To reactant
1N hydrochloric acid is slowly added dropwise in system and stirs 10min, liquid separation, organic phase uses saturated sodium bicarbonate (200mL) and saturated common salt successively
Water (200mL) is respectively washed once, anhydrous Na2SO4It is concentrated after drying, obtains crude product 20g.It is recrystallized in crude product with methanol (100mL), is cold
But drying obtains compound VIII (17.5g, yield 81%) after crystallization, suction filtration.
The preparation of 8. compound Ⅸ of embodiment
N2Under protection, tetrahydrofuran (100mL) is added in into reaction kettle, -15 DEG C of temperature is controlled, sequentially adds (R) -2- first
Base-CBS- oxazaborolidines (8.12g, 29.3mmol) and borane dimethylsulfide ether complexes (2mol/L, 25mL).After stirring 1h, control
Tetrahydrofuran (50mL) solution of compound VIII (12.0g, 24.4mmol) is slowly added dropwise in temperature processed at -15 DEG C, is added dropwise
Afterwards, the reaction system the reaction was continued 1h.After completion of the reaction, methanol (50mL) is added dropwise at -15 DEG C and reaction is quenched, be slow added into
Simultaneously 1h is stirred at room temperature in 1N hydrochloric acid.Dichloromethane (200mL) and water (200mL) are added in, organic phase, saturation food are collected in stirring
Salt water washing, anhydrous magnesium sulfate is dry, filters, is concentrated to give faint yellow compound Ⅸ (9.5g, yield 79%, purity 90%).
The preparation of 9. compound Ⅹ (Ezetimibe finished product) of embodiment
Compound Ⅸ (9.0g, 18.2mmol) is dissolved in tetrahydrofuran (50mL), is cooled to -20 DEG C, adds in hydroxide
Methanol (15mL) solution of sodium (2.19g, 54.7mmol).Charging finishes reaction 45min.After completion of the reaction, reaction solution pours into 1N
Hydrochloric acid (100mL) is layered after standing with reaction is quenched in the mixed solution of ethyl acetate (100mL), collects organic phase, saturation food
Salt water washing, anhydrous magnesium sulfate drying, filtering are concentrated to give crude product 7.4g, purity is about 90%, and isomers total content is about
0.7%.Above-mentioned crude product obtains Ezetimibe finished product (6.5g, yield 84%, purity with 95% ethyl alcohol (50mL) recrystallizing and refining>
99%, isomers total content<0.15%).
1H NMR datas:(400Hz,DMSO-d6)δ1.72-1.90(m,4H),3.09-3.11(m,1H),4.51-4.54
(m, 1H), 4.81-4.82 (d, 1H, J=3.6Hz), 5.28-5.59 (d, 1H, J=3.6Hz), 6.78-6.80 (m, 2H),
7.10-7.15(m,4H),7.22-7.25(m,4H),7.31-7.34(m,2H),9.52(s,1H).
More than, embodiments of the present invention are illustrated.But the present invention is not limited to the above embodiments.It is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in the guarantor of the present invention
Within the scope of shield.
Claims (10)
1. a kind of preparation method of Ezetimibe, process route are:
2. the preparation method of Ezetimibe as described in claim 1, comprises the following steps:
Step (1), comprising step (a) and step (b),
(a) fluorobenzoyl butyric acid is reacted in the presence of a base with acyl chlorides;
(b) above-mentioned reaction product is reacted in the presence of a catalyst with (S) -4- oxazolyl phenyl alkane -2- ketone, obtains compound II;It is described
The preferred lithium chloride of catalyst;
Step (2), compound ii are reacted with ethylene glycol, trimethyl orthoformate, N- bromo-succinimides (NBS), obtain chemical combination
Object III;
Step (3), 4- [[(4- fluorophenyls) imines] methyl]-phenol and tert-butyl chloro-silicane react in the presence of a base,
Obtain compounds Ⅳ;
Step (4), compound III and compounds Ⅳ react in the presence of a catalyst, obtain compound V;The preferred titanium of catalyst
Reagent;
Double (trimethyl silicon substrate) acetamide reactions of step (5), compound V and N, O-, obtain compound VI, it is preferred to use four fourths
Base ammonium fluoride is as catalyst;
Step (6), compound VI are deprotected group in acid condition, obtain compound VII;
Step (7), compound VII and pivaloyl chloride react in the presence of a base, obtain compound VIII;
Step (8), compound VIII reduce, and obtain compound Ⅸ;It is preferred that (R) -2- methyl-CBS- oxazaborolidines, borane dimethylsulfide
It is reacted in the presence of ether complexes;
Step (9), compound Ⅸ hydrolyze in alkaline conditions, obtain compound X.
