CN106397292A - Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe - Google Patents

Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe Download PDF

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CN106397292A
CN106397292A CN201610831623.2A CN201610831623A CN106397292A CN 106397292 A CN106397292 A CN 106397292A CN 201610831623 A CN201610831623 A CN 201610831623A CN 106397292 A CN106397292 A CN 106397292A
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compound
acid
reaction
ezetimibe
catalyst
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罗瑞雪
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Suzhou Puluoda Biological Science and Technology Co Ltd
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Suzhou Puluoda Biological Science and Technology Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides an ezetimibe intermediate, a synthesis method of the intermediate and a synthesis method of ezetimibe. The method is short in synthetic route. The method includes the steps of making fluorobenzene as the initial raw material sequentially have acylation reaction with glutaric anhydride and 4(S)-4-phenyl oxazolidinone to generate a compound II, protecting carbonyl through 2,2-bis-substituted-1,3-propylene glycol to obtain a compound III, generating a compound V through the compound III and a compound IV under the catalysis of titanium tetrachloride, cyclizing the compound V to generate a compound VI, hydrolyzing the compound VI to obtain a compound VII, and reducing the compound VII through a borane chiral reducing agent and removing a benzyl protecting group in a hydrogenated mode to obtain the ezetimibe. The method is high in yield, little in side reaction and suitable for industrial mass production.

Description

The intermediate of ezetimibe and its synthetic method of synthetic method and ezetimibe
Technical field
The present invention relates to a kind of synthetic method of cholesterol absorption inhibitor is and in particular to arrive ezetimibe and its centre Body, i.e. (3R, 4S) -1- (4- fluorophenyl) -3- [3- (4- fluorophenyl) -3 (S)-hydroxypropyl] -4- (4- hydroxyphenyl) -2- azacyclo- Butanone and its a kind of novel synthesis of intermediate.
Background technology
Ezetimibe
(Ezetimibe), chemical entitled (3R, 4S) -1- (4- fluorophenyl) -3- [3- (4- fluorophenyl) -3 (S)-hydroxypropyl Base] -4- (4- hydroxyphenyl) -2- aza cyclo-butanone, its structural formula is as follows：
Ezetimibe is the new cholesterol-lowering drug developed jointly by Merck company and Schering-Plough company, Obtain U.S. FDA approval in October, 2002, November in the same year is in Germany's listing.Ezetimibe is that first selective cholesterol is inhaled Receive inhibitor, it by suppress foreign aid's property cholesterol small intestine absorption reduce in blood plasma LDL-C and The concentration of T-CHOL, and do not affect the absorption to other nutrient contents.Low degree fat egg can be reduced when being clinically used alone White cholesterol (LDL-C), T-CHOL is significantly reduced, increasing high density lipoprotein (HDL-C)；Sharing with statins can Reduce the usage frequency of statins high dose, drug effect is 8 times of alone statins norcholesterol effect.
The method that United States Patent (USP) US57671115 adopts be by (4- benzyloxy-benzylidene)-(4- fluorophenyl)-amine and 4- chloroformyl methyl butyrate reacts, and is then converted into acyl chlorides after product hydrolysis, under tetra-triphenylphosphine palladium catalysis and to fluorophenyl Zinc chloride reacts, and then catalytic hydrogenation obtains ezetimibe to chiral reduction again, and the synthesis of azepine cyclic ketones in this method does not have hand Sexual behavior mode, midbody compound will pass through column chromatography chiral separation, thus increased cost, is not suitable for industrialized production.
World patent WO2000/34240 first passes through chiral reduction and obtains (S) -3- hydroxy compounds, then adjacent in carbonyl Position connects side chain (E)-N- (4- fluorophenyl) -4- hydroxy benzenes methylene amine, and finally cyclization deprotection obtains ezetimibe again.The method exists During chiral reduction carbonyl, due to chiral radicals from carbonyl farther out, the activity chiral carbon content obtaining after reduction is low, and chiral reduction tries Agent consumption is big, and it is low to connect chain reaction yield, causes this route high cost.
World patent WO2007/072088 provides a kind of method that spent glycol protects the other carbonyl of phenyl ring, due to second Glycol activity is weaker, so reaction is relatively difficult, and the hydrolysis carrying out in deprotection can cause many side reactions.
World patent WO20061157080 is synthesized beta-lactam nucleus by staudinger, in step behind Use the tetra-triphenylphosphine palladium catalyst of costliness, be also performed to the grignard reaction of anhydrous and oxygen-free, severe reaction conditions, cost is held high Expensive, be not suitable for industrialized production.
