CN102477008B - Method for synthesizing ezetimibe - Google Patents
Method for synthesizing ezetimibe Download PDFInfo
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- CN102477008B CN102477008B CN201010553070.1A CN201010553070A CN102477008B CN 102477008 B CN102477008 B CN 102477008B CN 201010553070 A CN201010553070 A CN 201010553070A CN 102477008 B CN102477008 B CN 102477008B
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Abstract
The invention belongs to the technical field of medicines and relates to a method for synthesizing ezetimibe. The method comprises the steps of taking parahydroxybenzaldehyde and R-fluoromandelic acid as starting raw materials and synthesizing the ezetimibe through the conventional methods, such as protection, condensation, cyclization, reduction, bromination, protection, butt joint, deprotection and the like, under the action of a catalyst. The method disclosed by the invention has the advantages of high yield, greatly reduced cost because expensive chiral ligands or chiral catalysts are prevented from being used, and less side reactions and is applied to industrialized production.
Description
technical field:
The invention belongs to medical technical field, relate to the synthetic method of ezetimibe, be specifically related to a kind of method of utilizing the synthetic ezetimibe of intermediate.
background technology:
Ezetimibe (Ezetimibe) is the people such as Harry Davis, Margaret Van Heek and the Kevin Alton research and development in Schering Plough (Schering-Plough) company research centre, in October, 2002, ezetimibe (Zetia) obtains the approval of FDA, and first go on the market in Germany November in the same year, trade(brand)name ezetrol.Ezetimibe is first selectivity cholesterol absorption inhibitor, and it can disturb the absorption of the cholesterol of being synthesized by liver in the cholesterol of food source and enterohepatic circulation simultaneously, and the absorption of other nutritive ingredient is not exerted an influence.Its pharmacology only acts on small intestine, reduces intestinal cholesterol turn to liver by the absorption of inhibition cholesterol, reduces its storage; Can strengthen the removing of Blood Cholesterol, thereby reduce blood plasma cholesterol level.It combines use with Statins and can reduce the frequency of utilization of statins high dosage, and drug effect is 8 times of alone statins deposits yields decreasing cholesterol effect.Ezetimibe is individually dosed or all good with HMG-CoA reductase inhibitor Combined Preparation tolerance, and adverse reaction rate is similar to placebo.
The chemistry of ezetimibe is by name: (3R, 4S)-1-(4-fluorophenyl)-3-［ (3S)-3-(4-fluorophenyl)-3-hydroxypropyl ］-4-(4-hydroxyphenyl)-2-azetidinone) there is following structure:
In prior art, the synthetic route of ezetimibe has a variety of, but all exists many deficiencies:
Schering Plough company of the patent WO2000/34240(U.S.) method of the synthetic ezetimibe of a kind of improved chirality disclosed; in the method, first make (S)-3-oxy-compound by chiral reduction agent; then connect side chain (E)-N-(4-fluorophenyl by single step reaction in carbonyl α position) two hydroxyls in product structure are protected by trimethylsilyl in-4-hydroxybenzene methylene amine; then Cheng Huan, remove blocking group, obtain ezetimibe.This synthetic method is in the time of the carbonyl of chiral reduction, and owing to having, the group of chiral structure is far away apart from carbonyl, and the content of the activity chiral carbon obtaining after reduction is low, and the amount ratio of chiral reduction agent is larger; And the yield that step that connects side chain is reacted is very low, so this synthetic route cost is high, is not suitable for suitability for industrialized production.
Patent WO2007072088 discloses the another kind of synthetic route of preparing ezetimibe, and this synthetic method reactions steps is few, and concrete synthetic route is as follows:
In patent WO2007072088, in the route of synthetic ezetimibe, the hydroxyl in the chiral carbon of 3 side chains is to be obtained by carbonyl chiral reduction, before chiral reduction not, this carbonyl is destroyed when making spent glycol protection to carrying out other chemical reactions, the midbody compound IV of gained, compound VI is thinner solid matter, in last handling process, more difficult crystallization, and because its granularity is very thin, in crystallisation process, extremely easily there is impurity to separate out, in filtration procedure, small part product can flow out along with filtrate, cause the second-rate of product, subsequent reactions is more difficult to carry out completely, entirety yield is lower, increase synthetic cost.