3. the preparation method of Ezetimibe as claimed in claim 1 or 2, concrete operation step are as follows:
Step (1), comprising step (a) and step (b),
(a) it will suspend at room temperature to fluorobenzoyl butyric acid in organic solvent, and add in organic base, acyl chlorides is slowly added dropwise, react
When 1-6 is small;
(b) above-mentioned reaction solution adds in organic solvent after being concentrated to dryness, add (S) -4- oxazolyl phenyls alkane -2- ketone and catalytic amount without
Water lithium chloride when reaction 1-10 is small, obtains compound II after separation;Further preferably, gained compound II alcohols solvent weights
Crystallization, obtains purified product;
Step (2), compound ii is suspended in ethylene glycol, sequentially adds trimethyl orthoformate, N- bromo-succinimides
(NBS), 80~120 DEG C are heated to, reacts 1-10h, reaction solution natural cooling is precipitated solid, compound III is obtained by filtration;
4- [[(4- fluorophenyls) imines] methyl]-phenol is dissolved in organic solvent, is cooled at 0 DEG C and sequentially adds by step (3)
Organic base and tert-butyl chloro-silicane are stirred at room temperature lower reaction 1-10h, compounds Ⅳ are obtained after separation;
Step (4) dissolves in organic solvent after mixing compound III and compounds Ⅳ, and titanium examination is slowly added at -60~0 DEG C
Agent, insulation reaction 1-5h, is quenched, and compound V is obtained after separation;Further preferably, gained compound V adds in ethyl acetate,
0.5-5h is stirred, purified product is obtained by filtration;
Step (5), compound V is added in into organic solvent, adds in N at room temperature, and double (trimethyl silicon substrate) acetamides of O- stir
Reaction 1-5h is mixed, tetrabutyl ammonium fluoride is added in and continues to be stirred to react 1-10h, be quenched, isolated compound VI;
Step (6), compound VI is dissolved in organic solvent, then adds in acid, and reaction system is heated to 50~100 DEG C instead
Should, it is stirred to react 1-10h, isolated compound VII;
Step (7), compound VII is dissolved in organic solvent, and organic base and pivaloyl chloride is added dropwise to above-mentioned reaction system, is added dropwise
After react 2-10h, be quenched after the reaction was complete with dilute hydrochloric acid, isolated compound VIII;Further preferably, gained chemical combination
Object VIII is recrystallized to give refined product;
Step (8) adds in (R) -2- methyl-CBS- oxazaborolidines, borane dimethylsulfide ether complexes to organic solvent, and -30~-5
The tetrahydrofuran solution of compound VIII is slowly added dropwise at DEG C, after completion of the reaction, alcohols and diluted acid are added dropwise successively, stirring separates
To compound Ⅸ;
Step (9), compound Ⅸ is dissolved in organic solvent, is added in alkali and is reacted 0.5~10h, separation obtains compound X;Further
It is preferred that gained compound X is through being recrystallized to give Ezetimibe finished product.