World patent WO2005/049592 first becomes hydroxyl the carbonyl reduction on phenyl ring side, then uses chlorosilane reagent To protect hydroxyl, because this hydroxyl activity is weaker it is impossible to well and chlorosilane reagent reacting, protected effect is poor.
In the synthetic method of above-mentioned ezetimibe all there is problems that synthetic route is long, yield than relatively low, have More than 50% intermediate is wasted by reaction scheme, or the chiral reducing agent consumption using is big, expensive, cost Height, all these technology bring very big inconvenience to industrialized production.
Based on above-mentioned consideration, the present invention adopts 2,2-, bis- replacements -1,3-PD as carbonyl protective agent, and reaction yield is high (>=89%), deprotection is fast rapid, yield is affected little.
Content of the invention
It is an object of the present invention to provide the new synthesis route of ezetimibe, this reaction method can economic convenient realization industry It is combined to ezetimibe.
A kind of intermediate for synthesizing ezetimibe is it is characterised in that it is compound III.
Wherein, R1、R2It independently is hydrogen or C1-C4 low alkyl group.
Compound II generates with replacing the reaction in atent solvent in the presence of dehydrating agent, acidic catalyst of 1,3- propane diols Compound III
Described compound II and 2,2- bis- replacement -1,3- propane diols molar equivalent is than for 1:Replacement 1,3- third described in 1～5 The structural formula of glycol is compound VIIII, and wherein R1、R2It independently is hydrogen or C1-C4 low alkyl group
.It is R wherein as a kind of optimal way1、R2For methyl.
Described dehydrating agent is molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, phosphorus pentoxide, calcium chloride, silica gel, oxidation Calcium, magnesium nitrate, alchlor, phosphorus trichloride, phosphorus pentachloride, POCl3 or TFAA.
Described acidic catalyst is inorganic acid or organic acid.Inorganic acid is sulfuric acid, hydrogen chloride, hydrobromic acid, hydroiodic acid, nitre Acid, phosphoric acid or polyphosphoric acids, organic acid is C1-C4 carboxylic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
Described atent solvent is the aromatic hydrocarbons of the ether, the nitrile of C2-C12 or C6-C12 of C2-C12.
Another kind of intermediate for synthesizing ezetimibe is it is characterised in that it is compound V
Wherein, R1、R2It independently is hydrogen or C1-C4 low alkyl group.
Compound III and compound IV do the bar of catalyst in the protection of inert gas, inert organic solvents, titanium compound Under part, reaction generates V compound.
Titanium compound catalyst is different oxygen propyl group titanium trichloride.Described different oxygen propyl group titanium trichloride is that have titanium tetrachloride and four Isopropyl titanate is obtained by mixing.
A kind of synthetic method of new ezetimibe, realizes as follows：
(1) fluorobenzene and glutaric anhydride react generation 5- (4- fluorophenyl) -5- oxopentanoic acid I；
(2) in anhydrous solvent, add 5- (4- fluorophenyl) -5- oxopentanoic acid I, then be separately added into chlorinating agent, catalyst, In the environment of -25 DEG C to 25 DEG C, condensation reaction generates compound II；
(3) compound II reacts in the presence of dehydrating agent, acidic catalyst with replacing 1,3- propane diols in atent solvent Generate compound III
(4) compound III and N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine IV has in the protection of inert gas, inertia Machine solvent and titanium compound are reacting generating compound V under conditions of catalyst
(5) in N, the double trimethylsilyl acetamide of O- carries out the compound that ring-closure reaction generates Formula V to compound IV；
(6) compound V and formic acid back flow reaction deprotection in dichloromethane generates compound VI；
(7) compound VI and boranes chiral reduction agent reacting generating compound VII；
(8) compound VII carries out hydrogenation reaction generation ezetimibe VIII in the presence of palladium-carbon catalyst
5- (4- fluorophenyl) -5- oxopentanoic acid I and 4 (S) -4- oxazolyl phenyl alkanone molar equivalent ratio in described step (2) For 1:The molar equivalent of 1～3,5- (4- fluorophenyl) -5- oxopentanoic acid I and chlorinating agent is than for 1:1.5-2.5；Described is no water-soluble Agent is THF or CH2Cl2；Chlorinating agent is pivaloyl chloride；Described catalyst is 4,4- dimethylamino pyridine) or 4 (S) -4- phenyl evil Oxazolidone.