Another US:5739321; US:5886171 has reported route 1: with (4
s)-hydroxyl tetrahydrofuran-2-ketone and N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine is that starting raw material is prepared ezetimibe, and its reaction scheme is as follows:
This synthetic method is: N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine (1) and (4
s)-hydroxyl tetrahydrofuran-2-ketone (2) at low temperatures, carries out cyclization with lithium diisopropylamine (LDA), carries out after completion of the reaction recrystallization and can obtain compound (3).Compound (3) obtains product (4) after the oxidation of NaIO, reacts and obtains compound (6) with 4-fluoro acetophenone and trimethysilyl chloride (TMS-Cl), uses TiCl
4carry out condensation and generate compound (7), after TsOH catalytic dehydration, obtain compound (8).After Pd/C shortening, reduction is sloughed benzyl simultaneously and is finally carried out asymmetric reduction with chiral catalyst CBS and reductive agent boronation hydrogen at low temperatures, obtains target product again.This reaction process can produce cis-isomeride, and content can reach 5% left and right, can in subsequent disposal, remove with recrystallization.Making target product by compound (8) reduction also can be through chlorinated triphenyl phosphorus base rhodium [(PPh
3)
3rhCl] the two keys of catalytic hydrogenation, then through BH
3/ CBS asymmetric reduction, catalytic hydrogenation debenzylation obtain compound (9).This method is except cyclization reaction yield 60%, and other respectively walks yield all more than 70%.
In route 1, (4
s)-hydroxyl tetrahydrofuran-2-ketone cost is higher, and character is unstable, has certain difficulty in production.
Another report route 2: prepare ezetimibe take (5S)-acetoxyl group-5-(4-fluorophenyl) valeric acid as reaction intermediate, its synthesis technique is as follows:
First with (5
s)-acetoxyl group-5-(4-fluorophenyl) valeric acid (27) and (4
s)-4-phenyl-oxazolidones (13) carry out condensation, obtain compound (28).Product is at TiCl
4with in the dichloromethane solution of DIPEA, obtain compound (30) with N-(4-fluorophenyl) 4-acetyloxy phenyl methylene amine (29) through condensation, this step reaction yield can reach 51%.Compound (30) carries out cyclization in the toluene solution that adds BSA and catalyzer TBAF, generates compound (31), and reaction yield can reach 91%.Compound (31) is hydrolyzed after ethanoyl via lithium hydroxide, obtains target product.
The raw material of route 2 is all more expensive, and technique more complicated, and reaction conditions is harsher, and uses column chromatography on to the fractionation of isomer, and industrialization is very difficult.
Report route 3: prepare ezetimibe take Pyroglutaric acid and N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine as starting raw material; it is prepared by following reaction: Pyroglutaric acid and methyl alcohol effect generate monomethyl glutarate, after sulfur oxychloride reaction, generates 4-(chloroformyl) methyl-butyrate (21).There is amidate action with (4S)-4-phenyl-oxazolidones (13) in compound (21), obtain (4 in the dichloromethane solution of triethylamine and DMAP
s)-3-(4-methyl-formiate base-1-oxo butyl)-4-phenyl-2-oxazolidone (22), under the effect of alkaline condition and titanium tetrachloride, titanium tetraisopropylate and DIPEA with the condensation of N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine, obtain compound (24) by BSA/TBAF (tetrabutyl ammonium fluoride) effect closed loop, after LiOH hydrolysis, obtain compound (25).Compound (25) is prepared into acyl chlorides (26) by oxalyl chloride, through to fluorophenyl magnesium bromide (27) at ZnCl
2and Pd (PPh
3)
4effect is lower generates compound (17), then through CBS/BH
3asymmetric reduction carbonyl, Pd/C and H
2remove benzyl and obtain target product.Its reaction formula is as follows:
The raw material of route 3 is cheap and easy to get, and intermediate productive rate is relatively all higher, is applicable to suitability for industrialized production, but it is in the fractionation of optical isomer, uses column chromatography, and it is had a greatly reduced quality in practical.