4. the preparation method of Ezetimibe as claimed in claim 3, in step (a), the organic solvent is aprotic solvent,
It is preferred that dichloromethane, tetrahydrofuran, n,N-Dimethylformamide or acetonitrile, most preferably dichloromethane;The organic base is three second
Amine, DBU, pyridine or DMAP;The acyl chlorides be pivaloyl chloride, methylchloroformate, ethyl chloroformate or isopropyl chlorocarbonate, preferably
Pivaloyl chloride;
In step (b), the organic solvent is dichloromethane, chloroform, tetrahydrofuran, n,N-Dimethylformamide or acetonitrile;
The alcohols solvent is methanol, ethyl alcohol, isopropanol or the tert-butyl alcohol.
5. the preparation method of Ezetimibe as claimed in claim 3, organic solvent described in step (3) is aprotic solvent,
It is preferred that dichloromethane, tetrahydrofuran, n,N-Dimethylformamide or acetonitrile, most preferably dichloromethane;The organic base is three second
Amine, DBU, pyridine, DMAP or imidazoles, preferably imidazoles.
6. the preparation method of Ezetimibe as claimed in claim 3, in step (4), the organic solvent is dichloromethane, chlorine
Imitative, carbon tetrachloride, tetrahydrofuran, n,N-Dimethylformamide or acetonitrile, preferably dichloromethane;The tiron is titanium tetrachloride
Or one or two kinds of combination in tetraisopropyl titanate, it is preferable that the tiron is molten by titanium tetrachloride and tetraisopropyl titanate
It is stirred in dichloromethane and at 0-5 DEG C obtained by 30min preparations;
Preferably, ethyl acetate whipping temp is 50~60 DEG C;It is furthermore preferred that the amount that every gram of product adds in ethyl acetate is 1-
10mL。
7. the preparation method of Ezetimibe according to claim 3, organic solvent described in step (5) is dichloromethane,
One or more kinds of combinations in chloroform, carbon tetrachloride, tetrahydrofuran, n,N-Dimethylformamide or acetonitrile, preferably acetonitrile;
Agents useful for same is quenched as water or alcohols solvent, alcohols solvent is methanol, ethyl alcohol, isopropanol or n-butanol.
8. the preparation method of Ezetimibe as claimed in claim 3, organic solvent described in step (6) is chloroform, four chlorinations
Carbon, tetrahydrofuran, n,N-Dimethylformamide or alcohols solvent, the alcohols solvent are methanol, ethyl alcohol, isopropanol or positive fourth
Alcohol, preferably isopropanol;The acid is hydrochloric acid, sulfuric acid, glacial acetic acid or p-methyl benzenesulfonic acid.
9. the preparation method of Ezetimibe as claimed in claim 3, in step (7), the organic solvent is aprotic solvent,
It is preferred that dichloromethane, tetrahydrofuran, N,N-dimethylformamide or acetonitrile;The organic base is triethylamine, DBU or pyridine;
The concentration of the dilute hydrochloric acid is 1mol/L;Recrystallization solvent for use is methanol.
10. the preparation method of Ezetimibe as claimed in claim 3, in step (8), the organic solvent is dichloromethane,
One or more in tetrahydrofuran or dioxane;The alcohols is methanol, ethyl alcohol, isopropanol or n-butanol;The diluted acid
For dilute hydrochloric acid, dilute sulfuric acid or spirit of vinegar;
In step (9), the organic solvent is methanol, ethyl alcohol, dichloromethane, tetrahydrofuran or dioxane;The alkali includes
The alcoholic solution of organic base or metal hydroxides, preferably metal hydroxides are sodium hydroxide, potassium hydroxide, lithium hydroxide or hydrogen
Cesium oxide, preferred alcoholic solution is methanol, ethyl alcohol;Preferably, solvent for use is recrystallized as water, methanol, ethyl alcohol, isopropanol, uncle
One or more kinds of combinations of butanol.
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CN106986806A (en) * | 2017-04-07 | 2017-07-28 | 四川智强医药科技开发有限公司 | The process for purification of Ezetimibe |
CN106986806B (en) * | 2017-04-07 | 2019-12-31 | 四川智强医药科技开发有限公司 | Ezetimibe refining method |
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