In described step (3) compound II with replace 1,3- propane diols molar equivalent ratio for 1:1～5, wherein said R1, R2 is respectively C1-C5, and wherein optimum mode is all methyl for R1 and R2；Described dehydrating agent be molecular sieve, anhydrous magnesium sulfate, Anhydrous sodium sulfate, phosphorus pentoxide, calcium chloride, silica gel, calcium oxide, magnesium nitrate, alchlor, phosphorus trichloride, phosphorus pentachloride, three Chlorethoxyfos or TFAA；Described acidic catalyst is inorganic acid or organic acid, and wherein inorganic acid is sulfuric acid, hydrogen chloride, hydrogen Bromic acid, hydroiodic acid, nitric acid, phosphoric acid or polyphosphoric acids；Described organic acid is C1-C4 carboxylic acid, methanesulfonic acid or p-methyl benzenesulfonic acid；Institute State the aromatic hydrocarbons of the ether, the nitrile of C2-C12 or C6-C12 that atent solvent is C2-C12；Reaction time is 3-6 hour；
In step (4), compound of reaction III and N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine are in the guarantor of inert gas Shield, inert organic solvents and titanium compound are reacting generating compound IV under conditions of catalyst；Wherein said titanizing is closed Thing catalyst is different oxygen propyl group titanium trichloride.
In step (5), reaction temperature is -5 DEG C.
Boranes chiral reduction agent in described step (7) is R-CBS or borane dimethyl sulphide.
In described step (8), palladium-carbon catalyst is 10% palladium carbon, and hydrogen source is ammonium formate.
Ezetimibe synthetic route of the present invention is as follows：
In the synthesis of step (1) 5- (4- fluorophenyl) -5- oxopentanoic acid (compound I) of the present invention, solvent be carbon disulfide, Any one in dichloromethane or fluorobenzene, first-selected fluorobenzene, catalyst is from AlCl3、ZnCl2、TiCl4Select Deng in lewis acid, First-selected AlCl3, reaction temperature elects reflux temperature as.
In the synthesis of step (2) compound II of the present invention, in a kind of anhydrous inert solvent, such as in THF or CH2Cl2In, With 1.5～2.5 parts of chlorinating agent, in such as pivaloyl chloride, it is simultaneously introduced liquid base (such as triethylamine), reaction temperature is -20 DEG C～20 DEG C between, reaction 1～2h after add 4 (S) -4- oxazolyl phenyl alkanone, be simultaneously introduced suitable catalyst 4,4- diformazan Amido pyridine, stirring reaction 4～8 hours, at 0～25 DEG C, product can pass through Crystallization Separation to temperature control.
In the synthesis of step (3) compound III of the present invention, compound II is dissolved in benzene or toluene, adds 2,2- diformazan Base -1,3-PD, 2,2- diethyl -1,3-PD, 2,2- dipropyl -1,3-PD, first-selected 2,2- dimethyl -1,3- Propane diols, adding the concentrated sulfuric acid is catalyst, and phosphorus pentoxide is dehydrating agent.Back flow reaction 5 hours, is extracted with dichloromethane, Concentrate.
The synthesis of step (4) compound IV of the present invention
By 4- hydroxy benzaldehyde be dissolved in acetone, DMF, ethanol equal solvent any one, be slowly dropped into cylite or chlorination Benzyl, adds the potassium carbonate of 1.5 equivalents, is heated to reflux more than 8 hours.Reactant liquor is cooled to and filters when 40 DEG C.Slow in filtrate Slow addition para-fluoroaniline, reaction has a large amount of white precipitates to produce soon.Reaction temperature controls between 30 DEG C～50 DEG C, reaction 1～2 hour time.Cooling crystallization after completion of the reaction, filters, and washs post-drying filter cake, obtains final product N- (4- fluorophenyl) -4- benzyloxy Benzene methylene amine (compound IV).
The synthesis of step (5) compound V of the present invention
Compound III, IV are dissolved in anhydrous CH2Cl2, and be cooled to -5 DEG C, be slowly added to equivalent diisopropylamine or Triethylamine, adds the tetraisopropoxy titanium of equivalent and the mixed solution of titanium tetrachloride, maintains -5 DEG C to be incubated 3 hours, reaction Under ice bath cooling after end, reaction is poured into PH=2 tartaric acid solution, stirring is warmed to room temperature for 0.5 hour naturally.Separate organic layer, It is dried with magnesium sulfate after washing with water.
In the synthesis of step (6) compound VI of the present invention, compound V is dissolved in dichloromethane, toluene equal solvent, adds double Trimethylsilyl acetamide (BSA), back flow reaction 24 hours, it is subsequently adding tetrabutyl ammonium fluoride (TBAF), be further continued for flowing back 24 little When, reaction lets cool precipitation solid after terminating, and solid is recrystallized with petroleum ether, obtains white solid, as compound VI.