Report route 4: prepare ezetimibe take 5-(4-fluorophenyl)-4-pentenoic acid as reaction intermediate, it is prepared by the following method: 5-(4-fluorophenyl)-4-pentenoic acid is after oxalyl chloride is prepared into acyl chlorides, with chiral reagent (4
s)-4-phenyl-2-oxazolidone carries out amidate action under DMAP catalysis, and product obtains compound (A) through recrystallization.By TiC1
4, DPEA and imines add in dichloromethane solution, drips at low temperatures compound (A), keeps low temperature to reaction to finish, and with acetic acid quencher reaction, processed rear crude product and carry out recrystallization and obtain compound (B).Compound (B) cyclization in the toluene solution of TBAF obtains compound (C), and is splashed into Pd (OAc)
2, HClO
4in the acetonitrile solution of benzoquinones, reaction finishes after dilute with water, then uses organic solvent extraction, removes catalyzer, after separating filtrate evaporate to dryness, use column chromatography separating optical isomers to obtain compound (D), then the operation of premenstrual method obtains target compound.Its reaction formula is as follows:
Route 4 is identical with 2, and raw material is somewhat expensive, complex process, and industrialization is more difficult.
US:627882B; WO:2005-IB2393 has reported route 5: prepare ezetimibe take 5-(4-fluorophenyl)-5-oxopentanoic acid as reaction intermediate, this route is take fluorobenzene as starting raw material, under ice-water bath, use Using Aluminium Trichloride as Catalyst with Pyroglutaric acid, there is Friedel-Crafts reaction, generate 5-(4-fluorophenyl)-5-oxopentanoic acid (33).5-(4-fluorophenyl)-5-oxopentanoic acid (33) adds the dichloromethane solution that is dissolved with triethylamine, is added dropwise to the synthetic mixed acid anhydride (34) of pivaloyl chloride retrude of equivalent.Mixed acid anhydride (34) under the catalysis of DMAP with (4
sthere is amidate action in)-4-phenyl-2-oxazolidone (13), thick product after Virahol recrystallization purifying, obtain 4 (
s)-3-[5-(4-fluorophenyl)-1,5-dioxo amyl group]-4-phenyl-2-oxazolidone (35).Compound (35) as catalyzer generation asymmetric reduction reaction, uses after completion of the reaction hydrogen peroxide and sulphuric acid soln processing to make (4 take [(R)-MeCBS)] in low temperature tetrahydrofuran solution
s)-3-[(5
s)-(4-fluorophenyl)-5-hydroxyl-1-oxo amyl group]-4-phenyl-2-oxazolidone (36).Compound (36) adds containing DIPEA, TMS-Cl and TiCl
4dichloromethane solution in, at low temperatures, slowly add 4-(4-fluorophenyl imido grpup) phenol (37), condensation reaction finishes rear with glacial acetic acid, 7% tartaric acid solution and 20% sodium sulfite solution processing, add again the abundant back flow reaction of BSA, then concentrated product recrystallization is obtained to compound (38), compound (38) carries out cyclization under BSA and TBAF effect, and removes (4
s)-4-phenyl-2-oxazolidone.By cyclization product in Virahol and H
2sO
4in mixing solutions, de-protected silane, obtains target product (10).Its reaction formula is as follows:
Route 5 is the patent of 2005, owing to relating to patent protection, its research is restricted.
The problem all existing in the synthetic method of above-mentioned ezetimibe is that synthetic route is long; Or yield, purity are low, and some synthetic routes have been wasted more than 50% intermediate; Or the amount of the chiral reduction agent using is many, solvent toxicity is large, and in sum, in prior art, the cost compare of the synthetic method of ezetimibe is high, bring very large inconvenience to its suitability for industrialized production.
summary of the invention:
Technical problem to be solved by this invention is to provide a kind of synthetic method of new ezetimibe, thereby it is high to overcome the synthetic method cost existing in prior art, is not suitable for the shortcomings such as industrialization.
The present invention is achieved through the following technical solutions:
The synthetic route of ezetimibe of the present invention is:
It is prepared by the following method:
(1) p-Hydroxybenzaldehyde and benzyl, in solvent, under alkali effect, are reacted and are generated P-benzyloxybenzaldehyde 2 by benzyl protection;
(2) in anhydrous protic solvent, add para-fluoroaniline and P-benzyloxybenzaldehyde 2, condensation reaction generates N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine 3;
(3) N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine (3) is in toluene, with organic base catalytic, obtain Trans-1-(4-fluorophenyl)-3-(2-chloromethyl)-4-(4-benzyloxy phenyl)-2-azetidinone 4 with the cyclization of 3-chlorpromazine chloride;
(4) R-obtains (2R)-4-fluorophenethyl glycol 5 to fluorine amygdalic acid through reduction;
(5) (2R)-4-fluorophenethyl glycol (5) obtains Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6 through bromo;
(6) through TMSCl, protection obtains (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 to Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6;
(7) (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 is with Trans-1-(4-fluorophenyl)-3-(2-chloromethyl)-4-(4-benzyloxy phenyl)-2-azetidinone 4 in THF, and process grignard reaction, metal linked reaction, Deprotection generate Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-benzyloxy phenyl)-2-azetidinone 8;
(8) Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-benzyloxy phenyl)-2-azetidinone 8 Deprotection under Pd/C condition obtains formula 9;
(9) formula 9, through recrystallization purifying, obtains target product ezetimibe.
Solvent described in step (1) be in acetone, DMF any one; Alkali is selected from Na
2cO
3, K
2cO
3, NaOH, KOH, the benzyl of protection use is selected from bromobenzyl and benzyl chloride, and temperature of reaction is reflux temperature.
Anhydrous protic solvent described in step (2) is selected from anhydrous methanol, dehydrated alcohol, anhydrous isopropyl alcohol; P-benzyloxybenzaldehyde is that the 2-4 of para-fluoroaniline doubly measures, reflux time 2-5h.
Benzyloxy phenyl)-2-azetidinone (4) prepared by the following method:
N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine (3) is dissolved in toluene, adds alkali, add 3-chlorpromazine chloride, finish 80 ℃-120 ℃ reaction 8-12 h of rear temperature control, be cooled to room temperature, add hydrochloric acid cancellation, add water stratification, water layer dichloromethane extraction, saturated sodium bicarbonate washing, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, described alkali is selected from TEA, DIEA, 3-n-butylamine.
Described (2R)-4-fluorophenethyl glycol (5) is prepared by the following method
:
Get R-4-fluorine amygdalic acid and be dissolved in tetrahydrofuran (THF) or diethyl ether solution, under ice bath, drip borine tetrahydrofuran solution or LAH, finish, stirring at room temperature 2h, drips the shrend reaction of going out, decompression concentrated solution under ice bath, add ethyl acetate or the extraction of methylene dichloride separatory, dry, concentrated.
(R) Alpha-hydroxy (4-fluorine) phenyl-bromide ethane (6) is prepared by the following method:
(2R)-4-fluorophenethyl glycol (5) is dissolved in methylene dichloride, adds NBS, PBr
3, any one brominated reagent in lithiumbromide, drip the vitriol oil or glacial acetic acid, stirring at room temperature, stopped reaction after 2-4 hour, adds water, separatory, a small amount of dichloromethane extraction, merges organic phase, saturated sodium bicarbonate washing, saturated common salt washing, dry, concentrated.
The preparation by the following method of monobromethane (7):
Getting (R) Alpha-hydroxy (4-fluorine) phenyl-bromide ethane (6) is dissolved in methylene dichloride, under ice bath, add DIEA, TMSCl or TBSCl, stirring at room temperature 2-4h, stopped reaction, add water, separatory, water layer is with a small amount of dichloromethane extraction, merge organic phase, washing, dry, concentrated.