In the synthesis of step (7) compound VII of the present invention, compound VI is dissolved in dichloromethane, adds 1-1.5 equivalent Formic acid back flow reaction 12 hours, reaction after terminating, reactant liquor is poured in frozen water, the anhydrous sulphur of organic layer dichloromethane layer Sour sodium is dried, and concentrates, and concentrate ethyl acetate/petroleum ether mixed solvent recrystallization obtains final product compound VII.
The synthesis of step (8) compound VIII of the present invention, compound VII is dissolved in benzene or oxolane, adds R-CBS Toluene solution, then drips the dichloromethane solution of borane dimethylsulf iotade, and after 15 DEG C of insulation reaction 12h, reaction cools down after terminating Under sequentially add hydrogen peroxide, aqueous sulfuric acid, final reaction liquid with dichloromethane extract, anhydrous sodium sulfate drying, concentrate, dense Contracting thing ethyl acetate/petroleum ether mixed solvent recrystallizes to obtain compound VIII.
In the synthesis of step (9) ezetimibe of the present invention, compound VIII is dissolved in acetic acid, adds appropriate 10% palladium carbon Catalyst and ammonium formate, back flow reaction 5h, Filtration of catalyst, boil off solvent and obtain final product ezetimibe finished product.
For the inventive point of the present invention, further describe：
1st, the synthetic method of the intermediate-compound III of synthesis ezetimibe is：Compound II and 2,2- bis- replacement -1, Ammediol reaction in atent solvent in the presence of dehydrating agent, acidic catalyst generates
Compound II and 2,2- bis- replacement -1,3- propane diols molar equivalent is than for 1:1～5.
Dehydrating agent described in the compounds of this invention III synthetic method be molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, five Aoxidize two phosphorus, calcium chloride, silica gel, calcium oxide, magnesium nitrate, alchlor, phosphorus trichloride, phosphorus pentachloride, POCl3 or trifluoro Acetic anhydride.
Acidic catalyst described in the compounds of this invention III synthetic method is inorganic acid or organic acid.Inorganic acid be sulfuric acid, Hydrogen chloride, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or polyphosphoric acids, organic acid is C1-C4 carboxylic acid, methanesulfonic acid or to toluene sulphur Acid.
Atent solvent described in the compounds of this invention III synthetic method is ether, the nitrile of C2-C12 or the C6-C12 of C2-C12 Aromatic hydrocarbons.
Reaction time in the compounds of this invention III synthetic method is 3-6 hour.
2nd, another one point of the present invention is：The synthetic method of the intermediate of ezetimibe-compound V is：Compound III with N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine IV makees catalyst in the protection of inert gas, inert organic solvents, titanium compound Conditioned response generate V compound.
Described titanium compound catalyst is different oxygen propyl group titanium trichloride.Described different oxygen propyl group titanium trichloride is that have titanium tetrachloride It is obtained by mixing with titanium tetraisopropylate.
Beneficial effect：
1st, the present invention protects the compound III that the carbonyl of compound II obtains spatially to belong to six using replacing propane diols Ring structure, steric strain is little, Stability Analysis of Structures, stable under the conditions of weak acid and weak base, so compound III is in subsequent reactions Middle stable chemical nature, reaction yield is high.
2nd, the present invention reacts acquisitionization using compound III and N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine IV first Compound V, because III space structure is stable, does not allow facile hydrolysis under the conditions of the lewis acid catalyst of different oxygen propyl group titanium trichloride, Reaction temperature is gentle, gets final product the synthesis compound V of high yield at -5 DEG C.And we have found that and be higher than -5 DEG C, reaction too acutely it is difficult to Control, the short time discharges amount of heat, causes low yield, accessory substance is many.Patent CN101346349A adopts ethylene glycol to protect II The IV that protects with silylation of the compound III that obtains of carbonyl react, because silylation protection group is active, unstable, need- 40 DEG C just can complete to react under -25 DEG C of harsh conditions.Patent CN101423515A is obtained using the carbonyl that sulphur protects II Compound III and IV reacts, and formed during due to sulphur protection carbonyl is five-ring heterocycles, and five-ring heterocycles steric strain is big, unstable Fixed, need also exist for temperature very low in the case of (- 30 DEG C to -20 DEG C) just can complete reaction.Although patent CN101423511A is adopted The compound III that obtains of carbonyl protecting II with propane diols carries out condensation reaction, but due in IV hydroxy-protective group be three Methyl-monosilane base protection group, and TMS protection group is easy under the Louis acid catalysis of different oxygen propyl group titanium trichloride Take off, cause reaction yield very low.
3rd, it is reacting generating compound IV under conditions of catalyst using titanium compound in step (4)；Wherein said titanium Compound catalyst is different oxygen propyl group titanium trichloride.Described different oxygen propyl group titanium trichloride is that have titanium tetrachloride to mix with titanium tetraisopropylate Obtained from conjunction.The preferred titanium compound catalyst of the present invention is different oxygen propyl group titanium trichloride, and it can be greatly promoted with reaction efficiency, Reaction yield is up to 78%.