Benzyloxy phenyl)-2-azetidinone (8) prepared by the following method:
By magnesium chips, catalytic amount iodine grain, be suspended in tetrahydrofuran (THF) or ether, (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane (7) is dissolved in dry tetrahydrofuran and is dropped in reaction system, observation solution colour is decorporated, after stirring at room temperature 1-2h, make Grignard reagent, under ice bath, compound (4) is dissolved in dry tetrahydrofuran, add coupling reagent, described coupling reagent is selected from Pd(PPh
3)
4, CuI, PdCl
2(dppf), ZnCl
2; Under ice bath, stir, now Grignard reagent processed joins in reaction solution, room temperature reaction 8-12h, stopped reaction; Under ice bath, add aqueous ammonium chloride solution cancellation reaction, separatory, a small amount of dichloromethane extraction of water, saturated common salt water washing organic phase, dry, concentrated.Crude product is dissolved in dry tetrahydrofuran solution, adds tetrabutyl ammonium fluoride stirring at room temperature 3-6h, concentration of reaction solution, adds water, the extraction of methylene dichloride separatory, and washing, dry, concentrated.
Compound (8) is dissolved in any one solvent of methyl alcohol, ethanol, Virahol, adds ammonium formiate, formic acid, catalytic amount palladium carbon, reaction 3-6h, reaction finishes.Suction filtration, filtrate is concentrated, silica gel column chromatography, obtain compound trans ezetimibe, after be dissolved in ethyl acetate or methylene dichloride, drip any one two optical isomers in dioxane, tetrahydrofuran (THF), methyl tertiary butyl ether, anhydrous diethyl ether and split, insolubles is filtered, get filtrate concentrated dry after, carry out recrystallization by ethyl acetate/petroleum ether, obtain ezetimibe.
Described (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane (7), take to fluoro acetophenone (11) as starting raw material, under bromine, Glacial acetic acid condition, obtain α-bromo to fluoro acetophenone (12).Formula (12) is dissolved in dry ether or tetrahydrofuran solution, under room temperature condition, slowly drip CBS/ hexane solution, under condition of ice bath, drip borine-tetrahydrofuran solution, stir 2 hours, drip the shrend reaction of going out, decompression concentrated solution obtains formula (6).Formula (6) obtains formula (7) through TMSCl protection.
Invention provides a kind of new synthetic method of ezetimibe.Present method take p-Hydroxybenzaldehyde, R-to fluorine amygdalic acid as starting raw material, under the effect of catalyzer, through the synthetic ezetimibe of the ordinary methods such as protection, condensation, cyclization, reduction, bromo, protection, docking, deprotection.The method yield is high, avoids using expensive chiral ligand or chiral catalyst, reduces costs on a large scale, and side reaction is few, is applicable to industrialized production.
embodiment:
By p-Hydroxybenzaldehyde 5 g, Na
2cO
36.2 g are dissolved in 150 mL acetone, add cylite 6.7 mL back flow reaction 3.5 h, are cooled to room temperature, and reaction solution is poured into and in frozen water, separated out solid, stir 10 minutes, suction filtration, a small amount of washing for filter cake, dry, obtain white solid 4-benzyloxy phenyl aldehyde (2), 8.5 g, yield 98%.
Embodiment bis-
4-benzyloxy phenyl aldehyde 8.5 g are dissolved in 120 mL anhydrous isopropyl alcohols, be heated to 85 degrees Celsius, stir the lower 4-of dropping fluoroaniline 11.5 mL, back flow reaction 4h, is cooled to room temperature and separates out solid, suction filtration, the a small amount of washing with alcohol of filter cake, dries, and obtains white solid N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine (3), meter 11g, yield 90%.
Embodiment tri-
Compound (3) 11 g are dissolved in 100 mL toluene, under nitrogen protection, add DIEA 18 mL to be warming up to backflow.Slowly drip 3-chlorpromazine chloride 6.3 mL, dropwise 100 ℃ of reaction 12 h of rear temperature control, be cooled to room temperature, add 1 M hydrochloric acid 2 mL cancellation, add 20 mL water stratifications, dichloromethane extraction for water layer (2 × 10 mL), merge organic phase, saturated sodium bicarbonate washing, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated that Off-white solid Trans-1-(4-fluorophenyl)-3-(2-chloromethyl)-4-(4-benzyloxy phenyl)-2-azetidinone (4) is counted 12.5 g, yield 85%.
Embodiment tetra-
Get R-4-fluorine amygdalic acid 4.7 g and be dissolved in the tetrahydrofuran solution that 20 mL are dry, under ice bath, add 2.4gLAH, stirring at room temperature 3h, drips the 10 mL shrends reaction of going out under ice bath.Concentrating under reduced pressure reclaims tetrahydrofuran solution, adds ethyl acetate separatory extraction (2 × 10 mL), and saturated common salt washing is dry, concentrated, obtains colourless liquid (2R)-4-fluorophenethyl glycol (5) meter 4.2 g, yield 97.6%.
Embodiment five
Compound (5) 4.2 g are dissolved in 20 mL methylene dichloride, drip PBr
3solution 7.8mL, stirring at room temperature, stopped reaction after 3 hours, add 10 mL water, separatory, a small amount of dichloromethane extraction, merge organic phase, saturated sodium bicarbonate washing, saturated common salt washing, dry, concentrated, silica gel column chromatography, obtains colorless oil (R)-α hydroxyl (4-fluorine) phenyl-bromide ethane (6) meter 4.8 g, yield 80%.
Embodiment six
Get compound (6) 4.8 g and be dissolved in 20 mL dry methylene chloride, under ice bath, add DIEA 3.3mL, TMSCl4.2 mL, stirring at room temperature 3h, stopped reaction.Add 10 mL water, separatory, water layer, with a small amount of dichloromethane extraction, merges organic phase, washing, dry, concentrated, silica gel column chromatography, obtains white solid (R)-α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane (7) meter 5.1 g, yield 80 %.
Embodiment seven
By magnesium chips 620 mg catalytic amount iodine grains, be suspended in 10 dry mL tetrahydrofuran (THF)s, compound (7) 5.1 g be dissolved in to 10mL dry tetrahydrofuran and drop to reaction system, observe solution colour and decorporate, continue, after stirring at room temperature 2h, to make Grignard reagent.Under ice bath, compound (4) 7.1 g are dissolved in dry tetrahydrofuran, add anhydrous cuprous iodide 570mg, stir after 20 min under ice bath, now Grignard reagent processed joins in reaction solution, room temperature reaction 10h, stopped reaction.Under ice bath, add aqueous ammonium chloride solution cancellation reaction.Stirring at room temperature 10 minutes, separatory, the a small amount of dichloromethane extraction of water, saturated common salt water washing organic phase, dry, concentrated, crude product 2.3 g are dissolved in dry tetrahydrofuran solution, add tetrabutyl ammonium fluoride 1.5 g, stirring at room temperature 4h, concentration of reaction solution, add water, the extraction of methylene dichloride separatory, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography, obtain Off-white solid Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-benzyloxy phenyl)-2-azetidinone (8) meter 2.0 g, yield 30%.
Embodiment eight
Compound (8) 2.0 g are dissolved in dehydrated alcohol, add ammonium formiate 820 mg, formic acid 2.5 mL, catalytic amount palladium carbon, 60 ℃ of reaction 3h of temperature control, reaction finishes.Suction filtration, filtrate is concentrated, silica gel column chromatography, obtains compound trans ezetimibe 1.3 g, after be dissolved in ethyl acetate, dripping anhydrous diethyl ether splits two optical isomers, insolubles is filtered, get filtrate concentrated dry after, carry out recrystallization by ethyl acetate/petroleum ether, obtain ezetimibe (1) meter 600 mg, yield 40%.
Embodiment nine
To be dissolved in 20ml Glacial acetic acid fluoro acetophenone (11) 5ml 0.037mol, under room temperature condition, slowly drip bromine 6.25g 0.039mol, the clarification of question response liquid, reaction finishes.Steam except Glacial acetic acid, obtain yellowish white solid, obtain white solid α-bromo to fluoro acetophenone (12) 6.69g yield 79.6% through toluene/normal hexane recrystallization.
Embodiment ten
Getting α-bromo is dissolved in the tetrahydrofuran solution that 20 mL are dry fluoro acetophenone 2.16g, under ice bath, drip 1mol/L CBS hexane solution 1ml, borine-tetrahydrofuran solution 22 mL of 2.5 mol/L, after dropwising, stirring at room temperature 3h, drips the 10 mL shrends reaction of going out under ice bath.Concentrating under reduced pressure dry thf solution, adds ethyl acetate separatory extraction (2 × 10 mL), saturated common salt washing, dry, concentrated, colorless oil (R)-α hydroxyl (4-fluorine) phenyl-bromide ethane (6) meter 2.17 g, yield 99.6%.