4th, the present invention adopts brand-new synthetic route, and this final product yield is up to 90%, is particularly suitable for the big production of industry Or prepare on a large scale, and energy reduces cost, reduce pollution.
Specific embodiments：
Embodiment 1
The synthesis of compound I
Add fluorobenzene 200ml in 1000ml three-necked bottle, be subsequently adding alchlor (59.4g, 0.45mol), and use ice Bath is cooled to 15 DEG C, is then incubated fluorobenzene (100ml) solution of dropping glutaric anhydride (30g, 0.3mol) at 15 DEG C, drips React 5 hours at 30 DEG C after finishing, be cooled to 0 DEG C about, drip 1M hydrochloric acid 200ml, during noting dropping, temperature is less than 20 DEG C. After completion of dropping, reactant liquor is added in a large amount of frozen water, separates out solid, filter, with distilled water washing filter cake, then by filter cake Add in saturated sodium bicarbonate solution 800ml, 1h is stirred at room temperature, filter, in filtrate, add decolorizing with activated carbon.Enriching hydrochloric acid adjusts PH Be worth to 1, solid separates out, and filters and wash with water filter cake, after drying 51.7g compound as white solid I, yield 82%.1H NMR(DMSO-d6, 500MHz) δ 1.81 (m, 2H), 2.23 (m, 2H), 2.61 (m, 2H), 7.14 (dd, J=2.0,9.2Hz, 2H), 7.92 (d, dd, J=2.0,9.2Hz, 2H), 11.58 (s, 1H).13C NMR(DMSO-d6,125MHz)δ17.9,32.7, 36.4,117.1,134.7,137.3,165.9,174.1,201.3.
Embodiment 2
The synthesis of compound II
Compound I (21g, 0.1mol), triethylamine 20ml and dichloromethane 250ml, dropping is added in 500ml three-necked bottle Pivaloyl chloride (14.4g, 0.12mol), after back flow reaction 3h add (4S) -4- phenyl -2- oxazolidone (24.5g, 0.15mol), DMF5ml, 4,4- dimethylamino pyridine (1.22g, 0.01mol), after back flow reaction 10h, ice bath cools down, Ran Hou 0 DEG C of dropping 200ml 5M hydrochloric acid, stratification, lower floor's dichloromethane layer uses saturated sodium bicarbonate solution and water washing successively, no Aqueous sodium persulfate is dried.Filtrate is concentrated to dryness, and obtains 24.9g compound as white solid II, yield 70%.1H NMR(DMSO-d6, 500MHz)δ1.82(m,2H),2.21(m,2H),2.60(m,2H),4.53(m,1H),4.79(m,1H),5.52(m,1H), 7.05-7.21 (m, 7H), 7.94 (dd, J=2.0,9.2Hz, 2H).13C NMR(DMSO-d6,125MHz)δ18.8,33.4, 37.5,58.9,70.4,117.3,126.8,128.1,129.3,132.9,143.7,157.3,167.3,173.7,200.9.
Embodiment 3
Synthesis (the wherein R1=R2=CH of compound III3)
Add compound II (35.5g, 0.1mol), dichloromethane 200ml in 500ml three-necked bottle, be subsequently adding 2,2- Dimethyl -1,3 propane diols (15.6g, 0.15mol), phosphorus pentoxide (14.2g, 01mol) and the concentrated sulfuric acid (0.98g, 0.01mol), back flow reaction 5 hours, reaction terminates rear ice bath and cools, and then adjusts pH value with saturated sodium bicarbonate aqueous solution To 7, stratification, dichloromethane layer is washed, and anhydrous sodium sulfate drying is concentrated to dryness, obtains 41.2g compound as white solid III, yield 89%.1H NMR(DMSO-d6,500MHz)δ1.12(s,6H),1.59(m,2H),1.98(m,2H),2.32(m, 2H), 3.62-3.71 (m, 4H), 4.63 (m, 1H), 4.80 (m, 1H), 5.54 (m, 1H), 7.01 (dd, J=2.0,9.2Hz, 2H),7.05-7.21(m,7H).13C NMR(DMSO-d6,125MHz)δ14.2,19.3,32.2,36.3,39.1,59.2, 74.3,105.3,117.6,118.3,120.1,134.7,143.9,154.2,166.4,174.8.