Claims (10)
1. the synthetic method of ezetimibe, is characterized in that, by the following method preparation:
(1) p-Hydroxybenzaldehyde and bromobenzyl or benzyl chloride, in solvent, under alkali effect, are reacted and are generated P-benzyloxybenzaldehyde 2 by benzyl protection;
(2) in anhydrous protic solvent, add para-fluoroaniline and P-benzyloxybenzaldehyde 2, condensation reaction generates N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine 3;
(3) N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine 3 is in toluene, with organic base catalytic, obtain Trans-1-(4-fluorophenyl)-3-(2-chloromethyl)-4-(4-benzyloxy phenyl)-2-azetidinone 4 with the cyclization of 3-chlorpromazine chloride;
(4) R-obtains (2R)-4-fluorophenethyl glycol 5 to fluorine amygdalic acid through reduction;
(5) (2R)-4-fluorophenethyl glycol 5 obtains (R) Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6 through bromo;
(6) (R) Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6 is protected and is obtained (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 through TMSCl;
(7) (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 is with Trans-1-(4-fluorophenyl)-3-(2-chloromethyl)-4-(4-benzyloxy phenyl)-2-azetidinone 4 in THF, and process grignard reaction, metal linked reaction, Deprotection generate Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-benzyloxy phenyl)-2-azetidinone 8;
(8) Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-benzyloxy phenyl)-2-azetidinone 8 Deprotection under Pd/C condition obtains Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-hydroxy phenyl)-2-azetidinone 9;
(9) Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-hydroxy phenyl)-2-azetidinone 9 process recrystallization purifyings, obtain target product ezetimibe.
2. synthetic method according to claim 1, is characterized in that, the solvent described in step (1) is acetone; Alkali is selected from Na
2cO
3, K
2cO
3, NaOH, KOH, temperature of reaction is reflux temperature.
3. synthetic method according to claim 1, is characterized in that, the anhydrous protic solvent described in step (2) is selected from anhydrous methanol, dehydrated alcohol, anhydrous isopropyl alcohol; P-benzyloxybenzaldehyde is that the 2-4 of para-fluoroaniline doubly measures, reflux time 2-5h.
4. synthetic method according to claim 1, is characterized in that, described Trans-1-(4-fluorophenyl)-3-(2-chloromethyl)-4-(4-benzyloxy phenyl)-2-azetidinone 4 is prepared by the following method:
N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine 3 is dissolved in toluene, adds alkali, add 3-chlorpromazine chloride, finish 80 ℃-120 ℃ reaction 8-12 h of rear temperature control, be cooled to room temperature, add hydrochloric acid cancellation, add water stratification, water layer dichloromethane extraction, saturated sodium bicarbonate washing, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, described alkali is selected from TEA, DIEA, 3-n-butylamine.
5. synthetic method according to claim 1, is characterized in that, described (2R)-4-fluorophenethyl glycol 5 is prepared by the following method
:
Get R-4-fluorine amygdalic acid and be dissolved in THF or diethyl ether solution, under ice bath, drip borine tetrahydrofuran solution or LAH, finish, stirring at room temperature 2h, drips the shrend reaction of going out, decompression concentrated solution under ice bath, add ethyl acetate or the extraction of methylene dichloride separatory, dry, concentrated.
6. synthetic method according to claim 1, is characterized in that, described (R) Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6 is prepared by the following method:
(2R)-4-fluorophenethyl glycol 5 is dissolved in methylene dichloride, adds NBS, PBr
3, any one brominated reagent in lithiumbromide, drip the vitriol oil or glacial acetic acid, stirring at room temperature, stopped reaction after 2-4 hour, adds water, separatory, a small amount of dichloromethane extraction, merges organic phase, saturated sodium bicarbonate washing, saturated common salt washing, dry, concentrated.