Embodiment 4
The synthesis of compound IV
100mlDMF, parahydroxyben-zaldehyde (12.2g, 0.1mol), potassium carbonate is sequentially added in 250ml three-necked bottle After (16.6g, 0.12mol), it is slowly added dropwise into bromobenzyl (20.4g, 0.12mol), room temperature reaction 12 hours, reactant liquor is poured into In frozen water, solid separates out, and filters, and washes filter cake, filtration cakes torrefaction.Obtain benzyl protection parahydroxyben-zaldehyde 26.2g, yield 91%.Then take the mono- neck round-bottom flask of another 250ml, sequentially add acetone 100ml, benzyl protection parahydroxyben-zaldehyde Reactant liquor is cooled to 5 DEG C of precipitations after back flow reaction reaction 4h by (14.4g, 0.05mol), para-fluoroaniline (5.55g, 0.05mol) Solid, filters, washs solid with cold acetone, solid is drying to obtain N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine (compound IV), 14g, yield 92% are counted.1H NMR(DMSO-d6, 500MHz) and δ 5.21 (s, 2H), 6.88 (dd, J=2.0,9.2Hz, 2H), 7.15-7.23(m,12H),8.40(s,1H).13C NMR(DMSO-d6,125MHz)δ71.2,114.2,116.8,123.6, 126.1,127.3,128.1,129.3,131.4,141.6,149.8,161.2,162.9,164.6.
Embodiment 5
The synthesis of compound V
In 1000ml three-necked bottle, sequentially add III compound (44.1g, 0.1mol), IV (45.8g, 0.15mmol) two Chloromethanes 400ml, ice bath is cooled to -5 DEG C, adds DIPEA (18.5g, 0.15mol), maintains the temperature at -5 DEG C and be slowly added dropwise four (two solution molar equivalents are than for 1 for the mixed solution of titanium isopropoxide and titanium tetrachloride：1), it is incubated at -5 DEG C after completion of dropping Reaction 3 hours, after reaction terminates, reactant liquor is poured in the tartaric acid buffer solution of 500mlPH=2, quiet after stirring 30 minutes Put and be divided into, separate organic dichloromethane layer, water layer dichloromethane extracts, is then combined with dichloromethane layer, anhydrous sodium sulfate again It is dried, concentrates, the solid with ethyl acetate/petroleum ether obtaining is recrystallized to give 58.2g compound as white solid V, yield 78% .1H NMR(DMSO-d6,500MHz)δ1.13(s,6H),1.56(m,2H),1.91(m,2H),3.06(m,1H),3.63-3.74 (m,4H),4.02(s,1H),4.14(m,1H),4.65(m,1H),4.80(m,1H),5.40(m,2H),5.47(m,1H),6.42 (dd, J=2.0,9.2Hz, 2H), 6.74 (dd, J=2.0,9.2Hz, 2H), 6.91 (dd, J=2.0,9.2Hz, 2H), 7.01- 7.27(m,14H).13C NMR(DMSO-d6,125MHz)δ13.9,19.6,31.4,36.6,47.3,58.1,59.4,71.2, 72.5,74.8,105.7,117.4,118.6,119.3,120.1,123.4,125,2,125.9,127.1,128.9,132.6, 135.2,140.1,143.8,152.3,153.8,158.9,160.1,175.4.
Embodiment 6
The synthesis of compound VI
Take a 250ml mono- neck bottle, sequentially add dry toluene 150ml, compound V (74.6g, 0.1mol), double front three silicon Yl acetamide (BSA) (40.6g, 0.2mol), charging finishes rear back flow reaction 24 hours, is subsequently adding tetrabutyl ammonium fluoride (TBAF) (13.1g, 0.05mol), continues back flow reaction 24 hours, and cooling is placed and separated out solid, suction filtration, filter cake petroleum ether weight Crystallization obtains 46.1g compound as white solid VI, yield 79%.1H NMR(DMSO-d6,500MHz)δ1.12(s,6H),1.62 (m, 2H), 1.92 (m, 2H), 3.44 (m, 1H), 3.61-3.73 (m, 4H), 4.84 (d, J=2.4Hz, 1H), 5.26 (s, 2H), 6.74 (dd, J=2.0,9.2Hz, 2H), 6.91 (dd, J=2.0,9.2Hz, 2H), 7.02-7.23 (m, 12H).13C NMR (DMSO-d6,125MHz)δ18.2,19.6,19.8,31.2,36.5,46.5,60.2,72.3,75.6,106.8,113.6, 134.8,139.1,123.4,126.3,127,2,127.9,128.1,129.9,132.4,135.1,138.9,142.7, 157.9,158.4,160.3,175.8.
Embodiment 7
The synthesis of compound VII
Take a 250ml mono- neck bottle, add compound VI (58.3g, 0.1mol), dichloromethane 150ml, formic acid adds (4.6g, 0.1mol), back flow reaction 12h, reaction after terminating, reactant liquor is poured in 150ml frozen water, layering, organic layer dichloro Methane layer anhydrous sodium sulfate drying, concentrates, and concentrate is recrystallized with ethyl acetate/petroleum ether mixed solvent, obtains final product 44.7gization Compound VII, yield 90%.1H NMR(DMSO-d6,500MHz)δ1.84(m,2H),2.62(m,2H),3.46(m,1H),4.83 (d, J=2.4Hz, 1H), 5.29 (s, 2H), 6.78 (dd, J=2.0,9.2Hz, 2H), 7.01-7.28 (m, 16H), 7.91 (dd, J=2.0,9.2Hz, 2H).13C NMR(DMSO-d6,125MHz)δ21.3,35.4,42.3,60.7,71.4,113.5,115.4, 115.6,123.7,127.3,128.2,129.1,129.4,130.8,132.6,132.8,137.6,141.8,156.8, 157.9,167.4,168.2,201.3.
Embodiment 8
The synthesis of compound VIII
Take a 1000ml mono- neck bottle, add anhydrous tetrahydro furan 100ml, compound VII (49.7g, 0.1mol), 100ml The R-CBS toluene solution of 1mol/L, ice bath is cooled to 15 DEG C, is slowly added dropwise the dichloro of the borane dimethylsulf iotade of 200ml 1mol/L Dichloromethane, adds rear insulation reaction 12h, and reaction sequentially adds 50ml5% hydrogen peroxide, 200ml under cooling down after terminating 10mol/L aqueous sulfuric acid, final reaction liquid is extracted with dichloromethane, and extract is washed, anhydrous sodium sulfate drying, concentrates, dense Contracting thing is recrystallized with ethyl acetate/petroleum ether mixed solvent, obtains final product compound VIII, counts 41.4g, yield 83%.1H NMR (DMSO-d6,500MHz)δ1.65(m,2H),1.79(m,2H),2.11(s,1H),3.47(m,1H),4.51(m,1H),4.82 (d, J=2.4Hz, 1H), 5.27 (s, 2H), 6.79 (dd, J=2.0,9.2Hz, 2H), 6.91 (dd, J=2.0,9.2Hz, 2H), 7.02-7.30(m,12H).13C NMR(DMSO-d6,125MHz)δ22.7,35.6,43.8,60.9,71.6,77.4,114.2, 115.7,115.9,123.4,127.2,128.1,129.0,129.5,130.6,131.7,132.5,136.9,142.7, 158.6,159.3,161.2,165.7.
Embodiment 9
The synthesis of ezetimibe
Take the mono- neck round-bottom flask of a 500ml, sequentially add acetic acid 200ml, compound VIII (49.9g, 0.1mol), formic acid Amine (6.3g, 0.1mol), 5g palladium-carbon catalyst (10% palladium content), back flow reaction 6h.Reaction is filtered to remove palladium carbon after terminating and urges Agent, filtrate is evaporated and obtains solid crude product, and solid crude product ethyl acetate/petroleum ether mixed solvent recrystallization obtains final product according to for rice Shellfish, counts 36.8g, yield 90%.1H NMR(DMSO-d6,500MHz)δ1.63(m,2H),1.78(m,2H),2.14(s,1H), 3.48 (m, 1H), 4.53 (m, 1H), 4.87 (d, J=2.4Hz, 1H), 5.04 (s, 1H), 6.78 (dd, J=2.0,9.2Hz, 2H),7.02-7.34(m,10H).13C NMR(DMSO-d6,125MHz)δ22.6,35.8,44.3,60.8,78.2,114.6, 115.0,123.6,129.1,129.4,133.5,135.2,137.8,157.4,158.2,160.1,166.3.

Claims (10)

1. a kind of intermediate for synthesizing ezetimibe is it is characterised in that it is compound III.
Wherein, R1、R2It independently is hydrogen or C1-C4 low alkyl group.
2. synthesize an intermediate as claimed in claim 1 method it is characterised in that compound II with replace 1,3-PD In the presence of dehydrating agent, acidic catalyst in atent solvent reacting generating compound III
3. according to claim 2 a kind of method of the intermediate for synthesizing ezetimibe it is characterised in that described chemical combination Thing II with replace 1,3- propane diols molar equivalent ratio for 1:1～1:5, the structural formula of described replacement 1,3-PD is compound VIIII, and wherein R1、R2It independently is hydrogen or C1-C4 low alkyl group
4. according to claim 2 a kind of method of the intermediate for synthesizing ezetimibe it is characterised in that described dehydration Agent is molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, phosphorus pentoxide, calcium chloride, silica gel, calcium oxide, magnesium nitrate, tri-chlorination Aluminium, phosphorus trichloride, phosphorus pentachloride, POCl3 or TFAA.