7. synthetic method according to claim 1, is characterized in that, described (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 is prepared by the following method:
Get (R) Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6 and be dissolved in methylene dichloride, under ice bath, add DIEA, TMSCl or TBSCl, stirring at room temperature 2-4h, stopped reaction, adds water, separatory, and water layer is with a small amount of dichloromethane extraction, merge organic phase, washing, dry, concentrated.
8. synthetic method according to claim 1, it is characterized in that described Trans-1-(4-fluorophenyl)-3-[3R-hydroxyl-3-(4-fluorophenyl) propyl group]-4-(4-benzyloxy phenyl)-2-azetidinone 8 prepared by the following method:
By magnesium chips, catalytic amount iodine grain, be suspended in tetrahydrofuran (THF) or ether, (R) α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 is dissolved in dry tetrahydrofuran and is dropped in reaction system, observation solution colour is decorporated, after stirring at room temperature 1-2h, make Grignard reagent, under ice bath, compound 4 is dissolved in dry tetrahydrofuran, add coupling reagent, described coupling reagent is selected from Pd(PPh
3)
4, CuI, PdCl
2(dppf), ZnCl
2; Under ice bath, stir, now Grignard reagent processed joins in reaction solution, room temperature reaction 8-12h, stopped reaction; Under ice bath, add aqueous ammonium chloride solution cancellation reaction, separatory, a small amount of dichloromethane extraction of water, saturated common salt water washing organic phase, dry, concentrated;
Crude product is dissolved in dry tetrahydrofuran solution, adds tetrabutyl ammonium fluoride stirring at room temperature 3-6h, concentration of reaction solution, adds water, the extraction of methylene dichloride separatory, and washing, dry, concentrated.
9. synthetic method according to claim 1, is characterized in that,
Compound 8 is dissolved in to methyl alcohol, ethanol, in any one solvent of Virahol, add ammonium formiate, formic acid, catalytic amount palladium carbon, 30 ℃-75 ℃ reaction 3-6h of temperature control, reaction finishes, suction filtration, filtrate is concentrated, silica gel column chromatography, obtain compound trans ezetimibe, after be dissolved in ethyl acetate or methylene dichloride, drip dioxane, tetrahydrofuran (THF), methyl tertiary butyl ether, in anhydrous diethyl ether, any one two optical isomers split, insolubles is filtered, get filtrate concentrated dry after, carry out recrystallization by ethyl acetate/petroleum ether, obtain ezetimibe.
10. synthetic method according to claim 1, it is characterized in that, described (R)-α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7, take to fluoro acetophenone 11 as starting raw material, at bromine, under Glacial acetic acid condition, obtain alpha-brominated to fluoro acetophenone 12, alpha-brominated fluoro acetophenone is dissolved in dry ether or tetrahydrofuran solution, under room temperature condition, slowly drip CBS/ hexane solution, under condition of ice bath, drip borine-tetrahydrofuran solution, stir 2 hours, drip the shrend reaction of going out, decompression concentrated solution obtains (R)-Alpha-hydroxy (4-fluorine) phenyl-bromide ethane 6, (R)-Alpha-hydroxy (4-fluorine) phenyl-bromide ethane obtains (R)-α-trimethyl silicon based oxygen base (4-fluorine) phenyl-bromide ethane 7 through TMSCl protection.
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| US5739321A (en) * | 1996-05-31 | 1998-04-14 | Schering Corporation | 3-hydroxy γ-lactone based enantionselective synthesis of azetidinones |
| CN101346349A (en) * | 2005-12-20 | 2009-01-14 | 吉瑞工厂 | Process for the production of ezetimibe and intermediates used in this proces |
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| US5739321A (en) * | 1996-05-31 | 1998-04-14 | Schering Corporation | 3-hydroxy γ-lactone based enantionselective synthesis of azetidinones |
| CN101346349A (en) * | 2005-12-20 | 2009-01-14 | 吉瑞工厂 | Process for the production of ezetimibe and intermediates used in this proces |
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| Title |
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| Ezetimibe的合成;黄伟 等;《中国医药工业杂志》;20061231;第37卷(第6期);第364-366页 * |
| 黄伟 等.Ezetimibe的合成.《中国医药工业杂志》.2006,第37卷(第6期),第364-366页. |
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