5. according to claim 2 a kind of method of the intermediate for synthesizing ezetimibe it is characterised in that described acidity Catalyst is inorganic acid or organic acid；Inorganic acid is sulfuric acid, hydrogen chloride, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or polyphosphoric acids, Organic acid is C1-C4 carboxylic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
6. according to claim 2 a kind of method of the intermediate for synthesizing ezetimibe it is characterised in that described inertia Solvent is the aromatic hydrocarbons of the ether, the nitrile of C2-C12 or C6-C12 of C2-C12.
7. a kind of intermediate for synthesizing ezetimibe is it is characterised in that it is compound V
Wherein, R1、R2It independently is hydrogen or C1-C4 low alkyl group.
8. a kind of method of the intermediate for synthesizing ezetimibe described in synthesis claim 7 is it is characterised in that compound III With compound IV in the protection of inert gas, inert organic solvents, under conditions of titanium compound makees catalyst reaction generate V chemical combination Thing.
9. a kind of method of intermediate for synthesizing ezetimibe according to claim 8 is it is characterised in that titanizing is closed Thing catalyst is different oxygen propyl group titanium trichloride.
10. a kind of synthetic method of new ezetimibe is it is characterised in that realize as follows：
(1) fluorobenzene and glutaric anhydride react generation 5- (4- fluorophenyl) -5- oxopentanoic acid I；
(2) in anhydrous solvent, add 5- (4- fluorophenyl) -5- oxopentanoic acid I, then be separately added into chlorinating agent, catalyst, - In the environment of 25 DEG C to 25 DEG C, condensation reaction generates compound II；
(3) compound II generates with replacing the reaction in atent solvent in the presence of dehydrating agent, acidic catalyst of 1,3- propane diols Generate compound III
(4) compound III and N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine IV is organic molten in the protection of inert gas, inertia Agent and titanium compound are reacting generating compound V under conditions of catalyst
(5) in N, the double trimethylsilyl acetamide of O- carries out the compound that ring-closure reaction generates Formula IV to compound V；
(6) compound V and formic acid back flow reaction deprotection in dichloromethane generates compound VII；
(7) compound VI and boranes chiral reduction agent reacting generating compound VIII；
(8) compound VIII carries out hydrogenation reaction generation ezetimibe in the presence of palladium-carbon catalyst
It is characterized in that in described step (3) compound II with replace 1,3- propane diols molar equivalent ratio for 1:1～5, wherein R1、 R2It independently is hydrogen or C1-C4 low alkyl group；Described dehydrating agent be molecular sieve, anhydrous magnesium sulfate, anhydrous sodium sulfate, five oxidation Two phosphorus, calcium chloride, silica gel, calcium oxide, magnesium nitrate, alchlor, phosphorus trichloride, phosphorus pentachloride, POCl3 or trifluoroacetic acid Acid anhydride；Described acidic catalyst be inorganic acid or organic acid, wherein inorganic acid be sulfuric acid, hydrogen chloride, hydrobromic acid, hydroiodic acid, nitric acid, Phosphoric acid or polyphosphoric acids；Described organic acid is C1-C4 carboxylic acid, methanesulfonic acid or p-methyl benzenesulfonic acid；Described atent solvent is C2- The aromatic hydrocarbons of the ether of C12, the nitrile of C2-C12 or C6-C12；Reaction time is 3-6 hour；
In step (4) compound of reaction III and N- (4- fluorophenyl) -4- benzyloxy benzene methylene amine IV inert gas protection, The conditioned response that inert organic solvents and titanium compound make catalyst generates compound V；Wherein said titanium compound catalysis Agent is different oxygen propyl group titanium trichloride.
In step (5), reaction temperature is -5 DEG C.
In described step (2), 5- (4- fluorophenyl) -5- oxopentanoic acid I and 4 (S) -4- oxazolyl phenyl alkanone molar equivalent is than for 1:1 The molar equivalent of～3,5- (4- fluorophenyl) -5- oxopentanoic acid I and chlorinating agent is than for 1:1.5-2.5；Described anhydrous solvent is THF or CH2Cl2；Chlorinating agent is pivaloyl chloride；Described catalyst is 4,4- dimethylamino pyridine) or 4 (S) -4- oxazolyl phenyl alkane Ketone.
Boranes chiral reduction agent be R-CBS or borane dimethyl sulphide.
In described step (8), palladium-carbon catalyst is 10% palladium carbon, and hydrogen source is ammonium formate.
CN201610831623.2A 2016-09-20 2016-09-20 Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe Pending CN106397292A (en)

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